ORLANDO—New targeted therapies for locally advanced and metastatic renal cell carcinoma (RCC) have ushered in a new era in systemic therapy, according to Christopher Wood, MD, Professor of Urology at the University of Texas M.D. Anderson Cancer Center in Houston.

These therapies have resulted in unprecedented tumor response rates, resulting in dramatic improvements in progression-free and overall survival. However, the most appropriate integration of surgery with systemic targeted therapy remains to be defined, Dr. Wood told attendees at the 2011 Genitourinary Cancers Symposium.

Some clinicians and researchers question the need for surgical therapy in light of the impressive responses seen with agents such as sunitinib and sorafenib, Dr. Wood said. The lack of reliable or complete responses, however, and the inevitable development of therapeutic resistance, suggest that surgery will remain an important part of the treatment paradigm for locally advanced and metastatic RCC, he said.

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“I don’t see systemic therapy replacing surgery because there are no [durable] complete responses associated with systemic therapy,” Dr. Wood told Renal & Urology News. “Patients respond or have stable disease for a period of time but ultimately progress.”

The concept of neoadjuvant or pre-surgical therapy is now being applied in the setting of locally advanced and metastatic disease, he noted. The goal is to downstage or downsize the primary tumor and thus decrease surgical morbidity through the use of nephron-sparing procedures.

“There are numerous anecdotes in the literature about tumors having these dramatic downstagings as a consequence of targeted therapy, but in fact if you look at the data the vast majority of patients either have no response or may progress on therapy,” Dr. Wood said.

Ongoing clinical trials are examining the role of tyrosine kinase inhibition with either sunitinib or sorafenib as an adjuvant strategy as well as its proper “integration with surgery” in the setting of metastatic disease. A clinical trial with pazopanib started accruing patients within just the past six months. Early reports indicate that toxicity from all of these agents may be a significant problem in ensuring compliance with therapy, he said.  

Dr. Wood and his colleagues retrospectively examined primary tumor response to neoadjuvant or pre-surgical therapy in a cohort of more than 160 patients. Dramatic changes in the primary tumor “were the exception rather than the rule,” he said. The primary tumor showed little response in most patients. Some patients had impressive tumor regression as a consequence of therapy, but there were a significant number of patients who had dramatic progression of their tumor while on therapy.

Michael Atkins, MD, Professor of Medicine at Harvard Medical School and head of the Kidney Cancer Program at the Dana-Farber Cancer Center in Boston, agrees with Dr. Wood, noting that clinical trials are required to determine the optimal role of surgery in the management of patients with metastatic RCC.

“With advanced disease, it is conceivable that if you had agents that could be as effective at the primary sites as well as the secondary sites, then you may not need surgery,” Dr. Atkins said. “There are clinical trials that are going to address these questions but they will take five years or longer and so it is uncertain how to proceed.”