Lambros Vamvakas

Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study.

PurposeTo evaluate the efficacy and the toxicity of front line FOLFOX4 combined with bevacizumab in patients with metastatsic CRC (mCRC).Patients and MethodsChemotherapy-naïve patients with mCRC, received bevacizumab (5 mg/kg every 2 weeks d1), oxaliplatin (85 mg/m2 on d1), leucovorin (200 mg/m2) on days 1 and 2 and 5-Fluorouracil (400 mg/m2 as i.v. bolus and 600 mg/m2 as 22 h i.v. continuous infusion on days 1 and 2) every 2 weeks.ResultsFifty three patients (46 with a PS 0–1) were enrolled. Complete and partial response was achieved in eight (15.1%) and 28 (52.8%) patients, respectively (ORR: 67.9%; 95% C.I.: 53.8%–92%); 11 (20.7%) patients had stable disease and six (11.3%) progressive disease. With a median follow up period of 13.5 months, time to tumor progression was 11 months while the median survival has not yet been reached; the probability of 1-, 2- and 3- year survival was 79.8%, 63.8% and 58.3%, respectively; Two patients relapsed during the follow up period. Eight (15%) patients underwent metastasectomy with R0 resections. Grade 3–4 neutropenia occurred in 15.1% of patients and one (1.9%) of them presented febrile neutropenia. Non-hematologic toxicity included grade 3 diarrhea (7.6%) and grade 2 and 3 neurotoxicity in 16.9 and 15.1% of patients, respectively. One (1.9%) patient presented pulmonary embolism and one (1.9%) cardiac ischaemia. There was one (1.9%) sudden death after the first cycle.ConclusionThe combination of FOLFOX4/bevacizumab appears to be highly effective, well tolerated and merits further evaluation in patients with mCRC.

Pemetrexed versus erlotinib in pretreated patients with advanced non–small cell lung cancer: A Hellenic Oncology Research Group (HORG) randomized phase 3 study

In this superiority study, pemetrexed was compared with erlotinib in pre‐treated patients with metastatic non–small cell lung cancer (NSCLC).

A multicenter phase II study of docetaxel in combination with gefitinib in gemcitabine-pretreated patients with advanced/metastatic pancreatic cancer

Purpose: To evaluate the efficacy and tolerance of the docetaxel/gefitinib combination as second-line treatment in patients with advanced pancreatic cancer. Patients and Methods: Twenty-six patients pretreated with gemcitabine-based chemotherapy were enrolled in the study. Docetaxel (75 mg/m2, i.v.) was administered every 3 weeks for a maximum of 6 cycles and gefitinib (250 mg/day, p.o.) was given continuously. Results: Five (19.2%) patients achieved stable disease. The median duration of disease control was 4.8 months (range 1–13.2), the median time to disease progression 2.1 months (range 1–7.3) and the median survival time 2.9 months (range 1–13.9). Grade 3/4 neutropenia was recorded in 9 (34.6%) patients, although only 1 (3.8%) developed grade 2 febrile neutropenia. One (3.8%) patient experienced grade 3 fatigue and 2 (7.7%) grade 3 diarrhea. Grade 1/2 rash was observed in 13 (50%) patients. There were no treatment-related deaths. Conclusion: The docetaxel/gefitinib combination, although safe, has no activity as salvage treatment for advanced pancreatic cancer after failure of gemcitabine-based chemotherapy.

Oxaliplatin for Pretreated Patients with Advanced or Metastatic Pancreatic Cancer: A Multicenter Phase II Study

A phase II study was designed to evaluate the efficacy and safety of oxaliplatin as second-line treatment in patients with locally advanced or metastatic pancreatic cancer. Eighteen patients with advanced pancreatic cancer previously treated with gemcitabine-based chemotherapy, received oxaliplatin 130 mg/m2 i.v. every 21 days. Patients were treated until tumor progression or unacceptable toxicity. No objective response was observed among the 18 treated patients. Three (16.7%) patients had stable disease for > 2 months. A clinical benefit response was observed in five (27.7%) patients. Toxicity was mild. Oxaliplatin as second-line treatment for patients with unresectable pancreatic cancer is well tolerated and associated with improvement of tumor-related symptoms despite its failure to induce objective responses. LOHP merits further investigation in combination with other drugs as palliative treatment of pretreated patients with advanced pancreatic cancer.

Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status

IntroductionTo evaluate the incidence of central nervous system (CNS) involvement in patients with breast cancer treated with a taxane-based chemotherapy regimen and to determine predictive factors for CNS relapse.MethodsThe medical files of patients with early breast cancer (n = 253) or advanced stage breast cancer (n = 239) as well of those with other solid tumors (n = 336) treated with or without a taxane-based chemotherapy regimen during a 42-month period were reviewed. HER2/neu overexpression was identified by immunohistochemistry, whereas cytokeratin 19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in the peripheral blood were identified by real-time PCR.ResultsThe incidence of CNS relapse was similar in patients suffering from breast cancer or other solid tumors (10.4% and 11.4%, respectively; P = 0.517). The incidence of CNS relapse was significantly higher in breast cancer patients with advanced disease (P = 0.041), visceral disease and bone disease (P = 0.036), in those who were treated with a taxane-containing regimen (P = 0.024), in those with HER2/neu-overexpressing tumors (P = 0.022) and, finally, in those with detectable CK-19 mRNA-positive CTCs (P = 0.008). Multivariate analysis revealed that the stage of disease (odds ratio, 0.23; 95% confidence interval, 0.007–0.23; P = 0.0001), the HER2/neu status (odds ratio, 29.4; 95% confidence interval, 7.51–101.21; P = 0.0001) and the presence of CK-19 mRNA-positive CTCs (odds ratio, 8.31; 95% confidence interval, 3.97–12.84; P = 0.001) were independent predictive factors for CNS relapse.ConclusionCNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen, patients with HER2/neu-positive tumor and patients with CK-19 mRNA-positive CTCs.

Oxaliplatin as first-line treatment in inoperable biliary tract carcinoma: a multicenter phase II study.

Background: A multicenter phase II study was conducted in order to evaluate the efficacy and safety of oxaliplatin as first-line treatment of patients with locally advanced or metastatic carcinoma of the biliary tract. Patients and Methods: Twenty-nine chemo-naïve patients with locally advanced or metastatic biliary tract carcinoma received oxaliplatin 130 mg/m2 i.v. every 21 days. Patients were treated until tumor progression or unacceptable toxicity. Results: An objective response (3 complete responses, 3 partial responses) was achieved in 6 patients (20.6%, 95% CI 5.95–35.4). Disease control (complete response, partial response and stable disease) was observed in 14 patients (48.2%). The median time to tumor progression was 3 months (range 0.7–39) and the median overall survival was 7 months (range 1–39). The 1-year survival rate was 32%. Toxicity was mild. Conclusion: Oxaliplatin is an active agent against biliary tract carcinoma and therefore should be further investigated in combination with other cytotoxic drugs.

Docetaxel vs. vinorelbine in elderly patients with advanced non--small-cell lung cancer: a hellenic oncology research group randomized phase III study.

BACKGROUND/PURPOSE This study compared front-line treatment with docetaxel or vinorelbine in elderly patients with advanced/metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Chemotherapy-naive patients with inoperable stage IIIB and stage IV NSCLC who were > 65 years of age with performance status (PS) of 0-2 were enrolled. Patients were assigned to receive either docetaxel 38 mg/m(2) or vinorelbine 25 mg/m(2) by intravenous (I.V.) infusion on days 1 and 8 every 3 weeks. RESULTS One hundred thirty elderly patients were enrolled in the study (docetaxel n = 66 and vinorelbine n = 64 patients). The objective response rate was 12.1% and 14.1% in patients treated with docetaxel and vinorelbine, respectively (2P = .799). The median time to tumor progression (TTP) was 2.33 and 1.9 months (2P = .298) and the median overall survival (OS) was 6.07 and 3.87 months (2P = .090) in the docetaxel and vinorelbine arms, respectively. Grade 3/4 neutropenia occurred in 4.5% and 29.7% of patients in the docetaxel arm and vinorelbine arm, respectively (2P < .001). Febrile neutropenia occurred in 1.5% and 1.6% of patients in the docetaxel arm and the vinorelbine arm, respectively (2P = .950) and the use of granulocyte colony-stimulating factor (G-CSF) was more frequent in patients treated with vinorelbine (37.1% vs. 22.5%; 2P < .001). There were no deaths from toxicity. Nonhematologic toxicity was mild. CONCLUSIONS Docetaxel has an efficacy comparable to that of vinorelbine as first-line treatment in elderly patients with NSCLC and has an acceptable toxicity profile. The trial was closed prematurely because of low accrual, thus limiting the strength of the conclusions derived.

Salvage chemotherapy with paclitaxel, vinorelbine, and cisplatin (PVC) in anthracycline-resistant advanced breast cancer

The tolerance and the efficacy of the paclitaxel-vinorelbine-cisplatin combination (PVC regimen) was evaluated in 33 patients with anthracycline-resistant stage IV breast cancer, who had disease progression under anthracycline- or mitoxantrone-based chemotherapy. Fourteen (42%) and 19 (58%) patients had primary and secondary resistance to anthracyclines, respectively; 70% had visceral metastases. Patients received vinorelbine (25 mg/m2) followed by paclitaxel (135 mg/m2) in a 3-hour infusion on day 1, and cisplatin (CDDP; 80 mg/m2) on day 2, in a 3-week schedule. A total of 208 chemotherapy courses were administered (median six courses per patient). Grade 3/4 neutropenia occurred in 13 patients (39%), seven of whom were hospitalized for neutropenic fever (5% of the courses). There was no toxic death. Grade 4 thrombocytopenia occurred in two patients (6%) and grade 3 anemia in three patients (9%). Grade 2 and 3 neurosensory toxicity occurred in 11 patients (32%) and two patients (6%), respectively, and grade 3/4 fatigue was observed in four patients (12%). Two (6%) complete and 17 partial responses (52%) (total, 58%; 95% confidence interval, 42%-75%) were documented. Stable disease was observed in eight patients (24%) and progression in six patients (18%). The median duration of response was 6.5+ months. The median survival was 15+ months, and the 1-year survival was 67%. In conclusion, PVC regimen is an active and well-tolerated salvage chemotherapy in patients resistant to anthracycline.

Irinotecan (CPT-11) in combination with infusional 5-fluorouracil and leucovorin (de Gramont regimen) as first-line treatment in patients with advanced colorectal cancer: a multicenter phase II study.

The combination of CPT-11 with 5-fluorouracil (5-FU) in advanced colorectal cancer (ACC) represents an attractive approach. A phase II study was conducted to assess the tolerance and efficacy of CPT-11 in combination with leucovorin-modulated bolus plus infusional 5-FU given according to the de Gramont regimen in chemonaive patients with ACC. Fifty-four patients with histologically confirmed ACC were enrolled. The patients’ median age was 65 years; 30 (55.5%) patients were men; performance status (World Health Organization) was 0 in 27 (50%) patients, 1 in 22 (41%), and 2 in 5 (9%). Patients received leucovorin (200 mg/m2/d) as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at 400 mg/m2/d, and then as a 22-hour continuous infusion at 600 mg/m2/d, repeated on 2 consecutive days. CPT-11 (180 mg/m2; 30-minute intravenous infusion) was administered on day 1, simultaneously with leucovorin administration. This cycle was repeated every 2 weeks. Complete response was achieved in 4 patients (8%) and partial response in 19 (37%) (overall response rate: 45%; 95% CI: 24–50.5%). Stable disease was achieved in 16 (31%) patients and progressive disease in 13 (25%). The median duration of response and the median TTP were 5 and 8 months, respectively. After a median follow-up period of 11 months, 33 (61%) patients are still alive; the median overall survival has not yet been reached. Thrombocytopenia and anemia were very rare. Grade III/IV neutropenia developed in 19 patients (36%); febrile neutropenia developed in 4 patients, and 1 of them died of sepsis. Grade IV diarrhea was seen in 7 (13%) patients, and 4 of them required hospitalization. Grade III and IV mucositis was observed in two (4%) and one (2%) patients, respectively. Other toxicities were mild. The combination of CPT-11 and bolus plus infusional 5-FU is a relatively well-tolerated and effective first-line treatment in ACC. Final results from large phase III trials are awaited to clarify whether the CPT-11/5-FU combinations should be considered as “standard” first-line treatment in ACC.

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.