SPECIAL SUPPLEMENT * SUPPLEMENT SPECIAL

Safety of polyurethane-covered breast implants Expert Panel on the Safety of Polyurethane-covered Breast Implants* T he safety of polyurethane-covered breast implants has been the subject of professional and public controversy for several months, culminating in the recent voluntary withdrawal of the product from the market by the manufacturer. At the request of and with the funding support of the Department of National Health and Welfare, the Canadian Medical Association coordinated an expert panel to provide physicians with an independent review of the safety of polyurethane-covered breast implants. The panel was constituted with a breadth of expertise in different areas of medicine, surgery, epidemiology and toxicology. The findings and recommendations expressed in this statement represent those of the expert panel and not necessarily those of the Canadian Medical Association or the Department of National Health and Welfare. The Expert Panel was asked to consider the safety of polyurethane-covered breast implants (Meme, Replicon and Optimam). Specifically, the panel addressed the evidence on the carcinogenicity, mutagenicity and teratogenicity related to breakdown products of the polyurethane coating. The panel reviewed the scientific literature and risk assessments from the Food and Drug Administration (FDA) in the United States and the Department of National Health and Welfare, and it invited input from other sources with concerns on this issue. It did not attempt to review the overall psychosocial/cultural context of breast implants.

Definition and use These implants consist of a standard smoothwalled, silicone-gel-filled implant covered with a 1-mm layer of polyurethane foam (approximate weight 1.4 g), which is secured to the underlying silicone shell with a silicone adhesive/glue. The polyurethane implants are intended for women seeking breast enlargement (augmentation) or breast reconstruction following therapeutic mastectomy or prophylactic subcutaneous mastectomy.

Alternative interventions Alternatives to the use of polyurethane-covered breast implants include the following: * an external breast prosthesis or padded bra * smooth-walled implants with silicone gel or saline fillers * an autogenous tissue graft (a major surgical procedure with both advantages and disadvantages; it is used primarily for breast reconstruction rather than augmentation) Other options that have been used in the past include silicone injections, paraffin injections and fat injections, all of which are considered unacceptable because of complications.'

Clinical discussion All breast implants

are

associated with various

*Members: Dr. David C. Boyes (chmn), Clinical Professor Emeritis, University ofBritish Columbia, and Chairman, Medical Ethics Advisory Committee, Province ofBritish Columbia, Vancouver; Dr. Christopher K Adey, Department ofDiagnostic Radiology, Ottawa Civic Hospital, Ottawa; Dr. John Bailar, Department ofEpidemiology and Biostatistics, McGill University, Montreal; Dr. Cornelia Baines, Department ofPreventive Medicine, University of Toronto, Toronto; Dr. Carolyn Kerrigan, Associate Professor of Surgery, Royal Victoria Hospital, Montreal; Dr. Pierre Langlois, Polyclinique de la Capitale, Charlesbourg, PQ; Dr. Naomi Miller,

Department of Pathology, Wellesley Hospital, Toronto; Dr. John Osterman, Department ofEpidemiology and Biostatistics and School of Occupational Health, McGill University, Montreal.

CMA Liaison: Dr. David Walters, Director ofHealth Care and Promotion, Canadian Medical Association, Ottawa; Dr. John Atkinson, John Atkinson Health Care Professionals Inc., Ottawa. Reprint requests to: Department ofMembership Services, Canadian Medical Association, 1867 Alta Vista Dr., Ottawa, ON KIG 3Y6 Version francaise commence & la page 1129. NOVEMBER 1, 1991

This report has not been peer reviewed.

CAN MED ASSOC J 199 1; 145 (9)

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I~~~~~~~~~~~~~b eurdt nueta oto h rattsu potential problems (Table 1). However, polyure- be required to ensure that most of the breast tissue thane-covered implants can cause additional potential problems related to the polyurethane foam. In 10% of women a skin rash may develop that lasts about 7 to 10 days.2 The rate of biodegradation of the polyurethane foam remains uncertain, but a nation-wide study of implants removed from humans is currently under way in conjunction with the Department of National Health and Welfare. The limited number of published studies show that breast implants provide most patients with the benefits they sought from the operation. Between 80% and 95% of patients are satisfied with their results and would have the operation again.34 However, close to half of these women will report that their breasts are unnaturally firm. This is secondary to fibrosis around the implant. It occurs to some degree with all implants, but, when marked, it results in distortion of the implant shape and a firm mass known as "capsular contracture." Modifications in technique, use of adjuvant drugs, massage and other techniques have been used to improve breast softness; however, there has been only a modest decrease in the rates of capsular contracture. Many surgeons have found that polyurethanecovered breast implants are associated with a considerably lower frequency of abnormally firm breasts in both cosmetic breast augmentation and breast reconstruction and reduce the need for further intervention.2'5'6 It is for this reason that polyurethanecovered breast implants have gained popularity. In a 7-year follow-up study, lower rates of capsular contracture have resulted in a reduction in the need for further surgery (Kerrigan CL: Report on the Meme Breast Implant, prepared for the Minister of Health and Welfare: unpublished, 1989). The presence of any form of breast implant may complicate the performance of mammographic examination. In many cases, additional projections will Table 1. Potential problems associated with all types of breast implants

Surgical Infection (10% or less) Hematoma (1 /% to 40/c)

Skin necrosis or wound dehiscence with implant exposure (rare) Need for surgical removal of implant and/or fibrous capsuie (4% to 200/c) Sensory changes in the nipple-areolar complex (1 %

to 1 0/c) Breast asymmetry (10% to 1 0%) Implant related Capsular contraction (30% to 40% for smooth implants, 2% to 100% for polyurethane-covered

implants)

Tumour detection (mammography) possibly hindered Gel bleed/implant rupture with associated granuloma formation and regional adenopathy

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has been imaged.

Apparent risks Breast implants in general and polyurethanecovered implants in particular elicit questions about safety - that is, there are rare but well-characterized risks from surgery and anesthetic agents; small, specific risks related to implants of all types including hemorrhage, infection, capsular contraction and rupture of the implant;5 and unresolved issues about possible carcinogenic and reproductive problems. The panel is aware of concerns in some quarters about the long-term safety of silicone gel in breast implants, but that matter has not been a major public issue in Canada and was not part of the panel's mandate. Reproductive toxicity and mutagenicity were also not considered in depth because the panel was unable to find relevant and reliable data with which to study the issue. Polyurethane itself seems to be innocuous. It is a very long-chain polymer that is insoluble in body fluids and is not known to affect living cells. Urethane molecules and short-chain polymers that may remain after the polymerization process are also considered innocuous, but would, in any event, be locked into the physical structure of the longer chains and hence not be available for biologic interaction. However, body fluids do cause polyurethane to break down, and the decomposition products include 2,4-toluene diamine (TDA). TDA has been shown to cause cancer in laboratory animals: there is evidence of increased cancer rates when TDA is injected subcutaneously,7 painted on the skin8 or added to the diet.9'10 High rates of cancer have been found in both rats and mice at the injection site and in the liver, lung and breast. Estimates of the risks of breast cancer should be based on exposure levels or on TDA levels in body tissues generally. In one study, rats were fed at TDA levels of 0, 125 and 250 ppm (parts per million) in the diet;9 the diets were changed at 20 weeks to 0, 50 and 100 ppm because the 125- and 250-ppm doses caused weight loss. The number of malignant breast cancers were 0, 9 and 10 in groups of 20, 50 and 50 female rats respectively. The elevations of risk in treated animals are statistically significant, and the rates are considered to be much higher than those seen in historical untreated controls of these animals. TDA has not been shown to be carcinogenic in humans, but the data are limited, with a poor statistical power for detecting even a large effect on cancer rates. The documented carcinogenicity in two nonhuman species, by multiple routes of administration and with cancer in multiple organs, suggests that LE ler NOVEMBRE 1991

TDA may well be a human carcinogen. Thus, the FDA estimate may be too high are as follows. question becomes How large is the cancer risk to * The FDA estimate included benign ar,i mahumans at various doses or exposure levels? lignant neoplasms. * Implants may be removed well before 35 Estimated risk of cancer years, and it is not clear whether they will be replaced and with what. A quantitative estimation of chemical hazards * The average recipient may weigh more than to human health is plagued by uncertainty, especially 50 kg; therefore, body concentrations would be lower when data for humans are scanty or absent. Some of than estimated. the major uncertainties include the translation from * Not all cancers induced by TDA would be results in animals to expected effects in humans; lethal. Whatever the errors in estimates, the Expert extrapolation from the high doses that are necessary in small studies of animals to much lower doses for Panel believes that the risk of breast cancer is very humans; differences in routes of administration (e.g., small. Overall, the panel considers the FDA estimate by diet in the laboratory rather than by implant); to be as good as can be attained at present, though it and lifetime exposure in animals versus exposure may be in error in either direction. over only a part of the human life span. Risk Reports in the lay press that the risk may be far assessors recognize these uncertainties and have higher - even 1 per 100 women - do not seem to developed sets of default procedures and assump- be documented in any original sources, and the tions designed to reduce the likelihood of serious panel believes that these estimates cannot be dupliunderestimation of risks. cated by any plausible variation in the FDA apThe panel did not undertake a quantitative proach. In the absence of further information at this assessment of the carcinogenic risk of TDA but, time, the panel thinks that very high risk estimates rather, reviewed the risk assessment discussed at a are devoid of any scientific foundation and are best meeting convened by the FDA on June 26, 1991.11,12 regarded as speculation. If new evidence is forthcomThe estimated increase in lifetime risk of breast ing, or if older evidence is reinterpreted so as to cancer was five cancers per 10 million women, each warrant an approach other than that of the FDA, with two implants. This estimate assumes that this conclusion should be re-examined. * two implants contain 2.7 g of polyester polyurethane foam, which will release 2.36 x 10 4mg/d of Recommendations TDA * a woman will be exposed to the implant for * Surgical removal of polyurethane-foam-covan average of 35 years ered breast implants solely for reasons of potential * the average woman receiving a breast implant risk of cancer does not appear to be indicated, weighs 50 kg according to the current risk estimates reviewed by * the FDA has correctly estimated the risk of the panel. The decision about whether a breast breast cancer per milligram/kilogram per day. implant should be removed should be made by a The FDA report discusses the assumptions and woman only after a fully informed consultation uncertainties in this estimate and provides an esti- (including a discussion of the potential risk of mate of 82 cancers per million based on the highly cancer) with her physician. unlikely event of 100% degradation (80% to TDA). * In discussing whether to proceed with a These estimates are subject to the substantial polyurethane-covered breast implant (if and when uncertainties that affect all such risk assessment. they again become available), physicians should Some additional reasons why the FDA estimates inform patients of the potential but small risk of may be too low are as follows: cancer in relation to the apparent benefits of this * Treated animals had reduced life expectancy device when compared with other implants or surgiand may not have lived long enough to express the cal procedures designed to achieve the same results. full cancer risk. The absence of reliable data on mutagenicity and * Cancers at sites other than the breast are not teratogenicity should also be considered. included. * The current guidelines for mammographic * No evidence was cited on the absorption of screening (e.g., screening every 2 years after age 50)'3 TDA from dietary exposure or on tissue levels in apply to women with breast implants. If the presence treated animals. of an implant excludes a woman from eligibility in a * The carcinogen dose-response curve seems to provincial breast screening program, she should be reach a plateau somewhere before the lowest positive referred to a conventional diagnostic mammographic dose tested. facility for the examination. On the other hand, some special reasons why the * Additional scientific research is required to NOVEMBER 1, 1991

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address the biochemistry and toxicology of polyurethane-foam-covered implants, their components and their breakdown products. Short- and long-term exposure to possible carcinogens derived from such devices should be monitored adequately. The longterm safety and efficacy of the device merits continued investigation, particularly with regard to potential carcinogenicity, mutagenicity and teratogenicity. The panel notes that an implant registry would be useful for conducting research; the feasibility of establishing such a registry should therefore be investigated. * These recommendations should be reviewed and updated periodically in the light of further evidence and study.

References 1. Goldwyn RM (ed): The Unfavourable Result in Plastic Surgery: Avoidance and Treatment, Little, Boston, 1984 2. Hester TR Jr, Nahai F, Bostwick J et al: A 5-year experience with polyurethane-covered mammary prostheses for treatment of capsular contracture, primary augmentation mammoplasty, and breast reconstruction. Clin Plast Surg 1988; 15: 569-585 3. Ohlsen L, Ponten B, Hambert G: Augmentation mammoplasty: a surgical and psychological evaluation of the results. Ann

Plast Surg 1979; 2: 42-52 4. Meyer L, Ringberg A: Augmentation mammoplasty: psychological and psychosocial characteristics and outcome in a group of Swedish women. Scand J Plast Reconstr Surg Hand Surg 1987; 21: 199-208 5. Dolsky RL: Polyurethane-coated implants [C]. Plast Reconstr Surg 1985; 76: 974-975 6. Melmed EP: Polyurethane implants: a 6-year review of 416 patients. Plast Reconstr Surg 1988; 82: 285-290 7. Umeda M: Production of rat sarcoma by injections of propylene glycol solution of m-toluylenediamine. GANN 1955; 46: 597-603 8. Giles AL, Chung CW: Dermal carcinogenicity study by mouse-skin painting with 2,4-toluenediamine alone or in representative hair dye formulations. J Toxicol Health 1976; 1:433-440 9. Cardy RH: Carcinogenicity and chronic toxicity of 2,4-toluenediamine in F344 rats. J Natl Cancer Inst 1979; 62: 1107-1116 10. Sontag JM: Carcinogenicity of substituted-benzenediamines (phenylenediamines) in rats and mice. J Natl Cancer Inst 1981; 66: 591-602 11. Risk Assessment Meeting on Polyurethane-Coated Breast Implants, US Food & Drug Administration, Washington, June 26, 1991 12. Talk Paper, FDA Advisory Committee Meeting on Polyurethane-Coated Breast Implants, US Food & Drug Administration, Washington, Aug 1, 1991 13. The Workshop Group: Working Guidelines: Reducing Deaths from Breast Cancer in Canada. Can Med Assoc J 1989; 141: 199-201

EAnaprox® DS 550 mg EAnaprox® 275 mg

given to a starting dose lower than usual. The safety of Anaprox and Anaprox DS in pregnancy and lactation has not been established and its use is therefore not recommended.

(naproxen sodium) Indications: Relief of mild to moderately severe pain, accompanied by inflammation such as musculoskeletal trauma, postdental extraction, relief of post-partum cramping and dysmenorrhea. Contraindications: Anaprox and Anaprox DS (naproxen sodium) are contraindicated in patients, with active ulcers or active inflammatory diseases of the gastrointestinal tract. They are also contraindicated in patients who have shown hypersensitivity to it or to naproxen. Since cross-sensitivity has been demonstrated, Anaprox or Anaprox DS should not be given to patients in whom ASA or other nonsteroidal anti-inflammatory drugs induce the syndrome of asthma, rhinitis, or uticaria. Sometimes severe and occasionally fatal anaphylactic reactions have occurred in such individuals. Warnings: Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal, have been reported during therapy with non-steroidal anti-inflammatory drugs (NSAID's) including Anaprox and Anaprox DS. Anaprox and Anaprox DS should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory diseases of the gastrointestinal tract. Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning at any time during the treatment. Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from NSAIDs. For such patients, consideration should be

Precautions: Anaprox or Anaprox DS (naproxen sodium) should not be used concomitantly with the related drug Naprosync (naproxen) since they circulate in plasma as the naproxen anion. G.l system: If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs Anaprox or Anaprox DS should be discontinued, and appropriate treatment instituted. Renal effects: Patients with impaired renal function, extracellular volume depletion, sodium restrictions, heart failure, liver dysfunction, those taking diuretics, and the elderly, are at greater risk of developing overt renal decompensation. Assessment of renal function in these patients before and during therapy is recommended. Naproxen sodium and its metabolites are eliminated primarily by the kidneys, and therefore, a reduction in daily dosage should be anticipated to avoid the possibility of drug accumulation in patients with significantly impaired renal function. Naproxen sodium should not be used chronically in patients having baseline creatinine clearance less than 20 mI/minute. Peripheral edema has been observed, consequently, patients with compromised cardiac function should be kept under observation when taking Anaprox or Anaprox DS. Each Anaprox tablet contains approximately 25mg of sodium and each Anaprox DS tablet contains approximately 50mg of sodium. This should be considered in patients whose overall intake of sodium must be markedly restricted. As with other drugs used in the elderly or those with impaired liver function it is prudent to use the lowest effective dose. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with NSAIDs. The prescriber should be alert to the fact that the anti-inflammatory, analgesic and antipyretic effects of Anaprox or Anaprox DS (naproxen sodium) may mask the usual signs of infection. Periodic liver function tests and ophthalmic studies are recommended

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CAN MED ASSOC J 1991; 145 (9)

for patients on chronic therapy. Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with the drug. The naproxen anion may displace other albumin-bound drugs from their binding sites and may lead to drug interactions or interfere with certain laboratory tests. See product monograph for specific examples. The safety and efficacy of this drug in children has not been established and its use in children is therefore not recommended. Adverse reactions: Adverse reactions which occur in >1% of patients include: G.l: heartburn, constipation, abdominal pain, nausea, diarrhea, dyspepsia, stomatitis and diverticulitis. CNS: headache, dizziness, drowsiness, light-headedness, vertigo, depression and fatigue. Skin: pruritus, ecchymoses, skin eruptions, sweating and purpura. CVS: dyspnea, peripheral edema and palpitations. Special Senses: tinnitus and hearing disturbances. Others: thirst. For additional adverse reactions please refer to the product monograph. Availability: Anaproxs is available in OVAL-SHAPED, BLUE filmcoated tablets of 275mg in bottles of 100, 500 and 1000 tablets. Anaprox DS is available in OVAL-SHAPED, BLUE film-coated tablets of 550mg in bottles of 100 tablets. Dosage: Anaproxc 275mg: Two tablets (550mg) followed by one tablet (275 mg) every 6 - 8 hours as required. Anaproxc DS: One tablet (550 mg) twice daily. Maximum daily dose: 1375 mg. Product monograph available on request.

*

N Syntex lnc* Mississauga, Ont./Montreal, Que. *Reg. user of all T trademarks. LE

ler NOVEMBRE 1991

SUPPLEMENT SPECIAL * SPECIAL SUPPLEMENT

Securite des protheses mammaires recouvertes de polyurethane Groupe d'experts sur la securite des protheses mammaires recouvertes de polyurethane* L a securite des protheses mammaires recouvertes de polyurethane fait l'objet d'une controverse professionnelle et publique depuis plusieurs mois, celle-ci atteignant son paroxysme lorsque le fabricant a procede recemment au retrait volontaire de son produit du marche. A la demande du ministere de la Sante et du Bien-etre et grace au soutien financier de celui-ci, l'Association des medecins du Canada a coordonne un groupe d'experts pour fournir aux medecins une etude independante sur l'innocuite des protheses mammaires recouvertes de polyurethane. Le groupe etait constitue d'un eventail d'experts dans les divers domaines de la medecine, de la chirurgie, de l'epidemiologie et de la toxicologie. Les constatations et les recommandations exprimees dans cet enonce representent celles du groupe d'experts mais pas forcement celles de I'Association des medecins du Canada ou du ministere de la Sante et du Bien-etre social. Le groupe d'experts avait pour mandat d'examiner la securite des protheses mammaires recouvertes de polyurethane (Meme, Replicon et Op-

timam).

et les evaluations du risque effectuees par la Food and Drug Administration (FDA) aux Etats-Unis et le ministere de la Sante et du Bien-etre social, et il a

invite d'autres sources a faire valoir leurs inquietudes a ce sujet. Le groupe d'experts n'a pas tente d'etudier le contexte psychosocial et culturel global des protheses mammaires.

Definition et utilisation La prothese est constituee d'une prothese ordinaire a paroi lisse, remplie de gel de silicone et recouverte d'une couche de 1 mm de mousse de polyurethane (poids d'environ 1,4 g) et qui est fixee a l'enveloppe de silicone sous-jacente par un adhesif ou une colle de silicone. Les protheses recouvertes de polyurethane sont indiquees chez les femmes qui veulent un accroissement du volume des seins (augmentation) ou une reconstruction des seins apres une mastectomie therapeutique ou une mastectomie prophylactique souscutanee.

Autres possibilites d'interventions

Le groupe d'experts s'est interesse particuliereAu lieu des protheses mammaires recouvertes de ment a la verification des pouvoirs carcinogenes, polyurethane, on peut avoir recours aux solutions mutagenes et teratogenes relies aux produits suivantes: degrades a partir de la couche de polyurethane. Le 0 une prothese mammaire externe ou un sougroupe d'experts a examine la litterature scientifique tien-gorge a bonnets ouatines; *Membres: Dr David C. Boyes (pres.) Professeur clinique emerite, Universite' de la Colombie-Britannique et Comite consultatif d'ethique medicale, province de la Colombie-Britannique, Vancouver; Dr Christopher K Adey, Service de radiodiagnostic, h6pital Civic d'Ottawa, Ottawa; Dr John Bailar, Ddpartement d'epidemiologie et de biostatistique, Universite McGill, Montreal; Dr Cornelia Baines, Departement de medecine preventive, Universitei de Toronto, Toronto; Dr Carolyn Kerrigan, professeure agreee de chirurgie, hopital Royal Victoria, Montreal; Dr Pierre Langlois, Polyclinique de la Capitale, Charlesbourg; Dr Naomi Miller, Service de pathologie, hopital Wellesley, Toronto; Dr John Osterman, Departement d'epidemiologie et de biostatistique et Ecole de medecine du travail, Universite, McGill, Montreal. Agent de liaison de l'AMC: Dr David Walters, directeur, Departement des soins et de la promotion de la sante, Association des medecins du Canada, Ottawa; Dr John Atkinson, John Atkinson Health Care Professionals Inc., Ottawa.

Adresser vos demandes de rdimpression a: Departement des Service aux membres, Association des medecins du Canada, 1867, prom. Alta Vista, Ottawa, ONKIG 3Y6 English version begins on page 1125. NOVEMBER 1, 1991

Non soumis a un examen critique par les pairs. CAN MED ASSOC J 1991; 145 (9)

1129

I

* des protheses a paroi lisse contenant un gel Des modifications a la technique, l'utilisation d'adde silicone ou des solutions salees; juvants, le massage et d'autres techniques ont ete * une autogreffe (une intervention chirurgicale utilisees afin d'ameliorer la plasticite des seins; on a lourde qui presente des avantages et des inconve- toutefois observe une faible diminution des taux de nients; elle sert principalement a la reconstruction contracture capsulaire. du sein, de preference a son augmentation). De nombreux chirurgiens ont constate que les Dans le passe, on a utilise d'autres methodes, protheses mammaires recouvertes de polyurethane notamment les injections de silicone, de paraffine et sont reliees a une frequence considerablement moins de graisses qui sont toutes considerees comme inac- elevee de seins anormalement fermes a la fois dans ceptables en raison de leurs complications.' l'augmentation et la reconstruction esthetiques des seins et qu'elles reduisent le besoin d'une intervenExpose clinique tion ulterieure.256 C'est pour cette raison que les protheses mammaires recouvertes de polyurethane Toutes les protheses mammaires sont reliees a sont devenues populaires. Dans une etude de suivi divers problemes eventuels (Tableau 1). Les pro- de 7 ans, des taux de contracture capsulaire moins theses couvertes de polyurethane peuvent toutefois eleves ont donne lieu a une reduction des besoins en causer des problemes supplementaires relies a la chirurgie supplementaire (Kerrigan CL: Rapport sur mousse de polyurethane. Chez 10 % des femmes, une l'implant mammaire Meme, a l'intention du ministre eruption cutanee peut survenir et durer environ 7 a de la Sante et du Bien-etre social : non publie, 1989). 10 jours.2 Le taux de degradation biologique de la La presence d'un type quelconque de prothese mousse de polyurethane demeure inconnu, mais une mammaire peut compliquer la mammographie. etude nationale sur des protheses retirees du corps Dans de nombreux cas, il faudra des radiographies humain est actuellement menee en collaboration supplementaires pour s'assurer que la plus grande avec le ministere de la Sante et du Bien-etre social. partie des tissus mammaires a ete representee. Le nombre limite d'etudes qui ont ete publiees indiquent que les protheses mammaires fournissent Risques manifestes a la plupart des malades qui ont subi l'intervention Les protheses mammaires en general et les les avantages recherchees. Entre 80 % et 95 % des malades sont satisfaites des resultats et subiraient de protheses recouvertes de polyurethane en particulier nouveau l'intervention.3,4 Pres de la moitie de ces suscitent des questions au sujet de la securite femmes signalent toutefois que leurs seins sont c.-a-d. que la chirurgie et les agents anesthesiques anormalement fermes. Cela est attribuable a une font courir des risques qui sont rares mais bien fibrose autour de la prothese. Dans une certaine definis; des risques legers et specifiques qui sont mesure, cette reaction est commune a toutes les relies aux protheses de tous les types, notamment protheses, mais lorsqu'elle est prononcee, la fibrose l'hemorragie, l'infection, la contraction capsulaire et entraine une distorsion de la forme de la prothese et la perforation de la prothese;5 et elles soulevent des une masse ferme appelee ocontracture capsulaire>>. questions non resolues entourant des problemes eventuels de pouvoir carcinogene et de reproduction. Le groupe d'experts est conscient des inquiTableau 1: Problemes eventuels reli6s a totis les types etudes suscitees dans certains milieux au sujet de la de protheses mammaires securite a long terme du gel de silicone dans les Chirurgicaux protheses mammaires, mais ce probleme n'a jamais Infection (1 O/% ou moins) ete une grande question d'interet public au Canada 4 /o H6matome (1 a %) et elle se situait hors du mandat du groupe. Les N6crose cutanee ou lachage de sutures avec exposition de la prothese (rare) pouvoirs toxiques et mutagenes par rapport a la Besoin d'extirpation chirurgicale de la prothese et reproduction n'ont pas non plus ete examines en (ou) de la capsule fibreuse (4 % a 20 %) profondeur parce que le groupe d'experts a ete Changements sensoriels dans le complexe incapable de decouvrir des donnees pertinentes et mamelon-ar6ole (1 % a 10 %o) fiables pour etudier cette question. Symetrie des seins (1 % a 10 %) Relies a a prothese Le polyurethane semble lui-meme etre sans Contraction capsulaire (30 O/o a 40 % pour les I1 s'agit d'un polymere a tres longue chaine danger. protheses lisses, de 2 % a 10 % pour les insoluble dans le liquide corporel et qui est qui protheses recouvertes de polyurethane) aucune action connue sur les cellules vin'exerce Gene possible au depistage des tumeurs Les molecules d'urethane et les polymeres a vantes. (mammographie) Ecoulement du gel ou perforation de la prothese courte chaine qui peuvent demeurer apres le procesrelies a la formation de granulomes et a sus de polymerisation sont aussi consideres comme I'ad6nopathie regionale inoffensifs, mais ils seraient de toute facon bloques a 1130

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LE I er NOVEMBRE 1991

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l'interieur de la structure physique des chaines plus longues et donc incapables d'interaction biologique. Les liquides corporels provoquent toutefois la degradation du polyurethane, et les produits de decomposition comprennent le toluene-2.4 diamine (TDA). Chez les animaux de laboratoire, on a demontre que le TDA cause le cancer: on a constate l'augmentation des taux de cancer lorsque le TDA est injecte par voie sous-cutanee,7 peint sur la peau 8 ou ajoute a l'alimentation.9 '0 Des taux eleves de cancer ont ete decouverts chez les rats et les souris au point d'injection et au foie, aux poumons et aux mammelles. Les estimations des risques de cancer du sein devraient etre fondees sur les taux d'exposition ou sur les taux de TDA dans les tissus corporels en general. Dans une etude, des rats ont recu du TDA a des taux de 0,125 et 250 ppm (parties par million) dans leur alimentation;9 apres 20 semaines, les taux ont ete reduits a 0, 50 et 100 ppm parce que les doses de 125 et de 250 ppm causaient une perte de poids. Le nombre de cancers malins mammaires etait respectivement de 0, 9 et 10 dans les groupes de 20, 50 et 50 rates. Les augmentations du risque chez les animaux traites etaient statistiquement significatives, et les taux sont consideres comme beaucoup plus eleves que ceux observes chez les temoins historiques sans traitement parmi ces animaux. Chez les humains, on n'a pas demontre que le TDA est carcinogene, mais les donnees sont limitees, avec une faible puissance statistique pour depister meme un effet important sur les taux de cancer. Le pouvoir carcinogene documente chez deux especes animales, par de multiples voies d'administration et de multiples organes cancereux, suggere que le TDA pourrait bien etre un agent cancerigene chez les humains. Ainsi, la question devient : Quelle est l'importance du risque de cancer chez les humains a diverses doses ou taux d'exposition?

reconnaissent ces incertitudes, et ils ont elabore des ensembles de procedures par defaut et des postulats pour reduire la possibilite d'une sous-estimation importante des risques. Le groupe d'experts ne s'est pas livre a une evaluation quantitative du risque carcinogene du TDA, mais il a plut6t examine l'evaluation des risques discutes a une reunion convoquee par la FDA, le 26 juin 1991 .11,12 L'accroissement estime' du risque de cancer du sein au cours de la vie etait de cinq cancers par 10 millions de femmes ayant chacune deux protheses. Cette estimation suppose que: * deux protheses contiennent 2,7 g de mousse polyester de polyurethane qui vont liberer 2,36 x 104 mg/j de TDA; * une femme sera exposee a la prothese pendant 35 ans en moyenne; * le poids moyen d'une femme recevant une prothese mammaire est de 50 kg; * la FDA a correctement estime le risque de cancer du sein par milligramme/kilogramme et par

jour. Le rapport de la FDA aborde les suppositions et les incertitudes de cette estimation, et il comporte une estimation de 82 cancers par million, en fonction de la tres grande improbabilite d'une degradation a 100 % (80 % par le TDA). Ces estimations comportent des incertitudes substantielles qui influent sur toute evaluation analogue des risques. Voici certaines raisons supplementaires selon lesquelles les estimations de la FDA pourraient etre trop optimistes: * Les animaux traites avaient une esperance de vie reduite, et ils n'ont peut-etre pas vecu assez longtemps pour exprimer pleinement le risque de cancer.

* Les cancers situes hors du sein sont exclus. * Aucune preuve n'a ete mentionnee sur l'absorption du TDA a partir de l'exposition alimentaire ou sur les taux tissulaires chez les animaux traites. Estimation du risque de cancer * La courbe dose-reponse carcinogene semble atteindre un plateau un peu avant la plus faible dose Une estimation quantitative des dangers chi- positive testee. miques pour la sante humaine est truff6e d'incertiVoici certaines raisons particulieres pour lestudes, surtout en raison de la rarete ou de l'absence quelles 1'estimation de la FDA peut etre trop exdes donnees chez les humains. Parmi les principales ageree: incertitudes, notons la traduction des resultats chez * L'estimation de la FDA tient compte des les animaux en effets escomptes chez les humains; neoplasmes benins et malins. 1'extrapolation des doses elevees qui sont necessaires * Les protheses peuvent etre enlevees bien dans les etudes a petite echelle chez les animaux a avant 35 ans, et on ne precise pas si elles seront des doses beaucoup plus faibles chez les humains; remplacees et par quoi. des differences dans les voies d'administration * Le poids moyen de la receveuse pourrait etre (p. ex., par l'alimentation en laboratoire plutot que superieur a 50 kg; ainsi, les concentrations corpar une prothese); et l'exposition pendant toute la porelles seraient inferieures aux estimations. duree de la vie des animaux par rapport a une * Les cancers provoques par le TDA ne sont exposition au cours d'une partie seulement de la pas tous mortels. duree de la vie humaine. Les evaluateurs du risque Quelles que soient les erreurs dans les estimaNOVEMBER 1, 1991

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tions, le groupe d'experts croit que le risque de cancer du sein est tres faible. Dans l'ensemble, le groupe considere que I'estimation de la FDA est la meilleure dans les circonstances actuelles, bien qu'elle puisse &tre erronee dans un sens ou dans l'autre. Les rapports publies dans la presse non specialis&e selon lesquels le risque peut etre beaucoup plus eleve - meme de 1 femme sur 100 - ne semblent pas etre documentes dans les sources originales, et le groupe d'experts croit que ces estimations ne peuvent etre reproduites par aucune variation plausible de la demarche de la FDA. En l'absence d'informations supplementaires pour le moment, le groupe pense que les estimations de risque tres eleve sont denu&es de tout fondement scientifique et que mieux vaut les considerer comme de la speculation. Si une nouvelle preuve est apport&e ou si une preuve plus ancienne est reinterpretee de facon a justifier une demarche autre que celle de la FDA, cette conclusion devra etre reexaminee.

Recommandations

* Des recherches scientifiques supplementaires sont necessaires pour connaitre la biochimie et la toxicologie des protheses recouvertes de mousse de polyurethane, de leurs composantes et de leurs produits de degradation. L'exposition a court et a long terme aux carcinogenes qui peuvent &tre issus de tels dispositifs devrait faire l'objet d'un contr6le approprie. La securite et l'efficacite a long terme de ce dispositif meritent qu'on en poursuive l'etude, en particulier par rapport aux pouvoirs carcinogenes, mutagenes et teratogenes. Le groupe note qu'un registre des protheses serait utile pour mener des recherches; on devrait donc etudier la faisabilite de l'etablissement d'un tel registre. * Ces recommandations devraient etre examinees periodiquement et mises a jour en fonction de preuves et d'etudes supplementaires.

References 1. Goldwyn RM (ed): The Unfavourable Result in Plastic Surgery: Avoidance and Treatment, Little, Boston, 1984 2. Hester TR Jr, Nahai F, Bostwick J et al: A 5-year experience with polyurethane-covered mammary prostheses for treatment of capsular contracture, primary augmentation mammoplasty, and breast reconstruction. Clin Plast Surg 1988; 15: 569-585 3. Ohlsen L, Ponten B, Hambert G : Augmentation mammoplasty: a surgical and psychological evaluation of the results. Ann Plast Surg 1979; 2 : 42-52 4. Meyer L, Ringberg A : Augmentation mammoplasty psychological and psychosocial characteristics and outcome in a group of Swedish women. Scand J Plast Reconstr Surg Hand Surg 1987; 21: 199-208 5. Dolsky RL: Polyurethane-coated implants [C]. Plast Reconstr Surg 1985; 76: 974-975 6. Melmed EP: Polyurethane implants: a 6-year review of 416 patients. Plast Reconstr Surg 1988; 82: 285-290 7. Umeda M : Production of rat sarcoma by injections of propylene glycol solution of m-toluylenediamine. GANN 1955; 46: 597-603 8. Giles AL, Chung CW : Dermal carcinogenicity study by mouse-skin painting with 2,4-toluenediamine alone or in representative hair dye formulations. J Toxicol Health 1976; 1: 433-440 9. Cardy RH Carcinogenicity and chronic toxicity of 2,4-toluenediamine in F344 rats. J Natl Cancer Inst 1979; 62:

* L'extirpation chirurgicale des protheses mammaires recouvertes de mousse de polyurethane pour des raisons de risque potentiel de cancer ne semble pas etre indiquee selon les estimations actuelles du risque etudiees par le groupe. La decision d'enlever ou non une prothese mammaire ne devrait &tre prise par une femme qu'apres une consultation pleinement eclairee (y compris une discussion du risque potentiel de cancer) avec son medecin. * Au cours d'une discussion sur l'indication d'une prothese mammaire recouverte de polyurethane (si et quand elles seront a nouveau offertes), les medecins devraient informer leurs malades du risque potentiel mais faible de cancer en fonction des avantages manifestes de ce dispositif par comparaison avec d'autres protheses ou techniques chirurgicales visant a obtenir les memes resultats. L'absence de donnees fiables sur le pouvoir mutagene et 1107-1116 10. Sontag JM : Carcinogenicity of substituted-benzenediamines teratogene devrait aussi &tre prise en consideration. (phenylenediamines) in rats and mice. J Natl Cancer Inst * Les lignes directrices actuelles de depistage 1981; 66: 591-602 mammographique (p. ex., un examen aux deux ans 11. Risk Assessment Meeting on Polyurethane-Coated Breast Imapres l'age de 50 ans)'3 sont applicables aux femmes plants, US Food & Drug Administration, Washington, June qui ont des protheses mammaires. Si la presence 26, 1991 on Polyured'une prothese rend une femme inadmissible a un 12. Talk Paper, FDA Advisory Committee Meeting Administra& US Food Breast Drug thane-Coated Implants, du du cancer programme provincial de depistage tion, Washington, Aug 1, 1991 sein, elle devrait &tre dirig&e vers un etablissement 13. The Workshop Group : Working Guidelines : Reducing Deaths from Breast Cancer in Canada. Can Med Assoc J traditionnel de diagnostic par mammographie pour un examen.

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