A phase 1 study of biweekly nab-paclitaxel/oxaliplatin/S-1/LV for advanced upper gastrointestinal cancers: TCOG T1216 study.

BACKGROUND: Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers. METHODS: A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively. CONCLUSION: The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation. CLINICALTRIALS.GOV IDENTIFIER: NCT03162510.

Translational research on drug development and biomarker discovery for hepatocellular carcinoma.

Translational research plays a key role in drug development and biomarker discovery for hepatocellular carcinoma (HCC). However, unique challenges exist in this field because of the limited availability of human tumor samples from surgery, the lack of homogenous oncogenic driver mutations, and the paucity of adequate experimental models. In this review, we provide insights into these challenges and review recent advancements, with a particular focus on the two main agents currently used as mainstream therapies for HCC: anti-angiogenic agents and immunotherapy. First, we examine the pre-clinical and clinical studies to highlight the challenges of determining the optimal therapeutic combinations with biologically effective dosage for HCC. Second, we discuss biomarker studies focusing on anti-PD1/anti-PD-L1-based combination therapy. Finally, we discuss the progress made in our collective understanding of tumor immunology and in multi-omics analysis technology, which enhance our understanding of the mechanisms underlying immunotherapy, characterize different patient subgroups, and facilitate the development of novel combination approaches to improve treatment efficacy. In summary, this review provides a comprehensive overview of efforts in translational research aiming at advancing our understanding of and improving the treatment of HCC.

Combination of GT90001 and nivolumab in patients with advanced hepatocellular carcinoma: a multicenter, single-arm, phase 1b/2 study.

BACKGROUND: GT90001 (also known as PF-03446962) is an anti-ALK-1 monoclonal antibody and has shown activity in hepatocellular carcinoma (HCC). This phase 1b/2 study was designed to determine the recommended phase 2 dose (RP2D) of GT90001 plus nivolumab, and assess the safety and anti-tumor activity in patients with advanced HCC. METHODS: Patients with advanced HCC were recruited from 3 centers. Eligible patients in the dose de-escalation stage received the GT90001 on day 1 of a 14-day cycle in a rolling-six design with a fixed dose of nivolumab (3.0 mg/kg). Patients in dose-expansion stage received the RP2D of GT90001 plus nivolumab. Primary endpoint was safety. Key secondary endpoint was objective response rate (ORR) as per RECIST 1.1. RESULTS: Between July 9, 2019, and August 8, 2022, 20 patients were treated (6 in phase 1b; 14 in phase 2) and evaluable for analysis. In phase 1b, no dose-limiting toxicities were observed, and GT90001 7.0 mg/kg was confirmed as the RP2D. Common grade 3/4 adverse events (AEs) were platelet count decreased (15%). No deaths due to AEs were reported. Confirmed ORR and disease control rate were 30% (95% CI, 14.6%-51.9%) and 40% (95% CI, 21.9%-61.3%), respectively. Median duration of response was not calculated (95% CI, 7.39 months to not calculated). Median progression-free survival (PFS) was 2.81 months (95% CI, 1.71-9.33), with 6-month and 12-month PFS rates of 35% and 25%, respectively. One patient with multiple intra- and extra-hepatic metastases was diagnosed with pseudo-progression upon GT90001 plus nivolumab exposure. CONCLUSIONS: GT90001 plus nivolumab has a manageable safety profile and promising anti-tumor activity in patients with advanced HCC. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03893695.

Sarcopenia and myosteatosis are associated with survival in patients receiving immunotherapy for advanced hepatocellular carcinoma.

OBJECTIVES: To investigate the association of sarcopenia, myosteatosis, and sarcopenic obesity with survival outcomes among patients who underwent immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective analysis, patients who initiated immunotherapy for advanced HCC were enrolled. Sarcopenia and myosteatosis were evaluated on pretreatment CT at L3 level by skeletal muscle index and mean muscle attenuation using predefined cutoff values. Sarcopenic obesity was defined as concurrent sarcopenia and body mass index > 25 kg/m2. The log-rank test and the Cox proportional hazards model were used to compare overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 138 patients was included (discovery cohort n = 111, validation cohort n = 27). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (p = 0.048) and OS (p = 0.002) than patients without sarcopenia. Patients with myosteatosis exhibited significantly poorer PFS (p < 0.001) and OS (p < 0.001) than patients without myosteatosis. Patients with sarcopenic obesity compared to patients without sarcopenic obesity exhibited significantly poorer OS (p = 0.006) but not PFS (p = 0.31). In multivariate analysis adjusting for patient demographics, tumor extent, and liver function reserve, myosteatosis remained an independent predictor of poor PFS (p = 0.014) and OS (p = 0.007); sarcopenia remained an independent predictor for poor OS (p = 0.007). The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort. CONCLUSIONS: Sarcopenia and myosteatosis are independent prognostic factors in patients who received immunotherapy for advanced HCC. KEY POINTS: • Sarcopenia and myosteatosis can be evaluated by CT at L3 level. • Sarcopenia, myosteatosis, and sarcopenic obesity were associated with poor survival outcomes in patients who underwent immunotherapy for advanced HCC. • Myosteatosis was an independent predictor of PFS and OS, and sarcopenia was independent for OS in these patients.

Low miR-10b-3p associated with sorafenib resistance in hepatocellular carcinoma.

BACKGROUND: Sorafenib is one of the standard first-line therapies for advanced hepatocellular carcinoma (HCC). Unfortunately, there are currently no appropriate biomarkers to predict the clinical efficacy of sorafenib in HCC patients. MicroRNAs (miRNAs) have been studied for their biological functions and clinical applications in human cancers. METHODS: In this study, we found that miR-10b-3p expression was suppressed in sorafenib-resistant HCC cell lines through miRNA microarray analysis. RESULTS: Sorafenib-induced apoptosis in HCC cells was significantly enhanced by miR-10b-3p overexpression and partially abrogated by miR-10b-3p depletion. Among 45 patients who received sorafenib for advanced HCC, those with high miR-10b-3p levels, compared to those with low levels, exhibited significantly longer overall survival (OS) (median, 13.9 vs. 3.5 months, p = 0.021), suggesting that high serum miR-10b-3p level in patients treated with sorafenib for advanced HCC serves as a biomarker for predicting sorafenib efficacy. Furthermore, we confirmed that cyclin E1, a known promoter of sorafenib resistance reported by our previous study, is the downstream target for miR-10b-3p in HCC cells. CONCLUSIONS: This study not only identified the molecular target for miR-10b-3p, but also provided evidence that circulating miR-10b-3p may be used as a biomarker for predicting sorafenib sensitivity in patients with HCC.

Association of annexin A10 expression with poor prognosis of intrahepatic cholangiocarcinoma.

BACKGROUND: Annexin A10 expression influences the prognosis of several gastrointestinal cancers. We explored the association of annexin A10 expression with the overall survival (OS) of patients who underwent curative surgery for cholangiocarcinoma. METHODS: Patients who underwent curative surgery for cholangiocarcinoma (except gallbladder cancer) and had pathological stage T1-3N0M0 disease were enrolled. Annexin A10 expression was examined by performing immunohistochemical staining. Patient demographics and survival outcome data were retrieved from medical records. RESULTS: In total, 185 patients were enrolled. The primary tumor location was intrahepatic and extrahepatic (including the perihilar region) for 89% and 11% of patients, respectively. Positive annexin A10 staining was detected for 61 (33%) patients and associated with extrahepatic or perihilar cholangiocarcinoma (p = 0.001) and lower histological grade (p < 0.001). Patients with positive annexin A10 staining exhibited significantly poorer survival relative to patients with negative staining results (median OS, 2.5 vs. 4.9 years, p = 0.025). In the multivariate analysis adjusting for age, sex, tumor location, tumor grade, hepatitis infection, and disease stage, positive annexin A10 remained an independent predictor of poor OS (hazard ratio 1.572, p = 0.034). In the subgroup analysis, the association between annexin A10 and prognosis was restricted to intrahepatic cholangiocarcinoma. Among patients with intrahepatic cholangiocarcinoma, patients with positive annexin A10 staining exhibited significantly poorer survival compared with patients with negative annexin A10 staining (median OS, 2.3 vs. 4.9 years, p = 0.008). CONCLUSION: Positive annexin A10 expression was associated with poor prognosis of intrahepatic cholangiocarcinoma.

Effectiveness of tutor shadowing on faculty development in problem-based learning.

BACKGROUND: To enhance tutors' teaching skills, tutor shadowing for novice tutors of problem-based learning (PBL) in addition to conventional faculty development (FD) was applied. This study aimed to develop a tutoring-skill scale (TS-scale) and evaluate the effect of shadowing on PBL tutors. METHODS: This study employed a before-and-after study design with three phases. In phase 1, a TS-scale was elaborated. A validity examination was performed in phase 2. Phase 3 was a study of the effectiveness using a TS-scale survey of novice PBL tutors before and after the FD course. The FD course for novice PBL tutors included an FD workshop and PBL shadowing activities. RESULTS: A TS-scale with a 32-item questionnaire of self-rated confidence for PBL tutors was identified in phase 1. In phase 2, 7 experienced specialists in medical education were invited to evaluate the content validity of the scale. The item content validity index (I-CVI) ranged from 0.86 to 1, and the scale-CVI (S-CVI) was 0.95. A total of 85 novice PBL tutors completed the TS-scale before the FD course, yielding a Cronbach's alpha of 0.98. An exploratory factor analysis with varimax rotation was performed. The twenty-four items with significant loadings greater than 0.5 were incorporated into a new TS-scale and were grouped into three factors: student contact, medical expertise, and teaching expertise. In phase 3, 76 novice PBL tutors completed the 24-item TS-scale before (pretest) and after (posttest) the FD course. Their self-rated confidence improved significantly across the three factors after the FD course. The pretest and posttest scores did not differ according to the tutors' gender, the grades they taught, or their specialty background. CONCLUSIONS: Novice PBL tutors benefit from FD that incorporates tutor shadowing in the 3 key domains of tutoring competencies. The TS-scale developed in this study can be applied in future research on FD design.

Moving from tangibility toward digitalization: investigating team dynamics and facilitator support among medical students in conventional and digital small-group tutorials.

BACKGROUND: Small group tutorials (SGT) promotes self-directed learning and is widely used in medical education. The coronavirus pandemic (COVID-19) has accelerated the trend toward SGT digitalization, with unclear effect. We hypothesize that team dynamics and facilitator support influence SGT satisfaction in digital versus conventional SGT. METHODS: During the spring semester of year 2021, medical students (the second, third, and fourth year; n = 433) participating in conventional face-to-face and digital SGT curricula were enrolled. Participating students completed the collaborative learning attitude scale (including team dynamics, team acquaintance, and facilitator support dimensions) and teamwork satisfaction scale, previously validated for small-group collaborative learning, and chose preference between conventional or digital SGT in future curricula. Exploratory factor analysis (EFA) was performed to extract the essential structural factors of these scales. Paired t-tests were conducted to compare differences in different dimensions and satisfaction between the conventional and digital SGT settings. Two sets of multiple regression analyses were done; one with team satisfaction scale results and the other with preference for digital SGT as the dependent variable were used to evaluate determinants of these two variables. RESULTS: The EFA results revealed that the original collaborative learning attitude scale was concentrated on two dimensions: team dynamics and facilitator support. No significant differences were noted between the SGT settings for the two dimensions and teamwork satisfaction. Regression analyses showed that teamwork dynamics was independently correlated with teamwork satisfaction in both conventional and digital SGT. Facilitator support was positively correlated with teamwork satisfaction in conventional, but not digital SGT. Higher teamwork satisfaction was an important determinant of preference for digital SGT among medical students. CONCLUSIONS: Team dynamics were closely linked to teamwork satisfaction among medical students in both conventional and digital SGT, while the role of facilitator support became less obvious during digital SGT.

Fully digital problem-based learning for undergraduate medical students during the COVID-19 period: Practical considerations.

Digital problem-based learning (PBL) was originally introduced as a means to improve student engagement and increase flexibility. However, its use becomes mandatory during the coronavirus disease 2019 (COVID-19) period, accelerating changes in medical education. Few elaborated on the implementation details of digital PBL curricula. Technical guidance can be important but under-recognized prerequisite of a successful digital PBL session. In National Taiwan University College of Medicine, we established a digital PBL curriculum and previously validated a confidence questionnaire for surveying undergraduate students receiving digital PBL sessions. In this opinion piece, we gleaned multiple procedural details from our experiences based on students'/tutors' feedback, which we summarized in a 5″W″ recommendations (Who), timing/duration (When), location (Where), software/hardware/topics (What), and evaluation aspects (Why). Suggestions on how to optimally prepare for digital PBL session are also provided. We believe that these tips can further facilitate the wide adoption of digital PBL.

Spectrum of cancer patients receiving renal biopsy.

BACKGROUND: The frontier of onco-nephrology, particularly renal complications of cancer and treatment, remains unexplored. We revisit the fundamental tool of diagnosing kidney disease, renal biopsy, in cancer patients with renal manifestation. METHODS: Patients who received renal biopsy from July 2015 to July 2019 were analyzed. Primary outcomes included end-stage renal disease (ESRD), mortality, and catastrophic outcome defined as either ESRD or mortality. A Cox proportional hazards model and Kaplan-Meier technique were used to assess the association with outcome measurements and survival analyses. Immunosuppression after renal biopsy and response to the treatment were evaluated. RESULTS: Among the 77 patients, the median age was 66 years (interquartile range [IQR] 59-73 years) and 46 (59.7%) were male. At the time of renal biopsy, 57 patients (74%) had various degrees of renal insufficiency. Tubulointerstitial damage score, quantified by renal pathology, were associated with higher hazards of ESRD (hazard ratio [HR], 1.77; 95% confidence interval [95% CI], 1.20 to 2.61; P = 0.004) and catastrophic outcome (HR, 1.30; 95% CI, 0.99 to 1.70; P = 0.058). The response rate to immunosuppression was lower in those diagnosed with tubulointerstitial nephritis (1 of 4 patients, 25%) than those with glomerulopathy (10 of 20 patients, 50%). CONCLUSION: Renal biopsy may improve diagnostic accuracy and assist in treatment guidance of cancer patients with renal manifestation. Renal biopsy should be encouraged with clinical indication. Collaboration between oncologists and nephrologists is of paramount importance to provide more comprehensive care for caner patients.

Adjuvant versus Neoadjuvant Immunotherapy for Hepatocellular Carcinoma: Clinical and Immunologic Perspectives.

Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advancement in systemic therapy also provides new opportunities of reducing recurrence after curative therapy through adjuvant therapy or improving resectability through neoadjuvant therapy. Improved recurrence-free survival by adjuvant or neoadjuvant ICI-based therapy has been reported in other cancer types. In this article, developments of systemic therapy in adjuvant and neoadjuvant settings for HCC were reviewed. The design of adjuvant and neoadjuvant therapy using ICI-based regimens and potential challenges of trial conduct and result analysis was discussed. Results from these trials may extend the therapeutic benefit of ICI-based systemic therapy beyond the advanced-stage disease and lead to a new era of multidisciplinary management for HCC.

The unique characteristic in peripheral immune cells in patients with advanced hepatocellular carcinoma.

BACKGROUND/PURPOSE: Recent progress in cancer immunology provides more insight in immune evasion of cancer cells. Cancer cells may achieve immune evasion through several ways including ineffective antigen presentation, T cell checkpoint utilization, immunosuppressive cytokines secretion and immunosuppressive cells recruitment. However, few literatures mentioned about the change of peripheral blood immune cells in advanced hepatocellular carcinoma (HCC) patients. To answer this question, we initiated a pilot study through detailed flow cytometry. METHODS: We enrolled patients with advanced HCC patients who had informed consent to the collection of their peripheral blood. We also recruited healthy individuals for the control group. Using flow cytometry, we analyzed lymphocyte subclasses and the PD-1 or PD-L1 positivity of immune cells in peripheral blood from HCC patients and healthy individuals. RESULTS: Twenty-four HCC patients were enrolled and twenty healthy individuals were enrolled. Most of the HCC patients were HBV carrier (58.3%), and the mean age was 61 years old. Among 55 immune cell parameters we examined in peripheral blood, 16 were significantly different between advanced HCC patients and healthy individuals by univariate analysis. Multivariate analysis was then conducted by fitting logistic regression model and showed that CD69-CD25- Naïve CD4αßT cell percentage and dendritic cell percentage can reasonably predict the advanced HCC status from peripheral blood. By our regression model, the adjusted generalized R2 = 0.918 and the estimated area under the Receiver Operating Characteristic (ROC) curve was 0.99. CONCLUSION: CD69-CD25- Naïve CD4αßT cell percentage and dendritic cell percentage in peripheral blood are highly correlated with the advanced HCC status. The change may result from immune evasion initiated by hepatocellular carcinoma cells and further investigation is warranted. Validation study is ongoing and this mechanism may be utilized to treat advanced HCC patient in the future.

Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study.

BACKGROUND: Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs. METHODS: Patients with PD-L1-positive, locally advanced or metastatic carcinoid or well-differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint. RESULTS: Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1-positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated.

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma.

Immune checkpoint inhibitor (ICI) therapy targeting anti-programmed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is the backbone of numerous combination regimens aimed at improving the objective response and survival of patients with hepatocellular carcinoma (HCC). Clinical trials of immuno-oncology regimens in other cancer types have shed light on issues of study design, including how to choose candidate regimens based on early-phase trial results, statistical considerations in trials with multiple primary endpoints, and the importance of predictive biomarkers. In this review, the updated data from early-phase trials of combination immunotherapy for HCC are summarised. Since the most extensively tested combination regimens for advanced HCC comprise anti-PD-1/anti-PD-L1 agents plus antiangiogenic agents, the relative benefit and antitumor mechanism of antiangiogenic multikinase inhibitors versus specific VEGF/VEGFR inhibitors are discussed. Other critical issues in the development of combination immunotherapy, including optimal management of immune-related adverse events and the value of ICI therapy in combination with locoregional treatment for HCC, are also explored.

Safety and Preliminary Efficacy of Ramucirumab in Combination with FOLFOX4 in Patients with Advanced Hepatocellular Carcinoma: A Nonrandomized, Open-Label, Phase Ib Study.

LESSONS LEARNED: The combination of ramucirumab (8 mg/kg intravenous, day 1 every 2 weeks) and FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC) was not sufficiently tolerated. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with HCC. Dose modification and patient selection should be considered for the future development of ramucirumab plus FOLFOX chemotherapy for advanced HCC. BACKGROUND: The objective of this study was to investigate the safety, preliminary efficacy, pharmacokinetics, and immunogenicity of ramucirumab plus FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients received ramucirumab (8 mg/kg) intravenously (IV) on day 1, followed by FOLFOX4 (oxaliplatin 85 mg/m2 IV on day 1, folinic acid 200 mg/m2 IV, bolus fluorouracil [5-FU] 400 mg/m2 , and a continuous infusion of 5-FU 600 mg/m2 over 22 hours, on days 1 and 2) every 2 weeks. The primary endpoint was to assess the safety and tolerability of the combination therapy. RESULTS: Eight patients (6 men, 2 women) were treated; all eight patients experienced at least one treatment-emergent adverse event (TEAE) of grade ≥3. Dose-limiting toxicities occurred in three patients (37.5%): hepatic hemorrhage (grade 4), blood bilirubin increased (grade 3), and febrile neutropenia (grade 3). Two patients discontinued study because of hepatic hemorrhage (grade 4) and blood bilirubin increase (grade 3). Six deaths occurred due to progressive disease, and no deaths due to TEAEs. CONCLUSION: There were no unexpected safety findings with ramucirumab plus FOLFOX4 based on the known safety and toxicity of this regimen. The combination was not sufficiently tolerated in patients with advanced HCC at the specified dose and schedule.

A Multicenter Phase II Study of Second-Line Axitinib for Patients with Advanced Hepatocellular Carcinoma Failing First-Line Sorafenib Monotherapy.

LESSONS LEARNED: For patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers. BACKGROUND: Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC. METHODS: Patients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control. RESULTS: From April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib. CONCLUSION: Second-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy.

An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy of TLC388 and Genomic Analysis for Poorly Differentiated Neuroendocrine Carcinomas.

BACKGROUND: The discovery of effective therapeutic options for treating metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy remains elusive. This study analyzed the efficacy of TLC388 (Lipotecan) Hydrochloride, a novel camptothecin analog, for pretreated patients with metastatic NEC. METHODS: This single-arm, two-stage, phase II clinical trial was conducted at four community and academic centers in Taiwan. Patients aged 20 years or older with confirmed metastatic NEC and who had received prior systemic therapy with etoposide plus cisplatin were enrolled between July 2015 and May 2018. Patients received 40 mg/m2 of TLC388 intravenously on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Gene mutations were analyzed by next-generation sequencing. RESULTS: Twenty-three patients with a median age of 61 (range, 44-73) years, 18 of whom were men (78%), were enrolled. Patients received a median of 2 (range, 0-6) treatment cycles. Among 20 evaluable patients, 3 patients exhibited stable disease and no patient experienced a complete or partial remission, resulting in a disease control rate of 15%. Median progression-free survival was 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival was 4.3 (95% CI, 1.7-15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%). The most frequent mutated genes in 35 patients with NEC were ARSA, DPYD, HEXB, BRCA1, HPD, MYBPC3, BBS2, IL7R, HSD17B4, and PRODH. CONCLUSION: TLC388 demonstrates limited antitumor activity in metastatic NEC. ClinicalTrials.gov identifier: NCT02457273. IMPLICATIONS FOR PRACTICE: Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive. Currently, effective therapeutic options for treating metastatic poorly differentiated NECs beyond platinum-based chemotherapy remain elusive. In this single-arm, multicenter, phase II study, 23 patients with NEC were enrolled and received TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog. The results demonstrated the disease control rate of 15%, the median progression-free survival of 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival of 4.3 (95% CI, 1.7-15) months. Most importantly, several novel genetic mutations and pathways were identified. These results offer the opportunity to develop future treatment strategies in this rare cancer.

Multicentre, phase II study of gemcitabine and S-1 in patients with advanced biliary tract cancer: TG1308 study.

BACKGROUND & AIMS: Gemcitabine plus cisplatin (GC) remains the standard, frontline therapy for advanced biliary tract cancer (ABTC). The JCOG1113 study suggested that gemcitabine plus S-1 (GS) had noninferior median overall survival and comparable incidence of significant neutropenia as compared to GC treatments. This study evaluates the efficacy and safety of a modified GS regimen. METHODS: The eligible patients with chemonaive, measurable ABTC received 800 mg/m2 of gemcitabine on day 1 and 80 mg/m2 /day of S-1 (80/100/120 mg for patients with body surface <1.25/ ≥1.25 and <1.5/ ≥1.5 m2 respectively). The primary endpoint was the 12-week disease control rate (12-week DCR: objective response and stable disease ≥ 12 weeks). Per the p0 = 40% and p1 = 60% (α/ß = 0.05/0.2) assumption, Simon's optimal two-stage design indicated 12-week DCR in ≥ 24 of 46 evaluable patients for significant activity. Tumour responses were assessed every 6 weeks. RESULTS: Fifty-one patients were enrolled and most of them had intrahepatic cholangiocarcinoma (64.7%), metastatic disease (84.3%) and disease-related symptoms (82.4%). On intention-to-treat analysis, 11 (21.6%) patients showed partial response, whereas 21 (41.2%) showed stable disease ≥ 12 weeks. The progression-free and overall survival were 5.4 months (95% confidence interval [CI]: 3.5-7.0), and 12.7 months (95% CI: 6.1-15.6) respectively. The study met its primary endpoint with a 12-week DCR of 69.6% in 46 evaluable patients. Grade 3/4 treatment-related adverse eventsoccurred in < 6% of patients of all individual items. The mean dose intensities of S-1 and gemcitabine were 87.1% and 92.5% respectively. CONCLUSIONS: Modified GS showed moderate efficacy with a favourable safety profile in ABTC patients, thus mandating further assessment. ClinicalTrials.gov number: NCT02425137.

Low-dose nab-paclitaxel-based combination chemotherapy in heavily pretreated pancreatic cancer patients.

BACKGROUND: Heavily pretreated pancreatic cancer patients have a grave prognosis. In this case series study, we evaluated the safety and efficacy of nab-paclitaxel-based chemotherapy for such patients. METHODS: The data of pancreatic adenocarcinoma patients (n = 40) treated with nab-paclitaxel after the failure of gemcitabine or fluoropyrimidines at our institution in 2013-2015 were reviewed. RESULTS: The median number of prior chemotherapy regimens was two (range, 1-6). Eighteen patients had an Eastern Cooperative Oncology Group performance status of ≥2. The regimens comprised nab-paclitaxel combined with the following drugs: gemcitabine (n = 28), gemcitabine and fluoropyrimidine (n = 3), platinum and fluoropyrimidine (n = 4), fluoropyrimidine (n = 4), and irinotecan and fluoropyrimidine (n = 1). The median dose of nab-paclitaxel was 63 (range, 51-72) mg/m2/dose, with the schedule of D1/15, D1/8, and D1/8/15 followed in 23, 14, and 3 patients, respectively. The median overall survival was 5.1 (95% CI, 4.6-5.7) months. Among 32 evaluable patients, two partial responses and six stable diseases were observed. The median progression-free survival was 2.6 (95% CI, 1.9-3.2) months. Grade 3/4 leucopenia or neutropenia was observed in three and two patients, respectively. Grade 3/4 anemia was observed in four patients. Other significant (grade 3 or more) nonhematological toxicities were not frequent, except for sepsis/infection (n = 7). However, more severe anemia or sepsis/infection was significantly associated with disease control. CONCLUSION: In heavily pretreated pancreatic adenocarcinoma patients, low-dose nab-paclitaxel-based chemotherapy was fairly tolerable with modest efficacy.

Cost-effectiveness of preventing hepatitis B virus reactivation in patients with lymphoma and resolved HBV infection.

BACKGROUND/PURPOSE: Hepatitis B virus (HBV) reactivation may occur in >10% of patients with lymphoma and resolved HBV infection who undergo rituximab-containing chemotherapy. Preventive strategies may have marked impact on resource allocation in HBV endemic areas. This study aims to compare the cost-effectiveness between prophylactic antiviral therapy and HBV DNA monitoring for the prevention of HBV-related complications. METHODS: Data sources are studies of HBV-related events and survival for patients with lymphoma and resolved HBV infection published since 2006. Decision tree analysis was used to compare the incremental cost-effectiveness ratio (ICER) of preventing HBV-related death or liver decompensation for patients who undergo first-line rituximab-containing chemotherapy. Sensitivity analysis was performed to examine the impact of the preventive efficacy, the duration of prophylactic antiviral therapy, and the cost of different interventions. The direct medical cost was derived from the database of the NHI Administration, Taiwan. The time frame of our analysis was set to 3 years after the completion of chemotherapy. RESULTS: The median ICER of prophylactic antiviral therapy, according to current practice guidelines, ranged between USD 150,000 and 250,000 if we apply the guidelines generally. When a long-course (12 months after completion of chemotherapy according to clinical guidelines) prophylactic therapy was assumed, Option A was cheaper and more effective only in the anti-HBs-negative subgroup (median ICER US$149,932 vs. US$161,526, p = 0.013). CONCLUSION: Identification of anti-HBs-negative subgroups is critical to improve the cost-effectiveness of prophylactic antiviral therapy in lymphoma patients with resolved HBV infection.