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Page 2 of 9 Sawhney et al. J Cancer Metastasis Treat 2021;7:48 https://dx.doi.org/10.20517/2394-4722.2021.64

endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) convincingly failing to
provide benefit, across no fewer than six large phase 2-3 trials. One important caveat is sunitinib, which has
been approved by the US Food and Drug Administration (FDA) in the adjuvant setting post-nephrectomy
in those with high risk of recurrence based on the Sunitinib as Adjuvant Treatment for High-risk Renal Cell
Carcinoma Following Nephrectomy (S-TRAC) study, a trial which is discussed below. Thus, the results of
several phase 3 trials involving immune-checkpoint inhibitors (ICIs) are eagerly awaited. It is likely that
differential tumor biology between metastatic disease and localized disease has a significant role to play in
the failure of TKIs. There are several validated clinical models which are prognostic for recurrence to
metastatic disease after surgery or overall survival. These stratify patients into risk groups which are used for
patient selection into clinical trials, and they are discussed in the next section. In all the trials, we discuss
below, the disease-free survival (DFS) has been chosen as a primary endpoint due to long durations of
follow-up required to accumulate events with overall survival (OS) as an endpoint, although it is
contentious as to whether DFS represents a good surrogate marker for OS in the adjuvant setting.

RISK STRATIFICATION AND PROGNOSTIC MODELS
There are several validated risk stratification and prognostic models for use in localized RCC, designed for
the postoperative setting. The SSIGN (Stage, Size, Grade, and Necrosis) score was developed in 2002 using a
cohort of 1801 patients with localized clear-cell RCC (ccRCC) treated with radical nephrectomy from 1970
to 1988. It found TNM stage, size, nuclear grade, and tumor necrosis to significantly correlate with cancer
[1]
specific survival . This model retained its prognostic ability when evaluated against more recent patients
(1999-2010) undergoing both radical and partial nephrectomy .
[2]
The UCLA Integrated Staging System (UISS) was developed in 2001 and validated on a smaller set of
patients, 661, who had nephrectomies between 1989 and 1999 where the TNM stage, Fuhrman’s grade, and
Eastern Cooperative Oncology Group (ECOG) performance status was found to be prognostic for survival.
[3]
The model stratifies patients into 5 survival groups designated UISS I-V . Around the time the UISS model
was developed, the Memorial Sloan Kettering Cancer Center postoperative nomogram was also developed
and validated against 601 RCC patients treated with nephrectomy, to predict 5-year recurrence after
surgery. Symptoms, histology, tumor size, and pathological stage are combined to create a score out of 180
[4]
which is prognostic for recurrence at five years .

Later, the Leibovich score, developed in 2003, was validated against 1671 patients with ccRCC undergoing
nephrectomy between 1970 and 2000 to predict progression to metastatic RCC (mRCC). Tumor stage,
tumor size, regional lymph node status, nuclear grade, and histologic tumor necrosis were all determined as
being prognostic, and a scoring algorithm was developed based on these factors .
[5]

ADJUVANT TREATMENTS - PAST, PRESENT, AND FUTURE
Interferon-alpha
In the 1990s and 2000s, interferon-alpha was evaluated in the adjuvant setting after promising results in the
mRCC setting in the 1980s. However, two trials failed to show benefit. In 2001, Pizzocaro et al. published
[6]
results of a randomized trial of 247 patients with Robson stage II and III RCC comparing adjuvant
recombinant interferon-alpha 2b with observation post-radical nephrectomy. The trial showed the resulting
5-year OS probability was 0.665 for treated patients vs. 0.660 for controls, while the event-free survival (EFS)
probability was 0.671 for treated patients vs. 0.567 for controls. These differences were not statistically
significant, with a 2P value of 0.861 for OS and a 2P value of 0.107 for EFS. Interestingly, interferon-alpha
was found to have a harmful effect in 97 pN0 patients but a beneficial effect in a small subset of 13 cases of
pN2/pN3 patients compared with 13 controls. This finding might be useful as a hypothesis that there was an