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)

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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 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.

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.

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.

A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial.

BACKGROUND: We conducted an open-label, pilot phase II trial to evaluate the efficacy and safety of FOLFOXIRI plus cetuximab as first-line treatment of patients with metastatic colorectal cancer (mCRC). METHODS: Thirty patients with KRAS wild-type mCRC, <70 years and with performance status 0-1 were included in the trial. RESULTS: Complete and partial responses were observed in 4 (13.3%) and 17 (56.7%) patients, respectively (overall response rate (ORR)=70%; 95% confidence interval (CI): 53.6%-86.4%); 8 patients (26.7%) had stable disease and 1 had progressive disease. The median time to tumour progression was 10.2 months (95% CI: 7.1-13.4) and the overall median survival time was 30.3 months (95% CI: 18.8-41.9). Secondary R0 resection was performed in 11 (37%) patients. Grade 3 or 4 diarrhoea and neutropenia were observed in 16 (53%) and 7 (23.3%) patients, respectively, and febrile neutropenia observed in 2 (6.6%) patients. Neurotoxicity grade 2 or 3 was reported in 7 (23.3%) and in 2 (6.7%) patients, respectively, and grade 3 rush was reported in 1 patient. CONCLUSION: The FOLFOXIRI/cetuximab combination presented increased activity in terms of response rate and R0 secondary liver metastases resection, and merits further investigation, especially in patients with initially unresectable disease confined to the liver.

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.

Efficacy and treatment tolerance in older patients with NSCLC: a meta-analysis of five phase III randomized trials conducted by the Hellenic Oncology Research Group.

BACKGROUND: Approximately 50% of newly diagnosed cases of non-small-cell lung cancer (NSCLC) are observed in patients >65 years, while 30%-40% of cases occur in patients >70 years. PATIENTS AND METHODS: The objective of the current study was to determine (i) the number of elderly (>70 years) patients with advanced/metastatic NSCLC enrolled in phase III trials of the Hellenic Oncology Research Group, (ii) the treatment-related toxicity observed in these patients compared with their younger counterparts, and (iii) the differences in terms of response rate, time to tumor progression (TTP), and overall survival (OS) between younger and older patients. RESULTS: Pooled data from five clinical trials including 1845 patients were analyzed; 1421 (77%) and 424 (23%) were <70 years and ≥70 years, respectively. No difference was observed in terms of the overall response rate and TTP. There was an OS difference between young and older patients, with higher risk for death in older patients. However, when the analysis was carried out after omitting a trial that showed a different trend, no difference was observed. Older patients experienced higher toxicity. CONCLUSIONS: This report supports the feasibility of chemotherapy treatment for older NSCLC patients. Optimization of treatment of older NSCLC patients requires the design of prospective older-specific phase III trials for these patients.

Clinical outcome of elderly patients with metastatic colorectal cancer treated with FOLFOXIRI versus FOLFIRI: Subgroup analysis of a randomized phase III trial from the Hellenic Oncology Research Group (HORG).

BACKGROUND: A subgroup analysis of oxaliplatin (LOHP)+irinotecan (CPT-11)+5-fluorouracil (5FU) and leucovorin (LV) (FOLFOXIRI regimen) versus irinotecan+5FU/LV (FOLFIRI regimen) as first-line treatment of patients >65 years old with metastatic colorectal cancer is presented. PATIENTS AND METHODS: Eighty-two (56%) and 75 (55%) patients with metastatic colorectal cancer aged >65 years were enrolled in the FOLFOXIRI and FOLFIRI regimen, respectively. RESULTS: There was no statistically statistical difference in terms of overall survival or time-to-tumor progression between young and aged patients between the two chemotherapy arms. The objective response rate was significantly lower in older patients treated with FOLFOXIRI (32% vs. 52%; OR: 1.45, 95% CI: 1.06-2.09; p=0.03). Elderly patients experienced a significantly higher incidence of grade 3/4 diarrhea compared to younger patients, irrespectively of the chemotherapy regimen (p=0.005 for FOLFIRI; p=0.017 for FOLFOXIRI). Dose reductions and treatment delays were more frequent in the FOLFOXIRI arm. CONCLUSION: FOLFOXIRI does not seem to offer substantial benefit compared to FOLFIRI regimen in elderly patients with metastatic colorectal cancer.

Etoposide plus cisplatin followed by concurrent chemo-radiotherapy and irinotecan plus cisplatin for patients with limited-stage small cell lung cancer: A multicenter phase II study.

PURPOSE: The combination of irinotecan and cisplatin (IP) has shown at least comparable efficacy to that of etoposide/cisplatin (EP) in patients with extensive-stage small cell lung cancer. We conducted a phase II study to evaluate the efficacy and tolerance of EP regimen followed by thoracic radiotherapy (TRT) and IP consolidation chemotherapy in patients with limited-stage small cell lung cancer. PATIENTS AND METHODS: Thirty-three chemotherapy-naive patients with limited-stage small cell lung cancer (LS-SCLC) were treated with etoposide 100mg/m(2) on days 1-3 and cisplatin 80mg/m(2) on day 1. Radiotherapy was given 3 weeks after the first treatment cycle concurrently with weekly cisplatin 20mg/m(2) on day 1 and etoposide 50mg/m(2) on day 4 within 5-6 weeks, followed by three courses of irinotecan 60mg/m(2) on days 1, 8, and 15 and cisplatin 60mg/m(2) on day 1 of a 4-week cycle. RESULTS: There were no treatment-related deaths. Toxicities during chemo-radiotherapy were mild including grade 3/4 neutropenia (24%) and grade 2 esophagitis (6%). The major toxicity observed during consolidation chemotherapy was grades 3-4 neutropenia which affected 42% of patients. In an intention-to-treat analysis the overall response rate was 66% (CR: 30% and PR: 36%). After a median follow-up period of 35.7 months (range: 9.6-41.2 months), the median survival time was 19 months (95% CI: 14.5-23.5 months), the median time to tumor progression 8.3 months and the 1- and 2-year survival rates 72% and 27.5%, respectively. CONCLUSIONS: Consolidation chemotherapy with IP following concurrent EP plus TRT is a safe and with acceptable toxicity regimen and deserves further phase III testing in patients with LS-SCLC.

Docetaxel plus gemcitabine as front-line chemotherapy in elderly patients with lung adenocarcinomas: a multicenter phase II study.

BACKGROUND: The docetaxel/gemcitabine (DG) combination is an active and well-tolerated regimen against non-small cell lung cancer (NSCLC). A phase II study was conducted in order to evaluate its efficacy in elderly patients with lung adenocarcinomas. METHODS: Chemotherapy-naive patients, aged > or =70 years, with locally advanced or metastatic lung adenocarcinomas and performance status (PS) < or =2 (ECOG) received gemcitabine 1100 mg/m(2) (days 1+8) and docetaxel 100 mg/m(2) (day 8) with rhG-CSF support. RESULTS: Seventy-seven patients were enrolled. One (1.3%) complete and 23 (29.9%) partial responses were achieved (intention to treat analysis: ORR 31.2%; 95% CI 20.82-41.51%) whereas tumor growth control was achieved in 53.3% of patients. The median TTP was 4.1 months, the median overall survival 9.4 months and the 1- and 2-year survival rate 37.9% and 10.7%, respectively. Grade 3-4 neutropenia occurred in 18.2% and febrile neutropenia in 3 (3.9%) patients. Non-haematological toxicity was mild with grade 2-3 asthenia occurring in 22.1% patients. CONCLUSIONS: The DG regimen is an active and well-tolerated front-line chemotherapy for elderly patients with lung adenocarcinomas and merits further evaluation in prospective randomized trials.

Modified CAPOX (capecitabine plus oxaliplatin) regimen every two weeks as second-line treatment in patients with advanced colorectal cancer previously treated with irinotecan-based frontline therapy: a multicenter phase II study.

BACKGROUND: To evaluate the efficacy and tolerance of capecitabine (CAP) given every other week and biweekly oxaliplatin (OX; modified CAPOX regimen) in patients with advanced colorectal cancer previously treated with irinote- can-based frontline chemotherapy. METHODS: Sixty-seven patients were enrolled; the median age was 62 years and 62 (92.5%) had a performance status (ECOG) of 0-1. OX and CAP were administered at the dose of 100 mg/m(2) on day 1 and 2,000 mg/m(2) on days 1-7, respectively, every 2 weeks. RESULTS: A total of 429 treatment cycles were administered. Grade 3/4 neutropenia and thrombocytopenia were observed in 4 (6%) and 2 (3%) patients, respectively. Febrile neutropenia complicated 1 treatment cycle. The main nonhematologic toxicities were grade 2/3 peripheral sensory neurotoxicity (10% of patients) and grade 3/4 diarrhea (7%). In an intention-to-treat analysis, 3 (4.5%) complete and 13 (19.4%) partial responses (overall response rate 24%) were observed. Seventeen (24.5%) patients had stable and 27 (40.3%) progressive disease. The median time to tumor progression and overall survival were 5 months and 11.3 months, respectively. CONCLUSIONS: The results indicate that the modified CAPOX regimen is safe and effective as salvage treatment in patients with advanced colorectal cancer who were previously treated with irinotecan-based frontline therapy.

A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and gemcitabine in patients with advanced solid tumours.

To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of pegylated liposomal doxorubicin (PLD), paclitaxel (PCX) and gemcitabine (GEM) combination administered biweekly in patients with advanced solid tumours. Twenty-two patients with advanced-stage solid tumours were treated with escalated doses of PLD on day 1 and PCX plus GEM on day 2 (starting doses: 10, 100 and 800 mg m(-2), respectively) every 2 weeks. DLTs and pharmacokinetic (PK) parameters of all drugs were determined during the first cycle of treatment. All but six (73%) patients had previously received at least one chemotherapy regimen. The DLT dose level was reached at PLD 12 mg m(-2), PCX 110 mg m(-2) and GEM 1000 mg m(-2) with neutropaenia being the dose-limiting event. Of the 86 chemotherapy cycles delivered, grade 3 and 4 neutropaenia occurred in 20% with no cases of febrile neutropaenia. Non-haematological toxicities were mild. The recommended MTDs are PLD 12 mg m(-2), PCX 100 mg m(-2) and GEM 1000 mg m(-2) administered every 2 weeks. The PK data revealed no obvious drug interactions. Biweekly administration of PLD, PCX and GEM is a well-tolerated chemotherapy regimen, which merits further evaluation in various types of solid tumours.

Circulating HER2 mRNA-positive cells in the peripheral blood of patients with stage I and II breast cancer after the administration of adjuvant chemotherapy: evaluation of their clinical relevance.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of circulating tumor cells (CTCs) expressing HER2 messenger RNA (mRNA) after the administration of adjuvant chemotherapy in women with operable breast cancer. PATIENTS AND METHODS: HER2 mRNA-positive CTCs were detected by nested RT-PCR in the peripheral blood of 214 patients with stage I and II breast cancer after the completion of adjuvant chemotherapy. RESULTS: HER2 mRNA-positive CTCs were detected in 45 (21%) patients. Adjuvant chemotherapy could eliminate HER2 mRNA-positive CTCs in 16 (30.2%) prechemotherapy-positive patients. Moreover, HER2 mRNA-positive CTCs were detected in eight (5%) of 161 prechemotherapy-negative patients. The detection of HER2 mRNA-positive CTCs after chemotherapy was associated with reduced disease-free interval (DFI) (P = 0.006) but not with overall survival (P = 0.2); this effect was mainly observed in node-negative patients (P = 0.04) and to a lesser extent in node-positive (P = 0.06). Multivariate analysis revealed that the detection of HER2 mRNA-positive CTCs was an independent predictive factor for DFI (hazard ratio 3.238, P < 0.0005). CONCLUSIONS: The detection of HER2 mRNA-positive CTCs after the completion of adjuvant chemotherapy may provide clinically useful information concerning the efficacy of treatment and the prognosis of patients with operable breast cancer.

Sequential administration of docetaxel followed by maintenance gefitinib, as salvage treatment in patients with advanced NSCLC: a multicenter phase II trial.

PURPOSE: To evaluate the activity and toxicity of the sequential administration of docetaxel followed by gefitinib in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND TREATMENT: Forty-one patients pre-treated with at least one prior chemotherapy regimen (platinum- or taxane-based) for advanced/metastatic NSCLC received three cycles of docetaxel 30 mg/m2, administered as a 1-h IV infusion, on days 1, 8 and 15 of each 4-week cycle followed by gefitinib 250 mg daily po. Gefitinib treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of patients consent. RESULTS: Two (4.9%) patients achieved a partial response and 10 (24.4%) stable disease, for a disease control rate of 29.3% (95% CI: 15.3%-43.2%) while on weekly docetaxel treatment. Additionally, progressive disease (PD) was observed in 29 (70.7%). No objective responses were observed during the gefitinib maintenance therapy; however, 17 (41.5%) patients presented stable disease maintained for more than 2 months. Median time to progression was 3.0 months (range: 1-38.3 months; 95% CI: 2.4-3.6); median overall survival 6.9 months (range: 1.2-40.2 months; 95% CI: 5.34-8.52) while the 1-year survival was 28.8%. Therapy was generally well tolerated with diarrhea and rash being the most frequent toxicities. CONCLUSIONS: The sequential administration of docetaxel and gefitinib was well tolerated and moderately active against advanced pre-treated NSCLC.

Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy.

BACKGROUND: Cetuximab is an IgG1 monoclonal antibody targeting the epidermal growth factor receptor and is able to reverse the resistance to irinotecan in patients with metastatic colorectal cancer (mCRC). This phase II trial evaluates the safety and efficacy of cetuximab combined with capecitabine and oxaliplatin (CAPOX) in the treatment of patients with mCRC progressing under oxaliplatin-based chemotherapy. PATIENTS AND TREATMENT: Forty patients with mCRC were treated with cetuximab (loading dose 400 mg/m(2) and then 250 mg/m(2) i.v. weekly) in combination with CAPOX (d(1): L-OHP 85 mg/m(2) and d(1-7) capecitabine 2000 mg/m(2) every 2 weeks). Thirty-one (77.5%) and nine (22.5%) patients had oxaliplatin-refractory and -resistant disease, respectively; in addition, 32 (80%) patients had also progressed on prior irinotecan-based chemotherapy. RESULTS: One hundred and thirty-four cycles were administered (median of four cycles per patient). Main toxic effects included grade 3-4 neutropenia (12.5%), grade 3/4 diarrhea (7.5%), grade 3 fatigue (2.5%), and grade 2-3 neurotoxicity (22.5%). One (2.5%) complete and seven (17.5%) partial responses were achieved [overall objective response rate (ORR): 20%; 95% confidence interval (CI): 9% to 32%)], whereas 11 (27.5%) patients had stable disease [disease control rate (DCR): 47.5%; 95% CI: 30.2% to 64.5%]. The ORR and DCR were 18.7% and 46.8%, respectively, in patients with oxaliplatin-refractory disease. The median time to tumor progression was 3 months, the median survival 10.7 months and the probability of 1-year survival rate 53.4%. CONCLUSIONS: The combination of cetuximab plus CAPOX is safe and has a promising activity in patients with mCRC refractory or resistant to oxaliplatin.

Salvage chemotherapy with gemcitabine and oxaliplatin in heavily pretreated patients with metastatic breast cancer: a multicenter phase II study.

PURPOSE: It was the aim of this study to evaluate the activity and tolerance of gemcitabine and oxaliplatin in pretreated metastatic breast cancer patients. METHODS: Thirty-one patients who had disease relapse or progression after completion of an anthracycline- and/or taxane-based front-line regimen were treated with gemcitabine 1,500 mg/m(2) on days 1 and 8 as a 30-min intravenous infusion and oxaliplatin 130 mg/m(2) on day 8 as a 4-hour intravenous infusion, in cycles of 21 days. RESULTS: Complete response occurred in 1 patient (3%) and partial response in 4 patients (13%) (overall response rate 16%; 95% confidence interval 3.2-29.1). Nine patients (29%) had stable disease and 17 (55%) progressive disease. Three partial responses (13%) were achieved among 23 patients receiving the regimen as third-line treatment. The median duration of response was 6 months (range 3-44.8), the median time to tumor progression 4.6 months (range 0.8-43.8), and the median survival 14.4 months (range 2.1-44.8). Grade 3 and 4 neutropenia occurred in 14 patients (45%), grade 3 and 4 thrombocytopenia in 6 patients (20%), and grade 2 and 3 asthenia in 4 patients (13%). There was no episode of febrile neutropenia. CONCLUSION: The gemcitabine-oxaliplatin combination is a relatively active and well-tolerated salvage regimen in patients with heavily pretreated metastatic breast cancer.