Original Article
Treatment of Lymphedema of the Arms and Legs with 5,6-Benzo-[alpha]-pyrone
N Engl J Med 1993; 329:1158-1163October 14, 1993
- Abstract
Background
Benzopyrones can reduce the volume of high-protein edema fluid by stimulating proteolysis. These compounds provide a method for removing excess protein and its consequent edema and reduce its clinical sequelae, such as chronic inflammation and secondary infections.
Methods
We conducted a randomized, double-blind, placebo-controlled, crossover trial of 5,6-benzo-[alpha]-pyrone in 31 patients with postmastectomy lymphedema of the arm and 21 patients with lymphedema of the leg of various causes. This agent is also known as 56 BaP, 1,2-benzopyrone, and coumarin, although it has no anticoagulant activity. The patients received 400 mg of the active drug or placebo, each for six months.
Results
During the placebo period, lymphedema often worsened, especially in the arms. Measurements of limb volume showed that the active drug reduced the mean amount of edema fluid in the arms from 46 percent above normal to 26 percent above normal (P<0.001) and the amount in the legs from 25 percent to 17 percent above normal (P<0.001). The circumference of the arms was reduced from 17 percent to 13 percent above normal, and the circumference of the legs from 11 percent to 7 percent above normal (P<0.001). The softness of the limb tissue was increased (P<0.001), and elevated skin temperatures were reduced (P<0.001). There were fewer attacks of secondary acute inflammation (P = 0.01). Bursting pains and feelings of hardness were decreased, as were feelings of tightness, tension, swelling, and heaviness; limb mobility also improved. The active drug was preferred to the placebo by 93 percent of the patients (P<0.001). Side effects -- mild nausea or diarrhea -- occurred in seven patients taking the active drug. None withdrew from the trial, and the side effects disappeared after the first month of therapy.
Conclusions
5,6-Benzo-[alpha]-pyrone results in slow but safe reduction of lymphedema of the extremities.
Media in This Article
Figure 1
Measurements of Edematous Arms during the Placebo Period (Dashed Lines) and the Active-Drug Period (Solid Lines).Figure 2
Measurements of Edematous Legs during the Placebo Period (Dashed Lines) and the Active-Drug Period (Solid Lines).Article Activity
- Article
Lymphedema, a form of high-protein edema, is a serious, long-lasting, and common problem; there are about 140 million cases throughout the world1,2. Correctly applied, physical methods of treatment rapidly reduce edema fluid,3-6 but they require intensive work and special training, and few centers offer them. Even then, only about half the fluid is removed; a year must elapse before half of the remainder can be removed. In a few cases surgery is beneficial, but often it is not1,4,7.
Benzopyrones reduce lymphedema in both humans and animals1,8-16. These drugs have very low toxicity and are effective when given orally, and some are inexpensive1. They reduce lymphedema by increasing proteolysis by tissue macrophages1. Thus, they serve as an alternative pathway for the removal of the excess protein. Once excess protein is eliminated, the edema fluid that it causes is no longer retained. Removal of the excess protein also reduces the medium in which secondary bacterial and fungal infections may incubate1,9,10,12,14,16.
Chronic high-protein edema, such as lymphedema, also gives rise to a chronic inflammatory state and consequent fibrosis1,8. If the excess protein is removed by benzopyrones, the chronic inflammatory condition disappears and the fibrosis diminishes1,8.
The benzopyrone 5,6-benzo-[alpha]-pyrone (also known as 56 BaP, coumarin, or 1,2-benzopyrone; it is not yet available for general use in North America) was effective in the treatment of postmastectomy lymphedema in a large open, controlled trial,9 a small double-blind, crossover trial,10 and other trials11,12. It even reduced lymphedema due to filariasis and elephantiasis13,14. Other benzopyrones have also been shown to reduce lymphedema1,15,16. It is important to note that although “coumarin” is the correct common chemical name of 5,6-benzo-[alpha]-pyrone, this agent is not an anticoagulant like its derivatives the bis-4-hydroxycoumarins1. In the present double-blind, crossover trial, we tested the efficacy of 5,6-benzo-[alpha]-pyrone in several forms of chronic lymphedemas.
Methods
We studied 31 patients with unilateral postmastectomy lymphedema (lymphedema affecting the arms) and 21 patients with unilateral leg lymphedema of various causes. The lymphedema was a primary condition in 15 patients and developed after surgery or in a setting of extensive inflammation in the other 37; it was diagnosed by history and physical examination, with computed tomography and venography performed if there was any doubt about the diagnosis. Patients were excluded if there was any suspicion of metastases as a result of clinical examination, chest radiography, or radionuclide bone scanning. All had moderately severe to severe grade 2 lymphedema, without elephantiasis (according to the classification of the International Society for Lymphology3) -- i.e., the edema was not spontaneously reversible by elevation or compression of the limb, moderate-to-severe fibrosis was present, and elephantiasis was absent.
Informed consent was obtained from all patients, and the trial was approved by the ethics committees of all institutions. In addition to the 52 patients described in this report, 11 patients were enrolled who were later excluded: 5 with postmastectomy lymphedema and 5 with leg lymphedema withdrew for reasons unconnected with the trial (i.e., they moved away from the study center or had difficulty getting to it), and 1 patient with leg edema was excluded because she seldom returned for follow-up. The age, sex, and duration of lymphedema in the patients are shown in Table 1Table 1
Prestudy Characteristics of 52 Patients with Lymphedema..“Conservative” measures for lymphedema had usually been tried -- e.g., physiotherapy or compression by a pump or elastic sleeves or stockings. Except for short courses of antibiotics given for attacks of secondary acute inflammation, all other therapy was stopped one month before the trial and during its course. The patients agreed to forgo further conservative treatment during the trial. We strongly believe in correct conservative treatment, but did not use it during the study period in order to test the effect of 5,6-benzo-[alpha]-pyrone alone.
The trial was a randomized, double-blind, placebo-controlled study with a crossover design. There were two six-month treatment periods, with no washout period. Blinding was performed by the pharmacist, who used a random-number table to assign patients to treatment groups. The code was broken only after the end of the trial. Two tablets, each containing 200 mg of medication (5,6-benzo-[alpha]-pyrone or placebo) were given orally once a day.
Follow-up examinations were performed once a month. Compliance was checked by counting tablets, and the patients were asked about any side effects and the particular symptoms that they reported. A symptom was recorded as being better, the same, or worse. Usually, symptoms were present at the start of a period, but some developed during a period. If a symptom disappeared during the first period and did not reappear during the second, it was included only in the first.
Limb volumes were measured twice at each examination by means of a water-displacement tank and standardized procedures17. Limb circumferences were measured at up to eight points on the legs and six points on the arms, at 10-cm intervals. Tissue tonometry was performed three times at two sites: 10 cm proximal and distal to the elbow on the anterior surface of the arm, or 20 cm above and below the knee on the posterior surface of the leg. The plunger of the tonometer depresses the skin under a constant weight18; the softer the tissue, the deeper it is pushed, producing a higher positive reading. Skin temperatures were measured 10 cm proximal to the elbow or 20 cm distal to the knee (CIG Medishield medical digital skin thermometer, CIG, Melbourne, Australia), with a second remote electrode on the normal limb, in a temperature-controlled room.
Statistical Analysis
Both the edematous and the normal limbs were measured at each examination, because the size of the normal limb is important in relation to the actual amount of edema. In addition, because of the effect of ambient temperature and exercise on edema, using a normal limb as a control greatly reduces the standard error by excluding the considerable variations in all measurements. In each patient at each examination, the value for the edematous limb was expressed as the ratio of its measurement to the measurement of the normal limb. Linear regression lines were fitted to the ratios for each patient. These lines were only combined to give the grand means (overall means) and grand slopes (average slopes) of the regression lines as the final step, thus reducing between-patient variation.
The differences between the grand means and grand slopes were evaluated for significance by two-tailed t-tests (Microsoft Excel, version 4 [Microsoft, New York], was used for all the tests), as were the differences between the means of the volumes and the means of the average circumferences at the start and end of each treatment period. F-tests showed that the variances were not significantly different. Changes in symptoms were evaluated with chi-square tests (using Yates' correction if five or fewer patients were being evaluated). The placebo period was compared for symptoms with the active-drug period, in terms of the numbers of patients reporting that they felt better, the same, or worse during these periods. Patients' preferences for treatment periods were assessed by binomial distribution.
Since there were no significant differences between the values for the patients given the placebo first and those for the patients given the active drug first, these values were combined for greater accuracy. For this reason also, all the measurements of circumferences were combined, as were those of proximal and distal sites by tonometry. In addition, the measurements of arms and legs were combined to evaluate changes in symptoms. All P values are two-tailed.
Results
Changes in symptoms during the placebo and the active-drug periods are shown in Table 2Table 2
Changes in Symptoms after Each Treatment Period.. The symptoms experienced by the majority of patients were significantly reduced by the active drug but not by the placebo. The improvement was not rapid, usually becoming evident only by the fourth or fifth month. When treatment was switched from the active drug to the placebo, worsening of symptoms only became noticeable after one to three months. The active drug was preferred to the placebo by 93 percent of patients.The results of measurement of the arms and legs are shown in Table 3Table 3
Differences between Measurements of Edematous and Normal Limbs in 31 Patients with Lymphedema of the Arms. and Table 4Table 4
Differences between Measurements of Edematous and Normal Limbs in 21 Patients with Lymphedema of the Legs. and Figure 1Figure 1Measurements of Edematous Arms during the Placebo Period (Dashed Lines) and the Active-Drug Period (Solid Lines). and Figure 2Figure 2Measurements of Edematous Legs during the Placebo Period (Dashed Lines) and the Active-Drug Period (Solid Lines).. During the placebo period, the slopes of the regression lines for the arms all showed significant worsening (P = 0.01 to 0.001), except the slope for skin temperature. None of the regression lines for the legs showed significant worsening (P = 0.4 to 0.1).The differences between the limb volumes and the average limb circumferences at the end of the placebo period and those at the end of the active-drug period were significant, as were the percentages for measurements in which a normal limb was used as a control. The differences between the means of the regression lines for the placebo and active-drug periods were significant for all measurements of both the arms and legs (Table 3 and Table 4). The slopes of the lines for measurements other than temperature measurement also reflected significant improvement during the active-drug period as compared with the placebo period. Volume measurements showed that in six months the active drug reduced the edema of the arms from an amount 46 percent above normal to 26 percent above normal; the amount of edema of the legs was reduced from 25 percent to 17 percent above normal. The 95 percent confidence intervals for the reduction in the arms were 44 to 48 percent at the start of the active-drug period and 25 to 28 percent at the end; the confidence intervals for the reduction in the legs were 24 to 27 percent and 16 to 18 percent. Thus, nearly half of the edema fluid was removed from the arms and nearly one third from the legs. During the six months of the placebo period, the amount of edema of the legs was unchanged from 24 percent above normal, and that of the arms increased from 38 to 45 percent above normal -- i.e., nearly one fifth.
For the active-drug periods there were inverse correlations between the slopes of the individual regression lines and the initial differences between the values for the edematous and normal limbs. The following correlation coefficients were found for the arms and legs, respectively: volumes, -0.603 (P<0.001) and -0.596 (P<0.001); circumferences, -0.303 (P = 0.1) and -0.688 (P<0.001); tonometry, -0.243 (P = 0.2) and -0.408 (P = 0.06); and skin temperature, -0.099 (P = 0.6) and -0.492 (P = 0.02). The more edematous the limb, the more rapidly it tended to improve. The corresponding coefficients for the placebo period were not significant (P = 0.8 to 0.3).
The compliance rate was 99 percent. Of the 17,472 tablets to be taken during each period, only 245 were not taken during the placebo period and 227 during the active-drug period. No serious side effects were reported, but seven patients taking the active drug had slight gastrointestinal disturbances (mild nausea or diarrhea). These were not severe enough to cause any patient to leave the trial and disappeared after the first month.
Discussion
Our data show that 5,6-benzo-[alpha]-pyrone effectively reduces the volume of lymphedema. The improvement was both statistically significant and clinically meaningful. These results confirm previous studies of this and other benzopyrones in the treatment of lymphedema with diverse causes1,9-16. Reduction of the increased skin temperature has also been observed before1,10,16. It is encouraging that the more lymphedematous the limb, the more rapid its improvement, as has been shown in other studies13,14.
Improvement in the symptoms related to lymphedema has also been observed in other double-blind studies,10-14,16 including studies of lymphedema resulting from filariasis and elephantiasis13,14. Efforts to increase patients' comfort are greatly needed; contrary to what is sometimes asserted, lymphedema can be very painful, especially if it develops rapidly. Such pain, together with loss of mobility and of the use of the limb, is often of great concern to patients1,19.
As in the other trials,1 side effects were infrequent and mild. The mild gastrointestinal problems reported here were not sufficient to cause any patient to leave the trial, and all side effects disappeared after the first month. We have since found that coating the tablets with a lacquer prevents these side effects almost completely13. Many patients reported a feeling of increased general well-being, quite apart from a lessening of the symptoms related to lymphedema. This has been noted in other trials, particularly among the elderly, whose diets often have only low levels of benzopyrones1,16.
Many benzopyrones have been shown to reduce the amount of high-protein edema fluid due to various factors in humans and animals1. These agents may have many effects on the body, almost all of which may help reduce edema fluid1; they may increase the pumping action of collecting lymphatics, reduce abnormal permeability of blood vessels, stabilize plasma and lysosomal membranes, and reduce the effects of many mediators of inflammation such as scavenging free radicals.
However, all the benzopyrones that have been tested have one effect in common: they reduce the volume of high-protein edema fluid by increasing proteolysis by macrophages1,8. These cells normally lyse some protein in the tissues. All the benzopyrones increased both the rate of proteolysis per macrophage and the numbers of macrophages at the site of edema1. The drugs' ability to reduce high-protein edema fluid largely disappears if the macrophages are selectively poisoned with silica1. 5,6-Benzo-[alpha]-pyrone has also been shown to increase macrophage proteolysis in vitro1. In chronic lymphedema, many macrophages are present but their activity is greatly reduced; this state can also be reversed by the benzopyrones1. These drugs still reduce experimentally induced lymphedema even when all lymphatics are completely occluded1. All these observations indicate that benzopyrones reduce lymphedema by increasing proteolysis by macrophages.
Any form of edema can cause symptoms such as pain, disfigurement, and disability1,19. Edema fluid also reduces the oxygenation of the tissues, impairing cellular function and slowing healing,1 reducing mobility, and increasing vulnerability to injury. However, edema fluid with high levels of protein injures tissues more than fluid with low levels. After 64 days, a simple excess of an animal's own protein produced all the signs of chronic inflammation, including considerable fibrosis; 5,6-benzo-[alpha]-pyrone virtually eliminated the changes due to chronic inflammation, including the excess fibrosis, along with the excess interstitial protein, and the excess numbers of new blood and lymph vessels8.
Any excess protein also acts as a good growth medium for bacteria, which worsen preexisting lymphedema1,3. The elimination of such protein by 5,6-benzo-[alpha]-pyrone accounts for the reduction in the episodes of secondary acute inflammation (so-called erysipelas3), as shown in the present trial and others1,9,10,13,14,16. This finding does not mean that antibiotics are unnecessary when such episodes occur, but that they are needed far less frequently.
Although benzopyrones quite rapidly reduce acute edema involving high-protein fluid (e.g., edema due to accidental or surgical trauma1), they do not rapidly reduce chronic forms of edema (e.g., lymphedema). Even complex physical therapy, the most rapid and effective treatment, removes only about 50 percent of the fluid per year4-6. This proportion is removed in about four weeks, but another year is required before tissue remodeling will allow much more to be removed. Also, such removal requires four weeks of intensive treatment by specially trained therapists (for one to two hours a day per limb). This is expensive and time-consuming, as is surgery, which is often ineffective1,4,7.
The benzopyrones offer slow but safe and effective treatment. They convert an inexorable increase in edema and discomfort into a slow reduction of the volume of edema fluid and a more rapid reduction of discomfort. 5,6-Benzo-[alpha]-pyrone combined with complex physical therapy will reduce volume and discomfort more than either treatment alone20. Thus, 5,6-benzo-[alpha]-pyrone is best used as a complement to adequate conservative therapy, but can be used alone if the patient cannot wear compression garments. Indeed, the slow reduction of edema by the benzopyrones is an advantage when compression garments cannot be worn13,14. If the reduction were rapid, the elimination of the excess fluid might leave huge cavities. In the absence of limb compression, these would rapidly refill with protein and edema fluid, providing good sites for bacterial growth in a limb prone to injury.
5,6-Benzo-[alpha]-pyrone is not yet available for use in North America. Flavonoids (benzo-[gamma]-pyrones) are available, and may also be beneficial in the treatment of lymphedema,16 although gastric irritation may be a problem.
Supported by the Lymphoedema Association of Australia.
We are indebted to Mrs. G.A. Piller, Miss J. Newman, and Miss R. McLauchlan for performing the measurements, to the Flinders Medical Centre for the use of its facilities, and to Hamilton Laboratories (Adelaide, Australia) for providing the tablets of the drug and its placebo.
Source Information
From the Henry Thomas Laboratory (Microcirculation Research), University of Adelaide, Adelaide (J.R.C.-S.); the Department of Surgery, Flinders Medical Centre, Bedford Park (R.G.M.); and the Faculty of Health Sciences, Flinders University, Bedford Park (N.B.P.) -- all in Australia.
Address reprint requests to Dr. Casley-Smith at the Henry Thomas Laboratory, University of Adelaide, Box 498 G.P.O., Adelaide, S.A. 5001, Australia.
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