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Adding liposome-encapsulated irinotecan to standard chemotherapy failed to improve survival as second-line treatment for advanced biliary cancer, a small randomized study showed.

Median progression-free survival (PFS) improved nonsignificantly from 2.3 to 2.6 months with the addition of nanoliposomal irinotecan to fluorouracil and leucovorin. Overall survival (OS) declined slightly from 8.2 months without irinotecan to 6.9 with it. Response rate increased from 4% with fluorouracil-leucovorin to 14% with the addition of the liposomal agent.

Grade ≥3 and serious adverse events (SAEs) occurred more often with nanoliposomal irinotecan, reported Arndt Vogel, MD, of Hannover Medical School in Germany, and co-authors in .

"Although adding nanoliposomal irinotecan to fluorouracil plus leucovorin increased the overall response rate [ORR] compared with fluorouracil plus leucovorin alone, this improvement did not result in a prolonged progression-free survival, which was the primary endpoint of our study," the authors wrote in conclusion. "Despite the overall manageable safety profile, the combination's toxicity might have contributed to reduced treatment exposure, thereby failing to improve progression-free survival in the nanoliposomal irinotecan group."

"Furthermore, the frequent use of subsequent therapies and significant crossover to irinotecan-based combinations in the control group probably affected overall survival," they continued.

The findings did suggest a potential efficacy benefit with second-line fluorouracil plus leucovorin, which was not specifically investigated in the trial, Vogel and co-authors stated. Additional research is needed to determine the role of irinotecan-based combinations in advanced biliary cancer.

Irinotecan for advanced biliary tract cancers remains controversial, noted the authors of an . The development of nanoliposomal irinotecan created hope for enhanced tumor exposure and improved survival. A in South Korea appeared to support the hope, showing significant improvement in PFS, OS, and ORR with the addition of nanoliposomal irinotecan to fluorouracil and leucovorin.

The German trial did nothing to settle the controversy, but limitations of the trial preclude "definitely discarding nanoliposomal irinotecan," according to David Malka, MD, and Raphaël Colle, MD, of Institut Mutualiste Montsouris in Paris.

"Certainly, nanoliposomal irinotecan and fluorouracil plus leucovorin had some efficacy in advanced biliary tract cancer, as suggested by the numerically higher objective response rate than with fluorouracil plus leucovorin alone," they wrote. "The HR [hazard ratio] target for progression-free survival (0.50) was unquestionably optimistic, probably because of the limited number of patients who could be included on a country-wide scale."

Higher levels of cancer markers in the experimental arm might have reflected poor prognosis, Malka and Colle continued. Other limitations related to first-line therapies the patients received. Lower dose intensity in the experimental group probably contributed to higher rates of grade ≥3 toxicity. The investigators' limited experience with nanoliposomal irinotecan might also have contributed to inferior outcomes.

"Although the NALIRICC results preclude proposing the use of nanoliposomal irinotecan-based chemotherapy as second-line therapy for advanced biliary tract cancers in the western European population, nanoliposomal irinotecan (and irinotecan) deserve to be studied in this setting in better-sized trials and, perhaps, trials dedicated to specific biliary tract cancer subtypes," they concluded.

The trial included 100 patients with metastatic biliary tract cancer and disease progression after first-line gemcitabine-based therapy. They were randomized to receive fluorouracil plus leucovorin with or without nanoliposomal irinotecan. The primary endpoint was PFS.

The study population had a median age of 65, and men accounted for 55% of the patients. Two-thirds of the patients had intrahepatic cholangiocarcinoma, 19% had extrahepatic cholangiocarcinoma, and 17% had gallbladder carcinoma. All but six patients had previously received gemcitabine plus a platinum agent. Median treatment duration was 1.6 months in the nanoliposomal irinotecan group and 1.4 months in the control group.

With a median follow-up of 5.9 months, the median PFS was increased by 13% in the nanoliposomal irinotecan group, falling well short of the statistically powered estimate of 50%. The 6-month PFS was 23% in both groups. The analysis of OS yielded an HR of 1.08 in favor of the control group.

Subgroup analysis showed a significant interaction between higher baseline C-reactive protein and worse OS. No significant interactions for OS were observed baseline carcinoembryonic antigen, cancer antigen 19-9, or sex.

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