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Drug Tolerability in the Choice of Second-Line Therapy for Metastatic Renal Cell Carcinoma
Sequential treatment with targeted therapies is the current standard of care for patients with metastatic renal cell carcinoma (mRCC).[1, 2, 3, 4] Targeted therapies approved for use in patients with mRCC include the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, the VEGF receptor-tyrosine kinase inhibitors (VEGFr-TKIs) sorafenib, sunitinib, pazopanib, and axitinib, and the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus. VEGF-targeted agents form the first-line standard of care in patients of good or intermediate risk according to the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model. The mTOR inhibitor temsirolimus is recommended in MSKCC poor-risk patients. Systemic treatment options for second-line therapy of VEGFr-TKI-refractory patients include everolimus and axitinib.
Drug tolerability and quality-of-life (QOL) issues are experienced by all patients receiving systemic therapy for mRCC. Adverse event (AE) profiles differ from one targeted agent to another. Hypertension and hand-foot syndrome are more frequently observed in patients receiving VEGFr-TKIs, while pneumonitis and dyslipidemia are more frequently observed in patients receiving mTOR inhibitors. In general, drug-related AEs can be managed throughout therapy, but in some patients, they can lead to drug interruptions or discontinuation, which in some cases translate into reduced efficacy. In a recent meta-analysis of patients treated with sunitinib, those with the highest exposure to drug displayed longer time-to-progression, longer overall survival, a higher probability of response to treatment, and greater reductions in tumor size; this highlights the importance of maintaining patients on recommended dosing and, if possible, avoiding unscheduled dose reductions or interruptions during treatment.
In patients receiving either axitinib or sorafenib following first-line sunitinib in the pivotal AXIS trial supporting the recent approval of axitinib, one or more dose reductions or drug interruptions were reported in 31% and 77% of patients, respectively, in the axitinib arm and 52% and 80% of patients, respectively, in the sorafenib arm. In the pivotal RECORD-1 trial supporting the approval of everolimus, one or more dose reductions or drug interruptions were reported in only 7% and 38%, respectively, of patients receiving everolimus following first-line sunitinib, sorafenib, or both agents.[9,10] Patients receiving either axitinib or sorafenib following first-line sunitinib in the AXIS trial reported higher incidences of AEs than those receiving axitinib or sorafenib after first-line cytokine therapy (Figures 1 and 2). These data suggest a possible higher propensity for class-effect toxicity with sequential administration of VEGF-targeted agents. Class-effect AEs reported in the axitinib and sorafenib arms included diarrhea, hypertension, fatigue, palmar-plantar erythrodysesthesia, rash, and alopecia.
Drug tolerability and patient QOL need to be considered carefully by physicians when choosing a second-line agent, especially when a patient has discontinued life-sparing therapy because of unacceptable toxicity. Patients who experience intolerance to VEGFr-TKI therapy may benefit from switching to an mTOR inhibitor because the AE profile of mTOR inhibitors generally does not overlap with that of VEGFr-TKIs.[10,11,12] In the subgroup analysis of patients in the RECORD-1 trial who were intolerant to a first-line VEGFr-TKI (sunitinib, sorafenib, or both agents), the majority (86.7%) of patients not only tolerated but also benefited from treatment with everolimus. The median progression-free survival (PFS) observed in everolimus-treated patients who were intolerant to previous VEGFr-TKI therapy (5.4 months) was similar to the median PFS of all everolimus-treated patients in RECORD-1 (4.9 months).[10,13] These results provide further evidence that everolimus should be the preferred choice for second-line therapy in mRCC patients intolerant to VEGFr-TKIs.
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- Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.
- Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134.
- Bracarda S, Hutson TE, Porta C, et al. Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis. Br J Cancer. 2012;106:1475-1480. http://dx.doi.org/10.1038/bjc.2012.89.
Sergio Bracarda, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Specialist in Oncology & Urology
Head, UOC of Medical Oncology
Department of Oncology, USL-8
Istituto Toscano Tumori (ITT)
Ospedale San Donato
Via Pietro Nenni, 20
52100 Arezzo, Italy