保护年轻乳腺癌女性卵巢的化疗方案

　　广谱抗癌药环磷酰胺是大多数化疗方案的基本用药。不过，环磷酰胺还可抑制卵巢，引起提前绝经，造成不孕等后果。对于年轻乳腺癌患者，我们不仅关心其近期疗效与长期生存问题，也关心其生活质量与生育问题。那么，对于年轻女性，乳腺癌术后辅助化疗能否不用环磷酰胺？

　　2021年4月2日，英国牛津大学出版社旗下美国《国家癌症研究所杂志》在线发表复旦大学附属肿瘤医院余科达、葛靖宇、刘西禹、莫淼、贺敏、邵志敏等学者的SPECTRUM研究报告，探讨了年轻女性乳腺癌术后无环磷酰胺辅助化疗方案能否增加月经恢复可能性并改善生存结局。

SPECTRUM (NCT01026116): Substitution of Paclitaxel for cyclophosphamide on survival outcomes and resumption of menses in young women with ER-positive breast cancer (SHBCC09007)

　　该多中心非盲随机对照研究于2011年1月～2016年12月从全国8家医院入组雌激素受体阳性HER2阴性乳腺癌术后年轻女性521例（年龄中位34岁、四分距31～38岁）按1∶1随机分为两组：

  • EC-wP组261例：表柔比星＋环磷酰胺→每周紫杉醇

  • EP-wP组260例：表柔比星＋紫杉醇→每周紫杉醇

　　全部患者化疗后都接受至少5年内分泌治疗。主要研究终点为全部意向治疗患者的化疗后1年月经恢复率和5年无病生存率，次要终点包括5年总体生存率。通过患者报告结局问卷，对其中228例完成问卷患者的2年成功妊娠率进行事后探索性分析。由于月经恢复为无病生存的竞争风险，故采用竞争风险回归模型对双终点进行统计学校正。全部统计学检验均为双侧。

　　结果，中位随访62个月，EC-wP与EP-wP相比：

  • 1年月经恢复率：48.3%比63.1%（95%置信区间：42.2%～54.3%、57.2%～68.9%；绝对差异：14.8%，95%置信区间：6.37%～23.2%，P<0.001).

  • 5年无病生存率：78.3%比84.7%（95%置信区间：72.2%～83.3%、79.3%～88.8%，分层对数秩P=0.07）

  • 5年总体生存率：99.6%比99.6%（风险比：0.81，95%置信区间：0.38～1.69，P=0.54）

  • 2年成功妊娠率：2.7%比9.6%（P=0.03）

　　安全性数据与相关药物已知安全性一致。

　　因此，该前瞻研究结果首次证实，对于早期雌激素受体阳性HER2阴性乳腺癌术后年轻女性，无环磷酰胺辅助化疗方案的月经恢复率较高、无病生存率不低、总体生存率相似、妊娠成功率较高。

　　对此，意大利热那亚大学圣马蒂诺综合医院、美国哈佛大学达纳法伯癌症研究所发表同期评论：无环磷酰胺辅助化疗可能预防乳腺癌年轻女性的卵巢早衰和不育。

J Natl Cancer Inst. 2021 Apr 2. Online ahead of print.

Cyclophosphamide-free Adjuvant Chemotherapy for Ovarian Protection in Young Women with Breast Cancer: a Randomized Phase 3 Trial.

Ke-Da Yu, Jing-Yu Ge, Xi-Yu Liu, Miao Mo, Min He, Zhi-Ming Shao; SPECTRUM Investigators.

Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.

BACKGROUND: Chemotherapy-induced premature menopause leads to some consequences, including infertility. We initiated this randomized phase 3 trial to determine whether a cyclophosphamide-free adjuvant chemotherapy regimen would increase the likelihood of menses resumption and improve survival outcomes.

METHODS: Young women with operable ER-positive HER2-negative breast cancer after definitive surgery were randomized to receive adjuvant epirubicin/cyclophosphamide followed by weekly paclitaxel (EC-wP) or epirubicin/paclitaxel followed by weekly paclitaxel (EP-wP). All patients received at least 5-year adjuvant endocrine therapy after chemotherapy. Two coprimary endpoints were the rate of menstrual resumption at 12 months after chemotherapy and 5-year disease-free survival (DFS) in the intention-to-treat population. This study is registered at ClinicalTrials.gov (NCT01026116). All statistical tests were 2-sided.

RESULTS: Between Jan 2011 and Dec 2016, 521 patients (median age = 34 years; interquartile range = 31-38 years) were enrolled, with 261 in the EC-wP group and 260 in the EP-wP group. The rate of menstrual resumption at 12 months after chemotherapy was 48.3% in EC-wP (95% confidence interval [CI] = 42.2% to 54.3%) and 63.1% in EP-wP (95% CI=57.2% to 68.9%), with an absolute difference of 14.8% (95% CI=6.37% to 23.2%, P<0.001). The post-hoc exploratory analysis by patient-reported outcome questionnaires indicated that pregnancy might occur in fewer women in the EC-wP group than in the EP-wP group. At a median follow-up of 62 months, the 5-year DFS was 78.3% (95% CI=72.2% to 83.3%) in EC-wP and 84.7% (95% CI=79.3% to 88.8%) in EP-wP (stratified log-rank P=0.07). The safety data were consistent with the known safety profiles of relevant drugs.

CONCLUSIONS: The cyclophosphamide-free chemotherapy regimen might be associated with a higher probability of menses resumption.

KEYWORDS: early-onset breast cancer, adjuvant chemotherapy, menses resumption, cyclophosphamide, paclitaxel

DOI: 10.1093/jnci/djab065

J Natl Cancer Inst. 2021 Apr 2. Online ahead of print.

Cyclophosphamide-free Adjuvant Chemotherapy for the Potential Prevention of Premature Ovarian Insufficiency and Infertility in Young Women with Breast Cancer.

Matteo Lambertini, Ann H Partridge.

University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy; Dana-Farber Cancer Institute, Boston, MA, USA.

DOI: 10.1093/jnci/djab066

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