S. Bursi

Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer

Purpose: The aims of the present study were to evaluate the clinical activity and the pharmacodynamic profile of the novel schedule of a single i.v. standard dose of cyclophosphamide (CTX) immediately followed by an oral metronomic CTX regimen with celecoxib (CXB) and dexamethasone (DEX) in advanced hormone-refractory prostate cancer patients. Experimental Design: Twenty-eight patients (68% docetaxel-resistant) received 500 mg/m2 CTX i.v. bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 200 mg/twice a day CXB p.o. and 1 mg/day DEX p.o. until disease progression. Plasma vascular endothelial growth factor (VEGF) and thrombospondin-1 were detected by ELISA, and real-time reverse transcription-PCR of VEGF and thrombospondin-1 gene expression on peripheral blood mononuclear cell and of VE-cadherin (VE-C) in blood samples was done. Results: A confirmed prostate-specific antigen decrease of ≥50% from baseline was observed in 9 of 28 patients (32%). Median progression-free survival and overall survival were 3 months (95% confidence interval, 2.2-4.2 months) and 21 months (95% confidence interval, 12.4-29.4 months), respectively. Toxicity was mild and no grade 3 to 4 toxicities occurred. A significant relationship was found between plasma VEGF and prostate-specific antigen values (r = 0.4223; P < 0.001). VEGF levels significantly increased in nonresponders, whereas the responder patients maintained significantly lower levels of VE-C gene expression after the beginning of the treatment if compared with nonresponder ones. Conclusion: Metronomic CTX plus CXB and DEX showed favorable toxicity and activity profile in patients. VE-C gene expression and VEGF levels represent potentially useful pharmacodynamic markers for the clinical response.

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer

The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m−2 and oxaliplatin 85 mg m−2 on day 1 plus capecitabine 2000 mg m−2 per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3–4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4–82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively.The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI.

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

Triplet Combination of Fluoropyrimidines, Oxaliplatin, and Irinotecan in the First-Line Treatment of Metastatic Colorectal Cancer

In recent years, the treatment of metastatic colorectal cancer has improved because of the availability of 3 active cytotoxic drugs, 2 monoclonal antibodies, and the expanded use of surgery on metastases in selected patients, leading to a median overall survival of almost 2 years. Chemotherapy remains the primary option for these patients, and the development of first-line chemotherapy regimens associated with higher activity and improved efficacy is still a major topic of interest. This article provides an overview of the development of a first-line treatment combination of irinotecan and oxaliplatin plus 5-fluorouracil (5-FU; FOLFOXIRI) or oral fluoropyrimidines in patients with metastatic colorectal cancer, evaluating the feasibility and the activity of these regimens in phase I/II studies and the results of a recent phase III study that demonstrates that FOLFOXIRI significantly increases response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with an infusional 5-FU-containing doublet such as FOLFIRI (5-FU/leucovorin/irinotecan).

Consequences of targeted treatments for second-line therapy

The paradigm for first-line treatment of relapsed or metastatic non-small cell lung cancer (NSCLC) is changing. Large phase III trials demonstrated that, in 2010, we cannot select a therapy without an accurate definition of tumor histology and epidermal growth factor receptor (EGFR) status. Patients harboring an EGFR-activating mutation have a better prognosis and certainly are extremely sensitive to EGFR-tyrosine kinase inhibitors, while other agents, such as bevacizumab or pemetrexed, are more effective and less toxic in patients with non-squamous histology. Moreover, data from large phase III trials demonstrated that maintenance therapy with pemetrexed, docetaxel or erlotinib is an effective strategy against metastatic NSCLC. Overall, the changing paradigm in first-line treatment of NSCLC inevitably is changing the second-line strategy. In addition, the emerging role of maintenance therapy is leading to early use of all agents potentially active in a second- or third-line setting, with the consequence that very few options are available at disease progression. The aim of this article is to discuss the consequences of targeted treatments for second-line therapy in metastatic NSCLC.