Pavlos Papakostas

Paclitaxel Plus Carboplatin Versus Gemcitabine Plus Paclitaxel in Advanced Non–Small-Cell Lung Cancer: A Phase III Randomized Trial

PURPOSE We conducted this randomized study comparing the activity and toxicity of paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Chemotherapy-naive patients were randomized to paclitaxel 200 mg/m(2) on day 1 plus either carboplatin at an area under the concentration-time curve of 6 on day 1 (group A) or gemcitabine 1,000 mg/m(2) on days 1 and 8 (group B) every 3 weeks. A retrospective cost analysis was conducted using Students t test to compare independent samples between groups. RESULTS A total of 509 patients (group A, 252 patients; group B, 257 patients) were enrolled; all characteristics were well balanced. The median survival time was 10.4 months (95% confidence interval [CI], 8.8 to 12 months) for group A and 9.8 months (95% CI, 8.0 to 11.7 months) for group B (P =.32). Respective 1-year survival rates were 41.7% and 41.4%. The response rate for group A was 28.0% (2% complete response [CR], 26% partial response [PR] [95% CI, 22% to 34%]), and the response rate for group B was 35.0% (5% CR, 30% PR) [95% CI, 29% to 41%]) (P =.12). Toxicity was mild. Grades 3/4 neutropenia, thrombocytopenia, and anemia for groups A and B were seen in 15% and 15%, 2% and 1%, and 5% and 2%, respectively. The mean total cost (outpatient clinic visits plus chemotherapy drug fee) for group A (euro; 7,612.64) versus group B (euro; 7,484.77) was not statistically significant (P <.66). CONCLUSION The PG combination is as equally active and well tolerated as the PC combination in patients with advanced NSCLC.

Docetaxel and Cisplatin With Granulocyte Colony-Stimulating Factor (G-CSF) Versus MVAC With G-CSF in Advanced Urothelial Carcinoma: A Multicenter, Randomized, Phase III Study From the Hellenic Cooperative Oncology Group

PURPOSE The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC. PATIENTS AND METHODS Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status < or = 2 were randomly assigned to receive MVAC at standard doses or docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) support. RESULT Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P =.017), median time to progression (TTP; 9.4 v 6.1 months; P =.003) and median survival (14.2 v 9.3 months; P =.026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P =.005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P =.089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P =.006), thrombocytopenia (5.7% v 0.9%; P =.046), and neutropenic sepsis (11.6% v 3.8%; P =.001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF. CONCLUSION MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma.

Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases

PURPOSE To determine the efficacy, tolerability, and safety of temozolomide in heavily pretreated patients with solid tumors and brain metastases. PATIENTS AND METHODS Twenty-seven of twenty-eight enrolled patients with brain metastases from solid tumors received temozolomide (150 mg/m2/day for five days every 28 days). Twelve patients had non-small-cell lung cancer, five patients had small-cell lung cancer, four patients had breast cancer, and seven patients had other solid tumors. The majority of the patients had multiple metastatic sites, a poor performance status, and had been heavily pretreated. The primary end points were objective response rate, time to progression, and overall survival. Secondary end points included safety and tolerability, and neurologic performance status. RESULTS A partial response was achieved in 1 (4%) of 24 evaluable patients. Disease stabilization was observed in four (17%) patients. Overall median survival was 4.5 months and median time to progression was 3 months. Improvements in clinical neurologic status were achieved in 10 (37%) patients. Treatment with temozolomide was well tolerated. Four patients had grade 3 nausea and vomiting. No grade 4 toxicity or treatment-related deaths were observed. CONCLUSIONS Temozolomide demonstrated encouraging activity in the treatment of brain metastases in heavily pretreated patients with solid tumors, and was safe and well tolerated.

Potential value of PTEN in predicting cetuximab response in colorectal cancer: An exploratory study

BackgroundThe epidermal growth factor receptor (EGFR) is over-expressed in 70–75% of colorectal adenocarcinomas (CRC). The anti-EGFR monoclonal antibody cetuximab has been approved for the treatment of metastatic CRC, however tumor response to cetuximab has not been found to be associated with EGFR over-expression by immunohistochemistry (IHC). The aim of this study was to explore EGFR and the downstream effector phosphatase and tensin homologue deleted on chromosome 10 (PTEN) as potential predictors of response to cetuximab.MethodsCRC patients treated with cetuximab by the Hellenic Cooperative Oncology group, whose formalin-fixed paraffin-embedded tumor tissue was available, were included. Tissue was tested for EGFR and PTEN by IHC and fluorescence in situ hybridization (FISH).ResultsEighty-eight patients were identified and 72 were included based on the availability of tissue blocks with adequate material for analysis on them. All patients, except one, received cetuximab in combination with chemotherapy. Median follow-up was 53 months from diagnosis and 17 months from cetuximab initiation. At the time of the analysis 53% of the patients had died. Best response was complete response in one and partial response in 23 patients. In 16 patients disease stabilized. Lack of PTEN gene amplification was associated with more responses to cetuximab and longer time to progression (p = 0.042).ConclusionPTEN could be one of the molecular determinants of cetuximab response. Due to the heterogeneity of the population and the retrospective nature of the study, our results are hypothesis generating and should be approached with caution. Further prospective studies are needed to validate this finding.

Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer A Hellenic Cooperative Oncology Group phase II study*

AIM To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line chemotherapy and trastuzumab, in patients with HER-2/neu overexpressing advanced breast cancer (ABC). BACKGROUND Weekly paclitaxel has been shown to be a well tolerated treatment with considerable activity in patients with ABC. Clinical trials with transtuzumab, a humanized anti-p185 HER-2/neu monoclonal antibody have demonstrated that this agent produces objective responses in patients with ABC. PATIENTS AND METHODS From December 1998 to April 2000, 34 patients with HER-2/neu overexpressing ABC were treated with weekly paclitaxel; given by one-hour infusion at a dose of 90 mg/m2 immediately followed by trastuzumab, 4 mg/kg as a loading dose and 2 mg/kg i.v. given over 30 min, thereafter weekly for at least 12 weeks. Expression of HER-2/neu was determined by immunohistochemical analysis on fixed, paraffin-embedded tissues. Eligible patients were required to have > or = 25% stained tumor cells. RESULTS Thirty-three patients completed at least 12 weeks of combined treatment. After completion of the 12th week of treatment, four patients (12%) achieved complete and 17 (50%) partial response. Median duration of response was 11.6 months. More frequent side effects included anemia (56%). neutropenia (27%), peripheral neuropathy (78%), diarrhea (30%), alopecia (70%), arthralgias/myalgias (62%), fatigue (59%) and hypersensitivity reactions (62%). Median time to progression was nine months while median survival had not been reached CONCLUSIONS The combination of weekly paclitaxel and trastuzumab is a safe and active regimen for patients with HER-2/neu overexpressing ABC. Randomized phase III studies with this combination are warranted.

Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes

BackgroundMore than half of patients with KRAS-wild type advanced colorectal cancer (CRC) fail anti-EGFR monoclonal antibodies. We studied EGFR-axis messenger RNA (mRNA) expression and RAS, RAF, PIK3CA mutations in order to identify additional biomarkers of cetuximab efficacy.MethodsPreviously genotyped (KRAS, NRAS, BRAF, PIK3CA mutations) formalin-fixed paraffin-embedded tumour biopsies of 226 cetuximab-treated CRC patients (1st to 3rd line therapy) were assessed for mRNA expression of epidermal growth factor receptor (EGFR) and its ligands EGF, Transofrming Growth Factor-a (TGFA), Amphiregulin (AREG) and Epiregulin (EREG) with real time quantitative PCR. Mutations were detected in 72 (31.9%) tumours for KRAS, in 6 (2.65%) for BRAF, in 7 (3.1%) for NRAS and in 37 (16.4%) for PIK3CA.ResultsOnly PIK3CA mutations occasionally coexisted with other gene mutations. In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7). EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1). In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA. Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC. Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20–35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25–35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19 months, 95% CI 15–26).ConclusionsBRAF and codon 12 KRAS mutations predict for adverse outcome of CRC patients receiving cetuximab. AREG mRNA reflects EGFR signalling in KRAS wild type tumours, predicting for cetuximab efficacy when high and failure when low. EREG may have a prognostic role independent of KRAS mutation.

XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis

BackgroundThe aim was to compare two standard chemotherapy regimens combined with bevacizumab as first-line treatment in patients with metastatic colorectal cancer.MethodsPatients previously untreated for metastatic disease were randomized in: group A (irinotecan, capecitabine, bevacizumab, every 3 weeks; XELIRI-bevacizumab) and group B (irinotecan, leucovorin, fluorouracil, bevacizumab, every 2 weeks; FOLFIRI-bevacizumab). Primary endpoint was progression-free survival (PFS). Plasma concentrations of nitric oxide, osteopontin, TGF-β1 and VEGF-A were measured at baseline and during treatment.ResultsAmong 285 eligible patients, 143 were randomized to group A and 142 to group B. Fifty-five patients (38.5%) in group A and 57 (40.1%) in group B responded (p = 0.81). After a median follow-up of 42 months, median PFS was 10.2 and 10.8 months (p = 0.74), while median OS was 20.0 and 25.3 months (p = 0.099), for groups A and B, respectively. Most frequent grade 3–4 toxicities (group A vs group B) were neutropenia (13% vs 22%, p = 0.053) and diarrhea (19% vs 11%, p = 0.082). Baseline plasma osteopontin concentrations demonstrated prognostic significance for both PFS and OS.ConclusionsThis trial did not show significant differences in efficacy between the groups. However, the toxicity profile was different. Baseline plasma osteopontin concentrations demonstrated independent prognostic significance. (Registration number: ACTRN12610000270011)

Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) study

The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT–PCR). The overall concordance between kRT–PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT–PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas.

Second-line chemotherapy with weekly oxaliplatin and high-dose 5-fluorouracil with folinic acid in metastatic colorectal carcinoma: A Hellenic Cooperative Oncology Group (HeCOG) phase II feasibility study

BACKGROUND Oxaliplatin is a novel platinum derivative, which, combined with 5-fluorouracil (5-FU), and folinic acid (FA), demonstrates synergistic activity in metastatic colorectal cancer (MCC). The HeCOG performed a multicenter phase II study of a weekly oxaliplatin administration schedule in patients with previously treated MCC to evaluate the antitumor efficacy and toxicity of this combination. PATIENTS AND METHODS Eligible patients included those who relapsed after or during chemotherapy with 5-FU and FA and/or irinotecan. Prior radiotherapy was accepted provided that measurable disease was outside the radiation fields. Other eligibility criteria included written informed consent, a WHO performance status < or = 2 and adequate bone marrow, liver and renal function. Treatment consisted of Oxaliplatin 50 mg/m2 by two-hour intravenous (i.v.) infusion followed by FA 500 mg/m2 (two-hour i.v. infusion) and 5-FU 2,500 mg/m2 (24-hour continuous i.v. infusion) on days 1, 8, 15, 22, 29, 36. The regimen was repeated every 50 days. RESULTS Thirty-two patients (Median age 61 years, range 25-76) entered the trial. The majority (75%) had progressed after receiving first-line chemotherapy. Diarrhea was the main non-hematologic toxicity. More than half of the patients (53%) developed grades 3 or 4 diarrhea. Due to this side effect only 29% of cycles were given with at least 90% of the planned dose of 5-FU. Hematologic toxicity included grade 3 neutropenia and thrombocytopenia (10% for each), and grade 4 thrombocytopenia (3%). Two patients (6%) died of sepsis, one related to neutropenia and one due to urinary tract sepsis. Sixteen patients (50%) developed grades 1 and 2 neurotoxicity in the form of sensory neuropathy, which was mild and transient. The objective response rate was 13% (95% CI: 3%-29%). All four responses were partial. Twelve patients (38%) had stable disease and 8 (25%) progressive disease. The median time to progression was three months and the median survival was nine months from the start of therapy. The Kaplan-Meier estimated probability of one-year survival for the group as a whole was 32%. CONCLUSIONS The weekly administration of oxaliplatin with 5-FU and FA was associated with considerably less neurotoxicity than other schedules. However, the high percentage of diarrhea suggests that a dose reduction of 5-FU in this regimen may result in better therapeutic synergy.

Palliative chemotherapy in elderly patients with common metastatic malignancies: A Hellenic Cooperative Oncology Group registry analysis of management, outcome and clinical benefit predictors

INTRODUCTION Cancer in the elderly is a common health issue in developed societies. We sought to present epidemiology, management and outcome data on fit elderly patients with common metastatic cancers and to identify predictors of clinical benefit from palliative chemotherapy. METHODS All patients aged >65 years who were diagnosed with metastatic breast, colorectal or non-small cell lung carcinomas and managed with palliative chemotherapy in the context of Hellenic Cooperative Oncology Group (HeCOG) clinical trials or protocols were eligible for electronic data retrieval and analysis. Common eligibility criteria included adequate performance status (ECOG 0-3), organ function and absence of severe co-morbidity forbidding cytotoxic chemotherapy. RESULTS One thousand three hundred and seventy-two fit patients (PS 0-1 in 73%) with a median age of 70 years diagnosed with metastatic breast (n=250), colorectal (n=621) or lung cancer (n=501) received chemotherapy from 1991 until 2006. Most patients received modern full-dose chemotherapy regimens including platinum, taxanes, anthracyclines, fluoropyrimidines, oxaliplatin or irinotecan. Mild to moderate co-morbidity was present in 35%. At a median follow-up of 3 years, objective responses were seen in 41% of patients with breast cancer, 25% with colorectal cancer and 31% with lung cancer, while median survival was 21, 16 and 9.4 months, respectively. Grade 3 or 4 toxicity was seen in a quarter of patients, the most common being neutropenia (14%), diarrhoea (6%), neurotoxicity (4%), fatigue, nausea and febrile neutropenia (each 2%). In multivariate analysis, diagnosis of colorectal or lung cancer, metastases in multiple organ sites, presence of liver/brain/peritoneal deposits, impaired PS and low baseline serum albumin levels were prognostic factors for adverse outcome. The same factors excluding metastatic sites and with the addition of anemia predicted for resistance to chemotherapy. Toxicity was more likely in females with low serum albumin and renal dysfunction. A six-variable geriatric assessment for palliation (GAP) score that included tumour type, sites of metastatic dissemination, impaired PS, low serum albumin and anemia classified elderly patients to groups with low, intermediate and high risk for disease progression and death (relative risks of 1.59 and 2.50 for resistance to therapy and 1.87 and 3.12 for death in the intermediate and high-risk groups). CONCLUSIONS Our data indicate that relatively fit elderly patients with advanced cancer safely tolerate modern chemotherapy and enjoy disease control in a manner comparable to younger patients. Our GAP score, if further validated, offers promise for geriatric application in combination to comprehensive geriatric assessment tools for the optimisation of palliative therapy on an individualised basis.