晚期乳腺癌全口服节拍化疗效果好

　　对于雌激素受体阳性HER2阴性晚期乳腺癌，虽然内分泌治疗＋CDK4/6抑制剂一线治疗有效，但是患者最终发生耐药，大多数将接受化疗。传统化疗以大剂量、长间歇、静脉用药为主，不良反应发生率较高，治疗耐受性较差。从21世纪初开始被用于临床的节拍化疗以小剂量、短间歇、口服用药为主，不良反应发生率较低，治疗耐受性较好。那么，对于雌激素受体阳性HER2阴性晚期乳腺癌，全口服节拍化疗效果如何？

　　2023年7月13日，《美国医学会杂志》肿瘤学分册在线发表意大利米兰大学欧洲肿瘤研究院、佩里诺医院、法恩扎医院、罗马涅医院、罗马尼奥洛肿瘤研究所、贝加莫西医院、托斯卡纳慈善医院、的里雅斯特大学克雷莫纳医院、西米兰莱尼亚诺医院、阿维亚诺国家癌症研究所、乌迪内大学、南蒂罗尔医院、博洛尼亚大学医院、马奇基金会西克罗医院、美国哈佛大学医学院和达纳法伯癌症研究院、瑞士欧洲胸部肿瘤协作组（ETOP）国际乳腺癌研究协作组（IBCSG）基金会、澳大利亚墨尔本大学彼得麦卡伦癌症中心的迈泰奥拉二期（METEORA-II）研究报告，对长春瑞滨＋环磷酰胺＋卡培他滨（长环卡）口服节拍化疗与紫杉醇每周静脉化疗用于雌激素受体阳性HER2阴性晚期乳腺癌患者的有效性和安全性进行了比较。

• METEORA-II (NCT02954055): MEtronomic TrEatment Option in Advanced bReast cAncer (A Randomized Phase II Trial of Metronomic Oral Vinorelbine Plus Cyclophosphamide and Capecitabine (VEX) Versus Weekly Paclitaxel as First-line or Second-line Treatment in Patients With ER-positive/HER2-negative Advanced or Metastatic Breast Cancer)

• 迈泰奥拉（Metéora）原意为悬浮的石头、悬浮在空中或在天空之上，位于希腊中部，是东正教修道院中最大、最陡峭的建筑群之一，其中有24座寺院（其中6座为完好）矗立在天然的砂岩支柱上。1988年，迈泰奥拉被列入联合国教科文组织世界遗产名录，为复合遗产。

　　该多中心非盲随机对照二期临床试验于2017年9月13日～2021年1月14日从意大利全国15家医院入组年龄≥18岁、雌激素受体阳性、HER2阴性晚期乳腺癌女性140例（可接受过1种晚期乳腺癌化疗和/或2种内分泌治疗，包括CDK4/6抑制剂）按1∶1的比例随机分为两组：

• 紫杉醇组69例：每4周第1、8、15天静脉注射紫杉醇每平方米体表面积90毫克，直至疾病进展或无法耐受
• 长环卡组71例：每周第1、3、5天口服长春瑞滨40毫克，每天口服环磷酰胺50毫克，每天3次口服卡培他滨500毫克，直至疾病进展或无法耐受

　　主要终点为研究者评定的治疗有效时间，定义为随机分组日期至治疗结束（由于疾病进展或无法耐受或拒绝治疗）间隔时间。次要终点包括无进展生存、总生存、疾病控制率（完全或部分缓解或疾病稳定持续至少24周）。

　　结果，共计133例患者开始长环卡（70例）或紫杉醇（63例）治疗，年龄30～80岁，中位61岁。7例患者在治疗前退出研究，其中紫杉醇组6例，理由是拒绝静脉治疗或希望口服治疗。

　　长环卡与紫杉醇相比：

• 治疗有效时间：中位8.3个月比5.7个月（95%置信区间：5.6～11.1、4.1～6.1）
• 治疗失败风险：减少39%（风险比：0.61，95%置信区间：0.42～0.88，P=0.008）
• 12个月完成率：34.3%比8.6%
• 无进展生存期：中位11.1个月比6.9个月（95%置信区间：8.3～13.8、5.4～10.1）
• 进展死亡风险：减少33%（风险比：0.67，95%置信区间：0.46～0.96，P=0.03）
• 12个月无进展生存率：43.5%比21.9%
• 总生存期：中位29.5个月比33.7个月（95%置信区间：19.4～未达终点、20.0～未达终点）
• 总死亡风险：减少2%（风险比：0.98，95%置信区间：0.59～1.63，P=0.90）
• 疾病控制率：68.6%比55.6%

　　值得注意的是，即使对于经过CDK4/6抑制剂治疗的患者，长环卡与紫杉醇相比，治疗有效时间仍然显著较长。

　　治疗失败事件：疾病进展占55.6%，不良事件占23%。

　　3或4级不良事件发生至少1次的患者比例：

• 长环卡：42.9%（95%置信区间：31.1%～55.3%）基本均未脱发
• 紫杉醇：28.6%（95%置信区间：17.9%～41.3%）

　　因此，该多中心小样本随机对照二期临床研究结果表明，口服长环卡节拍化疗与静脉紫杉醇每周化疗相比，治疗有效时间和无进展生存期显著延长，疾病控制率较高，总生存相似，虽然毒性反应有所增加，但是仍然可以控制。对于雌激素受体阳性HER2阴性晚期乳腺癌，口服长环卡节拍化疗可以作为选择之一。此外，口服长环卡可以在家治疗，医院就诊次数较少，并且较少引起脱发，故有必要进一步开展多中心大样本随机对照三期临床研究进行验证。

JAMA Oncol. 2023 Jul 13. IF: 28.4

Efficacy of Metronomic Oral Vinorelbine, Cyclophosphamide, and Capecitabine vs Weekly Intravenous Paclitaxel in Patients With Estrogen Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: Final Results From the Phase 2 METEORA-II Randomized Clinical Trial.

Munzone E, Regan MM, Cinieri S, Montagna E, Orlando L, Shi R, Campadelli E, Gianni L, Palleschi M, Petrelli F, Bengala C, Generali D, Collovà E, Puglisi F, Cretella E, Zamagni C, Chini C, Ruepp B, Loi S, Colleoni M; International Breast Cancer Study Group (IBCSG).

European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; Perrino Hospital, ASL Brindisi, Brindisi, Italy; Faenza Hospital "degli Infermi," Oncology, Faenza, Italy; Ospedale Infermi, AUSL Della Romagna, Rimini, Italy; Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori," Meldola, Italy; ASST Bergamo Ovest, Treviglio, Bergamo, Italy; Azienda USL Toscana, Misericordia Hospital, Grosseto, Italy; Azienda Socio-Sanitaria Territoriale di Cremona and University of Trieste, Cremona, Italy; ASST Ovest Milanese Legnano, Milan, Italy; National Cancer Institute, IRCCS, Aviano, Italy; University of Udine, Udine, Italy; Azienda Sanitaria Dell'Alto Adige, Bolzano, Italy; IRCCS Azienda Ospedaliero-universitaria di Bologna, Bologna, Italy; Ospedale di Circolo e Fondazione Macchi, Varese, Italy; Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; ETOP IBCSG Partners Foundation, Bern, Switzerland; Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, Victoria, Australia.

This randomized clinical trial compares the efficacy, in terms of clinical outcomes and disease control rate, of an all-oral metronomic vinorelbine plus cyclophosphamide plus capecitabine regimen with weekly paclitaxel among patients with estrogen receptor-positive, ERBB2-negative metastatic breast cancer.

QUESTION: Does the all-oral metronomic chemotherapy regimen vinorelbine plus cyclophosphamide plus capecitabine (VEX) provide a better clinical outcome and longer disease control compared with weekly paclitaxel for patients with estrogen receptor (ER)-positive, ERBB2 [formerly HER2/neu])-negative advanced breast cancer requiring chemotherapy?

FINDINGS: In this phase 2 randomized clinical trial of 140 patients, time to treatment failure among patients receiving VEX was significantly improved, with a median of 8.3 months vs 5.7 months among patients receiving paclitaxel, as was progression-free survival, to a median of 11.1 months with VEX vs 6.9 months with paclitaxel.

MEANING: These results suggest that metronomic VEX may be one of the chemotherapy options for patients with ER+/ERBB2- advanced breast cancer.

IMPORTANCE: In spite of the effectiveness of endocrine therapy plus cyclin-dependent kinase (CDK) 4/6 inhibitors as the first-line treatment for estrogen receptor (ER)-positive, erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly HER2/neu])-negative (ER+/ERBB2-) metastatic breast cancer (MBC), patients eventually develop resistance, and eventually most will receive chemotherapy. The METEORA-II trial compared a metronomic all-oral treatment with intravenous (IV) chemotherapy.

OBJECTIVE: To compare the efficacy of the oral vinorelbine plus cyclophosphamide plus capecitabine (VEX) regimen vs weekly IV paclitaxel among patients with ER+/ERBB2- MBC who are candidates for chemotherapy.

DESIGN, SETTING, AND PARTICIPANTS: This phase 2 randomized clinical trial including 140 women 18 years and older (randomized 1:1) with ER+/ERBB2- MBC was carried out from September 13, 2017, to January 14, 2021 at 15 centers in Italy. Eligible patients could have received 1 prior line of chemotherapy for MBC and/or 2 lines of endocrine therapy (including CDK4/6 inhibitors).

INTERVENTIONS: In 4-week cycles, patients received either metronomic oral VEX or weekly IV paclitaxel.

MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed time to treatment failure (TTF) defined as the interval between the date of randomization to the end of treatment (because of disease progression or lack of tolerability or because further trial treatment was declined). Secondary end points included progression-free survival (PFS), overall survival (OS), and disease control rate (complete or partial response or stable disease lasting for at least 24 weeks).

RESULTS: In total, 133 patients received either VEX (n = 70) or paclitaxel (n = 63) in 4-weekly cycles. The median age was 61 (range, 30-80) years. The VEX treatment significantly prolonged TTF vs paclitaxel (hazard ratio [HR], 0.61; 95% CI, 0.42-0.88; P = .008), median TTF was 8.3 (95% CI, 5.6-11.1) months for VEX vs 5.7 (95% CI, 4.1-6.1) months for paclitaxel, and the 12-month TTF was 34.3% for VEX vs 8.6% for paclitaxel. The median PFS was 11.1 (95% CI, 8.3-13.8) months vs 6.9 (95% CI, 5.4-10.1) months favoring VEX (HR, 0.67; 95% CI, 0.46-0.96, P = .03). The 12-month PFS was 43.5% for VEX vs 21.9% for paclitaxel. No difference in OS was found. The TF event for 55.6% of patients was progression of disease; for 23% it was AEs. More patients assigned to VEX had at least 1 grade 3 or 4 targeted adverse event (VEX, 42.9%; 95% CI, 31.1%-55.3% vs paclitaxel, 28.6%; 95% CI, 17.9%-41.3%), but essentially no alopecia.

CONCLUSION AND RELEVANCE: This randomized clinical trial found significantly prolonged TTF and PFS for oral VEX but no improvement in OS compared with intravenous paclitaxel, despite increased but still manageable toxic effects. The VEX regimen may provide more prolonged disease control than weekly paclitaxel for ER+/ERBB2- MBC.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02954055

PMID: 37440239

DOI: 10.1001/jamaoncol.2023.2150