A randomised phase III trial of adjuvant radio-chemotherapy comparing Irinotecan, 5FU and Leucovorin to 5FU and Leucovorin in patients with rectal cancer: a Hellenic Cooperative Oncology Group Study.

The primary objective was to compare the 3-year survival of rectal cancer patients randomised postoperatively to irinotecan (IRI), Leucovorin (LV) and bolus 5-fluorouracil (5FU) or LV-bolus 5FU with radiotherapy. Secondary objectives included disease-free survival, local relapse and toxicity. The study included 321 eligible patients. The treatment consisted of weekly administration of IRI 80 mg/m(2) intravenously (IV), LV 200 mg/m(2) and 5FU 450 mg/m(2) bolus (arm A) versus LV 200 mg/m(2) and 5FU 450 mg/m(2) IV bolus (arm B). One cycle included four infusions and treatment was continued for a total of six cycles. The first cycle was followed by pelvic irradiation plus 5FU. There were no differences between the arms in 3-year overall, disease-free and local relapse-free survival. Grades 3 and 4 toxicity was similar in both the arms with the exception of leucopaenia, neutropaenia and alopecia, which were higher in the IRI arm. IRI added to adjuvant radiochemotherapy with LV and bolus 5FU was not shown to improve survival, whereas the incidence of severe leucopaenia was significantly higher in the IRI arm.

Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00.

BACKGROUND: A randomized phase III trial in high-risk breast cancer patients was conducted, to further explore the impact of dose-density in the adjuvant treatment for breast cancer. The safety analysis is presented. PATIENTS AND METHODS: From October 2000 until June 2005, 1121 node-positive patients were randomized to sequential dose-dense epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, New Jersey, USA) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of 'intensified' combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments. RESULTS: Median dose intensity of epirubicin and paclitaxel was double in group A, as designed, with significantly less cycles administered at full dose (P < 0.001). Median cumulative dose of all drugs and total treatment duration, however, were identical between groups. Severe taxane-related toxic effects were more frequent in group A, while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects, including febrile neutropenia. The rates of secondary malignancies were low. CONCLUSION: Both regimens as used in the present study are well tolerated and safe. The rates of severe taxane-related toxic effects and thrombocytopenia, although low overall, are significantly increased with the dose-dense sequential regimen.

Evaluation of the prognostic and predictive value of p53 and Bcl-2 in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy.

PURPOSE: To assess the prognostic and predictive significance of p53 and Bcl-2 protein expression in high risk patients with breast cancer treated with dose-dense sequential chemotherapy. PATIENTS AND METHODS: From June 1997 until November 2000, 595 patients were randomized to three cycles of epirubicin (E) 110 mg/m2 followed by three cycles of paclitaxel (P) 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) or to four cycles of E, followed by four cycles of CMF. p53 and Bcl-2 expression was investigated by immunohistochemistry in 392 and 397 patients respectively. RESULTS: Positive expression of p53 was detected in 104 (26.5%) patients and was significantly associated with negative hormonal status, worse histologic grade, higher incidence of disease relapse and higher rate of death. p53 positive expression was a significant negative predictor of overall survival (OS) (P = 0.002) and disease-free survival (DFS) (P = 0.001). Negative expression of Bcl-2 was detected in 203 (51%) patients and was significantly associated with negative hormonal status. Multivariate analysis revealed that, positive p53 expression, higher number of positive nodes and worse tumor grade were related to significantly poorer OS and DFS. CONCLUSIONS: For both treatments, p53 positive expression was a significant negative prognostic factor for OS and DFS while Bcl-2 was not. No predictive ability of p53 status or Bcl-2 status for paclitaxel treatment was evident.

Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group.

PURPOSE: The aim of this study was to explore the effect of dose-dense sequential chemotherapy with or without paclitaxel primarily on disease-free survival (DFS) and secondarily on overall survival (OS) in patients with high-risk operable breast cancer. PATIENTS AND METHODS: From June 1997 until November 2000, 604 patients with T1-3N1M0 or T3N0M0 tumors were randomized to three cycles of epirubicin 110 mg/m2 followed by three cycles of paclitaxel 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) (group A), or to four cycles of epirubicin followed by four cycles of CMF, as in group A (group B). All cycles were given every 2 weeks with granulocyte colony-stimulating factor support. RESULTS: A total of 595 patients were eligible. Median follow-up was 61.7 months for group A and 62 months for group B. The 3-year DFS was 80% in group A and 77% in group B. Survival rates were 93% and 90%, respectively. The effect of treatment on the hazard of death was different according to hormonal receptor status. More specifically, in patients with negative receptor status the hazard of death was significantly higher for group B (hazard ratio 2.42). Both regimens were well tolerated and severe acute side-effects were infrequent. No cases of severe cardiotoxicity or acute leukemia were recorded. CONCLUSIONS: The present study failed to demonstrate a significant difference in DFS or OS between the two treatment groups. However, our study has shown clearly that high-dose paclitaxel can be safely incorporated to dose-dense sequential chemotherapy.

Adjuvant cytotoxic and endocrine therapy in pre- and postmenopausal patients with breast cancer and one to nine infiltrated nodes: five-year results of the Hellenic Cooperative Oncology Group randomized HE 10/92 study.

SUMMARY: The present randomized phase III trial was designed to detect a 15% benefit in relapse-free survival (RFS) or overall survival (OS) from the incorporation of adjuvant tamoxifen to the combination of CNF [cyclophosphamide, 500 mg/m2; mitoxantrone (Novantrone), 10 mg/m2; fluorouracil, 500 mg/m2 chemotherapy and ovarian ablation in premenopausal patients with node-positive breast cancer and conversely from the incorporation of CNF chemotherapy to adjuvant tamoxifen in node-positive postmenopausal patients. From April 1992 until March 1998, 456 patients with operable breast cancer and one to nine infiltrated axillary nodes entered the study. Premenopausal patients were treated with six cycles of CNF chemotherapy followed by ovarian ablation with monthly injections of triptoreline 3.75 mg for 1 year (Group A, 84 patients) or the same treatment followed by 5 years of tamoxifen (Group B, 92 patients). Postmenopausal patients received 5 years of tamoxifen (Group C, 145 patients) or 6 cycles of CNF followed by 5 years of tamoxifen (Group D, 135 patients). Adjuvant radiation was administered to all patients with partial mastectomy. After a median follow-up period of 5 years, 125 patients (27%) relapsed and 79 (17%) died. The 5-year actuarial RFS for premenopausal patients was 65% in Group A and 68% in Group B (p = 0.86) and for postmenopausal patients 70% in Group C and 67% in Group D (p = 0.36). Also, the respective OS rates were 77% and 80% (p = 0.68) for premenopausal and 84% and 78% (p = 0.10) for postmenopausal patients. Severe toxicities were infrequently seen, with the exception of leukopenia (18%), among the 311 patients treated with CNF. In conclusion, the present study failed to demonstrate a 15% difference in RFS in favor of node-positive premenopausal patients treated with an additional 5 years of tamoxifen after CNF adjuvant chemotherapy and ovarian ablation. Similarly, six cycles of CNF preceding 5 years of tamoxifen did not translate to a 15% RFS benefit in node-positive postmenopausal patients.

A phase II study with CPT-11 plus leucovorin and bolus IV 5-fluorouracil in patients with advanced colorectal carcinoma.

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m2 (7 patients) or 70 mg/m2 (48 patients). After completion of CPT-11 infusion, LV 200 mg/m2 was administered over 2 hr followed immediately by 5-FU 450 mg/m2, IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m2 weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m2. Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m2. Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.

Malignant fibrous histiocytoma of the trunk metastatic to the liver: treatment with transcatheter intrahepatic chemoembolization.

We report a patient with symptomatic liver metastases as the sole site of recurrence of a previously resected malignant fibrous histiocytoma of the trunk. We treated the patient with two sessions of transcatheter chemoembolization. Tumor regression was achieved, and the patient remained free of symptoms 23 months after the diagnosis of liver involvement, when he died of acute myocardial infarction. To our knowledge, this is the only case of transcatheter chemoembolization of liver metastases from soft-tissue sarcoma reported in the literature. Although it is a single case, it shows that this method may be a promising therapy for this grave disease.

Dose-dense sequential adjuvant chemotherapy with epirubicin, paclitaxel and CMF in high-risk breast cancer.

Dose-dense sequential chemotherapy appears to be a promising approach in the management of patients with operable breast cancer. We evaluated the tolerability of such a novel chemotherapeutic regimen in high-risk patients. From February 1995 until September 1997, 49 women with histologically confirmed breast cancer and > or =10 involved axillary nodes were treated postoperatively with three cycles of epirubicin (110 mg/m(2)) followed by three cycles of paclitaxel (250 mg/m(2) in a 3-hour infusion) followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m(2), methotrexate 57 mg/m(2), fluorouracil 840 mg/m(2); E-T-CMF). All cycles were repeated every 2 weeks with G-CSF support. Ovarian ablation with monthly injections of triptorelin for 1 year was performed in premenopausal patients and tamoxifen was prescribed for 5 years to all women with positive receptor status after the completion of chemotherapy. A total of 456 cycles of chemotherapy were administered, 363 (80%) of them at full dose. Forty-seven (96%) patients received all 9 cycles of chemotherapy. Relative dose intensity of epirubicin was 0.98, of paclitaxel 0.97, of cyclophosphamide 0.99, of methotrexate 0.98 and of fluorouracil 0.99. Grade 3--4 toxicities included anemia (8%), leukopenia (8%), peripheral neuropathy (6%), neutropenia (4%), thrombocytopenia (4%), stomatitis (2%), diarrhea (2%), fatigue (2%) and hypersensitivity reaction (2%). Febrile neutropenia occurred in 2 patients. Alopecia was universal. After a median follow-up of 3 years, 11 women (22%) relapsed and 4 (8%) died. The 3-year actuarial disease-free survival rate was 72% and the 3-year overall survival rate 90%. The E-T-CMF regimen is well tolerated, as adjuvant treatment, in patients with operable breast cancer with promising activity and deserves further evaluation in phase III studies.