Cytoreduction with or without HIPEC: Where do we go from here?

The American Cancer Society estimates that 97,220 new cases of colon cancer were diagnosed in the U.S. in 2018.1 Approximately 20 percent of these patients may develop peritoneal metastasis.2 For select patients with colon cancer and low-volume peritoneal metastasis, National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of cytoreduction and intraperitoneal chemotherapy at experienced centers.3 This recommendation is supported by a 2003 randomized controlled trial in the Netherlands that demonstrated a doubling of survival (22.3 months versus 12.6 months) for patients treated with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C for 90 minutes compared with systemic 5-fluorouracil (FU) alone.4

Subsequently, significant improvements have been made in the efficacy of systemic chemotherapy, which warrant reevaluation of this question. To reconcile the contribution of intraperitoneal chemotherapy to cytoreduction in the modern era of multi-agent systemic chemotherapy and targeted biological agents, the recently presented PRODIGE 7 trial compared the addition of HIPEC with contemporary perioperative systemic chemotherapy and cytoreduction.5

PRODIGE 7 trial

The results of the PRODIGE 7 trial were presented at the American Society of Clinical Oncology 2018 meeting in Chicago, IL.5 PRODIGE 7 is the first successful prospective phase III trial with HIPEC in colorectal cancer since the 2003 trial. The PRODIGE 7 trial enrolled 265 patients with colorectal cancer and isolated peritoneal carcinomatosis from 17 experienced institutions across France. The trial schema is outlined in Figure 1. Briefly, all patients received 12 cycles of perioperative systemic chemotherapy consisting of multidrug chemotherapy combinations, including FOLFOX (5-FU, leucovorin, and oxaliplatin) or FOLFIRI (5-FU, leucovorin, and irinotecan) with or without biologic agents such as bevacizumab and cetuximab. Patients were then randomized to cytoreduction with or without HIPEC. HIPEC was delivered with oxaliplatin (460 mg/m2) in 2 L/m2 of dextrose 5 percent for 30 minutes at a minimal temperature of 42°C. One hour before the HIPEC, 20 mg/m2 of leucovorin and 400 mg/m2 of 5-FU were given intravenously.

Figure 1. PRODIGE 7 trial design

Figure 1. PRODIGE 7 trial design

Of the patients, 90 percent underwent a complete cytoreduction. The primary outcome was overall survival (OS) and secondary outcomes were recurrence-free survival (RFS) and morbidity and mortality. After a robust median follow-up of 63.8 months, the investigators reported similar median OS of 41.7 months for patients treated with HIPEC and 41.2 months for patients who did not receive HIPEC (p = 0.99). The corresponding survival rates at five years were 39.4 percent and 36.7 percent, respectively. The median RFS was 13.1 months for patients treated with HIPEC versus 11.1 months for patients treated without HIPEC.

To identify a subgroup of patients who may benefit from the addition of HIPEC, the investigators stratified patients by peritoneal carcinomatosis index (PCI)—a calculated measure of the volume and distribution of metastasis within the peritoneum—and reported a statistically significant improvement in median OS with HIPEC (41.6 months) compared with cytoreductive surgery alone (32.7 months, p = 0.02) for the patients with an intermediate PCI (11–15). However, this finding must be interpreted with caution, as it involved an unplanned subgroup analysis with a small sample size (n = 18 and 28, respectively). Additional analysis failed to identify a difference in survival among other subgroups.

These data suggest that although HIPEC may delay recurrence initially, long-term outcomes are equivalent regardless of whether HIPEC is used. Nevertheless, this study clearly establishes perioperative systemic chemotherapy and complete cytoreduction as the standard of care for select patients with limited-volume peritoneal carcinomatosis from colorectal cancer. The 36.7 percent five-year OS suggests that this multimodality approach may lead to long-term survival in some patients with peritoneal carcinomatosis from colon cancer. The significance of this finding should be underscored as this potentially curative treatment of peritoneal carcinomatosis from colon cancer represents a paradigm shift in oncology.

These results were achieved by experienced surgeons at high-volume peritoneal centers, and may not translate to the general community. It is imperative to note that all patients, regardless of whether they received HIPEC, underwent a thorough exploratory laparotomy where all visceral and parietal peritoneal surfaces were examined for evidence of disease. Cytoreductions can be extensive, involving parietal peritonectomies, small and large bowel resections, gastrectomy, splenectomy, hysterectomy, and oophorectomy among other procedures requiring significant expertise as demonstrated in the long learning curve reported of 90–180 cases.6

The authors report similar 30-day morbidity, with grade 3–5 complications occurring in 40.6 percent of HIPEC-treated participants and 31.1 percent of patients not given HIPEC. Mortality (1.5 percent) was also similar between the groups. However, there was a significantly higher rate of major (grade 3–5) complications at 60 days (24.1 percent versus 13.6 percent, p = 0.03) for patients treated with HIPEC versus cytoreduction alone.5,7 These late complications may be specific to the intraperitoneal use of oxaliplatin, as several other prospective HIPEC trials using different intraperitoneal chemotherapeutic agents have shown that HIPEC has a limited effect on complication rates.

The oncology community has expressed considerable concern regarding the possibility of increased anastomotic leaks, fistula, and infectious complications with the use of HIPEC. However, this study demonstrated that HIPEC can be safely performed at experienced centers. It also highlights the necessity of extended postoperative follow-up for patients treated with HIPEC to identify and manage late complications. Further investigation into the late complications to determine how they can be successfully mitigated is warranted.

Implications for the future

Based on the results of the PRODIGE 7 trial, complete surgical resection of all visible disease is the treatment standard for select patients with completely resectable and isolated peritoneal metastasis from colorectal cancer. Furthermore, these data suggest that HIPEC should no longer be offered to patients with colorectal carcinomatosis outside the setting of a clinical trial. Nonetheless, HIPEC may still be beneficial in the treatment of peritoneal carcinomatosis. Although HIPEC with oxaliplatin for 30 minutes in this patient population offered no additional benefit, the benefit of the regional administration of high doses of cytotoxic chemotherapy directly to the peritoneum after complete cytoreduction to eradicate microscopic residual cells has been demonstrated in recent randomized trials to improve survival over surgery alone for both gastric cancer and ovarian cancer.

For example, a phase III trial in China randomized 68 patients with gastric cancer and peritoneal carcinomatosis to cytoreductive surgery and HIPEC versus cytoreduction alone. The trial demonstrated a statistically significant but clinically modest absolute improvement of 3.5 months for the HIPEC arm.8 Subsequently, the prospective CYTO-CHIP study in France confirmed the benefit of HIPEC in gastric peritoneal carcinomatosis in the Western population with a five-year OS of 19.9 percent for patients treated with cytoreduction and HIPEC versus 6.4 percent for patient treated with cytoreduction alone.9 Similarly, the Dutch phase III trial randomized 245 patients with stage III epithelial ovarian cancer to perioperative systemic chemotherapy, cytoreduction, and HIPEC or perioperative systemic chemotherapy and cytoreduction alone. The trial demonstrated a significant improvement in OS for ovarian cancer treated with cytoreduction and HIPEC with a 45.7 months median survival versus 33.9 months for the non-HIPEC arm.10 See Table 1 for more information on randomized trials.

Explanations for the lack of difference in survival for patients in the PRODIGE 7 trial could be related to the improved efficacy of multi-agent and targeted systemic chemotherapy, the choice of intraperitoneal chemotherapeutic agent, the dose of intraperitoneal chemotherapy, and/or the duration of perfusion. Therefore, the PRODIGE 7 trial results may either refine patient selection by identifying patients for whom HIPEC is not a useful adjunct therapy for the treatment of peritoneal metastasis, or it may refine intraperitoneal drug selection for HIPEC. Regardless, the trial demonstrates that large-scale prospective trials including HIPEC are feasible and further investigation is warranted, including the use of other chemotherapy agents (mitomycin C, melphalen, or others); longer duration of HIPEC (such as the more common 60–120 minute intervals); and other procedural sequencing, such as neoadjuvant perfusion using laparoscopy or postoperatively using indwelling catheters. At present, 27 active clinical trials are listed on clinicaltrials.gov ensuring that we continue to expand and improve upon our treatments for our patients with peritoneal carcinomatosis.

Table 1. Randomized trials

Table 1. Randomized trials


References

  1. American Cancer Society. Cancer Facts & Figures 2018. Atlanta, GA: American Cancer Society; 2018.
  2. Franko J, Shi Q, Goldman CD, et al. Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: A pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. J Clin Oncol. 2012;30(3):263-267.
  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Colon Cancer (Version 4.2018). Available at: www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed November 6, 2018.
  4. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21(20):3737-3743.
  5. Quenet F, Elias D, Roca L, et al. A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7. J Clin Oncol. June 7, 2018 [Epub ahead of print].
  6. Polanco PM, Ding Y, Knox JM, et al. Institutional learning curve of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for peritoneal malignancies. Ann Surg Oncol. 2015;22(5):1673.
  7. Quénet F, Elias D, Roca L, et al. Perioperative outcomes of cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal carcinomatosis: PRODIGE 7 randomized trial. Euro J Surg Onc. 2016;42(9):S107.
  8. Yang XJ, Huang CQ, Suo T, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: Final results of a phase III randomized clinical trial. Ann Surg Oncol. 2011;18(6):1575-1581.
  9. Bonnot PE, Piessen G, Pocard M, et al. CYTO-CHIP: Cytoreductive surgery versus cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis: A propensity-score analysis from BIG RENAPE and FREGAT working groups. J Clin Oncol. February 26, 2018 [Epub ahead of print].
  10. Van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018;378(3):230-240.

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