Renal cell carcinoma (RCC), the most frequent type of kidney cancer, responsible for 5% of oncological diagnosis in men and for 3% in women, representing the sixth most frequent cancer worldwide, is a constant challenge for uro-oncologists(1).
The use of imagistic methods at large scale for other indications in recent years has influenced the stage at diagnosis, allowing incidental diagnosis at an early stage and shifting stage distribution at diagnosis, with only 16% of patients nowadays presenting with metastatic disease(2). The clinical presentation of a patient with metastatic RCC can be different, ranging from incidental detection to highly symptomatic systemic disease. In order to establish in which risk category falls the patient and what treatment is the best choice for him, there are two publish risk models to direct the treatment: the MSKCC (Memorial Sloan-Kettering Cancer Center) and the IMDC (International Metastatic RCC Consortium) risk scores. They contain five or six pre-treatment factors, such as anemia, serum calcium concentration and performance status. Although these scores can provide a good insight of the prognosis for the patient and for determining which type of treatment is the best (cytoreductive nephrectomy, systemic therapy, or both) in day-to-day practice there exist a lot of patients in which cases the decision is debatable.
Cytoreductive nephrectomy (CNT) is defined as the surgical removal of the primary RCC lesion before the initiation of systemic therapy. Starting in the late ’80, CNT has become a therapeutic strategy frequently used, especially after 2001, when two randomized phase III trials, Southwest Oncology Group (SWOG) 8949 and the European Organization for Research and Treatment of Cancer (EORTC) 30947, validated this treatment strategy(3,4).
With a therapeutic arsenal comprising tyrosine kinase inhibitors, m-TOR inhibitors and immunotherapy and continuing to expand, the role of CNT in the metastatic setting is now questioned. CARMENA (The Clinical Trial to Assess the Importance of Nephrectomy; NCT00930033), a randomized phase III non-inferiority trial, tried to determine if upfront surgery is necessary before the initiation of sunitinib systemic treatment(5). In the trial, the median overall survival (OS) was non-inferior in the sunitinib arm, and the updated results presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting revealed that only a very selected group of patients benefited from nephrectomy in the metastatic setting, but before abandoning cytoreductive nephrectomy, significant clinical evidence is needed to support this strategy(6).
Data in favor of cytoreductive nephrectomy
Nephrectomy for stage IV disease can be done for clinical issues, but also for the possibility of a good response to treatment. The removal of the primary tumor together with its potential for bleeding or pain during subsequent systemic therapy can also eliminate a potential source of immunosuppression or tumor- promoting growth antigens(7).
The median survival of 120 eligible patients enrolled in the SWOG8949 trial, assigned to surgery followed by interferon, was 11.1 months, and among the 121 eligible patients assigned to interferon alone, it was 8.1 months (p=0.05). The 3-month difference in median survival between the two groups was independent of performance status, metastatic site, and the presence or absence of a measurable metastatic lesion(3).
EORTC 30947 included 85 patients and compared interferon-based immunotherapy with combined surgery and interferon treatment, with a median duration of survival significantly better in the group receiving surgery in addition to immunotherapy (17 versus 7 months)(4). The survival benefit observed in these two trials supported the benefit of CNT and it became a standard of care, especially for patients with a good performance status.
A study published in 2009 by Zini et al. examined the survival rates for 5372 patients with metastatic renal cancer identified in the 1988-2004 Surveillance, Epidemiology and End Results database. Out of those, 2447 were treated with CNT (45.5%) and 2925 (54.5%) were not treated with CNT. With a 1-, 2-, 5-, and 10-year overall survival rate of 53.6%, 36.3%, 19.4% and 12.7%, respectively, for the surgery group, compared with 18.5%, 7.4%, 2.3% and 1.2% for the no-surgery patients, the conclusion of the study was that CNT significantly improves the survival of patients with metastatic RCC, a dogma that is now under question(8).
The reason for improved survival with CNT is still a matter of intense debate; the removal of the primary tumor may inhibit angiogenesis inside metastatic sites by reducing the circulating levels of different growth factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGF-b)(9).
Beside decreasing the total tumor burden, and its theoretical systemic effect on angiogenesis, CNT allows for the palliation of pain, hematuria and remission of paraneoplastic symptoms, such as hypercalciuria and anemia, allowing for a better tolerance to systemic treatment.
Data against cytoreductive nephrectomy
Being associated with perioperative morbidity and a mortality of up to 8%, CNT is a serious surgical intervention that can be harmful to patients(10). The time the patient recovers from surgery can delay the systemic treatment, especially for anti-VEGF therapy, which associates a high risk of bleeding and can’t be started immediately after surgery.
This limitations encouraged researchers to further explore the role of cytoreduction in the metastatic setting.
Two large randomized trials investigated the use of CNT in the era of targeted therapy. The CARMENA trial enrolled 450 patients, from September 2009 to September 2017. At the first planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed.
The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. No significant differences in response rate or progression-free survival were observed.
In conclusion, sunitinib alone was not inferior to CNT followed by sunitinib in patients with metastatic RCC classified as having intermediate-risk or poor-risk disease(11).
An ASCO 2019 meeting update presented a subgroup analysis based on risk group, which confirmed that CNT is not superior to sunitinib alone in the intention to treat population, but for patients with only one IMDC risk factor CNT may be beneficial, with a median OS of 30.5 and 25.2 months in the arm including CNT and the arm with sunitinib monotherapy, respectively (HR 1.24; 0.81-1.90)(6). This supplementary analysis also revealed that 40 patients who had a secondary nephrectomy had a median OS of 48.5 months (95% CI; 27.9-64.4) versus 15.7 months (95% CI; 13.3-20.5) in patients who had never had surgery, raising the question on an alternative strategy that would include sunitinib treatment followed by debulking surgery.
SURTIME is a randomized phase II trial that explored the administration of three cycles of sunitinib prior to CNT, compared to sunitinib followed by surgery. With the deferred approach, the OS results were higher, with 32.4 months (95% CI; 14.5-65.3 months) compared with 15 months (95% CI; 9.3-29.5 months) in the immediate CNT arm(12).
One strong argument against CNT is the lack of evidence regarding the role of debulking surgery for patients who are treated with novel medications, that are associated with a better prognostic when compared with sunitinib, such as the nivolumab-ipilimumab combination, especially among intermediate-risk and poor-risk patients with previously untreated advanced renal cell carcinoma(13).
New clinical trials evaluating the role of CNT in this group of patients are urgently required in order to correctly tailor the treatment for our patients.
Based on CARMENA and SURTIME, the European Society of Medical Oncology (ESMO) guidelines considers, with a level of evidence IA, that upfront CNT should no longer be considered the standard of care in MSKCC intermediate-risk and poor-risk patients with asymptomatic primary tumors when medical treatment is required(14).
The National Comprehensive Cancer Network (NCCN) guidelines for kidney cancer, version 1.2021, endorsed CNT in selective cases for symptomatic patients and for patients with resectable primary tumor and oligometastatic disease, that can be completely resected or treated by ablative techniques.
The European Association of Urology guidelines on renal cell carcinoma, updated in 2019, considers that there is a strong level of evidence in order not to perform CNT in MSKCC poor-risk patients, with a weak level of support for the following recommendations: not performing immediate CNT in MSKCC intermediate-risk patients who have an asymptomatic synchronous primary tumor and require systemic therapy with VEGFR-TKI, starting systemic therapy without CNT in MSKCC intermediate-risk patients who have an asymptomatic synchronous primary tumor and require systemic therapy with VEGFR-TKI, discussing delayed CNT in MSKCC intermediate-risk patients under VEGFR-TKI therapy who derive long-term sustained benefit and/or minimal residual metastatic burden, performing immediate CNT in patients with good performance who do not require systemic therapy and performing immediate CNT in patients with oligometastatic disease when the complete local treatment of the metastases can be achieved(15).
What the future will bring
With at least four clinical trials in progress evaluating nivolumab with or without bevacizumab or ipilimumab, sorafenib, pembrolizumab with or without axitinib or nivolumab monotherapy before or after surgery, new and exciting data will allow a better selection of treatment strategies for patients with metastatic kidney cancer and will hopefully provide guidelines in order to better tailor the therapy sequences in order to obtain the most durable response with the smallest toxicity costs.
Despite all the clinical studies done until now, the selection of patients in day-to-day practice care is very important and it must be done in each patient. Prognostic models have been and continue to be developed to help identifying the patients who most likely will have a benefit from CNT.
The pre-treatment risk features, such as the performance status, the possibility of radical resection of the primary tumor, but also the two risk models published are very important aspects when patients are proposed for surgery. It is very important that the final decision is taken in multidisciplinary teams, ideally managed by experienced institutions.
The evidence regarding the combination of systemic therapy and nephrectomy in metastatic RCC is limited to studies conducted in the targeted therapy era. In the immunotherapy era, the role of CNT remains undefined and is supported by case reports. The ongoing studies and new clinical trials have to confirm not only the role of CNT, but also the timing of this surgery, in order to offer our patients the best sequence of treatment.