amrubicin and Brain-Neoplasms

Small-cell lung cancer (SCLC) is a rapidly progressing tumor in which chemotherapy has a limited impact on survival. Unfortunately, little progress has been made in the medical management of SCLC during the last 30 years, which is best exemplified by the fact that standard first-line chemotherapy has remained platinum-based over time. On the other hand, improvements in survival have been obtained only with the introduction of innovative radiation strategies such as accelerated hyperfractionation to the thorax for limited-stage disease and prophylactic cranial irradiation for both limited- and extensive-stage disease. However, recent advances in the understanding of SCLC biology have renewed the interest in the clinical development of active drugs for SCLC. In this review, we address the most promising agents under clinical evaluation, discussing both novel chemotherapeutic agents and targeted agents. Particularly, amrubicin, a fully synthetic anthracycline, is a very active agent for SCLC, and ongoing Phase III trials are evaluating this agent either in the first-line setting of extensive-stage or relapsed disease. Among targeted agents, anti-angiogenic strategies and Bcl-2 inhibitors represent the most promising approaches, and they are being specifically tested in combination with and/or as maintenance therapy after first-line platinum-based chemotherapy.

Topics: Animals; Anthracyclines; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Cranial Irradiation; Drug Administration Schedule; Drug Design; Drug Resistance, Neoplasm; Evidence-Based Medicine; Hematopoietic Stem Cell Transplantation; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Radiotherapy Dosage; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma; Treatment Outcome

Over 25,000 people are diagnosed with small-cell lung cancer (SCLC) in the United States annually. SCLC is a highly aggressive tumor with a propensity for early metastases and a high case-fatality rate. Systemic treatment with etoposide plus a platinum agent is recommended for all stages of this disease and has been a standard first-line therapy for SCLC since the 1980s. Three recently presented randomized clinical trials failed to show superiority of newer regimens over etoposide and cisplatin. Patients with limited-stage (LS) disease benefit from the addition of radiotherapy to systemic chemotherapy, a combination that affords high complete response rates and potential cures. Incremental improvements in radiotherapy delivery over the past decade include the use of accelerated hyperfractionated thoracic radiotherapy for LS disease. Prophylactic cranial irradiation, previously recommended for patients with LS disease, has recently been shown to benefit those with extensive-stage (ES) disease as well. Surgery, largely abandoned in the 1970s, is being reevaluated as primary local therapy in patients with very early-stage SCLC. Topotecan remains the only US Food and Drug Administration-approved therapy for recurrent disease. Amrubicin has demonstrated single-agent activity in multiple phase II trials in both chemotherapy-sensitive and -refractory relapse. The past 2 decades have been marked by an improved understanding of SCLC biology, and these discoveries are reflected in the number and diversity of novel therapies entering early-phase testing in this disease.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Chemotherapy, Adjuvant; Cisplatin; Clinical Trials, Phase II as Topic; Cranial Irradiation; Dose Fractionation, Radiation; Etoposide; Humans; Lung Neoplasms; Neoplasm Staging; Practice Guidelines as Topic; Prognosis; Radiotherapy, Adjuvant; Radiotherapy, High-Energy; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma; Survival Analysis; Topotecan; Treatment Outcome

Idarubicin showed the superior activity against Acute Non-Lymphocytic Leukemia (ANLL) in the prospective randomized trials comparing to daunorubicin and it is judged that the analog will become the first choice in the treatment on ANLL. Anthracyclines including SM-5887, KRN-8602, ME-2303 under studies in Japan have shown comparable or superior antitumor activities and lower cardiac toxicities compared to doxorubicin in preclinical studies and therefore the results obtained in clinical trials are expected. Phase II trials of anthrapyrazoles which is an analog of mitoxantrone are in progress. Among three compounds entered it is of note that CI-941 has demonstrated an excellent activity against advanced breast cancer.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Brain Neoplasms; Carubicin; Doxorubicin; Humans; Idarubicin; Leukemia, Experimental; Leukemia, Myeloid, Acute; Menogaril; Stomach Neoplasms

The efficacy and safety of amrubicin, a third-generation synthetic anthracycline, were evaluated by comparison with carboplatin/etoposide combination therapy in elderly Japanese patients with extensive-disease small-cell lung cancer (ED-SCLC).. Eligibility included histologically or cytologically proven SCLC, no previous systemic chemotherapy, performance status of 0 to 2, and age ≥ 70 years. Patients received amrubicin (70-74 years old, 40-45 mg/m(2); ≥ 75 years old, 40 mg/m(2)) intravenously on days 1 to 3 every 3 weeks for 4 to 6 cycles or carboplatin (area under the curve of 5 intravenously on day 1) and etoposide (80 mg/m(2) intravenously on days 1 to 3) every 3 weeks for 4 to 6 cycles.. The target number of patients was 130 with 65 in each arm. However, the study was terminated early owing to 3 treatment-related deaths in the amrubicin arm, and only 62 patients (median age, 76 years; range, 70-88 years) were enrolled. The characteristics of the patients in the amrubicin and carboplatin/etoposide arms did not differ significantly. Overall survival, time to progression, and objective response rate were 10.9 vs. 11.3 months (P = .7353), 4.7 vs. 4.4 months, and 74.2% (23 of 31) vs. 60.0% (18 of 30), respectively, and quality of life showed no significant difference between the 2 arms. Higher incidences of febrile neutropenia and interstitial lung disease of grade 3 or worse occurred with amrubicin (34.4% vs. 3.3% and 12.5% vs. 0%, respectively).. These results indicate that amrubicin monotherapy at 40 to 45 mg/m(2) is toxic and intolerable in elderly Japanese patients with ED-SCLC.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Etoposide; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Neoplasm Staging; Prognosis; Quality of Life; Small Cell Lung Carcinoma; Survival Rate

Combination chemotherapy of irinotecan, a topoisomerase I inhibitor, and cisplatin is a standard treatment in patients with extensive-stage small cell lung cancer (SCLC). Amrubicin, a novel 9-aminoanthracycline, inhibits topoisomerase II. We investigated a sequential triplet chemotherapy consisting of irinotecan and cisplatin followed by amrubicin in patients with extensive-stage SCLC.. Eligible patients were aged 20 to 70 years and had Eastern Cooperative Oncology Group performance status of 0 or 1, measurable lesions, and adequate organ functions. Chemotherapy consisted of irinotecan 60 mg/m on days 1 and 8 plus cisplatin 60 mg/m on day 1 every 3 weeks for three cycles and then amrubicin 40 mg/m alone on days 1 to 3 every 3 weeks for three cycles.. From September 2004 to September 2006, 45 patients were enrolled, 43 were evaluable for response and survival, and 44 were evaluable for toxicity. Twenty-eight patients (64%) completed the full planned chemotherapy. One patient achieved complete response and 33 had partial response for an overall response rate of 79%. Median progression-free survival was 6.5 months. Median overall survival was 15.4 months. Major toxicity was myelosuppression. Grade 3 or 4 neutropenia, anemia, thrombocytopenia, and febrile neutropenia occurred in 57%, 7%, 0%, and 7% of patients during irinotecan/cisplatin cycles and in 91%, 27%, 9%, and 15% of patients during amrubicin cycles, respectively.. The sequential triplet chemotherapy, irinotecan and cisplatin followed by amrubicin, is an effective and well-tolerated treatment in patients with extensive-stage SCLC. Further investigation of this treatment is warranted.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Camptothecin; Cisplatin; Female; Humans; Irinotecan; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Small Cell Lung Carcinoma; Survival Rate; Treatment Outcome; Young Adult

Idarubicin showed the superior activity against Acute Non-Lymphocytic Leukemia (ANLL) in the prospective randomized trials comparing to daunorubicin and it is judged that the analog will become the first choice in the treatment on ANLL. Anthracyclines including SM-5887, KRN-8602, ME-2303 under studies in Japan have shown comparable or superior antitumor activities and lower cardiac toxicities compared to doxorubicin in preclinical studies and therefore the results obtained in clinical trials are expected. Phase II trials of anthrapyrazoles which is an analog of mitoxantrone are in progress. Among three compounds entered it is of note that CI-941 has demonstrated an excellent activity against advanced breast cancer.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Brain Neoplasms; Carubicin; Doxorubicin; Humans; Idarubicin; Leukemia, Experimental; Leukemia, Myeloid, Acute; Menogaril; Stomach Neoplasms

Small cell carcinoma of the esophagus (SmCCE) is a rare and aggressive disease known to have a poor prognosis. SmCCE patients are generally treated with a chemotherapeutic regimen for small cell lung cancer. Salvage therapy for patients with relapsed or refractory tumors has not yet been established. A 63-year-old man with extensive SmCCE was treated with chemotherapy consisting of cisplatin (CDDP) and irinotecan (CPT-11). After the second course of CPT-11/CDDP, the celiac lymph node increased in size. Amrubicin (AMR) as second-line chemotherapy was started. The patient had a complete response after the fifth course of AMR, resulting in an 8-month progression-free survival after initial administration. This case suggests that, as in small cell lung cancer, AMR is effective for SmCCE.

Topics: Anthracyclines; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Small Cell; Disease-Free Survival; Esophageal Neoplasms; Fatal Outcome; Humans; Male; Middle Aged