A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7.

Abstract

LBA3503 Background: Promising results have been obtained during the last decade using cytoreductive surgery (CRS) plus HIPEC for selected patients with colorectal PC who are amenable to complete macroscopic resection. This is the first trial to evaluate the specific role of HIPEC, after CRS, for the treatment of PC of colorectal origin. Methods: Prodige 7 is a randomized phase III, multicenter trial. Patients with histologically proven and isolated PC, peritoneal cancer index (PCI) ≤25 were eligible. Randomization (1:1) was stratified by center, complete macroscopic resection (R0/1 vs R2), and neoadjuvant systemic chemotherapy. Patients were treated with CRS plus HIPEC with oxaliplatin or CRS alone, in association with systemic chemotherapy. The primary endpoint was the overall survival (OS). Secondary endpoints were relapse-free survival (RFS) and toxicity. 264 patients were required to show a gain in median OS from 30 to 48 months (HR = 0.625) with a two-sided α = 0,046 and 80% power. Results: 265 patients from 17 centers were included between February 2008 and January 2014: 132 in Arm without HIPEC and 133 in Arm with HIPEC. The median age was 60 years (range: 30-74). Baseline characteristics were well balanced. The overall post-operative mortality rate was 1.5% and was not different between the two arms. The morbidity rates did not differ statistically at 30 days. At 60 days, the grade 3-5 morbidity rate was significantly higher with HIPEC (24.1% vs. 13.6%, p= 0.030). After a median follow up of 63.8 months (95% CI: 58.9-69.8), the median OS was 41.2 months (95% CI 35.1-49.7) in the non-HIPEC Arm and 41.7 months (95% CI: 36.2-52.8) in the HIPEC Arm, HR = 1.00 (95% CI: 0.73-1.37) p = 0.995. The median RFS was 11.1 months (95% CI: 9-12.7) in non-HIPEC Arm and 13.1 months (95% CI: 12.1-15.7) in HIPEC Arm, HR = 0.90 (95% CI: 0.69-1.90) (p = 0.486), whilst the 1-year RFS rates were 46.1% in non-HIPEC Arm and 59 % in the HIPEC Arm. Conclusions: The therapeutic curative management of PC from colorectal cancer by CRS shows satisfactory survival results. While the addition of HIPEC with oxaliplatin does not influence the OS. Clinical trial information: NCT00769405.

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy

“…Moreover, hyperthermic chemotherapy at commonly attained clinical doses had only a minor effect on the viability of several organoid lines. This indicates that current HIPEC regimens are insufficient to eradicate residual microscopic disease at least in a subgroup of patients with colorectal PMs, and this is consistent with the high recurrence rates observed after CRS–HIPEC and the negative result from the Prodige 7 trial.…”

“…As a consequence, there is currently no consensus on the choice of chemotherapy, the dose administered or the duration of perfusion. Regardless of the chemotherapy drug used in HIPEC, recurrence rates after CRS–HIPEC are high and more than half of patients experience disease recurrence within 2 years. The added value of HIPEC after CRS has recently been questioned in light of results from the Prodige 7 RCT, which showed that adding oxaliplatin‐based HIPEC to CRS provided no survival benefit.…”

“…Regardless of the chemotherapy drug used in HIPEC, recurrence rates after CRS–HIPEC are high and more than half of patients experience disease recurrence within 2 years. The added value of HIPEC after CRS has recently been questioned in light of results from the Prodige 7 RCT, which showed that adding oxaliplatin‐based HIPEC to CRS provided no survival benefit. However, clinical proof that HIPEC after CRS can effectively target minimal residual disease in the peritoneum has been provided by a large phase III study in ovarian cancer.…”

Body surface area‐based vs concentration‐based perioperative intraperitoneal chemotherapy after optimal cytoreductive surgery in colorectal peritoneal surface malignancy treatment: COBOX trial

“…PRODIGE 7 (NCT00769405) randomized patients after optimal CRS to oxaliplatin‐based HIPEC or no HIPEC. Median overall survival in the HIPEC arm was 41.7 and 41.2 months in the CRS‐only arm (results presented at the ASCO annual meeting in Chicago) . We now know that the current high quality standardized CRS procedures are paramount in determining the patients' outcome.…”

“…In the last decades, the therapeutic strategy for colorectal peritoneal surface malignancy (PSM) has changed considerably from a palliative approach to an approach with curative intent by the introduction of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) . This combined treatment modality has resulted in significant survival improvements with a median overall survival of 41.7 months and should now be considered standard of care for colorectal PSM (results presented at the American Society of Clinical Oncology [ASCO] annual meeting in Chicago) . Although, there is now a clearly defined standardization of CRS procedures, based on the work of Sugarbaker et al, there is still a large variety in HIPEC treatment modalities used in current clinical practice.…”