An article published Online First in The Lancet Oncology reports that 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). This is a disease with few treatment options. The treatment combines a maximum tolerated dose (MTD) chemotherapy (gemcitabine) with metronomic chemotherapy (frequent low-dose chemotherapy with capecitabine) plus sorafenib (a targeted drug). It results in greater progression-free survival (PFS). The tumour response is better than previously reported with sorafenib alone or with chemotherapy. These findings might provide a new first-line treatment option for patients with advanced kidney cancer.
Causing over 102,000 deaths worldwide each year, RCC is the most common form of kidney cancer. However, treatment options are limited and survival is poor. The responses to chemotherapy, hormonal and biological therapy, and standard treatment with targeted drugs remain modest.
But, the latest preclinical studies have indicated that response to treatment and survival could improve by combining treatment options. This therapy entails initial treatment at the MTD of one chemotherapy drug in order to kill all rapidly growing cells. It is then followed by maintenance with a metronomic dose of a second chemotherapy drug. Giving patients lower doses more frequently prevents the cancer from growing by inhibiting the development of new blood vessels. It includes also a targeted inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGFR) to increase anti-tumour activity.
Researchers investigated whether this multi-targeted “chemo-switch” strategy might improve outcomes in patients with metastatic RCC. Joaquim Bellmunt from University Hospital del Mar, Barcelona, Spain, and colleagues from the Spanish Oncology Genitourinary Group (SOGUG) carried out a phase 2 study. It involved 44 patients from eight centres across Spain. A total of 40 patients 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 to 21), followed by sorafenib monotherapy.
Results indicated that median PFS was 11.1 months, compared with previous results with gemcitabine and capecitabine of 5 to 8 months, and less than 7 months with sorafenib alone. In addition, a partial response was reported in 50 percent of patients. This compared with 16 percent of patients in earlier studies with gemcitabine and capecitabine, and less than 5 percent of patients with sorafenib alone. Stable disease was achieved in 17 (42.5 percent) patients.
During the study, all patients reported at least one adverse event. Over half reported a grade 3 event. However, these events were manageable in most patients. Fatigue and asthenia, hand-foot skin reactions, and neutropenia were the only grade 3 adverse events reported in more than 10 percent of patients.
The authors explain: “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.”
They comment: “Further studies are therefore needed to confirm the effect on a broader patient population, to clearly identify the optimal balance between clinically meaningful efficacy and manageable toxicity, and to attempt to define prognostic factors for identifying those patients in whom the treatment is most likely to be effective and least likely to be toxic.”
“Activity of a multitargeted chemo-switch regimen (sorafenib,gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02-06)”
Joaquim Bellmunt, José Manuel Trigo, Emiliano Calvo, Joan Carles, José L Pérez-Gracia, Jordi Rubió, Juan Antonio Virizuela, Rafael López, Martín Lázaro, Joan Albanell
DOI: 10.1016/S1470-2045(09)70383-3
Written by Stephanie Brunner (B.A.)