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* From the Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine (Drs. Zisman, Lynch, Toews, and Martinez), and the Departments of Radiology (Dr. Kazerooni) and Pathology (Dr. Flint), University of Michigan, Ann Arbor, MI.
Correspondence to: Fernando J. Martinez, MD, FCCP, Associate Professor of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, 3916 Taubman Center, Box 0360, Ann Arbor, MI 48109-0360
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: Prospective study.
Setting: Tertiary referral center.
Patients: Nineteen patients with biopsy specimen-proven usual interstitial pneumonia who failed to respond (n = 16) or experienced adverse effects (n = 3) from corticosteroid treatment (1 mg/kg/d for 3 months).
Intervention: Steroid therapy was tapered quickly, and oral cyclophosphamide, 2 mg/kg/d, was prescribed (mean duration of treatment, 6.0 ± 0.9 months).
Measurements and results: In 10 patients, response to therapy was determined by pretreatment and posttreatment clinical (dyspnea), radiographic (chest radiograph), and physiologic (pulmonary function, including exercise saturation) scores (CRP). Response was defined as a > 10-point drop in CRP; stable as ± 10-point change in CRP; and nonresponders as > 10-point rise in CRP. In nine patients, physiologic criteria were used to assess response; significant changes in pulmonary function were defined as follows: total lung capacity, ± 10% of baseline value; FVC, ± 10% of baseline value, diffusion capacity of the lung for carbon monoxide, ± 20% of baseline value; and resting pulse oximetry, ± 4% of baseline value. Patients who died while receiving or shortly after discontinuing cyclophosphamide were classified as nonresponders (n = 2). Among 19 patients treated with cyclophosphamide, only 1 patient demonstrated sustained response; 7 patients remained stable and 11 deteriorated while receiving the drug. Toxicity associated with cyclophosphamide was substantial; more than two thirds of the patients developed drug-related adverse effects, and almost half discontinued the drug prematurely due to side effects. In the remaining patients, cyclophosphamide therapy was discontinued due to lack of improvement or progressive deterioration.
Conclusions: Cyclophosphamide therapy is of limited efficacy in patients with idiopathic pulmonary fibrosis who fail to respond or who experience adverse effects from corticosteroid treatment, and adverse effects often complicate its use.
Key Words: corticosteroids • cyclophosphamide • pulmonary fibrosis • therapy • treatment
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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from the onset of symptoms, is characteristic.1 2 3 4 5 Corticosteroids are the mainstay of therapy, but < 30% of patients show objective response.2 5 6 7 Immunosuppressive agents or cytotoxic agents (azathio- prine or cyclophosphamide) have been recommended for steroid nonresponders, for patients experiencing serious adverse effects from corticosteroids, and for patients at high risk for corticosteroid complications.6 8 9 10 11 The reported use of cyclophosphamide is limited to a few anecdotal reports and two controlled studies.1 6 8 12 13 14 15 16 17 18 19 20 21 22 Despite the lack of convincing data supporting its use in patients with IPF unresponsive or intolerant to corticosteroid therapy, cyclophosphamide continues to be frequently prescribed in this group of patients.23 Our experience with the use of this agent in IPF has been disappointing. We report on 19 patients with IPF who failed to respond or experienced adverse effects from corticosteroids and were prospectively treated with oral cyclophosphamide, 2 mg/kg/d; responses were marginal, and toxicities were significant.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BAL
The technique used for BAL has been previously
described.24
Informed consent was obtained from all
patients. The procedure was performed using an Olympus fiberoptic
bronchoscope (Olympus Corporation of America; New Hyde Park, NY) after
premedication with atropine and meperidine hydrochloride, and under
local anesthesia with lidocaine. The tip of the bronchoscope was wedged
into the right middle lobe, and 60-mL aliquots of normal saline
solution were introduced and aspirated. The total fluid introduced
ranged from 120 to 300 mL, and approximately one third of the
introduced fluid was retrieved. The aspirated fluid was collected in a
sterile container and transported on ice immediately to the laboratory.
Cells in the fluid were collected by low-speed centrifugation; for
morphologic examination, slide preparations were made according to
techniques previously described.24
Differential cell
counts were made from total counts of 500 cells. Macrophages,
lymphocytes, neutrophils, and eosinophils were identified and counted.
Physiologic Assessment
Physiologic assessment was performed before surgical (open or
thoracoscopic) lung biopsy and initiation of therapy, at 3 months
following treatment with corticosteroids, and after 6 months (or at the
time of discontinuation) of treatment with cyclophosphamide. Pulmonary
function tests, including spirometry, lung volumes, and diffusion
capacity of the lung for carbon monoxide (DLCO), were
performed on the same day but before cardiopulmonary exercise testing.
All spirometric studies were performed using a calibrated
pneumotachograph (Medical Graphics; St. Paul, MN) and values were
expressed as a percent of the predicted values published by Morris et
al.25
Lung volumes were measured in a whole-body
plethysmograph, and data were expressed as a percent of the predicted
values published by Goldman and Becklake.26
DLCO was corrected for measured hemoglobin and expressed as
a percent of the predicted values published by Crapo and
Morris.27
Cardiopulmonary exercise tests were performed on
an electronically-braked, calibrated cycle ergometer (Warren E.
Collins; Braintree, MA). Workload was increased by 20 W/min until
maximal symptom-limited exercise was achieved. Expired gases and
ventilation were measured using a calibrated metabolic cart (2001
System; Medical Graphics; or Collins CPXII; Warren E. Collins).
Arterial blood gases were obtained at rest and every 2 min during
exercise via an indwelling radial artery catheter. The
alveolar-arterial oxygen pressure difference was calculated for each
sample by the alveolar gas equation, using the measured respiratory
quotient during the same time point of exercise. Oxygen saturation was
measured by co-oximetry of the blood gas sample. Twelve-lead ECGs and
noninvasive measurements of BP were recorded every minute of exercise.
Clinical, Radiographic, and Physiologic Scoring System
Clinical severity was assessed for each patient using a
previously developed clinical, radiographic, and physiologic (CRP)
composite score for IPF.28
The total CRP score ranges from
0 to 100 points (100 being the most severe disease), based on the
following seven variables: level of dyspnea, 0 to 20 points; chest
radiograph, 0 to 10 points; spirometry (FVC, 0 to 12 points;
FEV1, 0 to 3 points); lung volume, 0 to 10
points; DLCO (corrected for alveolar volume), 0 to 5
points; resting alveolar-arterial oxygen pressure difference, 0 to 10
points; and oxygen saturation corrected for maximal achieved oxygen
consumption, 0 to 30 points. CRP scores were obtained at study entry,
at 3 months of corticosteroid therapy, and at 6 months (or at the time
of discontinuation) of cyclophosphamide treatment.
High-Resolution CT Protocol
All high-resolution CTs (HRCTs) were performed with 1.0- or
1.5-mm thick sections taken at 1-cm intervals throughout the entire
thorax, and were reconstructed using a high-spatial-frequency
algorithm. No IV contrast was administered. The scans were performed
using a General Electric Advantage CT/T scanner (G.E. Medical Systems;
Milwaukee, WI). Four experienced thoracic radiologists independently
evaluated all HRCTs, as previously reported.29
All HRCTs
were obtained 1 to 4 weeks before open lung biopsy and, as such, prior
to commencement of corticosteroid therapy, and again prior to the
initiation of cyclophosphamide therapy. The radiologists scored
ground-glass opacity and reticular opacity on a scale of 0 to 5, as
previously reported.29
For the purpose of analysis, each
lobe was scored by the interpreters, and the mean of all lobes was
incorporated into an HRCT ground-glass opacity score (HRCT-fib), an
HRCT reticular opacity score (HRCT-alv), and a total score for each
patient.
Biopsy Technique
All patients underwent bronchoscopy with BAL and transbronchial
biopsies before surgical lung biopsy. Patients were referred for
surgical lung biopsy when the results of transbronchial biopsy did not
reveal a clear-cut alternative diagnosis. Surgical lung biopsy was
performed by formal thoracotomy or video-assisted thoracoscopy.
Similar-sized biopsy specimens were obtained by either technique.
Biopsy specimens were obtained from all three lobes on the right side,
or from the upper and lower lobe on the left with exclusion of the
lingula.
Therapy
All patients were treated with prednisone, 1 mg/kg/d, for 3
months after confirmatory surgical lung biopsy and baseline studies
were completed. Changes in the CRP score at 3 months were used to
assess therapeutic response. Responders (a > 10-point drop in CRP
score), stable individuals (a ± 10-point change in CRP score), or
nonresponders to prednisone (a > 10-point increase in CRP score or
death) were identified. Only patients classified as stable,
nonresponders, and responders requiring discontinuation of prednisone
due to side effects were included for the study. In all patients,
corticosteroids were rapidly tapered and discontinued within 4 weeks;
none of the patients experienced rapid deterioration or relapse during
tapering. Patients were prescribed oral cyclophosphamide, 2 mg/kg/d,
for a 6-month trial of therapy.
Response to Cyclophosphamide Therapy
Changes in the CRP score at 6 months (or at the time of
discontinuation of cyclophosphamide therapy) were used to assess
therapeutic response (mean duration of cyclophosphamide therapy,
6.0 ± 0.9 months). In those patients in whom CRP data were
unavailable because they were unable to complete an exercise protocol
(n = 9), physiologic criteria were used to assess response to
treatment; significant changes in pulmonary function were defined as
follows: total lung capacity (TLC), ± 10% of baseline value; FVC,
± 10% of baseline value; DLCO, ± 20% of baseline
value; or resting pulse oximetry
(SpO2), ± 4% of baseline value as
used in prior studies.6
7
8
9
12
20
24
30
31
32
Response was
defined by a significant improvement in one or more lung function test
results if it was sustained at 1 year. Nonresponders were defined as
those patients who had decrements of similar magnitude in one or more
lung function test results, or those who died while receiving or
shortly after discontinuing cyclophosphamide therapy. Follow-up
concluded with patient death or last evaluation (no patient was
unavailable for follow-up).
Statistical Analysis
Those individuals remaining in stable condition were grouped and
compared to those not responding to cyclophosphamide therapy using a
Mann-Whitney test. Clinical features, physiologic data, and
radiographic data were compared in this way. In a similar analysis,
those individuals surviving were compared to those dying during
long-term follow-up. There was agreement between response status as
decided by CRP score and physiologic criteria using McNemar’s test
(
= 0.57; p = 0.57). In all analyses, a p value < 0.05 was
considered significant.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Seven patients (37%) remained in stable condition during cyclophosphamide therapy (mean duration of therapy, 5.4 ± 0.7 months; range, 2.4 to 8 months). In these patients, response to cyclophosphamide therapy was assessed by CRP in four patients and by lung function in three patients. When lung function criteria were applied to patients with available CRP scores, all remained in the stable group. Interestingly, most of these patients remained in stable condition, and one patient improved on long-term follow-up even after treatment was discontinued. Among the six patients in stable condition in whom lung function was available after cyclophosphamide was stopped (2.9 ± 0.9 years after cyclophosphamide treatment ended; range, 41 days to 5.4 years), four patients remained in stable condition (three patients were receiving no specific treatment, and one patient was receiving a low-dose prednisone/azathioprine combination), one patient improved (a 14% increase in TLC), and one patient deteriorated (a 10% decrement in TLC). When compared to nonresponders, the patients in stable condition exhibited a trend toward a lower HRCT-fib score before initiation of cyclophosphamide therapy (Table 2) .
Eleven patients (59%) were classified as nonresponders to cyclophosphamide (mean duration of therapy, 5.3 ± 0.9 months; range, 1 to 12.5 months). In these patients, the response to cyclophosphamide therapy was assessed by CRP in five patients and by lung function in four patients. Two patients died of respiratory failure while receiving or shortly after discontinuing cyclophosphamide and were classified as nonresponders (one patient died during therapy, and one patient died 3 months after discontinuing cyclophosphamide). When lung function criteria were applied to patients with available CRP scores, two patients would have been classified as being in stable condition.
Long-term Survival
At the end of the follow-up period (4.2 ± 0.4 years),
seven patients died (respiratory failure [n = 6] and
complications of small cell lung cancer [n = 1]). All
were cyclophosphamide nonresponders. As shown in Table 3
, the patients who died (n = 7) exhibited a higher pretherapy CRP
score, a higher HRCT-fib score, and a higher level of dyspnea, and a
trend toward a lower DLCO when compared to those who
remained alive (n = 12). These data suggest that patients who died
had more severe disease and increased lung fibrosis at the time of
initiation of therapy compared to those who lived.
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Toxicity
Thirteen patients (68%) suffered adverse effects attributable to
cyclophosphamide, requiring discontinuation of therapy in 9 patients
(47%). These are enumerated in Table 4
. In three patients with hematologic toxicity, the reduced neutrophil
and platelet counts returned to normal once the dose was reduced. In
the seven patients experiencing GI toxicity (nausea, vomiting,
anorexia/weight loss, or diarrhea), therapy was discontinued because of
these adverse effects. Skin manifestations included skin
hyperpigmentation in one patient and a morbiliform rash in one patient.
None of the adverse effects were life threatening. However, a decision
to discontinue therapy was made on the basis of no clinical or
physiologic improvement while receiving cyclophosphamide therapy, and
the desires of the patients not to continue therapy.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our prospective study evaluated oral cyclophosphamide therapy in a cohort of 19 patients with biopsy specimen-proven UIP who either failed to respond, remained in stable condition, or developed adverse effects from corticosteroids. Unfortunately, a sustained response to cyclophosphamide therapy was evident in only 1 patient; 7 patients remained in stable condition and the conditions of 11 patients deteriorated while receiving cyclophosphamide. The reported use of cyclophosphamide is limited to a few anecdotal reports and two controlled studies.1 4 6 7 8 12 13 14 15 16 17 18 19 20 21 22 30 34 35 Unfortunately, from these disparate studies, the efficacy of cyclophosphamide is difficult to assess for the following reasons: the uncontrolled, retrospective, or anecdotal nature of the study6 7 12 14 16 17 18 20 21 22 30 35 ; the unbalanced disease severity and substantial crossover between groups8 ; the varying diagnostic criteria without consistent use of lung biopsy4 6 7 11 12 17 18 29 ; the inclusion of patients with CTD who may exhibit better response to cytotoxic treatment6 14 15 16 30 ; the variable treatment regimens and follow-up14 15 17 20 21 30 ; the concurrent use of corticosteroids8 12 14 15 16 18 20 21 22 30 ; and the variable criteria used to assess response to therapy.6 8 12 15 16 19 20 21 22 30 In contrast to previous investigations, all of our patients had histologic diagnosis of UIP and were prospectively treated with high-dose corticosteroids followed by cyclophosphamide alone. Patients with CTD and other interstitial lung diseases were excluded. In addition, objective response to cyclophosphamide was determined by rigorous pulmonary function criteria. Because the utility of pulmonary function tests to predict natural history, prognosis, and histology in IPF is limited, and a lack of consensus with regard to the variables studied exists in the literature,4 8 12 32 we utilized the CRP scoring system because it has been shown to improve the correlation with histologic abnormalities in IPF.28 Interestingly, although no statistical difference was evident when response to treatment was determined by CRP or by pulmonary function criteria for the group as a whole, there was a tendency to overestimate response to treatment when pulmonary function parameters were used (two nonresponder patients by CRP score would have been classified as being in stable condition by physiologic criteria); this likely contributes to the more favorable outcomes reported by other investigators.
An additional, important finding of our study is that most patients who were in stable condition while receiving cyclophosphamide therapy remained so on long-term follow-up even after treatment had been discontinued (the condition of only one patient worsened). Previous studies have reported the presence of a similar group of patients who remain in stable condition after discontinuation of therapy,8 20 30 suggesting that cyclophosphamide may not alter the natural history of the lung disease in patients who remain in stable condition after a course of treatment. These observations cast doubt on the need to continue long-term cyclophosphamide therapy in patients with UIP who do not show a convincing response to this agent. Patients with UIP who remain in stable condition after 6 months of cyclophosphamide therapy could be advised that present therapy is unlikely to be of benefit; discontinuation of therapy in such patients would avoid potential adverse effects and reduce costs.
Toxicities associated with cyclophosphamide were frequent in our patients. More than two thirds of the patients developed drug-related adverse effects, and almost half of the patients discontinued the drug prematurely due to side effects. All seven patients with GI toxicity eventually discontinued therapy. We believe that toxicities associated with cyclophosphamide (particularly nausea and other GI adverse effects) are likely to be significantly underestimated in retrospective studies. Prospective studies employing oral cyclophosphamide, 1 to 2 mg/kg/d, combined with corticosteroids as therapy for Wegener’s granulomatosis have also shown a high rate of adverse effects (> 60%).36 37 38 39 We did not observe life-threatening complications or malignancies in any of our patients. Other investigators have reported more serious side effects with the use cyclophosphamide with doses similar to ours, particularly when the duration of treatment has been more prolonged.8 30 36 37 38 40 Enthusiasm for use of cyclophosphamide for corticosteroid-recalcitrant IPF should be tempered by potentially serious toxicities. Discriminating the patients most likely to respond to therapy is warranted to avoid unnecessarily long exposure and potential side effects.
Unfortunately, in our study, the condition of only one patient improved with cyclophosphamide therapy. Thus, no valid statistical conclusions can be generated with regard to pretreatment features associated with response to therapy. Previous studies of IPF have cited pretreatment variables associated with improved prognosis and a higher rate or response to corticosteroids, including the following: younger age, shorter duration of symptoms, female sex, a high cellularity with less fibrosis on biopsy specimens, and a high lymphocyte count in BAL fluid.2 6 24 41 Further, in a prospective study, we demonstrated that higher pretreatment HRCT ground-glass opacities were associated with a higher likelihood of response to corticosteroids.2 Interestingly, in our present study, the only patient who responded to cyclophosphamide was female, younger (when compared to the mean age of the other groups), had a shorter duration of symptoms (compared to nonresponders), and had a higher HRCT-alv score at initiation of therapy than the other groups. A previous report associated response to cyclophosphamide therapy with an improvement in FVC following corticosteroid therapy12 ; other retrospective studies noted a better response to cyclophosphamide therapy in patients with increased eosinophils or neutrophils in BAL fluid.6 24 In contrast, the FVC of our responder deteriorated (from 2.42 to 1.97 L) after 3 months of corticosteroid therapy, and BAL eosinophil counts were similar among the groups. Furthermore, a higher pretreatment BAL neutrophil percentage was observed in patients who died compared to those who were alive at the end of the study. Clearly, additional studies are needed to characterize pretreatment features associated with response to cyclophosphamide.
An additional finding of our study is that all patients who died at the end of the study period failed to respond to cyclophosphamide therapy. These patients had higher pretherapy CRP score, a higher HRCT-fib score, higher levels of dyspnea, and a trend toward a lower DLCO when compared to those who were alive at the end of the study. These data suggest that these patients had more severe disease and increased lung fibrosis at the time of initiation of treatment and thus were less likely to respond to treatment. We have demonstrated that a HRCT-fib score > 2 is highly predictive of greater mortality in patients with IPF.2 In agreement with these findings, the mean HRCT-fib score in the group of patients who died in the current study was > 2. We believe that a higher pretreatment HRCT-fib score may identify a group of patients who have a worse prognosis and are unlikely to respond to therapy. Withholding cyclophosphamide therapy in such patients would avoid unnecessary exposure and potential side effects.
In summary, this prospective study of patients with open biopsy specimen-proven IPF has generated several important findings: (1) cyclophosphamide is of marginal efficacy in improving pulmonary function in patients with UIP who fail to respond to or do not tolerate corticosteroids; (2) most patients who remain in stable condition when treated with cyclophosphamide remain so once the agent is stopped; (3) cyclophosphamide therapy is frequently complicated by side effects; and (4) more severe disease and increased fibrosis, as noted by a higher pretreatment HRCT-fib score, are associated with a worse prognosis and identify patients unlikely to benefit from cyclophosphamide therapy.
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Footnotes |
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Supported in part by National Institutes of Health NHLBI Grant P50HL46487, NIH/NCRR 3 MO1 RR00042–33S3, and NIH/NIA P60 AG08808–06.
Received for publication June 14, 1999. Accepted for publication January 26, 2000.
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