Metastatic renal cell carcinoma: Should targeted therapy be continued after CR?
• FDA-approved targeted therapies include multi-targeted TKIs sunitinib, sorafenib, axitinib, and pazopanib; mTOR inhibitors temsirolimus and everolimus; and VEGF inhibitor bevacizumab in combination with interferon alfa.
• Arguments for continuing treatment include preventing disease recurrence due to residual cancer cells, possible rebound effect with fast regrowth and metastasis.
• Discontinuing therapy may lead to less toxicity (including fatigue, GI symptoms, skin toxicities, and hand-foot syndrome), reduced risk of developing resistant cancer cells, and an opportunity to maintain healthcare costs.
Renal cancer is expected to affect approximately 60,000 people in the United States each year. It accounts for up to three percent of all adult cancers and is the seventh most common cancer in men and eighth most common cancer in woman. Renal cell carcinoma (RCC) comprises nearly 90% of these cases and has an overall 5-year survival rate of 70%. In patients with Stage IV metastatic disease (mRCC), 5-year survival rates are lowest at only about 20%. A growing need for improved management of this disease has led to the investigation of different treatment strategies utilizing systemic targeted therapies.1
According to a recently published population-based analysis using Surveillance, Epidemiology and End Results (SEER), the incidence of renal cancer has more than doubled from 1976 to 2006. Moreover, the rate of increase has been various among different age groups, genders, and ethnic backgrounds. The increase in annual incidence rates was highest among young patients (20 to 39 years of age) and rose from 4.5% to 5.2%, while patients 79 years of age and older experienced decreased incidence rates from 6.7% to 0.8%. The proportion of patients getting diagnosed at 65 years of age or younger has decreased by nearly 10% from 1991 to 2006. This is believed to be the result of early detection with cross-sectional imaging and earlier exposure to environmental risk factors such as obesity, unhealthy diet, and hypertension. The incidence rates in female patients, as well as nonwhite patients also increased. The implications of these findings suggest that there is an immediate and growing need for the development of targeted therapies and treatment regimens that can prolong life while minimizing toxicity.2
Currently, RCC patients with localized disease (Stage I through III) are primarily treated with surgical resection, partial nephrectomy, or radical nephrectomy. No systemic therapies have been shown to reduce the risk of recurrence, and the benefit of adjuvant therapy has not been established. For patients with Stage IV mRCC, primary treatment consists of cytoreductive nephrectomy, and possible surgical resection of local and distant metastases followed by systemic therapy. The NCCN (National Comprehensive Cancer Network®) Kidney Cancer Panel recommends cytokine therapy with IL-2 as first line treatment, however long-lasting complete response or partial remissions have only been observed in a small subset of patients. The use of IL-2 is associated with significant toxicities such as, capillary-leak syndrome and serious infection, and is limited to patients with good performance status and few medical co-morbidities.1,3
The advent of targeted therapies in the last decade has led to improved management of renal cancer and is now considered the mainstay of therapy for mRCC. FDA-approved targeted therapies include multi-targeted TKIs (tyrosine kinase inhibitors) sunitinib, sorafenib, axitinib, and pazopanib; mTOR (mammalian target of rapamycin kinase) inhibitors temsirolimus and everolimus; and VEGF (vascular endothelial growth factor) inhibitor bevacizumab in combination with interferon alfa. These agents work by targeting different signaling pathways that are affected in cancer patients. Objective responses, mostly partial responses, have been reported in 8% to 39% of patients treated with targeted therapies and overall survival of more than 2 years with sunitinib and VEGF-targeted therapy has been observed.4,5
The question remains as to whether or not these targeted therapies should be continued as maintenance therapy in patients who achieve a response. While prolonged therapy with TKIs leading to response has been demonstrated, there are significant concerns as to the safety and efficacy of using this approach. Arguments for continuing treatment include preventing disease recurrence due to residual cancer cells, possible rebound effect with fast regrowth and metastasis. However, discontinuing therapy may lead to less toxicity (including fatigue, GI symptoms, skin toxicities, and hand-foot syndrome), reduced risk of developing resistant cancer cells, and an opportunity to maintain healthcare costs.4
Two recently published studies have demonstrated that stopping therapy after patients achieve a complete response may in fact be beneficial. 4,5 A retrospective analysis conducted by Albiges and colleagues examined the characteristics of patients with mRCC who achieved a complete response (CR) while treated with a TKI. The authors also investigated the effect of discontinuing targeted therapy on overall patient outcome. This analysis included 64 patients who experienced CR during treatment with either sunitinib (n=59) or sorafenib (n=5). Out of 36 patients who achieved CR with TKI treatment alone, 28 patients discontinued treatment, and 17 of the 28 patients (61%) remained in CR after a median follow-up of 255 days. Out of 28 patients treated with TKI in addition to either surgery or radiation, 25 patients discontinued treatment and 12 of the 25 patients (48%) remained in CR with a median follow-up of 322 days. Furthermore, patients who relapsed after TKI discontinuation remained sensitive to targeted therapy when rechallenged with systemic targeted therapy. Out of 24 patients who relapsed after discontinuation, 11 patients received further treatment with the same TKI and 4 patients were treated with a different targeted therapy (3 with a TKI and 1 with bevacizumab). Of these, 11 patients achieved partial response (PR) (n=8) or stable disease (SD0 (n=3). Predictive factors to help guide which patients are better candidates for stopping or continuing therapy were not identified. 4
According to another recent report published by Sadeghi and colleagues, cessation of VEGF-targeted therapy in a select subset of patients with mRCC achieving stable disease or better was also found to be a feasible option. In this retrospective analysis, patients with mRCC received VEGF-targeted therapy of either sunitinib (55%), bevacizumab (23%), or sorafenib (18%). After a median duration of therapy of 14.6 months, 6 patients had achieved CR, 29 achieved PR, and 5 achieved SD. Patients (n=40) were then followed for a median of 29.7 months to determine clinical outcome after discontinuation of therapy. At the time of data cutoff, 15 patients (37%) had continued observation without therapy or disease progression for a median of 8.9 months. The overall progression-free survival (PFS) was 13.5 months for all patients included in the study. Independent predictors of prolonged PFS were found to be more favorable Heng risk group (HR, 2.24; 95%CI, 1.05-4.80; P=0.04) and achievement of CR prior to discontinuation of therapy (HR, 0.19; 95% CI, 0.42-0.84; P=0.03). 5
Complete responses in mRCC patients are rare yet have been observed in some patients treated with targeted agents. The debate continues as to whether or not these patients should continue therapy or discontinue treatment once a response has been achieved. The reduction in treatment-related toxicity coupled with reduced risk of resistance makes the case for stopping therapy once a response has been achieved. It has also been suggested that administering therapy intermittently (periodic breaks in treatment) may be beneficial in minimizing the overall risk-benefit ratio associated with targeted therapies. While patients with a more favorable risk profile and those who have achieved prior CR have been identified as candidates for this approach, predictive factors of response in the broader mRCC patient population have yet to be defined. Prospective studies are needed to determine optimal approaches for managing mRCC patients who respond to treatment.4,5
1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Kidney Cancer (V.1.2012). www.nccn.org. Accessed January 30, 2012.
2. Nepple KG, Yang L, Grubb RL, et al. Population based analysis of the increasing incidence of kidney cancer in the United States: evaluation of age specific trends from 1975 to 2006. J Urol. 2012;187(1):32-38.
3. Proleukin® [package insert]. San Diego, CA: Prometheus Laboratories Inc.; 2011.
4. Albiges L, Oudard S, Negrier S, et al. Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. [published online ahead of print January 9, 2012]. J Clin Oncol. doi:10.1200/JCO.2011.37.2516.
5. Sadeghi S, Albiges L, Wood LS, et al. Cessation of vascular endothelial growth factor-targeted therapy in patients with metastatic renal cell carcinoma: feasibility and clinical outcome. [published online ahead of print December 2, 2011]. Cancer. doi:10.1002/cncr.26666.