Affiliation of authors: Istituto Nazionale Tumori, Milan, Italy.
Correspondence to: Romano Demicheli, M.D., Direzione Sanitaria, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.
Karrison et al. (1) retrospectively studied 1547 patients with breast cancer operated on during the period from 1945 through mid-1987 to evaluate the limit of breast cancer dormancy. In the report, the authors stated that they "did not see evidence for a second peak in the hazard curve as reported by Demicheli et al." (2) and drew evidence for tumor dormancy from the elevation of mortality rates out to 20 years after primary tumor removal and from the detection of new recurrences even after this time. While we agree with the authors' conclusions about the occurrence of tumor dormancy, we wish to focus on the question of why they did not observe a two-peaked hazard curve, as has been confirmed by other reports (3-5).
In our opinion, the fact that two peaks were not observed could be due to both the chosen end point and to the characteristics of their data base. While the events "first recurrence" and "death from breast cancer" reliably identify patients who are not cured, the combined event "first recurrence or death from breast cancer" is not a useful end point for study of the time-dependent structure of the hazard of each of the two events. First recurrence and death may have different time distributions, and the use of the combined end point may obscure the fine structure of the hazard curve of each event. Moreover, since Karrison et al. showed that an association existed between the time from mastectomy to first recurrence and the subsequent residual survival time, such an association may affect the hazard curve of "first recurrence or death from breast cancer." Even more confounding noise, masking the time dependence of hazard function, may have resulted from the possible inadequate reliability of their event dating. Indeed, the examined time period, during which patients underwent their surgical treatment, presumably outside clinical trials, is quite long. Moreover, about half of the patients had some local or systemic treatment in addition to surgery. Last, data were obtained indirectly. We are aware of difficulties encountered when time to recurrence is to be accurately identified or when cause of death has to be labeled. These difficulties even occur for patients entering controlled clinical trials and undergoing direct follow-up in a single institution.
There are other issues to be considered, however. We analyzed the mortality data reported in
Table 1 by Karrison et al. (1). To reduce the uncertainties involved in
assigning causes of death, we used the life-table method (6) to estimate
the yearly discrete hazard for time to death from all causesi.e., the conditional
probability of death within each 1-year interval, given that the patient is alive at the beginning of
the interval. Similar analysis was performed for the 1173 patients who underwent mastectomy in
the Milan study (2), a population whose first treatment failure was
reported to be double peaked. The results are reported in Fig. 1. The
quantitative and qualitative similarity in pattern between the Karrison et al. and Milan data is
impressive, and the difference in early mortality could reasonably be thought to depend on the
absence of American Joint Commission on Cancer stage III (7) patients
in the Milan series. Both curves display an initial, wide peak at about 3 to 4 years and a second,
narrower peak at 8 years.
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REFERENCES
1
Karrison TG, Ferguson DJ, Meier P. Dormancy of mammary
carcinoma after mastectomy. J Natl Cancer Inst 1999;91:80-5.
2 Demicheli R, Abbattista A, Miceli R, Valagussa P, Bonadonna G. Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy. Breast Cancer Res Treat 1996;41:177-85.[Medline]
3 Demicheli R, Miceli R, Brambilla C, Ferrari L, Moliterni A, Zambetti M, et al. Comparative analysis of breast cancer recurrence risk for patients receiving or not receiving adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF). Data supporting the occurrence of "cures." Breast Cancer Res Treat 1999;53:209-15.[Medline]
4 Baum M, Badwe RA. Does surgery influence the natural history of breast cancer. In: Wise L, Johnson H Jr, editors. Breast cancer: controversies in management. Armonk (NY): Futura Publishing Company Inc.; 1994. p. 61-9.
5 Fortin A, Larochelle M, Laverdiere J, Lavertu S, Tremblay D. Local failure is responsible for the decrease in survival for patients with breast cancer treated with conservative surgery and postoperative radiotherapy. J Clin Oncol 1999;1:101-9.
6 Gehan AE. Estimating survival functions from the life tables. J Chron Dis 1969;21:629-44.[Medline]
7 Beahrs OH, Henson DE, Hutter RV, Myers MH, editors. Manual for staging of cancer. 3rd ed. American Joint Commission on Cancer. Philadelphia (PA): Lippincott; 1988.
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