Impact of Chemotherapy Dose Intensity on Cancer Patient Outcomes

Author: Gary H. Lyman MD, MPH, FRCP (Edin) 1
View More View Less
  • 1 Duke University and Duke Comprehensive Cancer Center, Durham, North Carolina

Chemotherapy dose intensity represents unit dose of chemotherapy administered per unit time. Dose intensity can be increased or decreased through altering dose administered, time interval of administration, or both. Evidence supporting the importance of delivered chemotherapy dose intensity on clinical outcomes in patients with potentially curable malignancies comes from in vitro studies of cancer cell lines and abundant in vivo preclinical studies, in addition to retrospective and prospective clinical trials in both advanced and early-stage disease settings. Myelosuppression continues to represent the major dose-limiting toxicity of cancer chemotherapy, resulting in considerable morbidity and mortality along with frequent reductions in chemotherapy dose intensity, which may compromise disease control and survival. Several retrospective and prospective randomized trials have shown that reductions in the chemotherapy dose intensity established in efficacy studies may compromise long-term disease control and survival. Despite compelling data, surveys in the United States and elsewhere have reported that dose reductions and delays frequently occur in clinical practice, even in the potentially curative setting. Alternatively, an increase in dose intensity above standard may be achieved through either increasing the dose of individual agents (dose escalation) or compressing or shortening the treatment interval (dose-dense). In early studies, dose-dense schedules showed an increase in survival, whereas the benefit of dose escalation studies has been less consistent and may be accompanied by other dose-limiting toxicities. This article focuses on the rationale for delivering full chemotherapy dose intensity, the apparent reasons for failing to deliver optimal treatment, and available strategies for sustaining full chemotherapy dose intensity when indicated. The delivery of full chemotherapy dose intensity in patients with potentially curable malignancies should be considered a quality of care indicator in clinical oncology.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Gary H. Lyman, MD, MPH, Health Services and Outcomes Research in Oncology, Duke University, 2424 Erwin Road, Suite 205, Durham, NC 27705. E-mail: Gary.Lyman@duke.edu
  • 1

    Crawford J, Dale DC, Kuderer NM. Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice. J Natl Compr Canc Netw 2008;6:109118.

    • Search Google Scholar
    • Export Citation
  • 2

    Kuderer NM, Dale DC, Crawford J. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 2006;106:22582266.

    • Search Google Scholar
    • Export Citation
  • 3

    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;21:45244531.

    • Search Google Scholar
    • Export Citation
  • 4

    Lyman GH, Dale DC, Friedberg J. Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin Oncol 2004;22:43024311.

    • Search Google Scholar
    • Export Citation
  • 5

    Bonadonna G, Valagussa P, Moliterni A. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995;332:901906.

    • Search Google Scholar
    • Export Citation
  • 6

    Budman DR, Berry DA, Cirrincione CT. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 1998;90:12051211.

    • Search Google Scholar
    • Export Citation
  • 7

    Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007;25:31583167.

    • Search Google Scholar
    • Export Citation
  • 8

    Aapro MS, Cameron DA, Pettengell R. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 2006;42:24332453.

    • Search Google Scholar
    • Export Citation
  • 9

    Crawford J, Althaus B, Armitage J. NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors. J Natl Compr Canc Netw 2007;5:188202.

    • Search Google Scholar
    • Export Citation
  • 10

    Smith TJ, Khatcheressian J, Lyman GH. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:31873205.

    • Search Google Scholar
    • Export Citation
  • 11

    Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64:328340.

    • Search Google Scholar
    • Export Citation
  • 12

    Dale D, Crawford J, Lyman GH. Myelotoxicity and dose intensity of chemotherapy: reporting practices from randomized clinical trials. J Natl Compr Canc Netw 2003;1:440454.

    • Search Google Scholar
    • Export Citation
  • 13

    Hassett MJ, O’Malley AJ, Pakes JR. Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer. J Natl Cancer Inst 2006;98:11081117.

    • Search Google Scholar
    • Export Citation
  • 14

    Lyman GH, Delgado DJ. Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma. Cancer 2003;98:24022409.

    • Search Google Scholar
    • Export Citation
  • 15

    Lyman GH, Morrison VA & Dale DC Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin’s lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 2003;44:20692076.

    • Search Google Scholar
    • Export Citation
  • 16

    Lyman GH. Guidelines of the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy: a review of the evidence. J Natl Compr Canc Netw 2005;3:557571.

    • Search Google Scholar
    • Export Citation
  • 17

    Chouaid C, Bassinet L, Fuhrman C. Routine use of granulocyte colony-stimulating factor is not cost-effective and does not increase patient comfort in the treatment of small-cell lung cancer: an analysis using a Markov model. J Clin Oncol 1998;16:27002707.

    • Search Google Scholar
    • Export Citation
  • 18

    Lyman GH. Time is money for both the healthy and the sick. Med Care 2005;43:637639.

  • 19

    Lyman GH, Hauser RS. Optimal cancer care across the spectrum of life and disease. Am J Manag Care 2008;14:262264.

  • 20

    Lyman GH. Chemotherapy dose intensity and quality cancer care. Oncology (Williston Park) 2006;20(14 Suppl 9):1625.

  • 21

    Longo DL, Duffey PL, DeVita VT Jr. The calculation of actual or received dose intensity: a comparison of published methods. J Clin Oncol 1991;9:20422051.

    • Search Google Scholar
    • Export Citation
  • 22

    Chu E, DeVita VT Jr. Principles of medical oncology. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Vol 7. Philadelphia: Lippincott Williams and Wilkins; 2005:295306.

    • Search Google Scholar
    • Export Citation
  • 23

    Skipper HE. Kinetics of mammary tumor cell growth and implications for therapy. Cancer 1971;28:14791499.

  • 24

    Hryniuk W, Bush H. The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 1984;2:12811288.

  • 25

    Meyer RM, Hryniuk WM, Goodyear MD. The role of dose intensity in determining outcome in intermediate-grade non-Hodgkin’s lymphoma. J Clin Oncol 1991;9:339347.

    • Search Google Scholar
    • Export Citation
  • 26

    Colleoni M, Li S, Gelber RD. Relation between chemotherapy dose, oestrogen receptor expression, and body-mass index. Lancet 2005;366:11081110.

    • Search Google Scholar
    • Export Citation
  • 27

    Hershman DL, Wang X, McBride R. Delay of adjuvant chemotherapy initiation following breast cancer surgery among elderly women. Breast Cancer Res Treat 2006;99:313321.

    • Search Google Scholar
    • Export Citation
  • 28

    Epelbaum R, Faraggi D, Ben-Arie Y. Survival of diffuse large cell lymphoma. A multivariate analysis including dose intensity variables. Cancer 1990;66:11241129.

    • Search Google Scholar
    • Export Citation
  • 29

    Lepage E, Gisselbrecht C, Haioun C. Prognostic significance of received relative dose intensity in non-Hodgkin’s lymphoma patients: application to LNH-87 protocol. The GELA. (Groupe d’Etude des Lymphomes de l’Adulte.) Ann Oncol 1993;4:651656.

    • Search Google Scholar
    • Export Citation
  • 30

    Kwak LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol 1990;8:963977.

    • Search Google Scholar
    • Export Citation
  • 31

    Lee KW, Kim DY, Yun T. Doxorubicin-based chemotherapy for diffuse large B-cell lymphoma in elderly patients: comparison of treatment outcomes between young and elderly patients and the significance of doxorubicin dosage. Cancer 2003;98:26512656.

    • Search Google Scholar
    • Export Citation
  • 32

    Mayers C, Panzarella T, Tannock IF. Analysis of the prognostic effects of inclusion in a clinical trial and of myelosuppression on survival after adjuvant chemotherapy for breast carcinoma. Cancer 2001;91:22462257.

    • Search Google Scholar
    • Export Citation
  • 33

    Di Maio M, Gridelli C, Gallo C. Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol 2005;6:669677.

    • Search Google Scholar
    • Export Citation
  • 34

    Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:16871717.

    • Search Google Scholar
    • Export Citation
  • 35

    Bonneterre J, Roche H, Kerbrat P. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2005;23:26862693.

    • Search Google Scholar
    • Export Citation
  • 36

    Ardizzoni A, Favaretto A, Boni L. Platinum-etoposide chemotherapy in elderly patients with small-cell lung cancer: results of a randomized multicenter phase II study assessing attenuated-dose or full-dose with lenograstim prophylaxis—a Forza Operativa Nazionale Italiana Carcinoma Polmonare and Gruppo Studio Tumori Polmonari Veneto (FONICAP-GSTPV) study. J Clin Oncol 2005;23:569575.

    • Search Google Scholar
    • Export Citation
  • 37

    Norton L, Simon R. Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 1977;61:13071317.

  • 38

    Citron ML, Berry DA, Cirrincione C. 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;21:14311439.

    • Search Google Scholar
    • Export Citation
  • 39

    Pfreundschuh M, Trumper L, Kloess M. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004;104:634641.

    • Search Google Scholar
    • Export Citation
  • 40

    Griggs JJ, Culakova E, Sorbero ME. Effect of patient socioeconomic status and body mass index on the quality of breast cancer adjuvant chemotherapy. J Clin Oncol 2007;25:277284.

    • Search Google Scholar
    • Export Citation
  • 41

    Griggs JJ, Sorbero ME, Lyman GH. Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 2005;165:12671273.

  • 42

    Shayne M, Crawford J, Dale DC. Predictors of reduced dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy. Breast Cancer Res Treat 2006;100:255262.

    • Search Google Scholar
    • Export Citation
  • 43

    Shayne M, Culakova E, Poniewierski MS. Dose intensity and hematologic toxicity in older cancer patients receiving systemic chemotherapy. Cancer 2007;110:16111620.

    • Search Google Scholar
    • Export Citation
  • 44

    Field KM, Kosmider S, Jefford M. Chemotherapy dosing strategies in the obese, elderly and thin patients: results of a nationwide survey. Journal of Oncology Practice 2008;4:108133.

    • Search Google Scholar
    • Export Citation
  • 45

    Madarnas Y, Sawka CA, Franssen E, Bjarnason GA. Are medical oncologists biased in their treatment of the large woman with breast cancer? Breast Cancer Res Treat 2001;66:123133.

    • Search Google Scholar
    • Export Citation
  • 46

    Rosner GL, Hargis JB, Hollis DR. Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541. J Clin Oncol 1996;14:30003008.

    • Search Google Scholar
    • Export Citation
  • 47

    Sparreboom A, Verweij J. Paclitaxel pharmacokinetics, threshold models, and dosing strategies. J Clin Oncol 2003;21:28032804; author reply 2805–2806.

    • Search Google Scholar
    • Export Citation
  • 48

    Sparreboom A, Wolff AC, Mathijssen RH. Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol 2007;25:47074713.

    • Search Google Scholar
    • Export Citation
  • 49

    Griggs JJ, Sorbero ME, Stark AT. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat 2003;81:2131.

    • Search Google Scholar
    • Export Citation
  • 50

    Griggs JJ, Culakova E, Sorbero ME. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol 2007;25:25222527.

    • Search Google Scholar
    • Export Citation
  • 51

    Lyman GH, Kuderer N, Poniewierski MS. Factors associated with reductions in chemotherapy dose intensity: impact of clinical, sociodemographic and practice setting [abstract]. J Clin Oncol 2007;25(Suppl 1):Abstract 6550.

    • Search Google Scholar
    • Export Citation
  • 52

    Balducci L, Hardy CL, Lyman GH. Hemopoiesis and aging. Cancer Treat Res 2005;124:109134.

  • 53

    Lyman GH, Lyman CH, Agboola O. Risk models for predicting chemotherapy-induced neutropenia. Oncologist 2005;10:427437.

  • 54

    Lyman GH, Kuderer NM, Djulbegovic B. Prophylactic granulocyte colony-stimulating factor in patients receiving dose-intensive cancer chemotherapy: a meta-analysis. Am J Med 2002;112:406411.

    • Search Google Scholar
    • Export Citation
  • 55

    Doorduijn JK, van der Holt B, van Imhoff GW. CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin’s lymphoma. J Clin Oncol 2003;21:30413050.

    • Search Google Scholar
    • Export Citation
  • 56

    Osby E, Hagberg H, Kvaloy S. CHOP is superior to CNOP in elderly patients with aggressive lymphoma while outcome is unaffected by filgrastim treatment: results of a Nordic Lymphoma Group randomized trial. Blood 2003;101:38403848.

    • Search Google Scholar
    • Export Citation
  • 57

    Hewitt M, Simone JV. Institute of Medicine: Ensuring Quality Cancer Care. Washington, D.C.: National Academy Press; 1999.

  • 58

    Malin JL, Schneider EC, Epstein AM. Results of the National Initiative for Cancer Care Quality: how can we improve the quality of cancer care in the United States? J Clin Oncol 2006;24:626634.

    • Search Google Scholar
    • Export Citation
  • 59

    Morrow T, Siegel M, Boone S. Chemotherapy dose intensity determination as a quality of care measure for managed care organizations in the treatment of early-stage breast cancer. Am J Med Qual 2002;17:218224.

    • Search Google Scholar
    • Export Citation
  • 60

    Ottevanger PB, De Mulder PH. The quality of chemotherapy and its quality assurance. Eur J Surg Oncol 2005;31:656666.

  • 61

    Greenman CG, Jagielski CH, Griggs JJ. Breast cancer adjuvant chemotherapy dosing in obese patients: dissemination of information from clinical trials to clinical practice. Cancer 2008;112:21592165.

    • Search Google Scholar
    • Export Citation
  • 62

    Dignam JJ, Polite BN, Yothers G. Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J Natl Cancer Inst 2006;98:16471654.

    • Search Google Scholar
    • Export Citation
  • 63

    Meyerhardt JA, Niedzwiecki D, Hollis D. Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: findings from Cancer and Leukemia Group B 89803. J Clin Oncol 2008;26:41094115.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1459 630 53
PDF Downloads 1634 651 53
EPUB Downloads 0 0 0