Clinical implication of using up both fluoropyrimidine (FU) and paclitaxel (PTX) in patients with severe peritoneal metastases (SPM) of gastric cancer (GC).
Authors: Arai Hiroyuki , Inoue Eisuke , Yamaguchi Kensei , Boku Narikazu , Hara Hiroki , Nisina Tomohiro , Tsuda Masahiro , Shitara Kohei , Shinozaki Katsunori , Nakamura Shinichiro , Hyodo Ichinosuke , Muro Kei , Sasako Mitsuru , Terashima Masanori , Nakajima Takako Eguchi 
Published: January 2021

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Background: JCOG1108/WJOG7312G trial showed favorable but not significantly better outcomes of 5-FU/ l-leucovorin ( l-LV) /PTX combination (FLTAX) compared to 5-FU/ l-LV (FL) in untreated patients with SPM of GC. However, a half of patients treated with FL could not sequentially use PTX which is a key drug for peritoneal metastasis. We conducted a post hoc analysis to investigate the clinical implication of using up both FU and PTX in either combination or sequential strategy for GC patients with SPM. Methods: Among 101 patients enrolled in the trial (FL: N = 51; FLTAX: N = 50), overall survival (OS) was compared between three subgroups: patients treated with FL followed by PTX (FL/PTX: N = 25), those treated with FL followed by best supportive care (BSC) (FL/BSC: N = 21), and those treated with FLTAX (per protocol population, N = 48). To identify the factors affecting the likelihood of using sequential PTX (LUSP), we compared baseline characteristics between the FL/PTX and FL/BSC subgroups. Each baseline covariate was tested for the impact on LUSP by logistic regression model. The difference of treatment efficacy between FL and FLTAX was assessed in subgroups stratified by the factors identified to affect LUSP. Results: Patients in the FL/PTX subgroup showed significantly better OS than those in the FL/BSC subgroup (median OS, 7.8 vs 2.0 months; hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.12-0.48, p < 0.01) and equivalent OS compared to those in the FLTAX subgroup (median OS, 7.8 vs 8.0 months; HR 0.83, 95% CI 0.50-1.39, p = 0.49). Compared with patients in the FL/BSC subgroup, those in the FL/PTX subgroup had a trend for lower frequency of Glasgow prognostic score (GPS) 2 (40.0% vs 66.7%, p = 0.17) and unresectable type (76.0% vs 95.2%, p = 0.07). GPS 2 and unresectable type were identified as factors with a worse impact on LUSP compared to GPS 0 and recurrent type, with odds ratio (OR) of 0.29 (95% CI 0.05-1.78, p = 0.18) and that of 0.16 (95% CI 0.02-1.44, p = 0.10), respectively. Among all patients enrolled in the trial, 43 patients had both GPS2 and unresectable type (score 2), 45 had either (score 1), 11 had neither (score 0), and two lacked the data of GPS. Median OS in the patients with score 2, 1, and 0 was 4.7, 7.8, and 18.8 months, respectively (score 2 vs 0, HR 4.37, 95% CI 1.84-10.42; score 1 vs 0, HR = 2.80, 95% CI 1.19-6.64). Compared to FL, FLTAX showed better OS in patients with score 2 (HR = 0.60, 95% CI 0.32-1.13) and in those with score 1 (HR = 0.77, 95% CI 0.42-1.42), but worse OS in those with score 0 (HR = 4.74, 95% CI 0.49-45.85). Conclusions: Combination or sequential use of active two drugs, 5-FU and PTX, might contribute to better OS of GC patients with SPM. However, because selection of patients suitable to sequential use is difficult, the combination strategy FLTAX is a favorable treatment option.