P&T News: January 1996, Vol. 16, No. 7
Charles S. Dayton, R.Ph.
Peer Review Status: Internally Peer Reviewed by Gary W.
Hunninghake, M.D., Professor and Director, Division of Pulmonary
Diseases, Department of Internal Medicine
This review focuses on the most commonly used and accepted chemotherapy agents in the treatment of these diseases: cyclophosphamide, chlorambucil, and methotrexate. Other agents such as azathioprine and busulfan are less well described in the medical literature and are not included in this review, even though they have enjoyed limited use in the treatment of some rare lung diseases.1 The discussion of the individual agents takes place in the context of the diseases in which they are used.
Sarcoidosis
Sarcoidosis is a multisystem disease most often affecting the lungs
or skin. Patients may initially complain of shortness of breath,
feeling tired, skin lesions (erythema nodosum), and a host of other
initial clinical presentations. Any organ of the body may be affected
by the disease, but most patients are diagnosed at bronchoscopy,
performed because of a suspicious chest x-ray finding. The pathologic
diagnosis is made when non-caseating granulomas are found on biopsy,
and infectious etiologies have been ruled out.2 Most patients with
sarcoidosis do not require therapy, but those with progressive
pulmonary disease as measured by pulmonary function testing or those
with significant extrapulmonary disease may require therapy with
prednisone. Recently, in a report from the pulmonary Specialized
Center of Research (SCOR) at UIHC, 91 previously untreated patients
with sarcoidosis were studied, and 36 were treated with
corticosteroids. Patients were treated because of deterioration of
lung function or severe extra-pulmonary disease. Therapy consisted of
high dose prednisone (60 mg daily) for six weeks, followed by a taper
to 15 to 20 mg daily over six weeks. This lower dose of prednisone
was continued for one year total. All of these patients eventually
improved after therapy with prednisone.3
In contrast to this success, there are occasional patients with sarcoidosis who require therapy other than or in addition to prednisone. Two reasons for the use of other agents in sarcoidosis are: 1) difficult to treat forms of the disease (e.g., dermatologic lesions or cardiac sarcoidosis) in which prednisone alone may not be effective; and 2) cases of recalcitrant sarcoidosis in which prolonged therapy with prednisone leads to unacceptable adverse reactions to the drug. The cytotoxic agent of choice in these instances is currently methotrexate.4 5 In weekly, low-dose regimens, methotrexate has been shown to be safe and effective in the treatment of sarcoidosis and other diseases, such as rheumatoid arthritis.
Methotrexate has been studied in sarcoidosis both for difficult to treat cases, and in prolonged therapy as a steroid-sparing agent. Lower and Baughman 4 looked at low-dose methotrexate in sarcoidosis refractory to prednisone therapy. Low-dose methotrexate is defined by the authors as a dose of approximately 10 mg per week. These authors showed that methotrexate was effective in reducing symptoms in 12 of 14 evaluable subjects. Recently, the same two authors studied the prolonged use of methotrexate in sarcoidosis patients.5 The same average dose of 10 mg per week was used in the treatment of chronic symptomatic sarcoidosis. A total of 50 patients completed at least two years of methotrexate therapy. Prednisone doses were significantly reduced, and in some cases prednisone was completely stopped without recurrence of symptoms due to sarcoidosis. Toxicity was acceptably low, with the main adverse reactions being hepatic (6 patients), leukopenia requiring hospitalization (1 patient), and cough (1 patient). Forty-one liver biopsy procedures were done; six demonstrated changes related to the administration of methotrexate, leading to the discontinuation of the drug. This patient group was predominantly female, with an average age of 39 years.
Methotrexate has been associated with the development of pulmonary disease.6 A recent study from the pulmonary SCOR at UIHC looked at 31 patients with a diagnosis of rheumatoid arthritis given low-dose weekly methotrexate.7 This group of patients was followed for approximately four years, with an average methotrexate dose of 17 mg per week which is a slightly higher average weekly dose than reported in the sarcoidosis studies quoted earlier. It was found that a mild degree of air trapping was seen in this patient group, although administration of methotrexate did not appear to cause restrictive lung disease or abnormalities in gas exchange.
In summary, methotrexate appears to be a suitable, safe alternative agent in the treatment of sarcoidosis. The two instances in which alternative or additional therapy (with prednisone) is indicated are prolonged therapy in which steroid dose reduction is desirable, and difficult to treat cases of sarcoidosis, such as extrapulmonary disease, in which more than one drug is required for disease control.
Idiopathic Pulmonary Fibrosis (IPF)
IPF is perhaps the interstitial lung disease that is most difficult
to treat. Thus, opinion - rather than solid scientific evidence is
often used to support various claims to the "right" approach to
therapy. This issue is even more clouded by early reports that the
natural history of untreated and treated IPF is not different, with
the median survival after diagnosis being about five years in both
groups.8~10
IPF is an interstitial pulmonary disease diagnosed by tissue biopsy showing formation of fibrotic tissue (usual interstitial fibrosis).11 Other causes of pulmonary fibrosis, such as infectious, environmental, aspiration or occupational sources, must be ruled out utilizing the patient history and appropriate laboratory tests. Currently, no etiology for IPF is known.
Various parameters have been used in an attempt to categorize patients with IPF into those who might or might not respond to immunosuppressive therapy. Physiologic (pulmonary function test results), biologic (results of bronchoalveolar lavage analysis), and patient demographics have all been used in an attempt to categorize those patients who have reversible airways disease due to IPF.8-'0 Thus far, these efforts have been less than satisfactory in predicting who will benefit from therapy. In a report from the pulmonary SCOR at UIHC, 31 patients with IPF who had received prednisone for at least six months were studied. In this study, three parameters were found to correlate with response to prednisone therapy: 1) female gender; 7) never having smoked cigarettes; and 3) lack of a honeycombing pattern on high resolution chest CT scans.l2 Although these results may not be applicable in all instances, they hint at categories of patients who might benefit the most from immunosuppressive therapy.
Standard therapy for IPF is generally high-dose prednisone given for an extended trial. Doses of 40 to 60 mg per day for 4 to 6 weeks, then tapering to 15 to 20 mg per day for up to one year are often recommended.11 Combination with cytotoxic drugs such as cyclophosphamide or chlorambucil is also recommended by some authors. i3 Various dosages and combinations of these agents have been studied, none with large enough numbers of patients or long enough follow-up time to draw firm scientific conclusions relating to the efficacy of any therapy.
The current recommendation for the treatment of IPF based on experience from the pulmonary SCOR program is to give prednisone in lower doses of 20 mg per day and initially add chlorambucil in doses of 2 mg per day for 4 to 6 weeks. Recommended continued therapy includes reducing the prednisone to 20 mg every other day, and increasing the chlorambucil to 4 mg daily (Table 1).
|
Table 1. Current Pulmonary SCOR IPF Drug Therapy Protocol | |
|
INITIAL THERAPY |
Prednisone 20 mg/day for 4 to 6 weeks Chlorambucil 2 mg/day for 4 to 6 weeks |
|
CONTINUED THERAPY |
Reduce prednisone by tapering to 20 mg every other day Increase chlorambucil to 4 mg/day |
It is important to carefully monitor hematologic parameters. A complete blood count (CBC) every two weeks for the first three months of therapy, then monthly thereafter, is suggested. Because white blood cell counts and hemoglobin may decline slowly over time, the serial data on the trend of these parameters are very important. Total white blood cell counts should remain greater than 3.0 K/MM3. Counseling the patient about adverse effects of chlorambucil, including the possible later development of malignancies, is very important.
This regimen offers the advantage of using lower doses of prednisone, thereby minimizing the side effect profile. Additionally, both toxicity and cost of medication to the patient are lower with chlorambucil than with other cytotoxic agents such as cyclophosphamide.l4
Cyclophosphamide is used by some clinicians for the treatment of IPF. 15 Doses may be given either as oral daily therapy, or intravenously (IV) on a monthly basis for chronic lung disease such as IPF. Oral doses range from 1 to 3 mg/kg/day (50 to 150 mg/day), and IV doses range from 500 to 1000 mg/m2 given once per month, usually not exceeding 1500 mg per dose.l6l7 One disadvantage of long-term cyclophosphamide therapy is the possible development of hemorrhagic cystitis. Acrolein, one of the metabolites of the breakdown of cyclophosphamide, is thought to be the causative agent. 14 It is important that the patient maintain a generous intake of fluids during and immediately after the administration of cyclophosphamide. Chlorambucil lacks the acrolein metabolite found with cyclophosphamide breakdown; this eliminates the concern for hemorrhagic cystitis during treatment.
Additionally, suppression of white blood cell count must be closely monitored during cyclophosphamide administration. A total white blood cell count of greater than 3.0 K/MM3 and a neutrophil count greater than 1.5 K/MM3 should be maintained. Appropriate premedication with anti-emetic agents is important for patient comfort.
Wegener's Granulomatosis
Wegener's granulomatosis is a disease consisting chiefly of
necrotizing granulomatous vasculitis of the upper and lower
respiratory tract and glomerulonephritis. Patients often present with
upper respiratory symptoms including rhinorrhea, paranasal sinus pain
and drainage, and nasopharyngeal mucosal ulceration. Cough,
hemoptysis, and pleuritic chest pain may accompany these upper
respiratory symptoms. The cause of the disease is unknown. However,
speculation of an immunopathogenesis is supported by the presence of
circulating antibodies in patients with this disorder.'8
The use of cytotoxic drug therapy in Wegener's granulomatosis has dramatically changed the course and prognosis of this disease. Prior to the introduction of cyclophosphamide therapy, Wegener's granulomatosis was uniformly fatal, with a mean survival time of five months after diagnosis, and a one-year survival rate of 20 % . With the use of cyclophosphamide therapy, long-term remissions have been achieved in 75% to 90% of patients treated.19 In this disease, cytotoxic drug therapy has made an impact and is the current therapy of choice.
Cyclophosphamide is the current treatment of choice. 19 In most cases, oral cyclophosphamide in doses of 1 to 2 mg/kg/day is administered, along with prednisone 1 mg/kg/day. The cyclophosphamide component of the regimen is usually continued for one year after a decline in disease activity is noted. The prednisone is continued at a high dose (about 60 mg/day) for 1 to 2 months, then reduced by tapering the dose to zero at the end of 6 to 12 months.
In more urgent cases, the intravenous form of cyclophosphamide may be used 20,21 (Figure 1). This treatment regimen usually consists of cyclophosphamide given in daily doses of 250 mg IV for five consecutive days in patients over 50 kg in body weight and with normal renal function. Lower doses may be administered in cases of renal impairment (Table 2). Premedication with appropriate anti-emetic therapy should be given as well as attention to appropriate hydration. Assessment of patient status is made at the end of the five-day course of therapy; a maintenance regimen (with oral cyclophosphamide) is initiated or a decision to treat with additional IV therapy is considered.
Summary
Cytotoxic agents are also used to treat other, rare diseases that can
cause pulmonary fibrosis (e.g., polymyositis, dermatomyositis). These
drugs have been used in a wide variety of conditions with a similar
underlying pathology. The desired effect of the cytotoxic agents is
the interruption of the immunologic process that hastens the
formation of fibrosis.
New, more inventive ways of treating pulmonary fibrosis are on the horizon. A long list of potentially useful agents was reviewed at a recent workshop convened by the National Heart, Lung and Blood Institute, National Institutes of Health.22 Among those agents discussed were cytokine inhibitors, growth factor inhibitors, anti-fibrotic agents, anti-proteases, and many others including gene therapy. Clinical trials to evaluate the effectiveness and safety of these agents are needed. However, until the safe and effective use of these agents has been demonstrated, the strategies outlined here are the current state of the art for the treatment of interstitial lung diseases. Corticosteroids and cytotoxic agents form the cornerstone of therapy. Major concerns associated with the use of these agents include efficacy of therapy, particularly in IPF, and the toxicity of the drugs. Hopefully, newer agents with proven clinical efficacy and enhanced safety profiles will soon be available to resolve these concerns.
|
Table 2. Cytotoxic Drugs for Non-mailignant Pulmonary Disease | |||
|
DRUG |
DOSE |
DISEASE |
MONITORING |
|
Methotrexate |
5 to 20 mg/week |
Sarcoidosis |
Liver Function Tests |
|
Cyclophosphamide Monthly Intravenous[a] Daily Intravenous[a] |
1 to 3 mg/kg 500 to 1000 mg/m2 250 mg/day x 5 days (Wt more than 50 kg, normal renal function) 1250 mg total dose 250 mg/day x 4 days (Wt less than 50 kg, Serum Cr more than 2.5 mg/dl) 1000 mg total dose |
Wegener's Granulomatosis |
Complete Blood Counts (White Blood Cell counts and
Neutrophil Counts) |
|
Chlorambucil[b] |
2 mg/day for 4 to 6 weeks; increase to 4 mg/day thereafter |
IPF |
Complete Blood Count (White blood counts, platelets and hemoglobin) |
|
[a] For control of nausea and vomiting during the infusion of IV cyclophosphamide, administer dexamethasone 10 mg IV and prochlorperazine 10 mg IV or PO 30 minutes prior to infusion. [b] Hematologic monitoring is important after prolonged therapy. References:4,5,13,15,16,17,20,21 | |||
References
Drugs Added to Stock
PRAZIQUANTAL Tablets: 600 mg Praziquantal (Biltricide2 - Bayer) is a trematodicide indicated for the treatment of schistosome infections and infections due to liver flukes.
SUMATRIPTAN Tablets: 25 mg, 50 mg Sumatriptan (Imitrex(R) Glaxo Wellcome) tablets are indicated for the acute treatment of migraine headaches with or without aura.
Additional Actions
ACTIVATED CHARCOAL SUSPENSION 50 g per 240 ml in sorbitol and 50 g per 240 ml in water have been added to stock for the management of poisonings. These products replace activated charcoal powder.
AZITHROMYCIN SUSPENSION The 600 mg per 15 ml bottle (40 mg/ ml) concentration has been added to stock.
DIAZEPAM EMULSIFIED INJECTION This form of diazepam (Dizac(R) - Ohmeda) is used as a premeditation for patients undergoing diagnostic and surgical procedures.
ESTRADIOL The 0.5 mg and I mg strengths have been added to stock.
FLUCONAZOLE The 150 mg tablet has been added to stock; this product is indicated as a single-dose treatment of vaginal candidiasis.
OMEPRAZOLE CAPSULES The 10 mg strength has been added to stock.
PHENYLEPHRINE 0.125% NASAL DROPS This strength is indicated for pediatric patients 2 to 6 years of age.
Drugs Deleted From Stock
BENTIROMIDE ORAL SOLUTION Discontinued by the manufacturer.
CHARCOAL POWDER This product has been replaced with commercially available charcoal suspensions that are indicated for the management of poisonings.
PROCAINE 0.5% INJECTION Deleted due to low use. A 2% injection is available.
OXYMETAZOLINE 0.025% NASAL SOLUTION Discontinued by the manufacturer. Phenylephrine 0.125% nasal solution will be stocked for pediatric patients 2 to 6 years of age.