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) with metronomic chemotherapy (frequent low-dose chemotherapy with capecitabine) plus sorafenib (a targeted drug), 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, concludes an article published in The Lancet Oncology.

RCC 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 (to kill all rapidly growing cells), 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 RCC, 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 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 1–21), 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.

The authors say: “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 go on: “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.”




Source: The Lancet Oncology