Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Clinical characteristics and genetic HLA marker for patients with oxaliplatin-induced adverse drug reactions.

BACKGROUND: Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. METHODS: A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016-2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019-2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. RESULTS: The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4-8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3-63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P < 0.05). Only four patients (8.5%) with oxaliplatin-induced ADRs were positive for oxaliplatin-specific IgE. CONCLUSIONS: This study found that 26.0% of patients with oxaliplatin-induced ADRs could not undergo oxaliplatin rechallenge. HLA-DRB∗12:01 is regarded as a genetic marker for oxaliplatin-induced hypersensitivity.

Bevacizumab and atezolizumab as first-line therapy for advanced hepatocellular carcinoma: A Taiwanese subgroup analysis on efficacy and safety.

BACKGROUND: The combination of bevacizumab and atezolizumab has been established as a standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). We examined the treatment outcomes of patients in Taiwan who received the combination in 2 pivotal clinical trials. METHODS: All patients who resided in Taiwan, were enrolled in the IMbrave150 and GO30140 studies, and received bevacizumab and atezolizumab as the first-line systemic therapy for unresectable HCC were included. We extracted and pooled anonymous raw data from the study records. RESULTS: We enrolled 40 patients, with the median age of 62.5 years; 36 (90%) had Barcelona Clinic Liver Cancer stage C disease. The response rate was 37.5%, including 3 (7.5%) complete responses. The disease control rate was 85%. The median duration of response was 21.4 months (95% confidence interval [CI], 16.6-not estimable). The median progression-free survival (PFS) and overall survival (OS) were 8.6 (95% CI, 5.6-18.6) and 24.9 months (95% CI, 14.2-not estimable), respectively. The most common adverse events of all grades were proteinuria (50%) and hypertension (37.5%), the median onset of which were 157 and 127 days, respectively. Bevacizumab and atezolizumab treatment had to be interrupted in 20 (50%) and 13 (32.5%) patients, respectively. Among patients whose treatment duration was ≥6 months, 50% of them had to skip bevacizumab, but no signal of poorer PFS or OS was observed. CONCLUSION: In Taiwanese patients with advanced HCC, the efficacy and safety outcomes of bevacizumab and atezolizumab treatment were generally consistent with the global intent-to-treat populations.

Assessment of pegylated arginine deiminase and modified FOLFOX6 in patients with advanced hepatocellular carcinoma: Results of an international, single-arm, phase 2 study.

BACKGROUND: Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models. METHODS: This was a global, multicenter, open-label, single-arm, phase 2 trial of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child-Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression-free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 36 mg/m2 . RESULTS: In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30-85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%-15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression-free survival was 3.8 months (95% CI, 1.8-6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6-20.9 months). The most common grade ≥3 treatment-related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%). CONCLUSIONS: Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued. LAY SUMMARY: Arginine is an important nutrient for hepatocellular carcinoma (HCC). The depletion of arginine with pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial. To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI-PEG 20 and FOLFOX in the treatment of patients with refractory HCC. The study showed limited activity of ADI-PEG 20 and FOLFOX in advanced HCC and was stopped early.

Ramucirumab in patients with previously treated advanced hepatocellular carcinoma: Impact of liver disease aetiology.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying aetiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease aetiology and baseline serum viral load. METHODS: Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N = 542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by aetiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pre-treatment serum HBV DNA and HCV RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study). RESULTS: Baseline characteristics were generally balanced between arms in each subgroup (HBV: N = 225, HCV: N = 127, Other: N = 190). No significant difference in treatment effect by aetiology subgroup was detected (OS interaction P-value = .23). Median OS (ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74, 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82, 95% CI 0.55-1.23) for HCV and 8.5 versus 5.4 (HR 0.56, 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function and liver-specific adverse events. CONCLUSIONS: Ramucirumab improved survival across aetiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.

Real-world evidence of the safety and effectiveness of regorafenib in Taiwanese patients with metastatic colorectal cancer: CORRELATE Taiwan.

BACKGROUND/PURPOSE: This analysis reports safety and effectiveness data from the Taiwanese cohort of the CORRELATE study. METHODS: CORRELATE was a prospective, observational study to assess the safety and effectiveness of regorafenib for the treatment of metastatic colorectal cancer (CRC) in real-world clinical practice that was conducted in 13 different countries in Asia, Europe and Latin America. The primary endpoint of the study was incidence of all treatment-emergent AEs (TEAEs), and secondary endpoints included overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). RESULTS: The global study population (N = 1037) included 128 Taiwanese patients with a median age of 64 years, median weight of 62.02 kg and 66.41% were male. Reduced initiating doses of regorafenib and dose interruptions were common in Taiwanese patients (71.87% and 50.00%, respectively). The safety profile of regorafenib was consistent with that seen in Asian patients in the clinical development trials, including the CORRECT and CONCUR studies, with hand-foot-skin reactions (HFSR) of any grade occurring in 33.59% of patients. Median OS was 11.64 months in the Taiwanese patients (95% confidence interval [CI], 8.36-13.82) and median PFS was 2.17 months (95% CI, 1.97-2.89). CONCLUSION: The safety and effectiveness of regorafenib in this real-world study was generally consistent with the known efficacy and safety profile in Asian patients in clinical trials. TRIAL REGISTRATION: NCT02042144.

Postdiagnostic metformin use and survival of patients with colorectal cancer: A Nationwide cohort study.

Epidemiological evidence for the association between postdiagnostic metformin use and survival in patients with colorectal cancer (CRC) remains limited. Using the Taiwan Cancer Registry database, a cohort of 16,676 diabetic patients newly diagnosed with CRC from January 1, 2004 through December 31, 2014, followed until December 31, 2016, was identified. Postdiagnostic use of metformin (two or more prescriptions after CRC diagnosis) was defined as a time-dependent covariate with 6-month lag. Multivariate Cox regression model and stabilized inverse probability of treatment weighting (IPTW) were used to estimate adjusted effects of metformin on all-cause mortality and CRC-specific mortality during follow-up. A number of 11,438 (69%) received metformin after CRC diagnosis. Overall, 7,393 deaths, including 4,845 CRC-specific deaths, were observed during 64,322 person-years of follow-up. After adjustment for demographic and clinical covariates, metformin users had lower all-cause mortality than did nonusers (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.40-0.44) and lower CRC-specific mortality (HR, 0.41; 95% CI, 0.39-0.44). Similar but somewhat attenuated effects were observed after stabilized IPTW (HR for all-cause mortality, 0.56; 95% CI, 0.53-0.59; HR for CRC-specific mortality, 0.58; 95% CI, 0.55-0.61). Similar results were observed in stratified analyses of 2,112 patients with no prediagnostic metformin use and 14,564 patients with prediagnostic metformin use. Findings for both outcomes were consistent in multiple sensitivity analyses. Use of postdiagnostic metformin was associated with significantly lower all-cause mortality and CRC-specific mortality, regardless of prior metformin use. These findings support the use of metformin as an adjunct to standard care of diabetic patients with CRC.

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.

Changes in serum α-fetoprotein level predicts treatment response and survival in hepatocellular carcinoma patients and literature review.

BACKGROUND: Oxaliplatin-based chemotherapy is an alternative systemic treatment for patients with metastatic hepatocellular carcinoma (HCC) who were refractory or intolerant to sorafenib. To date, there have been no biomarkers reported to monitor the therapeutic efficacy and to predict the outcomes of HCC patients receiving oxaliplatin-based chemotherapy. METHODS: Eighty-one HCC patients with elevated baseline α-fetoprotein (AFP) levels and extrahepatic spreading who received oxaliplatin-based chemotherapy between 2012 and 2014 were retrospectively enrolled in this study. Two AFP tests were performed, at baseline and 2-4 weeks after the initiation of chemotherapy. The change in AFP levels was calculated for survival analysis. RESULTS: In the AFP decline group (decreased compared to baseline), the median progression-free survival (PFS) and overall survival (OS) were 7.0 months and 12.3 months, respectively. In the AFP nondecline group, the median PFS and OS were 2.3 months and 3.0 months, respectively. The difference in OS between the two groups was significant (p < 0.005). In the multivariate analysis for disease progression, the best response to chemotherapy and AFP decline were independent factors, with p values of 0.004 and 0.009, respectively. In the multivariate analysis for OS, the baseline Child-Pugh score, best response to chemotherapy, and AFP decline were independent prognostic factors, with p values of 0.01, 0.001, and 0.008, respectively. Additionally, the unit change in AFP level was predictive of PFS and OS with p values of 0.007 and 0.001, respectively. CONCLUSION: The change in AFP levels 2-4 weeks after initiating oxaliplatin-based chemotherapy is useful to predict treatment response and survival.

The effect of abdominal massage in reducing malignant ascites symptoms.

As many as 50% of end-stage cancer patients will develop ascites and associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, loss of appetite, dyspnea, perceived abdominal bloating, and immobility. Abdominal massage may stimulate lymph return to the venous system and reduce ascites-related symptoms. The purpose of this study was to test the effect of abdominal massage in reducing these symptoms and reducing ascites itself as reflected in body weight. For a randomized controlled design using repeated measures, a sample of 80 patients with malignant ascites was recruited from gastroenterology and oncology units of a medical center in northern Taiwan and randomly assigned to the intervention or the control group. A 15-minute gentle abdominal massage, using straight rubbing, point rubbing, and kneading, was administered twice daily for 3 days. The control group received a twice-daily 15-minute social interaction contact with the same nurse. Symptoms and body weight were measured in the morning for 4 consecutive days from pre- to post-test. In generalized estimation equation modeling, a significant group-by-time interaction on depression, anxiety, poor wellbeing, and perceived abdominal bloating, indicated that abdominal massage improved these four symptoms, with the greatest effect on perceived bloating. The intervention had no effect on pain, tiredness, nausea, drowsiness, poor appetite, shortness of breath, mobility limitation, or body weight. Abdominal massage appears useful for managing selected symptoms of malignant ascites.

Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer.

BACKGROUND: The leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is an adult intestinal stem cell marker frequently detected in human colorectal cancers (CRCs). However, the value of Lgr5 level in CRC prognosis and treatment prediction has not been well characterized. METHODS: We examined Lgr5 expression in 384 formalin-fixed paraffin-embedded CRC specimens from 296 CRC patients, including 64 patients treated with 5-fluorouracil (5-FU)-based chemotherapy. The effects of Lgr5 on cell proliferation, survival, and drug resistance were examined in cultured CRC cells. RESULTS: Elevated expression of Lgr5 was observed in CRC tissues, and Lgr5 protein levels were significantly correlated with an advanced American Joint Committee on Cancer stage (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), and distant metastasis (P < 0.001). High expression levels of Lgr5 were significantly associated with shorter disease-free survival (P < 0.001) and shorter cancer-specific survival (P = 0.007) in CRC patients. Among the chemotherapy-treated subgroups, patients with low Lgr5 level showed a better response rate (65 %) than patients with high Lgr5 level (37 %) towards 5-FU-based treatment (P = 0.025). In cultured CRC cell lines, knocking down Lgr5 suppressed cell proliferation and colony formation ability, while it enhanced apoptosis and rendered cells more sensitive to chemotherapeutic agents. In contrast, overexpression of Lgr5 increased cell proliferation and enhanced chemoresistance. CONCLUSION: These results suggest that elevated Lgr5 level is associated with CRC progression and treatment response and has the potential to serve as a therapeutic target in CRC patients.

Zinc supplementation decreased incidence of grade ≥2 hand-foot skin reaction induced by regorafenib: A phase II randomized clinical trial.

To the editor: Hand-foot skin reaction (HFSR), characterized by skin abnormalities on palmoplantar surfaces, has an overall incidence of about 35% upon vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) treatment.1 Zinc, which plays a role in maintaining skin health, may be implicated in the pathogenesis of HFSR.2 Zinc deficiency has been shown to associate with dermatological toxicities of epidermal growth factor receptor (EGFR)-TKI.3, 4 Regorafenib, an oral multi-kinase inhibitor targeting VEGFR 1-3, PDGFR, cKIT, BRAF, and RET1, is approved for the treatment of metastatic colorectal cancer (mCRC) but commonly causes HFSR.5 This phase II randomized trial aimed to investigate whether zinc supplementation can reduce the severity of HFSR induced by regorafenib within the first 8 weeks of treatment (NCT03898102).

Prospective, open-label, and observational study of cetuximab for metastatic colorectal carcinoma: The OPTIM1SE study.

AIM: The OPTIM1SE study observed long-term real-world outcomes of cetuximab-based infusional 5-fluorouracil (5-FU) regimens for first-line treatment of metastatic colorectal cancer (mCRC) across Asia-Pacific and Middle East regions, aiming to characterize their use, effectiveness, and safety in routine practice. METHODS: OPTIM1SE was a prospective, open-label, observational study. Patients with untreated KRAS wild-type mCRC and distant metastases were treated per locally approved labels and monitored for 3 years via electronic medical records. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). RESULTS: From November 19, 2013, to June 30, 2016, 520 patients were enrolled in 51 sites. Patients were mostly male (61.2%), with a mean age of 58.5 (±12.0) years; 420 patients received leucovorin, 5-FU, and irinotecan-based regimens and 94 received leucovorin, 5-FU, and oxaliplatin. The most common primary tumor site was the rectum (38.8%), with liver metastases (65.0%). ORR was 45.4% (95% CI, 41.1%-49.7%), including 26 patients (5.0%) with a complete response. Median PFS was 9.9 months (95% CI, 8.2-11.0); median OS (mOS) was 30.8 months (95% CI, 27.9-33.6). Higher mOS was associated with tumors of left compared with right-sided origin (hazard ratio, 0.69 [95% CI, 0.49-0.99]); higher ORR was also associated with liver metastases compared with all other metastases (55.4% vs. 40.2%). Adverse events were consistent with the known safety profile of cetuximab. CONCLUSION: Cetuximab-based 5-FU regimens were effective first-line treatments for mCRC in routine practice, particularly in patients with left-sided disease and liver metastases only.

Vandetanib in patients with inoperable hepatocellular carcinoma: a phase II, randomized, double-blind, placebo-controlled study.

BACKGROUND & AIMS: Inhibitors of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) have shown anti-tumor activities in advanced hepatocellular carcinoma (HCC). The present study evaluated the efficacy and safety of vandetanib, an oral inhibitor of both VEGFR and EGFR, in patients with unresectable advanced HCC. METHODS: Eligible patients were randomized 1:1:1 to receive vandetanib 300mg/day, vandetanib 100mg/day, or placebo. Upon disease progression, all patients had the option to receive open-label vandetanib 300mg/day. The primary objective was to evaluate tumor stabilization rate (complete response+partial response+stable disease ⩾4months). Secondary assessments included progression-free survival (PFS), overall survival (OS) and safety. Biomarker studies included circulating pro-angiogenic factors and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Sixty-seven patients were randomized to vandetanib 300mg (n=19), vandetanib 100mg (n=25) or placebo (n=23) groups. Twenty-nine patients entered open-label treatment. Vandetanib induced a significant increase in circulating VEGF and decrease in circulating VEGFR levels. In both vandetanib arms, tumor stabilization rate was not significantly different from placebo: 5.3% (vandetanib 300mg), 16.0% (vandetanib 100mg) and 8.7% (placebo). DCE-MRI did not detect significant vascular change after vandetanib treatment. Although trends of improved PFS and OS after vandetanib treatment were found, they were statistically insignificant. The most common adverse events were diarrhea and rash, whose incidence did not differ significantly between treatment groups. CONCLUSIONS: Vandetanib has limited clinical activity in HCC. The safety profile was consistent with previous studies.

Risk of cardiovascular disease among different fluoropyrimidine-based chemotherapy regimens as adjuvant treatment for resected colorectal cancer.

Background: Patients with colorectal cancer (CRC) are more likely to develop cardiovascular disease (CVD) than those without cancer. Little is known regarding their CV risk after operative chemotherapy. We aimed to compare the risk of CV disease among different fluoropyrimidine derivatives. Methods: We assembled a nationwide cohort of patients with newly diagnosed CRC between 2004 and 2015 who received fluoropyrimidine-based adjuvant chemotherapy for resected CRC by linking the Taiwan Cancer Registry (TCR), National Health Insurance Research Database (NHIRD), and Taiwan Death Registry (TDR). All eligible patients were followed from CRC diagnosis (index date) until a CV event, death, loss to follow-up, or December 31st 2018, whichever came first. CV outcomes included acute myocardial infarction (AMI), life-threatening arrhythmia (LTA), congestive heart failure (CHF), and ischemic stroke (IS). We used stabilized inverse probability of treatment weighting using propensity score (SIPTW) to balance all covariates among the three chemotherapy groups: tegafur-uracil (UFT), non-UFT, and mixed. In addition, survival analysis was conducted to examine the association between study outcomes and chemotherapy groups. Results: From 2004 to 2015, 10,615 (32.8%) patients received UFT alone, 14,511 (44.8%) patients received non-UFT, and 7,224 (22.3%) patients received mixed chemotherapy. After SIPTW, the UFT group had significantly lower all-cause mortality and cancer-related death rates than the other two chemotherapy groups. However, the UFT group had significantly higher rates of cancer death, ischemic stroke, and heart failure than those of the other two chemotherapy groups. The UFT group also had a significantly higher AMI rate than the mixed group. There was no significant difference in LTA among the three groups. Similar findings were observed in the subgroup analysis (stage II and age <70 years, stage II and age ≥70 years, stage III and age <70 years, stage III and age ≥70 years) as the overall population was observed. Conclusion: Higher heart failure and ischemic stroke rates were found in the UFT group than in the other two chemotherapy groups, especially those with stage III CRC and ≥70 years of age. Careful monitoring of this subset of patients when prescribing UFT is warranted.

Real-World Effectiveness of Adjuvant Oxaliplatin Chemotherapy in Stage III Colon Cancer: A Controlled Interrupted Time Series Analysis.

Background: The real-world effectiveness of oxaliplatin in stage III colon cancer has not been determined in a large-scale population. We aimed to assess the real-world impact of adjuvant oxaliplatin treatment on the survival of these patients. Methods: Based on Taiwan cancer registry, we evaluated 17,801 patients with resected stage III colon cancer, including 14,168 patients receiving adjuvant chemotherapy and 3,633 not receiving adjuvant chemotherapy as the control group between 2004 and 2014. We used the controlled interrupted time-series analysis to assess the three-year disease-free survival and five-year overall survival rates before (2004-2008) and after (2009-2014) the addition of oxaliplatin. Results: The introduction of oxaliplatin was associated with no significant improvement in the slopes (per half-year) of the three-year disease-free survival rate (0.2%, 95% CI: -1.7∼2.2%) and five-year overall survival rate (0.6%, 95% CI: -1.8∼3%). The patients receiving oxaliplatin-based chemotherapy also showed no significant increase in the slopes (per half-year) of the three-year disease-free survival rate (0.6%, 95% CI: -1.4∼2.6%) and five-year overall survival rate (1%, 95% CI: -1.5∼3.5%). The nonsignificant results were consistent across subgroup analyses of age (<70 vs. ≥70 years), recurrence risk (T1-3 or N1 vs. T4 or N2), and cycle of oxaliplatin use (≤6 vs. >6). However, oxaliplatin-based chemotherapy significantly increased the slope (per half-year) of the five-year OS (2%, 95% CI: 0.2∼3.8%) for patients in the high-risk group (T4 or N2). The present results were robust in several sensitivity analyses. Conclusion: Among real-world patients with stage III colon cancer, the introduction of oxaliplatin does not yield a significant improvement in survival. Future work should identify the subpopulation(s) of patients who benefit significantly from the addition of oxaliplatin.

Preference criteria for regorafenib in treating refractory metastatic colorectal cancer are the small tumor burden, slow growth and poor/scanty spread.

Given the unclear preference criteria for regorafenib in treating refractory metastatic colorectal cancer (mCRC), this study aimed to construct an algorithm in selecting right patients for regorafenib. This was a multicenter retrospective cohort study. Patients with pathology confirmed mCRC and administered with regorafenib for > 3 weeks were enrolled. Patients with good response were defined to have progression-free survival (PFS) of ≥ 4 months. The Kaplan-Meier plot was used to analyze survival. A Cox proportional hazards model was used to analyze univariate and multivariate prognostic factors and was visualized using forest plot. A clustering heatmap was used to classify patients according to responses. The decision tree and nomogram were used to construct the approaching algorithm. A total of 613 patients was analyzed. The median PFS and overall survival (OS) were 2.7 and 10.6 months, respectively. The partial response and stable disease rate are 2.4% and 36.4%. The interval between metastasis (M1) and regorafenib, metastatic status (number, liver, and brain), and CEA level were independent prognostics factors of PFS that classifies patients into three groups: good, bad and modest-1/modest-2 group with PFS > = 4 months rates of 51%, 20%, 39% and 30%, respectively. Results were used to develop the decision tree and nomogram for approaching patients indicated with regorafenib. The preference criteria for regorafenib in treating patients with refractory mCRC are small tumor burden (CEA), slow growth (interval between metastasis and regorafenib) and poor/scanty spread (metastatic status: number and sites of metastasis): The 3S rules.TRIAL registration ClinicalTrials.gov Identifier: NCT03829852; Date of first registration (February 11, 2019).

Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.

BACKGROUND: Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. METHODS: Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. FINDINGS: 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. INTERPRETATION: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.