Julia Calzas

Patient selection in high-dose chemotherapy trials: relevance in high-risk breast cancer.

PURPOSE To evaluate the impact of the selection criteria that are used in current high-dose consolidation chemotherapy (HDCT) trials on the outcome of high-risk breast cancer patients treated with conventional adjuvant chemotherapy. PATIENTS AND METHODS From 1975 to 1995, 265 breast cancer patients at our institution showed involvement of ten or more positive axillary lymph nodes. Of these, 171 received standard adjuvant combination chemotherapy, but not HDCT consolidation, and were the subjects of our study. One hundred twenty-eight patients met the standard selection criteria for HDCT with hematological support (< 60 years, no significant concomitant disease, and no progression during adjuvant treatment), whereas 43 did not. Clinical outcome was analyzed by using disease-free survival (DFS) and overall survival (OS) as endpoints. To provide an assessment of the short-term efficacy of HDCT, we also evaluated the outcome in a cohort of 39 patients from the last 4 years who met the criteria for, and were actually treated with, HDCT after adjuvant chemotherapy. RESULTS With a median follow-up of 4.4 years (range, 0.7 to 17.2 years), 112 of the 171 patients have had a relapse, and 87 have died. The estimated 5-year DFS was 32.3%, and OS was 49.4%. DFS was significantly higher for patients who met the HDCT criteria (36.6% at 5 years) than for those who did not (15.8% at 5 years; P < .05). OS was also significantly more favorable in patients meeting HDCT criteria (55.4% at 5 years) than in patients not meeting HDCT criteria (22.7% at 5 years; P < .01). We performed a multivariate analysis to adjust for other potential prognostic factors and found that meeting the HDCT criteria and having undergone locoregional radiotherapy were the only significant independent predictors for DFS and OS. Finally, we compared the outcome of the 128 patients who met the HDCT criteria and were treated with conventional adjuvant chemotherapy only with that of the 39 patients who met the criteria and who actually underwent HDCT, and we did not observe significant differences in the DFS or OS between these groups. CONCLUSIONS Meeting HDCT inclusion criteria is an independent indicator of favorable prognosis in high-risk breast cancer patients. The selection of patients by these criteria may explain, at least in part, the promising short-term results of nonrandomized adjuvant HDCT trials in high-risk breast cancer.

A phase II study of a novel gemcitabine plus cisplatin regimen administered every three weeks for advanced non-small-cell lung cancer

BACKGROUND The aim of this study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine plus cisplatin, administered every three weeks, in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Twenty-six previously untreated stages III (14) and IV (12) patients were included. Gemcitabine was administered on days 1 and 8 at a dose of 1250 mg/m2 and cisplatin was administered at a dose of 100 mg/m2 on day 1, every 21 days. RESULTS Twenty-five patients were evaluable for response. One patient achieved a complete response, and 16 patients partial responses. The overall response rate was 65.3% (95% CI: 45%-82%). The main toxicity was hematological: neutropenia NCIC-CTC grade 3-4 in 54% of the patients, and thrombocytopenia grade 3-4 in 23%. The non-hematological toxicity was mild and tolerable. Only 13% of gemcitabine injections were dose-reduced or omitted due to toxicity. The actual dose-intensity of gemcitabine was 715 mg/m2/week, and 31 mg/m2/week for cisplatin. These figures represent the 86% and 93% of the theoretical dose intensity of both drugs, respectively. With a median follow-up of 10 months (range 7-13), 17 patients are still alive and nine have died. The median overall survival is 12 months. CONCLUSION This novel combination of gemcitabine and cisplatin administered every three weeks is well tolerated and induces a remarkably high response rate. The regimen proves more interesting than the four-week schedules, particularly regarding patients who are candidates for local therapy.

Long-Term Follow-Up of an Anthracycline-Containing Metronomic Chemotherapy Schedule in Advanced Breast Cancer

To the Editor: Breast cancer is the most frequent neoplasm in women, and one of the leading causes of cancer death, accounting for 212,920 new cases per year and 40,970 deaths in the United States in 2006 (1). Continuous chemotherapy has been extensively used in breast cancer treatment during the past years. In the later sixties, Cooper (2) reported a highly effective five-drug weekly combination chemotherapy [cyclophosphamide, epirubicin, 5-fluorouracil, vincristine, and prednisone (CEFVP)]. Recent advances in tumor biology have demonstrated that many classical cytotoxic agents (cyclophosphamide, anthracyclines, fluorouracil, and vinca alkaloids) when administered in low continuous doses induce a tumor suppressive effect through an anti-angiogenic mechanism additive to the known cytotoxic activity (3). In February 1988, we began to treat metastatic breast cancer with an original Cooper-liker regimen in five drug weekly schedule with lower fixed doses of CEFVP we called ‘‘mini-Cooper.’’ Between February 1988 and February 1997, we treated 63 metastatic breast cancer patients (44 on first line and 19 on second line). Here, we report our long time results. All the evaluated patients had histologically confirmed metastatic breast cancer, adequate organ function, and bidimensional measurable disease. All patients firmed informed consent. The regimen consisted of continuous daily oral administration of cyclophosphamide 100 mg, weekly intravenous fixed doses of 4-epirubicin 30 mg, 5-fluorouracil 500 mg, and vincristine 25 mg and orally prednisone 20 mg every other day. Treatment was continued until disease progression, intolerable toxicity or death. After intolerable dose of 4-epirubicin (>950 mg ⁄ m), decrease greater than 10% or under 50% of left ventricular ejection fraction (LVEF) or cardiac toxicity, 4-epirubicin was substituted by weekly intravenous methotrexate 25 mg. Hematologic test was repeated every 2 weeks and a complete analysis with clinical examination and evaluation of toxicity was performed every 28 days. Treatment was delayed in case of neutrophil count <1,000 mm, platelet counts <100,000 mm, or severe non-hematologic toxicity. Tumor responses were evaluated on the basis of World Health Organization criteria every 3 months. Statistical analysis was performed with the SPSS version 14.0 (SPSS Inc., Chicago, IL, USA). Survival and time to progression were estimated using the Kaplan–Meier method. The median age was 54 years (range 33–94). Median Eastern Cooperative Oncology Group performance status was 2 (range 1–3), 46% were premenopausal and 35% were estrogen receptor and progestagen receptor negative. Seventy percent of patients had two or more organs involved. Bone, lung, and liver were the most frequent metastatic sites. More than one-half of patients (64%) had received prior chemotherapy, 34% in the adjuvant setting. One-fourth of patients (24%) had received prior anthracyclines with adequate baseline LVEF. A total of 2,120 cycles of chemotherapy were administered. The median number of cycles was 28 (range 9–93). The median cumulative dose of 4-epirubicin was 810 mg and methotrexate was used in 162 cycles. Dose intensity and median relative dose intensity of 4-epirubicin were 24 mg ⁄ week and 0.86, respectively. All 63 patients were evaluated for tolerability and toxicity. No toxic deaths were observed and the study treatment was well tolerated. The main toxicities were hematologic: grade 4 neutropenia was observed in 19% of patients, and febrile neutropenia in 6%. Severe thrombocytopenia was rarely observed, and only one patient developed grade IV anemia. No severe mucositis was observed. Forty-one patients were evaluated for LVEF. Eleven patients experienced Address correspondence and reprint requests to: Enrique GonzálezBillalabeitia, MD, PhD, Servicio de Hematologı́a y Oncologı́a Médica, Hospital General Universitario Morales Meseguer, Murcia, Spain, or e-mail: engonbil@um.es.

Corazón y neoplasias

La afectacion cardiaca por enfermedades neoplasicas puede deberse a invasion cardiaca por el propio tumor, a compresion del corazon y/o de los grandes vasos por neoplasias extracardiacas, embolizacion y fundamentalmente a los efectos de la terapeutica antitumoral. El tratamiento del cancer ha experimentado un importante avance en las ultimas decadas por la gran expansion de agentes quimioterapicos y el refinamiento de las tecnicas de radioterapia; no obstante, muchos de los mas efectivos farmacos antineoplasicos y la irradiacion toracica ocasionan cardiotoxicidad aguda y cronica. Asi, el seguimiento a largo plazo de pacientes que han recibido antraciclinas, farmacos cruciales en la terapia de muchas neoplasias, demuestra fallo cardiaco clinico en el 4,5 al 7% de los pacientes, incrementandose la incidencia de anomalias en la funcion cardiaca con el tiempo. Su patogenia probablemente incluya la formacion de radicales libres, alteraciones en el transporte del calcio, disfuncion adrenergica o liberacion de aminas vasoactivas. El dexrazoxano es el unico cardioprotector de uso clinico comercializado para un grupo seleccionado de pacientes con carcinoma de mama, por lo que es necesario el desarrollo de nuevos agentes que protejan de la cardiotoxicidad de este grupo de farmacos y reduzcan la morbimortalidad secundaria a los mismos.

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

BackgroundVenous thromboembolism (VTE) is a leading cause of death among patients with cancer. Outpatients with cancer should be periodically assessed for VTE risk, for which the Khorana score is commonly recommended. However, it has been questioned whether this tool is sufficiently accurate at identifying patients who should receive thromboprophylaxis. The present work proposes a new index, TiC-Onco risk score to be calculated at the time of diagnosis of cancer, that examines patients’ clinical and genetic risk factors for thrombosis.MethodsWe included 391 outpatients with a recent diagnosis of cancer and candidates for systemic outpatient chemotherapy. All were treated according to standard guidelines. The study population was monitored for 6 months, and VTEs were recorded. The Khorana and the TiC-Onco scores were calculated for each patient and their VTE predictive accuracy VTEs was compared.ResultsWe recorded 71 VTEs. The TiC-Onco risk score was significantly better at predicting VTE than the Khorana score (AUC 0.73 vs. 0.58, sensitivity 49 vs. 22%, specificity 81 vs. 82%, PPV 37 vs. 22%, and NPV 88 vs. 82%).ConclusionsTiC-Onco risk score performed significantly better than Khorana score at identifying cancer patients at high risk of VTE who would benefit from personalised thromboprophylaxis.

Incidence, predictors and prognostic significance of thromboembolic disease in patients with advanced ALK-rearranged non-small cell lung cancer

Thromboembolic disease is fairly common in patients with lung cancer [1–3]. This incidence seems to be higher in patients with lung adenocarcinomas [4], with approximately 15% of those with advanced stage disease developing venous thromboembolisms (VTE) during the whole course of their disease [5–7]. Pulmonary adenocarcinomas are a heterogeneous group of diseases that can be stratified according to the presence of major oncogenic driver alterations. Anaplastic lymphoma kinase (ALK) rearrangements are detected in approximately 4% of these cases [8]. Isolated reports have suggested that patients bearing ALK-rearranged tumours might have a higher than expected incidence of thromboembolisms [9, 10]. In the present study, we have analysed the incidence, predictors and prognostic significance of thromboembolic events in a large, multi-institutional and homogeneous cohort of advanced stage patients with ALK-rearranged lung cancers from Spain and Portugal. Our primary objective was to estimate the incidence of thromboembolic events and their association with overall survival in these patients. High incidence and prognostic relevance of thromboembolic disease in patients with ALK-rearranged NSCLCs http://ow.ly/DEZr30j6kC8