Tumor flare of brain metastases upon dose interruption of sunitinib in a patient with metastatic renal cell carcinoma.

Brain metastases from renal cell carcinoma are associated with poor prognosis. Sunitinib is a multi-targeted tyrosine kinase inhibitor used for the treatment of metastatic renal cell carcinoma. It is taken orally on a traditional dosing schedule of 4-week on/2-week off cycles or an alternate dosing schedule of 2-week on/1-week off cycles. Although patients with brain metastases were excluded from the original phase 3 sunitinib registration trial, case reports and an expanded access trial suggest that sunitinib penetrates the blood brain barrier and has central nervous system (CNS) activity. We present a case report which illustrates an unusual presentation of symptomatic brain metastasis progression during the prescribed breaks in treatment during sunitinib monotherapy, and rapid clinical improvement upon resuming sunitinib during the cycle. Patients who develop increased symptoms during the "off treatment" period of sunitinib therapy may have new sites of metastasis. In such patients, appropriate imaging should be obtained to evaluate for disease progression and either a continuous sunitinib dosing schedule or an alternative therapy should be considered.

Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma.

Increases in the mean corpuscular volume (MCV) have been observed in patients with metastatic renal cell carcinoma (mRCC) on tyrosine kinase inhibitor (TKI) treatment; however, its association with progression-free-survival (PFS) is unknown. We aimed to characterize TKI-associated macrocytosis in mRCC and its relationship with PFS. Retrospective review of data on macrocytosis and thyroid dysfunction on mRCC patients treated with sunitinib and/or sorafenib. These results are evaluated in the context of our previous report on the association of hypothyroidism in this setting. We assessed PFS as clinically defined by the treating physician. Seventy-four patients, 29 of whom received both drugs, were included. A treatment period was defined as time from initiation to discontinuation of either sunitinib or sorafenib; 103 treatment periods [sorafenib (47), sunitinib (56)] were analyzed. Macrocytosis was found in 55 and 8% of sunitinib- and sorafenib-treated patients, respectively, P < 0.001. The median time to developing macrocytosis was 3 months (m, range 1-7). Median PFS in sunitinib-treated patients was 11 m (95% CI: 6-19). Median PFS was higher among those with macrocytosis compared to normocytosis (21 m [95% CI: 11-25] vs. 4 m [95% CI: 3-8] P = 0.0001). Macrocytosis and hypothyroidism were two significant predictors of PFS. The greatest difference in PFS among all patients was observed in patients with both macrocytosis and hypothyroidism (25 m), compared to the normocytic and euthyroid patients (5 m) (P < 0.0001). Sunitinib-related macrocytosis was associated with prolonged PFS, and concurrent development of hypothyroidism and macrocytosis further prolonged PFS. Increased MCV may have a role as a predictive biomarker for sunitinib. Prospective studies accounting for other known prognostic factors are needed to confirm this finding.

Skin cancer associated with the use of sorafenib and sunitinib for renal cell carcinoma.

BACKGROUND: Several case series have reported an association between sorafenib and the development of skin cancer, but they differ in the reported rapidity of skin cancer onset and the frequency of recurrence with ongoing multikinase inhibitor (MKI) treatment. OBJECTIVE: To compare the presentation and incidence of skin cancer in patients with renal cell carcinoma (RCC) treated with sorafenib and sunitinib. MATERIALS AND METHODS: This retrospective study reviewed the records of 69 patients with RCC treated with sorafenib or sunitinib at the University of Colorado Hospital between January 2005 and July 2009. RESULTS: Seven patients treated with MKI developed skin cancer (5 (13.5%) with sorafenib, 2 (6.3%) with sunitinib; 5 squamous cell carcinomas (SCC), 3 basal cell carcinomas (BCC)); all developed in sun-exposed areas during first-line MKI therapy. The median time from the start of MKI therapy until observation of a skin cancer lesion was 13.5 months. CONCLUSION: We observed more cases of skin cancer during sorafenib treatment than during sunitinib treatment for advanced RCC; median MKI treatment duration before the identification of skin cancer was longer than 1 year.

Thyroid dysfunction in patients treated with sunitinib or sorafenib.

INTRODUCTION: Sunitinib and sorafenib are tyrosine kinase inhibitors used in metastatic renal cell carcinoma and are known to cause hypothyroidism in a subset of patients. The goal of this study was to better characterize the development of hypothyroidism in patients and to examine its relationship to progression-free survival. PATIENTS AND METHODS: A retrospective chart review was performed on patients treated with sunitinib or sorafenib from January 1, 2005, to January 1, 2011. Data pertaining to the treatment course and development of hypothyroidism were extracted. Patients with hypothyroidism at the beginning of treatment were analyzed separately. RESULTS: A total of 73 treatment periods had sufficient data to analyze. Among patients with normal baseline thyroid function, 15 (44%) of 34 patients treated with sunitinib and 6 (27%) of 22 patients treated with sorafenib developed hypothyroidism. The hazard ratio for the development of hypothyroidism with sorafenib vs. sunitinib treatment was significant, at 0.38 (95% CI, 0.14-0.97). There was a statistically significant difference in the progression-free survival between patients who developed hypothyroidism while receiving treatment compared with those who did not, 18.2 vs. 10.1 months (P = .01). CONCLUSIONS: This study demonstrated a significant difference in the incidence of hypothyroidism during treatment with sunitinib and sorafenib, with a higher incidence of hypothyroidism in patients treated with sunitinib. The development of hypothyroidism was associated with a longer progression-free survival.