Sunitinib in Older Renal Cell Carcinoma Patients

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a six-site Italian retrospective analysis, treatment of elderly patients with metastatic renal cell carcinoma with sunitinib was shown to be effective but associated with significant toxicity. Although only applied to a subset, pretreatment comprehensive geriatric assessment did not offer predictive value with regard to severe toxicity or efficacy.

Source: Brunello A, et al. Safety and activity of sunitinib in elderly patients (≥ 70 years) with metastatic renal cell carcinoma: A multicenter study. Ann Oncol 2013;24:329-336.

Sunitinib is a tyrosine-kinase inhibitor (TKI) active at vascular endothelial and platelet-derived growth factor receptors.1 Its use has been shown to significantly prolong progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC).2 The drug, however, is not without side effects including hypertension, fatigue, diarrhea, hypothyroidism, and hand foot syndrome,3 and its safety and efficacy in elderly patients has yet to be established. This is not merely an academic question as the median age at diagnosis is approximately 65 years,4 and an increasing percentage of patients present with comorbidities and/or functional impairments that may well lead to a higher risk of intolerance to treatment.

To address this, Brunello and colleagues examined medical records of elderly mRCC patients treated with sunitinib at six Italian centers. Their goal was to assess safety (primary objective), efficacy, and the correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives).

Their analysis included 68 elderly treated patients (median age of 74 years). CGA had been carried out in 34 patients prior to treatment (41% fit, 41% vulnerable, and 18.5% frail). A dose reduction from 60 mg to 37.5 mg was made up front or soon after the first cycle in 69.1%. More frequent toxic effects were fatigue (80.9%), mucositis (61.8%), and hypertension (58.8%). Cardiac events occurred in nine patients. In 10 patients, therapy was interrupted early due to rapidly progressive disease (10.3%) or severe toxicity (4.4%; 1 cardiac failure, 1 fatigue, 1 febrile neutropenia). At a median follow-up of 27.1 months, the median OS was 18.3 months and the median PFS was 13.6 months. Correlation was not found between frailty at CGA with severe toxicity nor with response.

Commentary

The introduction of targeted therapies has dramatically changed the treatment approach for metastatic renal cell carcinoma (mRCC). However, as is often the case, there remain few data to balance efficacy vs toxicity when prescribing for older patients, particularly for those who are frail. This is primarily because pivotal clinical trials in drug development typically enroll younger patients with less comorbidity and functional impairment. Yet a subset analysis of older patients enrolled on pivotal trials of selected targeted therapies for mRCC suggest similar rates of favorable response.5 This, of course, is also subject to bias because elderly patients enrolled on trial may not represent the typical frail patient with comorbidities.

The current report is important, for it details the age-related toxicity profile for one such targeted therapy (sunitinib). Although the numbers were small, pretreatment CGA was shown not to offer predictive value with regard to either toxicity or efficacy. This disappointing finding would suggest that much work needs to be done on refining the CGA. It is possible that an instrument proven useful for one set of circumstances (e.g., for predicting tolerability of chemotherapeutic approaches) might be different for another (e.g., tyrosine kinase inhibitors). It remains a major goal in geriatric oncology to develop a feasible assessment instrument on which appropriate treatments can be prescribed, enriching for those who are likely to respond and reducing toxicities for those who are not.

One may conclude from the current report that sunitinib is effective in at least some elderly mRCC patients, although early treatment interruptions and dose modifications were common. A prospective clinical trial in which treatment initiation at a reduced dose with escalation as tolerated might be a reasonable next step.

References

1. Chow LQ, Eckhardt SG. Sunitinib: From rational design to clinical efficacy. J Clin Oncol 2007;25:884-896.

2. Motzer RJ, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-3590.

3. Wood L. Sunitinib malate for the treatment of renal cell carcinoma. Expert Opin Pharmacother 2012;13:1323-1336.

4. SEER. Surveillance Epidemiology and End Results: Kidney and Renal Pelvis. 2011. Available at: http://seer.cancer.gov/csr/1975_2009_pops09/results_single/sect_01_table.11_2pgs.pdf. Accessed Feb. 19, 2013.

5. Pal SK, et al. Systemic therapies for metastatic renal cell carcinoma in older adults. Drugs Aging 2011;28:635-649.