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Colorectal Cancer

Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal MetastasesA Phase 2 Randomized Clinical Trial

Educational Objective To assess the feasibility and safety of perioperative systemic therapy in patients with resectable colorectal peritoneal metastasis and the response of colorectal peritoneal metastasis to neoadjuvant treatment.

1 Credit CME

JAMA Surgery

Published Online: May 19, 2021

Original Investigation

Article Information and Disclosures

Koen P. Rovers, MD¹;

Checca Bakkers, MD¹;

Simon W. Nienhuijs, PhD¹;

Jacobus W. A. Burger, PhD¹;

Geert-Jan M. Creemers, PhD²;

Anna M. J. Thijs, PhD²;

Alexandra R. M. Brandt-Kerkhof, MD³;

Eva V. E. Madsen, PhD³;

Esther van Meerten, PhD⁴;

Jurriaan B. Tuynman, PhD⁵;

Miranda Kusters, PhD⁵;

Kathelijn S. Versteeg, MD⁶;

Arend G. J. Aalbers, MD⁷;

Niels F. M. Kok, PhD⁷;

Tineke E. Buffart, PhD⁸;

Marinus J. Wiezer, PhD⁹;

Djamila Boerma, PhD⁹;

Maartje Los, PhD¹⁰;

Philip R. de Reuver, PhD¹¹;

Andreas J. A. Bremers, PhD¹¹;

Henk M. W. Verheul, PhD¹²;

Schelto Kruijff, PhD¹³;

Derk Jan A. de Groot, PhD¹⁴;

Arjen J. Witkamp, PhD¹⁵;

Wilhelmina M. U. van Grevenstein, PhD¹⁵;

Miriam Koopman, PhD¹⁶;

Joost Nederend, PhD¹⁷;

Max J. Lahaye, PhD¹⁸;

Onno Kranenburg, PhD¹⁹;

Remond J. A. Fijneman, PhD²⁰;

Iris van ’t Erve, MSc²⁰;

Petur Snaebjornsson, PhD²⁰;

Patrick H. J. Hemmer, MD¹³;

Marcel G. W. Dijkgraaf, PhD²¹;

Cornelis J. A. Punt, PhD²²;

Pieter J. Tanis, PhD²³;

Ignace H. J. T. de Hingh, PhD^1,24;

for the Dutch Peritoneal Oncology Group and the Dutch Colorectal Cancer Group

Author Affiliations

¹Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
²Department of Medical Oncology, Catharina Cancer Institute, Eindhoven, the Netherlands
³Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
⁴Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
⁵Department of Surgery, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands
⁶Department of Medical Oncology, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands
⁷Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands
⁸Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
⁹Department of Surgery, Sint Antonius Hospital, Nieuwegein, the Netherlands
¹⁰Department of Medical Oncology, Sint Antonius Hospital, Nieuwegein, the Netherlands
¹¹Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
¹²Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
¹³Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
¹⁴Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands
¹⁵Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
¹⁶Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
¹⁷Department of Radiology, Catharina Cancer Institute, Eindhoven, the Netherlands
¹⁸Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
¹⁹Cancer Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
²⁰Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
²¹Department of Epidemiology and Data Science, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
²²Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
²³Department of Surgery, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
²⁴GROW–School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands

Dutch Peritoneal Oncology Group and the Dutch Colorectal Cancer Groupfor the

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Key Points

Question Is perioperative systemic therapy feasible and safe in patients with resectable colorectal peritoneal metastases?

Findings In this phase 2 clinical trial analyzing 79 patients randomized to perioperative systemic therapy (experimental arm) or cytoreductive surgery and hyperthermic intraperitoneal chemotherapy alone (control arm), the trial arms did not differ significantly regarding the proportions of macroscopic complete cytoreductive surgery (experimental arm, 89%; control arm, 86%) and major postoperative morbidity (experimental arm, 22%; control arm, 33%).

Meaning Results of this phase 2 trial suggest that perioperative systemic therapy seems feasible and safe in patients diagnosed with resectable colorectal peritoneal metastases, justifying a phase 3 trial.

Abstract

Importance To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM).

Objective To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment.

Design, Setting, and Participants An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment.

Interventions Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles.

Main Outcomes and Measures Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm).

Results In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively.

Conclusions and Relevance In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial.

Trial Registration ClinicalTrials.gov Identifier: NCT02758951

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Article Information

Accepted for Publication: March 3, 2021.

Published Online: May 19, 2021. doi:10.1001/jamasurg.2021.1642

Corresponding Author: Ignace H. J. T. de Hingh, PhD, Department of Surgery, Catharina Cancer Institute, PO Box 1350, 5602 ZA, Eindhoven, the Netherlands (ignace.d.hingh@catharinaziekenhuis.nl).

Author Contributions: Drs Rovers and de Hingh had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Rovers and Bakkers are co–first authors.

Concept and design: Rovers, Bakkers, Nienhuijs, Burger, Creemers, Thijs, Madsen, van Meerten, Tuynman, Versteeg, Aalbers, Kok, Buffart, Wiezer, Los, Kruijff, de Groot, Witkamp, van Grevenstein, Nederend, Fijneman, Snaebjornsson, Hemmer, Dijkgraaf, Punt, Tanis, de Hingh.

Acquisition, analysis, or interpretation of data: Rovers, Bakkers, Brandt-Kerkhof, Kusters, Aalbers, Boerma, de Reuver, Bremers, Verheul, van Grevenstein, Koopman, Nederend, Lahaye, Kranenburg, van 't Erve, Snaebjornsson, Punt, Tanis, de Hingh.

Drafting of the manuscript: Rovers, Bakkers, Creemers, van 't Erve, de Hingh.

Critical revision of the manuscript for important intellectual content: Nienhuijs, Burger, Thijs, Brandt-Kerkhof, Madsen, van Meerten, Tuynman, Kusters, Versteeg, Aalbers, Kok, Buffart, Wiezer, Boerma, Los, de Reuver, Bremers, Verheul, Kruijff, de Groot, Witkamp, van Grevenstein, Koopman, Nederend, Lahaye, Kranenburg, Fijneman, van 't Erve, Snaebjornsson, Hemmer, Dijkgraaf, Punt, Tanis.

Statistical analysis: Rovers, Bakkers, van 't Erve, Dijkgraaf.

Administrative, technical, or material support: Burger, Kusters, Bremers, Nederend, van 't Erve, Snaebjornsson.

Supervision: Brandt-Kerkhof, Tuynman, Kusters, Aalbers, Wiezer, Boerma, Bremers, Verheul, Lahaye, Dijkgraaf, Punt, Tanis, de Hingh.

Conflict of Interest Disclosures: Dr Koopman reported serving as a paid advisor for Nordic Farma Merck-Serono, Pierre Fabre, and Servier, and receiving institutional scientific grants from Bayer, Bristol Myers Squibb, Merck, Roche, and Servier outside the submitted work. Dr Punt reported serving as a paid advisor for Nordic Pharma and Servier. Dr Tanis reported receiving unrestricted research grants from Allergan (LifeCell) outside the submitted work. Dr de Hingh reported receiving grants from Roche, QP&S, and RanD Biotech outside the submitted work. No other disclosures were reported.

Funding/Support: This work was funded by Dutch Cancer Society grant 10795 and F. Hoffmann-La Roche grant ML39718.

Role of the Funder/Sponsor: The funding organizations 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: The members of the Dutch Peritoneal Oncology Group and the Dutch Colorectal Cancer Group appear in Supplement 4.

Meeting Presentation: The present work was presented at the virtual European Society for Medical Oncology (ESMO) World Conference on Gastrointestinal Cancer; July 3, 2020; https://esmoworldgivirtual2020.com/.

Additional Contributions: The Netherlands Comprehensive Cancer Organization provided data management and trial monitoring.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.