Hepatic arterial chemotherapy with raltitrexed and oxaliplatin versus standard chemotherapy in unresectable liver metastases from colorectal cancer after conventional chemotherapy failure (HEARTO): a randomized phase-II study
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Hepatic arterial infusion (HAI) of chemotherapy could be used in patients with liver-only metastatic colorectal cancer (mCRC) to fight against chemoresistance. We previously reported the efficacy of raltitrexed plus oxaliplatin (HAI) in a retrospective series. We performed a randomized two-stage phase-II study to evaluate the efficacy of HAI of the combination of raltitrexed and oxaliplatin in refractory mCRC with only liver metastases in comparison with standard of care.
Patients and methods
Eligible patients had unresectable mCRC and were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were randomized between HAI raltitrexed (3 mg/m2 over 1 h) followed by oxaliplatin (130 mg/m2 over 2 h) every 3 weeks and standard of care in a 2:1 ratio. A total of 57 patients (38 in the experimental arm and 19 in the standard of care arm) were to be included. The main objective was to demonstrate 6-month PFS of 45% by intention-to-treat analysis in the experimental arm, compared to theoretical PFS of 20%, with a unilateral alpha risk of 5% and beta risk of 10%.
After inclusion of 27 patients, the trial was terminated due to insufficient accrual. In the experimental arm, 11 and 4 patients experienced grade 3 and 4 toxicities, respectively. The most frequent grade 3–4 toxicities were neutropenia, liver toxicity, and abdominal pain. Median progression-free survival was 6.7 months (95% Confidence Interval; 3.9–7.2) in the HAI group and 2.2 months (95% CI 1.2–4.3) with standard of care [HR 0.32 (95% CI 0.14–0.76), p = 0.01]. Median overall survival did not differ between the two groups, at 11.2 months (95% CI 4.8–17.6) for the HAI group and 11.9 months (95% CI 2.8–14.3) for standard of care [HR 0.86 (95% CI 0.36–2.04), p = 0.73].
Although stopped prematurely, this randomized trial provides evidence for the benefit and safety of HAI of a combination of raltitrexed and oxaliplatin in liver-only mCRC with chemoresistant disease.
KeywordsColorectal cancer Liver metastasis Hepatic arterial infusion Oxaliplatin Raltitrexed
FG and AB were the main authors of the manuscript. They were involved in the conception, design and coordination of the study as well as in data analysis, interpretation of results, and drafting of the manuscript. JV, LB, JLJ, CB, BG, and RL participated in the collection and analysis of data. JB performed statistical analysis. All authors contributed to the interpretation of data and critically revised the manuscript. All authors read and approved the final manuscript.
INCA-PHRC-2009. Funding has been received form Institut National Du Cancer with Grand No. 2019.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
This study was prospective and approved by the Ethics Review Committee od Dijon (CCP EST 1).
All participants provided written informed consent to participate.
Availability of data and materials
The data sets generated and analyzed during the current study were not approved for public release by the Ethics Committee, but are available from the corresponding author on reasonable request.
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