A new multi-targeted chemo-switch drug regimen shows promising anti-tumour activity with manageable side effects in patients with metastatic renal-cell carcinoma ( RCC ), a disease with few treatment options. Combining maximum tolerated dose ( MTD ) chemotherapy ( Gemcitabine; Gemzar ) with metronomic chemotherapy ( frequent low-dose chemotherapy with Capecitabine; Xeloda ) plus Sorafenib ( Nexavar ), results in greater progression-free survival ( PFS ) and tumour response than previously reported with Sorafenib alone or with chemotherapy, and might provide a new first-line treatment option for patients with advanced kidney cancer.

Renal-cell carcinoma is the most common form of kidney cancer, causing over 102,000 deaths worldwide each year. But treatment options are limited and survival is poor, with responses to chemotherapy, hormonal and biological therapy, and standard treatment with targeted drugs remaining modest.

However, recent preclinical studies have suggested that combining treatment options could improve response to treatment and survival. Combined treatment entails initial treatment at the MTD of one chemotherapy drug, followed by maintenance with a metronomic dose of a second chemotherapy drug ( giving patients lower doses more frequently to prevent the cancer from growing by inhibiting the development of new blood vessels ) plus a targeted inhibitor of vascular endothelial growth factor ( VEGF ) and platelet-derived growth factor receptor ( PDGFR ) to increase anti-tumour activity.

To investigate whether this multi-targeted chemo-switch strategy might improve outcomes in patients with metastatic renal-cell carcinoma, Joaquim Bellmunt from University Hospital del Mar, Barcelona, Spain, and colleagues from the Spanish Oncology Genitourinary Group ( SOGUG ) did a phase 2 study involving 44 patients from eight centres across Spain; 40% received six cycles of treatment consisting of MTD Gemcitabine ( days 1 and 8) with metronomic capecitabine twice a day, and VEGFR and PDGFR inhibitor Sorafenib twice a day ( days 1-21 ), followed by Sorafenib monotherapy.

Findings showed that median PFS was 11.1 months, compared with previous results with Gemcitabine and Capecitabine of 5-8 months, and less than 7 months with Sorafenib alone. Additionally, a partial response was reported in 50% of patients, compared with 16% of patients in previous studies with Gemcitabine and Capecitabine, and less than 5% of patients with Sorafenib alone. Stable disease was achieved in 17 ( 42.5% ) patients.

All patients reported at least one adverse event during the study, with over half reporting a grade 3 event. However, these events were manageable in most patients, with fatigue and asthenia, hand-foot skin reactions, and neutropenia the only grade 3 adverse events reported in more than 10% of patients.

In conclusion, the combination of Sorafenib with MTD Gemcitabine and metronomic Capecitabine resulted in a clinical benefit rate of over 90%, with an acceptable level of toxicity.

Source: Lancet Oncology, 2010

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