Javier Hornedo

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.

Breast Cancer–Specific mRNA Transcripts Presence in Peripheral Blood After Adjuvant Chemotherapy Predicts Poor Survival Among High-Risk Breast Cancer Patients Treated With High-Dose Chemotherapy With Peripheral Blood Stem Cell Support

PURPOSE To study the prognostic significance of the presence of breast cancer-specific mRNA transcripts in peripheral blood (PB), defined by serial analysis of gene expression, in high-risk breast cancer (HRBC) patients undergoing high-dose chemotherapy after receiving adjuvant chemotherapy. METHODS From 1994 to 2000, 84 HRBC patients (median age, 44 years; > 10 nodes; 74%) received adjuvant chemotherapy (fluorouracil, epirubicin, and cyclophosphamide for six cycles [83%] or doxorubicin and cyclophosphamide followed by paclitaxel) before undergoing one course of cyclophosphamide plus thiotepa plus carboplatin (STAMP V). Radiotherapy or hormone therapy was administered whenever indicated. Aliquots of apheresis-mononuclear blood cells were frozen from each patient. mRNA was isolated using an automatic nucleic acid extractor based on the magnetic beads technology; reverse transcription was performed using random hexamers. Cytokeratin 19, HER-2, P1B, PS2, and EGP2 transcripts were quantified to B-glucuronidase by real-time polymerase chain reaction (RT-PCR) using a linear DNA probe marked with a quencher and reporter fluorophores used in RT-PCR. Presence of PB micrometastases, estrogen receptor and progesterone receptor status, tumor size, age, tumor grade, number of nodes affected, and treatment with paclitaxel were included in the statistical analysis. RESULTS Median follow-up was 68.3 months (range, 6 months to 103 months). Forty-seven relapses (56%) and 35 deaths (41.7%) were registered. Both tumor size and presence of micrometastases reached statistical significance according to the Cox multivariate model. Relapse hazard ratio (HR) for those patients with PB micrometastases was 269% (P = .006); death HR, 300% (P = .011). Time relapse was 53 months longer for patients without micrometastases: 31.3 v 84.2 months (P = .021). CONCLUSION PB micrometastases presence after adjuvant chemotherapy predicts both relapse and death more powerful than classical factors in HRBC patients undergoing high-dose chemotherapy. Micrometastases search using a gene panel appears to be a more accurate procedure than classical approaches involving only one or two genes.

Rifampin Does Not Improve the Efficacy of Quinolone Antibacterial Prophylaxis in Neutropenic Cancer Patients: Results of a Randomized Clinical Trial

PURPOSE To determine whether the addition of rifampin to a quinolone-based antibacterial prophylactic regimen in patients undergoing high-dose chemotherapy (HDC) with peripheral-blood stem-cell transplantation (PBSCT) decreases the incidence of neutropenia and fever, Gram-positive bacteremia, and infection-related morbidity. PATIENTS AND METHODS Patients with solid tumors undergoing HDC with PBSCT were randomized to receive prophylactic antibiotics with either ciprofloxacin 500 mg orally every 8 hours or the same ciprofloxacin regimen with rifampin 300 mg orally every 12 hours. Prophylaxis was started 48 hours before stem-cell reinfusion. Patients were monitored to document the occurrence of neutropenia and fever, incidence and cause of bacterial infection, time to onset and duration of fever, requirement for intravenous antimicrobials, and length of hospital admission. RESULTS Sixty-five patients were randomized to receive ciprofloxacin and 65 to receive ciprofloxacin plus rifampin, and from these groups, 62 and 61 were assessable, respectively. The proportion of patients who developed neutropenia and fever was 87% in the group treated with ciprofloxacin and 78% in the group treated with ciprofloxacin and rifampin (P =.25). Although there was a trend toward a reduction in the overall incidence of bacteremia (12 v 4 patients), and Gram-positive bacteremia (8 v 2 patients) with the addition of rifampin, none of these comparisons was statistically significant (P =.05 and P =.09, respectively). CONCLUSION The results of this study, which demonstrate that rifampin does not improve ciprofloxacin antibacterial prophylaxis in cancer patients undergoing HDC with PBSCT support but that it does increase the occurrence of undesirable side effects, do not support the routine use of rifampin in this setting.

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.

PO-0736: Tumour staging using MRI in prostate cancer: improvement of treatment decisions for radiotherapy

Hospital Quiron, Radiology, Madrid, Spain Universidad Europea, Clinical DepartmentFaculty of Biomedicine, Madrid, Spain Universidad Europea, Department of Research, Madrid, Spain Universidad Europea, School of Medicine, Madrid, Spain Hospital Quiron, Medical Physics, Madrid, Spain Hospital Quiron, Pathology, Madrid, Spain Hospital Quiron, Urology, Madrid, Spain Hospital Quiron, Clinical Oncology, Madrid, Spain Hospital Quiron, Assistant manager, Madrid, Spain