As systemic therapies continue to improve and change for advanced/metastatic RCC and are better tolerated, there has been increasing question of the role of cytoreductive nephrectomy (CNx) in this setting. Rendon was tasked to develop the CUA guidelines for this topic – unfortunately, after accumulating the data for this space, the recent CARMENA results were presented at ASCO 2018 and he was forced to adjust his report and slides significantly.
The current guidelines, such as the EAU guidelines, recommend CNx for favorable/intermediate risk patients with metastatic RCC and to perform immediate CNx in patients with oligometastatic disease when complete resection can be achieved; they also recommend avoiding CNx in IMDC poor-risk patients and to offer defect CNx in intermediate-risk patients with clear cell RCC who require systemic therapy. However, the strength of these recommendations is “weak” for all.
Theoretical advantages of upfront CNx:
1. palliative/reduce complications related to primary tumor
2. Remove potential sources of new metastases and new mutations
3. Improve immune function
4. Treat within a window of respectability
5. Best response (CR) to systemic therapy alone is relatively low
6. The primary tumor is often minimally responsive to TT (targeted therapy)
7. 90% of patients in TT trials had CNx
Theoretical advantages of initial systemic therapy:
1. Palliation of symptoms of metastases
2. Stabilize/regression of the disease
3. Shrinkage of tumor (albeit modest) – rarely affects surgery
4. “Litmus test” - ~30% of patients won’t make it to CNx due to disease progression, and probably wouldn’t have done well with a surgery anyway.
He then briefly reviewed the data leading to this point. In the IL-2/immunomodulator era, Flanigan et al. (NEJM 2001, JUrol 2004) and Mickisch et al. (Lancet 2001) demonstrated that removal of the kidney was associated with improved overall survival (OS). As a result, it has become an established paradigm in the management of mRCC, and patients who are surgically fit, are often recommended for cytoreductive nephrectomy prior to systemic therapy.
However, the introduction of targeted therapies, including tyrosine kinase inhibitors and mTOR inhibitors, have drastically changed the outcomes of mRCC patients. While not providing a cure, they are able to provide long-term response in some patients. In doing so, they have significantly extended the survival of patients with mRCC. Unfortunately, with this advancement in systemic therapy, the need for cytoreductive nephrectomy has been called into question. Especially in patients with advanced RCC (intermediate and poor risk) who have high volume disease outside of the kidney, there has been increasing emphasis on providing systemic therapy up-front and avoiding delays by putting the patient through a major operation.
Retrospective series and meta-analyses have continued to demonstrate a survival benefit to CNx in the setting of mRCC. (Heng et al. EU 2014, Bhindi et al. J Urol 2018) However, this has primarily been in IMDC favorable or intermediate risk patients (IMDC 1-3 risk factors). His own recent unpublished work, a meta-analysis of all CNx trials/studies in the TT era, looked at 18,570 patients – and found that CNx benefited patients (HR 0.57 favoring CNx).
However, he noted that patient stratification is important. A subset of patients experience rapid progression of disease (~30%) and likely won’t benefit from surgery or systemic therapy. There have been different attempts to risk stratify. The IMDC nomogram is one of the more commonly used ones – but the one risk factor (“<1 year from diagnosis to treatment”) makes it almost impossible for de novo mRCC patients to be considered favorable risk.
We can also use biology as a risk stratifier, which is essentially what the SURTIME study did. In SURTIME, an EORTC sponsored randomized control trial, patients were randomized to sunitinib followed by CNx (deferred CNx arm) and subsequent sunitinib versus upfront CNx followed by sunitinib. SURTIME closed early in 2016 due to poor accrual (likely due to difficulty enrollment criteria) – and was likely underpowered. SURTIME results were presented at ESMO 2017. On intent to treat analysis, deferred CNx was non-inferior to up front CNx – HR 0.57 favoring deferred nephrectomy (p=0.032). However, as they did not meet their sample size requirements, the study was technically underpowered. Yet, the data suggests that deferring CNx was likely not detrimental in targeted therapy era.
Lastly, he discussed the CARMENA study (ASCO 2018, Mejean et al.) – in this study, patients were randomized to either CNx or systemic therapy (sunitinib). Patients with low-volume metastatic disease (low-intermediate risk) were actively excluded by the investigators due to low equipoise – leaving a population that was heavily high-intermediate (60%) or poor risk (40%). They also only recruited 450 of the expected 576 patients. Sunitinib alone was not inferior to CNx + sunitinib (median OS 18.4 vs. 13.9 months, HR 0.89, favoring sunitinib). However, most of the benefit appeared to come from switching from progressive disease to stabilizing disease – no net improvement in CR or partial responses. Mortality for nephrectomy was minimal (4 deaths, 2%). Most complications were Clavian-Dindo Grade 1-2. 16% were Grade 3-4. Secondary nephrectomy in the sunitib arm was completed in 38 patients (17%) - 7 (18.9%) were due to symptoms and considered emergent. Importantly, 22.5% of patients never recovered enough after CNx to receive sunitinib.
Based on this consolidated results, he concluded, as many did, that our daily practice was unlikely to change. His recommendations, which is likely what is being done by most:
1. For patients with good performance status, young age, no systemic symptoms, the relatively limited burden of disease (favorable risk or low-intermediate risk), offer CNx and manage metastases with metastasectomy and surveillance
2. For patients with high-intermediate and poor risk disease, significant systemic symptoms from metastatic burden, active CNS mets, limited burden of disease within kidney compared to extra-renal, or rapidly progressing disease, plan for systemic therapy before considering CNx.
Presented by: Ricardo Rendon, MD, Dalhousie University, Halifax, NS, Canada
Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto Twitter: @tchandra_uromd at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia