{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T09:06:11Z","timestamp":1789549571949,"version":"build-2803163510"},"reference-count":31,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: The optimal use of chemotherapy rechallenge in later-line metastatic colorectal cancer (mCRC) remains uncertain. We compared third-line FOLFOX plus bevacizumab rechallenge with regorafenib and examined whether the oxaliplatin-free interval was associated with treatment outcomes. Methods: This retrospective single-center study included 122 patients with metastatic left-sided, RAS (KRAS\/NRAS) and BRAF wild-type, proficient mismatch repair (pMMR) colorectal adenocarcinoma treated between 2018 and 2025. All patients had received first-line FOLFOX plus cetuximab or panitumumab, followed by FOLFIRI plus bevacizumab after progression. In the third-line setting, 65 patients received FOLFOX plus bevacizumab as oxaliplatin rechallenge and 57 received regorafenib. The primary endpoint was progression-free survival (PFS). Cox regression, propensity score-based inverse probability of treatment weighting (IPTW), and treatment-by-oxaliplatin-free interval interaction analyses were performed. Results: Median third-line PFS was 7.33 months with FOLFOX plus bevacizumab rechallenge and 6.17 months with regorafenib (log-rank p &lt; 0.001). FOLFOX plus bevacizumab rechallenge was associated with a lower hazard of progression in multivariable analysis (adjusted HR, 0.58; 95% CI, 0.39\u20130.88; p = 0.009), with consistent results in the propensity score-based IPTW sensitivity analysis (HR, 0.58; 95% CI, 0.40\u20130.86; p = 0.006). Restricted cubic spline analysis indicated a nonlinear association between OFI and PFS (p for nonlinearity = 0.005), while flexible modeling did not provide robust evidence of a treatment-by-OFI interaction (global p = 0.806). In exploratory subgroup analyses, FOLFOX plus bevacizumab rechallenge was associated with longer PFS than regorafenib among patients with an OFI of \u22656 months (adjusted HR, 0.39; 95% CI, 0.24\u20130.65; p &lt; 0.001), whereas no significant difference was observed among those with an OFI of &lt;6 months (adjusted HR, 0.66; 95% CI, 0.35\u20131.25; p = 0.199). Conclusions: FOLFOX plus bevacizumab rechallenge was associated with longer third-line PFS than regorafenib in this selected and uniformly treated mCRC cohort. OFI was associated with PFS in a nonlinear manner, but there was no robust evidence that it modified the relative treatment effect across its continuous range. Exploratory subgroup findings based on a 6-month cutoff require external validation.<\/jats:p>","DOI":"10.3390\/cancers18182987","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:58:59Z","timestamp":1789545539000},"page":"2987","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FOLFOX Plus Bevacizumab Rechallenge Versus Regorafenib as Third-Line Treatment in Metastatic Colorectal Cancer: The Role of the Oxaliplatin-Free Interval"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8527-1392","authenticated-orcid":false,"given":"Ugur","family":"Ozkerim","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5983-3291","authenticated-orcid":false,"given":"Oguzcan","family":"K\u0131n\u0131koglu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4721-0585","authenticated-orcid":false,"given":"Sila","family":"Oksuz","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4398-5148","authenticated-orcid":false,"given":"Deniz","family":"Isik","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0634-7350","authenticated-orcid":false,"given":"Yunus Emre","family":"Altintas","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2423-6902","authenticated-orcid":false,"given":"Sedat","family":"Yildirim","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6221-0623","authenticated-orcid":false,"given":"Goncagul","family":"Akdag","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6942-9858","authenticated-orcid":false,"given":"Asl\u0131","family":"Gecgel","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5757-4705","authenticated-orcid":false,"given":"Hatice","family":"Odabas","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2059-5502","authenticated-orcid":false,"given":"Tugba","family":"Basoglu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1140-8779","authenticated-orcid":false,"given":"Nedim","family":"Turan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kartal Dr. L\u00fctfi Kirdar City Hospital, University of Health Sciences, Istanbul 34865, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.annonc.2022.10.003","article-title":"Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"34","author":"Cervantes","year":"2023","journal-title":"Ann. 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