Cyclophosphamide

Survey of Use, Training, and Practitioner Knowledge Base

Objective: To assess pulmonologists' use training in the use, and knowledge of the drug cyclophosphamide.

Design: Survey through questionnaire. Testing of knowledge base before and after instructional conference.

Participants and methods: Pulmonologists (94 attendings, 31 fellows), selected randomly at the 1996 and 1997 annual meetings of The American Thoracic Society, completed surveys of their use and training in the use of cyclophosphamide. Thirty-five attending at the 1998 meeting completed a test of knowledge base of the drug. Members of the pulmonary teaching service at The University of Chicago Hospitals completed the test before and after a case-based conference designed to educate pulmonologists in the use of the drug.

Results: Forty-three percent of the attending pulmonologists and 55% of the fellows were currently using the drug in the management of their patients; 77% of the attending pulmonologists had prescribed the drug in the past. Nonmalignant diseases for which the drug was prescribed included usual interstitial pneumonitis/desquamative interstitial pneumonitis, vasculitis, collagen vascular disease, constrictive bronchiolitis, sarcoid, and Goodpasture's disease. Sixty-eight percent of attending pulmonologists and 81% of fellows had no training in the drug's use. Of the attending pulmonologists who made use of the drug, 64% were prescribing and managing its use themselves. Of those who prescribed and managed the drug's use themselves, 65% had had no training in its use. Of those fellows who prescribed and managed the drug's use themselves, 73% had had no training in the drug's use. On knowledge-based testing, the average correct score was 30 [+ or -] 10%. With an educational conference, average pre- and post-test scores rose from 40 [+ or -] 10% to 80 [+ or -] 10% (p [is less than] 0.001).

Conclusion: Cyclophosphamide had been used by the vast majority of pulmonologists, either currently or in the past, for a wide variety of lung diseases. Its use is commonly managed by physicians who have no specific training relevant to this agent. Practitioner knowledge base of the drug is poor, and case-based conferences in fellowship maybe an effective means of imparting information concerning this drug. (CHEST 1999; 116:1159-1162)

Key words: cyclophosphamide; survey; training; knowledge base

Although initially used to treat malignancies, cytotoxic drugs have been used in the management of multiple other pulmonary diseases cyclophosphamide is the most widely used agent in this class, having complex modulatory effects on the immune response.[1] Pulmonary rheumatic diseases, vasculitides, granulomatous states, and a variety of other conditions have been treated with cyclophosphamide.[2] Serious side effects, including cytopenias, nausea, hepatotoxicity, pneumonitis, pulmonary interstial fibrosis, hemorrhagic cystitis, gonadal toxicity, teratogenicity, carcinoma of the bladder, and induction of other neoplasms, have limited the drug's use.[3] Although cyclophosphamide is considered integral to the management of Wegener's granulomatosis,[4] uncertainty regarding efficacy has further limited the drug's use for other pulmonary and systemic inflammatory disorders.

Little is known about the extent of use of cyclophosphamide by pulmonologists nor the familiarity of these physicians with the pharmacokinetics, immune effects, and toxicities of cyclophosphamide. Considering the profile of serious side effects, training in the management of the drug's use is considered critical. We hypothesized that cyclophosphamide is commonly used by pulmonologists, but that training in the use of the drug is uncommon and that practitioner knowledge base of the drug's use is poor. Accordingly, we surveyed pulmonologists' use, training in the use, and knowledge base of cyclophosphamide. One potential means of improving the practitioner knowledge base of cyclophosphamide is the case-based educational conference. We therefore tested the attendees' knowledge base before and after a case-based conference designed specifically to educate in the use of cyclophosphamide.

MATERIALS AND METHODS

At the 1996 and 1997 annual meetings of The American Thoracic Society, we randomly surveyed 125 attending pulmonologists and fellows regarding their use and training in the use f cyclophosphamide. The survey instrument consisted of a single sheet of paper, one-sided, with eight questions: name, country of practice, whether attending pulmonologist or pulmonary fellow, number of patients they were currently treating with cyclophosphamide, number of patients they had treated with cyclophosphamide in the past, disease states for which they had used cyclophosphamide, whether or not they had received any training in the use of cyclophosphamide, and whether they managed the drug's use themselves or in conjunction with other specialists.

Thirty-five randomly selected attending pulmonologists at the 1998 meeting of the American Thoracic Society completed a 10-question test of knowledge base of cyclophosphamide, including dosing, metabolism, and screening for side effects. A case-presentation conference focusing on the management of cyclophosphamide use was given to the University of Chicago pulmonary teaching service. Pre-and postconference knowledge base testing was performed, using the same 10-question test. The participants then completed knowledge base testing again at the 1-year interval.

Data are reported as means [+ or -] SD. Statistics were performed using [chi square] analyses. Statistical significance was considered to exist when p [is less than] 0.05.

RESULTS

The number of respondents from each country of origin represented in the survey is shown in Table 1. Pulmonologists from 14 different countries were surveyed, with 62% being from the United States.

The respondents cited a variety of disease states for which they have used cyclophosphamide (Table 2). Sarcoidosis pulmonary fibrosis, and Wegener's granulomatosis were the three most commonly cited disease. Only five pulmonologists cited lung cancer as a disease for which they have used cyclophosphamide.

Table 2--Diseases Cited for Which cyclophosphamide Has Been Prescribed by Survey Respondents(*)

(*) UIP/DIP = usual interstitial pneumonitis/desquamative interstitial pneumonitis; P-ANCA = perinuclear antinuclear cytoplasmic antibody.

Responses to questions regarding any current or past cyclophosphamide use, and training in cyclophosphamide use, are shown in Table 3. In the 1996 and 1997 American Thoracic Society surveys, 43% of attending pulmonologists and 55% of fellows were currently prescribing the drug. Seventy-seven percent of attending pulmonologists and 81% of fellows had prescribed the drug in the past.

Table 3--Cyclophosphamide Use and Training in the Use of Cyclophosphamide Among Pulmonologists(*)

(*) Data are presented as mean [+ or -] SEM unless otherwise indicated.

Among attending pulmonologists, the mean number of patients currently being treated with cyclophosphamide was 3.1; among fellows, the corresponding number was 1.9. Among attending pulmonologists, the mean number of current or past patients treated with cyclophosphamide was 14.9; among fellows, the corresponding number was 3.7. Among only those attending pulmonologists who had used cyclophosphamide, the mean number of patients currently being treated with cyclophosphamide was 7.2; among only those fellows who have used cyclophosphamide, the corresponding number was 3.4.

Among all respondents who had used cyclophosphamide, 64% of the attending pulmonologists and 60% of the fellow were prescribing and managing the drug's use themselves. Twenty-three physicians (attendings and fellows) were prescribing in conjunction with a rheumatologist. Eight physicians were prescribing in conjunction with an oncologist. One attending was managing the drug's use in conjunction with a nephrologist. Only two fellow were prescribing and managing the drug's use in conjunction with attending pulmonologists.

Sixty-eight percent of the attending pulmonologists had no training in the drug's use; 81% of the fellows had no training in the drug's use. Among all attendings who prescribe and manage cyclophosphamide use themselves, 65% had no training in the drug's use. Among all fellows who are prescribing and managing cyclophosphamide use themselves, 73% had no training in the drug's use.

Among the thirty-five pulmonologists who completed the knowledge base test at the 1998 American Thoracic Society meeting, the average correct score was 30%. The third phase of the study, which tested members of the pulmonary teaching service at the University of Chicago Hospitals, demonstrated that significant learning was achieved after an educational conference. Average pre- and postconference test scores rose from 40 to 80% (p [is less than] 0.0001). Thirteen of the 15 participants completed repeat testing at the 1-year interval with average scores of 60% (p [is less than] 0.001, compared to preconference testing), suggesting sustained learning.

DISCUSSION

Recognizing the limitation that a "survey" methodology relies on physician recall, cyclophosphamide has been used by the vast majority of practicing pulmonologists (77%) in one or more of their patients. However, the average number of patients being currently treated by attending pulmonologists is small.[3] Concerns regarding the efficacy of the drug and the profile of serious side effects have limited the drug's use. As a second- or third-line therapeutic, the drug is occasionally used when few alternatives exist. Many of the disease states for which pulmonologists are currently using cyclophosphamide are so-called "off-label" uses.

Despite the well-known risks of cyclophosphamide, training in the use of the drug is relatively uncommon. Sixty-five percent of those who prescribe and manage the drug's use themselves had no training in the use of the drug. One could argue that those physicians completed fellowships before the availability of cyclophosphamide, yet few pulmonary fellows today are being trained in the use of the drug. Low scores on knowledge base testing of cyclophosphamide dosing, metabolism, and screening for side effects suggest that pulmonologists have a poor understanding of the drug's use. Considering the serious risks associated with cyclophosphamide use and the observation that most pulmonologists have used or are currently using the drug, we believe formal training in the use of cyclophosphamide should be incorporated into all pulmonary fellowship programs.

Our data demonstrate that pulmonary practitioners and fellows use cyclophosphamide, and that their training and knowledge base of the drug is often meager or nonexistent. This begs the question as to how to train them. We held a teaching conference with a case-presentation format designed to be instructive in cyclophosphamide management. The case-representation format has been a traditional mode of medical education and, in this circumstance, was very easily applied. Questions for pre- and postconference testing were designed to assay knowledge base of dosing, appropriate use, and avoidable toxicities. Significant improvement in test scores suggest this may be one effective mode of education in cyclophosphamide use, and the learning appears to be sustained over a 1-year period. A potential limitation of the study was the use of the same questions for the pre- and postconference testing, and participants may have keyed into topics addressed in both the pretest and the conference. Additionally, we note that even though lack of training in cyclophosphamide use in common, we have no information about whether this leads to inappropriate use or avoidable toxicities.

REFERENCES

[1] Fox DA, McClune WJ. Immunosuppressive drug therapy of systemic lupus erythematosis. Rheum Dis Clin North Am 1994; 20:265-299

[2] Lynch JP, McClune WJ. Immunosuppressive and cytotoxic pharmacotheraphy for pulmonary disorders. Am J Respir Crit Care Med 1997; 155:395-420

[3] Radis CD, Kahl LE, Baker GL, et al. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis: a 20-year follow-up study. Arthritis Rheum 1995; 38:1220-1127

[4] Fauci AS, Haynes BF, Katz P, et al. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983; 98:76-85

[5] Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener's granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116:488-498

(*) From the Critical Care Section (Dr. Cozzi), Elmhurst Memorial Hospital, Elmhurst, IL; and the Section of Pulmonary and Critical Care Medicine (Dr. Hall), Department of Medicine, University of Chicago, Pritzker School of Medicine, Chicago IL. Manuscript received January 26, 1999; revision accepted July 7, 1999. Correspondence to: Jesse B. Hall, MD, FCCP, Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Pritzker School of Medicine, 5841 S. Maryland Ave, Chicago , IL 60637; e-mail: jhall@medicine.bsd.uchicago.edu3

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