Let's talk about cytotoxic chemotherapy dosing: unravelling adjustments and off‐protocol prescribing

Angelina Tjokrowidjaja, Elizabeth Hovey and Craig R Lewis
Med J Aust 2019; 210 (2): . || doi: 10.5694/mja2.12072
Published online: 4 February 2019

Individualised dosing is important in cancer treatment in real‐world settings and may require departure from trial‐based protocols

Adequate and appropriate dosing of cytotoxic chemotherapy is an important issue, highlighted recently by public concerns about underdosing.1,2,3 Most cytotoxic agents have a steep dose–response curve and narrow therapeutic index. Underdosing may have significant implications for patient outcomes, while overdosing can result in life‐threatening adverse effects.1 Cancer chemotherapy dosing differs from drug prescribing in other areas of medicine. Phase 1 trials in patients with cancer identify safety and dose‐limiting toxicities, and determine the maximum tolerated dose and recommended phase 2 dose. Phase 2 trials focus on efficacy assessment within specific tumour types.4,5 Phase 3 trials, considered the key criteria for approval by drug regulatory agencies, validate the efficacy of the drug compared with a standard of care. A challenge has emerged with new molecularly targeted agents and immuno‐oncology drugs frequently having different toxicity profiles to chemotherapy, which may not be dose or time dependent. Accordingly, the traditional phase 1 and 2 model may not be as adaptable, resulting in evolution of trial design, such as phase 1 trials combining safety and efficacy expansion cohorts.6

  • 1 Prince of Wales Hospital and Community Health Services, Sydney, NSW
  • 2 Prince of Wales Clinical School, University of New South Wales, Sydney, NSW

Competing interests:

No relevant disclosures.

  • 1. Frei E, Canellos GP. Dose: A critical factor in cancer chemotherapy. Am J Med 1980; 69: 585–594.
  • 2. Gerathy S, Woodburn J. Chemotherapy under‐dosing: investigation finds 28 patients affected in western NSW hospitals. ABC News 2016; 20 Sept. (viewed Oct 2017).
  • 3. Andreatta D. Dilution of chemo drugs was result of ‘gaps in communication,’ report says. Globe and Mail 2013; 7 Aug. (viewed Oct 2017).
  • 4. Eisenhauer EA, O'Dwyer PJ, Christian M, Humphrey JS. Phase I clinical trial design in cancer drug development. J Clin Oncol 2000; 18: 684–692.
  • 5. Kummar S, Gutierrez M, Doroshaw JH, Murgo AJ. Drug development in oncology: classical cytotoxics and molecularly targeted agents. Br J Clin Pharmacol 2006; 62: 15–26.
  • 6. Kern K. Trial design and efficacy thresholds for granting breakthrough therapy designation in oncology. J Oncol Pract 2016; 12: e810–e817.
  • 7. Mathijssen RH, de Jong FA, Loos WJ, et al. Flat‐fixed dosing versus body surface area–based dosing of anticancer drugs in adults: does it make a difference? Oncologist 2007; 12: 913–923.
  • 8. Du Bois D, Du Bois E. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916; 17: 863.
  • 9. Field KM, Kosmider S, Jefford M, et al. Chemotherapy dosing strategies in the obese, elderly, and thin patient: results of a nationwide survey. J Oncol Pract 2008; 4: 108–113.
  • 10. Griggs JJ, Sorbero ME, Lyman GH. Undertreatment of obese women receiving breast cancer chemotherapy JAMA Int Med 2005; 165: 1267–1273.
  • 11. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2012; 30: 1553–1561.
  • 12. Bonadonna G, Valagussa P. Dose‐response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981; 304: 10–15.
  • 13. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose‐dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node‐positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21: 1431–1439.
  • 14. Gray R, Bradley R, Braybrooke J, et al. Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: an EBCTCG meta‐analysis of 21,000 women in 16 randomised trials [abstract]. Abstracts from the 40th Annual San Antonio Breast Cancer Symposium; 2017 Dec 5‐9; San Antonio, Texas. (viewed May 2018).
  • 15. Grimison PS, Stockler MR, Thomson DB, et al. Comparison of two standard chemotherapy regimens for good‐prognosis germ cell tumors: updated analysis of a randomized trial. J Natl Cancer Inst 2010; 102: 1253–1262.
  • 16. Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node‐positive breast cancer: the results of 20 years of follow‐up. N Engl J Med 1995; 332: 901–906.
  • 17. Wildiers H, Reiser M. Relative dose intensity of chemotherapy and its impact on outcomes in patients with early breast cancer or aggressive lymphoma. Crit Rev Oncol Hematol 2011; 77: 221–240.
  • 18. Lyman GH, Dale DC, Crawford J. Incidence and predictors of low dose‐intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J Clin Oncol 2003; 21: 4524–4531.
  • 19. Denduluri N, Patt DA, Wang Y, et al. Dose delays, dose reductions, and relative dose intensity in patients with cancer who received adjuvant or neoadjuvant chemotherapy in community oncology practices. J Natl Compr Canc Netw 2015; 13: 1383–1393.
  • 20. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration‐resistant prostate cancer progressing after docetaxel treatment: a randomised open‐label trial. Lancet 2010; 376: 1147–1154.
  • 21. Tannock IF, Boyd NF, DeBoer G, et al. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 1988; 6: 1377–1387.
  • 22. Loibl S, Skacel T, Nekljudova V, et al. Evaluating the impact of relative total dose intensity (RTDI) on patients’ short and long‐term outcome in taxane‐ and anthracycline‐based chemotherapy of metastatic breast cancer—a pooled analysis. BMC Cancer 2011; 11: 131.
  • 23. Hanna RK, Poniewierski MS, Laskey RA, et al. Predictors of reduced relative dose intensity and its relationship to mortality in women receiving multi‐agent chemotherapy for epithelial ovarian cancer. Gynecol Oncol 2013; 129: 74–80.
  • 24. Select Committee on Off‐Protocol Prescribing of Chemotherapy in New South Wales. Off‐protocol prescribing of chemotherapy in New South Wales. Sydney: NSW Parliament, 2017.
  • 25. Mohile SG, Velarde C, Hurria A, et al. Geriatric assessment‐guided care processes for older adults: a Delphi Consensus of Geriatric Oncology experts. J Natl Compr Canc Netw 2015; 13: 1120–1130.
  • 26. Australian Commission on Safety and Quality in Health Care and NSW Therapeutic Advisory Group Inc. National Quality Use of Medicines Indicators for Australian Hospitals. Sydney: ACSQHC, 2014. (viewed Nov 2018).


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