Letter to the Editor
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Adjuvant tyrosine kinase inhibitors for renal cell carcinoma? No, thank you (at least for the present) Alessandro Leonetti1 , Teresa Zielli1 & Sebastiano Buti*,1 1 Medical Oncology Unit, University Hospital of Parma, Parma, Italy *Author for correspondence: Tel.: + 0039 0521 702316;
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First draft submitted: 16 April 2018; Accepted for publication: 19 June 2018; Published online: 1 August 2018 Keywords: adjuvant • kidney cancer • meta-analysis • RCC • renal cell carcinoma • TKI • tyrosine kinase inhibitors
Dear Editor, We read with interest the meta-analysis performed by Kourie and colleagues aimed to evaluate the role of both sunitinib and pazopanib for the adjuvant treatment of renal cell carcinoma (RCC) recently published in Future Oncology journal [1]. Even though tyrosine kinase inhibitors (TKIs) demonstrated a positive trend on overall effect when pooling the published data through the statistical fixed-effects model (HR: 0.91; 95% CI: 0.83–0.99; p = 0.03), we would recommend to consider this result with caution, by wondering: could we merely transfer this finding in our clinical practice? In particular, some considerations can be made. First, the conclusions of the meta-analysis by Kourie et al. diverged from the results of the previous one published by Gyawali and collaborators [2], in which the PROTECT study [3] was not included. Of note, the latter trial failed to meet the primary end point of disease-free survival (DFS) in the pazopanib intention-to-treat (ITT) 600 mg population (HR: 0.86; 95% CI: 0.70–1.06; p = 0.16) [3]. Therefore, observing an overall trend in favor of TKIs when adding the PROTECT study into the meta-analysis by Kourie was unexpected. Additionally, the meta-analysis incorporated the pazopanib ITT 800 mg population (analyzed as secondary end point in the original study) in which the placebo arm performed clearly worse than pazopanib ITT 600 mg, despite the similar performances of the two treatment arms (3-year DFS: 67 vs 64% [in ITT 600 mg] and 66 vs 56% [in ITT 800 mg] in treatment and placebo arms, respectively) [3]. Second, the authors referred to the specific population of high-risk resected RCC when enhancing TKI advantage on DFS, even though the three trials (ASSURE [4], S-TRAC [5] and PROTECT [3]) also enrolled patients with both low and intermediate risk of recurrence, who were represented at different percentages among the studies [6]. Moreover, the updated results of the ASSURE trial specifically addressed to high-risk subset of patients (only pT3-T4 and/or pN1-N2) were relentlessly negative [7]. Considering this, it seems not reasonable to ascribe the negative results of ASSURE trial only to the risk of recurrence of the patients. Third, we must not neglect that two out of the three trials were sponsored, and funded by pharmaceutical companies, with the only nonsponsored trial [4] being clearly negative even though it was the largest (1923 ASSURE [4] vs 1538 PROTECT [3] vs 615 S-TRAC [5] patients): should we trust so faithfully in the reported results? Curiously, in the only formally positive trial (S-TRAC), the outcome in terms of DFS was statistically significant when measured by independent central review (HR: 0.76; 95% CI: 0.59–0.98; p = 0.03) but not if measured by investigators (HR: 0.81; 95% CI: 0.64–1.02; p = 0.08): it seems that the investigators recognized the relapse events earlier than the independent central review, more often for sunitinib than for placebo [5]. Fourth, no survival advantage was observed in any study. Fifth, concerning ongoing immunotherapy trials for the adjuvant treatment of RCC, placebo has been further confirmed to be the acceptable comparator arm [8–10], sensing that perhaps there will be no place for TKIs in this setting in the next future.
C 2018 Future Medicine Ltd 10.2217/fon-2018-0304
Future Oncol. (Epub ahead of print)
ISSN 1479-6694
Letter to the Editor
Leonetti, Zielli & Buti
In conclusion, we undoubtedly appreciated the meta-analysis by Kourie et al. However, for the above mentioned reasons, we currently believe that adjuvant TKIs therapy should not be recommended to our patients in the clinical practice. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Conflict of interests None of the contributing authors have any conflict of interest, including specific financial interests or relationships and affiliations relevant to the subject matter or materials discussed in the manuscript.
References 1.
Kourie HR, Bakouny Z, Eid R, Haddad FG, Kattan J. The merit of tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma: a meta-analysis. Future Oncol. 14(9), 829–835 (2018).
2.
Gyawali B, Ando Y. Adjuvant sunitinib for high-risk-resected renal cell carcinoma: a meta-analysis of ASSURE and S-TRAC trials. Ann. Oncol. 28(4), 898–899 (2017).
3.
Motzer RJ, Haas NB, Donskov F et al. Randomized Phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J. Clin. Oncol. 35(35), 3916–3923 (2017).
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Haas NB, Manola J, Uzzo RG et al. Adjuvant sunitinib or sorafenib for high-risk, nonmetastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomized, Phase III trial. Lancet 387(10032), 2008–2016 (2016).
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Ravaud A, Motzer RJ, Pandha HS et al. Adjuvant sunitinib in high-risk renal cell carcinoma after nephrectomy. N. Engl. J. Med. 375(23), 2246–2254 (2016).
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Figlin RA, Leibovich BC, Stewart GD, Negrier S. Adjuvant therapy in renal cell carcinoma: does higher risk for recurrence improve the chance for success? Ann. Oncol. 29(2), 324–331 (2018).
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Haas NB, Manola J, Dutcher JP et al. Adjuvant treatment for high-risk clear cell renal cancer. JAMA Oncol. 3(9), 1249–1252 (2017).
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10. US National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03024996
10.2217/fon-2018-0304
Future Oncol. (Epub ahead of print)
future science group
