OUTCOMES OF FIRST-LINE PALLIATIVE SYSTEMIC THERAPY ALTERNATED WITH OXALIPLATIN-BASED PRESSURIZED INTRAPERITONEAL AEROSOL CHEMOTHERAPY IN PATIENTS WITH UNRESECTABLE COLORECTAL PERITONEAL METASTASES IN A MULTICENTER, SINGLE-ARM, PHASE II TRIAL
Vincent C. van de Vlasakker*1, Paulien Rauwerdink2, Koen P. Rovers1, Emma Wassenaar2, Maarten J. Deenen1, Joost Nederend1, Clement Huysentruyt1, Remond J. Fijneman3, Erik van der Hoeven2, G. Raicu2, Alexander Constantinidis4, Onno Kranenburg4, Maartje Los2, Geert-Jan Creemers1, Jacobus burger1, Marinus Wiezer2, Simon Nienhuijs1, Robin Lurvink1, Djamila Boerma2, Ignace H. de Hingh1
1Surgery, Catharina Ziekenhuis, Eindhoven, North Brabant, Netherlands; 2Sint Antonius Ziekenhuis, Nieuwegein, Utrecht, Netherlands; 3Antoni van Leeuwenhoek Nederlands Kanker Instituut, Amsterdam, Noord-Holland, Netherlands; 4Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
The CRC-PIPAC-II trial aimed to assess feasibility, safety, antitumor activity, survival outcomes and patient-reported outcomes of first-line bidirectional therapy (i.e. systemic therapy alternated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy [PIPAC-OX]) in patients with isolated unresectable colorectal peritoneal metastases (CPM).
Material and methods:
This two-centre, single-arm, phase II CRC-PIPAC-II trial enrolled patients with pathologically proven isolated unresectable peritoneal metastases of a colorectal carcinoma, who did not receive systemic therapy ≤6 months prior to enrolment. Enrolled patients underwent three cycles of bidirectional therapy, each consisting of six weeks of systemic therapy (CAPOX-bevacizumab, FOLFOX-bevacizumab, or FOLFIRI-bevacizumab) followed by PIPAC-OX (92 mg/m2) with intraoperative intravenous boluses of leucovorin and 5-fluorouracil. The primary outcome was the number of patients with grade ≥3 treatment-related adverse events. Secondary outcomes were grade ≤2 adverse events, tumor response, progression-free survival, and overall survival.
Twenty patients were enrolled in this study, undergoing a total of 52 complete cycles of bidirectional therapy. After central histopathological revision of post-enrolment peritoneal biopsies, two patients appeared to have pseudomyxoma peritonei (PMP).
A total of fourteen grade ≥3 treatment-related adverse events occurred in 7 of 20 (35%). Seven events were related to PIPAC treatment (50%) and seven events were related to systemic therapy treatment (50%). Treatment related mortality did not occur. The most frequently observed grade ≥3 was abdominal pain (21.4% of grade ≥3 events). Minor treatment-related adverse events occurred in all patients after 51 of 52 (98%) cycles, the most common being abdominal pain (100% of patients), peripheral neuropathy (79% of patients), and nausea (63% of patients). Eligibility for treatment with curative intent was achieved in 5 of 20 (25%) patients, including both PMP patients. Peritoneal regression grading scale (PRGS) analyses of biopsies taken after the third PIPAC procedure in 16 patients showed 12 complete responses (36%), 18 major responses (55%), 3 minor responses (9%), and zero (0%) no responses. Median progression-free and overall survival were 9.5 months (95% confidence interval [95% CI] 8.0 – 13.0) and 16.0 months (95% CI 14 – not reached), respectively.
Conclusions: Bidirectional therapy consisting of first-line palliative systemic therapy with bevacizumab alternated with PIPAC-OX appeared to be feasible and safe in patients with unresectable, isolated colorectal peritoneal metastases. Antitumor activity of bidirectional therapy is promising. However, randomized trials are needed to investigate the efficacy of PIPAC-OX treatment for unresectable, isolated colorectal peritoneal metastases.
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