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L’osteoradionecrosi (ORN) e una complicanza legata alla radioterapia della cavita orale o dell’orofaringe. Il rischio di ORN e piu frequentemente post-traumatico sulla mandibola che sulla mascella e persiste anche dopo molti anni dall’irradiazione. Questo rischio dipende dalla dose e persiste nonostante i cambiamenti nelle tecniche di irradiazione e il loro potenziale di preservazione della secrezione salivare e di limitazione della dose trasmessa all’osso di sostegno. La prevenzione consiste nell’evitare terapie dentarie invasive e nell’attuare una fluoroprofilassi finche resta insufficiente il recupero salivare. Il trattamento medico precoce viene realizzato a scopo antifibrosante, anti-infiammatorio e anti-infettivo e si associa a tecniche di detersione dei tessuti necrotici, ma non deve, comunque, ritardare il ricorso a un trattamento radicale.

L’osteonecrosi dei mascellari (ONM) sotto bifosfonati (BP) e secondaria a una sostanza farmacologica che modifica il rimodellamento osseo. L’incidenza di ONM in pazienti trattati con BP per affezioni maligne varia dall’1% al 10%, e dallo 0,001% allo 0,1% in caso di affezione benigna. Questo rischio e maggiore per via endovenosa che per via orale e aumenta con la durata della somministrazione. Tutto cio richiede di ridurre l’infiammazione e l’infezione locale attraverso misure di detersione parodontale (rimozione del tartaro, lucidatura) preliminarmente alla realizzazione di interventi chirurgici (con collutorio e antibioticoprofilassi). Il posizionamento di impianti dentari non e raccomandato nei pazienti in terapia con BP per via endovenosa nel quadro di patologie maligne. Il posizionamento di impianti e possibile nei pazienti con osteoporosi trattata con BP orali, dopo un’attenta valutazione del rischio. La gestione dei pazienti a rischio di sviluppare ONM da BP richiede una stretta collaborazione del medico che prescrive BP con il dentista, cosi come un rigoroso controllo dentario prima della terapia durante e dopo.

Resume Introduction Avec l’amelioration du pronostic de nombreux cancers, les complications tardives des traitements deviennent un enjeu de sante publique. Les neuropathies post-radiques, en dehors des plexopathies brachiales faisant suite a l’irradiation de cancers du sein, sont toutefois mal connues. Cet article a pour objectif de clarifier, par une revue actualisee, les principales atteintes du systeme nerveux peripherique liees a la radiotherapie. Etat des connaissances Des formes cliniques nouvelles de neuropathies post-radiques ont ete decrites, soulignant leur heterogeneite. Cette heterogeneite est topographique, liee a la diversite des sites anatomiques irradies qui peuvent inclure les racines, plexus ou troncs nerveux. Elle est egalement evolutive avec une difference entre des formes precoces d’evolution souvent favorable et des formes tardives progressives. L’amelioration des methodes d’investigation constitue un progres majeur pour le diagnostic differentiel grâce a l’apport de l’IRM, du PET-scan et plus recemment, de la radiotherapie conformationnelle a posteriori. Perspectives et conclusions L’importance de diagnostiquer precocement les complications tardives de la radiotherapie est soulignee par l’emergence de nouveaux traitements, agissant notamment sur le processus fibrotique. C’est le cas de l’association pentoxyfilline-tocopherol-clodronate (PENTOCLO, NCT01291433 ) pour laquelle un essai de phase III dans les neuropathies post-radiques est en cours.

Postoperative fibrosis (POF) is a rare, localized, and irreversible delayed effect of surgery, described in numerous tissues and organs. Is this fibrotic process amenable to therapeutic intervention? A synthesis of various clinical and histopathological aspects, and of cellular and molecular process regulation is described. In summary, there exists a prefibrotic chronic inflammatory phase, a constituted and cellular phase, and lastly a matricial densification and remodelling phase. The respective phases and the roles played over time by the main protagonists, namely myofibroblasts, extracellular matrix and growth factor (TGFbeta1) are clarified. Understanding the mechanism of POF leads logically to treatments derived from our knowledge of the treatment of radiation-induced fibrosis: anti-inflammatory drugs help in the prefibrotic phase, pentoxifylline-tocopherol combination (PE) in the organized fibrotic phase, and pentoclo (PE-clodronate) in the late fibronecrotic phase. Randomized trials are necessary to validate the preliminary results of phase II trials.

Today, the good prognosis of girl's cancers raises the question of her future fertility. Several studies have focused on preservation of ovarian function, but the uterus, irradiated in childhood, is a crucial component to bear in mind because the somatic damages, in terms of endometrial and myometrial atrophy, scar fibrosis and hypovascularization, are negative factors for the establishment and maintenance of a pregnancy and for a convenient labour. Consequences for procreation are related to the morphologic uterine sequelae and its altered function: early miscarriages, abnormal placentation etc. In addition to some spontaneous pregnancies reported in literature, a few pregnancies, for women experiencing a premature iatrogenic ovarian failure due to mild irradiation, have been obtained after in vitro fertilization and oocyte donation with increased estrogen treatment. Recently, a real hope has surged in relation to the opportunity to reverse the radio-induced fibrosis and thus to obtain a better trophic uterus, using the antioxidant pathway. So, a treatment combining pentoxifylline 800 mg/d and tocopherol 1000 IU/d for 12 months allowed improvement of local uterine conditions such as endometrial thickness (x2), myometrial dimensions (x1.5) and uterine vascularization in all six sterile women studied, who have received high irradiation in childhood (>or=45 Gy). Moreover, two women mildly irradiated (#20 Gy) with endometrium resisting to physiological estrogen status, became spontaneously pregnant after using this combined treatment, and gave birth to healthy children. Further studies are in progress to assess, among other questions, the interest of this therapeutic direction.

Resume L’osteoradionecrose est une complication severe de la radiotherapie liee a un echec de cicatrisation, evenement tardif et spontanement irreversible par mort tissulaire. L’histopathologie montre une mosaique pagetoide associant une osteogenese defectueuse a une osteolyse osteoclastique et plus marginalement osteocytique, au profit d’une fibrose fibroblastique et collagenique. Plusieurs hypotheses pathogeniques ont privilegie, tantot une hypothese vasculaire hypoxique, tantot une hypothese fibroatrophique. Par ailleurs, divers elements declenchent ou favorisent l’osteoradionecrose tels que les traumatismes (extraction dentaire, chirurgie etc.) ou une infection bacterienne sur fistule. Typiquement, en clinique, l’os adulte mature concerne est la mandibule apres irradiation ORL, par osteoradionecrose septique, et la hanche apres irradiation pelvienne, par osteoradionecrose aseptique. Pour ces deux situations exemplaires, l’epidemiologie, la clinique et la conduite a tenir sont envisagees. Sur le plan therapeutique, la conduite habituelle est la limitation des facteurs d’aggravation associes (extraction dentaire, infection, dose d’irradiation, chimiotherapie, etc.) et l’exerese de tissus devitalises. Des perspectives therapeutiques innovantes, a partir d’une reflexion physiopathologique, sont proposees : d’une part limiter la destruction osseuse, d’autre part pour lutter contre la fibrose radio-induite associee.

Resume Propos. – La fibroatrophie radio-induite decrite dans de nombreux tissus et organes est une sequelle ineluctable, localisee et tardive de la radiotherapie a forte dose, classiquement irreversible. Notre objectif est de montrer quˈa ce jour ce processus est reversible. Actualites et points forts. – Cette revue presente une synthese de differents aspects statiques et dynamiques du processus fibroatrophique radio-induit dans ses aspects cliniques et paracliniques, histopathologiques, et dans ses regulations cellulaires et moleculaires. Schematiquement, on peut decrire une phase prefibrotique inflammatoire aspecifique, puis une phase fibreuse constituee cellulaire, puis une phase de densification–remodelage matriciel eventuellement associee a une necrose tissulaire terminale. Les roles respectifs et lˈevolution au cours du temps, des protagonistes principaux tels que le myofibroblaste, la matrice extracellulaire et les facteurs de croissance dont le TGFβ1 sont precises. A la lueur des mecanismes physiopathologiques decrits, des conduites therapeutiques curatives sont proposees selon les differentes phases evolutives. En particulier la superoxyde dismutase (non disponible), comme l’association durable de pentoxifylline–tocopherol semblent permettre une reduction, voire une reversibilite du processus fibroatrophique radio-induit etabli, en experimentation animale comme en clinique. Perspectives et projets. – Diverses phases II en cours tentent dˈevaluer lˈinteret therapeutique de lˈassociation pentoxifylline–tocopherol dans diverses sequelles radio-induites, en particulier dans les osteo-radionecroses. Un essai randomise de phase III pentoxifylline–tocopherol versus placebo vient de sˈachever et devrait permettre dˈetayer les resultats de ces essais experimentaux et cliniques retrospectifs.

Resume Objectif. – Les modifications de la microcirculation tissulaire apres irradiation accidentelle contribuent aux effets precoces radio-induits cutanes. L’interet pronostique du laser doppler cutane a ete teste dans un modele experimental d’irradiation aigue accidentelle β. Methodes. – Dix porcs Large White ont recu une irradiation β localisee unique au 90Sr/90Y, a forte dose (32 ou 64 Gy sous 7 mg/cm2) au niveau du flanc, et ont ete evalues a j2, j7, j14, j21 et j28 apres irradiation. La microcirculation locale de repos et au cours d’une stimulation thermique a 42 °C a ete mesuree a l’aide d’un laser doppler cutane Periflux® a sonde p413®. L’enregistrement en continu a evalue trois periodes de six minutes : P1 perfusion cutanee de base au repos, p la pente correspondant a l’augmentation de la perfusion lors de la stimulation thermique a 42 °C pendant deux minutes, P2 la perfusion en plateau lors du chauffage, et P3 lors du retour a l’equilibre. Resultats. – Chez le porc apres irradiation aigue β, il existe a j2 une augmentation d’un facteur 2 a 4 selon la dose (p Conclusion. – Apres irradiation aigue localisee, l’augmentation de la microcirculation cutanee de repos peut correspondre a une vasodilatation capillaire immediate et transitoire qui accompagne l’erytheme initial en situation d’irradiation accidentelle. L’absence de reponse vasculaire a la stimulation thermique peut etre un bon moyen de diagnostic precoce d’une radionecrose cutanee differee.

Resume Objectif. – Les modifications de la microcirculation tissulaire apres irradiation therapeutique contribuent aux effets tardifs radio-induits, en particulier cutanes. Les methodes d’exploration de la microcirculation superficielle analysent en general le debit sanguin de maniere indirecte. Seul le laser doppler peut donner une mesure directe des parametres sanguins in vivo chez l’homme. Methodes. – Trente femmes qui avaient recu une irradiation fractionnee adjuvante locoregionale de 65 Gy pour un cancer du sein, ont eu une fibrose radio-induite localisee six ans (± cinq ans) apres. La microcirculation locale de repos et au cours d’une stimulation thermique a 42 °C, a ete mesuree a l’aide d’un laser doppler cutane Periflux® a sonde p413®. L’enregistrement en continu a evalue trois periodes de six minutes : P1 la perfusion cutanee de base au repos, p la pente correspondant a l’augmentation de la perfusion lors de la stimulation thermique a 42 °C pendant deux minutes, P2 la perfusion en plateau lors du chauffage, et P3 lors du retour a l’equilibre. Resultats. – La microcirculation de repos P1 est augmentee d’un facteur 2 (p Conclusion. – S’il existe une hypovascularisation globale dans les sequelles superficielles tardives de la radiotherapie, nous avons observe une augmentation de la microcirculation cutanee, associee a une inadaptation des cellules endotheliales lors d’une stimulation thermique. Ces observations semblent correspondre a la presence de neocapillaires dilates a type de telangiectasies, indecelables macroscopiquement.

Resume La fibrose radio-induite est une sequelle tardive des irradiations therapeutiques ou accidentelles, qui a ete decrite dans de nombreux tissus et organes. Cette revue presente des donnees recentes sur la fibrose superficielle, qui atteint la peau et les tissus sous-cutanes, son developpement et son traitement. Nous developperons particulierement l’etude d’une cytokine, le TGF-β1, qui joue un role determinant dans la constitution de la fibrose, et qui peut etre proposee comme une cible therapeutique majeure.

Late damages to the skin and subcutaneous tissues are almost inescapable because of the high skin doses required in the irradiation of breast tumours. While the clinical and histological descriptions date back to the first decades of the therapeutic use of ionising radiation, the recent advances in cellular and molecular biology have significantly contributed to the increased understanding of late skin injury mechanisms. In particular, sub-cutaneous fibrosis appears to be the partly reversible results of a continuous and self-maintained local process, possibly sensitive to therapeutic intervention. A second very active research avenue is the development of biologic assays potentially able to predict the probability of increased normal tissue injury after irradiation in individual patients. Such a test would allow the adaptation of the treatment modalities to the radiobiological behaviour of normal tissues. To date, these expectations have not been met. The quality of the irradiation and its modalities (total dose, fractionation, inter fraction interval) remain the main ways to achieve an optimal functional and cosmetic outcome.

Postoperative fibrosis (POF) is a rare, localized, and irreversible delayed effect of surgery, described in numerous tissues and organs. Is this fibrotic process amenable to therapeutic intervention? A synthesis of various clinical and histopathological aspects, and of cellular and molecular process regulation is described. In summary, there exists a prefibrotic chronic inflammatory phase, a constituted and cellular phase, and lastly a matricial densification and remodelling phase. The respective phases and the roles played over time by the main protagonists, namely myofibroblasts, extracellular matrix and growth factor (TGFbeta1) are clarified. Understanding the mechanism of POF leads logically to treatments derived from our knowledge of the treatment of radiation-induced fibrosis: anti-inflammatory drugs help in the prefibrotic phase, pentoxifylline-tocopherol combination (PE) in the organized fibrotic phase, and pentoclo (PE-clodronate) in the late fibronecrotic phase. Randomized trials are necessary to validate the preliminary results of phase II trials.

Today, the good prognosis of girl's cancers raises the question of her future fertility. Several studies have focused on preservation of ovarian function, but the uterus, irradiated in childhood, is a crucial component to bear in mind because the somatic damages, in terms of endometrial and myometrial atrophy, scar fibrosis and hypovascularization, are negative factors for the establishment and maintenance of a pregnancy and for a convenient labour. Consequences for procreation are related to the morphologic uterine sequelae and its altered function: early miscarriages, abnormal placentation etc. In addition to some spontaneous pregnancies reported in literature, a few pregnancies, for women experiencing a premature iatrogenic ovarian failure due to mild irradiation, have been obtained after in vitro fertilization and oocyte donation with increased estrogen treatment. Recently, a real hope has surged in relation to the opportunity to reverse the radio-induced fibrosis and thus to obtain a better trophic uterus, using the antioxidant pathway. So, a treatment combining pentoxifylline 800 mg/d and tocopherol 1000 IU/d for 12 months allowed improvement of local uterine conditions such as endometrial thickness (x2), myometrial dimensions (x1.5) and uterine vascularization in all six sterile women studied, who have received high irradiation in childhood (or=45 Gy). Moreover, two women mildly irradiated (#20 Gy) with endometrium resisting to physiological estrogen status, became spontaneously pregnant after using this combined treatment, and gave birth to healthy children. Further studies are in progress to assess, among other questions, the interest of this therapeutic direction.

Osteoradionecrosis is a severe radiotherapy (RT) injury by healing failure, late effect and spontaneously irreversible by tissue death. Histologically, it consists in a pagetoid mosaic that combines a defective osteogenesis with an osteoclastic osteolysis and more marginally an osteolytic osteolysis, turned to account to fibroblastic and collagenic fibrosis. Several pathogenic hypotheses favor sometimes a vascular hypoxic hypotheses, sometimes a fibro-atrophic hypothesis. Various events start up or favour ORN as traumatisms (dental extraction, surgery,...) or bacterian infection on fistula. In clinic, adult mature bone concerned is the mandible after head and neck RT by septic ORN, and the hip after pelvic RT by aseptic ORN. For each, epidemiology, clinic and therapeutic aspects are developed. Usual therapeutic attitudes consisted in restriction of defavorable associated events (dental extraction, infection, RT dose, chemotherapy,...) and devitalized tissue removal. Physiopathological therapeutic innovatives aspects are proposed to struggle against radiation-induced fibrosis associated and to limit bone destruction.

The radiation-induced fibro-atrophic process described in numerous tissues and organs is a localized and irreversible late effect of high-dose radiation therapy. Our purpose is to show that this process is today reversible.This review describes a synthesis of various clinical, paraclinical and histopathological aspects of radiation-induced fibro-atrophic process, and of cellular and molecular process regulation. Schematically, there exists a prefibrotic aspecific inflammatory phase, then a constituted and cellular phase, then a matricial densification and remodeling phase, associated in some cases with a tissular terminal necrosis. The respective parts and their evolution during time of the main protagonists as myofibroblast, extracellular matrix and growth factor TGF beta 1 are clarified. From the pathophysiological mechanisms described, curative therapeutic attitudes are proposed for the different progressive phases. Especially, superoxide dismutase (not available) and the pentoxifylline-tocopherol combination seem to allow reduction and reversibility of the fibro-atrophic radiation-induced established process, in clinics as in animal experiments.Some phase II trials try to assess the therapeutic interest of combined pentoxifylline-tocopherol in various radiation-induced sequelae, as in osteo-radionecrosis. A clinical randomized trial phase III has just been achieved and could support the results of these experimental and retrospective clinical trials.

Objectif L’osteoradionecrose mandibulaire est une complication de la radiotherapie : defect muqueux et lyse osseuse. La fracture mandibulaire en est une evolution tres severe qui requiert une chirurgie de rattrapage (hemi-mandibulectomie-reconstruction par lambeau libre osteocutane). Durant la derniere decennie, l’osteoradionecrose mandibulaire refractaire a beneficie d’un traitement medical, a partir de son concept physiopathologique : atteintes directe par osteolyse osteoclastique (macrophage) et osteocytique amplifiee par infection chronique et osteoporose (osteoblaste), et indirecte par fibrose radio-induite et microcirculation defectueuse. Existe-t-il une place pour une approche conservatrice de la fracture sur osteoradionecrose mandibulaire ? Patients et methodes Vingt-neuf patients, irradies pour un cancer ORL 7 ans auparavant, etaient atteints d’une osteoradionecrose mandibulaire exteriorisee sans cicatrisation depuis 2 a 3 ans. Apres echec de l’antibiotherapie, chirurgie locale et oxygenotherapie hyperbare, l’os expose moyen etait de 20 ± 9 mm. Les osteoradionecroses mandibulaires refractaires (confiees par les chirurgiens) avec fracture mandibulaire deplacee, engrainee, ou avec desunion depuis un an, etaient associees a un sepsis permanent avec ou sans cellulite faciale, fistule orocutanee, trismus, neuropathie dentaire inferieure. Un traitement « desinfiltrant » de quatre semaines (par amoxicilline, clavulanate, ciprofloxacine, prednisone et fluconazole), a precede dans tous les cas, l’association « Pentoclo » (pentoxifylline 800 mg, tocopherol 1000 mg et clodronate 1600 mg), et l’antibiotherapie chronique (clindamycine) en cas de purulence. Pour eviter un effet rebond et creer un cal, un traitement d’entretien « Trico » (clodronate et colchicine) a ete institue jusqu’a consolidation. Resultats La tolerance a ete bonne. Une reponse complete (recouvrement muqueux) de l’osteoradionecrose mandibulaire a ete obtenue en mediane en 15 ± 7 mois. Tous les patients ont elimine un ou des sequestres osseux volumineux, avec une amelioration progressive : l’antibiotique a ete stoppe en 7 ± 4 mois, ainsi que les antalgiques, avec fermeture de fistule. Le traitement « Trico » a permis d’achever la consolidation osseuse : resolution du trait de fracture en 18 a 42 mois, avec une consolidation progressive radiologique differee. Conclusion Une osteoradionecrose mandibulaire mandibulaire avec fracture peut beneficier d’un traitement conservateur « Pentoclo », suivi d’un entretien « Trico », avec un resultat progressif et perenne. La chirurgie pourrait alors etre reservee aux echecs du traitement medical.

The changes that occur in the tissular microcirculation after accidental acute irradiation account for some of the early effects of such irradiation, especially at the cutaneous level. The prognostic importance of the cutaneous laser doppler was tested in an experimental model of acute beta-irradiation.Ten pigs were given beta-irradiation with a high single localized dose of 90Sr/90Y (32 or 64 Gy, 7 mg/cm2) delivered to the flank, and were evaluated 2, 7, 14, 21 and 28 days thereafter. Each individual was its own control. The local microcirculation was measured in the resting state and during thermal stimulation at 42 degrees C, using a Periflux cutaneous Doppler laser with p413 probes. Three periods of six minutes each were continuously recorded: period 1 (P1) represented basal resting cutaneous perfusion, with the slope p corresponding to the increase in perfusion when two minutes of thermal stimulation at 42 degrees C began; P2 to plateau perfusion during this stimulation; and P3 to perfusion on the return to equilibrium.After acute beta-irradiation in the pig, all the cutaneous microcirculation parameters measured (P1, p, P2 and P3) had risen at day 2 in the irradiated area by a factor of 2 to 4, depending on the dose (p0.001), compared to the adjacent control area. On the other hand, as from day 7, the resting and the stimulated microcirculation varied little, except for a reduction of the slope p by a factor of 2 (p0.05) after the strongest radiation dose.After acute irradiation, the increase in the resting cutaneous microcirculation may correspond to immediate but transitory capillary vasodilatation that accompanies the initial erythema in accidental irradiation. The absence of vascular response to thermal stimulation seems to be a good means of reaching an early diagnosis of delayed cutaneous radiation necrosis.

The changes that occur in the tissular microcirculation after therapeutic irradiation (RT) account for some of the late effects of irradiation, especially on the cutaneous level. As a rule, the methods of exploring the superficial microcirculation only measure blood flow indirectly. Only the Doppler laser can provide direct measurements of blood parameters in vivo in man.Thirty women who had been irradiated with 45 + 20 Gy of locoregional fractionated adjuvant RT for breast cancer developed local radiation-induced fibrosis six years later (+/- 5). The local microcirculation was measured in the resting state and during thermal stimulation at 42 degrees C, using a Periflux cutaneous Doppler laser with p413 probes. Three periods of six minutes each were continuously recorded: period 1 (P1) represented basal resting cutaneous perfusion, with the slope p corresponding to the increase in perfusion when two minutes of thermal stimulation at 42 degrees C began; P2 to plateau perfusion during this stimulation; and P3 to perfusion on the return to equilibrium. Each individual was its own control.In the women treated by RT, the resting microcirculation in the skin underlying an area of late fibrosis rose by a factor of 2 during P1 (p0.001), and the P2/P1 ratio decreased by a factor of 2 (p0.001), compared to the control area. After thermal stimulation, there was no change in p, P2 or P3.Although a hypovascularization is frequently found in late sequelae of RT, we observed an increase of the cutaneous microcirculation associated with a maladjustment of the endothelial response to a thermal stimulation. These observations seem to reflect the presence of dilated new capillaries of the telangiectatic type, which are macroscopically undetectable.

Radiation-induced fibrosis is a late sequela of both therapeutic and accidental irradiations, which has been described in various tissues, including the lung, liver, kidney and skin. This review presents different aspects of superficial radiation-induced fibrosis, such as clinical observations, histological changes, cellular and molecular regulations, and medical management. Recent evidence on the critical role played by TGF-beta 1 in the initiation, development and persistence of fibrosis are discussed, as well as the possibility that this cytokine may constitute a specific target for antifibrotic agents.

Late damages to the skin and subcutaneous tissues are almost inescapable because of the high skin doses required in the irradiation of breast tumours. While the clinical and histological descriptions date back to the first decades of the therapeutic use of ionising radiation, the recent advances in cellular and molecular biology have significantly contributed to the increased understanding of late skin injury mechanisms. In particular, sub-cutaneous fibrosis appears to be the partly reversible results of a continuous and self-maintained local process, possibly sensitive to therapeutic intervention. A second very active research avenue is the development of biologic assays potentially able to predict the probability of increased normal tissue injury after irradiation in individual patients. Such a test would allow the adaptation of the treatment modalities to the radiobiological behaviour of normal tissues. To date, these expectations have not been met. The quality of the irradiation and its modalities (total dose, fractionation, inter fraction interval) remain the main ways to achieve an optimal functional and cosmetic outcome.

To establish how far liposomal copper/zinc superoxide dismutase (Cu/Zn-SOD) and manganese superoxide dismutase (Mn-SOD), respectively, reduce radiation-induced fibrosis (RIF), using a well-characterized pig model of RIF permitting the design of a controlled laboratory experiment.In this model of acute localized gamma irradiation simulating accidental overexposure in humans, three groups of five large white pigs were irradiated using a collimated 192Ir source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of subcutaneous fibrosis involving skin and skeletal muscle developed 6 months after irradiation. One experimental group of five pigs was then injected i.m. with 10 mg/10 kg b.wt. of Cu/Zn-SOD, twice a week for 3 weeks, and another experimental group of five was injected with 10 mg/10 kg b.wt. of Mn-SOD, three times a week for 3 weeks. Five irradiated control pigs were injected with physiological serum. Animals were assessed for changes in the density of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Block depth was determined by ultrasound. Physical and sonographic findings were confirmed by autopsy 12-14 weeks after completing SOD injections. The density, length, width, and depth of the fibrotic block, and the areas and volume of its projected cutaneous surface were compared before treatment, 1, 3, and 6 weeks thereafter, and at autopsy, 12-14 weeks after treatment ended.The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. Whether they were given Cu/Zn- or Mn-SOD, significant and roughly equivalent softening and shrinking of the fibrotic block were noted in all treated animals between the first week after treatment ended and autopsy, when mean regression was 45% for length and width, 30% for depth, and 70% for area and volume. Histologic examination showed completely normal muscle and subcutaneous tissue surrounding the residual scar. This replacement of scar tissue by normal tissue in experimental animals and the 50% decrease in the linear dimensions of the scar were comparable to the results obtained in previous clinical studies and highly significant compared to the clinical and autopsy results for the control animals.Our results are striking and comparable to the results obtained in our previous clinical study after liposomal Cu/Zn-SOD treatment. To our knowledge, this is the first time that two agents have been shown to reverse the radiation-induced fibrotic process in experimental animals and to permit the regeneration of normal tissue in a zone of well-established postirradiation fibrosis.

The use of exclusive radiation therapy as loco-regional treatment of breast cancer is indicated only if this approach is both effective and well tolerated. After the pioneer work of B. Pierquin [1], we began using exclusive radiation therapy including interstitial brachytherapy boosts in 1977. Treatment was begun using large field external beams to deliver 45 Gy to the breast and regional nodes in 5 fractions of 1.8 Gy per week. All portals were used each treatment day. The internal mammary nodes were irradiated using a direct beam. Interstitial implants were used to boost the dose to the primary site by 30 to 35 Gy. Guide needles implanted on the same plane were spaced 2 cm apart with a 1.5 cm separation between planes if 2 or more planes were used. Patients with palpable nodes and/or rapidly growing or inflammatory primary lesions received adjuvant chemotherapy.