Peter C Gøtzsche, Institute for Scientific Freedom
If you get cancer, one of the most important questions is to decide if you should accept or decline chemotherapy. By far most patients accept chemotherapy, likely because they think that if it wasn’t worthwhile, it wouldn’t be offered.
This is a mistake.
Chemotherapy is rarely worthwhile
We hear a lot about progress against cancer. This narrative increases donations to cancer charities and benefits doctors who do research on cancer therapies, and it affects not only the public but the doctors themselves. Their belief in the effectiveness of chemotherapy is so strong that virtually every cancer patient is offered chemotherapy, even in the last few weeks before they die.1
The truth is that, with a few exceptions, little progress has been made the last 70 years when it comes to chemotherapy.2,3
A 2004 review of the randomised trials showed that the overall contribution of curative and adjuvant cytotoxic chemotherapy to five-year survival of adult cancer patients in USA and Australia was only 2%.3 In the vast majority of cancer cases, over 90%,4 the effect of chemotherapy was marginal, corresponding to a life extension of only three months. And new drugs for solid cancers approved by the European Medicines Agency increased survival by only one month compared to other regimes.4
But when you analyse specific types of cancers, there are a few where chemotherapy has significant benefits. The contribution to five-year survival was 39% for testicular cancer, 39% for Hodgkin’s disease, 12% for cervical cancer, 11% for lymphoma, and 9% for ovarian cancer.3
Would doctors accept chemotherapy for themselves?
In Denmark, two journalists asked two prominent doctors what they would do if they got cancer and were offered chemotherapy that gave them a poor chance of surviving. Both would refuse the chemotherapy and one explained he would prefer to enjoy the life he had left.5
Such reasonable ideas have powerful enemies in interest groups. The chair of the Danish Cancer Society, Frede Olesen, reprimanded the doctors, saying they harmed the trust between patients and doctors.6
They didn’t, in my opinion. They gave sound and honest advice to the public, which is what the public needs. The patients should enjoy the same privileges as health professionals, and few oncologists and nurses are willing to accept the chemotherapy their patients endure for minimal benefit.7 In elderly patients, aggressive treatment is even more misplaced. What is most important to them is to maintain their independence and dignity,8 not to gain a few extra weeks of doubtful quality. Ending our lives spending time with our loved ones is far more attractive than being pestered by the toxic effects of chemotherapy, with frequent hospital admissions, which increase the risk that we will die in a hospital bed rather than at home.
I have often witnessed the horrible consequences for the patients, their friends and relatives of fighting till the bitter end. I have also met with people who have been ruthlessly exploited by charlatans, and here is an example.
Regional chemotherapy in Germany
In 2010, the Danish Cancer Society asked me to review the evidence for regional chemotherapy, which was offered by Professor Thomas J. Vogl at the Göthe University in Frankfurt, because hundreds of Danish cancer patients had sought treatment there, at their own expense. For example, patients with bowel cancer with liver metastases could have chemotherapy injected directly into the metastases.
My deputy director reviewed 43 original studies and 8 review articles, and we concluded that there was no evidence that the treatment had any effect on survival.9 Vogel’s scientific articles were of appallingly poor quality. He described some treated patients, with no control group, and with no explanation of who was included and who was not. The methods used to analyse the data were flawed and Vogl consistently confused a decrease in the size of the cancerous nodule with an improvement for the patient even though it is well known that some forms of chemotherapy that shrink tumours increase mortality. In the extreme, if the dose of the chemotherapy is very high, while it might kill the tumour, it might also kill the patient.
Misleading statistics about progress against cancer
The type of data we see most often in scientific papers and in the media is the survival after the diagnosis is made, e.g. the 5-year survival rate, but such results are misleading.
Today, if someone receives a cancer diagnosis, as opposed to getting a diagnosis a decade ago, there could be an increase in 5-year survival, even though people with that diagnosis die at the same age, on average, as ten years ago.
This can happen, for example, if people become more cancer aware and see doctors at earlier stages of the disease. Or if they attend cancer screening, as the next examples illustrate.
In 2016, a journalist wrote that, after Denmark had had the poorest cancer survival, cancer treatment in Denmark was now equally good as in our neighbouring countries.10 The title of his article was sensationalist: “Cancer – has the code been broken?”
His argument was that 5-year survival for breast cancer had risen from 82% to 88% in 20 years. But in the meantime, we had introduced screening for breast cancer in Denmark, which leads to 33% overdiagnosis.11 Many healthy women who would never have received this diagnosis in their lifetime if they had not gone to screening will get a diagnosis of breast cancer. As none of them would have died from breast cancer, this improves 5-year breast cancer survival. I calculated that, because of the overdiagnosis, the true increase in survival is nowhere near 6% but closer to 2%.12
Sometimes, the annual number of cancer deaths is related to the number of cancers, but such information can be similarly misleading.
As an example, the mortality rate (number of cancer deaths per 100,000 inhabitants) for malignant melanoma was fairly constant for many years, whereas the incidence was steeply increasing.13 If the detected cancers were always deadly without treatment, it would mean outstanding progress in the treatment of malignant melanoma. But this was not the case. Many more diagnoses are made in recent years because people are more likely to get their brown spots examined. The surprising fact is that almost all these additional cancers are harmless.10 Chemotherapy doesn’t work for malignant melanoma, but biological substances have been introduced that improve survival.14
Screening for a cancer is useless if it does not make people live longer.10 When the patients do not live longer, but live longer with the knowledge that they have cancer because the clock started earlier, the “early detection” of cancer is unequivocally harmful. There are many such offers of useless screenings on the private market.12
Randomised trials
In randomised trials, there is no problem with using 5-year survival rates because everyone has cancer to begin with and, on average, they will have had the cancer for a similar length of time in the two groups.
But even these studies can be seriously biased. A popular outcome is disease-free survival, but, as already noted, some cancer treatments that do not improve survival lead to tumour shrinkage. It therefore takes longer before “the disease comes back” on a scan, which, moreover, is a misleading concept because it never went away.
A related problem in cancer trials is that the outcome is almost always cancer-specific mortality. As chemotherapy is toxic, it increases mortality, e.g. because of infections. Therefore, the only unbiased mortality measure is mortality from any cause, which is also what matters for patients. They want to stay alive and are not concerned about which cause of death that will eventually be written on their death certificate.
A worked-through example: polychemotherapy for breast cancer
In the review mentioned above, the contribution of chemotherapy to 5-year survival of breast cancer was only 1.4%.3
This is not what people are being told, and even I thought that chemotherapy was quite effective until I looked up the evidence when I wrote a book about how people can find reliable information on the Internet.12
I found a large meta-analysis of trials in early breast cancer15 (early means that the cancer and any affected lymph nodes can be surgically removed). For women aged 50 to 69 years who received polychemotherapy, the breast cancer mortality was 47.4% after 15 years, compared to 50.4% in women who did not get polychemotherapy. The difference was only 3.0%, but it was reassuring that half of the women had not died from breast cancer after 15 years, which is because this cancer usually has a good prognosis.
Although the meta-analysis takes up 31 pages in The Lancet, total mortality is nowhere to be found. The readers are referred to graphs in a web appendix, but the paper does not say where one can find the appendix, which hurled me into the most bizarre type of academic playing hide-and-seek I have ever encountered.12 I used a lot of time on this and had given up when I decided to try one last time. I found the relevant graph in a document with 249 pages of graphs, often more than one on each page, and with no meaningful legends or index to help readers find what they were looking for. The difference in total mortality was only 2.1% (53.6% versus 55.7%), which means that quite a few women had been killed by the polychemotherapy who would not have been killed with single agent chemotherapy.
People – including doctors – often say that a small average benefit can be worthwhile because some patients benefit more than others: “Perhaps I will be one of the lucky ones who adds 6-12 months to my life, and not the 1-3-month average.” And sometimes, patients refer to other patients who lived many years after chemotherapy.
These are false hopes. Cancer has highly variable growth rates, and some patients are therefore destined to live longer than others. We can only make rational decisions if we base them on the average life extension obtained in randomised trials and also know if the chemotherapy has any effect on total mortality.
Our spineless drug regulators
Our drug regulators are part of the problem with the current level of overtreatment with chemotherapy. Over the last couple of decades, they have lowered the standards considerably for approval of new cancer drugs, particularly in the USA.
Drug regulators approve new cancer drugs without having a clue whether they are better or worse than those we already have, or even just better than doing nothing.16,17 This broken system has resulted in huge expenditures on cancer drugs with certain toxicity but uncertain benefit.
The authors of a 2019 review reported that approximately one-third of cancer drugs are approved by the US Food and Drug Administration based on response rate, which is the percentage of patients whose tumours shrink beyond an arbitrary threshold, typically assessed in a single-arm study.18 Thus, some new cancer drugs are approved without any evidence from a randomised trial that they work.
Even when randomised trials have been performed and marginal effects have been found, these trivial differences may disappear when the drugs are used in real life on patients suffering from co-morbidities.17
Conclusions
I agree with my Danish colleagues.5 Apart from testicular cancer and lymphomas, I cannot imagine any cancer that would make me accept chemotherapy should I get cancer.
Obituaries often say: “He lost the battle against cancer.” But why the war rhetoric? Why not say something positive, like “He had a good life,” as most of the life was not about fighting cancer?
And should we fight at all? We should not fight a battle we have already lost, and it will surprise most people, doctors included, that, unfortunately, this is the case for most cancer patients.
References
1 Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol 2015;1:778-84.
2 Bailar JC 3rd, Smith EM. Progress against cancer? N Engl J Med 1986;314:1226-32.
3 Morgan G, Ward R, Barton M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin Oncol 2004;16:549-60.
4 Wise PH. Cancer drugs, survival, and ethics. BMJ 2016;355:i5792.
5 Jensen JH, Korsgaard P. Vi ville droppe kemoen og nyde livet. Ekstra Bladet 2012;16. marts.
6 Dreier J. Kemoterapi eller ej? Kræftens Bekæmpelse 2012;19. marts.
7 Slevin ML, Stubbs L, Plant HJ, et al. Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses, and general public. BMJ 1990;300:1458–60.
8 Watts G. Why the exclusion of older people from clinical research must stop. BMJ 2012;344:e3445.
9 Regional kemoterapi – ingen mirakelkur. Pressemeddelelse, Danish Cancer Society 2010;16. april.
10 Larsen K. Kræft – er koden knækket? Ugeskr Læger 2016;178:1566-9.
11 Jørgensen KJ, Zahl P-H, Gøtzsche PC. Overdiagnosis in organised mammography screening in Denmark: a comparative study. BMC Women’s Health 2009;9:36.
12 Gøtzsche PC. Survival in an overmedicated world: look up the evidence yourself. Copenhagen: People’s Press; 2019.
13 Welch HG, Schwartz L, Woloshin S. Overdiagnosed: making people sick in the pursuit of health. Boston: Beacon Press; 2011.
14 Pasquali S, Hadjinicolaou AV, Chiarion Sileni V, et al. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2018;2:CD011123.
15 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687-717.
16 Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing; 2013.
17 Prasad V. Do cancer drugs improve survival or quality of life? BMJ 2017;359:j4528.
18 Chen EY, Raghunathan V, Prasad V. An overview of cancer drugs approved by the US Food and Drug Administration based on the surrogate end point of response rate. JAMA Intern Med 2019;179:915-21.