Shapiro C L, Gelman R S, Hayes D F, Osteen R, Obando A, Canellos G P, Frei E, Henderson I C
Dana-Farber Cancer Institute, Boston, Mass. 02115.
J Natl Cancer Inst. 1993 May 19;85(10):812-7. doi: 10.1093/jnci/85.10.812.
Alkylating agents administered as single agents or in combination with antimetabolites or anthracyclines delay the appearance of metastases and prolong the survival of breast cancer patients after surgery.
This phase III clinical trial was designed to evaluate the therapeutic efficacy and toxicity of the alkylating agent cyclophosphamide in combination with the antimetabolites methotrexate and fluorouracil adjuvant to breast cancer surgery.
This study consisted of 255 breast cancer patients (a) with one to three histologically positive axillary lymph nodes and either no detectable primary tumor or operable primary tumors 5 cm or less (T0-T2) (95% of the patients) or (b) with tumors larger than 5 cm (T3) and with negative axillary nodes. Patients were randomly allocated to receive either methotrexate (60 mg/m2) and fluorouracil (600 mg/m2) (MF) intravenously on days 1 and 8 every 28 days for eight cycles or cyclophosphamide (100 mg/m2) orally on days 1-14 plus MF (CMF) every 28 days for the same duration. Median follow-up was 7.8 years, and maximum follow-up was 13 years.
There were no statistically significant differences in time to treatment failure or overall survival for patients treated with MF or CMF. At 8 years after completion of treatment, time to treatment failure was 55% (95% confidence interval [CI] = 50%-60%) and 59% (95% CI = 54%-64%) and overall survival was 69% (95% CI = 65%-73%) and 67% (95% CI = 62%-72%) for MF- and CMF-treated patients, respectively. The hazard ratios (MF to CMF) for time to treatment failure and for survival, estimated with a proportional hazards model, were 1.02 (95% CI = 0.69-1.50) and 0.87 (95% CI = 0.56-1.34), respectively. Myelosuppression was significantly greater (P < .0001) in CMF-treated patients during cycles 1-6. Median white blood cell count nadirs were between 4.4 x 10(3)/microL and 3.5 x 10(3)/microL in patients receiving MF and between 3.0 x 10(3)/microL and 2.4 x 10(3)/microL in those receiving CMF. Dose reductions were more frequent in CMF-treated patients, which led to statistically significant differences (P < .0001) in amounts of methotrexate and fluorouracil administered. Primary cancers at other sites occurred in 14 patients (5.5%)--six treated with MF and eight treated with CMF.
Our findings suggest that the addition of cyclophosphamide to adjuvant chemotherapy with MF offers no therapeutic advantage but results in increased myelosuppression.
Future trials will define the possible advantages of antimetabolites in adjuvant therapy. Further information will also become available when results of the ongoing National Surgical Adjuvant Breast and Bowel Project trial comparing adjuvant MF to CMF in node-negative breast cancer patients are presented.
烷化剂作为单一药物或与抗代谢物或蒽环类药物联合使用，可延迟转移的出现并延长乳腺癌患者术后的生存期。
本III期临床试验旨在评估烷化剂环磷酰胺联合抗代谢物甲氨蝶呤和氟尿嘧啶作为乳腺癌手术辅助治疗的疗效和毒性。
本研究纳入了255例乳腺癌患者，其中（a）组有1至3个组织学检查阳性的腋窝淋巴结，且未检测到原发性肿瘤或原发性肿瘤可手术切除且直径小于或等于5 cm（T0 - T2）（95%的患者），或（b）组肿瘤直径大于5 cm（T3）且腋窝淋巴结阴性。患者被随机分配接受以下治疗：每28天在第1天和第8天静脉注射甲氨蝶呤（60 mg/m²）和氟尿嘧啶（600 mg/m²）（MF），共8个周期；或每28天在第1 - 14天口服环磷酰胺（100 mg/m²）加MF（CMF），持续相同时间。中位随访时间为7.8年，最长随访时间为13年。
接受MF或CMF治疗的患者在治疗失败时间或总生存期方面无统计学显著差异。治疗结束8年后，MF治疗组和CMF治疗组的治疗失败时间分别为55%（95%置信区间[CI]=50% - 60%）和59%（95% CI = 54% - 64%），总生存期分别为69%（95% CI = 65% - 73%）和67%（95% CI = 62% - 72%）。用比例风险模型估计的治疗失败时间和生存期的风险比（MF与CMF）分别为1.02（95% CI = 0.69 - 1.50）和0.87（95% CI = 0.56 - 1.34）。在第1 - 6周期，CMF治疗组的骨髓抑制明显更严重（P <.0001）。接受MF治疗的患者白细胞计数最低点中位数在4.4×10³/μL至3.5×10³/μL之间，接受CMF治疗的患者在3.0×10³/μL至2.4×10³/μL之间。CMF治疗组更频繁地进行剂量减少，这导致甲氨蝶呤和氟尿嘧啶的给药量存在统计学显著差异（P <.0001）。其他部位的原发性癌症发生在14例患者（5.5%）中，其中6例接受MF治疗，8例接受CMF治疗。
我们的研究结果表明，在MF辅助化疗中添加环磷酰胺没有治疗优势，但会导致骨髓抑制增加。
未来的试验将确定抗代谢物在辅助治疗中的可能优势。当正在进行的国家外科辅助乳腺和肠道项目试验比较MF与CMF在淋巴结阴性乳腺癌患者中的辅助治疗结果公布时，也将获得更多信息。
