Cytoreductive Nephrectomy: Current Uses and Indications

Kidney cancer continues to be one of the top 10 cancers diagnosed in the United States, and is the third most commonly diagnosed urologic cancer in both men and women.¹ Of the more than 80,000 cases diagnosed annually, a significant portion (approximately 30%) of patients will present with locally advanced or metastatic disease at time of diagnosis.²

Managing patients with metastatic renal cell carcinoma (mRCC) has continued to evolve since 2006, and the treatment of this patient population with targeted therapeutics such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors has become a mainstay of therapy. The role of surgery in advanced disease also continues to evolve. Specifically, cytoreductive nephrectomy (CRN), the surgical removal of a primary renal mass in the setting of synchronous metastatic disease, has come into question. The approach requires further clarification on when and how it should be utilized.²

Originally, CRN was used to lower rates of hemorrhage and alleviate symptoms from the primary tumor, such as gross hematuria and abdominal pain. The 2022 update to the European Association of Urology (EAU) Guidelines on Renal Cell Carcinoma suggests that surgical resection of all tumor deposits can be potentially therapeutically curative.³

Results from the CARMENA trial, which is one of several trials that explored the utility of CRN, suggested a similar overall survival (OS) benefit between patients receiving sunitinib alone versus CRN followed by sunitinib (18.4 months vs 13.9 months).⁴ However, patients in this trial were categorized as primarily intermediate to poor risk according to the Memorial Sloan Kettering Cancer Center/Motzer score, suggesting that the results are not easily translated to patients with good-risk disease or those with low-volume metastatic disease. For patients who do not need immediate combination VEGFR-TKI therapy, the EAU guidelines recommend that immediate CRN should be utilized until progression of disease is noted and systemic therapy is required.³

In the current era of immunotherapy, what are the exact roles for CRN? Shapiro et al explored this very topic in a recent review article, condensing much of the literature surrounding the role of CRN in patients with mRCC. The authors sought to investigate the optimal integration pathway for CRN in the immunotherapy era.² To preface, the authors highlighted several of the biologic principles related to performing CRN. In addition to improving patient symptoms, they cited that removing the primary tumor harboring cancer cells can prevent the cells from metastasizing and creating further disease.²

In 2015, nivolumab became the first US Food and Drug Administration-approved checkpoint inhibitor therapy for mRCC, and many of the phase 3 trials that came after that approval and led to further drug combination approvals (eg, Checkmate 214) heavily enrolled patients who had prior nephrectomy. The authors noted that is a major point in favor of CRN. The survival benefits that many of the recent immunotherapy trials demonstrate must be interpreted knowing that the primary tumor was removed.²

The review also commented on the data provided by the CARMENA trial and highlighted many of that trial’s limitations, including the heavy population of patients with high-volume mRCC with poor-risk disease and the fact that some patients in both the surgical and therapeutic arms did not receive their intended therapy.² They also pointed out that the OS benefits from sunitinib were significantly lower in CARMENA compared with other phase 3 trials, suggesting that the patient population may have played a significant role in the CRN results for that trial. These factors and more, the authors suggested, emphasize the importance of appropriate patient selection. In addition to these limitations, CARMENA also had issues with slow patient accrual, and over the course of the trial’s timeline, the standard of care for mRCC shifted away from sunitinib therapy.

In the last segment of the review, the authors featured several scenarios in which CRN should be highly considered. Patients with oligometastatic disease, especially when the primary tumor is 90% or more, should be considered for metastasectomy and CRN.² Additionally, patients with higher clinical stage disease who have caval thrombus involvement with tumor thrombi below the diaphragm have stable outcomes, and CRN should be considered in this setting.² CRN is also useful for reducing the symptoms of paraneoplastic syndromes of RCC, as well as pain, gross hematuria, and other RCC-related symptoms.

The authors noted that outcomes for CRN in non-clear cell histology are less certain but suggested patients should be managed in a similar fashion.

The final factor worth discussing is exactly what role CRN has in the modern era of immunotherapy for mRCC. Many trials demonstrating benefit in mRCC included a significant number of patients who had prior nephrectomy. The authors noted that in a large multi-institutional series, patients undergoing CRN even postimmunotherapy had excellent outcomes with only an overall 3% complication rate, suggesting that CRN in this setting is safe and reproducible.

The decision to perform CRN is highly dependent on various factors, including stage and risk categorization of the disease and patient performance status. As with any surgery, CRN has risks, including bleeding, possible injury to surrounding intra-abdominal organs, and complications from anesthesia. Patents should be counseled on the risks, as well as the symptomatic and oncologic benefits that CRN can provide in advanced RCC, before deciding.

The authors noted the importance of access to cancer centers where multidisciplinary care is available since the effective management of mRCC involves specialists from urology, medical oncology, and radiology, among other disciplines. They concluded that CRN has been shown to be an effective tool in the fight against mRCC, especially for patients with low-volume metastatic disease and good baseline performance status.

Akhil Abraham Saji, MD, Fellow at the University of Southern California, is a urologist specializing in minimally invasive surgery and urologic oncology with an interest in technology-driven innovation within health care.

References

1. Cancer stat facts: kidney and renal pelvis cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed October 26, 2023. https://seer.cancer.gov/statfacts/html/kidrp.html
2. Shapiro DD, Abel EJ, Master VA, et al. Cytoreductive nephrectomy for metastatic renal cell carcinoma – current concepts and contentions in the era of immune checkpoint inhibitors. KCJ. 2023;21(3):76-85. doi:10.52733/KCJ21n3-r1
3. Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update. Euro Urol. 2022;82(4):399-410. doi:10.1016/j.eururo.2022.03.006
4. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675