Reply to the article "Metronomic therapy with cyclophosphamide induces rat lymphoma and sarcoma regression, and is devoid of toxicity" by V. R. Rozados et al. (Ann Oncol 2004; 15: 1543–1550): ... and in humans?

T. De Pas*, M. Colleoni, L. Orlando, G. Masci, A. Rocca, C. Catania, G. Curigliano, S. Manzoni, A. Goldhirsch and F. de Braud

Department of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy

* Email: tommaso.de-pas{at}ieo.it

We congratulate Rozados et al. [1Go] on conducting this important clinical trial, which investigates the antitumour effect of a metronomic administration of low-dose cyclophosphamide (CTX) in sarcoma rat tumour models.

The use of ‘metronomic’ drug delivery is increasing in solid tumours. Animal models and clinical studies support the delivery of non-toxic, low-dose chronic chemotherapy that has a target not only in the tumour but also in other compartments, mainly the vasculature [2Go, 3Go]. The combination of low-dose metronomic chemotherapy with proapoptotic biomodulators has demonstrated activity in heavily pretreated sarcomas [4Go], and we recently demonstrated that low-dose CTX and methotrexate (MTX) can induce tumour regression in a high percentage of patients with advanced breast cancer [5Go].

We report the results of a prospective mono-institutional experience that tested the activity of a metronomic chemotherapy with oral CTX (50 mg/day) and MTX (2.5 mg twice daily on days 1 and 2 each week) given continuously to 21 advanced soft tissue sarcoma (STS) patients. Treatment administration was planned until disease progression or patient refusal.

Seventeen patients were valuable for toxicity and response (four patients were lost to follow-up). The median age was 56 years (range 32–67), and median Eastern Cooperative Oncology Group performance status was 1 (range 0–2).

Median treatment duration was 3 months (range 2–13). Treatment was very well tolerated: no grade 3–4 (National Cancer Institute Common Toxicity Criteria) toxicity was registered, but grade 3 thrombocytopenia and transaminitis occurred in one and two patients, respectively. Two patients required an MTX dose reduction and two patients a treatment delay.

No complete or partial responses were registered. Overall, eight patients obtained a disease stabilisation (median time to progression 4 months; range 4–47+), five of eight patients having a progressing disease at the time of study entry. The histotypes of these five patients were leiomiosarcoma (three) and haemangioendothelioma (two).

The low antitumour activity of low-dose MTX and CTX obtained in this negatively selected population of patients with STS is not consistent with the impressive results obtained by Rozados et al. [1Go] in rats.

Nevertheless, it should be considered that the CTX–MTX combination aimed at inhibiting angiogenesis, and therefore might require a prolonged administration to be active. As a consequence, better results might be obtained in patients with limited and slowly progressing disease. The evidence of disease stabilisation obtained in patients with progressing disease, and the low toxicity profile registered in this preliminary experience support further investigation in a selected subset of patients with low-grade and limited-burden STS.


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1. Rozados VR, Sanchez AM, Gervasoni SI et al. Metronomic therapy with cyclophosphamide induces rat lymphoma and sarcoma regression, and is devoid of toxicity. Ann Oncol 2004; 15: 1543–1550.[Abstract/Free Full Text]

2. Klement G, Baruchel S, Rak J et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000; 105: R15–R24.[ISI][Medline]

3. Klement G, Huang P, Mayer B et al. Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenograft. Clin Cancer Res 2002; 8: 221–232.[Abstract/Free Full Text]

4. Vogt T, Hafner C, Bross K et al. Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors. Cancer 2003; 98: 2251–2256.[CrossRef][ISI][Medline]

5. Colleoni M, Rocca A, Sandri MT et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002; 13: 73–80.[Free Full Text]





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