Clinical Pharmacokinetics

, Volume 45, Issue 6, pp 611–622 | Cite as

Predicting the Toxicity of Weekly Docetaxel in Advanced Cancer

  • Kellie A. Charles
  • Laurent P. Rivory
  • Martin R. Stockier
  • Philip Beale
  • Jane Beith
  • Michael Boyer
  • Stephen J. Clarke
Original Research Article

Abstract

Objectives

To determine the safety profile of 40 mg/m2 docetaxel administered weekly to a mixed population of advanced cancer patients and identify predictors of toxicity and survival following treatment with weekly docetaxel in this population.

Patients and methods

68 patients with advanced cancer were enrolled into the study. Various patient characteristics, including inflammatory and nutritional status, docetaxel pharmacokinetics and liver function were investigated. Predictors of treatment-related toxicity and survival were analysed using multivariate logistic regression and Cox proportional hazards analysis, respectively.

Results

27 patients (40%) experienced grade 3 or 4 toxicity, mainly gastrointestinal toxicities (20%), leukopenia (16%) and neutropenia (12%), during the first 8 weeks of docetaxel treatment. Docetaxel pharmacokinetics were the only predictive factor for haematological toxicity. The odds of severe haematological toxicity were approximately 9-fold higher for patients with reduced docetaxel clearance (e.g. <30 L/h). The odds of non-haematological toxicity were about 3-fold higher for patients with elevated levels of inflammatory markers: α1-acid glycoprotein (AAGP) >1.5 g/L or C-reactive protein >10 mg/L). Multivariate analysis indicated that weight loss, liver dysfunction and elevated levels of AAGP were independently significant predictors of survival.

Conclusion

This is the first description of factors predictive of the toxicity and survival following weekly administration of docetaxel. Patients with reduced clearance of docetaxel and elevated markers of inflammation experienced worse adverse effects, while patients with weight loss, liver dysfunction and elevated markers of inflammation had worse survival.

References

  1. 1.
    Bruno R, Vivier N, Vergniol JC, et al. A population pharmacokinetic model for docetaxel (Taxotere): model building and validation. J Pharmacokinetic Biopharm 1996 Apr; 24(2): 153–72Google Scholar
  2. 2.
    Yamamoto N, Tamura T, Kamiya Y, et al. Correlation between docetaxel clearance and estimated cytochrome P450 activity by urinary metabolite of exogenous Cortisol. J Clin Oncol 2000 Jun; 18(11): 2301–8PubMedGoogle Scholar
  3. 3.
    Hirth J, Watkins PB, Strawderman M, et al. The effect of an individual’s cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res 2000 Apr; 6(4): 1255–8PubMedGoogle Scholar
  4. 4.
    Rougier P, Adenis A, Ducreux M, et al. A phase II study: docetaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma. Eur J Cancer 2000 May; 36(8): 1016–25PubMedCrossRefGoogle Scholar
  5. 5.
    Couteau C, Chouaki N, Leyvraz S, et al. A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck. Br J Cancer 1999 Oct; 81(3): 457–62PubMedCrossRefGoogle Scholar
  6. 6.
    Bruno R, Hille D, Riva A, et al. Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 1998 Jan; 16(1): 187–96PubMedGoogle Scholar
  7. 7.
    Greco FA. Docetaxel (taxotere) administered in weekly schedules. Semin Oncol 1999 Jun; 26 (3 Suppl 11): 28–31PubMedGoogle Scholar
  8. 8.
    Hainsworth JD, Burris III HA, Greco FA. Weekly administration of docetaxel (taxotere): summary of clinical data. Semin Oncol 1999 Jun; 26 (3 Suppl 10): 19–24PubMedGoogle Scholar
  9. 9.
    Loffler TM. Is there a place for ‘dose-dense’ weekly schedules of the taxoids? Semin Oncol 1998 Oct; 25(5 Suppl. 12): 32–4PubMedGoogle Scholar
  10. 10.
    Burstein HJ, Manola J, Younger J, et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000 Mar; 18(6): 1212–9PubMedGoogle Scholar
  11. 11.
    Hainsworth JD, Burris III HA, Greco FA. Weekly docetaxel as a single agent and in combination with gemcitabine in elderly and poor performance status patients with advanced non-small cell lung cancer. Semin Oncol 2001 Jun; 28 (3 Suppl. 9): 21–5PubMedCrossRefGoogle Scholar
  12. 12.
    Gusmao AB, Bines J, Martins RG, et al. Primary chemotherapy with weekly docetaxel (Taxotere) in poor prognosis advanced breast cancer [abstract]. Proc Am Soc Clin Oncol 2002; 21: 42bGoogle Scholar
  13. 13.
    Gervais R, Ducolone AMD, Breton J-L, et al. Mult-centre, randomised, Phase II trial of docetaxel (Taxotere) 75mg.m2 q3w versus 40mg/m2 weekly in patients with pretreated nonsmall cell lung cancer [abstract]. Proc Am Soc Clin Oncol 2002; 21: 310aGoogle Scholar
  14. 14.
    Sedky L, Saad El-Dine I, Hashem B, et al. Weekly docetaxel vs every 3-week in advanced breast cancer: results of a pilot comparative study [abstract]. Proc Am Soc Clin Oncol 2002; 21: 50bGoogle Scholar
  15. 15.
    Slaviero KA, Clarke SJ, McLachlan AJ, et al. Population pharmacokinetics of weekly docetaxel in patients with advanced cancer. Br J Clin Pharmacol 2004 Jan; 57(1): 44–53PubMedCrossRefGoogle Scholar
  16. 16.
    Falconer JS, Fearon KC, Ross JA, et al. Acute-phase protein response and survival duration of patients with pancreatic cancer. Cancer 1995 Apr 15; 75(8): 2077–82PubMedCrossRefGoogle Scholar
  17. 17.
    Nozoe T, Matsumata T, Kitamura M, et al. Significance of preoperative elevation of serum C-reactive protein as an indicator for prognosis in colorectal cancer. Am J Surg 1998 Oct; 176(4): 335–8PubMedCrossRefGoogle Scholar
  18. 18.
    Mahmoud FA, Rivera N. The role of C-reactive protein as a prognostic indicator in advanced cancer. Curr Oncol Rep 2002 May; 4(3): 250–5PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang GJ, Adachi I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res 1999 Mar–Apr; 19(2B): 1427–32PubMedGoogle Scholar
  20. 20.
    Extermann M. Comprehensive geriatric assessment basics for the cancer professional. J Oncol Manag 2003 Mar–Apr; 12(2): 13–7PubMedGoogle Scholar
  21. 21.
    Slaviero KA, Read JA, Clarke SJ, et al. Baseline nutritional assessment in advanced cancer patients receiving palliative chemotherapy. Nutr Cancer 2003; 46(2): 148–57PubMedCrossRefGoogle Scholar
  22. 22.
    Guigoz Y, Vellas B, Garry PJ. Assessing the nutritional status of the elderly: the mini nutritional assessment as part of the geriatric evaluation. Nutr Rev 1996 Jan; 54 (1 Pt 2): S59–65PubMedCrossRefGoogle Scholar
  23. 23.
    Rivory LP, Slaviero K, Seale JP, et al. Optimizing the erythromycin breath test for use in cancer patients. Clin Cancer Res 2000 Sep; 6(9): 3480–5PubMedGoogle Scholar
  24. 24.
    Bruno R, Olivares R, Berille J, et al. alpha-1-acid glycoprotein as an independent predictor for treatment effect and a prognostic factor of survival in patients with non-small cell lung cancer treated with docetaxel. Clin Cancer Res 2003 Mar; 9(3): 1077–82PubMedGoogle Scholar
  25. 25.
    Graf W, Pahlman L, Bergstrom R, et al. The relationship between an objective response to chemotherapy and survival in advanced colorectal cancer. Br J Cancer 1994 Sep; 70(3): 559–63PubMedCrossRefGoogle Scholar
  26. 26.
    Buyse M, Thirion P, Carlson RW, et al. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Lancet 2000 Jul 29; 356(9227): 373–8PubMedCrossRefGoogle Scholar
  27. 27.
    Salgado R, Junius S, Benoy I, et al. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer 2003 Feb 20; 103(5): 642–6PubMedCrossRefGoogle Scholar
  28. 28.
    Engelken FJ, Bettschart V, Rahman MQ, et al. Prognostic factors in the palliation of pancreatic cancer. Eur J Surg Oncol 2003 May; 29(4): 368–73PubMedCrossRefGoogle Scholar
  29. 29.
    McMillan DC, Canna K, McArdle CS. Systemic inflammatory response predicts survival following curative resection of colorectal cancer. Br J Surg 2003 Feb; 90(2): 215–9PubMedCrossRefGoogle Scholar
  30. 30.
    Scott HR, McMillan DC, Forrest LM, et al. The systemic inflammatory response, weight loss, performance status and survival in patients with inoperable non-small cell lung cancer. Br J Cancer 2002 Jul 29; 87(3): 264–7PubMedCrossRefGoogle Scholar
  31. 31.
    Thompson DK, Haddow JE, Smith DE, et al. Elevated serum acute phase protein levels as predictors of disseminated disease. Cancer 1983 Jun 1; 51(11): 2100–4PubMedCrossRefGoogle Scholar
  32. 32.
    Ardestani SK, Inserra P, Solkoff D, et al. The role of cytokines and chemokines on tumor progression: a review. Cancer Detect Prev 1999; 23(3): 215–25PubMedCrossRefGoogle Scholar
  33. 33.
    Balkwill F. Cytokine amplification and inhibition of immune and inflammatory responses. J Viral Hepat 1997; 4 Suppl. 2: 6–15PubMedCrossRefGoogle Scholar
  34. 34.
    Hirano T. Interleukin-6 and its relation to inflammation and disease. Clin Immunol Immunopathol 1992 Jan; 62 (1 Pt 2): S60–5PubMedCrossRefGoogle Scholar
  35. 35.
    Kulmatycki KM, Jamali F. Therapeutic relevance of altered cytokine expression. Cytokine 2001 Apr 7; 14(1): 1–10PubMedCrossRefGoogle Scholar
  36. 36.
    Deeg HJ, Scidel K, Bruemmer B, et al. Impact of weight loss on non-relapse mortality after marrow transplantation. Bone Marrow Transplant 1995 Mar; 15(3): 461–8PubMedGoogle Scholar
  37. 37.
    Andreyev HJ, Norman AR, Oates J, et al. Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur J Cancer 1998 Mar; 34(4): 503–9PubMedCrossRefGoogle Scholar
  38. 38.
    Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med 1980 Oct; 69(4): 491–7PubMedCrossRefGoogle Scholar
  39. 39.
    Thoresen L, Fjeldstad I, Krogstad K, et al. Nutritional status of patients with advanced cancer: the value of using the subjective global assessment of nutritional status as a screening tool. Palliat Med 2002 Jan; 16(1): 33–42PubMedCrossRefGoogle Scholar
  40. 40.
    Zulian GB, Gold G, Herrmann F, et al. Mini nutritional assessment and cancer. Nestle Nutr Workshop Ser Clin Perform Programme 1999; 1: 93-8, 99–100Google Scholar
  41. 41.
    Persson C, Glimelius B. The relevance of weight loss for survival and quality of life with advanced gastrointestinal cancer treated with palliative chemotherapy. Anticancer Res 2002 Nov-Dec; 22(6B): 3661–8PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Kellie A. Charles
    • 1
  • Laurent P. Rivory
    • 1
    • 2
  • Martin R. Stockier
    • 2
    • 3
  • Philip Beale
    • 2
  • Jane Beith
    • 2
  • Michael Boyer
    • 2
  • Stephen J. Clarke
    • 2
  1. 1.Department of PharmacologyUniversity of SydneySydneyAustralia
  2. 2.Department of Medical Oncology, Level 6 Gloucester HouseSydney Cancer CentreCamperdown, SydneyAustralia
  3. 3.Division of Medicine and School of Public HealthUniversity of SydneySydneyAustralia

Personalised recommendations