Phase II Trial of Trifluridine/Tipiracil in Patients with Advanced, Refractory Biliary Tract Carcinoma.

LESSONS LEARNED: Trifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5-fluorouracil refractory tumors. FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first-line therapy. BACKGROUND: Patients with advanced biliary tract carcinoma (BTC) refractory to first-line therapy lack an established second-line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine-sensitive and -resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC. METHODS: Patients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression-free survival (PFS), and toxicity. RESULTS: Of 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%-53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2-5.8 months) and 6.1 (95% CI, 4.4-11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted. CONCLUSION: FTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC.

Association between treatment facility volume, therapy types and overall survival in patients with intrahepatic cholangiocarcinoma.

BACKGROUND: To determine the association between the number of patients with intra-hepatic cholangiocarcinoma (IHCC) treated annually at a treatment facility (volume) and overall survival (outcome). METHODS: Patients with IHCC reported to the National Cancer Database (years 2004-2015) were included. We classified facilities by tertiles (T; mean IHCC patients treated/year): T1: <2.56; T2: 2.57-5.39 and T3: ≥5.40. Volume-outcome relationship was determined by using Cox regression adjusting for patient demographics, comorbidities, tumor characteristics, insurance type and therapy received. RESULTS: There were 11,344 IHCC patients treated at 1106 facilities. On multivariable analysis, facility volume was independently associated with all-cause mortality (p < 0.001). The unadjusted median OS by facility volume was: T1: 5 months (m), T2: 8.1 m, and T3: 13.1 m (p < 0.001). Compared with patients treated at T3 facilities, patients treated at lower-tertile facilities had significantly higher risk of death [T2 hazard ratio (HR), 1.12 [95% CI, 1.05-1.23]; T1 HR, 1.21 [95% CI, 1.11-1.33]. Patients treated at high-volume centers were more likely to get surgery (34.6 vs 13.1%) and adjuvant therapy. CONCLUSION: IHCC patients treated at high-volume facilities had a significant improvement in OS and were more likely to receive surgery and adjuvant therapy as compared to that of patients at low-volume facilities.

Survival and prognostic factors in patients with rectal squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma (SCC) of the rectum is a rare form of gastrointestinal malignancy. The current knowledge on the natural history is primarily derived from case series. METHODS: Using the National Cancer Data Base (NCDB), we determined the prognostic factors and overall survival (OS) outcomes of rectal SCC reported to NCDB between 2004 and 2015. Kaplan-Meier method and log-rank test were used to perform OS analysis. Propensity matched analysis was undertaken to compare the OS outcomes between rectal and anal SCC. RESULTS: Of the 3405 cases included in our analysis, 67% were female. Median age at diagnosis was 61 years and did not differ by sex. In stages I-III, patients who received definitive chemoradiation only (108 months) had a better median OS as compared to surgery alone (76 months) (p = 0.012). On multivariate analysis, age <60 years, female sex, and receipt of chemoradiation with or without surgery were independent predictors of better OS in stage I-III disease. Administration of chemoradiation was associated with better OS in stage IV disease. On propensity matched analysis comparing outcomes to anal SCC, OS of rectal SCC was inferior (79 months) to anal SCC (113 months) (p < 0.001), no such difference in OS was noted in the cohorts that received surgery plus post-surgical chemoradiation (p = 0.12). CONCLUSION: Outcomes of rectal SCC were dependent upon age, sex, comorbidity score, and therapy received. Chemoradiation alone or in combination with surgery was associated with a better median OS in patients with stages I-III.

Novel staging system using carbohydrate antigen (CA) 19-9 in extra-hepatic cholangiocarcinoma and its implications on overall survival.

BACKGROUND: CA19-9 elevation has shown to be associated with poor prognosis in extrahepatic cholangiocarcinoma (ECCA). However, the role of CA19-9 in staging of ECCA has not been evaluated. We hypothesized that CA19-9 elevation is a marker of aggressive biology in ECCA and that inclusion of CA19-9 in the staging system may improve overall survival (OS) discrimination. METHODS: Patients with ECCA whose CA19-9 levels, irrespective of surgical status, were reported to the National Cancer Database (2004-2015) were included. The patients were classified based on their CA19-9 levels and a new staging system was proposed. Net reclassification improvement (NRI) model was used to assess the predictive improvement in the proposed survival model as compared to AJCC-TNM staging. RESULTS: Of the 2100 patients included in the study, 626 (32%) and 1474 (68%) had normal and elevated CA19-9 levels (>38 U/ml), respectively. Median OS was lower among patients with elevated CA19-9 level compared to those with CA19-9 level ≤38 U/ml (8.5 vs 16 months, p < 0.01). On multivariate analysis, CA19-9 elevation independently predicted poor prognosis [HR:1.72 (1.46-2.02); p < 0.01] with similar impact as node-positivity, positive resection margins and non-receipt of chemotherapy. We developed a new staging system by incorporating CA19-9 into the 7th edition AJCC TNM staging system. NRI of 46% (95%CI: 39-57%) indicates that the new staging system is substantially effective at re-classifying events at 12 months as compared to AJCC 7th edition. CONCLUSION: Elevated CA19-9 was found to be an independent risk factor for mortality in ECCA and its inclusion in the proposed staging system improved OS discrimination.

Survival and prognostic factors in patients with pancreatic squamous cell carcinoma.

OBJECTIVES: Squamous cell carcinoma (SCC) of pancreas is rare entity with poorly defined prognostic factors and therapeutic outcomes. We sought to determine the overall survival (OS) and prognostic factors of patients with pancreatic SCC using National Cancer Database (NCDB) (2004-15). METHODS: Kaplan-Meier method and log-rank test were used to perform OS analysis. Propensity-matched analysis was used to compare the OS of pancreatic SCC and adenocarcinoma. RESULTS: Of the 515 cases included in our analysis, 46% were female. Approximately half of the cohort (48%) received chemotherapy or radiation therapy or both. Twenty six percent (33/125) of stage I and II disease (localized disease), 11% (8/72) of stage III, and 2% (6/318) of stage IV disease underwent surgical resection of the primary tumor. Median OS for the entire cohort was 4 months and was significantly higher in patients who underwent surgical resection of the primary tumor (17 vs 4 months, p < 0.001). In localized disease, adjuvant chemotherapy was not associated with improved OS in early stage disease (20 vs 24 months, p = 0.60). Stage IV patients treated with chemotherapy had a better OS than those without (5 vs 2 months, p < 0.0001). Propensity matched analysis demonstrated no significant differences in median OS between pancreatic adenocarcinoma (4.8 months) and SCC (4 months, p = 0.09). CONCLUSIONS: Pancreatic SCC had a diverse OS that varied significantly according to increasing age (>70 years) and stage of the disease at presentation (p < 0.01). Surgical resection of primary tumor was associated with longer OS in stages I-II, whereas chemotherapy was associated with longer OS in stage IV disease.