The history of cytoreductive nephrectomy began in 2001 when two large publications demonstrated its benefit. In a New England Journal of Medicine paper, Flanigan et al. showed a 3-months survival benefit for metastatic RCC patients undergoing cytoreductive nephrectomy following treatment with Interferon Alfa (an immunotherapy that enhances the proliferation of human immune B cells, as well as being able to activate natural killer cells) compared to those treated with only interferon alfa.1 Another similar but smaller study showed an even longer benefit with 10 months overall survival difference favoring patients undergoing cytoreductive nephrectomy.2 In that year, cytoreductive nephrectomy together with interferon alfa was considered the optimum therapy for oligo-metastatic RCC patients.
In 2007, a study comparing Sunitinib to interferon alfa in metastatic RCC patients demonstrated a significant advantage in favor of sunitinib. The advantage was in progression-free survival, with 90% of the patients in this study undergoing cytoreductive nephrectomy.3 This lead Dr. Kauffman to ask whether we can apply the finding described in 2001 on the successful combination of cytoreductive nephrectomy and interferon alfa to VEGF/TKI drugs (sunitinib)?
The mechanisms behind the survival benefit of cytoreductive nephrectomy were next discussed. Cytoreductive nephrectomy reduces seeding from the primary tumor, it enhances the responsiveness against current metastases, increases the performance status of the patient, stops the systemic effects of the primary tumor (paraneoplastic syndrome), stops local effects of the primary tumor, improves host-immune response (causing in 0.2-3% of cases for the spontaneous regression of al RCC metastases), and significantly reduces the tumor burden (possibly making any drug therapy more effective). Lastly, it provides tissue for direct systemic therapy.
The role of cytoreductive nephrectomy in the targeted era was next discussed. Validated risk groups have been formulated, using the Memorial Sloan Kettering Cancer Center (MSKCC) criteria or the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria, shown in figure 1.
Figure 1 – Metastatic RCC validated risk scores (Low, Intermediate, and High):
There is data showing a benefit for performing metastasectomy in metastatic RCC patients. In a meta-analysis of 2267 patients, 958 patients (42.2%) underwent complete metastasectomy vs. 1309 (57.8%) who underwent incomplete metastasectomy. The overall survival was improved in those who underwent the complete procedure (36-142 vs. 8-27 months).4
Although it would seem cytoreductive nephrectomy has significant benefits, it is important to recognize its downsides. The two major ones are the morbidity associated with this procedure and the delay to systemic therapy. In a large database from Florida, with over 17,000 patients who underwent nephrectomy, approximately 1063 (6%) were patients who underwent cytoreductive nephrectomy.5 Data demonstrated that the mortality from this procedure was 2.4%, with 26.5% of patients having some form of complications, and 24.3% of patients requiring a blood transfusion. A multivariable analysis demonstrated that the predictors of perioperative complications include tumor size >10 cm, need for inferior vena cava exploration, increasing number of metastatic sites, the patient’s performance status, and older age.6 In minimally invasive procedures, the complication rate was similar to open procedures and was around 23%.7 The next problem with cytoreductive nephrectomy is the delay it causes in receiving systemic therapy. Data show that the delay is usually more than 2 months, with about 50% of the delay being disease-related and 20% being surgery related. It had also been shown that laparoscopic procedure is associated with a shorter time to systemic treatment, while lymph node dissection lengthens the time to treatment with systemic therapy.8 However, the answer to the question of whether the delay in systemic treatment in this scenario is bad for the patients is still not clear.
The possible alternative to cytoreductive nephrectomy upfront is primary systemic therapy with delayed cytoreductive nephrectomy. Primary systemic therapy has been shown to cause a minor change in the primary tumor in more than 90% of the patients.
The real question should be whether to sequence cytoreductive nephrectomy before or after systemic therapy. It is also interesting to know whether systemic therapy can reduce the perioperative complications of cytoreductive nephrectomy, and increase the recovery speed from this procedure.
The CARMENA trial, comparing sunitinib alone or after cytoreductive nephrectomy in metastatic RCC patients was a multicenter trial including 79 centers and 450 patients.9 In the cytoreductive nephrectomy arm there was a higher percentage of poor risk patients (44% vs. 41.5%), and also a higher percentage of T3/T4 disease (70.1% vs. 53%). The study demonstrated similar findings in per-protocol analyses and similar survival outcomes in intermediate and poor risk subgroup analyses. There was a 2% postoperative mortality rate for the surgery and 39% postoperative complication rate. The results of this study have shifted the guidelines to recommend systemic therapy without performing cytoreductive nephrectomy.
The last topic discussed was the role of immune checkpoint inhibitors (ICPI) in advanced metastatic RCC patients. In the study comparing Nivolumab plus ipillimumab vs. Sunitinib in advanced RCC, overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients.10 It is still unclear whether it is possible to apply the CARMENA study findings to the era of immune checkpoint inhibitors.
Dr. Kauffman concluded his talk and gave his personal practice:
- In poor risk patients – primary systemic therapy with no role for cytoreductive nephrectomy.
- In good risk patients – cytoreductive nephrectomy is favored as the initial treatment
- In intermediate-risk patients – if they are planned to be treated with immune checkpoint inhibitors – cytoreductive nephrectomy is preferred first.
- There is a low oncologic risk
- Low morbidity expected as a result of the surgery
Presented by: Eric Kauffman, MD Assistant Professor, Roswell Park Cancer Institute Department of Urology, Roswell Park Comprehensive Cancer Center
1. Flanigan et al. NEJM 2001
2. Mickisch GHJ, et al. Lancet 2001
3. Motzer RJ et al. NEJM 2007
4. Zaid HB et al. J Urol 2017
5. Abdollah F et al. Ann Surg Oncol 2011
6. Jackson BL et al. BJU Int 2015
7. Bragayrac LN et al. World J Urol 2016
8. Gershmn B et al. Eur Urol 2016
9. Mejean A et al. NEJM 2018
10. Motzer RJ et al. NEJM 2018
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 70th Northeastern Section of the American Urological Association (NSAUA) - October 11-13, 2018 - Fairmont Royal York Toronto, ON Canada