Colleoni M, Rocca A, Sandri M T, Zorzino L, Masci G, Nolè F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de Braud F, Viale G, Goldhirsch A
Division of Medical Oncology, European Institute of Oncology, Milan, Italy.
Ann Oncol. 2002 Jan;13(1):73-80. doi: 10.1093/annonc/mdf013.
Anticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents, including cyclophosphamide (CTX), methotrexate (MTX), anthracyclines and taxanes, postulating an antiangiogenic activity.
We evaluated the clinical efficacy and impact on serum vascular endothelial growth factor (VEGF) levels of low-dose oral MTX and CTX in patients with metastatic breast cancer. MTX was administered 2.5 mg bd on days 1 and 2 each week and CTX 50 mg/day administered continuously.
Sixty-four patients were enrolled, 63 were evaluable: Eastern Cooperative Oncology Group (ECOG) performance status 0-1, > or =2 sites of metastatic disease (n = 50 patients), progressive disease at study entry (n = 51), 1 regimen for metastatic disease (n = 32) and > or =2 regimens (n = 20). Among the 63 evaluable patients, there were two complete remissions (CR), 10 partial remissions (PR) for an overall response rate of 19.0% (95% CI 10.2% to 30.9%) and an overall clinical benefit (CR+ PR+ stable disease >24 weeks) of 31.7% (95% CI 20.6% to 44.7%). Grade > or =2 leucopenia was registered in only 13 patients. The median serum VEGF level for the subgroup of patients on treatment for at least 2 months decreased with treatment from 315 pg/ml (95% CI 245 to 435) at baseline to 248 pg/ml (95% CI 205 to 311) at 2 months (P <0.001). Both responders and non-responders showed similar reductions in serum VEGF (P = 0.78). After 6 months patients still on treatment had a median VEGF level of 195 pg/ml (95% CI 96 to 355), which was significantly lower than the median baseline values (P = 0.001).
Continuously low-dose CTX and MTX is minimally toxic and effective in heavily pretreated breast cancer patients. A drop in VEGF was associated with the treatment and so alternative hypotheses, other than that of direct toxicity on tumor cells, must be favored when trying to explain the anticancer effect.
抗癌化疗被认为是通过对肿瘤细胞的直接细胞毒性发挥作用。几种常见的抗癌药物，包括环磷酰胺（CTX）、甲氨蝶呤（MTX）、蒽环类药物和紫杉烷类药物，其疗效的其他机制被归因于抗血管生成活性。
我们评估了低剂量口服MTX和CTX对转移性乳腺癌患者的临床疗效以及对血清血管内皮生长因子（VEGF）水平的影响。MTX每周第1天和第2天各口服2.5mg，CTX每天50mg持续给药。
共纳入64例患者，63例可评估：东部肿瘤协作组（ECOG）体能状态为0 - 1，转移性疾病部位≥2处（n = 50例患者），研究入组时为疾病进展期（n = 51例），转移性疾病采用1种治疗方案（n = 32例）以及≥2种治疗方案（n = 20例）。在63例可评估患者中，有2例完全缓解（CR），10例部分缓解（PR），总缓解率为19.0%（95%可信区间10.2%至30.9%），总临床获益率（CR + PR + 疾病稳定>24周）为31.7%（95%可信区间20.6%至44.7%）。仅13例患者出现≥2级白细胞减少。治疗至少2个月的患者亚组中，血清VEGF水平中位数随治疗从基线时每毫升315皮克（95%可信区间245至435）降至2个月时每毫升248皮克（95%可信区间205至311）（P <0.001）。缓解者和未缓解者血清VEGF水平下降程度相似（P = 0.78）。6个月后仍在接受治疗的患者VEGF水平中位数为每毫升195皮克（95%可信区间96至355），显著低于基线中位数（P = 0.001）。
持续低剂量CTX和MTX对经过大量预处理的乳腺癌患者毒性极小且有效。VEGF水平下降与治疗相关，因此在试图解释抗癌作用时，除了对肿瘤细胞的直接毒性外，必须考虑其他假设。
