Systematic Review of the Role of Targeted Therapy in Metastatic Neuroendocrine Tumors.

BACKGROUND: Targeted therapies [interferon (IFN), vascular endothelial growth factor (VEGF) inhibitors, and somatostatin analogs (SSA)] have become an integral part of the neuroendocrine tumor (NET) treatment paradigm. We systematically reviewed the available literature to assess the overall beneficial and negative effects of targeted therapy on progression-free survival (PFS), overall survival (OS), response rate (RR), and toxicity. METHODS: Randomized controlled trials (RCT) were identified from MEDLINE, Embase, other major databases, and an electronic search of major conferences. Abstract review, quality assessment, and data abstraction were performed independently by 2 investigators. Meta-analyses were conducted using the generic inverse variance method with a random-effects model, with studies pooled according to drug class and/or control arm for clinical homogeneity. RESULTS: Fifteen RCT [SSA, n = 2; mammalian target of rapamycin (mTOR)/VEGF inhibitors, n = 4; IFN, n = 3; targeted therapy added to everolimus, n = 2, and other, n = 4] investigating 2,790 patients were included. Overall, targeted agents improved PFS (HR 0.54; 95% CI 0.40-0.73) but not OS (HR 0.86; 95% CI 0.72-1.01). SSA improved PFS (HR 0.41; 95% CI 0.29-0.58) but not OS (HR 1.00; 95% CI 0.58-1.74). mTOR/VEGF inhibitors improved PFS (HR 0.48; 95% CI 0.32-0.72) but not OS (HR 0.82; 95% CI 0.58-1.17). Targeted therapies added to everolimus or IFN did not improve either PFS or OS. The RR overall was improved (OR 2.85; 95% CI 1.77-4.59) but toxicity was increased (meta-analysis not performed). CONCLUSIONS: The addition of targeted therapies improves PFS but not OS in NET. The evidence is strongest for VEGF inhibitors and SSA. There is an ongoing need for well-designed RCT to inform the optimal use of targeted therapies in NET.

Systematic Review and Meta-Analysis on the Role of Chemotherapy in Advanced and Metastatic Neuroendocrine Tumor (NET).

BACKGROUND/OBJECTIVES: In the era of somatostatin analogues and targeted therapies, the role of chemotherapy in NET remains largely undefined. This systematic review aimed to assess the effect of chemotherapy on response rates (RR), progression-free survival (PFS), overall survival (OS) and toxicity compared to other chemotherapies/systemic therapies or best supportive care in patients with advanced or metastatic NET. METHODS: Randomised controlled trials (RCTs) from 1946 to 2015 were identified from MEDLINE, EMBASE, other databases and conference proceedings. Review of abstracts, quality assessment and data abstraction were performed independently by two investigators. Meta-analyses were conducted using Mantel-Haenszel analysis with random-effects modelling. RESULTS: Six RCTs comparing standard streptozotocin plus 5-fluorouacil (STZ/5FU) chemotherapy to other chemotherapy regimens, and 2 comparing this to interferon (IFN) were included. Only 1 study was considered at low risk of bias. STZ/5-FU was no different to other chemotherapies in response rate [RR 0.96; 95% confidence interval (CI) 0.72-1.27], PFS (RR 0.95; CI 0.81-1.13), or OS (RR 1.03; CI 0.77-1.39). IFN may produce higher response than STZ/5FU (RR 0.20; CI 0.04-1.13), but event rates were small and survival was no different. Interferon was associated with higher overall haematological (RR 0.47; CI 0.27-0.82) and lower overall renal toxicity (RR 3.61; CI 1.24-10.51). CONCLUSION: Strong evidence is lacking in the area of chemotherapy in neuroendocrine tumors. There is currently no evidence that one chemotherapeutic regimen is significantly better than the other, nor is interferon better than chemotherapy. There is an urgent need to design RCTs comparing modern chemotherapy to other agents in NET.

Estimation of an optimal chemotherapy utilization rate for malignant pleural mesothelioma: an evidence-based benchmark for cancer care.

AIMS: Chemotherapy with cisplatin and pemetrexed has been shown to provide a survival benefit and improvement in quality of life in patients with malignant pleural mesothelioma (MPM). The reported chemotherapy utilization rates range from 18% to 61%. This study aimed to estimate the proportion of MPM patients that should receive chemotherapy based on best available evidence. METHODS: An optimal chemotherapy utilization model for MPM was constructed using indications for chemotherapy identified from evidence-based MPM treatment guidelines. Epidemiological data on the proportion of patients and their tumor-related attributes were combined with the chemotherapy indications to estimate the optimal chemotherapy utilization rate using decision analysis software (TreeAge Pro 2007). Sensitivity analyses were performed to assess the impact of major variations in the epidemiological data on the optimal chemotherapy utilization rate. The optimal rate was compared with the actual rate reported in the literature. RESULTS: Chemotherapy is recommended at least once during the disease trajectory in 65% of MPM patients. Sensitivity analyses indicate an optimal utilization rate ranging from 50% to 65%. This optimal rate is relatively comparable to the rates mentioned in contemporary reports from Canada (61% between 2003 and 2005) and Australia (54% between 2007 and 2009) and high when compared with data from the Netherlands (36% during 2005-2006). CONCLUSION: An evidence-based model provided an optimal chemotherapy utilization rate of 65% for patients with MPM. Chemotherapy for MPM may be underutilized and barriers are likely multifactorial.