Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial
Koen P Rovers, Checca Bakkers, Simon W Nienhuijs, Jacobus W A Burger, Geert-Jan M Creemers, Anna M J Thijs, Alexandra R M Brandt-Kerkhof, Eva V E Madsen, Esther van Meerten, Jurriaan B Tuynman, Miranda Kusters, Kathelijn S Versteeg, Arend G J Aalbers, Niels F M Kok, Tineke E Buffart, Marinus J Wiezer, Djamila Boerma, Maartje Los, Philip R de Reuver, Andreas J A Bremers, Henk M W Verheul, Schelto Kruijff, Derk Jan A de Groot, Arjen J Witkamp, Wilhelmina M U van Grevenstein, Miriam Koopman, Joost Nederend, Max J Lahaye, Onno Kranenburg, Remond J A Fijneman, Iris van 't Erve, Petur Snaebjornsson, Patrick H J Hemmer, Marcel G W Dijkgraaf, Cornelis J A Punt, Pieter J Tanis, Ignace H J T de Hingh, Dutch Peritoneal Oncology Group and the Dutch Colorectal Cancer Group, Jeanette M Bouma, Vincent Cj van de Vlasakker, Robin J Lurvink, Geert Aam Simkens, Johanne G Bloemen, Jeroen Eh Ponten, Jennifer Demelinne, Birgit Epj Vriens, Joost Rothbarth, Ninos Ayez, Nadine L de Boer, Job P van Kooten, Marjolein Diepeveen, Mark Tenhagen, Sander Bach, Stefan E van Oostendorp, Lisanne Jh Smits, Nina R Sluiter, Sacha Spoor, Hans J van der Vliet, Koert Fd Kuhlmann, Brechtje A Grotenhuis, Charlotte J Verberne, Patricia D Bottenberg, Myriam Chalabi, Emma Ce Wassenaar, Paulien Rauwerdink, Mendy Sm Hermans, Karin H Herbschleb, Johannes Hw de Wilt, Fortuné Mk Elekonawo, Jan Marie de Gooyer, Nanneke Meijer, Lukas B Been, Robert J van Ginkel, Frederik Jh Hoogwater, Judith Ekr Hentzen, Linde Olsder, Rudolf Sn Fehrmann, Karin K van Diepen, Jeanine Ml Roodhart, Eino B van Duyn, Walter Jb Mastboom, Leonie Jm Mekenkamp, Koen P Rovers, Checca Bakkers, Simon W Nienhuijs, Jacobus W A Burger, Geert-Jan M Creemers, Anna M J Thijs, Alexandra R M Brandt-Kerkhof, Eva V E Madsen, Esther van Meerten, Jurriaan B Tuynman, Miranda Kusters, Kathelijn S Versteeg, Arend G J Aalbers, Niels F M Kok, Tineke E Buffart, Marinus J Wiezer, Djamila Boerma, Maartje Los, Philip R de Reuver, Andreas J A Bremers, Henk M W Verheul, Schelto Kruijff, Derk Jan A de Groot, Arjen J Witkamp, Wilhelmina M U van Grevenstein, Miriam Koopman, Joost Nederend, Max J Lahaye, Onno Kranenburg, Remond J A Fijneman, Iris van 't Erve, Petur Snaebjornsson, Patrick H J Hemmer, Marcel G W Dijkgraaf, Cornelis J A Punt, Pieter J Tanis, Ignace H J T de Hingh, Dutch Peritoneal Oncology Group and the Dutch Colorectal Cancer Group, Jeanette M Bouma, Vincent Cj van de Vlasakker, Robin J Lurvink, Geert Aam Simkens, Johanne G Bloemen, Jeroen Eh Ponten, Jennifer Demelinne, Birgit Epj Vriens, Joost Rothbarth, Ninos Ayez, Nadine L de Boer, Job P van Kooten, Marjolein Diepeveen, Mark Tenhagen, Sander Bach, Stefan E van Oostendorp, Lisanne Jh Smits, Nina R Sluiter, Sacha Spoor, Hans J van der Vliet, Koert Fd Kuhlmann, Brechtje A Grotenhuis, Charlotte J Verberne, Patricia D Bottenberg, Myriam Chalabi, Emma Ce Wassenaar, Paulien Rauwerdink, Mendy Sm Hermans, Karin H Herbschleb, Johannes Hw de Wilt, Fortuné Mk Elekonawo, Jan Marie de Gooyer, Nanneke Meijer, Lukas B Been, Robert J van Ginkel, Frederik Jh Hoogwater, Judith Ekr Hentzen, Linde Olsder, Rudolf Sn Fehrmann, Karin K van Diepen, Jeanine Ml Roodhart, Eino B van Duyn, Walter Jb Mastboom, Leonie Jm Mekenkamp
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.
Conflict of interest statement
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.
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Source: PubMed