Cancer Chemotherapy and Pharmacology

, Volume 60, Issue 1, pp 135–141 | Cite as

A phase II trial of continuous low-dose oral cyclophosphamide and celecoxib in patients with renal cell carcinoma

  • Monika K. Krzyzanowska
  • Ian F. Tannock
  • Gina Lockwood
  • Jennifer Knox
  • Malcolm Moore
  • Georg A. Bjarnason
Clinical Trial Report

Abstract

Purpose

The lack of effective systemic therapies for patients with advanced renal cell carcinoma (RCC) has stimulated interest in evaluating novel treatment strategies for this disease.

Methods

This was a two-institution, two-stage, phase II trial of continuous low-dose oral cyclophosphamide (50 mg daily) in combination with celecoxib (400 mg twice daily) in patients with progressive, locally advanced or metastatic RCC. The primary endpoint was disease control rate (DCR) defined as the number of patients with complete (CR) or partial response (PR) or prolonged (≥6 months) stable disease (SD). Secondary endpoints included time to progression and toxicity.

Results

Between May 2001 and January 2003, 36 patients were enrolled onto the trial of which 32 were evaluable for response. One patient had a PR and three others had SD for longer than 6 months (DCR 12.5%, 95% CI 3.5–29.0%). The median progression free survival was 3.5 months (95% CI, 1.9–4.1 months) and the median overall survival was 14.5 months (95% CI, 8.4–20.8 months). One patient experienced grade five gastrointestinal bleeding. Otherwise, the treatment was well tolerated.

Conclusions

Although generally well tolerated, continuous therapy with low-dose cyclophosphamide and celecoxib had limited activity in RCC.

References

  1. 1.
    Yagoda A, Abi-Rached B, Petrylak D (1995) Chemotherapy for advanced renal-cell carcinoma: 1983–1993. Semin Oncol 22:42–60PubMedGoogle Scholar
  2. 2.
    Fojo AT, Shen DW, Mickley LA et al (1987) Intrinsic drug resistance in human kidney cancer is associated with expression of a human multidrug-resistance gene. J Clin Oncol 5:1922–1927PubMedGoogle Scholar
  3. 3.
    Negrier S, Escudier B, Lasset C et al (1998) Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med 338:1272–1278PubMedCrossRefGoogle Scholar
  4. 4.
    Bukowski RM (1997) Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin-2. Cancer 80:1198–1220PubMedCrossRefGoogle Scholar
  5. 5.
    Medical Research Council Renal Cancer Collaborators (1999) Interferon-alpha, survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 353:14–17Google Scholar
  6. 6.
    Brown LF, Berse B, Jackman RW et al (1993) Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 143:1255–1262PubMedGoogle Scholar
  7. 7.
    Nicol D, Hii SI, Walsh M et al (1997) Vascular endothelial growth factor expression is increased in renal cell carcinoma. J Urol 157:1482–1486PubMedCrossRefGoogle Scholar
  8. 8.
    Wechsel HW, Bichler KH, Feil G et al (1999) Renal cell carcinoma: relevance of angiogenetic factors. Anticancer Res 19:1537–1540PubMedGoogle Scholar
  9. 9.
    Linehan WM, Lerman MI, Zbar B (1995) Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer. JAMA 273:564–570PubMedCrossRefGoogle Scholar
  10. 10.
    Mulders P, Figlin R, deKernion JB et al (1997) Renal cell carcinoma: recent progress and future directions. Cancer Res 57:5189–5195PubMedGoogle Scholar
  11. 11.
    Gnarra JR, Zhou S, Merrill MJ et al (1996) Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA 93:10589–10594PubMedCrossRefGoogle Scholar
  12. 12.
    Schirner M, Hoffmann J, Menrad A et al (1998) Antiangiogenic chemotherapeutic agents: characterization in comparison to their tumor growth inhibition in human renal cell carcinoma models. Clin Cancer Res 4:1331–1336PubMedGoogle Scholar
  13. 13.
    Vacca A, Iurlaro M, Ribatti D et al (1999) Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 94:4143–4155PubMedGoogle Scholar
  14. 14.
    Browder T, Butterfield CE, Kraling BM et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886PubMedGoogle Scholar
  15. 15.
    Dana BW, Alberts DS (1981) Combination chemoimmunotherapy for advanced renal carcinoma with Adriamycin, bleomycin, vincristine, cyclophosphamide, plus BCG. Cancer Clin Trials 4:205–207PubMedGoogle Scholar
  16. 16.
    Lupera H, Theodore C, Ghosn M et al (1989) Phase II trial of combination chemotherapy with dacarbazine, cyclophosphamide, cisplatin, doxorubicin, and vindesine (DECAV) in advanced renal cell cancer. Urology 34:281–283PubMedCrossRefGoogle Scholar
  17. 17.
    Lindemann A, Hoeffken K, Schmidt RE et al (1989) A multicenter trial of interleukin-2 and low-dose cyclophosphamide in highly chemotherapy-resistant malignancies. Cancer Treat Rev 16(Suppl A):53–57PubMedCrossRefGoogle Scholar
  18. 18.
    Glover D, Trump D, Kvols L et al (1986) Phase II trial of misonidazole (MISO) and cyclophosphamide (CYC) in metastatic renal cell carcinoma. Int J Radiat Oncol Biol Phys 12:1405–1408PubMedGoogle Scholar
  19. 19.
    Berd D, Mastrangelo MJ (1988) Effect of low dose cyclophosphamide on the immune system of cancer patients: depletion of CD4+, 2H4+ suppressor-inducer T-cells. Cancer Res 48:1671–1675PubMedGoogle Scholar
  20. 20.
    Motoyoshi Y, Kaminoda K, Saitoh O et al (2006) Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide. Oncol Rep 16:141–146PubMedGoogle Scholar
  21. 21.
    Klement G, Baruchel S, Rak J et al (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15–R24PubMedCrossRefGoogle Scholar
  22. 22.
    Colleoni M, Rocca A, Sandri MT et al (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13:73–80PubMedCrossRefGoogle Scholar
  23. 23.
    Fosslien E (2000) Molecular pathology of cyclooxygenase-2 in neoplasia. Ann Clin Lab Sci 30:3–21PubMedGoogle Scholar
  24. 24.
    Chen Q, Shinohara N, Abe T et al (2004) Significance of COX-2 expression in human renal cell carcinoma cell lines. Int J Cancer 108:825–832PubMedCrossRefGoogle Scholar
  25. 25.
    Miyata Y, Koga S, Kanda S et al (2003) Expression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival. Clin Cancer Res 9:1741–1749PubMedGoogle Scholar
  26. 26.
    Hashimoto Y, Kondo Y, Kimura G et al (2004) Cyclooxygenase-2 expression and relationship to tumour progression in human renal cell carcinoma. Histopathology 44:353–359PubMedCrossRefGoogle Scholar
  27. 27.
    Tuna B, Yorukoglu K, Gurel D et al (2004) Significance of COX-2 expression in human renal cell carcinoma. Urology 64:1116–1120PubMedCrossRefGoogle Scholar
  28. 28.
    Masferrer JL, Leahy KM, Koki AT et al (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311PubMedGoogle Scholar
  29. 29.
    Reddy BS, Hirose Y, Lubet R et al (2000) Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res 60:293–297PubMedGoogle Scholar
  30. 30.
    Moore RJ, Zweifel BS, Heuvelman DM et al (2000) Enhanced antitumor activity by co-administration of celecoxib and the chemotherapeutic agents cyclophosphamide and 5-FU. Proc Am Assoc Cancer Res 41:409 (abstr 2600)Google Scholar
  31. 31.
    Steinbach G, Lynch PM, Phillips RK et al (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946–1952PubMedCrossRefGoogle Scholar
  32. 32.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10PubMedCrossRefGoogle Scholar
  33. 33.
    Psaty BM, Furberg CD (2005) COX-2 inhibitors–lessons in drug safety. N Engl J Med 352:1133–1135PubMedCrossRefGoogle Scholar
  34. 34.
    Escudier B, Lassau N, Couanet D et al (2002) Phase II trial of thalidomide in renal-cell carcinoma. Ann Oncol 13:1029–1035PubMedCrossRefGoogle Scholar
  35. 35.
    Stadler WM, Kuzel T, Shapiro C et al (1999) Multi-institutional study of the angiogenesis inhibitor TNP-470 in metastatic renal carcinoma. J Clin Oncol 17:2541–2545PubMedGoogle Scholar
  36. 36.
    Rini BI, Weinberg V, Dunlap S et al (2006) Maximal COX-2 immunostaining and clinical response to celecoxib and interferon alpha therapy in metastatic renal cell carcinoma. Cancer 106:566–575PubMedCrossRefGoogle Scholar
  37. 37.
    Escudier B, Szczylik C, Eisen T et al (2005) Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 23(suppl 16S):1093s (abstr 4510)Google Scholar
  38. 38.
    Motzer RJ, Michaelson MD, Redman BG et al (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24PubMedCrossRefGoogle Scholar
  39. 39.
    Yang JC, Haworth L, Sherry RM et al (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434PubMedCrossRefGoogle Scholar
  40. 40.
    Motzer RJ, Mazumdar M, Bacik J et al (1999) Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17:2530–2540PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Monika K. Krzyzanowska
    • 1
  • Ian F. Tannock
    • 1
  • Gina Lockwood
    • 2
  • Jennifer Knox
    • 1
  • Malcolm Moore
    • 1
  • Georg A. Bjarnason
    • 3
  1. 1.Department of Medical Oncology and HematologyPrincess Margaret HospitalTorontoCanada
  2. 2.Department of BiostatisticsPrincess Margaret HospitalTorontoCanada
  3. 3.Department of Medical Oncology and HematologyToronto-Sunnybrook Regional Cancer CenterTorontoCanada

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