tag:theconversation.com,2011:/fr/topics/cancer-drugs-6897/articlesCancer drugs – The Conversation2023-11-08T17:36:49Ztag:theconversation.com,2011:article/2172182023-11-08T17:36:49Z2023-11-08T17:36:49ZBreast cancer prevention drug approved for post-menopausal women in the UK – here’s how it works<figure><img src="https://images.theconversation.com/files/558434/original/file-20231108-21-8cqks7.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C5577%2C3706&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Anastrozole may stop breast cancer before it starts.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/just-awaken-senior-lady-holding-morning-1950650434">fizkes/ Shutterstock</a></span></figcaption></figure><p>A drug that can <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961114/">halve the risk</a> of developing breast cancer in post-menopausal women has been approved for use in the UK. This drug, called anastrozole, could benefit an estimated 289,000 women in the UK who are at <a href="https://www.nice.org.uk/guidance/cg164/ifp/chapter/how-breast-cancer-risk-is-described">increased risk of breast cancer</a>. </p>
<p>Anastrozole was already approved for use in the UK as a breast cancer treatment. It belongs to a group of drugs called <a href="https://www.ncbi.nlm.nih.gov/books/NBK557856/">aromatase inhibitors</a> that were first developed to treat breast cancer in women who had undergone menopause.</p>
<p>The key to anaztrozole’s success both in treating and preventing breast cancer, is due to its effects on the body’s oestrogen levels.</p>
<p><a href="https://www.cancerresearchuk.org/about-cancer/breast-cancer/getting-diagnosed/tests-breast-cancer-cells">Up to 80%</a> of all breast cancers produce a protein called the oestrogen receptor, which binds to the hormone oestrogen. When it binds, this protein tells breast cancer cells to divide. This overrides the normal controls that prevent cells from dividing too much – causing a tumour to grow. The more oestrogen circulating around the body, the more likely it is that tumour growth will be stimulated.</p>
<p>But anastrozole reduces oestrogen levels, preventing breast cancer cells from dividing. It does this by targeting a specific enzyme in the body.</p>
<p>Before the menopause, most of the body’s oestrogen is produced in the ovaries. But after the menopause, oestrogen is instead produced by an enzyme called <a href="https://academic.oup.com/edrv/article/30/4/343/2355213">aromatase</a>. This oestrogen is typically made in our fat tissue. Aromatase produces oestrogen by converting other hormones – such as testosterone and androstenedione.</p>
<p>Anastrozole and similar drugs – such as letrozole and exemestane – stop aromatase from working and drastically reduce the amount of oestrogen in the body. This means that in post-menopausal breast cancer patients, the drug is <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564654/">very effective</a> at stopping cancers which produce the oestrogen receptor from recurring after surgery or chemotherapy.</p>
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<img alt="A nurse looks at a breast cancer scan on a computer screen." src="https://images.theconversation.com/files/558436/original/file-20231108-19-ipcdma.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/558436/original/file-20231108-19-ipcdma.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=386&fit=crop&dpr=1 600w, https://images.theconversation.com/files/558436/original/file-20231108-19-ipcdma.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=386&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/558436/original/file-20231108-19-ipcdma.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=386&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/558436/original/file-20231108-19-ipcdma.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=486&fit=crop&dpr=1 754w, https://images.theconversation.com/files/558436/original/file-20231108-19-ipcdma.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=486&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/558436/original/file-20231108-19-ipcdma.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=486&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">The majority of breast cancers produce a protein which bind to the hormone oestrogen.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/hospital-patient-undergoes-screening-procedure-mammogram-1951533499">ORION PRODUCTION/ Shutterstock</a></span>
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<p>The reason anastrozole also works to prevent breast cancer is because often the earliest stages of normal breast tissue becoming cancerous depend on oestrogen. Indeed, many of the <a href="https://breastcancernow.org/about-breast-cancer/awareness/breast-cancer-causes">known risk factors</a> for developing breast cancer – such as <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488186/">late menopause</a> and <a href="https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet">obesity</a> – are associated with increased oestrogen levels. But using anastrozole to reduce oestrogen levels can stop breast cancer before it even starts in at-risk post-menopausal women.</p>
<h2>Preventative drug</h2>
<p>Thanks to the new licence, post-menopausal women in the UK who are at moderate to high risk of developing breast cancer will now be offered the chance to take anastrozole to protect themselves. Women who have a <a href="https://www.nice.org.uk/guidance/cg164/ifp/chapter/First-steps-finding-out-about-your-family-history">family history of the disease</a> should talk to their doctor about their risk and whether they could benefit from taking anastrozole.</p>
<p>It’s worth noting, however, that the drastic reductions in oestrogen levels caused by an aromatase inhibitor such as anastrozole are not without their drawbacks. Not only may it <a href="https://www.breastcancer.org/treatment-side-effects/menopause/types/hormonal-therapy">worsen menopause symptoms</a>, it may also cause other <a href="https://www.frontiersin.org/articles/10.3389/fendo.2021.713700/full">side-effects</a> – such as a decrease in bone density and increased risk of fractures. These side-effects <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2104162">can become more serious</a> the longer the drug is taken. This is why it’s currently recommended that anastrozole is only taken for prevention for five years.</p>
<p>Women who are at increased risk of breast cancer and are considering using anastrozole need to be supported in making an informed decision that’s right for them. Women with osteoporosis or serious kidney or liver disease are <a href="https://www.nhs.uk/medicines/anastrozole/">particularly advised</a> to discuss this decision with their doctor first.</p>
<p>In the UK, there are <a href="https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer">almost 56,000 new diagnoses of breast cancer</a> annually. The NHS estimates that if just 25% of eligible patients opt to take anastrozole, then <a href="https://www.england.nhs.uk/2023/11/tens-of-thousands-of-women-set-to-benefit-from-repurposed-nhs-drug-to-prevent-breast-cancer">2,000 breast cancer cases</a> could be prevented each year in the UK. </p>
<p>Breast cancer is the <a href="https://www.who.int/news-room/fact-sheets/detail/breast-cancer">most common cancer in the world</a>. An estimated 2.3 million people – mainly women – will develop the disease each year. Preventing even a fraction of these cancers has the potential to save many lives and reduce suffering. Although anastrozole is prescribed off-label to prevent breast cancer in <a href="https://www.cancer.org/cancer/types/breast-cancer/risk-and-prevention/aromatase-inhibitors-for-lowering-breast-cancer-risk.html">other countries</a>, the UK is the first to license it for this specific use. Given the burden of breast cancer, it’s hoped that other countries will follow suit.</p><img src="https://counter.theconversation.com/content/217218/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sarah Allinson does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Anastrozole was already approved for use in the UK to treat breast cancer.Sarah Allinson, Professor, Department of Biomedical and Life Sciences, Lancaster UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1849222022-07-11T12:29:55Z2022-07-11T12:29:55ZMany medications affect more than one target in the body – some drug designers are embracing the ‘side effects’ that had been seen as a drawback<figure><img src="https://images.theconversation.com/files/473235/original/file-20220708-14-kbl694.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2035%2C1471&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Depending on how you look at it, drugs that can act on multiple targets could be a boon instead of a challenge.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/multi-exposure-photogram-of-molecular-structure-of-royalty-free-image/886907874">Andrew Brookes/Image Source via Getty Images</a></span></figcaption></figure><p>Drugs don’t always behave exactly as expected. While researchers may develop a drug to perform one specific function that’s perhaps tailored to work for a specific genetic profile, sometimes the drug might perform several other functions outside of its intended purpose. </p>
<p>This concept of drugs having multiple functions, called <a href="https://doi.org/10.1021/acs.jmedchem.8b00760">polypharmacology</a>, may lead to unintended consequences. This is a common occurrence for <a href="https://doi.org/10.1126/scitranslmed.aaw8412">cancer drugs in clinical trials</a> that can have <a href="https://doi.org/10.1586/ecp.12.74">harmful side effects and treatment toxity</a>. </p>
<p>But polypharmacology may in fact be the norm for most drugs, not the exception. So rather than seeing a drug’s ability to perform many functions as a flaw, <a href="https://scholar.google.com/citations?user=iDKZaA4AAAAJ&hl=en">biomedical data scientists like me</a> and my <a href="https://www.waysciencelab.com/">lab colleagues</a> believe that it can be used to our advantage in designing drugs that address the full complexity of biology.</p>
<h2>Drugs often multitask in cells</h2>
<p>When scientists talk about drugs, they like to refer to its <a href="https://www.verywellmind.com/meaning-of-mechanism-of-action-in-health-care-425245">mechanism of action, or MOA</a> – essentially, exactly what a drug does when it enters the body. A drug’s official MOA, however, may not actually include all the ways it can affect cells.</p>
<p>For example, the mechanism of action of a drug labeled as a <a href="https://www.drugs.com/drug-class/vegf-vegfr-inhibitors.html">VEGF inhibitor</a> is to block the activity of a protein called VEGF, or vascular endothelial growth factor, in a cell. While VEGF plays an important role making new blood vessels, a process that’s integral to healthy tissue development, it can also be a <a href="https://doi.org/10.1016/j.cell.2011.02.013">hallmark of cancer</a>. <a href="https://www.webmd.com/cancer/cancer-angiogenesis-inhibitors">Blocking VEGF</a> can stop the formation of new blood vessels that supply nutrients to tumors and prevent the growth and spread of many types of cancers.</p>
<p>There are currently <a href="https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet">14 drugs inhibiting new blood vessel formation</a> approved in the U.S. to treat cancer, and most target VEGF. You may be wondering why there are so many different drugs available if they’re all inhibiting the same protein. The answer comes down to polypharmacology: While they all most likely work by blocking VEGF in some way, each likely has some other function that may be unique to that drug. That alternative function might cause side effects, or only work in certain conditions. </p>
<p>VEGF belongs to a larger group of proteins called <a href="https://doi.org/10.3390/cancers12030731">receptor tyrosine kinases, or RTKs</a>, that are challenging to target individually. Many drugs that target one type of RTK, like VEGF, also end up indiscriminately <a href="https://pubmed.ncbi.nlm.nih.gov/29888050/">targeting other RTKs</a> because they share a <a href="https://doi.org/10.1016/j.chembiol.2018.11.005">similar chemical structure</a>, potentially causing unwanted side effects.</p>
<p>For example, in 1999, scientists discovered that the infamous morning sickness drug thalidomide also worked as a VEGF inhibitor to <a href="https://doi.org/10.1056/nejm199911183412102">treat multiple myeloma</a>, a type of blood cancer. This was a triumph for a drug that, just 70 years prior, was banned worldwide after causing severe birth detects in an estimated <a href="https://doi.org/10.1016/s0140-6736(04)16308-3">10,000 infants</a>, not including miscarriages and stillbirths.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/mrTHfBCduRA?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">As in the case of thalidomide, a slight difference in chemical structure can make a huge difference in how a drug affects the body.</span></figcaption>
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<p>Like thalidomide, many chemicals affect the body in many different ways, and their full mechanism of action still isn’t fully understood. Even some approved drugs like lithium, acetaminophen and many antidepressants still have an <a href="https://doi.org/10.1016/j.isci.2020.101487">unclear MOA</a>.</p>
<p>Perhaps the most famous example of the serendipity of polypharmacology is <a href="https://www.history.com/this-day-in-history/fda-approves-viagra">Viagra</a>, a drug that was originally developed for cardiovascular problems but was later approved for erectile dysfunction. Interestingly, there is emerging evidence that Viagra also works as a <a href="https://doi.org/10.1111%2Fj.1582-4934.2008.00319.x">VEGF activator</a>, which may help treat stroke or heart attack. </p>
<h2>Taking advantage of polypharmacology</h2>
<p>The problem is that when you take a drug with multiple functions, you can’t isolate one desired effect from all the others – you get all of them all at once. Researchers can react to polypharmacology in two ways. Scientists can try to design better drugs that home in on just one specific target. Alternatively, scientists can instead embrace the complexity of biology and try to leverage the multifaceted effects drugs can offer.</p>
<p>Many existing drugs have unknown mechanisms that can be harnessed as a strength, rather than a weakness. Researchers can use polypharmacology to <a href="https://theconversation.com/repurposing-generic-drugs-can-reduce-time-and-cost-to-develop-new-treatments-but-low-profitability-remains-a-barrier-174874">repurpose existing drugs</a> to use for other conditions, reducing the time and cost of developing new treatments. There is an entire industry of doctors and scientists currently trying to do exactly that. Chemists and drug designers are also purposefully <a href="https://doi.org/10.1021/acs.jmedchem.8b00760">designing drugs with multiple functions</a> to combat complex diseases like cancer and type 2 diabetes, which may have multiple targets that can escape single-function treatments.</p>
<p>But in order to take advantage of the polypharmacology of existing drugs, researchers require a way to measure it. Typically, chemists study drug mechanisms through laborious experiments that test drugs one at a time and don’t always lead to conclusive answers. However, new experimental approaches, like <a href="https://doi.org/10.1038/s41573-022-00472-w">phenotypic drug screening</a>, that measure the overall effect of the drug instead of trying to narrow down its mechanism of action, allow researchers to measure thousands of different drugs in a single experiment.</p>
<p>My colleagues and I <a href="https://doi.org/10.1371/journal.pcbi.1009888">used this approach</a> to predict all the effects of specific drugs, using nothing but images of cells. We collected 159 million snapshots of cells reacting to over 1,300 different drugs, then applied a machine learning algorithm to identify important patterns in the images. Instead of teaching the algorithm to look for specific details, we allowed it to search for pieces of data in the pictures that allowed it to better predict how a cell would react to different types of drugs. </p>
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<figcaption><span class="caption">Machine learning can help predict how the chemical structure of any particular drug might affect the body.</span></figcaption>
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<p>Our model repurposed an approach called <a href="http://dx.doi.org/10.48550/arXiv.1511.06434">latent space arithmetic</a>, originally developed using pictures of human faces, to predict drugs with polypharmacology. Just as the original algorithm could simulate a picture of a man wearing glasses, we could simulate what a cell looks like when treated with a drug that has multiple mechanisms of action.</p>
<p>Our model was far from perfect, though. Many drug mechanisms of action could not be simulated well, and we were limited by existing, likely incomplete, knowledge about how different drugs worked. Additional work to demystify how different drug mechanisms affect cells in a wider context could help improve predicting all of a drug’s potential functions, leading to more treatment possibilities for each compound. </p>
<p>I believe that embracing polypharmacology as an unavoidable consequence of using drugs to treat diseases can help researchers reimagine the drug discovery process. Could we design a drug that targets all the receptors going haywire in a specific patient’s tumor? Could we use artificial intelligence to simulate how such a potential drug compound might look and behave in the body? Could polypharmacology actually be the answer to precision medicine instead of one of its biggest challenges? A shift in mindset might be the first step to answering these questions.</p><img src="https://counter.theconversation.com/content/184922/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gregory Way does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Many approved drugs work on the body in ways that researchers still aren’t entirely clear about. Seeing this as an opportunity instead of a flaw may lead to better treatments for complex conditions.Gregory Way, Assistant Professor of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1824002022-05-23T12:22:52Z2022-05-23T12:22:52ZCancer groundshot: Access to proven treatments must parallel development of new therapies<figure><img src="https://images.theconversation.com/files/464445/original/file-20220520-20-9y62l9.jpg?ixlib=rb-1.1.0&rect=476%2C233%2C4994%2C3601&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Cancer groundshot highlights that investment in improving access to treatments already proven to work saves more lives than discovery of a new treatment.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Where should investment be made today in order to save the maximum number of lives from cancer tomorrow? That is the underlying principle behind the “<a href="https://doi.org/10.1016/S1470-2045(18)30076-7">cancer groundshot</a>” philosophy.</p>
<p>Annually, billions of dollars are spent on ambitious “<a href="https://doi.org/10.1038/d41586-022-00376-0">cancer moonshot</a>” programs. These programs focus on the discovery of new drugs and technologies aimed at solving the cancer burden. The hope is that discovery of a new target, a new drug or a new mechanism will help to cure cancer or reduce the cancer burden. </p>
<p>The United States’ ambitious Cancer Moonshot program marks its fifth anniversary in 2022, and certainly, cancer is still very much a global problem that needs addressing. Some new drugs have been developed in this time frame, but the <a href="https://dx.doi.org/10.1001%2Fjamaoncol.2018.1660">percentage of patients</a> who has benefited from these newer drugs has <a href="https://doi.org/10.1001/jamanetworkopen.2019.2535">remained small</a>. </p>
<p>Globally, most patients with cancer die not because they don’t have access to these newer drugs, but because they do not have access to even the basic treatments. </p>
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<a href="https://images.theconversation.com/files/463052/original/file-20220513-14-eo9b54.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A man in a suit at a podium beside a blue display reading 'Cancer Moonshot'" src="https://images.theconversation.com/files/463052/original/file-20220513-14-eo9b54.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/463052/original/file-20220513-14-eo9b54.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/463052/original/file-20220513-14-eo9b54.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/463052/original/file-20220513-14-eo9b54.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/463052/original/file-20220513-14-eo9b54.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/463052/original/file-20220513-14-eo9b54.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/463052/original/file-20220513-14-eo9b54.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">President Joe Biden speaks during a Cancer Moonshot event at the White House on Feb. 2, 2022.</span>
<span class="attribution"><span class="source">(AP Photo/Alex Brandon)</span></span>
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<p><a href="https://doi.org/10.1016/j.clon.2014.10.006">More than 90 per cent of patients in low-income countries, and more than half of patients in low- and middle-income countries,</a> do not have access to basic radiotherapy services. <a href="https://doi.org/10.1016/s1470-2045(15)00223-5">More than half of patients globally who need cancer surgery</a> will go without, and services needed for accurate cancer diagnosis are lacking. </p>
<p>These are interventions that help cure cancer and save the most lives, as opposed to newer drugs that only marginally extend survival or delay cancer growth. If inequity in access to proven effective interventions persists, newer treatment options will not reduce global cancer burden.</p>
<h2>Cancer groundshot</h2>
<p>I coined the term <a href="https://ecancer.org/en/news/10659-last-month-in-immuno-oncology-with-dr-bishal-gyawali-november-2016">“cancer groundshot” in 2016 in a blog post</a> to encourage prioritization in cancer care and research. It is a part of the <a href="https://doi.org/10.1038/s41591-021-01662-6">common-sense revolution in oncology</a>. </p>
<p>Cancer groundshot highlights that investing in improved access to interventions already proven to work saves more lives than discovery of a new intervention. When patients are dying due to lack of access to surgery or accurate diagnosis, a new cancer drug is not going to solve the problem. </p>
<p>Cervical cancer is a good example. It is probably the only cancer for which <a href="https://www.who.int/publications/i/item/9789240014107">elimination is a realistic goal</a>. HPV vaccination, cervical cancer screening and effective treatment of early detected cervical cancers may help us eliminate this cancer. </p>
<p>At the same time, newer drugs like <a href="https://doi.org/10.1056/NEJMoa2112435">pembrolizumab reportedly improve two-year survival rates</a> in metastatic cervical cancer by 10 percentage points. While not discounting this medical advancement, it is more prudent for countries around the world to invest in cervical cancer screening, HPV vaccination and early treatment, rather than investing in access to pembrolizumab (one year of this drug <a href="https://www.fiercepharma.com/pharma/updated-merck-s-melanoma-game-changer-keytruda-likely-to-bolster-drug-pricing-debate">costs roughly US$150,000</a>). </p>
<p>In this example, the use of pembrolizumab represents the cancer moonshot approach to cervical cancer. Focusing on vaccination, screening and early treatment represents the cancer groundshot approach.</p>
<h2>Costs and priorities</h2>
<p>The cost of pembrolizumab is not an outlier. Modern cancer treatments are quite expensive. On average, based on 2018 data, a new cancer drug costs <a href="https://doi.org/10.1001/jamainternmed.2020.5921">more than US$150,000 per patient per year</a>. On the other hand, barring a few good drugs, the benefits these drugs provide are <a href="https://doi.org/10.1001/jamainternmed.2020.8588">not very impressive on average</a>. For example, some new cancer drugs <a href="https://doi.org/10.1038/s41571-021-00504-1">delay progression by a median of only three days</a>. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/464441/original/file-20220520-11-plryu4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A boy in a hat with an IV line in his arm sits at a table drawing with a woman wearing a face mask as another child looks on" src="https://images.theconversation.com/files/464441/original/file-20220520-11-plryu4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/464441/original/file-20220520-11-plryu4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/464441/original/file-20220520-11-plryu4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/464441/original/file-20220520-11-plryu4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/464441/original/file-20220520-11-plryu4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/464441/original/file-20220520-11-plryu4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/464441/original/file-20220520-11-plryu4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Children play as they receive treatment at the cancer ward of the Children’s Hospital in March, in Damascus, Syria, where more than a decade of war has brought the Syrian health sector close to collapse, and cancer treatment is often unaffordable or in short supply.</span>
<span class="attribution"><span class="source">(AP Photo/Omar Sanadiki)</span></span>
</figcaption>
</figure>
<p>Although valuation of life is inherently an impossible task, I think as a society we can agree that our resources can be better allocated than spending $16,000 per month for delaying tumour growth by three days. <a href="https://doi.org/10.1001/jamaoncol.2022.0864">A new study</a> shows that these extra days of delayed tumour growth may not necessarily mean good quality of life, either. </p>
<p>Cancer groundshot is a philosophy that calls for prioritization of strategies in global cancer control. The underlying principle of cancer groundshot is that one must ensure access to interventions that are already proven to work before focusing on the development of new interventions. We need to realign our priorities and invest on equitable access to high-value interventions. </p>
<p>This is not only an issue in low- and middle-income countries. Severe disparities in access to care exist within high-income countries as well. There are several pockets of population in countries like the <a href="https://www.cancer.gov/about-cancer/understanding/disparities">United States</a> and <a href="https://dx.doi.org/10.3747%2Fco.19.1177">Canada</a>, that are underserved and lack access to timely and adequate cancer care. There are disparities in socio-economic status, awareness levels, insurance coverage and other <a href="https://www.doi.org/10.25318/82-003-x202100600002-eng">factors that lead to differential outcomes, even within the same country</a>. </p>
<h2>Advocacy and implementation</h2>
<p>I laid out the details of the cancer groundshot philosophy in a <a href="https://doi.org/10.1016/S1470-2045(18)30076-7">2018 paper in the journal <em>Lancet Oncology</em></a>. Since then, it has been gaining momentum in the cancer policy world. I have spoken about this at several international and national meetings, and this concept has been discussed both in academia and beyond. This year at the <a href="https://meetinglibrary.asco.org/session/14456">Annual Meeting of the American Society of Clinical Oncology</a> (ASCO), the world’s largest oncology conference, I am chairing a session on cancer groundshot. </p>
<p>This recognition from ASCO will certainly add to its recognition, and hopefully, adoption. The session is organized into three talks, which have also been compiled into a <a href="https://ascopubs.org/doi/full/10.1200/EDBK_359521">book chapter</a>: </p>
<ul>
<li><p>Cancer groundshot and how clinical trials fit into this philosophy.</p></li>
<li><p>Disparities in low- and middle-income countries, and if technology can help address this challenge.</p></li>
<li><p>Disparities in cancer care within high-income countries.</p></li>
</ul>
<p>However, the real metric for the cancer groundshot is implementation of the philosophy and reduction in the inequities in access to proven therapies. Advocacy is the first step to achieve that end.</p><img src="https://counter.theconversation.com/content/182400/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Bishal Gyawali receives funding from Ontario Institute for Cancer Research and Conquer Cancer Foundation. </span></em></p>Globally, most cancer patients die not because they don’t have access to newer drugs, but because they don’t have access to even basic treatments. Cancer groundshot aims to improve treatment access.Bishal Gyawali, Associate Professor of Oncology and Public Health Sciences, Queen's University, OntarioLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1683482021-10-25T12:35:20Z2021-10-25T12:35:20ZA new way to organize cancer mutations could lead to better treatment matches for patients<figure><img src="https://images.theconversation.com/files/426247/original/file-20211013-21-6i7ojz.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1732%2C1732&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Lung cancer is the No. 1 cause of cancer-related deaths worldwide.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/lungs-cancer-illness-or-lung-pneumonia-and-royalty-free-illustration/1223142317">vladwel/iStock via Getty Images Plus</a></span></figcaption></figure><p>There are <a href="https://www.cancer.gov/about-cancer/treatment/types">many types of cancer treatments</a>. But which ones work best varies from patient to patient. Currently, doctors determine which treatment to try for a patient based on where in their DNA, or genetic code, the error that caused the cancer is located.</p>
<p>But a new approach that groups patients by the changes in protein structure and function caused by that error, rather than by the location of the changes in DNA, could lead to both more inclusive clinical trials and better treatment matches for patients.</p>
<p>I am part of a team that <a href="https://scholar.google.com/citations?user=0m5yXZUAAAAJ&hl=en">researches targeted therapies for cancer</a> and ways to make treatment more patient-specific. A <a href="https://doi.org/10.1038/s41586-021-03898-1">recent study</a> by our research team determined that grouping DNA errors by structure may better personalize cancer therapies.</p>
<h2>Targeted therapies hone in on cancer cells</h2>
<p><a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/mutation">Mutations</a> are errors made during cell replication when the genetic material of that cell, or DNA, makes a new copy of itself. These mutations are usually harmless and caught by the cell’s proofreading machinery. </p>
<p>However, the proofreader occasionally fails. And on rare instances, these mutations occur in parts of the DNA called <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/oncogene">oncogenes</a>. Under normal conditions, oncogenes are essential to normal growth and development, such as <a href="https://doi.org/10.1111/j.1600-0897.1991.tb01080.x">fetal organ development</a> and <a href="https://doi.org/10.1002/jcp.21635">general tissue repair and maintenance</a>. But when mutations cause oncogenes to signal for unregulated growth, cancer can form. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/BmFEoCFDi-w?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Cancer results from mutations that direct a cell to undergo unfettered growth.</span></figcaption>
</figure>
<p>One way to kill these tumor cells is to use <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/targeted-therapy">targeted therapy</a>. Cancer-targeted therapies bind specifically to the defective proteins produced by mutated oncogenes and prevent them from sending a “grow” signal.</p>
<p>Because targeted therapies bind directly to the cancerous protein, they spare most noncancerous cells from being harmed. This results in more specific cancer cell killing and less overall treatment toxicity. In contrast, chemotherapy attacks all <a href="https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/how-chemotherapy-drugs-work.html">actively dividing cells</a>, which includes not just cancer but also hair follicles, the digestive tract and other parts of the body.</p>
<p>To make targeted therapies more specific, scientists often study the physical or structural changes that mutations cause in proteins. They <a href="https://doi.org/10.3390/ijms20112783">design drugs</a> that preferentially bind to these particular changes to prevent the defective protein from causing uncontrolled growth.</p>
<p>However, because mutations can occur in <a href="https://doi.org/10.1016/j.ccell.2018.01.021">many different areas of a protein</a>, multiple targeted therapies are often necessary to bind all the different mutations that occur across cancer types. This leads to a difficult clinical problem: How do physicians match patients to the most effective targeted therapy for their mutations? </p>
<h2>Traditional treatments use mutation location</h2>
<p>To attempt to answer this question, our research team chose to focus on one oncogene in lung cancer, <a href="https://lcfamerica.org/lung-cancer-info/types-lung-cancer/egfr-mutation/">EGFR</a>, or epidermal growth factor receptor. We did this for two reasons. First, lung cancer remains the <a href="https://doi.org/10.3322/caac.21492">No. 1 cause</a> of cancer-related deaths worldwide. Second, EGFR mutations are among the <a href="https://doi.org/10.1038/s41568-019-0179-8">most common forms of lung cancer</a> – they occur in approximately <a href="https://doi.org/10.1016/j.jtho.2016.08.030">a third of non-small-cell lung cancers worldwide</a>, amounting to <a href="https://canceratlas.cancer.org/the-burden/lung-cancer/">over 550,000 patients annually</a>.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/426066/original/file-20211012-15-s10h1g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="EGFR protein structure." src="https://images.theconversation.com/files/426066/original/file-20211012-15-s10h1g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/426066/original/file-20211012-15-s10h1g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=677&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426066/original/file-20211012-15-s10h1g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=677&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426066/original/file-20211012-15-s10h1g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=677&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426066/original/file-20211012-15-s10h1g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=851&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426066/original/file-20211012-15-s10h1g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=851&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426066/original/file-20211012-15-s10h1g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=851&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Mutations in EGFR, one of the most commonly mutated oncogenes in lung cancer, change the shape of the protein, which directly affects how it functions.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:EGFR_kinase_(9125080896).jpg">F. Gervasio/UCL Chemistry and ISMB</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>EGFR has many different mutations that cause unregulated growth. <a href="https://doi.org/10.1016/j.jtho.2020.11.028">Multiple generations of targeted therapies</a> are available for this population of patients. </p>
<p>Clinical trials and treatment options for patients with oncogene-driven lung cancer, particularly with EGFR, are currently based on the <a href="https://doi.org/10.1056/NEJMoa1612674">type</a> and <a href="https://doi.org/10.1200/JCO.21.00662">location of the mutation in the DNA</a>.</p>
<p>However, mutation location is not the best approach to predict how well patients will respond to a drug. Because mutations change the shape of a protein, they can <a href="https://doi.org/10.1016/j.ccell.2019.09.001">alter the way targeted therapies interact with the protein</a>.</p>
<h2>Regrouping cancer mutations</h2>
<p>By examining the mutated structures of different EGFR proteins, our team found that they could be categorized into distinct subgroups. </p>
<p>For example, we found that mutations that form away from the areas of the protein that drugs target don’t noticeably affect how well the drug binds to the protein. Cells with this kind of protein mutation were thus killed by all types of EGFR inhibitors. Although these mutations occurred across many locations in the DNA, they shared the same overall structural and functional effect on proteins. </p>
<p>Conversely, mutations that form near typical drug target areas compress this region and prevent certain EGFR inhibitors from attaching to the protein. These mutations also occurred in several different DNA locations.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/426260/original/file-20211013-19-1536z6n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Pathology slide of lung adenocarcinoma." src="https://images.theconversation.com/files/426260/original/file-20211013-19-1536z6n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/426260/original/file-20211013-19-1536z6n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426260/original/file-20211013-19-1536z6n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426260/original/file-20211013-19-1536z6n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426260/original/file-20211013-19-1536z6n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426260/original/file-20211013-19-1536z6n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426260/original/file-20211013-19-1536z6n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Targeted therapies hone in on cancerous cells to spare healthy cells from damage.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/adenocarcinoma-royalty-free-image/531314260">rightdx/iStrock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>Based on these findings, our team hypothesized that structural changes in similar protein regions, not DNA location, would cause similar changes in how well a drug works.</p>
<p>To <a href="https://doi.org/10.1038/s41586-021-03898-1">test our hypothesis</a>, we retrospectively analyzed public and hospital data on how well patients responded to cancer treatments. We sorted patients into traditional DNA location-based groups and our newly defined structure/function-based subgroups to determine whether one group had more patients who responded better than the other to different drugs. </p>
<p>We found that the structure/function-based subgroups identified nearly twice as many patients that benefited from a particular drug compared with the DNA location-based groups. Grouping patients by structure/function also identified which EGFR inhibitor provided the longest clinical benefit for patients.</p>
<h2>More inclusive clinical trials</h2>
<p>In addition to potentially matching patients to more effective treatments, clinical trials using structure-based subgroups may lead to broader access to therapies. </p>
<p>Current clinical trials <a href="https://doi.org/10.1038/s41586-021-03898-1">exclude up to a fifth of patients</a> with EGFR mutant non-small-cell lung cancer because each clinical trial typically focuses on only a handful of specific mutation types. Reframing clinical studies to be based on the changes that mutations cause to protein structure and function, as opposed to their location on DNA, could expand treatment options to include patients with more rare EGFR mutant cancers.</p>
<p>This approach provides a framework that clinical trials could use to make studies more inclusive of all types of mutations. And it may also identify previously ignored or hidden mutation subgroups that can lead to additional drug development and ultimately improve patient care.</p>
<p>[<em>Understand new developments in science, health and technology, each week.</em> <a href="https://theconversation.com/us/newsletters/science-editors-picks-71/?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=science-understand">Subscribe to The Conversation’s science newsletter</a>.]</p><img src="https://counter.theconversation.com/content/168348/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jacqulyne Robichaux works for MD Anderson Cancer Center. She receives funding from the NIH, CPRIT, Takeda Pharmaceuticals and Spectrum Pharmaceuticals. She is also an inventor on patents held by MD Anderson Cancer center related to the treatment of patients with poziotinib and EGFR subgroups. </span></em></p>Every cancer is different. Grouping cancer mutations by their structure and function could help make treatments more personalized.Jacqulyne Robichaux, Assistant Professor of Thoracic & Head and Neck Oncology, The University of Texas MD Anderson Cancer CenterLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1650822021-08-03T20:06:32Z2021-08-03T20:06:32ZCOVID vaccines offer the pharma industry a once-in-a-generation opportunity to reset its reputation. But it’s after decades of big profits and scandals<figure><img src="https://images.theconversation.com/files/414139/original/file-20210802-24-bh8h6h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://unsplash.com/photos/QwFyqPKyyY0">Elsa Olofsson/Unsplash</a></span></figcaption></figure><p>Just weeks before the first COVID-19 cases emerged, Gallup published its <a href="https://news.gallup.com/poll/266060/big-pharma-sinks-bottom-industry-rankings.aspx">latest poll</a> on America’s views about business. At the bottom of the list of 25 sectors was the pharmaceutical industry. Below advertising. Below oil and gas. Below the banks. </p>
<p>The pandemic and the new vaccines have of course <a href="https://theconversation.com/big-pharmas-covid-19-reputation-boost-may-not-last-heres-why-162975">turned that reputation around</a>, but let’s not forget why the pharmaceutical industry’s credibility sank so low. </p>
<p>Or how the industry got so big. One company, Johnson & Johnson, is currently worth around US$450 billion. About the same as the economy of Norway. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/big-pharmas-covid-19-reputation-boost-may-not-last-heres-why-162975">Big Pharma's COVID-19 reputation boost may not last — here’s why</a>
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</em>
</p>
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<h2>The birth of the behemoths</h2>
<p>The idea of the miraculous potion or cure-all dates back at least as far as Greek mythology. The goddess Panacea even gets a mention in the <a href="https://en.wikipedia.org/wiki/Hippocratic_Oath">Hippocratic Oath</a>. </p>
<p>The rise of the modern pharmaceutical industry is more recent, coming through the 19th century. On the eve of the 20th century, the German company Bayer famously launched its early blockbusters, including “Aspirin” and “Heroin.”</p>
<p>Around this time, US drug-makers were arguing for <a href="https://theconversation.com/the-us-drug-industry-used-to-oppose-patents-what-changed-161319">patent protections</a>, or exclusive rights to market a drug for a specific period of time. By the 1950s, they’d won those arguments, and the US soon became the world’s biggest market for medicines. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/the-us-drug-industry-used-to-oppose-patents-what-changed-161319">The US drug industry used to oppose patents – what changed?</a>
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</em>
</p>
<hr>
<p>In addition to patents, the other special ingredient for success was the right to market pills directly to doctors, and in the US, directly to consumers via television commercials. </p>
<p>At the dawn of the 21st century, in those dark ages before Facebook and Big Tech, pharmaceuticals was among the most profitable industries on the planet.</p>
<h2>Wonder drugs, miracle cures</h2>
<p>Clearly many medicines extend lives and reduce suffering. And while we need caution with hyperbole, some discoveries are major breakthroughs. </p>
<p>Antibiotics revolutionised the treatment of deadly infections, and gave a boost to science at the same time. </p>
<p>In the 1940s, one of the first-published “<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164257/">randomised controlled trials</a>” was a test of Streptomycin for the treatment of tuberculosis. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/414244/original/file-20210803-13-1q9a091.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/414244/original/file-20210803-13-1q9a091.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/414244/original/file-20210803-13-1q9a091.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/414244/original/file-20210803-13-1q9a091.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/414244/original/file-20210803-13-1q9a091.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/414244/original/file-20210803-13-1q9a091.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/414244/original/file-20210803-13-1q9a091.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Streptomycin inventor Selman Waksman and two associates test the drug.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Waksman,_selman.jpg">New Jersey Agriculture Experimental Station at Rutgers University/Wikimedia Commons</a></span>
</figcaption>
</figure>
<p>In the 1980s, another famous class of wonder drugs was developed, this time to tackle the HIV-AIDS epidemic. The mysterious new virus bringing many people a death sentence would soon become a manageable disease. </p>
<p>And while some cancers remain incurable, others are treated and even prevented with medicines that are simply miraculous.</p>
<h2>Extortionate prices, avoided taxes</h2>
<p>Yet, in each case, the golden drugs have a dark side. As the World Health Organization notes, <a href="https://onlinelibrary.wiley.com/doi/abs/10.5694/mja16.01042">overuse of antibiotics</a> helped make antibiotic-resistance “<a href="https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance">one of the biggest threats to global health</a>”. </p>
<p>Over-pricing and patent protections for HIV medicines put them out of reach of the world’s poorest, and prices only came down after <a href="https://www.msf.org/access-medicines-depth-access-campaign">massive global campaigns</a> for greater access. </p>
<p>With <a href="https://www.bmj.com/content/325/7358/269?tab=responses">cancer</a>, companies have demanded huge prices for products offering sometimes minimal benefits. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/if-we-dont-talk-about-value-cancer-drugs-will-become-terminal-for-health-systems-44072">If we don't talk about value, cancer drugs will become terminal for health systems</a>
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</p>
<hr>
<p>Extortionate prices were feeding drug company mega-profits, and at the same time driving down the industry’s reputation. In a notorious example, the cost of the life-saving Epipen skyrocketed more than 400%, helping make drug prices <a href="https://www.forbes.com/sites/arleneweintraub/2016/09/01/epipen-only-scratches-the-surface-of-the-drug-price-crisis-jama-study-says/?sh=3d3292d41c7a">a big issue</a> in the 2016 US presidential election. </p>
<figure class="align-center ">
<img alt="Two epipens sit in front of their pack." src="https://images.theconversation.com/files/414246/original/file-20210803-23-1iib9o9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/414246/original/file-20210803-23-1iib9o9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/414246/original/file-20210803-23-1iib9o9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/414246/original/file-20210803-23-1iib9o9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/414246/original/file-20210803-23-1iib9o9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/414246/original/file-20210803-23-1iib9o9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/414246/original/file-20210803-23-1iib9o9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The price of Epipens rose by more than 400%.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/saint-louis-united-states-august-25-473806648">Shutterstock</a></span>
</figcaption>
</figure>
<p>Industry argues high prices fund vital research. Critics say companies can spend more on marketing than research, and their profits sometimes derive from taxpayer-funded science. </p>
<p>To make matters worse, the big pharmaceutical companies are also among the big tax avoiders. A 2015 <a href="https://www.michaelwest.com.au/big-pharma-bosses-front-up-to-senate-inquiry-into-corporate-tax-avoidance/">Senate hearing</a> in Australia heard companies were paying rates as low as one cent in the dollar. </p>
<p>A global <a href="https://www.oxfam.org/en/press-releases/drug-companies-cheating-countries-out-billions-tax-revenues">report from Oxfam</a> in 2018 concluded the pharmaceutical industry was “cheating countries out of billions in tax revenues”. </p>
<h2>Toxic marketing causes harm</h2>
<p>The major problem with the drug giants is their <a href="https://theconversation.com/time-to-end-drug-company-distortion-of-medical-evidence-127495">unhealthy influence</a> over medical science. The industry dominates research, and there’s <a href="https://www.cochrane.org/MR000033/METHOD_industry-sponsorship-and-research-outcome">strong evidence</a> that company-sponsored studies tend to have a bias which favours the sponsor’s product. </p>
<p>Medical education is also heavily sponsored, with evidence suggesting an association between a doctor accepting <a href="https://theconversation.com/drug-companies-are-buying-doctors-for-as-little-as-a-16-meal-61364">just one meal</a> at an “educational event”, and prescribing more of the sponsor’s drugs. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/influential-doctors-arent-disclosing-their-drug-company-ties-110888">Influential doctors aren't disclosing their drug company ties</a>
</strong>
</em>
</p>
<hr>
<p>And the guidelines which can be so influential over a doctor’s prescribing decisions are too often <a href="https://bmjopen.bmj.com/content/9/2/e025864">written by medical experts</a> with ties to drug companies. </p>
<p>Central to this marketing effort are these senior medical experts, sometimes called “<a href="https://www.bmj.com/content/336/7658/1402">key opinion leaders</a>”, who claim to be independent yet accept fees for advice, consultancies or “educational” presentations to other doctors. </p>
<figure class="align-center ">
<img alt="Male doctor types at his computer." src="https://images.theconversation.com/files/414248/original/file-20210803-15-rn30tb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/414248/original/file-20210803-15-rn30tb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/414248/original/file-20210803-15-rn30tb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/414248/original/file-20210803-15-rn30tb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/414248/original/file-20210803-15-rn30tb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/414248/original/file-20210803-15-rn30tb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/414248/original/file-20210803-15-rn30tb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Just one meal at a sponsored educational event can result in a doctor prescribing more of that company’s drugs.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/doctor-typing-on-his-computer-office-142168426">Shutterstock</a></span>
</figcaption>
</figure>
<p>A former top-selling drug company sales representative turned whistleblower put it plainly in a 2008 piece in <a href="https://www.bmj.com/content/336/7658/1402">The BMJ</a>: </p>
<blockquote>
<p>Key opinion leaders were salespeople for us, and we would routinely measure the return on our investment, by tracking prescriptions before and after their presentations. </p>
<p>If that speaker didn’t make the impact the company was looking for, then you wouldn’t invite them back.</p>
</blockquote>
<p>Unhealthy marketing means the latest most expensive pill is too often favoured over older cheaper options, or doing nothing at all, causing much harm and wasting precious resources. </p>
<h2>Corporate crime</h2>
<p>In 2009 came the biggest health-care fraud settlement in history. Pfizer was forced to fork out a <a href="https://web.archive.org/web/20091212121012/http://www.stopmedicarefraud.gov/index.html">US$2.3 billion fine</a> for illegal promotion, false and misleading claims about drug safety, and paying kickbacks to doctors. That included a US$1.2 billion criminal fine, the largest ever in a US criminal prosecution.</p>
<p>One of the whistleblowers in that case happened to be a <a href="https://www.allenandunwin.com/browse/books/academic-professional/health/Sex-Lies--Pharmaceuticals-Ray-Moynihan-9781742370187">member of a special Pfizer sales team</a> promoting Viagra. He revealed doctors were taken to breakfasts, lunches, dinners, Broadway shows, baseball games, golf courses, ski fields, casinos and strip clubs. </p>
<p>In 2013, Johnson & Johnson paid out US$2.2 billion in civil and criminal fines for putting “<a href="https://www.justice.gov/opa/pr/johnson-johnson-pay-more-22-billion-resolve-criminal-and-civil-investigations">profit over patients’ health</a>”. The company had illegally promoted powerful anti-psychotic drugs as behaviour control for the elderly and most vulnerable, overstating benefits and playing down dangerous side effects, including stroke. </p>
<figure class="align-center ">
<img alt="Older man holds pill to his mouth in one hand and a glass of water in the other." src="https://images.theconversation.com/files/414247/original/file-20210803-23-13hydnm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/414247/original/file-20210803-23-13hydnm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/414247/original/file-20210803-23-13hydnm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/414247/original/file-20210803-23-13hydnm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/414247/original/file-20210803-23-13hydnm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/414247/original/file-20210803-23-13hydnm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/414247/original/file-20210803-23-13hydnm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Drug companies have faced massive fines for putting profits over health.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/asian-old-man-taking-pill-another-1679120026">Shutterstock</a></span>
</figcaption>
</figure>
<p>Other court documents around the same time exposed how the giant global company Merck used <a href="https://www.bmj.com/content/338/bmj.b1914.extract">dirty tricks</a> to try and defend its controversial anti-arthritis drug Vioxx. Merck created a fake medical journal and drew up secret lists of academic critics to “neutralise” and “discredit”. </p>
<p>In the end, Vioxx was taken off the market because it was causing heart attacks, with estimates in <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)17864-7/fulltext">The Lancet</a> suggesting it may have led to 140,000 cases of serious coronary heart disease.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/the-most-powerful-companies-youve-never-heard-of-merck-3187">The most powerful companies you've never heard of: Merck</a>
</strong>
</em>
</p>
<hr>
<h2>Investigation and reform</h2>
<p>Scandals like Vioxx tarnished the industry’s image, and brought more intense scrutiny. </p>
<p>The US National Academy of Sciences produced a <a href="https://www.ncbi.nlm.nih.gov/books/NBK22942/">landmark report</a> arguing the closeness between doctors and drug companies could jeopardise the integrity of science, the objectivity of education, the quality of care, and public trust in medicine. </p>
<p>A series of US congressional hearings on unhealthy marketing produced the <a href="https://openpaymentsdata.cms.gov/">Open Payments</a> register, mandated by US law to publicly list every company payment to every doctor. </p>
<p>Many around the world are <a href="https://www.bmj.com/content/367/bmj.l6576">reforming further</a>, moving from transparency to independence. Italy brought in a <a href="https://pubmed.ncbi.nlm.nih.gov/20055898/">special tax</a> on drug company promotion to fund public interest research. Norway doesn’t give doctors full credit anymore for <a href="https://www.legeforeningen.no/om-oss/Styrende-dokumenter/legeforeningens-lover-og-andre-organisatoriske-regler/avtale-mellom-legemiddelindustriforeningen-og-den-norske-lageforening-om-retningslinjer-for-samarbeid-og-samhandling-mellom-leger-legeforeningen-og-legemiddelindustrien/#23800">industry-sponsored</a> education. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/guidelines-governing-canadian-doctors-relationships-with-pharma-companies-under-review-149519">Guidelines governing Canadian doctors' relationships with pharma companies under review</a>
</strong>
</em>
</p>
<hr>
<p>But there’s a long way to go. A <a href="https://www.bmj.com/content/369/bmj.m1505">study</a> in 2020 found 80% of the medicos who run the world’s most powerful doctors organisations still take money from drug and device companies. For research, for consultancies, for hospitality. </p>
<p>Even some agencies which assess drugs, notably the <a href="https://www.fda.gov/about-fda/fda-basics/fact-sheet-fda-glance">US Food and Drug Administration</a> (FDA), still rely on significant funding from industry, which pays to have its products assessed. </p>
<p>And the harmful marketing has continued. Just last month, a group of drug companies, including Johnson & Johnson, <a href="https://www.theguardian.com/us-news/2021/jul/21/us-opioid-settlement-state-attorneys-general-johnson-and-johnson">agreed to pay</a> a total of US$26 billion for their roles in fuelling the opioid epidemic. </p>
<h2>A prescription for trust</h2>
<p>One drug company chief <a href="https://www.fiercepharma.com/pharma/amid-challenges-a-covid-19-opportunity-for-pharma-a-chance-to-bolster-its-reputation-lilly">reportedly said</a> last year the industry had a “once-in-a-generation opportunity to reset” its reputation. </p>
<p>Given the dark arts that drove pharma’s credibility to rock bottom, its fanciful to imagine the pandemic will magically end the misleading marketing and the price gouging.</p>
<p>Any post-pandemic recovery requires meaningful reform. </p>
<hr>
<p><em>This article is part of a global Conversation series, <a href="https://theconversation.com/au/topics/the-business-of-pharmaceuticals-108206">The business of pharmaceuticals</a>. You can read the other articles <a href="https://theconversation.com/au/topics/the-business-of-pharmaceuticals-108206">here</a>.</em></p><img src="https://counter.theconversation.com/content/165082/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ray Moynihan is Assistant Professor at Bond University's Institute for Evidence-Based Healthcare and Adjunct Associate Professor at the University of Sydney. He receives funding via competitive grants from Australia's publicly funded National Health and Medical Research Council. Ray has written about and researched the pharmaceutical industry's influence for almost 25 years and is the author of 4 books on the business of medicine. </span></em></p>The COVID pandemic is giving drug companies an opportunity to reset their image. So how did they get so big and their credibility sink so low?Ray Moynihan, Assistant Professor, Bond UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1399552020-06-28T14:05:20Z2020-06-28T14:05:20ZCoronavirus and cancer hijack the same parts in human cells to spread – and our team identified existing cancer drugs that could fight COVID-19<figure><img src="https://images.theconversation.com/files/344289/original/file-20200626-104504-govlob.jpg?ixlib=rb-1.1.0&rect=3%2C22%2C2402%2C1690&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">SARS-CoV-2 turns on a cellular switch to build the tubes in this photo – called filopodia – that might help viral particles – the little spheres – spread more easily.</span> <span class="attribution"><a class="source" href="https://www.cell.com/cell/fulltext/S0092-8674(20)30811-4">Dr Elizabeth Fischer, NIAID NIH / Bouhaddou et al. Elsevier 2020</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>Most antivirals in use today <a href="https://dx.doi.org/10.1089%2Fdna.2017.4033">target parts of an invading virus itself</a>. Unfortunately, SARS-CoV-2 – the virus that causes COVID-19 – has proven hard to kill. But viruses rely on cellular mechanisms in human cells to help them spread, so it should be possible to change an aspect of a person’s body to prevent that and slow down the virus enough to allow the immune system to fight the invader off.</p>
<p>I am a quantitative biologist, and <a href="https://kroganlab.ucsf.edu/krogan-lab">my lab</a> built a <a href="https://ppi.zoiclabs.io/#/">map of how the coronavirus uses human cells</a>. We used that map to find already existing drugs that <a href="https://theconversation.com/covid-19-treatment-might-already-exist-in-old-drugs-were-using-pieces-of-the-coronavirus-itself-to-find-them-133701">could be repurposed to fight COVID-19</a> and have been working with an international group of researchers called the <a href="http://qbi.ucsf.edu/COVID-19#support-covid">QBI Coronavirus Research Group</a> to see if the drugs we identified <a href="https://doi.org/10.1038/s41586-020-2286-9">showed any promise</a>. <a href="https://theconversation.com/we-found-and-tested-47-old-drugs-that-might-treat-the-coronavirus-results-show-promising-leads-and-a-whole-new-way-to-fight-covid-19-136789">Many have</a>. </p>
<p>For years, researchers have suspected that kinases – biological <a href="https://doi.org/10.1101/cshperspect.a006114">control switches that viruses use to take over cells</a> – could be <a href="https://doi.org/10.1038/nrd.2018.21">targeted to fight infections</a>. Over the last few months, we built a second, more detailed map looking specifically for the kinases that the coronavirus is hijacking. </p>
<p>Using this map, we identified a few already existing cancer drugs which alter the function of the kinases that SARS-CoV-2 hijacks, and began testing them in coronavirus-infected cells. The <a href="https://www.cell.com/cell/fulltext/S0092-8674(20)30811-4">results of these early tests</a> are promising enough that we are working with some groups and have already begun human clinical trials. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/344291/original/file-20200626-104516-kcrln4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/344291/original/file-20200626-104516-kcrln4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/344291/original/file-20200626-104516-kcrln4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=413&fit=crop&dpr=1 600w, https://images.theconversation.com/files/344291/original/file-20200626-104516-kcrln4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=413&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/344291/original/file-20200626-104516-kcrln4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=413&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/344291/original/file-20200626-104516-kcrln4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=519&fit=crop&dpr=1 754w, https://images.theconversation.com/files/344291/original/file-20200626-104516-kcrln4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=519&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/344291/original/file-20200626-104516-kcrln4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=519&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This map shows how the coronavirus changes the function of kinases – cellular switches involved in most biological processes – and the proteins they control. It guided researchers from UCSF to cancer drugs that could fight COVID-19.</span>
<span class="attribution"><a class="source" href="https://www.cell.com/cell/fulltext/S0092-8674(20)30811-4">Bouhaddou et al. Elsevier 2020</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Kinases in disease and as drug targets</h2>
<p>Kinases are proteins found in every cell of our body. There are <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/kinase">518 human kinases</a>, and they act as major control hubs for virtually all processes in the body. They are able to add a small marker – a process called phosphorylation – to other proteins and thus change how, if and when a phosphorylated protein can do its work. </p>
<p>For example, if a cell is preparing to grow – say to heal a cut on your finger – specific kinases will turn on and start telling proteins involved in cell growth what to do. Many cancers are caused by overactive kinases leading to uncontrolled cell growth, and <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/kinase-inhibitor">drugs that slow kinases down</a> can be highly effective at treating cancer. </p>
<p>Kinases are central players in cellular function as well as in most diseases, so researchers and <a href="https://player.vimeo.com/video/180302656">pharmaceutical companies have studied them in great detail</a>.</p>
<p>Kinases are also fairly easy to target with drugs because of <a href="https://www.youtube.com/watch?v=xG2WOd_fWqo">how they add phosphorylation markers to proteins</a>. Researchers have developed a huge number of drugs, particularly cancer drugs, that work by essentially throwing a wrench into the mechanics of specific kinases in order to stop cell growth.</p>
<p>So what does this have to do with the coronavirus? Well, viruses and cancer actually have more in common than you might think. Cancer is essentially a <a href="https://www.cancer.gov/about-cancer/understanding/what-is-cancer">malfunctioning of cellular machinery</a> that causes runaway cell growth. </p>
<p>Viruses also change the function of cellular machinery – albeit on purpose – but instead of causing cell growth, the machinery is repurposed to produce more viruses. Not surprisingly, <a href="https://doi.org/10.1016/B978-0-12-396456-4.00002-X">viruses take control</a> over many kinases to do this.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/344288/original/file-20200626-104480-10lbkwn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/344288/original/file-20200626-104480-10lbkwn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/344288/original/file-20200626-104480-10lbkwn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/344288/original/file-20200626-104480-10lbkwn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/344288/original/file-20200626-104480-10lbkwn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/344288/original/file-20200626-104480-10lbkwn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/344288/original/file-20200626-104480-10lbkwn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/344288/original/file-20200626-104480-10lbkwn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Microscope image shows a cell infected with SARS-CoV-2 and filopodia growths (in white) extending out from the cell surface containing viral particles (in red).</span>
<span class="attribution"><a class="source" href="https://www.cell.com/cell/fulltext/S0092-8674(20)30811-4">Dr. Robert Grosse, CIBSS, University of Freiburg / Bouhaddou et al. Elsevier 2020</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Coronavirus at the controls</h2>
<p>This idea – that SARS-CoV-2 is using kinases to hijack cellular machinery – is why we wanted to build a map of every kinase that is taken over by the coronavirus. Any virus–kinase interaction could be a potential target for drugs.</p>
<p>To do this, we first infected green monkey cells – which are fairly good surrogates for human cells <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC190510/">when it comes to virus infection</a> – with SARS-CoV-2. We then ground up these infected cells and used a device called a <a href="https://qbi.ucsf.edu/mass-spec-specific">mass spectrometer</a> to see which proteins were phosphorylated in these infected cells. We then did the same thing with healthy cells. </p>
<p>It is impossible to actually see which kinases are activated at any time, but since each kinase can <a href="https://doi.org/10.1038/nrm2203">attach phosphorylation markers to only a few specific proteins</a>, researchers can look at the phosphorylated proteins to determine what kinases are active at any time.</p>
<p>We made two lists: one list of phosphorylated proteins in healthy cells and one list of phosphorylated proteins in infected cells. We then compared the two, and by looking at the differences between the infected and uninfected lists, we were able to determine which kinases the coronavirus uses to reproduce.</p>
<p>Because researchers still <a href="https://doi.org/10.1186/1478-811X-9-23">don’t fully understand what all 518 human kinases do</a>, we were able to look for effects in only 97 of the ones we know most about. But that turned out to be more than enough. Of those 97 kinases, we found 49 that the virus affects.</p>
<p>Some of the more interesting ones include <a href="https://en.wikipedia.org/wiki/Casein_kinase_2">Casein Kinase 2</a>, which is involved in controlling how a cell is shaped. We also identified several kinases that work together in what is called the <a href="https://en.wikipedia.org/wiki/P38_mitogen-activated_protein_kinases">p38/MAPK signaling pathway</a>. This pathway responds to and controls our body’s inflammation reaction. It is possible these kinases could be involved in <a href="https://theconversation.com/blocking-the-deadly-cytokine-storm-is-a-vital-weapon-for-treating-covid-19-137690">the cytokine storm</a> – a dangerous immune system overreaction – that some patients with severe COVID-19 experience.</p>
<p>While identifying the kinases involved in SARS-CoV-2 replication, we were also able to learn a lot about how the virus changes our bodies. For example, CK2 becomes much more active during the course of coronavirus infection and causes the growth of little tubes that extend from the surface of the cell. Under a microscope, it looks as if the cell has a full head of hair. We think SARS-CoV-2 might be using these long cell outgrowths – <a href="https://doi.org/10.1038/nrm2406">called filopodia</a> – as viral highways to get new viruses closer to neighboring cells, thereby making infection easier.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/344292/original/file-20200626-104494-1o8ti4l.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/344292/original/file-20200626-104494-1o8ti4l.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/344292/original/file-20200626-104494-1o8ti4l.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/344292/original/file-20200626-104494-1o8ti4l.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/344292/original/file-20200626-104494-1o8ti4l.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/344292/original/file-20200626-104494-1o8ti4l.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/344292/original/file-20200626-104494-1o8ti4l.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/344292/original/file-20200626-104494-1o8ti4l.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Testing the promising cancer drugs in the lab was the first step, and after dozens showed promise, we began the process of starting clinical trials.</span>
<span class="attribution"><a class="source" href="http://qbi.ucsf.edu/COVID-19#support-covid">QBI UCSF</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Kinases inhibitors in the lab and clinical trials</h2>
<p>Learning more about the virus’s function is interesting for a biologist like me and could be useful down the road, but the ultimate goal of our project was to find drugs to treat COVID-19.</p>
<p>Once we knew which kinases SARS-CoV-2 uses to replicate and the proteins they change, we looked through a <a href="https://www.proteomicsdb.org/#projects/4257">database of around 250 kinase-inhibiting drugs</a> to see if any of them targeted the kinases used by the virus. To increase our chances, we also looked for drugs that hit some of the proteins the kinases act on. And sure enough, we found some.</p>
<p>There are 87 existing drugs that change the kinase-controlled pathways used by the coronavirus. Most of these drugs are already approved for human use or are currently in clinical trials to treat cancer, and could be quickly repurposed to treat COVID-19 patients. </p>
<p>With these leads, our collaborators in <a href="https://labs.icahn.mssm.edu/garcia-sastre/">New York</a> and <a href="http://www.vignuzzilab.eu/">Paris</a> tested the effect of 68 of those drugs on cells infected with SARS-CoV-2. Several of these were effective in killing the virus in cells. A few that we are especially excited about – silmitasertib, gilteritinib, ralimetinib, apilimod and dinaciclib – are either approved for treatment, in clinical testing or under preclinical development for various diseases. </p>
<p>Silmitasertib stops Casein Kinase 2, the kinase that causes cells to grow the virus spreading filopodia tubes. As soon as the company that makes silmitasertib heard this news, they announced that they wanted to <a href="https://www.prnewswire.com/news-releases/senhwa-biosciences-silmitasertib-named-as-potential-covid-19-therapy-301032362.html">test the drug against COVID-19 in the clinic</a>. </p>
<p>Drugs hitting kinase pathways have been on the radar of researchers as potential powerful antivirals for years, but none have come to fruition. By looking to this new area of drug applications and using our new mapping approach, our team has added dozens of drugs to the growing list of potential tools to help fight this pandemic. </p>
<p>It is still too early to say whether any of these will work to treat COVID-19 in patients, but the more chances we have, the better. </p>
<p>[<em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>.]</p><img src="https://counter.theconversation.com/content/139955/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Nevan Krogan receives funding from NIH, DARPA and Roche Pharmaceuticals.</span></em></p>Kinases are cellular control switches. When they malfunction, they can cause cancer. The coronavirus hijacks these kinases to replicate, and cancer drugs that target them could fight COVID-19.Nevan Krogan, Professor and Director of Quantitative Biosciences Institute & Senior Investigator at the Gladstone Institutes, University of California, San FranciscoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1284432019-12-11T12:28:02Z2019-12-11T12:28:02ZAntibiotic resistance and cancer: six surprising places scientists are looking for new drugs<figure><img src="https://images.theconversation.com/files/306295/original/file-20191211-95159-1lr70g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Tetraponera leafcutter ant.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/close-tetraponera-rufonigra-arboreal-bicolored-ant-1111251950">Phattipol/Shutterstock</a></span></figcaption></figure><p>Scientists recently announced the discovery of a novel antibiotic produced by bacteria living inside a nematode (roundworm). Although this molecule needs further analyses, the finding, <a href="https://www.nature.com/articles/s41586-019-1791-1">published in Nature</a>, brings hope to the fight against antimicrobial or <a href="https://theconversation.com/uk/topics/antibiotic-resistance-6035">antibiotic resistance</a>, the growing ability of infectious and sometimes lethal bacteria to survive drug treatment.</p>
<p>Some nematodes living in the soil harbour bacteria (<em>Photorrabdus khanii</em>) in their gut to help them when feeding on insect larvae. To kill other bacteria trying to feast on the larvae, <em>P khanii</em> releases the molecule <a href="https://www.nature.com/articles/s41586-019-1791-1">darobactin</a>.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/306200/original/file-20191210-95159-hybflr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/306200/original/file-20191210-95159-hybflr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/306200/original/file-20191210-95159-hybflr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/306200/original/file-20191210-95159-hybflr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/306200/original/file-20191210-95159-hybflr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/306200/original/file-20191210-95159-hybflr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/306200/original/file-20191210-95159-hybflr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Nematodes emerging from a dead moth larva.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Entomopathogenic_nematode_(Heterorhabditis_bacteriophora_)_Poinar,_1975.jpg">Peggy Greb</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>The researchers found that this compound is also very effective against another group of bacteria responsible for difficult-to-treat infections. Interestingly, the molecule acts without needing to cross the bacteria’s outer cell wall, which is an obstacle for many other compounds. They also found that bacteria that spontaneously develop resistance to darobactin seem to lose the ability to infect their host.</p>
<p>The hope is that this compound could lead to an effective new drug. In which case, the nematode where <em>P khanii</em> inhabits would join a growing list of unexpected sources of novel antibiotics and anticancer drugs. Here are a few others:</p>
<h2>The seabed of the Bahamas</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/306301/original/file-20191211-95111-1txvbr1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/306301/original/file-20191211-95111-1txvbr1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/306301/original/file-20191211-95111-1txvbr1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/306301/original/file-20191211-95111-1txvbr1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/306301/original/file-20191211-95111-1txvbr1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/306301/original/file-20191211-95111-1txvbr1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/306301/original/file-20191211-95111-1txvbr1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Bahamas seabed.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/group-starfish-underwater-near-coral-reef-144850168">Damsea</a></span>
</figcaption>
</figure>
<p>As many drugs have been found in the soil, researchers have also spent a lot of time scouring the seabed for new compounds. A survey of marine sediments from the Caribbean island nation of the Bahamas in the late 1980s yielded some potentially interesting bacteria. But it took more than a decade to establish that they represented a distinct new species, <em>Salinispora tropica</em>. </p>
<p>The researchers at the University of California, San Diego, then identified that the bacteria produced a molecule called <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814440/">salinisporamide A</a>. They found that this compound blocks the degradation of proteins in different types of cancer cells and causes them to die. The firm Nereus Pharmaceuticals has turned this compound into an anti-cancer drug called Marizomib, which has reached phase three in clinical trials for myeloma blood cancer and glioblastoma brain cancer.</p>
<h2>The hyper-arid Atacama Desert</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/306203/original/file-20191210-95111-zfa1ea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/306203/original/file-20191210-95111-zfa1ea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/306203/original/file-20191210-95111-zfa1ea.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/306203/original/file-20191210-95111-zfa1ea.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/306203/original/file-20191210-95111-zfa1ea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/306203/original/file-20191210-95111-zfa1ea.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/306203/original/file-20191210-95111-zfa1ea.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The Atacama Desert in Chile.</span>
<span class="attribution"><a class="source" href="https://pixabay.com/photos/chile-atacama-desert-bolivia-4388206/">Grebmot/Pixabay</a></span>
</figcaption>
</figure>
<p>The Atacama Desert in South America has caught the attention of researchers because of the unique characteristics of species that thrive there, despite the seemingly inhospitable conditions. The extreme dryness combined with high ultraviolet radiation levels, toxic elements and scarce soil carbon create an environment not that different from the soil on Mars. Only microorganisms that have evolved mechanisms to deal with these extreme conditions can survive. </p>
<p>Researchers in the UK and Chile have worked for years on bacteria found in the Atacama Desert to identify several antibiotic compounds, such as <a href="https://pubs.acs.org/doi/10.1021/acs.joc.5b01878">chaxapeptins</a> and chaxalactins. Experiments have shown that some of these molecules can kill microbes such as <em>E. coli</em> and the thrush-causing yeast <em>Candida albicans</em>, as well as limiting the ability of cancer cells to invade tissue.</p>
<h2>Leafcutter ants</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/306147/original/file-20191210-95149-13a9xa6.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/306147/original/file-20191210-95149-13a9xa6.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/306147/original/file-20191210-95149-13a9xa6.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/306147/original/file-20191210-95149-13a9xa6.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/306147/original/file-20191210-95149-13a9xa6.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/306147/original/file-20191210-95149-13a9xa6.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/306147/original/file-20191210-95149-13a9xa6.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Tetraponera leafcutter ants.</span>
<span class="attribution"><a class="source" href="https://www.antwiki.org/wiki/File:Tetraponera_penzigi_Dino_Martins.jpg">Dino Martins</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Ants and other insects practice fungiculture, meaning they help fungus to grow to use it for food or building material. Researchers in the UK and South Africa studying this symbiotic <a href="https://www.ncbi.nlm.nih.gov/pubmed/23417898">relationship</a> found it can include bacteria too. In order to protect themselves and their food against infection, leafcutter ants support antibiotic-producing bacteria. </p>
<p>In particular, they found that the bacteria <em>Streptomyces formicae KY5</em> produced <a href="https://pubs.rsc.org/en/content/articlepdf/2017/sc/c6sc04265a">formicamycins</a>. These compounds can kill infectious microbes that are resistant to common antibiotics such as the “superbug” methicillin-resistant <em>Staphylococcus aureus</em> (MRSA). What’s more, experiments suggest that these microbes find it harder to develop resistance to formicamycins than other compounds. However, despite the great potential for therapeutic drug development, no clinical trials testing the formicamycins have started yet.</p>
<h2>The human nose</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/306205/original/file-20191210-95173-60cxj1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/306205/original/file-20191210-95173-60cxj1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/306205/original/file-20191210-95173-60cxj1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/306205/original/file-20191210-95173-60cxj1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/306205/original/file-20191210-95173-60cxj1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/306205/original/file-20191210-95173-60cxj1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/306205/original/file-20191210-95173-60cxj1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Bless you.</span>
<span class="attribution"><a class="source" href="https://pixabay.com/photos/nose-nostrils-nose-hairs-blackheads-2790325/">derneuemann/Pixabay</a></span>
</figcaption>
</figure>
<p>Your nose is full of life – and German scientists’ exploration of exactly what lives in there led to the discovery that the bacterium <em><a href="https://www.nature.com/articles/nature18634">Staphylococcus lugdunensis</a></em> is really good at stopping several other antibiotic-resistant species from growing. This makes the nose one of your body’s first lines of defence against harmful airborne microbes.</p>
<p>Experiments with mice have revealed that <em>S. lugdunensis</em> produces a compound called lugdunin that prevents infection with MRSA. Although the development of a therapeutic drug is still in early stages, <a href="https://www.nature.com/articles/s41467-019-10646-7">results</a> so far have confirmed lugdunin’s potential for treating skin infections.</p>
<h2>Komodo dragon blood</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/306317/original/file-20191211-95159-1dcn3wq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/306317/original/file-20191211-95159-1dcn3wq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=426&fit=crop&dpr=1 600w, https://images.theconversation.com/files/306317/original/file-20191211-95159-1dcn3wq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=426&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/306317/original/file-20191211-95159-1dcn3wq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=426&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/306317/original/file-20191211-95159-1dcn3wq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=535&fit=crop&dpr=1 754w, https://images.theconversation.com/files/306317/original/file-20191211-95159-1dcn3wq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=535&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/306317/original/file-20191211-95159-1dcn3wq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=535&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Komodo dragon.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/komodo-dragon-largest-lizard-world-walks-116793451">Anna Kucherova/Shutterstock</a></span>
</figcaption>
</figure>
<p>As well as taking antibiotic compounds directly from nature, scientists are also able to synthesise artificial ones. In 2017 researchers in the US identified a compound with antibiotic activity in the blood of the Komodo dragon. They were then able to design a modified synthetic version named DRGN-1 that was even more effective than the original compound.</p>
<p>DRGN-1 could be particularly useful if developed into a therapeutic agent because it reduces the number of bacteria while speeding the healing of a wound. Although its development is still in early stages, <a href="https://www.nature.com/articles/s41522-017-0017-2">preliminary experiments</a> carried out in mice suggest it is worth developing.</p><img src="https://counter.theconversation.com/content/128443/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Leafcutter ants, Komodo dragons and even your nose are potential sources of new antimicrobial compounds.Linamaria Pintor Escobar, PhD student in Natural Products Discovery, Edge Hill UniversityAlba Iglesias Vilches, PhD Candidate, Synthetic Biology of Natural Products, Newcastle UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1237682019-09-24T05:02:47Z2019-09-24T05:02:47ZDo new cancer drugs work? Too often we don’t really know (and neither does your doctor)<figure><img src="https://images.theconversation.com/files/293510/original/file-20190923-23822-1kn8g6y.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C4294%2C3027&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The effectiveness of a drug may be evaluated based on its potential to shrink tumours – but this doesn't necessarily equate to improved survival rates.</span> <span class="attribution"><span class="source">From shutterstock.com</span></span></figcaption></figure><p>It’s hard to find anyone who hasn’t been touched by cancer. People who haven’t had cancer themselves will likely have a close friend or family member who has been diagnosed with the disease. </p>
<p>If the cancer has already spread, the diagnosis may feel like a death sentence. News that a new drug is available can be a big relief. </p>
<p>But imagine a cancer patient asks their doctor: “Can this drug help me stay alive longer?” And in all honesty the doctor answers: “I don’t know. There’s one study that says the drug works, but it didn’t show whether patients lived longer, or even if they felt any better.”</p>
<p>This might sound like an unlikely scenario, but it’s precisely what a team of <a href="https://www.bmj.com/content/366/bmj.l5221">UK researchers</a> found to be the case when it comes to many new cancer drugs. </p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/we-dont-need-to-change-how-we-subsidise-breakthrough-cancer-treatments-87185">We don't need to change how we subsidise 'breakthrough' cancer treatments</a>
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<h2>A look at the research</h2>
<p>A study published last week in the <a href="https://www.bmj.com/content/366/bmj.l5221">British Medical Journal</a> reviewed 39 clinical trials supporting approval of all new cancer drugs in Europe from 2014 to 2016.</p>
<p>The researchers found more than half of these trials had serious flaws likely to exaggerate treatment benefits. Only one-quarter measured survival as a key outcome, and fewer than half reported on patients’ quality of life.</p>
<p>Of 32 new cancer drugs examined in the study, only nine had at least one study without seriously flawed methods. </p>
<p>The researchers evaluated methods in two ways. First, they used a standard “risk of bias” scale that measures shortcomings shown to lead to biased results, such as if doctors knew which drug patients were taking, or if too many people dropped out of the trial early. </p>
<p>Second, they looked at whether the European Medicines Agency (EMA) had identified serious flaws, such as a study being stopped early, or if the drug was compared to substandard treatment. The EMA identified serious flaws in trials for ten of the 32 drugs. These flaws were rarely mentioned in the trials’ published reports.</p>
<h2>From clinical trials to treatment – faster isn’t always better</h2>
<p>Before a medicine is approved for marketing, the manufacturer must carry out studies to show it’s effective. Regulators such as the EMA, the US Food and Drug Administration (FDA) or Australia’s Therapeutic Goods Administration (TGA) then judge whether to allow it to be marketed to doctors. </p>
<p>National regulators mainly examine the same clinical trials, so the findings from this research are relevant internationally, including in Australia.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/spot-the-snake-oil-telling-good-cancer-research-from-bad-36344">Spot the snake oil: telling good cancer research from bad</a>
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</em>
</p>
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<p>There’s strong public pressure on regulators to approve new cancer drugs more quickly, based on less evidence, especially for poorly treated cancers. The aim is to get treatments to patients more quickly by allowing medicines to be marketed <a href="https://ascpt.onlinelibrary.wiley.com/doi/full/10.1002/cpt.59">at an earlier stage</a>. The downside of faster approval, however, is more uncertainty about treatment effects. </p>
<p>One of the arguments for earlier approvals is the required studies can be carried out later on, and sick patients can be given an increased chance of survival before it’s too late. However, <a href="https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2733561">a US study</a> concluded that post-approval studies found a survival advantage for only 19 of 93 new cancer drugs approved from 1992 to 2017.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/293512/original/file-20190923-23822-zn3gbl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/293512/original/file-20190923-23822-zn3gbl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/293512/original/file-20190923-23822-zn3gbl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/293512/original/file-20190923-23822-zn3gbl.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/293512/original/file-20190923-23822-zn3gbl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/293512/original/file-20190923-23822-zn3gbl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/293512/original/file-20190923-23822-zn3gbl.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">If the evidence for a new cancer drug is flawed, this leaves patients vulnerable to false hope.</span>
<span class="attribution"><span class="source">From shutterstock.com</span></span>
</figcaption>
</figure>
<h2>So how is effectiveness measured currently?</h2>
<p>Approval of new cancer drugs is often based on short-term health outcomes, referred to as “surrogate outcomes”, such as shrinking or slower growth of tumours. The hope is these surrogate outcomes predict longer-term benefits. For many cancers, however, they have been found to do a poor job of <a href="https://www.sciencedirect.com/science/article/pii/S095980491831476X?via%3Dihub">predicting improved survival</a>. </p>
<p><a href="https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2729389">A study of cancer trials</a> for more than 100 medicines found on average, clinical trials that measure whether patients stay alive for longer take an extra year to complete, compared to trials based on the most commonly used surrogate outcome, called “progression free survival”. This <a href="https://ascopubs.org/doi/10.1200/JCO.2011.38.7571">measure</a> describes the amount of time a person lives with a cancer without tumours getting larger or spreading further. It’s often poorly correlated with overall survival.</p>
<p>A year may seem like a long wait for someone with a grim diagnosis. But there are policies to help patients access experimental treatments, such as participating in clinical trials or compassionate access programmes. If that year means certainty about survival benefits, it’s worth waiting for. </p>
<h2>Approving drugs without enough evidence can cause harm</h2>
<p>In an <a href="https://www.bmj.com/content/366/bmj.l5399">editorial</a> accompanying this study, we argue that exaggeration and uncertainty about treatment benefits cause direct harm to patients, if they risk severe or life-threatening harm without likely benefit, or if they forgo more effective and safer treatments. </p>
<p>For example, the drug <a href="https://english.prescrire.org/en/81/168/57219/0/NewsDetails.aspx">panobinostat</a>, which is used for multiple myeloma patients who have not responded to other treatments, has not been shown to help patients live longer, and can lead to serious infections and bleeding.</p>
<p>Inaccurate information can also encourage false hope and create a distraction from needed palliative care. </p>
<p>And importantly, the ideal of shared informed decision-making based on patients’ values and preferences falls apart if neither the doctor nor the patient has accurate evidence to inform decisions.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/if-we-dont-talk-about-value-cancer-drugs-will-become-terminal-for-health-systems-44072">If we don't talk about value, cancer drugs will become terminal for health systems</a>
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<p>In countries with public health insurance, such as Australia’s Pharmaceutical Benefits Scheme (PBS), patients’ access to new cancer drugs depends not just on market approval but also on payment decisions. The PBS often refuses the pay for new cancer drugs because of <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/imj.13350">uncertain clinical evidence</a>. In the cases of the drugs in this research, some are available on the PBS, while others are not.</p>
<p>New cancer drugs are often very expensive. On average in the US, a course of treatment with a new cancer drug costs more than US$100,000 (A$148,000).</p>
<p>Cancer patients need treatments that help them to live longer, or at the very least to have a better quality of life during the time that they have left. In this light, we need stronger evidence standards, to be sure there are real health benefits when new cancer drugs are approved for use. </p>
<p><em>The article has been updated to reflect Agnes Vitry’s current role at the University of South Australia.</em></p><img src="https://counter.theconversation.com/content/123768/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Barbara Mintzes receives funding from the National Health and Medical Research Council (NHMRC) for a research project on post-market regulatory safety advisories on medicines. She is also a member of Health Action International (HAI-Europe), a network of health and consumer organisations that promotes access to essential medicines and quality use of medicines. </span></em></p><p class="fine-print"><em><span>Agnes Vitry is affiliated with Cancer Voices, SA.</span></em></p>National drug regulators use evidence from clinical trials to decide whether new cancer drugs will be approved for use. But these studies are often flawed.Barbara Mintzes, Senior Lecturer, Faculty of Pharmacy, University of SydneyAgnes Vitry, Senior lecturer, University of South AustraliaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1144452019-04-29T13:52:21Z2019-04-29T13:52:21ZHow we are developing immunotherapies relevant to Africa<figure><img src="https://images.theconversation.com/files/269546/original/file-20190416-147505-366981.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">For developing countries in Africa immunotherapy solutions is important given the high cost of cancer drugs.</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>The <a href="https://www.cansa.org.za/why-is-the-cost-of-oncology-drugs-so-high/">exorbitant costs</a> of cancer drugs make it difficult for public and private health care systems to provide the latest treatments to patients. If this trend continues it will become increasingly difficult for patients to access basic cancer treatment, let alone the new generation of immunotherapy drugs.</p>
<p><a href="https://www.frontiersin.org/articles/10.3389/fmicb.2018.03158/full">Immunotherapy</a> refers to a therapeutic approach that targets or manipulates the immune system to fight disease without harming normal cells. </p>
<p>In March 2019, the US released the first immunotherapy drug for breast cancer to be approved by the Food and Drug Administration. The drug, called <a href="https://www.breastcancer.org/research-news/tecentriq-approved-as-first-bc-immunotherapy">Tecentriq</a>, is used to treat triple-negative breast cancer. This type of cancer is resistant to surgery and chemotherapy. It highlights the major benefits of immunotherapy in patients who have limited – if any –treatment options. </p>
<p>For developing countries like South Africa, finding immunotherapy solutions is particularly important given the country’s weak health system and the high cost of cancer drugs. The <a href="http://www.news.uct.ac.za/news/debates/ccwg/-article/2018-10-11-antibodies-as-tools-in-cancer-treatment">University of Cape Town</a> has set up the country’s first medical biotechnology-based immunotherapy laboratory. The lab, where we do our research, is strongly committed to the development of novel <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=26618&path%5B%5D=82774">therapeutic</a> and <a href="https://onlinelibrary.wiley.com/doi/epdf/10.1002/hsr2.103">diagnostic</a> tools for cancer.</p>
<p>Most cancer research has been done on populations of European descent. This means that there’s minimal data on African populations. Our lab aims to fill this knowledge gap by diagnosing and treating patients of African descent. The aim is to identify immunotherapy targets in this underrepresented population.</p>
<h2>Our research</h2>
<p>There are <a href="https://www.nanalyze.com/2017/12/introduction-cancer-immunotherapy-treatments">five main classes</a> of immunotherapies. These are:</p>
<ul>
<li><p><strong>Cancer vaccines:</strong> These are a collection of immune cells that have been removed from a cancer patient and manipulated to enhance their ability to attack cancer before being readministered into the patient.</p></li>
<li><p><strong>Cytokine immunotherapy:</strong> This involves treating a patient with cytokines, which are proteins made by immune cells that signal other immune cells to kill a cancerous cell.</p></li>
<li><p><strong>Antibody-based therapies:</strong> These represent the largest class of approved immunotherapies and are our lab’s main research focus. Antibodies are proteins produced by the body’s immune cells. These can identify pathogens and elicit a response to eradicate diseased cells or disease-causing agents. </p></li>
</ul>
<p>Antibodies are like puzzle pieces – and diseases are like an incomplete puzzle. Therefore, only antibodies with a specific shape will fit into the “cancer puzzle”. Antibodies with other shapes would fit other puzzles, but not cancer. The ability of antibodies to discriminate between different cells and diseases is the basis for antibody-based immunotherapies.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/268598/original/file-20190410-2935-guayh4.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/268598/original/file-20190410-2935-guayh4.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=177&fit=crop&dpr=1 600w, https://images.theconversation.com/files/268598/original/file-20190410-2935-guayh4.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=177&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/268598/original/file-20190410-2935-guayh4.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=177&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/268598/original/file-20190410-2935-guayh4.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=223&fit=crop&dpr=1 754w, https://images.theconversation.com/files/268598/original/file-20190410-2935-guayh4.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=223&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/268598/original/file-20190410-2935-guayh4.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=223&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Only antibodies with a specific shape will fit into the cancer puzzle.</span>
</figcaption>
</figure>
<p>Our current research involves attaching a light detectable agent to the puzzle piece. This allows us to visualise where a cancer cell is located in a cancer patient’s tissues. We can characterise different types of cancer cells by attaching different coloured light detectable agents to different antibodies. We then generate antibody-drug conjugates that deliver the drug directly to the cancer without harming healthy cells by replacing the light detectable agent on a cancer-fitting antibody with a toxic drug.</p>
<ul>
<li><p><strong>Immune checkpoint inhibitors:</strong> These are essentially antibodies that target specific proteins on tumour cells or T-cells (the main immune cells responsible for killing cancer). These proteins normally send inhibitory signals from cancer cells to T-cells, resulting in T-cell inactivation. By interfering with this signalling, immune checkpoint inhibitors allow T-cells to be activated and tumour cells to be killed. </p></li>
<li><p><strong>Adoptive cell therapies:</strong> These include the popular CAR-T cell therapies that enhance the natural ability of T-cells to fight cancer. Similar to antibodies, T-cells express different “puzzle pieces” on their surface. These allow them to attach to an incomplete diseased puzzle and to then kill the disease. CAR-T cells are T-cells that have been removed from a patient and modified to have a cancer-specific puzzle piece, allowing the T-cells to directly target the cancer once it’s put back into the patient.</p></li>
</ul>
<h2>Future of cancer treatment</h2>
<p>Preliminary research from around the world indicates that immunotherapies for cancer are less toxic than conventional therapies like chemotherapy and radiation. They also have the potential for fewer and less severe side effects. This means that immunotherapies could improve patients’ quality of life. </p>
<p>Immunotherapies are effective, safe and relatively easy to manufacture. But they aren’t a standalone wonder drug that can bring about the end of cancer. </p>
<p>A multi-pronged approach that involves a combination of the best treatment options has been heralded as the next wave of therapeutic strategies for cancer and may provide a curative treatment.</p><img src="https://counter.theconversation.com/content/114445/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Neelakshi Mungra receives funding from the National Research Foundation South African Research Chair (SARChI) in Cancer Biotechnology. She is affiliated with the University of Cape Town as a PhD candidate.</span></em></p><p class="fine-print"><em><span>Krupa Naran receives funding from The National Research Foundation. </span></em></p><p class="fine-print"><em><span>Trishana Nundalall receives funding from the National Research Foundation for completion of her PhD.</span></em></p>Most cancer research has been done in Europe, there’s minimal data on African populations.Neelakshi Mungra, PhD Candidate at the MB&I Unit, University of Cape TownKrupa Naran, Postdoctoral Research Fellow, Institute of Infectious Diseases and Molecular Medicine, University of Cape TownTrishana Nundalall, PhD Candidate at the MB&I UnitLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1116802019-02-13T11:47:45Z2019-02-13T11:47:45ZConfusing and high bills for cancer patients add to anxiety and suffering<figure><img src="https://images.theconversation.com/files/258586/original/file-20190212-174894-1t4wykc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Having cancer is bad enough, and dealing with the costs and confusion of billing systems makes things harder.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/young-woman-patient-lying-hospital-bed-626815895?src=GItKPrntz3VolOt88zSy8A-1-0">KieferPix/Shutterstock.com</a></span></figcaption></figure><p>Weeks after my father passed away from cancer in 2010, my newly widowed mother received a bill for US$11,000. </p>
<p>Insurance retroactively denied a submitted claim for one of his last chemotherapy treatments, claiming it was “experimental.” All of the prior identical chemotherapy treatments he had received had been covered, and the doctors had received pre-authorization for the treatment. </p>
<p>Was it suddenly experimental because it was not prolonging life anymore? Was it a clerical error, with one insurance claim submitted differently than the others? </p>
<p>As my mother and family grieved, we had this bill looming in the backs of our minds. We took turns calling the insurance company and the hospital billing office, checking websites, and deciphering billing codes on various pieces of paper.</p>
<p>Advances in cancer treatments have improved patient outcomes overall, but many of these interventions have <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647336/">increased costs of care</a>. Even when care is “covered,” the definition of “coverage” can include <a href="https://www.fightcancer.org/sites/default/files/Costs%20of%20Cancer%20-%20Final%20Web.pdf">high deductibles, copayments, coinsurance, and surprise out-of-pocket bills</a> for patients. As one participant in a <a href="https://doi.org/10.1177/1077558718820232">recently published qualitative study</a> of cancer survivors told us, “You just have to call both parties and figure out, what are you chargin’ me for? Plus … you’re getting billed for months ago.” </p>
<p>By the time patients receive these delayed bills, they may be unable to recall the particular visit in question, which makes it exhausting for them to manage their finances and diagnosis. The problem is so significant that the National Cancer Institute has a term for this: <a href="https://www.cancer.gov/about-cancer/managing-care/track-care-costs/financial-toxicity-hp-pdq">financial toxicity.</a></p>
<h2>A scary disease, an opaque system</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/258588/original/file-20190212-174887-y2pkhp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/258588/original/file-20190212-174887-y2pkhp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=250&fit=crop&dpr=1 600w, https://images.theconversation.com/files/258588/original/file-20190212-174887-y2pkhp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=250&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/258588/original/file-20190212-174887-y2pkhp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=250&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/258588/original/file-20190212-174887-y2pkhp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=314&fit=crop&dpr=1 754w, https://images.theconversation.com/files/258588/original/file-20190212-174887-y2pkhp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=314&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/258588/original/file-20190212-174887-y2pkhp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=314&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Cancer is one of the scariest and most expensive diagnoses a patient can receive.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/young-depressed-cancer-patient-standing-front-554782237?src=4O7lcsk0EicSd1HxhZ3Pow-1-4">Sasa Prudkov/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>In the U.S., cancer is <a href="https://meps.ahrq.gov/data_files/publications/st470/stat470.shtml">one of the most expensive diseases to treat</a>; only heart disease costs more. This cost burden is often passed on to patients. </p>
<p>And to make matters worse, lack of transparency about cost and coverage can be confusing. Seemingly arbitrary changes in insurance decisions can contribute to patients’ <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523887/">financial toxicity</a>, or the hardship, psychological stress and behavioral adjustments associated with costs of care. For example, some patients have unexpected <a href="https://www.npr.org/sections/health-shots/2016/08/30/491839847/when-a-screening-test-for-colon-cancer-leads-to-a-pricey-follow-up">bills</a> after they receive a diagnosis or abnormal result on a screening test.</p>
<p>In these cases, care that was previously categorized as preventive (and free from out-of-pocket costs) can become a diagnostic or surveillance test, with associated fees. Other patients are surprised when they receive a bill for physician time as well as a <a href="https://publicintegrity.org/health/hospital-facility-fees-boosting-medical-bills-and-not-just-for-hospital-care/">hospital facility fee</a>. It is difficult for patients to keep track of all of these changes and adjust cost expectations.</p>
<p>The impact of high care costs is substantial. People with high out-of-pocket costs are <a href="https://www.businesswire.com/news/home/20180214006069/en/New-CarePayment-Research-Shows-Americans-Can%E2%80%99t-Afford">less likely to receive necessary care</a>, which can compromise cancer treatment and may affect overall or cancer-specific mortality. In a recent study, almost a third of adults said they <a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2714507?resultClick=3">delayed or avoided care due to costs</a>.</p>
<p>A patient participant in a <a href="https://doi.org/10.1177/1077558718820232">study we conducted</a> talked about the time she spent navigating the billing process, commenting, “The billing was extremely daunting. I kept a three-ring binder that was three inches thick … tried to match things up. It was a mess.” That time and effort could be spent healing or engaging in valued activities, she relayed to us.</p>
<h2>Hidden costs of care</h2>
<p>In addition to direct costs of care, there are indirect costs of care, such as fees for transportation, parking, housing when needed, and the time spent managing the financial aspects of care on top of treatment.</p>
<p>My father had to pay between $18 and $30 per day just to park at the hospital in New York City where he received his treatments, depending on how long he stayed. This parking fee was on top of tolls ($15) and the time spent traveling to and from the hospital. For him, this meant anywhere from 45 minutes to two hours, depending on traffic and road conditions. Transportation and parking costs are typically not covered by insurance, though some hospitals, health centers and nonprofit organizations <a href="https://www.cancer.org/treatment/finding-and-paying-for-treatment/understanding-health-insurance/if-you-have-trouble-paying-a-bill/programs-and-resources-to-help-with-cancer-related-expenses.html">offer assistance with these</a> indirect care costs.</p>
<p>Many other patients have to take time off <a href="https://theconversation.com/we-need-more-support-systems-for-people-who-want-to-work-during-and-after-cancer-treatment-65540">work</a> while they are undergoing cancer treatment or follow-up care. Cancer patients who are unemployed may even have <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00577-8/fulltext">lower survival rates</a>. One patient in <a href="https://journals.sagepub.com/doi/full/10.1177/1077558718820232">our study</a> commented, “It takes me two-and-a-half hours to get here. I was coming every month, then every two months. Now I’m every three months. Eventually, I go to six months, but I have to take off work every time to come.” Another patient stated, “My vacation and sick time ran out … I had to go on disability.”</p>
<h2>Policy suggestions</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/258590/original/file-20190212-174857-1scs4pw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/258590/original/file-20190212-174857-1scs4pw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=398&fit=crop&dpr=1 600w, https://images.theconversation.com/files/258590/original/file-20190212-174857-1scs4pw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=398&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/258590/original/file-20190212-174857-1scs4pw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=398&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/258590/original/file-20190212-174857-1scs4pw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/258590/original/file-20190212-174857-1scs4pw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/258590/original/file-20190212-174857-1scs4pw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A cancer patient and her doctor discuss her treatment. Talking with doctors about costs may make a difference.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/doctor-telling-patient-woman-results-her-645685942?src=NH0EqD2pGC_rxPebluxvpg-1-0">Rido/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>Although addressing out-of-pocket care costs for patients requires multiple systemic changes, there are strategies that can help.</p>
<p>First, patients and their clinicians can discuss the costs of care and create <a href="https://journals.sagepub.com/doi/10.1177/0272989X15626384">cost-saving strategies</a>. Patient-clinician cost discussions can reduce overall costs to <a href="https://europepmc.org/abstract/med/26618364">patients</a>, but many clinicians are hesitant to talk about costs with <a href="https://www.healthaffairs.org/doi/10.1377/hlthaff.2015.1280">patients</a>.</p>
<p>If there is more than one treatment option available with equal effectiveness data, patients can ask, “<a href="https://theconversation.com/why-treating-breast-cancer-with-less-may-be-more-78514">is there a difference in price between options”</a>? Developers of <a href="https://www.bmj.com/content/347/bmj.f4147">patient-centered decision aids</a> can also add the relative costs of treatments so that patients can weigh cost along with other aspects of treatment to support their choice.</p>
<p>Health care institutions may be underutilizing social workers, financial navigators and other care center resources. Social workers, financial navigators and other care center resources staff with adequate training that promotes patients’ access to care and assistance can help manage their out-of-pocket expenses. This process can yield positive outcomes for both patients and <a href="http://ajmc.s3.amazonaws.com/_media/_pdf/AJMC_03_2018_PAN_SpecialIssue_Yezefski%20final.pdf">health care institutions</a>.</p>
<h2>Less may be more</h2>
<p>Sometimes, treatments are not needed and may add burden to patients. For example, a <a href="https://theconversation.com/why-treating-breast-cancer-with-less-may-be-more-78514">shorter duration of radiation for early stage breast cancer</a> works just as well as longer durations; chemotherapy might not benefit some patients at <a href="https://wa.kaiserpermanente.org/kbase/topic.jhtml?docId=tv8464">earlier stages of cancer</a> or some <a href="https://www.gotoper.com/publications/ajho/2015/2015mar/adjuvant-chemotherapy-in-older-adults-with-colon-cancer">older adults</a>; and some scans <a href="http://www.choosingwisely.org/patient-resources/tests-and-treatments-for-women-with-breast-cancer/">may be excessive</a>. </p>
<p>Until we change norms and engage patients, clinicians and systems to weigh the pros and cons of care that is considered unnecessary or even harmful, many patients and clinicians might fear less aggressive treatment. There’s also the Choosing Wisely <a href="http://www.choosingwisely.org/">campaign</a> which is designed to help by summarizing evidence in plain language and recommending commonly overused interventions.</p>
<p>Finding sustainable solutions to reducing cancer-related financial toxicity requires a collaborative effort between doctors, patients, policymakers, health insurance companies and health care institutions. Easing the cognitive burden associated with the financial stress that comes with cancer care can lead to better outcomes for cancer patients’ health and quality of life.</p>
<p><em>Research coordinator Nerissa George, MPH, contributed to this article.</em></p><img src="https://counter.theconversation.com/content/111680/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mary Politi receives funding from the Agency for Healthcare Research and Quality (AHRQ), the American Cancer Society (ACS)
the Barnes Jewish Hospital Foundation (BJHF), Merck & Co, the National Institute of Health (NIH), the Patient Centered Outcomes Research Institute (PCORI), and the Society of Family Planning (SFP). </span></em></p>A cancer diagnosis is one of the scariest of all. The pain and fear are worsened by a confusing landscape of bills, opaque billing systems and changing insurance rules, rates and reimbursements.Mary C Politi, Associate Professor of Surgery, Division of Public Health Sciences, Washington University in St. LouisLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/871852017-11-27T05:04:15Z2017-11-27T05:04:15ZWe don’t need to change how we subsidise ‘breakthrough’ cancer treatments<figure><img src="https://images.theconversation.com/files/194963/original/file-20171116-17109-odtazf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Applications to list drugs on the PBS are usually submitted by the manufacturers of those drugs.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>New therapies that arm the immune system to fight cancer, such as Keytruda (pembrolizumab) and Yervoy (ipilimumab), have offered patients with advanced melanoma real hope of effective treatment. </p>
<p>But until these drugs, known as immunotherapies, were publicly subsidised, they were prohibitively expensive for Australian patients. A patient using Keytruda, for example, would be out of pocket an estimated <a href="http://www.abc.net.au/news/2015-06-28/melanoma-drug-listed-on-pbs-saving-patients-thousands/6578554">A$150,000</a> per year of treatment.</p>
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Read more:
<a href="https://theconversation.com/explainer-how-does-keytruda-treat-melanoma-and-why-is-it-so-costly-40558">Explainer: how does Keytruda treat melanoma and why is it so costly?</a>
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<p>The <a href="http://www.pbs.gov.au/info/industry/listing/participants/pbac">Pharmaceutical Benefits Advisory Committee</a> (PBAC) recommends which drugs to subsidise and list on the Pharmaceutical Benefits Scheme (PBS). The PBAC uses the same <a href="http://www.pbs.gov.au/info/industry/listing/listing-steps">process</a> for all drugs, regardless of the health condition the drug will treat. </p>
<p><a href="https://www.aph.gov.au/Parliamentary_Business/Committees/Senate/Community_Affairs/Cancer_Drugs">Some argue</a> considerations of cost-effectiveness that have been used for years are not a good fit for new cancer therapies, particularly immunotherapies. The argument is that these considerations overlook some unique benefits new drugs offer that aren’t relevant to old medications, and that we should <a href="https://jitc.biomedcentral.com/articles/10.1186/s40425-017-0241-6">review how</a> we consider such drugs for funding.</p>
<p>But looking at the processes that led to Keytruda and Yervoy being listed on the PBS, we argue the way PBAC currently works serves us well.</p>
<h2>How the PBAC makes decisions</h2>
<p>The health minister can’t list a drug on the PBS without a PBAC recommendation to do so. For the PBAC to consider a drug, it has to receive an application. Generally, the manufacturer of the drug submits the application.</p>
<p>The process has a fixed 17-week period from submission of the application to the PBAC meeting. During this time, applicants can provide evidence for the committee to consider. A list of all submissions being considered by the PBAC is published prior to the meeting so members of the community can provide their views. </p>
<p>More recently, the PBAC has invited patient groups to attend hearings and provide evidence. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/194981/original/file-20171116-8015-3jxgqm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/194981/original/file-20171116-8015-3jxgqm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/194981/original/file-20171116-8015-3jxgqm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/194981/original/file-20171116-8015-3jxgqm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/194981/original/file-20171116-8015-3jxgqm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/194981/original/file-20171116-8015-3jxgqm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/194981/original/file-20171116-8015-3jxgqm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/194981/original/file-20171116-8015-3jxgqm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">A drug needs to be recommended by the Pharmaceutical Benefits Advisory Committee to be listed on the PBS.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>Since 1993, <a href="https://www.legislation.gov.au/Details/C2017C00250">legislation</a> has required the PBAC to consider the health outcomes and costs of a new medicine relative to currently available treatments. Typically, the PBAC assesses the effectiveness of a drug according to its impact on the length and quality of life of the patient taking it. This is expressed in a measure called the quality adjusted life year (QALY). </p>
<p>The committee then judges whether each cost per QALY represents value for money for society, and whether it has confidence in those values given the data available. The PBAC also considers other factors, including equity of access and the availability of alternatives.</p>
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Read more:
<a href="https://theconversation.com/new-cancer-drugs-are-very-expensive-heres-how-we-work-out-value-for-our-money-44014">New cancer drugs are very expensive - here's how we work out value for our money</a>
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<p>But there have recently <a href="https://jitc.biomedcentral.com/articles/10.1186/s40425-017-0241-6">been suggestions</a> that some of the benefits of immunotherapies are overlooked when the focus is on the cost per QALY. These include increased durability of the response for some patients, reduced treatment costs for the future, improved productivity and the value of hope to patients.</p>
<p>But if these benefits were indeed being overlooked, we might expect immunotherapies not to be listed on the PBS, or delays in listing. This has not been the case.</p>
<h2>Immunotherapy case studies</h2>
<p>The PBS recently added two immunotherapy drugs for patients with metastatic melanoma (melanoma that has spread): Yervoy (ipilimumab) and Keytruda (pembrolizumab).</p>
<p><strong>Yervoy</strong></p>
<p>PBAC first considered an application from Yervoy’s manufacturer in July 2011. Despite the drug being seen as a <a href="http://www.abc.net.au/news/2015-04-20/doctors-hail-melanoma-breakthrough/6404426">breakthrough</a> in the treatment of metastatic melanoma, the PBAC didn’t recommended it for listing then. It only <a href="http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2012-11/ipilimumab">did so in November 2012</a> after two <a href="http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2012-03/ipilimumab">subsequent applications</a> from the manufacturer. Yervoy was <a href="https://www.nps.org.au/australian-prescriber/articles/medical-management-of-malignant-melanoma">added to the PBS</a> in August 2013.</p>
<p>The reason for this delay was that the PBAC was <a href="http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2012-11/ipilimumab">initially uncertain</a> of the drug’s efficacy and cost-effectiveness, based on the evidence it was given. This was in part because the primary evidence was a <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1003466#t=article">study that compared Yervoy with a vaccine</a> not used in Australian practice. </p>
<p>In the study, 50% of patients treated with Yervoy lived 3.7 months longer than those who received just the vaccine. But these results couldn’t be directly translated to Australian practice, where treatment at that time was different. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/195153/original/file-20171117-14675-1nps0r8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/195153/original/file-20171117-14675-1nps0r8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/195153/original/file-20171117-14675-1nps0r8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/195153/original/file-20171117-14675-1nps0r8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/195153/original/file-20171117-14675-1nps0r8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/195153/original/file-20171117-14675-1nps0r8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/195153/original/file-20171117-14675-1nps0r8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/195153/original/file-20171117-14675-1nps0r8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Cancer immunotherapy drugs work by arming the immune system to fight the cancer.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<p>PBAC accepted evidence for the prolonged response and survival for people on Yervoy, as a result of the two resubmissions. But the magnitude of those gains was uncertain as they reflected the experience of around 10% of the study’s patients. The ongoing costs were also uncertain – there was no answer as to how long patients would need to remain on Yervoy, or whether they would need treatment again.</p>
<p>But, overall, the PBAC <a href="http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2011-07/pbac-psd-ipilimumab-july11">recognised the potential benefits</a> of the drug. It was made available through the government and the manufacturer entering into a <a href="http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2012-11/ipilimumab">risk-sharing arrangement</a>. Under this agreement, the government would review what it paid for Yervoy to take account of the outcomes being achieved in patients, as well as how much the drug was being used. </p>
<p><strong>Keytruda</strong></p>
<p>Keytruda had a faster, but no less complex, passage to PBS listing. PBAC <a href="http://www.pbs.gov.au/pbs/industry/listing/elements/pbac-meetings/psd/2015-03/pembrolizumab-keytruda-psd-03-2015">considered the application</a> in March 2015 to list the drug for metastatic melanoma. This was after a series of stakeholder meetings, including representatives from government, patients, clinicians and the manufacturers, as well as a rolling submission of evidence during the 17-week PBAC evaluation process.</p>
<p>Initially, no evidence was available of a direct comparison between Keytuda and the relevant comparator, which was the previously listed Yervoy. But a randomised <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1503093">controlled trial</a> became available as evidence during the evaluation.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/cancer-immunotherapy-drugs-like-keytruda-and-opdivo-hold-hope-for-some-but-theres-still-a-way-to-go-81320">Cancer immunotherapy drugs like Keytruda and Opdivo hold hope for some, but there's still a way to go</a>
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<p>These data showed Keytruda was likely to be at least as beneficial as Yervoy, with the potential for better long-term survival. This, together with a risk-sharing arrangement similar to the one applied to Yervoy, was sufficient for the PBAC to recommend PBS listing from the first submission.</p>
<p>Keytruda became available as a PBS-listed item for melanoma in September 2015. This provided access to an additional care option for around <a href="http://www.abc.net.au/news/2015-06-28/melanoma-drug-listed-on-pbs-saving-patients-thousands/6578554">1,100</a> patients. </p>
<p>In both cases, the process was sufficiently flexible in response to the available data to make a positive recommendation for listing. It is unclear how changing requirements for evidence for these or other cancer drugs, or introducing different <a href="http://www.smh.com.au/national/health/new-report-proposes-radical-reforms-for-rare-cancer-regulation-20170808-gxrh02.html">reimbursement models</a>, would have better served these drugs or the patients who use them.</p><img src="https://counter.theconversation.com/content/87185/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard De Abreu Lourenco receives funding from NHMRC, Cancer Australia, the Victorian Cancer Agency and the Department of Health. None of the views expressed in the piece relfect the views of those agencies.</span></em></p><p class="fine-print"><em><span>Marion Haas receives funding from the NHMRC and Cancer Australia. She is a member of the CanTeen Strategic Advisory Committee. None of the opinions expressed in this article reflect the views of these organisations. </span></em></p><p class="fine-print"><em><span>Rosalie Viney was previously a member of the Pharmaceutical Benefits Advisory Committee. She receives funding from Cancer Australia and the NHMRC. </span></em></p>Some argue the current system of subsidising drugs in Australia needs changing to accommodate new cancer therapies. But two recent drug listings show the current system is working perfectly well.Richard De Abreu Lourenco, Senior Research Fellow, University of Technology SydneyMarion Haas, Professor of Health Economics, Deputy Director of CHERE, University of Technology SydneyRosalie Viney, Professor of Health Economics, University of Technology SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/814922017-08-23T15:44:55Z2017-08-23T15:44:55ZHow poverty is killing Kenya’s children with cancer<figure><img src="https://images.theconversation.com/files/181148/original/file-20170807-16792-vfvgq4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Most common childhood cancers are leukemia and Hodgkin lymphoma.</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>In the last decade, the <a href="http://onlinelibrary.wiley.com/doi/10.3322/caac.21219/full">survival rates</a> for most types of cancer in children have improved in developed countries. Up to <a href="https://www.sandoz.com/news/media-releases/sandoz-expands-partnership-world-child-cancer-help-children-access-treatment">80% of the patients survive</a>, thanks to early diagnosis, timely treatment and advances in medicine.</p>
<p>But most children who have cancer live in the developing world where their survival rate is <a href="https://www.healio.com/hematology-oncology/palliative-care/news/print/hemonc-today/%7B73828ce7-bd54-4570-9ef9-aa35c9389ce9%7D/a-global-challenge-treating-children-with-cancer-in-developing-countries">less than 25%</a>.</p>
<p>A study in Kenya sought to understand why. </p>
<p>At the <a href="http://www.mtrh.or.ke/">Moi Teaching and Referral Hospital</a> in Western Kenya, the survival rate for all childhood cancers is about <a href="https://www.ncbi.nlm.nih.gov/pubmed/24347434">19%</a>. The <a href="https://www.ncbi.nlm.nih.gov/pubmed/24681695">study</a> found that awareness of cancer in children under 18 was low, the country’s health care resources were inadequate for diagnosis and treatment, and poor families could not afford medical insurance or transport to hospital. </p>
<h2>Childhood cancer around the world</h2>
<p>Cancer is <a href="http://www.who.int/cancer/media/news/Childhood_cancer_day/en/">rare</a> in children under 18. It represents between <a href="http://www.who.int/cancer/media/news/Childhood_cancer_day/en/"> 0.5% and 4.6% </a> of all cancers globally. </p>
<p>Cancer of the <a href="https://www.cancer.gov/types/leukemia/patient/child-all-treatment-pdq">white blood cells</a>and brain tumours are the leading childhood cancers globally. In sub-Saharan Africa, the commonest types are <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207091/">non-Hodgkins lymphoma</a> which starts in the immune system , kidney cancer and cancer of the bone marrow.</p>
<p>In <a href="http://canceratlas.cancer.org/the-burden/cancer-in-children/">developing countries</a> the reported rate of childhood cancer is low because it is undiagnosed. Awareness of cancer is low in less educated populations, and
health budgets are too small to provide enough diagnostic equipment and specialised health workers. In some African countries, only <a href="http://www.who.int/dg/speeches/2010/iaea_forum_20100921/en/">20% of patients survive cancers</a>.</p>
<p>Kenya does not have a national childhood cancer registry. It relies on a <a href="http://afcrn.org/membership/members/101-eldoret">hospital based registries</a>. About 2,500 children in Kenya develop cancer every year out of about 20 million children, as calculated from the global estimate in this <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461370/">study</a>.</p>
<h2>The Kenyan study</h2>
<p>Between January 2007 and January 2009, 222 children were newly diagnosed with cancer at the Moi Teaching and Referral Hospital in Eldoret, Western Kenya. Of these, 180 began treatment but 98 (54%) stopped. From December 2011 until August 2012, 53 (54%) of the 98 families were contacted to discuss reasons for discontinuation. The respondents thus represent 24% of the children diagnosed.</p>
<p>The <a href="https://www.ncbi.nlm.nih.gov/pubmed/24681695">study</a> investigated the reasons for discontinuation of treatment by childhood cancer patients. The most common reasons given were financial difficulties (46% of respondents), lack of health insurance (27%) and transport difficulties (23%). These are all related to poverty.</p>
<p>The referral hospital is located in an urban area with a population of about 18 million people. Being a public referral health facility, the patients travel long distances to get services that are not available at the satellite health facilities so transport costs are unaffordable to most of them.</p>
<p>Treatment abandonment is the failure to return to hospital for more than <a href="https://books.google.co.ke/books?id=2_O8BAAAQBAJ&pg=PA232&lpg=PA232&dq=abandonment+of+treatment+definition+and+four+weeks&source=bl&ots=4zphmt782c&sig=lyqVU7qPw4e2gL4f6PY6ORyWw4U&hl=en&sa=X&redir_esc=y#v=onepage&q&f=false">four weeks</a> for scheduled appointments.</p>
<p>About four out of every five children who stopped treatment had died by the time of the survey. The survival rate when we did the study was 20%. About 66% of those alive but untreated were very sick. Their families were discouraged by the cost of cancer treatment and the cost of transport to the hospital.</p>
<h2>Reasons for discontinuing treatment</h2>
<p>The reasons given for stopping treatment include: </p>
<ul>
<li><p>Financial constraints: almost half of the families interviewed said they did not have money to pay for cancer treatment. About three out of every ten families had an average monthly income of about 44 dollars per household. About 85% of the patients’ families said cancer treatment had adversely affected other family costs like education and food.</p></li>
<li><p>Lack of health insurance: some families were not members of the <a href="http://www.nhif.or.ke/healthinsurance/">national health insurance fund</a>. The fund is owned by the government and members without formal employment are expected to pay a minimum of five dollars a month in premiums. At the beginning of the study, only 22% of families surveyed had this health insurance. An additional 26% subsequently registered but 52% did not have insurance because they did not apply for it.</p></li>
<li><p>Access to health services: about half of the families interviewed lived more than 100 kilometres from the treatment centre and could not afford the fare for public transport. Most of the patients’ families are unemployed, are farmers and live on less than a dollar a day for their household expenses. Transport expenses can be estimated at about three dollars per hospital visit. These are estimates however the actual figures depend on the type of cancer and the frequency of travel to the hospital.</p></li>
<li><p>Other reasons: the patients families were discouraged by families and communities with negative attitudes on the poor cancer survival rates hence they did not take their children to hospital. The long delays in hospital queues and <a href="https://vector.childrenshospital.org/2011/07/treatment-abandonment-in-childhood-cancer-are-we-willing-to-face-this-challenge/">mistrust</a> of the health care system also kept the patients away from going for treatment. Some also expressed fear of the side effects of treatments like chemotherapy and surgery which could worsen the disease.</p></li>
</ul>
<h2>Way forward</h2>
<p>In countries with universal health, the government pays for most of the hospital costs while in other the health insurance does. However the individual families still have to cater for transport costs. </p>
<p>There is a need for a more cohesive multi-sectoral approach to set up effective and affordable childhood cancer treatment programmes for screening, early diagnosis, treatment and palliative care for childhood cancers.</p>
<p>The government should enrol more Kenyans on the <a href="http://www.nation.co.ke/health/Health-insurance-Why-you-should-get-an-NHIF-cover/3476990-3893140-3yqsxj/index.html">health insurance</a> so that all children diagnosed with cancer can seek treatment in public health facilities. Currently some of the benefits members receive include payment of chemotherapy and radiotherapy sessions especially needy patients.</p>
<p>Kenya should increase <a href="http://www.nation.co.ke/lifestyle/DN2/957860-2769356-w8ne3z/index.html">public health awareness </a> campaigns to provide information on screening for childhood cancers and give information on the available treatment options. These campaigns have worked for other non communicable diseases like <a href="http://www.nation.co.ke/health/Watch-out-you-are-likely-to-contract-TB-in-these-places/3476990-3988036-12c5ahhz/index.html">Tuberculosis</a>, <a href="http://www.nation.co.ke/oped/Opinion/Child-s-HIV-victory-offers-great-hope/440808-4038844-qklhndz/index.html">HIV</a> and some forms of cancers like <a href="http://www.nation.co.ke/lifestyle/family/No-woman-needs-to-go-home-without-a-breast/1954198-4044402-460rucz/index.html">breast cancer</a>.</p><img src="https://counter.theconversation.com/content/81492/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Festus Njuguna does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Most children who have cancer live in the developing world where their survival rate is less than 25%. In Kenya awareness about childhood cancer is low and treatment isn’t always readily available.Festus Njuguna, Department of Child Health and Paediatrics, consultant Paediatrician, Moi University Licensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/813202017-07-31T02:40:03Z2017-07-31T02:40:03ZCancer immunotherapy drugs like Keytruda and Opdivo hold hope for some, but there’s still a way to go<figure><img src="https://images.theconversation.com/files/179585/original/file-20170725-7881-3ml7zo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Some people taking these drugs can see their cancer completely disappear – there's nothing left to see on their x-rays</span> <span class="attribution"><span class="source">from www.shutterstock.com.au</span></span></figcaption></figure><p>Imagine being able to offer hope to people with cancers that were once thought untreatable. Checkpoint immune drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo) are heralding this new era in cancer treatment. Some people taking these drugs can see their cancer completely disappear; <a href="http://ascopubs.org/doi/full/10.1200/jco.2014.59.4358">there’s nothing left to see on their x-rays</a>.</p>
<p>We rightly celebrate these successes, but must face the sobering truth that only a minority of people experience these dramatic benefits. Decades of research have helped us reach this point. Now scientists and doctors from Australia and around the world are working furiously to learn more about how these immune treatments work or fail.</p>
<h2>Who it works for now</h2>
<p>Nivolumab and pembrolizumab are checkpoint immunotherapy antibodies. They work by blocking barriers (or “checkpoints”) created by cancer cells to protect against attack from the immune system. Remove the barrier and the immune system can destroy the cancer. </p>
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<img alt="" src="https://images.theconversation.com/files/179933/original/file-20170727-14757-yfdtme.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/179933/original/file-20170727-14757-yfdtme.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=939&fit=crop&dpr=1 600w, https://images.theconversation.com/files/179933/original/file-20170727-14757-yfdtme.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=939&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/179933/original/file-20170727-14757-yfdtme.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=939&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/179933/original/file-20170727-14757-yfdtme.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1181&fit=crop&dpr=1 754w, https://images.theconversation.com/files/179933/original/file-20170727-14757-yfdtme.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1181&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/179933/original/file-20170727-14757-yfdtme.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1181&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="attribution"><span class="source">The Conversation</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
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<p>The most success so far for these drugs is with melanoma, which has long been known to respond to immunotherapy. In Australia, single or combination checkpoint immunotherapy <a href="https://melanomanewstoday.com/2017/04/06/opdivo-yervoy-combo-improved-survival-advanced-melanoma-phase-3-trial/">substantially helps about half of people with melanoma</a>, and will soon be available for people with kidney and lung cancers. </p>
<p><a href="http://www.clintrial.org.au/">Trials continue in most types of cancer</a>. Checkpoint immunotherapy has proven beneficial in patients with <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2017/approvals-fda-checkpoint-bladder">bladder cancer</a>, <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2016/fda-pembrolizumab-hnscc">head and neck cancer</a> and <a href="https://www.cancer.org/cancer/hodgkin-lymphoma/treating/monoclonal-antibodies.html">Hodgkin lymphoma</a>. A smaller proportion of people, typically around 20-30%, are helped in most of these cancers. These successes and failures start to show us how checkpoint immunotherapy works, and how it might work better.</p>
<iframe src="https://datawrapper.dwcdn.net/khbIy/1/" scrolling="no" frameborder="0" allowtransparency="true" allowfullscreen="allowfullscreen" webkitallowfullscreen="webkitallowfullscreen" mozallowfullscreen="mozallowfullscreen" oallowfullscreen="oallowfullscreen" msallowfullscreen="msallowfullscreen" width="100%" height="720"></iframe>
<h2>Who it might help soon</h2>
<p>Patients whose cancers are already under attack from immune cells are the people who seem most likely to be helped by checkpoint immunotherapy. But many patients’ cancers are devoid of immune cells – so removing checkpoints doesn’t help. </p>
<p>This is why the first strategy to improve checkpoint immunotherapy is to diversify and muster the immune system into tumours. Some checkpoint immunotherapy drugs (such as ipilimumab, brand name “Yervoy”) work this way. In effect they “vaccinate” the patient against their cancer, educating the immune system on how to fight the cancer, and recruiting immune cells to attack tumours.</p>
<p>A similar method uses <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2015/t-vec-melanoma">modified viruses that infect and explode immune cells</a>. These can be directly injected into cancers, drawing in immune cells to attack the cancer. This is the basis of the <a href="http://discovermagazine.com/2016/april/11-germ-of-an-idea">very first immune therapy for cancer</a>, first used in 1896.</p>
<p>Finally, identifying the minority of people who naturally have immune-infiltrated cancers may identify those likely to benefit from checkpoint immunotherapy (such as <a href="http://www.ascopost.com/News/55733">aggressive breast cancer needing chemotherapy before surgery</a>).</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-how-does-keytruda-treat-melanoma-and-why-is-it-so-costly-40558">Explainer: how does Keytruda treat melanoma and why is it so costly?</a>
</strong>
</em>
</p>
<hr>
<p>We may be able to identify a few people within various types of cancer most likely to benefit from checkpoint immunotherapy. For example, while checkpoint immunotherapy doesn’t help most bowel and prostate cancer patients, a small group of people whose cancers’ DNA isn’t able to repair properly <a href="http://science.sciencemag.org/content/early/2017/06/07/science.aan6733/tab-pdf">have dramatic outcomes from checkpoint immunotherapy</a>.</p>
<p>This lack of efficient DNA repair is called “mismatch repair deficiency”. Mismatch repair is one of the tools cells use to repair their DNA. Loss of mismatch repair leads to aggressive cancers that don’t respond to chemotherapy, but which throw up lots of targets for the immune system.</p>
<p>Up to a third of uterine cancers, 15% of bowel cancers, 15% of stomach cancers and perhaps 5% each of prostate, oesophageal, cervical and ovarian cancers <a href="http://oncologypro.esmo.org/Education-Library/Factsheets-on-Biomarkers/Microsatellite-Instability-Defective-DNA-Mismatch-Repair">have mismatch repair deficiency</a>, potentially making them treatable with checkpoint immunotherapy.</p>
<h2>How we might improve immune therapy further</h2>
<p>Even when fully implemented, these strategies will leave many people who won’t benefit from checkpoint immunotherapy – but a <a href="http://www.cell.com/cell/pdf/S0092-8674(17)30065-X.pdf">huge number of new treatments, combinations and ideas</a> are being tested in clinical trials.</p>
<p>Drugs that <a href="https://www.nature.com/articles/n-12336794">protect immune cells from toxic chemicals</a> released by nearby cancer cells appear very promising. A myriad of new antibodies that block other immune checkpoints are in development. And we haven’t abandoned standard cancer treatments like <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649476/">blood-supply blocking drugs</a>, radiotherapy or chemotherapy; these may help immunotherapy by killing enough cancer cells to recruit immune cells into tumours.</p>
<p>Should everyone with cancer take checkpoint immunotherapy? <a href="https://www.cancercouncil.com.au/wp-content/uploads/2017/06/UC-Pub-Immunotherapy-CAN6479-lo-res_June-2017.pdf">These drugs are safe overall</a>, though people with autoimmune diseases (such as rheumatoid arthritis) need to be very cautious. This is because the underlying cause of checkpoint immunotherapy side effects, an overactive immune system, is very similar to the causes of autoimmune diseases.</p>
<p>And there is a social challenge: cost. We are privileged to have many publicly funded PBS-reimbursed cancer treatments in Australia, but <a href="http://dx.doi.org/10.1111/imj.12399">drug costs are rising sharply</a>. One solution will be to find more ways to <a href="http://www.cell.com/cell/abstract/S0092-8674(17)30429-4">identify the patients most likely to benefit from these drugs</a>, so we’re not using expensive drugs to treat people for whom they won’t have an effect. </p>
<p>Another, perhaps complementary, strategy would be <a href="http://catalyst.nejm.org/a-new-way-to-define-value-in-drug-pricing/">pay-for-performance</a> – treat everyone, but only reimburse the manufacturer if the patient is helped. This might particularly assist people with rare cancers, where clinical trials are extremely hard to perform.</p>
<p>Checkpoint immunotherapy is a triumph – when it works. It’s important to temper our hopes with the knowledge that these promising drugs can’t yet help every person, with every cancer. But we’re working on it.</p><img src="https://counter.theconversation.com/content/81320/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Craig Gedye is the principal investigator on ANZUP cooperative group clinical trials supported by the manufacturers of nivolumab and pembrolizumab. He participates in pharmaceutical company advisory boards, but any and all fees are donated directly to the Hunter Medical Research Institute, University of Newcastle.</span></em></p>Imagine being able to offer hope to people with cancers once thought untreatable. Checkpoint immune drugs like Opdivo and Keytruda lead this new era in treatment. But they don’t work for everyone.Craig Gedye, Oncologist and Senior Lecturer, University of NewcastleLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/797682017-06-22T15:04:41Z2017-06-22T15:04:41ZWhy competition is key to cutting the cost of cancer drugs in South Africa<figure><img src="https://images.theconversation.com/files/175155/original/file-20170622-11971-1xbml5b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Shutterstock</span> </figcaption></figure><p>South Africa’s Competition Commission has launched an <a href="http://www.gov.za/speeches/media-statement-commissioner-investigation-manufacturers-cancer-drugs-13-jun-2017-0000">investigation</a> into excessive pricing by three major pharmaceutical companies that have the sole rights to distribute cancer drugs in the country. </p>
<p>The commission’s job is to protect ordinary South Africans from abuse by dominant players. It has <a href="http://www.compcom.co.za/">powers</a> to investigate and evaluate restrictive business practices, abuse of dominant positions and mergers. </p>
<p>Its investigation into the drug companies is vital as cancer treatment is <a href="http://www.cansa.org.za/competition-commission-investigating-pharmaceutical-companies-for-cancer-medicine-prices/">unaffordable for most South Africans</a>. Many medical schemes – which offer medical cover to 16% of the population or 7 million people – refuse to pay for the medication because of the cost. </p>
<p>In South Africa all drug prices are approved and signed off by the medicines pricing committee in the National Department of Health. But our hope is that the commission’s investigation could still drive competition among suppliers, and in turn more affordable prices for cancer treatment. This should result in better access to affordable drugs, particularly for poor people.</p>
<h2>The drugs in question</h2>
<p>Three companies are being probed: Swiss-based <a href="http://www.roche.co.za/home/about-roche/companyprofile.html">Roche</a>, US-based Pfizer and South African company Aspen Pharmacare.</p>
<p>The cancer drugs in the spotlight are used mainly to treat lung and breast cancer but they can also be used in the treatment for other types of cancers.</p>
<p>One of the drugs is trastuzumab which is supplied by Roche and <a href="http://www.who.int/bulletin/volumes/94/10/15-163998/en/">recommended</a> by the World Health Organisation to treat breast cancer and can be used in combination with other drugs for some types of stomach cancer. Roche’s branded versions of the medication is Herceptin. This is the only trastuzumab product currently available in South Africa.</p>
<p>Pfizer provides the only crizotinib product to South Africa for the treatment of lung cancer. Its product, Xalkori, is not yet registered in South Africa, and is only accessed through a special application process under the Medicines Act which enables clinicians to prescribe and use medicines not yet registered by the MCC to treat patients.</p>
<p>Aspen is being investigated for three of the oncology drugs it supplies: Chlorambucil (Leukeran), Melphalan (Alkeran) and Busulfan (Myleran). All are generic drugs but Aspen is the only pharmaceutical company in the country that’s registered with the Medicines Control Council to sell the drugs in South Africa.</p>
<p>Competition authorities in a number of European countries, including the European Union, are also <a href="http://europa.eu/rapid/press-release_MEX-17-1326_en.htm">investigating Aspen</a> for alleged excessive pricing on these and other products. </p>
<h2>Why are they so expensive?</h2>
<p>The cost of a drug is related to its development. Before a cancer drug reaches the market there is a complex clinical research process and an expensive administrative process that requires millions of dollars of investment. This includes regulatory studies and three phases of clinical trials. </p>
<p>In the pharmaceutical industry, the initial patent holder is usually the pharmaceutical company that researched and developed a drug . </p>
<p>Although the patent life from the date that it is filed is 20 years, the average time to bring a cancer drug from the start of clinical testing to regulatory approval is between eight and 12 years. </p>
<p>This means that the actual patent life of a drug from the time of initial marketing can be limited – often less than 10 years. In addition, only 16% to 19% of cancer drugs that enter clinical trials successfully make it to market.</p>
<p>There’s an added challenge in cancer treatments. Even with the arrival of “new and improved” versions of a previously approved drug, the older (and by now generic) drug tends to be viewed as substandard treatment. This perpetuates the situation. And in the last 59 years the health sector has increased its knowledge of cancer and treatment immensely. But it’s not yet at a curative phase. Faced with the seriousness of the diagnosis, patients, family and physicians are often willing to pay the high price of treatment even for marginal improvements in someone’s health.</p>
<p>Drug companies also have to go through a lengthy process before they can start selling a drug. Once a drug is approved by a regulatory authority it needs to be registered with a country’s medical control council before it can be prescribed by oncologists. This registration process can take a long time. </p>
<h2>What needs to be done</h2>
<p>The biggest problem with the price of cancer drugs is that there is no competition among truly effective cancer drugs to lower their cost. Healthy competition between different drugs would drive lower prices and keep prices reasonable for the consumer.</p>
<p>One way that competition has been achieved for other pharmaceutical drugs has been through the generic route. Once the patent expires, manufacturers of generic versions can produce more cost-effective versions. This is happening for some cancer drugs. But there are two limitations: one is that it takes a long time to develop cancer treatments. And generic versions of cancer drugs are much higher than those used to treat non-malignant (non-cancerous) diseases. </p>
<p>So what can be done? There are three options:</p>
<ul>
<li><p>encourage oncologists to prescribe drug treatment that isn’t as expensive,where possible. </p></li>
<li><p>reduce prices by introducing a form of generic price control, where predetermined pricing limits are prescribed, and </p></li>
<li><p>promoting a non-profit generics model, where certain designated generics would be made available at cost, as opposed to be sold at a profit.</p></li>
</ul>
<p>The competition case in South Africa is also an important part of the campaign to make sure that cancer drugs are more affordable. As incidence of cancer <a href="http://www.cansa.org.za/category/recent-posts/cope-with-cancer/about-cancer/statistics/">continue to rise</a>, massive resources are being poured into cutting-edge research and biotechnology to successfully treat this dread disease. But these benefits aren’t being felt by the vast majority of people in the world.</p><img src="https://counter.theconversation.com/content/79768/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Natalie Schellack does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The high cost of cancer drugs in South Africa has come under the spotlight with an investigation by the Competition Commission in the country.Natalie Schellack, Associate Professor and Course Leader: Post Graduate Programmes in Clinical Pharmacy in the Department of Pharmacy, Sefako Makgatho Health Sciences UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/698972017-05-23T04:31:56Z2017-05-23T04:31:56ZExplainer: what is nanomedicine and how can it improve childhood cancer treatment?<figure><img src="https://images.theconversation.com/files/162310/original/image-20170324-4934-1axxk5x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Therapies on a nano scale rely on engineered nanoparticles designed to package and deliver drugs to exactly where they’re needed.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>A recent <a href="http://www.cancerresearchuk.org/about-us/cancer-news/news-report/2016-11-08-childhood-cancer-survivors-live-longer-but-not-necessarily-with-better-health">US study of people treated for cancer as children</a> from the 1970s to 1999 showed that although survival rates have improved over the years, the quality of life for survivors is low. It also showed this was worse for those who were treated in the 1990s.</p>
<p>About 70% of childhood cancer survivors experience side effects from their treatment, including secondary cancers. And as survival rates improve, the worldwide population of childhood cancer survivors is growing. </p>
<p>Side effects cause stress for survivors and families and increase demand on health systems. But an emerging area of medicine, nanomedicine, offers hope for better children’s cancer treatment that will have fewer side effects and improve quality of life for survivors.</p>
<h2>What is nanomedicine?</h2>
<p>Nanomedicine is the application of nanomaterials, or nanoparticles, to medicine. Nanoparticles are a form of transport for drugs and can go places drugs wouldn’t be able to go on their own.</p>
<p>Nano means tiny. A nanometre (nm) is one-billionth of a metre. Nanoparticles used for drug delivery are usually in the 20 to 100 nanometre range, although this can vary depending on the design of the nanoparticle.</p>
<p>Nanoparticles can be engineered and designed to package and transport drugs directly to where they’re needed. This targeted approach means the drugs cause most harm in the particular, and intended, area of the tumour they are delivered to. This minimises collateral damage to surrounding healthy tissues, and therefore the side effects.</p>
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<p>The first cancer nanomedicine approved by the US Food and Drug Administration was
<a href="http://www.sciencedirect.com/science/article/pii/S0169409X16301351">Doxil</a>. Since 1995, it has been used to treat adult cancers including ovarian cancer, multiple myeloma and Karposi’s sarcoma (a rare cancer that often affects people with immune deficiency such as HIV and AIDS).</p>
<p>Currently, there is <a href="http://www.sciencedirect.com/science/article/pii/S0169409X16301351">a stream of new nanomedicine treatments</a> for adult cancers in clinical trials (trials in humans), or on the market. But only a limited number of these have been approved for children’s cancers, although this is arguably where nanomedicine’s strengths could have the most benefit. </p>
<h2>How does nanomedicine work?</h2>
<p>The nanoparticle drug-delivery systems can work in different ways. Along with carrying the drug for delivery, nanoparticles can be engineered to carry specific compounds that will let them bind, or attach, to molecules on tumour cells. Once attached, they can safety deliver the drug to the specific tumour site.</p>
<p>Nanoparticles can also help with drug solubility. For a drug to work, it must be able to enter the bloodstream, which means it needs to be soluble. For example, the cancer drug paclitaxel (Taxol) is insoluble so has to be dissolved in a delivery agent to get into the blood. But this agent can <a href="https://www.ncbi.nlm.nih.gov/pubmed/24740483">cause allergic reactions</a> in patients. </p>
<p>To overcome these issues, <a href="https://www.ncbi.nlm.nih.gov/pubmed/16722814">chemists have developed</a> a nanoparticle out of the naturally occurring protein albumin. It carries the paclitaxel and makes it soluble but without the allergic reactions.</p>
<p>Tumours commonly have disordered and leaky blood vessels sprouting through and off them. These vessels allow chemotherapy drugs to readily enter the tumour, but because chemotherapy molecules are so small, they also diffuse through the vessels and out of the tumour, attacking surrounding tissues. Nanoparticles are larger molecules that get trapped inside the tumour, where they do all the damage.</p>
<p>Once they have delivered their drug cargo to cells, nanoparticles can be designed to break down into harmless byproducts. This is particularly important for children who are still developing. </p>
<h2>Types of nanoparticles</h2>
<p>Nanoparticles vary in characteristics like shape and size. Researchers need to match the right nanoparticle to the drug it’s to deliver and the particular tumour.</p>
<p>An array of nanoparticle structures are currently being engineered. One example of an interesting structure is the shape of a DNA origami. Because DNA is a biological material, nanoparticles engineered into DNA origami shapes won’t be seen as foreign by the immune system. So these can transport a drug to diseased cells while evading the body’s immune system, therefore lessening the side effects of drugs. </p>
<p>Another example of nanomedicine structures are polymeric nanocarriers. We have recently identified a gene that promotes the growth of tumours, cancer spread and resistance to chemotherapy in pancreatic cancers. </p>
<p>We used a <a href="https://www.ncbi.nlm.nih.gov/pubmed/27305597">nanomedicine called a polymeric nanocarrier</a> and combined it with a drug that silences the cancer gene. We <a href="https://newsroom.unsw.edu.au/news/health/new-cancer-nanomedicine-reduces-pancreatic-tumour-growth">packaged this up to form a nanomedicine and delivered the drugs</a> into the tumour. </p>
<p>These nanomedicines reduced the expression of the cancer gene, blocked tumour growth and reduced the spread of pancreatic cancer. But we also showed that polymeric nanocarriers can be combined in the lab with other gene-silencing drugs. This means the method can be used for a range of other gene-based cancers.</p>
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<img alt="" src="https://images.theconversation.com/files/162142/original/image-20170323-13480-1tzet75.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/162142/original/image-20170323-13480-1tzet75.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=522&fit=crop&dpr=1 600w, https://images.theconversation.com/files/162142/original/image-20170323-13480-1tzet75.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=522&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/162142/original/image-20170323-13480-1tzet75.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=522&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/162142/original/image-20170323-13480-1tzet75.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=656&fit=crop&dpr=1 754w, https://images.theconversation.com/files/162142/original/image-20170323-13480-1tzet75.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=656&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/162142/original/image-20170323-13480-1tzet75.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=656&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="attribution"><span class="source">The Conversation</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<h2>How can nanomedicines help treat kids’ cancer?</h2>
<p>In standard treatment for children’s cancer, chemotherapy drugs are often prescribed at the maximum tolerable dose for a child’s age or size, based on adult dosages. But children aren’t small adults. The processes underlying children’s growth and development might lead to a different effect and response to a chemotherapy drug not seen in adults.</p>
<p>Also, if a child becomes resistant to a drug and they’re on the maximum tolerable dose, there’s no scope to increase it without toxic side effects. By packaging up drugs and moving them through the body directly to diseased cells to reduce collateral damage, in theory, nanomedicine allows higher doses of drugs to be used.</p>
<p>Nanomedicine has great potential to safely treat children’s cancer. However, it is currently stymied by <a href="http://austinpublishinggroup.com/material-science-engineering/fulltext/amse-v1-id1006.php">too little research</a>. About <a href="https://www.ncbi.nlm.nih.gov/pubmed/22684017">two-thirds of research attention</a> in nanomedicine therapeutics, of more 250 nanomedicine products, is focused on cancer. Yet this isn’t translating into new cancer treatments for children coming to market.</p>
<p>But we are making progress. Our work is exploring the design of nanoparticles to deliver gene-silencing drugs to treat the most common brain cancer in children – medulloblastoma. </p>
<p>We’re also working on nanomedicines for other significant childhood cancers. These include drug-refractory acute lymphoblastic leukaemia, the most common childhood cancer, and neuroblastoma, the cancer that claims more lives of those under five than any other.</p><img src="https://counter.theconversation.com/content/69897/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Maria Kavallaris receives funding from the National Health and Medical Research Council, Australian Research Council, Cancer Council NSW, and The Kids Cancer Project.</span></em></p><p class="fine-print"><em><span>Thomas P Davis receives funding from the Australian Research Council and the National Health and Medical Research Council</span></em></p><p class="fine-print"><em><span>Joshua McCarroll does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Nanoparticles are a form of transport for drugs and can go places drugs wouldn’t be able to go on their own. They make drug delivery more targeted, reducing collateral damage to healthy tissues.Maria Kavallaris, Professor, Children's Cancer InstituteJoshua McCarroll, Project Leader, Children's Cancer Institute and Senior Lecturer, Medicine, UNSW SydneyThomas P Davis, ARC Laureate Fellow, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/743692017-03-15T00:05:04Z2017-03-15T00:05:04ZFaster access to new drugs doesn’t always mean better treatment<figure><img src="https://images.theconversation.com/files/160645/original/image-20170314-9634-uieodg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Weaker regulatory standards in the US can impact health everywhere.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>US President Donald Trump <a href="http://www.reuters.com/article/us-usa-health-fda-gottlieb-idUSKBN16H2AM">recently chose an adviser</a> to a large pharmaceutical company to lead the country’s drug regulation agency.</p>
<p>Scott Gottlieb – who reportedly sits on the boards of several small drug companies and is an adviser to GlaxoSmithKline – is expected to <a href="http://www.reuters.com/article/us-usa-health-fda-gottlieb-idUSKBN16H2AM">introduce greater flexibility</a> to the evidence standards used by the Food and Drug Administration (FDA) to evaluate the benefit and risks of new medicines. </p>
<p>This is consistent with Trump’s message to pharmaceutical executives in January, when <a href="https://www.nytimes.com/2017/01/31/health/trump-vows-to-ease-rules-for-drug-makers-but-prices-remain-a-focus.html">he said</a>:</p>
<blockquote>
<p>We’re going to be cutting regulations at a level nobody’s ever seen before […] You’re going to get your products – either approved or not approved – but it’s going to be a quick process.</p>
</blockquote>
<p>Trump’s views might seem extreme but his comments are not entirely out of step with the views of previous US governments. An example is the <a href="http://jamanetwork.com/journals/jama/article-abstract/2597296">21st Century Cures Act</a>, which was passed late last year after heated debate. This aims to speed up innovation and the search for cures by setting lower thresholds for evaluating the safety and effectiveness of new medicines. </p>
<p>The Act is an addition to a range of <a href="https://www.fda.gov/forpatients/approvals/fast/ucm20041766.htm">expedited programs</a> the US already had in place for some time to permit drugs to enter the market based on less robust evidence than traditionally required. So Gottlieb already has the tools to make it easier to get drugs onto the market in the US.</p>
<p>But what does this mean for Australia? A recent comment piece published in the journal Nature noted that weaker regulatory standards in the US <a href="http://www.nature.com/news/show-drugs-work-before-selling-them-1.21582">can impact</a> health everywhere. One reason is companies will have far less incentive to run the expensive high-quality trials needed to inform decision-making if the biggest market in the world does not demand it.</p>
<h2>Dangers of deregulation</h2>
<p>Intuitively, it might seem desirable to speed up access to medicines. But this means more drugs will be approved that may subsequently prove unsafe or ineffective.</p>
<p>One could also argue regulatory standards are already lax. For example, <a href="http://jamanetwork.com/journals/jamaotolaryngology/article-abstract/1891387">one study showed</a> all the cancer drugs approved for solid tumours between 2002 and 2014 had only a minor effect on patients’ survival rates – a median increase of just more than two months. </p>
<p>And an FDA <a href="https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM535780.pdf">report released in January</a> outlined details of 22 drugs with early promise that either proved unsafe or ineffective in subsequent research. </p>
<p>Some may believe easing restrictions for companies to get their drugs to market will make investing in drug development less risky and more attractive, enhancing innovation. But true innovation demands taking greater risks.</p>
<p>If companies can get their drugs approved more quickly and make money off drugs that are less risky to develop, this actually takes away the incentive for innovation. In the case of <a href="http://jamanetwork.com/journals/jamaotolaryngology/article-abstract/1891387">cancer drugs development</a>, some experts have blamed the marginal improvements in outcomes on regulators and payers being too lax rather than too strict.</p>
<h2>Forces at play</h2>
<p>There are social and political forces dictating the push to deregulate the drug market. Pressure to speed up access to medicines is framed as being in the best interest of patients. But this debate can’t ignore that countries like the US have an economic interest in keeping the pharmaceutical industry producing medicines, and ensuring people buy them at a premium. </p>
<p>These companies also want to get their drugs onto the market as quickly as possible before generic (copycat) drugs come in and drive down prices. A report by consultancy group IMS Health <a href="https://www.imshealth.com/files/web/IMSH%20Institute/Reports/The%20Global%20Use%20of%20Medicines%20Outlook%20Through%202016/Medicines_Outlook_Through_2016_Report.pdf">predicted patent-protected medicines</a> will lose US$127 billion in revenue due to generic medicines entering the market by 2016. </p>
<p>In 2004, at the request of the US Congress, <a href="https://www.selectusa.gov/pharmaceutical-and-biotech-industries-united-states">the US Commerce Department</a> published a report about the implications of strategies used by other governments to limit medicine prices. If price controls were removed, it concluded, pharmaceutical revenues from patented medicines would increase significantly, including in Australia. </p>
<p>As US firms hold most of the intellectual property rights for new medicines, most of this income would then funnel back into the US and support US jobs. It should not be a surprise, then, that the US leads the way in deregulating pharmaceutical markets. </p>
<p>US Medicare, for instance, cannot negotiate prices and the FDA seems set to make it easier for drugs to enter the market. Trump has been open about his view that <a href="http://www.cnbc.com/2017/01/31/trump-tells-drugmakers-he-wants-them-to-manufacture-in-the-us.htmlhttp://www.cnbc.com/2017/01/31/trump-tells-drugmakers-he-wants-them-to-manufacture-in-the-us.html">foreign countries should pay more for drugs</a> and that foreign price controls are unfair for the United States.</p>
<p>This is understandable because the US economy has the most to lose from the reticence of regulators to approve medicines, and insurers to pay for them. A US biotech <a href="http://catalyst.phrma.org/nearly-4.5-million-jobs-and-counting">industry lobby group reports</a> the industry supports 4.5 million jobs and is responsible for US$1.2 trillion in economic output. It says the average employee in the bio-pharmaceutical sector is paid double the average US wage. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/160825/original/image-20170314-10763-1iap4ti.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/160825/original/image-20170314-10763-1iap4ti.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/160825/original/image-20170314-10763-1iap4ti.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/160825/original/image-20170314-10763-1iap4ti.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/160825/original/image-20170314-10763-1iap4ti.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/160825/original/image-20170314-10763-1iap4ti.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/160825/original/image-20170314-10763-1iap4ti.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/160825/original/image-20170314-10763-1iap4ti.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Patients in Australia may see new drugs becoming available overseas and wonder why they don’t have access to the same.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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</figure>
<h2>How does all this affect Australians?</h2>
<p>When the US is more lenient in its regulatory processes, this creates a dilemma for Australia’s Therapeutic Goods Administration – our version of the FDA. It also creates issues for the Pharmaceutical Benefits Advisory Committee, which advises the government which drugs to subsidise. </p>
<p>Patients in Australia may see new drugs becoming available overseas and wonder why they don’t have access to the same. Australian regulators and payers are then accused of being old-fashioned, while patients believe they are missing out on the latest and greatest drugs. </p>
<p>This puts immense pressure on Australian regulators and payers to keep up with the rest of the developed world, which means becoming more lenient with evidence standards and prices.</p>
<p>This trend is evident in the case of cancer medicines. Australia’s <a href="http://www.cancerdrugsalliance.org.au/">Cancer Drug Alliance</a> claims Australian patients are already falling behind in access to new cancer medicines.</p>
<p>This sentiment was echoed in the Senate inquiry on the <a href="http://www.aph.gov.au/Parliamentary_Business/Committees/Senate/Community_Affairs/Cancer_Drugs">availability of new, innovative and specialist cancer drugs</a> in Australia conducted in 2014-2015. This highlighted concerns about “delays” in access to cancer medicines available overseas. </p>
<p>In parallel with this inquiry, the Australian government <a href="http://www.health.gov.au/internet/main/publishing.nsf/Content/CCB4916435683A5BCA257FA100839F95/$File/govresp.pdf">set up an expert panel</a> in 2014 to review medicines regulation. The panel’s conclusion supported expediting access to medicines in Australia. </p>
<p>US pressure to deregulate medicine markets no doubt speeds up access to new drugs. But the rationale isn’t always to help patients. It often has more to do with the economic interests of countries with a strong research-based pharmaceutical industry.</p><img src="https://counter.theconversation.com/content/74369/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Narcyz Ghinea receives funding from the National Health and Medical Research Council for a project on improving funding/access of high cost cancer medicines in Australia.</span></em></p><p class="fine-print"><em><span>Wendy Lipworth receives funding from National Health and Medical Research Council. She is affiliated with DIA.</span></em></p>Intuitively, it might seem desirable to speed up access to medicines. But this means more drugs will be approved that may subsequently prove unsafe or ineffective.Narcyz Ghinea, Doctoral Researcher, Centre for Values, Ethics and the Law in Medicine, University of SydneyWendy Lipworth, Senior Research Fellow, Bioethics, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/667742016-12-05T01:01:02Z2016-12-05T01:01:02ZCould a cannabis pill reduce chemotherapy-induced nausea and vomiting? Here’s how we find out<p>For some cancer patients undergoing chemotherapy, the thought of joining their loved ones for a meal can be, quite literally, sickening. Nausea and vomiting due to chemotherapy can cause devastating physical side effects and wreck a patient’s social and family life.</p>
<p>Patients say they find it difficult to manage the expectations of well-meaning family members and friends who want to “feed them up”, when their favourite foods become tasteless.</p>
<p>We need to do more to make chemotherapy as comfortable as possible for patients.</p>
<p>That’s why our research team at <a href="http://www.mylifehouse.org.au/">Chris O’Brien Lifehouse</a> in Sydney is about to embark on the largest and most definitive Randomised Controlled Trial ever in the world of medicinal cannabis for the prevention of chemotherapy-induced nausea and vomiting. With the help of more than 300 patients from several NSW hospitals, we hope to learn more over the next few years about how effective medicinal cannabis may or may not be for preventing chemotherapy-induced nausea and vomiting.</p>
<h2>New strategies for an old problem</h2>
<p>Cancer kills more Australians than any other disease. Almost half the 100,000 people diagnosed each year will be offered chemotherapy as an integral part of their treatment. While there have been significant advances in anti-nausea drugs over the past decade, more than one-third of patients receiving potent intravenous chemotherapy still suffer from nausea or vomiting.</p>
<p>Our team includes leading Australian researchers from Chris O'Brien Lifehouse, the University of Sydney and Royal Prince Alfred Hospital, specialising in cancer, addiction medicine and clinical toxicology.</p>
<p>We’re hoping to determine if giving patients an oral capsule of medicinal cannabis reduces nausea and vomiting during and after intravenous chemotherapy for cancer.</p>
<h2>Jury still out</h2>
<p>The jury is still out on the ability of cannabis and cannabis-derived medicines to treat a range of debilitating illnesses – and how to do it safely and effectively.</p>
<p>Despite dozens of trials internationally, the <a href="http://www.cochrane.org/CD009464/GYNAECA_cannabis-based-medicine-nausea-and-vomiting-people-treated-chemotherapy-cancer">evidence</a> is unconvincing. Some <a href="http://www.cochrane.org/CD009464/GYNAECA_cannabis-based-medicine-nausea-and-vomiting-people-treated-chemotherapy-cancer">research</a> failed to compare cannabis medicine against the best standard treatment of today. Some research had design flaws, such as failure to adequately account for the placebo effect, inappropriate dosing, small sample sizes and poor documentation of side effects and harms.</p>
<p>There remain many potentially valid reasons to use medicinal cannabis products. But we still don’t know how best to formulate and administer the drug, how well it might work, how safe it is and what the long-term side effects could be.</p>
<p>This is not to say medicinal cannabis for therapeutic use is a pipe dream – we just need to do the work first, and do it properly. And that takes time.</p>
<h2>A scientific approach</h2>
<p>However, using a scientific approach will give the best hope for patients and their families. It will give us better understanding of side effects and ideal dosages.</p>
<p>Producers of medicinal cannabis products will be encouraged to develop the most suitable formulations, delivery methods, and cannabinoid content.</p>
<p>Australian regulatory and funding authorities will have the evidence they need to decide which formulations of medicinal cannabis should be approved for which conditions, so they can be made safely available to the patients who need them.</p>
<p>Clearly, more research needs to be done. NSW is doing groundbreaking research on the use of medicinal cannabis for treatment-resistant childhood epilepsy, palliative care and chemotherapy-induced nausea and vomiting.</p>
<p>Many of my patients do not use illegal cannabis preparations because they are concerned about breaking the law. But if we were to pursue broad legalisation, as opposed to a medical pathway based on scientific evidence, we would miss the opportunity to create a safe, secure supply of cannabis medicines.</p>
<p>These medicines could be supervised by qualified practitioners to maximise the benefit to patients and manage side effects, and could potentially be subsidised under the Pharmaceutical Benefits Scheme.</p>
<p>Many of the cannabinoid products available overseas have little quality control, testing or certification.</p>
<h2>Relaxed but not “stoned”</h2>
<p>The cannabis plant varies considerably depending on its type and how it is grown. The cannabis plant contains hundreds of compounds, more than 60 of which are cannabinoids. The main cannabinoids studied in trials are delta-9-tetrahydrocannabidiol (THC), and cannabidiol (CBD).</p>
<p>THC is the type of cannabis that can make people feel “stoned”, while cannabidiol can make people feel relaxed and can hopefully relieve nausea.</p>
<p>Older cannabis medicines, such as Dronabinol and Nabilone, are made of synthetic THC. They are still sometimes used overseas as last-line options for treating nausea and vomiting caused by chemotherapy, but they’re not very effective, and can cause a lot of side effects.</p>
<p>The oral capsule for our NSW government-funded study contains equal amounts of THC and CBD. We think this will be more effective and have fewer side effects.</p>
<p>We worked with the Canadian company <a href="https://www.tilray.ca/">Tilray</a>, which developed the capsule to our specifications. It aims to minimise THC levels that have mood-altering characteristics, which means our patients are less likely to get “stoned”.</p>
<p>The trial is building on a small <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997305/">Spanish study</a> which found that a spray form of cannabis medicine containing THC and CBD in equal amounts (not routinely available in Australia) seemed to dramatically reduce nausea and vomiting in cancer patients receiving chemotherapy. The results, which found a 50% reduction in the number of patients suffering these effects, seem too good to be true, and need to be repeated in a rigorous clinical trial using a capsule that is available in Australia.</p>
<p>The NSW clinical trials exploring the use of medicinal cannabis are very significant. We don’t want to repeat past mistakes, and we want the investment in time and money to be worthwhile.</p>
<p>We can’t predict the outcome. The trials could show a benefit of medicinal cannabis, but they could also show that medicinal cannabis doesn’t work or has overwhelming side effects.</p>
<p>We are hopeful that, at the very least, NSW patients will be given a clear, scientific basis upon which to make important decisions about their treatment in the future.</p><img src="https://counter.theconversation.com/content/66774/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Peter Grimison is a medical oncologist from Chris O`Brien Lifehouse cancer hospital and The University of Sydney and is leading the research team for the NSW Government’s clinical trial into the role of cannabis-derived medicines in chemotherapy-induced nausea and vomiting. The University of Sydney and Chris O'Brien Lifehouse receives funding from NSW Health to conduct a clinical trial of cannabis for chemotherapy-induced nausea and vomiting, for whom Tilray have provided the study drug.</span></em></p>NSW is about to embark on the largest and most definitive clinical trial ever of medicinal cannabis for chemotherapy-induced nausea and vomiting.Peter Grimison, Medical oncologist from Chris O`Brien Lifehouse cancer hospital, Lead researcher NSW Government clinical trial into the role of cannabis-derived medicines in chemotherapy-induced nausea and vomiting, Clinical Associate Professor., University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/673462016-10-24T15:02:41Z2016-10-24T15:02:41ZHow an old antidepressant could provide the next brain cancer breakthrough<figure><img src="https://images.theconversation.com/files/142909/original/image-20161024-28382-6t8lqg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>In 1998, I received an intriguing handwritten note. It came from David Wilkie, emeritus professor at University College London, and asked if I thought the antidepressant drug clomipramine could affect brain tumours. I had been investigating how brain cancer spreads and Wilkie wondered if his own work on how clomipramine could kill cells might be of relevance.</p>
<p>This sparked a series of investigations over the last 18 years into how this old drug that was once commonly used as an antidepressant might find a new purpose in cancer treatment. <a href="http://meeting.ascopubs.org/cgi/content/short/23/16_suppl/1535">Research has now linked</a> it to increased survival rates for brain tumour patients and, because its patent has expired, it is cheaply available at less than <a href="http://www.evidence.nhs.uk/formulary/bnf/current/4-central-nervous-system/43-antidepressant-drugs/431-tricyclic-and-related-antidepressant-drugs/tricyclic-antidepressants/clomipramine-hydrochloride">10p a tablet</a>. Clomipramine (sold under the brand name Anafranil) has been used for decades to treat patients with depression. Yet surprisingly – some might say scandalously – it has still not been through the clinical trials that would allow it to be prescribed for brain tumour patients.</p>
<p>Clomipramine’s use as an antidepressant has somewhat declined since it was first introduced in the 1950s, due to the development of selective serotonin reuptake inhibitor (SSRI) drugs such as Prozac. But its potential use as a brain cancer drug comes from the fact that it can cross the blood-brain barrier, which protects the brain from toxins in the blood but can also prevent drugs from entering.</p>
<p>The <a href="http://europepmc.org/theses/eth/272349">first piece of research</a>, carried out by a PhD student in my lab, made the important discovery that clomipramine specifically targeted brain tumour cells – but not healthy brain cells. <a href="http://eprints.port.ac.uk/7632/">Additional studies</a> confirmed that clomipramine worked by targeting these cells’ energy source (mitochondria). Depending on the dose used, this would set up <a href="https://theconversation.com/how-self-destructing-cells-may-hold-key-to-cancer-cure-31707">cell death</a> in a way that was reversible after 24 hours but irreversible after 48 hours, even at a relatively low dose.</p>
<p>This is very different from the way that current gold-standard brain tumour therapy works, which <a href="http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/cancer-drugs/temozolomide">typically involves</a> killing both cancer and normal cells by targeting their nuclei.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=377&fit=crop&dpr=1 600w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=377&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=377&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=474&fit=crop&dpr=1 754w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=474&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=474&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Brain barrier.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p><a href="http://www.nature.com/bjc/journal/v104/n1/full/6605996a.html">Research has shown</a> that clomipramine is linked to a reduction in the likelihood of developing a tumour by 40%-50% depending on the dose, and 64% for patients taking the drug long-term. We (<a href="https://www.ncbi.nlm.nih.gov/pubmed/8927228">and others</a>) <a href="https://www.ncbi.nlm.nih.gov/pubmed/20332444">have also shown</a> that using other repurposed drugs as well can make cancer cells more sensitive to clomipramine and enhance its anti-tumour effect.</p>
<p>But the evidence needed to change a drug’s licence so it can be prescribed for a specific condition can only be obtained with a robust clinical trial. <a href="http://meeting.ascopubs.org/cgi/content/short/23/16_suppl/1535">The trials</a> that have so far been carried out with brain tumour patients unfortunately are not enough. One was a pilot with a small sample size (50 patients) and the second was halted because it had too few patients who complied with the trial rules after the initial 12 months.</p>
<h2>Anecdotal evidence</h2>
<p>Publicity for the drug has resulted in many doctors giving their brain tumour patients clomipramine anyway. In these anecdotal cases, some patients have gone on to survive for periods of up to ten years – and even 17 years in a couple of instances.</p>
<p>But because these patients were not controlled by a clinical trial – for example taking recorded doses and consistent biological measurements – any results can’t be used to change the licence. So even with compelling laboratory and anecdotal evidence, many doctors still only prescribe within the existing guidelines. This helps them to avoid being liable for negligence if a patient is harmed.</p>
<p>Some politicians in the UK have tried to alter the law to make it easier to for promising off-patent drugs to be used for cancer treatment within the regulations. But the <a href="http://services.parliament.uk/bills/2015-16/accesstomedicaltreatmentsinnovation/documents.html">latest law</a>, which came into effect in March 2016, was very watered down. Its main outcome was a searchable database that will record doctor’s medical innovations. This could be a useful reference but doesn’t provide any protection against negligence to encourage more doctors to trial drugs like clomipramine.</p>
<p>So this brings us back to the need for a robust clinical trial. Our laboratory research aims to find partner drugs that can target multiple specific biological pathways and to personalise patient therapies. But finding the funds for a clinical trial is difficult, especially <a href="https://www.braintumourresearch.org/statistics">less than 2%</a> of national cancer research money may be spent on brain tumour research. But without this funding, we won’t be able to reveal the full potential of clomipramine to save the lives of brain cancer patients.</p>
<p><em>Listen to Geoff talk in more depth about clomipramine on The Conversation’s podcast, The Anthill.</em></p>
<iframe width="100%" height="166" scrolling="no" frameborder="no" src="https://w.soundcloud.com/player/?url=https%3A//api.soundcloud.com/tracks/283008303&color=ff5500&auto_play=false&hide_related=false&show_comments=true&show_user=true&show_reposts=false"></iframe><img src="https://counter.theconversation.com/content/67346/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Geoff Pilkington receives funding from Brain Tumour Research. </span></em></p>The well-used drug clomipramine could target tumour cells and leave normal cells healthy – if scientists could get enough evidence for it.Geoff Pilkington, Professor of Cellular and Molecular Neuro-Oncology, University of PortsmouthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/591572016-05-12T04:28:37Z2016-05-12T04:28:37ZUnfair if rare: should the PBS change the way it lists cancer drugs?<figure><img src="https://images.theconversation.com/files/122028/original/image-20160511-20698-1rn69bu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Rare cancers are those where the incidence is less than six cases per 100,000 people.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>The Pharmaceutical Benefits Scheme (PBS) <a href="https://theconversation.com/new-cancer-drugs-are-very-expensive-heres-how-we-work-out-value-for-our-money-44014">spends over A$9 billion a year</a> subsidising a wide range of drugs to ensure affordability for all Australians. But when it comes to rare cancers – such as bone and soft tissue tumours called sarcomas – the scheme falls short.</p>
<p>This happens for a number of reasons. The main one is that rarity means less value for money. But should our new understanding of how cancers develop and could be treated mean we should change the way the scheme registers cancer drugs?</p>
<h2>Diagnosing cancers</h2>
<p>Cancers used to be diagnosed by determining the organ, such as breast or lung, from which they came. Drugs were, and still are, registered by the Therapeutic Goods Administration (TGA) to use against these cancers if they are effective in clinical trials with acceptable side effects. </p>
<p>Because there are more patients for common cancer trials, and a larger market if the drugs are effective, more drugs to treat these are being tested and therefore registered. Rare cancers are those with an incidence of less than six cases for every 100,000 people. Their rarity means it’s not possible to do the gold standard large randomised controlled trials to determine efficacy. </p>
<p>The TGA refers to drugs used to treat rare diseases as <a href="https://www.tga.gov.au/orphan-drugs">orphan drugs</a> and offers reduced application fees to register these. Despite this, there are still many small bowel cancers or neuroendocrine cancers for which potentially effective drugs are not registered.</p>
<p>Only once the TGA registers a drug for a particular cancer can an application be made for it to be subsidised on the PBS. Drugs are therefore more likely to be subsidised for common cancers, as the PBS evaluates whether the drug’s effectiveness warrants the price sought by the pharmaceutical developer.</p>
<p>But recently there has been a shift in how cancer researchers and doctors classify and treat cancers that could potentially influence the way drugs become registered.</p>
<h2>From location to tumour type</h2>
<p>Previously, chemotherapy drugs killed all dividing cells and relied on normal cells to repair themselves while the cancer cells died. Therapies are now being developed to <a href="https://theconversation.com/how-cancer-doctors-use-personalised-medicine-to-target-variations-unique-to-each-tumour-47349">specifically target</a> the genetic makeup in each tumour - a wave of medicine referred to as “personalised”.</p>
<p>Other therapies – known as immunotherapies – target <a href="https://theconversation.com/the-fourth-pillar-how-were-arming-the-immune-system-to-help-fight-cancer-48152">proteins that prevent the body’s immune cells</a> from killing the cancer. The target proteins are found by looking at which genes in a particular cancer are altered (or mutated) to make the cells replicate and grow into unhealthy tumours. </p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/122022/original/image-20160511-20742-35knta.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/122022/original/image-20160511-20742-35knta.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=699&fit=crop&dpr=1 600w, https://images.theconversation.com/files/122022/original/image-20160511-20742-35knta.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=699&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/122022/original/image-20160511-20742-35knta.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=699&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/122022/original/image-20160511-20742-35knta.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=879&fit=crop&dpr=1 754w, https://images.theconversation.com/files/122022/original/image-20160511-20742-35knta.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=879&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/122022/original/image-20160511-20742-35knta.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=879&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Immunotherapy for Danielle Tindle’s rare cancer is not subsidised by the PBS.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/77073214@N00/5633942440">dingram_kiwi/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>So cancer treatment is becoming more dependent on the tumour’s genetic makeup rather than the organ of origin. Cancers at different locations, such as breast and prostate cancer for instance, may have identical targets that can respond to the same therapies. And cancers from the same organ can have different patterns of gene mutations, which means only those with the target may respond to specific drugs.</p>
<p>Drugs called PARP inhibitors, for instance, <a href="http://www.ncbi.nlm.nih.gov/pubmed/27065456">have been successful in breast cancers</a> that carry the BRCA1 or BRCA2 gene mutations. These are being trialled in ovarian cancers with the same gene mutations. </p>
<p>Targeted therapies can be used to treat a rare cancer that shares the same mutations as a common cancer. The immunotherapy drug nivolumab, for instance, is successful in treating melanoma and lung cancer. And, as reported in <a href="http://www.abc.net.au/news/2016-05-09/rare-cancer-patient-dealt-'unfair'-drug-costs/7391874">ABC’s Australian Story program this week</a>, it is being tried as a treatment for 36-year-old Danielle Tindle’s rare neuroendocrine tumour, which shares some characteristics with melanoma and lung cancers. </p>
<p>The issue is that targeted therapies are often coming onto the market at <a href="https://theconversation.com/explainer-how-does-keytruda-treat-melanoma-and-why-is-it-so-costly-40558">over A$100,000</a> for several months of treatment. And while nivolumab is subsidised to treat melanoma, a patient like Danielle has to pay full price, which is reportedly A$5,000 a shot.</p>
<h2>Can we change the system?</h2>
<p>To overcome this disparity, a specific fund could be established for rare cancers so they would not have to compete with more common cancers. Fees for TGA and PBS submissions would be set to encourage pharmaceutical companies to apply to register and list drugs for rare cancers.</p>
<p>Of course, the equity of that solution would depend on the size of the fund relative to need and whether the fund’s money was new or simply reduced the subsidy pool for more common cancers.</p>
<p>Another option is for the TGA to start registering targeted therapies on the basis of the target’s presence in the cancer, irrespective of the cancer’s organ of origin. The issue with this approach is that the evidence for efficacy would only be available from trials of more common cancers.</p>
<p>Also, although a targeted therapy isn’t effective in cancer that doesn’t have the target, the presence of the target <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1113205">doesn’t guarantee its effectiveness</a>. This is because the tumour’s altered gene may not be responsible for driving the cancer’s growth, or may represent only one of the targets that need to be hit to stop it developing.</p>
<p>So limited trials that show efficacy of targeted therapies for rare cancers could lead to subsidising potentially ineffective drugs. A possible solution would be a risk-sharing model where, for example, a pharmaceutical company could fund initial courses of rare cancer drugs until there was enough evidence of efficacy, at which point the government subsidy would become available. </p>
<p>Such schemes <a href="http://www.ispor.org/research_pdfs/35/pdffiles/PHP15.pdf">have been used in</a> France, Italy, Sweden, the United Kingdom and parts of the United States.</p>
<p>The challenge is to achieve a balance between allocating funding for the greatest good for the largest number of people, while also ensuring patients with rare cancers aren’t unfairly disadvantaged.</p><img src="https://counter.theconversation.com/content/59157/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Olver has consulted for Teasro. He receives funding for research from the NHMRC, ARC and Cancer Australia.</span></em></p>Should new understandings of how cancers develop and could be targeted mean we should change the way the scheme registers cancer drugs?Ian Olver, Director, Sansom Institute for Health Research; Chair of Translational Cancer Research, University of South AustraliaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/569492016-04-06T10:59:11Z2016-04-06T10:59:11ZThe high cost of publicly funded cancer drugs<figure><img src="https://images.theconversation.com/files/116637/original/image-20160329-13709-30gfrw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">yari2000/Shutterstock</span></span></figcaption></figure><p>Patients with prostate cancer in England and Wales <a href="http://www.bbc.co.uk/news/health-35861202">will now have</a> early access to <a href="http://prostatecanceruk.org/prostate-information/treatments/abiraterone">abiraterone</a>, a drug which can delay the need for chemotherapy. The drug previously cost £3,000 a month, and was not considered “<a href="https://www.nice.org.uk/nice-appraisal-of-earlier-treatment-with-abiraterone-for-prostate-cancer">cost-effective</a>” for the NHS until cancers were more advanced – even though patients in Scotland <a href="http://www.dailymail.co.uk/health/article-3278615/Prostate-cancer-sufferers-denied-wonder-pill-s-widely-available-Scots.html">had access</a> to it.</p>
<p>The U-turn comes after a lower price was agreed with the manufacturer Janssen – making abiraterone affordable for widespread use. Janssen is also said to have submitted <a href="https://www.nice.org.uk/news/press-and-media/nice-recommends-abiraterone-for-prostate-cancer">fresh data</a> about the drug’s effectiveness to the National Institute for Health and Care Excellence (NICE), <a href="http://www.cancerresearchuk.org/about-cancer/cancers-in-general/cancer-questions/what-is-nice-and-how-does-it-work">which decides which drugs and treatments are available</a> on the NHS in England and Wales.</p>
<p>This change in price now means that abiraterone can be given to prostate cancer patients who have mild symptoms but evidence of the disease spreading. The drug will also be used in patients who have not previously responded to hormone therapy and have not undergone radiotherapy. </p>
<p>While this new widespread use of the drug is great news for cancer patients, why has it taken so long to get things to this point? It does not seem entirely clear what this <a href="https://www.nice.org.uk/guidance/GID-TAG434/documents/final-appraisal-determination-document">new data</a> is, or why the current, <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1209096">published data</a> was considered to be insufficient. And it’s not the first time decisions on life-saving drugs have come into question.</p>
<h2>Dying for treatment</h2>
<p>There are a wide and generally effective range of treatment options for prostate cancer available. The main one is hormone therapy, which is aimed at blocking androgen (testosterone) production. </p>
<p>The rationale for this treatment is that most prostate tumours, especially in the earlier stages of the disease, require <a href="http://prostatecanceruk.org/prostate-information/treatments/hormone-therapy">androgens</a> for their continued growth and survival, in much the same way that some breast cancers are dependent on oestrogen. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/ygoQ_kWf5ZQ?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Prostate Cancer kills one man every hour in the UK.</span></figcaption>
</figure>
<p>The original treatment for depriving prostate tumours of androgen was the removal of the testicles, giving rise to the delightful term “<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935714/">castration resistant prostate cancer</a>”. </p>
<p>Abiraterone delays the need for chemotherapy by helping to overcome the problem of “castration resistant tumours” – where the cancer cells become more and more sensitive to androgen in response to its reduced levels after hormone therapy.</p>
<p>Castration was subsequently replaced with drug-based therapy, with abiraterone developed in the early 1990s by scientists at <a href="http://www.icr.ac.uk/news-features/latest-features/abiraterone-a-story-of-scientific-innovation-and-commercial-partnership">Cancer Research UK’s</a> Centre for Cancer Therapeutics – using money donated by cancer survivors, the families of cancer patients, and numerous other individuals and organisations.</p>
<p>And yet the final product has until recently been prohibitively expensive, to the point where thousands of men may have missed out on its potential benefits, and it has <a href="http://www.dailymail.co.uk/health/article-2627653/Prostate-cancer-pill-extend-life-years-delay-need-chemotherapy-set-ban-not-cost-effective.html">severely strained NHS budgets</a>.</p>
<h2>Drug of choice</h2>
<p>Abiraterone has long been considered to be one of the most effective treatments for prostate cancer as it almost completely blocks testosterone production. This has been supported by a number of large <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1209096">clinical trials</a>, including one that recruited 1,088 men and revealed that abiraterone increased the average time taken for prostate cancer to spread from eight months to 16.5 months.</p>
<p>Despite this, NICE refused to approve the use of abiraterone for prostate cancer on the grounds that its cost was not justified by its proven clinical benefits. </p>
<p>While NICE have now reversed this decision, it still doesn’t take away from the fact that for so long, so many men have been unable to access an effective treatment for prostate cancer, which could have helped to delay the spread of the disease.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/116640/original/image-20160329-13718-1b6yaom.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/116640/original/image-20160329-13718-1b6yaom.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/116640/original/image-20160329-13718-1b6yaom.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/116640/original/image-20160329-13718-1b6yaom.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/116640/original/image-20160329-13718-1b6yaom.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/116640/original/image-20160329-13718-1b6yaom.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/116640/original/image-20160329-13718-1b6yaom.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">One in seven men will be diagnosed with prostate cancer during their lifetime.</span>
<span class="attribution"><span class="source">Image Point Fr/Shutterstock</span></span>
</figcaption>
</figure>
<p>Of course, hormone therapy is not without side effects – it can (and usually does) lead to varying degrees of feminisation, alongside erection problems, hot flushes and breast tenderness. However, these side effects are generally far less severe than those associated with therapies used when tumours fail to respond to hormone treatment. </p>
<p>This type of treatment includes conventional chemotherapy with <a href="http://www.evidence.nhs.uk/formulary/bnf/current/8-malignant-disease-and-immunosuppression/81-cytotoxic-drugs/side-effects-of-cytotoxic-drugs">cytotoxic drugs</a> that are generally designed to selectively kill rapidly dividing cells. </p>
<p>Many normal adult cells also need to divide quickly though – for example those involved in replacing the lining of the gut or in generating new blood cells – meaning this type of chemotherapy can have a broad and significant range of unpleasant side effects including hair loss, mouth ulcers, nausea and vomiting as well as increased chance of infection from the drop in white blood cells.</p>
<p>When you consider the debilitating side effects associated with chemotherapy, and the fact that prostate cancer is the most common male-specific cancer with around <a href="http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/prostate-cancer#heading-Zero">35,000 new cases</a> and about <a href="http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/prostate-cancer#heading-Zero">10,000 deaths</a> every year in the UK, the fact that drug therapy is withheld in treatment is very concerning.</p>
<p>But abiraterone is not the first anti-cancer drug to prove prohibitively expensive. Consider the small sum of <a href="http://www.bbc.co.uk/news/health-34831197">£90,000</a> required for a course of the breast cancer drug Kadcyla. Or the <a href="http://www.theguardian.com/business/2015/sep/23/uk-cancer-patients-being-denied-drugs-due-to-inflated-prices-say-experts">£24,000</a> cost per patient per year for another breast cancer drug, lapatinib. </p>
<p>Then there is also growing disquiet about the regional differences in the cost of drugs with lapatinib costing considerably less in a number of <a href="http://www.theguardian.com/business/2015/sep/23/uk-cancer-patients-being-denied-drugs-due-to-inflated-prices-say-experts">other countries</a>. </p>
<p>Questions need to be asked around drug costs and accessibility across the whole of the UK. Because although abiraterone isn’t the first high-cost cancer drug, sadly it won’t be the last.</p><img src="https://counter.theconversation.com/content/56949/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard Morgan does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The cost of cancer drugs is killing patients and it needs to stopRichard Morgan, Professor of Molecular Oncology, University of BradfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/565082016-03-30T03:31:39Z2016-03-30T03:31:39ZWeekly dose: Taxol, the anticancer drug discovered in the bark of a tree<figure><img src="https://images.theconversation.com/files/116704/original/image-20160330-28459-1rox4o9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The US National Cancer Institute tested tens of thousands of plants and made this miraculous find. </span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/hetspul/8016588945/in/photolist-ddp7AM-8p3d6s-dUgwC7-2bgws-6RwkFU-fUtzMK-7WrG9w-2DHuQ-nnnMt7-nKxB3t-butqjs-5tsW82-7B38wc-h2Cfgc-cxdCxh-8t6LpN-dYwKKE-rjq4Gq-36BwyV-6tSgGP-5TrSsR-srmjC1-5BZueu-9W2G4s-akZQpB-ELRJHU-h5jZGt-2qFZuT-EsYq6-25Rg1U-iE5C3x-6UsEU-n2SdyZ-r34Kmb-4sQqwG-hmAnbg-7yTdKR-dRe2V2-7HTwvZ-5d5BkR-az4Wwy-snb81-d5oSaQ-dHYfwr-f39tMZ-7ZfSRA-9HVzb7-7Q8PtH-9VhfXb-7tZ6DR">Het Spul/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Taxol is a chemotherapy drug used in the treatment of specific human cancers. It is a member of the taxane family of drugs, which includes cabazitaxel and docetaxel.</p>
<p>The drug is also sold under its generic name of paclitaxel (pronounced pack-lee-tax-elle). Taxol is available by prescription only and is administered via an intravenous injection in a hospital setting. The dose each patient is administered is calculated taking into account their underlying health, height and weight.</p>
<figure class="align-center ">
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<h2>History</h2>
<p>Arthur Barclay was a botanist working for the US Department of Agriculture in the 1960s. Under contract to the US National Cancer Institute, Barclay collected samples of plants to find new drugs. </p>
<p>The National Cancer Institute screened 35,000 plants. One particular sample Barclay collected, the bark of the Pacific Yew tree, went on to provide what is now one of the most highly prescribed chemotherapy drugs for cancer. </p>
<p>Taxol, which is a chemical extracted from the bark, was selected for commercial development in 1977 and was first tested in patients in 1984. It was approved for use by the US Food and Drug administration in 1992 and by 2000 had annual sales of A$2.1 billion per year.</p>
<p>The drug’s name is derived from the Latin term for the tree, <em>Taxus brevifolia</em>.</p>
<h2>How it works</h2>
<p>Every cell in the body has long rod-like structures, which scientists call <a href="http://www.ncbi.nlm.nih.gov/books/NBK9932/">microtubules</a>. These microtubules have several functions, one of which is to act like a type of skeleton structure that helps give cells their shape.</p>
<p>When cells replicate, they break down this skeleton, divide into two cells, then rebuild it. Taxol acts by promoting the formation of these microtubules, which means they get in the way when the cells try to divide. </p>
<p>Preventing cells from replicating sends them into a process of programmed cell death called <a href="http://www.thefreedictionary.com/apoptosis">apoptosis</a>, which kills the tumour.</p>
<h2>Who is administered Taxol?</h2>
<p>Taxol is used in combination with other chemotherapy drugs and surgery. In Australia, it is used to treat ovarian, breast, cervical, endometrial and non-small cell lung cancers. </p>
<p>It is also used to treat <a href="https://www.rarecancers.org.au/directory/139/kaposi-sarcoma-">AIDS-related Kaposi’s sarcoma</a>, a rare type of cancer that develops as tumours on the skin and inside the mouth.</p>
<h2>Problems with the drug</h2>
<p>The biggest problem of Taxol is its poor solubility in water. Water solubility is important because a drug must be fully dissolved to be safe for injection. Any solid particles in an intravenous injection can lead to blood clots and inflammation of the veins.</p>
<p>Because of this, Taxol is typically dissolved in alcohol with the addition of a soap-like chemical called polyoxyethylated 35 castor oil (also referred to as <a href="http://www.ncbi.nlm.nih.gov/pubmed/11527683">Chremophor EL</a>).</p>
<p>A new formulation of protein-bound Taxol called abraxane is available in Australia. In this formulation, Taxol is combined with albumin, the most abundant protein in human blood serum. Binding the drug to the protein makes it take on the albumin’s solubility, and it can then be administered to patients in water-based formulations.</p>
<h2>Controversy</h2>
<p>The Pacific Yew tree grows only in the northwest region of America. It is slow growing and found only in old-growth forests. </p>
<p>In the early days of the drug’s development, the bark was obtained from the tree by logging, which killed the trees. This meant supply of the drug was limited and the process was nonrenewable and not environmentally friendly. At least one kilogram of bark was required to produce <a href="http://www.ncbi.nlm.nih.gov/pubmed/8097872">just 10 grams of drug</a>.</p>
<p>Thankfully, while the drug cannot yet be completely synthesised in a factory, chemists have developed ways to produce it using precursor chemicals found in the needles of a related tree, <em>Taxus baccata</em>. </p>
<p>They can also manufacture the drug by culturing plant cells. This latter process is renewable and can produce <a href="http://pubs.rsc.org/en/content/articlepdf/2001/cc/b100070p">up to 50 grams of drug per kilogram</a> of plant material.</p>
<h2>Side effects</h2>
<p>Like all chemotherapy drugs, Taxol has some common side effects, which many patients experience. These include the production of fewer blood cells, which can make patients anaemic and susceptible to infections; nausea; vomiting; diarrhoea; hair loss; muscle and joint pain; nerve problems, which include weakness, tingling, pain or numbness in the hands or feet; and changes in heart rate and blood pressure.</p>
<p>These side effects can be managed by giving the patient additional medicines or by adjusting the dose of the drug.</p>
<p>Taxol also has another side effect that can be life-threatening. Some patients experience a severe allergic reaction the first time they are given the drug. This is due to the Chremophor EL included in the formulation. </p>
<p>In these cases, the doctor may give the patient a different taxane drug, use albumin-bound Taxol instead, or develop a plan to desensitise the patient to Taxol. </p>
<h2>Cost</h2>
<p>Whether a patient is charged for this drug depends on how the hospital classifies them. Anyone classified as a public <em>in-patient</em> will be not be charged for Taxol as its cost will be covered under <a href="https://www.humanservices.gov.au/customer/subjects/medicare-services">Medicare</a>.</p>
<p>Anyone classified as a public <em>out-patient</em> will be charged at a maximum rate of A$38.30 per treatment.</p>
<p>Under a special arrangement, the <a href="http://www.pbs.gov.au/medicine/item/10150F-10165B-4531L-7270P">price the government pays</a> for the albumin-bound formulation of Taxol depends on the type of cancer it is being used to treat and costs between A$1,287 to A$2,562 for 275 mg of the drug. </p>
<p>In contrast, the normal Taxol formulation is much cheaper, although less safe, for the government at A$222.90 for 450 mg of the drug.</p>
<hr>
<p><em>Information provided in this article is based primarily on the <a href="https://shop.amh.net.au/products/books/2016">Australian Medicines Handbook 2016</a>. If you would like more information, the patient information sheet on Taxol is available <a href="http://www.nps.org.au/__data/assets/pdf_file/0005/13946/bqctaxol10505.pdf">here</a></em>.</p><img src="https://counter.theconversation.com/content/56508/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Dr Wheate in the past has received funding from the ACT Cancer Council, Tenovus Scotland, Medical Research Scotland, Scottish Crucible and the Scottish Universities Life Sciences Alliance for research into chemotherapy and drug delivery. Dr Wheate is a named inventor on two international patents dealing with drug delivery.</span></em></p>The US National Cancer Institute screened 35,000 plants, but one particular sample collected from the bark of the Pacific Yew tree provided what is now one of the most highly prescribed cancer drugs.Nial Wheate, Senior Lecturer in Pharmaceutics, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/440142015-09-08T20:03:44Z2015-09-08T20:03:44ZNew cancer drugs are very expensive - here’s how we work out value for our money<p>The Senate Standing Committee on Community Affairs is expected to table its report on the “<a href="http://www.aph.gov.au/Parliamentary_Business/Committees/Senate/Community_Affairs/Cancer_Drugs">Availability of new, innovative and specialist cancer drugs in Australia</a>” today. Initiated by South Australian senator Nick Xenophon, the inquiry, which was initially slated to report in late March, is focusing on timely access and affordability of cancer drugs, and how this impacts the quality of cancer care.</p>
<p>The <a href="http://www.pbs.gov.au/pbs/home">Pharmaceuticals Benefits Scheme</a> (PBS) spends over A$9 billion a year subsidising a wide range of drugs to ensure their affordability. But the growing number of expensive medicines has raised questions about its long-term viability. In 2012/13, for instance, spending on chemotherapy for the treatment of cancer increased by over A$250 million. Funding for cancer drugs now accounts for <a href="https://www.health.gov.au/internet/ministers/publishing.nsf/Content/health-mediarel-yr2015-ley065.htm">$1 in every $6 spent</a> on the PBS, up from $1 in every $8 in the previous year.</p>
<p>And this amount is predicted to continue increasing: a <a href="https://www.health.gov.au/internet/main/publishing.nsf/Content/F53CF35CC217853DCA257E27001C14F7/$File/Dept%20of%20Health%20submission%20-%20Senate%20Inquiry%20into%20cancer%20medicines%20for%20website.pdf">recent round of applications</a> for listing new pharmaceuticals included 11 cancer drugs, at an estimated cost of A$589 million. And a 2014 US <a href="http://www.obroncology.com/imshealth/content/IMSH_Oncology_Trend_Report_020514F4_screen.pdf">review of cancer care</a> identified almost 1,000 drugs in development, suggesting a continuing flow of applications for listing on the PBS.</p>
<h2>Value for money?</h2>
<p>The remit of the PBS is to provide access to effective and safe pharmaceuticals at a price that provides value for money to the Australian taxpayer. It decides which new drugs it will subsidise based on recommendations from the <a href="http://www.pbs.gov.au/info/industry/listing/participants/pbac">Pharmaceutical Benefits Advisory Committee</a> (PBAC). But how does the PBAC assess value for money?</p>
<p>It compares the costs and health benefits of a new drug to the costs and health benefits of the treatment it will replace if funded. Health benefits are represented by the number of “quality-adjusted life years” (QALYs) experienced by patients from the time they start treatment.</p>
<p>The QALY measure reflects improvements in quality of life, as well as quantity of life, or life expectancy. And since most health care is intended to improve quantity or quality of life, QALYs can be used to represent the benefits of most health-care interventions.</p>
<p>One QALY is the equivalent to a year of life lived without any form of ill health. You accumulate one QALY for every year you experience no ill health, and a fraction of one QALY for every year of illness. Using data collected from large-scale surveys of the Australian population, people experiencing illness are assigned a QALY value between zero and one.</p>
<p>A value of 0.5 is quality of life that’s half as good as living in perfect health, for instance, and zero is equivalent to being dead because no QALYs are accumulated after death. But quality of life declines over time for everyone; it just falls more slowly for people not receiving the intervention (in this case, cancer drugs).</p>
<p>The benefits of a new drug are defined as the additional number of QALYs experienced by patients receiving it, compared to the existing treatment option. We also estimate the difference in expected costs incurred by people receiving the new and current treatments.</p>
<p>Consider if a new drug could be used to treat 1,000 people every year who currently receive a different drug. Patients receiving the new drug are expected to gain an additional five QALYs compared to patients receiving the current drug, which is a total of 5,000 QALYs across the 1,000 patients. </p>
<p>But the new drug is estimated to cost A$100 million more to treat the 1,000 patients. How then should we use this information to determine whether the new drug provides value for money?</p>
<h2>Opportunity cost</h2>
<p>Well, we compare the gain of 5,000 QALYs to the lost opportunity (this is known in economics as an opportunity cost) of spending A$100 million on the new drug. In other words, if the new drug isn’t funded, could that A$100 million generate other benefits valued at more than 5,000 QALYs?</p>
<p>Of course, if the drug isn’t funded, the A$100 million might not be spent on health care at all, but on education, transport or defence. But it’s difficult to compare the benefits of spending across government sectors; it’s easier to assess whether the health of the population can be more improved if we allocated the A$100 million to another form of health care. </p>
<p>The money could be used to reduce public hospital waiting times, for instance, or on unimplemented health-care programs we know to be effective. But such comparisons are also difficult because these kinds of funding decisions aren’t informed by the same open assessment of value for money that informs PBS listings.</p>
<p>In the absence of transparent and consistent processes for assessing value for money, how are new pharmaceuticals assessed? The expected additional costs of the new drug (A$100 million) are divided by the expected gain in QALYs (5,000). This provides an estimate for the expected cost of producing one additional QALY (A$20,000), and a decision about whether this represents good value for money is made based on this figure.</p>
<p>In Australia, public summaries for each assessed pharmaceutical are published. <a href="http://www.pbs.gov.au/industry/listing/elements/pbac-meetings/psd/2014-07/infliximab-psd-07-2014.pdf">Recent documents</a> suggest new drugs are generally recommended if their expected incremental cost per QALY is somewhere between $45,000 and $75,000. Often, the <a href="http://www.pbs.gov.au/industry/listing/elements/pbac-meetings/psd/2014-07/brentuximab-psd-07-2014.pdf">price of a new drug is lowered</a> until the cost per QALY becomes acceptable. </p>
<p>But the source of this “threshold” value is unknown as there’s never been any open discussion about the basis of defining it in Australia. One way to understand the value of gaining additional QALYs is to analyse health system data and estimate the average cost at which QALYs have been gained in the past. If a new drug is gaining QALYs at a lower cost, we can have more confidence that the health system is becoming more efficient over time.</p>
<p>Estimating the average incremental cost at which additional QALYs are gained in Australia will provide a stronger basis for assessing the value of new drugs. It will also inform health-care funding decisions more generally. Specifying the basis for assessing value for money would improve the transparency of decision-making, and <a href="http://www.health.gov.au/internet/main/publishing.nsf/Content/govt-response-cancer-drugs">allow Australian taxpayers to participate</a> in an open discussion about the value of cancer drugs.</p><img src="https://counter.theconversation.com/content/44014/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jonathan Karnon receives funding from NHMRC. </span></em></p><p class="fine-print"><em><span>I am a member of the Evaluation Sub-Committee of the Medical Services Advisory Committee </span></em></p><p class="fine-print"><em><span>Laura C Edney does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Most of us would agree that cancer drugs should be listed on the PBS, no matter how dear. But our health system can’t afford all of them. How then are decisions about which drugs to subsidise made?Jonathan Karnon, Professor of Health Economics, University of AdelaideHossein Haji Ali Afzali, Senior Research Fellow, University of AdelaideLaura C Edney, Research Fellow, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/440722015-07-26T20:12:12Z2015-07-26T20:12:12ZIf we don’t talk about value, cancer drugs will become terminal for health systems<figure><img src="https://images.theconversation.com/files/89712/original/image-20150726-8474-72m20i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A group of oncologists have called on cancer patients to challenge the high prices charged by pharmaceutical companies for new cancer drugs.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/ep_jhu/3308079338/in/photolist-63jLJE-6sSezB-4cXa6D-9bH4ur-8VPze4-4nVDsE-8Pomnt-7V1PRy-4CZCmU-jR9gc-oH4rdU-pCYRsM-35k1qw-95qvZs-sCTxH-5ybjn2-5VQHuA-9sw3y4-9Xcshz-e8UEr-dAjLrS-kxHJW-bqRwgf-cqiNS1-6m4PWH-6ZHdXN-9d5WGV-dEWvJE-4M7pV-ncFSjE-78ePNM-2JagVw-7kihrz-jK2whx-9XtRCC-oK4qob-bq31mE-dg7YLC-e59Fxe-2zyGn9-6nrmLQ-bDvpYV-ardcyt-bkbW8T-vdvJCW-5S73oK-wnYnx-3vuBP9-vdUfav-dErKR5">ep_jhu/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span></figcaption></figure><p><a href="http://www.mayoclinicproceedings.org/article/S0025-6196(15)00430-9/abstract">More than 100 prominent oncologists</a> from across the United States have called on <a href="http://www.nytimes.com/2015/07/23/business/drug-companies-pushed-from-far-and-wide-to-explain-high-prices.html?_r=1">cancer patients to challenge the high prices</a> charged by pharmaceutical companies for new cancer drugs. They claim drug companies, insurance companies, some patient advocacy groups and many hospitals and physicians are <a href="http://newsnetwork.mayoclinic.org/discussion/leading-experts-prescribe-how-to-make-cancer-drugs-more-affordable/">too financially conflicted to be driving the debate</a>. </p>
<p>Their call is motivated by the astronomical prices charged for some new cancer drugs. And Australia is in the same boat. Earlier this year, for instance, the Pharmaceutical Benefits Scheme (PBS) <a href="http://www.smh.com.au/national/health/ron-walkers-150000-cancer-drug-keytruda-approved-for-melanoma-patients-20150420-1more8.html">started subsidising pembrolizumab (Keytruda)</a> for the treatment of patients with advanced melanoma. The drug is expected to cost A$150,000 per patient for each year of treatment, which is <a href="http://www.abs.gov.au/ausstats/abs@.nsf/mf/6302.0">almost twice</a> the national average annual income.</p>
<p>Unlike in the United States, where patients’ insurance covers the costs, the Australian taxpayer subsidises <a href="http://www.pbs.gov.au/pbs/home">drugs listed on the PBS</a>. In cases where new drugs are not subsidised, they’re paid for directly by patients, or by state-funded hospitals (often after approval by drug committees). They can also be provided free or subsidised by pharmaceutical companies for “compassionate use”. </p>
<h2>Blurred by emotion</h2>
<p>Decisions to subsidise drugs and improve their accessibility should be based on an assessment of their value. In Australia, for instance, the <a href="http://www.pbs.gov.au/info/industry/listing/participants/pbac">Pharmaceutical Benefits Advisory Committee</a> examines new drugs for effectiveness, safety and value for money compared to other treatments before recommending PBS listing – or not. </p>
<p>But the imperative to “save lives” or “beat cancer” — particularly where there’s vigorous public, professional and industry advocacy — can be so profound that it overwhelms the requirement that medicines should be efficacious and cost-effective. This tension between emotional and economic considerations frequently challenges and compromises public decision-making about the value of drugs. </p>
<p>Consider the case of eribulin (Halaven), a drug for treating advanced breast cancer. The UK <a href="https://www.nice.org.uk/about">National Institute for Health and Clinical Excellence</a> (NICE is the rough equivalent of PBAC although it has a broader role) considered the drug but rejected it as too expensive. </p>
<p><a href="http://www.economist.com/news/britain/21640343-well-meaning-gesture-causing-more-and-more-trouble-benign-or-malignant">Eribulin was subsequently covered</a> by the <a href="http://www.cancerresearchuk.org/about-cancer/cancers-in-general/cancer-questions/cancer-drugs-fund">UK Cancer Drugs Fund</a>, a pool of public money allocated to pay for drugs not approved via the usual route. The price accepted by the fund was among the highest in Europe for the drug; the price rejected by NICE had been the lowest. </p>
<p>Clearly, when standards of cost-effectiveness are reduced in the name of “improved access”, prices can rise arbitrarily. In most markets, supply and demand, competition and consumer choice curtail such arbitrary fluctuations in price. </p>
<p>But the market for innovative cancer drugs doesn’t follow this pattern because prices can increase dramatically even in “growing” markets, without clear reasons. In 2013, for example, a group of <a href="http://www.bloodjournal.org/content/121/22/4439">experts in chronic myeloid leukemia described</a> how the price of imatinib (Gleevec) increased three-fold over a decade. This happened even though all research and development costs were accounted for in the original price, and the number of people using the drug was dramatically increasing. Heightened demand alone cannot explain such an increase.</p>
<h2>What makes cancer drugs different</h2>
<p>Cancer drug markets clearly behave quite differently to what we might expect. There are three key reasons for this. </p>
<p>First, governments are creating a “price deregulation eco-system” for cancer drugs by establishing special funds that challenge accepted standards of value, and by curtailing the ability of payers to negotiate prices. The UK government has the Cancer Drugs Fund discussed above, while US legislation limits the ability of <a href="https://www.medicare.gov/">Medicare</a> – the US government’s health insurance program for people who are 65 and older and certain others –
<a href="http://ww_w.nejm.org/doi/full/10.1056/NEJMhpr0807774">to negotiate drug prices</a>. Laws in the latter country effectively force the health insurer to pay for cancer drugs used for a “medically accepted indication”, and prevent it from considering related cancer drugs as interchangeable. </p>
<p>In other words, US Medicare cannot make the call about whether the drug is worth its asking price, or negotiate prices based on cheaper available alternatives. The fact that the US pays the most for many drugs — including many cancer drugs — should therefore be no surprise. And if other countries are paying high prices for drugs, it makes it easier to justify these high prices elsewhere.</p>
<p>Second, there’s a lack of significant competition for many new cancer drugs. In an attempt to understand why South Korea paid so much less for drugs used to treat chronic myeloid leukemia — in some instances less than 20% of the US price — the <a href="http://www.bloodjournal.org/content/121/22/4439">same group of experts mentioned previously</a> noted the country had its own locally discovered drug for treating this disease. The price of competing products appeared to be based on this local drug’s price.</p>
<p>The lack of competition in the cancer drugs market is exacerbated by the rise of new “<a href="https://www.cornerstone.com/GetAttachment/4274a2ec-56b5-403f-af6d-022aae98b97a/Emerging-Competition-Issues-in-Biologics.pdf">biological agents</a>”, which are more difficult to replicate than small-molecule drugs, and <a href="http://healthaffairs.org/blog/2013/12/04/why-are-cancer-drugs-commonly-the-target-of-schemes-to-extend-patent-exclusivity/">by industry practices</a> aimed at extending the patent lives of existing products, thwarting generic competition.</p>
<p>Finally, markets in health care, including for high-cost cancer drugs, are powerfully influenced by existential and moral considerations — specifically fear of death and disability, and desire for greater quantity and quality of life. Cancer patients, their families and the oncologists who care for them are often willing to try drugs in the hope they will work, regardless of the price or prospect of benefit, which is frequently quite limited in the case of new, expensive cancer therapies. And as long as there are people willing to pay high prices or, as is usually the case, to demand subsidised access to cancer drugs, there’s no reason for the industry to reduce its prices.</p>
<p>Hope, fear and desperation, along with the unique characteristics of the cancer drug market, create a “perfect storm” that continues to drive up prices for cancer drugs. Unless we regain sight of the need to use regulatory incentives to reward only genuine innovation and ensure that we receive sufficient value for the money we spend on new medicines, this upward trend for cancer drug prices is set to continue. </p>
<p>The call by the <a href="http://www.reuters.com/article/2015/07/23/cancer-costs-protest-idUSL1N1022Y420150723">US oncologists</a> for patients to demand reductions in the price of the new drugs may be too much of an ask as these people have more to lose in this debate. It may also be too narrowly focused as it’s not just cancer patients but all of us who should demand the drugs we need at a price that our publicly funded health systems can afford.</p>
<p><strong>CORRECTION:</strong> <em>This article has been amended to reflect the fact that the PBS lists subsidised drugs, not the Therapeutic Goods Administration it said originally.</em></p><img src="https://counter.theconversation.com/content/44072/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Narcyz Ghinea receives funding from the National Health and Medical Research Council.</span></em></p><p class="fine-print"><em><span>Ian Kerridge receives funding from NHMRC for research into high cost drugs and for the study of conflicts of interest in medicine and science.</span></em></p><p class="fine-print"><em><span>Wendy Lipworth receives funding from the National Health and Medical Research Council. She is affiliated with the DIA..</span></em></p>Hope, fear, and desperation, along with the unique characteristics of the cancer drug market, create a “perfect storm” that continues to drive up prices for cancer drugs.Narcyz Ghinea, Research Associate, Centre for Values, Ethics and the Law in Medicine, University of SydneyIan Kerridge, Associate Professor in Bioethics & Director, Centre for Values and Ethics and the Law in Medicine, University of SydneyWendy Lipworth, Senior Research Fellow, Bioethics, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/395842015-04-01T14:08:37Z2015-04-01T14:08:37ZManifesto Check: Plaid Cymru wants more doctors, but do we need them?<figure><img src="https://images.theconversation.com/files/76795/original/image-20150401-31312-317bol.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Doctors will be asking: am I needed here?</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/cat.mhtml?lang=en&language=en&ref_site=photo&search_source=search_form&version=llv1&anyorall=all&safesearch=1&use_local_boost=1&searchterm=doctor&show_color_wheel=1&orient=&commercial_ok=&media_type=images&search_cat=&searchtermx=&photographer_name=&people_gender=&people_age=&people_ethnicity=&people_number=&color=&page=1&inline=130682090">from www.shutterstock.com</a></span></figcaption></figure><p><a href="http://www.partyof.wales/2015-manifesto/">Plaid Cymru’s plans</a> imply greater expenditure on the NHS in Wales – notably on more doctors, for air ambulances, and for the “New Medicines and Treatments Fund”. The expenditure increase is unlikely to be offset entirely by their pledge to move “towards a paperless NHS that will save money and bureaucracy”. This means additional funding will have to come from elsewhere, if Plaid Cymru’s ambitions are to be realised.</p>
<h2>Some standards, and a few novelties</h2>
<p>Plaid Cymru opposes privatisation of the NHS and wants to keep prescriptions free. The party promises to increase doctor numbers, and to improve quality of and access to care. The manifesto recites a familiar mantra of wanting care to be provided closer to home, improving integration of health and social care, and investing in eHealth and telemedicine. </p>
<p>But Plaid also offers distinct policies, such as easier access to “wellbeing facilities” to increase physical activity, supporting the <a href="http://www.alltrials.net">All Trials campaign</a> to underpin evidence-based medicine, and a “New Medicines and Treatments Fund for treatments not ordinarily available for patients in the NHS”. One concern is that the latter could prove similar to England’s <a href="http://www.bbc.co.uk/news/health-31507861">controversial Cancer Drugs Fund</a> which diverts money from other patient services. </p>
<p>Plaid Cymru also pledges to develop a workforce plan and National Cancer Plan and will propose a Medical Accountability Bill, “so that healthcare professionals are legally bound to tell the truth”, which is likely to prove challenging to enact and enforce.</p>
<h2>Improving staffing</h2>
<p>Plaid Cymru will develop a national workforce plan, claiming that Wales has fewer doctors than “any other country in the UK”. The number of hospital doctors <a href="http://gov.wales/docs/statistics/2015/150311-staff-directly-employed-nhs-30-september-2014-en.pdf">increased by 5.1% since the last election</a>, to 5,819 in 2014, while the number of general practitioners has remained virtually the same: there were 2,006 in 2014. This amounts to <a href="http://gov.wales/statistics-and-research/general-medical-practitioners/?lang=en">6.5 per 10,000 population</a> which is slightly lower than the ratio in England (6.6 per 10,000), but slightly higher than that in Northern Ireland (though data for 2014 are unavailable). The UK average is pulled up by Scotland, with a ratio of 8.1 per 10,000.</p>
<p>Plaid Cymru’s ambition is to increase Wales’ ratio to meet the UK average. But <a href="http://www.wales.nhs.uk/sitesplus/863/opendoc/190937">a major workforce review</a> published in 2012 claimed that “Wales is likely to have more than enough new GPs to both maintain its current GP workforce, and to continue historical rates of workforce growth” and that “Health Boards and Trusts anticipated maintaining a relatively static medical workforce during 2010- 2016”. So although Plaid Cymru promises to “train and recruit 1,000 additional doctors”, it has yet to demonstrate that so many more doctors are needed.</p>
<h2>Quality of care</h2>
<p>Having more staff might help arrest recent declines in the performance of the NHS in Wales. Plaid Cymru promise to implement a National Cancer Plan to provide access to specialist cancer nurses and to tackle “unacceptably long waiting times for diagnostic tests”. Despite the target maximum wait for access being eight weeks, over the course of the parliamentary term ever more people have been waiting longer than this, the number (proportion) increasing from 2,588 (5.6%) <a href="http://gov.wales/docs/statistics/2010/100708sdr1072010en.pdf">in May 2010</a> to 20,945 (29.5%) <a href="http://gov.wales/docs/statistics/2015/150312-nhs-diagnostic-therapy-services-waiting-times-january-2015-en.pdf">in January 2015</a>.</p>
<p>The party will also increase resources for ambulance (and air ambulance) services to tackle “undue delays”, the percentage of emergency responses at scene within 8 minutes falling from 64.8% in December 2011 to 51.2% <a href="https://statswales.wales.gov.uk/Catalogue/Health-and-Social-Care/NHS-Performance/Ambulance-Services/ambulancecallsandemergencyresponses-by-area-categoryofcall">in February 2015</a></p>
<h2>Public health</h2>
<p>The party supports plain packaging for cigarettes, though <a href="http://www.bbc.co.uk/news/health-31839859">MPs have already voted in favour of this</a>, and the devolved governments of Scotland, Wales, and Northern Ireland have <a href="http://www.cancerresearchuk.org/support-us/campaign-for-us/setting-the-standard-for-plain-cigarette-packaging">all passed legislative consent motions</a> to apply the changes. Plaid also promises to introduce a 50p minimum price per unit for alcohol, which the coalition Government <a href="http://www.parliament.uk/business/publications/research/briefing-papers/SN05021/alcohol-minimum-pricing">retreated from enacting</a>. </p>
<p>Legislative progress regarding sugar in food and drinks <a href="http://services.parliament.uk/bills/2014-15/sugarinfoodanddrinkstargetslabellingandadvertising.html">has stalled</a> but Plaid Cymru “supports a tax on sugary drinks and will work with manufacturers to reduce sugar in food and drink”.</p>
<p><em>The Conversation’s <a href="https://theconversation.com/uk/manifesto-check-2015">Manifesto Check</a> deploys academic expertise to scrutinise the parties’ plans.</em></p><img src="https://counter.theconversation.com/content/39584/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Street receives funding from receives funding from the National Institute of Health Research and the English Department of Health's Policy Research Programme, but this article reflects his own expert opinion. The Conversation's Manifesto Checks are produced in partnership with Nesta and the Alliance for Useful Evidence. </span></em></p>Plaid Cyrmu’s manifesto promises greater expenditure, but at what cost?Andrew Street, Professor, Centre for Health Economics, University of YorkLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/383822015-03-10T04:29:52Z2015-03-10T04:29:52ZHappy 50th anniversary to cisplatin, the drug that changed cancer treatment<figure><img src="https://images.theconversation.com/files/74251/original/image-20150310-13564-zowlv9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">This year marks the 50th anniversary of cisplatin's accidental discovery as an anticancer drug</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/fabcom/12640416043/sizes/o/">fabcom/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>This year marks the 50th anniversary of cisplatin’s accidental discovery as an anti-cancer drug. Despite its horrible side effects, and the ability of cancers to become resistant to it, the drug remains as relevant now as it was when it first reached the market. </p>
<p>And the good news is that the drug can, and is, being made better. New formulations are being designed to make it more effective and less toxic.</p>
<h2>The history of cisplatin</h2>
<p>The history of cisplatin starts not in 1965, but in 1844, when it was first created by Italian chemist <a href="http://www.technology.matthey.com/article/54/4/250-256/">Michele Peyrone</a>. For a long time it was known as Peyrone’s chloride. But the really important event was its accidental discovery as a cancer treatment by <a href="http://cancerres.aacrjournals.org/content/70/1/428.full">Barnett Rosenberg</a>, a biophysical chemist. </p>
<p>At the time, Rosenberg was trying to study the effect electric fields had on bacterial growth. During his experiments, he found bacteria grew 300 times their normal size, a very unusual result, when he used platinum electrodes to generate the electric fields. It took a while to figure out what was going on, but in the end he discovered the platinum electrodes were corroding in the test solution, producing cisplatin. </p>
<p>Rosenberg published his remarkable findings in the journal <a href="http://www.nature.com/nature/journal/v205/n4972/abs/205698a0.html">Nature</a> and followed this up three years later with <a href="http://www.nature.com/nature/journal/v222/n5191/abs/222385a0.html">another paper</a> showing cisplatin could cure tumours in mice. </p>
<p>Cisplatin has been used as a treatment for cancer since its approval by the US <a href="http://www.fda.gov">Food and Drug Administration</a> in 1978. And while five other platinum drugs based on the structure of cisplatin have been developed since, it has never been replaced.</p>
<p>Platinum drugs are now used in 40% of all chemotherapy treatments. This has completely changed how some cancers are treated. For instance, before cisplatin’s discovery <a href="http://tcrc.acor.org/chemo.html">the cure rate of testicular cancer was just 10%</a>, but when combined with early detection the cure rate is now approaching 100%.</p>
<h2>The good and the bad</h2>
<p>Cisplatin has to be given as an intravenous injection because it’s not effective when delivered orally. Once in the veins, it moves from the blood stream into cancer cells where it bonds with water to form a more reactive form of the drug. </p>
<p>In this form, the drug can stop DNA from replicating and from acting as a blueprint for making proteins. This causes cancer cells to recognise something is wrong and initiate a type of <a href="http://science.howstuffworks.com/life/cellular-microscopic/apoptosis.htm">cell suicide called apoptosis</a>.</p>
<p>But cisplatin is not without its problems. Its suite of horrible side effects includes severe nausea and vomiting. These two side effects are, in fact, so bad that the drug’s development was almost stopped when it was first tested on people. It was only the invention of effective anti-nausea drugs that led to cisplatin’s approval by drug authorities.</p>
<p>Cisplatin also makes patients anaemic and susceptible to infections. It destroys their kidneys too, although giving the patient lots of water before and after treatment has been found to be effective in reducing this.</p>
<p>Worse still, because these side effects are so severe, they limit the dose of the drug that can be given to patients. Many cancers end up getting treated with less than optimal doses as a result, which leads to tumours rapidly developing resistance to further treatment. This is a particular <a href="http://louisville.edu/faculty/jcstat01/recent-funding/mechanisms-of-cisplatin-resistance-in-ovarian-cancer.html">problem in the treatment of ovarian cancer</a> because it develops resistance faster than other types of cancer.</p>
<h2>The future of cisplatin</h2>
<p>But there’s good news on this front. Over the last two decades, many researchers, including my research team, have been developing new formulations of cisplatin in an effort to reduce its side effects. The best way to do this is through the use of <a href="http://www.sciencedaily.com/articles/n/nanoparticle.htm">nanoparticles</a> to better target cisplatin to cancer cells. Better targeting cancer drugs is important so they don’t attack non-cancerous tissue. </p>
<p>One such nanoparticle formulation being commercially developed is <a href="http://lipoplatin.com/">Lipoplatin</a>. This formulation encloses cisplatin in a shell called a <a href="http://www.news-medical.net/health/What-is-a-Liposome.aspx">liposome</a>, which is similar in structure to the walls of human cells. As a result, it floats in the bloodstream for longer and gets trapped selectively in tumours but not normal tissue. </p>
<p>And it doesn’t stop there. Novel nanoparticle formulations of cisplatin using exotic materials are also being developed, although these are much further away from being ready for human testing. To date, cisplatin has been attached to <a href="http://en.wikipedia.org/wiki/Carbon_nanotube">carbon nanotubes</a>, <a href="http://www.sigmaaldrich.com/materials-science/nanomaterials/gold-nanoparticles.html">gold nanoparticles</a> and even spaghetti ball-like polymers called <a href="http://en.wikipedia.org/wiki/Dendrimer">dendrimers</a>. </p>
<p>My team has also attached cisplatin to the outside of nanoparticles made of rust. Because rust contains iron, we could control the movement of the <a href="http://dx.doi.org/10.1016/j.ica.2012.05.012">nanoparticles with magnets</a>, ensuring the drug only goes to the sites in the body where it’s needed.</p>
<p>This drug has revolutionised the treatment of many types of cancer, especially testicular, and remains as critically important now as when it was first discovered. So happy 50th anniversary to cisplatin and good luck to all those working to make it better.</p><img src="https://counter.theconversation.com/content/38382/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Dr Wheate in the past has received funding from the ACT Cancer Council, Tenovus Scotland, Medical Research Scotland, Scottish Crucible and the Scottish Universities Life Sciences Alliance for research into platinum drugs. Dr Wheate is a named inventor on two international patents dealing with the drug delivery of platinum drugs.</span></em></p><p class="fine-print"><em><span>Michael Apps is completing a PhD involving platinum-based drugs and drug delivery vehicles.</span></em></p>Cancer drug cisplatin was accidentally discovered to help treat cancer in 1965. And it’s been doing exactly that since it was approved for use in 1978.Nial Wheate, Senior Lecturer in Pharmaceutical Chemistry, University of SydneyMichael Apps, PhD Candidate, University of SydneyLicensed as Creative Commons – attribution, no derivatives.