Skip to main content

Advertisement

SpringerLink
Log in

Designing clinical trials for kidney cancer based on newly developed prognostic and predictive tools

  • Published:
Current Urology Reports Aims and scope Submit manuscript

Abstract

Several advances have been made in our understanding of the molecular aberrations in renal cell carcinoma that have led to the identification of novel prognostic and predictive biomarkers. At the same time, several novel agents targeting these molecular aberrations have shown promising efficacy in the therapy of advanced renal cancer. As these agents enter more advancedstage clinical trials, efforts must be made to integrate exploration of these novel prognostic and predictive markers into clinical trial design. These elements then can be combined with more traditional prognostic features to form more robust prognostic models. Finally, predictive markers and prognostic models should be validated prospectively, either as part of clinical trials designed specifically for that purpose or as part of large phase-3 trials. Once validated, these features can be used to best inform prognosis and guide therapy based on individual patient characteristics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Jemal A, Murray T, Ward E, et al.: Cancer Statistics, 2005. CA Cancer J Clin 2005, 55:10–30.

    Article  PubMed  Google Scholar 

  2. Janzen NK, Kim HL, Figlin RA, Belldegrun AS: Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003, 30:843.

    Article  PubMed  Google Scholar 

  3. Fyfe GA, Fisher RI, Rosenberg SA, et al.: Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy. J Clin Oncol 1996, 14:2410–2411.

    Google Scholar 

  4. Rosenberg S, Yang J, Top, et al.: Treatment of 283 patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin-2. JAMA 1994, 271:907–913.

    Article  PubMed  CAS  Google Scholar 

  5. Yang JC, Sherry RM, Steinberg SM, et al.: Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003, 21:3127–3132.

    Article  PubMed  CAS  Google Scholar 

  6. Pyrhonen S, Salminen E, Ruutu M, et al.: Prospective, randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 1999, 17:2859–2867.

    PubMed  CAS  Google Scholar 

  7. Medical Research Council and Collaborators: Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 1999, 353:14–17.

    Article  Google Scholar 

  8. Tsui KH, Shvarts O, Smith RB, et al.: Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TMN staging criteria. J Urol 2000, 163:1090–1095.

    Article  PubMed  CAS  Google Scholar 

  9. Lam JS, Shvarts O, Leppert JT, et al.: Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005, 173:1853–1862. An in-depth review of the current status of staging and methods of prognostication.

    Article  PubMed  Google Scholar 

  10. Lohse CM, Cheville JC: A review of prognostic pathologic features and algorithms for patients treated surgically for renal cell carcinoma. Clin Lab Med 2005, 25:433–464.

    Article  PubMed  Google Scholar 

  11. Kim HL, Zisman A, Han KR, et al.: Prognostic significance of venous thrombus in renal cell carcinoma: Are renal vein and inferior vena cava involvement different? J Urol 2004, 171:588–591.

    Article  PubMed  Google Scholar 

  12. Pantuck AJ, Zisman A, Dorey F, et al.: Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 2003, 169:899.

    Article  PubMed  Google Scholar 

  13. Vasselli JR, Yang JC, Linehan WM, et al.: Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma. J Urol 2001, 166:68–72.

    Article  PubMed  CAS  Google Scholar 

  14. Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982, 6:655–663.

    Article  PubMed  CAS  Google Scholar 

  15. Kovacs G, Akhtar M, Beckwith BJ, et al.: The Heidelberg classification of renal cell tumours. J Pathol 1997, 183:131–133.

    Article  PubMed  CAS  Google Scholar 

  16. Reuter VE, Presti JC Jr: Contemporary approach to the classification of renal epithelial tumors. Semin Onc 2000, 27:124–137.

    CAS  Google Scholar 

  17. Cheville JC, Lohse CM, Zincke H, et al.: Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Sug Pathol 2003, 27:612–624.

    Article  Google Scholar 

  18. Patard JJ, Rioux-Leclercq N, Cindolo L, et al.: The prognostic value of histologic subtypes in renal cell carcinoma (RCC): a multicenter experience in 4063 patients [Abstract 1757]. J Urol 2004, 171(suppl):464.

    Article  Google Scholar 

  19. Motzer RJ, Bacik J, Mariani T, et al.: Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear cell histology. J Clin Oncol 2002, 20:2376–2381.

    Article  PubMed  Google Scholar 

  20. Upton MP, Parker RA, Youmans A, et al.: Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother 2005, 28:488–495.

    Article  PubMed  CAS  Google Scholar 

  21. Motzer RJ, Mazumdar M, Bacik J, et al.: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999, 17:3530–3540.

    Google Scholar 

  22. Escudier B, Venner P, Stern L, et al.: Prognostic factors in metastatic renal cell carcinoma after failure of immunotherapy: lessons from a large phase-III trial. J Clin Oncol 2004, 22(suppl):4547.

    Google Scholar 

  23. Motzer RJ, Bacik J, Murphy BA, et al.: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002, 20:289–296.

    Article  PubMed  CAS  Google Scholar 

  24. Motzer RJ, Bacik J, Schwartz LH, et al.: Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004, 22:454–463.

    Article  PubMed  Google Scholar 

  25. Frank I, Blute ML, Cheville JC, et al.: An outcome prediction model for patients with clear cell renal carcinoma treated with radical nephrectomy based on tumor stage, size, grade, and necrosis: the SSIGN score. J Urol 2002, 168:2395–2400.

    Article  PubMed  Google Scholar 

  26. Zisman A, Pantuck AJ, Dorey F, et al.: Improved prognostication of RCC using an integrated staging system. J Clin Oncol 2001, 19:1649–1657.

    PubMed  CAS  Google Scholar 

  27. Zisman A, Pantuck AJ, Wieder J, et al.: Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 2002, 20:4559–4566.

    Article  PubMed  Google Scholar 

  28. Kenck C, Wilhelm M, Bugert P, et al.: Mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinomas. J Pathol 1996, 179:157–161.

    Article  Google Scholar 

  29. Foster K, Prowse A, van den Berg A, et al.: Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet 1994, 3:2169–2173.

    Article  PubMed  CAS  Google Scholar 

  30. Jaakkola P, Mole DR, Tian YM, et al.: Targeting of HIFalpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001, 292:468–472.

    PubMed  CAS  Google Scholar 

  31. Iliopoulos O, Kibel A, Gray S, et al.: Tumour suppression by the human von Hippel-Lindau gene product. Nat Med 1995, 1:822–826.

    Article  PubMed  CAS  Google Scholar 

  32. de Paulsen N, Brychzy A, Fournier MC, et al.: Role of transforming growth factor-alpha in von Hippel-Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: a possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci U S A 2000, 98:1387–1392.

    Article  Google Scholar 

  33. Kondo K, Kico J, Nakamura E, et al.: Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002, 1:237–246.

    Article  PubMed  CAS  Google Scholar 

  34. Bui MH, Seligson D, Han KR, et al.: Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res 2003, 9:802–811.

    PubMed  CAS  Google Scholar 

  35. Atkins M, Regan M, McDermott D, et al.: Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 2005, 11:3714–3721.

    Article  PubMed  CAS  Google Scholar 

  36. Thompson RH, Gillet MD, Cheville JC, et al.: Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 2004, 101:17174–17179.

    Article  PubMed  CAS  Google Scholar 

  37. Kim HL, Seligson D, Liu X, et al.: Molecular prognostic modeling using protein expression profile in clear cell renal carcinoma. J Urol 2004, 171:436. The authors propose a novel prognostic model integrating certain molecular features with clinical and histopathologic factors.

    Google Scholar 

  38. Takahashi M, Rhodes DR, Furge KA, et al.: Gene expression profiling and clear cell renal cell carcinoma: gene identification and prognostic classification. Proc Natl Acad Sci USA 2004, 98:9754–9759.

    Article  Google Scholar 

  39. Febbo P, Signoretti S, Regan M, et al.: Gene expression patterns associated with renal cancer (RCC) response and resistance to IL-2 based therapy. J Immunother 2004, 27:S12-S13.

    Article  Google Scholar 

  40. Pantuck AJ, Fang Z, Liu X, et al.: Gene expression and tissue microarray analysis of interleukin-2 complete responders in patients with metastatic renal cell carcinoma. ASCO Proceedings 2005, 24:4535.

    Google Scholar 

  41. Simon R, Wittes RE, Ellenberg SS: Randomized phase-II clinical trials. Cancer Treat Rep 1985, 69:1375–1381.

    PubMed  CAS  Google Scholar 

  42. Ratain MJ, Eisen T, Stadler WM, et al.: Final findings from a phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43-9006 in patients with advanced renal cell carcinoma (RCC) [Abstract 4544]. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando: May 13–17, 2005.

  43. Friedlin B, Simon R: Evaluation of randomized discontinuation design. J Clin Oncol 2005, 23:5094–5098.

    Article  Google Scholar 

  44. McDermott DH, Regan MM, Clark DI, et al.: Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005, 23:2877.

    Google Scholar 

  45. Sargent DJ, Conley BA, Allegra C, Collette L: Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol 2005, 23:2020–2027. A comprehensive review of strategies for designing clinical trials for the specific purpose of prospectively validating predictive markers.

    Article  PubMed  Google Scholar 

  46. Flanigan RC, Salmon SE, Blumenstein BA, et al.: Nephrectomy followed by interferon-alpha-2b compared with interferon-alpha-2b alone for metastatic renal-cell cancer. N Engl J Med 2001, 345:1655–1659.

    Article  PubMed  CAS  Google Scholar 

  47. Mickisch GH, Garin A, van Poppel H, et al.: European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alpha-based immunotherapy compared with interferon alpha alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001, 358:966–970.

    Article  PubMed  CAS  Google Scholar 

  48. Fallick ML, McDermott DF, LaRock D, et al.: Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma. J Urol 1997, 158:1691–1695.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Beth Israel Deaconess Medical Center, Kirstein 157, 330 Brookline Avenue, 02215, Boston, MA, USA

    Michael Atkins MD

Authors
  1. Daniel Cho MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David McDermott MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Atkins MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Atkins MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cho, D., McDermott, D. & Atkins, M. Designing clinical trials for kidney cancer based on newly developed prognostic and predictive tools. Curr Urol Rep 7, 8–15 (2006). https://doi.org/10.1007/s11934-006-0032-y

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11934-006-0032-y

Keywords

Search

Navigation