Dose-finding study of capecitabine in combination with weekly paclitaxel for patients with anthracycline-pretreated metastatic breast cancer.

PURPOSE: Capecitabine and paclitaxel show high efficacy, non-overlapping toxicity profiles and preclinical synergism, providing the rationale for their combination in metastatic breast cancer (MBC). This dose-escalation study aimed at determining the maximum tolerated dose (MTD) of capecitabine plus paclitaxel in anthracycline-pretreated MBC patients. PATIENTS AND METHODS: Patients with MBC received fl at-dose of oral capecitabine (1,000 mg/m(2) twice daily, days 1-14) plus weekly paclitaxel 60, 75, or 90 mg/m(2), i.v., days 1, 8 and 15, every 3 weeks. RESULTS: All 11 patients enrolled onto study were evaluable for toxicity and response. Two patients receiving paclitaxel 75 mg/m(2) experienced grade 3 nail toxicity, with grade 3 hand-foot syndrome (HFS) in one patient and grade 2 dermatitis in the other. Although not life-threatening, these were considered unacceptable and the preceding dose level was selected. Eight of 11 patients achieved objective responses. CONCLUSION: The recommended regimen is capecitabine 1,000 mg/m(2) twice daily, days 1-14, plus paclitaxel 60 mg/m(2)/week. Escalation of the paclitaxel dose above 60 mg/m(2)/week is not feasible due to severe skin toxicity.

The principles of chemotherapy of colorectal cancer in elderly.

The prevalence of colorectal cancer (CRC) increases significantly with age, with 40% of patients in Europe being older than 74 years of age at the time of initial diagnosis. The individualized management of the older-aged patient with cancer is based on the answers to the following questions: 1) will the patient die of cancer or with cancer; 2) will the patient suffer cancer-related morbidity; and 3) is the patient able to handle the toxicity of treatment? More than chronological age, the following parameters are important when elderly patients are to be treated with antineoplastic agents: general condition, liver function, kidney function and bone marrow status. Frail elderly with malignant disease should not be treated with cytostatic therapy. In the case of fit elderly, the standard chemotherapy (i.e. FOLFOX) regimen could be administered. In elderly ineligible for combination chemotherapy, the capecitabine used orally, as a single-agent therapy, is an important therapeutic option for colorectal cancer.

Use of high-dose cytarabine to enhance cisplatin cytotoxicity-effects on the response and overall survival rates of advanced head and neck cancer patients.

UNLABELLED: It has been reported that cytarabine, acting by at least two different mechanisms, enhances the cytotoxic effect of cisplatin in in vitro systems. The aim of this open, prospective, randomised study was to estimate the eventual benefits from the inclusion of high-dose cytarabine in the cisplatin-5-fluorouracil (5-FU) regimen as first-line treatment of patients with advanced head and neck cancer. The study recruited successive patients with unresectable grade I/II head and neck cancer who were not suitable for irradiation treatment (T any N3 or T4 N2C), metastatic or previously irradiated. All patients gave their informed consent. A joint ear, nose and throat (ENT) oncological committee performed the selection. A total of 170 patients were included in the study. Patients randomised to arm A were given 1000 mg/m(2) cytarabine on day 1 preceding for 6 h cisplatin infusion, 30 mg/m(2)/24 h cisplatin intravenous (i.v.) bolus days 1-4 and 1000 mg/m(2)/24 h 5-FU in a 4-h infusion on days 1-4. Patients in arm B were given cisplatin and 5-FU in the same dosage and schedule as in arm A. Additional irradiation+/-surgery was performed if and when feasible. Patients in both arms were well balanced with regard to clinical variables. The following results were obtained: Arm A: 84 patients were included, 74 were evaluable for activity; RESPONSE: complete response (CR) 8 (11%), partial response (PR) 40 (54%), stable disease (SD) 11 (15%), progressive disease (PD) 15 (20%). The overall response rate (RR) based on the evaluable patients was 48/74 (65%, 95% confidence interval (CI) 54-75%); The RR based on an intent-to-treat analysis was 57%, 95% CI 47-67%; Median survival was 13 months; There were 50 episodes of granulocytopenia grade IV and 15 of febrile neutropenia per 316 cycles. Arm B: 86 patients were included, 80 were evaluable for activity; RESPONSE: CR 7 (9%), PR 29 (36%), SD 10 (12.5%), PD 34 (42.5%); The overall RR based on the evaluable patients was 36/80 (45%, 95% CI 35-56%); The RR based on an intent-to-treat analysis was 42%, 95% CI 32-52%; Median survival was 8 months; There were 14 episodes of granulocytopenia grade IV and 7 febrile neutropenias per 324 cycles. The RR was significantly higher in arm A (P=0.013), power (one-sided) 80%. The proportion of patients from the appropriate subset who achieved a clinical response making additional treatment feasible was higher in arm A (P=0.00015), as well as the proportion of patients with a performance status 2+3 achieving a response (P<0.0001). Using the Log-rank test, patients from arm A achieved a significantly longer survival (P=0.009), with the probability of survival at 12 months of 0.58 for patients in arm A and 0.28 for patients in arm B. Grade IV granulocytopenia and thrombocytopenia were more frequent in arm A. Due to its haematological side-effects, cytarabine might not be the ideal drug to modulate the cytotoxicity of cisplatin. However, other modulators of its activity could be of interest for further studies in head and neck cancer patients.

Vinblastin-carboplatin for metastatic cutaneous melanoma as first-line chemotherapy and in dacarbazine failures: a single-center study.

First-line treatments of metastatic melanoma are usually decarbazine (DTIC) and/or alpha-interferon based, with response rates in the range of at most 20-30%. In this study, initiated, in fact, by a temporary DTIC shortage in the country, we have assessed the efficacy and toxicity of a vinblastine-carboplatin regimen for metastatic melanoma. The regimen was subsequently applied in two cohorts of patients: a chemotherapy-naive one and in DTIC failures (because the regimen was claimed non-cross-resistant). The regimen contained 6 mg/m2 vinblastine on d 1 and 450 mg/m2 carboplatin on d 1 for 3 wk. In the chemotherapy-naïve cohort, 50 patients were included, 29 males and 21 females, median age 54 yr (range: 33-68), performance status 0+1 for 26 patients and 2+3 for 24 patients. Forty-eight patients were evaluable for activity. The response was the following: complete response (CR), 1/48 (2%); partial response (PR), 13/48 (27%); stable disease (SD), 20/48 (42%); progressive disease (PD), 14/48 (29%). The overall response rate was 14/48 (29%). The median response duration was 7 mo (range: 3-14); the median time to progression was 4 mo (range: 2-14). Toxicity included granulocytopenia and thrombocytopenia grade IV in 3/50 patients and nausea grade II in 8/50 patients. In the DTIC-failures cohort, 58 patients were included, 38 males and 20 females, median age 51 yr (range: 20-65), performance status 0+1 for 25 patients and 2+3 for 33 patients. All 58 patients were evaluable for activity. The response was the following: CR 3/58 (5%), PR 4/58 (7%), SD 10/58 (17%), PD 41/58 (71%). The overall response rate was 7/58 (12%). The median response duration was 11 mo (range: 3-24); the median time to progression was 4 mo (range: 2-24). Toxicities included granulocytopenia grade IV in 4/58 patients and nausea grade II in 4/58 patients. Thus, despite the fact that the regimen achieved a response rate comparable to DTIC in a first-line setting, the lack of cross-resistance did not prevent it from being of limited activity in DTIC failures, although, even in this group, several long-lasting responses and stabilizations were noted.

Epirubicin 150 mg/m2-cisplatin versus epirubicin 180 mg/m2-cisplatin for advanced soft tissue sarcoma.

We have previously reported the superiority of the epirubicin 180 mg/m2-cisplatin combination over single drug epirubicin 180 mg/m2 for advanced soft tissue sarcoma both in terms of response (54% vs. 29%, p = 0.025) and survival (p = 0.001). The aim of the present study was to establish whether decreasing the dosage of epirubicin to 150 mg/m2 would result in the same activity but with less hematological toxicity. One hundred fifty-nine patients with advanced soft tissue sarcoma were randomized for either epirubicin 150 mg/m2-cisplatin 120 mg/m2 (group A) or epirubicin 180 mg/m2-cisplatin 120 mg/m2 (group B). The results were as follows: group A: 79 patients were evaluated. Overall response rate was 24/79 (30%) (95% CI 21-41%). Median survival was 11 months and probability of survival at 1 year was 0.46. Grade IV granulocytopenia was present in 111/274 cycles and febrile neutropenia in 22/274. Group B: 73 patients were evaluated. The overall response rate was 39/73 (53%), (95% CI 42-64%). Median survival was 14 months and probability of survival at 1 year was 0.58. Grade IV granulocytopenia was present in 136/295 cycles and febrile neutropenia in 30/295. The differences were as follows: for overall response rate p = 0.004; power (for p = 0.05) 85%; for survival p = 0.09; for grade IV granulocytopenia p = 0.3; and for febrile neutropenia p = 0.61. A survival advantage (p = 0.043) was evident for patients randomized to group B and with performance status 0 or 1 compared with similar patients from group A. A plateau-like formation on the probability level of 0.26 on the survival curve started from month 26 onwards. In conclusion, both regimens share the same toxicity but epirubicin 180 mg/m2-cisplatin seems more active in soft tissue sarcoma, possibly indicating a breakthrough for activity between an epirubicin dosage of 150 mg/m2 and 180 mg/m2 in combination with cisplatin. The superiority of the epirubicin 180 mg/m2-cisplatin regimen appears evident both in terms of response and survival.

Randomized study of zorubicin versus zorubicin-cisplatin in undifferentiated carcinoma of the nasopharynx (UCNT)

BACKGROUND: The most active chemotherapy regimens in UCNT were those combining anthracyclines (doxorubicin or epirubicin) and cisplatin. Our previous pilot study on 37 patients treated with the zorubicin-cisplatin combination with a RR of 67% and literature data about other anthracyclines such as epirubicin achieving a response rate of over 50% were the basis of this randomized study comparing efficacy and toxicity of the combination vs. zorubicin as monotherapy. PATIENTS AND METHODS: A total of 80 patients entered the study. The diagnosis of UCNT was confirmed by two independent pathologists. All patients had their primary tumors in the nasopharynx. The patients were randomized in two groups: group A (zorubicin 325 mg/m2, day 1), and group B (zorubicin 250 mg/m2, day 1 and cisplatin 30 mg/m2, days 2-5). The inter-cycle interval was four weeks. The two groups were well balanced according to sex, age, stage Ho and TNM stage. RESULTS: Group A: 40 patients included, 34/40 evaluable for activity. Activity on evaluable patient basis: CR 4/34 (11.75%), PR 4/34, SD 14/34, PD 12/34, response rate 8/34 (23.5%); response rate on intent to treat basis 8/40 (20%). TOXICITY: granulocytopenia grade 3-4 6/40, thrombocytopenia grade 3-4 2/40, no febrile neutropenias, nausea/vomiting any grade 3/40, cardiac toxicity any grade (rhythm) 3/40 other toxicities minor or absent. Group B: 40 patients included, 36/40 evaluable for activity. Activity on evaluable patient basis: CR 10/36 (27.78%), PR 17/36, SD 3/36, PD 6/36, response rate 27/36 (75%); response rate on intent to treat basis 27/40 (67.5%). TOXICITY: granulocytopenia grade 3-4 10/40, thrombocytopenia grade 3-4 8/40, two febrile neutropenias, nausea/vomiting any grade 13/40, other toxicities mild or absent. Of the group of patients achieving a CR, four relapsed following 7, 11, 22 and 23 months, one was lost to follow-up, one died after six months from fulminant hepatitis B and eight are in complete remission lasting for 30+ to 66+ months. Following CR achievement none received any consolidation radiotherapy, and the projected five years of freedom from relapse for complete responders is about 60%. CONCLUSION: Zorubicin is an effective drug in UCNT and its combination with cisplatin has a significant activity and an acceptable toxicity.

Randomised study of high-dose epirubicin versus high-dose epirubicin-cisplatin chemotherapy for advanced soft tissue sarcoma.

A randomised study was started in chemotherapy-naive patients with advanced soft tissue sarcomas who received either epirubicin 60 mg/m2/24 h (total dose for cycle 180 mg/m2) days 1, 2 and 3, (group A) or epirubicin 60 mg/m2/24 h days 1, 2 and 3 and cisplatin 30 mg/m2/24 h days 2, 3, 4 and 5 (group B). The maximal number of cycles foreseen in both groups was eight. Cardiotoxicity of the regimens was monitored by serial LVEF determinations. 106 patients entered this study, 50 (45 evaluable for activity) randomised to group A, and 56 (54 evaluable for activity) to group B. The groups were well balanced for age, sex, performance status and histological type. In group A, there was 1 complete response (CR) and 12 partial responses (PR), the overall response being 13/45 (29%); in group B, there were 7 CRs and 22 PRs, the overall response being 29/54 (54%). The difference between the overall response was statistically significant (chi 2 = 6.19, P < 0.025). The epirubicin-cisplatin regimen was found to be more toxic for platelets and more emetogenic, but cardiotoxicity, either acute or cumulative, was not found to be a major problem in both groups. However, a complete responder receiving a cumulative epirubicin dose of 1440 mg/m2 died from congestive heart failure after a disease-free interval of 27 months. The high response in group B could be the result of the synergism between high-dose epirubicin and cisplatin in patients with advanced soft tissue sarcomas.

[A pilot study of high-dose zorubicin in advanced stages of soft tissue sarcoma in adults]. / Etude pilote de la zorubicine à hautes doses dans les stades avancés des sarcomes des tissus mous de l'adulte.

High-dose anthracyclines, doxorubicin 75 mg/m2 and epirubicin 150-180 mg/m2, are the most active drugs in the treatment of advanced soft tissue sarcoma. These dosages are associated with significant hematological toxicity for both drugs and a high risk of cardiotoxicity for doxorubicin. The aim of this pilot study was to investigate the activity of zorubicin in advanced soft tissue sarcoma, with a dosage supposed to be equihematotoxic to epirubicin 180 mg/m2. Twenty of 21 patients who had been included in the study were evaluable for response, 15 males and five females, median age 41 (range 20-67) years. All patients received zorubicin 600 mg/m2 per cycle divided in 3 days, the intercycle interval being 4 weeks. The cardiac function was monitored by determinations of left ventricular ejection fraction before each cycle. Therapeutic response was the following: 2/20 patients (10%) complete response, 6/20 (30%) partial response, 6/20 (30%) stable disease and 6/20 (30%) progressive disease, the overall response rate being 8/20 (40%). Complete responses were observed in a patient with undifferentiated sarcoma of the mediastinum and in a patient with unresectable angiosarcoma of subcutaneous tissues. The major toxicity was hematological, with granulocytopenia grade 4 occurring in 42/66 cycles, and the nadir on day 10 of the treatment cycle. Nine of 66 cycles were complicated by febrile neutropenia and stomatitis of any grade was recorded in only 1/66 cycles. No cumulative cardiotoxicity was observed up to a total cumulative zorubicin dose of 3,000 mg/m2.

Cardioprotection with ICRF-187 (Cardioxane) in patients with advanced breast cancer having cardiac risk factors for doxorubicin cardiotoxicity, treated with the FDC regimen.

A study of cardioprotection with ICRF-187 (Cardioxane, Eurocetus) has been performed in 35 patients with metastatic breast cancer treated with the FDC regimen (5-fluorouracil 500 mg/m2 i.v., day 1; doxorubicin 50 mg/m2 i.v., day 1; cyclophosphamide 500 mg/m2 i.v., day 1). All patients had one or more cardiac risk factors for doxorubicin cardiotoxicity including 24 who had previously received left-chest-wall irradiation. Cardioxane was applied at a dosage of 1000 mg/m2 as a 15-min infusion in Ringer lactate solution 30 min before doxorubicin administration. Cardiological monitoring included left-ventricular ejection fraction (LVEF) determination by echocardiography before treatment and before each cycle following the cumulative doxorubicin dose of 200 mg/m2. Of the 35 patients, 34 were evaluable fore response, and the overall response rate was 19/34 (56%) with 3/34 complete responses and 16/34 partial responses. Statistical analysis of LVEF values in relation to increasing cumulative doxorubicin doses with Wilcoxon's test of equivalent pairs and Friedman's test has demonstrated that no cardiotoxicity was detected up to a cumulative doxorubicin dose of between 800 mg/m2 and 1000 mg/m2, except for 2 patients in whom a decrease of 20% in relation to the LVEF pretreatment level was demonstrated following a cumulative drug dose of 250 mg/m2. Thus Cardioxane provides an effective cardioprotection even in breast cancer patients with cardiac risk factors for doxorubicin cardiotoxicity treated with the FDC regimen.