Journal of Surgical Oncology 43:199-202 (1990)
EDITORIAL COMMENT
Are We Positive About Node Negative Breast Cancer? Patients without nodal metastases now account for 50-60% of all potentially curable patients with breast cancer. This should be a source of satisfaction in view of the relatively good prognosis. The truth is that a substantial number of these patients will eventualy die of dissemination originating from metastases that were present but undetected at the time of initial treatment. For the last 15 years studies periodically have suggested that systemic adjuvant chemotherapy favorably influenced the course of patients without nodal metastases. Randomized trials of adjuvant therapy for selected cases in England, Scotland, Vienna, Milan, and the United States have demonstrated increased freedom from recurrence and in some instances improved survival [ 1-71. Treatment of node negative patients has not had official sanction, however, until recently when a “Clinical Alert” from the National Cancer Institute (May 16, 1988) identified them as appropriate candidates for systemic adjuvant therapy, stating that it could have a “meaningful impact” on the natural history of stage I cancers. The alert made reference to forthcoming papers on the subject that subsequently appeared in the February 23, 1989, issue of The New England Journal of Medicine. The publications concerned four large randomized trials conducted by prestigious cooperative groups. Two were conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), the first of which involved 2,644 women 70 years of age or less with estrogen receptor (ER)-positive tumors who were randomized to receive tamoxifen or a placebo twice daily for 5 years in double-blind fashion (protocol B-14) [8]. At the end of 4 years a 6% improvement in survival free from disease was observed (83% vs. 77%), and this was shared by both premenopausal and postmenopausal patients. Tamoxifen more than trebled the risk of phlebitis, and one treated patient died of pulmonary embolism. The second NSABP study (protocol B-13) involved 679 women and the same patient selection except that tumors were ER negative [9]. l’hese patients received 1 year of cyclic sequential methotrexate and fluorouracil parenterally with leucovorin rescue. After 4 years a 9% improve0 1990 Wiley-Liss, Inc.
ment in disease-free survival was observed (80% vs. 71%), and the gain was significant in both pre- and postmenopausal patients. The third report, an intergroup study led by the Eastern Cooperative Oncology Group, involved 406 women with ER-negative tumors of any size or ER-positive tumors 3 cm or greater in diameter [lo]. The treated patients received six 4 week cycles of combination chemotherapy with cytoxan, methotrexate, fluorouracil, and prednisone (CMFP). After a median of 3 years, a 15% improvement in disease-free survival was evident in favor of the group that received chemotherapy (69% vs. 84%). Although all age groups benefitted, the effect was greatest for premenopausal women. Severe drug related toxicity was sustained by 33% of treated patients and caused one death. Finally, the Ludwig Breast Cancer Study Group, based in Switzerland, randomized 1,275 women 65 years of age or less to a single 2 week perioperative cycle of cytoxan, methotrexate, and fluorouracil (CMF) plus leucovorin or to no treatment and, after a mean follow-up of 4 years, found a 4% improvement in disease-free survival (77% vs. 73%) [ 1 I]. The difference was significant overall and for the subgroup of ER-negative patients. Unfortunately, three patients died from treatment. These reports raised the issue of whether systemic adjuvant therapy should now be standard for all node negative patients with breast cancer, whether this is cost effective, and whether the anticipated benefits justify the risks. Two editorials that accompanied the articles presented entirely different assessments [12,13]. Dr. Vincent DeVita considered the reductions in the risk of recurrence “impressive,” remarked on the minimal toxicity of two of the chemotherapy programs, and concluded that “all women with newly diagnosed localized invasive breast cancer can and should be offered some form of systemic treatment.” William McGuire, on the
Accepted for publication December 5, 1989 Address reprint requests to Dr. William L. Donegan, Department of Surgery, 950 North 12th Street, Milwaukee, W1 53201.
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YEARS AFTER MASTECTOMY Fig. 1. The prognosis of patients treated surgically with radical or modified radical mastectomy for invasive carcinoma of the breast with uninvolved axillary lymph nodes shows progressive improvement with
decreasing clinical size of the primary tumor. No recurrences were observed during the first 5 years among 17 patients with tumors less than 1.0 cm in diameter.
other hand, was not convinced. He saw the benefits as limited, pointed to the absence of an improvement in survival and the considerable toxic effects, and questioned whether the benefits justified the cost of treating all node negative patients. The direct cost of treating each patient in the four studies varied from $398 to $5,920. For the estimated 5,040 patients who would benefit from treatment, 64,960 node negative patients would have to be treated with regimens to which they could not respond at a cost of approximately $338,000,000 per year. McGuire urged that only patients with high risk for recurrence as judged by tumor size, steroid receptors, mitotic index, nuclear grade, and ploidy be considered for adjuvant treatment and not those with tumors less than 2 cm in diameter or diploid tumors with a low S phase. Commenting in a separate publication on the ethical considerations involved in clinical trials, and on these trials in particular, Mueller cautioned that minimal benefits do not of themselves create standard therapy [ 141. Speaking to the American College of Surgeons, Balch questioned whether the patients in the studies were representative and also recommended treatment only of high-risk patients [15]. In three of the studies, most tumors less than 1 cm in diameter were excluded by the requirement for quantitative measurement of tumor estrogen receptors, as were many elderly patients because of arbitrary age limitations. He estimated that restrictions
permitted no more than one-third of node negative patients to be eligible for the NSABP protocols. The disease-free survivals of controls in these studies, which ranged from 69 to 77% after only 3-4 years, were less than is commonly observed among node negative patients with small tumors. Balch also advised against treating patients with small (
EDITORIAL COMMENT
Are We Positive About Node Negative Breast Cancer? Patients without nodal metastases now account for 50-60% of all potentially curable patients with breast cancer. This should be a source of satisfaction in view of the relatively good prognosis. The truth is that a substantial number of these patients will eventualy die of dissemination originating from metastases that were present but undetected at the time of initial treatment. For the last 15 years studies periodically have suggested that systemic adjuvant chemotherapy favorably influenced the course of patients without nodal metastases. Randomized trials of adjuvant therapy for selected cases in England, Scotland, Vienna, Milan, and the United States have demonstrated increased freedom from recurrence and in some instances improved survival [ 1-71. Treatment of node negative patients has not had official sanction, however, until recently when a “Clinical Alert” from the National Cancer Institute (May 16, 1988) identified them as appropriate candidates for systemic adjuvant therapy, stating that it could have a “meaningful impact” on the natural history of stage I cancers. The alert made reference to forthcoming papers on the subject that subsequently appeared in the February 23, 1989, issue of The New England Journal of Medicine. The publications concerned four large randomized trials conducted by prestigious cooperative groups. Two were conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), the first of which involved 2,644 women 70 years of age or less with estrogen receptor (ER)-positive tumors who were randomized to receive tamoxifen or a placebo twice daily for 5 years in double-blind fashion (protocol B-14) [8]. At the end of 4 years a 6% improvement in survival free from disease was observed (83% vs. 77%), and this was shared by both premenopausal and postmenopausal patients. Tamoxifen more than trebled the risk of phlebitis, and one treated patient died of pulmonary embolism. The second NSABP study (protocol B-13) involved 679 women and the same patient selection except that tumors were ER negative [9]. l’hese patients received 1 year of cyclic sequential methotrexate and fluorouracil parenterally with leucovorin rescue. After 4 years a 9% improve0 1990 Wiley-Liss, Inc.
ment in disease-free survival was observed (80% vs. 71%), and the gain was significant in both pre- and postmenopausal patients. The third report, an intergroup study led by the Eastern Cooperative Oncology Group, involved 406 women with ER-negative tumors of any size or ER-positive tumors 3 cm or greater in diameter [lo]. The treated patients received six 4 week cycles of combination chemotherapy with cytoxan, methotrexate, fluorouracil, and prednisone (CMFP). After a median of 3 years, a 15% improvement in disease-free survival was evident in favor of the group that received chemotherapy (69% vs. 84%). Although all age groups benefitted, the effect was greatest for premenopausal women. Severe drug related toxicity was sustained by 33% of treated patients and caused one death. Finally, the Ludwig Breast Cancer Study Group, based in Switzerland, randomized 1,275 women 65 years of age or less to a single 2 week perioperative cycle of cytoxan, methotrexate, and fluorouracil (CMF) plus leucovorin or to no treatment and, after a mean follow-up of 4 years, found a 4% improvement in disease-free survival (77% vs. 73%) [ 1 I]. The difference was significant overall and for the subgroup of ER-negative patients. Unfortunately, three patients died from treatment. These reports raised the issue of whether systemic adjuvant therapy should now be standard for all node negative patients with breast cancer, whether this is cost effective, and whether the anticipated benefits justify the risks. Two editorials that accompanied the articles presented entirely different assessments [12,13]. Dr. Vincent DeVita considered the reductions in the risk of recurrence “impressive,” remarked on the minimal toxicity of two of the chemotherapy programs, and concluded that “all women with newly diagnosed localized invasive breast cancer can and should be offered some form of systemic treatment.” William McGuire, on the
Accepted for publication December 5, 1989 Address reprint requests to Dr. William L. Donegan, Department of Surgery, 950 North 12th Street, Milwaukee, W1 53201.
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YEARS AFTER MASTECTOMY Fig. 1. The prognosis of patients treated surgically with radical or modified radical mastectomy for invasive carcinoma of the breast with uninvolved axillary lymph nodes shows progressive improvement with
decreasing clinical size of the primary tumor. No recurrences were observed during the first 5 years among 17 patients with tumors less than 1.0 cm in diameter.
other hand, was not convinced. He saw the benefits as limited, pointed to the absence of an improvement in survival and the considerable toxic effects, and questioned whether the benefits justified the cost of treating all node negative patients. The direct cost of treating each patient in the four studies varied from $398 to $5,920. For the estimated 5,040 patients who would benefit from treatment, 64,960 node negative patients would have to be treated with regimens to which they could not respond at a cost of approximately $338,000,000 per year. McGuire urged that only patients with high risk for recurrence as judged by tumor size, steroid receptors, mitotic index, nuclear grade, and ploidy be considered for adjuvant treatment and not those with tumors less than 2 cm in diameter or diploid tumors with a low S phase. Commenting in a separate publication on the ethical considerations involved in clinical trials, and on these trials in particular, Mueller cautioned that minimal benefits do not of themselves create standard therapy [ 141. Speaking to the American College of Surgeons, Balch questioned whether the patients in the studies were representative and also recommended treatment only of high-risk patients [15]. In three of the studies, most tumors less than 1 cm in diameter were excluded by the requirement for quantitative measurement of tumor estrogen receptors, as were many elderly patients because of arbitrary age limitations. He estimated that restrictions
permitted no more than one-third of node negative patients to be eligible for the NSABP protocols. The disease-free survivals of controls in these studies, which ranged from 69 to 77% after only 3-4 years, were less than is commonly observed among node negative patients with small tumors. Balch also advised against treating patients with small (
