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The death of cancer? Part 3: Searching for cure or long-term control

In a special three-part essay, ICR Chief Executive Professor Paul Workman reflects on five decades of advances in cancer treatment – inspired by The Death of Cancer, an account by clinical research pioneer and ex-Director of the US National Cancer Institute Vincent DeVita. In part three, Professor Workman explores the transition from classical chemotherapy drugs to new molecularly targeted treatments and immunotherapy – and the prospects for long-term survival and cure. He also discusses the attitudes and language that animate the drive to defeat cancer.

A scientist at work

In 1988, after eight years in charge, Vince DeVita left his job as Director of the US National Cancer Institute (NCI) with the aim of making a further difference to national cancer outcomes by working at prestigious, independent institutions away from the nation’s capital. He refers to these independent centres as being ‘where rubber meets the road’. DeVita describes in candid detail – as elsewhere in his book, The Death of Cancer, written with his daughter Elizabeth DeVita-Raeburn – his challenges in attempting to bring about essential organisational changes in those earlier times at the Memorial Sloan Kettering Cancer Center and then at Yale University.

We see familiar age-old challenges. There are tensions and rivalries between the different professional groups competing for patients – and also between basic and translational/clinical researchers competing for funds. And tensions too between the modernisers urgently seeking better outcomes for patients based on research and the conservatives and traditionalists hanging on to the status quo.

Towards the end of the book in Chapter 10 – titled, like the book itself, ‘The Death of Cancer’ – DeVita comes back to the criticism of the War on Cancer, which clearly became seared on his soul. Not surprisingly since he was NCI Director during those difficult years.

He lists some of the higher-profile pieces of written criticism – of which the most well-known is probably journalist Clinton Leaf’s 2004 article in Fortune magazine and Leaf’s subsequent book, The Truth in Small Doses: Why We Are Losing the War on Cancer and How to Win It.

DeVita insists – and I agree with him – that the view that as a cancer community we have lost the War on Cancer is wrong. For example, figures for the UK show that overall cancer survival is now double what it was in the 1970s, with more than half of all cancer patients surviving 10 years or more.

On the other hand, survival in many cancers – such as those of the lung, pancreas, gullet and brain – is still very poor indeed. For example, the five-year survival for lung cancer in the UK is less than 10%.

The promises made by US President Richard Nixon, philanthropist Mary Lasker and others to get support for the US National Cancer Act undoubtedly underestimated the difficulty of treating more than 200 different cancers – with, as we now know, even greater genetic subdivisions. And the expectation of discovering what some perceived would be a single magic bullet cure for all these different cancers in five years was of course hopelessly ill-conceived. Medical and scientific challenges are always tough to crack and timescales for breakthroughs are extremely difficult to predict.

But while advances in survival may not have matched the unrealistic expectations of the War on Cancer, DeVita himself is in no doubt of the progress that has been made. He declares: ‘The evidence is clear: we are winning the War on Cancer!’

DeVita summarises very well the much greater understanding we now have of the fundamental molecular changes leading to cancer, including our extraordinary discoveries of the many genes and molecular mechanisms involved. These insights have come from basic, fundamental, blue-skies research that in fact benefited greatly from the increased funding allocated to the War on Cancer since 1971. Interestingly, DeVita hardly mentions basic discovery research earlier in the book – his own personal experience being firmly rooted in translational and clinical research. But he clearly believes that future therapies will arise from our dramatically improved comprehension of cancer biology, as well as through new technologies including genome sequencing.

I think DeVita is right in this analysis. It is remarkable that we have so many effective old-school chemotherapy drugs that were discovered during a time when we were essentially ignorant of the molecular and genetic basis of cancer cell biology. Indeed we still don’t understand why these cytotoxic drugs have the definite therapeutic window – albeit often a limited one – that they exhibit towards cancer compared with normal cells. And why, for example, childhood leukaemia, lymphoma and testicular cancer respond to cytotoxic chemotherapy so unusually well. Presumably the answer lies in the intricacies of the DNA damage response to chemo drugs.

Having made his own research reputation through improving cytotoxic chemotherapy – and particularly developing very effective and sometimes curative chemotherapy drug combinations – DeVita now enthuses about the new generation of molecularly targeted drugs. These next-generation treatments exploit our growing knowledge of cancer biology by attacking the molecular vulnerabilities and hallmarks of cancer.

Among his selected examples of the new generation of molecularly targeted agents, DeVita stresses the paradigm-shifting importance of the drug imatinib (also known as Gleevec), which has converted the previously fatal disease chronic myeloid leukaemia (CML) into a chronically managed condition. A very large number of patients have now been taking the oral pills containing imatinib (or its successors) continuously since its approval in 2002, gaining long-term survival benefit with minimal side-effects.

Imatinib works by counteracting the single genetic aberration that drives CML cells. This aberration is called the BCR-ABL translocation and it activates a biochemical switch mechanism that involves the so-called ‘kinase’ activity of the ABL part of the protein encoded by the BCR-ABL gene.

Alongside the impact of imatinib as probably the most effective agent in the new era of targeted therapies, De Vita also discusses the ICR’s abiraterone and another agent acting by a different mechanism, enzalutamide, which have moved the needle by extending survival in advanced prostate cancer through blockade of the drive provided by male hormones.

And he also talks about the exciting emerging promise of the new generation of immune therapies – precursors of which were pioneered in the early days by DeVita’s close friend and colleague at the NCI, Steve Rosenberg – with whom, together with radiation oncologist Sam Hellman, DeVita wrote numerous editions of the famous, enduring and comprehensive textbook Cancer: Principles and Practice of Oncology, of which I have a copy on my shelf.

As with drugs targeted to oncogene pathways, the recent clinical advances in immune treatment are founded on breakthroughs in fundamental research, starting with the discovery at the ICR by Jaques Miller of the function of the thymus, leading to his elucidation of the function of the two main subsets of lymphocytes, T cells and B cells. This research provided the fundamental basis for modern immunology and the immune therapies which are already approved and are showing great potential across different cancers.

As I read DeVita’s summary of the revolutionary transition from cytotoxic chemotherapy to personalised medicine, exploiting the genomic and other vulnerabilities of cancers, I reflected that my own scientific career path has spanned this transformation as well. I did my PhD at Leeds University in the 1970s on modified forms of the original nitrogen mustards that I discussed in the first part of this essay. The new form of mustards that I worked on, like the still widely used drugs melphalan and chorambucil before them, emerged from the work of Walter Ross, Tom Connors and colleagues at the ICR. While the active ‘warheads’ of these novel prototype drugs were still the same type of chemical, causing cancer cell death by DNA crosslinking, the new versions were designed as inert ‘pro-drugs’ that would undergo activation by enzymes that were present at high levels in certain tumours.

My PhD thesis research in fact revealed that the success of this particular approach was limited by the high levels of the activating enzymes that occur in the blood and certain normal tissues. But the underlying principle of selective pro-drug activation went on to be applied in subsequent therapies known as ADEPT and GDEPT – which relied in addition on delivery by antibodies and gene therapy – created by scientists including Caroline Springer and colleagues at the ICR.

My work with the nitrogen mustard prodrugs provided an excellent training which I put to good use at the Medical Research Council Oncology Unit in Cambridge University in the UK from the late 1970s to 1990 and during a brief sabbatical period at Stanford University in California – working on drugs targeted to exploit the low oxygen levels present in solid tumours. And in my subsequent work at the Cancer Research UK Beatson Laboratories in Glasgow, at AstraZeneca, in the biotech companies I have founded (Chroma Therapeutics and Piramed Pharma), and finally here at the ICR, I have concentrated my efforts on designing drugs to exploit the range of abnormal genetic and biological features of cancers – which I refer to as ‘drugging the cancer genome’. My focus now is on overcoming cancer evolution, heterogeneity and drug resistance as a strategic institutional as well as personal research goal.

Comparison of two drugs DeVita discusses – imatinib and abiraterone – emphasises the continuing importance of the phenomenon of drug resistance, which he mentions a number of times in the book. Resistance was in fact seen in the very first patients receiving nitrogen mustard in the 1940s and endures in all drug treatments to this day. It is less of a problem in CML because this is a relatively simple genetic disease – essentially a pre-cancer with only one key genetic abnormality, the BCR-ABL translocation. Prostate and most other cancers are genetically more deranged and complex, and as a consequence resistance develops more rapidly.

The mechanisms underlying resistance to cancer drugs are complicated in their details, although quite simple in principle. They involve feedback loops in the biochemical circuitry of cancer cells along with genetic instability and Darwinian evolution – leading to heterogeneous and resistant cell clones. Some of the key research discoveries on this evolutionary behaviour were made by Professor Mel Greaves and colleagues at the ICR. I have described this evolution of resistance as ‘the survival of the nastiest’.

I have discussed three ways that we at the ICR are seeking to overcome clonal evolution and resistance – which I believe is the major scientific and clinical challenge that we face. It is a challenge we need to tackle if we are to deliver the next level of impact on the long-term survival or cure of cancer patients in the future.

The solutions I have highlighted are:

  1. Drugging the many parts of the cancer genome that have not yet been addressed, including new classes of drug target in cancer gene networks.
  2. Discovering and implementing of the best drug combinations.
  3. Designing new ‘cancer network medicines’ that target more than one of the major cancer-causing mechanisms and attack multiple hallmarks of cancer, or which block the biological mechanism of evolution directly – one form of which may be a class of drug I have helped discover and develop known as Hsp90 inhibitors.

On the key subject of the future curability of otherwise of cancers, near the end of the book, DeVita makes the following comment: ‘I do, however, think that we’re heading for a time when we’ll be able to cure all cancers. And those we can’t cure readily will be converted to chronic, manageable diseases.’ There is an ongoing debate about whether we should be aiming for – and talking publicly about – cures for cancer, or whether it is more realistic to deliver chronic, long-term control. I think this difference is not simply semantic and is worth discussing further.

For some people with cancer the term ‘cure’ is a tremendously important one and carries with it not only the notion of living the full length of life they would have had without cancer – but also of being free of all cancer cells. For others with cancer, being offered a treatment regimen that will allow them to live with their cancer – such that they eventually die of another cause – can also be seen as a very acceptable outcome.

Managing cancer as a chronic disease in this way is probably more akin to the treatment of HIV than to the long-term treatment of high cholesterol, high blood pressure, arthritis or diabetes.

Cancer patients and families understandably value being given the ‘all clear’. In practice this effectively means that cancer cells cannot be detected, rather than necessarily that none are present in the body. And the word ‘cure’ is sometimes used to describe achievement of survival at, say, five or 10 years. Furthermore, the attractiveness or otherwise of chronic long-term management will relate to the side-effects of any ongoing treatment – as distinct from simply having a once-a-year follow-up.

In the end, how these terms are viewed by people with cancer will vary with the individual patient and the treatment options that may or may not be available for potential cure, chronic long-term management or palliation.

I would emphasise to the critics of cure-versus-control terminology, on each respective side, that:

  1. Aiming for cure does not necessarily mean hubris or hype, although care is needed in our language; and
  2. Aiming for long-term control does not mean lack of ambition to achieve eventual cure.

Furthermore, in terms of research strategies taken, I think there is unlikely to be a much difference: the same scientific approaches will generally be pursued whether the aim is enhancing long-term survival or achieving full ‘cure’. Enhancing long-term survival can be seen as a route to eventual cure.

It’s important though to have a healthy debate about this subject and I welcome readers’ views. We need to have a clear understanding of what cancer research is aiming to deliver, shared with the public, if we are to avoid the mismatch between expectations and achievements seen with the War in Cancer in 1970s and the subsequent adverse repercussions, as I discussed in the second part of this essay.  

A final thought I have on the cure-versus-chronic-treatment discussion is that this debate is also connected to a point I referred to in the firost part of this essay about the military language and metaphors used to describe cancer and its treatment.

In her 1978 book Illness as Metaphor, the author Susan Sontag criticises using metaphors that involve illnesses such as cancer and tuberculosis. And she is equally critical of using military metaphors to describe cancer itself. Sontag says for example: ‘With the patient’s body considered to be under attack (‘invasion’), the only treatment is counter-attack.’ And: ‘The controlling metaphors in descriptions of cancer are, in fact, drawn not from economics but from the language of warfare; every physician and every attentive patient is familiar with, if perhaps inured to, the military terminology.’ And again: ‘Treatment also has military flavour. Radiotherapy uses the metaphors of aerial warfare; patients are ‘bombarded’ with toxic rays.’

Sontag’s book has had its critics as well as its supporters. In fact, the use of military metaphors goes back as far as disease itself and was common in the 19th Century. This is exemplified by popularisation of the term ‘magic bullet’ (often applied to cancer) coined by the great scientific researcher Paul Ehrlich to describe his discovery in 1910 of the arsephenamine (Salvarsan) as the first effective treatment for syphilis – and still commonly used to describe the overall goal of targeted therapy. I was in fact inspired as a schoolboy by the successes in overcoming disease achieved by Ehrlich, Robert Koch, Louis Pasteur and other pioneers of drug and vaccine research  

I have talked to many oncologists and numerous people with cancer and their family members about the use of military language. Opinion is clearly divided. There is criticism that if we expect patients to fight against their cancer then the patient has somehow failed if they ‘lose the battle’. But it’s clear that some patients and their supporters do want to fight against cancer and find the concept fitting and helpful for them. I think in the end it comes down to individual choice.

Use of the language of battling and fighting cancer is common in the media, whether they are discussing members of the general public or the famous – as exemplified with the recent coverage of the death of rockstar David Bowie and many others.

Personally, and also generally at the ICR, we tend to avoid the most aggressive military language but we feel comfortable in stating that ‘our mission is to make the discoveries that defeat cancer’. Cancer Research UK talks about its ‘strategy to beat cancer sooner’. This sort of language seems to resonate well with the public.

I’ve been thinking about how I view this subject personally, prompted by reading The Death of Cancer. I don’t know exactly how I myself would react as a cancer patient. I can imagine a strong desire to try, first of all, the proven standard-of-care treatments – and then to explore experimental therapies where these had scientific underpinnings. And I might potentially conceptualise my experience as a fight. Equally well, I can imagine circumstances where the desire would be to maximise quality time with family and friends. Perhaps the ideal would be a treatment journey that allowed for both possibilities.

De Vita himself makes interesting further comments (Never Give Up) in this blog response to a review of The Death of Cancer in the Sunday New York Times Book Review.

It’s fascinating and informative that in DeVita’s book he makes it clear that his experience has been influenced not only by his scientific experience and his compassion towards cancer patients – with numerous examples provided – but also through his own recent personal experience of having prostate cancer, and by the illness and death of his young son who suffered from aplastic anaemia.

Describing his own journey with prostate cancer, DeVita reveals his fear of bad news and describes how he ignored his symptoms until his problem was revealed by complications following knee surgery, by which time the tumour was quite advanced. He seeks out the best physicians – as he relates doing often in helping many others – and undergoes surgery and radiotherapy at the Memorial Sloan Kettering Cancer Center, but he decides not at this stage to have hormone treatment or chemotherapy. He does not appear to refer to a personal ‘battle’.

In an extraordinary and touching section of the book, DeVita describes how his son Ted was diagnosed, aged nine years, with aplastic anaemia – a vicious disease where the bone marrow stops producing white blood cells and platelets. When standard treatment failed to work, the solution was to keep Ted in one of the sterile rooms that DeVita’s hero Jay Freireich had invented to protect leukaemic patients undergoing chemotherapy from infection. Extraordinarily, Ted survived in that sterile room for eight years, at which point in 1980 DeVita says they ‘lost the battle’. Remarkably, throughout his son’s illness, Ted was located one floor above DeVita in the same building where DeVita worked in the NIH Clinical Center – and his son’s window is visible above his left shoulder in the photograph taken to commemorate his time in office.

Returning to the subject of how to organise and fund cancer research, DeVita explains in the book how an effort was made in the US to launch in 1998 a new War on Cancer, underpinned by a modern cancer Act, developed through the formation of a broadly based ‘New Dialogue on Cancer’. But according to DeVita, this initiative was opposed by the incumbent NCI Director and fell victim in 2001 to politics and arguments between groups with vested interests, and also to the terrible distraction of 9/11.

De Vita surprised me a bit by calling for a Cancer Tzar to oversee all national budgets and strategies in the US. This suggestion is no doubt well intended and based on his experiences inside and then outside the NCI – but the role strikes me as potentially being a huge and difficult one to fill, and one that might arguably have too much centralised power. On the other hand and at the same time, DeVita also calls for the greater delegation of authority for clinical trials to individual free-standing cancer centres – and even harks back to the discussion forum known as the Society of Jabbering Idiots that so influenced him in his early days at the NCI. There is a balance to be struck I think between these two extremes – that is between strong central organisation and co-ordination, and the freedom for individual centres (and indeed individual scientists and clinicians) to be creative and innovative.

History repeated itself on the War in Cancer when in 2003, Andrew von Eschenbach, as NCI Director, issued a challenge ‘to eliminate the suffering and death from cancer, and to do so by 2015’. Although this was viewed as well-intentioned and received some support, many scientists felt that this goal was, again, impossible to achieve.

And just recently, in his State of the Union speech, current US President Barack Obama stated: ‘… last year, Vice President Biden said that, with a new ‘moonshot’, America can cure cancer. Last month, he worked with this Congress to give scientists at the National Institutes of Health the strongest resources that they’ve had in over a decade. Well, so tonight, I’m announcing a new national effort to get it done. And because he’s gone to the mat for all of us on so many issues over the past 40 years, I’m putting Joe in charge of mission control. For the loved ones we’ve all lost, for the families that we can still save, let’s make America the country that cures cancer once and for all. What do you think? Let’s make it happen.’

Biden, in turn, made important points when he said: ‘Over the next year, I will lead a dedicated, combined effort by governments, private industry, researchers, physicians, patients, and philanthropies to target investment, coordinate across silos, and increase access to information for everyone in the cancer community.’.

Overall, the reception to the new moonshot proposals has been mixed, with both support and criticism – such as these comments, for example.

Some critics dislike the moonshot analogy. A consistent concern is that, although formidably challenging technically, putting a man on the moon was really a feat of engineering – and engineering is very different from biomedical research where there are many more uncertainties and unknowns, the discoveries we need to make are difficult or impossible to predict, and the time-scales for success are very hard to estimate. And furthermore the complexities of cancer – especially clonal evolution, cancer heterogeneity and drug resistance – are especially challenging.

Moreover, eradicating all cancer will not just require the research to find cures, including effective combinatorial therapies and almost certainly including immunotherapy, but also the political will, organisation and resources to make new treatments available to all people with cancer. Indeed Biden recognises this when he says: ‘It’s not just about developing game-changing treatments – it’s about delivering them to those who need them.’

There are some similarities between the proposed moonshot proposals of today and the War on Cancer in 1971 – with talk about curing cancer once and for all, for example. I think the main lesson from history is that we need to be very careful in our language, but open and transparent within the professional community as well as in our dialogue with politicians and the public.

I do think that that we should be ambitious in our goals for achieving transformational breakthroughs in research, by pursuing excellence and a range of new exciting ideas – and also equally ambitious in seeking real impact on the lives of people with cancer. But we need also to be careful and transparent in discussing with the public how science and medicine really work, and not make promises that cannot be delivered.

I personally am comfortable arguing for more resources and national and global efforts with which we can make the discoveries that defeat cancer – through a combination of fundamental, basic research, bench-to bedside translational research, clinical research and excellent and affordable cancer care.

I think a healthy balance is needed between large strategic projects that involve for example international, often multidisciplinary collaborations and team science – especially perhaps those with a technology delivery focus – and the smaller bottom-up projects that will occasionally throw up the unexpected new breakthrough.

Outside of the US, other nations and organisations are considering and developing strategic policies, some of which may be far-reaching and share elements of the War on Cancer. The World Oncology Forum for example has developed recommendations that I have contributed to. These proposals aim to balance the dichotomy of expensive state-of-the-art research, treatment and healthcare in the wealthier nations with the realities of delivering basic treatment in poorer countries, including the quite appropriate current focus on the importance of prevention.

In the UK we have important national initiatives such as the Cancer Task Force which has produced its report Achieving world-class cancer outcomes: a strategy for England 2015-2020. This features a series of important recommendations which must now be delivered on, including early and accurate diagnosis as well as new treatments.

And following the highly successful Human Genome Project, and alongside genome-sequencing and related initiatives such as the Cancer Genome Project, the Cancer Genome Atlas and the International Cancer Genome Consortium, the UK Government has established the 100,000 Genomes Project aimed at creating a new genomic medicine service within the National Health Service – to support better diagnosis and better treatments for patients – as well as enabling medical research.

In the week that I finished writing this essay, the UK Times newspaper published a leader article that finished with the words: ‘The death of cancer may have been exaggerated, but the war on cancer is unmistakably being won.’

This is an extraordinary time when we can sequence cancer genomes for less than $1,000 and follow our progress in health and disease with smartphones and wearable devices. And yet inequalities in healthcare are such that vast numbers of patients around the world are deprived of access to even quite basic cancer treatments – because of poverty. Indeed there are unacceptable inequalities of access and outcomes even in wealthy nations.

Furthermore, this is a time when despite the clear and widely disseminated knowledge that the risk of many cancers can be reduced by taking in fewer calories, drinking less alcohol, taking more exercise and quitting smoking, many of us choose to disregard this advice – seemingly in the hope that a pill will be found to treat cancer when it arises.

Tackling prevention and early diagnosis are as important as finding new cures for established cancers.

Having read The Death of Cancer and been inspired by it to write this three-part essay, it is clear to me that it is an extraordinarily powerful personal memoir – albeit with a strong NCI and US focus – of a man who can truly be described as a warrior against cancer. It is a professional biography of Vince DeVita and his views about, and from, the NCI, yet it also opens up for debate the key issues and challenges that we all face in cancer research and treatment, and discusses some potential solutions to these.

As I finished reading the book, I reflected that much of DeVita’s views on cancer research and treatment must surely have been formed in the heady days when he, along with Frei, Freireich and colleagues, succeeded in changing the world by curing childhood leukaemia and Hodgkin lymphoma. This was certainly a time when there seemed, at the NCI, to be a buccaneering, never-say-die spirit; where rules were there to be broken, barriers torn down and those who stood in the way of progress removed. The extent to which it is possible or desirable to recapture exactly that spirit today is debatable – but there are lessons to be learned I think, particularly about stimulating creativity and innovation while encouraging collaboration and team science.

One aspect that I feel is somewhat neglected in the book is the importance of encouraging partnership between academia and industry. This must be an important part of the solution, not only for discovering and developing drugs, but also getting them approved for widespread use.

The Death of Cancer is different from, but certainly as riveting as, Siddhartha Mukkerjee’s equally enthralling but broader-scope and less personal 2011 book The Emperor of all Maladies. Reading both together will I think make the reader ponder where cancer research and treatment have come from and where the field should be heading. They certainly gave me pause for thought and reflection.

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