The Grand Illusion of Chemotherapy[1]

It is five years since I wrote “Questioning Chemotherapy”

In those five years, about 275,000 peer-reviewed articles have appeared in Medline on the topic of cancer, including 25,000 on cancer chemotherapy. An additional 10,000 abstracts have been presented at the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research annual meetings. Out of this vast amount of research a total of 70 new approvals have been made by the US Food and Drug Administration (FDA) for drugs used in the treatment of cancer patients.

Has all this activity resulted in more effective treatments for cancer? Have I modified the views expressed at prior meetings of the German Society of Oncology meetings that chemotherapy is both ineffective and inappropriate for the vast majority of patients to whom it is given? Has the current crop of anticancer drugs been proven to improve the lot of cancer patients?

The brief answer is, No. If anything, the value of cancer chemotherapy is less documented today than it was five years ago. In fact, randomized clinical trials with appropriate controls are rarely performed in conventional oncology before or after the approval of a new drug. When studies are reported as positive that is usually in comparisons with other agents, or it is a measurements of surrogate markers rather than of increased survival.

Drugs may be reported to increase survival but upon closer examination this turns out to be an increase in “relapse-free survival,” or “time to recurrence,” and not an actual increase in median overall survival. Yet, I would argue that only an increase in overall survival conveys a true benefit to the patient. A patient who has an increased relapse-free period, but no increase in actual life time, is not actually benefited by treatment, except in a psychological sense. Real benefit in terms of overall survival is rarely demonstrated by chemotherapy for the solid tumors of adults.

This is what I call the “Grand Illusion of Chemotherapy.” It is the idea that the shrinkage of tumors, or improvement in tumor markers, or increased relapse-free survival, necessarily correlate with actual benefit to patients. Surveys have shown, and common sense tells us as well, that the two outcomes that cancer patients seek from chemotherapy are [[1]] an improvement in quality of life, and [[2]] an increase in their actual survival. Tumor shrinkages are not a high priority [[1]].

Medical oncologists, by contrast, tend to concentrate on the shrinkage of tumors. Such shrinkages are called “responses.” The FDA defines a complete response as a complete disappearance of all clinical and X-ray signs of cancer for one month or more. A partial response refers to a 50 percent or greater decrease in measurable tumor size for one month or more. In the past, the FDA also required some proof of life prolongation. But this stringent requirement led to very few drug approvals. From the 1940s to the mid-1990s, in fact, only about three dozen drugs had been approved by the FDA, less than one per year. The FDA's reluctance to approve drugs based on shrinkages angered the pharmaceutical industry, as well as some oncologists and patient activists. So, in the mid-1990s the government relaxed these requirements and since then FDA has approved many new drugs. Our task is to see if these new approvals have actually resulted in improved treatments.

MAJOR ONCOLOGY DRUG APPROVALS SINCE 1996 (in order of approval) GENERIC DATE* BRAND NAME INDICATION APPROVAL 1. anastrozole Arimidex breast IV 1996 2. docetaxel Taxotere breast IV, lung IV 1996 3. mitoxantrone Novantrone prostate (pain) 1996 4. irinotecan Camptostar colon IV 1996 5. gemcitabine Gemzar NSCLC 1996+ 6. topotecan Hycamptin ovarian 1996 7. letrozole Femara breast IV 1997 8. rituximab Rituxan lymphoma 1997 9. porfimer sodium Photofrin lung IV 1998 10. capecitabine Xeloda breast IV 1998 11. trastuzumab Herceptin breast IV 1998++ 12. temozolomide Temodar brain (AA) 1999 * Drugs are listed in order of initial approval. Some have had additional indications at later date. A complete list is available at http://www.fda.gov/oashi/cancer/cdrug.html. In my discussion I have rearranged the order somewhat, but have roughly adhered to this chronological order.+ Approved for use with cisplatin++ Approved for use with paclitaxel

I will briefly review the record of six of these drugs, plus oxaliplatin. These are the major products that have generated publicity that at times has bordered on hysteria.

01 A speech to German Society of Oncology (DGO) October 28, 2000, Baden-Baden

References

• 01 CA Cancer J Clin. 2000;  50 123-32
• 02 Cancer. 1998;  83 1142-1152
• 03 J Clin Oncol. 1999;  17 2341-54
• 04 J Clin Oncol. 2000;  18 2354-62
• 05 Lancet. 2000;  (355) 1041-1047
• 06 Anticancer Drugs. 1999;  10 155-62
• 07 Semin Oncol. 1996;  23 (5 Suppl 10) 77-81
• 08 Semin Oncol. 1999;  26 89-95
• 09 Semin Oncol. 1999;  26 78-83
• 10 Blood. 1998;  92 414a-415a
• 11 J clin Oncol. 2000;  18 136-47

01 A speech to German Society of Oncology (DGO) October 28, 2000, Baden-Baden

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