|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2003 American Society for Clinical Oncology Incidence and Predictors of Low Dose-Intensity in Adjuvant Breast Cancer Chemotherapy: A Nationwide Study of Community PracticesFrom the University of Rochester Medical Center, Rochester, NY; University of Washington, Seattle, WA; and Duke University, Durham, NC. Address reprint requests to Gary H. Lyman, MD, MPH, James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642; e-mail: gary_lyman{at}urmc.rochester.edu.
Purpose: This retrospective study was undertaken to assess practice patterns in adjuvant chemotherapy for early-stage breast cancer (ESBC) and to define the incidence and predictive factors of reduced relative dose-intensity (RDI). Patients and Methods: A nationwide survey of 1,243 community oncology practices was conducted, with data extracted from records of 20,799 ESBC patients treated with adjuvant chemotherapy. Assessments included demographic and clinical characteristics, chemotherapy dose modifications, incidence of febrile neutropenia, and patterns of use of colony-stimulating factor (CSF). Dose-intensity was compared with published reference standard regimens.
Results: Dose reductions Conclusion: Patients with ESBC are at substantial risk for reduced RDI when treated with adjuvant chemotherapy. Patients at greatest risk include older patients, overweight patients, and those receiving three-drug combinations or 28-day schedules. Predictive models based on such risk factors should enable the selective application of supportive measures in an effort to deliver full dose-intensity chemotherapy.
BREAST CANCER is the most common form of cancer among women in the United States, with more than 190,000 new cases and 40,000 deaths annually.1 The current standard of care for early-stage breast cancer (ESBC) includes breast-conserving surgery, local radiation therapy, and systemic adjuvant chemotherapy.2 The survival benefit conferred by adjuvant chemotherapy in patients with ESBC is well established. Results of the most recent Early Breast Cancer Trialists’ Collaborative Group meta-analysis showed reductions in the annual hazard rate for recurrence and death of 23.5% and 14.3%, respectively, and clear evidence of benefit for women up to age 70 years.3 The Early Breast Cancer Trialists’ Collaborative Group results also suggest an increased benefit with anthracycline-containing regimens,3 which have been used increasingly over the past decade. A recent report by Henderson et al4 (Intergroup Study 0148) also provides support for the adjuvant use of taxanes after an anthracycline-containing regimen. Despite this evidence of benefit with adjuvant chemotherapy, important questions remain with regard to the relative effectiveness and toxicities of different chemotherapy regimens. The nature of the relationship between chemotherapy dose-intensity and clinical outcome, in particular, remains the subject of much controversy. Recent clinical trials support the importance of sustaining full dose-intensity in adjuvant chemotherapy for ESBC. There is good evidence for a threshold of relative dose-intensity (RDI) for some regimens below which patients may receive little or no clinical benefit.2,5–10 Thus substantial reductions in RDI may compromise outcomes. Neutropenia is the major dose-limiting toxicity of chemotherapy and the primary driver of the dose delays and reductions that result in low RDI.11 Indeed, current American Society of Clinical Oncology guidelines for the use of colony-stimulating factor (CSF) encourage physicians to consider chemotherapy dose modifications as the primary response to risk of hematologic toxicity.12 Given the existence of a threshold RDI below which the benefits of chemotherapy may be compromised, this practice conveys risk particularly for patients with ESBC, for whom long-term survival is a readily achieved goal. Many clinicians and quality assurance programs have adopted the criterion of Bonadonna et al5 of RDI less than 85% as an indicator of a clinically important reduction in adjuvant chemotherapy dose-intensity for ESBC. In light of these considerations, the chemotherapy regimen and the actual dose delivered to patients with ESBC have important public health implications. For this reason, we have reviewed practice patterns from a unique database containing more than 20,000 records of patients receiving adjuvant chemotherapy for ESBC in community practice settings. The primary objective of the study was to assess the RDI delivered, along with the frequency of chemotherapy RDI less than 85%. The secondary objective was to identify factors associated with reduced RDI that might guide the use of various supportive care modalities. This analysis represents the largest study to date evaluating community practice patterns and treatment complications in patients being treated with adjuvant chemotherapy for ESBC.
Study Design and Outcomes A nationwide survey of 1,243 community oncology practices was undertaken between August 1997 and May 2000. Data were collected retrospectively from 20,799 patients who were treated with adjuvant chemotherapy for ESBC. Patients and practices were distributed across the United States, with approximately equal numbers from West, Central, Great Lakes, Northeast, and Southeast regions. Participating oncology practices were asked to submit data extracted from the charts of the most recent 15 to 20 patients who had completed adjuvant chemotherapy for ESBC. The investigators were blinded to the identities of patients and physicians/practices participating in this study through the use of anonymous numeric codes.
Pretreatment demographics and clinical characteristics collected included age at diagnosis, menopausal status, weight, height, body mass index (BMI), body-surface area (BSA), lymph node status, estrogen receptor status, chemotherapy regimen, and planned dose and schedule. Cycle-specific information included actual chemotherapy dose and interval and pretreatment WBC count or absolute neutrophil count. Occurrences of febrile neutropenia were captured for each patient over all cycles, but not separately for each cycle. The primary outcome was the average RDI, defined as the proportion of the reference standard dose-intensity for each regimen actually received. The proportion of patients receiving less than 85% of the reference standard was also evaluated. Reduced dose-intensity was shown to consist of two components: planned reduced dose-intensity based on the indicated intention at the time of treatment initiation and unplanned reduced dose-intensity associated with dose reductions and treatment delays that occurred during the course of therapy. Secondary outcomes included the incidence of chemotherapy dose delays Estimates of the summation dose-intensity (SDI) for each regimen were based on the work of Hryniuk et al.13 SDI was defined as the sum of the fractional unit dose-intensity contributed by each drug in the regimen. The unit dose-intensity for each drug was defined as that dose required to produce a 30% complete and partial response rate in first-line single-agent trials in breast cancer patients with metastatic disease. In randomized trials that tested dose-intensity in metastatic disease, response rates and survival were found to be linearly associated with the SDI of each treatment arm. The SDI was normalized to the most frequently used regimen (doxorubicin and cyclophosphamide [AC]) by dividing the SDI of each regimen by that estimated for AC. An adjusted RDI was then estimated as the product of the actual RDI and the normalized SDI. The interval and duration of CSF usage was tabulated for each cycle. CSF prophylaxis was defined as the initiation of treatment within 3 days of chemotherapy with a duration of at least 7 days. Primary prophylaxis was defined as prophylactic administration of CSF starting within the first 3 days of the first cycle of chemotherapy.
Statistical Methods
Patient Characteristics and Chemotherapy Regimens Patient characteristics are listed in Table 1  . The scope and size of this database from 1,243 community oncology practices strongly suggest consistency with demographics and clinical characteristics of women with ESBC in the general population. The mean age of the study population was 52 years (range, 11 to 90 years), with 17% of patients  65 years of age at diagnosis (Fig 1A). Forty-nine percent of patients were reported to be postmenopausal.
The majority of patients (96%) received one of five common chemotherapy regimens (Fig 1B  ): AC14; cyclophosphamide, methotrexate, and fluorouracil (CMF; 21- and 28-day regimens)15,16; and cyclophosphamide, doxorubicin, and fluorouracil (CAF; 21- and 28-day regimens).17 The remaining 4% of patients received doxorubicin and cyclophosphamide followed by paclitaxel,18 or doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil,5 with a small number of patients (n = 33) receiving doxorubicin followed by paclitaxel followed by cyclophosphamide.19 Because they represented a small and heterogeneous portion of the patients in this survey, these latter patients were not included in further analyses.
RDI
Dose reductions 15% were observed in 37% of patients, whereas delays 7 days were seen in 25% of patients, resulting in 56% of patients overall receiving less than 85% of standard reference dose-intensity. The frequency of dose reductions and treatment delays as well as reduced dose-intensity increased progressively across the cycles of chemotherapy delivered (Fig 3). However, as shown in Figure 4, much of the reduction in dose and overall reduced RDI compared with reference standard doses was either planned and already seen during the first cycle or apparent in patients scheduled to receive more than four cycles of chemotherapy. Cycle-specific RDIs were consistently lower among patients aged 65 years and older across all cycles of chemotherapy.
Dose reduction, treatment delay, and reduced RDI were observed across all chemotherapy regimens. Figure 5 presents the actual and adjusted RDI (mean and 95% CI) across chemotherapy regimens and schedules. As shown in Fig 6, planned reductions in RDI were most common in patients receiving 28-day schedules of either CAF or CMF. Patients receiving CAF regimens were more likely to receive fewer than the standard number of treatment cycles than those receiving AC or CMF (Fig 7). Figure 8 presents the proportion of treatment delays and dose reductions as well as the proportion of patients receiving less than 85% of standard reference RDI. As shown, the proportion of patients receiving less than 85% RDI adjusted to the reference dose-intensity of AC reached 65% overall. In addition to regimen and schedule, several additional measures were found to be associated with reduced RDI in this population. Older patients were more likely than younger patients to receive an RDI less than 85% (P < .0001). BMI as a measure of obesity was associated with increasing reductions in RDI. As shown in Figure 9, the association between BMI based on World Health Organization criteria and RDI was related to a reduction in planned dose-intensity.
CSF Use As shown in Table 1 , approximately one fourth of patients received CSF during their treatment course. Most hematopoietic support seems to have been reactive or therapeutic and not prophylactic in nature. The proportion of patients receiving CSF support either prophylactically or in all other uses is shown in Figure 10. Although the majority of patients received no growth factor support, CSF use increased after the first cycle through the fourth cycle of chemotherapy. The dose and schedule of CSF therapy varied widely. The median number of days from chemotherapy to the start of CSF administration and the duration of CSF use by cycle is shown in Figure 11. There was a trend toward use of CSF earlier in the cycle and for longer durations over the course of treatment.
Predictive Factors for Reduced RDI: Multivariate Analyses In multiple logistic regression analyses, covariates associated with actual RDI less than 85% included age, BSA, year of treatment, chemotherapy regimen, chemotherapy schedule (21-day v 28-day), and primary CSF prophylaxis. Table 3 presents the patient- and treatment-related variables that were significant independent predictors of reduced RDI. Increased risk of dose reduction was associated with higher age, high BSA, CAF and CMF regimens, and 28-day schedules. Significant decreased risk was associated with more recent years of treatment and primary CSF prophylaxis. The mean area under the receiver operating characteristic curve (c-statistic) was 0.733 (95% CI, 0.608 to 0.884; P < .0001).
Retrospective analysis of the records for more than 20,000 patients with ESBC who were treated with adjuvant chemotherapy in the community setting reveals that more than one half of patients experienced substantial planned or unplanned reductions in RDI. After adjustment for the inherent differences in regimen intensity, nearly two thirds of these patients experienced notable reduction in dose-intensity. Such observations are alarming in the light of an increasing number of studies that support the importance of maintaining full standard dose-intensity in responsive and potentially curable malignancies such as ESBC. Mayers et al20 demonstrated a trend toward improved outcomes in ESBC patients receiving CMF who experienced greater myelosuppression during treatment. In a large clinical trial in patients with operable breast cancer, Budman et al6 (Cancer and Leukemia Group B Study 8541) explored the efficacy of varying dose-intensity and total dose of CAF. After a median follow-up period of 9 years, both disease-free survival and overall survival were found to be superior in those patients who received greater dose-intensity of CAF. Further, the recently reported initial results of Cancer and Leukemia Group B Study 9741 comparing dose-dense (14-day cycles with primary prophylactic CSF support) and standard (21-day cycles) schedules in patients with node-positive breast cancer revealed that the dose-dense schedules were associated with significantly improved disease-free and overall survival.8 Given the evidence supporting the importance of maintaining full dose-intensity for best chemotherapy outcomes in ESBC,2,5–10 the data reported here have important implications with respect to the quality of breast cancer care delivered in the community setting. This large, practice-based study demonstrates that both planned and subsequent chemotherapy dose modifications resulting in reduced RDI are frequently implemented despite the risk of compromised outcome. In a subset analysis of the study data by year of treatment (data not shown), the percentage of patients receiving reduced RDI less than 85% was found to fall progressively with increasing year of treatment, from approximately two thirds of patients in the early 1990s to one third in the later 1990s. Although it is encouraging that there were fewer occurrences of reduced RDI among patients treated in more recent years, our results nonetheless demonstrate that a substantial proportion of women receiving adjuvant breast cancer chemotherapy receive less than 85% of the dose-intensity associated with reference standard regimens. A number of factors were found to be significantly associated with reduced dose-intensity in univariate analysis, including the specific treatment regimen and schedule, older age, and obesity. Greater reductions in RDI were observed in patients receiving 28-day cycles of either CMF or CAF. Patients receiving CAF on either 21- or 28-day cycles more often received fewer than the standard number of cycles. However, after adjusting for differences in SDI between the regimens, the 21-day CMF regimen was associated with the greatest reduction in adjusted RDI. Reduced RDI was of particular concern in older patients. Advanced age is associated with an increased incidence of neutropenic complications,21,22 which are, in turn, associated with more severe clinical consequences.23 Other studies have found that older women with breast cancer are more likely than younger women to receive reduced RDI,5,21 although older breast cancer patients who receive adjuvant chemotherapy experience reductions in rates of recurrence similar to those of younger patients.24 The implementation of strategies aimed at improving the delivery of standard dose-intensity may be particularly beneficial for these patients. Patients with high BMI or BSA of 2 m2 or greater also experienced greater reductions in dose-intensity. Most of the difference in RDI observed with increasing obesity was in planned dose, with virtually no difference in the need for unplanned dose modifications owing to toxicity. Therefore, there seems to be a consistent tendency to underdose obese or larger patients. An important limitation to the study presented here is the lack of detailed information concerning the frequency of nonhematologic toxicity and its potential influence on reduced dose-intensity. Considerable information is available about planned or scheduled reductions in dose-intensity. It is likely that some of the unplanned reductions in dose-intensity relate to nonhematologic chemotherapy toxicity. Nonetheless, randomized clinical trials of the regimens discussed here have repeatedly reported that myelosuppression in general and neutropenia in particular are the major dose-limiting toxicities encountered.
Overall, 26.4% of patients in this survey received CSF at some point during the course of their chemotherapy. Despite the increased risk and greater impact of neutropenic complications in older patients,22,23 age had limited influence on CSF use, with 26.1% and 27.8% of patients younger than 65 years and Encouragingly, the multivariate analysis reported here suggests that improved dose-intensity has been observed over time and with the selective use of prophylactic CSFs. Given the negative clinical and quality-of-life impact of neutropenia and the potential for compromised outcomes with reduced RDI, these factors may help identify which patients would benefit most from available supportive care modalities. Ultimately, these and other factors may be incorporated into clinical prediction models that may be used to select those patients most likely to benefit from prophylactic or supportive care, including CSFs. Prospective trials evaluating the impact of such strategies on outcomes for women with ESBC are warranted.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: David C. Dale, Amgen; Jeffrey Crawford, Amgen. Performed contract work within the last 2 years: Gary H. Lyman, Amgen; David C. Dale, Amgen; Jeffrey Crawford, Amgen. Received more than $2,000 a year from a company for either of the last 2 years: Gary H. Lyman, Amgen; David C. Dale, Amgen; Jeffrey Crawford, Amgen.
We thank Olayemi Agboola for her assistance with data analysis.
1. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15–36, 2001 2. National Institutes of Health: Adjuvant therapy for breast cancer. NIH Consensus Statement 17:1–35, 2000[Medline] 3. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930–942, 1998[CrossRef][Medline]
4. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983, 2003
5. Bonadonna G, Zambetti M, Valagussa P, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med 332:901–906, 1995
6. Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst 90:1205–1211, 1998 7. Chang J: Chemotherapy dose reduction and delay in clinical practice: Evaluating the risk to patient outcome in adjuvant chemotherapy for breast cancer. Eur J Cancer 36:S11–S14, 2000 (suppl 1)
8. 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 21:1431–1439, 2003 9. Piccart MJ, Biganzoli L, Di Leo A: The impact of chemotherapy dose density and dose intensity on breast cancer outcome: What have we learned? Eur J Cancer 36:S4–S10, 2000 (suppl 1)
10. Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330:1253–1259, 1994 11. Link BK, Budd GT, Scott S, et al: Delivering adjuvant chemotherapy to women with early-stage breast cancer: Current patterns of care. Cancer 92:1354–1367, 2001[CrossRef][Medline]
12. Ozer H, Armitage JO, Bennett CL, et al: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 18:3558–3585, 2000
13. Hryniuk W, Frei E, Wright FA: A single scale for comparing dose-intensity for all chemotherapy regimens in breast cancer: Summation dose intensity. J Clin Oncol 16:3137–3147, 1998 14. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483–1496, 1990[Abstract] 15. Moliterni A, Bonadonna G, Valagussa P, et al: Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes. J Clin Oncol 9:1124–1130, 1991[Abstract] 16. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405–410, 1976[Abstract] 17. Buzdar AU, Hortobagyi GN, Kau S-W: Doxorubicin-containing adjuvant therapy for patients with stage II breast cancer: MD Anderson Cancer Center experience, in Salmon SE (ed): Adjuvant Therapy of Cancer VI. Philadelphia, PA, WB Saunders, 1990, pp 210–215 18. Henderson IC, Berry D, Demetri G, et al: Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (PTS) with node-positive primary breast cancer (BC). Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 390A)
19. Hudis C, Seidman A, Baselga J, et al: Sequential dose-dense doxorubicin, paclitaxel and cyclophosphamide for resectable high-risk breast cancer: Feasibility and efficacy. J Clin Oncol 17:93–100, 1999 20. 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 91:2246–2257, 2001[CrossRef][Medline]
21. Crivellari D, Bonetti M, Castiglione-Gertsch M, et al: Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: The International Breast Cancer Study Group trial VII. J Clin Oncol 18:1412–1422, 2000 22. Dees EC, O’Reilly S, Goodman SN, et al: A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest 18:521–529, 2000[Medline] 23. Balducci L, Yates J: General guidelines for the management of older patients with cancer. Oncology (Huntingt) 14:221–227, 2000
24. Extermann M, Balducci L, Lyman GH: What threshold for adjuvant therapy in older breast cancer patients? J Clin Oncol 18:1709–1717, 2000 25. Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 325:164–170, 1991[Abstract] 26. Trillet-Lenoir V, Green J, Manegold C, et al: Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 29A:319–324, 1993[CrossRef][Medline] 27. Lyman GH: A novel approach to maintain planned dose chemotherapy on time: A decision-making tool to improve patient care. Eur J Cancer 36:S15–S21, 2000 (suppl 1) 28. de Graaf H, Willemse PHB, Bong SB, et al: Dose intensity of standard adjuvant CMF with granulocyte colony-stimulating factor for premenopausal patients with node-positive breast cancer. Oncology 53:289–294, 1996[Medline]
29. Pettengell R, Gurney H, Radford JA, et al: Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin’s lymphoma: A randomized controlled trial. Blood 80:1430–1436, 1992 30. Webster J, Lyman GH: Use of G-CSF to sustain dose intensity in breast cancer patients receiving adjuvant chemotherapy: A pilot study. Cancer Control 3:519–523, 1996[Medline] 31. Silber JH, Fridman M, DiPaola RS, et al: First-cycle blood counts and subsequent neutropenia, dose reduction, or delay in early-stage breast cancer therapy. J Clin Oncol 16:2392–2400, 1998[Abstract] 32. Silber JH, Fridman M, Shpilsky A, et al: Modeling the cost-effectiveness of granulocyte colony-stimulating factor use in early-stage breast cancer. J Clin Oncol 16:2435–2444, 1998[Abstract] Submitted May 1, 2003; accepted October 2, 2003. This article has been cited by other articles:
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
2 distributions for categoric variables. Group comparisons of continuous variables were based on the Student’s t test for normally distributed variables and the Mann-Whitney U statistic for all other variables. For univariate comparisons and multivariate analyses, RDI was categorized on the basis of values less than 85% or 
