Neoadjuvant VEGF-Targeted Therapy in Renal Cell Carcinoma

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Recent therapeutic advances in metastatic renal cell carcinoma (RCC) have included agents targeted against vascular endothelial growth factor (VEGF).

The agents, which target circulating VEGF ligand (e.g., bevacizumab) or the tyrosine kinase portion of the VEGF receptor (e.g., sunitinib, sorafenib), have dramatically altered the therapeutic landscape of this disease. Initially tested in patients with distant metastatic disease, most of whom had undergone primary tumor resection, the agents have become standards of care.

One remarkable feature of all these agents is a high objective response rate of 10%-40%; approximately 70% of patients experience some degree of tumor burden reduction. Further, some reduction of primary tumor size has been observed in patients with primary tumor in place, an unusual occurrence in the cytokine era. Consequently, a natural extension of the use of these agents is to downstage the primary tumor in locally advanced disease prior to nephrectomy.

Locally advanced RCC presents challenges to both the urologist and medical oncologist. Local disease is often surgically difficult to resect entirely because of invasion of local organs, tumor size, bulky lymphadenopathy, or involvement of such critical structures as mesenteric blood vessels.

Further, without proven effective adjuvant therapy, these patients are at very high risk for recurrence. A recently published Cleveland Clinic experience administered sunitinib 50 mg alternating 4 weeks on with 2 weeks off to 12 patients. The tumors of these patients were deemed unresectable because of invasion into adjacent organs, proximity to vital structures, bulky regional lymph nodes, or vascular invasion, with many patients possessing multiple such adverse features.

Partial responses of the primary tumor were noted in three patients (25%). Primary tumor shrinkage was observed in eight patients (67%), with an average decrease in primary tumor size of 24% (range 2%-46%). Three patients demonstrated sufficient tumor size reduction to facilitate resection, with mean primary tumor shrinkage of 16% (range 11%-24%). Viable tumor was present in all pathologic specimens after nephrectomy. No issues with wound healing, bleeding, or thromboembolic events were encountered.

A prospective trial of sunitinib in RCC patients with unresectable primary tumors (with or without distant metastases) is currently ongoing at Cleveland Clinic. Patients who have histologically confirmed RCC with an unresectable primary tumor (with or without distant metastases) and no prior treatment are being enrolled in this single-arm phase 2 trial.

Primary tumors are deemed unresectable by the surgeon based on various combinations of the following: large tumor size, bulky lymphadenopathy, proximity to vital structures, or high-level venous thrombosis. Patients receive 50 mg sunitinib continuous dosing in repeated six-week cycles. Preliminary results in 18 patients treated to date have shown a reduction in some primary tumors substantial enough to permit subsequent surgical resection.

A total of 71% of patients had a reduction in the primary RCC tumor, permitting resection in three patients whose tumors had previously been considered unresectable. The median primary tumor shrinkage is 15.0% (range 2.0%-58.5%). C

ontinued investigation is needed to identify the optimal neoadjuvant setting and approach, determine the timing of surgical intervention, and further define safety considerations, such as time needed off the drug before and after surgery.

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