Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis, S Delanian, R Porcher, S Balla

Tags: radiotherapy, PTX, RIF, Vit E, fibrosis, experimental study, surface area, American Society of Clinical Oncology, placebo, Br J Dermatol, alternative treatment, pentoxifylline, Fajardo L: Pathology, soft tissue necrosis, pulmonary fibrosis, Williams J, extracellular matrix, fibroblasts, Int J Radiat Oncol Biol Phys, Martin M, linear regression, Sylvie Delanian, balanced treatment groups, RIF surface area, areas, surface depth, endometrial thickness, Wilcoxon rank sum test, SOMA, relative changes, clinical trial
Content: Randomized, Placebo-Controlled Trial of Combined Pentoxifylline and Tocopherol for Regression of Superficial Radiation-Induced Fibrosis
By Sylvie Delanian, Raphael Porcher, Saida Balla-Mekias, and Jean-Louis Lefaix
Purpose: Radiation-induced fibrosis (RIF) is a rare morbid complication of radiotherapy, without an established method of management. RIF treatment with a combination of pentoxifylline (PTX) and alpha-tocopherol (vitamin E; Vit E) was recently prompted by the good results of a clinical trial and an animal study. The present double-blind, placebo-controlled, monocentric study was designed to assess the efficacy of this combination in treating RIF sequelae. Patients and Methods: Twenty-four eligible women with 29 RIF areas involving the skin and underlying tissues were enrolled from December 1998 to April 2000. These patients, previously irradiated for breast cancer, were randomly assigned to four balanced treatment groups: (A) 800 mg/d of PTX and 1,000 U/d of Vit E; (B) PTX plus placebo; (C) placebo plus Vit E; and (D) placebo-placebo. The main end point measure was the relative regression of measurable RIF surface after 6 months of treatment. Assessment was
completed by depth (with ultrasonography) and associated symptom measures. Results: Twenty-two patients with 27 RIF areas were analyzed at 6 months. Mean RIF surface regression was significant with combined PTX/Vit E versus double placebo (60% 10% v 43% 17%; P .038). The median slope for the speed of RIF surface area and volume regression was significantly higher for group A than groups B, C, and D. All treatments were well tolerated. Conclusion: Six months' treatment of combined PTX/Vit E can significantly reduce superficial RIF. Synergism between PTX and Vit E is likely, as treatment with each drug alone is ineffective, but these results require confirmation in larger series. J Clin Oncol 21:2545-2550. © 2003 by American Society of Clinical Oncology.
T REATMENT OF malignant tumors by radiation therapy is limited by the need to avoid excessive late damage to normal tissues.1 Although new strategies designed to improve the therapeutic ratio have reduced the incidence of radiationinduced fibrosis (RIF), it is still sometimes severe and unavoidable, and slight differences exist in its clinical presentation.1 Like fibrotic sequelae of any origin, RIF is mainly characterized by nonspecific changes in the connective tissue involving excessive extracellular matrix deposition and hyperactive fibroblasts.2,3 Constituted RIF does not regress spontaneously,4 but no effective treatment for it has yet been established: RIF either stabilizes or gradually worsens, with acute inflammatory periods. Several categories of drug seem potentially useful for managing all types of fibrotic sequelae, but are only effective when administered early in the fibrotic process. These include corticosteroids, nonsteroidal anti-inflammatory agents, hemorheologic and vasodilator drugs, zinc, antioxidants, and interferon.1 Corticosteroids have proved useful in reducing the acute inflammatory reaction associated with fibrosis, but are relatively ineffective in reversing the fibrotic process. In our clinical and experimental experience, vasodilators have no effect on constituted RIF, probably because of the lack of reactivity in irradiated capillaries and the presence of arteriovenous shunts.2 We showed some years ago that superficial RIF regressed after treatment with exogenous superoxide dismutase, but this drug is not yet available.5,6 Despite the scant literature on the pathophysiologic mechanisms and management of chronic radiotherapy damage, we have tried to develop an etiology-based treatment for RIF. For this, we considered that pentoxifylline (PTX) and alpha-toco-
pherol (vitamin E; Vit E) might be effective by interacting with the fibrotic process. In addition, radiation-induced soft tissue necrosis has been shown to heal significantly faster with PTX.7 In one case, PTX was reported to relieve pain,8 which was later confirmed in six patients with fibrosis.9 In a preliminary PTX trial comprising eight patients with nonmeasurable RIF, functional improvement was reported in some of them, although there were three cases of poor tolerance.10 As superoxide dismutase has proved effective in treating RIF partly because of its action as an antioxidant, we believed that Vit E might also be of interest in this respect. However, in a preliminary unpublished study in which 700 U/d of Vit E was administered to 53 patients, the mean linear regression of superficial RIF areas was only 20% after 4 months.11 In the end, we found that when used separately, neither PTX nor Vit E constituted a treatment for RIF. Consequently, we conducted a phase II clinical study of combined From the Service d'Oncologie-Radiotheґrapie and Deґpartement de Biostatistique et Informatique Meґdicale, Ho^pital Saint-Louis, Paris; and Direction des Sciences du Vivant/Deґpartement de Radiobiologie et de Radiopathologie, Commissariat a` l'Energie Atomique/Fontenay-aux-Roses, Fontenayaux-Roses, France. Submitted June 12, 2002; accepted April 8, 2003. The study was supported by the Deґleґgation a` la Recherche Clinique of Assistance Publique des Ho^pitaux de Paris, Paris, France. Address reprint requests to Sylvie Delanian, MD, Service d'OncologieRadiotheґrapie, Ho^pital Saint Louis 1, Ave Claude Vellefaux, 75010 Paris, France; email: [email protected] © 2003 by American Society of Clinical Oncology. 0732-183X/03/2113-2545/$20.00
Journal of Clinical Oncology, Vol 21, No 13 (July 1), 2003: pp 2545-2550 DOI: 10.1200/JCO.2003.06.064
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PTX/Vit E treatment, and observed that at 6 months, RIF surface area had regressed by 53%.12 We also tested this treatment in our experimental pig RIF model, and at 6 months we observed highly significant regressions of 56% and 79% in RIF surface and volume, respectively, whereas no response was recorded in PTX-treated and control animals.13 To assess the efficacy and synergism of PTX and Vit E as an antifibrotic treatment in patients with measurable areas of symptomatic chronic radiotherapy damage, we performed the present monocentric, double-blind, randomized clinical trial of combined PTX/Vit E versus placebo. A 2 2 factorial design was used to allow testing for drug interactions and the marginal effects of each treatment. PATIENTS AND METHODS The targeted population was defined as women who had had radiotherapy for breast cancer and exhibited clinically measurable RIF that had occurred more than 6 months after radiotherapy completion, without evidence of recurrent or evolutionary cancer or skin pathology. Written informed consent was obtained from all patients before treatment started. The study was approved by the French Ethics Committee of the Saint-Louis Hospital in Paris. Randomization The randomization code was generated by computer (FORTRAN code using the IMSL library [Visual Numerics Inc, San Ramon, CA] routine) with random blocks of four allocations, equally divided between regimens and concealed in sealed envelopes, which were safely stored close to the investigators (Fig 1). The tablets and capsules for drugs and placebo were identical in appearance, taste, and labeling. The drug code was revealed after the database had been completed and locked. In an individual double-blind design, the 24 women included were randomly assigned, for 6 months, to a combination of 800 mg/d of PTX in two 400-mg tablets and 1,000 U/d of Vit E in two 500-U capsules (group A), PTX and placebo capsules (group B), placebo tablets and Vit E (group C), and placebo tablets and capsules (group D). Outcome Measures Participants were reviewed by the clinical investigators before randomization. Routine evaluation included palpation of the edges of the subcutaneous fibrotic block and measurement of the length (L) and width (W) of the Fig 1. Trial profile. RIF, radiation-induced fibrosis; RT, radiotherapy; PTX, pentoxyfylline; vit.E, vitamin E.
projected cutaneous surface. The main end point was the relative regression of the fibrosis surface area at 6 months, defined as (measure at 6 months measure at inclusion)/measure at inclusion. Fibrosis depth and then mean depth were measured by ultrasonography. Objective signs and subjective symptoms relating to the site of fibrotic involvement were graded from 1 to 4, according to the Subjective Objective medical management and Analytic evaluation of injury (SOMA). The items assessed included scaliness, pruritus or pain, local edema, pigmentation changes, ulcer or necrosis, telangiectasia, fibrotic scarring, atrophy or tissue contraction, and medical management of local pain or compressive edema. Secondary end points were the relative regression of fibrosis surface area at 3 months, the relative regressions of fibrosis volume (surface depth) and SOMA scores at 3 and 6 months, and the individual slopes of the linear regression of the RIF response plotted against time and computed for each individual using relative changes from baseline. Sample size Sample size was determined from the main end point to allow the main comparison of combined PTX/Vit E versus placebo. From the Pilot Study of 43 patients with 50 RIF areas mentioned above,12 a mean value of 53% of relative surface area regression was expected at 6 months with a SD of 20%, compared with a mean variation of 0% 10% in the placebo group D. Accordingly, to achieve 0.05 type I and II error rates,14 four patients per group were required. To estimate the marginal effects of treatment (ie, PTX or Vit E alone), four equal groups were constituted. To allow for possible loss to follow-up, each group finally included six patients, as in our experimental study, so that the total sample comprised 24 patients. This sample size was validated by the ethics committee of the Saint Louis Hospital. statistical analysis For the main treatment comparison (A v D) involving the main and secondary end points, we used the Wilcoxon rank sum test. Baseline between-group characteristics at inclusion were compared by the KruskallWallis test. Two-way analyses of variance (ANOVA) were performed to test the respective marginal effects of PTX and Vit E and their interactions, resulting in a procedure that involved comparison of the four groups. All tests were two-sided, with a 5% significance level. Analyses were done with SAS version 8.0 software (SAS Institute, Cary, NC). RESULTS Between December 1998 and April 2000, 31 patients were recruited from various centers by clinical investigators at the Saint Louis Hospital in Paris. Seven were excluded from the study because they did not meet the protocol requirements: two patients had nonmeasurable RIF, three patients had breast hardness within 6 months of radiotherapy completion, and two patients were not interested in the study because the drugs tested were available immediately. Consequently, 24 eligible women (meanSD [standard deviation] age, 57 8 years) with 29 gradually worsening RIF areas were treated (Table 1). The mean latency period between the end of radiotherapy and the start of the study was 7 4 years (Table 1). RIF was correlated with excessive local radiation doses resulting from overlapping at field junctions (12 areas), or from an interstitial brachytherapy boost in the surgically removed breast area (17 areas). Several personal sensitivity factors predisposed patients to RIF: prior radiotherapy for Hodgkin's disease (two patients), postoperative abscess or hematoma (three patients), and combined chemotherapy (15 patients). Five of the 24 women had developed two RIF areas in the breast and/or at
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Table 1. Baseline Screening of the 24 Participants at Inclusion: Clinical and Ultrasonography Data in 29 Areas of RadiationInduced Fibrosis
Group A PTX/Vit E
Group B PTX/Placebo
Group C Placebo/Vit E
Group D Placebo/Placebo
No. of patients Age, years Mean SD No. of RIF areas Years since RT Mean SD RIF diameter, cm Mean SD RIF surface, cm2 Mean SD Range RIF death, cm Mean SD RIF volume, cm3 Mean SD Range SOMA score Mean SD Range
6 52.7 3.7 7 7.5 6 6.5 3 43.9 39.4 12.0-128.0 2.3 0.6 108.9 102.9 13.2-320.0 11.0 2.2 8-14
6 50.2 7.1 6 4.5 3 7 3 50.8 41.3 18.8-127.5 2.1 0.4 113.0 107.3 28.1-318.7 11.5 1.8 9-13
6 61.7 8.8 9 8 4.5 6.5 5 36.2 24.4 11.0-76.5 2.0 0.1 87.6 88.8 16.5-256.0 9.6 2.6 6-14
6 58.5 7.0 7 8 2.5 6 3 34.0 38.2 15.0-120.0 1.9 0.8 84.1 132.8 16.2-384.0 11.4 3.4 7-17
Abbreviations: SD, standard deviation; RIF, radiation-induced fibrosis; RT, radiotherapy; SOMA, Subjective Objective Medical Management and Analytic evaluation of injury; PTX, pentoxifylline; Vit E, vitamin E.
a field junction. Mean initial RIF dimensions were a diameter (ie, LW/2) of 6.5 2.6 cm, depth of 2.1 0.7 cm, and a projected cutaneous surface area of 41 34 cm2 (Table 1). Seven patients with chronic RIF had associated symptoms in the upper limbs, including restricted arm movement in three patients, severe arm edema in three, and sensorimotor nerve dysfunction with symptomatic plexitis in two. The mean initial SOMA score for the 24 patients was 10.8 2.6. Complete data were available for 22 (92%) of 24 of the eligible participants and 27 RIF areas. Of the two patients who dropped out, one changed her mind at baseline, and the other was withdrawn at 2 months because of acute psoriasis requiring PUVA (psoralens plus ultraviolet light) treatment. No significant differences at baseline were found between the four groups. Adverse Events Immediate and long-term tolerance were very satisfactory, and no patient stopped the treatment because of an adverse event.
Ten (45%) of 22 patients experienced discomfort during treatment, owing to 13 events, including hot flushes, nausea and epigastralgia, severe asthenia, headache, or vertigo; but all 10 remained in the study (Table 2). There were no significant differences between groups for tolerance. Primary Analyses Clinical regression was defined as centripetal reduction of the edges of the fibrotic block in all 27 areas documented, without any RIF contraction. At 6 months, we observed a significant mean RIF surface regression of 60% with combined PTX/Vit E in group A, versus 43% for double placebo in group D (P .038). Detailed results are given in Table 3 and Figure 2, and are illustrated in Figure 3. Two-way ANOVA for the four groups disclosed no significant effects, though there was a trend toward significance for the effect of PTX and Vit E interaction (P .09).
Table 2. Adverse Events During PTX and Vit E Treatment in 22 Eligible Randomized Patients
Event
Group A PTX/Vit E
Group B PTX/Placebo
Group C Placebo/Vit E
Group D Placebo/Placebo
Hot flushes (n 3)
1
1
0
1
Nausea, epigastralgia (n 5)
0
2
0
3
Asthenia (n 4)
1
3
0
0
Vertigo, headache (n 1)
1
0
0
0
Patients with events/total patients per group
2/5
4/5
0/6
4/6
Abbreviations: PTX, pentoxifylline; Vit E, vitamin E.
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Table 3. Regression of 27 Radiation-Induced Fibrosis Areas in 22 Assessable Patients After 3 and 6 Months of Treatment
Group A PTX/Vit E (N 6/n 5)
Mean
SD
Group B PTX/Placebo (N 5/n 5)
Mean
SD
Group C Placebo/Vit E (N 9/n 6)
Mean
SD
Group D Placebo/Placebo (N 7/n 6)
Mean
SD
At 3 months Surface, cm2 Index 3 months, % At 6 months Surface, cm2 Index 6 months, % At 3 months Volume, cm3 Index 3 months, % At 6 months Volume, cm3 Index 6 months, % Surface slope regression, % per month Volume slope regression, % per month At 3 months SOMA score Index 3 months, % At 6 months SOMA score Index 6 months, %
30.5 34.7 19.2 60.2 63.8 45.1 34.3 73.0 10.1 12.8 8.7 20.2 7.0 39.1
30.5 20.6 13.6 10.7 64.0 22.4 25.6 7.2 1.6 2.0 1.7 10.6 1.7 12.1
38.0 18.9 23.7 39.1 85.8 18.9 47.1 48.6 6.5 8.1 10.0 10.5 7.6 32.4
32.5 18.3 14.5 37.4 85.0 18.3 38.2 35.9 6.2 6.0 2.0 11.5 2.9 20.8
26.7 25.8 20.7 40.0 51.7 34.8 29.3 52.8 6.7 8.8 8.2 15.2 6.0 37.1
21.2 21.8 17.1 32.0 51.9 23.8 28.4 29.4 0.3 4.9 3.1 16.1 2.2 15.5
24.7 29.2 19.3 42.6 51.2 36.2 31.9 50.8 7.1 8.5 8.6 24.7 7.4 32.9
29 10.3 21.7 17.4 77.3 13.5 38.1 23.9 2.9 4.0 3.0 13.1 2.2 18.5
NOTE. In boxheads, first number (N) denotes number of areas of radiation-induced fibrosis and second number (n) denotes number of patients. Abbreviations: SD, standard deviation; PTX, pentoxifylline; Vit E, vitamin E; SOMA, Subjective Objective Medical Management, and Analytic Evaluation of Injury.
Secondary Analyses These analyses showed a trend toward significance (P .054) for the differences between mean RIF volume regression at 6 months with combined PTX/Vit E and with double placebo (73% v 51%; Table 3). However, none of the between-group differences was significant in the ANOVA that took account of the four groups. The slopes of RIF surface and volume regression were significantly steeper with combined PTX/Vit E than with double placebo (P .018 and P .025, respectively). For group A
versus groups B, C, and D, slope analysis yielded significantly faster volume regression for group A (P .036). When clinical responses were graded qualitatively according to the SOMA score for symptom severity, no significant difference emerged between the four groups at 6 months of treatment (A v D, 39% v 33%; Table 3). DISCUSSION The significant reduction of chronic radiotherapy damage obtained with the PTX/Vit E combination does not support the concept that established radiotherapy sequelae such as RIF are irreversible. Not only did this combination lead to mean regressions of 53% and 66% in our phase II trial of 50 superficial RIF areas at 6 and 12 months of treatment, respectively,12 but our previous in vivo experimental data for PTX/Vit E­treated pigs
Fig 2. Histogram showing the regression of radiation-induced fibrosis in surface area after 6 months of treatment in the four randomized groups.
Fig 3. Photographs of a group A patient with two radiation-induced fibrosis areas overlapping at a field junction (axillo-clavicular and intern mammary chain) (A) at inclusion and (B) after 6 months of pentoxyfylline and vitamin E treatment, with 65% radiation-induced fibrosis surface regression.
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showed histopathologic normalization of the subcutaneous tissues surrounding a small residual scar, as well as a large reduction in the immunohistochemical expression of the transforming growth factor beta-1 (TGF1). In these six pigs, the 79% RIF volume regression at 6 months of treatment with combined PTX/Vit E was highly significant compared with the fibrosis stability observed in the six pigs treated with PTX alone and six control pigs.13 In the present patients in group A, an objective response at 6 months of PTX/Vit E treatment was recorded in six of six RIF areas, with a significant mean decrease in surface area of 60% 10% v 43% 17% in the doubleplacebo group, and without notable side effects. The response in this PTX/Vit E group, with an SD of 10%, was more homogeneous than the responses in groups B, C, and D, which exhibited greater variability (Table 3). Surprisingly, the response in the double placebo group was also strong, although no change in RIF volume had been recorded in these patients during the 6 months before the study. This was probably due to the major psychologic impact of participation in a study. Nevertheless, despite the small sample size, the results of the present randomized trial confirmed those of our previous clinical trial, and of the experimental animal study in which there was no psychologic impact. The 6-month duration of the present study was almost too short to observe a significant improvement in the SOMA score for the treatment in group A. Long-term follow-up of previous phase II patients, in fact, helped us to understand that improvement under combined PTX/Vit E treatment is slow, progressive, and continuous, with a maximum effect after periods ranging from18 months to 3 years (Delanian et al, unpublished data, 2003), to take account of patient-to-patient variability. Recent advances in THE UNDERSTANDING of chronic radiotherapy damage to normal tissue might partly help to explain why we observed fibroatrophic process reversibility, because these advances have enabled the main protagonists in this pathology to be identified.1,15,16 The production of free radicals caused by the interaction of ionizing radiation with living tissues plays an important role in the initial stress and ensuing inflammatory response leading to fibrosis. The latter is apparently induced by a continuous self-maintaining local process. The fibroblastic populations implicated in tissues with chronic radiotherapy damage contain proliferative myofibroblasts2,17 and senescent nonproliferating fibrocytes3,18; this cell heterogeneity is probably due to a variable balance between reactive oxygen species and the antioxidant defense system.19 Whereas exhausted cells mainly characterized senescent and atrophic irradiated tissues,3 early RIF was found to be more active, displaying excess fibroblastic and endothelial cell proliferation and increased production of TGF1 and extracellular matrix.20,21 From a clinical point of view, chronic radiotherapy damage is a dynamic process that combines atrophycontraction and connective hypertrophy-fibrosis in the same volume of damaged tissue. Using the PTX/Vit E combination, we recently described, in 12 patients, complete healing of small mandible osteoradionecrosis after 3 to 5 months of treatment, and more than 50%
healing of large aseptic bone necrosis after 12 months.22,23 We also reported partial uterine restoration in six women with fibroatrophic lesions induced by childhood cancer irradiation, with significant improvements in endometrial thickness (6 v 3 mm) and myometrial dimensions after 12 months of combined PTX/Vit E treatment.24 In addition, we reported that in 18 recipient women with a thin endometrium due in three cases to radiotherapy, who had enrolled in an oocyte donation program, 6 months of combined PTX/Vit E increased endometrial thickness from 4.9 to 6.2 mm and allowed a pregnancy rate of 33% (five patients).25 As far as we know, such clinical improvements have never been obtained before. The precise mechanisms by which the PTX/Vit E combination interacts with fibro-atrophic tissues and allows fibrotic process reversibility are not yet known. However, several items of biologic information shed some light on the reasons why this combination has proved useful. The use of PTX in vascular diseases has been reported in vivo to have an antitumor necrosis factor effect, increase erythrocyte flexibility, vasodilate, and inhibit inflammatory reactions. In vitro studies have indicated that PTX inhibits human dermal fibroblast proliferation and extracellular matrix production26,27 and increases collagenase activity.26,27 However, in our experimental pig study, we did not observe any clinical or histologic changes in RIF after 6 months of treatment with PTX alone.13 The high concentration of PTX necessary to suppress fibroblast collagen synthesis or to increase collagenase activity, deduced by extrapolating the results of in vitro studies, might be extremely toxic and suggests that administration of PTX alone does not constitute an antifibrotic treatment. The physiologic role of Vit E, used in clinical practice to lower the cholesterol level, is to scavenge the reactive oxygen species generated during oxidative stress and protect cell membranes against lipid peroxidation.18 Fifty years ago, it was already observed in humans that endogenous Vit E deficiency was associated with abnormal connective tissue repair, resulting in the formation of scar-like tissues. As stated above, PTX or Vit E alone have proved unable to reverse the development of human fibrosis. Nevertheless, they have all the major properties necessary to make them good antifibrotic agents, and we explored here the action of two different but complementary mechanisms whose effect is not simply additive. Combined PTX/Vit E exerts synergistic action on both extracellular matrix and cell regulation. The combination's beneficial effects observed on human fibroatrophic lesions and in our experimental study13 suggest that during treatment, great changes take place in the genetic programming of the RIF Cell differentiation. We therefore postulated that the target of the PTX/Vit E combination is phenotype reversion of the abnormal RIF fibroblasts into a normal phenotype via the TGF1 pathway.13 In conclusion, RIF is a rare and possibly orphan disease, which is usually irreversible. In the present randomized trial, the PTX/Vit E combination reduced chronic radiotherapy damage significantly. Better results could be obtained with a longer period of treatment. Both drugs are available, well tolerated, and inexpensive, and we believe that together, they constitute an effective treatment. In any
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case, no alternative treatment presently exists. This trial might help to open up a path through the desert of fibrosis treatment. Nevertheless, its results raise many questions about the precise mechanisms of action of these drugs when used together, and further larger randomized trials are therefore necessary to confirm the antifibrotic action of the PTX/Vit E combination.
ACKNOWLEDGMENT We thank many physicians from several Parisian institutions for entrusting their fibrosis patients to us for treatment and S. Chevret for her advice. We also thank Hoechst-Houde (presently, Aventis Pharmaceuticals, Inc, Kansas City, MO) and Pharma 2000 Laboratories for gifts of pentoxifylline (Torental), tocopherol (Toco 500), and placebos.
REFERENCES
1. Delanian S, Lefaix J-L: Reversibility of radiation-induced fibroatrophy (in French). Rev Med Interne 23:164-174, 2002 2. Lefaix J-L, Daburon F: Diagnosis of acute localized irradiation lesions: A review of the French experimental experience. Health Phys 75:375-384, 1998 3. Delanian S, Martin M, Bravard A, et al: Cu/Zn superoxide dismutase modulates phenotypic changes in cultured fibroblasts from human skin with chronic radiotherapy damage. Radiother Oncol 58:325-331, 2001 4. Fajardo L: Pathology of radiation injury, in Masson Monographics in Diagnostic Pathology New York, NY, Sternberg ed. 1982, p 285 5. Lefaix J-L, Delanian S, Leplat J-J, et al: Successful treatment of radiation-induced fibrosis using Cu/Zn-SOD and Mn-SOD: An experimental study. Int J Radiat Oncol Biol Phys 35:305-312, 1996 6. Delanian S, Baillet F, Huart J, et al: Successful treatment of radiationinduced fibrosis using liposomal Cu/Zn superoxide dismutase: Clinical trial. Radiother Oncol 32:12-20, 1994 7. Dion M, Hussey D, Doornbos J, et al: Preliminary results of a pilot study of pentoxifylline in the treatment of late radiation soft tissue necrosis. Int J Radiat Oncol Biol Phys 19:401-407, 1990 8. Werner-Wasik M, Madoc-Jones H: Trental relieves pain from postradiation fibrosis. Int J Radiat Oncol Biol Phys 25:757-758, 1993 9. Cornelison T, Okunieff P, Naydich B, et al: Trial of Pentoxifylline in patients with functional disability caused by radiation-induced advanced regional fibrosis: Preliminary report. Proc Am Assoc Cancer Res 37:615, 1996 (abstr 4185) 10. Futran N, Trotti A, Gwede C: Pentoxifylline in the treatment of radiation-related soft tissue injury: Preliminary observations. Laryngoscope 107:391-395, 1997 11. Baillet F: Alpha-tocopherol treatment of radio-fibrosis post-brachytherapy for breast cancer. Radiother Oncol 43:S3, 1997 (abstr 9) 12. Delanian S, Balla-Mekias S, Lefaix J-L: Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol 17: 3283-3290, 1999 13. Lefaix J-L, Delanian S, Vozenin M-C, et al: Striking regression of subcutaneous fibrosis induced by high-doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: An experimental study. Int J Radiat Oncol Biol Phys 43:839-847, 1999 14. Machin D, Campbell M. Statistical tables for the design of clinical trials. Oxford/Blackwell Scientific Publications. 1987 15. Rodeman H, Bamberg M: Cellular basis of radiation induced fibrosis. Radiother Oncol 35:83-90, 1995
16. Rubin P, Johnston C, Williams J, et al: A perpetual cascade of cytokines post-irradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 33:99-109, 1995 17. Martin M, Lefaix J-L, Crechet F, et al: Temporal modulation of TGF-beta1 and b-actin gene expression in pig skin and muscular fibrosis after ionizing radiation. Radiat Res 134:63-70, 1993 18. Rudolph R, Vandeberg J, Schneider J, et al: Slowed growth of cultured fibroblasts from human radiation wounds. Plast Reconstr Surg 82:669-675, 1988 19. Remacle J, Raes M, Toussaint O, et al: Low levels of reactive oxygen species as modulators of cell function. Mutation Res 316:103-122, 1995 20. Martin M, Lefaix J-L, Delanian S: TGF-beta1 and radiation fibrosis: A master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 47:277-290, 2000 21. Border W, Noble N: Transforming growth factor beta in tissue fibrosis. N Engl J Med 331:1286-1292, 1994 22. Delanian S, Lefaix J-L: Refractory osteoradionecrosis: Striking healing with combination of pentoxifylline-tocopherol: Proceedings of ESTRO. Radiother Oncol 56:S129, 2000 (abstr 474) 23. Delanian S, Lefaix J-L: Complete healing of severe osteoradionecrosis by treatment combining pentoxifylline, tocopherol and clodronate. Br J Radiol 75: 467-469, 2002 24. Letur-Konirsch H, Guis F, Delanian S: Major uterine restoration by radiation sequelae regression with a combination of pentoxifylline-tocopherol: A phase II study. Fertil Steril 77:1219-1226, 2002 25. Ledee-Bataille N, Olivennes F, Lefaix J-L, et al: Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation program. Hum Reprod 17:1249-1253, 2002 26. Berman B, Duncan M: Pentoxifylline inhibits normal human dermal fibroblast in vitro proliferation, collagen, glycosaminoglycan, and fibronectin production, and increases collagenase activity. J Invest Dermatol 92:605610, 1989 27. Berman B, Duncan M: Pentoxifylline inhibits the proliferation of human fibroblasts derived from keloid, scleroderma and morphoea skin and their production of collagen, glycosaminoglycans and fibronectin. Br J Dermatol 123:339-346, 1990 28. Duncan M, Berger R, Berman B: Pentoxifylline and interferon regulated mechanisms in inhibition of dermal fibroblast collagen synthesis. J Invest Dermatol 100:549, 1993 (abstr) 29. Duncan M, Hasan A, Berman B: Pentoxifylline and interferons decrease type I and III procollagen mRNA levels in dermal fibroblasts: Evidence for mediation by nuclear factor 1 down-regulation. J Invest Dermatol 104:282-286, 1995

S Delanian, R Porcher, S Balla

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