Gianluca Tomasello

Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer

BACKGROUND A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects. METHODS We randomly assigned 508 patients with untreated metastatic colorectal cancer to receive either FOLFIRI plus bevacizumab (control group) or FOLFOXIRI plus bevacizumab (experimental group). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival. RESULTS The median progression-free survival was 12.1 months in the experimental group, as compared with 9.7 months in the control group (hazard ratio for progression, 0.75; 95% confidence interval [CI], 0.62 to 0.90; P=0.003). The objective response rate was 65% in the experimental group and 53% in the control group (P=0.006). Overall survival was longer, but not significantly so, in the experimental group (31.0 vs. 25.8 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 1.00; P=0.054). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the experimental group. CONCLUSIONS FOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in patients with metastatic colorectal cancer and increased the incidence of some adverse events. (Funded by the Gruppo Oncologico Nord Ovest and others; ClinicalTrials.gov number, NCT00719797.).

FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study

BACKGROUND In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival-a secondary endpoint-and report treatment efficacy in RAS and BRAF molecular subgroups. METHODS TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m(2) intravenous infusion of irinotecan for 60 min followed by a 200 mg/m(2) intravenous infusion of leucovorin for 120 min, a 400 mg/m(2) intravenous bolus of fluorouracil, and a 2400 mg/m(2) continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m(2) intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m(2) intravenous infusion of oxaliplatin given concurrently with 200 mg/m(2) leucovorin for 120 min, followed by a 3200 mg/m(2) continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014. The trial is registered with ClinicalTrials.gov, number NCT00719797. FINDINGS Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7-55·6), median overall survival was 29·8 months (95% CI 26·0-34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5-29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65-0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7-42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4-28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11-1·99) and 13·4 months (8·2-24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75-4·46; likelihood-ratio test p<0·0001). Treatment effect was not significantly different across molecular subgroups (pinteraction=0·52). INTERPRETATION FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study, irrespective of baseline clinical characteristics and RAS or BRAF mutational status.

Prognostic Survival Associated With Left-Sided vs Right-Sided Colon Cancer: A Systematic Review and Meta-analysis.

Importance Primary tumor location is emerging as an important prognostic factor owing to distinct biological features. However, the side of origin of colon cancer (CC) still does not represent a prognostic parameter when deciding for adjuvant or palliative chemotherapy. Objective To determine the prognostic role of left vs right-sidedness of primary tumor location in patients with CC. Data Sources We searched PubMed, EMBASE, The Cochrane Library, Web of Science, LILACS, CINAHL, and SCOPUS for prospective or retrospective studies reporting data on overall survival for left-sided colon cancer (LCC) compared with right-sided colon cancer (RCC). Study Selection Studies were selected if: (1) side of CC was reported among variables entered into survival analysis, (2) survival information was available (overall survival [OS] was reported in the article as hazard ratio (HR) according to multivariate analysis, (3) articles were published in the English language. Data Extraction and Synthesis Data were pooled using HRs for OS of LCC vs RCC according to fixed or random-effects models. Subgroup analysis and multivariate random-effects model meta-regression was also implemented adjusting for stage distribution, sample size, race, year of publication, type and quality of studies, and adjuvant chemotherapy. Main Outcomes and Measures HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. In this analysis, all HRs with 95% CIs were pooled to obtain prognostic information on the location of the primary tumor (left vs right location site of CC) independent of other common clinicopathological covariates. Results An analysis was made from the 66 studies conducted. It included 1 437 846 patients with a median follow-up of 65 months. Left sided primary tumor location was associated with a significantly reduced risk of death (HR, 0.82; 95% CI, 0.79-0.84; P < .001) and this was independent of stage, race, adjuvant chemotherapy, year of study, number of participants, and quality of included studies. Conclusions and Relevance Based on these results, CC side should be acknowledged as a criterion for establishing prognosis in all stages of disease. It should be considered when deciding treatment intensity in metastatic settings, and should represent a stratification factor for future adjuvant studies.

Jumping higher: is it still possible? The ALTTO trial challenge

Trastuzumab, a humanized monoclonal antibody directed against HER2, used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in the metastatic setting, as well as halving the recurrence rate and improving survival in HER2-positive early breast cancer. Lapatinib is an orally active, reversible, small-molecule tyrosine kinase inhibitor that potently inhibits both HER1 and HER2 tyrosine kinase activity. This agent is the most advanced in terms of clinical trials and has been shown to have a favorable safety profile. Owing to the promising activity seen in advanced breast cancer, lapatinib is the ideal candidate for testing in the adjuvant setting. Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) is a four-arm randomized trial designed to compare trastuzumab and lapatinib in women with early-stage HER2-positive breast cancer. Specifically, ALTTO will examine which anti-HER2 agent is more effective and which is their best schedule of administration, namely, what benefit will be derived by taking the drugs separately, in tandem order or in combination. Overall, 8000 patients will be enrolled worldwide.

Brain metastases in HER2-positive breast cancer: The evolving role of lapatinib

Due to improvements in diagnosis and systemic therapy, brain metastases are an increasingly common cause of morbidity and mortality for patients with advanced breast cancer. The incidence of symptomatic brain metastases among women with metastatic breast cancer ranges from 10% to 16%. The HER2 receptor, which is overexpressed in approximately 25% of all breast cancers, is an important risk factor for the development of central nervous system metastases. Surgery and radiation therapy are the primary approaches to the treatment of brain metastases but new chemotherapy and biological agents promise to play an important role in the future management of central nervous system disease. This article reviews the epidemiology, current treatment options and recent advances in the field, with a focus on HER2-positive disease and the emerging role of lapatinib for the treatment and prevention of brain metastases.

Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC).

There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with low doses of interleukin-2 (IL-2)+interferon-&agr; (IFN-&agr;) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2+IFN-&agr; or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were secondary endpoints. ClinicalTrials.gov registration number was NCT00502034. 303/310 randomized patients (156 in the immunotherapy arm and 154 in the observation group) were evaluable at the intention-to-treat analyses. The 2 arms were well balanced. At a median follow-up of 52 months (range, 12–151 mo), RFS, and OS were similar, with an estimated hazard ratio (HR) of 0.84 [95% confidence interval (CI), 0.54–1.31; P=0.44] and of 1.07 (95% CI, 0.64–1.79; P=0.79), respectively in the 2 groups. Unplanned, subgroup analysis showed a positive effect of the treatment for patients with age 60 years and younger, pN0, tumor grades 1-2, and pT3a stage. Among patients with the combined presence of ≥2 of these factors, immunotherapy had a positive effect on RFS (HR=0.44; 95% CI, 0.24–0.82; P⩽0.01), whereas patients with <2 factors in the treatment arm exhibited a significant poorer OS (HR=2.27; 95% CI, 1.03–5.03 P=0.037). Toxicity of immunotherapy was mild and limited to World Health Organization grade 1-2 in most cases. Adjuvant immunotherapy with IL-2+IFN-&agr; showed no RFS or OS improvement in RCC patients who underwent radical surgery. The results of subset analysis here presented are only hypothesis generating.

Adjuvant chemotherapy for gastric cancer: current evidence and future challenges.

Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients survival is mainly related to stage, with a high proportion of patients with metastatic disease at presentation. Thus, the cure rate largely depend upon surgical resection. Despite the additional, albeit small, benefit of adjuvant chemotherapy has been clearly demonstrated, no general consensus has been reached on the best treatment option. Moreover, the narrow therapeutic index of adjuvant chemotherapy (i.e., limited survival benefit with considerable toxicity) requires a careful assessment of expected risks and benefits for individual patients. Treatment choices vary widely based on the different geographic areas, with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States. In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses. The most recent patient-level meta-analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery; the same Authors also showed that disease-free survival may be used as a surrogate end-point for overall survival. We finally discuss future research issues such as the need of economic evaluations, development of prognostic or predictive biomarkers, and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment.

Emerging combination therapies to overcome resistance in EGFR-driven tumors.

The epidermal growth factor receptor (EGFR) is responsible for the growth and progression of tumor cells; its overexpression and deregulation of its downstream signaling pathway have been found in many different neoplasms. These characteristics make it an ideal target for cancer treatment. Two classes of EGFR inhibitors, which bind to different parts of this molecule, have been developed and studied: monoclonal antibodies, such as cetuximab and panitumumab and tyrosine kinase inhibitors, including erlotinib and gefitinib. The effectiveness of these new drugs is considerably reduced by a number of mechanisms of resistance developed by tumor cells. Hence, there is a clear need for better characterization of these processes and finding new therapeutic strategies to make the action of these drugs more incisive. Here, we describe some of the mechanisms of resistance to EGFR inhibitors and review the main innovations attempting to overcome these drawbacks.

FOLFOXIRI Plus Bevacizumab as Conversion Therapy for Patients With Initially Unresectable Metastatic Colorectal Cancer: A Systematic Review and Pooled Analysis

Importance The combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial. Objective To assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions. Data Sources A systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer). Study Selection Clinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded. Data Extraction and Synthesis Data were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial. Main Outcomes and Measures Median overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions. Results Eleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30.2 months (95% CI, 26.5-33.7 months) in 6 trials with data available, and progression-free survival was 12.4 months (95% CI, 10.0-14.3 months) in 9 trials with data available. In meta-regression analysis, variables significantly associated with conversion surgery were disease limited to the liver and a higher median number of cycles (close to 12). Conclusions and Relevance For patients with surgically unresectable metastatic colorectal cancer, FOLFOXIRI-Bev is associated with a significant overall response rate. Such an effective regimen leads to a probability of surgical conversion of distant metastases approaching 40%, with more than one-fourth of patients having an R0 resection.

Immunotherapy options in metastatic renal cell cancer : where we are and where we are going

The treatment of renal cell carcinoma is rapidly changing as a result of recent evidence concerning the efficacy of biological drugs, antiangiogenetic agents and signal-transduction inhibitors. This paper will provide a critical overview of the use of immunotherapy in renal cell carcinoma and review the available data concerning the efficacy of interferons, interleukin-2 and other forms of immunological treatment, particularly allogenic transplantation and vaccines. Moreover, it will focus on the new mechanisms of regulation of the immune system with a better understanding of the interaction between host and tumor, the role of T regulatory cells, heat-shock proteins and vaccines. The mechanism of action and the results obtained in renal cell carcinoma using the new molecular targeted drugs will be examined, along with the possibility of using immunotherapy combined with the new biological agents. Future research will not only need to make every effort to optimize the use of the new molecules and to define their efficacy precisely, but also to consider how to integrate these drugs with the traditional immunotherapy.