Treatment of Lymphangioleiomyomatosis

Treatment of Lymphangioleiomyomatosis* A Meta-analysis Arn H. Eliasson, M.D.; Yancy Y Phillips, M.D., F.C.C.P.; and Michael F. Tenholder, M.D., F.C.C.P.

Lymphangioleiomyomatosis is a rare disease which afBicts young women of childbearing age. It is sufficiently uncommon that randomization or any other systematic evaluation of regimens of treatment has been difficult. Review of scattered case reports implies that a number of hormonal manipulations may be equally effective. Acomprehensive review of the literature revealed 30 cases of LAM treated with eight regimens of treatment. Evaluation with prede-

termined criteria (meta-analysis) shows that administration of progesterone or oophorectomy or both are the most effective treatments, resulting in improvement or stabilization of the disease in the majority of cases. (Cheat 1989; 196:1352-55)

ulmonary LAM is a disease which presents with Pprogressive dyspnea, spontaneous pneumothorax,

reports more objectively, we subjected them to a systematic process of evaluation using predetermined criteria, or meta-analysis.8

chylous effusions and hemoptysis. These signs and symptoms result from the proliferation of immature smooth muscle throughout the tissue surrounding bronchi, blood vessels, and lymphatic vessels. Most patients die from progressive pulmonary insufficiency within ten years. 1 Previously reported attempts to treat this disease with surgery, 2-5 irradiation, 2•5 and conventional chemotherapy& have not altered the progression of the disease. Lymphangioleiomyomatosis occurs only in women, usually of childbearing age, and has been observed to be rapidly progressive during pregnancy.7 These observations suggest a potential therapeutic opportunity through sex hormonal manipulation, to include discontinuation of oral contraceptives, administration of either androgen or progesterone, and induction of menopause; however, the disease is sufficiently rare to preclude randomized trials or even a series using a single regimen. Based simply on reported conclusions, a number of potential hormonal regimens may be effective. No individual therapy can be readily identified as the most effective. There is a marked heterogeneity among the cases with respect to the data presented to substantiate outcomes. In order to evaluate these

*From the Pulmonary Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, and the Dei>BTtment of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as re8ecting the views of the Department of the Army or the Department of Defense. Manuscript received January 26; revision accepted April 27. Reprint requests: Dr: Elituaon, \\biter Reed Anny Medical Center;

\\bahlngton, DC 20307-5000

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LAM= lymphangioleiomyomatosis

INDEX CASE

A 25-yeaN>Id white woman first noted episodes of hemoptysis in October 1985. The hemoptysis occurred approximately once per month and was always associated with running. Running would provoke a coughing spell which produced about one teaspoon of heavily blood-tinged sputum. The patient also noted mild dyspnea on exertion but could run two miles in 19 minutes. She denied a regular cough, production of mucus, wheezing, and chest pain. She was referred for evaluation in March 1986. The findings from her physical examination were normal. The results of PFTs were as follows: FVC, 3.59 L (92 percent of predicted noJ"IIIal9); FEV, 3.01 Us (91 percent of predicted normal); and FEV,IFVC, 89 percent). The chest roentgenogram showed a slight increase in interstitial markings. Fiberoptic bronchoscopy was performed, with transbronchial biopsy showing alveolar hemosiderosis. The patient was discharged with no specific diagnosis and closely followed. Over the ensuing year, she remained asymptomatic. In March 1987, she again noted increased dyspnea on exertion and exertional hemoptysis and returned for evaluation. The patient had never smoked cigarettes, did not take oral contraceptives, and denied exposures. She was approximately three weeks late for her menses. The findings from physical examination were normal except for a slightly enlarged uterus. Laboratory data included a positive urinary HCC. The PFTs in Aprill987 showed the following values: FVC, 3.20 L (83 percent); FEV, 2. 76 Us (86 percent); FEV,IFVC, 86 percent; SVC, 3.22 L (83 percent); ERY, 1.15 L (92 percent); FRC, 2.10 L (72 percent); Rv, 0.95 L (56 percent); and TLC, 4.17 L (75 percent). Repeat fiberoptic bronchoscopy was performed. Biopsy specimens showed focal areas of smooth muscle proliferation in perivascular and peribronchial areas, along with collections of hemosiderin-laden macrophages (consistent with LAM). With the poor prognosis in this symptomatically limited young woman, and with therapeutic options that may be only marginally effective, we elected to do an open lung biopsy to provide certainty in her diagnosis. Biopsies from right upper and lower lobes confirmed LAM . Estrogen and progesterone receptor assays were negative. The patient noted marked progression in her symptoms with the pregnancy and chose to terminate it. In October 1987, she started Trealment d Lymphangioleiorn (EiiaNon, Philips, Tenholcler)

Table !-Serial PFTt* PFT

FVC,L FEV,. Us FEV,IFVC.~

PROGESTERONE

3186

4/87

9187

10188

3.30 (92) 3.01 (91)

3.20 (83) 2.76 (86) 86

1.89 (49) 1.60 (50)

2.32 (56) 1.83 (55) 79

89

85

•Parentheses indicate percentage of predicted normal.• In August 1987, open lung biopsy was performed. In October 1987, therapy ~ begun with monthly intramuscular medroxyprogesterone.

intramuscular therapy with medroxyprogesterone (400 mglmo). Over the ensuing 11 months. she noted no further worsening in her dyspnea. Follow-up PFTs showed improvement in pulmonary volume and flow (see 'Illble I•). The gratifying response to the treatment chosen prompted us to review therapeutic options for this unusual disease.

PROGESTERONE AND TAMOXIFEN

METHODS

The search for reports of LAM was performed by a computerassisted elWllination of the literature. Keywords used were lymphangioleiomyomatosis and lymphangiomyomatosis. The reference

lists of each retrieved report were scanned for other potential reports. A manual search of Index Medicus was performed as well.

REsuLTS A review of all identified reports revealed 30 cases of LAM treated with the eight different regimens listed in Table 2. Figure 1 details the combination and sequential application of ther.lpies in each case. Twenty-three of the 30 patients received only one treatment regimen. Four patients were treated with two sequential regimens. Two patients received three sequential attempts at therapy, and one patient had four separate trials of treatment. These 30 patients thus represented 41 separate .attempts at treatment

Hormonal Therapy

Claimed Success

Cases Excludedt

Objective Success

Progesterone alone Oophorectomy alone 'Ilunoxifen alone AndrQgen alone Oophorectomy and progesterone Oophorectomy and tamomen Progesterone and tamomen Oophorectomy, progesterone, and tamoxifen

7/13 (54) 519 (56) 217 (29) Qll

5 2 4 0

1/J (33) Qll

315 (60)

3

21'2 (100)

Q/1

1

0

112 (50)

2

0

1/J (33)

1

112 (50)

4/8 (50) 517 (71)

Numben within parentheses are percentages. tin sequential evaluation of each case, ten cases were excl11ded because ~rapy was started too late in course of disease; six additional cases were excluded due to lack of data on dosage; and of cases remaining, two were excluded due to insufficient data to judge outcome of therapy.

FIGURE 1. Flow diagram of case reports by reference. Numben refer to references of case reports. Underlined references are cases judged to be unevaluable. Starred references are cases judged to be failures of the regimen indicated. Thirty cases were found, constituting 41 separate trials of treatment.

which could be evaluated for efficacy. The individual authors' reported successes or failures are presented in Table 2. Our conclusion, drawn from these individual reports, suggested that single therapy with progesterone or oophorectomy or combined therapies with oophorectomy and progesterone or with progesterone and tamoxifen are equally effective, with success rates lJpproximating 50 percent. Single therapy with tamoxifen and combined therapy with oophorectomy, progesterone, and tamoxifen were successful in approximately 30 percent of the cases; however, the variability in the reporting made verification of the claims difficult. Some reports included no objective data showing response to therapy. A few reports omitted dosages of medications used. In some cases, therapy was instituted only after the disease was so far advanced it may have precluded a chance for the therapy to work. We evaluated each report with meta-analysis to answer two basic questions: was the therapy given an adequate tri~; and, was the method successful? META-ANALYSIS METHODS

To determine if therapy was adequate, we set these criteria: (1) adequate dose (equivalent of progesterone at 10 mglday or tamoxifen at 20 mglday); (2) minimum duration of therapy at least three months; and (3) therapy initiated sufficiently early in the coune of the disease to allow a chance for therapeutic effect (eg, no evidence CHEST /96 16 I DECEMBER. 1989

1353

of cor pulmonale, honeycomb fibrosis on roentgenogram, or refractory hypoxemia). If therapy was considered to be adequate based on these criteria, then the success of therapy was determined by the following: (1) objective data reported (PFrs, arterial blood gas levels, and chest roentgenograms); (2) subjective reports of the patient; or (3) objective scales of subjective symptoms. The authors evaluated each case report independently using these criteria. The concurrence of two of us determined inclusion of a case and the evaluation of response to therapy. META-ANALYSIS REsuLTS

After meta-analysis, only 12 of the 30 cases {23 trials of treatment) were judged to be evaluable. The most common reasons to exclude a case were institution of therapy too late in the course of disease, insufficient data on the specifics of therapy, or inadequate documentation of response. Many cases contained no information on dosage, timing, or duration of therapy and suffered from lack of data or unclear presentation of the facts. These omissions unfortunately made them uninterpretable and thereby in~ligible for inclusion in the analysis {Table 2). The remaining studies support the hypothesis that the most effective therapeutic option is oophorectomy (five of seven showing improvement or stabilization) or oophorectomy plus progesterone (two of two successful). Progesterone alope was successful therapy in four of eight cases, while aQ other regimens failed to show other than anecdotal benefit. Unfortunately, the small number of patients in each regimen precluded any differences from ~aching statistjcal significance by x_2 analysis. Inclusion of our patient improves the therapeutic record of single-agent progesterone to five successes in nine reports, or a 56 percent success rate. DISCUSSION

Lymphangioleiomyomatosis is a devastating disease which strikes young women of childbearing age. .~Jecause of the implications of the diagnosis, one should be cautious in labelling a patient as Q3v~ng this disorder. This most often requires an open hmg biopsy; however, jn the proper clinical setting of interstitial pulmonary disease in a young woman with other characteristic findings (~hylous effusions; intra-abdominal leiomyomata; air trapping), a transbronchiallung biopsy may be adequate. We believe that therapy should be initiated as soon as the d~gnosis is established, because of the progressive nature of LAM in most reports. As a first step, physicians should advise against pregnancy and the use of preparations containing es~rogens. Oophorectomy and progesterone, either alone or in combination, appear to offer the greatest chance of benefit {Table 2 and Fig 1). Progesterone should be given in closes equivalent to at least 10 mg of medroxyprogesterone per day. This may be conveniently given as a 1354

monthly injection. The paucity of data on other forms of hormonal therapy is striking. Response to treatment must be followed with objective measures, which may include chest roentgenograms, PITs, and objective measures of exercise capacity. . If monotherapy fails, the combination of oophorectomy and progesterone may be successful. 14 We recommend that in cases which present with significant pulmonary compromise, patients be counselled to consider oophor~tomy and progesterone as a first option. This does not automatically commit the patient tq surgery, as chemical oophorectomy using a gonadotropin-releasing hormonal analog may provide a suitable, although yet unproven, alternative. 33 Since LAM is an unusual disease, it is likely that the only way to resolve questiqns of therapy and prognosis will be through a multicenter trial. We believe that this meta-analysis p~vides a framework for the design of such trials. REFERENCES

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