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Aim: The survival benefit of using a non‐cross resistant second‐line chemotherapy in the third‐line setting in metastatic gastroesophageal cancer is unproven. We evaluated the utility of third‐line chemotherapy in patients treated at a single institution. Methods: Between 2010 and 2014, efficacy and toxicity data of patients who received three or more lines of systemic therapies for metastatic gastroesophageal adenocarcinoma at the National Cancer Centre Singapore was retrospectively analyzed. Results: Thirty‐two (6%) patients received three or more lines of chemotherapy. The median age and ECOG performance status were 59 years (36–82) and 1 (0–2), respectively. Majority of patients (88%) had tumor located in the stomach and 13 patients (41%) had diffuse histology or poorly cohesive or signet ring cells. Four (12%) patients had HER2‐positive disease. Prior therapy was platinum (100%), fluoropyrimidine (97%), taxane (63%), irinotecan (28%), anthracycline (13%) and ramucirumab (3%). Third‐line therapy consisted of 24 (75%) monotherapy, 6 (19%) doublet, 1 (3%) triplet chemotherapy and 1 (3%) clinical trial. Monotherapy irinotecan (44%) was most common, followed by docetaxel (19%) and paclitaxel (9%). Of 22 patients evaluable for response, there was 1 (5%) partial response, 9 (41%) stable disease. Median overall survival was 18.3 weeks (4.3–65.1). Of 30 patients evaluable for toxicities, 17 (57%) experienced at least one grade 3 or 4 toxicities. Conclusion: The benefit of using non‐cross resistant second‐line regimens as third‐line chemotherapy was small with moderate toxicity. Newer agents such as nivolumab or TAS‐102 or clinical trial may be preferred. [ABSTRACT FROM AUTHOR]

Introduction: Combination therapy with immune checkpoint inhibitor (ICI) and antivascular endothelial growth factor (anti‐VEGF) is currently the first line treatment for advanced hepatocellular carcinoma (aHCC). However, there are many patients who may not be able to receive combination therapy due to underlying comorbidities or resource limitations. For these patients, systemic treatment options include single agent tyrosine kinase inhibitors (TKIs) or ICI monotherapy. However, whether an optimal sequence of systemic therapy exists remains unknown. We aim to explore the impact of sequencing of TKI and ICI therapy in terms of response rates and to examine the safety of their use in sequential order. Methods: Patients with aHCC treated with both ICI and TKI between December 30, 2013 and June 13, 2018 were retrospectively identified. Patients were classified into two groups: those who received TKI in the first‐line (TKI1), followed by ICI (ICI2) and those who received ICI (ICI1) in the first‐line followed by TKI (TKI2). The primary objective of the study was to identify differences in objective response rate (ORR) and disease control rate (DCR), as evaluated based on response evaluation criteria in solid tumor v1.1 for TKI1, TKI2, ICI1, and ICI2. Secondary objectives included comparison of progression free survival (PFS) for each line of therapy, overall survival (OS) and adverse events (AEs). Results: Twenty‐seven and 23 patients were classified into group 1 and 2, respectively. Objective response rates of TKI1 and TKI2 were 3.8% and 17.6%, respectively (p =.28); DCR to TKI1 versus TKI2 was 23.1% versus 35.3% (p =.49). ORRs of ICI1 and ICI2 were 8.7% and 14.3%, respectively (p =.66); DCR to ICI2 versus ICI1 was 56.5% versus 42.9% (p =.37). Median PFS was not significant between TKI1 and TKI2 (PFS 3.06 versus 1.61 months, p =.097) as well as between ICI2 and ICI1 (PFS 1.84 versus 2.37 month, p =.32). Median OS was also not significantly different between both groups (OS 20.63 versus 13.93 months, p =.20) on univariable and multivariable analysis (OS adjusted hazard ratio [HR] 2.07, 95% CI.83–5.18, p =.118). The proportion of patients who experienced adverse events of any grade was similar in both groups (TKI1 59.3% versus TKI2 52.2%; ICI1 78.3% versus ICI2 70.4%). Conclusion: Our study suggests that the sequence of TKI versus ICI therapy in patients with aHCC may not matter, given similar efficacy and toxicity profile when either agent is received in the first or second‐line setting. This finding is of value in the real‐world setting, where patients may be frail or have comorbidities that render them unable to tolerate combination therapy (ICI and TKI/anti‐VEGF). For these patients, sequential exposure to both classes of drugs (ICI and TKI) may be a suitable option. [ABSTRACT FROM AUTHOR]

The occurrence of neurotrophic tyrosine receptor kinase (NTRK) gene fusions in a wide range of tumor types presents an attractive opportunity for using a tropomyosin receptor kinase (TRK) inhibitor as cancer therapy. Recent clinical studies have demonstrated highly efficacious outcomes associated with the use of TRK inhibitors, such as larotrectinib and entrectinib in NTRK fusion‐bearing cancers, in both adult and pediatric populations. While NTRK gene fusions are commonly found in some uncommon adult and pediatric malignancies, they are also found, albeit rarely, in a wide range of more common malignancies. The potential value of testing for NTRK gene fusions in practically all advanced malignancies is underpinned by the remarkable therapeutic outcomes that TRK inhibitors offer. This requirement presents practical and financial challenges in real‐world oncological practice. Furthermore, different testing platforms exist to detect NTRK gene fusions, each with its advantages and disadvantages. It is, therefore, imperative to develop strategies for NTRK gene fusion testing in an attempt to optimize the use of limited tissue specimen and financial resources, and to minimize the turnaround time. A multidisciplinary task force of Singapore medical experts in both public and private sectors was convened in late 2020 to propose testing algorithms for adult colorectal tumors, sarcomas, non‐small cell lung cancer, and pediatric cancers, with particular adaptation to the Singapore oncological practice. The recommendations presented here highlight the heterogeneity of NTRK‐fusion positive cancers, and emphasize the need to customize the testing methods to each tumor type to optimize the workflow. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) constitutes a major cause of cancer deaths worldwide. Recent improvements in both surgical techniques and adjuvant and neoadjuvant radiotherapy and chemotherapy approaches have increased the survival of patients with loco-regional disease. However most patients with GC have advanced disease either at diagnosis or at follow up. Despite recent advances in the treatment of advanced disease, these patients still have poor outcomes. An emerging understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. In this review we describe the current status of targeted therapies in the treatment of GC. These therapeutic strategies include epidermal growth factor receptor inhibitors, antiangiogenic agents, cell cycle inhibitors, apoptosis, promoters and matrix metalloproteinases inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitor (ICI) use in advanced hepatocellular carcinoma (HCC) is increasing. Real‐world data on efficacy and safety, however, are lacking. Methods: We conducted a retrospective review of all patients with advanced HCC seen at our center who received at least one dose of an ICI between May 2015 and June 2018. Data cutoff was December 31, 2018. Responses were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Results: Of 114 patients, 88.6% were male. Median age was 66 years, 96.5% had an Eastern Cooperative Oncology Group of 0–1. 62.3% received monotherapy ICI. 18.4% of patients had Child‐Pugh (CP) B disease on initiation of ICI, and 69.3% had an ALBI grade of 2. 54.4% were known to have chronic hepatitis B (HBV) or were previously infected, and 11.4% had hepatitis C. Baseline HBV viral load (VL) ranged from undetectable to 8 210 000 IU/mL. 35.1% received prior systemic treatment. 28.9% received prior sorafenib. Over a median follow‐up duration of 13.8 months (10.4–15.8), ORR was 18.4%, and DCR was 50.9%. Median progression‐free survival was 2.7 months (1.3–4.0), and median overall survival (OS) was 13.9 months (6.9–16.2). Thirty‐one patients (27.2%) received further systemic therapy after ICI discontinuation. On multivariable analyses, lower albumin level, higher bilirubin level, diuretic‐refractory ascites, and HBV‐associated HCC were associated with poorer OS. 69.3% of patients experienced adverse events (AE) of any grade, 14.9% of these being grade 3–4. No grade 5 AE were observed. Use of antiviral therapy was associated with a lower risk of grade 3 or above hepatic AEs (P = 0.048), whereas high baseline HBV VL was not associated with an increased risk of reactivation or hepatic AE. Discussion: We have demonstrated that the real‐world performance of ICIs in advanced HCC appears comparable to that observed in clinical trials for HCC patients with CP A cirrhosis. While prognosis of patients with advanced HCC and CP B cirrhosis remains poor even with ICI, usage of ICI is likely to be safe. Patients with HBV with a baseline HBV VL ≥100 IU/mL may receive ICI safely, especially if they are on antiviral treatment. [ABSTRACT FROM AUTHOR]

Next‐generation sequencing (NGS)‐based diagnostics have demonstrated clinical utility in predicting improved survival benefits with targeted treatment in certain cancer types, and positive cost–benefit in several healthcare systems. However, clinical adoption in Singapore remains low despite commercial availability of these diagnostics. This expert opinion review examines the key challenges to the clinical adoption of NGS‐based diagnostics in Singapore, provides recommendations on impactful initiatives to improve adoption, and also offers practical guidance on specific cancer types in which NGS‐based diagnostics are appropriate for use in Singapore. Limited patient affordability is one major challenge to clinical adoption of NGS‐based diagnostics, which could be improved by enabling patient access to more funds for specific cancer types with clear benefits. Expert opinion based on current evidence and clinical experience supports the upfront use of hotspot panels in advanced non–small cell lung cancer (NSCLC), metastatic colorectal cancer, advanced and recurrent ovarian cancer, and acute myeloid leukemia. Comprehensive genomic profiling could be considered for upfront use in select patients with NSCLC and ovarian cancer, or in refractory patients with the four cancer types. Wider adoption of NGS‐based diagnostics will improve the delivery of cancer care in Singapore and Asia‐Pacific, and thus lead to better patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Metastatic gastric cancer has a poor prognosis. We aim to study how clinical features and prognosis differs between different metastatic sites, and to identify prognostic factors for overall survival. Methods: We retrospectively reviewed patients with metastatic gastric adenocarcinoma managed at a tertiary referral cancer center over a 5‐year period. We divided our cohort into three groups based on the site(s) of metastasis at presentation—peritoneal metastasis only (P), distant metastasis only (D), and peritoneal and distant metastases (PD). Results: We studied 470 patients with 175 (37.2%), 193 (41.1%) and 102 (21.7%) patients in the P, D and PD groups, respectively. Patients with peritoneal disease (both P and PD) had higher proportions of patients experiencing chemotherapy disruption due to unplanned hospitalizations, which were also of a longer average duration. The P group had the longest overall median survival of 8.9 months compared to the PD and D groups with 7.4 and 5.5 months, respectively (P < 0.001). On multivariate Cox regression analysis, the presence of ≥1 metastatic site (hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.23–2.28; P  =  0.001) was significantly associated with increased overall mortality, whereas palliative systemic chemotherapy (HR 0.29; 95% CI, 0.22–0.37; P < 0.001) and palliative gastrectomy (HR 0.24; 95% CI, 0.15–0.39; P < 0.001) were significantly associated with decreased overall mortality. Conclusion: Metastatic gastric cancer represents a heterogeneous disease, with specific disease complications and treatment outcomes unique to different metastatic sites. We can consider novel multimodality therapies for patient subgroups with isolated metastatic disease and good prognostic factors in a bid to improve long‐term survival. [ABSTRACT FROM AUTHOR]

Aim To evaluate the safety and efficacy of the combination therapy of fluorouracil, leucovorin and irinotecan (FOLFIRI) and aflibercept in Asian patients with metastatic colorectal cancer (mCRC), who had progressed after oxaliplatin-based chemotherapy. Methods This is a retrospective analysis of 19 mCRC patients who received FOLFIRI and aflibercept (4 mg/kg intravenously) every 2 weeks via a Named Patient Program (supported by Sanofi Aventis) in Singapore. Treatment was administered until disease progression or unacceptable toxicities. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Efficacy and toxicities were summarized using descriptive statistics. Statistical analysis was performed using STATA 12.0 software. Results The majority (84%) of the patients were of chinese ethnicity. The median age was 59 years, with 63.2% of the patients having an Eastern Cooperative Oncology Group status of 1. Four patients (21.1%) achieved partial response and 8 patients (42.1%) achieved stable disease. After a median follow-up of 9.6 months [95% confidence interval (CI), 2.2-13.1 months], the median OS was 11.6 months (95% CI, 6.1 to not-estimable), and median PFS was 4.1 months (95% CI, 2.2-5.9). Majority of the toxicities were grade 1-2, and include leucopenia (84.2%), anemia (73.7%), liver enzyme elevation (68.4%) and fatigue (68.4%). The most frequently reported grade 3 toxicities were neutropenia and neutropenic complications (both 15.8%). All adverse events resolved with supportive management. Conclusion The clinical benefit and safety profile of the combination of FOLFIRI/aflibercept in Asian patients with mCRC are consistent with that of Western population. FOLFIRI/aflibercept may be an appropriate therapeutic option in Asian patients with mCRC previously treated with an oxaliplatin-based regimen. [ABSTRACT FROM AUTHOR]

Oxaliplatin-related neurotoxicity is frequently dose-limiting. Following retrospective studies suggesting neuroprotective effects of calcium and magnesium (Ca and Mg), we conducted a prospective study using nerve conduction studies (NCS) to evaluate the effectiveness of such infusions in oxaliplatin-related neuropathy. Colorectal cancer patients receiving FOLFOX-4 or capecitabine plus oxaliplatin were randomized to (Arm A) calcium gluconate 1g +15% magnesium sulphate 1g diluted in 100 mL of dextrose 5% or (Arm B) placebo. Neuropathy was assessed using the National Cancer Center common toxicity criteria, oxaliplatin-specific scale and NCS. This study was terminated prematurely based on the initial negative results of the CONcePT trial. Median follow up was 8.7 months. Overall 22 out of 27 patients experienced neuropathy. The subjective neuropathy rate was 77% in Arm A and 86% in Arm B, ( P = 0.6). At the end of treatment, three patients in Arm A and 0 in Arm B had grade 3 numbness ( P = 0.09). There was no significant difference in neuropathy between arms, whether during or at the end of treatment. Median objective neuropathy score was 6 in Arm A and 0 in Arm B, ( P = 0.02). Premature closure of this study limits the interpretation of results. While there was a trend towards reduced subjective acute sensory neuropathy with Ca and Mg, this was not significant. Ca and Mg failed to reduce the rate of cumulative sensory neuropathy and instead increased the rate of abnormal NCS, suggesting a significant difference in perceived sensory and objective neuropathy. [ABSTRACT FROM AUTHOR]