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The Cancer Journal - Volume 9, Number 1 (January-February 1996)

editorial


Adjuvant chemotherapy of breast cancer should be banned



Despite continuing efforts to eradicate breast cancer upon its detection, from 1930 to 1990, age-adjusted mortality from breast cancer had remained virtually constant (1-3). Sixty years of continuous debate about the best treatment for breast cancer has failed to improve the life prospect of the average patient. No other epidemiological phenomenon is so stable. All other statistics vary continually. This statistic highlights the failure of breast cancer treatment and its underlying theories, particularly that of W. S. Halsted (1852-1922). According to this theory, the tumor is initially localized, subsequently it spreads to adjacent tissues, and only at later stages seeds metastases. As tumor removal generally fails to cure most patients, it obviously spreads before its detection. The alternative approach attempts to destroy tumor cells with chemotherapy, either before metastasis detection, or afterwards. As these agents are poisons, both approaches are risky for the patient. Should chemotherapy be given before metastasis is detected as suggested by the adherents of adjuvant chemotherapy, or should one wait until they emerge? The conservative approach is justified by the following statistics.

Long survival with micrometastasis - The cancer survival report No. 5 from the US National Institutes of Health describes survival of 3369 patients with regional breast cancer diagnosed during 1950-1954 (4,5). Treatment consisted of mastectomy with or without irradiation. Fig. 1 illustrates two facts. While 76% patients succumbed to the disease, 24% survived 20 years. Most of the time they were in remission and healthy. Since they eventually died from their disease, we can conclude retrospectively that all carried undetected micrometastases. Some carried metastasis for at least 19 years. For example, in a woman who lived with micrometastasis that long, during this prolonged remission her organism apparently "knew" how to live with, and adapt to micrometastasis. Let us examine the fate of the 10% of women who died in the period between 10-20 years. 34% survived 10 years, 24% survived 20 years, and 10% died from breast cancer between year 10 and 20. Since they lived at least 10 years we may conclude that they carried hidden micro-metastases for 10 years. For most of these years they were healthy, otherwise they would have been treated. Micro-metastasis itself may not be harmful. In the U.S., 33.6% of white females with breast cancer have regional disease (6). The age-adjusted incidence for all stages was 113.6/100,000 (7). 38/100,000 females carried micrometastases for at least 10 years (= 0.336*113.6) which makes about 9,500 patients per year in the entire country. This estimate is extremely conservative. Actually, thousands of apparently healthy females carry micro-metastasis for at least 10 years. Should they be poisoned with adjuvant chemotherapy? The nature of this adaptation to micro-metastasis is still unknown. Supposing that medicine could harness it for another 20 years, cancer would turn into a benign disease. We may thus conclude that unless a metastasis impinges upon a vital organ, it is relatively harmless.

Long survival after adjuvant chemotherapy - Twenty years ago the Instituto Nationale Tumori in Milan, Italy, started treating females with regional breast cancer with 12 cycles of CMF (cyclophosphamide, methotrexate, and fluorouracil) (8). "386 women were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant combination chemotherapy (207 women)." The 20-year survival of untreated Italian and American females was the same 24.6% (=44/179) (Fig. 1). CMF-treated females managed somewhat better, 33.8% (=70/207) survived 20 years ( p=0.04). These results are somewhat disappointing. A more significant difference, e.g., p=0.001, would be more convincing. Since 24.6% survived without treatment, only about 10% (=33.8%-24.6%), benefited from chemotherapy. 90% would be better off without treatment. The probability of relapse-free survival was 26.8% (=48/179) in untreated, and 35.7% (=74/207) (p=0.004). As all "relapse free" patients carried undetected metastases, this statistic is clinically meaningless. The authors seek support for their approach in a meta-analysis study (9), with all its obvious flaws (10). In addition to these meager results, adjuvant chemotherapy for micro-metastasis is also unjustified for other reasons: 1. Tumor cells are dormant and do not cycle, while chemotherapy destroys only cycling cells. 2. Initially, the tumor looks like normal tissue and is called minimal deviation tumor. At this early stage, the therapeutic margin of the chemotherapy poisons is extremely narrow. Treatment destroys "bad" and "good" cells, and the risk to the patient is high. 3. With time, tumors become resistant to chemotherapy. The earlier the treatment, the greater the risk of resistance. Prudent treatment requires therefore postponing chemotherapy to later stages when other means fail. 4. The 90% of CMF treated patients may not have responded to treatment since their tumor was already resistant. 5. Apparently, chemotherapy slows metastatic growth indirectly, by chemical castration. Particularly since "CMF failed to improve outcome significantly in post-menopausal women" (8). Imagine chemical castration in younger women. Adjuvant chemotherapy is toxic and useless and should therefore be forbidden!

Gershom Zajicek
Gershom@md2.huji.ac.il


1. McKay FW, Hanson MR, Miller RW. Cancer mortality in the US: 1950-1977. NIH Publication No. 82-2435, 1982.

2. Silverberg E, Lubera J. Cancer statistics. CA -A Cancer Journal for Clinicians 40, 16-17, 1990.

3. Zajicek G. How to evaluate unproved methods in oncology? The Cancer J. 5, 180, 1992.

4. Axtell LM, Ardyce J, Asire MS et al. Cancer patient survival report No. 5 DHEW Publ No. (NIH) 77-992, 1976.

5. Zajicek G. Wisdom of the body in cancer.The Cancer J. 7, 96-97,1994.

6. Miller BA, Gloeckler Ries L, Hankey BF et al. SEER Cancer Statistics Review 1973-1990. NIH Publication No. 93-2789, 1993.

7. Gloeckler Ries L, Miller BA, Hankey BF et al. SEER Cancer Statistics Review 1973-1990. Tables and Graphs NIH Publication No. 94-2789, 1994.

8. Bonadonna G, Valagussa P, Moliterini A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer.The results of 20 years of follow-up. N Engl J Med. 332, 901-906, 1995.

9. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1-15, 71-85, 1982.

10. Zajicek G. Meta-analysis and chaos. The Cancer J. 4, 152-153, 1991.

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