Originally published as JCO Early Release 10.1200/JCO.2005.02.4729 on October 31 2005

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Delanian, S. Articles by Lefaix, J.-L. Search for Related Content PubMed PubMed Citation Articles by Delanian, S. Articles by Lefaix, J.-L. Related Articles Related Editorial

Kinetics of Response to Long-Term Treatment Combining Pentoxifylline and Tocopherol in Patients With Superficial Radiation-Induced Fibrosis

From the Service d'Oncologie-Radiothérapie; Département Biostatistique Informatique Médicale/L'Institut National de la Santé et de la Recherche Médicale U717, Hôpital Saint-Louis, Paris; and Commissariat à l’Energie Atomique, Direction des Sciences du Vivant, and Département de Radiobiologie et de Radipathologie, Fontenay aux Roses, France

Address reprint requests to Sylvie Delanian, MD, PhD, Service d'Oncologie-Radiothérapie, Hôpital Saint-Louis, 1 Ave Claude Vellefaux, 75010 Paris, France; e-mail: sylvie.delanian{at}sls.ap-hop-paris.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Significant regression of radiation (RT) -induced fibrosis (RIF) has been achieved after treatment combining pentoxifylline (PTX) and alpha-tocopherol (vitE). In this study, we focus on the maximum response, how long it takes to achieve response, and changes after treatment discontinuation.

PATIENTS AND METHODS: Measurable superficial RIF was assessed in patients treated by RT for breast cancer in a long-treatment (24 to 48 months) PTX-vitE (LPE) group of 37 patients (47 RIFs) and in a short-treatment (6 to 12 months) PTX-vitE (SPE) group of seven patients (eight RIFs). Between April 1995 and April 2000, women were treated with a daily combination of PTX (800 mg) and VitE (1,000 IU).

RESULTS: Combined PTX-vitE was continuously effective and resulted in exponential RIF surface area regression (–46% for LPE and –68% for SPE at 6 months, –58% for LPE and –69% for SPE at 12 months, –63% for LPE and –62% for SPE at 18 months, and –68% for LPE at 24 and 36 months). The mean estimated maximal treatment effect was 68% RIF surface area regression. The mean time to this effect was 24 months and was shorter (16 months) in more recent RIF (< 6 years since RT) than in older RIF (28 months; P = .0003). Symptom severity (Subjective Objective Medical Management and Analytic Evaluation score) was halved in both groups. After treatment discontinuation, mean RIF surface area at 1 year had increased by +40% in the SPE group (rebound) and +8.5% in the LPE group.

CONCLUSION: Under combined PTX-vitE treatment, RIF regression was exponential, with a two-thirds maximum response after a mean of 2 years. There was a risk of a rebound effect if treatment was too short. Long treatment ( 3 years) is recommended in patients with severe RIF.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Radiation (RT) -induced fibrosis (RIF) constitutes late, local, and unavoidable damage to normal tissue after high-dose RT and is traditionally considered irreversible.^1,2 It is mainly characterized by nonspecific changes in the vascular connective tissues involving excessive extracellular matrix deposition, fibroblast proliferation, and the presence of an inflammatory infiltrate.^3-5

Today, this process is partly reversible thanks to recent progress in understanding the pathophysiology of the lesions RIF causes and the results of recent clinical trials using antioxidant therapy.⁶ In a first report in 1998, we showed a significant reversal of superficial and deep cervicothoracic RIF after 18 months of a treatment combining pentoxifylline (PTX) 800 mg/d and alpha-tocopherol (vitE) 1,000 U/d.⁷ In 1999, a phase II trial used this PTX-vitE combination to treat patients with superficial RIF who had been previously irradiated for head and neck or breast cancer, with a 53% mean RIF surface area regression at 6 months.⁸ Recently, the first randomized trial in established superficial RIF after breast cancer demonstrated that RIF regression rate was 60% after 6 months of combined PTX-vitE therapy, which was significantly better than the rate of 40% observed with double placebo.⁹

However, the maximum response and the time taken to achieve response after PTX-vitE treatment have not yet been determined. To assess the maximal efficacy and the time it takes to achieve maximal efficacy after combined PTX-vitE as an antifibrotic treatment in patients with measurable areas of symptomatic chronic RT damage, we performed a prolonged trial with both short (months) and long (years) treatment durations. The data describe the updated follow-up of patients from prior published studies (phase II and III) with the intention of defining the optimal duration of combined PTX-vitE treatment.^8,9

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Population
Between April 1995 and April 2000, 62 patients presenting with 74 distinct measurable zones of superficial chronic RT damage were treated with combined PTX-vitE. Patients were recruited from various centers by clinical investigators at Saint-Louis Hospital (Paris, France), but patients with nonmeasurable RIF or breast hardness within 6 months of RT completion or who were not interested in the study because the drugs were available immediately were not included. Eighteen patients were excluded from this study because they did not meet the protocol requirements (head/neck RIF, second cancer, patient changed mind, or initial withdrawal because of drug intolerance; Fig 1). Consequently, we had complete, available, and long-term homogeneous data for 44 eligible treated women with 55 gradually worsening RIF zones (Table 1). Informed consent was obtained from all patients before treatment started. The initial study was approved by the Hospital Ethics Committee. Patients' ages ranged from 37 to 82 years (mean ± standard deviation, 59 ± 8 years). All 44 patients were women and had had adjuvant postoperative RT for malignant breast tumor with no evidence of recurrent disease on entering the trial.

View larger version (18K): [in this window] [in a new window]   Fig 1. Trial profile. Among more than 300 heterogeneous patients with chronic radiotherapy damage of various locations treated with pentoxifylline and alpha-tocopherol (PE) in the last 5 years, 62 homogeneous patients with measurable superficial radiation-induced fibrosis (RIF) were selected for this study (deep and/or nonmeasurable RT sequelae were not included here).

Modalities of Combined PTX-vitE Treatment
The drug combination was based on pharmacokinetic data, clinical use, and long-term tolerance in other diseases. Each patient was administered a combination of twice-daily PTX 400 mg (800 mg/d) and vitE 500 U (1,000 U/d). PTX was chosen to avoid severe adverse effects in patients without vascular disease (reduced dosage), and vitE was chosen to supply sufficient antioxidant activity.

Duration of treatment was based on clinical observation of the timing of fibrosis regression: delayed start, from 3 weeks to 6 months, and long-term continuation of response, from several months to years. The seven patients (eight RIF sites) included before 1997 had short PTX-vitE (SPE) treatment (mean, 9 months; range, 6 to 12 months); reasons for SPE were sufficient symptomatic improvement without any guidelines for treatment, intolerance, and lack of desire to continue a long treatment. With increasing experience gained over several years, we treated the subsequent 37 patients (47 RIF sites) until fibrosis regression peaked at a mean of 36 months (range, 24 to 48 months); these patients were considered as having received long PTX-vitE (LPE) treatment (Fig 1). All RIF sites were assessed at 6 and 12 months after stopping the PTX-vitE treatment (off-drug variation).

Outcome Measures
Participants were reviewed by clinical investigators before, during, and after stopping the treatment. Assessment included palpation of the edges of the fibrotic block, with measurements of the length and width of the projected cutaneous surface. One year before treatment and at the inclusion in the trial, clinical assessment showed that RIF was stable (the patients were their own controls). The main end point was the relative regression of the fibrosis surface area every 6 months (during a mean period of 5 years), which was defined as follows: (measurement at x months–measurement at inclusion)/measurement at inclusion (Table 1).

A secondary end point was the Subjective Objective Medical Management and Analytic Evaluation of Injury (SOMA) score, which was assessed every 6 months according to the SOMA system devised in 1995 and modified recently, Cancer Terminology Criteria for Adverse Events, http://ctep.cancer.gov/reporting/ctc.html).^10,11 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 (Table 1).

Results of treatment were evaluated at 6, 12, 18, 24, 36, and 48 months by measuring the percent changes in the surface area and the SOMA score. Patients were used as their own controls (paired data).

RIF
RIF developed in the year after irradiation and gradually worsened. Mean initial RIF parameters in the SPE group and LPE group were as follows: diameter (length + width/2), 4.3 ± 1 and 6.5 ± 3 cm, respectively; and surface area (length x width), 19.2 ± 12 and 48.3 ± 55 cm², respectively (Table 1). Seven patients with chronic RIF had associated symptoms in the extremities, including restricted arm movement, severe arm edema, and symptomatic plexitis. The mean initial SOMA scores in the SPE and LPE groups were 9 ± 3 and 11 ± 3, respectively (Table 1).

Statistical Analysis
Data are presented as numbers and percentages for qualitative variables and as means ± standard deviations for quantitative variables. Comparisons of variables across groups were performed using Fisher's exact test initially and then the Wilcoxon rank sum test.

Change in RIF surface area with treatment was analyzed relative to baseline using nonlinear mixed models.^12,13 Several competing models were consecutively considered and compared using the Bayesian Information Criterion model.¹⁴ This included determination of the random effects and the residual variance correlation structures best modeling the data. Models were fitted using restricted maximum likelihood.¹² However, comparisons of the models involving different fixed effects were based on maximum likelihood estimates because likelihood comparisons between restricted maximum likelihood fits with different fixed effects are not valid.¹³ Specific hypotheses regarding fixed effects were tested using the Wald or likelihood ratio tests. CIs for predicted values were obtained using the parametric bootstrap of estimated models based on 100,000 numerical simulations.¹⁵ Changes in RIF surface area after the end of treatment were analyzed using linear mixed models; therefore, a linearity hypothesis seemed reasonable from the clinical data, and the number of observations per RIF was not sufficient to consider more complex nonlinear models. Model selection, both for fixed and random effects, was performed using the same procedures as described for the analysis of change in RIF surface area with treatment.

All tests were two sided, and P < .05 was considered significant. All analyses were performed using R.1.7.1 software (The R Development Core Team; http://www.r-project.org/foundation/main.html).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Adverse Events
Acute tolerance was satisfactory, and no patient stopped the treatment because of an adverse event. Fourteen (32%) of 44 patients experienced discomfort during the first weeks of treatment as a result of some transient events, including hot flushes, nausea and epigastralgia, asthenia (low blood pressure), headache, and vertigo, but these patients remained in the study after a transient reduction (2 weeks) in PTX dosage (400 mg/d) and after, in some cases, symptomatic treatment with omeprazole or heptaminol. This discomfort did not differ from that observed in the placebo group in our prior randomized study.

Long-term tolerance was excellent. No patient stopped the treatment as a result of adverse effects or death.

Primary Analyses
Combined PTX-vitE was continuously effective over several months and years and resulted in exponential RIF surface area regression.

Surface area regression during PTX-vitE treatment: Observed values. Significant mean RIF regressions of –44% ± 21%, –69% ± 15%, and –69% ± 24% were observed at 3, 6, and 12 months, respectively in the SPE group. In the LPE group, mean regressions were –30% ± 15%, –46% ± 19%, –58% ± 17%, –63% ± 20%, –68% ± 16%, and –68% ± 17% at 3, 6, 12, 18, 24, and 36 months, respectively (Table 2). Detailed results are listed in Table 2 and shown in Figure 2.

View larger version (27K): [in this window] [in a new window]   Fig 2. Relative radiation-induced fibrosis surface area variation during treatment and follow-up: long treatment duration (A) and short treatment duration (B). Some patients experienced a transient failure to respond to pentoxifylline and alpha-tocopherol treatment for several months, which was linked to transient emotional problems.

View larger version (11K): [in this window] [in a new window]   Fig 3. Estimated models: mean relative radiation-induced fibrosis (RIF) surface area variation under pentoxifylline and alpha-tocopherol treatment for the 47 RIFs treated over a long-term period ( 24 months). RT, radiotherapy.

View larger version (36K): [in this window] [in a new window]   Fig 4. Individual relative surface area variation under pentoxifylline and alpha-tocopherol treatment for the 47 radiation-induced fibroses treated over a long-term period: observed values () and model-based predictions (full lines).

After stopping PTX-vitE: Rebound effect. After stopping PTX-vitE treatment, a significant initial increase (P = .037) in RIF surface area was observed (Fig 2, dotted lines). This fibrotic increase was significantly lower and asymptomatic in the LPE group with (8.5%/yr; 95% CI, 1% to16%/yr) compared with the SPE group with (40%/yr; 95% CI, 24% to 56%/yr; P = .0012). However, this follow-up was limited to 2 years after stopping treatment because no extrapolation was possible beyond this time. Three of the seven symptomatic patients with rebound effect in the SPE group were then included in the LPE group 18 to 24 months after stopping PTX-vitE treatment.

Secondary Analyses
All RIF areas responded well to treatment, and symptom severity diminished exponentially by half as assessed by the SOMA score (–54% ± 7% in the SPE group at 6 months and –47% ± 15% in the LPE group at 18 months; Table 3). Mean SOMA scores improved significantly (Table 3), from 10.7 at baseline to 6 at 12 months, 5 at 24 months, and 4.7 at 36 months, and this improvement was similar to the RIF surface area regression, with an average slope of 0.6 (P < .0001). All RIF areas improved rapidly with regard to local pain after withdrawal of analgesic drugs. All RIF areas exhibited various but evident softening of the tissues involved with a regression of fibrosis adhesion to underlying tissues. Telangiectasias were difficult to assess, but their number and density seemed stable. Patients with two RIF zones displayed a proportional mean decrease in both zones.

View larger version (75K): [in this window] [in a new window]   Fig 5. Mammographic macrocalcification inside a small residual palpated radiation-induced fibrosis zone after several months of pentoxifyline and alpha-tocopherol treatment.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

Long-term follow-up of our patients, most of whom were from the previous phase II and III trials, helped us to understand that RIF regression after PTX-vitE treatment is a slow, progressive, and continuous improvement with reproducible results^8,9 that follow an exponential curve [f(t) = a.exp(–bt) – a], with a 68% (range, 64% to 73%) maximum effect obtained in 24 months (range, 16 to 28 months). Model-based predictions fitted the observed values well (Fig 4), with a small CI. This helps clinicians to predict the mean time to RIF maximum response under combined PTX-vitE treatment for recent (< 6 years since RT) and older ( 6 years) RIF.

After a mean of 2 years, the residual RIF was often small. But in patients with RIF located in the breast, the residual palpated RIF surface area was focused on a large 5- to 20-mm macrocalcification, slowly constituted, and without any possible reduction. The observed rebound effect (40%/yr) after stopping treatment too early (6 to 12 months) indicates that longer treatment is necessary to sustain benefit over a long time. We observed a mean 8.5% RIF progression rate in the year after stopping treatment of PTX-vitE after an average of 3 years on treatment, which corresponds to both definitive stable RIF results and progressive RIF results. The follow-up of this study was not long enough to address all the clinical and pathologic issues that were raised.

Clinically, PTX or vitE alone proved unable to reverse human RIF. Nevertheless, they possess all the major properties necessary to make them excellent antifibrotic agents. PTX, which is used clinically to treat vascular diseases, has been reported in vivo to have an anti–tumor necrosis factor alpha effect, increase erythrocyte flexibility, and vasodilate and inhibit inflammatory reactions; in vitro, PTX has been shown to have antioxidant properties and inhibit dermal fibroblast proliferation and matrix production. However, no clinical or histologic change was observed in RIF after 6 months of treatment with PTX alone in our experimental pig study.¹⁹ Clinical reports of PTX as the sole agent in RIF seem to be contradictory.¹ One case report mentioned relieved RIF pain.²⁰ In a recent report, 22 patients with RIF treated with 1,200 mg/d PTX for 8 weeks showed one-third improvement in functional deficits,^21,22 but a rebound effect occurred in some patients after the end of treatment at 16 weeks. An 8-week course of 1,200 mg/d PTX seemed to have a modest effect in 16 patients with severe trismus by increasing dental gap.²³ Finally, in a recent randomized trial, superficial RIF response was identical in the group treated with PTX alone (800 mg/d) compared with the placebo group.⁹ The main functions of vitE are to scavenge the reactive oxygen species generated during oxidative stress not limited in vivo by antioxidant enzymes and to protect cell membranes against lipid peroxidation.^24,25

In a preliminary clinical study in which 700 U/d of vitE as sole agent were administered to 53 patients, the mean linear regression of superficial breast RIF areas was 20% after 4 months.²⁶ However, in the randomized trial, the 6-month RIF response was identical in the group treated with vitE alone (1,000 IU/d) and the placebo group.⁸ In a phase II trial, combined PTX-vitE (PTX 800 mg/d and vitE 1,000 U/d) administered to patients with superficial RIF, who had previously been irradiated for head and neck or breast cancer,⁸ resulted in a mean regression of 53% and 66% in the RIF surface area and 53% and 48% in the SOMA score at 6 and 12 months, respectively, with a continuous therapeutic effect. A randomized trial using the PTX-vitE combination and including the same type of patients confirmed that the 6-month RIF regression was significantly better with PTX-vitE than with double placebo,⁹ but the peak response was not reached. A similar study was conducted in vivo, with a 6-month RIF surface and volume regression of 70% in PTX-vitE–treated pigs compared with pigs treated with PTX alone or placebo.¹⁹ Recent in vitro studies using a PTX-vitE combination in irradiated fibroblasts showed an antioxidant effect by reduction in both immediate and late reactive oxygen species production. However, a decrease in DNA strand breaks measured by the comet assay suggests that this combination could interfere with the DNA repair process.²⁷ Further studies are necessary to understand the immediate and delayed effects of the combined PTX-vitE treatment on irradiated tissues.

Long-term tolerance of combined PTX-vitE in this study was excellent. However, we did not include patients with active cancer because of the high potential of healing we observed with combined PTX-vitE treatment. In particular, interference between vitE and cancer is not always clear. VitE is described as protective against prostate cancer in men,²⁸ whereas some epidemiologic studies of lung cancer prevention have not been conclusive regarding vitE supplementation.²⁹

VitE is usually considered relatively safe.²⁴ It may reduce free radical–induced chromosomal damage by increasing the rate of removal of damaged DNA.³⁰ A recent meta-analysis of various randomized trials in the treatment and prevention of cardiovascular disease found no beneficial or adverse effect of vitE on survival.^31,32 However, another meta-analysis³³ of randomized trials³⁴ that considered the dose-response relationship between vitE supplementation and total mortality showed that high-dose ( 400 U/d) vitE supplements administered for longer than 1 year in chronic cardiovascular disease may increase all-cause mortality. However, this meta-analysis suffers from bias because it excluded trials in which there were fewer than 10 deaths (ie, half of all the randomized trials).³³ Literature reports of nonsignificant increase in mortality associated with vitE often refer to a combination of vitE with beta-carotene, rather than vitE alone. Moreover, some in vitro studies showed pro-oxidant effects at high-doses via low-density lipoproteins.²⁵ This effect has been reported to be inhibited by coantioxidants, such as vitamin C,^35,36 and among the 20,536 high-risk individuals studied, 600 mg of vitE plus 250 mg of vitamin C seemed to be safe.³⁷

RIF is a rare and usually irreversible disease. Previous phase II randomized trials and experimental studies showed that a PTX-vitE combination could significantly reduce chronic RT damage at 6 and 12 months. Better results have been obtained with prolonged treatment; RIF regression was exponential with a two-thirds maximum response after a mean of 2 years. There is a risk of a rebound effect if treatment is too short, and a long treatment (3 years or more) can be recommended in patients with severe RIF.

Present cellular knowledge of this chronic, active fibrosis has enabled us to influence key components of RIF (ie, reactive oxygen species) by using a highly curative treatment mainly involving the antioxidant pathway. These results raise many questions about the precise mechanisms of action of these drugs when used together in long-term treatment. Finally, further large, randomized, clinical trials are necessary to confirm these results and to assess the safety of combined PTX-vitE.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Presented at the 15th Congress of Société Française de Radiothérapie Oncologique, Paris, France, November 3-5, 2004.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Delanian S, Lefaix J-L: The radiation-induced fibro-atrophic process: Therapeutic perspective via the antioxidant pathway. Radiother Oncol 73: 119-131, 2004[CrossRef][Medline]

2. Hill C, Rodemann H, Hendry J, et al: Normal tissue radiobiology: From the laboratory to the clinic. Int J Radiat Oncol Biol Phys 49: 353-365, 2001[CrossRef][Medline]

3. Burger A, Loffler H, Bamberg M, et al: Molecular and cellular basis of radiation fibrosis. Int J Radiat Biol 73: 401-408, 1998[CrossRef][Medline]

4. Denham J, Hauer-Jensen M: The radiotherapeutic injury: A complex wound. Radiother Oncol 63: 129-145, 2002[CrossRef][Medline]

5. 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[CrossRef][Medline]

6. Stone H, Coleman N, Ansher M, et al: Effects of radiation on normal tissue: Consequences and mechanisms. Lancet Oncol 4: 529-536, 2003[CrossRef][Medline]

7. Delanian S: Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol (case report). Br J Radiol 71: 892-894, 1998[Abstract]

8. 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[Abstract/Free Full Text]

9. Delanian S, Porcher R, Balla-Mekias S, et al: Randomized placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol 21: 2545-2550, 2003[Abstract/Free Full Text]

10. Radiotherapy Oncology Group and European Organisation for Research and Treatment of Cancer: Late effects consensus conference: RTOG/EORTC. Radiother Oncol 35: 5-7, 1995[CrossRef][Medline]

11. Stone H, McBride W, Coleman N: Modifying normal tissue damage post-irradiation: Report of a workshop sponsored by the Radiation Research Program, NCI, Bethesda, Maryland, September 6-8, 2000. Radiat Res 157: 204-223, 2002[CrossRef][Medline]

12. Davidian M, Giltinan DM: Nonlinear Models for Repeated Measurement Data: Monographs on Statistics and Applied Probability. Boca Raton, FL, Chapman & Hall, 1995, p 359

13. Pinheiro J, Bates D: Mixed-Effects Models in S and S-Plus. New York, NY, Statistics and Computing Series, Springer-Verlag, 2000

14. Schwartz G: Estimating the dimension of a model. Ann Stat 6: 461-464, 1978

15. Shao J, Tu D: The Jackknife and Bootstrap. New York, NY, Springer Series in Statistics, Springer-Verlag, 1995

16. Yancik R, Ganz P, Varrichio C, et al: Perspectives on comorbidity and cancer in older patients: Approaches to expand the knowledge base. J Clin Oncol 19: 1147-1151, 2001[Abstract/Free Full Text]

17. Delanian S, Baillet F, Huart J, et al: Successful treatment of radiation-induced fibrosis using liposomal Cu/Zn superoxide dismutase: Clinical trial. Radiother Oncol 32: 12-20, 1994[CrossRef][Medline]

18. 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[CrossRef][Medline]

19. Lefaix J-L, Delanian S, Vozenin MC, 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[CrossRef][Medline]

20. Werner-Wasik M, Madoc-Jones H: Trental (pentoxifylline) relieves pain from postradiation fibrosis. Int J Radiat Oncol Biol Phys 25: 757-758, 1993

21. Futran N, Trotti A, Gwede C: Pentoxifylline in the treatment of radiation-related soft tissue injury: Preliminary observations. Laryngoscope 107: 391-395, 1997[CrossRef][Medline]

22. Okunieff P, Augustine E, Hicks JE, et al: Pentoxifylline in the treatment of radiation-induced fibrosis. J Clin Oncol 22: 2207-2213, 2004[Abstract/Free Full Text]

23. Chua D, Lo C, Yuen J, et al: A pilot study of pentoxifylline in the treatment of radiation-induced trismus. Am J Clin Oncol 24: 366-369, 2001[CrossRef][Medline]

24. Bendich A, Machlin L: Safety of oral intake of vitamin E. Am J Clin Nutr 48: 612-619, 1988[Abstract/Free Full Text]

25. Brigelius-Flohe R, Traber M: Vitamin E: Function and metabolism. FASEB J 13: 1145-1155, 1999[Abstract/Free Full Text]

26. Baillet F: Alpha-tocopherol treatment of radiofibrosis post-brachytherapy for breast cancer. Radiother Oncol 43: S3, 1997 (suppl 1, abstr)[CrossRef]

27. Laurent C, Pouget J-P, Voisin P: Modulation of DNA damage by pentoxifylline and alpha-tocopherol in skin fibroblasts exposed to gamma-rays. Radiat Res 164: 63-72, 2005[CrossRef][Medline]

28. Israel K, Sanders B, Kline K: RRR-alpha-tocopheryl succinate inhibits the proliferation of human prostatic tumor cells with defective cell cycle/differentiation pathways. Nutr Cancer 24: 161-169, 1995[Medline]

29. Albanes D, Heinonen O, Taylor P, et al: Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: Effects of baseline characteristics and study compliance. J Natl Cancer Inst 88: 1560-1570, 1996[Abstract/Free Full Text]

30. Claycombe K, Meydani S: Vitamin E and genome stability. Mutat Res 475: 37-44, 2001[Medline]

31. Eidelman R, Hollar D, Hebert P, et al: Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med 164: 1552-1556, 2004[Abstract/Free Full Text]

32. Vivekananthan D, Penn M, Sapp S, et al: Use of antioxidant vitamins for the prevention of cardiovascular disease: Meta-analysis of randomised trials. Lancet 361: 2017-2023, 2003[CrossRef][Medline]

33. Miller E, Pastor-Bariuso R, Dalal D, et al: Meta-analysis: High dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142: 37-46, 2005[Abstract/Free Full Text]

34. Lonn E, Bosch J, Yusuf S, et al: Effects of long term vitamin E supplementation on cardiovascular events and cancer: A randomized controlled trial. JAMA 293: 1338-1347, 2005[Abstract/Free Full Text]

35. Bowry V, Stocker R: Tocopherol-mediated peroxidation: The prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J Am Chem Soc 115: 6029-6044, 1993[CrossRef]

36. Bowry V, Mohr D, Cleary J, et al: Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein. J Bio Chem 270: 5756-5763, 1995[Abstract/Free Full Text]

37. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 360: 23-33, 2002[CrossRef][Medline]

Submitted April 25, 2005; accepted June 27, 2005.

Related Editorial

• The Irreversibility of Radiation-Induced Fibrosis: Fact or Folklore?
  Mitchell S. Anscher
  JCO 2005 23: 8551-8552 [Full Text]

This article has been cited by other articles:

				C. Bourgier, M.-C. Vozenin-Brotons, and R. Arriagada Enhanced Local Control by Radiation Boost in Breast Cancer: Back Side of the Coin? J. Clin. Oncol., December 20, 2007; 25(36): 5841 - 5843. [Full Text] [PDF]

				V. Haydont, C. Bourgier, M. Pocard, A. Lusinchi, J. Aigueperse, D. Mathe, J. Bourhis, and M.-C. Vozenin-Brotons Pravastatin Inhibits the Rho/CCN2/Extracellular Matrix Cascade in Human Fibrosis Explants and Improves Radiation-Induced Intestinal Fibrosis in Rats Clin. Cancer Res., September 15, 2007; 13(18): 5331 - 5340. [Abstract] [Full Text] [PDF]

				R. W. Moss Do Antioxidants Interfere With Radiation Therapy for Cancer? Integr Cancer Ther, September 1, 2007; 6(3): 281 - 292. [Abstract] [PDF]

				V Haydont, C Bourgier, and M-C Vozenin-Brotons Rho/ROCK pathway as a molecular target for modulation of intestinal radiation-induced toxicity Br. J. Radiol., September 1, 2007; 80(Special_Issue_1): S32 - S40. [Abstract] [Full Text] [PDF]

				M. S. Anscher The Irreversibility of Radiation-Induced Fibrosis: Fact or Folklore? J. Clin. Oncol., December 1, 2005; 23(34): 8551 - 8552. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Delanian, S. Articles by Lefaix, J.-L. Search for Related Content PubMed PubMed Citation Articles by Delanian, S. Articles by Lefaix, J.-L. Related Articles Related Editorial