Nagourney Cancer Institute, Irvine, CA, USA.
Center for Gastrointestinal Malignancies, MedStar Washington Hospital Center, Washington, DC, USA.
Eur J Surg Oncol. 2021 Apr;47(4):738-742. doi: 10.1016/j.ejso.2020.09.017. Epub 2020 Sep 19.
Numerous studies have suggested benefit for heated intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal metastases from colon cancer. However, the PRODIGE 7 trial that randomized 265 colon cancer patients to surgery plus HIPEC vs. surgery alone after neoadjuvant chemotherapy (NACT) did not confirm benefit. These data were published as an abstract and not as a peer-reviewed manuscript. One concern is that prior drug exposure may select for drug resistance and blunt HIPEC efficacy.
A database query identified colon cancer specimens evaluated for chemotherapy sensitivity by ex-vivo analysis of programmed cell death (EVA/PCD), a primary culture platform that examines drug-induced cell death (apoptotic & non-apoptotic) by morphologic, metabolic and histologic endpoints.
Of 87 fresh colon cancer specimens, 54 (62%) were untreated and 33 (38%) had received prior folinic acid, 5-fluorouracil, oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX). In an apoptosis assay, the lethal concentration of 50% (LC50) in untreated patients was significantly lower than in patients treated by FOLFOX (p = 0.002). Then to approximate PRODIGE 7, treated patients were separated by having received oxaliplatin treatment less than or greater than 2 months before EVA/PCD analysis. The degree of resistance increasing significantly for patients who received treatment less than 2 months prior to EVA/PCD (p < 0.002). Activity for mitomycin and irinotecan was not significantly different for untreated vs. treated patients, but 5-FU was more resistant (P = 0.048).
The failure of PRODIGE 7 to improve survival with surgery plus HIPEC following NACT may reflect diminished oxaliplatin cytotoxicity in patients whose residual disease has been selected for oxaliplatin and 5-FU resistance.
许多研究表明，加热腹腔内化疗（HIPEC）对结直肠癌腹膜转移的治疗有益。然而，PRODIGE 7 试验将 265 例结直肠癌患者随机分为新辅助化疗（NACT）后手术加 HIPEC 组与单纯手术组，并未证实获益。这些数据以摘要形式发表，而不是经过同行评议的手稿。人们担心的一个问题是，先前的药物暴露可能会选择耐药性，从而削弱 HIPEC 的疗效。
通过对程序性细胞死亡（EVA/PCD）进行离体分析来评估化疗敏感性的数据库查询，鉴定了结直肠癌标本，EVA/PCD 是一种主要的培养平台，通过形态学、代谢和组织学终点来检查药物诱导的细胞死亡（凋亡和非凋亡）。
在 87 个新鲜结直肠癌标本中，54 个（62%）未经治疗，33 个（38%）接受了先前的亚叶酸、5-氟尿嘧啶、奥沙利铂（FOLFOX）或卡培他滨和奥沙利铂（CAPOX）治疗。在凋亡测定中，未经治疗患者的 50%致死浓度（LC50）显著低于接受 FOLFOX 治疗的患者（p=0.002）。然后为了近似 PRODIGE 7，根据接受奥沙利铂治疗的时间将治疗过的患者分为少于或多于 2 个月前进行 EVA/PCD 分析的患者。在接受 EVA/PCD 分析前少于 2 个月接受治疗的患者中，耐药性显著增加（p<0.002）。未治疗患者和治疗患者之间米托蒽醌和伊立替康的活性无显著差异，但 5-FU 的耐药性更强（P=0.048）。
PRODIGE 7 在 NACT 后手术加 HIPEC 治疗未能改善生存率，这可能反映出残留疾病对奥沙利铂和 5-FU 耐药性的选择降低了奥沙利铂的细胞毒性。
