Hellenic Oncology Research Group Research Articles

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.

Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project.

The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) aimed to investigate whether a 3 months (3M) of oxaliplatin/fluoropyrimidine-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) administration in 3-year disease-free survival (3yDFS) in high-risk (HR) stage II or stage III colon cancer (CC). Hellenic Oncology Research Group (HORG)-IDEA randomized patients between 3M and 6M of CT with FOLFOX4 or CAPOX. In total 1115 patients, 413 with HR stage II and 702 with stage III CC, were randomized. The median follow-up was 67.0 (38.3-126.0) months. Overall, 394 DFS events (202 in 3M arm and 192 in 6M arm) where recorded. The 3yDFS rate was 77.2% [95% confidence interval (CI) 72.1% to 82.3%] for 3M and 77.9% (72.6% to 82.5%) for 6M of treatment [hazard ratio (HR) 1.05 (95% CI 0.61-1.55); P = 0.647]. Eighty DFS events (3M N = 41; 6M N = 39) were observed in HR stage II patients for a 3yDFS rate of 82.7% and 83.4%, respectively (HR 1.05; 95% CI 0.68-1.63, P = 0.829). For stage III patients, 314 DFS events (3M N = 161 and 6M N = 153) were observed, for a 3yDFS rate of 72.9% for 3M versus 74.1% for 6M (HR 1.06; 95% CI 0.81-1.42, P = 0.622). For HR stage II patients receiving FOLFOX4, 3yDFS rate was 76.7% for 3M and 79.3% for 6M (HR 1.21; 95% CI 0.54-2.70). For HR stage II patients receiving CAPOX the 3yDFS rate was 85.4% for 3M and 83.8% for 6M (HR 0.99; 95% CI 0.59-1.67). For stage III patients receiving FOLFOX4, the 3yDFS rate was 71.5% for 3M and 77.3% for 6M (HR 1.18; 95% CI 0.74-1.86). For stage III patients receiving CAPOX, the 3yDFS rate was 74.5% for 3M and 74.7% for 6M (HR 0.99; 95% CI 0.70-1.44). The results of the HORG-IDEA study are in line with those of the global IDEA project, indicating that the 3yDFS is dependent on the administered adjuvant regimen and the choice and duration of regimen should be personalized. NCT01308086.

Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: The efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project.

3500 Background: The IDEA aimed to investigate whether a 3-month (3M) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) in 3-year disease free survival (DFS) in stage high risk stage II and in stage III colon cancer (CC). Methods: HORG-IDEA randomized patients between 3M and 6M of CT with FOLFOX4 or CAPOX with primary end point the 3 years DFS (3yDFS). Results: In total 1121 patients, 413 with high risk stage and 708 with stage IIICC, were randomized between May 2009 and October 2015. The median follow-up was 67 (38-126) months. There were 79 DFS events (43 in 3M and 38 in 6M arm) in high risk stage II patients leading to 3yDFS rate of 82.7 and 83.4% for 3M and 6M, respectively (HR: 1.05; 95%CI: 0.68-1.63, p = 0.829). Similarly, 214 DFS events (161 in 3M and 153 in 6M arm) has been recorded in stage III patients, leading to a 3yDFS rate of 72.9% in the 3M vs. 74.1% in the 6M (HR = 1.06; 95%CI: 0.81–1.42, p = 0.622). For high risk stage II patients receiving FOLFOX4, 3yDFS rate was 76.7% in the 3M vs.79.3% in the 6M (HR = 1.21; 95%CI: 0.54–2.70 p = 0.641). For high risk stage II patients receiving CAPOX 3-year DFS rate was 85.4% in the 3M vs. 83.8% in the 6M (HR = 0.99; 95%CI: 0.59–1.67 p = 0.968). For stage III CC patients receiving mFOLFOX6, 3-year DFS rate was 71.5% in the 3M vs.77.3% in the 6M (HR = 1.18; 95%CI: 0.74–1.86 p = 0.479). For stage III CC patients receiving CAPOX 3-year DFS rate was 74.5% in the 3M vs. 74.7% in the 6M (HR = 0.99; 95%CI: 0.70–1.44 p = 0.991). Conclusions: The results of the HORG-IDEA study are in line with those of the global IDEA project, indicating that 3yDFS is depended on the administered adjuvant regimen, and the choice of regimen and duration should be personalized. Clinical trial information: NCT01308086.

897 - Circulating tumour cells in patients with metastatic castration resistant prostate cancer under treatment with cabazitaxel - a prospective biomarker study from the Hellenic Oncology Research Group

897 - Circulating tumour cells in patients with metastatic castration resistant prostate cancer under treatment with cabazitaxel - a prospective biomarker study from the Hellenic Oncology Research Group

Taxane & cyclophosphamide vs anthracycline & taxane-based chemotherapy as adjuvant treatment for breast cancer: a pooled analysis of randomized controlled trials by the Hellenic Academy of Oncology.

BackgroundAdjuvant chemotherapy has an indisputable value for early breast cancer patients. Anthracycline and taxane-based regimens (TaxAC) have not been proven superior to taxane & cyclophosphamide (TC), a less toxic combination. Our objective was to estimate the cumulative evidence for non-inferiority of TC against TaxAC, in the adjuvant setting of patients with HER2-negative, breast cancer.ResultsOverall, 7,341 patients were included in this analysis. Superiority of TaxAC or non-inferiority of TC was not established either for the overall population (DFS HR, 1.11; 95% CI, 0.95–1.30; p = 0.18), or for the node-negative patients (HR, 1.05; 95% CI, 0.82–1.34; p = 0.71). A difference in DFS of 1.28% (TC DFS, 89.04%; 95% CI, 88%–90% & TaxAC DFS, 90.32%; 95% CI, 89%–91%) was found in favor of TaxAC. Lower risk of death was not established for either treatment regimen (OS-HR, 1.02; 95% CI, 0.82–1.25; p = 0.88). Overall, the toxicity profile favored TC.ConclusionAlthough non-inferiority of TC was not proven, superiority of TaxAC is still questioned. The present analysis narrows the risk of recurrence between the treatment groups. Considering TC has a more favorable safety profile, the question as to which treatment regimen should be preferred under what circumstances, needs to be individualized according to patients’ characteristics and desires.MethodsTreatment efficacy data from The ABC trials, the Plan B trial and a trial by the Hellenic Oncology Research group (HORG) were pooled. Disease free survival (DFS) and overall survival (OS) were scrutinized. A HR of 1.18 for TC versus TaxAC was chosen to demonstrate inferiority.

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

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. Τhe efficacy of panitumumab-based chemotherapy as front-line treatment in older patients with mCRC was assessed. 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. The results of this retrospective study provide the evidence that combination chemotherapy plus panitumumab is active and well tolerated in older patients with mCRC.

Implications of KRAS status in first line chemotherapy with bevacizumab in advanced colorectal cancer: A phase IV study of Hellenic Oncology Research Group (HORG).

e15521Background: Bevacizumab (BEV) is an active antiangiogenic agent for the treatment of all patients (pts) with advanced colorectal cancer (CRC). We investigated the toxicity, compliance and sur...

Three versus six months adjuvant oxaliplatin plus fluoropyrimidine chemotherapy for patients with stage III colon cancer: The Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant (IDEA) chemotherapy project.

730 Background: The IDEA international collaboration aimed to combine data from 6 randomized trials to investigate whether a 3-month (3m) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month(6m) for 3-year disease free survival (DFS)in stage III colon cancer (CC). Methods: HORG-IDEA randomized patients between 3Mand 6M of CT with mFOLFOX6 or CAPOX. DFS was estimated using the Kaplan–Meier method and described using 3 years DFS rate. Results: In total708 patients were randomized between May 2009 and October2015, 354in each arm. Among them the basic characteristics was: median age 63.9 years; mFOLFOX6: 41.8% and CAPOX 58.2%, N1: 74.9%, N2: 25.2%; T1-3: 86.4%, T4: 13.6%. DFS median follow-up was 54.2 months. There were 214 DFS events (109in 3M and 105 in 6M arm) leading to a 3-year DFS rate of 73.2% in the 3M vs. 74.9% in the 6M (HR = 1.03; 95%CI 0.80–1.43, p = 0.622).For patients receiving mFOLFOX6, 3-year DFS rate was 71.8% in the 3M vs.77.7% in the 6M (HR = 1.18; 95%CI 0.74–1.88 p = 0.478). For patients receiving CAPOX 3-year DFS rate was 74.7% in the 3M vs. 74.8% in the 6M (HR = 0.99; 95%CI 0.69–1.45 p = 0.994).94.2% and 78.0% of pts completed 3 and 6 months of CT, respectively. Overall, 96.9% and 89.5% of patients completed 3 months (arm A) and 6 months (arm B) of CT, respectively. Median oxaliplatin doses intensity were 97.3% in 3M and 73.2% in 6M (505.0 and 738.3 mg/m2).Overall maximum neuropathy during treatment grade 2/3-4 was 23.9/5.9%in 3M and38.7/13.7%in 6M; p &lt; 0.0001. In addition, worst grade 2/3-4 diarrhea was 11.1/4/0 in 3M and in 12.3/7.36M; p = 0.03. Conclusions: Since the HORG-IDEA study was designed in order to contribute patients in the IDEA project, the result on the study should be interpreted together with those of the whole IDEA project. Nevertheless, the results of the HORG-IDEA study are in line with those of the whole IDEA project, indicating that the results are depended on the administered adjuvant regimen, and the choice of regimen and duration should be depended on tumor characteristics and patient preference. Clinical trial information: NCT01308086.

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.

BackgroundA 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.MethodsIn 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%.ResultsThe 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.ConclusionsmDCF/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.

Weekly Paclitaxel and Carboplatin Plus Bevacizumab as First-Line Treatment of Metastatic Triple-Negative Breast Cancer. A Multicenter Phase II Trial by the Hellenic Oncology Research Group

BackgroundTriple-negative breast cancer (TNBC) lacks a standard targeted therapeutic strategy and is treated with conventional cytotoxic agents. Because of the sensitivity of TNBC to platinum compounds and the synergistic effect of bevacizumab with paclitaxel we investigated the efficacy and toxicity of weekly paclitaxel and carboplatin in combination with bevacizumab as first-line treatment in metastatic TNBC. Patients and MethodsThis phase II study followed the Simon’s 2-stage optimal design. Paclitaxel (90 mg/m2) and carboplatin (2 area under the curve) were administered on days 1, 8, and 15 every 4 weeks, preceded by bevacizumab 10 mg/kg on days 1 and 15. The primary end point was the objective response rate (ORR). The null hypothesis that the ORR is ≤ 40% could be rejected if the number of objective responses was ≥ 23 among 46 evaluable patients. ResultsA total of 46 patients were enrolled. Seven (15.2%) complete and 23 (50%) partial responses were observed for an ORR of 65.2% (95% confidence interval, 52.9%-80.4%). The median progression-free survival was 10.3 months, the median overall survival 25.7 months, and the median duration of response 18.2 months. Neutropenia Grade III and IV was experienced by 13 (28.3%) and 6 (13.04%) patients, respectively. One patient developed an uneventful Grade IV thrombocytopenia. There was 1 toxic death due to febrile neutropenia. Other Grade III toxicities included anemia (n = 2), neurotoxicity (n = 2), thrombocytopenia (n = 1), and diarrhea (n = 1). No serious bevacizumab-related toxicities were observed. ConclusionThe study achieved its primary end point by showing clinical activity for weekly paclitaxel with carboplatin and bevacizumab combination. This regimen merits further evaluation in this setting.

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.

Long-term clinical benefit from salvage EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer patients with EGFR wild-type tumors.

Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond. Patients with EGFRwt NSCLC who received salvage (≥2nd line) treatment with erlotinib for a prolonged period (>6months), were sought from the database of the Hellenic Oncology Research Group. We retrospectively analyzed the clinical, pathological and molecular characteristics of the patients with available tumor material. Forty-four patients that received erlotinib for >6months (median 10.1months) were enrolled in the study. The majority of them were male, never-smokers with adenocarcinoma histology and a good performance status. KRAS and PIK3CA mutations were detected in 21% (9/42 tested) and 13% (4/30 tested) of the patients, respectively. The ALK-EML4 translocation was found in 10% (2/20 tested); there was no patient with HER2 or BRAF mutated tumor. Twelve (54.5%) tumor specimens were considered positive for EGFR-overexpression. Eleven patients experienced a partial response (objective response rate 25%; 95% CI 12-38%) and the remaining 33 had stable disease. The median progression-free survival and overall survival were 10.1 (95% CI 8.6-11.6months) and 24.1 (95% CI 11.2-37months), respectively. Treatment with erlotinib significantly improves the clinical outcome in a subset of NSCLC patients with EGFRwt tumors. Further molecular analysis of such tumor specimens could provide a more comprehensive characterization of this particular group of patients. Nevertheless, the presence of other mutations should not prevent the treating physician from using erlotinib at later lines of salvage therapy for NSCLC patients.

Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group

Background:Pazopanib is a tyrosine kinase inhibitor with antiangiogenic activity. Vascular endothelial growth factor expression is increased in SCLC and is correlated with poor prognosis. The efficacy and tolerance of second-line pazopanib in SCLC was evaluated.Patients and methods:Patients with platinum-sensitive (cohort A; n=39) and -resistant/refractory (cohort B; n=19) SCLC were enrolled in a multicentre phase II study. The primary end point was the progression-free survival rate (PFS-R) at week 8 in each cohort. Pazopanib (800 mg per day per os) was administered until progressive disease (PD). Circulating tumour cells (CTCs) were enumerated using the Cellsearch assay.Results:All patients were evaluable for response and toxicity. In the intention-to-treat analysis, eight (13.8%) patients achieved partial response (PR) (95% confidence interval (CI): 5.0–22.7), 20 (34.5%) stable disease (SD) and 30 (51.7%) PD. Accrual in cohort B was halted because the hard-stop rule was met; in cohort A, the PFS-R was 59% (95% CI: 43.5–74.4; PR=7, SD=16). Nine (23.1%) patients received pazopanib for >6 months and 3 of them for >12 months. One pazopanib cycle resulted to a significant decrease to the number of patients with ⩾5 CTCs/7.5 ml of blood (20%) compared with baseline (50%). The median PFS and OS for all patients was 2.5 months (95% CI: 1.9–3.1 months) and 6.0 months (95% CI: 3.8–8.2 months), respectively (cohort A: PFS=3.7 months and OS=8.0 months). No unexpected toxicity was observed.Conclusions:Second-line treatment with pazopanib in platinum-sensitive SCLC is well tolerated and resulted in promising objective responses and disease control; CTC enumeration might serve as a reliable surrogate biomarker of response.

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.

Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG)

Sequential administration of anthracycline and taxane is the current standard of care adjuvant regimen for node-positive early breast cancer. Due to long-term toxicity concerns, anthracycline-free regimens have been developed. We compared a sequential dose-dense anthracycline and taxane regimen with the anthracycline-free regimen of docetaxel and cyclophosphamide. In this randomized, non-inferiority, phase III trial, women with HER2-negative invasive breast cancer and at least one positive axillary lymph node were randomized to receive either epirubicin (75 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and cyclophosphamide (500 mg/m(2)) every 2 weeks for four cycles, followed by four cycles of docetaxel (75 mg/m(2)) every 2 weeks with prophylactic G-CSF support (FEC → D) or docetaxel (75 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every 21 days for six cycles (TC). The primary end point of the study was the 3-year disease-free survival (DFS) rate. Six hundred and fifty women were randomized to either FEC → D (n = 326) or TC (n = 324). After a median follow-up of 46 and 47 months, the 3-year DFS rate was 89.5% and 91.1% for the FEC → D and TC arm, respectively (hazard ratio = 1.147, 95% confidence interval 0.716-1.839, P = 0.568). Grade 3-4 neutropenia was higher in the TC arm (32.4% versus 10.5%, P = 0.0001). The incidence of neutropenic fever was low (<1%). Nausea, vomiting, hand-foot syndrome and fatigue (grade 3-4) were more common with FEC → D. Acute cardiotoxicity was rare (1 event in each group). There were no toxic deaths. This trial did not clearly demonstrate that TC is non-inferior to dose-dense FEC → D. However, 3-year DFS rates were excellent in both arms for women with node-positive, HER2-negative early breast cancer. NCT01985724.

206P - Bevacizumab plus dose-dense neoadjuvant FEC followed by docetaxel chemotherapy in patients with HER2-negative breast cancer: a multicentre, phase 2 study by the Hellenic Oncology Research Group

Addition of bevacizumab to standard chemotherapy in the neoadjuvant setting improves the proportion of patients with HER2-negative breast cancer who achieve pathological complete response. We aimed to assess the addition of bevacizumab to dose-dense neoadjuvant chemotherapy. We enrolled women with operable HER2-negative breast cancer (T1c-T4 and N0-3). Patients underwent treatment every 2 weeks (with pegfilgrastim support) of fluorouracil (500 mg/m2), epirubicin (75 mg/m2), cyclophosphamide (500 mg/m2), and bevacizumab (10 mg/kg) for 4 cycles followed by docetaxel (75 mg/m2) and bevacizumab for 4 cycles. After surgery, patients received adjuvant radiotherapy, and hormone therapy (if indicated). The primary endpoint was pathological complete response in breast and the axilla, and safety of the combination. A two-stage trial design was planned with 15 and 33 patients to enroll, respectively. The trial was terminated early due to slow accrual and follow-up is ongoing. Between Oct, 2011, and Apr, 2015, we enrolled 34 patients, of whom 3 didn't undergo surgery, leaving 31 patients in the primary endpoint analysis. After neoadjuvant therapy, 5 (16.1%) of 31 patients achieved a pathological complete response according to centralized review. No patient discontinued treatment due to adverse events. The most frequent grade 3–4 toxicities were neutropenia (23.5%), nausea and vomiting (5,8%), and febrile neutropenia (2,9%). Only one patient developed grade III bevacizumab-related toxicity (hypertention). One patient died of pneumonia after cycle 8 and before surgery, which was thought to be unrelated to bevacizumab. After 25,2 months of median follow-up (range: 2,3-43,3) five patients experienced a disease relapse (16,1%). Our results seem to indicate that the addition of bevacizumab to dose-dense neoadjuvant chemotherapy with FEC and docetaxel, although safe and feasible, does not provide clinical benefit to patients with non-metastatic HER2-negative breast cancer. Translational research to identify patients who might benefit from bevacizumab is needed.

242P - Final results of weekly paclitaxel and carboplatin plus bevacizumab as first-line treatment of triple-negative breast cancer. A multicenter phase I-II trial by the Hellenic Oncology Research Group

242P - Final results of weekly paclitaxel and carboplatin plus bevacizumab as first-line treatment of triple-negative breast cancer. A multicenter phase I-II trial by the Hellenic Oncology Research Group

Biweekly Carboplatin Plus Gemcitabine as First-Line Treatment of Elderly Patients With Advanced Squamous Non–Small-cell Lung Cancer: A Multicenter Phase I-II Trial by the Hellenic Oncology Research Group

BackgroundThe present study was a phase I/II study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities of the biweekly carboplatin/gemcitabine combination and evaluate its safety and efficacy in patients aged ≥ 70 years with advanced squamous non–small-cell lung cancer (NSCLC). Patients and MethodsPatients aged ≥ 70 years with advanced or metastatic squamous NSCLC received escalated doses of carboplatin (area under the curve [AUC] 2-2.5 intravenously) and gemcitabine (800-1100 mg/m2 intravenously) every 2 weeks (phase I). In the phase II, the drugs were administered at their previously defined MTDs (carboplatin, AUC 2.5; gemcitabine, 1100 mg/m2). The primary endpoint was the overall response rate. ResultsA total of 69 patients were enrolled (phase I, n = 15). The median age was 76 years (range, 70-84 years); 52 patients had stage IV disease, and 61 and 8 patients had Eastern Cooperative Oncology Group performance status of 0 to 1 and 2, respectively. The MTDs could not be reached at the predefined last dose levels. The dose-limiting toxicities were grade 5 renal toxicity and grade 3 thrombocytopenia. In the phase II study, the overall response rate was 35.8% (95% confidence interval [CI], 23.0%-48.8%). In the intention-to-treat analysis, the median progression-free survival was 6.7 months (95% CI, 4.2-8.8 months), and the median overall survival was 13.3 months (95% CI, 7.1-19.6 months). Grade 3 or 4 neutropenia was observed in 7 patients (12.3%), grade 3 or 4 thrombocytopenia in 4 patients (7.1%), and grade 2 or 3 fatigue in 10 patients (17.5%). One toxic death occurred in the phase I of the study. ConclusionThe biweekly regimen of gemcitabine and carboplatin showed satisfactory efficacy and a favorable toxicity profile in elderly patients with advanced or metastatic squamous cell NSCLC.

Docetaxel plus gemcitabine versus gemcitabine in elderly patients with advanced non-small cell lung cancer and use of a geriatric assessment: Lessons from a prematurely closed Hellenic Oncology Research Group randomized phase III study.

To compare first-line treatment with docetaxel plus gemcitabine (DG) versus gemcitabine (G) in elderly patients with advanced/metastatic non-small-cell lung cancer (NSCLC). Chemotherapy-naïve patients with inoperable stage IIIB/IV NSCLC, ≥70years, with an ECOG performance status (PS) of 0-2 were enrolled. Patients were stratified by PS and disease stage and randomized to either DG (docetaxel 30mg/m2 plus gemcitabine 900mg/m2 i.v.) or G (gemcitabine 1200mg/m2 i.v.) on days 1 and 8, every 3weeks. The study's primary end-point was overall survival (OS). In this prematurely closed study, 106 patients with a median age of 75years (range, 70-92) were enrolled (DG: n=54; G: n=52); 77 (73%) had stage IV disease and 18 (17%) a PS of 2. There was no difference in terms of median OS (14.6 vs 12.2months; p=0.121), progression-free survival (PFS) (3.4 vs 2.6months; p=0.757) and overall response rate (26.0% vs 15.4%; p=0.233) between DG and G arm, respectively. Patients with an Instrumental Activities of Daily Living (IADL) score<7 had significantly lower median OS (7.6 vs 15.4months; p=0.002) and median PFS (1.7 vs 4.4months; p=0.009) than patients with higher IADL score. The regimens were well tolerated with no significant difference in severe toxicity. DG and G demonstrated comparable efficacy in elderly patients with NSCLC and high IADL score was correlated with superior clinical outcome.

Salvage treatment of relapsed/refractory small cell lung cancer with pazopanib: A Hellenic Oncology Research Group’s (HORG) phase II study.

8561Background: Pazopanib (PZB) is a small anti-angiogenic molecule inhibiting the tyrosine kinase of VEGFR-1, VEGFR-2, VEGFR-3, PDGF, and c-kit. Several studies have shown that angiogenesis is of ...