From Radical to Partial Nephrectomy in the Setting of Solitary Functioning Kidney: Neoadjuvant Treatment of Renal Cell Carcinoma

CASE REVIEW Corrected PDF From Radical to Partial Nephrectomy in the Setting of Solitary Functioning Kidney: Neoadjuvant Treatment of Renal Cell Carcinoma G. Farha, MS4,1 K James Kallail, PhD,2 Shaker Dakhil, MD,3 A. J. Farha, David D. Watson, MS4,1 Nicole M. MD4 1University of Kansas School of Medicine, Wichita, KS; 2Department of Research, University of Kansas School of Medicine, Wichita, KS; 3Cancer Center of Kansas, Wichita, KS; 4Wichita Urology Group, Wichita, KS Immunotherapy has revolutionized the treatment of metastatic renal cell carcinoma (RCC). This case evaluates the use of neoadjuvant immunotherapy for localized RCC in a patient with solitary functioning kidney. A retrospective chart review was conducted between September 2019 and January 2020 on a single patient. Before treatment, the tumor was 7 cm 3 8 cm 3 8.5 cm. The patient trialed nivolumab 1 ipilimumab then cabozantinib. The tumor shrunk to 6.3 cm 3 5.5 cm and was removed via partial nephrectomy. This case demonstrates the efficacy of immunotherapy in neoadjuvant treatment of RCC. Expansion of guidelines could allow for patients with RCC to undergo partial nephrectomy. [Rev Urol. 2020;22(3):126–129] © 2020 MedReviews®, LLC KEY WORDS Neoadjuvant immunotherapy • Immunotherapy • Renal cell carcinoma • Solitary kidney n recent years, the use of immunotherapy has revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Immunotherapy agents such as nivolumab (PD-1 inhibitor), ipilimumab (CTLA-4 inhibitor), and cabozantinib (tyrosine kinase inhibitor) have all been approved as first-line I 126 • Vol. 22 No. 3 • 2020 • Reviews in Urology therapy for mRCC.1 Although there are growing treatment options for mRCC and an ever-changing landscape of immunotherapy agents, there have been few changes in the management of localized renal cell carcinoma (RCC). The current gold standard of treatment is partial or radical nephrectomy, with Neoadjuvant Treatment of Renal Cell Carcinoma partial preferred when possible, as it preserves renal function.2,3 Unfortunately, patients with poor kidney function or a solitary kidney who are not candidates for partial nephrectomy may resort to radical nephrectomy, necessitating longterm and possibly lifelong dialysis. Although the safety profile of dialysis has improved considerably over the past two decades, there are still serious risks and high costs associated with prolonged dialysis treatment.4 Therefore, it is important to consider all treatment options, prioritizing kidney-sparing treatments, in populations with reduced kidney function. The immunotherapies included in the current treatment guidelines for mRCC could show benefit as neoadjuvant treatment of localized RCC, allowing for partial nephrectomies in patient populations that were previously not candidates due to tumor size or location. Here, we describe the use of neoadjuvant immunotherapy for localized RCC in a patient with a solitary functioning kidney who was previously not a candidate for partial nephrectomy. Following treatment, he was able to undergo a curative partial nephrectomy with preservation of kidney function, thus avoiding dialysis. Case Report A 43-year-old White man presented with severe bladder outlet obstruction, left kidney hydronephrosis with total loss of function in the left kidney, and preserved function in the right. He underwent a transurethral resection of the prostate (TURP), which resolved the obstruction. At age 60, he presented to the emergency department (ED) with right flank pain and gross hematuria. While in the ED, a CT scan of the abdomen and pelvis was obtained Figure 1. Renal cell carcinoma of the right kidney before initiation of immunotherapy. that revealed new right-sided hydronephrosis without kidney stones, and a 10.2-cm lobulated mass with calcifications arising off the upper pole of the right kidney. The patient was discharged that evening and referred to a urologist for follow-up. An MRI study was performed, which revealed a 7 cm 3 8 cm 3 8.5 cm mass and no evidence of metastatic disease (Figure 1). Following biopsy of the mass, pathology confirmed the presence of clear cell carcinoma, stage T2aNxM0. Upon review of imaging, it was concluded that a partial nephrectomy could not be performed due to the tumor size and proximity to the renal vasculature. Rather, the only appropriate surgical approach was a radical nephrectomy. However, with the patient’s history of solitary kidney function, it was understood that performing a right-sided radical nephrectomy would restrict the patient to lifelong dialysis. The patient was referred to an oncologist to discuss non-surgical treatment options, after which the patient opted to proceed with a course of off-label immunotherapy treatment. The goal was to shrink the tumor such that partial nephrectomy could be performed, avoiding the need for lifelong dialysis. The patient began a course of immunotherapy: nivolumab, 3 mg/ kg, and ipilimumab, 1 mg/kg, every 42 days for a total of 4 treatments. After the third infusion, treatment was stopped due to elevated transaminases (AST 588 U/L, ALT 221 U/L) secondary to autoimmune hepatitis. The patient was started on corticosteroids to treat the autoimmune hepatitis, but within 2 weeks of finishing the treatment, he presented to a hospital with confusion and lower extremity weakness. He was diagnosed with aseptic meningitis and admitted to the hospital. The following week, he was discharged on another course of corticosteroids. Upon discharge, an MRI was ordered to assess treatment response, which revealed that the tumor was smaller than prior scans, indicating Vol. 22 No. 3 • 2020 • Reviews in Urology • 127 Neoadjuvant Treatment of Renal Cell Carcinoma continued Figure 2. Renal cell carcinoma of the right kidney after completion of immunotherapy. a positive response. Pending full recovery, the patient and oncologist agreed to continue immunotherapy with cabozantinib, maintaining the same goal of partial nephrectomy. Cabozantinib was started 4 months after discontinuation of nivolumab 1 ipilimumab. The patient began a 40-mg dose daily and tolerated it well, exhibiting side effects of hypertension and grade 1 palmar-plantar erythrodysesthesia (hand-foot) syndrome. The hypertension was treated with a combination of losartan, amlodipine, and metoprolol, and the handfoot syndrome was alleviated by skipping weekend doses. Following the fifth month of treatment with cabozantinib, the oncologist ordered a CT scan which revealed the tumor had shrunk to 6.3 cm 3 5.5 cm (Figure 2). After assessment by the urologist, the patient was deemed a candidate for partial nephrectomy. An open partial nephrectomy was performed successfully using intraoperative ultrasound and icecooling technique with a clamp time of 25 minutes. The patient tolerated the procedure well. The tumor was in the upper pole of the renal collecting system with some invasion into the renal pelvis. However, with the use of neoadjuvant immunotherapy, the tumor had shrunk enough to avoid the renal vessels. The tumor was resected with clear margins, and the final pathology report was Fuhrman nuclear grade 3 RCC, with numerous areas of necrosis and calcification, and 5.3 cm in greatest dimension. Post-operatively, the patient had a creatinine of 3.0 mg/ dL, elevated from his baseline of 1.6 mg/dL. However, at his 2-month post-surgery follow-up, his creatinine had returned to baseline. The patient has not had any complications related to the surgery, and his overall kidney function has been stable, allowing him to avoid the need for lifetime dialysis. Discussion This case demonstrated the potential of immunotherapy in the neoadjuvant treatment of localized RCC, identifying a potential paradigm shift in the approach to this disease. With an increasing number of immunotherapeutic agents available for mRCC, it is important to look at efficacy and safety before identifying an agent for the neoadjuvant setting. Recent studies have shown that nivolumab 1 Main POintS • With immunotherapy leading the way in the treatment of metastatic renal cell carcinoma (RCC), it is crucial to continue investigating new applications for these agents, specifically in the treatment of localized RCC. • The gold-standard treatment for localized RCC may always be a partial or radical nephrectomy, as these procedures are curative, but other avenues should be considered in patients with decreased kidney function or those unable to undergo surgery. • This case demonstrated the versatility of nivolumab 1 ipilimumab and cabozantinib, and should prompt further research into the management of localized renal cell carcinoma. 128 • Vol. 22 No. 3 • 2020 • Reviews in Urology Neoadjuvant Treatment of Renal Cell Carcinoma ipilimumab has an efficacy and overall survival rate equal to or better than current first-line therapies.5-7 This combination also has demonstrated a manageable safety profile and a lower rate of immune-related adverse events (irAEs) in comparison to other first-line therapies.5,7 During his fourth month of treatment, the patient experienced irAEs of hepatitis and aseptic meningitis. Although hepatic AEs of all grades events occur in 25% of patients taking nivolumab 1 ipilimumab, nearly half are grade 3 or grade 4.5 Neurologic AEs are rare, but are potentially fatal AEs associated with the use of nivolumab, ipilimumab, and other immune checkpoint inhibitors.8,9 In the management of irAEs, the patient was treated with corticosteroids, as current guidelines recommend.10 Cabozantinib is preferred in the management of previously treated mRCC.11 However, there is growing evidence that supports the use of cabozantinib as a firstline agent in the management of mRCC.12 Along with its high efficacy, cabozantinib’s safety profile is similar to other first- and second-line immunotherapies, especially in lower doses.12-14 Although this patient’s tumor responded to nivolumab 1 ipilimumab, it was decided that the next course of treatment should be efficacious in the setting of previously treated mRCC, which lead to the choice of cabozantinib. Although the patient experienced side effects of hypertension and hand-foot syndrome, neither were concerning as these are two of the most frequent and treatable side effects, occurring in 35% and 22% of patients, respectively.15 The safety of dialysis is continually improving. Since 2001, there has been a reduction in mortality by 28% in patients receiving hemodialysis and 40% in patients receiving peritoneal dialysis. However, the 5-year survival of patients undergoing hemodialysis or peritoneal dialysis is 42% and 52%, respectively.16 In addition, each subsequent year of dialysis treatment is associated with a 6% increase in the risk of death.4 In patients with a single functioning kidney or poor renal function that require surgery to remove a tumor, different treatment modalities should be discussed with the goal of preserving renal function. Looking at current treatment guidelines for mRCC is a good starting point, as newer immunotherapies approved for mRCC likely would show benefit in the treatment of non-metastatic disease. Specifically, investigation into the efficacy of lower doses of immunotherapy could prove beneficial for both treatment of RCC and reduction in side effects. In this case, neoadjuvant immunotherapy allowed the patient to undergo a partial nephrectomy and preserve renal function, preventing the need for long-term dialysis. With immunotherapy leading the way in the treatment of mRCC, it is crucial to continue investigating new applications for these agents, specifically in the treatment of localized RCC. The gold-standard treatment for localized RCC may always be a partial or radical nephrectomy, as these procedures are curative, but other avenues should be considered in patients with decreased kidney function or those unable to undergo surgery. 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US Renal Data System 2018 Annual Data Report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2019;73(3 suppl 1):A7-A8. Vol. 22 No. 3 • 2020 • Reviews in Urology • 129