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Patterns of Chemotherapy Administration in Patients With Intermediate-Grade Non-Hodgkin’s Lymphoma

Patterns of Chemotherapy Administration in Patients With Intermediate-Grade Non-Hodgkin’s Lymphoma

ABSTRACT: Records from 653 patients treated between 1991 and 1998 in the Oncology Practice Patterns Study (OPPS) were analyzed to determine contemporary chemotherapy delivery patterns in patients with intermediate-grade non-Hodgkin’s lymphoma (NHL). Of the 653 patient records reviewed, 90 (14%) omitted an anthracycline or mitoxantrone (Novantrone) from primary therapy. Among patients receiving CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) or CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisone), 134 (27%) of 492 received an average relative dose intensity of less than 80% of the literature-referenced dose, due either to an inadequate planned or delivered dose. Of 181 advanced-stage patients with responsive disease, 28 (15%) failed to receive at least six treatment cycles. Overall, 283 (43%) of 653 patients potentially received suboptimal chemotherapy due either to choice of regimen or chemotherapy delivered. Patient 65 years of age or older and cardiac comorbidity appeared to have the greatest influence on a physician’s decision regarding chemotherapy administration. Among the 492 patients who received CHOP or CNOP, 235 (48%) experienced a delay or reduction in chemotherapy dose (usually neutropenia-related), 100 (20%) developed mucositis, and 116 (24%) were hospitalized for febrile neutropenia. Growth factor was administered to 261 patients (53%), and its primary prophylactic use was associated with a significant reduction in the incidence of hospitalizations for febrile neutropenia in all patient subgroups receiving appropriate chemotherapeutic dose intensity (P = .02). This assessment of chemotherapy delivery to patients with intermediate-grade NHL showed significant variation from current standards. Further analysis of factors influencing chemotherapy delivery might improve therapeutic outcomes. [ONCOLOGY 15:1296-1314, 2001.]

Non-Hodgkin’s lymphoma (NHL) is the seventh most common cancer in the United States, with approximately 56,200 new cases diagnosed each year.[1] Recent evidence shows that the mortality rate is increasing.[2] Although many patient- and disease-related factors such as age, performance status, comorbidities, stage, histology, laboratory values (eg, lactate dehydrogenase [LDH] level), and treatment affect survival, clinicians can only alter treatment. Among NHL patients, those with intermediate-grade disease are considered potentially curable, based on data from randomized clinical trials.[3-5]

Overview of Treatment

Selection of a chemotherapy regimen is a primary factor in the survival of intermediate-grade NHL patients. Common chemotherapy regimens used for NHL over the past 25 years have included CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone),[6-9] CNOP (cyclophosphamide, mitoxantrone [Novantrone], vincristine, prednisone),[10] and two different schedules of cyclophosphamide, vincristine, and prednisone (COP[11,12] and CVP[13,14]).

Of these, however, only CHOP and CNOP are currently considered curative treatments for intermediate-grade NHL, along with newer regimens such as m-BACOD (methotrexate, leucovorin, bleomycin [Blenoxane], doxorubicin [Adriamycin], cyclophosphamide, vincristine, dexamethasone), ProMACE-CytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, mitoxantrone, leucovorin), and MACOP-B (methotrexate, leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin).[9] Additionally, two studies have suggested that the CHOP regimen is superior to the CNOP regimen in achieving a cure in these patients.[10,15]

In addition to the choice of initial chemotherapy regimen, the planning and delivery of full-dose chemotherapy, both with respect to the total number of cycles administered and the dose intensity, are considered important factors in the outcome of patients with intermediate-grade NHL. Kwak et al have shown that intermediate-grade NHL patients who received less than 75% of their planned dose had worse 5-year survivals than those who received 75% to 100% of their planned dose.[16] Also, Epelbaum et al showed that intermediate-grade NHL patients who received less than 70% to 80% of their planned dose had a worse response and 5-year survival than did those who received their full planned dose.[17]

Unfortunately, retrospective studies cannot clearly differentiate the patients who were able to tolerate a higher dose of therapy and thus achieve a better survival from those who achieved better survival for other reasons. Few prospective randomized clinical trials have evaluated the effects of both total dose and dose intensity on survival in NHL.[8]

Dose-Limiting Factors

Delivery of standard-dose chemotherapy is often interrupted by the development of myelosuppression. The most common myelosuppressive dose-limiting phenomena is neutropenia. Neutropenia, defined as an absolute neutrophil count (ANC) less than 1,000 cells/µL, occurs frequently with the standard chemotherapy regimens used to treat NHL—in 78% to 91% of patients receiving CHOP[10,18,19]—and often leads to dose reductions or dose delays and sometimes to infection, hospitalization, and death.[20] Although dose reductions or delays may reduce the risk of neutropenia in subsequent cycles, they may also reduce the opportunity for prolonged survival and/or cure.

Variations in the treatment and outcomes of patients with NHL are largely undocumented in many therapeutic settings. For example, there are multiple reports on chemotherapy-related complication rates from randomized trials (often in academic settings); however, their effect on the delivery of chemotherapy in community practices is largely unknown.

The purpose of this article is to describe contemporary practices in the use of chemotherapy from a population-based perspective. In particular, we will consider (1) the choice of initial chemotherapy regimen, (2) the number of chemotherapy cycles administered, (3) variations in the planned and delivered doses of chemotherapy from referenced standards, (4) the incidence and management of chemotherapy-related neutropenia, and (5) the incidence and management of neutropenia-induced complications (including growth factor use). Herein are our findings from the ongoing Oncology Practice Pattern Study (OPPS) conducted at large managed-care, community, and academic practices.

Methods

Study Design and Data Collection

This study was conducted in nine large diverse practice settings across the United States, including health maintenance organizations, academic medical centers, integrated delivery systems, independent practice associations, and physician practice management associations. To be included, each study site needed the following two essential characteristics. First, there had to have been a minimum of 30 to 40 analyzable patients with intermediate-grade NHL who had been treated during the 3 years prior to the proposed study initiation date. The population of potentially eligible patients at each site was screened using existing databases such as tumor registry, billing, and pharmacy data. Second, each site needed to have documentation of the requisite information, as identified below. According to the institutional review board (IRB) guidelines for human subjects, 5 to 10 medical records were reviewed to ensure the completeness of the medical record relative to the case report form at each site.

Data collection started on the date the study was initiated, entailing the compilation of approximately 100 consecutive, eligible, and retrospective patient records (or data covering a 3-year span). Data were collected for patients who had been treated between 1991 and 1998 (with 98% from 1993 onward). Patients were eligible if they received their first course of chemotherapy for intermediate-grade NHL (stages I-IV) within 3 years of study initiation and were at least 18 years old. Patients were excluded if they had been entered into a clinical trial treatment protocol, had other primary invasive cancers, received another course of chemotherapy within 3 years before the treatment studied (ie, no relapses and no retreatments), or tested HIV positive.

The medical records were abstracted using uniform case report forms under the supervision of the site’s principal investigator. Information collected included (1) patient characteristics, ie, age, gender, race, comorbidity, size (height, weight, and body surface area for each cycle), stage, histology, number of extranodal sites involved, elevated LDH, and B symptoms (systemic symptoms); (2) the planned chemotherapy regimen (drugs, dose, route, length, and number of cycles); (3) the delivered chemotherapy regimen (drugs, dose, route, and the dates of delivery for each cycle); (4) all complete blood counts and differential information available; (5) growth factor and antibiotic use during the course of therapy, including drugs, dose, number of doses, and dates delivered; (6) prior and concurrent radiation therapy, including courses, total doses, and dates delivered; (7) characteristics of any surgical treatment; (8) short-term treatment complications, including presence of mucositis, febrile neutropenia, and hospitalizations, along with event dates, supporting documentation (pertinent notes from the medical record), and laboratory results; and (9) any medical record notation regarding chemotherapy dose modifications, complications, use of supportive-care agents, and early termination of chemotherapy.

Data Processing

The OPPS Data Coordinating Center within Pharmacoeconomics at Amgen Inc, Thousand Oaks, Calif, conducted quality assurance, data entry, and data analyses for this study. Staff included data entry personnel, statistical analysis software (SAS) programmers, and a multidisciplinary team of scientists including clinicians (oncologists, pharmacists, and oncology nurses), a biostatistician, an epidemiologist, a health economist, and a health services researcher.

Quality assurance and data analysis were coordinated and reviewed with the principal investigators and data collection coordinators at each site. An experienced oncology nurse reviewed all case report forms for completeness and consistency. Questions were returned to the study site for verification against the medical record. After forms were reviewed and corrected, data were double entered to minimize data entry errors. Quality assurance checks were performed prior to data analyses, examining variables for appropriate ranges of values and for consistency across related fields.

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