Antonio Febbraro

Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study

PurposeAdvanced hepatocellular carcinoma (HCC) not eligible for local therapies has limited chances of cure. Sorafenib is a multikinase inhibitor with proven activity in advanced HCC. Octreotide is used in this setting with conflicting results. Treatment with sorafenib and long-acting octreotide was tested in advanced HCC to evaluate safety and activity.MethodsFifty patients with advanced HCC, Child-Pugh A or B, received sorafenib at a dosage of 800xa0mg/day for 28xa0days with a following week of rest and long-acting octreotide at a dose of 40xa0mg, administered every 28xa0days.ResultsAll patients were assessable for safety and efficacy. Sixteen patients out of 50 (34%) were naïve from other therapies, while all the others were previously treated with local and/or systemic treatments. We achieved 5 partial responses (10%), 33 stable diseases (66%) and 12 progressions of disease (24%). Median time to progression was 7.0xa0months (95% CI, 3.0–10.9xa0months), and median overall survival was 12xa0months (95% CI, 6.3–17.4xa0months). Treatment was well tolerated. Diarrhoea (6%) and hypertension (4%) were the most frequent grade 3 toxicities.ConclusionsOur data suggest that the combination between sorafenib and long-acting octreotide is active and well tolerated in patients with advanced HCC and could represent another efficacious chance for the management of this population.

Cancer-Associated Immune Resistance and Evasion of Immune Surveillance in Colorectal Cancer

Data from molecular profiles of tumors and tumor associated cells provide a model in which cancer cells can acquire the capability of avoiding immune surveillance by expressing an immune-like phenotype. Recent works reveal that expression of immune antigens (PDL1, CD47, CD73, CD14, CD68, MAC387, CD163, DAP12, and CD15) by tumor cells “immune resistance,” combined with prometastatic function of nonmalignant infiltrating cells, may represent a strategy to overcome the rate-limiting steps of metastatic cascade through (a) enhanced interactions with protumorigenic myeloid cells and escape from T-dependent immune response mediated by CD8+ and natural killer (NK) cells; (b) production of immune mediators that establish a local and systemic tumor-supportive environment (premetastatic niche); (c) ability to survive either in the peripheral blood as circulating tumor cells (CTCs) or at the metastatic site forming a cooperative prometastatic loop with foreign “myeloid” cells, macrophages, and neutrophils, respectively. The development of cancer-specific “immune resistance” can be orchestrated either by cooperation with tumor microenvironment or by successive rounds of genetic/epigenetic changes. Recognition of the applicability of this model may provide effective therapeutic avenues for complete elimination of immune-resistant metastatic cells and for enhanced antitumor immunity as part of a combinatorial strategy.

Cisplatin/Pemetrexed Followed by Maintenance Pemetrexed Versus Carboplatin/Paclitaxel/Bevacizumab Followed by Maintenance Bevacizumab in Advanced Nonsquamous Lung Cancer: The GOIM (Gruppo Oncologico Italia Meridionale) ERACLE Phase III Randomized Trial

INTRODUCTIONnCisplatin with pemetrexed (CP) and carboplatin with paclitaxel and bevacizumab (CbTB) are standard first-line treatments for patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC). Quality of life (QoL) is a key objective in the management of advanced NSCLC. Thus, effect on QoL could be an additional factor in the choice of treatment.nnnPATIENTS AND METHODSnPatients with untreated stage IIIB/IV NS-NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomized to receive first-line chemotherapy with cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2), every 3 weeks, for 6 cycles followed by maintenance pemetrexed; or carboplatin area under the curve 6, paclitaxel 200 mg/m(2), and bevacizumab 15 mg/kg, every 3 weeks, for 6 cycles followed by maintenance bevacizumab. The primary end point was the difference in QoL between the 2 treatment arms after 12 weeks of maintenance, measured using the EuroQoL 5 Dimensions-Index (EQ5D-I) and EQ5D-visual analogue scale (EQ5D-VAS).nnnRESULTSnOne hundred eighteen patients were randomized to CP (n = 60) or CbTB (n = 58). Baseline characteristics were well balanced. The proportion of patients evaluable for the primary end point was lower than planned. After 12 weeks of maintenance, the difference between mean changes in EQ5D-I was 0.137, favoring CP (95% confidence interval [CI], -0.02 to 0.29, Wilcoxon P = .078), although not statistically significant; and the difference between mean changes in EQ5D-VAS was 0.97 (95% CI, -9.37 to 11.31, Wilcoxon P = .41).nnnCONCLUSIONnAlthough the study was underpowered because of a small number of patients evaluable for the primary end point, QoL did not differ between treatment arms. Other factors such as comorbidities and schedule should be used when deciding on first-line treatment.

NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): from clinical trials to clinical practice

BackgroundPancreatic adenocarcinoma is an aggressive disease with poor prognosis. In a randomized phase III trial, combination of Nab-paclitaxel (Nab-P) plus gemcitabine showed superior activity and efficacy in first-line treatment compared with gemcitabine alone.MethodsNab-P is not dispensed in Italy; however, we obtained this drug from our Ethics Committee for compassionate use. The aim of this study was to evaluate the efficacy and safety profile of this Nab-P and gemcitabine combination in a cohort of patients treated outside clinical trials. From January 2012 to May 2014, we included 41 patients with advanced pancreatic adenocarcinoma receiving combination of 125xa0mg/m2 Nab-P and 1xa0g/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle, as first-line treatment. Median age of patients was 67 (range 41–77) years, and 11 patients were aged ≥70xa0years.ResultsEastern Co-operative Oncology Group performance status was 0 or 1 in 32 patients (78xa0%) and 2 in nine patients (22xa0%). Primary tumor was located in the pancreatic head or body/tail in 24 (58.5xa0%) and 17 (41.5xa0%) patients, respectively, and nine patients had received biliary stent implantation before starting chemotherapy. Median carbohydrate antigen 19–9 level was 469 U/l (range 17.4–61546 U/l) and 29 patients (70.7xa0%) had referred pain at the time of diagnosis. Patients received a median six cycles (range 1–14) of treatment. Overall response rate was 36.6xa0%; median progression-free survival was 6.7xa0months [(95xa0% confidence interval (CI) 5.966–8.034), and median overall survival was 10xa0months (95xa0% CI 7.864–12.136). Treatment was well tolerated. No grade 4 toxicity was reported. Grade 3 toxicity included neutropenia in 10 patients (24.3xa0%), thrombocytopenia in five (12xa0%), anemia in three (7.3xa0%), diarrhea in four (9.7xa0%), nausea and vomiting in two (4.9xa0%), and fatigue in six (14.6xa0%). Finally, pain control was achieved in 24 of 29 patients (82.3xa0%) with a performance status improvement of 10xa0% according to the Karnofsky scale.ConclusionsOur results confirm that combination of gemcitabine plus Nab-P is effective both in terms of overall response rate, progression-free survival and overall survival, with a good safety profile.

BAG3 is a novel serum biomarker for pancreatic adenocarcinomas.

to the small number of patients (62.5 vs. 37.5 % , P = 0.11). However, when comparing median cumulative exposure to RBV between groups as measured by the area under the drug exposure curve from week 0 to 12 based on biweekly measurements of RBV plasma levels rather than RBV dosage per se , cumulative exposure to RBV above ≥ 224.3 μ g / dl / day was signifi cantly associated with SVR (odds ratio 8.8; confi dence interval 1.35 – 57.43, P = 0.02) ( Figure 1 ). Anemia in group A was more severe than in group B (mean hemoglobin 99.6 vs. 106.3 g / l; P < 0.001), but well manageable with erythropoietin beta at doses between 9,000 and 30,000 IU per week according to a recently proposed consensus ( 10 ) Except for anemia, adverse events were similar in both groups. In conclusion — and in accordance with the study by Jin et al. ( 7 ) — optimal exposure to RBV guided by therapeutic drug monitoring signifi cantly improves SVR in patients with CHC genotype 1. Th erefore, regular RBV plasma level measurements at least for the fi rst 12 weeks of therapy and RBV dose adjustment may be advocated.

Everolimus as second-line therapy for metastatic renal cell carcinoma: a ‘real-life’ study

AIMSnThis study, conducted in a field-practice scenario, investigates the effectiveness and safety of everolimus in the second-line treatment of metastatic renal cell carcinoma (mRCC) patients.nnnPATIENTS & METHODSnmRCC patients, who started everolimus 10 mg/day after failure of first-line VEGF receptor-targeted tyrosine kinase inhibitor, were included in this study. Study end points were treatment response, progression-free survival and tolerability.nnnRESULTSnIn total, 100 patients were assessed; the median duration of everolimus treatment was 7.1 months (95% CI: 5.7-8.5). A total of 19% of patients experienced a partial response and 62% of patients reached a stable disease. Median progression-free survival was 8 months (95% CI: 6.7-9.3). A total of 75% of patients experienced adverse events; no grade 4 adverse events were reported.nnnCONCLUSIONnThese findings, obtained in a field-practice scenario, support the use of everolimus for mRCC patients who failed one VEGF receptor-targeted tyrosine kinase inhibitor.

Acceptance and adherence of oral endocrine therapy in women with metastatic breast cancer: exacampania group study.

Goals: Prognostic models or nomograms of early breast cancer could not be applied in neoadjuvant setting, because neoadjuvant chemotherapy (NAC) alters potential prognostic factor. The aim of this study was to combine clinical pathologic variables that are associated with pathologic complete response (pCR) and relapse-free survival (RFS) after NAC into prediction nomograms. Methods: A total of 370 stage II or III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. We developed the nomograms using logistic regression model for pCR and Cox proportional hazard regression model for RFS. Results: The nomogram for pCR based on initial tumor size, estrogen receptor (ER), human epidermal growth factor receptor 2, and Ki67 had good discrimination performance (AUROC=0.830). Multivariate Cox model identified age less than 35, initial clinical stage, pathologic stage, ER, Ki67 as prognostic factors, and the nomogram for RFS was developed based on these covariates. The concordance index for the second nomogram was 0.781, and calibration was also good. Conclusion: We developed nomograms based on clinical and pathologic characteristics to predict the probability of pCR and RFS for patients receiving neoadjuvant docetaxel/doxorubicin chemotherapy. We suggest that these nomograms allow individualized outcome prediction, which could aid clinicians in decision making process. Disclosure of Interest: None Declared

Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience

Aim This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5xa0mg daily versus 10xa0mg daily) and tolerability.Methods163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C).ResultsRR was 29.8% (A), 27.8% (B) (pxa0=xa00.953), and not evaluable (C). PFS was 9xa0months (95% CI 7–11) (A), 10xa0months (95% CI 9–11) (B), and 5xa0months (95% CI 2–8) (C), pxa0=xa00.956. OS was 38xa0months (95% CI 24–38) (A), median not reached (B), and 13xa0months (95% CI 10–25) (C), pxa0=xa00.002. Adverse events were stomatitis 57.7% (11.0% grade 3–4), asthenia 46.0% (6.1% grade 3–4), hypercholesterolemia 46.0% (0.6% grade 3–4), and hyperglycemia 35.6% (5.5% grade 3–4). The main reason for discontinuation/interruption was grade 2–3 stomatitis.ConclusionsNo correlation was found between dose intensity (5 vs. 10xa0mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

Eribulin for metastatic breast cancer (MBC) treatment: a retrospective, multicenter study based in Campania, south Italy (Eri-001 trial)

Background On the basis of the results of two pivotal phase III clinical trials, eribulin mesylate is currently approved in EU for the treatment of advanced breast cancer (aBC) in patients who have previously received an anthracycline and a taxane in either the adjuvant or the metastatic setting, and at least one chemotherapeutic regimen for metastatic disease. Methods In our study, we investigated the efficacy and tolerability of eribulin as second or further line chemotherapy in 137 women affected by aBC. Results Eribulin as monotherapy provided benefit in terms of progression-free survival (PFS), response rate (RR) and disease control rate (DCR) independently of its use as second or late-line therapy. The overall RR and DCR were 17.5% and 64%, respectively. In particular, DCR and overall RR were 50% and 13.6%, 65.4% and 21.1%, 70.4% and 14.8% and 66.7% and 16.7% in second, third, fourth and further lines of treatment, respectively. Median PFS (mPFS) according to the line of therapy was 5.7, 6.3, 4.5 and 4.0 months in patients treated with eribulin in second, third, fourth and over the fourth line, respectively. No significant difference in terms of mPFS was found between the various BC subtypes. Overall, eribulin resulted safe and most adverse events were of grade 1 or 2 and easily manageable. Grades 3–4 toxicities were neutropaenia and neurotoxicity. Conclusions With the limitations due to the observational nature of our findings, eribulin was shown to be an effective and safe therapeutic option in heavily pretreated patients with aBC.

Impact of anemia management with EPO on psychologic distress in cancer patients: results of a multicenter patient survey

AIMnWe investigated the role of erythropoietin (EPO) in reducing anemia and preventing the development of psychological distress in patients treated with chemotherapy.nnnPATIENTS & METHODSnThis prospective observational study enrolled 591 adult patients receiving EPO at a dose of 30,000 IU administered once weekly for chemotherapy-induced anemia (mean baseline hemoglobin [Hb] level was 9.55 g/dl) over a 12-month period.nnnRESULTSnThe majority of patients (371 [71%] patients) achieved a Hb increase >2 g/dl after 4 weeks of treatment. Interestingly, the nonresponder group had a statistically significant deterioration of their psychological conditions as indicated by psychological distress score (p = 0.01). However, within the group of responders to EPO, the Psychological Distress Inventory score remained unchanged. In the present study, severe side effects associated with EPO were not recorded.nnnCONCLUSIONnHb increase, induced by EPO, ameliorates the psychological conditions of cancer patients.