Cancer drugs, survival, and ethicsBMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i5792 (Published 09 November 2016) Cite this as: BMJ 2016;355:i5792
All rapid responses
The response of Pfizer UK contains many misquotes and unwarranted inferences, with apparent intent to discredit the conclusions of my analysis.
Firstly, their reference derived from Cancer Research UK simply restates a doubling of cancer survival in the UK over the last 40 years. It provides no support for Pfizer’s claim of a relationship to the use of ‘medicines’ (cancer drugs). Their accusation of ‘misrepresentation’ is therefore without basis.
To support their claim of drug-dependant improvement in survival in non-small cell lung cancer (NSCLC) over the period 1995 to 2008, Pfizer uses as reference point a 1995 meta-analysis of drug treated advanced cancer . They quote an erroneous 2.5-month overall survival (OS) figure – an obviously incorrect statistical derivation. Access to the actual source data of the relevant 11 heterogeneous trials shows OS varying from 5.5 to 11.3 months (mean 8.5 months) in the eight available data sets. The longer survivals are associated – as anticipated – with the broader ‘advanced’ cancer category (stage III plus stage IV) studies rather than those of exclusively metastatic disease. Those survival data are broadly in line with the median 10.3-month OS reported 13 years later in the 2008 Scagliotti et al.  (also ‘advanced’ cancer) study used for Pfizer’s comparison. Together with other published data, there is no evidence of significant drug-related improvement of survival in metastatic NSCLC patients over that period – also referred to by Cancer Research UK. It is only more recently that targeted therapy of smaller subgroups with driver oncogenic mutations has made a selective but still modest impact on cancer survival – as referred to in my paper.
Pfizer summarily dismiss the hallmark Morgan et al 2004  meta-analysis of metastatic disease trials as 'out of date'. That rare, comprehensive analysis of placebo-comparative trials of 250,000 patients presents sober outcomes upon which to 'graft' the results of now more ethical new vs. standard drug trials approved by the EMA, the FDA and other agencies. Together with accurate toxicity/tolerance data, this combined information is indispensable to both physicians and patients for judging clinical value of any treatment. Above all, in my paper I acknowledge clearly those cancers for which drugs show real benefit: neither I nor the readers need to be reminded that '….cancer is not a single disease.' Pfizer's further criticisms that I have taken '...an incredibly dangerous and irresponsible position' and that my paper could '...cause significant damage to clinical research' are thus wild accusations.
Nor did I link the current 3% global trial participation to any 2004 data: a meaningless non-sequitur of Pfizer. I used that figure for one purpose only: to highlight the importance and – currently unmet – need for confirmatory post-marketing (pharmacovigilance) data on drug benefit and adverse effects in the 97% of cancer patients not in trials. I regret not having mentioned the excellent trial participation in the UK – although that 14% figure is also now almost ten years out-of-date and – as Pfizer indicate – enrolment has since fallen.
There are further unpleasant falsehoods. Nowhere in my article do I '...imply that patients should not enrol in trials.'. Nor did I'...propose that patients will not benefit directly’ from trial involvement’. I stated that '...participating in a trial will primarily benefit others' – which can hardly be challenged since it is surely the prime purpose of trials. Pfizer then choose to overlook my recommendation that '…patients should be fully empowered by discussion and subsequent triage to receive cancer drugs, to enrol in a clinical trial, or to accept best supportive care.'
There is indeed no ethical obligation to prescribe an over-permissively approved and doubtfully-effective drug. If a decision for drug treatment is agreed, trial enrolment – if logistically feasible – devolves 'treatment' cost for such patients more appropriately on pharma, who may no longer need to abort the oft-quoted 60% of trials for lack of patient enrolment. We badly need more effective drugs. Current trials are now mostly standard drug vs trial drug comparisons that represent 'win-win' situations for participating patients.
Pfizer then challenge another of my ethical concerns: placing patients under undue pressure to enrol in trials. Trials outsourced by pharma to commercial contract research organisations (CRO) are often offshored to the Asian and South American continents. Rather than by physicians, enrolment of patients is then mostly carried out by non-medical staff working for CROs and their sponsors . CROs advertise their patient recruitment strategy on the Internet , write books about it , and run courses to help their assistants enhance their recruiting abilities. Even oncologists receive guidance on it . For Pfizer to insist that there is no risk of pressure is – may I say - naïve.
Pfizer also prefers the Saad and Buyse paper  on surrogate markers as being more 'nuanced' than those which I quoted. Their preference is understandable, since Buyse is founder and chairman of a CRO – the International Drug Development Institute – whose primary client is the pharmaceutical industry. Nevertheless, progression free survival (PFS) and other more rapidly-available surrogate endpoints have been widely shown to be unreliable predictors of all-important OS – an inconvenient truth for pharma. Understandably they may lose money if required to await results and (hopeful) approval based on OS results. Yet they could also lose from a 50% risk that disappointing OS data might follow premature PFS-based approval – resulting in withdrawal of that approval (although agencies are currently lax in implementing this) . My concern remains – the continuing approval of drugs based on misleading PFS and other surrogate endpoints carries negative ethical consequences for patients in both trial and treatment modes, and then also for the unfortunate pharma who supplies a PFS-disadvantaged comparator drug.
Finally, I can understand Pfizer's enthusiasm about preliminary OS data on sequential tyrosine kinase inhibitor (TKI) therapy for NSCLC  – although benefit is restricted to the 5% or less of NSCLC patients who have the ALK-positive genotype. Interpretation is also subject to the many limitations expressed by the authors, of which the most relevant are the lack of a control group and the highly-selected nature of the patients.
We return to the important initial theme: much more evidence is required before assuming significant contributions of expensive tumour-destructive drug therapy to population cancer survival, particularly in metastatic disease. Meanwhile, I would have appreciated a more valid and respectful contribution from Pfizer. Ethics is as important in scientific communication as it is in research and practice.
1. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995 Oct 7;311(7010):899-909
2. Scagliotti GV, Parikh P, von PJ, Biesma B et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008 Jul 20;26(21):3543-6
3. Morgan G, Ward R and Barton M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin Oncol (R Coll Radiol)2004;16:549-60
4. Van Huijstee M and Schipper I. Ethical concerns. In: Putting contract research organisations on the radar.Social Sciences Research Network, 2011: 55-72.
6. Sfera D Recruiting clinical trial study participants. Kindle edition (Amazon)
7. Barton E, Eggly S, and Winckles A. Strategies of persuasion in offers to participate in cancer clinical trials. Communication and Medicine 2014;11(1):1-14. [Part II: Communication and Medicine 2014;11(3):223-33.]
8. Saad ED and Buyse M. Statistical controversies in clinical research: end points other than overall survival are vital for regulatory approval of anticancer agents. Ann Oncol 2016;27(3):373-8.
9. Crowe S and Giles C. Making patient-relevant clinical research a reality. BMJ 2016:355;i6627
10. Gainor JF, Tan DS, De PT et al. Progression-Free and overall Survival in ALK-positive NSCLC patients treated with sequential crizotinib and ceritinib. Clin Cancer Res 2015;21(12):2745-52.
Competing interests: No competing interests
We read with interest the recent article by Dr Peter Wise on “Cancer Drugs, survival and ethics”.(1) The question posed was how much improvement in cancer survival over the last 40 years can we attribute to drugs? It’s an incredibly complex question given the heterogeneity of the biology of the underlying disease and the rapid changes in the development of novel therapeutics, radiotherapy and surgical techniques coupled with improvements in diagnostics, clinical patient pathways and the coordination of oncology services. It is a shame that Dr Wise has misrepresented the contribution that medicines have made to the doubling of overall survival in the UK since the 1970s(2) through cherrypicking of old studies and data. But more concerningly, he seems to imply patients should not enrol into trials. This is an incredibly dangerous and irresponsible position.
Cancer Trial Concerns
Dr Wise suggests that only 3% of adult patients are actively involved in clinical trials, based on data from 2004. This hides much truth.(3) While global participation was around 3%, the UK rate was 14% in 2007 and has continued to grow. However, some indicators suggest that trial participation in the UK is now beginning to decline, causing great concern not just to triallists, but to patients and patient groups as well and was extensively discussed at the inaugural ABPI – AMRC patient first conference in London in November 2016. All agreed more needed to be done to grow trial involvement.
Dr Wise proposes that patients participating in clinical trials may not benefit directly. In fact, being treated in Trusts with sustained high participation in research is independently associated with better outcomes.(4) This effect is seen across all NHS Trusts and is not restricted to academic centres or large institutions.(4) Other studies and reviews have highlighted that research participation improves processes of care.(5;6)
Increasingly patients are benefiting directly from trial involvement. Personalised medicines are targeted towards patients more likely to benefit. Later confirmatory studies often allow patient crossover because equipoise may not fully exist following very promising early results. In the 1st line study comparing crizotinib with chemotherapy in ALK+ advanced NSCLC, the trial was started after crizotinib received a conditional license from the FDA on the basis of phase 1 results. As such, progression free survival was chosen as the primary endpoint and 70% of patients crossed over from the chemotherapy to the crizotinib arm upon progression.(7) More on the issue of crossover below!!
Dr Wise suggests that patients are put under unethical pressure to enroll in studies. The 11 year old paper which he cites relates to Phase I/II trials.(8) The discussion from the paper adds important context: “We found that most participants felt they were well informed and that their decisions about trial participation were made independently. The main area of concern was that only half of the patients felt that they had ‘reasonable’ alternatives to trial participation explained. Those not aware of ‘reasonable’ alternative treatment were, however, predominantly participants in phase I trials, where the only alternative was likely to have been an alternative experimental therapy or best supportive care.”(8)
So what impact have medicines had? Relevant to the interpretation of the meta-analysis of survival outcomes published over 12 years ago, is the principle that cancer is not one disease. Cytotoxic chemotherapy has transformed outcomes in particular cancer subtypes such as lymphoma and testicular cancer. In tumour types with less inherent sensitivity to the available agents, development of novel therapies has been fundamental to support the aim of improving clinical outcomes for patients particularly with advanced cancers. Accurate classiﬁcation of non-small cell lung cancer (NSCLC) has transformed the management of advanced disease following the results of phase 3 clinical trials that showed improved progression-free survival (PFS) in EGFR mutation-positive adenocarcinoma treated with EGFR tyrosine kinase inhibitors (TKI).(9;10) The use of PFS as a ‘surrogate’ outcome for overall survival (OS) and the lack of OS gain seen in clinical trials is substantially over-simplifies by Dr Wise. Often, crossover of the type described above in the crizotinib study programme removes any survival benefit. A more nuanced and helpful discussion of the issues around correlation between PFS and OS, such as presented by Saad and Buyse (11), would have added strength to this opinion piece (although would have undermined the story somewhat).
Rather than providing no survival gain, systemic therapies for fit patients has shifted OS from approximately 2 1/2 months in 1995(12), to approximately a year in 2008(13). In molecular subtypes, gefitinib and erlotinib have resulted in a median OS gain of 20 to 30 months when used as first line therapy for patients with advanced NSCLC harbouring activating EGFR mutations (14). In ALK positive advanced NSCLC sequential therapies led to a documented median OS of over 4 years.(15) Other tumour types have seen similar breakthroughs.
In search of ethics
Dr Wise’s paper was provocative; we are glad for the debate it created. But it could cause significant damage to clinical research in the UK. We have many concerns about what is an opinion piece focussed on historic outcomes relating to cytotoxic chemotherapy, identified from an out of date evidence base. At a time where many patients still present with advanced cancer, associated with poor clinical outcomes, it is the duty of the healthcare community, including the pharmaceutical industry, to work together to develop innovative medicines which will improve symptoms, quality of life and survival. Novel approaches to doing this undertaken by our group include the CRUK/AZ/Pfizer Matrix trial.(16) It is a priority to continue to support the development of potentially curative agents aligned with an increasing understanding of the optimal use of radiotherapy and surgery, and again the work of the UK CTRad group (including industry members from our group) could be instrumental in expediting development of treatments in this area.(17)
(1) Wise HW. Cancer Drugs, survival and ethics. BMJ 2016 Nov 9;355:i1579.
(2) http://www.cancerresearchuk.org/health-professional/cancer-statistics/su... . 2016. 20-11-0016.
Ref Type: Online Source
(3) Sinha G. United Kingdom becomes the cancer clinical trials recruitment capital of the world. J Natl Cancer Inst 2007 Mar 21;99(6):420-2.
(4) Downing A, Morris EJ, Corrigan N, Sebag-Montefiore D, Finan PJ, Thomas JD, et al. High hospital research participation and improved colorectal cancer survival outcomes: a population-based study. Gut 2016 Oct 19.
(5) Clarke M, Loudon K. Effects on patients of their healthcare practitioner's or institution's participation in clinical trials: a systematic review. Trials 2011 Jan 20;12:16.
(6) Rochon J, du BA. Clinical research in epithelial ovarian cancer and patients' outcome. Ann Oncol 2011 Nov;22 Suppl 7:vii16-vii19.
(7) Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014 Dec 4;371(23):2167-77.
(8) Nurgat ZA, Craig W, Campbell NC, Bissett JD, Cassidy J, Nicolson MC. Patient motivations surrounding participation in phase I and phase II clinical trials of cancer chemotherapy. Br J Cancer 2005 Mar 28;92(6):1001-5.
(9) Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009 Sep 3;361(10):947-57.
(10) Rosell R, Ichinose Y, Taron M, Sarries C, Queralt C, Mendez P, et al. Mutations in the tyrosine kinase domain of the EGFR gene associated with gefitinib response in non-small-cell lung cancer. Lung Cancer 2005 Oct;50(1):25-33.
(11) Saad ED, Buyse M. Statistical controversies in clinical research: end points other than overall survival are vital for regulatory approval of anticancer agents. Ann Oncol 2016 Mar;27(3):373-8.
(12) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995 Oct 7;311(7010):899-909.
(13) Scagliotti GV, Parikh P, von PJ, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008 Jul 20;26(21):3543-51.
(14) Lin JJ, Cardarella S, Lydon CA, Dahlberg SE, Jackman DM, Janne PA, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol 2016 Apr;11(4):556-65.
(15) Gainor JF, Tan DS, De PT, Solomon BJ, Ahmad A, Lazzari C, et al. Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib. Clin Cancer Res 2015 Jun 15;21(12):2745-52.
(16) Middleton G, Crack LR, Popat S, Swanton C, Hollingsworth SJ, Buller R, et al. The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer. Ann Oncol 2015 Dec;26(12):2464-9.
(17) Sharma RA, Plummer R, Stock JK, Greenhalgh TA, Ataman O, Kelly S, et al. Clinical development of new drug-radiotherapy combinations. Nat Rev Clin Oncol 2016 Oct;13(10):627-42.
Competing interests: No competing interests
Dear Stephen Ashwell - with pleasure, just scroll down to 12th Nov. where you will see the relatively short list -- which of course would not limit anybody from adding to it. Regards, Susanne Stevens
Competing interests: No competing interests
In some countries, where health care is a right that is guaranteed by the state, drugs for metastatic cancer put at risk the sustainability of the health systems. Under the "unrealistic expectations offered," patients demand the coverage of these drugs based on "the right to life." I wonder, do they really offer life? (1-3)
The resolution of these dilemmas by judicial means is growing; the coverage of drugs with high financial impact with little (or no) therapeutic value cannot be decided in a court based on the premise: "one more day of life, it is a right to life." The new drugs in metastatic cancer sometimes offer a few days (less than 80 usually), and sometimes not even that. Judges proceed according to law, and it is not easy for them to understand that the results of palliative chemotherapy do not contribute to the overall improvement of the health of people with cancer, their families and their community. (4) The distorted discourse that puts these drugs in place is an attack against health, justice and equity in the distribution of resources. (3)
We are lost looking at the tree and not the great forest. When drugs that do not offer a reasonable improvement in quality of life are offered to patients, we are contributing to cruel therapeutics; that is unethical.
I cannot understand why the sustained increase in overall survival WITH quality of life (simultaneously) is not considered among the main variables in defining the effectiveness of a drug prior to its commercialization. This is what matters to patients, the quality of life. (5)
Life is finite; death is part of life. We need oncologists to always tell us the truth, in language we can understand, and take our hand and help us cross the inevitable threshold.
1. Fojo T, Mailankody S, Lo A. Unintended consequences of expensive cancer therapeutics—the pursuit of marginal indications and a me-too mentality that stifles innovation and creativity: The john conley lecture . JAMA Otolaryngol Neck Surg [Internet]. 2014 Dec 1;140(12):1225–36. Available from: http://dx.doi.org/10.1001/jamaoto.2014.1570
2. Salud. 55o Consejo Directivo de la Organización Mundial de la. Consejo directivo 61. 2016.
3. Aggarwal A, Ginsburg O, Fojo T. Cancer economics, policy and politics: What informs the debate? Perspectives from the EU, Canada and US. J Cancer Policy [Internet]. 2014;2(1):1–11. Available from: http://dx.doi.org/10.1016/j.jcpo.2014.02.002
4. Mailankody S, Prasad V. Five Years of Cancer Drug Approvals: Innovation, Efficacy, and Costs: Letter. JAMA Oncol. 2015;1(4):1–2.
5. Pérol M, Pérol D, Chouaid C. Reply to N. Singh et al. J Clin Oncol. 2013;31(9):1251–2.
Competing interests: No competing interests
Peter Wise rightly raises ethical concerns about the regulatory approval of high cost cancer drugs with limited survival benefit. . The unsustainable pricing model of newer cancer drugs is causing concern worldwide. .
But Pharmaceutical companies have a fiduciary duty to maximise profits for shareholders in market based economies. It is up to the society to draw the line on cost benefit ratio and for it to be politically feasible, public opinion would play a decisive role.
We surveyed UK public perception on the monetary worth of chemotherapy drugs. The results were presented at the European Society of Medical Oncology annual meeting at Copenhagen in October 2016..
In a face to face survey, members of public were asked "What price do you think it is reasonable for a pharmaceutical company to charge for the chemotherapy drug ?" and were provided various scenarios ranging from a drug with 50% cure rate to a drug with palliative benefit only without any life prolonging benefit.
Surprisingly, only a small minority (11%) were in favour of drug costs in excess of 100,000 pounds even if the drug has got the potential to cure 1 in 5 cancer patients. Of more relevance to the real world setting, only 5% were in favour of drug costs more than 100,000 pounds if a drug does not cure but makes cancer patients live longer by an extra 6 months. 
This UK survey provides strong public support for value based pricing in the NHS..
1 Wise PH. Cancer drugs, survival, and ethics. BMJ 2016;355:i5792. doi:10.1136/bmj.i5792
2 29 S, Kirzinger 2016 | Ashley, Wu B. Kaiser Health Tracking Poll: September 2016. http://kff.org/health-costs/report/kaiser-health-tracking-poll-september... (accessed 20 Nov2016).
3 Sundar S, Johnson HD, Taylor S, et al. Are the newer chemotherapy drugs worth their high cost? - A survey of UK public’s perception of reasonable price for chemotherapy drugs according to their health benefit. Ann Oncol 2016;27:1023P. doi:10.1093/annonc/mdw377.03
4 Raftery J. Value based pricing: can it work? BMJ 2013;347:f5941. doi:10.1136/bmj.f5941
Competing interests: Advisory boards, Conference sponsorship and Clinical trials funding from various Pharmaceutical companies. Past member of NHS England Urology CRG which provided service specifications for area commissioners. Also until recently, a member of NHS England Cancer Drug Fund (CDF) panel which entailed regular voting on drug funding requests.
This excellent article and the responses to it are all worthy of continued discussion by the medical community (including patients, researchers, pharmaceutical companies, practicing oncologists, and legislators). While there are no easy answers, it is clear that the cost/benefit ratio plays an important role in decision making. Pegging this to something like the cost/year of hemodialysis is often used, but for some societies, even this may be inappropriate, given the very high benefit for relatively inexpensive interventions like vaccination for infectious diseases. As a practicing oncologist, I often wondered whether patients who responded to the complex discussions engendered by the use of expensive and potentially toxic treatments really had a choice. Many would choose such treatments over palliative care options with comments such as "I guess so - what choice do I have?" as a means of voting for hope over resignation, and often with the encouragement of their well-meaning families.
Given that insured patients, or those in government sponsored programs do not directly bear the burden of cost, perhaps alternative scenarios should be considered. While ethicists may disagree, I am convinced that a patient offered a marginally effective drug versus some portion of the savings from NOT trying the drug being applied to a family need such as higher education for a grandchild would often choose the latter. The overall benefits to society from such a choice could be part of the discussion, just as the benefits from participation in clinical trials are highlighted in the author's discussion.
Competing interests: No competing interests
I would like to acknowledge with thanks the many excellent and helpful responses to my recent paper on cancer drugs.
Dr Gyawali acknowledges the misplaced media marketing of drugs to the community, but more importantly the higher cost/benefit and risk/benefit ratios in lower income countries. My paper was indeed written with global implications. The ethical malpractices in Africa (Mostert et al. Lancet Oncology 2015;16(8):e394-e404) and in India (Srinavasan et al. Indian J Med Ethics 2012;9(3):148-50) should be read in their entirety to realise that my concerns are expressed - in spades - for populations well beyond the Western world.
Mr Quick identifies accurately the basic questions that patients should ask. Yet there is more, as other contributors noted.
Dr Hamilton correctly adds his paper to two others showing the harm of cancer drugs towards the end of life - and there are more still. Thank you.
I thank Dr Hukkanen for pointing out my unfortunate use of the term 'cancer industry'. It should of course have read 'pharmaceutical industry."
I thank Dr Baum for his comment and will henceforth use his excellent term, 'false dawns' to express the hyperbole of pharma in the context of their brash announcements of 'progress' that actually do nothing but disappoint.
Ms Mawer identifies the neglected supportive care, and so accurately perceives the continued need for comparisons of drug responses with supportive care alone - now mostly considered un-ethical. Her term 'illusion of efficacy' is another which I will use in my talks!!!
Drs Levack and Paterson's comments about 'talking and not just treating' are also relevant. In the UK, I accept that patients are increasingly involved in decision making. But there are still enormous gaps, and again in low and middle-income countries where prescribing drugs has become a 'knee-jerk reaction' to metastatic cancer - particularly if there is money in it.
Dr Dangoor and colleagues from the Association of Cancer Physicians (UK) make some good points. Am I cynical? Yes, and I believe that I am justified - given the facts. The money motive is apparent throughout. Indeed I 'conflate' issues from various sites and sources, intentionally including situations beyond the UK's borders, since The BMJ is an international journal, and responses (also from other sites carrying my article) have indeed come from several continents. I could also have expanded on other functions of NICE (if space had allowed it), but I now acknowledge publicly their important monitoring function.
As I said in my article, I hope that NICE might initiate an ongoing post-marketing exercise in the UK - pharmacovigilance both for efficacy (PAES) and adverse effects (PASS). Only then might we ascertain cancer drugs' real value to individuals and society. It is surely a correct project for NICE, wouldn't the ACP agree? Dr Dangoor and colleagues' reference to the Cochrane Database as showing progress from drugs in lung cancer actually says the contrary: drugs increased OS only from 4.5 months to 6 months: my point precisely! The reference on breast cancer from Sweden is also not approriate, since it does not differentiate the effect of drugs from other treatments - only time-related overall survival progress, with which I would certainly concur. The reference to drug benefits on colon cancer (Kopetz et al) is out of date (2009) : that article anyway deals simultaneously with the role of hepatic metastatic resection. There are also better and more recent papers on colon cancer (eg Medical Care, 2016;54(5):490-7) based on US SEER data, which actually identify a still-modest 6 month survival benefit - but reducing to one month in not-so-aged patients over age 75. This age-related phenomenon is still neglected in much of the reported literature. Finally, Dr Dangoor and colleagues quote the non-approval by NICE for the use of erlotinib in pancreas cancer (it increased survival only by a median 10 days in the submitted US approval trials!). That was indeed a good decision. However, the FDA did indeed approve it, and it is used in the US. Furthermore, well beyond the Western hemisphere, other approval committees regularly take their cue from the FDA. How much money then is being wasted on using this drug in the world beyond the UK? That and similar approvals are unethical - and as I will keep on saying - act only in the interest of pharma, government and some oncologists.
Competing interests: No competing interests
Can Suzanne Stevens provide a link to Dr. Quick's list of questions for patients considering chemotherapy?
Competing interests: No competing interests
Dr Peter Wise does not mention that breast cancer survival also depends on rises or falls in hormone use (BMJ 2016;355:i5792). Professor Michael Baum reminds us of Sir George Beatson's publication of three cases of metastatic breast cancer being treated successfully by bilateral oophorectomy.1 The most important consequences of this discovery are, not only endocrine ablation in cancer management, but more importantly, that widespread use of progestogens and oestrogens has caused a predictable and therefore preventable breast cancer epidemic.
The rises and falls in the percentage increases in breast cancer registrations since 1962 in England and Wales have matched the increases and smaller falls in hormone use for contraception or hormone “therapy” with extra increases in diagnosis due to the introduction of screening for middle age women. Figure attached
The Womens’ Health Initiative (WHI) trials found “remarkably similar” increased risks of HT-associated breast cancer to the Million Women Study (MWS) and the worldwide Collaborative Group’s study (in which 80% of HT users had used oestrogen-only preparations). The estimated excess incidence of breast cancer with oestrogens increased from 2 to 6 per 1000 users in the Collaborative Group study and from 1.5 to 5 per 1000 users in the MWS for 5 and 10 years of use. The excess incidence for progestogen/oestrogen HT increased from 6 to 18 per 1000 users in for 5 and 7 years’ use in the WHI trial and from 6 to 19 per 1000 for 5 to 10 years of use in the MWS. Progestogen containing HT caused 4 times more breast cancer than oestrogen HT in both the WHI trial and the MWS. Longer use of oestrogen HT or combination HT for up to 10 years trebled breast cancer risks compared with use for up to 5 years.2
After the premature terminations of the WHI randomized trial of combined HT in 2002 and oestrogen only HT trial in 2004, the fall in HT use in hormone taking countries matched declines in breast cancer mortality.3 Professor Graham Colditz described the decline in breast cancer incidence as due to the removal of the promoter.4 Oestrogen positive breast cancers particularly decreased perhaps because women who had hysterectomies and oophorectomies may have taken oestrogens for longer than users of combined HT. www.harmfromhormones.co.uk
1 Beatson G. On Treatment of Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New Method of Treatment, with Illustrative Cases Lancet 1896, ii:104-107
2 Beral V. Banks E, Reeves G, Bull D, on behalf of the Million Women Study collaborators. Breast cancer and hormone replacement therapy: the Million Women Study. Lancet 2003;362:1330-1331.
3 Grant ECG. Reduction in mortality from breast cancer: fall in use of hormones could have reduced breast cancer mortality. BMJ. 2005 Apr 30;330(7498):1024.
4 Colditz GA. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Res. 2007;9:108.
5 Ravdin M, Cronin KA, Howlander N, Berg CD, Chlebowski RT, Feuer EJ, Edwards BK, Berry DA. The Decrease in Breast Cancer Incidence in 2003 in the United States. NEJM. Vol. 356, No.16. April 19, 2007
Competing interests: No competing interests
We read with great interest the analysis from Dr Wise on the benefits or otherwise of systemic treatments for cancer, and the ethics surrounding their use (1). As health professionals in the UK who specialise in the treatment of cancer using drugs, we of course have a vested interest in the subject but feel that his analysis strays into the territory of opinion piece rather than balanced assessment.
We are aware of the points he raises and welcome his discussion of issues that we are constantly debating and evaluating ourselves. His article is perhaps a useful counterpoint to some of the hyperbole we often see in the media surrounding some of the more incremental improvements in treatment. However, we feel that Dr Wise is taking an overly cynical position, and conflating issues from several different healthcare systems, whilst not giving enough credit to specialists such as ourselves to maintain high standards of ethics, and awareness of the limitations of the treatments we offer. Certainly, there are issues surrounding conflicts of interest and these may be most clearly demonstrated in the United States where reimbursement through the Medicare system currently means that doctors may benefit from prescribing more expensive drugs; fortunately, in the UK within the NHS there are no such perverse incentives. Whether a patient chooses chemotherapy or supportive care alone makes no difference financially to the oncologist, in fact with current overwhelming pressures in terms of workload and oncology unit capacity there are arguable incentives to reduce chemotherapy prescribing. The UK is also unique in the world in having established an England-wide single database of chemotherapy activity through which we are increasingly able to benchmark physician practice and outcomes against results of peers, and those described in licensing trials.
Dr Wise describes the approval of many drugs with evidence of only marginal gains in survival. However, he does not mention that many of those drugs will not be approved by NICE in the UK or be in routine use by UK oncologists. We are aware of the minimal benefit of erlotinib in pancreatic cancer alluded to by Dr Wise and therefore it is not approved for use in the NHS for that indication. However significant advances in survival due to systemic treatments have been seen in both the adjuvant and metastatic setting. Over the years, stepwise improvement in outcomes for those with metastatic breast (2), colorectal (3), and lung cancer (4) have occurred. Our focus now is on stratified medicine - the science of choosing the most effective treatments for individual patients. We understand that whilst some patients in our clinics benefit significantly from treatment, others may suffer toxicities without extending life. In this country we are amongst the leaders in the field thanks to the Cancer Research UK Stratified Medicine programme (5) which aims to match patients to the right drug treatments based on the molecular “fingerprint” of their individual cancer.
The Association of Cancer Physicians (ACP) and its members are very involved in initiatives to improve the efficacy and quality of care. These include, supporting data collection and the recent publication of mortality within 30 days of systemic anti-cancer treatment (6), organising educational workshops, which have recently focused on caring for elderly patients with cancer and, last month on patient centred and integrated cancer care, which featured prominently the issues of quality of life, holistic needs, and communication challenges. The ACP, in collaboration with patients, has also produced a strategy document to help drive improvements in cancer care (7). In addition, to encourage improved information for patients we have worked with Cancer Research UK on developing regimen-specific consent forms to clearly list the incidence of side-effects and other risks of treatment including death (8). They confirm that the person taking consent has discussed alternative options including no treatment; and indications for treatment (eg neoadjuvant, adjuvant, curative, maintenance, or palliative). This encourages a full and frank discussion with the patient before the decision to treat is finally made.
In short, oncologists in the UK are very conscious of the financial constraints on the healthcare systems here and around the world, we are keen to continue work with patients, charities, research institutions, government, and yes pharmaceutical companies, to develop more effective treatments, target them appropriately, and to explain to patients all the options, including that of palliation of symptoms alone. Supporting patients at the end of life to make the best decisions for them and their family, with empathy and kindness is one of the facets of our job that makes it so rewarding and why we choose it as a career. A common question patients ask us is what we would choose for ourselves or our family and hopefully the advice we give articulates as closely as possible our honest view.
Dr Adam Dangoor, Professor Johnathan Joffe, Dr Adam Januszewski, Dr Marcia Hall, Dr Ruth Board, Dr Janine Mansi, Professor Samreen Ahmed, Dr Caroline Archer, Dr Maung Moe, Dr Alison Jones, Dr Simon Grumett, Dr Janine Mansi, Dr Richard Baird, Dr Richard Griffiths, Dr Caroline Michie, Dr Eleni Karapanagiotou, Dr Sam Turnbull, Dr Alison Young, Dr Roshan Agarwal, Dr Mark Hill, Dr Mark Openshaw, Dr Helena Earl, Professor David Cunningham, Professor Peter Selby
Authors on behalf of the Association of Cancer Physicians, UK
1. Wise PH. Cancer drugs, survival, and ethics. BMJ. 2016 Nov 9;355:i5792.
2. Sundquist M, Brudin L, Tejler G. Improved survival in metastatic breast cancer 1985-2016. Breast Edinb Scotl. 2016 Oct 28;31:46–50.
3. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol Off J Am Soc Clin Oncol. 2009 Aug 1;27(22):3677–83.
4. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev. 2010 May 12;(5):CD007309.
5. Stratified Medicine Programme [Internet]. Cancer Research UK. 2014 [cited 2016 Nov 14]. Available from: http://www.cancerresearchuk.org/funding-for-researchers/how-we-deliver-r...
6. Wallington M, Saxon EB, Bomb M, Smittenaar R, Wickenden M, McPhail S, et al. 30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study. Lancet Oncol. 17(9):1203–16.
7. Baird R, Banks I, Cameron D, Chester J, Earl H, Flannagan M, et al. An Association of Cancer Physicians’ strategy for improving services and outcomes for cancer patients. Ecancermedicalscience. 2016;10:608.
8. Consent forms for SACT (Systemic Anti-Cancer Therapy) [Internet]. Cancer Research UK. 2016 [cited 2016 Nov 14]. Available from: http://www.cancerresearchuk.org/health-professional/information-for-your...
Competing interests: No competing interests