Search

The increase life expectancy led to an expected increase in skin cancer incidence in older patients. Their treatment can require a complex decision-making process. Limited data are available on characteristics, management and outcome of skin tumours in nonagenarian and centenarian patients. The aim of our study was to describe epidemiology, clinical-pathological features and treatment strategies of skin cancers in a cohort of patients aged ≧95 years. A total of 116 patients ≧95 years of age presented for the evaluation of 225 skin lesions (mean of 1.94 lesions per patient). The mean age was 97.4 years, 57.8% were women. Most patients had an ECOG score of 3 (49.3%) or 4 (32%). Lesions were mainly located on the head and neck area (74.2%), upper (7.1%) and lower (6,2%) limbs. The majority of patients presented with non-melanoma skin cancers (183/225; 81.3%), 25/225 (11.1%) had actinic keratosis, 5 (2.2%) melanoma and 2 (0.9%) atypical fibroxanthoma. Forty-eight lesions (21.3%) were treated with surgery, 58 (25.8%) with radiotherapy. The management of 73 lesion (32.4%) was discussed at the multidisciplinary tumour board meeting. One patient died for the progression of a squamous cell carcinoma; 74 patients died for causes unrelated to skin tumours, 36 are still alive after a mean follow-up of 27.27 months. This cohort study confirms that age is not per se a contraindication for treatment of skin cancers in elderly patients. Our results support the importance of a patient-centred care approach that should take into consideration patient's preferences, comorbidities, compliance and possible adverse events.

The international PRECONNECT Phase IIIb study demonstrated safety and efficacy of trifluridine/tipiracil in the management of patients with metastatic colorectal cancer. Post-hoc analyses in a national context are important because of the differences in disease management across countries. Post-hoc safety and efficacy analyses in the PRECONNECT Italian patient subset were conducted. Patients' quality of life was assessed from baseline to end of treatment. In Italy, 161 patients were enrolled. The median age was 64 years, with a performance status of 0–1. The most common hematological drug-related adverse events ≥grade 3 were neutropenia (41.0%) and anemia (13.7%). The median progression-free survival was reached at 3.0 months, with a disease control rate of 28.6%. The Quality of Life Questionnaire Core 30 score improved in 25.4% of the patients. Safety, efficacy and quality of life results confirmed trifluridine/tipiracil as a feasible and favorable treatment option for metastatic colorectal cancer patients.

Summary Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov , NCT02339116 . Findings Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Funding The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.

In patients with B-RAF-mutated cutaneous melanoma, targeted therapies are the treatment of choice to achieve a rapid response. In this multicentric, prospective, observational study, patients with B-RAF-mutated cutaneous melanoma who were treated with dabrafenib and trametinib were categorized in two cohorts (cohort A: limited disease (n = 104) and cohort B: bulky disease (n = 97)) according to lactate dehydrogenase levels. The primary endpoint was the progression pattern; the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety data. From baseline to time of progression, there was a progression from nodal to other sites of disease in cohort A and from skin and nodal to other sites in cohort B. In both the cohorts, the number of involved organs and metastases at each location decreased. The median OS was 32.4 months (95% CI: 20.1 months (not estimable)) for cohort A, and 10.5 months (95% CI: 8.3–14.4 months) for cohort B; median PFS was 12.4 months (95% CI: 10.9–17.0 months) for cohort A, and 8.1 months (95% CI: 6.3–9.4 months) for cohort B. No new safety signals were reported. This study describes the patterns of first-line treatment progression with dabrafenib and trametinib in Italian clinical practice. The effectiveness and safety data were consistent with previous trials and extended to a real-world heterogeneous population.

Background Real-world data on extended follow-up of patients with BRAF V600-mutant metastatic melanoma are limited. We investigated dabrafenib plus trametinib (dab + tram) outside of a clinical trial setting (Individual Patient Program; DESCRIBE Italy). Objective To describe the baseline features, treatment patterns, efficacy, and safety outcomes in patients with BRAF V600-mutant unresectable or metastatic melanoma who had received dab + tram as part of the Managed Access Program (MAP) in Italy. Patients and methods An observational, retrospective chart review was conducted in Italian patients with BRAF V600-mutant unresectable stage III/IV melanoma receiving dab + tram as part of the MAP. Baseline features, treatment patterns, efficacy, and safety outcomes were evaluated. Results Overall, 499 patients were included in this analysis. BRAF V600E mutation was seen in 81.4% of patients. Overall response rate achieved in 243 of the 390 evaluable patients was 62.3% (95% CI 57.5–67.1). Median progression-free survival (PFS) was 9.3 months (95% CI 8.6–10.6). Subgroup analyses revealed that patients with normal lactate dehydrogenase (LDH) and ≤ three metastatic sites without brain metastases at baseline had better outcomes. With normal LDH at baseline, median PFS for patients with one or two metastatic sites other than cerebral was 18 months. No new safety signals were observed. Treatment was permanently discontinued because of treatment-emergent adverse events (TEAEs) in 9.2% of patients, and pyrexia (27.3%) was the most common TEAE, with a lower incidence than that in the phase 3 studies of dab + tram. Conclusion Treatment of BRAF V600E-mutant metastatic melanoma with dab + tram in the real-world setting was effective and safe, including the unselected population with several patients having a high tumor burden – concordant with the results of the pivotal phase 3 studies of dab + tram. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00850-1.

Background Although American Society of Clinical Oncology and European Society for Medical Oncology guidelines have identified the negative prognostic factors that clinicians have to consider when treating their patients with stage II colon cancer (CC), the role of histological subtype is controversial. Subjects, Materials, and Methods The randomized, multicenter, phase III TOSCA trial compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. The objective of this substudy was to evaluate the influence of histological subtypes on the impact of the treatment duration of adjuvant chemotherapy in terms of relapse-free survival (RFS) and overall survival (OS) in 85 mucinous adenocarcinoma (MUC) and 389 nonmucinous adenocarcinoma (NMUC) patients with high-risk stage II, grade 3 CC. Results A significant interaction between treatment duration and histology was observed in both RFS (p = .027) and OS (p = .017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03–15.17; p = .045) and OS (HR, 9.56; 95% CI, 1.14–79.98; p = .037) were detected for patients treated in the 3-month arm. No statistically significant differences were found in the subgroup of patients with NMUC. Conclusion Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to assess the combined use of histology and other prognostic/predictive factors to define the administration of chemotherapy in patients with stage II CC and to improve their prognosis. Implications for Practice Although ASCO and ESMO guidelines define the prognostic factors for patients with stage II colon cancer to establish the use of adjuvant chemotherapy, the influence of histological subtypes is controversial in this population. This study underscores that patients with grade 3 mucinous adenocarcinomas may need adjuvant chemotherapy with oxaliplatin and fluoropyrimidines for a duration of 6 months rather than 3 months.

Background: Adjuvant treatment for stage II colon cancer (CC) can be proposed to patients with high-risk disease. Recently, 2.35 ng/mL carcinoembryonic antigen (CEA) was identified as the best cut-off value. This post hoc analysis of the MOSAIC trial assessed post-operative CEA prognostic value for survival outcomes and predictive value for the addition of oxaliplatin to adjuvant treatment. Methods: Prognostic and predictive values of post-operative CEA in patients with stage II CC were evaluated with Kaplan–Meier survival curves and Cox model with interaction terms. Disease-free survival (DFS) and overall survival (OS) were estimated. Results: Among 899 stage II CC patients, post-operative CEA was available in 867 (96.4%); and 434 (48.65%) had a high-risk stage II disease. The 3-year DFS rate was 88.5% and 78.7% in the ≤ 2.35 ng/mL and > 2.35 ng/mL group, respectively (P = 0.006). Use of oxaliplatin showed survival benefit only in patients with high-risk stage II CC and post-operative CEA > 2.35 ng/ml (interaction term P = 0.09 and 0.03 for DFS and OS). Conclusion: CEA is a strong prognostic factor for DFS and OS in stage II CC. In the MOSAIC trial, only high-risk stage II CC patients with post-operative CEA > 2.35 ng/mL benefited from the addition of oxaliplatin to LV5FU2. Trial registration: NCT00275210 (January 11, 2006)., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: We explored and validated the association of postoperative carcinoembryonic antigen (CEA) with disease-free survival (DFS) and overall survival (OS) in stage III colon cancer. Methods: Patients with stage III colon cancer from the MOSAIC and PETACC-8 trials were enrolled. The relation between CEA and outcomes was continuously modeled with the restricted cubic splines (RCS) method. Association of CEA with outcomes was assessed by the Kaplan–Meier method, with two risk groups among patients with a CEA level ≤5 ng/mL. Multivariate Cox proportional hazard models were constructed. Results: The CEA level was available in 1,292 (96%) and 2,477 (97%) patients in the discovery and validation cohorts. The RCS analysis confirmed that patients with a CEA level >5 ng/mL were at highest risk of recurrence or death and those with a CEA level ≤5 ng/mL presented a heterogeneous risk population. In the discovery cohort, the 3-year DFS rate was 75%, 65%, and 45% in a group of patients with CEA level of 0–1.30 ng/mL (n = 630), 1.30–5 ng/mL (n = 613), and >5 ng/mL (n = 49), respectively (P < 0.001). CEA was independently associated with endpoints. All findings were confirmed in the validation cohort. Conclusions: Postoperative CEA level was highly and independently associated with DFS and OS, especially in patients with a CEA level of ≤5 ng/mL, suggesting that this cutoff is not optimal. Impact: CEA levels should be applied more accurately in future trials and clinical practice.

Background Deleterious polymorphisms in the gene encoding DPD (DPYD) may result in severe reduction of DPD enzymatic activity that causes life-threatening toxicities when the standard dose of fluorouracil is used. The best panel of single-nucleotide polymorphism (SNPs) of DPYD is not well defined. Methods In 2011, we began screening DPYD*2A in patients candidate for fluoropyrimidine-based chemotherapy. We planned a case-control study with all cases of DPYD*2A wild type who developed toxicity ≥G3 and with a cohort of patients who did not present severe toxicities. Then, we tested the additional SNPs: c.2846A>T, c.1679T>G, c.2194G>A. Results From 2011 to 2016, we screened 1827 patients for DPD deficiency; of those, 31 subjects (1.7%) showed DPYD*2A SNP. We selected 146 subjects who developed severe toxicities (Cases) and 220 patients who experienced no or mild toxicities (Controls); 53 patients carried one of the additional SNPs: 35 subjects (66%) fell into the Cases and 18 (34%) into the Controls (p A was the most frequent SNP (12.5%) and showed a correlation with neutropenia. We confirmed that c.2846A>T and c.1679T>G were related to various toxicities. Conclusions The additional DPYD polymorphisms could enhance the prevention of fluoropyrimidine toxicity. c.2194G>A is the most frequent polymorphism and it was found to be associated with neutropenia.

LBA3513 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. pathologic complete remission (pCR) can be considered as surrogate endpoint of efficacy of treatment in terms of disease-free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multicentre study in patient with locally advanced rectal cancer who receive standard concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is the proportion of pCRs after at least 1 cycle of durvalumab; secondary endpoints are the proportion of clinical complete remissions (cCRs) after at least 1 cycle of durvalumab, the proportion of adverse and serious adverse events (NCI CTCAE v5.0). The sample size has been estimated by using the optimal Simon’s two-stage design assuming a null pCR proportion of 0.15 and an alternative pCR percentage of 0.30 (alpha = 0.05, power = 0.80). If more than 4 pCRs were observed in the first 19 enrolled patients, 36 additional patients were to be accrued for a total of 55 evaluable patients. The null hypothesis is rejected if ≥ 13 pCRs are observed in 55 patients. Results: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were evaluable for study objectives. Fifty-two of 55 treated patients received all 3 infusions of durvalumab. After treatment, a clinical response percentage of 81.8% was observed; 3 patients had progression of disease due to local and/or metastases before surgical intervention. Eighteen patients achieved complete pathological response (32.7%), confirmed by central revision. Near complete regression, moderate and minimal regression were observed in 14 (25.5%), 9 (16.4%) and 11 (20.0%) patients respectively. Regarding toxicity, 23 patients (41.8%) had adverse events (AEs) related to durvalumab treatment. Two patients (1.8%) discontinued durvalumab for toxicity. Grade 3 AEs occurred in 4 (7.3%) patients (diarrhea, skin toxicity, transaminase increase, lipase increase and pancolitis). No Grade 4 toxicity was observed. In 20 patients (36.4%) G1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypo-thyroidism), dermatologic toxicity (skin rash) and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). Conclusions: This study met its primary endpoint showing a promising activity of neoadjuvant chemo-radiotherapy plus durvalumab in terms of pCR rate and a safe toxicity profile. Clinical trial information: NCT04083365.

Background: Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results. Patients and methods: We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged

Background Regorafenib is a key agent in metastatic colorectal cancer (mCRC), but no validated factors predicting longer survival are available. Patients and Methods REALITY was a retrospective multicenter trial in regorafenib-treated mCRC patients with overall survival (OS) ≥ 6 months. We aimed to assess the association between clinical parameters and outcome to define a panel identifying long term survivors among regorafenib candidates. Primary and secondary endpoints were OS and progression free survival (PFS), respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; independent role of significant variables at univariate analysis: logistic regression). Results Hundred regorafenib-treated mCRC patients with OS ≥ 6 months were enrolled. Median OS was 11.5 m (95%CI:9.60-12.96); median PFS was 4.2 months (95% CI:3.43-43.03). The absence of liver progression and of dose and/or schedule changes during the first 4 cycles (mainly for good tolerability) were independently correlated at multivariate analysis with OS (Exp(b)1.8869, P= .0277and Exp(b)2.2000, P = .0313) and PFS (Exp(b)2.1583, P = .0065 and Exp(b)2.3036, P= .0169). Patients with neither of these variables had a significantly improved OS (n = 14, 20.8 months; 95% CI:12.967-55.267) versus others (n = 86, 10 months; 95% CI:8.367-12.167; HR = 0.4902, P = .0045) and PFS (11.3 months, 95%CI:4.267-35.8 vs. 3.9 months, 95% CI:3.167-43.033; HR = 0.4648, P = .0086). Conclusion These 2 factors might allow clinicians to better identify patients more likely to benefit from regorafenib. Toxicity management remains crucial.

Background The role of combination chemotherapy has not yet been established in unresectable locally advanced pancreatic cancer (LAPC) lacking dedicated randomized trials. Methods This phase II trial tested the efficacy of Nab-paclitaxel (NAB-P)/Gemcitabine (G) versus G alone. Patients were randomized, 1:1 to G 1000 mg/m2 on days 1, 8 and 15 every 28 days versus NAB-P 125 mg/m2 on days 1, 8 and 15 every 28 days plus G 1000 mg/m2 on days 1, 8 and 15 every 28 days. Disease progression rate after three cycles of chemotherapy was the primary end-point. Progression-free survival (PFS), overall survival (OS) and response rate were secondary end-points. Findings A total of124 patients were enrolled. The study showed a reduction of a progressive disease from 45.6% with G to 25.4% with NAB-P/G (P = 0.01) at 3 months. Noteworthy, at 6 months in the G arm, 35.6% of patients present a metastatic spread versus 20.8% in the NAB/G arm. The response rate was 5.3% in the G arm and 27% in the NAB/G arm. Median PFS was 4 months for the G arm and 7 months for the NAB-P/G arm. Median OS was 10.6 in the G arm and 12.7 months in the NAB-P/G arm. One patient died during treatment with G due to a stroke. Interpretation. NAB-P/G reduced the rate of LAPC patients progressing after three cycles of chemotherapy compared with G, especially in terms of distant relapses. It positively affects PFS. To the best of our knowledge, this is the first randomized trial providing evidence that combination chemotherapy is superior to gemcitabine alone in this setting. ClinicalTrials.gov Identifier NCT02043730 .

Background Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. Material and methods TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. Results From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was Conclusions The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov , registration number: NCT0064660.

Importance The addition of oxaliplatin to the standard 6-month fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer has been reported to reduce the risk of relapse although it does not increase survival. The Three or Six Colon Adjuvant (TOSCA) trial compared 3 months with 6 months of adjuvant fluoropyrimidine and oxaliplatin-based chemotherapy in patients with stage III colon cancer. The utility remains unknown. Objective To assess the noninferiority and toxic effects of 3 vs 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) adjunct chemotherapy among patients with high-risk stage II resected colorectal cancer enrolled in the TOSCA trial. Design, Setting, and Participants The TOSCA study was a noninferiority phase 3 randomized clinical trial conducted from June 2007 to March 2013 in 130 Italian centers. Included patients had resected colorectal cancer located 12 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. In this preplanned study assessing the per-protocol population, 5-year relapse-free survival was evaluated in 1254 patients with high-risk stage II resected colorectal cancer who had received adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Interventions Patients were originally randomized (1:1) in the TOSCA trial to receive 3 months (experimental group) or 6 months (control) of standard doses of FOLFOX or CAPOX at the discretion of the treating physician. Main Outcome and Measures A hazard ratio of at least 1.2 between the 3-month and 6-month chemotherapy groups was set to reject the null hypothesis of noninferiority. Results Overall, 1254 patients (mean [SD] age, 62.4 [9.8] years; 565 women [45.1%]) with clinical high-risk stage II resected colorectal cancer were analyzed at a median follow-up of 62 months (interquartile range, 53-71) months. Of them, 301 patients (24.0%) had pT4N0M0 tumors, and the remaining 953 patients (76.0%) had high-risk pT3N0M0 tumors; 776 patients (61.9%) received FOLFOX and 478 (38.1%) received CAPOX. The 5-year relapse-free survival was 82.2% for the 3-month arm and 88.2% for the 6-month arm, with an estimated hazard ratio of 1.41 (95% CI, 1.05-1.89;P = .86 for noninferiority). For CAPOX, the 5-year relapse-free survival was similar in the 2 arms (difference, 0.76% favoring the 6-month arm; 95% CI, −6.28% to 7.80%), whereas for FOLFOX, the difference was pronounced: 8.56% in favor of the longer-duration arm (95% CI, 3.45%-13.67%). Nevertheless, the test for an interaction between duration and regimen was not statistically significant. Neurotoxicity was approximately 5 times lower in the shorter duration arm than in the longer duration arm. Conclusions and Relevance In the 3-month arm, the treatment was significantly less toxic than in the 6-month arm. Noninferiority was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CAPOX or 6 months of FOLFOX therapy can be used whenever an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer. Trial Registration ClinicalTrials.gov Identifier:NCT0064660

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.

Background:This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events.Patients and methods:Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported.Results:Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3–2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5–3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza versus unvaccinated ( p = 0.009, p Conclusion:COVID-19 has a meaningful clinical impact on the cancer-patient population receiving ICIs, with high prevalence, hospitalization and an alarming mortality rate among symptomatic cases. Influenza vaccination does not protect from SARS-CoV-2 infection.

Background: Different antiangiogenics are currently indicated in the second-line treatment of metastatic colorectal cancer (mCRC), following a first-line bevacizumab-containing treatment. The magnitude of benefit is limited, but no predictors of benefit have been identified. Methods: A total of 184 mCRC patients progressing to a first-line bevacizumab-containing treatment were randomised in the BEBYP study to continue or not the antiangiogenic in combination with a second-line chemotherapy. A subgroup analysis according to baseline serum lactate dehydrogenase (LDH) levels was carried out. Results: A significant interaction effect between LDH levels and treatment was found in terms of progression-free survival (PFS; P=0.002). Although patients with low LDH levels achieved significant PFS benefit from the continuation of bevacizumab (HR: 0.39 (95% CI: 0.23–0.65)), patients with high levels did not (HR: 1.10 (95% CI: 0.74–1.64)). Consistent results were reported in overall survival (OS; P=0.075). Conclusions: As preclinical evidence suggests that serum LDH may be a marker of tumour angiogenesis activation, low levels may indicate that bevacizumab is still efficacious in inhibiting angiogenesis. Validation of present results in subgroup analyses of other randomised trials of second-line angiogenesis inhibitors is warranted.

Background: The risk of venous thromboembolic events (VTE) during adjuvant chemotherapy for colorectal cancer (CRC) is unknown. We aim to evaluate if the Khorana score (KS) can predict this risk, and if it represents a prognostic factor for overall survival (OS) through a post hoc analysis of the phase III TOSCA trial of different durations (3- versus 6-months) of adjuvant chemotherapy. Methods: A logistic regression model was used to test the associations between the risk of VTE and the KS. The results are expressed as odds ratios (OR) with 95% confidence intervals (95% CI). To assess the effect of the KS on OS, multivariable analyses using Cox regression models were performed. The results are expressed as hazard ratios (HR) with 95% CI. Results: Among 1380 CRC patients with available data, the VTE risk ( n = 72 events: 5.2%) was similar in the two duration arms (5.5% versus 4.9%), with 0.2% of patients belonging to the high-risk KS group. Rates of VTE were similar in the low- and intermediate-risk groups (4.8% versus 6.4%). KS did not represent an independent predictive factor for VTE occurrence. Chemotherapy duration was not associated with VTE risk. In addition, KS was not prognostic for OS in multivariate analysis (HR: 0.92, 95% CI, 0.63–1.36; p = 0.6835). Conclusions: The use of the KS did not predict VTEs in a low–moderate thromboembolic risk population as CRC. These data did not support the use of KS to predict VTE during adjuvant chemotherapy, and suggest that other risk assessment models should be researched.

Purpose Because the role of the primary tumour location in the adjuvant setting has not been clearly established in colon cancer, we analysed the clinical outcome according to the primary tumour location from three Italian trials assessing adjuvant therapy in colon cancer. Patients and methods Overall survival (OS) and disease-free survival (DFS) were assessed globally and in each trial, according to right-sided, transverse and left-sided primary colon cancer. Analysis was planned to provide overall and stage-specific results. Results Individual data of 5239 patients were included in this analysis. The right-sided tumours were 1540 (29%), tumours originating in the transverse were 815 (16%) and left-sided tumours were 2884 (55%). At the multivariate analysis, DFS findings from the comparison of the right-sided versus left-sided tumours (hazard ratio [HR] = 1.00; 95% confidence interval [CI] = 0.89–1.14) were not statistically associated with clinical outcomes in the overall population. On the contrary, OS findings, from the comparison of the right-sided versus left-sided tumours, were significantly associated with outcomes (HR = 1.20; 95% CI = 1.04–1.39). In stage II patients, there was no difference in terms of DFS and OS among the three different tumour locations, whereas in stage III patients, the left-sided tumours showed an improved prognosis in terms of OS (HR: 1.36 95% CI = 1.14–1.62, p Conclusion This is the largest analysis demonstrating a prognostic effect of the tumour location on patients with colon cancer receiving adjuvant chemotherapy. Nevertheless, the effect is limited to OS in stage III colon cancer. In stage II tumours, the primary location has a lesser impact. The transverse tumours should be prognostically considered in between the right-sided and left-sided tumours.

[Background] In the phase III CORRECT trial, regorafenib significantly improved survival in treatment‐refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization., [Methods] This prospective, single‐arm study enrolled patients in 25 countries at 186 sites. Patients with treatment‐refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4‐week cycle. The primary endpoint was safety. Progression‐free survival (PFS) per investigator assessment was the only efficacy evaluation., [Results] In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment‐emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib‐related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib‐related TEAEs occurred in, [Conclusion] In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680. [Implications for Practice] Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment‐refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events., This study was sponsored by Bayer. Editorial assistance in the preparation of this manuscript was provided by Ann Contijoch (Bayer) and Jennifer Tobin (SuccinctChoice Medical Communications, London, UK, with financial support from Bayer).

We explored and validated the association of postoperative carcinoembryonic antigen (CEA) with disease-free survival (DFS) and overall survival (OS) in stage III colon cancer.Patients with stage III colon cancer from the MOSAIC and PETACC-8 trials were enrolled. The relation between CEA and outcomes was continuously modeled with the restricted cubic splines (RCS) method. Association of CEA with outcomes was assessed by the Kaplan-Meier method, with two risk groups among patients with a CEA level ≤5 ng/mL. Multivariate Cox proportional hazard models were constructed.The CEA level was available in 1,292 (96%) and 2,477 (97%) patients in the discovery and validation cohorts. The RCS analysis confirmed that patients with a CEA level5 ng/mL were at highest risk of recurrence or death and those with a CEA level ≤5 ng/mL presented a heterogeneous risk population. In the discovery cohort, the 3-year DFS rate was 75%, 65%, and 45% in a group of patients with CEA level of 0-1.30 ng/mL (Postoperative CEA level was highly and independently associated with DFS and OS, especially in patients with a CEA level of ≤5 ng/mL, suggesting that this cutoff is not optimal.CEA levels should be applied more accurately in future trials and clinical practice.

Background Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. Materials and Methods This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. Results Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48–4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69–3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. Conclusions Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. Implications for Practice The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.

Background The role of a combination therapy is defined in metastatic pancreatic cancer but not in LAUPC. Lacking dedicated randomized trials, evidence mostly comes from retrospective or phase II studies. G alone remains the standard option following a subgroup LAUPC analysis of a GERCOR/GISCAD trial (J Clin Oncol 2005). Methods GAP is a multicentre, open-label, randomized, comparative phase II trial testing the efficacy of NabG vs G. Patients ≤75 years, PS 0-1, were randomized 1:1 to Nab/G (Nab 125 mg/mq plus G 1000 mg/mq on days 1, 8 and 15 every 28 days for 3 cycles) or G (same schedule and doses). Patients not progressing after 3 cycles had to receive capecitabine plus radiotherapy for 5 weeks. Disease progression rate (DPR) according to RECIST 1.1 after 3 cycles of chemotherapy is the primary endpoint. With 80% power in detecting a reduction of DPR from 40% to 20%, one-tailed alpha=0.05, 124 patients were required. Progression-free survival (PFS) is a secondary endpoint; with 109 events the study has 80% power, with one-tailed alpha=0.05, to detect a 0.62 hazard ratio of PFS. Results 124 patients were enrolled in this trial (4 withdrew consent after randomization in the G arm). Most of the patients were PS 0 (65.8%), and women (56.7%). The study met its primary endpoint DPR, with a reduction from 45.6% with G to 25.4% with Nab/G. There was no unexpected toxicity. One patient died during treatment with G due to a stroke. Table . 673PD Arm Patients DPR One-tail chi square Median PFS (102 events) HR of PFS Progression at distant site Median OS (82 events) HR of OS G 57 26 (45.6%) P = 0.01 5.1 mos 0.71 (90% CI 0.51-0.99) 18/26 10.7 mos 0.65 (90% CI 0.44-0.94) NabG 63 16 (25.4%) 7.6 mos 6/16 13.1 mos Conclusions NabG reduces the rate of LAUPC patients who progress after 3 cycles of chemotherapy compared with G, especially in terms of distant relapses, positively affecting PFS and overall survival. Nowadays it should be the therapeutic option in this setting. Clinical trial identification NCT02043730; 2013-002973-23. Legal entity responsible for the study Fondazione GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Funding Celgene. Disclosure S. Cascinu: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Advisory / Consultancy: Amgen; Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self): Sanofi; Research grant / Funding (self): Eisai. R. Bianco: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Italfarmaco; Advisory / Consultancy: AstraZeneca. D. Ferrari: Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bristol-Meyers Squibb; Travel / Accommodation / Expenses: Roche. L. Cavanna: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Celgene. G.D. Beretta: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Taiho Pharmaceutical. A. Sobrero: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy: Servier; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Bristol-Meyers Squibb. A. Morabito: Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Delphi Diagnostics; Honoraria (self): Servier; Research grant / Funding (institution): Celgene. M.C. Piccirillo: Advisory / Consultancy: Glaxo; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Bayer; Honoraria (self): MSD; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.

Purpose The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. Methods Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. Results After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX4) arms were 67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population, 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation. Conclusion The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation.

Oncogenic drivers in lung non-small-cell lung cancer (NSCLC) are considered mutually exclusive, but a review of the literature reveals that concomitant EGFR mutations and ALK rearrangement may occur in a subset of NSCLC. We report here a case of pulmonary adenocarcinoma with concomitant EGFR mutation in exon 21 (L858R) and ALK rearrangement in naive and relapsed tumors. Tumor cells seem to harbor both gene alterations and the patient had a long-lasting response both to EGFR inhibitor in second line and ALK inhibitor once tumor progressed. A speculative discussion on molecular mechanisms underlying this uncommon phenomenon and practical points about epidemiologic, clinicopathologic features and therapeutic options in this intriguing subset of double-positive tumor are reported.

Background The AVANT study did not demonstrate disease-free survival (DFS) benefit of the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III resected CC and suggested a potential detrimental effect on overall survival (OS) (A. de Gramont et al. Lancet Oncol. 2012). Here, we present the results of the AVANT study for stage II CC patients. Methods The primary endpoint of AVANT was DFS for stage III disease. As an exploratory measure, AVANT also included high-risk stage II CC defined by T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age Results 573 patients had stage II CC (arm A: FOLFOX4, n = 192; arm B: FOLFOX4-bevacizumab, n = 194; arm C: XELOX-bevacizumab, n = 187), of whom 38 (19.8%) in arm A, 36 (18.6%) in arm B, and 40 (21.4%) in arm C had relapsed, developed a new CC, or died after a median follow-up of 6.86 years (IQR: 6.13-11.34). The DFS hazard-ratio was 0.94 (95% CI 0.59-1.48; P = 0.78) for arm B vs arm A and 1.07 (95% CI 0.69-1.67; P = 0.76) for arm C vs arm A. The OS hazard ratio was 0.92 (95% CI 0.55-1.55; P = 0.76) for arm B vs arm A and 0.85 (95% CI 0·50-1.44; P = 0.55) for arm C vs arm A. Safety data of stage II and stage III CC have been reported previously. In multivariable analysis, T4 vs T3-1 (P = 0.041), number of examined nodes (P = 0.005), and age (P = 0.0008) were prognostic for DFS. The 3-year DFS and 5-year OS rates of stage II were 88.2% (95% CI 83.7%-93.0%) and 89.7% (95% CI 85.4%-94.2%) in arm A, 86.6% (95% CI 81.8%-91.6%) and 89.7% (95% CI 85.4%-94.2%) in arm B, 86.7% (95% CI 81.8%-91.8%) and 93.2% (95% CI 89.6%-97.0%) in arm C, respectively. Conclusions In this exploratory analysis, bevacizumab did not prolong DFS and OS when added to adjuvant oxaliplatin-based chemotherapy in resected high-risk stage II patients with CC. Clinical trial identification NCT00112918. Editorial acknowledgement Magdalena Benetkiewicz (GERCOR). Legal entity responsible for the study GERCOR. Funding Roche. Disclosure A. De Gramont: Honoraria (self): Yakult; Honoraria (self): Chugai Pharma. T.W. Kim: Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Pfizer; Research grant / Funding (self): AstraZeneca. J. Gallego-Plazas: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: Lilly; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Novartis; Leadership role, Study Coordinator of Agamenon study in advanced gastric cancer: Agamenon study. A. Cervantes: Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Servier; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Roche Beigene; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Foundation Medicine; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Fibrogen; Research grant / Funding (institution): Amcure; Research grant / Funding (institution): Sierra Oncology; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD; Leadership role, Executive Board member of ESMO: not remunerated Chair of Education of ESMO: not remunerated General and Scientific Director of INCLIVA: not remunerated Associate Editor of ESMO Open: not remunerated Associate Editor of Annals of Oncology: remunerated Editor in Chief of Cancer Treatment Reviews: remunerated: Executive Board member of ESMO: not remunerated Chair of Education of ESMO: not remunerated General and Scientific Director of INCLIVA: not remunerated Associate Editor of ESMO Open: not remunerated Associate Editor of Annals of Oncology: remunerated. D.J. Jonker: Research grant / Funding (institution): Hoffman-La Roche; Non-remunerated activity/ies, Chair of the GI Disease Site Committee of the Canadian Cancer Trials Group: Canadian Cancer Trials Group. A. Dewdney: Honoraria (self), Chairing evening meetings: Servier; Honoraria (self): Roche. T. (Sirisingha) Dejthevaporn: Honoraria (self): Roche; Honoraria (self): Eisai; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Leadership role: Thai Society of Clinical Oncology (TSCO). M. Moehler: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. T. Andre: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD Oncology; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Ventana; Honoraria (self): Sanofi; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self): Chugai; Honoraria (self): Yakult; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: HalioDx. All other authors have declared no conflicts of interest.

e14156 Background: Checkpoint inhibitors in cancer therapy have shown survival benefits in the treatment of several ATs. However, the risk of serious side effects seems greater in certain types of tumors presenting reduced compliance with therapy. The aim of this study is to evaluate the safety profile and clinical benefits of IT, as appraised using clinically related biomarkers of pts outside clinical trials. Methods: In this retrospective study, data were evaluated on pts in the Reggio Emilia Provincial Oncology Network who were treated for ATs using Nivolumab, Pembrolizumab and Ipilimumab monotherapy in clinical practice. The pts included in the study had received at least 1 dose of IT by June 2018. LDH and neutrophil–lymphocyte ratio (NLR) were collected at baseline, antibiotic therapy (ATB) was considered during IT, and immunorelated adverse events (irAEs) were assessed with CTCAE v.4.1. Results: A total of 169 pts were examined: 78 with NSCLC, 57 with melanoma, 29 with kidney cancer, 3 with head-neck cancer and 2 with colorectal cancer. 123 pts (73%) were treated with Nivolumab, 36 (21%) with Pembrolizumab and 10 (6%) with Ipilimumab. Overall, 62 pts (37%) experienced irAES of any degree: 17/29 (59%) pts with kidney cancer presented irAES, while only 35% (20/57) and 31% (24/78) of pts with melanoma and lung cancer did, respectively. A total of 27/62 (43%) pts delayed IT due to toxicity, but only 7/62 (11%) pts discontinued treatment due to irAEs. Statistically significant increases in PFS (11 vs. 5 months, p = 0.002) and OS (19.9 vs. 8.7 months, p = 0.002) were found between pts who experienced irAEs and those who did not. As previously demonstrated in other groups of pts, in the Cox regression performed for OS, a baseline value of LDH≥1.5xULN and median NLR ≥2.93 correlates with poor prognosis. Unlike what is already known, the use of ATB during IT (35% of pts) correlates with increased survival (HR 0.59; IC95% 0.37-0.94, p = 0.028). Conclusions: These data confirm the tolerability of IT in an unselected real-world population. In particular, the development of irAEs could be considered a positive predictor of outcome, but with a different incidence among MTS.

Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolic catabolism of 5-fluorouracil (5-FU) and its derivatives (capecitabine and tegafur). Complete or partial deficiency of DPD activity has been demonstrated to induce severe toxicities in cancer patients treated with fluoropyrimidine therapy. We analyzed 180 individuals that were candidates for a treatment with 5-FU class drugs for the most common DPD mutation, IVS14+1G>A, and detected four heterozygous patients. We recorded the toxicities for all 180 individuals after the first two chemotherapy cycles and found that three of the four patients, although they were treated with a dose reduction in 50 % on the basis of the genetic analysis, all showed severe toxicities that resulted in hospitalization of patient and premature discontinuation of treatment. One patient with mutated DPD was not treated with chemotherapy upon the clinician's decision because of his DPD mutated genotype and the presence of microsatellite instability. Our data suggest that greater dose reductions or alternative therapies are needed for patients with DPD IVS14+1G>A mutations. © 2013 SIMI

3568Background: CEA is a CC biological marker that correlates with tumor stage. Its measurement is recommended for follow up after surgery. CEA above 5 ng/mL is of poor prognosis, however this cuto...

2573Background: Deleterious polymorphisms in gene-encoding DPD (DPYD) may result in the severe reduction of DPD enzymatic activity that causes life-threatening toxicities when the standard dose of ...

Based on the results of the MOSAIC trial that were recently confirmed by the NSABP protocol C-07 study, the combination of oxaliplatin and 5-fluorouracil has become the standard adjuvant treatment for patients with stage III colon cancer. These pivotal studies confirm a similar, significant advantage in populations with stage II and III disease; however, they show a remarkable difference in toxicity, with greater risk of life-threatening complications (eg, diarrhea and bowel wall injury) in the NSABP C-07 trial. In this article, we analyze the differences and similarities between these studies.

3543Background: The combination of triple chemotherapy regimens with an anti-EGFR reported promising activity with some safety concerns in phase II trials. MACBETH trial aimed at evaluating the activity and safety of 1st-line mFOLFOXIRI plus cet and at exploring the role of maintenance with cet or bev in unresectable mCRC patients (pts). The study initially enrolled KRAS wt pts and, after an amendment in Oct 2013, only RAS/BRAF wt pts. Methods: Eligibility criteria included measurable, unresectable, RAS/BRAF wt disease (centrally screened), age 18-75 yrs, no prior therapy for advanced disease. Pts were randomized to receive up to 8 cycles of mFOLFOXIRI + cet (cet 500 mg/sqm, iri 130 mg/sqm, oxa 85 mg/sqm, I-LV 200 mg/sqm, 5FU 2400 mg/sqm over 48h q2w), followed by cet (arm A) or bev (arm B) until progression. The trial was a phase II randomized non-comparative study, with primary endpoint 10 months-Progression Free Rate (10m-PFR). Results: Between Nov 2011 and Feb 2015, 323 pts from 21 Italian centers wer...

2567 Background: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluorouracil. Deleterious polymorphisms in gene-encoding DPD ( DPYD) results in a DPD deficiency that causes life-threatening toxicities when the standard dose of fluorouracil is used. DPYD*2A (IVS14+1G > A) is the most common single-nucleotide polymorphism (SNP) associated with critical DPD deficiency. At present, most of the evidence supports screening for at least 3 SNPs (DPYD*2A, c.2846 A > T, c.1679T > G). The aim of this study is to confirm that the detection of additional polymorphisms of DPYD could enhance prevention of fluoropyrimidine toxicity. Methods: In 2011, we began to screen DPYD*2A in patients candidate for fluoropyrimidine based-chemotherapy. As the first step of the evaluation, we selected all cases of DPYD*2A wild type, from 2011 to 2012, who developed CTC-NCI-V.3 toxicity ≥ G3. In these patients, we researched the other 3 SNPs (c.2846 A > T, c.1679T > G, c.2194C > A). Mutational status was analyzed with real Time PCR. Results: From 2011 to 2016 we pre-emptively screened DPD deficiency in 1,863 patients and 32 subjects (1.6%), with results mutated for DPYD*2A. As the first step of the evaluation, 548 subjects were assessed from 2011 to 2012. We found 7 patients who were carriers of the DPYD*2A mutation (1.27%). Of the 541 wild type cases, 114 presented toxicities ≥ G3. In this subgroup, 22 patients (19%) proved to be mutated for the other SNPs of DPYP, as reported in the table below. Conclusions: Preliminary data show that in 22 (19%) of 114 patients who presented severe toxicity which was not correlated with DPYD*2A, we found other polymorphisms of gene encoding DPD. Out of the 3 SNPs evaluated, c.2194 C > A proved to be the most frequent, although it is the polymorphism that is least known and least studied. Such results suggest that the evaluation of additional polymorphisms could enhance the prevention of fluoropyrimidine toxicity. The results are expected to be clarified further in the second step, which is ongoing. [Table: see text]

3501 Background: Six months of oxaliplatin-based treatment has been the standard of care as adjuvant therapy for stage III colon cancer and an accepted option for high-risk stage II. Given the cumulative neurotoxicity associated to oxaliplatin, a shorter duration of therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods: TOSCA was an open-label, phase III, multicenter, non-inferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months or 6 months of FOLFOX4/XELOX. Primary end-point was relapse-free survival. Results: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Two thirds were stage III. At the cut-off time for analysis the median time of follow-up was 62 months and 772 relapses or deaths have been observed. The RFS rate at 8 years is 75%. This analysis was done when 82% of the planned number of events was reached, with a power of 72% instead of 80%. The decision to anticipate the analysis was based on the participation to the IDEA joint collaborative analysis of studies sharing this clinical question. The Hazard Ratio of the 3months vs 6 months for relapse/death was 1.14 (95%CI 0.99-1.31, p for non inferiority = 0.253) and the confidence interval crossed the non inferiority limit of 1.20. Conclusions: TOSCA was not able to demonstrate that 3 months of oxaliplatin-based adjuvant treatment is as efficacious as 6 months. Nevertheless , because the absolute difference in RFS between the two treatment durations is small ( less than 3 % at 5 years ), the decision to complete the whole 6-month program should be individualized based on toxicity and patients’ attitude. This study is registered with ClinicalTrials.gov Registration Number: NCT00646607. It was supported by a grant from AIFA (Agenzia Italiana del Farmaco) Grant Code FARM5RWTWZ. Clinical trial information: NCT00646607.

Background Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. Patients and methods A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19–21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] Results Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. Conclusion Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.