G. Fountzilas

Prognostic significance of UBE2C mRNA expression in high-risk early breast cancer. A Hellenic Cooperative Oncology Group (HeCOG) Study

BACKGROUND The ubiquitin-proteasome system (UPS) plays a pivotal role in tumorigenesis. Components of the UPS have recently been implicated in breast cancer progression. In the present study, we sought to explore the prognostic and/or predictive significance of UBE2C messenger RNA (mRNA) expression on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer patients. METHODS Five hundred and ninety-five high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative, dose-dense sequential chemotherapy with epirubicin followed by CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without paclitaxel (Taxol). RNA was extracted from 313 formalin-fixed primary tumor tissue samples followed by one-step quantitative RT-PCR for assessment of mRNA expression of UBE2C. RESULTS High UBE2C mRNA expression was associated with poor DFS (Walds P = 0.003) and OS (Walds P = 0.005). High tumor grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of UBE2C. Results of the Cox multivariate regression analysis revealed that high UBE2C mRNA expression remained an independent adverse prognostic factor for relapse (P = 0.037) and death (P = 0.05). CONCLUSIONS High UBE2C mRNA expression was found to be of adverse prognostic significance in high-risk breast cancer patients. These findings need to be validated in larger cohorts.

Carboplatin plus pemetrexed as first-line treatment of patients with malignant pleural mesothelioma: a phase II study.

INTRODUCTION Malignant pleural mesothelioma (MPM) is a rapidly progressive tumor that is increasing in frequency worldwide. Treatment options are limited, and response to chemotherapy is poor. The aim of this phase II study was to evaluate the activity of the carboplatin/pemetrexed combination as first-line chemotherapy in patients with unresectable MPM. PATIENTS AND METHODS Chemotherapy-naive patients with histologically confirmed MPM and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Treatment consisted of pemetrexed 500 mg/m2 and carboplatin area under the concentration-time curve of 5 mg/mL/min, both administered on day 1 of a 21-day cycle. The treatment continued until 6 cycles were completed or until unacceptable toxicity or disease progression were observed. RESULTS A total of 62 patients were enrolled. Of these patients, 18 (29%) had a confirmed partial response, whereas the disease remained stable in 34 patients (54.9%) and progressed in 10 patients (16.1%). The median overall survival (OS) was estimated at 14 months (95% CI, 11.8-16.2 months), and the median time to progression was 7 months (95% CI, 5.8-8.2 months). The difference in median OS between the epithelial histologic subtype (16 months) and the sarcomatoid subtype (11 months) was statistically significant. CONCLUSION This study confirmed the activity of the carboplatin/ pemetrexed combination in the first-line treatment of patients with MPM. It is a viable option, especially in cases in which side effects are generally anticipated.

Clinical Value of Ca 15-3, Mucin-like Carcinoma-associated Antigen, Tumor Polypeptide Antigen, and Carcinoembryonic Antigen in Monitoring Early Breast Cancer Patients

A total of 209 postsurgical breast cancer patients were prospectively monitored with simultaneous serum level estimations of CA 15,3, mucin-like carcinoma-associated antigen (MCA), tumor polypeptide antigen (TPA), and carcinoembryonic antigen (CEA); 141 (67.5%) were free of recurrence and 68 (32.5%) developed metastases during the follow-up. The mean values of tested tumor markers differed significantly in those with progressive disease compared with those free of disease recurrence. The sensitivity of tumor markers were CA 15-3, 68.2%; CEA, 34.1%; MCA, 72.7%; and TPA, 72.7%. The combination of CA 15-3 with TPA or MCA with TPA showed a trend for improved sensitivity of both markers (p = 0.06), with no specific loss of specificity (p = 0.11). The addition of CEA to CA 15-3 or MCA does not provide additional information for clinical evaluation. Patients with elevated tumor marker determinations had significantly shorter survival than those with values within the normal range. Two serial, progressively increasing values of tumor markers during the follow-up strongly predict recurrence. This study indicates that the comeasurement of CA 15-3 with TPA or MCA with TPA is justifiable in monitoring breast cancer patients postoperatively.

Docetaxel and carboplatin combination chemotherapy as outpatient palliative therapy in carcinoma of unknown primary: A multicentre Hellenic Cooperative Oncology Group phase II study

Introduction. Taxane/platinum combinations exhibit synergistic cytotoxicity and activity against a broad range of solid tumours. We sought to optimise the regimen as a suitable outpatient palliative treatment for cancer of unknown primary (CUP). Patients and methods. Eligible CUP patients with adenocarcinoma or poorly differentiated carcinoma, performance status of 0-2, adequate organ function and assessable disease were treated with docetaxel 75 mg/m2 and carboplatin at an area under the concentration time-curve (AUC) of 5, both as 30-minute intravenous infusions, every three weeks. Patients with isolated axillary adenopathy, squamous cell cervical or inguinal adenopathy and PSA or germ-cell serum tumour markers were excluded. Results. Forty-seven patients entered the trial, 24 with predominantly nodal disease or non-mucinous peritoneal carcinomatosis (favourable risk) and 23 with visceral metastases (unfavourable risk). A median of 6 cycles of chemotherapy were administered, with relative dose intensities of both drugs >90%. Response rates were 32% (46% in favourable risk, 17% in unfavourable), comparable to the activity of paclitaxel/platinum regimes, though complete remissions were seen only in favourable risk patients. Granulocyte-colony stimulating factor support was used in a third of treatment cycles. Toxicity was mild and manageable, with grade 3–4 neutropenia in 26% of patients, febrile neutropenia in 7% and severe non-hematologic side-effects in less than 8% of patients. No toxic deaths or severe neurotoxicity were seen. Median time to progression (TTP) and overall survival (OS) were 5.5 and 16.2 months respectively. Survival was driven mainly by favourable-risk patients (22.6 months), as those with visceral metastases had a poor median survival of only 5.3 months. Good performance status and low-volume disease predicted for superior outcome, while docetaxel relative dose-intensity was a positive prognosticator only in favourable-risk patients. Conclusions. One-hour docetaxel/carboplatin is a convenient, safe and effective outpatient palliative treatment for CUP patients, providing meaningful survival prolongation only in favourable-risk patients. Insights in the molecular biology of CUP are needed for the development of targeted therapeutic manipulations of malignant resistance and progression.

The combination of estramustine and mitoxantrone in hormone-refractory prostate cancer: a phase II feasibility study conducted by the Hellenic Cooperative Oncology Group.

OBJECTIVES To consider the safety profile and therapeutic value of the combination of estramustine and mitoxantrone in a bimonthly schedule to treat hormone-refractory prostate cancer. The survival of patients with prostate cancer who relapse after androgen ablation is limited and the therapeutic options are restricted. METHODS Twenty-nine patients with relapse after previous treatment were included in the study; however, 3 patients who refused to start treatment were not included in the analysis, leaving 26 eligible patients. The median age was 64 years (range 44 to 82), the World Health Organization performance status ranged from 1 to 3, and the mean prostate-specific antigen level was 103 ng/mL (range 1 to 620). The Gleason score ranged from 2 to 9. The patients received a total of 208 therapeutic cycles (mean 8, range 3 to 24). Every cycle consisted of oral estramustine 140 mg, 3 times a day continuously, and intravenous mitoxantrone 20 mg (total dose). The regimen was repeated every 2 weeks. RESULTS Twenty-seven percent of patients with measurable soft-tissue disease demonstrated an objective response, which included one complete and six partial responses. Thirteen patients (50%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 9.2 months, and the median survival for all patients was 15 months. The most common side effects were neutropenia and thrombocytopenia. CONCLUSIONS The combination of estramustine and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer. More patients are needed to partake in Phase III studies to establish the survival benefit that this combination may offer.

EGFR expression is associated with decreased benefit from trastuzumab in the NCCTG N9831 (Alliance) trial

Background:Epidermal growth factor receptor (EGFR) has been hypothesised to modulate the effectiveness of anti-HER2 therapy. We used a standardised, quantitative immunofluorescence assay and a novel EGFR antibody to evaluate the correlation between EGFR expression and clinical outcome in the North Central Cancer Treatment Group (NCCTG) N9831 trial.Methods:Tissue microarrays were constructed that allowed analysis of 1365 patients randomly assigned to receive chemotherapy alone (Arm A), sequential trastuzumab after chemotherapy (Arm B) and chemotherapy with concurrent trastuzumab (Arm C). Measurement of EGFR was performed using the EGFR antibody, D38B1, on the fluorescence-based AQUA platform. The result was validated using an independent retrospective metastatic breast cancer cohort (n=130).Results:Epidermal growth factor receptor assessed as a continuous (logarithmic transformed) variable shows an association with disease-free survival in Arm C (P=0.009) but not in Arm A or B. High EGFR expression was associated with worse outcome (Hazard ratio (HR)=2.15; 95% CI 1.28–3.60, P=0.004). Validation in a Greek metastatic breast cancer cohort showed an HR associated with high EGFR expression of 1.92 (P=0.0073).Conclusions:High expression of EGFR appears to be associated with decreased benefit from adjuvant concurrent trastuzumab. Since other treatment options exist for HER2-driven tumours, further validation of these data may select patients for alternative or additive therapy.

Recombinant interferon ALFA-2A in combination with carboplatin, vinblastine, and bleomycin in the treatment of advanced malignant melanoma.

Thirty-four patients with advanced malignant melanoma were treated with recombinant alpha-interferon (IFN) and chemotherapy consisting of carboplatin, vinblastine, and bleomycin (CVB). CVB was given for four cycles and IFN for 1 year or until progression. Of the 34 analyzed patients, 17 (50%) achieved an objective response, including two complete (6%) and 15 partial responses (44%). Responses were noted in cutaneous, lymph node, and pulmonary sites, with a median time to disease progression of 5 months (range, 3-20 months). The median survival from onset of therapy was 8 months (range, 1-22 months) for the 34 patients. Ninety-four percent of the patients experienced flu-like symptoms and 82% fatigue or weakness. Leukopenia grade 3-4 was observed in four patients (12%). There were two toxicity-related deaths (6%); one from bleomycin-induced pneumonitis and one from neutropenic sepsis. It is concluded that the addition of IFN to CVB regimen, in this study, showed no apparent advantage on response rates, disease-free interval, or survival. The observed treatment-related mortality was unacceptably high. IFN administered as maintenance therapy following CVB conferred no survival benefit.

Four cycles of paclitaxel and carboplatin as adjuvant treatment in early-stage ovarian cancer: A six-year experience of the Hellenic Cooperative Oncology Group

BackgroundSurgery can cure a significant percentage of ovarian carcinoma confined to the pelvis. Nevertheless, there is still a 10–50% recurrence rate. We administered paclitaxel/carboplatin as adjuvant treatment in early-stage ovarian carcinoma.MethodsPatients with stages Ia or Ib, Grade 2 or 3 and Ic to IIb (any grade) were included. Patients were treated with 4 cycles of Paclitaxel 175 mg/m2 and Carboplatin [area under the curve (AUC) 6 (Calvert Formula)] every 3 weeks.ResultsSixty-nine patients with no residual disease following cytoreductive surgery and minimal or modified surgical staging were included in this analysis. Grade 3 or 4 neutropenia occured in 29.9% of patients, while neutropenic fever was reported in 4.5%. Neurotoxicity (all Grade 1 or 2) was reported in 50% of cases. Median follow-up was 62 months. 5-year overall survival (OS) and relapse-free survival (RFS) were: 87% (95% confidence intervals [CI]: 78–96) and 79% (95% CI: 69–89), respectively. Significantly fewer patients with stages Ic-IIb and tumor grade 2 or 3 achieved a 5-year RFS than patients with only one of these two factors (73% vs 92%, p = 0.03).ConclusionPaclitaxel/Carboplatin chemotherapy is a safe and effective adjuvant treatment in early-stage ovarian carcinoma. Patients with stages Ic-IIb and tumor grade 2 or 3 may benefit from more extensive treatment.

A phase III study of 5-fluorouracil versus 5-fluorouracil plus interferon alpha 2b versus 5-fluorouracil plus leucovorin in patients with advanced colorectal cancer: a Hellenic Cooperative Oncology Group (HeCOG) study.

We conducted a phase III study in patients with advanced colorectal carcinoma (ACC). The total number of patients randomized from October 1993 until July 1998 was 192, whereas therapy was started on 179 and 158 (82.3%) have been evaluable. The treatment schedules consisted of weekly bolus administration for 6 weeks of 5-fluorouracil (5-FU), 600 mg/m2 (arm I) versus 5-FU (500 mg/m2) intravenous bolus and interferon-&agr;, 5 MU subcutaneously, three times a week (arm II) versus leucovorin 200 mg/m2 in 2-hour infusion and 5-FU 500 mg/m2 intravenous bolus at the midtime of leucovorin infusion (arm III) followed by a 2-week rest period. Treatment was continued for six cycles or until progression. This study failed to show any superiority of the modulated 5-FU versus single administration of 5-FU. There were no significant differences between the three arms in the overall response rate (10.3% versus 11.3% versus 12.9%, p = 0.95), the time to tumor progression (median, 3.9 versus 3.8 versus 6.0 months, p = 0.59), or survival duration (median, 14.7 versus 12.4 versus 16.3 months, p = 0.71). The incidence of severe (grades III and IV) toxicity was significantly higher in patients in arm II and III (24.5% and 18.6%) versus arm I (6.0%) (p = 0.01). Because modulated 5-FU failed to show superiority versus 5-FU, new agents and new strategies are needed for the treatment of advanced colorectal carcinoma.

Cost-Minimization Analysis of the Treatment of Patients With Metastatic Colorectal Cancer in Greece

BACKGROUND In 2008, colorectal cancer was the fourth most common cause of cancer-related death worldwide. Monotherapy with monoclonal antibodies directed against the epidermal growth factor receptor, such as cetuximab and panitumumab, has recently been introduced in the management of metastatic colorectal cancer (mCRC) patients. OBJECTIVE The aim of this study was to conduct a cost-minimization analysis comparing panitumumab with cetuximab in the treatment of patients with epidermal growth factor receptor-expressing mCRC with nonmutated (wild-type) Kirsten rat sarcoma viral oncogene homolog in Greece. The perspective of analysis was that of payers (Social Security Sickness Fund) and the countrys National Health Service (NHS). METHODS The model was designed to contain probabilistic parameters to account for uncertainty and variation in these parameters. All resources consumed in local hospitals in the management of patients in each case were evaluated. Two analyses were performed: 1 evaluating cost per milligram and another evaluating cost per vial. RESULTS From a payer perspective, the mean 20-week total cost per patient for panitumumab and cetuximab was: (1) per-milligram analysis: €16,349 and €18,242, respectively; and (2) per-vial analysis: €18,808 and €19,701. From the NHS perspective, the mean total costs per patient were slightly higher; however, the use of panitumumab was associated with a 17.7% and 12.4% cost reduction in per-milligram and per-vial analysis, respectively. The results of probabilistic models confirmed those of the deterministic analyses. CONCLUSION In the Greek NHS and Social Security Sickness Fund setting, panitumumab monotherapy potentially constitutes a cost-saving option (versus cetuximab monotherapy) in the management of patients with mCRC and no mutation of Kirsten rat sarcoma viral oncogene homolog.