M. T. Barletta

METRONOMIC CYCLOPHOSPHAMIDE IN ELDERLY PATIENTS WITH ADVANCED, CASTRATION‐RESISTANT PROSTATE CANCER

To the Editor: Metronomic chemotherapyFlow-dose, long-term, frequently administered chemotherapyFhas been found to have an important effect on the stabilization of cancer, including prostate cancer, without any highgrade toxicity. However, no data from prospective metronomic clinical trials are available in elderly patients with cancer. Anecdotal case reports and a small retrospective clinical study on metastatic melanoma have suggested metronomic chemotherapy as an alternative therapy in elderly patients requiring palliation. The present study was a retrospective review of 29 consecutive elderly patients (aged 78) with advanced castration-resistant prostate cancer (CRPC) who had been treated with metronomic cyclophosphamide (50 mg per day by mouth) plus celecoxib (200 mg twice a day by mouth) and dexamethasone (1 mg once daily by mouth) at Pisa University Hospital and Livorno General Hospital. The treatment was given for at least 12 weeks. Median age was 83 (range 78–92); six patients (20%) had an Eastern Cooperative Oncology Group Performance Status (PS) of 0 and 23 (80%) of 1 or more; the median number of comorbidities was 2 (range 0–6), and 19 patients (65%) were deemed frail. Median baseline serum prostate specific antigen (PSA) level was 49.4 ng/mL (range 6.7– 567.8 ng/mL); bone was the most frequent metastatic site (72.4%); two patients had measurable disease (7%). Ten patients (34.5%) received one or more previous chemotherapeutic lines, including docetaxel (9 patients, 31%), mitoxantrone (5 patients, 10%), estramustine phosphate (7 patients, 24%), and vinorelbine and etoposide (1 patient, 3.4%). Zoledronic acid was administered to 19 patients (65.5%). No Grade 3 or 4 hematological or nonhematological toxicities were observed in the 29 assessable patients. Four patients (14%) developed National Cancer InstituteF Common Toxicity Criteria Grade 2 anemia, and two patients (7%) developed Grade 2 thrombocytopenia (one of these patients required cyclophosphamide discontinuation). Neither major cardiovascular events nor toxicity-related deaths were observed. Overall, 18 patients (62%) experienced any reduction in PSA level (a decrease of 2% to 99%); 13 (45%) had a confirmed PSA decrease of 50% or greater. Of the 13 responders (77%), 10 had not received any prior chemotherapy, whereas the remaining three had previously received chemotherapy (median 2 lines of chemotherapy). Moreover, nine of the 16 nonresponders had previously been received chemotherapy, and seven had not. Based on these results, there was not any statistical difference in the clinical activity in this metronomic combination between patients previously treated or untreated (P 5.43; Fisher exact test). One of two patients (7%) with measurable disease according to the Response Evaluation Criteria In Solid Tumors obtained a partial response, and the other showed disease stabilization. Median duration of response of the 18 patients with any reduction in PSA levels was 8.6 months (95% confidence interval (CI) 5 7.6–9.6 months). After a median follow-up of 27.3 months (95% CI 5 18.8–35.8 months), median progression-free survival and median overall survival were 7.7 months (95% CI 5 2.3–13.1 months) and 19.7 months (95% CI 5 12.8– 26.6 months), respectively (Figure 1). Palliative docetaxel plus low-dose prednisone every 3 weeks is the standard treatment for CRPC. The clinical efficacy and tolerability of first-line docetaxel was recently reported on in 175 patients aged 75 and older. The authors observed a favorable safety and efficacy profile of 3 weeks of docetaxel only in ‘‘fit’’ elderly patients with prostate cancer (PS 1). Conversely, 46% of patients received an adapted docetaxel regimen (delivered on a weekly schedule in nearly 90% of the cases) because of their vulnerable condition: aged 80 and older or a PS of 2 or greater. However, this subgroup of patients also experienced severe nonhematological toxicity in approximately 40% of the cases. Such results lead the authors to consider the weekly regimen less safe than reported previously in elderly patients with prostate cancer. Despite the known limitations of a retrospective study with a small sample size, the regimen in the current study was feasible and demonstrated a favorable toxicity profile even in elderly and ‘‘unfit’’ patients with prostate cancer. A good toxicity profile was also seen in patients treated for longer

Discordant somatic and germline VEGF-A genotype in a cancer patient resistant to paclitaxel/bevacizumab with chemosensitive hepatic metastasis

Recent data reported an association between VEGF-A genotype of tumors and median overall survival as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer. In the present case we report a discordant VEGF-A genotype between tumor and normal tissue in a patient with a responsive hepatic lesion of chemoresistant breast cancer treated with bevacizumab and paclitaxel. Moreover, we show that, despite the very low VEGF-A protein expression, the neoplastic lesion was well vascularized and responded to bevacizumab therapy. The discordance of VEGF-A polymorphisms in tumor and germline DNA may suggest the importance of obtaining both information in order to predict a superior overall survival or a lower risk of hypertension in patients treated with taxanes and bevacizumab.