Evolving Neoadjuvant and Adjuvant Therapeutic Approaches in RCC

Ariela Katz
Published: Friday, Jun 16, 2017
David M. Nanus, MD

David M. Nanus, MD

Surgical resection, including cytoreductive nephrectomy, remains the standard of care for most patients with renal cell carcinoma (RCC). However, many patients will have a recurrence, and could benefit from additional therapy. Much research has been conducted to define the role of neoadjuvant and adjuvant therapies for patients with RCC, but the standard of care has not changed significantly in the past several years.

Role of Neoadjuvant Therapy

“The [benefit] of giving therapy, like a TKI for instance, would be to start systemic therapy right away, have the tumor shrink, so the nephrectomy will be easier,” said David M. Nanus, MD, during a presentation at the New York GU™: 10th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies that Physicians’ Education Resource® (PER®) hosted March 18 in New York City.

Nanus said that rapid initiation of systemic therapy prior to surgery could also decrease cancer-related mortality, and could eliminate these risks in patients who would not benefit from a nephrectomy. “The contrast to that is that it may add to the morbidity or mortality of surgery if you give the drug; there may be wound-healing issues, and you may ‘decondition’ the patient and [then] they can’t get systemic therapy. And it hasn’t been proven that it improves survival, so why should we do it,” commented Nanus, a Mark W. Pasmantier Professor of Hematology and Oncology in Medicine, Weill Cornell Medicine.

Previously there were several prospective clinical trials in the neoadjuvant setting prior to cytoreductive nephrectomy (Table 1), but such investigations have become less frequent due to the recent push for developing immunotherapies. One such study Nanus mentioned was a phase II study of pazopanib (Votrient) in patients with localized RCC to optimize preservation of the renal parenchyma.1 Of the 13 patients originally unable to undergo a partial nephrectomy, 6 underwent surgery. Significant decrease in the size of the tumors occured in the patients. “Keeping a patient from going on dialysis by shrinking the tumor preoperatively should be done,” Nanus commented.

Table 1.Selected Prospective Neoadjuvant Trials in RCC

 


In another phase II study assessing the safety and efficacy of pazopanib therapy prior to a planned nephrectomy in patients with metastatic clear cell RCC (ccRCC), investigators discovered that a nephrectomy could be performed safely after upfront treatment with pazopanib and was associated with good outcomes in patients with intermediate-risk disease.2 A significant size reduction in the primary tumor was observed, with a median reduction of 14.4% (range, 1.4%-21.1%).

“However, when you look at progression-free survival, in this study it was about 7 months, so it’s not very clear that giving preoperative [pazopanib]in the metastatic setting made a big difference,” Nanus said. “I think giving cytoreductive neoadjuvant therapy should be restricted to select patients.”

Role of Adjuvant Therapy

“There was no prospective randomized trial in the cytokine era that clearly demonstrated a benefit with adjuvant therapy,” Nanus said. “But obviously, there’s still a need for adjuvant therapy studies.” Nanus further explained that patients tend to relapse at high rates, with a tendency toward mortality for those who progress to metastatic disease. Patients in these populations could benefit from an adjuvant treatment if one were proven effective (Table 2), but investigations into adjuvant treatments have had several trials leading to negative results.

Table 2.Selected Phase III Clinical Trials for Agents in the Adjuvant Setting for RCC

 


In the PROTECT trial, Motzer et al reported at the 2017 ASCO Annual Meeting that adjuvant pazopanib administered following resection for locally advanced RCC did not significantly improve disease-free survival (DFS) compared with placebo, the primary endpoint.3 Pazopanib was administered at 800 mg when the phase III trial was launched in 2010, but the dosage was dropped to 600 mg because of a high treatment discontinuation rate due to adverse events (AEs).


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