Maria Ignez Braghiroli

Bevacizumab: overview of the literature.

Inhibiting the angiogenic process is a clever method of cancer care. Over the last decade, some antiangiogenic compounds have been developed and approved for cancer treatment. Bevacizumab is a humanized monoclonal antibody that inhibits VEGF activity. When used in combination with chemotherapy, it has an important role for treating many types of advanced cancer, including colorectal cancer, renal cell carcinoma, non-small-cell lung cancer, breast cancer, ovarian cancer and glioblastoma multiforme. In this paper we review the basic science behind this molecule’s development, as well the major clinical trials in which bevacizumab was involved in oncology.

Primary prevention of colorectal cancer: Myth or reality?

Colorectal cancer incidence has been rising strongly in parallel with economic development. In the past few decades, much has been learned about the lifestyle, dietary and medication risk factors for this malignancy. With respect to lifestyle, compelling evidence indicates that prevention of weight gain and maintenance of a reasonable level of physical activity can positively influence in lowering the risk. Although there is controversy about the role of specific nutritional factors, consideration of dietary pattern as a whole appears useful for formulating recommendations. Though quite often recommended, the role for many supplements, including omega-3, vitamin D, folate, and vitamin B6, remains unsettled. Only calcium and vitamin D supplementation appear to add a modest benefit, particularly in those with a low daily intake. With regard to chemoprevention, medications such as aspirin and nonsteroidal anti-inflammatory drugs, and postmenopausal hormonal replacement for women might be associated with substantial reductions in colorectal cancer risk, though their utility is affected by their side effect profile. However, the role of agents such as statins, bisphosphonates and antioxidants have yet to be determined. Ultimately, primary prevention strategies focusing on modifying environmental, lifestyle risk factors, and chemopreventive drugs are options that have already been tested, and may impact on colon cancer incidence.

Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas.

Background In patients with adenocarcinoma of the pancreas, there are no standard second-line regimens. Many pre-clinical studies have shown that metformin alone or when combined with paclitaxel has antitumour effects on this tumour. We have tested here the combination of paclitaxel and metformin for patients with gemcitabine-refractory pancreatic cancer. Methods An uncontrolled phase II trial was carried out based on a two–stage Simon’s design, with metformin and paclitaxel for patients with locally advanced or metastatic pancreatic cancer whose disease had progressed during first line treatment with a gemcitabine-based regimen. The primary endpoint was the disease control rate at eight weeks as per response evaluation criteria in solid tumours (RECIST) 1.1. Patients received paclitaxel 80 mg/m2 weekly for three weeks every 28 days and metformin 850 mg p.o. t.i.d. continuously until progression or intolerance state was reached. Results Twenty patients were enrolled from July 2011 to January 2014: N = 6 (31.6%) achieved the primary endpoint, with all presenting stable disease. Median overall survival (OS) was 128 days (range 17–697) and the median progression free survival (PFS) was 44 days (range 14–210). Eight patients (40%) presented treatment-related G3-4 toxicities with the most common one being diarrhoea. Conclusions Despite the encouraging pre-clinical evidence of the antitumour activity of metformin in adenocarcinoma of the pancreas, the primary endpoint of the disease control rate was not met. Besides, the treatment combination was poorly tolerated and could not be studied further. This study highlights the importance of performing clinical trials to reassure preclinical or observational data.

The Rising Incidence of Younger Patients With Colorectal Cancer: Questions About Screening, Biology, and Treatment

Opinion statementColorectal cancer (CRC) is the third leading cancer diagnosed globally and an important cause of cancer-related mortality. Of interest, while we have witnessed a declining incidence trend over the past few decades in the older population, incidence rates for adolescents and young adults have been increasing steadily. Several factors may well explain this apparent epidemic in the young, namely a lack of routine screening and emerging lifestyle issues such as obesity, lack of exercise, and dietary factors. It is known that both environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility is associated with the most striking increases in risk, and must always be considered in a young patient with CRC, the majority of CRCs are in fact sporadic rather than familial. Early-onset CRC is a truly heterogeneous disease, with mounting evidence to suggest that this patient population has a distinctive molecular profile, very different to late-onset CRC cases. Currently, both younger and older patients with CRC are treated in essentially the same manner, but with a better understanding of the molecular mechanisms underlying CRC in the young, we will have the opportunity to specifically tailor screening and clinical management strategies in this unique patient population in an effort to improve outcomes. The aim of this review is to outline our current knowledge of the distinguishing features of early-onset CRC, the ongoing research efforts, and the evolving evidence in this field.

Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer.

BACKGROUND Observational and preclinical studies have suggested that metformin has antitumor effects in solid tumors, including colorectal cancer (CRC). However, the effects of metformin in CRC have not been tested in clinical trials. PATIENTS AND METHODS This was a single-center, single-arm phase 2 clinical trial where histologically confirmed CRC patients with measurable and progressing metastatic disease previously treated with 5-fluorouracil (5-FU), irinotecan, oxaliplatin, and an anti-epidermal growth factor receptor (if the tumor was RAS wild type) were enrolled to receive metformin 850 mg orally continuously 2 times a day plus 5-FU 425 mg/m2 and leucovorin 50 mg intravenously weekly until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was disease control rate at 8 weeks. RESULTS Among 50 patients included, 11 (22%) met the primary end point. The median progression-free survival was 1.8 months and the median overall survival 7.9 months. Analyzing only the 11 patients who experienced disease control at 8 weeks, their median progression-free survival was 5.6 months and their median overall survival was 16.2 months. There was a trend for prolonged median survival for obese patients (12.4 vs. 5.8 months) and those longer off 5-FU. The treatment was well tolerated; the main adverse effects were diarrhea, nausea, vomiting, and myelotoxicity. CONCLUSION Metformin and 5-FU showed an overall modest but intriguing activity in patients with refractory CRC in this phase 2 study. Some patients experienced long-term disease control. Further trials are needed to confirm these results, particularly in obese patients with CRC.

Poor Evidence to Standardize Adjuvant Treatment for Patients With Biliary Tract Cancer

or both) compared with surgery alone for the entire group of biliary tract cancers (odds ratio [OR], 0.74; P .06). A sensitivity analysis demonstrated significant benefit in survival in patients with nodepositive and R1 disease (OR, 0.49; P .004; and OR, 0.36; P .002, respectively). With these results, the authors concluded that adjuvant therapy is the standard of care for high-risk patients and recommend againstano-treatmentarminfuturerandomizedtrialsinthissetting. We respectfully disagree with their conclusions. Selection bias, stagemigration,andheterogeneoustreatmentsarelikelytohaveconfoundedtheauthors’findings.Westronglybelievethatadjuvanttherapy for biliary tract cancer is not yet a standard and that the authors were hasty when they condemned a no-treatment arm as the control group in forthcoming trials. Basically, the quality of studies included in their meta-analysis was poor. Of the 20 studies included, there was only one randomized trialthatfoundanimproved5-yearsurvivalratewithadjuvantchemotherapyforpatientswithgallbladdercancer,butnotinthesubgroup of patients with cholangiocarcinomas. 2 The great majority of data were pooled from uncontrolled retrospective studies, in which mixed groups of patients with various tumor types (some studies included pancreatic and ampullary cancers) were treated with different adjuvant therapies. These factors combine to result in several intrinsic biases.First,becauseoftheretrospectivenatureofthestudiesincluded in this meta-analysis, selection bias could explain the better outcomes reported for adjuvant therapy. The authors discuss that patients with high-risk features could have been more likely to receive adjuvant therapy, which makes their results even more striking. We argue the opposite: similar to the case with other cancer types, patients with better performance status and/or younger age could have been more likely to receive adjuvant treatment in comparison with elderly patients, those with many comorbid illnesses, those who experienced serious postoperative complications, and/or patients who had poor clinical conditions. 3,4 Such confounders may have led to an overestimation of the adjuvant treatment and misinterpretation of the data. Second, the variability of diagnostic/staging tests used across the time spancoveredbythemeta-analysismayhaveledtostagemigrationasa result of instrumental bias. It is quite possible that patients who were stagedashavinglocalizeddiseaseinoldstudiesactuallyhadmetastatic disease; imbalances in the number of patients with metastatic disease between the adjuvant and control groups could have compromised the results. Third, the meta-analysis is based on literature-extracted data instead of individual patient information, which may produce different efficacy estimations and levels of evidence. 5 Fourth, many studies included do not report on resection margins. When margins are compromised, postoperative treatment is acceptable with the aim ofimprovinglocalcontrol,butthiscannotbeconsideredanadjuvant intervention per the definition of adjuvant. It simply involves early treatment of advanced disease. Other drawbacks such as unpublished negativetrials,shortfollow-up,andvariable,unscheduledtimepoints for recurrence evaluation across studies may have also generated biased interpretation with respect to the adjuvant treatment. The authors highlight some of these limitations in their discussion session. Nevertheless, they still endorse the use of adjuvant therapy for patients with node-positive disease and R1 resection. Although we agree that this could be an acceptable strategy, we advise against a definitive recommendation—particularly in the subset of node-positive tumors. High-risk status does not mean that a patient will benefit from adjuvant treatment. In fact, adjuvant treatments have been reportedly ineffective in certain tumor types that harbor high risk for recurrence such as rectal cancer and ampullary adenocarcinoma. 6,7

Combination of irinotecan and a platinum agent for poorly differentiated neuroendocrine carcinomas.

Extrapulmonary poorly differentiated neuroendocrine carcinoma (PDNEC) is a rare and highly aggressive neoplasm for which the optimal chemotherapy remains unclear. The objective of this study was to evaluate the outcomes of patients with PDNEC treated with cisplatin and irinotecan (IP) and perform a review of the literature. From 2008 to 2012, patients with advanced PDNEC (Ki67≥20%) who received the IP combination were selected for analysis. Radiologic responses were determined through Response Evaluation Criteria In Solid Tumors criteria. Twenty-eight patients were included. The median age at diagnosis was 57 years and the most common presentation was pancreatic PDNEC. Twenty-five patients (89%) received chemotherapy with cisplatin and irinotecan and three received carboplatin and irinotecan. Forty-six percent of the patients achieved objective response and the median time to tumor progression was 3.7 months. The median overall survival was 11.7 months. Thirteen patients (46%) had treatment interruptions or dose reductions due to grade 3/4 toxicity. This retrospective cohort of advanced extrapulmonary PDNEC patients suggests that the IP combination is feasible and resulted in similar response rate and median survival to other treatments previously reported.

Rivaroxaban: An Affordable and Effective Alternative in Cancer-Related Thrombosis?

Background Venous thromboembolic events (VTEs) are common and potentially fatal complications in cancer patients, and they are responsible for the second most common cause of death. Low molecular weight heparin (LMWH) is the gold-standard treatment, but the costs involved limit its use, especially in developing countries. Recently, the oral anticoagulant rivaroxaban, which directly inhibits factor Xa, was approved for VTE treatment. Methods We conducted a retrospective analysis from January 2009 to February 2014 with patients who had cancer and VTE who were receiving rivaroxaban. We compared the efficacy, safety, and cost of rivaroxaban and low molecular weight heparin (LMWH) alone or followed by vitamin K antagonists. Results Forty-one patients were identified, with a median age of 62.5 years. The most frequent tumor histology was adenocarcinoma (78%), which was most often found in the colon (26.8%). Most participants had advanced disease and an implanted central venous catheter. Patients’ VTE risk-assessment scores were low (12.5%), intermediate (50%), and high (35.5%). Pulmonary thromboembolism was reported in 41.4% of patients, but inferior limb thrombosis was reported only in 14.6%; 43.9% of patients received enoxaparin before starting rivaroxaban. Rivaroxaban was used for a median time of 5.5 months. Nonmajor bleeding was reported in 12.2% of patients, and rethrombosis was reported in 12.2%. In our study, rivaroxaban was as safe and effective as enoxaparin/vitamin K antagonists (P = .54 and P = .25, respectively) or LMWH (P = .46 and P = .29, respectively). Conclusion Although our study was a retrospective analysis, our results suggest that in this cohort of oncologic patients, rivaroxaban was safe and effective. Its oral route and lower cost make it an attractive alternative to LMWH, improving management of patients with cancer in low-income countries. Additional studies are necessary to confirm our data.

Review on TAS-102 development and its use for metastatic colorectal cancer

TAS-102 is the combination of trifluridine (TFT) with tipiracil (TPI) in a 1:0.5 molar ratio. TFT is a fluoropyrimidine that retains cytotoxic activity in 5-fluorouracil resistant cell lines. Due to TFT short half-life, early clinical development was discouraging. Thereafter, TFT was shown to be promptly degraded by thymidine phosphorylase, also known as platelet-derived endothelial cell growth factor, a pro-angiogenic protein and a poor prognosis marker in colorectal cancer. TPI is a specific antagonist of thymidine phosphorylase and led to an increase in TFT serum levels when both agents are combined. Moreover, TPI is a potential anti-angiogenic molecule and could exert antitumor actions per se. TAS-102 was tested in several Phase I studies published in the early 21st century. The best regimen was settled as 70mg/m(2)/day, q12h, orally given at days 1-5 and days 8-13, each 28days. Recently, the first Phase III trial evaluating TAS-102 in refractory colorectal cancer patients was published. The RECOURSE trial demonstrated a survival advantage of the agent over supportive care, and definitely established TAS-102 as a novel strategy in the current armamentarium against colorectal cancer. Here we review the preclinical data regarding TFT and TPI that led to the development of TAS-102, and the set of clinical data that ultimately proved that TAS-102 improved outcomes in colorectal cancer patients.

Erratum to: Do We Need another Antiangiogenesis Agent for Colorectal Cancer: are Bevacizumab and Aflibercept the Same?

Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide. Treatment of metastatic disease has improved survival in recent years. Angiogenesis is a multistep process, and the two most potent regulatory molecules stimulating the formation of new blood vessels are vascular endothelial growth factor (VEGF) and beta fibroblast growth factor (bFGF). Bevacizumab, a recombinant monoclonal antibody that inactivates VEGF-A, was the first antiangiogenic treatment approved for use against metastatic CRC. Aflibercept, also known as VEGF-trap, is a fully humanized recombinant protein that targets VEGF-A, VEGF-B, and placental growth factor-1 (PlGF). Bevacizumab is approved for first and second-line treatment associated with chemotherapy, and aflibercept has recently been approved for second-line treatment associated with irinotecan-based chemotherapy. Their mechanism of action and the preclinical and clinical data for both treatments will be reviewed in this article, with emphasis on their developmental process and their current and future use for treating CRC.