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Cross et al. J Cancer Metastasis Treat 2021;7:55 https://dx.doi.org/10.20517/2394-4722.2021.99 Page 7 of 9

Further criticism of the study included the fact that > 40% of the patients were MSKCC poor-risk and
probably would not be offered cytoreductive nephrectomy at most institutions, likely skewing the results
away from nephrectomy. It could explain why the overall survival in CARMENA was shorter than in other
studies of metastatic kidney cancer. Additionally, CARMENA patients had a significant metastatic disease
burden, comprising at least 40% of the overall tumor burden for most patients. If one of the primary goals of
cytoreductive nephrectomy is to debulk the tumor burden significantly, this would not have been possible
for these patients. Patients with low metastatic disease burden were excluded from CARMENA at the
investigator’s discretion, probably because most agree that those with low metastatic disease burden would
benefit from upfront nephrectomy. It also likely skewed the trial away from showing a benefit to
cytoreductive nephrectomy.

Lastly, CARMENA and SURTIME suffer from the same fate that ultimately led many physicians to question
the continued validity of the early cytoreductive nephrectomy trials. That is, sunitinib is no longer standard
first-line therapy for patients who present with synchronous metastatic kidney cancer. With the results of
recent randomized trials, first-line therapy for patients with metastatic kidney cancer now consists of
combination immunotherapy with either ipilimumab plus nivolumab (CheckMate 214) or axitinib plus
pembrolizumab (KEYNOTE-426) [16,17] .

PROBE trial
The recently activated Phase III trial of nivolumab plus ipilimumab with or without cytoreductive
nephrectomy for metastatic renal cell carcinoma (PROBE trial, SWOG 1931) will attempt to answer the
question regarding the benefit of cytoreductive nephrectomy in the immunotherapy era. As with the
previous trials, the primary outcome will be overall survival with an estimated enrollment of 364 patients
and a completion date of July 2033. Patients will receive PD-L1 inhibition combination therapy for 12-18
weeks, followed by updated imaging to evaluate their response. Patients with a partial response or stable
disease will then be randomized 1:1 to cytoreductive nephrectomy vs. continued immunotherapy
(https://clinicaltrials.gov/ct2/show/NCT04510597).

SUMMARY
In summary, the role of cytoreductive nephrectomy in the treatment algorithm of patients presenting with
synchronous metastatic RCC has evolved considerably since the original randomized trials were published
in 2001. While those original trials showed improved overall survival of up to 10 months, more recent trials
have called into question the blanket utilization of upfront nephrectomy in these patients. Others have
advocated for an initial course of systemic therapy followed by nephrectomy in those with a favorable
response. In particular, the CARMENA trial failed to show a benefit to cytoreductive nephrectomy when
combined with systemic therapy.

Certainly, those patients who progress through an upfront course of immunotherapy are unlikely to benefit
from cytoreductive nephrectomy, and a trial of systemic therapy may save them the morbidity of the
surgery. The deferred nephrectomy strategy is partly supported by data from the SURTIME trial, which
showed an improved overall survival as a secondary endpoint.

The current risk stratification models are suboptimal to assess patients who present with de novo metastatic
disease. Since even one prognostic point puts patients in an intermediate-risk category in either the MSKCC
or IMDC criteria, and both take the time between diagnosis and systemic therapy into account, those who
present with synchronous metastatic disease cannot be classified as good-risk. The current prognostic
models were designed for patients who have already undergone nephrectomy and subsequently develop