Is perioperative systemic therapy feasible and safe in patients with resectable colorectal peritoneal metastases?
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%).
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.
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).
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.
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).
In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62  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.
ClinicalTrials.gov Identifier: NCT02758951
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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 (email@example.com).
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/.
Data Sharing Statement: See Supplement 3.
Additional Contributions: The Netherlands Comprehensive Cancer Organization provided data management and trial monitoring.
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