The theoretical advantages of upfront cytoreductive nephrectomy include:
1. Palliation/reduction of the complications related to the primary tumor.
2. Removal of a potential source of new metastases and additional mutations
3. Improve the immune function
4. Treat within the window of resectability
5. The best response to systemic therapy alone is quite low
6. The primary tumor is minimally responsive to targeted therapy alone
7. 90% of patients in targeted therapy trials have undergone cytoreductive nephrectomy.
8. Cytoreductive nephrectomy does seem to confer a survival advantage
In contrast to upfront cytoreductive nephrectomy, there are also advantages of initial systemic therapy. These include:
1. Palliation of symptoms from metastases
2. Stabilization and regression of the disease
3. Shrinkage of the tumor by approximately 7-32% (clinical significance of this is unknown)
4.”Litmus test” – 30% of patients won’t reach the stage of cytoreductive nephrectomy due to disease progression. Therefore, a response to systemic therapy will give us an idea if this patient might be eligible for cytoreductive nephrectomy.
Cytoreductive nephrectomy has been shown to be associated with improved survival. In the initial report in 2003 by Flanigan RC et al. cytoreductive nephrectomy with interferon alpha was associated with 13.6 months of overall survival compared to 7.8 months in patients who received interferon alpha alone.1 In a more recent study from 2014, cytoreductive nephrectomy was shown to improve survival compared to patients who did not undergo cytoreductive nephrectomy, with a hazards ratio of 0.6 (95% CI 0.52-0.69, p<0.0001).2
Cytoreductive nephrectomy may be associated with perioperative morbidity, which may delay or prevent the receipt of systemic therapy. A subset of patients may experience rapid progression of the disease. Therefore, predicting who would benefit from the surgery is a key factor, as 30% of patients will die within six months. Dr. Rendon believes we need to learn how to properly risk stratify patients. This can be achieved by preoperative nomograms for prediction of cancer-specific survival at 6 and 12 months after cytoreductive nephrectomy.3 Another important risk stratification technique is using the Heng risk criteria (figure 1). It is also possible to use disease biology as a marker. We can assess the response to treatment with initial targeted therapy to select those patients most suitable for cytoreductive nephrectomy.
Figure 1 – Heng Risk Criteria for Metastatic Renal Cell Carcinoma:
In the SURTIME trial, immediate surgery was compared to deferred surgery after sunitinib in metastatic RCC patients.4 The trial took place in four countries between 2000 and 2016, but only 99 patients were randomized (despite the fact the authors originally intended to accrue 458 patients). The primary endpoint was progression-free survival. The trial demonstrated no difference in progression in either group with 40% progression at 28 weeks. There was a possible overall survival advantage to the deferred nephrectomy arm. A total of 29% of the patients in the deferred nephrectomy arm experienced disease progression before surgery. The surgical complications did not increase by initial systemic therapy. In summary, this trial demonstrated that deferred cytoreductive nephrectomy appears to select outpatients with inherent resistance to systemic therapy.
In the CARMENA study, metastatic RCC patients were randomized to either nephrectomy followed by sunitinib or sunitinib alone.5 The median follow-up was 50.9 months, and approximately 44% had poor risk disease, with almost half of them having Fuhrman grade 3 or 4. 70% of the nephrectomy group and 50% of the sunitinib groups had T3-T4 disease, respectively. The study demonstrated that sunitinib was not inferior to nephrectomy. The median overall survival was longer in the sunitinib alone arm for all patients and in intermediate-risk and poor-risk subgroups also. 22.5% of the patients in the nephrectomy group never recovered enough to receive sunitinib after surgery. The authors concluded that cytoreductive nephrectomy should no longer be part of the standard of care for patients with metastatic RCC. CARMENA has several limitations, including slow enrollment of 0.7 patients/site/year, incomplete enrollment, the fact that many favorable risk patients were not randomized, and there was a high proportion (43%) of patients with poor risk disease.
In a systematic review of the role of cytoreductive nephrectomy in the era of targeted therapy era, aside from CARMENA, most of the studies were demonstrated to favor cytoreductive nephrectomy over no nephrectomy.6 The discrepancy can be possibly explained by the fact that the primary tumor may serve as a source of neoantigens, (which may benefit from immunotherapy). Additionally, postoperative wound healing and inflammation may have a detrimental clinical effect and promote tumor growth. Lastly, a selection bias may have affected the results.
The limitation of the current published literature includes the fact that we still do not have data from randomized controlled trials in the present era, regarding cytoreductive nephrectomy for patients with limited disease. Much of the literature focuses on clear cell disease only and given the limited efficacy of systemic therapy in non-clear cell RCC, cytoreductive nephrectomy might have a greater role for this group of histologies.
Dr. Rendon concluded his talk providing some guidance on how to integrate cytoreductive nephrectomy in the multimodal treatment paradigm. According to the Kidney cancer research network of Canada (KCRNC) consensus statement on cytoreductive nephrectomy, cytoreductive nephrectomy should not be performed in these patients:
1. Poor performance status (ECOG >=2, KPS<80)
2. Limited life expectancy (<1 year)
KCRNC consensus statement on cytoreductive nephrectomy recommends systemic therapy before cytoreductive nephrectomy in the following cases:
1. Intermediate and poor risk patients
2. Significant systemic symptoms from the metastatic disease
3. Active central neurological system metastases
4. Limited burden of disease within the kidney relative to the volume of metastases
5. Rapidly progressive disease
The CARMENA trial did not address what to do for these patients and we need more prospective data to figure out the best treatment for this these specific patients:
1. good performance status
2. young age
3. no systemic symptoms
4. relatively limited burden of metastatic disease
Lastly, recognizing the complex nature of advanced kidney cancer management, decisions regarding cytoreductive nephrectomy should ideally be made in a multidisciplinary setting.
Presented by: Ricardo Rendon, MD, FRCSC, Medical Advisory and Research Board, Dalhousie University, Halifax, Novia Scotia
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan at the CUOS – Canadian Uro-Oncology Summit 2019, #CUOS19 January 10-12, 2019 Westin Harbour Castle, Toronto, Ontario, Canada
References:
1. Flanigan RC et al. J Urol 2004
2. Heng D. et al. Eur Urol 2014
3. Margulis V. et al. Eur Urol 2013
4. Bex A. et al. Jama Oncol 2018
5. Mejean A. et al. NEJM 2018
6. Bhindi B. et al. Eur Urol 2019