Survival of advanced/recurrent gastrointestinal stromal tumors treated with tyrosine kinase inhibitors in Taiwan: a nationwide registry study.

BACKGROUND: Most gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan. METHODS: Patients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan-Meier method. Cox regression analysis was used to analyze the prognostic factors of survival. RESULTS: A total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01-14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39-10.89). CONCLUSIONS: We present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.

Short-term and long-term outcomes of on-pump beating-heart coronary artery bypass surgery in dialysis and non-dialysis patients: a retrospective study in a single center.

BACKGROUND: This study aimed to evaluate the short-term and long-term outcomes of dialysis and non-dialysis patients after On-pump beating-heart coronary artery bypass grafting (OPBH-CABG). METHODS: We retrospectively reviewed medical records of 659 patients underwent OPBH-CABG at our hospital from 2009 to 2019, including 549 non-dialysis patients and 110 dialysis patients. Outcomes were in-hospital mortality, length of stay, surgical complications, post-CABG reintervention, and late mortality. The median follow-up was 3.88 years in non-dialysis patients and 2.24 years in dialysis patients. Propensity matching analysis was performed. RESULTS: After 1:1 matching, dialysis patients had significantly longer length of stay (14 (11-18) vs. 12 (10-15), p = 0.016), higher rates of myocardial infarction (16.85% vs. 6.74%, p = 0.037) and late mortality (25.93% vs. 9.4%, p = 0.005) after CABG compared to non-dialysis patients. No significant differences were observed in in-hospital mortality, complications, or post-CABG reintervention rate between dialysis and non-dialysis groups. CONCLUSIONS: OPBH-CABG could achieve comparable surgical mortality, surgical complication rates, and long-term revascularization in dialysis patients as those in non-dialysis patients. The results show that OPBH-CABG is a safe and effective surgical option for dialysis patients.

Impact of previous S-1 treatment on efficacy of liposomal irinotecan plus 5-fluorouracil and leucovorin in patients with metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to gemcitabine-based treatment, mainly gemcitabine plus nab-paclitaxel (GA), in current practice. Gemcitabine plus S-1 (GS) is another commonly administered first-line regimen before nab-paclitaxel reimbursement; however, the efficacy and safety of nal-IRI + 5-FU/LV for mPDAC after failed GS treatment has not been reported and was therefore explored in this study. METHODS: In total, 177 patients with mPDAC received first-line GS or GA treatment, followed by second-line nal-IRI + 5-FU/LV treatment (identified from a multicenter retrospective cohort in Taiwan from 2018 to 2020); 85 and 92 patients were allocated to the GS and GA groups, respectively. Overall survival (OS), time-to-treatment failure (TTF), and adverse events were compared between the two groups. RESULTS: The baseline characteristics of the two groups were generally similar; however, a higher median age (67 versus 62 years, p < 0.001) and fewer liver metastases (52% versus 78%, p < 0.001) were observed in the GS versus GA group. The median OS was 15.0 and 15.9 months in the GS and GA groups, respectively (p = 0.58). The TTF (3.1 versus 2.8 months, p = 0.36) and OS (7.6 versus 6.7 months, p = 0.83) after nal-IRI treatment were similar between the two groups. More patients in the GS group developed mucositis during nal-IRI treatment (15% versus 4%, p = 0.02). CONCLUSIONS: The efficacy of second-line nal-IRI +5-FU/LV treatment was unaffected by prior S-1 exposure. GS followed by nal-IRI treatment is an alternative treatment sequence for patients with mPDAC.

Combined Serum ALBUMIN with Neutrophil-to-Lymphocyte Ratio Predicts the Prognosis of Biliary Tract Cancer after Curative Resection.

BACKGROUND: The mainstay treatment of biliary tract cancer is complete tumor resection. Prior to surgery, risk stratification may help to predict and plan treatment approaches. In this study, we investigated the possibility of combining serum albumin concentrations and neutrophil-to-lymphocyte ratios (NLR) to create a score as ANS to predict the prognoses of biliary tract cancer before surgery. METHODS: This study retrospectively collected serum albumin concentration, neutrophil, and lymphocyte data measured in biliary tract cancer patients slated to receive complete tumor resections within two weeks before surgery. From January 2013 to December 2019, 268 biliary tract cancer patients who had received tumor resections at our hospital were categorized into 3 ANS groups: ANS = 0 (high albumin and low NLR), ANS = 1 (low albumin or high NLR), and ANS = 2 (low albumin and high NLR). RESULTS: Five-year survival rates were 70.1%, 47.6%, and 30.8% in the ANS = 0, 1, and 2 groups, respectively. The median overall survival time for the ANS = 0 group could not be determined by the end of the study, while those for ANS = 1 and ANS = 2 groups were 54.90 months and 16.62 months, respectively. The results of our multivariate analysis revealed that ANS could be used as an independent predictor of overall and recurrent-free survival. A high ANS was also correlated with other poor prognostic factors. CONCLUSIONS: The ANS devised for this study can be used to predict postoperative survival in patients with BTC and to guide treatment strategies.

Real-world comparison of pembrolizumab and nivolumab in advanced hepatocellular carcinoma.

BACKGROUND: Nivolumab and pembrolizumab have not been directly compared in clinical trials, and the aim of this study is to investigate the efficacy and safety of nivolumab versus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) in real-world practice. METHODS: We retrospectively reviewed patients with HCC who received intravenous nivolumab or pembrolizumab alone as second-line and later therapy. The objective response was determined according to the Response Evaluation Criteria in Solid Tumors criteria version 1.1. Adverse events (AEs) were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). Prognostic values were estimated using hazard ratios with 95% confidence intervals (CIs). RESULTS: In total, 120 patients were enrolled, including 95 who received nivolumab and 25 who received pembrolizumab. All patients were staged as Barcelona Clinic Liver Cancer stage C, and 29 patients were classified as Child-Pugh classification B (7). The response rate of the pembrolizumab and nivolumab groups were 8.0% and 7.4%, respectively. There was no significant difference in the median PFS between the pembrolizumab and nivolumab groups (2.7 months versus 2.9 months). The median OS in the nivolumab group was longer than that in the pembrolizumab group (10.8 months versus 8.1 months); however, the difference was not statistically significant. The effects of pembrolizumab and nivolumab on the median PFS and OS were consistent across the subgroups based on baseline characteristics. The severity of all AEs was grades 1-2 without treatment interruption or dose adjustment; there was no statistically significant difference in the incidence of treatment-related AEs between these two groups. Additionally, the percentage of patients receiving subsequent therapy was consistent between the two groups. CONCLUSION: The efficacy and safety of pembrolizumab and nivolumab were comparable in the management of patients with pretreated HCC in real-world practice.

The Efficacy and Safety of Ramucirumab in Heavily Pretreated Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: Ramucirumab has been approved for the management of hepatocellular carcinoma (HCC) after progression on sorafenib; however, the data on ramucirumab in heavily pretreated HCC are limited. This study aimed to investigate the real-world efficacy and safety of ramucirumab in patients with heavily pretreated advanced HCC. PATIENTS AND METHODS: Patients with advanced HCC who received intravenous ramucirumab as second-line and later therapy were retrospectively reviewed. Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). Additionally, prognostic factors were estimated using hazard ratios with 95% confidence intervals. RESULTS: In total, 31 patients with advanced HCC who received ramucirumab were enrolled, including 11 patients with second-line treatment and 20 with third-line and later-line treatment. The objective response rate was 3.2% with a disease control rate (DCR) of 45.2%, and the DCR of ramucirumab between the second-line group and the third-line and later-line groups did not differ. The median PFS and OS were 2.1 months and 6.7 months, respectively, in the whole population. In the multivariate analyses, alpha-fetoprotein <1,000 ng/ml was an independent prognostic factor for better PFS and OS. All adverse events were classified as grade 1-2 without grade 3-4 toxicities or drug-related mortality. Additionally, 51.6% of patients received subsequent therapy after progression on ramucirumab. CONCLUSION: The results of our study show the efficacy and safety of ramucirumab in patients with heavily pretreated HCC in real-world practice.

Real-World Data Validation of NAPOLI-1 Nomogram for the Prediction of Overall Survival in Metastatic Pancreatic Cancer.

BACKGROUND: The nomogram derived from the pivotal phase III NAPOLI-1 study demonstrated a significant ability to predict median overall survival (OS) in gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) treated with liposomal irinotecan plus fluorouracil and leucovorin (nal-IRI+5-FU/LV). However, the NAPOLI-1 nomogram has not been validated in a real-world setting and therefore the applicability of the NAPOLI-1 nomogram in daily practice remains unknown. This study aims to evaluate the NAPOLI-1 nomogram in a multicenter real-world cohort. METHODS: The NAPOLI-1 nomogram was applied to a previously established cohort of metastatic PDAC patients treated with nal-IRI+5-FU/LV in nine participating centers in Taiwan. Patients were divided into three risk groups according to the NAPOLI-1 nomogram. The survival impact of relative dose intensity at 6 weeks (RDI at 6 weeks) in different risk groups was also investigated. RESULTS: Of the 473 included patients, the median OSs of patients classified as low (n = 156), medium (n = 186), and high (n = 131) risk were 10.9, 6.3, and 4.3 months, respectively (p < 0.0001). The survival impact of RDI at 6 weeks remained significant after stratification by risk groups, adjustment with Cox regression, inverse probability weighting, or propensity score matching. CONCLUSIONS: Our results support the usefulness of the NAPOLI-1 nomogram for risk stratification in gemcitabine-refractory metastatic PDAC treated with nal-IRI+5-FU/LV in daily practice. We further showed that the RDI at 6 weeks is an independent prognostic factor beyond the NAPOLI-1 nomogram.

Combination of Lenvatinib and Proton Beam Therapy in the Management of Patients With Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: This retrospective study was designed to investigate the efficacy and safety of concurrent lenvatinib and proton beam therapy (PBT) in advanced hepatocellular carcinoma (HCC) patients. PATIENTS AND METHODS: Twenty HCC patients were identified, including Child-Pugh classification A in 16 patients and B (7) in four patients. Sixteen patients had macrovascular invasion, including four with main portal vein thrombosis (Vp4). The dose of lenvatinib depends on body weight; the median PBT dose was 72.6 Gy. RESULTS: The median progression-fee survival (PFS) and overall survival (OS) of the entire population were 8.3 months and 18.4 months, respectively. For PBT targeting intrahepatic lesions and great vessels, the objective response rate (ORR) showed a complete response and partial response (PR) of 20% and 65%, respectively. In the analysis of concurrent lenvatinib and PBT, the ORR included PR of 55% and stable disease of 25%, with disease control rate of 80%. For patients without distant metastasis upon treatment initiation, the time to local control failure (including proton in-field and out-field) was 14.3 months and distant metastasis-free survival was 17.7 months. There was no statistical difference in the analysis of PFS and OS in patients with or without portal vein thrombosis. The severity of most adverse events was grades 1-2, wherein most patients tolerated the toxicities. CONCLUSION: Our study confirmed the efficacy and safety of concurrent lenvatinib and PBT. Thus, this combination therapy may be a reasonable treatment option for selected patients with advanced HCC in clinical practice.

Efficacy and Safety of Lenvatinib After Progression on First-line Atezolizumab Plus Bevacizumab Treatment in Advanced Hepatocellular Carcinoma Patients.

BACKGROUND/AIM: This study aimed to assess the clinical impact of lenvatinib after disease progression on atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 14 patients who received lenvatinib after failure of atezolizumab plus bevacizumab and all patients were classified as having a Barcelona Clinic Liver Cancer stage C. Six patients had macrovascular invasion, and a liver occupation rate of >50% was reported in seven patients. The Kaplan-Meier method was performed to analyze the cumulative survival, while log-rank test was used to detect the differences. The dose of lenvatinib was determined based on body weight. RESULTS: The participants' responses to lenvatinib treatment were as follows: 21.4% achieved partial response (PR), while 35.7% had a stable disease, with a disease control rate of 57.1%. The median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 8.3 months, respectively; the median PFS and OS were 6.7 months and 10.5 months in the PR group. No significant difference was observed in the median PFS and OS between patients with and without macrovascular invasion or liver occupation rate of >50%. Most of the adverse events (AEs) were categorized as grade 1-2; all patients tolerated the AEs, and no drug-related mortality was reported. Additionally, half of the population underwent subsequent therapy after progression on lenvatinib treatment. CONCLUSION: Lenvatinib is effective and can be safely used as second-line systemic therapy after progression on atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice.

Systemic treatments in pancreatic cancer: Taiwan pancreas society recommendation.

Pancreatic cancer is a highly aggressive malignancy with a poor prognosis. Over the past decade, significant therapeutic advancements have improved the survival rates of patients with pancreatic cancer. One of the primary factors contributing to these positive outcomes is the evolution of chemotherapy, from monotherapy to doublet or triplet regimens, and the integration of multimodal approaches. Additionally, targeted agents tailored to patients with specific genetic alterations and the development of cell therapies show promise in benefiting certain subpopulations. This article focuses on examining pivotal studies that explore the role of chemotherapy in neoadjuvant, adjuvant, maintenance, and salvage settings; highlights interesting findings related to cell therapy; and provides an overview of ongoing trials concerning metastatic settings. This review primarily aimed to offer recommendations based on therapeutic evidence, recent advancements in new treatment combinations, and the most innovative approaches. A unique aspect of this review is the inclusion of published papers on clinical trials and real-world data in Taiwan, thus adding a valuable perspective to the overall analysis.

The impact of starting dose with or without subsequent dose escalation of liposomal irinotecan on treatment outcomes in patients with metastatic pancreatic ductal adenocarcinoma.

Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) improves survival in patients with pancreatic ductal adenocarcinoma (PDAC) after progression to gemcitabine-based therapy. Few studies have examined whether the starting dose and dose escalation of nal-IRI in subsequent treatment cycles may influence patient outcomes and toxicity profiles. A total of 667 patients who received nal-IRI + 5-FU/LV for PDAC treatment between August 2018 and November 2020 at nine medical centers in Taiwan were included and retrospectively analyzed. Patients were allocated to the standard starting dose (SD), reduced starting dose (RD) without escalation, and RD with escalation of nal-IRI groups for comparison of survival outcome and safety. Propensity score matching (PSM) was performed to adjust for possible confounding variables. Nal-IRI was prescribed at SD, RD without escalation, and RD with escalation in 465 (69.7%), 147 (22.0), and 55 (8.2%), respectively. RD with escalation patients had significantly longer treatment cycles (6, range 2-25) than SD (5, range 1-42, P<0.001) and RD without escalation patients (4, range 1-26, P<0.001). The median overall survival (OS) of the patients were as follows: SD, 6.2 months (95% confidence interval [CI], 5.7-6.7); RD with escalation, 7.6 months (95% CI, 6.1-9.2); and RD without escalation, 3.6 months (95% CI, 2.6-4.5). After PSM to adjust for potential confounders, RD without escalation patients still had the poorest OS compared to the other two groups (P<0.001), while the OS difference between SD and RD with escalation patients was insignificant (P=0.10). SD patients had higher incidences of ≥ grade 3 neutropenia and febrile neutropenia than the other two groups. Administering nal-IRI at RD followed by dose escalation in subsequent treatment cycles is safe and does not compromise survival outcomes in selected patients with PDAC receiving nal-IRI plus 5-FU/LV.

Low-dose nivolumab in advanced hepatocellular carcinoma.

BACKGROUND: The approved dose of nivolumab is 3 mg/kg or a flat dose of 240 mg for indications. There is no dose-response relationship for nivolumab; therefore, a low-dose regimen may be an option to reduce financial toxicity. This study was designed to investigate the efficacy and safety of low-dose nivolumab in the management of hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed patients with HCC who received 20 or 100 mg of nivolumab intravenously every 2 weeks. The objective response rate was determined in accordance with the Response Evaluation Criteria in Solid Tumors criteria version 1.1. The Cox regression model and Kaplan-Meier method were used to analyze hazard factors, progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. RESULTS: In total, 78 patients were enrolled, including 49 with hepatitis B virus (HBV) and 23 with hepatitis C virus (HCV). All patients were staged as Barcelona Clinic Liver Cancer stage C, and 20 patients were classified as having Child-Pugh classification B (7). Nivolumab 20 mg was an independent prognostic factor for better PFS, and albumin-bilirubin grade 1 was the independent prognostic factor for superior OS in the multivariate analyses. Patients with better HBV (HBV DNA < 500 IU/ml) and HCV (HCV RNA undetectable) controls had superior OS. All AEs were grade 1-2 in severity, and all patients tolerated nivolumab without treatment interruption or dose adjustment. Additionally, 31 patients underwent subsequent therapy after nivolumab treatment. CONCLUSION: Low-dose nivolumab may be effective with manageable toxicity and can be an alternative option to reduce financial toxicity in patients with advanced HCC who cannot afford the high cost of immune checkpoint inhibitors in real-world practice.

Predictive value of albumin combined with neutrophil-to-lymphocyte ratio for efficacy and safety profiles in patients with pancreatic ductal adenocarcinoma receiving liposomal irinotecan plus 5-fluorouracil and leucovorin.

Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) treatment has demonstrated survival benefits but noticeable side effects in patients with pancreatic ductal adenocarcinoma (PDAC) that is refractory to gemcitabine-based therapy. This study aimed to explore whether combining albumin with the neutrophil-to-lymphocyte ratio (NLR), herein known as the albumin and neutrophil-to-lymphocyte ratio score (ANS), could be utilized as a simple tool to predict survival and safety profiles in such patient groups. We retrospectively enrolled 434 consecutive PDAC patients treated with nal-IRI + 5-FU/LV between 2018 and 2020 at nine medical centers in Taiwan. Patients were divided into three groups: ANS 0 (high albumin and low NLR), ANS 1 (low albumin or high NLR), and ANS 2 (low albumin and high NLR), for comparison. The median overall survival times for the ANS 0, 1, and 2 groups were 8.7 months (95% confidence interval (CI), 7.0-10.3 months), 5.2 months (95% CI, 4.3-6.0 months), and 2.6 months (95% CI, 1.9-3.3 months), respectively. The ANS was found to be an independent variable for overall survival and time-to-treatment failure in multivariate analyses. Patients in the ANS 2 group had significantly higher incidences of grade 3 or higher treatment-related adverse events than those in the other two groups. The present study showed that the ANS was an independent prognosticator in PDAC patients receiving nal-IRI + 5-FU/LV therapy. The ANS can be a simple predictor of survival outcome and safety profiles in PDAC patients treated with nal-IRI + 5-FU/LV.

A prospective phase II study of biweekly S-1, leucovorin, and gemcitabine in elderly patients with locally advanced or metastatic pancreatic adenocarcinoma - The Taiwan Cooperative Oncology Group T1217 study.

BACKGROUND: Elderly patients with advanced pancreatic adenocarcinoma (APC) are conceived to be frailer and susceptible to treatment toxicity that has led to disparity in lower likelihood of receiving chemotherapy and survival. Optimal chemotherapy is an unmet medical need for elderly patients with APC. PATIENTS AND METHODS: Patients with chemo-naive APC, age ≥70 years, and Eastern Cooperative Oncology Group (ECOG) performance score ≤2 were eligible. The treatment was consisted of biweekly gemcitabine 800 mg/m2, 10 mg/m2/min infusion on day 1 plus oral S-1 and leucovorin (40-60 and 30 mg, respectively) twice daily on days 1-7, the GSL regimen. The primary end-point was progression-free survival with an interested P1 of 5.0 months. RESULTS: Of the 49 enrolled patients, the median age was 76 years, ECOG performance score ≥1 in 59.2%, metastatic diseases in 65.3%, Vulnerable Elders Survey-13 score ≥3 in 71.4%, and Geriatric 8 score ≤14 in 93.9%. After a median 11 cycles of treatment, the overall response rate and disease control rate were 26.5% and 75.5%, respectively. The median progression-free and overall survivals were 6.6 months (95% confidence interval [CI], 5.4-9.2) and 12.5 months (95% CI, 8.9-14.7), respectively. The most common grade 3-4 treatment-related toxicities were anaemia (20.4%), neutropenia (18.4%), and mucositis (12.2%). Patients had improved emotional function and global health status scores during the GSL treatment. CONCLUSION: The study met its primary end-point, which supports further investigation on the merit of GSL in Asian elderly APC patients.

Well-Controlled Viremia Predicts the Outcome of Hepatocellular Carcinoma in Chronic Viral Hepatitis Patients Treated with Sorafenib.

Without analyzing the status of viremia, hepatitis C virus-related hepatocellular carcinoma (HCV-HCC) patients are proposed to have better prognosis than hepatitis B virus-related HCC (HBV-HCC) patients using sorafenib. We aimed to elucidate the efficacy of concurrent sorafenib and anti-viral treatment for HCC patients with HBV or HCV infection in real world. Between January 2018 and January 2021, 256 unresectable HCC patients receiving first-line sorafenib were evaluated. High-potency nucleoside analogs were used for HBV control, whereas direct-acting antivirals were administered for HCV eradication. Well-controlled viremia was defined as patients who had undetectable viremia, or who had been receiving antivirals at least 6 months before sorafenib. We recruited 116 (65.2%) HBV-HCC patients and 62 (34.8%) HCV-HCC patients. Using sorafenib, progression-free survival and overall survival (OS) rates between these two groups were not different. Before sorafenib, 56% of HBV-HCC patients and 54.8% of HCV-HCC patients had well-controlled viremia and their OS was superior to those who had uncontrolled viremia (15.5 vs. 11.1 months, p = 0.001). Dividing our patients into four subgroups as well-controlled HCV viremia, well-controlled HBV viremia, uncontrolled HCV viremia, and uncontrolled HBV viremia, their OS rates were distributed with a significantly decreasing trend as 21.9 months, 15.0 months, 14.2 months, and 5.7 months (p = 0.009). Furthermore, well-controlled viremia was associated with mortality in multivariate analysis (Hazard ratio: 0.63, 95% confidence interval: 0.42-0.93, p = 0.022). In real-life, HBV or HCV infection did not contribute to the prognosis of HCC patients receiving sorafenib; however, whether viremia was controlled or not did contribute.

Dosing Pattern and Early Cumulative Dose of Liposomal Irinotecan in Metastatic Pancreatic Cancer: A Real-World Multicenter Study.

Introduction: This multicenter, real-world cohort study aimed to evaluate the effectiveness of early cumulative dose administration and dosing pattern of liposomal irinotecan plus fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (mPDAC). Material and Methods: The electronic medical records of mPDAC patients treated with nal-IRI+5-FU/LV in nine participating centers were manually reviewed. To accommodate to the NAPOLI-1 study population, only patients with an Eastern Cooperative Oncology Group Performance Score of 0-1 were included. The survival impact of the relative 6-week cumulative dose and dosing pattern (standard vs. reduced starting dose, with and without further dose modification) were investigated. Results: Of the 473 included patients, their median overall survival (mOS) was 6.8 [95% CI, 6.2-7.7] months. The mOS of patients who received a relative 6-week cumulative dose of >80%, 60%-80%, and <60% were 7.9, 8.2, and 4.3 months, respectively (p<0.0001). Their survival impact remained significant after covariate adjustment using Cox regression. The mOS was 8.0-8.2 months in patients with a standard starting dose with and without early dose modification, and 9.3 and 6.7 months in those who had a reduced starting dose with and without escalation in the subsequent treatment, respectively. The incidence of grade 3-4 neutropenia and diarrhea was 23.3% and 2.7%, respectively. Conclusion: Our results support the use of nal-IRI+5-FU/LV in gemcitabine-refractory mPDAC and suggest that a lower starting dose followed by a re-escalation strategy could achieve clinical outcomes comparable to those with standard starting doses in real-world practice.

The impact of spleen volume on the survival of metastatic pancreatic adenocarcinoma patients receiving nanoliposomal irinotecan.

Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (NalFL) comprises the current standard for gemcitabine-failed metastatic pancreatic ductal adenocarcinoma (PDAC). As liposomes generally accumulate in the spleen, we evaluated the impact of spleen volume on prognosis. We enrolled patients with metastatic PDAC who failed gemcitabine-based therapy and were initiated on NalFL between August 2018 and November 2020. The spleen volume before NalFL administration was evaluated. They were stratified into dose subgroups (i.e. low, < 48 mg/m2; intermediate, 48 - < 64 mg/m2; high, ≥ 64 mg/m2) by the average nal-IRI dose during the entire treatment, and multivariate analysis of overall survival (OS) was performed. We included 547 patients with a median age of 63 years (range, 27-89 years) and a median of 1 (range, 0-7) palliative chemotherapy regimen. The median spleen volume was 245 mL (range, 82-817 mL). Among patients with splenomegaly (≥ 245 mL), the low-dose subgroup had the worst median time to treatment failure (TTF, 1.8 months vs. 2.5 months vs. 2.5 months, P = 0.020) and OS (3.3 months vs. 5.9 months vs. 6.6 months, P = 0.018) as against no prognostic impact in patients without splenomegaly. In the multivariate analysis of patients with splenomegaly, performance status (PS) ≥ 2, body surface area (BSA) < 1.6 m2, prior fluoropyrimidine use, liver metastasis, and low-dose subgroup were independent poor prognostic factors. A low average nal-IRI dose was significantly associated with poor prognosis, especially among patients with splenomegaly. Further pharmacological studies should validate the relevance of spleen volume on the treatment outcomes of nal-IRI.

Effect of previous conventional irinotecan treatment in patients with pancreatic cancer being treated with liposomal irinotecan plus 5-fluorouracil and leucovorin.

BACKGROUND: Recent studies have suggested the suboptimal efficacy of liposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) patients previously treated with conventional irinotecan. This study investigated the effect of conventional irinotecan treatment in mPDAC patients receiving nal-IRI+5-FU/LV by analyzing a population-based dataset. METHODS: We reviewed 667 consecutive mPDAC patients treated with nal-IRI+5-FU/LV between August 2018 and November 2020 at Taiwanese medical centers. Eighty-six patients previously treated with conventional irinotecan were matched to 86 patients not treated with conventional irinotecan, following propensity matching for age, sex, performance status, metastatic organ site, pre-treatment carbohydrate antigen 19-9 level, lines of prior chemotherapy treatment, and time from first-line treatment to nal-IRI+5-FU/LV therapy. RESULTS: The median overall survival and time-to-treatment failure were 4.8 and 2.6 vs 4.1 and 2.1 months, respectively, for patients who were and were not previously treated with conventional irinotecan. The tumor response and disease control rates were 5.8% and 32.6% vs 5.8% and 37.2%, respectively, for patients previously treated and not treated with conventional irinotecan. No significant differences were observed in survival times and tumor response rates between the two groups. CONCLUSIONS: Previous conventional irinotecan treatment does not compromise the efficacy of subsequent nal-IRI+5-FU/LV treatment in mPDAC patients.

The Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Patients with Hepatocellular Carcinoma Receiving Atezolizumab Plus Bevacizumab.

Atezolizumab plus bevacizumab has been approved as the first-line systemic treatment for patients with unresectable hepatocellular carcinoma (uHCC). This study was designed to assess the clinical impact of atezolizumab plus bevacizumab in uHCC patients. A total of 48 uHCC patients receiving atezolizumab plus bevacizumab were identified, including first-line, second-line, third-line, and later-line settings. In these patients, the median progression-free survival (PFS) was 5.0 months, including 5.0 months for the first-line treatment, not reached for the second-line treatment, and 2.5 months for the third line and later line treatment. The objective response rate and disease control rate to atezolizumab plus bevacizumab were 27.1% and 68.8%, respectively. The severity of most adverse events was predominantly grade 1-2, and most patients tolerated the toxicities. The ratios of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) were used to predict PFS in these patients. The optimal cutoff values of NLR and PLR were 3 and 230, and NLR and PLR were independent prognostic factors for superior PFS in the univariate and multivariate analyses. Our study confirms the efficacy and safety of atezolizumab plus bevacizumab in uHCC patients in clinical practice and demonstrates the prognostic role of NLR and PLR for PFS in these patients.