The Role of Hyperthermic Intraperitoneal Chemotherapy in Pseudomyxoma Peritonei After Cytoreductive Surgery

Shigeki Kusamura; Francesco Barretta; Yutaka Yonemura; Paul Hendrick Sugarbaker; Brendan John Moran; Edward A Levine; Diane Goere; Dario Baratti; Eran Nizri; David Lawson Morris; Olivier Glehen; Armando Sardi; Pedro Barrios; François Quénet; Laurent Villeneuve; Alberto Gómez-Portilla; Ignace de Hingh; Wim Ceelen; Joerg O W Pelz; Pompiliu Piso; Santiago González-Moreno; Kurt Van Der Speeten; Marcello Deraco

doi:10.1001/jamasurg.2020.6363

. 2021 Jan 27;156(3):e206363. doi: 10.1001/jamasurg.2020.6363

The Role of Hyperthermic Intraperitoneal Chemotherapy in Pseudomyxoma Peritonei After Cytoreductive Surgery

Shigeki Kusamura ¹, Francesco Barretta ², Yutaka Yonemura ³, Paul Hendrick Sugarbaker ⁴, Brendan John Moran ⁵, Edward A Levine ⁶, Diane Goere ⁷, Dario Baratti ¹, Eran Nizri ^1,⁸, David Lawson Morris ⁹, Olivier Glehen ¹⁰, Armando Sardi ¹¹, Pedro Barrios ¹², François Quénet ¹³, Laurent Villeneuve ¹⁴, Alberto Gómez-Portilla ^15,^16,¹⁷, Ignace de Hingh ¹⁸, Wim Ceelen ¹⁹, Joerg O W Pelz ²⁰, Pompiliu Piso ²¹, Santiago González-Moreno ²², Kurt Van Der Speeten ²³, Marcello Deraco ^1,^✉, for the Peritoneal Surface Oncology Group International (PSOGI) and the French National Registry of Rare Peritoneal Surface Malignancies (RENAPE)

¹Peritoneal Surface Malignancies Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale Tumori dei Tumori di Milano, Milano, Italy

²Clinical Epidemiology and Trial Organization Unit, Fondazione IRCCS Istituto Nazionale Tumori dei Tumori di Milano, Milano, Italy

³Nonprofit Organization to Support Peritoneal Surface Malignancy Treatment, Kishiwada, Japan

⁴Washington Cancer Institute, Washington Hospital Center, Washington, DC

⁵Basingstoke and North Hampshire National Health Service Foundation Trust, Basingstoke, United Kingdom

⁶Surgical Oncology Service, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina

⁷Department of Visceral and Oncologic Surgery, Hôpital Saint-Louis, Assistance Publique–Hôpitaux de Paris, Paris, France

⁸fellow at European School of Peritoneal Surface Oncology, Milano, Italy

⁹Hepatobiliary and Surgical Oncology Unit, Department of Surgery, University of New South Wales, St George Hospital, Sydney, Australia

¹⁰Department of Digestive Surgery, Centre Hospitalo-Universitaire Lyon-Sud, Hospices Civils de Lyon, Lyon, France

¹¹Division of Surgery, Department of Surgical Oncology, The Institute for Cancer Care, Mercy Medical Center, Baltimore, Maryland

¹²Department of Oncological Surgery, Hospital Sant Joan Despí, Moises Broggi, Peritoneal Surface Malignancy Catalonian’s Programme, Sant Joan Despí, Barcelona, Spain

¹³Centre Régional de Lutte Contre le Cancer Val d’Aurell, Montpellier, France

¹⁴Réseau National de Prise en Charge des Tumeurs Rares du Péritoine, French National Registry of Rare Peritoneal Surface Malignancies, Lyon, France

¹⁵Department of General Surgery, Hospital Universitario de Araba, Hospital Universitario Araba Sede Hospital Santiago, Santiago, Spain

¹⁶Departamento de Cirugía General, Universidad del País Vasco, Vitoria, Spain

¹⁷Programa de Carcinomatosis Peritoneal, Hospital San José, Vitoria, Spain

¹⁸Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands

¹⁹Department of Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium

²⁰Department of Surgery I, University of Wuerzburg, Wuerzburg, Germany

²¹Department of General and Visceral Surgery, Krankenhaus Barmherzige Brüder, Regensburg, Germany

²²Peritoneal Surface Oncology Program, Department of Surgical Oncology, MD Anderson Cancer Center, Madrid, Spain

²³Department of Surgical Oncology, Ziekenhuis Oost-Limburg, Genk, Belgium

Group Information: Members of the PSOGI and RENAPE are listed at the end of the article.

Accepted for Publication: November 1, 2020.

Published Online: January 27, 2021. doi:10.1001/jamasurg.2020.6363

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Corresponding Author: Marcello Deraco, MD, Peritoneal Surface Malignancies Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, Milano, MI 20133, Italy (marcello.deraco@istitutotumori.mi.it).

Author Contributions: Drs Kusamura and Barretta had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kusamura, Glehen, Sardi, Gómez-Portilla, Van Der Speeten, Deraco.

Acquisition, analysis, or interpretation of data: Kusamura, Barretta, Yonemura, Sugarbaker, Moran, Levine, Goere, Baratti, Nizri, Morris, Glehen, Sardi, Barrios, Quénet, Villeneuve, de Hingh, Ceelen, Pelz, Piso, González-Moreno, Van Der Speeten.

Drafting of the manuscript: Kusamura, Yonemura, Sardi, Ceelen, Van Der Speeten, Deraco.

Critical revision of the manuscript for important intellectual content: Kusamura, Barretta, Yonemura, Sugarbaker, Moran, Levine, Goere, Baratti, Nizri, Morris, Glehen, Sardi, Barrios, Quénet, Villeneuve, Gómez-Portilla, de Hingh, Pelz, Piso, González-Moreno, Van Der Speeten, Deraco.

Statistical analysis: Kusamura, Barretta, Nizri, Ceelen.

Obtained funding: Kusamura, Deraco.

Administrative, technical, or material support: Kusamura, Yonemura, Levine, Baratti, Sardi, Villeneuve, de Hingh, Pelz.

Supervision: Kusamura, Goere, Glehen, Quénet, Gómez-Portilla, Piso, Van Der Speeten, Deraco.

Conflict of Interest Disclosures: Dr Glehen reported receiving personal fees from Gamida Cell, Ltd, during the conduct of the study. Dr de Hingh reported receiving grants from F. Hoffman–La Roche Ltd, Kankerbestrijding, and Quality in Products and Services/RanD outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported in part by the Italian Association for Cancer Research.

Role of the Funder/Sponsor: The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: Peritoneal Surface Oncology Group International (PSOGI) includes the following: Paul H. Sugarbaker, MD, Washington Cancer Institute, Washington Hospital Center, Washington, DC; Yutaka Yonemura, MD, PhD, NPO to Support Peritoneal Surface Malignancy Treatment; Brendan J. Moran, MCh, Basingstoke and North Hampshire National Health Service (NHS) Foundation Trust; Edward A. Levine, MD, Surgical Oncology Service, Wake Forest University Baptist Medical Center; Diane Goere, MD, PhD, Department of Visceral and Oncologic Surgery, Hôpital Saint-Louis, Assistance Publique–Hôpitaux de Paris (AP-HP); David L. Morris, MB, ChB, MD, PhD, Hepatobiliary and Surgical Oncology Unit, University of New South Wales Department of Surgery, St George Hospital; Olivier Glehen, MD, PhD, Department of Digestive Surgery, Centre Hospitalo-Universitaire Lyon-Sud, Hospices Civils de Lyon; Armando Sardi, MD, Division of Surgery, Department of Surgical Oncology, The Institute for Cancer Care, Mercy Medical Center; Pedro Barrios, MD, Department of Oncological Surgery, Hospital Sant Joan Despí, Moises Broggi, Peritoneal Surface Malignancy Catalonian’s Programme, Sant Joan Despí; François Quénet, MD, PhD, Centre Régional de Lutte Contre le Cancer Val d’Aurell; Alberto Gómez-Portilla, MD, PhD, Department of General Surgery, Hospital Universitario de Araba Sede Hospital Santiago, and Universidad Del País Vasco and Hospital San José; Ignace de Hingh, MD, PhD, Department of Surgery, Catharina Hospital; Wim Ceelen, MD, PhD, Department of Gastrointestinal Surgery, Ghent University Hospital; Joerg O. W. Pelz, MD, Department of Surgery I, University of Wuerzburg; Pompiliu Piso, MD, PhD, Department of General and Visceral Surgery, Krankenhaus Barmherzige Brüder; Santiago González-Moreno, MD, PhD, Peritoneal Surface Oncology Program, Department of Surgical Oncology, MD Anderson Cancer Center, Madrid; Kurt Van Der Speeten, MD, PhD, Department of Surgical Oncology, Ziekenhuis Oost-Limburg; Marcello Deraco, MD, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori dei Tumori di Milano, PSM Unit; Vic Verwaal, MD, Department of Surgical Oncology, Aarhus University Hospital; Jesus Esquivel, MD, Department of Surgical Oncology, Frederick Memorial Hospital; Yan Li, MD, Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital; Beatet Raw, MD, Oberärztin–Leitung Spezielle Onkologische Chirurgie; Shigeki Kusamura, MD, PhD, Fondazione IRCCS Istituto Nazionale Tumori dei Tumori di Milano, PSM Unit; Dario Baratti, MD, Fondazione IRCCS Istituto Nazionale Tumori dei Tumori di Milano, PSM Unit; Francesco Barretta, PhD, Fondazione IRCCS Istituto Nazionale Tumori dei Tumori di Milano, PSM Unit; Laurent Villeneuve, MBE, PhD, Réseau National de Prise en Charge des Tumeurs Rares du Péritoine RENAPE; and Eran Nizri, MD, PhD, European School of Peritoneal Surface Oncology fellow. RENAPE includes the following: Julio Abba, MD, Service de Chirurgie Digestive et de l’Urgence Hospitalier Universitarie (HU) Grenoble Alpes; Karine Abboud, MD, Service de Chirurgie Générale et Thoracique HU Nord; Mohammad Alyami, MD, Department of General Surgery and Surgical Oncology, King Khalid Hospital; Koceila Amroun, MD, Département de Chirurgie, Générale Institut Jean Godinotj; Thierry André, MD, PhD, Service d’Oncologie Médicale, AP-HP, Hôpital Saint Antoine; Catherine Arvieux, MD, PhD, Service de Chirurgie Digestive et de l’Urgence HU Grenoble Alpes; Gerlinde Averous-Lang, MD, Service d’Anatomie et Cytologie Pathologiques, Hospitalier Régional Universitaire (HRU) Hautepierre; Naoual Bakrin, MD, PhD, Service de Chirurgie Générale et Digestive Hôpital Lyon-Sud; Sandrine Barbois, MD, Service de Chirurgie Digestive et de l’Urgence, HU Grenoble Alpes; Houda Ben Rejeb, MD, Service d’Anatomie Pathologique Institut Bergonié; Nazim Benzerdjeb, MD, PhD, Service d’Anatomie et Cytologie Pathologiques, Hôpital Lyon-Sud; Jean-Marc Bereder, MD, Service de Chirurgie Viscérale et Générale HU L’Archet II; Frédéric Bibeau, MD, PhD, Laboratoire d’Anatomie Pathologique HU Caen Aen France; Pierre-Emmanuel Bonnot, MD, Service de Chirurgie Générale et Digestive, Hôpital Lyon-Sud; Olivier Bouché, MD, PhD, Service de Cancérologie Digestive, HU Robert Debré; Fatiha Bouhidel, MD, Laboratoire d’Anatomie Pathologique, AP-HP Hôpital Saint Louis; Marie-Dominique Bouzard, MD, Service de Chirurgie Digestive, AP-HP Hôpital Louis Mourier Colombes; Cécile Brigand, MD, PhD, Service de Chirurgie Générale et Digestive, HRU Hautepierre; Sébastien Carrère, MD, Service de Chirurgie Digestive Oncologique Institut du Cancer de Montpellier, Val d’Aurelle Montpellier; Bertrand Celerier, MD, Service de Chirurgie Digestive et Endocrinienne Groupe Hospitalier Sud Haut-Lévêque Centre Médico Chirurgical Magellan; Cécilia Ceribelli, MD, Service d’Oncologie Chirurgicale Institut de Cancérologie de Lorraine; Anne Chevallier, MD, Laboratoire d’Anatomie et Cytologie Pathologiques HU L’Archet II; Julien Coget, MD, Service de Chirurgie Digestive et de Physiologie Digestive HU Charles-Nicolle, Rouen; Romain Cohen, MD, Service d’Oncologie Médicale AP-HP Hôpital Saint Antoine; Thomas Courvoisier-Clément, MD, Service de Chirurgie Viscérale HU Poitiers; Sabrina Croce, MD, PhD, Service d’Anatomie Pathologique, Institut Bergonié; Peggy Dartigues, MD, Département d’Anatomie et Cytologie Pathologiques Institut Gustave Roussy; Cécile de Chaisemartin, MD, Service de Chirurgie Oncologique Digestive Institut Paoli Calmettes; Jean-Baptiste Delhorme, MD, PhD, Service de Chirurgie Générale et Digestive HRU Hautepierre; Anthony Dohan, MD, PhD, Service de Radiologie AP-HP Hôpital Cochin; Frédéric Dumont, MD, Département de Chirurgie Oncologique, Institut de Cancérologie de l’Ouest, René Gauducheau; Sylvaine Durand-Fontanier, MD, PhD, Service de Chirurgie Digestive Générale et Endocrinienne HU Dupuytren; Clarisse Eveno, MD, PhD, Service de Chirurgie Générale et Digestive HRU Claude Huriez, and Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche de Service (UMR-S 1172) entre de Recherche Jean-Pierre Aubert; Gwenaël Ferron, MD, PhD, Département de Chirurgie Institut Universitaire du Cancer Toulouse–Oncopole; Juliette Fontaine, MD, Service d’Anatomie et Cytologie Pathologiques; Johann Gagnière, MD, Service de Chirurgie Digestive et Hépatobiliaire HU Estaing Lermont-Ferrand; Alexandre Galan, MD, Service de Radiologie Hôpital Lyon-Sud; Maximiliano Gelli, MD, Unité de Chirurgie Digestive Oncologique, Institut Gustave Roussy; Laurent Ghouti, MD, Service de Chirurgie Digestive HU Rangueil; François-Noël Gilly, MD, PhD, Service de Chirurgie Générale et Digestive Hôpital Lyon-Sud; Laurence Gladieff, MD, Service d’Oncologie Médicale Institut Universitaire du Cancer Toulouse–Oncopole; Olivier Glehen, MD, PhD, Service de Chirurgie Générale et Digestive Hôpital Lyon-Sud; Diane Goere, MD, PhD, Service de Chirurgie Générale Digestive et Endocrinienne, AP-HP Hôpital Saint Louis; Jean-Marc Guilloit, MD, Service de Chirurgie Viscérale Entre François Baclesse aen France; Frédéric Guyon, MD, Service de Chirurgie Oncologique Institut Bergonié; Bruno Heyd, MD, PhD, Service de Chirurgie Digestive HU Jean Minjoz; Christine Hoeffel, MD, PhD, Service de Radiologie HU Robert Debré; Charles Honoré, MD, PhD, Unité de Chirurgie Digestive Oncologique, Institut Gustave Roussy; Eve Huart, MD, Service de Chirurgie Générale et Thoracique HU Nord; Martin Hübner, MD, PhD, Service de de Chirurgie Viscérale HUV; Sylvie Isaac, MD, Service d’Anatomie et Cytologie Pathologiques Hôpital Lyon-Sud; Rachid Kaci, MD, Service d’Anatomie et Cytologie Pathologiques, AP-HP Hôpital Lariboisière; Vahan Kepenekian, MD, PhD, Service de Chirurgie Générale et Digestive Hôpital Lyon-Sud; Reza Kianmanesh, MD, PhD, Service de Chirurgie Générale Digestive et Endocrinienne–Pôle Médico-Chirurgical Digestif Urologie Néphrologie Endocrinologie HU Robert Debré; Marie-Hélène Laverrière, MD, Service d’Anatomie Pathologique HU Grenoble Alpes; Valérie Lebrun-Ly, MD, Service d’Oncologie Médicale HU Dupuytren; Jérémie H. Lefevre, MD, PhD, Service de Chirurgie Générale et Digestive, AP-HP Hôpital Saint Antoine; Bernard Lelong, MD, Service de Chirurgie Oncologique Digestive, Institut Paoli-Calmettes; Agnès Leroux-Broussier, MD, Service d’Anatomie et Cytologie Pathologiques Institut de Cancérologie de Lorraine; Réa Lo Dico, MD, PhD, Service de Chirurgie Digestive et Cancérologique, AP-HP Hôpital Saint Louis; Brice Malgras, MD, PhD, Service de Chirurgie Viscérale Digestive et Endocrinienne, Hôpital D’instruction des Armées (HIA) Begin; Frédéric Marchal, MD, PhD, Service d’Oncologie Chirurgicale, Institut de Cancérologie de Lorraine; Pascale Mariani, MD, Service d’Oncologie Chirurgicale, Institut Curie; Pierre Meeus, MD, Service de Chirurgie Oncologique Entre Léon Bérard; Eliane Mery, MD, Service d’Anatomie et Cytologie Pathologiques, Institut Universitaire du Cancer Toulouse–Oncopole; Cédric Nadeau, MD, Service de Gynécologie HU Poitiers; Cécile Odin, MD, Service de Chirurgie Générale et Digestive; Pablo Ortega-Deballon, MD, PhD, Service de Chirurgie Digestive et Cancérologique, HU Dijon Bourgogne; Brice Paquette, MD, Service de Chirurgie Digestive, HU Jean Minjoz; Guillaume Passot, MD, PhD, Service de Chirurgie Générale et Digestive, Hôpital Lyon-Sud; Julien Péron, MD, PhD, Service d’Oncologie Médicale, Hôpital Lyon-Sud; Patrice Peyrat, MD, Service de Chirurgie Oncologique Entre Léon Bérard; Denis Pezet, MD, PhD, Service de Chirurgie Digestive et Hépatobiliaire, HU Estaing de Lermont-Ferrand; Guillaume Piessen, MD, PhD, Service de Chirurgie Générale et Digestive, HRU Claude Huriez; Nicolas Pirro, MD, PhD, Service de Chirurgie Digestive et Générale, HU La Timône; Marc Pocard, MD, PhD, Service de Chirurgie Digestive et Cancérologique, AP-HP Hôpital Lariboisière, and Service de Chirurgie Viscérale Digestive et Endocrinienne, HIA Begin; Flora Poizat, MD, Département de Biopathologie Institut Paoli-Calmettes; François Quénet, MD, Service de Chirurgie Digestive Oncologique, Institut du Cancer de Montpellier–Val d’Aurelle; Patrick Rat, MD, PhD, Service de Chirurgie Digestive et Cancérologique, HU Dijon Bourgogne; Pauline Ries, MD, Service de Chirurgie Oncologique Digestive, Institut Paoli-Calmettes; Pierre Rousselot, MD, Service d'Anatomie et Cytologie Pathologiques Entre François Baclesse Aen France; Pascal Rousset, MD, PhD, Service de Radiologie Hôpital Lyon-Sud; Hélène Senellart, MD, Service d’Oncologie Médicale Institut de Cancérologie de Ouest–René Gauducheau; Olivia Sgarbura, MD, Service de Chirurgie Digestive Oncologique, Institut du Cancer de Montpellier–Val d’Aurelle; Igor Sielezneff, MD, PhD, Service de Chirurgie Digestive et Générale, HU La Timône; Andrea Skanjeti, MD, Service de Médecine Nucléaire Hôpital Lyon-Sud; Isabelle Sourrouille, MD, Unité de Chirurgie Digestive Oncologique, Institut Gustave Roussy; Philippe Soyer, MD, PhD, Service de Radiologie, AP-HP Hôpital Lariboisière; Magali Svrcek, MD, PhD, Service d’Anatomie Pathologique, AP-HP Hôpital Saint Antoine; Abdelkader Taibi, MD, Service de Chirurgie Digestive Générale et Endocrinienne, HU Dupuytren; Emilie Thibaudeau, MD, Service de Chirurgie Oncologique, Institut de Cancérologie de l’Ouest–René Gauducheau; Olivier Tiffet, MD, PhD, Service de Chirurgie Générale et Thoracique, HU Nord; Jérémie Tordo, MD, Service de Médecine Nucléaire, Hôpital Lyon-Sud; Yann Touchefeu, MD, Unité de Gastroentérologie, HU Nantes Hôtel-Dieu; Bertrand Trilling, MD, Service de Chirurgie Digestive et de l’Urgence, HU Grenoble Alpes; Jean-Jacques Tuech, MD, PhD, Service de Chirurgie Digestive et de Physiologie Digestive, HU Charles-Nicolle; Dimitri Tzanis, MD, Service d’Oncologie Chirurgicale, Institut Curie; Séverine Valmary-Degano, MD, PhD, Service d’Anatomie Pathologique, HU Grenoble Alpes; Sharmini Varatharajah, MD, Service de Chirurgie Viscérale Entre François Baclesse Aen France; Delphine Vaudoyer, MD, Service de Chirurgie Générale et Digestive, Hôpital Lyon-Sud; Sophie Vermersch, MD, Service de Chirurgie Infantile, HU Nord; Véronique Verriele-Beurrier, MD, Service d’Anatomie Pathologique, Institut de Cancérologie de l’Ouest–Paul Papin; Laurent Villeneuve, PhD, Service de Recherche et Epidémiologie Cliniques Pôle de Santé Pubique Hospices Civils de Lyon; Guillaume Vogin, MD, PhD, Service de Radiothérapie Institut de Cancérologie de Lorraine; Romuald Wernert, MD, Service de Chirurgie Digestive, Institut de Cancérologie de l’Ouest-Paul Papin; and Benoit You, MD, PhD, Service d’Oncologie Médicale, Hôpital Lyon-Sud.

Meeting Presentation: This paper was presented in part at the Peritoneal Surface Oncology Group International Biannual Meeting; September 9, 2018; Paris, France.

Additional Contributions: The authors acknowledge the contributions of Isabelle Bonnefoy, BSc (Centre Hospitalo-Universitaire Lyon-Sud), Mary Cromer, BS (Wake Forest University Baptist Medical Center), Kandiah Chandrakumaran, PhD (Basingstoke and North Hampshire NHS Foundation Trust), Terence C. Chua, PhD (Royal North Shore Hospital, St Leonards, Australia), and Tristan D. Yan, PhD (Royal Prince Alfred Hospital, Sydney, Australia). These contributors did not fulfill authorship criteria or receive financial compensation for having participated in the study.

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Corresponding author.

PMCID: PMC7841579 PMID: 33502455

Key Points

Question

What is the association of hyperthermic intraperitoneal chemotherapy (HIPEC) with prognosis and surgical outcomes of patients who undergo cytoreductive surgery for pseudomyxoma peritonei (PMP)?

Findings

In this propensity score–matched cohort study that included 1924 patients with PMP, HIPEC was associated with a better overall survival, generally without worsening the postoperative outcomes in terms of 30- and 90-day mortality, severe morbidity, and return to operating room.

Meaning

HIPEC should be considered in conjunction with cytoreductive surgery in patients with PMP.

This cohort study compares the outcomes of patients with pseudomyxoma peritonei who undergo hyperthermic intraperitoneal chemotherapy with cytoreductive surgery vs cytoreductive surgery alone.

Abstract

Importance

Studies on the prognostic role of hyperthermic intraperitoneal chemotherapy (HIPEC) in pseudomyxoma peritonei (PMP) are currently not available.

Objectives

To evaluate outcomes after cytoreductive surgery (CRS) and HIPEC compared with CRS alone in patients with PMP.

Design, Setting, and Participants

This cohort study analyzed data from the Peritoneal Surface Oncology Group International (PSOGI) registry, including 1924 patients with histologically confirmed PMP due to an appendiceal mucinous neoplasm. Eligible patients were treated with CRS with or without HIPEC from February 1, 1993, to December 31, 2017, and had complete information on the main prognostic factors and intraperitoneal treatments. Inverse probability treatment weights based on the propensity score for HIPEC treatment containing the main prognostic factors were applied to all models to balance comparisons between the CRS-HIPEC vs CRS-alone groups in the entire series and in the following subsets: optimal cytoreduction, suboptimal cytoreduction, high- and low-grade histologic findings, and different HIPEC drug regimens. Data were analyzed from March 1 to June 1, 2018.

Interventions

HIPEC including oxaliplatin plus combined fluorouracil-leucovorin, cisplatin plus mitomycin, mitomycin, and other oxaliplatin-based regimens.

Main Outcomes and Measures

Overall survival, severe morbidity (determined using the National Cancer Institute Common Terminology for Adverse Events, version 3.0), return to operating room, and 30- and 90-day mortality. Differences in overall survival were compared using weighted Kaplan-Meier curves, log-rank tests, and Cox proportional hazards multivariable models. A sensitivity analysis was based on the E-value from the results of the main Cox proportional hazards model. Differences in surgical outcomes were compared using weighted multivariable logistic models.

Results

Of the 1924 patients included in the analysis (997 [51.8%] men; median age, 56 [interquartile range extremes (IQRE), 45-65] years), 376 were in the CRS-alone group and 1548 in the CRS-HIPEC group. Patients with CRS alone were older (median age, 60 [IQRE, 48-70] vs 54 [IQRE, 44-63] years), had less lymph node involvement (14 [3.7%] vs 119 [7.7%]), received more preoperative systemic chemotherapy (198 [52.7%] vs 529 [34.2%]), and had higher proportions of high-grade disease (179 [47.6%] vs 492 [31.8%]) and suboptimal cytoreduction residual disease (grade 3, 175 [46.5%] vs 117 [7.6%]). HIPEC was not associated with a higher risk of worse surgical outcomes except with mitomycin, with higher odds of morbidity (1.99; 95% CI, 1.25-3.19; P = .004). HIPEC was associated with a significantly better overall survival in all subsets (adjusted hazard ratios [HRs], 0.60-0.68, with 95% CIs not crossing 1.00). The weighted 5-year overall survival was 57.8% (95% CI, 50.8%-65.7%) vs 46.2% (95% CI, 40.3%-52.8%) for CRS-HIPEC and CRS alone, respectively (weighted HR, 0.65; 95% CI, 0.50-0.83; P < .001; E-value, 2.03). Such prognostic advantage was associated with oxaliplatin plus fluorouracil-leucovorin (HR, 0.42; 95% CI, 0.19-0.93; P = .03) and cisplatin plus mitomycin (HR, 0.57; 95% CI, 0.42-0.78; P = .001) schedules.

Conclusions and Relevance

In this cohort study, HIPEC was associated with better overall survival when performed after CRS in PMP, generally without adverse effects on surgical outcomes.

Introduction

Pseudomyxoma peritonei (PMP) is an unusual clinical entity characterized by mucinous ascites, eventually leading to abdominal distension and bowel obstruction.¹ The pathophysiology is a mucinous neoplasm, most commonly originating in the appendix.² The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been regarded as standard of care for PMP.³ Cytoreductive surgery aims to remove all visible tumor and includes peritonectomy and resection of the involved organs.⁴ The surgical phase is completed with local-regional administration of hyperthermic chemotherapy to eliminate microscopic residual neoplastic disease. Data on the efficacy of HIPEC after CRS in the treatment of peritoneal malignant neoplasms are inconsistent according to the primary tumor type. It has been shown to be beneficial in epithelial ovarian cancer (when preceded by neoadjuvant systemic chemotherapy)⁵ and in peritoneal metastasis from gastric cancer,⁶ but not in peritoneal metastasis from colorectal cancer (PM-CRC).⁷ Moreover, HIPEC in the latter PRODIGE-7 (Partenariat de Recherche en Oncologie Digestive 7) study has been reported to increase 60-day surgical morbidity, although full details and publication of the results presented are awaited.

Thus, the primary end point in the present study aimed to evaluate the prognostic effect of HIPEC with CRS, compared with CRS alone, in patients with PMP. We analyzed an international registry of patients with PMP and performed multiple parallel weighted analyses to test whether HIPEC is associated with therapeutic benefit in various patient subsets. Secondary end points were the effects associated with different HIPEC drug schedules and whether HIPEC was associated with adverse perioperative outcomes.

Methods

Study Design

We performed a secondary analysis of the Peritoneal Surface Oncology Group International (PSOGI) registry data. This cohort study received institutional review board approval by all participating centers, and patients were exempted from providing informed consent, according to European Union General Data Protection Regulation, owing to the observational nature of the study, pseudoanonymized data, and the fact that participation did not imply any further risk to the patients. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Setting

The PSOGI multicenter registry was set up in 2010 and represented a collaborative effort of main peritoneal surface malignancy international centers to prospectively collect data. Data were collected from 3495 patients with PMP who underwent CRS with or without HIPEC from February 1, 1993, to December 31, 2017.

Participants

Inclusion criteria consisted of histologically confirmed PMP from an appendiceal mucinous neoplasm and a CRS procedure alone or in combination with HIPEC. Data for 1924 of the 3495 registry patients with complete data regarding the preoperative and postoperative parameters and tumor characteristics established in the literature as main prognostic factors were retrieved (eFigure 1 in the Supplement).

Variables

The exposure variable was HIPEC (yes or no). The variables investigated as effect modifiers were histological subtype (high or low grade according to World Health Organization criteria),⁸ prior systemic chemotherapy (yes or no), prior surgical score (0 indicates no surgery or biopsy; 1, surgery in 1 abdominal region only; 2, surgery in 2 to 5 regions; and 3, surgery in ≥6 regions),⁹ peritoneal cancer index,⁹ lymph node status (positive or negative), and completeness of cytoreduction (complete [CC-0/1], defined as residual disease of <2.5 mm; residual disease of 2.5 mm to 2.5 cm [CC-2]; and residual disease of >2.5 cm [CC-3]).⁹ Age at surgery and early postoperative intraperitoneal chemotherapy (EPIC) (yes or no) were considered as possible confounders. The outcomes compared between exposure groups were overall survival (calculated from the time of the surgery of the primary tumor to death due to any cause or last follow-up for living patients), severe morbidity (grades 3-5 determined by the National Cancer Institute Common Terminology for Adverse Events, version 3.0), return to the operating room, and 30- and 90-day mortality. There were no differences in the assessment of variables between the groups exposed to HIPEC (CRS-HIPEC) and those unexposed (CRS-alone).

Treatments

The surgical approach involved peritonectomy procedures as described by Sugarbaker.⁹ HIPEC was administered after CRS using an open coliseum or closed technique, depending on the individual unit’s preference. The perfusate was heated to achieve a temperature ranging from 40 °C to 43 °C. The most frequent HIPEC drug regimens included mitomycin, 35 mg/m², or a fixed dose of 40 mg; oxaliplatin, 360 to 460 mg/m² plus combined fluorouracil and leucovorin, 400 mg/m²; oxaliplatin, 200 mg/m²; and cisplatin, 25 mg/m² per liter of perfusate associated with mitomycin, 3.3 mg/m² per liter of pefusate (eTable 1 in the Supplement). Some units administered EPIC consisting of intraperitoneal fluorouracil, 650 mg/m², on days 1 to 5 at room temperature. We classified perioperative morbidity according to National Cancer Institute Common Terminology for Adverse Events, version 3.0.¹⁰ Patients were followed up by clinical examination, computed tomographic scan of the chest and abdomen, and measurement of serum tumor marker levels every 4 to 6 months for the first 2 years and every 6 to 12 months thereafter.

Statistical Analysis

Data were analyzed from March 1 to June 1, 2018. We handled missing data with complete case analysis because the proportions of incomplete information in some key variables were too high to be managed with missing-imputation technique. Patients in the CRS-alone group were compared with those in the CRS-HIPEC group. We estimated propensity scores as balancing scores to account for the bias consistent with a nonrandom assignment of treatment in the study groups for each comparison.¹¹ For this purpose, we used multivariable logistic models with a binary response (CRS-HIPEC or CRS alone) and the retrieved above-mentioned prognostic factors. We used the method of stabilized weights.¹² To account for the bias introduced from the inverse probability treatment weight procedure in the estimation of the standard error of the β statistic in regression models, we used a bootstrap estimator to calculate the 95% CIs.¹³

Differences in means (numerical variables) and proportions (categorical variables) between baseline patient characteristics of the excluded and included patients and treatment groups were compared using the standardized mean difference.¹⁴ Standardized mean differences of at least 0.300 were considered indicative of a relevant between-group imbalance. We calculated the standardized mean difference before and after inverse probability treatment weighted adjustment in the study groups.

Overall survival differences were assessed between the CRS-alone and CRS-HIPEC groups overall and in the following subsets: optimal cytoreduction (CC-0/1), suboptimal cytoreduction (CC-2/3), low-grade PMP, and high-grade PMP. We decided not to distinguish between CC-2 and CC-3 because the former group was numerically small. We also tested the differences in overall survival between CRS alone and CRS-HIPEC according to different HIPEC drug regimens. We assessed differences in overall survival using weighted log-rank tests and multivariable Cox proportional hazards models including all the retrieved above-mentioned prognostic factors. The center factor was assessed as random effect in univariable and multivariable Cox models for the whole cohort and dropped as not statistically significant (likelihood ratio test P = .99 and P = .49, respectively). The median follow-up was estimated with the reverse Kaplan-Meier method on weighted data.¹⁵

We assessed differences in surgical outcomes between CRS-alone and CRS-HIPEC groups according to different HIPEC drug regimen subgroups, as previously described, using weighted multivariable logistic models. We performed penalized logistic models to obtain evaluable results for 90- and 30-day mortality in the oxaliplatin plus fluorouracil-leucovorin subgroup. We did not assess any interaction terms. We modeled age and peritoneal cancer index as continuous variables by using 3-knot restricted cubic splines to obtain flexible fit.¹⁶

We evaluated selection bias by means of difference in overall survival calculated by log-rank tests between included vs excluded patients and between CRS-alone vs CRS-HIPEC groups in the excluded patients group. We conducted a sensitivity analysis on hazard ratios (HRs) and the 95% CI limit (CL) closer to the CL of the main Cox proportional hazards model by means of the E-value. The latter is the minimal strength at which a confounder would need to be associated with both the outcome and the exposure of interest to fully explain away the observed association between treatment and outcome.¹⁷

Results

For the main analysis of the 1924 included patients (927 [48.2%] women and 997 [51.8%] men; median age, 56 [interquartile range extremes (IQRE), 45-65] years), we considered clinical-pathological and treatment data from 376 patients who underwent CRS alone and 1548 patients who underwent CRS-HIPEC (eFigure 1 in the Supplement). Patients who received CRS alone were older (median age, 60 [IQRE, 48-70] vs 54 [IQRE, 44-63] years), had less lymph node involvement (14 [3.7%] vs 119 [7.7%]), received more preoperative systemic chemotherapy (198 [52.7%] vs 529 [34.2%]), had a higher proportion of high-grade disease (179 [47.6%] vs 492 [31.8%]), and had a higher proportion of incomplete cytoreductions (CC-3, 175 [46.5%] vs 117 [7.6%]). After the weighting, we obtained a good balance in the distribution of prognostic factors (Table 1). Similarly, we obtained a good balance for all factors in every subset analysis (eTables 2-9 in the Supplement).

Table 1. Prognostic Factors in CRS-HIPEC and CRS-Alone Groups Before and After IPTW .

Factor	Study group, unweighted			Study group, IPTW weighted
Factor	CRS alone (n = 376)	CRS-HIPEC (n = 1548)	SMD	CRS alone (n = 305)	CRS-HIPEC (n = 300)	SMD
Age, median (IQRE), y	60 (48-70)	54 (44-63)	0.381	59 (46-67)	59 (46-68)	0.010
Prior systemic chemotherapy, No. (%)
Yes	198 (52.7)	529 (34.2)	0.380	149.4 (48.9)	149.0 (49.5)	0.013
No	178 (47.3)	1019 (65.8)	0.380	156.2 (51.1)	151.8 (50.5)	0.013
Lymph node involvement, No. (%)
Yes	14 (3.7)	119 (7.7)	0.172	12.9 (4.2)	12.9 (4.3)	0.003
No	362 (96.3)	1429 (92.3)	0.172	292.7 (95.8)	287.9 (95.7)	0.003
Peritoneal cancer index, median (IQRE)^a	25 (13-35)	19 (10-28)	0.314	24 (11-33)	23 (11-34)	0.002
Completeness of cytoreduction score, No. (%)^b
0/1	164 (43.6)	1352 (87.3)	1.065	163.9 (53.6)	167 (55.5)	0.099
2	37 (9.8)	79 (5.1)		35.4 (11.6)	25.9 (8.6)
3	175 (46.5)	117 (7.6)		106.3 (34.8)	108.0 (35.9)
Prior surgical score, No. (%)^c
0	118 (31.4)	355 (22.9)	0.335	86.7 (28.4)	89.0 (29.6)	0.039
1	99 (26.3)	467 (30.2)		86.9 (28.4)	87.4 (29.0)
2	129 (34.3)	456 (29.5)		103.8 (33.9)	97.1 (32.3)
3	30 (8.0)	270 (17.4)		28.3 (9.3)	27.4 (9.1)
EPIC
Yes	53 (14.1)	250 (16.1)	0.057	47.0 (15.4)	252.0 (83.8)	0.024
No	323 (85.9)	1298 (83.9)	0.057	258.7 (84.6)	48.8 (16.2)	0.024
Histologic finding, No. (%)
Low grade	197 (52.4)	1056 (68.2)	0.328	172.8 (56.5)	168.1 (55.9)	0.014
High grade	179 (47.6)	492 (31.8)	0.328	132.8 (43.5)	132.7 (44.1)	0.014

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Abbreviations: CC-0/1, complete cytoreduction; CC-2 and CC-3, suboptimal cytoreduction; CRS, cytoreductive surgery; EPIC, early postoperative intraperitoneal chemotherapy; HIPEC, hyperthermic intraperitoneal chemotherapy; IPTW, inverse probability treatment weighting; IQRE, interquartile range extremes; SMD, standardized mean difference.

^{^a}

Scores range from 0 to 39, with higher scores indicating worse prognosis.

^{^b}

CC-0/1 indicates residual disease of less than 2.5 mm; CC-2, residual disease of 2.5 mm to 2.5 cm; and CC-3, residual disease of greater than 2.5 cm.

^{^c}

Zero indicates no surgery or biopsy; 1, surgery in 1 abdominal region only; 2, surgery in 2 to 5 regions; and 3, surgery in 6 or more regions.

Survival Analysis in the Overall Series

During a median follow-up of 52 (IQRE, 23-83) months, we estimated a 5-year overall survival of 46.2% (95% CI, 40.3%-52.8%) for the CRS-alone group and 57.8% (95% CI, 50.8%-65.7%) for the CRS-HIPEC group (P < .001) (Figure 1A). After applying the multivariable Cox proportional hazards model, the HR was 0.65 (95% CI, 0.50-0.83; P = .001) (Figure 2 and Table 2). The HRs for influential prognostic factors included in the study ranged from 1.14 (95% CI, 0.82-1.58) for EPIC to 4.12 (95% CI, 2.75-6.18) for peritoneal cancer index (Table 2).

Figure 1. — Data in the overall series (A) include patients undergoing cytoreductive surgery (CRS) alone and those undergoing CRS with hyperthermic intraperitoneal chemotherapy (HIPEC). Remaining data are stratified by the HIPEC regimen compared with CRS alone (B-E). Data are shown as weighted comparisons.

Figure 2. — Data are presented as weighted hazard ratios (HRs) of death using multivariable Cox proportional hazards models and bootstrap 95% CI for HIPEC treatment. Arrow indicates 95% CI extends beyond boundary of the graph; diamond center, overall HR; ends of diamond, overall 95% CI. CC-0/1 indicates optimal cytoreduction (residual disease of <2.5 mm); CC-2/3, suboptimal cytoreduction (residual disease of ≥2.5 mm).

Table 2. Results of the Weighted Multivariable Cox Proportional Hazards Model Including HIPEC and the Main Prognostic Factors for Overall Survival.

Factor	HR (95% CI)	P value
HIPEC, yes vs no	0.65 (0.50-0.83)	.001
Age, 65 vs 45 y^a	1.24 (1.04-1.48)	.007
Prior systemic chemotherapy, yes vs no	1.58 (1.23-2.03)	<.001
Lymph node involvement, yes vs no	1.69 (0.95-3.01)	.08
Peritoneal cancer index, 29 vs 10^a	4.12 (2.75-6.18)	<.001
Prior surgical score
1 vs 0	1.41 (1.02-1.95)	.09
2 vs 0	1.41 (1.05-1.91)
3 vs 0	1.44 (0.90-2.30)
EPIC, yes vs no	1.14 (0.82-1.58)	.44
Higher histologic grade, yes vs no	2.36 (1.83-3.04)	<.001

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Abbreviations: EPIC, early postoperative intraperitoneal chemotherapy; HIPEC, hyperthermic intraperitoneal chemotherapy; HR, hazard ratio.

^{^a}

The 2 values are the third and first quartiles of the variable distribution, respectively.

Survival Analysis in the Subsets

Compared with the CRS-alone group, the CRS-HIPEC group had better 5-year overall survival in all subsets, including CC-0/1 (71.4% [95% CI, 64.2%-79.3%] vs 77.4% [95% CI, 69.2%-86.6%]; P = .009), CC-2/3 (16.1% [95% CI, 10.4%-24.8%] vs 28.4% [95% CI, 19.6%-41.1%]; P = .007), low-grade PMP (64.1% [95% CI, 56.3%-72.9%] vs 73.8% [95% CI, 65.0%-83.8%]; P < .001), and high-grade PMP (26.8% [95% CI, 20.0%-36.0%] vs 39.3% [95% CI, 30.0%-51.6%]; P = .002) (eFigure 2 in the Supplement). With multivariable Cox proportional hazards models, the HRs were 0.58 (95% CI, 0.35-0.95; P = .03) for CC-0/1, 0.66 (95% CI, 0.48-0.90; P = .009) for CC-2/3, 0.60 (95% CI, 0.37-0.96; P = .04) for low-grade PMP, and 0.68 (95% CI, 0.48-0.94; P = .02) for high-grade PMP (Figure 2).

Overall Survival According to Drug Schedules

Treatment with CRS-HIPEC was superior to CRS alone when the drug schedules were oxaliplatin plus fluorouracil-leucovorin (5-year overall survival, 86.1% [95% CI, 0.76%-0.97%] vs 62.6% [95% CI, 0.54%-0.73%]; P = .03) or cisplatin plus mitomycin (5-year overall survival, 64.9% [95% CI, 58.0%-72.7%] vs 52.2% [95% CI, 45.8%-59.4%]; P < .001) (Figure 1B and D). In multivariable Cox proportional hazards models, the HRs were 0.42 (95% CI, 0.19-0.93; P = .03) for oxaliplatin plus fluorouracil-leucovorin and 0.57 (95% CI, 0.42-0.78; P = .001) for cisplatin plus mitomycin subgroups (Figure 2).

No prognostic advantage was observed in subgroups receiving mitomycin (5-year overall survival, 58.8% [95% CI, 50.1%-69.0%] vs 59.1% [51.9%-67.2%]; P = .68) and other oxaliplatin-based HIPEC (5-year overall survival, 81.8% [95% CI, 69.7%-96.0%] vs 75.2% [95% CI, 64.4%-88.0%]; P = .95) (Figure 1C and E). After applying multivariable Cox proportional hazards models, the HRs were 0.93 (95% CI, 0.65-1.34; P = .71) for mitomycin and 1.01 (95% CI, 0.34-2.94; P = .99) for other oxaliplatin-based subgroups (Figure 2).

Postoperative Outcomes

Within the entire series (n = 1924), incidence of 90-day mortality was 4.2% (95% CI, 3.6%-5.2%); 30-day mortality, 2.1% (95% CI, 1.5%-2.8%); return to the operating room, 9.3% (95% CI, 8.0%-10.6%); and severe morbidity, 32.0% (95% CI, 30.0%-34.1%). The details of the incidence of complications in the entire series are outlined in eTable 10 in the Supplement. After applying multivariable logistic models, no significant differences between the CRS-HIPEC and CRS-alone groups were observed overall or according to HIPEC drug regimens except the mitomycin regimen (odds ratio for morbidity, 1.99; 95% CI, 1.25-3.19; P = .004) (Figure 3).

Figure 3. — Data are presented as weighted odds ratios (ORs) of unfavorable surgical outcomes from multivariable logistic models and bootstrap 95% CI for patients treated with HIPEC. Morbidity is determined by grades 3 to 5 in the National Cancer Institute Common Terminology for Adverse Events, version 3.0. Arrow indicates width of 95% CI extends beyond boundary of the graph. CRS indicates cytoreductive surgery.

Sensitivity Analysis and Assessment of Selection Bias

Comparing the prognostic factors between included and excluded patients (1924 vs 1571), we observed that only EPIC was more frequently performed in the excluded cases (525 of 1490 [35.2%] vs 303 of 1924 [15.7%]). The excluded cases had a better 10-year overall survival (66.9% [95% CI, 62.9%-71.0%] vs 51.3% [95% CI, 46.5%-56.7%]; P < .001) and substantially lower severe morbidity (283 of 1521 [18.6%] vs 615 of 1924 [32.0%]; P = .31) (eTable 11 in the Supplement). Within excluded patients (233 CRS alone vs 1342 CRS-HIPEC, with 6 missing), the CRS-HIPEC group was more frequently treated with EPIC (503 of 1304 [38.6%] vs 22 of 183 [12.0%]; P = .64) and showed better 10-year overall survival (71.7% [95% CI, 67.5%-76.0%] vs 30.7% [95% CI, 20.1%-46.7%]; P < .001). Incidence of severe morbidity was 19.0% (251 of 1323) in the CRS-HIPEC group and 16.2% (31 of 191) in the CRS group (eTable 12 in the Supplement).

The E-value for the HR was 2.03, so that the main result could be explained by an unmeasured confounder that was associated with both the treatment and the outcome by a risk ratio of 2-fold each, above and beyond the measured confounders. The E-value for the CL was 1.53, so that it could be moved to include 1 by an unmeasured confounder that was associated with both the treatment and the outcome by a risk ratio of 1.5-fold each, above and beyond the measured confounders.

Discussion

The combination CRS-HIPEC treatment has been regarded as a standard of care in PMP despite the lack of randomized data. In this cohort study, HIPEC was associated with a better overall survival in the entire series and in all subsets. Notably, patients in the CC-2/3 subgroup represent a particular circumstance in which HIPEC should not be effective owing to the limited capacity of the intraperitoneal drugs to penetrate in gross residual disease.¹⁸ Moreover, in the entire series, HIPEC was not associated with increased risks of severe morbidity, return to operating room, or 30- and 90-day mortality.

Concern is long-standing among some surgeons using HIPEC in addition to CRS in PMP. Some have suggested that HIPEC efficacy is limited owing to the poor response of PMP to chemotherapy. In fact, PMP is characterized by low cell proliferative activity,¹⁹ mucin overproduction,⁸ and high frequency of KRAS mutation.²⁰ All these properties are related to chemoresistance in colorectal cancer.²¹ Likewise, the PMP response percentages to systemic chemotherapy are low, ranging from 4% to 24%.^{22,23,24,25,26} Nevertheless, HIPEC conferred a survival advantage in PMP of similar magnitude to the recently published randomized clinical trial of secondary debulking surgery with or without HIPEC in epithelial ovarian cancer,⁵ with a 35% reduction of risk of mortality.

Of note, a higher prognostic advantage between the HIPEC regimens was observed in the cisplatin plus mitomycin and oxaliplatin plus fluorouracil-leucovorin HIPEC subgroups. Since its development in the early 2000s,²⁷ the oxaliplatin plus fluorouracil-leucovorin combination for HIPEC gained popularity until the recent preliminary results of the PRODIGE-7 trial.⁷ The short duration of the oxaliplatin regimen has raised concern because it is uncertain whether 30 minutes of delivery time could overcome de novo platinum resistance in PM-CRC.²⁸

The success of HIPEC with oxaliplatin plus fluorouracil-leucovorin in the present study, in contrast to the failure in PM-CRC, might be connected to differences in the biology of these clinical entities. Although PM-CRC is a locoregional disease, consistent evidence suggests that the mechanism of peritoneal spread occurs not only transcoelomically but also hematogeneously.^29,30

Pseudomyxoma peritonei progresses transcoelomically with a superficial invasion of the peritoneal lymphatics.³¹ Pseudomyxoma peritonei generally is confined to the peritoneal cavity for most of its natural history with a markedly low chance of distant metastasis. The negative results of initial reports of the PRODIGE-7 trial have shifted the investigator’s attention to mitomycin, which is the drug of choice for HIPEC use in PM-CRC according to the American Society of Peritoneal Surface Malignancies.³² In the present study, however, HIPEC with mitomycin did not seem to be associated as much with the prognosis as other regimens and was associated with an increased frequency of severe morbidity. These data contrast with some centers’ reports using a much lower dose (10 mg/m²) with low toxic effects and good outcomes, so that the dosage may also be an issue that should be cleared by future studies.³³

Also, the cisplatin plus mitomycin subgroup was associated with a significant reduction in the risk of death. This combination was developed in the late 1980s for the treatment of gastric cancer with peritoneal metastases. In particular, cisplatin is supported by level I evidence for HIPEC use in advanced epithelial ovarian cancer,⁵ whereas its combination with mitomycin is supported only by experimental data showing that mitomycin enhances the intracellular accumulation of cisplatin, thus favoring the production of platin DNA adducts.^34,35

Regarding short-term outcomes, we only observed the association of mitomycin with increased severe morbidity. This finding is interesting because it is well known that all intraperitoneal chemotherapies after surgery hamper the tissue-healing process and increase the chances of surgical complications.^{7,36,37,38,39} In PRODIGE-7, it has been reported that HIPEC with oxaliplatin plus fluorouracil-leucovorin was associated with a significantly higher 60-day complication rate.⁷

Considering these experimental and clinical data, an increased risk of HIPEC-associated adverse effects might have been expected for all drug regimens, although only mitomycin was associated with an increased risk of severe complications. Although the potential contribution of HIPEC in increasing postoperative morbidity is consistent, the primary determinant of surgical complications remains the extent of the CRS. In contrast to the PRODIGE-7 experience, the hazard produced by intraperitoneal chemotherapy in the present study might have been eclipsed by the effects of a generally more extensive surgical procedure required for PMP compared with PM-CRC. Therefore, in the present study, differences in surgical outcomes between CRS-HIPEC and CRS-alone groups are subsumed in the high incidences.

Limitations

The limitations of the present study are related to its retrospective nature, the adoption of outdated World Health Organization pathological classification for appendiceal tumors, the lack of information regarding the site of recurrence, the adoption of overall survival instead of disease-specific survival as the primary outcome, potential selection bias, and the potential bias due to unmeasured confounders that were not controlled by the inverse probability treatment weighted propensity score. The outdated World Health Organization pathological classification for appendiceal tumors could imply a potential imbalance between the study groups. However, in the present analysis, the HRs associated with World Health Organization categories (high- vs low-grade vs overall series) ranged from 0.58 to 0.66, with overlapping 95% CIs. We speculate that the HR associated with HIPEC, at least in the overall series, would not have changed, should the PSOGI pathological grading system be adopted, because definition of PMP syndrome did not change in the new system.⁸

Data on distant metastasis were not recorded because PMP is a disease that biologically harbors the nearly null potential for hematogeneous dissemination. Virtually every recurrence occurs locoregionally inside the abdominal cavity.⁸ Data on the site of recurrence would not have been very informative.

Data on disease-specific survival would have provided a more accurate estimation of the efficacy of HIPEC, allowing us to exclude concurrent causes of death unrelated to PMP. However, patient candidates for CRS-HIPEC are relatively young (median age, 56 [IQRE, 45-65] years) and not affected by severe comorbidities; otherwise, they may not withstand a major procedure. We do not expect disease-specific survival to be much different from overall survival, because chances of dying of causes other than PMP would not be clinically relevant. The Charlson comorbidity index is likely to be unbalanced, considering its noninclusion in the inverse probability treatment weighted propensity score analysis. However, this parameter might not have biased our main result, because it has not been associated with overall survival.⁴⁰

We did not find any relevant unbalanced factor between included and excluded patients of our initial cohort. Anyway, the possibility of selection bias is plausible, owing to the differences observed in overall survival and incidence of postoperative outcomes. However, such bias should not be large enough to explain away our main result in favor of HIPEC, because the CRS-HIPEC group had a better overall survival compared with the CRS-alone group among the excluded patients.

We conducted a sensitivity analysis to further scrutinize potential bias derived from selection and unmeasured confounders possibly related to patient, institution, or surgeon. The E-values assessing the robustness of the observed HR and CL were 2.03 and 1.53, respectively. The HRs for the known, influential prognostic factors included in the study ranged from 1.14 to 4.12. Even if the E-value we obtained seems to leave a strict margin, we are unaware of any other potential confounder of this strength that is not already included in the model.

Conclusions

This cohort study found that HIPEC was associated with better survival without worsening the postoperative outcomes in patients with PMP. Despite the relative robustness of our results to both selection bias and unmeasured confounders, confirmation by a large randomized clinical trial is warranted.

Supplement.

eFigure 1. Flowchart of Patients Selected for the Analysis (Unweighted Numbers)

eFigure 2. Kaplan-Meier Overall Survival Curves According to Treatment

eTable 1. HIPEC Schedules

eTable 2. Distribution of Prognostic Factors Between the Study Groups Before and After IPTW Weighting Adjustment in CC-0/1 Cases

eTable 3. Distribution of Prognostic Factors Between the Study Groups Before and After IPTW Weighting Adjustment in CC-2/3 Cases

eTable 4. Distribution of Prognostic Factors Between the Study Groups Before and After IPTW Weighting Adjustment in Low-Grade Disease

eTable 5. Distribution of Prognostic Factors Between the Study Groups Before and After IPTW Weighting Adjustment in High-Grade Disease

eTable 6. Distribution of Prognostic Factors Between the Study Groups Before and After IPTW Weighting Adjustment for HIPEC With Cisplatin Plus Mitomycin

eTable 7. Distribution of Prognostic Factors Between the Study Groups Before and After IPTW Weighting Adjustment for HIPEC With Mitomycin

eTable 8. Distribution of Prognostic Factors Between the Study Groups Before and After IPTW Weighting Adjustment for HIPEC With Oxaliplatin Plus Fluorouracil/Leucovorin

eTable 9. Distribution of Prognostic Factors Between the Study Groups Before and After IPTW Weighting Adjustment for HIPEC With Other Oxaliplatin-Based Combinations

eTable 10. Surgical Outcomes of Patients With PMP Undergoing CRS-HIPEC (n = 1548) and CRS Alone (n = 376)

eTable 11. Unweighted Comparison of the Distribution of the Prognostic Factors and Outcomes Between Included and Excluded Cases

eTable 12. Unweighted Distribution of Prognostic Factors Between the Study Groups in the Cases That Were Excluded Due to Incomplete Data

Click here for additional data file.^{(331KB, pdf)}

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