Background
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend a wide variety of myelosuppressive chemotherapy regimens for the treatment of cancer in adjuvant and neoadjuvant settings.1–7 Neutropenia is one of the leading dose-limiting toxicities of chemotherapy, and neutropenic complications, especially chemotherapy-induced febrile neutropenia (FN), often lead physicians to reduce or delay planned doses of chemotherapy so as to limit myelotoxicity and allow recovery of neutrophil counts.8–11
Accumulating clinical evidence suggests that optimal outcomes are achieved with standard chemotherapy regimens, and chemotherapy dose delays and dose reductions result in poorer disease-free, progression-free, and overall survivals among patients with curable malignancies receiving adjuvant and neoadjuvant therapies.8,10,12–21 An emphasis has therefore been placed on maintaining full-dose chemotherapy on the planned schedule in clinical practice as a means to improve patient outcomes.22
Relative dose intensity (RDI), or the ratio of delivered dose intensity to standard or planned dose intensity, is a summary measure that is commonly used to describe dose delays and/or reductions that occur within a chemotherapy course.20,23 An RDI less than 85% is generally considered to be a clinically significant reduction from standard or planned therapy.8,10,12,20,24 Prophylactic granulocyte colony-stimulating factor (G-CSF) use has been shown in randomized controlled trials and observational studies to reduce the risk of reduced RDI.8,10,17,25,26
In this retrospective cohort study, we estimated the incidence of chemotherapy dose delays, dose reductions, missing doses, and reduced RDI relative to standard chemotherapy regimens among 16,233 patients with 6 tumor types who were treated with adjuvant or neoadjuvant chemotherapy regimens currently in widespread use in community oncology practices in the United States.
Methods
Data Source and Study Design
The McKesson Specialty Health/US Oncology iKnowMed Electronic Health Record (EHR) database captures outpatient practice encounter history for patients treated by more than 1000 oncologists and hematologists in nearly 230 McKesson Specialty Health/US Oncology practices that are geographically distributed across the United States. iKnowMed captures demographic information, laboratory values, diagnoses, planned and actual therapy administration, line of therapy, stage at diagnosis, comorbidities, and performance status. Oncologists enter planned chemotherapy agents, planned cycle length, and planned number of cycles into coded data fields in the database before chemotherapy initiation.
Using the iKnowMed EHR database, we retrospectively identified the first course of adjuvant or neoadjuvant chemotherapy received by patients with nonmetastatic cancer and assigned patients to specific tumor chemotherapy regimen cohorts (see supplementary eTable 1) based on chemotherapy agents received in cycle 1, planned number of cycles, and planned duration of each cycle for all 6 tumor types. We then compared the treatment received by patients in each cohort with standard tumor regimens as described in the NCCN Guidelines.1–7
Study Population
The study included patients aged 18 years or older treated for stage I–IIIA female breast cancer, stage I–III ovarian cancer, stage I–IIIA non–small cell lung cancer (NSCLC), stage I–III Hodgkin lymphoma, stage I–III non-Hodgkin's lymphoma (NHL), or stage I–III colorectal cancer (CRC). All patients initiated adjuvant or neoadjuvant chemotherapy at McKesson Specialty Health/US Oncology sites using the full EHR capacities of the iKnowMed database between January 1, 2007, and March 31, 2011.
Patients included in the study received at least one intravenously administered myelosuppressive agent in the first chemotherapy cycle, had no evidence of distant metastasis before chemotherapy initiation, did not receive any oral myelosuppressive agents during the chemotherapy course, were not treated for another tumor type, and did not participate in any clinical trials during the chemotherapy course.
Adjuvant or neoadjuvant chemotherapy was determined based on the value of the “line of therapy” variable in the database: “adjuvant” or “neoadjuvant” for patients with breast cancer, ovarian cancer, NSCLC, or CRC; “first line” for patients with NHL or Hodgkin lymphoma.
Only standard tumor regimen cohorts consisting of 100 or more patients were included in this study. This cohort size was chosen so as to achieve a precision level (anticipated half width of 95% CIs) for the primary end point (% of patients with reduced RDI) of approximately 10% or less. Based on this precision level, we calculated the required minimum sample size for each regimen to be approximately 100.
Outcome Measures
A dose delay was identified if a patient experienced a delay of 7 or more days in the administration of at least 1 myelosuppressive agent in any chemotherapy cycle relative to the standard day of administration.8,10,22,27,28
A dose reduction was identified if a patient experienced a reduction of 15% or more in chemotherapy dose for at least 1 myelosuppressive agent in any chemotherapy cycle relative to the standard dose.8,10,22,27,28
A missing dose was identified if a patient did not receive at least 1 myelosuppressive agent that was part of the standard regimen in any cycle. A patient with a missing dose in a cycle was assumed to have both a dose delay and a dose reduction in that cycle. This same approach to missing doses was used in previous studies.8,10,22,27,28
RDI was defined as the ratio of delivered dose intensity to the dose intensity of the standard tumor regimen (standard dose, standard cycle length, and standard number of cycles as described in the NCCN Guidelines). Delivered dose intensity was defined as total delivered dose divided by actual time to complete chemotherapy or standard time to complete chemotherapy, whichever was longer. RDI was measured for each myelosuppressive agent in a regimen over the entire chemotherapy course and then averaged across all of the myelosuppressive agents in a regimen. An RDI less than 85% was designated as the clinically meaningful threshold for reduction in RDI based on previously published studies.8,10,14,17,19,20,22,27,28
Statistical Analyses
For each standard tumor regimen cohort, RDI was calculated during the first chemotherapy course, and dose delays and dose reductions were identified in any cycle of the course. Descriptive statistics were reported by standard tumor regimen cohort for patient baseline characteristics (measured at chemotherapy initiation), incidence of dose delays (≥7 days) in any cycle of the course, incidence of dose reductions (≥15%) in any cycle of the course, percentage of patients with any missing dose for any myelosuppressive agent, RDI (as a continuous variable), and incidence of reduced RDI (<85%) over the course. Similar analyses of incidence of reduced RDI were conducted on subgroups of patients based on patient and disease characteristics.
Sensitivity analyses were conducted using planned regimen (planned dose, planned cycle length, and planned number of cycles) as the benchmark for calculation of dose delays, dose reductions, and reduced RDI. Planned dose for a myelosuppressive agent was assumed to be the maximum of all doses received across cycles (which was the first administered dose for almost all patients included in the study). For patients with lymphoma and CRC, an alternative “hybrid” benchmark for RDI less than 85% was also used that included dose and cycle length from the standard regimen and number of cycles from the planned regimen. This hybrid benchmark was used because the NCCN Guidelines give physicians flexibility when determining the appropriate number of chemotherapy cycles. Sensitivity analyses were also conducted by varying the threshold for defining reduced RDI (<90%, <95%) or dose reduction (≥5%, ≥10%).
Patients with evidence of disease progression, unplanned regimen change, or death were censored beyond the first event date.
Results
Characteristics of the Study Population
This study included 16,233 patients with 6 different tumor types who received 1 of 20 chemotherapy regimens. Characteristics of the study population by standard regimen cohort and regimen definitions and abbreviations are shown in Table 1.
Dose Delays, Dose Reductions, and RDI
As shown in Figure 1, a considerable proportion of patients across regimens had dose delays (22.9%–88.4%) and dose reductions (22.3%–93.1%). A considerable proportion of patients (14.7%–87.6%) also missed at least 1 dose of a myelosuppressive agent that is part of the standard regimen. As shown in Figure 2, RDI less than 85% ranged from 15.6% for patients with breast cancer treated with dose-dense AC followed by paclitaxel every 2 weeks to 87.6% for patients with CRC treated with 5-FU (every 8 weeks).
Colony-stimulating factor (CSF) prophylaxis in cycle 1 was consistently high for the 3 breast cancer regimens with a high risk (>20%) of FN according to the NCCN Guidelines for Myeloid Growth Factors29 (from 89.1% for dose-dense AC followed by paclitaxel every 2 weeks to 92.1% for dose-dense AC followed by paclitaxel every week; Table 2) (for the most recent version of these guidelines, visit NCCN.org). The mean RDI was high in these regimens (0.857–0.935; Table 2), and RDI less than 85% was low (15.6%–27.1%; Figure 2). CSF prophylaxis in cycle 1 was much more variable for regimens with an intermediate risk (10%–20%) of FN according to the NCCN Guidelines for Myeloid Growth Factors29
Characteristics of the Study Population by Standard Regimen Cohort
The mean RDI ranged from 0.486 to 0.935, and was highest in the breast cancer regimens (Table 2). The median RDI ranged from 0.451 to 0.982, and was also highest in the breast cancer regimens.
Incidence of dose delays, dose reductions, and missing doses. Missing doses were based on percentage of patients with any missing dose for any myelosuppressive agent. Error bars indicate 95% CI.
Abbreviations: 5-FU, 5-fluorouracil; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; AC, doxorubicin, cyclophosphamide; CRC, colorectal cancer; FOLFOX4/mFOLFOX6, folinic acid, 5-fluorouracil, oxaliplatin; NHL, non-Hodgkin lymphoma; NSCLC, non–small cell lung cancer; R-CHOP/CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone ± rituximab; RCVP/CVP, cyclophosphamide, vincristine, prednisone ± rituximab; RDI, relative dose intensity; TAC, docetaxel, doxorubicin, cyclophosphamide; TC, docetaxel, cyclophosphamide; TCH, docetaxel, carboplatin, trastuzumab.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0166
For most tumor types, the incidences of reduced RDI were higher in older patients (age ≥65 years), in obese patients (body surface area [BSA] >2 m2), and in patients whose daily activities were restricted (ECOG performance status ≥1) (Table 3). The percentage of patients who received reduced RDI (<85%) generally increased with age among those with breast cancer, CRC, Hodgkin lymphoma, and NHL.
Sensitivity analyses showed that estimates for the incidence of reduced RDI and dose reduction were higher when more restrictive alternative thresholds were used (Table 4). Sensitivity analyses also showed that estimates for the incidence of dose delays, dose reductions, and reduced RDI were generally lower when a planned regimen was used as the benchmark (Table 4).
Limitations
The results presented herein reflect the patient population and treatment patterns for McKesson Specialty Health/US Oncology practices. Services, medications, and procedures provided to patients outside the McKesson Specialty Health/US Oncology Network were not captured by the iKnowMed EHR database and could not be ascertained in this study. This study relied on coded data fields in the iKnowMed database rather than on data extracted from medical charts; this limited our ability to comprehensively measure certain clinical characteristics (eg, comorbidities) and understand rationales for dose delays and reductions. Treatment history before a patient's first encounter at a US Oncology practice may only be available in physician progress notes
Incidence of reduced RDI. Error bars indicate 95% CI.
Abbreviations: 5-FU, 5-fluorouracil; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; AC, doxorubicin, cyclophosphamide; CRC, colorectal cancer; FOLFOX4/mFOLFOX6, folinic acid, 5-fluorouracil, oxaliplatin; NHL, non-Hodgkin lymphoma; NSCLC, non–small cell lung cancer; R-CHOP/CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone ± rituximab; RCVP/CVP, cyclophosphamide, vincristine, prednisone ± rituximab; RDI, relative dose intensity; TAC, docetaxel, doxorubicin, cyclophosphamide; TC, docetaxel, cyclophosphamide; TCH, docetaxel, carboplatin, trastuzumab.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0166
Discussion
Chemotherapy dose delays, dose reductions, and reduced RDI were common among patients treated in community oncology practices in the United States, but RDI was highly variable across patients, regimens, and tumor types. Incidences of dose delays, dose reductions, missing doses, and reduced RDI were lowest among patients with breast cancer and highest in those with CRC. Incidences of all of these measures exceeded 40% in NHL, 45% in NSCLC, and 55% in Hodgkin lymphoma.
Patients with breast cancer were generally younger than those with other cancer types except Hodgkin lymphoma. Young age may have contributed to the low incidence of reduced RDI, because physicians may have believed that the patients could cope with the dose intensity prescribed by standard regimens.30,31 Physicians may also have believed that the prognosis for patients with breast cancer was relatively good, and therefore may have administered full dose intensity as a result.22 Some of the most common regimens used to treat breast cancer incorporated primary prophylaxis with growth factors in their pivotal trials (eg, dose-dense AC-T).32 Practitioners therefore had a systematic guide to follow that included relatively aggressive treatment with adequate supportive care.
Patients with advanced age, high BSA, or poor performance status were at higher risk of receiving reduced RDI. In the case of older patients and patients with ECOG performance status of 1 or higher, physicians may have been cautious in their dosing out of concern for excessive toxicity.33,34 This concern may have inadvertently led to undertreatment.35,36
CSF Prophylaxis, Oral Antimicrobial Prophylaxis, and Distribution of RDI by Standard Tumor Regimen Cohort
Reduced RDI (<85% Over the Course) by Tumor Type and Patient and Disease Characteristicsa
In patients with some tumor types, dose reductions of 15% or greater and reduced RDI were less common when planned regimens were used for comparison than when standard regimens were used (Table 4). This suggests that some physicians planned reductions in RDI (eg, with planned dose reductions or planned number of cycles lower than standard) before actual chemotherapy initiation. In other words, physicians may have reduced the dose intensity both in anticipation of and in response to toxicity. Similar planned reductions in dose and RDI have been observed in patients with NHL8,10 and breast cancer,39 and in patients aged 65 years or older with solid tumors.40,41
Neutropenia and FN are the most common toxicity-related reason for dose delays and reductions among patients with breast cancer,22 NHL,27 and NSCLC.42 Other hematologic toxicities, including anemia,43 thrombocytopenia,44 and nonhematologic toxicities, such as fatigue,45,46 nausea and vomiting,47 neuropathy,42,48 mucositis,49 renal dysfunction,20 patient request, and weight change,22,27 may also lead to dose delays and reductions.
Deviations from standard regimens as a result of toxicity might potentially be reduced by increasing
Sensitivity Analysis of Dose Delays, Dose Reductions, and Reduced RDI by Tumor Type
In clinical practice, many patients received chemotherapy at dose intensities that were lower than those in standard regimens. Increased communication between physicians and patients regarding the survival benefits of using standard regimens and preserving RDI might improve adherence to prescribed chemotherapy dose and schedule. However, many physicians may also have well-justified reasons to delay or reduce doses of myelosuppressive agents (eg, for elderly patients and patients with serious comorbidities), and these delays and reductions may be planned before chemotherapy initiation.8,10 The reasons behind decisions by physicians to reduce or delay doses of myelosuppressive agents were not captured in the coded data fields of the iKnowMed database and were not analyzed in this study.
The standard regimens specified in the NCCN Guidelines are based on clinical trial protocols. Some patient groups who are not well represented in clinical trials (eg, older or obese patients) may fare poorly with standard regimens. In this study, patients with CRC who received 5-FU (every 8 weeks) were older than patients in many other cohorts (Table 1), and the prevalence of dose delays, dose reductions, missing doses, and reduced RDI were all very high (Figures 1 and 2). Although the NCCN Guidelines recommend dose adjustments based on individual patient risk factors,29 patients from underrepresented populations should ideally be included in clinical trials so as to better establish doses that show both reasonable toxicity and efficacy.
The findings of this study are qualitatively similar to those of other studies.9,22,27,28,50 Lyman et al22,27 and Weycker et al28 reported recent estimates for the incidence of reduced RDI among patients with early-stage breast cancer and NHL. Culakova et al50 reported incidence of reduced RDI in patients with solid tumors or lymphoma, and included patients with small cell lung cancer and those with stage IV disease (who were not captured in our study). Compared with corresponding estimates in previous studies with similar calculation algorithms for dose delays, dose reductions, and reduced RDI,8,10 more recent estimates are relatively lower, despite an increase in the use of taxane-based regimens that may be more myelotoxic.22,51 In 2003, Lyman et al8 reported reduced RDI in 56% of patients with early-stage breast cancer, whereas in the present study, the corresponding estimate was 27%. The publication of clinical practice guidelines by NCCN1–7,29 and by ASCO37,38; increased physician awareness of the benefits of maintaining high RDI; and increased G-CSF use may all have contributed to this increase in RDI.
Conclusions
This study provides current estimates for the incidence of reduced RDI among patients with early-stage breast cancer, NHL, NSCLC, ovarian cancer, CRC, and Hodgkin lymphoma treated with chemotherapy regimens that are in widespread use in clinical practice. This study also captures “real world” practice patterns over a wide range of geographic regions treated in both rural and urban settings. Further research should evaluate the impact of RDI on long-term patient outcomes (eg, overall survival) among the patients in this study. Future research should also examine the reasons behind physicians' decisions to reduce or delay doses of myelosuppressive agents. This might require a survey of physicians, because reasons for treatment decisions are not usually captured in databases that can be examined retrospectively. Such research would be an important first step toward improving NCCN Guideline adherence and evaluating the potential utility of additional supportive care guidelines.
Acknowledgments
Medical writing support was provided by Micah Robinson at Amgen Inc.
See JNCCN.org for supplemental online content.
Xiaoyan Li, Phuong Khanh Morrow, Richard L Barron, Yanli Li, and Jacob Garcia are employed by and own stock in Amgen Inc. Gary H. Lyman is the principal investigator of a research grant to the Fred Hutchinson Cancer Research Center from Amgen. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
This study was funded by Amgen Inc.
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