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Sunitinib Improves Overall Survival in Patients with Renal Cancer
Abstract & commentary
By William B. Ershler, MD
Synopsis: In a population-based retrospective review of first-line treatment of metastatic renal cell carcinoma, sunitinib was shown to double overall survival when compared to interferon alpha. The unique circumstances allowing the connection of tumor registry data with chemotherapy treatment and outcomes allowed a clear (albeit retrospective) demonstration that improvements in progression-free survival observed in clinical trials are likely to be reflected in improved overall survival as well.
Source: Heng DYC, et al. A population-based study evaluating the impact of sunitinib on overall survival in the treatment of patients with metastatic renal cell cancer. Cancer. 2009;115: 776-783.
For patients with metastatic renal cell carcinoma (mRCC), standard chemotherapy has proven ineffective, and immunotherapeutic approaches, such as interferon alpha or interleukin-2, offered only modest benefit in terms of progression-free and overall survival.1-3 However, in recent years, anti-angiogenic agents such as sunitinib, sorafenib, and bevacizumab have demonstrably improved the outlook for RCC patients.4-6
In the pivotal, randomized, phase 3 trial, sunitinib treatment resulted in progression-free survival (PFS) of 11 months, comparing favorably to five months associated with interferon alpha treatment (p < .001).6 Overall survival (OS) for that trial was also better for the sunitinib-treated patients (26.4 vs 21.8 months) (p = .051). The less striking difference in OS compared with PFS was considered possibly related to the crossover of many of the patients initially randomized to IFN to sunitinib upon recognition of progressive disease.
The current research aimed to compare overall survival in a population-based analysis comparing two cohorts of mRCC patients, those treated with IFN and those treated with sunitinib.
For this, the British Columbia Cancer Registry was cross-referenced with the Provincial Pharmacy Database to identify all patients with mRCC who were treated with IFN and/or sunitinib in the province of British Columbia between January 2000 and September 2007. The IFN group consisted of all patients who received IFN alone between January 2000 and October 2005. The sunitinib group included all patients treated with first-line sunitinib from October 2005 to September 2007, when sunitinib became available as standard therapy. Patients who received first-line IFN followed by second-line sunitinib were excluded.
Before October 2005, patients with mRCC were treated with IFN9x106 international units (IU) three times per week on nonconsecutive days. After October 2005, patients were treated with sunitinib at a starting dose of 50 mg daily for four weeks, followed by a two-week break each cycle. There were 131 and 69 patients in the IFN and sunitinib groups, respectively. The median follow-up of those still alive was 12.6 months. Despite the different years of treatment, the groups were comparable with regard to age (mean 62 vs 63 years), Memorial Sloan Kettering Cancer Center (MSKCC) prognostic criteria (poor in 19% vs 30%), and proportion with > 1 metastasis (53% vs 62) between the IFN and sunitinib groups, respectively.
The median survival of the IFN and sunitinib groups was 8.7 and 17.3 months, respectively (log-rank p = .004). The median survival of patients with favorable, intermediate, and poor MSKCC prognostic profiles in the IFN group was 22.9, 8.7, and 4.1 months, respectively (p < .001), whereas, in the sunitinib group, median survival was not reached, or reached in 16.8, or 10.7 months, respectively (p = .006). The hazard ratio of death after adjusting for MSKCC criteria was 0.49 (95% confidence interval, 0.31-0.76; p = .001).
Sunitinib is an oral tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) receptor types 1, 2, 3, platelet-derived growth factor receptors alpha and beta, c-kit, and FLT-3.7 With impressive findings from the aforementioned phase 3 studies, sunitinib has become the standard first-line treatment for patients with mRCC. We learn from the current report that such has been associated with a doubling of overall survival compared with patients treated with IFN alone. The strength of this observation is based upon the well-constructed tumor registry in British Columbia and a health care system that standardizes treatment protocols (albeit for reimbursement purposes). Thus, it is likely that all, or nearly all, mRCC patients in this province who received treatment were included in this analysis. This includes older and frailer patients who might not have been candidates for a phase 3 trial, but received the treatment nonetheless. Indeed, the benefits from sunitinib were shown to extend to patients with poor MSKCC prognostic profiles; a group that has been underrepresented on clinical research protocols in general.
Furthermore, although the phase 3 clinical trial demonstrated impressive improvements in PFS, the improvement in OS was modest and not quite statistically significant. Other phase 3 trials with similar anti-VEGF agents have resulted in similar findings (impressive improvement in PFS, lesser effect on OS).4,5 The unique circumstances provided by the British Columbia health care system and the fairly abrupt change in "standard" therapy has allowed for a real-world analysis of the effects of the two different treatments, albeit at the risk of studying two cohorts separated by time. Even so, the findings are quite clear: first-line mRCC treatment with sunitinib, compared with INF, enhanced OS by a factor of two.
Nonetheless, despite this impressive move in the right direction, one cannot lose sight that we are talking about differences in months, not years. Anti-VEGF targeted treatments represent the beginning, not the end of the quest to control this difficult disease.
1. McDermott DF, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23: 133-141.
2. Negrier S, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. N Engl J Med. 1998;338: 1272-1278.
3. Negrier S, et al. Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: results of a randomized controlled trial. Cancer. 2007;110: 2468-2477.
4. Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356: 125-134.
5. Escudier B, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370: 2103-2111.
6. Motzer RJ, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007; 356: 115-124.
7. Hutson TE, Figlin RA. Evolving role of novel targeted agents in renal cell carcinoma. Oncology (Williston Park). 2007;21: 1175-80.