Carmen Belli

(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial

Purpose: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action. Experimental Design: We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population. Results: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33–69] in the control group and 42% (95% CI, 24–59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin. Conclusions: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. Clin Cancer Res; 22(5); 1076–85. ©2015 AACR. See related commentary by Yang and Rustgi, p. 1031

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression.

Neoadjuvant therapy in resectable pancreatic cancer: a critical review.

BACKGROUND Pancreatic cancer is among the deadliest tumors. Due to intrinsic chemo- and radio-resistance, surgical resection remains the only chance for cure. However surgery alone is unable to considerably improve survival and complementary chemotherapy and radiotherapy in a multimodal approach have been tested. Adjuvant chemotherapy yielded a modest outcome improvement, whereas the use of adjuvant chemoradiation is highly controversial. In this scenario, the neoadjuvant approach has a strong theoretical rationale, but limited information on the efficacy of this strategy is available. MATERIALS AND METHODS This review critically overviews the current knowledge, the rationale, the available data and information on neoadjuvant treatment in resectable pancreatic cancer. RESULTS The very early systemic dissemination of pancreatic cancer endorses the rationale for an up-front use of systemic therapy. However, evidence collected so far depends on retrospective data, small case series that did not balance the different characteristics of patients suitable for surgery before or after neoadjuvant chemotherapy. CONCLUSION Currently there is no straightforward evidence to support the routine clinical use of this strategy. Only a properly designed randomized trial testing combination chemotherapy regimens selected on the basis of their efficacy and activity against metastatic disease can address this issue.

Malignant pleural mesothelioma: current treatments and emerging drugs

Background: Malignant pleural mesothelioma (MPM) is an uncommon disease whose incidence is increasing worldwide over the past 30 years. Surgical resection and radiotherapy represent the standard treatment in patient with resectable MPM. Chemotherapy is also necessary to reduce incidence of distant metastases, but the optimal setting of treatment (neoadjuvant, adjuvant and intrapleural) is not clarified. For the patients with unresectable MPM, the combination cisplatin and pemetrexed or ralitrexed is the standard treatment as supported by a Phase III study. Better understanding of molecular pathways involved in MPM has enabled inclusion of new drugs targeted against pathways responsible for proliferation, cell survival and angiogenesis. Objective: This review discusses the current treatment option, the specific signal pathways activated in MPM and the novel agents under evaluation in clinical trials. Methods: We use for this article abstracts, papers, oral presentations from ASCO and the website http://www.clinical-trials.gov. Results/ conclusion: This review summarizes the activity of chemotherapy and of new agents under evaluation in clinical trials. The better understanding of molecular pathways activated in MPM will hopefully provide new therapeutic options for these patients in the future.

Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: A phase II randomised trial

BACKGROUND New strategies to prolong disease control warrant investigation in patients with metastatic pancreatic adenocarcinoma. This open-label, randomised, multi-centre phase II trial explored the role of maintenance sunitinib after first-line chemotherapy in this setting. METHODS Patients with pathologic diagnosis of metastatic pancreatic adenocarcinoma, performance status >50%, no progression after 6 months of chemotherapy were centrally randomised by an independent contract research organisation, which was also responsible for data collection and monitoring, to observation (arm A) or sunitinib at 37.5mg daily until progression or a maximum of 6 months (arm B). The primary outcome measure was the probability of being progression-free at 6 months (PFS-6) from randomisation. Assuming P0 = 10%; P1 = 30%, α .10; β .10, the target accrual was 26 patients per arm. RESULTS 28 per arm were randomised. One arm B patient had kidney cancer and was excluded. Sunitinib was given for a median of 91 days (7-186). Main grade 3-4 toxicity was thrombocytopenia, neutropenia and hand-foot syndrome (12%), diarrhoea 8%. In arm A versus B, PFS-6 was 3.6% (95% confidence interval (CI): 0-10.6%) and 22.2% (95% CI: 6.2-38.2%; P<0.01); 2 y overall survival was 7.1% (95% CI: 0-16.8%) and 22.9% (95% CI: 5.8-40.0%; P = 0.11), stable disease 21.4% and 51.9% (P = 0.02). CONCLUSION This is the first randomised trial on maintenance therapy in metastatic pancreatic adenocarcinoma. The primary end-point was fulfilled and 2 y overall survival was remarkably high, suggesting that maintenance sunitinib is promising and should be further explored in this patient population.

Clinical Significance of Skin Toxicity due to EGFR-Targeted Therapies

Many small molecules and monoclonal antibodies blocking the activity of Epidermal Growth factor receptor (EGFR) have been developed and have shown clinical activity in patients with non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer (CRC), and are in clinical development for a range of other solid tumors. The toxicity profile of such agents is characterized by a typical pattern of cutaneous reactions. In this paper we reviewed the current available data regarding the clinical significance of skin reaction due to EGFR targeted agents. We show that skin toxicity can be considered as predictive marker of response to such drugs and that it is not disease specific; however its potential prognostic value is still to be proven.

Adjuvant treatment in biliary tract cancer: to treat or not to treat?

Biliary tract cancer is a rare malignant tumor. There is limited knowledge about biology and natural history of this disease and considerable uncertainty remains regarding its optimal diagnostic and therapeutic management. The role of adjuvant therapy is object of debate and controversy. Although resection is identified as the most effective and the only potentially curative treatment, there is no consensus on the impact of adjuvant chemotherapy and/or radiotherapy on the high incidence of disease recurrence and on survival. This is mainly due to the rarity of this disease and the consequent difficulty in performing randomized trials. The only two prospectively controlled trials concluded that adjuvant chemotherapy did not improve survival. Most of the retrospective trials, which had limited sample size and included heterogeneous patients population and non-standardized therapies, suggested a marginal benefit of chemoradiotherapy in reducing locoregional recurrence and an uncertain impact on survival. Well-designed multi-institutional randomized trials are necessary to clarify the role of adjuvant therapy. Two ongoing phase III trials may provide relevant information.

Antiangiogenic strategies in breast cancer management

Angiogenesis is considered one of the key mechanisms of tumour growth and survival. Therefore it represents an ideal pharmaceutical target. Many antiangiogenic agents have been developed so far in several solid tumours and also in breast cancer. Vascular endothelial growth factor (VEFG) is the main target and both monoclonal antibodies and small molecules belonging to the tyrosine kinase inhibitors directed against VEGF(R) have been developed. Some other therapeutic approaches have shown to exert some antiangiogenic activity, such as hormonal agents, metronomic chemotherapy, bisphosphonates and others. In this paper we provide an introduction of the current data supporting the angiogenesis in breast cancer and a review of the most relevant antiagiogenic therapies which have been investigated so far.

Second-line therapy in advanced biliary tract cancer: What should be the standard?

Biliary tract cancer is a rare malignant tumor. Accordingly, to perform prospective and randomized trials is difficult and the knowledge of its natural history and optimal management remains limited. Chemotherapy is commonly used to improve the outcome and to delay tumor progression in advanced disease. Only recently, cisplatin-gemcitabine combination was identified as the new standard first-line therapy. Despite the outcome improvement, disease progression is a constant and approximately half of patients failing upfront treatment maintain a good performance status and are willing to undergo further treatment. No standard salvage chemotherapy regimen has been identified yet. Experiences of salvage therapy in advanced biliary tract cancer are sparse and yielded disappointing results. Well designed multi-institutional randomized trials are warranted to clarify the role and the activity of a second-line therapy.

Immunomodulatory Agents with Antivascular Activity in the Treatment of Non-Small Cell Lung Cancer: Focus on TLR9 Agonists, IMiDs and NGR-TNF.

Standard treatments for nonsmall cell lung cancer (NSCLC), such as surgery, chemotherapy, and radiotherapy, often lead to disappointing results. Unfortunately, also the various immunotherapeutic approaches so far tested have not produced satisfactory results to be widely applied in the clinical practice. However, the recent development of new immunomodulatory agents may open promising therapeutic options. This paper focuses on PF3512676, lenalidomide, and NGR-TNF, that is, drugs belonging to three different classes of immunomodulatory agents, that are also capable to affect tumor blood vessels with different mechanisms, and discusses the potential role of such agents in NSCLC treatment strategy.