Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study

Our plain-English summary of Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study, by B. Malgras, E. Gayat, O. Aoun, et al (Annals of Surgical Oncology, 2018).

The study

• Authors: B. Malgras, E. Gayat, O. Aoun, R. Lo Dico, C. Eveno, K. Pautrat, J.B. Delhorme, G. Passot, F. Marchal, O. Sgarbura, G. Ferron, D. Goéré, T. Andre, M. Pocard, RENAPE Network
• Journal: Annals of Surgical Oncology
• Published: 2018;25(11):3271-3279
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: The introduction of cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) improved the prognosis of selected patients with peritoneal mesothelioma (PM).

Objective: The objective of our study was to evaluate whether different HIPEC agents were associated with different outcomes in patients with PM.

Methods: From the RENAPE database, we selected all patients with histology-proven PM who underwent CRS + HIPEC from 1989 to 2014. Inclusion criteria were age ≤ 80 years, performance status ≤ 2, and no extraperitoneal metastases.

Results: Overall, 249 patients underwent CRS + HIPEC for PM. The HIPEC regimen included five chemotherapeutic agents (CAs), consisting of cisplatin, doxorubicin, mitomycin-C, oxaliplatin, and irinotecan. When considering all CAs (alone or in combination), there was no significant statistical difference in regard to postoperative overall survival (OS). However, OS was better when using two CAs (group 2 drugs) versus one CA (group 1 drug) (p = 0.03). The different CA regimens were equally distributed between the two groups. This association between OS and HIPEC agent, as well as a trend for better progression-free survival, were both observed in the two-drug group versus the one-drug group (p = 0.009) for patients undergoing complete cytoreductive surgery (CC-0) with an epithelioid subtype.

Conclusions: This large study seems to show improved OS when combined CAs, especially with platinum-based regimens, are used for HIPEC in patients with PM, but needs to be confirmed by a randomized controlled trial.

In plain English

Using the French RENAPE database, the authors looked back at 249 patients with peritoneal mesothelioma treated at 20 referral centers between 1989 and 2014 with surgery to remove visible tumor followed by heated chemotherapy in the abdomen (HIPEC). Thirty-six patients were recorded as asbestos-exposed and 203 as not exposed. Across all individual drug regimens, overall survival did not differ significantly. Patients given two drugs (161) had better survival than those given one drug (88) (hazard ratio 0.54, 95% CI 0.31 to 0.95). In patients with complete tumor removal and the epithelioid subtype, the hazard ratio was 0.25 (95% CI 0.09 to 0.72), while progression-free survival showed only a non-significant trend. The one-drug group had more extensive disease at surgery. The authors noted the study was retrospective and had too few events for full adjustment for other factors. They concluded that combined, especially platinum-based, regimens seemed to improve survival, but that a randomized trial is needed to confirm this.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study of patients drawn from a prospective multicenter database (RENAPE, the French National Network of Peritoneal Surface Malignancies) comparing chemotherapy agents used during HIPEC
• Who was studied: 249 patients with histology-proven peritoneal mesothelioma who underwent cytoreductive surgery plus HIPEC from 1989 to 2014 at 20 French tertiary referral centers. Patients were aged 80 or under, had ECOG performance status 2 or better, and had no extraperitoneal metastases. Epithelioid was the most frequent subtype (132 patients).
• Exposure: The exposure compared was the HIPEC chemotherapy regimen: cisplatin alone (n = 21), cisplatin plus doxorubicin (n = 60), cisplatin plus mitomycin-C (n = 52), mitomycin-C alone (n = 15), oxaliplatin alone (n = 52) and oxaliplatin plus irinotecan (n = 49). These were grouped as a one-drug group (n = 88) and a two-drug group (n = 161). Asbestos exposure was recorded in Table 1 (36 exposed, 203 not exposed) and did not differ statistically between the drug groups.
• Main results:
  • Considering all chemotherapy agents alone or in combination, there was no statistical difference in postoperative overall survival.
  • Overall survival was better in the two-drug group than in the one-drug group: hazard ratio 0.54, 95% CI 0.31 to 0.95, p = 0.03.
  • Among patients with complete cytoreduction (CC-0) and the epithelioid subtype (23 one-drug and 38 two-drug patients in Fig. 2), overall survival was better in the two-drug group: hazard ratio 0.25, 95% CI 0.09 to 0.72, p = 0.009.
  • For all patients, after adjusting for CC-0 score and histologic subtype, combination chemotherapy was associated with improved overall survival: hazard ratio 0.53, 95% CI 0.28 to 1.00, p = 0.05. Among CC-0 patients, after adjusting for subtype, the hazard ratio was 0.29, 95% CI 0.11 to 0.78, p = 0.01.
  • There was no statistical difference in overall survival between the different two-drug regimens. The authors note that oxaliplatin plus irinotecan had the best prognostic impact.
  • In CC-0 patients with the epithelioid subtype, there was a trend toward improved progression-free survival with combination chemotherapy: hazard ratio 0.48, 95% CI 0.21 to 1.07, p = 0.07.
  • Major morbidity occurred in 37% of all patients. There was no statistical difference in morbidity or mortality between the groups. The 3-year mortality rate was 36% in the single-drug group and 26% in the two-drug group (p = 0.11).
  • The groups differed in disease extent and technique. The mean Peritoneal Carcinomatosis Index (PCI) was higher in the one-drug group than in the two-drug group (19 versus 15, p = 0.006), and the closed HIPEC technique was used more often in the two-drug group.
• The authors' conclusion: The authors concluded that the study found an association between overall survival (and sometimes progression-free survival) and the HIPEC agents used. Survival seemed better with combined agents, especially platinum-based regimens, in CC-0 patients with epithelioid tumors. They stated this needs to be confirmed by a randomized controlled trial.
• Limitations the authors state:
  • The study was retrospective, although it drew on a prospective database.
  • The single-drug and two-drug groups differed statistically in mean PCI, which was higher in the single-drug group and might have affected prognosis.
  • The small number of observed events, due to the small sample size, meant confounding factors could not be accounted for with multivariate analysis, and causal inference could not be estimated with tools such as propensity scores.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Peritoneal Mesothelioma, HIPEC, Cytoreductive Surgery, Prognosis, Histology, Performance Status, Cisplatin.

Related studies

• The Role of Ki-67 and Pre-cytoreduction Parameters in Selecting Diffuse Malignant Peritoneal Mesothelioma (DMPM) Patients for Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) — S. Kusamura, P.A. Torres Mesa, et al. (2016)
• Early recurrence after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) — G.H.C. Tan, C.S. Chia, et al. (2018)
• Dose-Dependent Effect of Red Blood Cells Transfusion on Perioperative and Long-Term Outcomes in Peritoneal Surface Malignancies Treated with Cytoreduction and HIPEC — E. Nizri, S. Kusamura, et al. (2018)
• Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for malignant peritoneal mesothelioma: mitomycin versus cisplatin — A.U. Blackham, P. Shen, et al. (2010)
• Iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent or progressive diffuse malignant peritoneal mesothelioma: clinicopathologic characteristics and survival outcome — C. Ihemelandu, L. Bijelic, et al. (2015)
• Conversion to Complete Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma After Bidirectional Chemotherapy — F. Le Roy, M. Gelli, et al. (2017)

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