Original Article
Lack of Effect of Coumarin in Women with Lymphedema after Treatment for Breast Cancer
N Engl J Med 1999; 340:346-350February 4, 1999
- Abstract
Background
Lymphedema of the arms can be a serious consequence of local and regional therapy in women with breast cancer. Coumarin has been reported to be effective for the treatment of women with lymphedema; we undertook a study in which we attempted to replicate those findings.
Methods
We studied 140 women with chronic lymphedema of the ipsilateral arm after treatment for breast cancer. The women received 200 mg of oral coumarin or placebo twice daily for six months and then the other treatment for the following six months. The end points of the study consisted of the volume of the arm (calculated from measurements of hand and arm circumference) and the answers on a questionnaire completed by the patient about symptoms potentially related to lymphedema.
Results
The volumes of the arms at 6 and 12 months were virtually identical, regardless of whether coumarin or placebo was given first. After six months, the average volume of the affected arm increased by 21 ml during placebo treatment and 58 ml during coumarin treatment (P=0.80). In addition, answers on the patients' questionnaires were similar in the two treatment groups. After six months, only 15 percent of the women in the coumarin group and 10 percent of those in the placebo group reported that the study medication had helped a moderate or large amount (P=0.19). Coumarin was well tolerated, except that it resulted in serologic evidence of liver toxicity in 6 percent of the women.
Conclusions
Coumarin is not effective therapy for women who have lymphedema of the arm after treatment for breast cancer.
Media in This Article
Figure 2
Grading of Arm Symptoms on Questionnaires by Women in the Two Treatment Groups.Figure 1
Mean Volumes of the Arms in the Women Receiving Coumarin and Placebo in a 12-Month Crossover Study.Article Activity
- Article
Lymphedema is an important long-term complication of local and regional therapy in women with breast cancer. It can result in cosmetic deformity, loss of functional ability, physical discomfort, and recurrent episodes of cellulitis and lymphangitis. It is more common in women who are obese1 and in women over the age of 60 years, presumably because of the loss of connections between lymph vessels and veins.2 Physical therapy can be effective in reducing the lymphedema but requires special training that is not widely available.3,4
Coumarin (5,6-benzo-[α]-pyrone, or 1,2-benzopyrone) and related drugs have been reported to reduce lymphedema,5-10 possibly through stimulation of proteolysis by tissue macrophages. In addition to findings that it decreases the pain and discomfort caused by lymphedema, coumarin has been reported to reduce the incidence of cellulitis or lymphangitis and to soften slowly the brawny edema that is often found in conjunction with lymphedema. In 1993, Casley-Smith et al. reported in the Journal the results of a double-blind, crossover trial of coumarin in 31 women with postmastectomy lymphedema and 21 men and women with lymphedema of the leg of various causes.10 Coumarin was reported to be more effective than placebo in reducing the volume of edema fluid in the arm, in reducing skin temperature, and in increasing the softness of the limb tissue. We undertook the current study in an attempt to confirm these results in women who had lymphedema after treatment for breast cancer.
Methods
Subjects
The subjects of the study were 140 women 33 to 84 years old with unilateral lymphedema of the arm attributed to earlier local or regional treatment of breast cancer (surgery or radiation therapy). In each case, both the woman and her physician had determined that the lymphedema was sufficiently severe to warrant treatment. The lymphedema had to have been present for at least one year and was not immediately reversible by elevation or compression of the arm. All the women were ambulatory. Women were not eligible for the study if they had taken coumarin previously, were currently undergoing radiation therapy or chemotherapy (with the exception of tamoxifen given as an adjuvant to local or regional treatment), had changed their regimen of physical therapy for lymphedema during the preceding month, or had an indwelling venous device; if they had an infection of either arm, had evidence of residual active cancer, had a life expectancy of less than 2 years, or had bilateral edema of the arms; if they were pregnant or nursing; or if they had a history of hepatitis or evidence of liver dysfunction (i.e., serum aminotransferase or conjugated bilirubin concentrations >50 percent above the upper limit of normal), a history of alcohol abuse, or a history of venous thrombosis in the preceding 12 months.
At the time of enrollment, a complete history was obtained from each woman, and a physical examination and liver-function tests were performed. In addition, the women completed a questionnaire designed to assess swelling, pressure, tightness, heaviness, and loss of mobility of the arms, which they graded from 0 to 3 according to the following scale: 0, none; 1, mild; 2, moderate; and 3, severe. These questionnaires also inquired about any infection in the affected arm. Measurements were taken of the circumference of each hand just distal to the thumb, of each wrist at its narrowest point, and of each arm 30, 40, and 50 cm proximal to the tip of the middle finger, as far as possible before the axilla was reached. The volume of each arm was calculated from these measurements as described by Casley-Smith11 and according to the formula for the volume of a cylinder. The women were also given written instructions that provided details about the planned study procedures and educational information about lymphedema. The study was approved by the appropriate institutional review committees, and all the women gave written informed consent.
Study Design
The women were stratified according to six characteristics (age, therapy for breast cancer, history of cellulitis in the involved arm, duration of lymphedema, time since surgery or radiation therapy, and tamoxifen therapy) and then randomly assigned to receive coumarin (two 100-mg tablets twice daily) or placebo (two identical lactose tablets twice daily) for six months, followed by the other treatment for six months. The coumarin and placebo tablets were provided by Drossapharm Pharmaceuticals (Basel, Switzerland).
The women were examined monthly, and on each occasion they were asked to complete questionnaires that included the items on the prestudy questionnaire as well as questions about whether they thought that the study medication was helpful, how often they took the study medication, and whether they had nausea, vomiting, diarrhea, or other symptoms that might be related to the medication. At the end of each six-month treatment period, the circumference of the hands and arms was measured in the same way as before the study.
Initially, we planned to measure serum aminotransferase concentrations at the end of each treatment period. However, as we have reported previously,12 two women had abnormal values three or four months after treatment started (the measurement was performed in one woman in whom jaundice developed and in another at the discretion of the attending physician). We therefore measured serum aminotransferase concentrations in the other women after three to four months of the initial treatment and then one and three months after crossover to the opposite treatment. Treatment was stopped if serum aminotransferase concentrations were two or more times the upper limit of normal.
The efficacy of treatment was judged according to changes in arm volume, which was calculated from measurements of circumference by the method of Casley-Smith,11 and according to the women's answers on the questionnaires.
Statistical Analysis
At the end of each treatment period, Student's t-tests and Wilcoxon's rank-sum tests were used to compare the average circumference of the affected arm at each measurement site, after normality had been established or refuted by Shapiro–Wilk testing.13 The average ratio of the circumference of the affected arm to that of the normal arm was compared in the same way at each site. The arm-circumference measurements were then combined into volumetric data for each arm at each time point according to the method of Casley-Smith11 and by application of the formula for the volume of a cylinder.
We evaluated the volumetric data using the geometric relations for arm measurements and the SAS Data Step Graphics Interface program.14 According to this method, the circumference measured at each site was used to construct ellipses with the geometric formula relating the circumference of an ellipse to its area. A second equation was formed by relating the relative length of the major and minor axes of each ellipse. The two equations, each with two unknown variables, were then solved to obtain the equation for an ellipse that represented the shape of the arm at each site. These ellipses were then joined by straight lines of the appropriate lengths, and a representation of the curvature of the hand was constructed with an additional ellipse. For each woman, the representation of the normal arm was then overlaid with the representation of the affected arm. Simulations demonstrated that the resulting image accurately reflected changes in arm volume.
The incidence scores for responses to the questionnaires were compared between the groups at the end of each treatment period by simple tests for the equality of binomial proportions. Ordinal responses were analyzed by standard Wilcoxon's rank-sum tests. All the statistical tests were two-sided.
Results
Of the 140 women enrolled in the study, 1 was found to be ineligible (she had a history of hepatitis) and 1 withdrew from the study (she never took any study medication after randomization). For analyses of toxicity, data from all 139 women who took any study medication (including the ineligible woman) were included. For the evaluation of efficacy, data were obtained on 130 of the 138 remaining women (94 percent) at 6 months and 113 (82 percent) at 12 months. Six women discontinued treatment before the evaluation at 6 months, and 12 more stopped before the 12-month evaluation. One woman was reportedly murdered after her six-month evaluation. Arm-volume data were not obtained in several additional cases in which women did not return for arm measurements; data were available for 120 at 6 months and 93 at 12 months.
The characteristics of the women in the two study groups were similar (Table 1Table 1
Base-Line Characteristics of Women with Breast Cancer and Lymphedema According to Stratification Factors.), as were their answers to questions on the base-line questionnaire about arm pressure, tightness, heaviness, swelling, and loss of mobility.Results of a crossover analysis demonstrated that there was no evidence of a carryover effect, and therefore results for each treatment were combined. After the administration of coumarin or placebo for six months, there were no significant differences from base line in total or distal edema; volume of the affected arm; ratio of the volume of the affected arm to that of the normal arm; or circumference of the hand, wrist, or arm at points 30, 40, and 50 cm from the tip of the middle finger. The average volume of the affected arm increased by 21 ml with placebo and 58 ml with coumarin. The volumes of both the affected and the normal arms were similar in the two groups at all times (Figure 1Figure 1
Mean Volumes of the Arms in the Women Receiving Coumarin and Placebo in a 12-Month Crossover Study.). Our assessment of the influence of evaluation on the results included analyses of the effects of variability between patients, treatment period, treatment sequence, base-line scores, severity of lymphedema, duration of lymphedema, age, handedness, use of tamoxifen, and history of cellulitis. Regardless of the covariates included in the analysis, coumarin had no effect that differed from that of placebo on any of the end points related to efficacy.Analysis of the data provided by the monthly questionnaires also supported this finding. The women's responses to questions about arm swelling, pressure, tightness, heaviness, and loss of mobility were similar for coumarin and placebo during both periods and demonstrated some positive changes with time but no differential effects associated with treatment (Figure 2Figure 2
Grading of Arm Symptoms on Questionnaires by Women in the Two Treatment Groups.). The frequency of infections of the arm was similar during the coumarin and placebo periods.After each six-month period the women were asked whether they thought that the study medication was helping them. Their responses did not suggest that coumarin had benefit during either period (Table 2Table 2
Benefit Perceived by the Women while Receiving Coumarin or Placebo.). After 12 months the women were asked which of the two treatment periods (the first or the second) they preferred. Of the 87 women who answered this question, 51 percent did not prefer one period over the other, 24 percent preferred the coumarin period, and 25 percent preferred the placebo period.The results of the monthly questionnaires with respect to compliance revealed that 88 percent of the women took at least 90 percent of their study medication during the first six months, and 81 percent did so during the second six months. There were no differences between treatments in compliance.
With regard to side effects, the information obtained from the questionnaires and by history taking at 6 and 12 months did not suggest any differences in the incidence of nausea, vomiting, or diarrhea between coumarin treatment and placebo. However, as we have previously reported,12 the incidence of hepatotoxic effects was substantially higher with coumarin than with placebo. In none of the women did serum aminotransferase concentrations reach 2.5 times the upper limit of normal during the placebo period, whereas in nine women (6 percent) the concentrations became high during treatment with coumarin (P=0.006). The most prominent instance of hepatotoxicity occurred in a woman in whom jaundice developed and the serum bilirubin concentration rose to 19.3 mg per deciliter (330 μmol per liter) while she was receiving coumarin. In these nine women the test results became normal after coumarin treatment was stopped (treatment was stopped when the elevated values were recorded).
Discussion
In our study we found that coumarin did not alleviate lymphedema and that coumarin-related hepatotoxic effects were more common than has been previously reported. We designed our protocol to duplicate that of a study by Casley-Smith et al., who reported that coumarin alleviated lymphedema.10 We are unable to explain the difference between the results of the two studies. The previous trial involved 31 women with lymphedema of an arm, whereas we studied 140 women. All the women had lymphedema after treatment for breast cancer, and review of the base-line characteristics of the women in the two studies suggests that they were similar. The circumferences of the arms were measured similarly in both studies.
Previous studies suggested that coumarin caused hepatotoxic effects in fewer than 1 percent of patients, and indeed it was claimed that hepatotoxicity was not clearly associated with this drug.15,16 Thus, our finding of hepatotoxic effects in 6 percent of the women in our study was unexpected. We were unable to identify any predisposing factors, such as therapy with tamoxifen or high body weight. During our trial, the deaths of patients receiving coumarin in other countries led to the removal of the drug from the market in at least two countries.
In conclusion, we found that coumarin was ineffective for ameliorating lymphedema of the arm in women who had undergone local or regional therapy for breast cancer.
Supported in part by grants (CA-25224, CA-37404, CA-35113, CA-35415, CA-35103, CA-63848, and CA-37417) from the National Cancer Institute.
We are indebted to Dr. John Casley-Smith for his help in reviewing the protocol after it was developed.
Source Information
From the Mayo Clinic and Mayo Foundation, Rochester, Minn. (C.L.L., J.A.S., T.W.R., S.K.Q., P.N.); the Illinois Oncology Research Association Community Clinical Oncology Program (CCOP), Peoria (J.W.K.); Toledo Community Hospital Oncology Program CCOP, Toledo, Ohio (R.B.M.); Siouxland Hematology–Oncology Associates, Sioux City, Iowa (J.C.M.); Ann Arbor Regional CCOP, Ann Arbor, Mich. (P.J.S.); Meritcare Hospital CCOP, Fargo, N.D. (R.L.); Sioux Community Cancer Consortium, Sioux Falls, S.D. (L.K.T.); and CentraCare Clinic, St. Cloud, Minn. (H.W.).
Address reprint requests to Dr. Loprinzi at the Mayo Clinic, 200 First St., SW, Rochester, MN 55905, or at loprinzi.charles@mayo.edu.
Appendix
This study was conducted as a trial of the North Central Cancer Treatment Group. Additional participating institutions and investigators included the following: Duluth Community Clinical Oncology Program (CCOP), Duluth, Minn. (J.E. Krook); Rapid City Regional Oncology Group, Rapid City, S.D. (L.P. Ebbert); Carle Cancer Center CCOP, Urbana, Ill. (A.K. Hatfield); Iowa Oncology Research Association CCOP, Des Moines (R.F. Morton); Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa (M. Wiesenfeld); Missouri Valley Cancer Consortium, Omaha, Nebr. (J.A. Mailliard); Ochsner CCOP, New Orleans (C.G. Kardinal); Scottsdale CCOP, Scottsdale, Ariz. (R. Wheeler); Geisinger Clinic and Medical Center CCOP, Danville, Pa. (S. Nair).
- References
References
1
Say CC ,Donegan W . A biostatistical evaluation of complications from mastectomy. Surg Gynecol Obstet 1974;138:370-376
Web of Science | Medline2
Pezner RD ,Patterson MP ,Hill LR , et al. Arm lymphedema in patients treated conservatively for breast cancer: relationship to patient age and axillary node dissection technique. Int J Radiat Oncol Biol Phys 1986;12:2079-2083
CrossRef | Web of Science | Medline3
Casley-Smith JR ,Casley-Smith JR . Modern treatment of lymphoedema. I. Complex physical therapy: the first 200 Australian limbs. Australas J Dermatol 1992;33:61-68
CrossRef | Medline4
Zanolla R, Monzeglio C, Balzarini A, Martino G. Evaluation of the results of three different methods of postmastectomy lymphedema treatment.J Surg Oncol 1984;26:210-3.
5
Jamal S ,Casley-Smith JR ,Casley-Smith JR . The effects of 5,6 benzo-[a]-pyrone (coumarin) and DEC on filaritic lymphoedema and elephantiasis in India: preliminary results. Ann Trop Med Parasitol 1989;83:287-290
Web of Science | Medline6
Braun HD ,Becker T ,Meyer U . Behandlung von Stauugserscheinungen nach Ablatio mammae und Bestrahlung: Erfahrungen mit physikalischer Therapie und Venoruton. Munch Med Wochenschr 1971;113:1630-1633
Medline7
Casley-Smith JR ,Jamal S ,Casley-Smith J . Reduction of filaritic lymphoedema and elephantiasis by 5,6-benzo-α-pyrone (coumarin), and the effects of diethylcarbamazine (DEC). Ann Trop Med Parasitol 1993;87:247-258
Web of Science | Medline8
Casley-Smith JR ,Wang CT ,Casley-Smith JR ,Zi-Hai C . Treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-α-pyrone (coumarin). BMJ 1993;307:1037-1041
CrossRef | Web of Science | Medline9
Piller NB ,Morgan RG ,Casley-Smith JR . A double-blind, crossover trial of 0-(β-hydroxyethyl)-rutosides (benzo-pyrones) in the treatment of lymphoedema of the arms and legs. Br J Plast Surg 1988;41:20-27
CrossRef | Medline10
Casley-Smith JR ,Morgan RG ,Piller NB . Treatment of lymphedema of the arms and legs with 5,6-benzo-α-pyrone. N Engl J Med 1993;329:1158-1163
Full Text | Web of Science | Medline11
Casley-Smith JR . Measuring and representing peripheral oedema and its alterations. Lymphology 1994;27:56-70
Web of Science | Medline12
Loprinzi CL ,Sloan JA ,Kugler J . Coumarin-induced hepatotoxicity. J Clin Oncol 1997;15:3167-3168
Web of Science | Medline13
Shapiro SS ,Wilk MB . An analysis of variance test for normality (complete samples). Biometrika 1965;52:591-611
Web of Science14
SAS/GRAPH software: reference, version 6. Vol. 1. Cary, N.C.: SAS Institute, 1990:599-736.
15
Cox D ,O'Kennedy R ,Thornes RD . The rarity of liver toxicity in patients treated with coumarin (1,2-benzopyrone). Hum Toxicol 1989;8:501-506
CrossRef | Medline16
Casley-Smith JR ,Casley-Smith JR . Frequency of coumarin hepatotoxicity. Med J Aust 1995;162:391-391
Web of Science | Medline
- Citing Articles (47)
Citing Articles
1
Elie A Akl, Nawman Labedi, Irene Terrenato, Maddalena Barba, Francesca Sperati, Elena V Sempos, Paola Muti, Deborah Cook, Holger Schünemann, Elie A Akl. 2011. Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer. .
CrossRef2
Chirag Shah, Frank A. Vicini. (2011) Breast Cancer-Related Arm Lymphedema: Incidence Rates, Diagnostic Techniques, Optimal Management and Risk Reduction Strategies. International Journal of Radiation Oncology*Biology*Physics 81:4, 907-914
CrossRef3
Stamatakos Michael, Stefanaki Charikleia, Kontzoglou Konstantinos. (2011) Lymphedema and breast cancer: a review of the literature. Breast Cancer 18:3, 174-180
CrossRef4
Elie A Akl, Nawman Labedi, Maddalena Barba, Irene Terrenato, Francesca Sperati, Paola Muti, Holger Schünemann, Elie A Akl. 2011. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. .
CrossRef5
Klaus Abraham, Michael Pfister, Friederike Wöhrlin, Alfonso Lampen. (2011) Relative bioavailability of coumarin from cinnamon and cinnamon-containing foods compared to isolated coumarin: A four-way crossover study in human volunteers. Molecular Nutrition & Food Research 55:4, 644-653
CrossRef6
2010. Toxicology and Risk Assessment of Coumarin: Focus on Human Data. , 272-360.
CrossRef7
2010. Contributions. , 38-159.
CrossRef8
2010. Posters. , 361-466.
CrossRef9
E. Cuello-Villaverde, I. Forner-Cordero, A. Forner-Cordero. (2010) Linfedema: métodos de medición y criterios diagnósticos. Rehabilitación 44, 21-28
CrossRef10
P. S. Mortimer. 2010. Disorders of Lymphatic Vessels. , 1-31.
CrossRef11
Ivonne M. C. M. Rietjens, Ans Punt, Benoît Schilter, Gabriele Scholz, Thierry Delatour, Peter J. van Bladeren. (2010) In silico methods for physiologically based biokinetic models describing bioactivation and detoxification of coumarin and estragole: Implications for risk assessment. Molecular Nutrition & Food Research 54:2, 195-207
CrossRef12
Klaus Abraham, Friederike Wöhrlin, Oliver Lindtner, Gerhard Heinemeyer, Alfonso Lampen. (2010) Toxicology and risk assessment of coumarin: Focus on human data. Molecular Nutrition & Food Research 54:2, 228-239
CrossRef13
P. S. Mortimer, K. G. Burnand, H. A. M. Neumann. 2010. , 1.
CrossRef14
Mei R. Fu, Sheila H. Ridner, Jane Armer. (2009) Post–Breast Cancer Lymphedema: Part 2. AJN, American Journal of Nursing 109:8, 34-41
CrossRef15
Andrea L. Cheville, Jeff A. Sloan, Donald W. Northfelt, Anand P. Jillella, Gilbert Y. Wong, James D. Bearden III, Heshan Liu, Paul L. Schaefer, Benjamin T. Marchello, Bradley J. Christensen, Charles L. Loprinzi. (2009) Use of a lidocaine patch in the management of postsurgical neuropathic pain in patients with cancer: a phase III double-blind crossover study (N01CB). Supportive Care in Cancer 17:4, 451-460
CrossRef16
R.L. Satarasinghe,, M.A.R. Jayawardana,. (2009) Lympidem® (a Coumarin Derivative) Induced Reversible Hepatotoxicity in an Adult Sri Lankan. Drug Metabolism and Drug Interactions 24:1, 89-94
CrossRef17
Eric Yarnell, Kathy Abascal. (2009) Plant Coumarins: Myths and Realities. Alternative and Complementary Therapies 15:1, 24-30
CrossRef18
Ivonne M.C.M. Rietjens, Marelle G. Boersma, Maria Zaleska, Ans Punt. (2008) Differences in simulated liver concentrations of toxic coumarin metabolites in rats and different human populations evaluated through physiologically based biokinetic (PBBK) modeling. Toxicology in Vitro 22:8, 1890-1901
CrossRef19
Bernhard Hammerl, Walter Döller. (2008) Das sekundäre maligne Lymphödem bei fortgeschrittenen HNO-Tumoren. Wiener Medizinische Wochenschrift 158:23-24, 695-701
CrossRef20
Ravi D. Rao, Patrick J. Flynn, Jeff A. Sloan, Gilbert Y. Wong, Paul Novotny, David B. Johnson, Howard M. Gross, Samer I. Renno, Mohammed Nashawaty, Charles L. Loprinzi. (2008) Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy. Cancer 112:12, 2802-2808
CrossRef21
Elie A Akl, Maddalena Barba, Sandeep Rohilla, Irene Terrenato, Francesca Sperati, Paola Muti, Holger Schünemann, Elie A Akl. 2008. Anticoagulation for the long term treatment of venous thromboembolism in patients with cancer. .
CrossRef22
Kristiana D Gordon, Peter S Mortimer. (2007) A guide to lymphedema. Expert Review of Dermatology 2:6, 741-752
CrossRef23
Irena Kostova. (2007) Studying plant-derived coumarins for their pharmacological and therapeutic properties as potential anticancer drugs. Expert Opinion on Drug Discovery 2:12, 1605-1618
CrossRef24
Nicholas Farinola, Neil B Piller. (2007) CYP2A6 polymorphisms: is there a role for pharmacogenomics in preventing coumarin-induced hepatotoxicity in lymphedema patients?. Pharmacogenomics 8:2, 151-158
CrossRef25
G SAKORAFAS, G PEROS, L CATALIOTTI, G VLASTOS. (2006) Lymphedema following axillary lymph node dissection for breast cancer. Surgical Oncology 15:3, 153-165
CrossRef26
S.P. Felter, J.D. Vassallo, B.D. Carlton, G.P. Daston. (2006) A safety assessment of coumarin taking into account species-specificity of toxicokinetics. Food and Chemical Toxicology 44:4, 462-475
CrossRef27
A.M. Calderón González, F.J. Cecilio Montero, C. Rodríguez Cerdeira, Y.M. Caeiro Muñoz. (2006) Linfofármacos en el linfedema postmastectomía: revisión sistemática. Rehabilitación 40:2, 86-95
CrossRef28
Mei R. Fu. (2005) Breast Cancer Survivors' Intentions of Managing Lymphedema. Cancer Nursing 28:6, 446-457
CrossRef29
R. M. Morrell, M. Y. Halyard, S. E. Schild, M. S. Ali, L. L. Gunderson, B. A. Pockaj. (2005) Breast Cancer-Related Lymphedema. Mayo Clinic Proceedings 80:11, 1480-1484
CrossRef30
Stanley G. Rockson. (2005) Lymphatic Research: A Global Concern. Lymphatic Research and Biology 3:2, 49-49
CrossRef31
Nicholas Farinola, Neil Piller. (2005) Pharmacogenomics: Its Role in Re-establishing Coumarin as Treatment for Lymphedema. Lymphatic Research and Biology 3:2, 81-86
CrossRef32
Adam M. Rotunda, Mathew M. Avram, Alison Sharpe Avram. (2005) Cellulite: Is there a role for injectables?. Journal of Cosmetic and Laser Therapy 7:3-4, 147-154
CrossRef33
Tammy E. Mondry, Robert H. Riffenburgh, Peter A. S. Johnstone. (2004) Prospective Trial of Complete Decongestive Therapy for Upper Extremity Lymphedema After Breast Cancer Therapy. The Cancer Journal 10:1, 42-48
CrossRef34
Jinelle A. Webb, Sarah E. Boston, Julie Armstrong, Noël M.M. Moens. (2004) Lymphangiosarcoma Associated with Primary Lymphedema in a Bouvier des Flandres. Journal of Veterinary Internal Medicine 18:1, 122-124
CrossRef35
Caroline M A Badger, Nancy J Preston, Kate Seers, Peter S Mortimer, Kate Seers. 2003. Benzo-pyrones for reducing and controlling lymphoedema of the limbs. .
CrossRef36
Gerhard Eisenbrand, Michael Otteneder, Weici Tang. (2003) Synthesis of N-acetyl-S-(3-coumarinyl)-cysteine methyl ester and HPLC analysis of urinary coumarin metabolites. Toxicology 190:3, 249-258
CrossRef37
A. C. Voogd, J. M. M. A. Ververs, A. J. J. M. Vingerhoets, R. M. H. Roumen, J. W. W. Coebergh, M. A. Crommelin. (2003) Lymphoedema and reduced shoulder function as indicators of quality of life after axillary lymph node dissection for invasive breast cancer. British Journal of Surgery 90:1, 76-81
CrossRef38
L.K.A.M. Leal, F.G. Oliveira, J.B. Fontenele, M.A.D. Ferreira, G.S.B. Viana. (2003) Toxicological Study of the Hydroalcoholic Extract from Amburana cearensis in Rats. Pharmaceutical Biology 41:4, 308-314
CrossRef39
V. Boursier. (2002) Lymphœdème : Quel traitement médicamenteux ?. La Revue de Médecine Interne 23, 421s-425s
CrossRef40
Sara R. Cohen, David K. Payne, Richard S. Tunkel. (2001) Lymphedema. Cancer 92:S4, 980-987
CrossRef41
V. S. Erickson, M. L. Pearson, P. A. Ganz, J. Adams, K. L. Kahn. (2001) Arm Edema in Breast Cancer Patients. JNCI Journal of the National Cancer Institute 93:2, 96-111
CrossRef42
Tammy E. Mondry. (2000) Part II. Physical therapy. Current Problems in Cancer 24:4, 195-213
CrossRef43
Caroline M. A. Badger, Janet L. Peacock, Peter S. Mortimer. (2000) A randomized, controlled, parallel-group clinical trial comparing multilayer bandaging followed by hosiery versus hosiery alone in the treatment of patients with lymphedema of the limb. Cancer 88:12, 2832-2837
CrossRef44
Lisa Loudon, Jeanne Petrek. (2000) Lymphedema in Women Treated for Breast Cancer. Cancer Practice 8:2, 65-71
CrossRef45
E. Shelley Hwang, Laura J. Esserman. (1999) MANAGEMENT OF DUCTAL CARCINOMA IN SITU. Surgical Clinics of North America 79:5, 1007-1030
CrossRef46
Ismail Jatoi. (1999) MANAGEMENT OF THE AXILLA IN PRIMARY BREAST CANCER. Surgical Clinics of North America 79:5, 1061-1073
CrossRef47
Ganz, Patricia A., . (1999) The Quality of Life after Breast Cancer — Solving the Problem of Lymphedema. New England Journal of Medicine 340:5, 383-385
Full Text
