Personalized Medicine for Sarcomas:
Have We Lost Perspective?
Medicine is surprisingly prone to fads. In cancer, the fad-du-jour is 'personalized' medicine. The term, like translational medicine, means many things at once. According to Wikipedia, personalized medicine means individualization of management of cancer, based particularly on molecular and genetic information about each person's cancer. In practice, personalizing cancer treatment is taken to mean the selection of cancer therapies on the basis of the tumor's genetic profile.
How does the concept of personalized medicine work? In the 1970s, Peter Nowell proposed that cancer is a clonal, genetic disease,1 driven by the progressive accumulation of mutations and chemical modifications in the DNA of cells, the collective effect of which is the pathological growth we know as cancer. The 'addiction' of cancer cells to the mutations in specific genes has led to the idea that targeting these genes represents a logical therapeutic strategy. Since each tumor has its own pattern of mutations, testing the tumor for its mutation content provides a basis for selecting the right drug for each patient. The successes of imatinib in two types of sarcoma, gastrointestinal stromal tumor and dermatofibrosarcoma protuberans,2,3 have been the poster children for the concept of using the mutation profile of a solid organ cancer to select the appropriate therapy—so called 'targeted' therapy.
An extraordinary amount of hope has been invested in this idea, supported by dozens of statements from the peak bodies representing researchers and clinicians globally. In turn, the biotechnology sector and the pharmaceutical industry are investing more than hope in 'personalized' medicine, for obvious reasons.
An unfortunate effect of exuberant enthusiasm is loss of perspective, something that is becoming increasingly apparent as the wave of excitement gives way to reality. In the remainder of this article, I would like to draw attention to some of those realities.
The first of these is the fact that these treatments rarely result in cure. For the most part, the focus has been on advanced cancers, for many of which there are no obvious standard treatments. Targeted therapies in many cases may control disease for weeks, rather than months. They often do not work at all, despite being matched to the relevant mutation. Even when a suitable mutation is identified, treatments are rarely readily accessible. They are increasingly recognized to carry side-effects in some cases comparable to our older chemotherapies. And they are costly.4
What about costs? In a series of recent papers in eminent clinical cancer journals, the costs of health care are increasingly becoming of concern. In publicly funded health systems, the costs must be divided amongst the many priorities for the common wealth, including other health conditions; while in privately funded health care systems, access to ideal health care has become a privilege, not a right. To make wise decisions along these lines, we need information we simply do not have. For example, how do we decide whether a prolongation of survival for 6 weeks on a targeted therapy, without any impact on overall survival, represents a better investment than reducing obesity? The metrics we typically use in clinical trials (response rates, relapse-free and overall survival) are simply not interoperable with other health states, let alone education, defense, and so on.
Is this important? A recent estimate suggested that over 60% of personal bankruptcies in the US were contributed to by health care costs; while 20% of the current US national debt (or 2.65 trillion US dollars) could have been saved over the past 30 years if health care had been based on a different model.5
Returning to cancer itself, the focus on targeted therapies comes at a different cost. Targeted therapies are focused on only one fragment of the cancer journey—advanced disease—comprising a fraction of those affected by cancer. This is the case for many reasons, both good and bad. However, clearly the cancer journey extends much more broadly. Beginning before a cancer is detected, it passes through diagnosis, initial curative therapy, and then relapse, palliative therapy or survivorship. It is arguable that the opportunities for increasing cancer survival are greatest at earlier stages in the cancer journey, when surgery is curative. Do we need reminding that, for the foreseeable future, surgery will remain critical to cure most solid organ cancers? For reasons that are unclear, the public health, screening and prevention opportunities of personalized medicine appear under-represented in the current debate. Put simply, a stitch in time saves nine.
But there are even more compelling reasons for doubt. Many excellent guidelines for sarcoma have been generated in centres of excellence in Europe and North America. Virtually none acknowledge the appalling gap between theory and practice that applies in most parts of the world. It is an important responsibility for the global community that we acknowledge this irony. The Asia-Pacific alone, with more than 4 billion people in almost 30 countries, is likely to contribute an annual incidence of 200,000 sarcoma cases. Chronic malaria, a hemoglobin of 2, human immunodeficiency virus, chronic hepatitis, no histology and rudimentary surgical resources, social unrest, poor roads and individual poverty mean that a twenty-five year old with osteosarcoma in Papua New Guinea in 2013 remains incurable. Moreover, even opiates to ease her death may be inaccessible. In developed countries, recommendations are for molecular testing and therapies that extend survival by a matter of weeks,6 while for the majority of people affected by sarcoma globally survival is a function of more basic aspects of society.
Like sport and art, science is measured by the high-water mark of its achievements. We don't remember the workers who built Versailles, or the hypotheses that failed before Watson, Crick, Franklin and Wilkins identified the structure of DNA. But medicine is different: In medicine, we should be concerned with those we leave behind. In all of the hype about what we have achieved in rare situations at enormous cost, we should not forget the work to be done in ensuring that as many as possible are carried along with the tide, and we need to consider the implications of health care within and beyond national boundaries. For this discussion, a broader debate will be critical, a debate that includes public health experts, ethicists, health economists, cancer geneticists, molecular geneticists and clinical triallists, those in the pharmaceutical industry and the biotechnology sector, and colleagues in more constrained resource settings, where simpler and more immediate ways of improving survival may be lying in wait and ready to be noticed.4
Comments and Responses
Dr. Thomas responds to Dr. Orentas:
I certainly agree with Dr. Orentas that undertaking genomic analyses is a critical part of cancer research. I also agree with Dr. Orentas that genomic technologies put the patient at the centre of cancer research. This alone is a major advance over the use of surrogate experimental systems, such as mouse models, which differ in many important ways from man.
A separate issue is whether genomic analyses are yet ready for standard of care, or direct-to-consumer marketing, is a topic of hot debate currently. The FDA recently withdrew marketing approval for one such direct-to-consumer genetic test (23andMe) on the basis that the company had failed to meet regulatory requirements, specifically with respect to the accuracy of the test. In addition, many are concerned that there is inadequate counselling available for people undergoing multi-gene panel testing for cancer risk (Multiple Genetic Testing for Cancer Susceptibility: Out on the High Wire without a Net. Domcheck et al., JCO, 2013:1267-1270).
While I believe strongly in the power of research to improve health outcomes, I also believe that genomic medicine is firmly the province of research, and will be for some time to come. What we need is more research--or to put it another way: research should be synonymous with best practice.
Rimas Orentas, PhD writes:
As a researcher, I would like to share that genomics (including next generation sequencing, and epigenetic studies) is highly important. And while an individual patient may not benefit in "real time," it is through these new approaches that we will begin to understand why a certain "type" of disease responds to a particular therapy and another does not. I say "type" because we do not yet know the subtypes of sarcoma that we will able to classify based on these studies. Our own studies in immunotherapy show that the tumor stroma (surrounding supportive tissues, vasculature, and immune cells-both immature and suppressive types) make a huge impact on outcome, and yet we don't yet have a way to classify different stromal subtypes in sarcoma. Currently a pathological approach to define the cell types present in tumor lesions is making such advances in certain adult malignancies (for example the Immuoscore approach supported by the SITC, Galon, G., et al., J of Transl Med, 10:1, 2012). The ability to make these types of advances will depend on the kindness, the generosity and, yes, the hope that patients have as they consent to genomic analysis, usually under the aegis of personalized therapy. It is pateints' combined willingness to:
a) shoot for the moon and find a treatable, albeit often rare, "druggable" target, and
b) contribute to the field as a whole by consenting to general genomic analysis that will keep advances in sarcoma treatment coming.
Best Regards,
Rimas Orentas, PhD
Pediatric Oncology Branch, National Cancer Institute
Dr. Thomas responds to Dr. Fletcher:
Dr. Fletcher picks up on some important new themes implicit in this discussion. One that deserves consideration is whether a focus on optimism, whether rational or not, can detract from good care. It is arguable that the transition from active anti-cancer treatment to palliative care is extremely difficult, for none more than those affected by cancer. In my experience, the last phases of each person's cancer journey are critical to the notion of a well-lived life. The tasks of the last months of life may include reconciliation, achieving important personal goals, spending time with loved family and friends, and saying good-bye. Sometimes, undue faith in science can lead people, at this critical point in their lives, to leave their families and friends, to travel long distances to strange cities, and to undergo treatments and investigations whose value is debatable and whose probability of success is marginal. What price hope? Of course, the transitions from a focus on the cancer to a focus on the person is one that can only be made by each person, with the support of her family and her physician. Moreover, hope is essential to purpose in life. The question is not whether hope is important, it is when the focus of that hope shifts from the cancer, to the person affected by cancer.
Dr. Christopher D.M. Fletcher writes:
As a thoughtful, caring sarcoma oncologist and researcher, David Thomas is honestly raising an important issue.
We are growing into a society, once only evident in the USA, in which reality is denied and fantasy or false hope are promoted - which usually profits someone, most often a less scrupulous company that promises to find a treatable target or else the pharmaceutical industry. The first molecularly targeted therapy, imatinib mesylate (Gleevec), now more than 10 years old, has proved to be by far the most successful to date - and patients with GIST and chronic myeloid leukemia are living significantly longer and undeniably better quality lives than had been possible previously.
None of the subsequent targeted (personalised) therapies come close, as yet - although a subset of lung cancer and melanoma patients now live some months (occasionally a year or more) longer at great expense, which should never realistically be borne by any socially responsible healthcare system. We simply do not have effective therapies for most of the "targets' (mutations) that we can presently identify - meanwhile the "target identifiers", who epitomise personalised medicine, many of whom are commercial, are charging substantial sums - with no clearly demonstrated benefit to patients.
At the same time, we have people, even in industrialised/developed countries, without access to health care, we spend huge amounts of money on treating the consequences of smoking and obesity (which are largely preventable) - and we pretend to people that keeping them alive for a few more months is worth hundreds of thousands of dollars. To offer false hope has nothing to do with being a doctor - one may as well be the fortune teller at the fair who takes no responsibility for reading the crystal ball and taking your cash. All of our lives are finite - that is not in question - it is a doctor's responsibility to make clear to patients when that time is coming to an end.
That's not paternalism – it is kindness and allows patients and their families to decide how best to spend that time. Running between specialist cancer centers, whether in your own country or around the world, looking for a (non-existent) miracle does not usually bring happiness or a comfortable death - it simply adds needless distress and unjustifiably ridiculous (yes, ridiculous) expense. As fellow human beings on this planet, with finite financial (and therapeutic) resources, we need to decide whether the needs of the (self-focused) individual or the needs of broader society should prevail.
As doctors, we need to do a more honest job of acknowledging when our ability to help is limited - and of course we should all hope that more effective therapies will emerge over time. I happily, willingly and even passionately commit most of my waking hours to trying to help patients with soft tissue tumors, both malignant and benign - but modern cancer care is sometimes an embarrassment to me - and more thoughtful (and self-critical) medical oncologists like David Thomas will only make the world (and a patient's journey) better than it is now.
I recognise that what I (and David) have to say is neither welcome nor fashionable - and may cause distress - but, when facing the harsh realities of our human condition, I firmly believe that honesty is paramount.
Christopher D.M. Fletcher, MD, FRCPath
Professor and Vice-Chair, Anatomic Pathology
Brigham & Women's Hospital in Boston, MA
Dr. Thomas responds to initial feedback about this piece:
I would like to follow up on several emails that I have received from individuals affected by sarcoma following my discussion piece on personalised medicine. I am grateful for these letters that carry passion for research into sarcomas and targeted therapies.
I would like to clarify my purpose in what I intended to be stimulus for discussion. I don't believe that molecularly targeted therapies have no place in the treatment of cancer, and I recognise and celebrate the benefit of these drugs to many people. Perhaps thousands of lives have been significantly improved by targeted therapies to date. It is ironic to think that my professional life has been devoted to research into and the treatment of sarcomas, including targeted therapies and genomics! Far from being fatalistic, I believe we have a remarkable range of opportunities in the era of genomic medicine that affect all stages of the cancer journey and may particularly benefit those suffering from rare diseases like sarcoma.
The proposition I wished to discuss in this piece was whether a focus on these drugs was not obscuring wider and perhaps more effective opportunities for lessening the impact of cancer. The debate has been too narrow to this point, and I don't want to replace personalised medicine so much as to add other perspectives to it. At the least, I think this is worth discussion.
As to the issue of money: I think it is increasingly clear that there are costs to cancer care. The recent global financial crisis reminds us of the consequences of a failure of fiscal prudence. These consequences not only impact upon more mundane aspects of life, but also directly upon research into cancer. Please don't take my word for this. Those tasked with thinking about cancer globally are increasingly raising this issue in our most eminent forums: the New England Journal of Medicine, the Journal of Clinical Oncology, Lancet Oncology and so forth.
On a separate note, I wanted to reflect on personalised medicine in a broader context. Having recently travelled to Papua, New Guinea, to vaccinate young women against papilloma virus-induced cervical cancer, the leading cause of cancer death in women from 20-40 years of age, I am personally struck by the massive burden of preventable and untreated cancer in the billions who live outside the first world. Again, this is not an argument to stop molecularly targeted research, but causes me to wonder how the Western concept of personalised medicine applies to the majority of the planet.
All of which is not to give in! It is because resources are inherently limited, that we need to question our assumptions to make sure we are true to our course: to alleviate the suffering sarcomas bring, and to improve survival.
To finish, let me again thank all who have written in for sharing their stories with us, and remind us of the great good that has been achieved so far.
Chris writes:
I am not a doctor, so my opinion may not be valued or welcomed, however I feel compelled to write it anyway. There has been little successful research or even hope in the areas of sarcomas, as you better then anyone knows, Bruce. This treatment approach give us all HOPE. Our only treatment options have been: cut it out, burn it out or poison it, with hope that we will live through the treatment before we die from the treatment killing our liver.
I'm sorry but this article made me think of, "Just let us all die. It's too expensive." I understand the money issue, but bot my daughter and I have two different rare and aggressive forms of cancer. I was diagnosed with uterine leiomyosarcoma and my daughter ocular melanoma, orphan cancers that have little research and no cures. We are both doing well, but if these cancer cells go on the run, what options do we have? This new research at least gave us and others HOPE, which is what keeps us from going off a deep end.Darla writes:
I am responding to the article that Dr. Thomas wrote about targeted treatments. I and my family have benefited greatly from them. Gleevec truly saved my life, and even though it is expensive, it has kept me going for seven years. I have earned a living, attended my daughter's wedding, saw my grandson born and have formed a close bond with him. It hasn't been all smooth sailing, but the good does outweigh the bad by far. I intend to keep fighting cancer as long as I can. I realize that one day I will die of either the cancer or its side effects. I also realize that one day I may need to decide it is time to stop treatment and let nature take its course. But that day is a long way off.
I keep fighting for two reasons: my family and the other GIST patients. If the doctors can learn from my experiences and help fellow cancer buddies, and perhaps future cancer patients, then I owe it to the world to fight on. I don't think that the good doctor could disagree with this, and perhaps that was not what he wanted to convey. One disease is not more important that the other, but sarcoma research is on fire right now, let's keep going!Rich writes:
I'm sorry sir, but targeted therapy does save lives. Without it I would not be alive today. No I am not cured, but I am alive for several extra years now. Wouldn't it be wonderful if we got to a point where the lab analyzes one's mutation types and prescribes a drug cocktail to extend your life! You can read my story about my BRAF V600e GIST mutation.
Mary writes:
I read with great interest the letter submitted by Dr. Thomas, primarily as a nurse practitioner who has traveled to Haiti before and after the earthquake, but also as the wife of a GIST "thriver." I know that my husband's metastatic disease or the side effects of his disease may ultimately cause his early death. But, I do hold great hope that some of the world's researchers will discover the next targeted therapy or find the cause of this cancer. I disagree with your opinion that we should rethink or forego spending our health care dollars on targeted therapies.
As one who spends time abroad helping build capacity in other countries, my husband's stable disease (in months not weeks) allows me to continue this global volunteer work. Furthermore, his ability to maintain current stable disease with his medication allows him to work and stall disability applications as we continue to save money so we can fully pay our high school son's college, without requesting precious scholarship money that can be used by others. This miracle drug may not save him, but it offers our family quality and productive time so we can continue to contribute in real dollars to tackle global health problems. In addition, our daughter recently graduated in global health from a top 10 university and is now is an obesity research associate with a pending publication on pediatric obesity and will be applying to medical school. Her plans may have been thwarted had my husband's disease progressed and not allowed her to pursue her early career plans.
In the early years of HIV, the research process was expensive and urgent, but the results of this research yielded stability for HIV patients around the world in places where resource limitations would not have allowed so many children to have parents and wage earners. The impact of HIV research is seen in Haiti where health care dollars are extremely limited and we have the resource able countries to thank.
I also found this recent topic quite interesting because of its incredible impact on children around the world. The animal study, published in the journal Cell, also sheds light on the molecular mechanism of folic acid (also known as folate) during development. Researchers from the universities of Calgary and Cambridge, UK, have discovered that a mutation in a gene necessary for the metabolism of folic acid not only impacts immediate offspring but can also have detrimental health effects, such as spina bifida and heart abnormalities, on subsequent generations.
I believe a dual prong approach is best in which parts of the world capable of continuing a search to learn about unique diseases or conditions more at the genetic molecular level should continue while we tackle high impact disease and conditions such as unattended births, malaria, obesity, and other ailments related to poverty and malnutrition. With both parallels working in tandem can we share our knowledge and efforts on a global stage to help all our brothers and sisters.
V11N1 ESUN. Copyright © 2014 Liddy Shriver Sarcoma Initiative.