[Rich66]

Breast. 2009 Oct 31. [Epub ahead of print] Metronomic administration of pegylated liposomal-doxorubicin in extensively pre-treated metastatic breast cancer patients: A mono-institutional case-series report. Munzone E, Di Pietro A, Goldhirsch A, Minchella I, Verri E, Cossu Rocca M, Marenghi C, Curigliano G, Radice D, Adamoli L, Nolè F. Division of Medical Oncology, European Institute of Oncology, via Ripamonti, 435, 20141 Milan, Italy. BACKGROUND: Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. Pegylated liposomal-doxorubicin (PLD) pharmacokinetic characteristics support the rationale for using the drug in a metronomic fashion, potentially able to combine anthracyclines efficacy to a low toxicity profile. PATIENTS AND METHODS: In a case-series report carried out in both anthracycline-naive and pre-treated metastatic breast cancer patients, we tested feasibility, clinical efficacy and tolerability of PLD administered with a novel metronomic schedule of 20mg/m(2) i.v. every two weeks. RESULTS: 52 patients were enrolled and 45 were evaluated. Forty-four patients were assessed for either response or toxicity. Eight patients (18%) had partial responses (PR) and 17 (39%) stable disease (SD), with a clinical benefit (CB) of 45% (95% CI: 30.3%-59.7%). Nineteen patients (43%) had progressive disease (PD). Neither grade 3 nor grade 4 haematological or clinical side effects were recorded, except for 2 patients with grade 3 palmar-plantar erythrodysesthesia (PPE). No cardiac toxicity was recorded. CONCLUSION: Metronomic administration of PLD is a feasible and active treatment for extensively pre-treated metastatic breast cancer patients, alternative to classic anthracyclines, balancing clinical efficacy with a good quality of life in terms of reduced side effects and low personal costs for the patient. PMID: 19884008 [PubMed - as supplied by publisher] J Clin Oncol. 2006 Aug 1;24(22):3623-8. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. FULL TEXT HERE Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, Allevi G, Aguggini S, Bodini G, Milani M, Dionisio R, Bernardi C, Montruccoli A, Bruzzi P, Harris AL, Dogliotti L, Berruti A. Breast Unit and Anatomia Patologica, Azienda Ospedaliera Istituti Ospitalieri Cremona, Italy. PURPOSE: To investigate the activity of letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment (PST) in elderly breast cancer patients. METHODS: One hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to primary letrozole therapy (2.5 mg daily for 6 months) or a combination of letrozole plus oral cyclophosphamide (50 mg/daily for 6 months) in an open-labeled, randomized phase II trial. Tumor response was assessed clinically, and tumor Ki67 index and vascular endothelial growth factor (VEGF) -A levels were measured before and after treatment. RESULTS: Overall response rate was 71.9% (95% CI, 60.0 to 83.8) in the 57 patients randomly assigned to receive primary letrozole and 87.7% (95% CI, 78.6 to 96.2) in the 57 patients randomly assigned to receive letrozole plus cyclophosphamide. The difference in activity between treatment arms was predominantly confined to patients with ductal histology. There was a significantly greater suppression of Ki67 and VEGF-A expression in the letrozole/cyclophosphamide-treated group than in the letrozole-treated group, leading to lower Ki67 and VEGF expression at post-treatment residual histology (P = .03 and P = .002, respectively). CONCLUSION: Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients. Metronomic scheduling of cyclophosphamide may have an antiangiogenic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial. PMID: 16877730 [PubMed - indexed for MEDLINE] Chemotherapy efficacy is dependent mainly on proliferative activity, whereas endocrine therapies are cytostatic, so that an antagonistic interaction between the two treatment modalities is expected when they are administered concomitantly.14 The results of a large randomized clinical trial published recently are in line with these assumptions.15 Because the target of the metronomic chemotherapy is not the proliferating cancer cells, this treatment modality could potentiate the efficacy of endocrine therapy. In this article, we explored the activity of the combination of LET-CYC administration as PST in elderly breast cancer patients as compared to standard LET. The response rate of 72% in patients randomly assigned to the LET arm was higher than the 60% obtained in a previous randomized trial with primary LET therapy.2 The different patient population and the longer exposure of our patients to LET (6 months v 4 months) can account for the observed difference. The response rate obtained in the LET-CYC arm(88%) was high. The study design was not aimed at testing the difference in response rates in the two treatment arms, and both passed the test of activity. However, the comparison with the randomized control arm indicates that the high activity of the experimental arm was not caused by a biased sample,22 and suggests that the addition of CYC is associated with an increase in the activity of LET in this patient population (OR, 2.79). Although these results are encouraging, they failed to be confirmed by pathCR, a known predictor of long-term outcome. pathCR was observed in two patients (3.5%), one in each arm. A very low pathCR with primary LET therapy (1.7%) was obtained in the randomized trial comparing LET versus tamoxifen,2 suggesting that this condition is not a sensitive end point for primary endocrine therapy. The addition of metronomic CYC failed to increase the pathCR rate. Others have also found that patients with ER tumors have a low propensity to obtain pathCR after chemotherapy.23,24 Novel antivascular efficacy of metronomic docetaxel therapy in prostate cancer: hnRNP K as a player

Roberto Benelli 1, Stefano Monteghirfo 1, Cecilia Balbi 2, Paola Barboro 2, Nicoletta Ferrari 1 *

1Oncologia Molecolare, Istituto Nazionale per la Ricerca sul Cancro, Largo R.Benzi 10, 16132 Genova, Italy 2Tumori Urologici, Istituto Nazionale per la Ricerca sul Cancro, Largo R.Benzi 10, 16132 Genova, Italy

email: Nicoletta Ferrari (nicoletta.ferrari@istge.it)

^*Correspondence to Nicoletta Ferrari, Oncologia Molecolare, Istituto Nazionale per la Ricerca sul Cancro, L.go R.Benzi 10, 16132 Genova, Italy
Fax: +39-010-573-7409.
Funded by:
Ministero della Salute (2005-conv 93)
Compagnia di San Paolo

Keywords

metronomic chemotherapy • prostate carcinoma • angiogenesis • hnRNP K • angiotensinogen

Abstract

Tumor growth requires a competent vascular supply and angiogenesis is now considered a potential target for cancer treatment. Chemotherapeutic drugs, and docetaxel in particular, chronically administered using a frequent schedule at low dose (metronomic dosing), can cause potent antiangiogenic effects by targeting the endothelial cells of newly growing blood vessels. Because the exposure to cytotoxic drugs could target both endothelial and tumor cells, we investigated the effects of metronomic docetaxel on hormone refractory prostate carcinoma cells. In vitro, metronomic therapy lowered tumor cell viability, inducing apoptosis and reducing the invasive potential at 10- to100-fold lower concentrations as compared with the maximum tolerated dose. Metronomic regimens resulted in a significant reduction of vascular endothelial cell growth factor expression and up-regulation of endogenous angiogenesis inhibitors. Our studies suggest that heterogeneous nuclear ribonucleoprotein K is a mediator of the effects we observed. Targeting heterogeneous nuclear ribonucleoprotein K may serve as a specific antimetastasis and antiangiogenic therapy and could be a potential predictive marker to determine the optimal dose and schedule for metronomic chemotherapy regimens. These findings highlight the multiple effects that may characterize antiangiogenic metronomic chemotherapy and suggest that docetaxel might act as antitumor compound by affecting both cancer and endothelial cells at the same drug concentration. Careful optimization of drug scheduling and dosages will be required to maximize antitumor responses with metronomic approaches. © 2009 UICC http://www3.interscience.wiley.com/j...TRY=1&SRETRY=0 Cancer Treat Rev. 2009 Nov 26. [Epub ahead of print] Overall survival benefit for weekly vs. three-weekly taxanes regimens in advanced breast cancer: A meta-analysis. Mauri D, Kamposioras K, Tsali L, Bristianou M, Valachis A, Karathanasi I, Georgiou C, Polyzos NP. Department of Medical Oncology, General Hospital of Lamia, Lamia, Greece; Panhellenic Association for Continual Medical Research (PACMeR), Greece. BACKGROUND: Taxanes have been extensively tested in patients with advanced breast cancer, but it is unclear whether their weekly use might offer any benefits against standard every three weeks administration. We therefore performed a meta-analysis of randomized controlled trials that compared weekly and every three weeks taxanes regimens in advanced breast cancer. METHODS: The endpoints that we assessed were objective response rate, progression free survival (PFS) and overall survival. Efficacy data for paclitaxel and docetaxel were separately analyzed. Trials were located through PubMed and Cochrane Library searches and abstracts of major international conferences. RESULTS: Omicronbjective response rate was notably better when paclitaxel was used as every three weeks regimen (7 studies, 1772 patients, fixed effect model pooled RR 1.20 95%CI 1.08-1.32 p<0.001). No difference were found for PFS (6 studies, 1610 patients, random effect model HR 1.02, 95%CI 0.81-1.30 p=0.860); while OS was statistically higher among patients receiving weekly paclitaxel (5 studies, 1471 patients, fixed effect model pooled HR 0.78, 95%CI 0.67-0.89 p=0.001). No differences were observed for the weekly compared to the every three weeks use of docetaxel either for objective response, PFS and OS. Overall, the incidence of serious adverse events, neutropenia, neutropenic fever, and peripheral neuropathy were significantly lower in weekly taxanes schedules. The incidence of nail changes and epiphora were significantly lower in the every three weeks docetaxel regimens. CONCLUSIONS: Use of paclitaxel in weekly regimen give overall survival advantages compared with the standard every three weeks regimen. The observed survival benefit does not seem to stem from an increased potency of the drug with weekly regimens. The use of weekly paclitaxel regimens is therefore recommended for the treatment of locally advanced/metastatic breast cancer. PMID: 19945225 [PubMed - as supplied by publisher]