Historically, cytoreductive nephrectomy for RCC has been for palliative purposes – back when we had no real systemic options for management. It was the primary treatment modality. It was used for palliation, pain relief, hematuria, control of paraneoplastic syndromes, but never for overall survival benefit. There was a question of possible metastatic disease regression in a small subset of patients (0.4-0.8%), but primarily anecdotal.
The, we moved into the era of cytokines (1980+) – IFN-alpha, IL-2. IFN-alpha came first, with response rates of 5-10% but well tolerated. IL-2, introduced later, had a 4% cure rate and a response rate of 20%, but significant toxicity. Subsequently, 2 RCTs (EORTC 30947 and SWOG 8949) in 2001 demonstrated that cytoreductive nephrectomy + IFN provided survival benefit of approximately 3-10 months over IGN-alpha alone. Flanigan et al completed a meta-analysis of these two papers and found a 4.8 median survival benefit with nephrectomy, which was the first Level 1 evidence supporting cytoreductive nephrectomy. However, only patients with clear cell histology, mRCC beyond LNs, no brain mets, and good performance status were included. Therefore, quite selective group that qualified. The Cochrane study confirmed the data.
However, in 2006, the targeted therapy era began to boom with the introduction of the tyrosine-kinase inhibitors (TKIs), and has gone on to include monoclonal antibodies and mTOR inhibitors. However, in this era, there is no Level 1 evidence supporting cytoreduction. There have been many smaller retrospective series that show potential survival benefit.
1. Zini 2009 – retrospective series of 5000 patients, 2447 with CRN. CRN one factor associated with survival advantage on MV analysis
2. Choueiri 2011 – multi-institutional study, 314 patients with 201 having undergone CRN. CRN patients had a 2-fold survival benefit
3. Conti 2014 – used SEER data from 1993-2010, found similar results favoring CRN
4. Heng DYC et al – used data from metastatic RCC consortium to compare patients – 1658 patients, 20 countries. Sunitinib used as first line in 72% of patients. CRN was associated with significant improvement in OS. Median OS 20 months vs. 9 months. Poor-risk factor patients did not do well – better for patients with good risk factors.
5. Petrelli 2014 – Meta-analysis of 11 trials, 39,943 patients. Again supported CRN – 54% reduction in risk of death.
How does CRN work? Many theories out there – but no clear etiology.
1) Removal of the primary as a source of metastases
2) Removal of primary tumor as a “sink” for the systemic therapy
3) RCC is an immunogenic tumor and primary may be immunomodulating
Optimal CRN – what does it involve?
1) Aim for R0 resection
2) Clearance of adrenal gland – may spare if radiographically not involved
3) Lymphadenectomy – template resection
4) Debulking of at least 75% of tumor is beneficial and an independent predictor of PFS
Many risk stratification models to help determine which patients will benefit from CRN – good or intermediate risk patients likely to benefit the month.
- IVC thrombus does have poor survival especially if thrombus above diaphragm
o Uncertain survival benefit
o Abel EJ 2017 (J. Urol)
- NSS can be considered in certain patients – but R0 resection is still the goal
o Complications can delay systemic therapy!
Sequencing with systemic therapy
- Traditionally has been given before systemic therapy to minimize disruption in therap
- However, there is a recent push to initiate systemic therapy for 2 cycles and evaluate response – if good response as a litmus test, then proceed with CRN before resuming systemic therapy
o SURTIME early results presented at ESMO study – sample size precluded definite conclusions
o SURTIME and CARMENA results pending
This was an excellent overview of CRN in the setting of metastatic RCC
Presented by: Makarand Khochikar
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal