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

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.


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

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

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

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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