A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer.

BACKGROUND: 5-fluorouracil (5-FU) combined with a folate remains an essential treatment component for metastatic colorectal cancer (mCRC). Leucovorin is the folate most often used, but requires intracellular conversion to a reduced folate, and has high pharmacokinetic variability and limited bioavailability in patients with low folate pathway gene expression. Arfolitixorin is an immediately active form of folate, [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF), and may improve outcomes. PATIENTS AND METHODS: This open-label, multicenter, phase I/II study in patients with mCRC (NCT02244632) assessed the tolerability and efficacy of first- or second-line arfolitixorin (30, 60, 120, or 240 mg/m2 intravenous) with 5-FU alone, or in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan, every 14 days. Safety, efficacy, and pharmacokinetics were assessed before and after four cycles (8 weeks) of treatment. RESULTS: In 105 treated patients, investigators reported 583 adverse events (AEs) in 86 patients (81.9%), and 256 AEs (43.9%) were potentially related to arfolitixorin and 5-FU. Dose adjustments were required in 16 patients (15.2%). At 8 weeks, 9 out of 57 patients assessed for efficacy achieved an objective response (15.8%), and all 9 achieved a partial response. Six of these nine patients had received arfolitixorin as a first-line treatment. A further 33 patients (57.9%) achieved stable disease. Pharmacokinetics were assessed in 35 patients. The average tmax was 10 min, and area under the plasma concentration-time curve from time 0 to 1 h increased linearly between 30 and 240 mg/m2. No accumulation was observed for [6R]-MTHF following repeated administration, and there were no major pharmacokinetic differences between cycle 1 and cycle 4 at any dose. CONCLUSIONS: Arfolitixorin is a well-tolerated moderator of 5-FU activity. It is suitable for further investigation in mCRC and has the potential to improve treatment outcomes in patients with low folate pathway gene expression. Arfolitixorin can easily be incorporated into current standard of care, requiring minimal changes to chemotherapy regimens.

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.

BACKGROUND: 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). METHODS: Hellenic Oncology Research Group (HORG)-IDEA randomized patients between 3M and 6M of CT with FOLFOX4 or CAPOX. RESULTS: 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). CONCLUSIONS: 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. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT01308086.

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.

Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pre-treated with a non-platinum-based regimen in the first-line setting: a randomized phase II study of the Hellenic Oncology Research Group (HORG)

Background. Platinum-based chemotherapy is the standard front-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, non-platinum combinations of third-generation chemotherapeutic agents are considered an alternative therapeutic option for patients who cannot tolerate the toxic effects of platinum compounds. In this study, the efficacy and toxicity of the combination of irinotecan plus cisplatin (IC) was compared to pemetrexed plus cisplatin (PC) regimen, in platinum-naïve patients with advanced NSCLC, who had been previously treated with the combination of a taxane plus gemcitabine. Patients and methods. A total of 124 patients with locally advanced or metastatic NSCLC were randomly assigned to either irinotecan 110 mg/m2 on day 1 and 100 mg/m2 on day 8 plus cisplatin 80 mg/m2 on day 8 every 3 weeks (IC arm) or pemetrexed 500 mg/m2 plus cisplatin 80 mg/m2 on day 1 every 3 weeks (PC arm). The primary endpoint of the study was the overall response rate (ORR). Results. The ORR and median progression-free survival (PFS) in the IC arm were 18 % and 3.3 months, respectively, while in the PC arm were 19 % and 4.2 months (p = ns). Median overall survival (OS) was significantly higher in patients with PC (6.9 vs. 10.9; p = 0.013). PC regimen had a better toxicity profile compared to IC, with a statistically significant lower incidence of grade 3/4 neutropenia (3 vs. 31 %; p = 0.0001) and diarrhea (1.6 vs. 14.7 %, p = 0.018). Conclusions. In patients with advanced NSCLC pretreated with docetaxel/gemcitabine, the combination of pemetrexed/cisplatin is associated with increased OS and is better tolerated than the combination of irinotecan/cisplatin and should be considered as a valid therapeutic option for platinum-naive, previously treated patients (AU)

No disponible

Heterogeneity of circulating tumor cells (CTCs) in patients with recurrent small cell lung cancer (SCLC) treated with pazopanib.

OBJECTIVES: To investigate the effect of pazopanib on different CTCs subpopulations in patients with recurrent SCLC and evaluate their clinical relevance. METHODS: Peripheral blood was obtained before the administration of pazopanib (n=56 patients), after the first cycle (n=35 patients) and at disease progression (n=45 patients). CTCs were detected by CellSearch and double immunofluorescent staining using antibodies against the cytokeratins (CK), TTF-1, CD56 and VEGFR2. RESULTS: Before treatment, CTCs could be detected in 50% of patients by CellSearch; phenotypic characterization of CTCs demonstrated that 50%, 46.6% and 27.6% of patients had CD45-/TTF1+, CD45-/CD56+ and TTF-1+/CD56+ CTCs, respectively. Additionally, 59% of CTCs were TTF-1+/VEGFR2+ and 53% CK+/VEGFR2+. One pazopanib cycle resulted to a significant decrease of the number of CTCs (CellSearch: p=0.043) and CK+/VEGFR2+ cells (p=0.027). At the time of PD, both the total number of CTCs (p=0.027) and the number of the different subpopulations were significantly increased compared to post-1st cycle values; this increased CTCs number was associated with a significant increase of TTF-1+/VEGFR2+ (p=0.028) and CK+/VEGFR2+ CTCs (p=0.018). In multivariate analysis, only the number of CTCs as assessed by CellSearch after one treatment cycle was significantly associated with OS (HR: 0.21; p=0.005). CONCLUSIONS: Pazopanib has a significant effect on different subpopulations of CTCs in patients with relapsed SCLC; the detection of VEGFR2+ CTCs during treatment could be a surrogate marker associated with resistance to pazopanib.

Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pre-treated with a non-platinum-based regimen in the first-line setting: a randomized phase II study of the Hellenic Oncology Research Group (HORG).

BACKGROUND: Platinum-based chemotherapy is the standard front-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, non-platinum combinations of third-generation chemotherapeutic agents are considered an alternative therapeutic option for patients who cannot tolerate the toxic effects of platinum compounds. In this study, the efficacy and toxicity of the combination of irinotecan plus cisplatin (IC) was compared to pemetrexed plus cisplatin (PC) regimen, in platinum-naïve patients with advanced NSCLC, who had been previously treated with the combination of a taxane plus gemcitabine. PATIENTS AND METHODS: A total of 124 patients with locally advanced or metastatic NSCLC were randomly assigned to either irinotecan 110 mg/m2 on day 1 and 100 mg/m2 on day 8 plus cisplatin 80 mg/m2 on day 8 every 3 weeks (IC arm) or pemetrexed 500 mg/m2 plus cisplatin 80 mg/m2 on day 1 every 3 weeks (PC arm). The primary endpoint of the study was the overall response rate (ORR). RESULTS: The ORR and median progression-free survival (PFS) in the IC arm were 18 % and 3.3 months, respectively, while in the PC arm were 19 % and 4.2 months (p = ns). Median overall survival (OS) was significantly higher in patients with PC (6.9 vs. 10.9; p = 0.013). PC regimen had a better toxicity profile compared to IC, with a statistically significant lower incidence of grade 3/4 neutropenia (3 vs. 31 %; p = 0.0001) and diarrhea (1.6 vs. 14.7 %, p = 0.018). CONCLUSIONS: In patients with advanced NSCLC pretreated with docetaxel/gemcitabine, the combination of pemetrexed/cisplatin is associated with increased OS and is better tolerated than the combination of irinotecan/cisplatin and should be considered as a valid therapeutic option for platinum-naive, previously treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT00614965.

A multicentre phase II trial of cabazitaxel in patients with advanced non-small-cell lung cancer progressing after docetaxel-based chemotherapy.

BACKGROUND: Cabazitaxel, a semisynthetic microtubule inhibitor, has shown antitumour activity in models resistant to paclitaxel and docetaxel, and it has been approved for the treatment of docetaxel-resistant prostate cancer. We investigated its activity in patients with advanced non-small-cell lung cancer (NSCLC) progressing under or after docetaxel-based regimens. METHODS: Patients with locally advanced unresectable or metastatic NSCLC, with an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled; patients had to have received up to two prior chemotherapy regimens for the treatment of advanced disease, including one docetaxel-containing regimen. Treatment consisted of cabazitaxel (25 mg m(-2) intravenously, every 21 days) until disease progression. The primary end point was the overall response rate. RESULTS: Among the 46 evaluable patients, 28.3% had squamous cell carcinoma and 54.3% had adenocarcinoma. Eight (17.4%) patients had received one and 38 (82.6%) two prior chemotherapy regimens. Treatment compliance was 95%; 26 (16%) cycles were delayed because of toxicity, (n=13) and dose reduction was required in 6 (13%) patients because of haematologic toxicity. Six (13%) patients achieved a partial response and 17 (37.0%) stable disease. The median progression-free survival and overall survival were 2.1 (95% confidence interval (CI): 1.0-3.2) and 7.4 (95% CI: 5.2-9.6) months, respectively. Grade 4 adverse events included neutropenia (n=8; 17%), febrile neutropenia (n=6; 13%) and thrombocytopenia (n=3; 6.5%). There was one treatment-related death. CONCLUSIONS: Cabazitaxel exhibits activity in NSCLC patients pre-treated with docetaxel-based chemotherapy with a substantial but manageable toxicity profile. The drug merits further evaluation in this indication.

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).

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICALTRIALSGOV: NCT01985724.

A phase II, open-label trial of bortezomib (VELCADE(®)) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer.

BACKGROUND: Bortezomib is a selective reversible proteasome inhibitor with proapoptotic effects. Preclinical and phase I clinical data suggest activity of bortezomib in NSCLC, either as monotherapy or in combination with chemotherapeutic agents including gemcitabine and cisplatin. METHODS: Chemotherapy-naïve patients with inoperable stage IIIB or IV NSCLC were administered bortezomib 1 mg/m(2) i.v. on days 1 and 8, and starting on day 21 (cycle 2), bortezomib (days 1 and 8) in combination with gemcitabine 1000 mg/m(2), (days 1 and 8), and cisplatin 70 mg/m(2) (day 1) in cycles of 21 days. Up to 8 cycles of combination therapy could be administered; single-agent bortezomib was continued until disease progression or unacceptable toxicity. RESULTS: Fifty-three patients [median age 66 years; 79.2 % male; 96.2 % stage IV; performance status (ECOG) 0/1 73.6/26.4 %; adenocarcinoma 45.3 %, squamous cell carcinoma 41.5 %] were enrolled. All patients were evaluable for toxicity and 43 for efficacy. Grade 3-4 hematologic toxicity consisted of neutropenia (22.6 %) and thrombocytopenia (17 %). Grade 2-4 non-hematologic adverse events were fever (9.4 %), fatigue (20.8 %), infection (18.9 %), and dyspnea (15.1 %). There was no >grade 2 neurotoxicity. Febrile neutropenia occurred in two (1.9 %) patients, and there were three possibly treatment-related deaths (5.4 %). In the intention-to-treat population, the objective response rate was 17 % (95 % CI 6.9-27.1 %). No difference in response rate was observed for squamous versus other histology (18.2 vs. 16.1 %, p = 0.845). The median progression-free survival was 2.5 months, the median overall survival 10.6 months and the 1-year survival rate 38.1 %. CONCLUSION: The incorporation of bortezomib into the gemcitabine/cisplatin regimen, in the dose and schedule used in this study, could not improve the efficacy of the chemotherapy regimen and has not to be further investigated.

Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG).

BACKGROUND: Adjuvant trastuzumab in combination with chemotherapy improves survival of women with HER2-positive early breast cancer. In this study, we compared 12 versus 6 months of adjuvant trastuzumab. PATIENTS AND METHODS: Axillary node-positive or high-risk node-negative women with HER2-positive early breast cancer were randomized to receive 12 or 6 months of adjuvant trastuzumab concurrently with dose-dense, granulocyte colony-stimulating factor (G-CSF)-supported docetaxel (75 mg/m(2) every 14 days for four cycles). All patients received upfront dose-dense, G-CSF-supported FEC (5-fluorouracil 700 mg/m(2), epirubicin 75 mg/m(2), cyclophosphamide 700 mg/m(2) every 14 days for four cycles). Randomization was carried out before commence of chemotherapy. The primary end point was the 3-year disease-free survival (DFS). RESULTS: A total of 481 patients were randomized to receive 12 months (n = 241) or 6 months (n = 240) of adjuvant trastuzumab. Chemotherapy was completed in 99% and 98% of patients, while trastuzumab therapy in 100% and 96% of patients in the 12- and 6-month groups, respectively. After 47 and 51 months of median follow-up, there were 17 (7.1%) and 28 (11.7%) disease relapses in the 12- and 6-month groups (P = 0.08). The 3-year DFS was 95.7% versus 93.3% in favor of the 12-month treatment group (hazard ratio = 1.57; 95% confidence interval 0.86-2.10; P = 0.137). There was no difference in terms of overall survival and cardiac toxicity between the two groups. CONCLUSIONS: Our study failed to show noninferiority for the 6-month arm. The results further support the current standard of care that is administration of adjuvant trastuzumab for 12 months.

Sequential administration of vinorelbine plus cisplatin and bevacizumab followed by docetaxel plus gemcitabine and bevacizumab compared to docetaxel plus cisplatin and bevacizumab regimen as first-line therapy for advanced or metastatic non-squamous non-small cell lung cancer: A multicenter randomized phase II trial of the Hellenic Oncology Research Group (HORG).

OBJECTIVES: To compare the activity and tolerance of the consecutive administration of four active chemotherapeutic agents in combination with bevacizumab to a bevacizumab- and platinum-based chemotherapy doublet as front-line treatment in patients with non-squamous NSCLC. PATIENTS AND METHODS: Patients with advanced/metastatic NSCLC, performance status of 0-2 and normal organ function were randomized to receive either 3 cycles every 3 weeks of cisplatin 80 mg/m(2) (day 1), oral vinorelbine 60 mg/m(2) (days 1 and 8) and bevacizumab 15 mg/kg (day 1) every 3 weeks (VCB regimen) followed by 3 cycles of docetaxel (75 mg/m(2), day 1), gemcitabine (1100 mg/m(2), days 1 and 8) and bevacizumab 15 mg/kg (day 1) (DGB regimen) (arm A) or 6 cycles of cisplatin 80 mg/m(2), docetaxel 75 mg/m(2) and bevacizumab 15 mg/kg on day 1 (DCB regimen; arm B) every 3 weeks. RESULTS: Thirty-eight and 39 patients were enrolled in arm A and B, respectively. The study did not meet its primary endpoint since, the ORR was 39.5% (95% CI: 23.9-55.0%; 1CR and 14 PR) and 46.2% (95% CI: 30.5-61.8%; 2 CR and 16 PR) in arm A and B, respectively (p=0.554). There was no significant difference in terms of response duration (7.4 versus 4.7 months in arm A and B, respectively; p=0.697), progression-free survival (5.8 versus 5.5 months, respectively; p=0.540) and overall survival (16.9 versus 10.9 months; p=0.390). No difference was recorded between the two arms regarding the toxicity profile. There were two drug-related deaths in arm B. CONCLUSION: Sequential therapy of VCB followed by DGB is a feasible and well-tolerated regimen but failed to show any superiority over the standard DCB regimen.

Cisplatin in combination with metronomic vinorelbine as front-line treatment in advanced non-small cell lung cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG).

PURPOSE: To evaluate the safety and efficacy of metronomic vinorelbine in combination with cisplatin as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 41 patients with inoperable stage IIIb or stage IV NSCLC (14 with adenocarcinomas, 19 with squamous cell carcinoma and eight with other types), PS = 0-2, were treated with cisplatin (80 mg/m(2)) in combination with oral metronomic vinorelbine (60 mg total dose, every other day) in cycles of 21 days. RESULTS: A total of 35 patients who received at least one cycle of chemotherapy were evaluable for toxicity and response. Partial response was achieved in 13 patients (ORR 37.1%; CI 21.1-53.1%) and stable disease in 10 (28.6%). After a median follow-up period of 26.2 months (range 0.5-33.4 months), the median progression-free survival was 4.2 months and the median overall survival 12.0 months. The 1-year survival rate was 52.6%. Myelosuppression was the main adverse event with grade 3 and 4 neutropenia occurring in five (14.3%) and six (17.1%) patients, respectively. Three of these patients presented with febrile neutropenia and there was one death due to sepsis. Non-hematologic toxicities were mild. CONCLUSION: Cisplatin in combination with metronomic vinorelbine is an active, although myelotoxic, therapeutic option in the first-line setting for the treatment of patients with locally advanced and metastatic non-small cell lung cancer, which merits further evaluation in randomized trials.

Docetaxel, gemcitabine and bevacizumab as salvage chemotherapy for HER-2-negative metastatic breast cancer.

PURPOSE: To evaluate the activity and safety of the docetaxel, gemcitabine and bevacizumab combination, administered biweekly, in pretreated patients with HER-2-negative metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with HER-2-negative MBC, and disease progression after at least one prior line of chemotherapy, were treated with docetaxel 50 mg/m², gemcitabine 1,500 mg/m² and bevacizumab 10 mg/kg every 2 weeks. Bevacizumab was continued until disease progression. RESULTS: Forty-eight patients have been enrolled. Their median age was 61 years, 95.8 % had a performance status 0-1, 83.3 % had hormone receptor-positive disease, and 47.9 % had received one prior line of chemotherapy. All patients were evaluable for toxicity and 45 for response. Partial response was achieved in 20 patients [PR = 44.4 %, 95 % confidence interval (CI) 29.9-59 %] and disease stabilization in 15 (33.3 %). The median progression-free survival was 7.1 months (95 % CI 4.7-9.5 months) and the median overall survival 21.1 months (95 % CI 10.3-31.9 months). Grade 3-4 neutropenia occurred in 19 patients (39.6 %) and febrile neutropenia in 2 (4.2 %). Most common grade 2-3 non-hematologic adverse events included nausea (10.4 %), diarrhea (10.5 %), neurotoxicity (12.5 %) and fatigue (31.3 %), whereas grade 2 hemorrhage and hypertension occurred in 6.3 and 10.4 %, respectively. There were no grade 4 non-hematologic toxicities or toxic deaths. CONCLUSION: The combination of docetaxel, gemcitabine and bevacizumab has promising activity and manageable toxicity as salvage chemotherapy for HER-2-negative MBC patients.

Frontline treatment with gemcitabine, oxaliplatin and erlotinib for the treatment of advanced or metastatic pancreatic cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG).

PURPOSE: Intravenous gemcitabine is the standard of care for patients with metastatic cancer of the pancreas. Gemcitabine-based chemotherapy combinations, either doublets or triplets, have been tested in the past but have offered a small advantage (Brodoefel et al. in Eur J Radiol 73:594-600, 2010). In the present study, we present the results of the triplet gemcitabine-oxaliplatin-erlotinib combination as firstline treatment in this setting. PATIENTS AND METHODS: Seventy-one eligible patients were included in this study. All patients received chemotherapy with gemcitabine (1,100 mg/m(2) on days 1 and 8) plus oxaliplatin (130 mg/m(2) on day 8) and erlotinib (100 mg p.o./day for 21 days). The treatment cycle was 21 days. RESULTS: Partial response was achieved in 15 patients (21%; 95% CI 11.63-30.62) and stable disease in 15 patients (21%). Forty-one patients (57.8%) experienced disease progression. Median progression-free survival was 5.2 months (range 0.6-34.7; 95% CI 3.71-6.76). The median overall survival was 10.5 months (95% CI 7.39-13.61) and the 1-year survival estimate 47.3%. The main adverse events were grade 3/4 anemia occurring in three (4.2%) patients and grade 3 and 4 thrombocytopenia occurring in eight (11.3%) and three (4.2%) patients, respectively. Grade 4 neutropenia was rare (1.4%), and one patient presented febrile neutropenia. CONCLUSION: This study demonstrated that the combination of gemcitabine, oxaliplatin and erlotinib is active, well tolerated and safe for patients with metastatic adenocarcinoma of the pancreas. However, the results do not seem to be better than those reported with chemotherapy alone.

Chemotherapy compliance, tolerance and efficacy in elderly and non-elderly patients with metastatic colorectal cancer: a single institution comparative study.

PURPOSE: To evaluate whether elderly patients with metastatic colorectal cancer (mCRC) receive chemotherapy of suboptimal intensity and duration, mainly due to fears of poor compliance and/or excessive toxicity. METHODS: We carried out a retrospective analysis in a series of 94 mCRC patients. Using the cut-off of 70 years, we compared elderly patients with their younger counterparts in terms of treatment delivery [type, dose intensity (DI), relative dose intensity (RDI), duration], chemotherapy toxicity and efficacy [objective response rate (ORR), overall survival (OS) and progression-free survival (PFS)]. RESULTS: Complete data were available for 72 patients (76.6%) among which 38 (52.8%) were elderly. As compared to the younger, elderly patients were more likely to receive single-agent chemotherapy (13.1 vs 0%, p<0.001). The mean number of chemotherapy cycles was 6.2 for the elderly and 8.3 for the non-elderly patients who received either the FOLFOX or FOLFIRI regimen (p=0.142) and 5.1 vs 5.0 for those who received either the XELOX or XELIRI regimen, respectively (p=0.831). In oxaliplatin-containing regimens, elderly patients received 42.8% of the planned dose, as compared to 78.4% for the younger ones (p=0.012). DI for oxaliplatin was higher in non-elderly than in the elderly (46.66 mg/ m(2)/week vs 32.47 mg/m(2)/week, p=0.008). No difference was observed in the rate of severe (grade III-IV) toxicities. ORR, PFS and OS were similar between the two groups. CONCLUSION: Despite the inferior type and intensity of chemotherapy, elderly patients derived equivalent benefit to their younger counterparts. These data further support the use of optimal chemotherapy in elderly patients with mCRC.

Docetaxel plus cisplatin and bevacizumab for untreated patients with advanced/metastatic non-squamous non-small-cell lung cancer: a multicenter phase II study of the Hellenic Oncology Research Group.

BACKGROUND: The docetaxel/cisplatin (DC) combination is an active regimen against advanced/metastatic non-small-cell lung cancer (NSCLC), and bevacizumab (B) improves the efficacy of frontline chemotherapy. This phase II study was designed in order to explore the efficacy and safety of DCB regiment in this setting. METHODS: Chemotherapy-naïve patients (n = 48) with measurable, histologically confirmed non-squamous, IIIB (wet)/IV NSCLC, and PS 0-2 were eligible. Patients received D (75 mg/m(2) IV), C (80 mg/m(2) IV), and B (15 mg/kg IV) every 3 weeks. Maintenance of bevacizumab was not mandatory. RESULTS: Complete and partial responses were achieved in two (4.2%) and 14 (29.2%) patients, respectively [overall response rate: 33.3%; 95% CI = 20.0-46.7%], whereas stable disease was documented in 14 [disease control rate = 62.5%; 95% CI = 48.8-76.2%]. The median progression-free survival was 4.4 months and the median overall survival 13.3 months. Treatment-related grade 3 or 4 hematologic adverse events were leukopenia, neutropenia, and anemia in 8.4, 18.7, and 2.1% of the patients, respectively. Febrile neutropenia occurred in three (6.3%) patients. Bleeding was documented in 4% of the patients, thrombotic episodes in 8%, and proteinuria in 3%. There was one treatment-related death. CONCLUSIONS: Frontline DCB in patients with advanced non-squamous NSCLC is an active regimen with manageable toxicity and merits to be further investigated.

Paclitaxel in combination with carboplatin as salvage treatment in patients with castration-resistant prostate cancer: a Hellenic oncology research group multicenter phase II study.

INTRODUCTION: To evaluate the efficacy and tolerance of biweekly paclitaxel and carboplatin combination in patients with castration-resistant prostate cancer. PATIENTS AND METHODS: Patients were treated with paclitaxel at the dose of 135 mg/m(2) followed by carboplatin AUC 3 on day 1 every 2 weeks in cycles of 28 days. RESULTS: Thirty-eight patients with castration-resistant prostate cancer were enrolled, and all of them had received frontline chemotherapy with docetaxel and prednisone, while 24 (63.2 %) had received 2 or more prior chemotherapy regimens. In an intention-to-treatment analysis, a clinical and/or biochemical response (>50 % decline) was observed in 10 patients (26.3 %; 95 % CI, 12.3-40.3 %), stable disease in 13 (34.2 %) and progressive disease in 15 (39.5 %). The median duration of response was 6.1 months (range, 1.0-9.8), the median time to tumor progression (TTP) 3.6 months (95 % CI, 2.1-5.2) and the median overall survival 9.9 months (95 % CI, 6.2-13.6). The probability for 1-year survival was 43 %. Grade 3 and 4 neutropenia was observed in three (7.9 %) and nine (23.7 %) patients, respectively. CONCLUSION: The biweekly administration of paclitaxel/carboplatin regimen in patients with castration-resistant prostate cancer is an active and well-tolerated regimen which merits to be further evaluated in the context of salvage treatment.

Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC).

BACKGROUND: To compare the efficacy and safety of CAPIRI+bevacizumab (Bev) in comparison with FOLFIRI+Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC). METHODS: Patients were randomised to receive either FOLFIRI plus Bev 5 mg kg(-1) every 2 weeks (Arm-A) or CAPIRI plus Bev 7.5 mg kg(-1) every 3 weeks (Arm-B). RESULTS: Three hundred thirty-three patients (Arm-A=167; Arm-B=166) were enrolled into the study. No difference was observed in median progression-free survival (PFS) (10.0 and 8.9 months; P=0.64), overall survival (25.7 and 27.5 months; P=0.55) or response rates (45.5 and 39.8.7%; P=0.32) for FOLFIRI-Bev and CAPIRI-Bev, respectively. Patients treated with CAPIRI-Bev presented significantly higher incidence of diarrhoea (P=0.005), febrile neutropenia (P=0.003) and hand-foot skin reactions (P=0.02) compared with patients treated with FOLFIRI-Bev. Treatment delays (P=0.05), dose reduction (P<0.001) and treatment discontinuation owing to toxicity (P=0.01) occurred more frequently in the CAPIRI-Bev arm. CONCLUSION: The PFS of FOLFIRI-BEV is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with mCRC.

Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer.

BACKGROUND: The purpose of this study was to compare docetaxel plus epirubicin versus docetaxel plus capecitabine combinations as front-line treatment in women with advanced breast cancer (ABC). PATIENTS AND METHODS: Previously untreated patients with ABC were randomly assigned to receive docetaxel 75 mg/m(2) plus epirubicin 75 mg/m(2) (DE) on day 1 or docetaxel 75 mg/m(2) on day 1 plus capecitabine 950 mg/m(2) orally twice daily on days 1-14 (DC) in 21-day cycles. Previous anthracycline-based (neo)-adjuvant chemotherapy was allowed if completed >1 year before enrollment. The primary objective of the study was to compare time to disease progression (TTP). RESULTS: One hundred and thirty-six women were treated on each arm and median TTP was 10.6 versus 11.0 months (P = 0.7), for DE and DC, respectively. According to RECIST criteria we observed 15 (11%) versus 11 (8%) complete responses and 55 (40%) versus 61 (45%) partial responses (P = 0.8), with DE and DC, respectively. Severe toxicity included grade 3-4 neutropenia (57% versus 46%; P = 0.07), febrile neutropenia (11% versus 8%; P = 0.4), hand-foot syndrome (0% versus 4%; P = 0.02), grade 2-3 anemia (20% versus 7%; P = 0.001) and asthenia (12% versus 6%; P = 0.09) with DE and DC, respectively. CONCLUSIONS: The DE and DC regimens have similar efficacy but different toxicity. Either regimen can be used as front-line treatment of ABC.