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Page 6 of 14 Atmaja et al. J Cancer Metastasis Treat 2021;7:xx https://dx.doi.org/10.20517/2394-4722.2021.66

[50]
A similar conclusion was attained from a prospective phase II trial conducted by Rini et al. . This study
involved 52 asymptomatic, treatment-naïve patients who received regular radiographic follow-up
throughout the surveillance period. Results suggested that deferred systemic therapy was favorable for
[50]
patients with 0-1 IMDC risk factors and < 2 organs with metastatic disease .

THE TREATMENT LANDSCAPE OF METASTATIC RENAL CELL CARCINOMA
Cytoreductive nephrectomy
An important element of an mRCC individualized treatment plan is the consideration that whether a
cytoreductive nephrectomy (CN) would be of benefit to the patient.

Retrospective analysis of 1658 patients, who all received targeted therapy, demonstrated that, in general,
[51]
survival outcomes are substantially improved with CN vs. without CN . However, patients with a poor
prognosis (≥ 4 IMDC factors) may not benefit from CN , and offering the procedure to this group could
[46]
therefore be detrimental. Other factors to consider would be the extent of tumor burden and whether
surgery is feasible.

The SURTIME randomized clinical trial investigated whether patient outcomes differed with immediate CN
vs. deferred CN, after an initial period of Sunitinib before surgery . Bex et al. concluded that there was
[52]
[52]
no significant difference between the 28-week progression-free rate; however, there was an improvement in
overall survival with the deferred approach.

The CARMENA phase 3 trial comparing CN followed by Sunitinib, with Sunitinib alone in the setting of
untreated MSKCC intermediate or poor-risk metastatic ccRCC showed that the median OS was 18.9
months with Sunitinib alone vs. 13.9 months with CN followed by Sunitinib (stratified HR for death,
0.89) [53,54] . There were no significant differences in response rate or PFS between both groups. A subsequent
analysis, reclassifying patients into IMDC risk groups, demonstrated that in the intermediate-risk group in
which 48.1% of patients had only one risk factor, the median OS was 30.5 months vs. 25.2 months in those
treated with CN followed by Sunitinib vs. Sunitinib alone, respectively. For the remaining 51.9% of patients
with two risk factors, the median OS was 16.6 months vs. 31.2 months with CN followed by Sunitinib vs.
Sunitinib alone. Thus, the study suggested that those with either 0 or 1 IMDC risk factor should be
considered for nephrectomy [53,54] .

First-line systemic treatment
In recent years, targeted therapies have supplanted cytokines in the management of mRCC, owing to a
better understanding of the biological factors driving cancer growth. A new standard of care was forged in
2007 when the VEGFR-TKI, Sunitinib, outperformed Interferon-alpha in ORR (47% vs. 12%) and median
[55]
PFS (11 months vs. 5 months) . Comparison of median disease-specific survival for newly diagnosed
mRCC between 1992-2004 (pre-targeted therapy era) and 2005-2009 (targeted therapy era) showed an
[56]
improvement from 13 months to 16 months . To date, nine targeted drugs have been approved for treating
mRCC: Sunitinib, Sorafenib, Pazopanib, Cabozantinib, Tivozanib, Axitinib, Everolimus, Temsirolimus and
Bevacizumab (in combination with Interferon-alpha) [22,57] .

An improved understanding of the biological immune response to cancer has led to the development of
immunotherapy as a new treatment modality for mRCC. PD-1 and CTLA-4 are both expressed on the T cell
surface, and their activation leads to a diminishing response of anti-tumor T cells. Enhanced T-cell-
mediated toxicity is therefore achieved by the blockade of these pathways with monoclonal antibodies
against CTLA-4 (Ipilimumab) and PD-1 (Nivolumab and Pembrolizumab) or their ligand, PDL-1