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Marina di Pisa, Italy

Bossi P.,Fondazione IRCCS | Lucchesi M.,Polo Oncologico | Antonuzzo A.,Polo Oncologico
Current Opinion in Supportive and Palliative Care

Purpose of review Gastrointestinal toxicities deriving from targeted therapies are main issues in the oncologic setting, as they can negatively impair quality of life, reducing patient's adherence to treatment and dose intensity, so ultimately possibly affecting outcome. We reviewed some methodological questions linked to the assessment of this kind of toxicity, in terms of way of measurement, duration of the assessed toxicity and impact on the global treatment program. Recent findings The scale of toxicity assessment may influence the evaluation itself; reporting the adverse events by the physician is generally less accurate than by the patient, and these two modalities should be integrated in the analysis of gastrointestinal toxicities by targeted treatment. Moreover, the duration of the symptoms and the attention to the lower grade toxicities estimation are generally underreported in clinical trials. The factors that may affect treatment's adherence by the patient are discussed, as they are strictly linked to the appearance and intensity of gastrointestinal toxicities. Summary Methodological issues should be considered in designing new trials with targeted therapies and evaluating the way of assessment of adverse events, mainly gastrointestinal. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Pietrantonio F.,Fondazione Istituto Nazionale Dei Tumori | Aprile G.,University of Udine | Rimassa L.,Medical oncology and hematology unit | Franco P.,TomoTherapy | And 18 more authors.
Radiotherapy and Oncology

Background The prognosis of brain metastases (BM) in colorectal cancer (CRC) is extremely poor, but the incidence is increasing. The performance of existing prognostic classifications such as recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) has never been evaluated in this specific setting. Moreover, the development of nomograms for estimating survival in such patients could be extremely helpful for treating physicians. Patients and methods Between 2000 and 2013, data from 227 patients with BM from CRC were collected at 8 Italian institutions. Overall survival (OS) was estimated with the Kaplan-Meier method and statistical comparison between curves was performed using the log-rank test. The discriminative ability for OS of RPA and GPA was assessed by the Harrell C-index from univariable Cox models. Putative prognostic factors for OS were also studied by multivariable Cox analysis, using the Harrell C index to evaluate the model discriminative ability. After a backward variable selection, a nomogram was developed to predict median survival time from individual patient- and tumor-related characteristics. The nomogram was externally validated on an independent series. Results After a median follow-up of 59 months, fifty percent of patients were still at risk at 5 months. The C index was 0.594 and 0.607 for the RPA and GPA classifications, respectively. The C-index associated with the final multivariable Cox model used for developing the nomogram was 0.643; the favorable prognostic factors for survival were lower age (p = 0.061), better Karnofsky performance status (p < 0.001), supratentorial site of BM (p < 0.001), and lower number of BM (p = 0.035). The C index evaluated on the validation series was 0.733, even better than in the development series; also, the calibration of nomogram predictions was good. Conclusion The C-index associated to the nomogram model was slightly higher than that obtained for the RPA and GPA classifications. Most importantly, the very satisfactory results of nomogram validation on the external series, make us confident that our instrument may assist in prognostic assessment, treatment decision making, and enrollment into clinical trials. © 2015 Elsevier Ireland Ltd. Source

Loupakis F.,University of Southern California | Cremolini C.,Polo Oncologico | Yang D.,University of Southern California | Salvatore L.,Polo Oncologico | And 16 more authors.

Purpose: The potential impact of different SNPs of VEGF/VEGFR pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of VEGFA rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of VEGF/VEGFR pathway genes was included. Experimental design: To detect a HR for PFS of 1.7 for VEGFA rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and β = 0.20, 199 events were required. VEGFA rs699946 A/G, rs699947 A/C, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS1 rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing. Results: Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to VEGFA rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05-1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95-1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082-1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14). Conclusion: This prospective experience failed to validate the hypothesized predictive impact of VEGFA rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab. © 2013 Loupakis et al. Source

Pietrantonio F.,Fondazione Istituto Nazionale Dei Tumori | Cremolini C.,Polo Oncologico | Lonardi S.,Unita Operativa Complessa Oncologia Medica 1 | Orlandi A.,Policlinico Universitario melli | And 14 more authors.

Background. No prospective trials have specifically addressed the efficacy and safety of panitumumab in elderly patients with metastatic colorectal cancer (CRC). We aimed at assessing the efficacy and safety of single agent panitumumab in "frail" elderly patients diagnosed with metastatic RAS and BRAFwildtype CRC. Materials and Methods. Forty elderly patients (aged $75 years) with metastatic RAS-BRAF wild-type CRC received off-label prescriptions of single-agent panitumumab at seven Italian institutions. Treatment was administered as first line in patients with absolute contraindication to any chemotherapy or as second-line treatment after failure of a fluoropyrimidine-based treatment, in the presence of contraindication to irinotecan. The outcome measures included objective response rate (ORR), as well as progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. Results. ThemedianPFS andOSwere6.4 months (95% confidence interval [CI]: 4.9-8 months) and 14.3 months (95% CI: 10.9-17.7 months), respectively. ORR was 32.5%, and DCR was 72.5%. Dose reductions related to adverse events (AEs) were reported in 9 (23%) patients, but no permanent treatment discontinuation caused by was reported. The most frequentgrade 3 AE was skin rash, with an incidence of 20%. Conclusion. Panitumumab is effective and well-tolerated in frail elderly patients with RAS-BRAF wild-type metastatic CRC and deemed unfit for chemotherapy. A randomized study is needed to confirm these data. © AlphaMed Press 2015. Source

Pietrantonio F.,Medical Oncology Unit | Cremolini C.,Polo Oncologico | Petrelli F.,Azienda Ospedaliera Treviglio | Di Bartolomeo M.,Medical Oncology Unit | And 7 more authors.
Critical Reviews in Oncology/Hematology

Background: The use of anti-EGFR monoclonal antibodies (MoAbs) is restricted in Europe to RAS wild-type metastatic colorectal cancer (mCRC) patients. While up today these targeted agents have been mainly chosen as salvage treatment in later lines, their use in first-line in combination with chemotherapy is highly debated. Methods: MEDLINE/PubMed, Cochrane Library, ASCO University, ESMO/ECCO conferences were searched for randomized controlled trials (RCTs) comparing first-line anti-EGFR MoAbs cetuximab or panitumumab plus chemotherapy to chemotherapy alone or with bevacizumab in patients with RAS wild-type colorectal cancer. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Seven eligible RCTs were identified. In the overall RAS wild-type population (N = 2719), anti-EGFR MoAbs significantly improved OS (HR = 0.81; 95%CI, 0.71-0.92; p = 0.002), PFS (HR = 0.77; 95%CI, 0.60-0.98; p = 0.03) and objective response rate (ORR) (RR = 1.33; 95%CI, 1.09-1.62; p = 0.004). The addition of an anti-EGFR MoAb to chemotherapy alone improved PFS (p< 0.001) and ORR (p< 0.001) with a trend toward longer OS (p = 0.07). As compared to bevacizumab, anti-EGFR MoAbs significantly improved OS (HR = 0.80; 95%CI, 0.69-0.92; p = 0.003), but not PFS (HR = 0.94; 95%CI, 0.74-1.19; p = 0.59) or ORR (RR = 1.10; 95%CI, 0.97-1.25; p = 0.12). No significant differences were found with respect to the chemotherapy backbone (oxaliplatin- versus irinotecan-based). Conclusions: The choice of an anti-EGFR MoAb as first-line biologic is a valid option in RAS wild-type patients candidate to a doublet with infusional 5-FU. While attempting to further refine molecular selection, clinical considerations are crucial in planning the treatment strategy. © 2015 Elsevier Ireland Ltd. Source

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