Reduced CNS Metastases in TKI-Treated Renal Cell Carcinoma: Data from a Retrospective Analysis
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In an analysis of outcomes for patients treated at M.D. Anderson for metastatic renal cell carcinoma before and since the advent of treatment with tyrosine kinase inhibitors (TKI), the development of brain metastases was shown to be significantly reduced. The authors speculate that TKI treatment is altering the natural history of renal carcinoma.
Source: Verma J, et al. Impact of tyrosine kinase inhibitors on the incidence of brain metastasis in metastatic renal cell carcinoma. Cancer 2011;117:4958-4965.
Prior to the introduction of tyrosine kinase inhibitors (TKI), there were few treatment options for patients with metastatic renal cell carcinoma (mRCC), and progression-free and overall survival were limited. Over the last decade, three TKIs have been approved for treatment and the outlook for patients with mRCC has improved substantially. The approval of sunitinib (2006) came after demonstration of superiority in terms of progression-free survival (PFS) to the previously established standard interferon when used as first-line treatment for patients with RCC.1 Sorafenib (approved in 2005) was shown to improve PFS when compared to placebo for patients with recurrent or refractory disease,2 and pazopanib (2009) for demonstration of superiority (compared with placebo) for both previously untreated and cytokine-refractory disease.3
Approximately 30% of RCC patients present with metastatic disease, most commonly to lung, bone, and lymph nodes, and a substantial portion of these ultimately will develop CNS metastases. There was a clue derived from the TARGET (Treatment Approaches in Renal Cancer Global Evaluation)trial that the incidence or rate of development of brain metastasis was reduced with sorafenib treatment.4 Inasmuch as the development of brain involvement has catastrophic consequences, this observation led to an expanded effort to determine if TKI treatment influences the incidence or duration to appearance of CNS metastases.
This current retrospective analysis from a single institution (University of Texas M.D. Anderson Cancer Center) was designed to evaluate the impact of TKIs on incidence of brain metastasis and overall survival (OS) in patients with mRCC. For this, all patients who presented with mRCC but no brain metastasis in the intervals 2002-2003 and 2006-2007 were identified using the institutional tumor registry. The following data were collected: age, sex, Fuhrman grade, disease sites, nephrectomy, systemic therapy including TKIs (sorafenib or sunitinib), Memorial Sloan-Kettering Cancer Center risk category, brain metastasis treatment, and vital status. Statistical analysis was performed using the Cox proportional hazards model and the Kaplan-Meier method.
Of the 338 patients with mRCC, 154 (46%) were treated with a TKI and 184 (54%) were not. There were no significant differences with regard to age, histology, prior nephrectomy, involved sites of disease other than lung, or Memorial Sloan-Kettering Cancer Center risk category between the groups. The latter is a risk stratification system calculated using serum LDH, hemoglobin, corrected serum calcium, performance status, and time from diagnosis to treatment, treatment with TKI or other systemic agent, and occurrence of CNS involvement (described in reference 5).
Median OS was longer in the TKI-treated group (25 months vs 12.1 months, P < 0.0001). In multivariate analysis, TKI treatment (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.38-0.74; P < 0.001) was associated with improved OS. Of the total analysis cohort, 44 (13%) developed a brain metastasis, including 29 (15.8%) of the non-TKI group and 15 (9.7%) of the TKI group. The 5-year actuarial rate of brain metastasis was 40% vs 17%, respectively (P < 0.001). TKI treatment was associated with lower incidence of brain metastasis in Cox multivariate analysis (HR, 0.39; 95% CI, 0.21-0.73; P = 0.003).
When stratified by the Memorial Sloan-Kettering Cancer Center score, patients with low risk (score of 0) had a median survival of 79.6 months, those with intermediate risk (score 1-2) 23.5 months, and those with high-risk (score 3-5) 11.6 months. For the most part, when this score as well as a number of other clinical variables were included in multivariate analysis, receipt of TKIs remained an independent predictor of better survival. Of particular note, the presence of lung metastasis increased the risk of brain metastasis (HR, 9.61; 95% CI, 2.97-31.1; P < 0.001).
This report provides additional impetus for the use of TKI as initial treatment for patients with metastatic RCC, as it appears such treatment reduces the incidence of brain metastases. Of course, clinicians already are aware of the value of these drugs for mRCC, as outcomes such as progression-free and overall survival far exceed those resulting from prior therapies.
The study needs to considered with the same reservations we hold for single institutional retrospective analyses, particularly when the study cohorts came from two distinct time periods. Nonetheless, the findings are consistent with expectations and the conclusions are clearly not overstated. Furthermore, it is unlikely we will see another randomized prospective study in the near future that will address this as drugs in this class have moved quickly to the front line. Perhaps, TKI administered in the adjuvant setting will be the next frontier for early management of RCC.
A clinically useful observation demonstrated high risk for the development of brain metastases among RCC patients with lung involvement (HR > 9 in both univariate and multivariate analysis). Of the 44 patients who developed brain metastasis, 90% had previously recognized lung metastases, whereas only 2.5% of patients without lung metastases ultimately developed brain metastases. Thus, for patients with lung metastases at the time of presentation, the data would support close surveillance for early recognition and treatment of CNS disease. This is particularly relevant, in light of the observation that brain metastases were asymptomatic in 50% of the cases.
1. Motzer RJ, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-124.
2. Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-134.
3. Sternberg CN, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol 2010;28:1061-1068.
4. Massard C, et al. Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol 2010;21:1027-1031.
5. Motzer RJ, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289-296.