High Doses Of Epirubicin Research Articles

22P BCL2 Negative Breast Tumors but not Axillary Lymph Nodes Predict a Better Overall Survival in Patients Treated with Higher Doses of Epirubicin at a Median follow-up of 15.6 Years

ABSTRACT Background High expression of bcl2 is associated with good prognosis while high p53 protein is associated with poor prognosis in breast cancer (BC) patients (pts). We examined the prognostic and/or predictive role of bcl2 and p53 in either primary tumor (TU) or axillary lymph nodes (N) in women with node positive BC treated with adjuvant CMF or 2 different doses of epirubicin-containing CT. Method Bcl2 and p53 expression were evaluated by immunohistochemistry in formalin-fixed paraffin-embedded sections of both TU and N in pts who were randomly assigned to one of the following regiments: classical CMF x 6 cycles, EC x 8 cycles (epirubicin (E) 60 mg/m2, cyclophosphamide (C) 500 mg/m2) or HEC x 8 cycles (E 100 mg/m2, C 830 mg/m2)(Piccart M et al, JCO 2001). Expression of bcl2 and p53 in TU and N were analysed in relation to overall survival (OS) and event-free survival (EFS). All hazard ratios (HR) were adjusted for tumor size, nodal status, histologic grade, ER status and HER2 status. Cut-offs for positivity were defined a priori as ≥25% moderate/strong positive cells. Results Tumor markers were assessed in 491 cases out of 777 randomized patients (63%): CMF 164 (33.4%), EC 172 (35.0%), HDE 155 (31.6%). The median follow-up was 15.6 years (range 15.2 to 16.0). High level of concordance between TU and N for both markers were observed: bcl2 85% (298/349), p53 94% (328/349). Bcl2 positivity in either TU or N was associated with better OS: HR 0.71 (95% CI, 0.52-0.97), p = 0.028, and HR 0.70 (95% CI, 0.51-0.97), p = 0.01, respectively. P53 positivity in TU and N was associated with a poor outcome independently of the CT type: HR 1.52 (95% CI, 1.08-2.13) p = 0.01 and HR 1.59 (95% CI, 1.16-2.18) p= 0.004, respectively. In contrast, BcL2 negative TU was associated with benefit to high dose epirubicin over CMF (CMF HR 2.16 95%CI 1.10-4.26, p = 0.02). Bcl2 positive TU predicted for increased benefit to CMF over anthracycline-based CT (interaction p = 0.038). Conclusion P53 positivity in TU or N was found to be associated with a poor prognosis independent of CT type. In contrast, Bcl2 positive status in TU seemed to be associated with differential benefit to CMF of anthracycline-based CT. Disclosure All authors have declared no conflicts of interest.

Acute myeloid leukaemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy

It is still controversial whether granulocyte colony-stimulating factors (G-CSF) per se increases the risk of secondary acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) or whether the requirements for its use cause an increased risk of AML/MDS. In fact, the apparent effects of G-CSF may be caused by the high doses of epirubicin and cyclophosphamide received by the patients included in the treatment arms to which G-CSF was assigned [1]. In the manuscript by Hershman et al. [2], of the 906 women with stages I–III breast cancer, who were treated with G-CSF concurrently with adjuvant chemotherapy, 16 (1.77%) developed AML/MDS. The hazard rate ratio for AML or MDS among those treated with G-CSF or granulocyte–macrophage colony-stimulating factor compared with those who were not was 2.14. One of the issues concerning this observational study is that no information was available about the cumulative dose and duration of G-CSF treatment [3]. Smith et al. [4] found a positive association between the use and the dose of G-CSF and the risk of secondary acute leukaemia (sAL) in patients receiving standard anthracycline and dose-intensified cyclophosphamide. Eighteen of the 22 patients enrolled in B-25 trial and diagnosed with AML/MDS received G-CSF doses in excess of the median dose administered to all patients (242 lg/kg). Controlling for treatment arm, patient age, and operation, the estimated risk of AML/MDS for patients receiving more than the median dose of G-CSF, relative to those receiving the median dose or less, was 3.58 (P = 0.02). On the other hand, in the study by Praga et al. [5], the patients allocated to receive G-CSF according to protocol received median cumulative doses of epirubicin and cyclophosphamide significantly (P = 0.0001) higher than the corresponding median cumulative doses in patients not mandated to receive G-CSF. According to Wilking et al. [6], the major pitfall with the tailored and dose-escalated FEC arm (5-fluorouracil, epirubicin, cyclophosphamide) was the increased risk for secondary AML or MDS. All patients received prophylactic filgrastim (5 lg/kg daily subcutaneously) on days 2–14. The dose of epirubicin in the tailored FEC was much higher than in the standard FEC followed by marrow-supported high-dose therapy (780 vs. 181 mg/m, respectively). By contrast, Crump et al. [7] found no case of sAL among patients given epirubicin-based adjuvant chemotherapy plus G-CSF and Citron et al. [8] reported no correlation between the use of G-CSF and the incidence of sAL among patients randomized to standard or dose-dense chemotherapy. In our experience [9], the crude incidence of sAL after adjuvant high dose epirubicin plus cyclophosphamide with G-CSF support was 0.41%. Future analyses should investigate the possible role of G-CSF cumulative dose and duration of exposure in causing leukaemia in patients treated with adjuvant epirubicin and cyclophosphamide.

Retrospektive Analyse zur Dosisintensität von Epirubicin beim Mammakarzinom

Fragestellung: Die Wirksamkeit von Epirubicin wird in der Therapie des Mammakarzinoms möglicherweise von der applizierten Dosisintensität (DI) beeinflusst. Wir haben den Einfluss der tatsächlich applizierten DI auf die Verträglichkeit und das Ansprechen in der adjuvanten und metastasierten Situation überprüft. Patientinnen und Methoden: Epirubicin, Fluorouracil und Cyclophosphamid (FEC) wurden entweder in einer Dosierung von 500/50/500 mg/m² (FE₅₀C) oder in einer intensivierten Dosierung von 500/75/500 mg/m² (FE₇₅C) 3-wöchentlich gegeben. Die tatsächlich applizierte DI wurde berechnet und mit den Nebenwirkungen und dem Therapieansprechen korreliert. Von 66 Patientinnen waren 63 auswertbar; 43 hatten eine metastasierte Erkrankung, und 20 wurden adjuvant behandelt. Ergebnisse: Adjuvant wurden für FE₅₀C und FE₇₅C 81 bzw. 96% der geplanten DI und 70 bzw. 88% der geplanten Gesamtdosis tatsächlich appliziert. In der metastasierten Situation wurden 94 bzw. 92% der geplanten FE₅₀C- bzw. FE₇₅C-DI gegeben. Dies entsprach einer tatsächlichen Erhöhung der DI von Epirubicin um 81% in der adjuvanten und um 53% in der metastasierten Situation. Die hämatologischen und nicht hämatologischen Toxizitäten beider Regime waren vergleichbar. Im retrospektiven Vergleich liess sich das mittlere Gesamtüberleben nach 4 Jahren in der adjuvanten Situation von 40 auf 48% verbessern (p = 0.47), und die Remissionsrate beim metastasierten Mammakarzinom konnte von 34 auf 44% erhöht werden. Schlussfolgerung: Die applizierte DI von Epirubicin war in allen Gruppen niedriger als initial geplant. Höhere DI von Epirubicin führten beim primären und fortgeschrittenen Mammakarzinom zu vergleichbaren Toxizitäten. Die Einhaltung der geplanten DI scheint eine wichtige Voraussetzung für den optimalen Therapieerfolg zu sein. Unsere Ergebnisse unterstreichen ferner die Notwendigkeit, eine Intensivierung von Anthrazyklinen beim Mammakarzinom weiter in prospektiven Studien zu untersuchen.

Prognostic factors in advanced soft tissue sarcomas (STS) treated with high doses of epirubicin and cisplatin

Prognostic factors in advanced soft tissue sarcomas (STS) treated with high doses of epirubicin and cisplatin

Epirubicin

Epirubicin is the 4' epimer of the anthracycline antibiotic doxorubicin, and has been used alone or in combination with other cytotoxic agents in the treatment of a variety of malignancies. Comparative and noncomparative clinical trials have demonstrated that regimens containing conventional doses of epirubicin achieved equivalent objective response rates and overall median survival as similar doxorubicin-containing regimens in the treatment of advanced and early breast cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), non-Hodgkin's lymphoma, ovarian cancer, gastric cancer and nonresectable primary hepatocellular carcinoma. Recently, dose-intensive regimens of epirubicin have achieved high response rates in a number of malignancies including early and advanced breast cancer and lung cancer. The major acute dose-limiting toxicity of anthracyclines is myelosuppression. In vitro and clinical studies have shown that, at equimolar doses, epirubicin is less myelotoxic than doxorubicin. The lower haematological toxicity of epirubicin, as well as the recent introduction of supportive measures such as colony-stimulating factors, has allowed dose-intensification of epirubicin-containing regimens, which is particularly significant because of the definite dose-response relationship of anthracyclines. Cardiotoxicity, which is manifested clinically as irreversible congestive heart failure and/or cardiomyopathy, is the most important chronic cumulative dose-limiting toxicity of anthracyclines. Epirubicin has a lower propensity to produce cardiotoxic effects than doxorubicin, and its recommended maximum cumulative dose is almost double that of doxorubicin, thus allowing for more treatment cycles and/or higher doses of epirubicin. In summary, dose-intensive epirubicin-containing regimens, which are feasible due to its lower myelosuppression and cardiotoxicity, have produced high response rates in early breast cancer, a potentially curable malignancy, as well as advanced breast, and lung cancers. Furthermore, there is evidence to suggest that improved response rates can improve quality of life in some clinical settings, but whether this leads to prolonged survival has not yet been determined. Recently implemented supportive measures such as colony-stimulating factors, prophylactic antimicrobials and peripheral blood stem cell support may help achieve other potential advantages of dose-intensive epirubicin-containing regimens such as reductions in morbidity and length of hospital admissions.

A pilot study comparing different dose levels and administration schedules of interferon-alpha 2b combined with epirubicin for prevention of recurrence in bladder cancer.

A pilot study in 62 patients has been carried out to evaluate the combination of epirubicin and interferon (IFN)-alpha 2b using different doses and schedules of intravesical administration in the prevention of recurrence of bladder cancer. Preliminary results show greater prophylactic efficacy not only when higher doses of epirubicin and IFN-alpha 2b are used but also when a larger interval between instillation of the compounds was used.

Epirubicin in advanced endometrial adenocarcinoma: a phase II study of the grupo ginecologico Español para el tratamiento oncologico (GGETO)

27 patients with FIGO stage III–IV endometrial adenocarcinoma were entered in a phase II trial evaluating activity and safety of epirubicin given at 80 mg/m 2 intravenously every 3 weeks. 2 complete remissions (including a pathological one) and 5 partial responses were observed for a response rate of 26% (95% confidence interval 11–46). The median time to progression and median survival for all treated patients was 6 and 9.5 months, respectively. Treatment was well tolerated. Haematological toxicity was mild. The median total cumulative dose of epirubicin was 480 mg/m 2 (160–880) and cardiac toxicity was not observed. Further studies with higher doses of epirubicin in combination with other active drugs are indicated.

High-Dose Epirubicin as a Single Agent in the Treatment of Patients with Advanced Breast Cancer

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.

Single Agent Epirubicin in Squamous Cell Cervical Cancer: A phase II trial

Thirty consecutive patients with FIGO stage III-IV, squamous cell uterine cervix cancer were entered in a phase II trial evaluating activity and safety of epirubicin when given at a dose of 80 mg/m2 i.v., every 3 weeks. Two complete responses (including a pathological complete remission) plus 3 partial responses were observed among 27 evaluable patients with a response rate of 18.5% (95% confidence limits = 7.6%-36.4%). The median time to progression and median survival for all treated patients were 3 and 8 months respectively. Treatment was well tolerated. Haematological toxicity was mild. WHO grade 4 toxicity was not observed. The median total cumulative dose of epirubicin was 360 mg/m2 (80-840 mg/m2). Congestive heart failure was not noted. Further studies in cervical cancer with higher doses of epirubicin as single agent or in combination with other nonmyelotoxic drugs are indicated.

Phase II Study with High Doses of Epirubicin in Patients with Advanced Rectal Cancer

We tested the possible role of epirubicin, 100 to 130 mg/m2 administered i.v. every 3 weeks, in patients with advanced adenocarcinoma of the rectum untreated with chemotherapy. Sixteen of 17 entered cases were evaluable. No complete or partial responses were observed. The median time to progression was 6 weeks, and the median survival was 36 weeks. Reversible leukopenia was the major toxic side effect. The median epirubicin cumulative dose was 330 mg/m2; no patient had clinical cardiac toxicity. With no responses recorded in 16 evaluable patients, the activity of epirubicin in rectal cancer ranged between 0 and 18%, with 95% probability. Further studies with epirubicin in this tumor are not indicated.