Kinetics of Response to Long-Term Treatment Combining Pentoxifylline and Tocopherol in Patients With Superficial Radiation-Induced Fibrosis
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▲還散笫雖悝◎
the Service d'Oncologie-Radioth谷rapie
D谷partement Biostatistique Informatique M谷dicale/L'Institut National de la Sant谷 et de la Recherche M谷dicale U717, H?pital Saint-Louis, Paris
Commissariat 角 l＊Energie Atomique, Direction des Sciences du Vivant, and D谷partement de Radiobiologie et de Radipathologie, Fontenay aux Roses, France
ABSTRACT
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 (每46% for LPE and 每68% for SPE at 6 months, 每58% for LPE and 每69% for SPE at 12 months, 每63% for LPE and 每62% for SPE at 18 months, and 每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
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
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.
RT Damage
RIF was caused by standard RT with 1.8 to 2.5 Gy per fraction, 4 to 5 days per week. The total doses prescribed ranged from 45 to 65 Gy. RIF correlated with excessive local RT doses resulting from overlapping at field junctions (the total dose received locally exceeded 90 Gy), large brachytherapy, or personal sensitivity factors. The 55 RIF areas were a result of breast cancer RT after conservative surgery, such as lumpectomy and axillary dissection; 18% of the patients also received chemotherapy. Twenty-six RIF areas (47%) were located inside the breast in a region previously treated by lumpectomy, external-beam RT, and interstitial brachytherapy boost. Twenty-nine RIF areas (53%) were located close to the breast in superficial tissue on the mammary chain in the chest wall or outside surgically removed areas; these RIFs occurred after external-beam RT alone but resulted from overlapping at field junctions. Eleven patients developed RIF in two parts of the irradiated volume.
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每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
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 每44% ㊣ 21%, 每69% ㊣ 15%, and 每69% ㊣ 24% were observed at 3, 6, and 12 months, respectively in the SPE group. In the LPE group, mean regressions were 每30% ㊣ 15%, 每46% ㊣ 19%, 每58% ㊣ 17%, 每63% ㊣ 20%, 每68% ㊣ 16%, and 每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.
Modeling. From the observed shape of the relative RIF regression under treatment in the LPE group (Fig 3), several models were postulated, and the best representative model of the time-course of regression was found to be of the following exponential form: f(t) = a.exp(每bt) 每 a, where t represents the time from treatment onset in months, and a and b correspond to the maximal surface area regression and the kinetics of response, respectively.
Model-based predictions fitted the observed values quite well for each individual patient RIF regression, as illustrated in Figure 4. This model showed significant RIF regression (P < .0001), with the maximal effect of treatment (a) corresponding to a mean of 68% (95% CI, 64% to 73%) RIF surface area regression. No variable was found to modify this treatment effect significantly. In contrast, the mean time to this effect was significantly shorter with recent RIF (< 6 years since RT) than older RIF (P = .0003).
RIF latency period. As shown previously, the time to maximum RIF regression was shorter in recent (< 6 years since RT) RIF than in older (> 6 years since RT) RIF (16 months; 95% CI, 12 to 19 months v 28 months; 95% CI, 23 to 33 months, respectively). For recent versus older RIF, the observed mean RIF regression rates were 55% v 38% at 6 months, 64% v 54% at 12 months, 68% v 63% at 18 months, 68% v 66% at 24 months, and 70% v 68% at 36 months, respectively.
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 (每54% ㊣ 7% in the SPE group at 6 months and 每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.
In the LPE group, after achievement of two-thirds maximal RIF surface area regression in 24 months, residual RIF (mean, 3.6 ㊣ 1.8 cm at 24 and 36 months) was often stable and approximately one third of the initial RIF surface area (mean, 6.7 ㊣ 3.4 cm at baseline). Regular x-rays and mammographic assessment showed a gradual constitution of a 5- to 20-mm macrocalcification inside the residual RIF volume in 13 (62%) of 21 breast RIF zones in the LPE group. This macrocalcification limited subsequent RIF reduction (Fig 5).
DISCUSSION
In recent decades, better pathophysiologic understanding of the fibrotic process has made it possible to regulate several biologic functions and to reduce fibrosis.1 RIF management is usually based on restriction of aggravating factors, such as stopping comorbidity factors (new trauma or sepsis) and controlling inflammation with corticosteroids.16 Various drugs have been reported to be suitable for clinical use in fibrotic disease, but to date, we have no valid reproducible clinical experience. The first positive clinical and experimental trials in reducing superficial RIF used liposomal superoxide dismutase,17,18 which is not yet available. A different and more recent approach via the antioxidant pathway uses a combination of PTX-vitE.1
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 results8,9 that follow an exponential curve [f(t) = a.exp(每bt) 每 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每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每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每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
The authors indicated no potential conflicts of interest.
NOTES
Presented at the 15th Congress of Soci谷t谷 Fran?aise de Radioth谷rapie Oncologique, Paris, France, November 3-5, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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D谷partement Biostatistique Informatique M谷dicale/L'Institut National de la Sant谷 et de la Recherche M谷dicale U717, H?pital Saint-Louis, Paris
Commissariat 角 l＊Energie Atomique, Direction des Sciences du Vivant, and D谷partement de Radiobiologie et de Radipathologie, Fontenay aux Roses, France
ABSTRACT
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 (每46% for LPE and 每68% for SPE at 6 months, 每58% for LPE and 每69% for SPE at 12 months, 每63% for LPE and 每62% for SPE at 18 months, and 每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
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
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.
RT Damage
RIF was caused by standard RT with 1.8 to 2.5 Gy per fraction, 4 to 5 days per week. The total doses prescribed ranged from 45 to 65 Gy. RIF correlated with excessive local RT doses resulting from overlapping at field junctions (the total dose received locally exceeded 90 Gy), large brachytherapy, or personal sensitivity factors. The 55 RIF areas were a result of breast cancer RT after conservative surgery, such as lumpectomy and axillary dissection; 18% of the patients also received chemotherapy. Twenty-six RIF areas (47%) were located inside the breast in a region previously treated by lumpectomy, external-beam RT, and interstitial brachytherapy boost. Twenty-nine RIF areas (53%) were located close to the breast in superficial tissue on the mammary chain in the chest wall or outside surgically removed areas; these RIFs occurred after external-beam RT alone but resulted from overlapping at field junctions. Eleven patients developed RIF in two parts of the irradiated volume.
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每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
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 每44% ㊣ 21%, 每69% ㊣ 15%, and 每69% ㊣ 24% were observed at 3, 6, and 12 months, respectively in the SPE group. In the LPE group, mean regressions were 每30% ㊣ 15%, 每46% ㊣ 19%, 每58% ㊣ 17%, 每63% ㊣ 20%, 每68% ㊣ 16%, and 每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.
Modeling. From the observed shape of the relative RIF regression under treatment in the LPE group (Fig 3), several models were postulated, and the best representative model of the time-course of regression was found to be of the following exponential form: f(t) = a.exp(每bt) 每 a, where t represents the time from treatment onset in months, and a and b correspond to the maximal surface area regression and the kinetics of response, respectively.
Model-based predictions fitted the observed values quite well for each individual patient RIF regression, as illustrated in Figure 4. This model showed significant RIF regression (P < .0001), with the maximal effect of treatment (a) corresponding to a mean of 68% (95% CI, 64% to 73%) RIF surface area regression. No variable was found to modify this treatment effect significantly. In contrast, the mean time to this effect was significantly shorter with recent RIF (< 6 years since RT) than older RIF (P = .0003).
RIF latency period. As shown previously, the time to maximum RIF regression was shorter in recent (< 6 years since RT) RIF than in older (> 6 years since RT) RIF (16 months; 95% CI, 12 to 19 months v 28 months; 95% CI, 23 to 33 months, respectively). For recent versus older RIF, the observed mean RIF regression rates were 55% v 38% at 6 months, 64% v 54% at 12 months, 68% v 63% at 18 months, 68% v 66% at 24 months, and 70% v 68% at 36 months, respectively.
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 (每54% ㊣ 7% in the SPE group at 6 months and 每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.
In the LPE group, after achievement of two-thirds maximal RIF surface area regression in 24 months, residual RIF (mean, 3.6 ㊣ 1.8 cm at 24 and 36 months) was often stable and approximately one third of the initial RIF surface area (mean, 6.7 ㊣ 3.4 cm at baseline). Regular x-rays and mammographic assessment showed a gradual constitution of a 5- to 20-mm macrocalcification inside the residual RIF volume in 13 (62%) of 21 breast RIF zones in the LPE group. This macrocalcification limited subsequent RIF reduction (Fig 5).
DISCUSSION
In recent decades, better pathophysiologic understanding of the fibrotic process has made it possible to regulate several biologic functions and to reduce fibrosis.1 RIF management is usually based on restriction of aggravating factors, such as stopping comorbidity factors (new trauma or sepsis) and controlling inflammation with corticosteroids.16 Various drugs have been reported to be suitable for clinical use in fibrotic disease, but to date, we have no valid reproducible clinical experience. The first positive clinical and experimental trials in reducing superficial RIF used liposomal superoxide dismutase,17,18 which is not yet available. A different and more recent approach via the antioxidant pathway uses a combination of PTX-vitE.1
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 results8,9 that follow an exponential curve [f(t) = a.exp(每bt) 每 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每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每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每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
The authors indicated no potential conflicts of interest.
NOTES
Presented at the 15th Congress of Soci谷t谷 Fran?aise de Radioth谷rapie Oncologique, Paris, France, November 3-5, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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