Paris Makrantonakis

RADIATION THERAPY AND CONCURRENT CISPLATIN ADMINISTRATION IN LOCALLY ADVANCED HEAD AND NECK CANCER A Hellenic co-operative oncology group study

In an attempt to improve local control of locally advanced head and neck cancer, radiation therapy was combined with cisplatin. Forty-eight patients entered into this study. All patients were irradiated with a 60Co unit and according to the protocol they should receive 70 Gy in the tumor area and 45 Gy in the rest of neck. Cisplatin was administered at a dose of 100 mg/m2 on days 2, 22 and 42. Thirty-seven (80%) patients received the total radiation dose as initially planned. Thirty-four (72%) patients achieved complete and 5 (10%) partial response. Grade 3-4 toxicities included vomiting (14%), stomatitis (4%), diarrhea (2%), myelotoxicity (14%), hoarseness (4%), dysphagia (30%), weight loss (32%), nephrotoxicity (4%) and dermatitis (2%). After a median follow-up of 26 (range, 18-33) months, 16 patients have died. Among the 35 complete responders 6 later on relapsed. Median relapse-free survival has not yet been reached. Combined radiation therapy and cisplatin appears to be a highly active treatment in patients with advanced head and neck cancer as far as primary locoregional response is concerned.

PLATINUM-BASED CHEMOTHERAPY FOLLOWED BY RADIATION THERAPY OF LOCALLY ADVANCED NASOPHARYNGEAL CANCER A retrospective analysis of 39 cases

A retrospective analysis was performed of 39 patients with locally advanced nasopharyngeal cancer treated with combined chemotherapy and radiation therapy during the last five years at our departments. There were 26 men and 13 women with median age 55 (24-75) years. Histology was squamous cell carcinoma in 6 patients and undifferentiated carcinoma in the remaining 33 patients. Induction chemotherapy consisted of either regimen A (cisplatin 100 mg/m2 day 1, 5-FU 1,000 mg/m2 days 2-6 as continuous infusion, bleomycin 15 mg days 15 and 29 i.m., mitomycin 4 mg/m2 day 22 and hydroxyurea 1,000 mg/m2 daily days 23-27) or regimen B (carboplatin 300 mg/m2 day 1, 5-FU 1,000 mg/m2 days 1-5 as continuous infusion and methotrexate 1.2 g/m2 day 14 with leucovorin rescue). After completion of induction chemotherapy 13 patients (33%) had complete remission (CR) and 19 (49%) partial remission (PR). The CR rate was increased after radiation therapy to 72%. Survival rates were 88% at 12 and 78% at 24 months. Median time to progression was 29.5 months. In conclusion, induction chemotherapy with a platinum-based regimen followed by radiation therapy achieved a high rate of local control. If the treatment also prolongs survival must, however, be studied by randomized trials.

Carboplatin alone compared with its combination with epirubicin and cyclophosphamide in untreated advanced epithelial ovarian cancer: a hellenic co-operative oncology group study

We compared, in a multicentric randomised prospective study, the efficacy and toxicity of carboplatin 400 mg/m2 as a single agent (CB) to a combination of carboplatin 300 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (CB-EC) in advanced ovarian cancer patients. The treatment was scheduled to be administered every 3 weeks for six courses. Following initial laparotomy and cytoreductive surgery, 130 previously untreated patients entered the study. 73 patients were treated with carboplatin alone while 57 received the combination chemotherapy. In the majority of the patients, the regimens had to be given every 4 weeks due to myelosuppression. Nausea, vomiting and alopecia were more severe in the CB-EC arm. Overall, clinical complete response was observed in 73 (56%) and partial response in 20 (15%) patients. The median time to progression was 16.89 months and median survival was 29.54 months. No significant differences in response rate, time to progression, disease-free survival and overall survival were observed between the two treatment arms. The prognostic role of residual disease after initial surgery, complete remission at second-look laparotomy, tumour stage and performance status was confirmed.

Concurrent radiation and intracarotid cisplatin infusion in malignant gliomas : A feasibility study

Twenty-two patients with supratentorial malignant gliomas were treated postoperatively with concurrent intracarotid chemotherapy and radiation therapy. There were seven women and 15 men with a median age of 56 years (range, 22-69) and median performance status (Karnofsky score) of 70 (range, 40-90). In all except two cases, histologic studies confirmed malignant glioma. All patients were irradiated with a cobalt 60 equipment. They should have received 45 Gy to the whole brain plus a 15-Gy coned-down boost to the tumor area. Chemotherapy consisted of cisplatin infusion at a dose of 60 mg/m2 on days 2, 22, and 42. Treatment was interrupted in two patients because of progressive disease and voluntary withdrawal in one patient each. In all, 63 courses of cisplatin infusion were administered, all at full dose. Two patients achieved a partial response, and nine had stable disease. Toxicities included nausea/vomiting in nine patients (41%) and transient hemiparesis, confusion, diarrhea, and thrombophlebitis in one patient each. Median time to progression was 26 weeks (range, 4-226+), and median survival was 58 weeks (range, 14-226+). In conclusion, the present study suggests that intracarotid cisplatin administered concurrently with radiation does not improve the therapeutic index in malignant gliomas.

High-dose epirubicin as a single agent in the treatment of patients with advanced breast cancer. A Hellenic Co-operative Oncology Group study.

Fifty-two women with advanced breast cancer were treated with 6 cycles of epirubicin. Even though the study was started with a dose schedule of 110 mg/m2 every 3 weeks, the average treatment interval was 26 days and the median weekly dose 78% of the protocol requirement. Forty-eight patients were evaluable for response; 3 achieved a complete remission which lasted for 17, 24 and 65 weeks, respectively, and 14 a partial remission. Median survival was 32 weeks. Toxicity included nausea/vomiting (68%), anemia (24%), leukopenia (37 %), thrombocytopenia (8 %), alopecia (81 %), stomatitis (24%), diarrhea (14%), fever (19%) and fatigue (14%). Also 1 treatment-related death occurred and 2 cases of arrhythmia. Monotherapy with high doses of epirubicin has definite activity in advanced breast cancer and deserves further study in combination with hematopoietic growth factors which might allow a higher dose Intensity.

Cyclophosphamide, mitoxantrone, fluorouracil versus conventional CMF as adjuvant treatment in node-positive breast cancer patients. A Hellenic Cooperative Oncology Group Study.

362 evaluable node-positive patients with stage II breast cancer were randomized, receiving either 6 cycles of conventional CMF or 6 cycles of the combination of cyclophosphamide (500 mg/m2), mitoxantrone (Novantrone 10 mg/m2), and fluorouracil (500 mg/m2; CNF). After a median follow-up of 51 months, 64 (36%) patients relapsed in the CMF group and 60 (33%) in the CNF group (p=0.8276). By Cox multivariate analysis, tumor size, menopausal status and number of involved nodes were retained as independently significant variables. Toxicities were remarkably similar in both groups. It appears that after a median follow-up of 51 months there is no significant difference in relapse-free survival between node-positive patients with breast cancer who received either 6 cycles of the conventional CMF or the CNF combination as adjuvant treatment.

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.

Carboplatin, continuous infusion fluorouracil and mid-cycle high-dose methotrexate as initial treatment in patients with locally advanced head and neck cancer. Hellenic Co-operative Oncology Group Study.

Forty-nine patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were treated with 3 cycles of induction chemotherapy prior to definitive local treatment (surgery and/or radiation therapy). Chemotherapy consisted of carboplatin 300 mg/m2 on day 1, fluorouracil 1000 mg/m2 daily as a continuous infusion on days 1 to 5 and high-dose methotrexate 1.2 g/m2 with leucovorin rescue on day 14. After completing the induction chemotherapy, 9 patients (18%) achieved a complete remission (CR), 26 (54 %) a partial remission (PR), 7 had stable disease and 7 a progression. The response rates increased to 53 % CR and 18 % PR following locoregional treatment. Survival at 12 months was 61 % and its actuarial probability at 24 months 31 %. Median time to progression was 14 months. Toxicity from chemotherapy was generally mild. Nausea was observed in 35 %, vomiting in 26 %, stomatitis in 57 %, anemia in 22 %, leukopenia in 36%, thrombocytopenia in 26% and diarrhea in 6% of the patients. In conclusion, the combination of carboplatin, 5-day continuous-infusion fluorouracil and mid-cycle high-dose methotrexate is a moderately effective, well tolerated regimen in patients with SCCHN but does not seem superior to the combination of carboplatin and fluorouracil only.

Squamous cell carcinoma antigen, circulating immune complexes, and immunoglobulins in monitoring squamous cell carcinoma of head and neck: a study of the hellenic co-operative oncology group (HeCOG).

This study investigates the clinical utility of squamous cell carcinoma antigen (SCC-Ag), circulating immune complexes (CIC), and immunoglobulins (IgA, IgG, IgM) in the diagnosis, monitoring, and prognosis of 117 squamous cell carcinoma of the head and neck (SCC-HN) patients having local and/or systemic treatment. Serum marker levels were measured in a prospective study. SCC-Ag was positive in 28.2% of patients, the CIC in 63.2%, the IgA in 11.1%, the IgG in 15.4%, and the IgM in 9.44%. Statistically significant correlation was found between the initial SCC-Ag levels and tumor localization, whereas the CIC levels were increasing significantly with progressing disease stages. It was also found that the significant decrease of SCC-Ag, IgA, and CIC levels at the end of treatment was correlated with an increased incidence of disease-free status. The initial values of IgG and the disease stage were significantly correlated with a favorable treatment outcome. The pretreatment elevated SCC-Ag and IgM serum values showed a significant trend to predict a disease progression. Using a Cox proportional hazards model the IgG serum values, the primary site, and the disease stage were significant predictors for time to progression. The significant decrease of SCC-Ag, IgA, and CIC values at the completion of treatment was correlated with an increased incidence of disease-free status. This study indicates that only the estimation of SCC-Ag and in some degree the IgM and/or IgG is a potential tool for monitoring the efficacy of treatment or disease recurrence in SCC-HN.

Long-term survival data and prognostic factors of a complete response to chemotherapy in patients with head and neck cancer treated with platinum-based induction chemotherapy: A hellenic co-operative oncology group study

A group of 154 patients with locally advanced head and neck cancer, treated with platinum-based induction chemotherapy, were followed up for 5 years and several pretreatment characteristics were analyzed for possible correlation to a complete response (CR) to chemotherapy, time to progression (TTP) and overall survival (OS). Clinical stage (p = 0.0024) and a history of smoking (p = 0.0125) were selected as important prognostic factors for CR by step wise logistic regression. We also identified response to chemotherapy (p = 0.0120), age (p = 0.0066), clinical stage (p = 0.0363), N stage (p = 0.0028), and tumor grade (p = 0.0101) as significant prognostic variables for TTP. Response to chemotherapy (p < 0.0001) and age (p = 0.0017) were found also significant for OS. These long-term prognostic factors which retain their prognostic significance after several years of follow-up could be helpful in the design of future trials in this patient population.