Real-world safety and efficacy data of immunotherapy in patients with cancer and autoimmune disease: the experience of the Hellenic Cooperative Oncology Group.

BACKGROUND: Data on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with concurrent autoimmune diseases (AID) are limited. METHODS: We performed a retrospective multicenter review of medical records of patients with cancer and underlying AID who received ICI. The primary endpoint was progression-free survival (PFS). RESULTS: Among 123 patients with pre-existing AID who received ICI, the majority had been diagnosed with non-small cell lung cancer (NSCLC, 68.3%) and melanoma (14.6%). Most patients had a rheumatologic (43.9%), or an endocrine disorder (21.1%). Overall, 74 (60.2%) patients experienced an immune-related adverse event (irAE) after ICI initiation, AID flare (25.2%), or new irAE (35%). Frequent irAEs included thyroiditis, dermatitis and colitis. ICI was permanently discontinued due to unacceptable (8.1%) or fatal (0.8%) toxicity. In patients with NSCLC, corticosteroid treatment at the initiation of immunotherapy was associated with poor PFS (HR = 2.78, 95% CI 1.40-5.50, p = 0.003). The occurrence of irAE was associated with increased PFS (HR = 0.48, 95% CI 0.25-0.92, p = 0.026). Both parameters maintained their independent prognostic significance. CONCLUSIONS: ICI in patients with cancer and pre-existing AID is associated with manageable toxicity that infrequently requires treatment discontinuation. However, since severe AID flare might occur, expected ICI efficacy and toxicity must be balanced. CLINICAL TRIAL IDENTIFIER: NCT04805099.

Targeting the Interplay between HDACs and DNA Damage Repair for Myeloma Therapy.

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells, and accounts for 10% of all hematologic malignancies and 1% of all cancers. MM is characterized by genomic instability which results from DNA damage with certain genomic rearrangements being prognostic factors for the disease and patients' clinical response. Following genotoxic stress, the evolutionary conserved DNA damage response (DDR) is activated and, in turn, coordinates DNA repair with cell-cycle events. However, the process of carcinogenesis cannot be attributed only to the genetic alterations, but also involves epigenetic processes. Regulation of expression and activity of key players in DNA repair and checkpoint proteins are essential and mediated partly by posttranslational modifications (PTM), such as acetylation. Crosstalk between different PTMs is important for regulation of DNA repair pathways. Acetylation, which is mediated by acetyltransferases (HAT) and histone deacetylases (HDAC), not only affects gene expression through its modulation of histone tails but also has recently been implicated in regulating non-histone proteins. Currently, several HDAC inhibitors (HDACi) have been developed both in pre-clinical and clinical studies, with some of them exhibiting significant anti-MM activities. Due to reversibility of epigenetic changes during the evolutionary process of myeloma genesis, the potency of epigenetic therapies seems to be of great importance. The aim of the present paper is the summary of all data on the role of HDACi in DDR, the interference with each DNA repair mechanism and the therapeutic implications of HDACi in MM.

Phase 2 study of cabazitaxel as second-line treatment in patients with HER2-negative metastatic breast cancer previously treated with taxanes-a Hellenic Cooperative Oncology Group (HeCOG) Trial.

BACKGROUND: Cabazitaxel is a novel taxane that might be active in breast cancer resistant to first-generation taxanes. METHODS: The purpose of the current multicentre phase II trial was to evaluate the activity and safety of cabazitaxel, as second-line treatment, in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with taxanes. The primary endpoint was objective response rate (ORR). RESULTS: Eighty-four patients were enrolled between October 2012 and November 2016. Taxane resistance to previous treatment was detected in 43 cases. The ORR was 22.6% in the intent-to-treat population, 23.3% in taxane-resistant and 20.5% in taxane-non-resistant cases. At a median follow-up of 39.6 months, the median progression-free survival and overall survival were 3.7 months (95% CI 2.2-4.4) and 15.2 months (95% CI 11.3-19.4), respectively. Regarding toxicity, grade 3-4 neutropenia was reported in 22.6% and febrile neutropenia in 6% of the patients, respectively. Two fatal events (one febrile neutropenia and one sepsis) were reported as being related to study treatment. CONCLUSIONS: This phase II trial suggests that cabazitaxel is active as second-line treatment in taxane-pretreated patients with HER2-negative MBC, with manageable toxicity.

Clinical activity of a htert (vx-001) cancer vaccine as post-chemotherapy maintenance immunotherapy in patients with stage IV non-small cell lung cancer: final results of a randomised phase 2 clinical trial.

BACKGROUND: The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT572 CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC). METHODS: A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS. RESULTS: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004). CONCLUSION: Vx-001 could induce specific CD8+ immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001. CLINICAL TRIAL REGISTRATION: NCT01935154.

Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group.

BACKGROUND: Sequential anthracyclines and taxanes are standard adjuvant chemotherapy for patients with high-risk axillary node-positive breast cancer. We compared a sequential to a concurrent regimen in high-risk node-negative early breast cancer. METHODS: Patients were eligible if they had tumours >2 cm or T1c with two of the following characteristics: no oestrogen receptor (ER) and progesterone receptor (PR) expression, histological grade III, Ki67 >40% and vascular, lymphovascular or perineural invasion. They were randomised to receive four cycles of epirubicin 90 mg m-2 followed by four cycles of docetaxel 75 mg m-2 (sequential regimen) or six cycles of epirubicin 75 mg m-2 plus docetaxel 75 mg m-2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with G-CSF prophylaxis only for the concurrent arm. The primary endpoint was disease-free survival (DFS). RESULTS: Between 2001 and 2013, 658 women received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 years, 43.9% of the patients were premenopausal and of the tumours 44.2% were ⩽2 cm, 52.7% histological grade 3 and 35.3% hormone receptor-negative. After a median follow-up of 70.5 months, there were 29 (8.8%) vs 42 (12.8%) disease relapses (P=0.102) and 11 (3.3%) vs 19 (5.8%) deaths (P=0.135), in the sequential and concurrent arm, respectively. The 5-year DFS rates were 92.6% vs 88.2% for sequential and concurrent arm, respectively (hazard ratio (HR): 1.591; 95% confidence interval (CI): 0.990-2.556; P=0.055). Toxicity included grade 2-4 neutropenia in 54% vs 41% (P=0.001), febrile neutropenia 2.7% vs 6.1% (P=0.06), nausea/vomiting 18.5% vs 12.4% (P=0.03) of patients in the sequential and concurrent arm. There were no toxic deaths. CONCLUSIONS: Sequential compared with the concurrent administration of anthracyclines and taxanes is associated with a non-significant but possibly clinically meaningful improvement in DFS. In the era of molecular selection of patients for adjuvant chemotherapy, this study offers valuable information for the optimal administration of anthracyclines and taxanes in patients with node-negative disease.

Dose-dense paclitaxel versus docetaxel following FEC as adjuvant chemotherapy in axillary node-positive early breast cancer: a multicenter randomized study of the Hellenic Oncology Research Group (HORG).

Adding a taxane to anthracycline-based adjuvant chemotherapy prolongs survival in node-positive early breast cancer. However, which is the preferable taxane in a dose-dense regimen remains unknown. We conducted a randomized study to compare the efficacy of dose-dense paclitaxel versus docetaxel following 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) as adjuvant chemotherapy in women with node-positive early breast cancer. Following surgery women with HER2-negative breast cancer and at least one infiltrated axillary lymph node were randomized to receive four cycles of FEC (700/75/700 mg/m(2)) followed by four cycles of either paclitaxel (175 mg/m(2)) or docetaxel (75 mg/m(2)). All cycles were administered every 14 days with G-CSF support. The primary endpoint was disease-free survival (DFS) at 3 years. Between 2004 and 2007, 481 women were randomized to paclitaxel (n = 241) and docetaxel (n = 240). After a median follow-up of 6 years, 51 (21%) and 48 (20%) women experienced disease relapse (p = 0.753) and there was no significant difference in DFS between the paclitaxel- and docetaxel-treated groups (3-year DFS 87.4 vs. 88.3%, respectively; median DFS not reached; p = 0.633). Toxicities were manageable, with grade 2-4 neutropenia in 21 versus 31% (p = 0.01), thrombocytopenia 0.8 versus 3.4% (p = 0.06), any grade neurotoxicity 17 versus 7.5% (p = 0.35) and onycholysis 4.9 versus 12.1% (p = 0.03) for patients receiving paclitaxel and docetaxel, respectively. There were no toxic deaths. Dose-dense paclitaxel versus docetaxel after FEC as adjuvant chemotherapy results in a similar 3-year DFS rate in women with axillary node-positive early breast cancer. Due to its more favorable toxicity profile, paclitaxel is the taxane of choice in this setting.

Safety and Efficacy of RAD001 (Everolimus) Administered Upon Relapse During or After Adjuvant Treatment in Post-menopausal Women With Hormone Receptor Positive, HER2/neu Negative Locally Advanced or Metastatic Breast Cancer (CRAD001JGR08 "MELPOMENI" study).

BACKGROUND/AIM: This study aimed to provide real-world safety and effectiveness data of everolimus (EVE) plus exemestane (EXE) in estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced breast cancer (aBC). PATIENTS AND METHODS: This prospective observational study was conducted by 19 hospital-based oncologists in Greece. Eligible patients were treated with EVE+EXE in the first-line setting; EVE was initiated according to the approved label. RESULTS: Overall, 75 eligible patients (mean age: 66.9 years; visceral metastases: 49.3%; bone-only metastases: 37.3%) were included in the effectiveness analyses. Over a median (interquartile range) of 12.1 months (range=4.2-20.5 months) of EVE treatment, the median progression-free survival was 18.0 months and the overall response rate was 22.7%. Among patients that received ≥1 EVE dose (n=80), the incidence of EVE-related adverse events was 72.5% (serious: 55.0%); stomatitis (22.5%), fatigue (22.5%), pneumonitis (18.8%); and cough (18.8%) were the most common. CONCLUSION: In the routine care in Greece, EVE demonstrates clinical benefit and a predictable safety profile.

Front-Line Bevacizumab plus Chemotherapy with or without Maintenance Therapy for Metastatic Breast Cancer: An Observational Study by the Hellenic Oncology Research Group.

Front-line bevacizumab (BEV) in combination with taxanes offers benefit in progression-free survival (PFS) in metastatic breast cancer (mBC). The medical records of mBC patients, treated with front-line BEV-based chemotherapy, were retrospectively reviewed in order to generate real life safety and efficacy data. Patients with human epidermal growth factor receptor 2 (HER2)-negative mBC treated with front-line BEV in combination with chemotherapy were eligible. Maintenance therapy with BEV and/or hormonal agents was at the physicians' discretion. Among the 387 included patients, the most common adverse events were anemia (61.9%, mainly grade 1), grade 3/4 neutropenia (16.5%), grade 1/2 fatigue (22.3%), and grade 1/2 neuropathy (19.6%). Dose reductions were required in 164 cycles (7.1%) and toxicity led to treatment discontinuation in 21 patients (5.4%). The median PFS and the median overall survival (OS) were 13.3 (95% CI: 11.7-14.8) and 32.3 months (95% CI: 27.7-36.9), respectively. Maintenance therapy, with hormonal agents (ET) and/or BEV, was associated with longer OS versus no maintenance therapy (47.2 versus 23.6 months; p < 0.001) in patients with hormone receptor (HR)-positive disease and BEV maintenance offered longer OS versus no maintenance in patients with HR-negative disease (52.8 versus 23.3; p = 0.023). These real-life data show that front-line BEV-based chemotherapy in HER2-negative mBC patients is an effective treatment with an acceptable toxicity profile. The potential benefit of maintenance treatment, especially ET, is important and warrants further research.

Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma.

Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including ATM (11, 2.0%) and BRCA2 (6, 1.1%), while 19 patients (3.5%) were heterozygotes for MUTYH P/LPVs and 9 (1.6%) carried the low-risk allele, CHEK2 p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, p = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers (p = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (p-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.

A multicenter phase II trial with irinotecan plus oxaliplatin as first-line treatment for inoperable/metastatic cancer of the biliary tract.

PURPOSE: To evaluate the efficacy and tolerability of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11) as first-line treatment of advanced biliary tract cancer. PATIENTS AND METHODS: Patients with histologically confirmed nonresectable biliary adenocarcinoma were treated with oxaliplatin (85 mg/m(2)) and irinotecan (200 mg/m(2)) every 3 weeks. RESULTS: Twenty-eight patients were enrolled between May 2005 and March 2009. The overall objective response rate was 17.9% with an additional 21.4% of patients with stable disease (disease control rate 39.3%). The median overall survival time was 9.2 months (95% CI 5.8-12.5) and the median progression-free survival time 2.7 months (95% CI 2.2-3.2). Grades 3 and 4 neutropenia occurred in 1 (3.6%) and 4 (14.3%) patients, respectively, and febrile neutropenia in 3 (10.7%). Grade 3-4 diarrhea was observed in 2 (7.1%) patients and grade 3 asthenia in 1 (6%). There were no treatment-related deaths. CONCLUSION: The combination of oxaliplatin and irinotecan has a modest antitumor activity with manageable toxicity as first-line treatment in metastatic cancer of the biliary tract and therefore it cannot be recommended as front-line treatment for unresectable biliary tract cancer.

A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer.

BACKGROUND: To compare the activity and toxicity of docetaxel/carboplatin (DC) doublet vs single agent docetaxel (D) as second-line treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients pre-treated with front-line platinum-free regimens, were randomized to receive either docetaxel/carboplatin (DC), (docetaxel 50 mg/m2; carboplatin AUC4; both drugs administered on days 1 and 15) or docetaxel single-agent (D), (docetaxel 50 mg/m2 on days 1 and 15). RESULTS: Response rate was similar between the two arms (DC vs D: 10.4% vs 7.7%; p = 0.764). After a median follow-up time of 28.0 months for DC arm and 34.5 months for D arm, progression free survival (PFS) was significantly higher in the DC arm (DC vs D:3.33 months vs 2.60 months; p-value = 0.012), while no significant difference was observed in terms of overall survival (OS) (DC vs D: 10.3 months vs 7.70 months; p-value = 0.550). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed. CONCLUSIONS: This study has not achieved its primary objective of significant OS prolongation with docetaxel/carboplatin combination over single-agent docetaxel in patients who had not received front-line docetaxel; however, the docetaxel/carboplatin combination was associated with a significant clinical benefit in terms of PFS.

Frequency and predictors of chemotherapy-associated venous thromboembolism: the prospective PREVENT study.

BACKGROUND: Our knowledge on the burden of symptomatic and asymptomatic venous thromboembolism (VTE) in patients with cancer undergoing chemotherapy is limited. The aim of our study was to prospectively investigate the frequency of symptomatic VTE and asymptomatic deep vein thrombosis of the lower limbs among cancer patients undergoing chemotherapy. METHODS: We studied 231 patients (164 men) with pancreatic (N.=36), lung (N.=136), ovarian (N.=32) or prostate (N.=27) cancer receiving first line (N.=192, 83.1%) or adjuvant chemotherapy, followed-up for 3-6 months. RESULTS: Some 17 patients were diagnosed with VTE, either asymptomatic detected on leg ultrasound (N.=7) or symptomatic (N.=10). The total frequency of VTE was 10.3% (17/165 with follow-up). Pancreatic cancer had the highest frequency of VTE (4/25, 16%) followed by ovarian (3/26, 11.5%) and lung cancer (10/94, 10.6%). There was no statistically significant difference in VTE rates among cancer types (P=0.36). VTE occurred more frequently in the presence of metastases (13/85, 15.3% vs. 4/80, 5.0%, for the remainder, P=0.03, OR 3.4). In the subgroup of patients receiving first line treatment, VTE occurred more frequently in patients with metastases (13/84, 15.5% vs. 2/53, 3.8%, for the remainder, P=0.033). In patients with pancreatic, lung or ovarian cancer receiving first line treatment, VTE occurred more frequently in patients with metastatic disease (19.1% vs. 4.0%, for the remainder, P=0.015). CONCLUSIONS: VTE occurrence in this real-world patient cohort was high, reaching almost 20% in certain groups, like those with disseminated pancreatic, lung or ovarian cancer receiving first-line chemotherapy. Furthermore, VTE occurs mostly as a symptomatic event, being likely a result of the prothrombotic state of malignancy.

Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer: a phase II study.

PURPOSE: Temozolomide, a novel triazene derivative, has shown activity in vitro against lung cancer as well as against brain metastases from a variety of solid tumors including non-small cell lung cancer (NSCLC). The aim of the study was to evaluate the efficacy and safety of temozolomide in pretreated patients with NSCLC. PATIENTS AND METHODS: Thirty-one pretreated patients (median age 60 years) with histologically confirmed NSCLC were enrolled. Sixteen (52%) patients had a performance status (ECOG) of 0-1, 12 (39%) had pretreated brain metastases and 28 (90.3%) had received >2 lines of treatment. Temozolomide was administered at a dose of 75 mg/m(2) daily for 21 days every 28 days. A total of 73 chemotherapy cycles were administered. RESULTS: In an intention-to-treat analysis, 2 patients (6.5%; 95% CI: -2.2 to 15.1%) achieved a partial response and 3 (10%) stable disease. The median time to progression was 2.4 months, the median survival time 3.3 months and the 1-year survival rate 22.5%. There was a toxic death due to grade 4 neutropenia. Grade 3 and 4 lymphopenia occurred in 4 (13%) and 2 (6%) patients, respectively. Nonhematological toxicity was mild, consisting of grade 2-3 asthenia (n = 14 patients) and grade 3 diarrhea (n = 1 patient). CONCLUSION: Prolonged low daily doses of temozolomide demonstrate minimal activity as salvage therapy in patients with advanced NSCLC. The combination of low daily doses of temozolomide with other anticancer drugs probably merits further evaluation.

Prognostic Significance of IGF-1 Signalling Pathway in Patients With Advanced Non-small Cell Lung Cancer.

BACKGROUND/AIM: Insulin-like growth factor 1 (IGF-1)-mediated molecular pathway has been implicated in non-small cell lung cancer (NSCLC) pathogenesis and progression. We aimed to evaluate serum levels of IGF-1, IGF-2 and IGF-binding protein 3 (IGF-BP3) before and after standard treatment in patients with advanced NSCLC and their prognostic and predictive correlations. PATIENTS AND METHODS: Seventy-three patients were prospectively included. Analysis and quantification of circulating levels of IGF1, IGF2, IGFBP3 were performed by total ELISA in peripheral blood samples at baseline and 3 months post-treatment. RESULTS: The median values of IGF-1 and IGF-1/IGF-BP3 ratios (125.82 vs. 133.4 ng/ml, p=0.087 and 0.01006 vs. 0.01252, p=0.011) were both decreased after treatment. Importantly, the post-treatment value of the ratio was significantly reduced only among responders to treatment (0.01044 from 0.01255, p=0.02). CONCLUSION: Reduction of IGF-1/IGF-BP3 ratio was statistically significant only among patients with NSCLC who responded to first-line treatment. If validated in larger cohorts, IGF-1/IGFBP3 might be a useful predictive tool for response to chemotherapy in NSCLC.

Combination of weekly topotecan and gemcitabine as a salvage treatment in patients with recurrent ovarian cancer: a phase I study.

BACKGROUND: Evaluation of safety of the weekly intravenous gemcitabine/topotecan combination as salvage treatment in patients with recurrent epithelial ovarian cancer. METHODS: Twenty-four women with histologically-proven relapsed ovarian cancer (ROC) were enrolled in the study. Topotecan (1.75 mg/m2 IV) along with escalated doses of gemcitabine (starting dose 700 mg/m2 with increments of 100 mg/m2) were administered on days 1, 8, and 15 every 28 days. The maximum tolerated dose (MTD) and the dose-limiting toxicity of the combination were evaluated at the first cycle. RESULTS: Twenty-four ROC patients were enrolled in six dose-levels. Most patients had high-grade serous metastatic ovarian cancer (41.7%) and performance status score of 0-1 (95.8%). For 12 patients (50%) treatment was 2nd line and for 12 >2nd line. Eighty-eight cycles were administered with a median of three cycles per patient. The MTD was not reached and grade 3-4 (3.4% and 2.3% of cycles, respectively) neutropenia and grade 4 (3.4% of cycles) thrombocytopenia were the main adverse events. There was no case of febrile neutropenia. Non-hematologic toxicity was mild with grade 2 fatigue being the most frequent complain. The recommended MTD doses of the combination were topotecan 1.75 mg/m2 and gemcitabine 1200 mg/m2 on days 1, 8, and 15 every 28 days. Two complete (8.3%) and three (12.5%) partial responses were achieved (ORR: 20.8%). CONCLUSIONS: The weekly administration of gemcitabine/topotecan regimen in patients with pretreated metastatic ovarian cancer is an active chemotherapy combination, even in heavily pretreated patients, with a manageable toxicity profile which merits further investigation.

Efficacy of panitumumab in older patients with metastatic colorectal cancer: a retrospective analysis using the database of the Hellenic Oncology Research Group (HORG).

BACKGROUND: Although colorectal cancer (CRC) is a disease of the older patients, older patients are under-represented from randomized trials. Herein we conducted a retrospective analysis for the effect of panitumumab in the management of older patients (≥65 years) patients with metastatic CRC (mCRC) in the Hellenic Oncology Research Group's (HORG) database. METHODS: Τhe efficacy of panitumumab-based chemotherapy as front-line treatment in older patients with mCRC was assessed. RESULTS: In total, 110 older patients with KRAS exon 2 wild type tumors were treated with chemotherapy plus panitumumab. The median age was 74 years; 69.9% of the patients were male, with left-sided primary tumors (78.2%), ECOG Performance Status 0-1 (95.4%) and median number of metastatic sites 2. Sixty-two (Overall Response Rate-ORR: 56.4%; 95% CI: 48.8%-68.1%) achieved an objective response, while 21 (19.1%) had stable disease. Median Progression free survival (PFS) was 9.4 months (95% CI: 7.8-11.0 months) and median Overall survival (OS) 23.0 months (95% CI: 20.6-25.3 months). Additionally, a statistically significant difference in ORR (62.7% vs. 33.3%; p = .014), median PFS (12.9 vs. 5.7 months; p = .001) and median OS (31.6 vs. 16.7 months; p < .001) was observed in patients with left-sided compared to right-sided primary tumor. There was no treatment-related death. Grade 3-4 toxicities were neutropenia (8.9%) and diarrhea (14.5%) whereas skin rash grade 2 or 3 was recorded in 41.1% and 10.7%, respectively. CONCLUSIONS: The results of this retrospective study provide the evidence that combination chemotherapy plus panitumumab is active and well tolerated in older patients with mCRC.

MINOAS: A Single-arm Translational Phase II Trial of FOLFIRI Plus Aflibercept as First-line Therapy in Unresectable, Metastatic Colorectal Cancer.

BACKGROUND: FOLFIRI/aflibercept is approved as a second-line treatment in metastatic colorectal cancer (mCRC) but there are limited data for its use as a first-line treatment. OBJECTIVE: To investigate the activity and safety of first-line FOLFIRI/aflibercept in mCRC, as well as to prospectively evaluate biomarkers of early response to treatment. PATIENTS AND METHODS: MINOAS was a phase II trial that aimed to evaluate the activity and toxicity of first-line FOLFIRI/aflibercept in mCRC. The primary endpoint was objective response rate (ORR). The secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), and the evaluation of CEACAM-positive circulating tumor cells (CTC) and diffusion-weighted (DW)-MRI as biomarkers. RESULTS: Thirty-one patients were enrolled and 259 chemotherapy cycles were administered. At the time of the preplanned interim analysis, all patients had discontinued treatment and the ORR was 61.3%, crossing the activity threshold for trial discontinuation. Median PFS was 8.4 months (95% CI 7.8-9.0). Median OS had not been reached. There was one toxic death due to sepsis; grade 3/4 adverse events included neutropenia (n = 5), diarrhea (n = 6), hypertension (n = 4), asthenia (n = 3), proteinuria (n = 1), and bowel perforation (n = 1). Retaining CTC-negative status predicted better OS compared to continuous detection of CTCs (p = 0.015). Early decrease of the apparent diffusion coefficient (ADC) in DW-MRI was associated with an objective response. CONCLUSION: The activity and safety of first-line FOLFIRI/aflibercept merit further evaluation in randomized studies. CLINICALTRIALS. GOV REGISTRATION NUMBER: NCT02624726.

Patterns of practice and pharmacoeconomic analysis of the management of patients with metastatic renal cell carcinoma (mRCC) in Greece--the CRISIS study. A retrospective analysis by the Hellenic Genitourinary Cancer Group (HGUCG).

Background:Metastatic RCC (mRCC) treatment has been revolutionized with 11 approved targeted agents. We report patterns of practice, outcomes and pharmacoeconomic analyses after the introduction of targeted therapy. Patients and methods: CRISIS was a retrospective multicenter study of mRCCpatients who received targeted therapy . Results were related to the start of 1st-line therapy, with a cut off at 1 January 2011 in order to depict the impact of increased availability of effective options. Results: 164 patients, were included. 70.1% and 44.5% received 2nd and 3rd-line therapy, respectively. More patients were treated in 2nd-line after 1 January 2011. After a median follow-up of 55.1 months, median progression-free (PFS) and overall survival (OS) were 10.7 (95% confidence intervals [CI]: 8.3-13.7), 7.3 (95% CI: 5.1-8.6), 5.8 (95% CI: 3.8-7.8) and 34 (95% CI: 28.5-39.8), 22.4 (95% CI: 16-32.1), 18.3 (95% CI: 12.4-26.4) months for first, second and third line, respectively. Efficacy of sunitinib and pazopanib in 1st-line were similar. The mean total cost/patient was 35,012.2 Euros (standard deviation [SD]: 28,971.5). Conclusions: Our study confirms previous real-world data suggesting that continuing advances in the treatment of mRCC produce favorable outcomes in everyday practice. Pharmacoeconomic analyses are important for cost-effective utilization of emerging novel therapies.

Panitumumab in combination with modified docetaxel/cisplatin/5-fluorouracil as first-line treatment in gastric and gastroesophageal junction adenocarcinomas: a multicenter phase II study by the Hellenic Oncology Research Group.

BACKGROUND: A phase I/II study to define the maximum tolerated dose (MTD) of biweekly docetaxel/cisplatin/5-fluorouracil (DCF) plus panitumumab (P), its efficacy, and tolerability as first-line treatment in advanced gastroesophageal cancer. METHODS: In phase I part, patients with unresectable locally advanced or metastatic adenocarcinomas of the stomach or the gastroesophageal junction received cisplatin (40 mg/m2 on day 1), leucovorin (400 mg/m2 on day 1), 5-fluorouracil (400 mg/m2 bolus on day 1), 5-fluorouracil (1000 mg/m2/daycontinuous infusion on days 1-2), and escalated doses of docetaxel (on day 1) plus P (6 mg/kg on day 1) every 2 weeks. In phase II part, patients were treated with DCF/P at the MTD and the primary endpoint was response rate. The expected response rate was set at >40%. RESULTS: The MTD for docetaxel in the mDCF/P was defined at 40 mg/m2 and a total of 40 evaluable patients were enrolled in phase II study. One (2.5%) complete and 13 (32.5%) partial responses (overall response rate: 35%), as well as 16 (40%) disease stabilizations were documented. The median progression-free survival was 6.9 months (95% confidence interval [CI] 3.5-10.3) and the median overall survival was 11.3 months (95%CI 7.7-14.8). Grade 3-4 neutropenia occurred in 10 patients (25%) and febrile neutropenia in 2 (5%). Allergic reactions (grade 1-4) occurred in 9 patients (22.5%). There was 1 treatment-related death. CONCLUSIONS: mDCF/P combination was feasible, though associated with a poor toxicity profile. However, the study failed to meet its primary endpoint and was terminated prematurely due to futility.

Nab-paclitaxel as second-line treatment in advanced gastric cancer: a multicenter phase II study of the Hellenic Oncology Research Group.

BACKGROUND: This study evaluated the safety and efficacy of nab-paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma. METHODS: Thirty-nine pretreated patients [33 with taxane-based regimens (docetaxel, cisplatin, and fluorouracil)] and 6 with combination of fluoropyrimidines plus cisplatin with locally advanced inoperable and metastatic gastric and gastroesophageal junction adenocarcinoma were treated with weekly nab-paclitaxel (150 mg/m2 d1, d8, d15 in cycles of 28 days). RESULTS: Partial response (PR) was documented in nine patients (23.1%; 95% confidence interval 10.1-37.2%), stable disease (SD) in 11 (28.2%) and disease progression in 18 (46.2%). The disease control rate (SD + PR + complete response) was 51.3%. Grade 3 and 4 neutropenia occurred in 10.2% and 5.1% of patients, respectively; grade 3 anemia in 5.1%; grade 3 neurotoxicity in 5.1%; and grade 2 pain in 5.1%. The median progression-free survival was 3.0 months (range 0.3-13.6) and the median overall survival 6.8 months (range 0.3-22). CONCLUSION: Nab-paclitaxel as second-line treatment in locally advanced inoperable or metastatic gastric and gastroesophageal junction carcinoma is an active chemotherapy regimen with a manageable toxicity profile and merits further evaluation.