Is control better than cure as a goal for cancer research?
Maxine Clarke
Tuesday, 16 June 2009 08:15 UTC
Patients and politicians anxiously await and increasingly demand a ‘cure’ for cancer. But trying to control the disease may prove a better plan than striving to cure it, says Robert A. Gatenby in a Nature Essay (Nature 459, 508; 2009). According to Professor Gatenby, the ‘war on cancer’ continues to be driven by the implicit assumption that magic bullets will one day be found for the disease. Yet lessons learned in dealing with exotic species, combined with recent mathematical models of the evolutionary dynamics of tumours, indicate that eradicating most disseminated cancers may be impossible. And, more importantly, trying to do so could make the problem worse. He is not suggesting that cancer researchers should abandon their search for more effective cancer therapies, or even for cures, rather that they should address the possible benefits of an uneasy stalemate in appropriate situations. “Even now, many oncologists agree in principle that therapeutic strategies aimed at controlling cancer could prove more effective than trying to cure it. But the idea of killing not the maximum number of tumour cells possible but the fewest necessary will be difficult for both physicians and patients to accept in practice. Certainly in a war that is steeped in the tradition of magic bullets and all-out attacks with high-dose chemotherapy, such an approach may seem defeatist. However, in battles against cancer, magic bullets may not exist and evolution dictates the rules of engagement.”
Updated 16 June 2009 08:16 UTC
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I suppose one of the clearest indications that a cancer ’ cure’ is not really a cure is the increased incidence of cancer in transplant patients – or cancers that recur after transplant. The cancer that the drugs have helped the immune system to hold in abeyance is no longer held back.
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Please forgive my naivety, but I seem to find a false dichotomy in this control versus cure argument. There is no one-size-fits-all kind of treatment. In certain cancers, chemotherapy and/or radiation is a must to aggressively eradicate the maximum number of cancerous cells; in certain other cancers, particularly in the early stages, eradication of the fewest necessary may be feasible.
I think that bickering over control or cure is rather disingenuous; the problem is much better approached if a single parameter pertaining to the patient is considered, namely: minimization of the harm to the patient, through risk-benefit analysis. We all know that the side effects of chemotherapy is particularly unpleasant for the patient, and may even make for a poorer quality of life. Therefore, the extent and level to which chemotherapy is to be given should be determined by considering whether the potential benefits outweigh the risks and problems. If that regimen is only able to achieve a control, it would still represent the best course of action everything considered. If, on the other hand, that regimen induces a remission, temporary or even permanent, all the better for the patient.
At the same time, the goal of continuing and newer research would continue to be – as it is now – the search for more effective therapies. Some cancers, particularly in the early stages, are supposed to be amenable to therapy that works in conjunction with the immune system – which is an attractive hypothesis. Research would continue to explore these options, as well as the possible causes and mechanisms of cancer. IMHO, therefore, unnecessary entanglement in the control-or-cure dichotomy produces no beneficial result, but ends up harming the prospect of cancer research in the long run.
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In the discussion about associations between cancers and lifestyle factors, no mention was made of tobacco. Yet, it’s been estimated that, in the USA, “reductions in lung cancer, resulting from reductions in tobacco smoking over the last half century, account for about 40% of the decrease in overall male cancer death rates” (Tobacco Control 2006; 15: 345-347). Strong evidence that tobacco smoking and lung cancer rates are related has been available for more than 50 years, since the research work of Richard Doll and Austin Bradford Hill.
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Thanks, Jim, I am sure nobody would disagree – rather, the Essay being discussed here was focused on a different aspect of the cancer problem – suggesting that treatment and control might often be more realistic than “cure”, and that this should be more generally appreciated.
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The tenet of the Robert Gatenby’s Essay is that the tumor should be controlled, rather than eradicated. An interesting point raised by Gatenby to support his view is that heavy killing of a chemosensitive tumor population would lead to the almost total replacement by the resistant ones. This scenario is reminiscent of tumor immunoediting, the consequence of immunosurveillance which leads to outgrowing of the tumor variants not recognised by the immune system. This state of immune tolerance can be broken by danger signals delivered by tumor cells dying from chemotherapy, which makes the tumor microenvironment highly permissive, by increasing dendritic cell activation and recruitment of cytotoxic T lymphocytes (C. Fonseca and G. Dranoff Clin Cancer Res 14, 1603-1698, 2008; L Zitvogel et al. The Journal of Clinical Investigation 118, 1991-2001, 2008; M E. Bianchi and A.A. Manfredi SCIENCE 323, 1683-1684, 2009). It follows that, if each chemotherapy intervention represents an endogenous vaccination, reasonable amount o tumor cells should available for a long period, so to allow repeated T cell boosting. This would only be possible if therapies aimed at sustaining a stable tumor mass rather than eradicate it, as suggested by the Gatemby’s model, are designed. A better immunogenic effect of low doses has been reported after photodinamic therapy (PDT) which provides the immune system with a formidable source of antigens (A.P. Castano , P. Mroz and M.R. Hamblin Nat Rev Cancer 6, 535-545. 2006). In a case study of an angiosarcoma patient. P.S. Thong et al. (J Environ Pathol Toxicol Oncol. 27:35-42, 2008) high fluence rate PDT resulted in local control of disease up to a year, whereas the recurrent disease was only eradicated by repeated PDT carried out at a low light fluence. Very recently it has been shown that the number of patient’s lymphocytes specific for the Hip1 antigen expressed by basal cell carcinoma following PDT are inversely correlated with treatment area and light dose (E Kabingu et al. Clin Cancer Res 15, 4460- 4466, 2009). It may certainly sound overoptimistic, but why not regard soft control of tumor not as a defeat, but as a more subtle strategy to win cancer?
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Professor Dr Gatenby’s “A change of strategy in the war on cancer”, was syndicated to our Straits Times newspaper here in Singapore, and to many other papers worldwide.
I see the need for mathematical modeling, and can appreciate that as a response to treatment some cancer cells may mutate and evolve using pathways that are less amenable to therapy. While I agree that sometimes the cure can be worse than the disease, I respectfully differ on the value of targeted therapies. Ehrlich’s “magic bullets” have indeed contributed to a perception that a cure for cancer is around the corner, but that is not their value.
Ehrlich pointed out that certain biological receptors can be targeted. Indeed that is the standard method of treatement for neuroendocrine tumors and the reason why octreotide earned Novartis US$ 1b last year. By binding radioisotopes to peptides such as octreotide, it is possible to deliver a knock-out punch to neuroendocrine tumors without damaging other tissues and without significant side effects. Hundreds if not thousands of patients are receiving such treatment each year, with remarkably improved quality of life and life expectancy.
However neuroendocrine tumors are not the only cancers which can be targeted in this way. For example, the gastrin releasing peptide receptor is a growth factor associated with several of the more prevalent cancers including prostate, breast, and small cell lung cancer. For that reason, gastrin-releasing peptide receptor (GRPR) antagonists have been developed as anticancer candidate compounds, exhibiting impressive antitumor activity both in the lab and in the clinic.
So we should not give up on targeted therapies for diagnosing and treating cancer, as the article seems to suggest.
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We hate cancer, however, the modern life made the cancer occur frequently.
In the war on cancer, what we have learned and done still far away from the success.
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