Correspondence
Adjuvant Chemotherapy in Breast Cancer
N Engl J Med 1995; 333:596-597August 31, 1995
- Article
To the Editor:
Bonadonna et al. (April 6 issue)1 addressed the effect of drug-induced amenorrhea on the outcomes of 78 premenopausal patients treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) (Table 2 of the article). In 50 patients who had drug-induced amenorrhea and in 28 patients who did not, the rates of 20-year relapse-free survival were 39 percent and 30 percent, respectively. The authors concluded that there was no significant difference in relapse-free survival between these two groups. We estimated the hazard ratio for relapse-free survival between women with drug-induced amenorrhea and those without it from 10 published studies. The hazard ratio ranged from 0.39 to 0.86, with a median of 0.56. Therefore, if we assume that drug-induced amenorrhea is associated with a 40 percent reduction in the rate of relapse, the analysis carried out by Bonadonna et al. in 78 patients had a power lower than 40 percent.
The authors' statement that “drug-induced amenorrhea is not an important predictor of response” contradicts almost all published studies and is not supported by their own data — which, incidentally, show a 22 percent reduction in the risk of relapse at 20 years. Nine of 10 published studies, some of them large,2-5 reported longer periods of relapse-free survival in patients with drug-induced amenorrhea than in those without it. The difference was statistically significant in eight studies. In one of these studies, the prognostic role of drug-induced amenorrhea was also confirmed in terms of overall survival.4
Although these findings do not necessarily imply that the main effect of chemotherapy in premenopausal patients is due to chemical castration, they do indicate that the predictive role of drug-induced amenorrhea should not be denied.
5 ReferencesLucia Del Mastro, M.D.
Massimo Costantini, M.D.
Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, ItalyAngelo Raffaele Bianco, M.D.
University of Naples Medical School, 80131 Naples, Italy1
Bonadonna G ,Valagussa P ,Moliterni A ,Zambetti M ,Brambilla C . Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer -- the results of 20 years of follow-up. N Engl J Med 1995;332:901-906
Full Text | Web of Science | Medline2
Bianco AR ,Del Mastro L ,Gallo C , et al. Prognostic role of amenorrhea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer 1991;63:799-803
CrossRef | Web of Science | Medline3
Goldhirsch A ,Gelber RD ,Castiglione M . The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. Ann Oncol 1990;1:183-188
Web of Science | Medline4
Tormey DC ,Gray R ,Abeloff MD , et al. Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. J Clin Oncol 1992;10:1848-1856
Web of Science | Medline5
Ludwig Breast Cancer Study Group
Web of Science | Medline
To the Editor:
The article by Bonadonna and colleagues is a welcome addition, since it involves a relatively long follow-up. I was confused, however, by two things in this article. The authors state that “48 of 179 patients in the control group were disease-free at 20 years,” yet only 44 of 179 patients in the control group were even alive at 20 years. Also, the authors discuss the “ease of administration and the virtual absence of severe acute toxicity” in relation to the chemotherapy regimen administered, yet only 42 of the 207 patients in the chemotherapy group received at least 85 percent of the planned dosages.
Michael D. Newman, M.D.
Clinton Memorial Hospital, Wilmington, OH 45177To the Editor:
In his editorial on breast-sparing surgery for breast cancer (April 6 issue),1 Henderson says, “Local failure is a particularly difficult consequence of therapy for most patients because it is readily apparent and is thus a constant reminder that the tumor is no longer curable.” This is incorrect. In 1991, the National Surgical Adjuvant Breast and Bowel Project concluded that local failure is curable, saying that “local recurrence is a marker of risk for, not a cause of, distant metastases.”2 Besides the studies cited by Henderson, other studies with 10 years of follow-up have supported this conclusion.3,4 No reliable data support a contrary conclusion. In the study by Jacobson et al. (also in the April 6 issue),5 recurrent disease confined to the ipsilateral breast developed in 19 patients, who were treated with salvage mastectomy. The projected rate of disease-free survival at 10 years is 67 percent. This is not significantly different from that of all the women initially treated with lumpectomy and radiation therapy. I found no data in Stablein's reanalysis of National Surgical Adjuvant Breast and Bowel Project Protocol B-06 suggesting that lumpectomy compromised survival.6 But that trial did not record the size of each recurrent tumor. Clearly, a recurrent tumor that exceeds the size of the primary lesion becomes an added survival threat. How does Henderson conclude that local failure is incurable?
6 ReferencesRichard A. Evans, M.D.
1011 Augusta Dr., Houston, TX 77057-20151
Henderson IC . Paradigmatic shifts in the management of breast cancer. N Engl J Med 1995;332:951-952
Full Text | Web of Science | Medline2
Fisher B ,Anderson S ,Fisher ER , et al. Significance of ipsilateral breast tumor recurrence after lumpectomy. Lancet 1991;338:327-331
CrossRef | Web of Science | Medline3
Crile G Jr ,Esselstyn CB Jr . Factors influencing local recurrence of cancer after partial mastectomy. Cleve Clin J Med 1990;57:143-146
Web of Science | Medline4
Nemoto T ,Patel JK ,Rosner D ,Dao TL ,Schuh M ,Penetrante R . Factors affecting recurrence in lumpectomy without irradiation for breast cancer. Cancer 1991;67:2079-2082
CrossRef | Web of Science | Medline5
Jacobson JA ,Danforth DN ,Cowan KH , et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995;332:907-911
Full Text | Web of Science | Medline6
Stablein DM. Reanalysis of NSABP Protocol B06. Cancer-Fax News from the National Cancer Institute. ID #400027. Potomac, Md.: EMMES Corporation, March 1, 1995.
Author/Editor Response
The authors reply:
To the Editor: Del Mastro et al. attempt to reintroduce the concept of a “prognostic” role for drug-induced amenorrhea following adjuvant chemotherapy in premenopausal women. Amenorrhea depends on the patient's age and the total dose of alkylating agents. Before this side effect begins, patients are at risk for relapse while still menstruating. There are a few techniques for taking this problem into account. In our medical records we reported the date of the last menstrual period for every patient; we therefore used a time-dependent model to analyze our data.1 Although we had a limited number of patients, in this model the relative risk of relapse for women in whom amenorrhea developed was 0.87 (95 percent confidence interval, 0.48 to 1.51; P = 0.65). We emphasize that in contrast to other studies in which amenorrhea was found to be a favorable prognostic factor, our protocol involved CMF chemotherapy alone — that is, without the addition of tamoxifen, prednisone, or fluoxymesterone (Halotestin).2,3
To answer Dr. Newman: we made clear in the Methods section, as well as at the bottom of Table 1, that in the analysis of relapse-free survival second malignant conditions other than contralateral breast cancer and deaths due to other causes were not considered events. At 20 years, 125 of the 179 patients in the control group have died of progressive breast cancer, 10 have died of other causes, 6 are alive with breast cancer, and 38 are alive and free of disease. Adjuvant CMF chemotherapy was indeed easy to administer, it was always given on an outpatient basis, and it was devoid of life-threatening toxicity. Acute hematologic and nonhematologic toxic effects were always mild to moderate and reversible. We have detailed the reasons why only a minority of our patients received the optimal dose of CMF4 — among them, that drug doses were calculated on the basis of ideal rather than actual body surface, that low starting doses of chemotherapy were used in women over 60 years of age, that some patients refused to complete the planned treatment cycles for psychological reasons, and that doses were adjusted downward to avert side effects.
4 ReferencesGianni Bonadonna, M.D.
Pinuccia Valagussa, B.S.
Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy1
Cox DR . Regression models and life-tables. J R Stat Soc [B] 1972;34:187-2202
Bianco AR ,Del Mastro L ,Gallo C , et al. Prognostic role of amenorrhea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer 1991;63:799-803
CrossRef | Web of Science | Medline3
Tormey DC ,Gray R ,Abeloff MD , et al. Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. J Clin Oncol 1992;10:1848-1856
Web of Science | Medline4
Bonadonna G ,Valagussa P . Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981;304:10-15
Full Text | Web of Science | Medline
Author/Editor Response
Dr. Evans contests the point that a local or regional recurrence in skin, lymph nodes, or muscle has the same prognostic effect on survival as recurrence at a distant site. I believe that confusion regarding this point, as with so many other issues of contention concerning breast cancer, arises from the relation between treatment and outcome. It is true that some patients with local recurrences have long survival times after treatment with surgery, radiotherapy, or both; the duration of survival can be decades. This is also true for some patients with distant recurrences. The critical questions are whether there is a relation between the treatment and the survival and whether any patient with recurrent disease is “curable.”
There is marked variation in the behavior of breast cancers. The disease may recur within a few months or up to 40 years after the first treatment. Similarly, survival after recurrence may vary from a few months to several decades. Therefore, an individual physician may treat a few patients who do well by chance alone and conclude that the treatment causes the good outcome. However, such claims based on a small number of patients have been refuted by properly controlled trials. It is in this context that the observations on the use of screening mammography followed by mastectomy and those on mastectomy or radiotherapy or both followed by adjuvant systemic therapy are so remarkable. No other interventions have been demonstrated to prolong survival to the same degree. Certainly there are no similar data for the treatment of recurrent breast cancer, including local recurrences.
A new cancer found entirely within the breast after radiotherapy does not appear to behave like a local recurrence, but rather like a new cancer in the contralateral breast after mastectomy. If the new cancer is of the same stage or a lower one than the original cancer, the patient's prognosis remains largely unchanged.1
1 ReferencesI. Craig Henderson, M.D.
University of California, San Francisco, San Francisco, CA 941431
Harris JR ,Recht A ,Amalric R , et al. Time course and prognosis of local recurrence following primary radiation therapy for early breast cancer. J Clin Oncol 1984;2:37-41
Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
(1998) Radiotherapy and Chemotherapy in High-Risk Breast Cancer. New England Journal of Medicine 338:5, 329-333
Full Text2
Lucia Del Mastro, Marco Venturini, Mario Roberto Sertoli, Riccardo Rosso. (1997) Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: prognostic role and clinical implications. Breast Cancer Research and Treatment 43:2, 183-190
CrossRef
