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Platinum Priority – Kidney Cancer Editorial by Amanda Leiter and Matthew D. Galsky on pp. 881–883 of this issue| Volume 66, ISSUE 5, P874-880, November 01, 2014

Phase 2 Trial of Neoadjuvant Axitinib in Patients with Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma

Published:February 10, 2014DOI:https://doi.org/10.1016/j.eururo.2014.01.035

      Abstract

      Background

      Previous studies have shown a modest impact of tyrosine kinase inhibitors on primary renal tumors. Those studies were mostly retrospective or heterogeneous in their eligibility criteria with regard to histology, disease stage, duration of therapy, and time off therapy prior to surgery.

      Objective

      To prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with nonmetastatic biopsy-proven clear cell renal cell carcinoma (ccRCC).

      Design, setting, and participants

      This was a single-institution, single-arm phase 2 clinical trial. Patients with locally advanced nonmetastatic biopsy-proven ccRCC were eligible.

      Intervention

      Patients received axitinib 5 mg for up to 12 wk. Axitinib was continued until 36 h prior to surgery. Patients underwent partial or radical nephrectomy after axitinib therapy.

      Outcome measurements and statistical analysis

      The primary outcome was objective response rate prior to surgery. Secondary outcomes included safety, tolerability, and quality of life. A dedicated radiologist independently reviewed all computed tomography scans to evaluate for response using Response Evaluation Criteria in Solid Tumors (RECIST).

      Results and limitations

      A total of 24 patients were treated. Twenty-two patients continued axitinib for 12 wk; 1 patient continued axitinib for 11 wk and underwent surgery as planned. One patient stopped treatment at 7 wk due to adverse events (AEs). Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response per RECIST; 13 had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted. No grade 4 or 5 complications occurred. Functional Assessment of Cancer Therapy-Kidney Specific Index-15 changed over time, with quality of life worsening while on therapy, but by week 19, it was not statistically different from screening. Limitations include single-arm design and small patient numbers.

      Conclusions

      Axitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally advanced nonmetastatic ccRCC.

      Patient summary

      In this prospective clinical trial, we found that axitinib, when given prior to surgery, results in significant shrinking of kidney cancers. Larger studies are needed prior to further clinical use.

      Trial registration

      This clinical trial was registered with clinicaltrials.gov (NCT01263769).

      Keywords

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      References

        • Rixe O.
        • Bukowski R.M.
        • Michaelson M.D.
        • et al.
        Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study.
        Lancet Oncol. 2007; 8: 975-984
        • Rini B.I.
        • Wilding G.
        • Hudes G.
        • et al.
        Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma.
        J Clin Oncol. 2009; 27: 4462-4468
        • Rini B.I.
        • Escudier B.
        • Tomczak P.
        • et al.
        Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
        Lancet. 2011; 378: 1931-1939
      1. Kidney.
        in: Edge S.B. Byrd D.R. Compton C.C. Frita A.G. Greene F.L. Trotti A. AJCC Cancer Staging Manual. ed. 7. Springer, New York, NY2010: 479-489
        • Oken M.M.
        • Creech R.H.
        • Tormey D.C.
        • et al.
        Toxicity and response criteria of the Eastern Cooperative Oncology Group.
        Am J Clin Oncol. 1982; : 5649-5655
        • Cella D.
        • Yount S.
        • Du H.
        • et al.
        Development and validation of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI).
        J Support Oncol. 2006; 4: 191-199
      2. Common Terminology Criteria for Adverse Events (CTCAE), v.4.03. National Cancer Institute Web site. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.

        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Bex A.
        • van der Veldt A.A.
        • Blank C.
        • et al.
        Neoadjuvant sunitinib for surgically complex advanced renal cell cancer of doubtful resectability: initial experience with downsizing to reconsider cytoreductive surgery.
        World J Urol. 2009; 27: 533-539
        • Thomas A.A.
        • Rini B.I.
        • Stephenson A.J.
        • et al.
        Surgical resection of renal cell carcinoma after targeted therapy.
        J Urol. 2009; 182: 881-886
        • Rini B.I.
        • Garcia J.
        • Elson P.
        • et al.
        The effect of sunitinib on primary renal cell carcinoma and facilitation of subsequent surgery.
        J Urol. 2012; 187: 1548-1554
        • Shuch B.
        • Riggs S.B.
        • LaRochelle J.C.
        • et al.
        Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm.
        BJU Int. 2008; 102: 692-696
        • Silberstein J.L.
        • Millard F.
        • Mehrazin R.
        • et al.
        Feasibility and efficacy of neoadjuvant sunitinib before nephron-sparing surgery.
        BJU Int. 2010; 106: 1270-1276
        • Cost N.G.
        • Delacroix Jr., S.E.
        • Sleeper J.P.
        • et al.
        The impact of targeted molecular therapies on the level of renal cell carcinoma vena caval tumor thrombus.
        Eur Urol. 2011; 59: 912-918
        • Bex A.
        • Van der Veldt A.A.
        • Blank C.
        • Meijerink M.R.
        • Boven E.
        • Haanen J.B.
        Progression of a caval vein thrombus in two patients with primary renal cell carcinoma on pretreatment with sunitinib.
        Acta Oncol. 2010; 49: 520-523
        • Gerlinger M.
        • Rowan A.J.
        • Horswell S.
        • et al.
        Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.
        N Engl J Med. 2012; 366: 883-892
        • Abel E.J.
        • Culp S.H.
        • Tannir N.M.
        • et al.
        Primary tumor response to targeted agents in patients with metastatic renal cell carcinoma.
        Eur Urol. 2011; 59: 10-15
        • Rini B.I.
        • Melichar B.
        • Ueda T.
        • et al.
        Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial.
        Lancet Oncol. 2013; 14: 1233-1242
        • Buti S.
        • Porta C.
        Axitinib dose titration: what's the limiting factor?.
        Lancet Oncol. 2013; 14: 1152-1154
        • Dindo D.
        • Demartines N.
        • Clavien P.A.
        Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
        Ann Surg. 2004; 240: 205-213