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Sawhney et al. J Cancer Metastasis Treat 2021;7:48 https://dx.doi.org/10.20517/2394-4722.2021.64 Page 3 of 9

interaction between pathologic node status and treatment response, but the finding could not be relied
[6]
upon to change clinical practice due to the small sample size .
[7]
In 2003, Messing et al. published the results of a phase 3 trial evaluating interferon-alpha in the setting of
resectable RCC. The study involved 283 patients with pT3-4a and/or node positive disease randomly
assigned to interferon-alpha-NL or observation after radical nephrectomy and lymphadenectomy. At a
median follow-up of 10.4 years, the median OS was 5.1 years in the treated group vs. 7.4 years in the
observation group (P = 0.9) and median relapse-free survival (RFS) was 2.2 years in the cohort receiving
[7]
interferon-alpha vs. 3.0 years in the group only under observation (P = 0.33) .
Interleukin-2
After the aforementioned trials, low-dose interleukin-2 plus interferon-alpha was evaluated by
Passalacqua et al. in a randomized, phase 3 trial in which 310 patients were randomized to receive
[8]
interleukin-2 plus interferon-alpha or observation after primary surgery for RCC, with 303 patients
evaluable in the intention-to-treat analyses. At a median follow-up of 54 months, the hazard ratios (HRs)
were 1.07 for OS [95% confidence interval (CI): 0.64-1.79, P = 0.79] and 0.84 for RFS (95%CI: 0.54-1.31, P =
0.44). However, despite this overall lack of benefit, an unplanned sub-group analysis found that the
treatment arm patients with ≥ 2 of the factors age ≤ 60 years, pN0, tumor grade 1-2, and pT3a stage had an
improved RFS with a HR of 0.44 (95%CI: 0.24-0.82, P ≤ 0.01), while patients with < 2 of these factors had a
significantly poorer OS (HR = 2.27, 95%CI: 1.03-5.03, P = 0.037), suggesting that patient stratification could
[8]
uncover patients most likely to benefit from adjuvant treatment .
Girentuximab
Girentuximab is a monoclonal antibody which binds to carbonic anhydrase-IX (CA-IX), a transmembrane
glycoprotein expressed on the surface of most RCC cells, and it triggers antibody-dependent cell-mediated
cytotoxicity, in a process thought to be mediated by natural killer cells and other immune effector cells. The
phase 3 randomized ARISER trial evaluated girentuximab in the setting of ccRCC with high risk of
recurrence after nephrectomy. In total, 864 patients were randomized to receive girentuximab or placebo,
but the study unfortunately found no statistically significant difference in DFS (HR = 0.97, 95%CI: 0.79-
1.18) or OS (HR = 0.99, 95%CI: 0.74-1.32) between the cohorts .
[9]
Tyrosine kinase inhibitors
The arrival of TKIs targeting VEGFRs in the 2000s changed the treatment paradigm for mRCC. Since then,
there has been interest in whether this benefit would translate to the adjuvant setting, based on the
knowledge that metastatic disease is highly vascularized and that biallelic inactivation of the VHL gene, a
tumor suppressor gene, appears to be an initiating event in sporadic ccRCCs which subsequently drives
VEGFA gene over-expression and thus angiogenesis . Several cohort studies have shown that VHL gene
[10]
inactivation is present in the majority of sporadic ccRCCs, which supports the rationale of targeting VEGFA
and VEGFR in RCC. With the relative success of VEGFR TKI therapy in the metastatic setting, it was hoped
[11]
that this strategy could be replicated in the adjuvant setting .

Unfortunately, after five large randomized controlled trials, VEGFR TKIs have not been shown to improve
survival outcomes in the adjuvant setting. Indeed, a recent meta-analysis of four of these trials showed no
improvement in DFS for patients receiving VEGFR TKIs after curative intent nephrectomy, although a
slight improvement in DFS was observed in higher-risk patients, opening the possibility that improved
[12]
patient stratification may uncover those who are likely to benefit more from adjuvant treatment . Table 1
shows the key inclusion criteria of different adjuvant VEGFR TKI trials.