A Real-world Multicenter Prospective Study of Everolimus in Pancreatic Neuroendocrine Tumors: The 'PROTOR' Study.

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (panNETs) are rare neoplasms with challenging disease management. We aimed to evaluate the progression-free survival (PFS) and overall response rate (ORR) in chemotherapy-naïve patients with unresectable or metastatic Grade (G) 1-2 panNETs treated with everolimus in the routine care in Greece. PATIENTS AND METHODS: This was a multicenter, prospective, observational study. Eligible patients were recently (≤4 weeks) initiated on treatment with everolimus and were followed for up to 48 months. RESULTS: Nineteen eligible patients (mean age 55.1 years) were enrolled. All patients had metastatic disease and 84.2% had G2 panNET. Everolimus was initiated in combination with somatostatin analogues in 84.2% of the patients. The mean everolimus treatment duration was 21.5 months. The median Kaplan-Meier-estimated PFS was 20.4 months (95% confidence interval=14.1-41.5). The ORR was 27.8%. The rate of everolimus-related adverse events was 84.2% (Grade ≥3: 31.6%). CONCLUSION: Everolimus displayed clinical benefit and a predictable safety profile in pancreatic neuroendocrine tumors.

Comprehensive tumor molecular profile analysis in clinical practice.

BACKGROUND: Tumor molecular profile analysis by Next Generation Sequencing technology is currently widely applied in clinical practice and has enabled the detection of predictive biomarkers of response to targeted treatment. In parallel with targeted therapies, immunotherapies are also evolving, revolutionizing cancer therapy, with Programmed Death-ligand 1 (PD-L1), Microsatellite instability (MSI), and Tumor Mutational Burden (TMB) analysis being the biomarkers employed most commonly. METHODS: In the present study, tumor molecular profile analysis was performed using a 161 gene NGS panel, containing the majority of clinically significant genes for cancer treatment selection. A variety of tumor types have been analyzed, including aggressive and hard to treat cancers such as pancreatic cancer. Besides, the clinical utility of immunotherapy biomarkers (TMB, MSI, PD-L1), was also studied. RESULTS: Molecular profile analysis was conducted in 610 cancer patients, while in 393 of them a at least one biomarker for immunotherapy response was requested. An actionable alteration was detected in 77.87% of the patients. 54.75% of them received information related to on-label or off-label treatment (Tiers 1A.1, 1A.2, 2B, and 2C.1) and 21.31% received a variant that could be used for clinical trial inclusion. The addition to immunotherapy biomarker to targeted biomarkers' analysis in 191 cases increased the number of patients with an on-label treatment recommendation by 22.92%, while an option for on-label or off-label treatment was provided in 71.35% of the cases. CONCLUSIONS: Tumor molecular profile analysis using NGS is a first-tier method for a variety of tumor types and provides important information for decision making in the treatment of cancer patients. Importantly, simultaneous analysis for targeted therapy and immunotherapy biomarkers could lead to better tumor characterization and offer actionable information in the majority of patients. Furthermore, our data suggest that one in two patients may be eligible for on-label ICI treatment based on biomarker analysis. However, appropriate interpretation of results from such analysis is essential for implementation in clinical practice and accurate refinement of treatment strategy.

Three-dimensional conformal radiotherapy for hepatocellular carcinoma in patients unfit for resection, ablation, or chemotherapy: a retrospective study.

PURPOSE: The purpose is to evaluate the feasibility, efficacy, and the toxicity of three-dimensional conformal radiotherapy (3DCRT) in patients with advanced hepatocelluar carcinoma (HCC) and inferior vena cava tumor thrombosis (IVCTT). METHODS: Between 2007 and 2012, in a retrospective way, 9 patients (median age 69 years) with advanced HCC and IVCTT unfit for surgery, radiofrequency ablation, embolization, or chemotherapy were treated with three-dimensional conformal radiotherapy (3DCRT). The radiotherapy volume included both primary tumor and IVTT. The radiotherapy schedule was 50-52 Gy in 2 Gy fractions. Overall survival (OS), response to radiotherapy, visual analogue scale (VAS), and toxicity were assessed. RESULTS: All patients demonstrated a response rate up to 60%. During radiotherapy, 3 patients experienced grade 1 nausea/vomit toxicity. All patients demonstrated an elevation of the liver enzymes (3 patients with grade 1 and 6 patients with grade 2). The mean VAS-score was decreased from 6.11 to 3.11, while the median overall survival was 24 months. CONCLUSION: 3DCRT achieves a very high local control rate and is suitable for patients with HCC and IVTT, while the documented radiation induced toxicity is moderate. It can be recommended for palliation in patients unable to undergo curative therapies.

Evaluation of the prognostic role of a panel of biomarkers in stage IB-IIIA non-small cell lung cancer patients.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains a highly lethal disease worldwide and research for more effective treatment strategies is ongoing. Identification of molecular prognostic and predictive markers remains under investigation with results that are often conflicting. PATIENTS AND METHODS: Seventy-three patients (n= 73) with stage IB-IIIA completely resected NSCLC who were postoperatively treated with 6 cycles of paclitaxel and carboplatin from July 1998 to September 2002 took part in this study. Most stage IIIA patients subsequently received adjuvant radiotherapy. Cyclooxygenase-2 (COX-2), vascular endorhelial growth factor (VEGF), dihydrodiol dehydrogenase (DDH), receptor-binding cancer antigen expressed on SiSo cells (RCAS-1) and epidermic growth factor receptor (EGFR/HER-1) expression were assessed immunohistochemically; Heregulin family (HER1-4), VEGF and p53 were analysed by RT-PCR. RESULTS: Totally, 61 (84%) men and 12 (16%) women with median age of 63 years and median PS of 0 were included in the study. There were 18 stage IB, 29 stage II and 26 stage IIIA patients. Sixty-seven samples were available for immunohistohemistry. COX-2 expression was detected in 24 patients (36%), VEGF in 14 (21%), RCAS1 in 31 (46%), DDH in 15 (22%). For EGFR, only 58 samples were evaluated, 13 of which were positive (22%). Messenger RNA expression data was only available for 60 patients; VEGF was detected in 32 (53%), p53 in 30 (50%), EGFR in 35 (58%), HER2 in 4 (7%) and HER3 in 19 (32%). HER4 was not detected in any sample. In the Cox analysis for overall survival (OS) and disease-free survival (DFS), none of the factors evaluated by IHC or RT-PCR reached statistical significance. CONCLUSION: Even though the biomarkers tested are expressed in a significant proportion of lung tumors, none of them was found to be of prognostic significance in patients with NSCLC.

Paclitaxel and carboplatin as first-line chemotherapy combined with gefitinib (IRESSA) in patients with advanced breast cancer: a phase I/II study conducted by the Hellenic Cooperative Oncology Group.

Paclitaxel (Taxol) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m(2) over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35-77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in > or =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27(kipl). The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.

Docetaxel and gemcitabine combination, as first-line treatment, in patients with extensive disease small-cell lung cancer. A phase II study of the Hellenic Cooperative Oncology Group.

There is some evidence that taxanes and gemcitabine are effective antitumor agents against small-cell lung cancer (SCLC). A total of 20 chemotherapy-naive patients with extensive disease (ED) SCLC, were treated as a part of the first step of a phase II study, with docetaxel 50 mg/m(2) and gemcitabine 1000 mg/m(2), both administered on day 1 and 8 every 3 weeks up to a total of six cycles. For patients who progressed after the first cycle or had stable disease after the second cycle of chemotherapy, protocol treatment was stopped and further treatment with the standard cisplatin or carboplatin-etoposide combination was administered. Patients were in the vast majority male smokers with a good performance status. A total of 72 cycles was delivered while patients managed to receive the 78 and 84% of the planned dose of docetaxel and gemcitabine, respectively. Only six patients responded partially and the trial ended prematurely since at least seven responses were required among the first 19 patients. With a median follow-up of 13 months, median time to progression (TTP) was 8 months and median survival 9.6 months. Hematological and non-hematological toxicity was generally acceptable while patients tolerated their treatment reasonably well. In conclusion, docetaxel-gemcitabine showed a modest response rate in chemotherapy-naive patients with ED SCLC.