Effect of oxaliplatin-based chemotherapy on chemosensitivity in patients with peritoneal metastasis from colorectal cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: proof-of-concept study

Abstract

Background Chemosensitivity testing, including collagen gel droplet-embedded culture drug sensitivity test, has proven to be a useful tool in therapeutic decision-making. This retrospective analysis investigated chemosensitivity testing of peritoneal metastases collected during cytoreductive surgery (CRS), and its impact on survival in patients with colorectal cancer. Methods All patients with peritoneal metastasis from colorectal cancer who underwent CRS with or without hyperthermic intraperitoneal chemotherapy (HIPEC) between November 2008 and October 2014 were included. The growth inhibition rate was expressed as the ratio between the image density after treatment (T) and that before treatment (control, C). Tumours with a reduction in T/C ratio of less than 20 per cent were defined as resistant and those with a reduction of 20 per cent or more as sensitive. Groups were compared for overall (OS) and disease-free (DFS) survival. Results Of 84 eligible patients, 81 received neoadjuvant chemotherapy (NACT), including 56 patients with an oxaliplatin-based regimen. Mean(s.d.) follow-up was 23·4(22·9) months. The median overall survival of all patients was 19·0 (i.q.r. 5·7–36·1) months, with a progression-free survival time of 10·1 (4·5–17·0) months. Patients who received oxaliplatin-based NACT had significantly altered chemosensitivity to oxaliplatin; only 20 of 51 such patients showed chemosensitivity to oxaliplatin compared with 16 of 24 who did not undergo oxaliplatin-based NACT (P = 0·046). However, patients who showed chemoresistance to oxaliplatin had similar OS to those with chemosensitivity (18·8 versus 18·1 months; P = 0·835). The choice of HIPEC agents in patients who received oxaliplatin-based NACT did not significantly influence survival (oxaliplatin versus mitomycin C: median OS 20·6 (10·9–24·8) versus 19·0 (10·5–34·6) months, P = 0·811; DFS 6·6 (2·8–25·7) versus 9·3 (4·1–13·9) months, P = 0·191). Conclusion Patients who had oxaliplatin-based NACT showed a higher rate of chemoresistance to oxaliplatin at the time of CRS and HIPEC. The impact of chemosensitivity testing on OS remains unclear and needs further investigation.

GECOP-MMC: phase IV randomized clinical trial to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases

“…Furthermore, IV 5-FU is used as only a bolus dose, anticipating a low response rate to oxaliplatin (continuous 48 h 5-FU infusion is today an integral part of oxaliplatin treatment); low duration of heat exposition is unlikely to have any major effect by itself; no study demonstrated a potentiation of oxaliplatin cytotoxicity by heat; and the high rate of postoperative complications may have a negative impact on survival of these metastatic patients. It seems increasingly clear that oxaliplatin-based preoperative SCT, commonly used in PRODIGE 7, can induce a certain degree of tumour resistance, worsening the efficacy of subsequent intraperitoneal oxaliplatin [ 37 ]. PRODIGE 7 included patients with PCI up to 25, when today it is known that cases with PCI > 20 do not benefit from CRS + HIPEC.…”

“…It seems increasingly clear that oxaliplatin-based preoperative SCT, commonly used in PRODIGE 7, can induce a certain degree of tumour resistance, worsening the efficacy of subsequent intraperitoneal oxaliplatin [ 37 ].…”

Neoadjuvant treatment of colorectal cancer: comprehensive review

“…Furthermore, COLOPEC is now the third consecutive clinical trial that has failed to demonstrate efficacy of oxaliplatin-based HIPEC either as an adjuvant treatment or in patients with metastatic CRC, after ProphyloCHIP and PRODIGE 7 109 , 110 . Shared criticisms of these trials are that they all used a short duration of HIPEC of 30 min and used single-agent oxaliplatin, in mainly oxaliplatin pretreated patients, which were proven to be less effective in preclinical models as well as in patient-derived organoids 111 , 112 .…”

Colorectal Cancer with Peritoneal Metastases: The Impact of the Results of PROPHYLOCHIP, COLOPEC, and PRODIGE 7 Trials on Peritoneal Disease Management

“…More than three-quarters of the patients (85%) have received oxaliplatin-based neoadjuvant chemotherapy (FOLFOX). In a recent study, oxaliplatin chemoresistance was demonstrated in the preoperative setting, potentially making the HIPEC regimen ineffective [21]. Patients who received oxaliplatin before CRS-HIPEC had significantly altered chemosensitivity to this drug.…”