Page 2 - Kidney Cancer Research Network of Canada (KCRNC) consensus statement on the role of adjuvant therapy after nephrectomy for high-risk, non-metastatic renal cell carcinoma: A comprehensive analysis of the literature and meta-analysis of randomized controlled trials

Karakiewicz et al

In this report, we review the current evidence regarding adju- Evidence synthesis
vant targeted agent therapy after nephrectomy for nmRCC and
provide a meta-analysis of the three published vascular endo-
thelial growth factor receptor (VEGFR) tyrosine kinase inhib- The ASSURE trial
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itors (TKIs)-based adjuvant trials, as discussed at the 2017
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Canadian Kidney Cancer Forum (CKCF) and endorsed by The ASSURE trial randomized 1943 patients with complete-
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the Kidney Cancer Research Network of Canada (KCRNC). 5 ly resected stage pT1b or greater nmRCC. Patients were
randomly assigned (1:1:1) to initially receive 54 weeks of
Evidence acquisition sunitinib (n=647) 50 mg once per day orally throughout the
first four weeks of each six-week (four weeks on/two weeks
off) cycle continuous, sorafenib (n=649) 400 mg twice per
Eligibility criteria day orally, or placebo (n=647). Treatment was discontinued
due to toxicity by 193 of 438 (44%) patients on sunitinib,
A review of the literature was performed in November 2017 199 of 441 (45%) patients on sorafenib, and 47 of 444
to identify relevant randomized controlled studies evaluating (11%) patients on placebo. Upon review of this data, the
the effect of adjuvant therapy in surgically treated nmRCC starting dose of each drug was subsequently reduced and
using PubMed, Embase, Medline, and Cochrane library, as then individually titrated up to the original full doses if pos-
well as ClinicalTrials.gov registry. The following key words sible. The most common grade 3 or worse adverse events
were used alone or in combination: renal cell carcinoma, were hypertension (17% sunitinib patients, 16% sorafen-
adjuvant therapy, antiangiogenic therapy TKI, nephrectomy, ib patients), hand-foot syndrome (15% sunitinib patients,
target agents, treatments, and prognosis. Only English lan- 33% sorafenib patients), rash (2% sunitinib patients, 15%
guage original articles were considered. sorafenib patients), and fatigue (18% sunitinib patients, 7%
sorafenib patients). The primary analysis showed no signifi-
Study selection cant differences in DFS between study arms: median of 5.8
years (interquartile range [IQR] 1.6−8.2) for sunitinib (HR
The search yielded seven prospective randomized trials of 1.02; 95% CI 0.85–1.23; p = 0.8), 6.1 years (IQR 1.7–not
adjuvant targeted agents after nephrectomy for patients with estimable [NE]) for sorafenib (HR 0.97; 95% CI 0.80-1.17;
high-risk nmRCC: ASSURE, S-TRAC, PROTECT, SORCE, 6 p=0·7184), and 6.6 years (IQR 1.5–NE) for placebo. In
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EVEREST, ATLAS, and ARISER (Table 1). The ARISER trial post-hoc subgroup analyses of pathological stage T3 or T4
examined a carbonic anhydrase IX inhibitor (girentuximab). patients, American Joint Committee on Cancer (AJCC) stage
It reported negative findings and was not considered in this III–IV patients, as well as patients with Fuhrman grade 3 or
review due to its different mechanism of action and treat- 4, sunitinib adjuvant therapy failed to demonstrate either
ment molecule unavailability in Canada. The EVEREST trial DFS or OS benefit compared to placebo. There were six
focused at mammalian target of rapamycin (m-TOR) inhibit- deaths related to treatment: four in sunitinib group vs. one
or (everolimus) and was not included due to lack of reported in sorafenib group and one in placebo group. The ASSURE
findings. Of five trials that focused on adjuvant TKI therapy, trial investigators concluded that adjuvant treatment with
three published their findings: ASSURE (sorafenib and sunit- the VEGFR TKI sorafenib or sunitinib did not improve sur-
inib), S-TRAC (sunitinib), and PROTECT (pazopanib), and vival relative to placebo. Furthermore, substantial treatment
represent the focus of this report and of the meta-analysis. discontinuation occurred in the treatment arm because of
excessive toxicity, despite dose reduction strategies. These
Statistical analyses results provided an important rationale against the use of
these drugs for high-risk nmRCC patients in the adjuvant
A quantitative synthesis (i.e., meta-analysis) was performed setting after nephrectomy for nmRCC.
on the ASSURE, S-TRAC, and PROTECT trials. For disease-
free survival (DFS) and overall survival (OS) data, hazard The S-TRAC trial
ratios (HR) and 95% confidence intervals (CI) obtained dir-
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ectly from studies were pooled to compare results. The S-TRAC trial randomized 615 patients with loco-region-
al, high-risk clear-cell nmRCC to receive either sunitinib (50
mg per day) or placebo on a four-weeks-on, two-weeks-off
schedule for one year or until disease recurrence, unaccept-
able toxicity, or consent withdrawal. The primary endpoint
of the study was DFS. Using central radiological review,
the median duration of DFS was 6.8 years (95% CI 5.8–

174 CUAJ • June 2018 • Volume 12, Issue 6