Predictive value of ATP7b, BRCA1, BRCA2, PARP1, UIMC1 (RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) genes in patients with epithelial ovarian cancer who received platinum-taxane first-line therapy.

To evaluate the predictive value of genes involved in resistance to platinum-taxane chemotherapy in patients with epithelial ovarian cancer (EOC). Microdissected formalin-fixed tumoral samples from 187 EOC patients' primary tumors (90 and 97 samples from matched patients in the experimental and validation sets, respectively) were analyzed. All specimens were analyzed for ATP7b, BRCA1, BRCA2, PARP1, UIMC1(RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) mRNA expression by quantitative real-time PCR. Most of the patients (172 out of 187) received front-line carboplatin-paclitaxel regimen. Expression levels were correlated with overall (OS) and progression-free (PFS) survival by multivariate analysis. Patients with high TXN and THBS1 expression presented longer PFS (P=0.001 and P<0.001, respectively) and OS (P=0.024 and P<0.001, respectively). High TXR1 expression was associated with decreased PFS (P<0.001) and OS (P<0.001). Multivariate analysis demonstrated that high PRR13/low THBS1 expression was an independent factor for decreased PFS (hazards ratio: 1.94; 95% confidence interval (CI): 1.48-2.92; P=0.008) and OS (hazard ratio: 3.89; 95% CI: 2.16-6.87; P<0.001), whereas low TXN expression was correlated with decreased PFS (hazard ratio: 1.44; 95% CI: 1.05-2.84; P=0.043) and OS (hazard ratio: 2.38; 95% CI: 1.78-2.77; P=0.009). These findings indicate that PRR13/THBS1 and TXN expression could be used for the prediction of resistance to treatment of EOC patients and, therefore, merit to be further evaluated.

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.

Differential effect of adjuvant taxane-based and taxane-free chemotherapy regimens on the CK-19 mRNA-positive circulating tumour cells in patients with early breast cancer.

BACKGROUND: To determine the effect of adjuvant taxane-free and taxane-based chemotherapy regimens on the elimination of circulating tumour cells (CTCs) in patients with early breast cancer. METHODS: The presence of CK-19 mRNA-positive CTCs in the peripheral blood was evaluated before and after chemotherapy, using a real-time RT-PCR assay, in a historical comparison of two cohorts of women with stage I-III breast cancer treated with adjuvant taxane-free (N=211; FE(75)C or E(75)C) and taxane-based (N=334; T/E(75)C or T/E(75)) chemotherapy. RESULTS: Taxane-based chemotherapy resulted in a higher incidence of CTCs' elimination than taxane-free regimens since 49.7% (74 of 149) and 33.0% (29 of 88) of patients with detectable CTCs before chemotherapy, respectively, turned negative post-chemotherapy (P=0.015). Patients treated with taxane-free regimens had a significantly lower disease-free survival (DFS) (P=0.035) than patients treated with taxane-based regimens; this difference was observed in patients with but not without detectable CTCs before chemotherapy (P=0.018 and P=0.481, respectively). The incidence of deaths was significantly higher in the taxane-free cohort of patients with but not without detectable CTCs before chemotherapy compared with that of the taxane-based cohort (P=0.002). Multivariate analysis revealed that the chemotherapy regimen was significantly associated with prolonged DFS (HR: 2.00; 95% CI=1.20-3.34). CONCLUSION: Elimination of CK-19 mRNA-positive CTCs during adjuvant chemotherapy seems to be an efficacy indicator of treatment and is associated with a favourable clinical outcome of patients with detectable CTCs before chemotherapy.

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.

A multicenter phase II trial of docetaxel and capecitabine as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer.

OBJECTIVE: To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC). PATIENTS AND TREATMENT: Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n = 29; 100 %) and taxanes (n = 11; 37.9 %) were treated with oral capecitabine 950 mg/m(2) twice daily on days 1-14 and docetaxel 75 mg/m(2) on day 1 every 3 weeks. Nineteen (65.5 %) patients received this regimen as second line and 10 (34.5 %) as ≥3rd line of therapy. All patients were evaluable for response and toxicity. RESULTS: Complete response occurred in two (6.9 %) patients and partial response in eleven (37.9 %) for an overall response rate of 44.8 % (95 % CI 26.7-62.9 %). Eleven women (37.9 %) had stable disease and five (17.2 %) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5 %) responded to DC combination. The median duration of response was 5.7 months (range 3.4-64.2), the median time to disease progression 9.3 months (range 1.2-58), and the median overall survival 25.5 months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6 % of patients and three of them (10.3 %) developed neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9 % of the patients, fatigue in 3.4 %, and neurotoxicity in 3.4 %. CONCLUSION: The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC.

Small cell ovarian cancer in adolescents: report of two cases and review of the literature.

Ovarian small cell carcinoma is a rare and highly malignant neoplasm carrying a poor prognosis. Although combination chemotherapy remains the cornerstone of treatment due to the rarity of these tumors, no regimen can be recommended as standard of care although in the majority of cases platinum-based regimens are used. Herein, we report two cases of small cell carcinoma of the ovaries along with a review of the relevant literature.

Metronomic vinorelbine plus bevacizumab as salvage therapy for patients with metastatic breast cancer.

PURPOSE: Continuous administration of oral vinorelbine, given 3 times a week (metronomic), is feasible and exceptionally well tolerated at doses up to 50 mg with clinical activity against refractory tumors. In this phase II study oral metronomic vinorelbine and bevacizumab were evaluated as salvage therapy in women with pretreated metastatic breast cancer (MBC). METHODS: Patients received oral vinorelbine (50 mg 3 times a week) and bevacizumab (10 mg/kg) biweekly in cycles of 28 days. The primary endpoint was objective response rate (ORR). A preplanned analysis was performed when the first 13 patients were evaluated for tumor response. RESULTS: One patient (7.7%) achieved partial response (PR) and 6 (46.1%) stable disease (SD). The combination was very well tolerated but, as per protocol, the study was closed prematurely due to lack of efficacy. CONCLUSION: The combination of oral metronomic vinorelbine and bevacizumab has good tolerance but minimal activity in terms of objective responses in pretreated patients with MBC.

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.

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.

Chemotherapy-induced neutropenia as a prognostic factor in patients with advanced non-small cell lung cancer treated with front-line docetaxel-gemcitabine chemotherapy.

BACKGROUND: Front-line docetaxel-gemcitabine (DG) combination represents an alternative to platinum-based chemotherapy in patients with advanced NSCLC. One of its more common side effects is neutropenia. The association between the grade of DG-induced neutropenia and the clinical outcome was analyzed. PATIENTS AND METHODS: Eight hundred fifty-eight patients with locally advanced/metastatic NSCLC, treated with front-line DG were retrospectively analyzed. Patients were categorized into three groups according to the presented worst neutropenia grade: absent (grade 0), mild (grades I/II) and severe (grades III/IV). RESULTS: Response rate, median time to tumor progression (TTP) and median overall survival (OS) were significantly better in patients developing any grade of neutropenia compared with those without neutropenia. The median TTPs were 3.0, 5.4 and 5.6 months for the groups with absent, mild and severe neutropenia, respectively; the median OSs were 7.9, 12.5 and 11.2 months for the same groups, respectively. Multivariate analysis revealed that both mild and severe chemotherapy-induced neutropenia were independent factors associated with a better TTP and OS survival. CONCLUSION: Although DG-induced neutropenia was emerged as an independent prognostic factor, it remains to be demonstrated in prospective studies that dose escalation of chemotherapy drugs in patients who do not develop neutropenia may improve the clinical efficacy.

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.

Sequential gemcitabine and cisplatin followed by docetaxel as first-line treatment of advanced urothelial carcinoma: a multicenter phase II study of the Hellenic Oncology Research Group.

BACKGROUND: The purpose of this study was to investigate the toxicity and efficacy of the sequential administration of gemcitabine (GMB) in combination with cisplatin (CDDP) followed by docetaxel (Taxotere) as first-line treatment of advanced urothelial carcinoma. PATIENTS AND METHODS: Patients [aged

Vinorelbine and cisplatin combination in pretreated patients with advanced non-small cell lung cancer pretreated with a taxane-based regimen: a multicenter phase II study.

PURPOSE: To assess the efficacy and tolerance of the vinorelbine/cisplatin combination in non-small cell lung cancer patients pre-treated with a taxane-based regimen. PATIENTS AND METHODS: Among the 32 enrolled patients, 28 (87.5%) had a PS (WHO) of 0-1 and 13 (40.6%) have previously received both platinum compounds and taxanes. Vinorelbine (25 mg/m2 on days 1 and 8) was given by a rapid i.v. infusion and cisplatin (80 mg/m2 on day 8) after appropriate hydration. The treatment was repeated every 3 weeks. RESULTS: A partial response was achieved in six patients (ORR=18.8%; 95% confidence interval: 5.23-32.27); 13 (44.8%) and 10 (34.5%) patients had stable and progressive disease, respectively (intention-to-treat analysis). Four partial responses were observed in patients who were previously treated with taxanes/platinum-containing regimens. The median time to tumor progression was 4.7 months (range, 1.3-15.4). After a median follow-up period of 6.3 months (range, 1.3-15.4) the median overall survival was 7.6 months and the 1-year survival rate 17.7%. Grade 3 and 4 granulocytopenia was observed in 11 (34.4%) patients and grade 4 thrombocytopenia in one (3.1%). Eleven (34.4%) patients presented grade 2 and 3 anemia. Febrile neutropenia occurred in one (3.1%) patient. Grade 3 and 4 nausea/vomiting was reported in one (9.3%) patient each and grade 2 fatigue in four (12.5%). CONCLUSIONS: The combination of vinorelbine and cisplatin is an active and well tolerated salvage regimen in NSCLC patients pre-treated with taxane-based chemotherapy.

FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG).

To compare the efficacy and toxicity of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFOXIRI) vs irinotecan and 5-FU/LV (FOLFIRI) as first-line treatment of patients with metastatic colorectal cancer (MCC). A total of 283 chemotherapy-naïve patients with MCC were enrolled (FOLFIRI arm: n=146; FOLFOXIRI arm: n=137). In the FOLFOXIRI arm, CPT-11 (150 mg m(-2)) was given on d1, L-OHP (65 mg m(-2)) on d2, LV (200 mg m(-2)) on days 2 and 3 and 5-FU (400 mg m(-2) as i.v. bolus and 600 mg m(-2) as 22 h i.v. continuous infusion) on days 2 and 3. In the FOLFIRI arm, CPT-11 (180 mg m(-2)) was given on d1 whereas LV and 5-FU were administered in the same way as in the FOLFOXIRI regimen. Both regimens were administered every 2 weeks. There was no difference in terms of overall survival (median OS: 19.5 and 21.5 months, for FOLFIRI and FOLFOXIRI, respectively; P=0.337), median time to disease progression (FOLFIRI: 6.9 and FOLFOXIRI: 8.4 months; P=0.17), response rates (33.6 and 43% for FOLFIRI and FOLFOXIRI, respectively; P=0.168). Patients treated with FOLFOXIRI had a significantly higher incidence of alopecia (P=0.0001), diarrhoea (P=0.0001) and neurosensory toxicity (P=0.001) compared with patients treated with FOLFIRI. The present study failed to demonstrate any superiority of the FOLFOXIRI combination compared with the FOLFIRI regimen, although the observed median OS is one of the best ever reported in the literature.

A dose-escalation study of pegylated liposomal Doxorubicin and oxaliplatin in patients with advanced solid tumors.

PURPOSE: A phase I study was conducted to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the pegylated liposomal doxorubicin (PLD) and oxaliplatin combination in patients with advanced solid tumors. PATIENTS AND METHODS: Forty-five patients with advanced-stage solid tumors received escalating doses of PLD 25-50 mg/m(2) as 60-min intravenous (i.v.) infusion and oxaliplatin 80-130 mg/m(2) as 2- to 4-hour i.v. infusion on day 1 every 3 weeks without growth factors. RESULTS: MTD was defined at PLD 45 mg/m(2) and oxaliplatin 130 mg/m(2). Eleven dose levels were evaluated and DLTs were grade 2-3 neutropenia resulting in treatment delays, grade 3 neurotoxicity and nausea/vomiting. A total of 187 cycles were administered with two episodes of febrile neutropenia and one toxic death due to sepsis. Two (4%) and 6 (13%) patients developed grade 4 and 3 neutropenia, respectively, 2 (4%) and 1 (2%) grade 4 and 3 thrombocytopenia, and 1 (2%) grade 4 anemia. The most common nonhematological toxicities were grade 2-3 nausea/vomiting and asthenia observed in 27 (60%) and 16 (36%) of patients, respectively. One complete and eight partial responses were observed. CONCLUSION: The combination of PLD and oxaliplatin has an acceptable toxicity profile with promising activity and merits further evaluation in phase II studies.

A dose escalation study of gemcitabine plus pemetrexed administered biweekly in patients with solid tumors.

PURPOSE: The study aimed to determine the maximum tolerated doses (MTDs) and identify the dose-limiting toxicities of the biweekly administration of pemetrexed plus gemcitabine in patients with solid tumors. PATIENTS AND METHODS: Patients with advanced malignancies were treated with escalated doses of gemcitabine and pemetrexed (starting doses 1,250 and 300 mg/m(2), respectively) both given on days 1 and 15 in cycles of 4 weeks. RESULTS: Forty-one patients were treated at 7 dose levels. The MTD was reached at the dose of 1,750 mg/m(2) for gemcitabine and 450 mg/m(2) for pemetrexed. Dose-limiting events were grade IV neutropenia, febrile neutropenia and treatment delay due to grade III hematological toxicities. One partial response in a pretreated patient with ovarian cancer was observed, while 4 other patients experienced stable disease. CONCLUSIONS: The biweekly administration of gemcitabine plus pemetrexed at the recommended MTDs is safe, well tolerated and demonstrates antitumor activity which merits further evaluation in phase II studies.

Phase I study of weekly docetaxel and liposomal doxorubicin in patients with advanced solid tumors.

PURPOSE: To determine the maximum-tolerated doses (MTDs) and the dose-limiting toxicities (DLTs) of the weekly administration of docetaxel and pegylated liposomal doxorubicin (PEG-LD) in patients with advanced solid tumors. PATIENTS AND METHODS: Forty-eight patients with solid tumors were enrolled in the study. Dose escalations of both drugs were given on a weekly basis for 3 consecutive weeks in cycles of 4 weeks. The starting dose for docetaxel was 20 mg/m(2)/week and for PEG-LD 6 mg/m(2)/week. RESULTS: The MTD was 35 mg/m(2)/week for docetaxel and 14 mg/m(2)/week for PEG-LD. The DLTs at this level were grade 3 diarrhea (n=1 patient) and grade 3 mucositis (n=2 patients). There was no grade 4 hematologic or non-hematologic toxicity. Grade 3 neutropenia and thrombocytopenia occurred only in 1 and 2 patients, respectively. The non-hematologic toxicity was also mild with grade 2/3 fatigue in 8 patients, grade 2/3 neurotoxicity in 4, grade 2/3 mucositis in 8, grade 2/3 diarrhea in 4 and grade 2/3 nausea and vomiting in 5 patients. Two (5.7%) complete and 6 (17%) partial responses (overall response rate=22.7%; 95% confidence interval 9.6--32.4%) were observed among 35 evaluable patients. In 12 (63%) of 19 patients with hormone-refractory prostate cancer, a decline in serum levels of prostate-specific antigen of >50% was observed. CONCLUSIONS: The weekly administration of docetaxel with PEG-LD is a well-tolerated regimen that merits further evaluation.