L. Del Mastro

Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study.

PURPOSE To evaluate the activity and tolerability of dimethylsulfoxide (DMSO) in the prevention of soft tissue toxicity after extravasation of cytotoxic drugs. PATIENTS AND METHODS From June 1991 to December 1994, all patients who had an extravasation during intravenous (IV) infusion of cytotoxic drugs in our institution were considered for an open, prospective study of preventive treatment with 99% DMSO, applied topically on the extravasation site every 8 hours for 7 days. Intermittent local cooling (for 1 hour three times daily) on the first 3 days was also used. RESULTS One hundred forty-four patients with extravasations of doxorubicin (n = 11), epirubicin (n = 46), mitomycin (n = 5), mitoxantrone (n = 13), cisplatin (n = 44), carboplatin (n = 6), ifosfamide (n = 14), and fluorouracil (n = 5) entered the study; 127 were assessable. Only one patient suffered an ulceration. The treatment was well tolerated, with mild local burning and a characteristic breath odor being the only side effects of DMSO application, even in cases in which treatment continued for up to 6 weeks to obtain remission of the symptoms of extravasation. CONCLUSION Topical DMSO is an effective and safe antidote that may be used with local cooling after extravasations of vesicant drugs other than those drugs for which standard interventions are defined.

Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer.

PURPOSE Dexrazoxane was found effective in reducing doxorubicin cardiotoxicity when given at a dose ratio (dexrazoxane: doxorubicin) of 20:1. Preclinical studies indicated that dexrazoxane at a dose ratio of 10 to 15:1 also protected against epirubicin-induced cardiotoxicity. The main objective of this study was to investigate the efficacy of dexrazoxane, given at a dose ratio of 10:1 against epirubicin cardiotoxicity. PATIENTS AND METHODS One hundred sixty-two advanced breast cancer patients were randomized to receive epirubicin-based chemotherapy with or without dexrazoxane. Patients who had previously received adjuvant chemotherapy that contained anthracyclines were treated with cyclophosphamide 600 mg/m2 intravenously (IV), epirubicin 60 mg/m2 IV, and fluorouracil 600 mg/m2 IV, on day 1 every 3 weeks. The other patients were treated with epirubicin 120 mg/m2 IV on day 1 every 3 weeks. Cardiac toxicity was defined as clinical signs of congestive heart failure, a decrease in resting left ventricular ejection fraction (LVEF) to < or = 45%, or a decrease from baseline resting LVEF of > or = 20 EF units. RESULTS One hundred sixty patients were evaluated. Cardiotoxicity was recorded in 18 of 78 patients (23.1%) in the control arm and in six of 82 (7.3%) in the dexrazoxone arm. The cumulative probability of developing cardiotoxicity was significantly lower in dexrazoxane-treated patients than in control patients (P = .006; odds ratio, 0.29; 95% confidence limit [CL], 0.09 to 0.78). Noncardiac toxicity, objective response, progression-free survival, and overall survival were similar in both arms. CONCLUSION Dexrazoxane given at a dexrazoxane:epirubicin dose ratio of 10:1 protects against epirubicin-induced cardiotoxicity and does not affect the clinical activity and the noncardiac toxicity of epirubicin. The clinical use of dexrazoxane should be recommended in patients whose risk of developing cardiotoxicity could hamper the eventual use and possible benefit of epirubicin.

Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia

PURPOSE Although erythropoietin (EPO) is known to be useful in treating chemotherapy-induced anemia, few data are available on its potential preventive role. The aim of this study was to evaluate the ability of EPO in preventing the development of clinically significant anemia in patients treated with chemotherapy. PATIENTS AND METHODS Sixty-two early-stage breast cancer patients undergoing accelerated adjuvant chemotherapy were randomized to receive EPO 150 U/kg three times a week or no additional treatment. Chemotherapy consisted of six cycles of cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF) intravenously on day 1, every 2 weeks with the support of granulocyte colony-stimulating factor (G-CSF), 5 microg/kg subcutaneously from day 4 to day 11. RESULTS Throughout the six cycles of chemotherapy, EPO-treated patients maintained stable values of hemoglobin, whereas control patients developed a progressive anemia. At the end of chemotherapy, the mean (+/- SD) hemoglobin decrease in the control group was 3.05 g/dL (+/- 1.0; 95% confidence interval [CI], 2.6 to 3.5), whereas in the EPO group it was 0.8 (+/- 1.4; 95% CI, 0.3 to 1.4). Clinically significant anemia (hemoglobin < or = 10 g/dL) occurred in 16 patients (52%; 95% CI, 33 to 69) in the control arm and in no patient (0%; 95% CI, 0 to 14) in the EPO arm (P = .00001). CONCLUSION EPO prevents anemia in patients undergoing chemotherapy. Further trials are required to identify subsets of patients in which the preventive use of this drug could be cost-effective.

Comparative Effects of Paclitaxel and Docetaxel on the Metabolism and Pharmacokinetics of Epirubicin in Breast Cancer Patients

PURPOSE To investigate whether paclitaxel and docetaxel influence the pharmacokinetics and metabolism of epirubicin. PATIENTS AND METHODS We studied the pharmacokinetics and biotransformation patterns of epirubicin in 27 cycles and 20 breast cancer patients. Four patients received epirubicin alone 90 mg/m(2) by intravenous (IV) bolus; eight patients received the same dose of epirubicin followed immediately by paclitaxel 175 mg/m(2) in a 3-hour infusion; the other eight patients received epirubicin 90 mg/m(2) followed immediately by docetaxel 70 mg/m(2) in a 1-hour infusion. Epirubicin and its metabolites, epirubicinol (EOL) and 7-deoxydoxorubicinone (7d-Aone), were identified by high-pressure liquid chromatography. RESULTS No pharmacokinetic interaction between the parent compound epirubicin and taxanes was detected. Conversely, a significant effect on epirubicin metabolism by both paclitaxel and docetaxel was found. Epirubicin given with paclitaxel or docetaxel yielded areas under the plasma concentration-time curves (AUC) for 7d-Aone 1. 7-fold and 1.9-fold higher (P <.05), respectively, than epirubicin alone. The appearance of two polar metabolites sensitive to glucuronidase was also significantly greater in both taxane groups. Quantitatively different metabolic rates and patterns for EOL were observed in the paclitaxel and docetaxel combinations. The EOL AUC after paclitaxel treatment (1,521 +/- 150 ng/mL*h) was significantly higher (P <.01) than the corresponding values after epirubicin administered either as a single agent (692 +/- 46 ng/mL*h) or in combination with docetaxel (848 +/- 237 ng/mL*h). CONCLUSION There is no apparent pharmacokinetic interaction between the parent compound epirubicin and paclitaxel or docetaxel. A different pattern of interaction between these taxanes and epirubicin metabolism is clearly evident.

Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line cyclophosphamide, epidoxorubicin, and fluorouracil in patients with metastatic breast cancer.

PURPOSE To evaluate the effect of previous adjuvant chemotherapy with or without anthracyclines on overall survival (OS), progression-free survival (PFS), and objective response (OR) rates of metastatic breast cancer patients treated with cyclophosphamide, epidoxorubicin, and fluorouracil (CEF) as first-line chemotherapy. PATIENTS AND METHODS Three-hundred twenty-six assessable metastatic breast cancer patients entered onto four consecutive randomized trials performed in our Institution and North-West Oncology Group (GONO) cooperative centers from 1983 to 1994. Patients received CEF-based chemotherapy as first-line therapy and were then evaluated. One hundred forty-four patients (44%) did not receive previous adjuvant chemotherapy, and 143 (44%) and 39 (12%) patients received cyclophosphamide, methotrexate, and fluorouracil (CMF)-based and anthracycline-based adjuvant chemotherapy, respectively. RESULTS ORs to CEF chemotherapy were observed in 161 patients (49.4%). On univariate analysis, patients who had received prior adjuvant chemotherapy had a significantly lower probability of response than patients who did not: 43% versus 58% (P=.02). No difference between CMF-based (OR rate, 43%) and anthracycline-based (OR rate, 44%) adjuvant chemotherapy was observed. Stepwise logistic regression analysis indicated that adjuvant chemotherapy (P=.005), bone as dominant metastatic site (P=.02), and previous hormonotherapy for metastatic disease (P=.005) were the most important factors in predicting a poor OR rate. The median PFS and OS times of the whole group were 9.8 and 17.9 months, respectively. Patients who did not receive adjuvant chemotherapy had a longer survival time (21.1 months) compared with patients previously treated with CMF-based (15.3 months) or anthracycline-based (15.8 months) adjuvant chemotherapy. Multivariate analysis confirmed adjuvant chemotherapy to be among the strongest prognostic factors associated with both a poor PFS and OS. CONCLUSION Previous adjuvant chemotherapy adversely affects OR, PFS, and OS in metastatic breast cancer patients treated with the CEF regimen as first-line chemotherapy. No difference was observed between patients previously treated with CMF-based or anthracycline-based adjuvant chemotherapy.

Randomized cooperative study of perioperative chemotherapy in breast cancer.

PURPOSE The aim of this multicentric randomized trial was to determine whether reducing the interval between surgery and chemotherapy improves the outcome of breast cancer patients. PATIENTS AND METHODS Between June 1985 and July 1992, 600 breast cancer patients, clinical stages T1-3A,N0-2,M0 were randomly assigned to a perioperative cycle (PC) of cyclophosphamide 600 mg/m2, epidoxorubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF). Node-negative (N-) patients did not receive any further treatment. Node positive (N+) patients received 11 cycles if previously given PC, or 12 cycles of CEF alternated with cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 (CMF). In addition, N+ patients received concomitant or sequential 5-year tamoxifen therapy. RESULTS At a median follow-up duration of 5.7 years, no significant difference in survival (88% v 84%, P = .3) between the two treatment arms was seen. However, a difference of borderline significance in relapse-free survival (RFS; 76% v 70%, P = .053) was evident. A significant survival advantage for the PC arm was detected only in the estrogen receptor-negative (ER-) patients (P = .003). RFS was significantly improved in N- patients, postmenopausal patients, and ER- patients. Multivariate analyses show that pathologic tumor size, nodal status, receptor status, and treatment (only in ER- patients) are significantly correlated with survival and RFS. PC toxicity did not influence wound healing. CONCLUSION This study provides preliminary evidence that PC positively affects relapse rate and survival in some subgroups, namely, ER- patients.

HER2 expression and efficacy of dose-dense anthracycline-containing adjuvant chemotherapy (CT) in early breast cancer (BC) patients

571 Background. The prognostic and predictive role of HER2 overexpression in BC is still controversial. We retrospectively evaluated such a role in patients (pts) enrolled in a phase III trial comparing adjuvant CT with standard FEC21 (Cyclophosphamide 600, epidoxorubicin 60, 5Fluorouracil 600 mg/m2 q21 days) versus accelerated FEC14 (same drug doses but administered every 14 days with G-CSF support). METHODS Central evaluation of HER2 was performed by IHC (CB-11 MoAb) in 731 cases (60% of the trial population). HER2 was considered positive (overexpressed) in presence of a 3+ score. The prognostic role of HER2 status was assessed by fitting a proportional hazard model to the data. An interaction term representing the modification of the effect of dose-dense therapy in HER2+ pts was included in the final models. Overall survival (OS) and Event Free Survival (EFS) in pts assigned to FEC14 or FEC21 were compared separately within each HER2 subgroup. RESULTS Median follow-up was 6.7 years. No difference in main characteristics were observed between pts with and without HER2 assessment. Overexpression of HER2 was observed in 103 pts (14.1%) and it was a factor associate with a poor EFS (HR=1.55; 95%CI 1.05-2.28; p=0.027) and overall survival OS (HR=2.00; 95% CI 1.22-3.26, p=0.006). The potential benefit of dose-dense epirubicin-containing CT seems restricted to HER2+ patients (Table). The interaction analysis suggested that that the use of dose-dense adjuvant CT completely removed the negative prognostic effect of HER2 overexpression on EFS and partially contrasted that on OS. CONCLUSIONS Our data indicate that HER2 overexpression is a poor prognostic factor in early BC pts and that it may be a strong predictor of the benefit of dose-dense epirubicin-containing adjuvant CT. [Figure: see text] No significant financial relationships to disclose.