SIU 2017: Cytoreductive Nephrectomy in the Era of Tyrosine Kinase Inhibitors: Is It the Standard?

Lisbon, Portugal ( In this State-of-the-Art Lecture, Dr. Uzzo discusses the role of cytoreductive nephrectomy in the era of targeted therapy. Of note, he makes a distinction between cytoreductive nephrectomy (up-front cytoreduction followed by systemic therapy) vs. consolidative nephrectomy (initial systemic therapy, nephrectomy if requested due to good response). 

Dr. Uzzo points to the diverging successes of medical therapy and surgery in the field of metastatic RCC. While surgery was utilized early on due to the lack of any other good options, it has made little progress in the past few decades – primarily based on retrospective data, anecdotal evidence and 2 RCTs that are 15+ years old. On the other hand, systemic therapy is evidence based, based on 100+ completed RCTs, 11+ approved medications since 2005, and has a large pipeline ahead. In order to move surgery forward, new ideas are needed and RCTs are required.

What is the therapeutic rationale for Cytoreductive nephrectomy?

1) Primary tumor is the source of continued new metastases
2) Removal of primary improves response to systemic therapy – not a sink for the medication
            - Primary is immunosuppressive?
            - Rare spontaneous regression?
3) Primary tumor causes metabolic derangements

He has previously discussed the role of treatment in metastatic therapy as 3 “eras”, and he did so again today. The three eras are the “dark ages” (historical), “the middle ages” (current), and “the future.”

In the Dark ages, there were no systemic options. Cytoreduction was for palliation and for paraneoplastic syndrome management. Anecdotally, some patients (1% or less) had spontaneous regression of metastases. But ultimately, surgery was used because systemic therapy was nonexistent. The systemic therapy was there, but ineffective – IFN-alpha. In the EORTC 30947 study, median survival was 7.8 months with IFN-alpha, and 13.6 months when surgery was added – but in patients with good performance status, no prior treatment, and clear cell histology alone. Similar results were seen in the Flanigan paper, but again, effect was primarily in patients with ECOG 0. As he puts it, there was INeffective systemic therapy with/without INeffective surgery!

In the Middle ages, there is now Effective systemic therapy with/without INeffective surgery. There is no Level 1 evidence of Cytoreductive nephrectomy in the TKI era. There are ongoing trials to help address this question. The first, CARMENA, is still accruing, with currently >400 patients included – results will take time. The other, the SURTIME study, is now complete and data is pending – preliminary data was presented at ESMO. It essentially compared Sunitib then nephrectomy (consolidative) vs. nephrectomy (cytoreductive) then sunitinib. They concluded that while PFS was no different between the arms, OS favored consolidative nephrectomy (but sample size of 99 precludes definitive conclusions). There continues to be systematic reviews based on population level data that suggests cytoreductive nephrectomy has benefit in the TKI era, but Dr. Uzzo (along with many others) now feel that systematic therapy is so good now that perhaps consolidative therapy may be best. 

  • His approach is typically 2 cycles of systematic therapy and assess response as a litmus test – if responding, then consolidative nephrectomy, and then resume systemic therapy.
  • Additionally, many in the audience suggested that the volume of disease matters – patients with large primary and small mets may benefit from nephrectomy. But patients with large volume mets and small primary may not.
  • Patients most eligible for nephrectomy – good performance status, large volume (>75% tumor burden) primary, clear cell histology
Ultimately, the future depends on a few things: the systemic therapy and further RCTs.
  • If systemic therapy continues to improve as a stabilizing rather than curative therapy, nephrectomy will still be part of the algorithm – though more likely as a consolidative therapy
  • If systemic therapy develops into cure rather than control, nephrectomy may be out of the question altogether!
However, we need to continue testing the role of surgery in high-quality randomized studies rather than retrospective series. 

Presented by: Robert Uzzo

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