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Originally published as JCO Early Release 10.1200/JCO.2004.03.213 on September 20 2004 © 2004 American Society of Clinical Oncology. Incidence and Predictors of Low Chemotherapy Dose-Intensity in Aggressive Non-Hodgkin's Lymphoma: A Nationwide StudyFrom the University of Rochester, 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: To assess the incidence of and risk factors for reduced relative dose-intensity (RDI) in patients treated with chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). METHODS: A nationwide survey was conducted of 567 oncology practices with data extracted from the records of 4,522 patients with aggressive NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); CHOP-rituximab (CHOP-R); or cyclophosphamide, mitoxantrone, vincristine, and prednisone (CNOP). The primary outcome was the average RDI for each regimen based on both planned and reference standards. Other assessments included the incidence of febrile neutropenia and patterns of colony-stimulating factor (CSF) use, as well as the average RDI in high-risk subgroups.
RESULTS: Dose reductions CONCLUSION: Patients with aggressive and potentially curable NHL treated with CHOP, CHOP-R, or CNOP frequently receive reduced RDI. Predictive models based on the risk factors identified for reduced RDI should enable the targeted use of appropriate supportive care, facilitating the delivery of full chemotherapy doses on schedule.
Malignant lymphoma, including both Hodgkin's disease and the non-Hodgkin's lymphomas (NHLs), afflicts more than 50,000 individuals annually in the United States, resulting in nearly 20,000 deaths.1 Combination therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is considered a standard treatment for patients with aggressive NHL.2 Variations of the CHOP regimen include the addition of rituximab (CHOP-R)3 and the substitution of mitoxantrone for doxorubicin (CNOP).4 Adding rituximab to standard CHOP recently has been shown to be more effective than CHOP alone in elderly patients with newly diagnosed diffuse large B-cell lymphoma.3 CNOP is frequently prescribed for older patients with NHL because mitoxantrone is perceived to be better tolerated and less cardiotoxic than doxorubicin.5 Two large studies that compared CHOP and CNOP in the treatment of elderly patients with aggressive NHL, however, found that CHOP produced higher complete response rates and longer overall survival, without significantly greater toxicity.5,6 The major dose-limiting toxicity with each of these regimens is myelosuppression and associated neutropenia, potentially compromising overall dose-intensity and long-term outcome.7-10 The risk of neutropenic complications and the frequency of dose reductions and treatment delays in patients with NHL treated in randomized controlled trials have received some attention, but the treatment patterns in oncology practice remain largely unknown.11 An analysis of data from patients with early-stage breast cancer has demonstrated that patients treated with adjuvant chemotherapy are at a substantial risk of chemotherapy dose attenuation, with more than half of all patients and two thirds of elderly patients being treated with a reduced chemotherapy dose-intensity.12 This investigation was conducted to study patterns of chemotherapy treatment, including administered relative dose-intensity (RDI), as well as to identify risk factors for reduced RDI in patients with aggressive and potentially curable NHL. This is the largest study to date to evaluate practice patterns and treatment complications in patients with NHL treated with systemic chemotherapy.
Study Design and Patient Selection Data were collected retrospectively between January 1, 1999, and December 31, 2001, on 6,314 patients with NHL who had been treated between 1993 and 2001 with chemotherapy at 567 oncology practices throughout the United States. Sites were instructed to obtain appropriate local institutional review board approval and were encouraged to use experienced oncology nurses, pharmacy personnel, or data management staff to collect the data. Patients were assigned unique numeric codes, with their identity known only to the individual sites. Sites were asked to identify and record data on 10 patients with NHL treated at the site, and reimbursement was based on the number of patient data forms submitted. The data were provided for analysis to the authors, who were blinded to the identities of the patients. Patients were included in the analysis if they had aggressive NHL (working formulation D to H)13 and were treated with CHOP, CHOP-R, or CNOP. Only summary results are presented, with no breakdown by individual patient or treatment site. Practice sites were reimbursed by Amgen Inc (Thousand Oaks, CA) for their participation in this study.
Chemotherapy Regimens and Study Outcomes
The dose and schedule of the CHOP, CHOP-R, and CNOP chemotherapy considered standard in this analysis are listed in Table 1. All regimens were administered in 21-day cycles. The agent-specific RDI in each patient was calculated as the ratio of the dose actually delivered over time to the standard dose-intensity. The ARDI was calculated by averaging the delivered RDIs of cyclophosphamide and doxorubicin for CHOP and CHOP-R, and by averaging the delivered RDIs of cyclophosphamide and mitoxantrone for CNOP. The following analyses were performed to address the stability of the RDI estimates under different clinical practice conditions and treatment policies: all patients according to the reference standard of a minimum of six cycles, and all patients according to the current National Comprehensive Cancer Network (NCCN) recommendation of a minimum of six cycles in high-risk patients and three cycles along with regional radiation therapy in low-risk, low-stage patients14 (Table 1). High-risk patients based on NCCN guidelines consist of those with stage II to IV disease and patients with stage I disease with one or more adverse risk factors, including age older than 60 years, Eastern Cooperative Oncology Group (ECOG) performance status
Study Independent Variables and Operational Definitions Patient demographics and clinical characteristics collected included age, sex, height, weight, body-surface area (BSA), chemotherapy regimen, and planned dose and schedule. In addition, disease histology by International Working Formulation, Ann Arbor stage, number of extranodal sites, presence of bone marrow involvement (where assessed), ECOG performance status, LDH, and serum albumin data were collected. Cycle-specific information included actual chemotherapy doses and interval and pretreatment WBC count or absolute neutrophil count (ANC). Episodes of FN were captured for each patient over all cycles, but not separately for each cycle. Age was dichotomized as  60 or older than 60 years because these patient groups have different risks of death according to the International Prognostic Index.15 BSA was categorized as 2 or more than 2 m2. Disease stage was categorized as limited stage (Ann Arbor stage I or II) or advanced stage (Ann Arbor stage III or IV). The number of extranodal sites was classified as less than 2 or  2. Serum LDH level was categorized as 500 or less than 500 U/L, and serum albumin level was classified as 3.5 or more than 3.5 g/dL. Lymphoma histology was originally categorized according to the International Working Formulation that was commonly used when the disease was diagnosed and the patients were treated.13 The analysis reported here was limited to aggressive histology NHL (Working Formulation D to H). Patterns of CSF use were determined by start date, duration, and dose assessed overall and for each cycle of chemotherapy. Prophylactic CSF was defined as its use within 72 hours of chemotherapy. Primary prophylactic CSF was defined as prophylactic use beginning in the first cycle of chemotherapy. Treatment response (complete, partial, stable disease, progressive disease, or unknown) and cycle-specific FN rates were added as variables during the course of the study and are only available for a subgroup (n = 1,400; 31%) of patients. Mortality was not reported in this study and the limited duration of follow-up does not permit any estimation of disease-free or overall survival as outcomes.
Statistical Methods
Patient Characteristics and Chemotherapy Regimens Of the 6,314 eligible patients, 4,839 (77%) were classified as having aggressive NHL, 655 (10%) were classified as having indolent NHL, and 132 (2%) were classified as having highly aggressive NHL, whereas 688 (11%) were unclassifiable or unclassified. The analysis reported here is limited to the 4,522 patients with aggressive histology NHL who were treated with CHOP (n = 3,871; 86%), CHOP-R (n = 117; 3%), or CNOP (n = 534; 11%). Patient characteristics are summarized in Table 2 on all patients (n = 4,522), high-risk patients according to NCCN criteria (n = 4,102), and patients with stage III or IV disease (n = 2,493). Diffuse large-cell lymphoma (DLCL) was the single most common histology (56.8%). The mean age of the study population was 61.2 years (range, 16 to 96 years); 58.3% of patients were older than 60 years of age, and more than half of the patients (52.6%) were female.
RDI Actual, planned, and reference chemotherapy doses were standardized to individual calculated BSA. Intention to deliver fewer than six cycles of chemotherapy was encountered in 30%, 28%, and 20% of all patients, NCCN high-risk patients, and patients with stage III or IV disease, respectively (Fig 1). As shown in Figure 2, the distributions of ARDI estimates were similar when compared with the different standards: Figure 2A, six cycles for all patients (median, 0.83); Figure 2B, based on NCCN guidelines (median, 0.86); Figure 2C, six cycles for high-risk patients based on NCCN guidelines (median, 0.83); and Figure 2D, six cycles for patients with stage III or IV disease (median, 0.86). Although some patients were treated with more than the reference standard dose-intensity, most received less. As shown in Figure 3, the incidences of dose reductions, treatment delays, and RDI less than 85% were comparable regardless of which standard or patient criteria were analyzed, with anywhere from 48% to 53% of patients receiving less than 85% of standard dose-intensity overall. Significantly greater dose reductions and treatment delays were observed in patients treated with CNOP than with CHOP or CHOP-R, with 62% of those treated with CNOP receiving less than 85% of the standard dose-intensity (P = .001). As shown in Figure 4, a range of threshold reductions in dose-intensity were studied.
Figure 5 shows the proportion of patients receiving less than 85% of standard dose-intensity during the first five cycles of treatment in all patients and by age group. A significant trend toward reduced dose-intensity was observed across cycles of chemotherapy (P = .001). However, the greatest change in either planned or standard RDI was at the start of treatment in cycle 1. As shown in Figure 5, elderly patients consistently received lower dose-intensity than did younger patients. A greater proportion of older patients (older than 60 years) received an RDI less than 85% during the first five cycles of treatment, with 60% receiving RDI less than 85% overall compared to 44% of those younger than 60 years of age. Response to treatment was available only in a subgroup of patients (n = 1,400). Reported responses included complete response (53%), partial response (17%), stable disease (4%), progressive disease (6%), and unknown (20%). The average RDI based on treatment response was complete response (0.79), partial response (0.82), stable disease (0.77), progressive disease (0.78), and unknown (0.75). The proportion of patients receiving an RDI less than 85% by response included complete response (51%), partial response (45%), stable disease (57%), progressive disease (56%), and unknown (59%). Fewer responding patients received RDI less than 85% than did nonresponding patients (P = .021).
When the actual dose-intensity was compared with that planned in all patients, the mean and median ARDI was 0.894 and 0.939, respectively, with 32.4% of patients receiving less than 85% of the planned dose-intensity. Similar proportions of high-risk patients and of those with stage III and IV disease received less than 85% of the planned dose-intensity (33.7% and 38.3%, respectively). The mean and median planned dose-intensity relative to standard six cycles of therapy in all patients was 0.901 and 0.975, respectively, with RDI less than 85% planned in 37.9% of patients. Similar proportions of patients treated with planned RDI less than 85% of the standard were observed in all patients based on NCCN guidelines (33.3%), in high-risk patients (36.5%), and in patients with stage III or IV disease (30.2%). Of the overall average reduction in ARDI of 0.213, 0.100 (47%) was planned from the start of therapy and 0.113 (53%) was unplanned and associated with subsequent dose reductions and treatment delays. Figure 6 illustrates the planned and unplanned reductions along with actual ARDI for all patients relative to either a standard six cycles or based on NCCN guidelines as well as for high-risk patients and for patients with stage III or IV disease. Planned and unplanned reductions in dose-intensity were greater in patients older than 60 years (12.7% v 11.7%) compared with younger patients (11.7% v 10.7%). As shown in Figure 7, significant linear trends were observed during the study period for decreases in unplanned dose reductions (P < .001) along with increases in planned dose reductions (P < .001), with minimal change in the overall ARDI.
Table 3 lists the adjusted ORs for RDI less than 85% based on multivariate models for the different reference standards considered. Significant predictors of reduced RDI that were common to most models were age older than 60 years, poor performance status, earlier year of treatment, and practice site, whereas prophylactic CSF was associated with significantly less reduction in dose-intensity. The odds ratios presented are adjusted for year of treatment, practice site, and planned number of cycles, which were also significant predictors in each of the models shown. Lower RDI was observed over time and was associated most notably with a decrease in planned RDI. Approximately half of the variance in reduced RDI was explained by the covariates in these models. Significant interaction was observed between CSF prophylaxis and age for reduced dose-intensity (P = .049). Older age was a significant predictor of reduced dose-intensity in patients not treated with prophylactic CSF (OR, 2.41) but did not reach significance in patients treated with prophylactic CSF (OR, 1.42). Multivariate models based on a range of threshold reductions in dose-intensity provided essentially identical results to those shown in Table 3.
FN Midcycle ANC less than 1 x 109/L occurred in 62% and ANC less than 0.5 x 109/L occurred in 35% of all patients. One or more episodes of FN occurred in 945 patients (20.9%), with hospitalization required in 717 (76%). The risk of FN was greatest in patients with age older than 60 years (24.8%), BSA 2 m2 (22.6%), ECOG performance status 2 (34.6%), stage III or IV disease (23.5%), International Prognostic Index 2 (26.7%), and treatment with CHOP-R (25.6%). In multivariate analysis, significant independent predictors of FN were older age, female sex, advanced disease stage, poor performance status, and low pretreatment ANC (Table 4). The odds ratios presented are adjusted for year of treatment and disease histology, which were also significant predictors of FN in this model. Lower risk of FN was observed over time and in those receiving primary CSF prophylaxis. A significant interaction was observed between CSF prophylaxis and age for risk of FN (P = .001). Older age was a significant risk factor for FN when prophylactic CSF was not used (OR, 1.80) but not when prophylactic CSF was used (OR, 0.77).
CSF Use CSF support was used during the course of chemotherapy in 2,444 patients (54%), including 1,325 (29.3%) during the first cycle. CSF was used as primary prophylaxis in 541 patients (12.0%), accounting for 22% of CSF use (Fig 8). First-cycle CSF use was initiated a mean of 7.2 days (median, 7.0 days) after chemotherapy, with CSF therapy started after an interval more than 5 days in 53% of patients. More than half of the patients were treated with CSF for less than 7 days. The use of prophylactic CSF increased during the first three cycles (Fig 8). The duration of CSF use also increased after the first cycle, whereas the interval between the administration of chemotherapy and that of CSF decreased. In multivariate analysis, the use of prophylactic CSF starting in cycle 1 was significantly associated with a lower risk of FN (Table 4). The initiation of prophylactic CSF later than cycle 1 was not associated with a significant reduction in the risk of FN. In addition, when CSF was initiated prophylactically during the treatment course, multivariate analysis showed less reduction in RDI (Table 3). As noted in Methods, cycle-specific rates of FN were available only in a subgroup of patients (n = 1,400). In patients not receiving CSFs during the first cycle, 10.2% without FN and 55.3% with FN went on to receive prophylactic CSF in cycle 2 (P < .0001). Similar numbers held for patients experiencing ANC less than 0.5 x 109/L or less than 1.0 x 109/L during cycle 1 (P < .0001). Likewise, significantly fewer patients experienced reduced dose-intensity in cycle 2 who received primary prophylaxis in cycle 1 (P = .05).
This retrospective analysis of records on more than 4,500 patients with aggressive-histology NHL treated with CHOP or CHOP-like chemotherapy in clinical practices throughout the United States found substantial reductions in chemotherapy dose-intensity in half of the patients. This large practice-based study has shown that both planned and unplanned chemotherapy dose modifications occur, resulting in reduced ARDI. A number of factors were found to be significantly associated with reduced dose-intensity in both univariate and multivariate analysis, including older age, poor performance status, advanced disease stage, year of treatment, and practice site. The age distribution of patients in this study reflects that of the broad population of patients in the United States with NHL: More than half are age 60 or older.16 Given that advanced age is associated with a higher incidence of neutropenic complications,17-20 the delivery of standard dose-intensity may be particularly problematic in the elderly.
The results reported here for aggressive NHL are similar to those recently observed in nearly 20,000 women receiving adjuvant breast cancer chemotherapy.12 Although data on long-term outcomes are not available from these surveys, previous studies have raised concern about the impact of reduced dose-intensity on survival in patients with NHL.7-10 Retrospective analysis of data on 115 patients with DLCL treated with chemotherapy found that an RDI of doxorubicin of more than 75% was the most important predictor of survival.8 Epelbaum et al7 reported a 5-year survival rate of 80% in patients with DLCL who were treated with more than 70% RDI of CHOP in their first cycle of chemotherapy and a 5-year survival rate of only 32% in those receiving less than 70% (P = .0001). In a recent study of doxorubicin-based chemotherapy for DLCL, 5-year survival was lower in patients age Recent studies in patients with aggressive NHL provide evidence for a possible advantage for increased chemotherapy dose-intensity based on administration every 14 days with granulocyte CSF support. In a study from the German High-Grade NHL Study Group, such dose-dense CHOP in elderly patients with NHL resulted in both longer time to treatment failure and improved overall survival than did standard 21-day CHOP.21 In a similar randomized controlled trial from the same group in younger patients with good-prognosis aggressive NHL treated with CHOP or CHOP-etoposide, 14-day schedules were associated with improved overall survival in univariate (P = .050) and multivariate (P = .044) analysis.22
Randomized clinical trials of the CHOP, CHOP-R, and CNOP regimens have consistently reported that myelosuppression in general and neutropenia in particular represent the major dose-limiting toxicities. In our study, a 20% incidence of FN was associated with a high degree of dose attenuation. However, it is possible that some of the unplanned reductions in dose-intensity were due to nonhematologic toxicity. Our study lacks detailed information on the frequency of nonhematologic toxicity and its potential influence on reduced dose-intensity. Of particular concern is the apparent trend toward increasing reductions in planned dose-intensity over time, given that such reductions cannot be accounted for on the basis of myelosuppression or patient compliance issues. Although some reductions may be considered appropriate in the elderly and those with serious comorbidities, the planned reductions may also represent a systematic intent to undertreat patients with aggressive NHL compared with published reference standard regimens in some practices and settings. In addition, of some concern is the significant variation in RDI between practice sites, although limited data are available on comorbidities that might have resulted in reductions in delivered dose-intensity. Such data were collected only during the last 2 years of the survey and are not available on the majority of the patients in this study. It is of interest that practice site was significantly associated with planned but not unplanned decreases in RDI. Likewise, stage A substantial proportion of patients either received no CSF support or received it only after a neutropenic complication. As reported, most patients receiving prophylactic CSF only after cycle 1 did so after experiencing either severe or febrile neutropenia during cycle 1. Randomized clinical trials have shown that prophylactic CSF can reduce the risk of neutropenic complications6,23-25 and facilitate the delivery of full dose-intensity.6,26-30 Although our study is not a randomized controlled trial, it is supportive of these trials in demonstrating that CSFs administered prophylactically starting with the first cycle are associated with a reduction in the risk of FN and reduced dose-intensity in multivariate analysis. A disturbing pattern of nonprophylactic use of the CSFs late in the treatment cycle was observed in this study. Such use of the CSFs has not clearly been demonstrated to be efficacious. Although prophylactic use appears to increase over reported cycles, much of the later use is secondary to previous severe and febrile neutropenia events. Two studies in patients with NHL treated with CHOP have shown that maintaining chemotherapy dose-intensity with growth factor support in both 21-day and dose-dense 14-day regimens was not associated with a higher incidence of nonhematologic toxicity.31,32
In our study, several factors were associated with reduced dose-intensity in both univariate and multivariate analysis. Older patients in this study had more than twice the risk of lower dose-intensity CHOP chemotherapy than did younger patients, after adjustment for other risk factors. These data are consistent with those from a retrospective study of 577 patients with intermediate-grade NHL who were treated with CHOP, which showed that planned and actual chemotherapy dose intensities were significantly lower in older patients (
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. Performed contract work within the last 2 years: Gary H. Lyman, Amgen, Glaxo. Received more than $2,000 a year from a company for either of the last 2 years: Gary H. Lyman, Amgen Speaker's Bureau, Orthobiotech Speaker's Bureau; Jeffrey Crawford, Amgen Speaker's Bureau; David C. Dale, Amgen Speaker's Bureau.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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12. 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 21:4524-4531, 2003 13. Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49:2112-2135, 1982[CrossRef][Medline] 14. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's Lymphoma, Version 1, 2003 http://www.nccn.org/professionals/physician-gls/pdf/nhl.pdf
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 distributions for categoric variables, and those for continuous variables were based on Student's t test for normally distributed variables and the Mann-Whitney U statistic for all other variables. For univariate comparisons and multivariate analyses, ARDI was categorized as less than 85% or 
