Safety and Efficacy of Trifluridine/Tipiracil Administered After Anti-PD-1 Therapies for Advanced Gastric Cancer.

BACKGROUND/AIM: The phase III TAGS trial of trifluridine/tipiracil showed a survival benefit compared with placebo as a third- or later-line treatment in patients with advanced gastric cancer (AGC), in which only a few patients had a history of previous treatment with immune checkpoint inhibitors. PATIENTS AND METHODS: We retrospectively reviewed consecutive patients with AGC who received trifluridine/tipiracil monotherapy as third- or later-line chemotherapy at our institution. Clinical outcomes were assessed in both overall population and patients with previous anti-PD-1 therapies. RESULTS: A total of 60 patients were included in this study. Eastern Cooperative Oncology Group performance status was 0, 1, and 2 in 37%, 52%, and 12% of patients, respectively. Median number of previous treatment regimens was 4 (range=2-7). Forty-nine (82%) patients had previously received anti-PD-1 therapies. In the overall population, the most common grade 3 or higher treatment-related adverse events were neutropenia (37%), anemia (32%) leukopenia (20%), thrombocytopenia (8%), and anorexia (7%). The frequencies of grade 3 or higher events were not increased among patients with previous anti-PD-1 therapies, and no delayed onset immune-related adverse events occurred. In the overall population, objective response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS) were 4%, 42%, and 1.8 months, respectively. Efficacy results in patients with previous anti-PD-1 therapies (ORR 5%, DCR 47%, and median PFS 2.1 months) were almost comparable with those in the overall population. CONCLUSION: Trifluridine/tipiracil monotherapy after exposure to anti-PD-1 therapies showed manageable safety profile and anti-tumor activity in AGC patients.

Significance of chemotherapy-free interval and tumor regression grade in patients with recurrent esophageal squamous cell carcinoma receiving chemotherapy with fluorouracil and platinum after esophagectomy following preoperative chemotherapy.

BACKGROUND: In Japan, standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC) includes preoperative chemotherapy with fluorouracil plus cisplatin followed by esophagectomy. However, its efficacy is unclear in patients with recurrent disease with < 6 months of chemotherapy-free interval (CFI) after preoperative chemotherapy followed by esophagectomy and in those with ≥ 6 months of CFI and poor pathological response to prior preoperative chemotherapy. METHOD: We retrospectively evaluated the efficacy of fluorouracil plus platinum in patients with recurrent ESCC who received preoperative chemotherapy followed by curative esophagectomy. RESULTS: Among 105 patients with recurrent ESCC after preoperative chemotherapy followed by esophagectomy, a total of 55 patients received fluorouracil plus platinum for recurrent disease. Patients with a CFI < 6 months (n = 20) had significantly shorter overall survival (OS) (median, 7.1 vs 14.5 months, P = 0.008) compared with those with a CFI ≥ 6 months (n = 35). Multivariate analysis showed that OS was worse in patients with a CFI < 6 months or a tumor regression grade (TRG) ≤ 1a. Furthermore, in patients with a CFI ≥ 6 months, TRG ≤ 1a was associated with significantly shorter OS (11.1 months vs. not reached, P = 0.001). CONCLUSION: Fluorouracil plus platinum was ineffective for recurrent ESCC in patients with a CFI < 6 months and in those with a CFI ≥ 6 months and a TRG ≤ 1a. Alternate regimens including nivolumab or pembrolizumab might be considered for the treatment for recurrence in these patients.

Relevance of pharmacogenetic polymorphisms with response to docetaxel, cisplatin, and 5-fluorouracil chemotherapy in esophageal cancer.

PURPOSE: Docetaxel, cisplatin, and 5-fluorouracil (DCF) have high response rates, but severe neutropenia is frequently observed. The occurrence of neutropenia is associated with high histological response in solid tumors, and it might be associated with tumor shrinkage after DCF therapy. This study aimed to determine the genetic polymorphisms involved in the clinical response to preoperative DCF therapy in esophageal cancer patients. METHODS: We included 56 patients with measurable lesions who received preoperative DCF therapy for esophageal cancer. Twenty-one genetic polymorphisms were analyzed, and univariate logistic regression analysis was used to evaluate the association between genetic polymorphisms and tumor shrinkage. A multivariate logistic regression analysis adjusted for T category and tumor location and a univariate analysis for potential genetic factors with P values < 0.05 were performed to explore the predictive factors and to estimate odds ratios and their 95% confidence intervals. RESULTS: No patient achieved a complete response, whereas 20 patients achieved a partial response, 31 patients had stable disease, and 5 patients had progressive disease. Although no association was found between pharmacokinetic-related gene polymorphisms, XRCC3 rs17997944 was extracted as the only genetic factor that affected tumor shrinkage (P = 0.033) by univariate analysis. The multivariate analysis adjusted for T category and tumor site also showed that XRCC3 rs1799794: AA was a predictive factor that affected tumor shrinkage (odds ratio, 0.243; 95% confidence interval, 0.065-0.914; P = 0.036). CONLUSIONS: XRCC3 rs1799794, which is involved in homologous recombination, is a genetic factor that affects clinical responses to DCF therapy.

Retrospective cohort study of nanoparticle albumin-bound paclitaxel plus ramucirumab versus paclitaxel plus ramucirumab as second-line treatment in patients with advanced gastric cancer.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) has shown non-inferiority to paclitaxel (PTX) as second-line therapy for advanced gastric cancer (AGC) with fewer infusion-related reactions. The efficacy and safety of nab-PTX plus ramucirumab (RAM) was reported in a phase II trial; however, there is no randomized trial comparing this regimen with PTX plus RAM in patients with AGC. This retrospective study aimed to investigate the efficacy and safety of nab-PTX plus RAM versus PTX plus RAM in patients with AGC. METHODS: This study included patients with AGC who received nab-PTX plus RAM from September 2017 to January 2019 or PTX plus RAM from June 2015 to August 2017 as second-line chemotherapy in our hospital. RESULTS: A total of 113 and 138 patients who received nab-PTX plus RAM and PTX plus RAM, respectively, were analyzed. Median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI]: 3.4-4.3) in the nab-PTX plus RAM group and 3.9 months (95% CI: 3.1-4.7) in the PTX plus RAM group (hazard ratio [HR]: 1.08; 95% CI: 0.83-1.40; P = 0.573). Median overall survival (OS) was 10.9 months (95% CI: 9.3-12.7) in the nab-PTX plus RAM group and 10.3 months (95% CI: 8.5-12.0) in the PTX plus RAM group (hazard ratio: 0.82; 95% CI: 0.61-1.10; P = 0.188). In patients with moderate/massive ascites, favorable outcomes for progression-free survival were observed in the nab-PTX plus RAM group compared with the PTX plus RAM group. Although anemia and fatigue (any grade) were more frequent in the nab-PTX plus RAM group, discontinuation of study treatment was not increased in the nab-PTX plus RAM group. There was no occurrence of hypersensitivity reaction in the nab-PTX plus RAM group, while two patients (1.4%) experienced grade 3 hypersensitivity reactions in the PTX plus RAM group. CONCLUSIONS: The combination of nab-PTX plus RAM showed a similar efficacy and safety profile to PTX plus RAM as second-line treatment for patients with AGC.

ABCB1 and ABCC2 genetic polymorphism as risk factors for neutropenia in esophageal cancer patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy.

PURPOSE: The combination of docetaxel, cisplatin and 5-fluorouracil (DCF) is a newly developed chemotherapy regimen for esophageal cancer. Severe neutropenia is dose-limiting toxicity of docetaxel and it is well known to be frequently occurred during DCF chemotherapy. This study aimed to investigate the relationship between severe neutropenia and genetic polymorphisms in patients treated with preoperative DCF chemotherapy. METHODS: A total of 158 patients were investigated for their absolute neutrophil count (ANC) within the first cycle of DCF chemotherapy at the National Cancer Center (NCC) Hospital East. DNA samples obtained from the NCC Biobank Registry were used for the analysis of nine genetic polymorphisms related to docetaxel pharmacokinetics. These genotypes were evaluated for their association with severe neutropenia, and further their risk factors were examined using a multivariate logistic regression. RESULTS: A total 81 (51.3%) patients developed severe neutropenia. Multivariate analysis revealed that age (OR 1.054; CI 1.008-1.102, P = 0.022), baseline ANC (OR 1.019; CI 1.002-1.037, P = 0.030), ABCB1 3435C>T (OR 2.191; CI 1.087-4.417, P = 0.028) and ABCC2 *+9383C>G (OR 2.342; CI 1.108-4.948, P = 0.026) were significant risk factors for severe neutropenia development. The results from this study showed that age, ANC, ABCB1 3435C>T, and ABCC2 *+9383 G>C increased the incidence of severe neutropenia with the number of identified risk factors. CONCLUSIONS: In addition to age and baseline ANC, ABCB1 3435C>T and ABCC2 *+9383C>G were identified as independent predictors for severe neutropenia in esophageal cancer patients treated with DCF chemotherapy.

Clinical impact of renal impairment on the safety and efficacy of S-1 plus oxaliplatin in patients with advanced gastric cancer: a single institutional study.

BACKGROUNDS: S-1 plus oxaliplatin appears effective in chemo-naïve patients with advanced gastric cancer. However, comprehensive safety and efficacy data for S-1 plus oxaliplatin is limited for patients with impaired renal function. METHODS: We retrospectively extracted data from advanced gastric cancer patients with normal renal function (normal group, CLcr ≥ 60 ml/min), who were treated with standard doses of S-1 (80 mg/m2) plus oxaliplatin (100 mg/m2), and patients with impaired renal function (impaired group, CLcr < 60 ml/min) who were treated with standard or reduced doses of S-1 (60 mg/m2 or 40 mg/m2) plus standard doses of oxaliplatin. Treatment efficacy and safety between the groups were compared. RESULTS: Data from 100 normal patients and 42 patients with impaired renal function were extracted. Baseline characteristics differed significantly between the two groups, including age (median, 64 vs 72 years, P < 0.0001) and body surface area (median, 1.68 vs 1.51 m2, P < 0.0001). In the impaired group, 66.6% (28/42) started with a reduced dose. Within the impaired group, more patients had a reduced initial S-1 dose when CLcr <50 ml/min (77.3%). The median progression-free and overall survival between the normal and impaired groups was 6.1 vs 5.7 months (P = 0.698) and 16.1 vs 18.5 months (P = 0.638), respectively. CONCLUSIONS: S-1 plus oxaliplatin in advanced gastric cancer patients with impaired renal function appears safe and has demonstrated efficacy given appropriate dose modification.

Impact of pharmacy collaborating services in an outpatient clinic on improving adverse drug reactions in outpatient cancer chemotherapy.

BACKGROUND: Collaboration between pharmacists, doctors, and nurses in outpatient treatment is beneficial; however, such services are limited in Japan due to the lack of a healthcare reimbursement fee for outpatient pharmacy services at outpatient clinic. OBJECTIVE: We evaluated the impact of a service in which clinical pharmacists collaborated with an oncologist at an outpatient clinic in the treatment of adverse drug reactions in outpatient cancer chemotherapy. METHODS: We performed a retrospective cohort study using patients' medical records and treatment diaries. Subjects were patients who received outpatient chemotherapy via a clinical pharmacist collaboration service provided by six outpatient pharmacists and an oncologist at an outpatient clinic between June and August 2016. RESULTS: During the study period, the total number of outpatient services was 2508, with 2055 (81%) related to chemotherapy. The six outpatient pharmacists provided interventions to 498 of the 2055 cases (24%). Of the 498 interventions, 103 (20%), in addition to oncologist's prescription, were suggested treatments for adverse drug reactions due to cancer chemotherapy. Oncologists approved a total of 82 prescription suggestions from pharmacists (79%) to 63 patients. Fifty-seven percent (n = 47) of the adverse drug reactions were improved following the pharmacists' suggested prescriptions. CONCLUSIONS: This is the first study to clarify the benefits of outpatient pharmacy services in which pharmacists collaborate with oncologists at an outpatient clinic for the management of adverse drug reactions in cancer patients in Japan.