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04
Feb
2016

The death of cancer? Part 1: the birth of effective drug therapy

In a special, three-part essay to mark World Cancer Day, ICR Chief Executive Professor Paul Workman reflects on five decades of advances in cancer treatment – inspired by The Death of Cancer, an account by early pioneer Vincent DeVita. In part one, Professor Workman discusses the early days of chemotherapy.

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Over the festive holiday period I very much enjoyed reading The Death of Cancer – a personal memoir by the hugely experienced cancer scientist, clinician, research leader and administrator, Vincent DeVita, co-written with his talented science writer daughter Elizabeth DeVita-Raeburn. My three-part essay reflects on the book and the subjects it covers – exploring the profound broader implications and often my own views as well.

Even before opening the book, I confess to being concerned about its title, especially lacking the question mark that I have given it in this essay’s subject. Some would see the title as overly optimistic, controversial or even hubristic – if not personally on behalf of the authors then for a field that has certainly made great progress in the last 50 years, but equally has surely not yet delivered on its full potential or on the promises made.

Others will worry that the title represents a continuation of the use of military metaphors in cancer – and indeed many are repeated throughout the book, including the infamous phrase ‘war on cancer’. They would argue that such language is inappropriate, out of date and strongly disliked by many (but very far from all) people with cancer along with their families, allies and advocates.

And yet, there will be others who would admire the positivity and defiance of this book’s title. Indeed there is a subtitle that reads: ‘After 50 years on the front lines of medicine, a pioneering oncologist reveals why the war on cancer is winnable – and how we can get there.’

You can get a sense from this interesting set of quotes about cancer of the range of views that different people hold. 

Regardless of your opinion on the use of military metaphors (I will return to this later) I recommend persevering beyond the title as there is much to learn and admire – as well as most probably to annoy and irritate. For this is a deeply individual, very frank and highly readable history, written by a man who should know what he is talking about, has much to say and speaks straight from the shoulder.

It is very much about one man’s personal journey through cancer research and treatment – and yet addresses the big questions that we still face today, scientifically, clinically and politically.

DeVita, now 80 years’ old and still very active in oncology, was during the 1960s a clinical trainee and junior clinical researcher at the US National Cancer Institute (NCI) in Bethesda, Maryland – close to Washington DC. He rapidly became a major participant during an extraordinary period in history (the 1960s and 70s) when the first major inroads were made into the treatment of cancer with drugs.

Previously, the principal successful treatments involved surgery and radiotherapy – often very successful but also, as DeVita tells us, at that time really quite primitive and often causing severe side-effects. And of course these local treatments are mostly ineffective when cancer has spread (metastasised) around the body. DeVita initially witnessed, and then became a major contributor to, the development of the first successful, curative chemotherapy regimens that required administration of drugs in various combinations. These drug cocktails were assembled upon a backbone of old school cytotoxic agents (not the modern targeted drugs), which showed definite but limited benefit when given alone and yet at the same time induced severe toxicities. Such treatments, still widely used today, are often referred to collectively as ‘chemo’ and the early practitioners were described as ‘chemotherapists’.

Vince DeVita not only devised and implemented some of the first curative combination treatments for solid cancers but went on to become the overall Director of the NCI, then Physician-in-Chief at Memorial Sloan Kettering Cancer Center in New York and subsequently Director of the Yale Cancer Center in New Haven – a serious CV of impressive accomplishment.

DeVita served as a warrior in the trenches (military language again!) and personally made landmark contributions to cancer research and treatment, as well as leading major cancer organisations and policy changes. He speaks from experience and he does not hold back from expressing strong views and withering criticism of the individuals (often named) and bureaucracies that stand in the way of progress as he sees it.

The book tells a surprisingly candid personal story. For example, when DeVita discusses in the early chapters of the book the brave, aggressive and far-sighted, clinicians who first dared to introduce combinations of cytotoxic chemotherapy drugs and to push the boundaries of what could be tolerated by patients – as high doses of these toxic agents were combined together – he recalls how those pioneer chemotherapists were ‘reviled’ by other clinical doctors. And while he understandably praises his heroes, who were indeed among the first giants of what we now call medical oncology and haematological oncology, he at the same time pulls no punches in describing their feet of clay (and party animal exploits!).

We hear how young Vince didn’t know at first if his bosses were ‘maniacs or geniuses’. Their seemingly chaotic regular internal discussion meeting was known as ‘the society for jabbering idiots’. Criticism at external scientific conferences was often ‘a verbal blood bath’.

There are no holds barred when DeVita is criticising others who he sees as holding back advancement through conservatism and lack of conviction.

Indeed at the end of the Introduction to the book, DeVita does not mince his words in expressing his impatience, if not disdain, towards those for whom he has no time – ‘the cynics, the press or the doubters’ – and makes the declaration: ‘sceptics be damned’. Later on DeVita is outspoken in criticising the US Food and Drug Administration (FDA) – a particular source of his frustration and ire – for delaying the approval of potentially effective new drugs. And he also faults the US Affordable Care Act for not covering the cost of these new drugs.

DeVita’s role models as a young intern were daring, visionary and tenacious clinical researchers and were the early pioneers of chemotherapy at the NCI in Bethesda in the heady days of the 1960s. In particular young Vince was enthralled by the bravado and rebellious brilliance of Emil (‘Tom’) Frei and Emil (‘Jay’) Freireich, who soon were to become the trailblazers of early combinatorial chemotherapy. Their work was in turn underpinned by the early successes of various classes of cytotoxic agents that were initially administered on their own as single drugs.

The story of early cytotoxic drug development is very important and illuminating. Particular early success is widely attributed to Louis Goodman and Alfred Gilman who showed as early as the 1940s the activity of the drug nitrogen mustard against lymphoid tumours (derived from cells responsible for the body’s immune response, including lymphocytes, lymphoblasts, and plasma cells). In fact, nitrogen mustard was a derivative of the highly chemically reactive war gas sulphur mustard and was itself first synthesised in the US chemical warfare programme – so genuine military involvement here. Experience with sulphur mustard during the First World War had demonstrated depletion of white blood cells (indicative of the bone marrow suppression that is also common to many cytotoxic chemotherapy drugs) in unfortunate people who were exposed to the agent. And this led in turn to the demonstration in 1931 by Adair and Bagg of therapeutic effects in patients treated with topical administration or intra-tumoural injections of sulphur mustard.

The early modest clinical success of Goodman and Gilman with nitrogen mustard inspired researchers here at The Institute of Cancer Research, London – led by a rather shy and retiring professor of chemistry, Walter Ross – to synthesise less chemically reactive and better tolerated derivatives of nitrogen mustards. These drugs were melphalan, chlorambucil and busulphan and they proved superior to nitrogen mustard itself and are still in wide clinical use. Further better behaved mustard derivatives cyclophosphamide and iphosphamide discovered elsewhere have also proved clinically valuable.

There is a story that Walter Ross used to assess the reactivity of new mustard drugs by testing them to see if they caused burns to his own skin. I will relate my own experience of meeting Water Ross and working on his ideas in a later essay in this series.

Ross and his ICR colleagues Reg Goldacre and Tony Loveless were, in 1949, the first to propose that the molecular mechanism of action of nitrogen mustard was ‘crosslinking of macromolecules involved in cell division’. Experimental evidence supporting this was obtained initially by Peter Brookes and Phil Lawley at ICR in the 1960s – you can read more on the ICR’s website or in this article in Nature.

Further lab work by Brookes and Lawley at the ICR – and also others elsewhere such as Kurt Kohn at the NCI – demonstrated that the mechanism of action of nitrogen and sulphur mustard and their successors involved chemical ‘crosslinking’ both within and especially between the twin strands of the Watson-Crick DNA double helix. 

Inter-strand crosslinking prevents the DNA strands from separating, blocking DNA replication and so causing cell death. The later drug cisplatin, and its better-tolerated successor carboplatin, also work by DNA crosslinking. Carboplatin was discovered at the ICR in partnership with the speciality chemicals company Johnson Matthey in association with the pharmaceutical company Bristol Myers Squibb, and was clinically trialled by the ICR and The Royal Marsden. 

Both these platinum drugs and others are still widely used in the clinic.

Alongside the nitrogen mustards, another class of cytotoxic agents that showed early promise were the so-called antimetabolites, including the antifolates aminopterin and amethopterin (the latter also known as methotrexate), and the antipurines like 6-mercaptopurine. Another antimetabolite drug 5-fluoruracil was also important and is still widely used.

These antimetabolite drugs work by inhibiting the synthesis of DNA from its chemical building blocks in the cell. In addition, products of nature were identified that blocked cell division by binding to tubulin – including vincristine, vinblastine and later paclitaxel (Taxol).

The enduring contribution of De Vita’s heroes Frei and Freireich, as well as their colleague James Holland also at the NCI, was to use cytotoxic chemotherapy drugs to create a revolutionary curative regimen for acute lymphoblastic leukaemia in children.

They achieved this pioneering feat by combining chemo drugs from different classes in a cocktail recipe. The combination therapy was known as VAMP – after the first letter of the individual drug names – and contained the anti-tubulin drug vincristine; the antifolate amethopterin/methotrexate; the antipurine 6-mercaptopurine; and the steroid prednisone. A subsequent variation of VAMP with the same drugs became known as POMP. Importantly, Frei and Freireich also used antibiotics and platelet transfusions as supportive therapy to help patients through the rigours of the treatment.

Inspired by this landmark success in achieving the first systematic cures of cancers with drugs, DeVita himself and his colleagues then developed the MOPP combination regimen and showed that it could cure Hodgkin lymphoma and later also non-Hodgkin lymphoma. The MOPP cocktail contained nitrogen mustard (also known as mustine); vincristine (another name for which was Oncovin); a further drug that originated as a monoamine oxidase inhibitor known as procarbazine that had been shown to have some activity in Hodgkin lymphoma; and once again the steroid prednisone.

It’s fascinating to read in the book the evidence that DeVita, Frei, Freireich and colleagues used as the scientific rationale for combination chemotherapy. The main idea was that by combining drugs from different classes – and with distinct cellular mechanisms of action and side-effects – it would be possible to achieve greater anti-tumour effects while at the same time avoiding lethal toxicity to the patient. The likely effectiveness of such combinations – and the notion that these could reduce the occurrence of drug resistance that had already been seen in the early days with single agents – was supported by experience of using combination therapy to treat infectious diseases such as tuberculosis.

DeVita also explains how he and his colleagues used lab research in mouse ‘models’ (cancer scientists use the term ‘model’ to mean a laboratory representation of a cancer) to provide powerful scientific support for their drug combinations. This research was carried out by the NCI’s ‘mouse doctor’ Howard Skipper, who received a General Motors Cancer Research Foundation Award for his work – see here and here.

Working with the NCI’s transplantable mouse leukaemia model known as L1210, Skipper provided crucial quantitative preclinical data on the numbers of leukaemia cells that were killed by drug treatment.

And he used his rigorous methodology to demonstrate that optimum treatment regimens should contain four different drugs in order to increase leukaemic cell kill while sparing (relatively speaking) the normal bone marrow cells in the body.

Skipper also established the important dual concepts of 1) ‘fractional cell kill’ – the finding that a given drug dose killed a constant proportion of cancer cells regardless of their actual starting number – and 2) the inverse relationship between cancer cell number and curability – with cures being more difficult to achieve the greater the number of cancer cells initially present.

These basic principles emphasised to the clinical researchers the importance of treating patients when the tumour cell load was as low as possible. This pointed DeVita towards using combination chemotherapy in Hodgkin disease – since, as he describes in the book, the proportion of cancer cells present in such tumours was lower than in many other cancers because of the presence of many white blood cells, lymphocytes and other cells associated with inflammation within the tumour mass. That meant there were relatively fewer cancer cells to kill than in other tumour types of comparable size. Skipper’s mouse models also provided valuable information on the optimal dose and schedules of the combination drugs.

DeVita further explains how his lab colleagues used tritiated thymidine – a radioactively labelled form of one of the four DNA bases – to measure the fraction of cancer cells and normal bone marrow cells undergoing DNA synthesis. And he relates how they used this information to justify more prolonged dosing in patients.

Despite the minimal understanding of the molecular biology and genomics of cancer at that time, many of the principles developed in the above research are still valid and important today.

Supported by this robust and quantitative lab science foundation, as well as through careful clinical studies, the cures that DeVita and colleagues achieved in patients with lymphoma using combination chemotherapy were dramatic. Their research was well received by the clinical research community – and together with the earlier work of Frei and Freireich did much to remove many of the doubts about what was initially seen as a foolhardy and cavalier approach.

So, given that, it’s both fascinating and frustrating to read DeVita’s account of how many other groups, even in the top cancer institutions of the day, initially failed to replicate the NCI’s success because they deviated – often quite markedly – from the carefully constructed treatment protocols developed at the NCI.

With stricter adherence to correct procedures the success of MOPP and its successors was eventually replicated in the US and around the world. Early leaders in chemotherapy and medical oncology who developed these approaches in the UK, for example, included Professors Gordon Hamilton-Fairley and Jim Malpas.

DeVita and colleagues’ MOPP regimen increased the cure rate for advanced Hodgkin disease from close to zero to over 70% and today the cure rate for Hodgkin’s lymphoma is around 90%.

The success of DeVita, Frei and Freireich was rightly recognised – along with the contributions of other early pioneering chemotherapists – with the award of the 1972 Lasker Clinical Medical Research Award.

And the American Society for Clinical Oncology named the MOPP protocol as one of the top five advances in 50 years of Modern Oncology

In addition, with George Canellos at the NCI, DeVita went on to develop the combination chemotherapy known as CMF (cyclophosphamide, methotrexate and fluorouracil) in the adjuvant (i.e. post-surgical) treatment of breast cancer. Then, working with medical oncologist Gianni Bonnadona and surgeon Umberto Veronesi in Italy (owing to medico-political factors in the US), the CMF regimen was shown in 1975 to contribute to an increase in breast cancer survival. It remains a useful therapy for breast cancer today

There is no doubt that the pioneering early work of DeVita and other pathfinders demonstrating the effectiveness of combination chemotherapy in leukaemia, lymphomas and to a degree other cancers changed medical history forever. It also had a broader social and political impact, as I will go on to describe next time.

NEXT: Read the second installment of our 'The Death of Cancer?' series

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