President Richard Nixon signs the 1971 National Cancer Act (photo: Linda Bartlett (Photographer) / National Cancer Institute, image in public domain)
The achievements of Vince DeVita and his colleagues in developing combination chemotherapy changed medical history. Not only that, they also played a major role in the passing in 1971 – after much politicking – of the US National Cancer Act, and in securing from the American federal government the increased research funding to support what became known as Richard Nixon’s War on Cancer.
Nixon had by this stage already told the nation: 'I will ask for an appropriation of an extra $100 million to launch an intensive campaign to find a cure for cancer, and I will ask later for whatever additional funds can effectively be used. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease. Let us make a total national commitment to achieve this goal.' Note the notion of 'a (single) cure for cancer', and the comparison with nuclear fission and the Apollo 11 moon landing.
DeVita also describes, in the chapter of the book titled ‘Boots on the Ground’ (more military terminology, see part one of this essay) how the increased funding was routed through the US National Cancer Institute in Bethesda (a suburb of Washington DC) and how the NCI Directorship was made a direct US presidential appointment.
However, DeVita explains that an attempt to wrestle the power of cancer drug approval away from the US Food and Drug Administration (FDA) and hand it over to the NCI proved unsuccessful. A good thing too in my view since having distinct governance procedures for the discovery and development of cancer drugs, on the one hand, and the regulatory approval of these drugs, on the other, provides an important separation of powers. More on the FDA later.
The success of combination chemotherapy in childhood leukaemia and in lymphomas discussed in the first part of this essay also led, according to DeVita, to the expansion of the NCI’s major preclinical drug screening effort (initiated as early as 1955), which was overseen by Gordon Zubrod within the Division of Cancer Treatment at the NCI.
DeVita emphasises the incredibly effective enabling role, in getting the National Cancer Act passed, of the impressively well-connected and dramatically coiffured socialite and philanthropist, Mary Lasker. However, Lasker was also responsible, according to DeVita, for spreading the word, repeated as a promise by Nixon to the US Congress, that the War on Cancer would result in 'cancer being cured' by 1976 – a mere five years after the signing of the bill into law.
DeVita states that this monstrously over-ambitious prediction (which Vince says he himself was not convinced about) was in fact a tactic – to get the Act passed, secure more funding for cancer research, and hence get the necessary 'boots on the ground' – rather than a belief that such a (single) 'cure' for all cancers was possible in that kind of timescale, or even if such a single magic bullet for cancer was conceivable at all.
But for all the best intentions, the claim was, nevertheless, hubris and hype – and although it was successful in gaining political commitment for massive federal funding, it also led to many unfortunate consequences when 1976 came around and 'cancer' was still not cured. And indeed the adverse repercussions continue to this day. This is an example of the perennial calculus of promise versus delivery. There is a lesson for us all here in managing expectations.
DeVita relates an extraordinary and hilarious example of Mary Lasker’s ability to touch hearts and open wallets. He recounts a tale of accompanying her to visit Senator and Vice President Hubert Humphrey – at which meeting, following a brief upbeat summary of cancer research by Vince, Lasker asks Humphrey directly for an astonishing $200 million over and above the already generous presidential budget. DeVita, having been warned by Mary beforehand of her imminent request, had indicated to her that he would not be able to think of ways to spend such a huge increase. Angered by his lack of imagination, Mary explained to Vince that since she usually got half of what she demanded, she was actually hoping for $100 million. As Lasker had predicted, the short conversation with Humphrey led to him picking up the phone on the spot and instructing staffers to pay the $100 million increase. As a way of getting research funding, this certainly beats writing a grant!
DeVita combined personal and team science successes in clinical cancer research with clear leadership abilities. He goes on to describe in the book – often with candid details about rivals, enemies and supporters – how, having joined the NCI in 1963 and in process avoiding the Vietnam War draft, he was then promoted through the NCI ranks. He first became Head of the Solid Tumour Service (1968), then Chief of the Medicine Branch (1971), Director of the Division of Cancer Treatment (1974), Clinical Director – and later overall Director of the entire NCI enterprise and head of the National Cancer Programme (1980-1988).
DeVita explains how he drove a hard bargain with the then NCI Director Dick Rauscher when Rauscher asked Vince to take over as Head of the Division of Cancer Treatment. DeVita insisted on the freedom to restructure the Division and bring all the extramural (external to the NCI) co-operative tumour groups as well as the intramural (internal) NCI programme under his sole direction – which he viewed as essential to make a real difference to cancer outcomes on a national level.
DeVita also modernised what was then a $100 million a year preclinical drug screening programme at the NCI. He shifted it away from dependence on the L1210 mouse leukaemia model – which as I described in part one had underpinned the clinical successes in childhood leukaemia and lymphoma – recognising that better models would be needed if progress was to be made against the common solid tumours which had very different and diverse biology.
In addition, DeVita reorganised the award of contracts and grants, reducing what he refers to as 'cronyism' in the contract system and supporting 'new and bright' researchers because he felt (I’m sure quite rightly) that the future of cancer research depended on them.
DeVita’s fascinating chapter in the book on his time as NCI Director, starting in 1980, is titled ‘Cleaning House at the National Cancer Institute’. One imagines DeVita’s road to progress being littered with the bodies of those who got in the way. Enemies were both internal within the NCI and also external – including notably Senator Edward Kennedy, with whom DeVita had several fallings-out.
But criticism works both ways. As described in a 1981 article in the US magazine People, as the high-profile Director of the NCI DeVita became 'the lightning rod for much of the criticism' of those (and they were many and varied) who protested against the lack of sufficient progress being made by the 'cancer establishment' in the War on Cancer. DeVita was described in the article as the 'bureaucracy’s point man in the drive to lick cancer – and the target of impatient critics'. There were accusations of mismanagement of billions of dollars of funding and of disregard for unorthodox approaches. At that time DeVita was quoted as saying: 'I hate the term War on Cancer. Biologists studying cells are not soldiers, and doctors helping patients through chemotherapy are not involved in some kind of My Lai' – referring to the infamous massacre in the Vietnam War in 1968.
It seems to me though that DeVita was and is anything but a standard bureaucrat – or if he had to be something of a bureaucrat as NCI Director he was a reluctant and feisty one. He comes over as a direct interventionist when needed and a street-fighter. Motivated he says to help save lives, in 1984 DeVita intervenes personally to help get published in The New England Journal of Medicine a landmark but at the time controversial research study by the legendary cancer surgeon Bernie Fisher. This research showed that there was no difference in survival outcome between the radical and disfiguring mastectomy operation and the more conservative lumpectomy for breast cancer. The paper was soon published.
And DeVita also tells how he took early action in 1987 to enshrine into clinical guidelines Fisher’s equally paradigm-shifting demonstration of the value of post-operative chemotherapy in the survival of breast cancer patients. Post-operative – also known as 'adjuvant' – chemotherapy was shown to have very clear benefits, even where the cancer cells appeared not to have spread.
Vince discusses how more personal criticism followed his interventions. And when on DeVita’s watch clear forward goals were published for cancer prevention and diagnosis for the period 1985-2000, further rebuke again came his way.
Even more controversy comes from Vince’s seemingly continuous and angry confrontations with the FDA. One of the rows described in the book concerned the criticism by the FDA of DeVita’s partnering of the NCI with the Kellogg Company to encourage uptake of a high-fibre diet aimed at preventing bowel cancer – by promoting the campaign on the backs of All-Bran breakfast cereal packets. FDA representatives threatened to clear the cereal packets from supermarket shelves and to serve a letter to get DeVita fired. Vince again won the fight.
DeVita devotes the whole of Chapter 8 – which he titles 'Frances Kelsey Syndrome' – to his trenchant criticism of FDA staff and their policies and actions. Frances Kelsey was hailed as the nation’s hero when, as a reviewer at the FDA, she blocked the approval of thalidomide in the US and requested additional safety studies. During the resulting delay, babies with severe limb abnormalities were born to women in other countries which had allowed taking the drug for morning sickness during pregnancy.
In fairness, DeVita recognises the benefit of Kelsey’s important role in the thalidomide story (interestingly thalidomide and new versions were subsequently approved for treatment of the bone marrow cancer multiple myeloma). And Vince also acknowledges the difficult job, between a rock and a hard place, that regulators like the FDA have in dealing with two totally incompatible demands. Firstly, from those who desire early, unfettered access to drugs, and secondly, from others who want the assurance of complete safety. But, despite the obvious benefit of the correct decision to be prudent, DeVita nevertheless sees the Kelsey thalidomide experience as a major contributor to the FDA becoming 'hypercautious in providing access to new drugs' and also excessively 'eager to regulate research and practice'.
DeVita goes on to cite several examples of what he sees as unacceptable delays in getting highly active drugs through to the cancer patients who need them. High among his concerns is that the FDA has, in his words, been 'mindlessly wedded to randomised controlled trials'. There is no doubt that large randomised trials can be very important – to allow benefit or otherwise to be shown over the current standard of care treatment. But inappropriate insistence on these, DeVita argues, led to a three-year delay before the widespead availability of the chemotherapy drug cisplatin – well known at the time to be highly effective in men with testicular cancer. The cisplatin instance also exemplifies another DeVita criticism of the FDA: not only, he argues, did the agency insist on inappropriate randomised trials but it also required that cisplatin be evaluated as a single agent – despite its likely use being in combination. Cisplatin was eventually approved by the FDA for testicular and ovarian cancer in 1978. It proved to play a major part in increasing the cure rate for testicular cancer, initially from 10% to 85% and now even higher.
DeVita provides as another, more contemporary example of what he sees as inappropriate regulatory delay – the case of the drug vemurafenib for lethal melanoma skin cancer. This breakthrough agent is one of the new breed of exciting molecularly targeted agents – of which more later. It works by blocking the effects of the protein product of the mutated BRAF oncogene – the structure and function of which was elucidated at the ICR. This mutation is the 'driver' in a high proportion of melanomas. It became clear around 2008 that vemurafenib was far more effective in causing tumour regression and extending survival – as well as being much better tolerated – than the weakly active and very toxic standard drug treatment dacarbazine. Despite this, according to DeVita, the FDA insisted on a trial comparing vemurafenib with dacarbazine. The trial was stopped after two years – and DeVita estimates a cost of $100 million – because the results were so clearly positive in favour of the new drug that it was unethical to continue the comparative study. Vemurafenib clearly showed improved survival in melanoma with the BRAF V600E mutation and became a standard of care for patients whose cancer harboured that mutation.
Rather ironically given his fights with the regulator, DeVita tells of how he was actually offered the job as the Director of the FDA. He turns down this poacher-turned-gamekeeper opportunity because he perceives the major structural and staff problems at the time as just too difficult to solve.
DeVita also relates how, when NCI Director, he was able to achieve some operational improvements in drug access from the FDA – but frustratingly this progress was subsequently overturned by Congress as part of legislative changes relating to HIV/AIDS drugs.
In addition to his withering criticism of what he sees as unnecessary trials, DeVita also criticises the FDA for holding up access to drugs on the basis of 'compassionate use', outside of the clinical trial setting. He cites what was a high-profile example of denial of access to another molecularly targeted agent, the antibody cetuximab. This was considered by physicians to be needed by a patient with head and neck cancer – a condition for which the drug is now approved. The resulting stand-off led to the creation of the Abigail Alliance for Better Access to Developmental Drugs, and several court cases and accompanying publicity.
A final example of what Vince sees as inappropriate refusal of drug access is that of DeVita’s friend Lee who was denied compassionate access to the prostate cancer drug abiraterone – which was designed and synthesised at the ICR and trialled with The Royal Marsden. Abiraterone was eventually made available through an expanded access scheme, two years before FDA approval in 2011 – but too late to help Lee.
Drug access and approval issues are incredibly complex and fraught with strongly held and often passionate views. They remain contentious in Europe as well as in the US. I have blogged on this subject and made several recommendations on how to speed up early access and accelerate approval. I agree with DeVita’s argument that over-reliance on the survival endpoint and restricted approval decisions are limiting the ability of innovative new drugs to show even greater value in earlier-stage, less drug-resistant cancer patients, and also when such drugs are subsequently included as part of combinations – both situations in which superior effectiveness can be expected and achieved.
We also now have the extra hurdle of cost-effectiveness analysis – by NICE in the UK and increasingly by healthcare systems worldwide, including in the US. Yet there is no doubt that healthcare costs are soaring and becoming unaffordable. Solving these challenges will require co-operative action by all participants in the ecosystem, including clinical doctors, academic scientists, regulators, government and companies – and indeed patients, families and society at large.
Of his time as NCI Director, speaking as ever very candidly, DeVita describes how the job 'when done right, [is] a crusher' – meaning I think an overwhelming and relentless pressure. And he says: 'From time to time I found myself mildly depressed.' At such times he was able to cope by making regular rounds to see patients on the cancer wards at the NCI. 'Rebuilding the NCI wasn’t a bureaucratic exercise,' he says. 'It was about saving lives.' More evidence of the reluctant bureaucrat I think.
DeVita goes on to relate how, after eight years as head of the NCI, he gets the call to be Physician-in-Chief at the prestigious Memorial Sloan Kettering Cancer Center in New York. He had become 'weary' of the NCI job, he relates, and especially of spending three months of each year 'preparing and testifying before Congress'. That must indeed have been gruelling for a passionate clinician and researcher. DeVita was also 'tired of the politics' and had concluded that government no longer saw cancer as a priority. He felt he had made his mark at the NCI and 'was done'. And he was also aware that after spending his whole career working for the government where salaries were low, a move would give him an opportunity to fund his retirement.
When he left the NCI, and to DeVita’s surprise, the Director of the National Institutes of Health described him as 'the best Institute Director NIH has ever had'.
Next time, in the third part of this essay, I will describe DeVita’s experience of 'where the rubber meets the road' as he moves out of the NCI to lead cancer research and treatment in other cancer institutions. I will also discuss the current status of the 'War on Cancer' and the latest 'moonshots' – looking especially at the impact of molecularly targeted therapies and the new immunotherapy drugs, and the potential of these if used creatively to meet the major challenge we face: that of the malign evolution of cancers to become resistant to treatment. And I will draw together some of the themes emerging from this three-part essay – and five decades of cancer research and treatment – into a contemporary synthesis, including the vision of long-term control and cure of cancer. I hope you’ll join me for that.