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Weighing the Benefits

Many people criticize chemotherapy for its deficiencies. For instance, it is common knowledge that chemo can cause serious adverse effects, some of which oncologists cannot easily overcome. Patients may lose their hair, become nauseous and vomit, experience pain or numbness in their hands and feet, lose some of their hearing, or suffer from lingering and debilitating “chemo brain.

Perhaps most insidiously, chemo can diminish the power of the immune system, upon which human survival ultimately depends.

[NOTE: To understand the likelihood of severe side effects of chemotherapy in any particular case, check out the valuable Chemo-Toxicity Calculator of the Cancer and Aging Research Group.]

“Do not neglect medical treatment when it is necessary, but leave it off when health has been restored. Treat disease through diet, by preference, and by refraining from the use of drugs. Abstain from drugs when the health is good, but administer them when necessary.”        
—Bahá’u’lláh (1817-1892), Tablet to a Physician

Chemo is Sometimes Necessary

That said, chemo is sometimes necessary. It is a component in the successful treatment of many pediatric cancers. It can shrink tumors to relieve symptoms and make them more amenable to surgery. After an operation, it can extend the life of people with high-risk cancers of the colon, breast, etc. Even when it does not cure, it may improve quality of life, extend survival, and provide hope to the hopeless. And, oddly, small doses may actually help the immune system in its fight against cancer. For example, it is well-known that:

  • “A single administration of low-dose cyclophosphamide (Cytoxan®) is able to selectively suppress regulatory T cells (Tregs). This effect can be used to counteract immunosuppression in cancer. Combination of cyclophosphamide with other immunomodulatory agents could be a promising approach to treat different forms of advanced cancer.”
  • (Ahlmann M, Hempel G. The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Cancer Chemother Pharmacol. 2016 Oct;78(4):661-71. doi: 10.1007/s00280-016-3152-1. Epub 2016 Sep 19. PMID: 27646791)

Unprotected Chemotherapy

Over the years, we have registered our opposition to what might be called “unprotected chemotherapy.” Over 40 years ago we published The Cancer Industry, one of the first exposés of the conventional approach. Midway in our career, we wrote Questioning Chemotherapy. Years later, we called for a thorough reform of oncology, Cancer, Incorporated. It is tempting to throw up one’s hands at this type of treatment. However, as part of a balanced view, chemo can sometimes be useful to cancer patients.

One big problem is that oncologists are unable to accurately predict whether or not a particular drug or drug combination will kill any individual’s cancer and bring about remission. Their prescription is almost always based on statistics. It is, in effect, an educated guess, driven by guidelines laid down by a committee of experts. These guidelines (especially those of the National Comprehensive Cancer Network, or NCCN) are usually based on the results of randomized controlled trials (RCTs) that are presented at big medical meetings and published in leading journals. But one big problem is that, almost always, only a middling portion of the patients in the trial actually have a meaningful response to the treatment.

The Case of Endometrial Cancer

We can illustrate this with reference to one randomly chosen type of cancer: advanced endometrial cancer (a.k.a. cancer of the uterus). These authors, associated with the MRC Clinical Trials Unit, London, U.K., evaluated 14 clinical trials performed between 1974 and 2005. Eight of these compared “more” with “less” chemotherapy. This review encompassed a total of 1,419 patients and showed that there was only a modest increase in overall survival (OS) with the higher dose of chemo. “However,” wrote the authors, “serious acute toxicities were more common in women randomized to the more-intense chemotherapy regimens.”

These independent reviewers found the following:

Best supportive care” (BSC) means essentially no attempt at a curative therapy, chemo, or otherwise, but just keeping the patient comfortable. Since there were no comparative studies of chemo versus no-chemo, we cannot really say that chemo works in this situation!

What was the actual gain in the median overall survival (OS) by taking the more intense chemo regimen? That is hard to know because many clinical trials only report “response rates” or “median progression-free survival” (which are both indirect, “surrogate” markers of benefit) instead of “median overall survival,” which is a measure of real benefit to the group as a whole.

One Study

We can, however, look at one large and representative study, that of J. Tate Thigpen, MD, of the University of Mississippi School of Medicine, Jackson. This trial examined the results among 150 patients who received either the drug doxorubicin (Adriamycin®) alone versus those receiving a “doublet” of two such agents: doxorubicin (Adriamycin®) and cisplatin (Platinol®). The “response rate” went up dramatically in those receiving the two-drug doublet, with the single drug at 25% versus 42% of those receiving the combination. This supports our conclusion that in the best-case scenario, 58% of these patients’ tumors did not “respond” to the treatment.

Similarly, the median progression-free survival (PFS) was almost double (3.8 months versus 5.7 months) with the combination. But, to repeat, neither “progression-free survival” (PFS) nor the “response rate” (RR) is a direct measure of real benefit. The real benefit has to be measured by an increase in median overall survival (OS), which means actual time added to the patient’s lifespan (not to mention the maintenance of a good quality of life). And here there was no significant difference; with the two-drug combination, it was 9.0 months versus 9.2 months with the single agent (i.e., a one-week non-significant decrease in survival with the more powerful combination).

Two-Drug Regimen

Meanwhile, with the two-drug regimen,

  • “Nausea, vomiting, and hematologic [blood] toxicities were common. The combination produced more grade 3 to 4 leukopenia [i.e. loss of white blood cells, 62% v 40%], thrombocytopenia [i.e., loss of platelets, 14% v 2%], anemia [i.e., loss of red blood cells, 22% v 4%], and nausea/vomiting (13% v 3%).”
  • (Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, Liao S. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a gynecologic oncology group study. J Clin Oncol. 2004 Oct 1;22(19):3902-8. doi: 10.1200/JCO.2004.02.088. PMID: 15459211)

Obviously, results vary from study to study. A few do show a slight improvement in overall survival. But the picture as a whole is not a positive one. And the same story could be written about many other cancers. It may surprise the reader how uncertain oncologists often are about the best treatment.

Summary

Even for this common cancer, in this situation, any particular single drug, or two-drug regimen, appeared almost as good as any other. And no one really knew that chemotherapy was better than endocrine (hormonal) therapy alone or no curative therapy at all. After all this effort, there was inadequate data overall for truly evidence-based decision-making.

Patients are rarely told that chemotherapy in such cases may only help them live, at best, an average of six weeks longer. (See the American Cancer Society’s write-up on this topic.) But during that time they may be exposed to numerous side effects from doxorubicin (Adriamycin®), paclitaxel (Taxol®), cyclophosphamide (Cytoxan®), methotrexate, cisplatin, and/or vinblastine.

Cochrane Collaboration

The National Comprehensive Cancer Network (NCCN), among others, recommends carboplatin and paclitaxel as the preferred systemic treatment for recurrent, metastatic, or high-risk diseases. But many other drugs and combinations are mentioned as possible substitutes. This is in line with the Cochrane Collaboration findings that one combination seemed about as good as any other, and none of them had been rigorously tested against best supportive care (or placebo).

This supports our general conclusion that cytotoxic drugs are good at several things, but that they have minimal effect on survival because they do not target the crucial cancer stem cells (CSCs) that actually drive cancer progression.

For more on the question of Chemotherapy, see Why Can’t We Get Low-Dose Chemotherapy?