Objective: To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. Methods: We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. Results: In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45–5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference –1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02–4.3, p = 0.003). Conclusion: The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use.

1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011;61:69–90.
2.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–134.
3.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA: Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584–3590.
4.
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE: Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061–1068.
5.
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N: Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370:2103–2111.
6.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–2281.
7.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–456.
8.
Tamaskar I, Garcia JA, Elson P, Wood L, Mekhail T, Dreicer R, Rini BI, Bukowski RM: Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy. J Urol 2008;179:81–86, discussion 86.
9.
Richter S, Pfister D, Thüer D, Engelmann UH, Heidenreich A: Second-line treatment of progressive metastatic renal cell cancer with temsirolimus following first-line therapy with sunitinib or sorafenib (abstract V684). Onkologie 2008;31:234.
10.
Zimmermann K, Schmittel A, Steiner U, Asemissen AM, Knoedler M, Thiel E, Miller K, Keilholz U: Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib. Oncology 2009;76:350–354.
11.
Shepard DR, Rini BI, Garcia JA, Hutson TE, Elson P, Gilligan T, Nemec C, Lopez R, Borner D, Dreicer R, Bukowski RM: A multicenter prospective trial of sorafenib in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) refractory to prior sunitinib or bevacizumab (abstract). J Clin Oncol 2008;26(suppl):5123.
12.
Choueiri TK, Brick AJ, Mcdermott D, Clement J, Kwabi C, Shah K, Chen K, Duh MS, Neary MP, Oh WK: Treatment and dosing patterns for angiogenesis inhibitor (AIS) therapies in patients with metastatic renal cell carcinoma (mRCC) (abstract). Ann Oncol 2008;19:593.
13.
Heuer R, Eichelberg C, Zacharias M, Heinzer H: Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib. J Urol 2009;181(suppl 1):501.
14.
Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C: Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer 2009;115:61–67.
15.
Di Lorenzo G, Carteni G, Autorino R, Bruni G, Tudini M, Rizzo M, Aieta M, Gonnella A, Rescigno P, Perdona S, Giannarini G, Pignata S, Longo N, Palmieri G, Imbimbo C, De Laurentiis M, Mirone V, Ficorella C, De Placido S: Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol 2009;27:4469–4474.
16.
Sablin MP, Negrier S, Ravaud A, Oudard S, Balleyguier C, Gautier J, Celier C, Medioni J, Escudier B: Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol 2009;182:29–34, discussion 34.
17.
Garcia JA, Hutson TE, Elson P, Cowey CL, Gilligan T, Nemec C, Dreicer R, Bukowski RM, Rini BI: Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab. Cancer 2010;116:5383–5390.
18.
Buchler T, Klapka R, Melichar B, Brabec P, Dusek L, Vyzula R, Abrahamova J: Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma – data from the Czech registry. Ann Oncol 2012;23:395–401.
19.
Herrmann E, Marschner N, Grimm MO, Ohlmann CH, Hutzschenreuter U, Overkamp F, Groschek M, Blumenstengel K, Puhse G, Steiner T: Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma. World J Urol 2011;29:361–366.
20.
Porta C, Procopio G, Carteni G, Sabbatini R, Bearz A, Chiappino I, Ruggeri EM, Re GL, Ricotta R, Zustovich F, Landi L, Calcagno A, Imarisio I, Verzoni E, Rizzo M, Paglino C, Guadalupi V, Bajetta E: Sequential use of sorafenib and sunitinib in advanced renal-cell carcinoma (RCC): an Italian multicentre retrospective analysis of 189 patient cases. BJU Int 2011;108(8 Pt 2):E250–E257.
21.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–247.
22.
R Development Core Team. R: A Language and Environment for Statistical Computing. Vienna, R Foundation for Statistical Computing, 2009 (http://www.R-project.Org).
23.
Rufibach K: Reporttools: R functions to generate latex tables of descriptive statistics. J Stat Soft 2009;31:1–7.
24.
Ambring A, Stierner, U, Anders O, Björholt I: Sorafenib and sunitinib in renal cell cancer: a study based on register data (abstract). J Clin Oncol 2011;29:4600.
25.
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931–1939.
26.
Vickers MM, Choueiri TK, Rogers M, Percy A, Finch D, Zama I, Cheng T, North S, Knox JJ, Kollmannsberger C, McDermott DF, Rini BI, Heng DY: Clinical outcome in metastatic renal cell carcinoma patients after failure of initial vascular endothelial growth factor-targeted therapy. Urology 2010;76:430–434.
27.
Busch J, Seidel C, Kempkensteffen C, Johannsen M, Wolff I, Hinz S, Magheli A, Miller K, Grunwald V, Weikert S: Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors. Eur Urol 2011;60:1163–1170.
28.
Grunwald V, Seidel C, Fenner M, Ganser A, Busch J, Weikert S: Treatment of everolimus-resistant metastatic renal cell carcinoma with VEGF-targeted therapies. Br J Cancer 2011;105:1635–1639.
29.
Calvo E, Escudier B, Motzer RJ, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Ravaud A, Kim D, Panneerselvam A, Anak O, Figlin RA: Everolimus in metastatic renal cell carcinoma: subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer 2012;48:333–339.
30.
Porta C, Bellmunt J, Eisen T, Szczylik C, Mulders P: Treating the individual: the need for a patient-focused approach to the management of renal cell carcinoma. Cancer Treat Rev 2010;36:16–23.
31.
Escudier BJ, Bellmunt J, Negrier S, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S: Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-α2a (IFN) in metastatic renal cell carcinoma (mRCC) (abstract). J Clin Oncol 2009;27(suppl):5020.
32.
Porta C, Procopio G, Carteni G, Sabbatini R, Bearz A, Chiappino I, Ruggeri EM, Lo Re G, Ricotta R, Zustovich F: An Italian multicentre retrospective analysis of 189 advanced renal-cell carcinoma patients treated sequentially, either with sorafenib followed by sunitinib, or vice versa (abstract 922P). Ann Oncol 2010;21:viii289.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.