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PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Peptide receptor radionuclide therapy (PRRT) is an effective therapeutic option in patients with metastatic neuroendocrine tumor (NET). However, PRRT fails in about 15–30% of cases. Identification of biomarkers predicting the response to PRRT is essential for treatment tailoring. We aimed to evaluate the predictive and prognostic role of semiquantitative and volumetric parameters obtained from the 68Ga-DOTATOC PET/CT before therapy (bPET) and after two cycles of PRRT (iPET). A total of 46 patients were included in this retrospective analysis. The primary tumor was 78% gastroenteropancreatic (GEP), 13% broncho-pulmonary and 9% of unknown origin. 35 patients (76.1%) with stable disease or partial response after PRRT were classified as responders and 11 (23.9%) as non-responders. Logistic regression analysis identified that baseline total volume (bTV) was associated with therapy outcome (OR 1.17; 95%CI 1.02–1.32; p = 0.02). No significant association with PRRT response was observed for other variables. High bTV was confirmed as the only variable independently associated with OS (HR 12.76, 95%CI 1.53–107, p = 0.01). In conclusion, high bTV is a negative predictor for PRRT response and is associated with worse OS rates. Early iPET during PRRT apparently does not provide information useful to change the management of NET patients.

Background: There is evidence that early integration of palliative care improves quality of life, lowers spending and helps clarify preferences and goals for advanced cancer patients. Little is known about the feasibility and acceptability of early integration. Aim: Assessing feasibility of early integration of palliative care, and exploring concerns perceived and problems encountered by patients, relatives and oncologists. Design: A phase 2 mixed-methods study ( ClinicalTrials.Gov :NCT02078700). Methods: Oncologists of two outpatient clinics offered a specialised palliative care intervention integrated with standard oncological care to all consecutive newly diagnosed metastatic respiratory/gastrointestinal cancer patients. We interviewed samples of patients, relatives and oncologists to explore strengths and weaknesses of the intervention. Results: The intervention was proposed to 44/54 eligible patients (81.5%), 40 (90.1%) accepted, 38 (95.0%) attended the first palliative care visit. The intervention was completed for 32 patients (80.0%). It did not start for three (7.5%) and was interrupted for three patients who refused (7.5%). The Palliative Care Unit performed 274 visits in 38 patients (median per patient 4.5), and 24 family meetings with relatives of 16 patients. All patients and most relatives referred to the usefulness of the intervention, specifically for symptoms management, information and support to strategies for coping. Oncologists highlighted their difficulties in informing patients on palliative intervention, sharing information and coordinating patient’s care with the palliative care team. Conclusion: Early integration of palliative care in oncological setting seems feasible and well accepted by patients, relatives and, to a lesser extent, oncologists. Some difficulties emerged concerning patient information and inter-professional communication.

Although lactate dehydrogenase (LDH) serum levels, indirect markers of angiogenesis, are associated with a worse outcome in several tumours, their prognostic value is not defined in pancreatic cancer. Moreover, high levels are associated even with a lack of efficacy of tyrosine kinase inhibitors, contributing to explain negative results in clinical trials. We assessed the role of LDH in advanced pancreatic cancer receiving sorafenib. Seventy-one of 114 patients included in the randomised phase II trial MAPS (chemotherapy plus or not sorafenib) and with available serum LDH levels, were included in this analysis. Patients were categorized according to serum LDH levels (LDH ≤ vs.> upper normal rate). A significant difference was found in progression free survival (PFS) and in overall survival (OS) between patients with LDH values under or above the cut-off (PFS: 5.2 vs. 2.7 months, p = 0.0287; OS: 10.7 vs. 5.9 months, p = 0.0021). After stratification according to LDH serum levels and sorafenib treatment, patients with low LDH serum levels treated with sorafenib showed an advantage in PFS (p = 0.05) and OS (p = 0.0012). LDH appears to be a reliable parameter to assess the prognosis of advanced pancreatic cancer patients, and it may be a predictive parameter to select patients candidate to receive sorafenib.

Aim: To assess the role of Notch activation in predicting bevacizumab efficacy in colorectal cancer (CRC). Materials & methods: Notch activation was evaluated by immunohistochemistry (IHC) on 65 CRC enrolled within randomized clinical trials assessing first-line bevacizumab-based chemotherapy and on 21 CRC treated with chemotherapy alone. Results: Strong Notch (IHC 3+) activation was negatively associated with response (18 vs 62% in low Notch cases [IHC 0, 1, 2+]; p = 0.016), progression-free survival (4.9 vs 12.1 months; p = 0.002) and overall survival (19.3 vs 30.4 months; p = 0.039). No correlation was found between Notch activation and clinical outcome in CRC treated with chemotherapy alone. Conclusion: A potential role of Notch activation in the antitumor activity of bevacizumab could be hypothesized.

Background & Aims The study aimed to evaluate the tissue expression of molecules involved in intracellular signalling pathways as predictors of response to sorafenib in advanced hepatocellular carcinoma (HCC). Methods We considered 77 patients enrolled into three prospective trials of sorafenib treatment for whom pretreatment tumour tissue was available. The tissue expression of β-catenin, glutamine synthetase (GS), phosphorylated extracellular signal regulated kinase (pERK), phosphorylated v-akt murine thymoma viral oncogene homolog (pAKT) and vascular endothelial growth factor receptor-2 (VEGFR-2) was analysed by immunostaining. Stains were scored semiquantitatively and compared with a reference group of 56 untreated HCCs. Results Overall, the expression of antigens was comparable between treated and untreated patients. Shorter progression-free survival (PFS) and overall survival (OS) were associated with increased pERK staining (≥ 2+ scores) (PFS: 75th percentile 4.4 vs 8.4 months; P = 0.01; OS: 75th percentile 7.0 vs 15.0 months; P = 0.005) and VEGFR-2 staining (≥ 2+ scores) (PFS: 75th percentile 3.8 vs 7.0 months; P = 0.039; OS: 75th percentile 6.3 vs 15.0 months; P = 0.004). At multivariate analysis, both pERK and VEGFR-2 staining maintained an independent effect on OS (HR 2.09; 95% CI, 1.13–3.86, P = 0.019 and HR 2.28; 95% CI, 1.13–4.61, P = 0.021 respectively). No effect was observed for the other tested biomarkers. Conclusions Elevated tissue expression of pERK and VEGFR-2 was predictive of poor outcome in advanced HCC treated with sorafenib.

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.

e15656Background: Neuroendocrine tumors (NETs) are considered rare tumors and can produce a variety of hormones. In this study, we examined the epidemiology and prognostic factors for NETs, in Ital...

Purpose Aim of this phase I study was to identify the maximum tolerated dose and dose limiting toxicity of continuous infusion of Irinotecan through a port-a-cath placed in the hepatic artery in patients with hepatocellular carcinoma and cirrhosis to explore new strategies in advanced hepatocellular carcinoma. Response rate and time-to-progression were analysed. Methods Irinotecan was delivered as a five-day continuous infusion every 21 days, with increases of 2.5 mg/m 2 /day every three patients, starting from 7.5 mg/m 2 /day. Dose limiting toxicity corresponded to one patient in each triplet developing G4 haematological or G3 non-haematological toxicity, confirmed in two triplets. Twenty-eight patients (17 Child-Pugh A, 11 B) received treatment and tumour response was assessed after three courses completed by 22 patients. Results Dose limiting toxicity was G3 diarrhoea in two patients, reached at 27.5 mg/m 2 /day and the recommended dose was set at 25 mg/m 2 /day. Nineteen of 30 patients experienced adverse events related to porth-a-cath placement and one died from liver ischemia and sepsis. Median time-to-progression was 11.3 months. Conclusion Intrarterial infusion of Irinotecan is feasible in patients with hepatocellular carcinoma on cirrhosis at a recommended dose of 25 mg/m 2 /day, with no major adverse drug-related events, but with some concerns about the insertion and management of the intra-arterial device.

We report the clinical history of a female affected by advanced colorectal cancer (CRC). The patient was treated with five subsequent therapeutic schedules (FOLFIRI, FOLFOXIRI, FOLFIRI, FOLFOX4, FOLFOX4 plus cetuximab) because of the progression of the disease. The sixth treatment was bevacizumab in combination with 5-fluorouracil and irinotecan (FOLFIRI). The CT scan and the FDG-PET/CT performed 3 months after the beginning of the treatment showed that some, even if not all, lesions had a reduction of both size and metabolic activity. After the second revaluation the disease progressed. This short report suggests that the response of CRC to antiangiogenetic therapy may also occur after several unsuccessful antineoplastic treatments. Different biological features may explain the nonhomogeneous objective response of the metastatic lesions. Molecular imaging techniques seem to be mandatory in the era of tailored therapy since it is useful to have an in vivo ‘biological picture’ of the neoplastic disease.

e15242 Background: FOLFIRINOX and nab-paclitaxel (nab-p) plus gemcitabine are approved regimens for metastatic pancreatic cancer (mPC).NabucCO study was a phase I/II trial designed in two steps.The...

15163 Background: No standard therapies are available for HCC patients (pts) ineligible for curative treatments. HCC has a rich neovasculature and neoangiogenesis is a negative prognostic factor: a high density of microvessels and hyperexpression of VEGF correlates with an increased propensity for invasion and metastatization and with a decreased DFS after resection. High level of circulating endothelial progenitors cells (CEPc) are related with insurgence and progression of HCC. Phase II trials with antiangiogenic agents in monotherapy had a response rate lower than 10% but stable disease (SD) is encouraging ranging between 30 and 60%. Retrospective analysis of standard capecitibine showed a response of 11% and similar SD rate. Experimental data on solid tumors suggest that metronomic CT prolongs inibihition of tumor growth, avoiding CEPc mobilization. Methods: Starting in september 2006, twenty-two patients were started on treatment (19 male; median age 63.7, range 47–82 ). BCLC (Barcelona Consensus Liver Cancer): 5 pts = B; 17 pts = C; Child: 12 pts =A, 8=B, 2=C. 14 pts had portal thrombosis. 15 pts were treated in front line, 7 in second line (4 pts previously treated with Sorafenib and 3 with experimental protocol of CPT-11 HAI; ASCO 2006 Abs 14061 ). The first cycle was carried out with standard capecitabine (2000 mg/sq.mt; 14 over 21 days), followed by metronomic capecitabine (1300 mg) without interruption. To compare the angiogenic role of metronomic capecitabine versus standard administration, VEGF and trombospondine have been dosed at baseline and after the first cycle of standard capecitabine and after one month of metronomic capecitabine. The response has been assessed by CT scan every three months. Results: Five out of 22 patients have been dismissed for toxicity (liver failure) during the standard capecitabine treatment. Among the 17 remaining patients, two have discontinued the treatment due to toxicity (liver failure) during the metronomic treatment and 10 have accomplished at least the first month of metronomic schedule. 6 patients have been evaluated for response: 2 PR (one second line), 3 SD (all in second line), 1 PD (second line). Conclusions: Metronomic capecitabine seems to have a better tolerability than standard schedule and promises good efficacy. No significant financial relationships to disclose.

18015 Background: There is increasing evidence that the expression of Cyclo-oxygenase 2 correlates with development and progression of malignant melanoma. Celecoxib (C) has demonstrated some kind of activity in monotherapy in melanoma. Temozolomide (T) has consistent activity in melanoma, either as monotherapy or in combination. We designed a phase II study to determine the efficacy and toxicity of the combination of Celecoxib and Temozolomide in advanced melanoma as first line of therapy Methods: From January 2004 to October 2005, 13 patients with metastatic melanoma were enrolled in the study. There were 4 males and 9 females. The median age was 59 years. Patients received Temozolomide 200/mg/mq day po for 5 days every 4 weeks and Celecoxib 400 mg BID for 10 days every 4 weeks. Results: Among 12 evaluable patients there were 4 partial responses (30.8%), no complete response or disease stabilization. Progression occurred in 8 patients (61.5%). The median TTP was 3.14 months and the median survival was 9.06 months. The median number of cycles was 2, only 2 patients completed four cycles of treatment. Most commonly seen toxicities were nausea/vomiting (46%), fatigue (93%), thrombocytopenia (15.3%), leukopenia (7.6%). Two patients discontinued the treatment due to grade 4 thrombocytopenia. Conclusions: The combination of Temozolomide and Celecoxib is safe, manageable and provides clinical benefit, but its activity is not superior to standard therapy. No significant financial relationships to disclose.