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Pentoxifylline in the Treatment of Radiation-Induced Fibrosis

From the Department of Radiation Oncology, James P. Wilmot Cancer Center at the University of Rochester Medical Center, Rochester, NY; the Rehabilitation Medicine Department, Clinical Center, National Institutes of Health, and the Radiation Oncology Branch, National Cancer Institute, Bethesda; Maryland Regional Cancer Care-Waldorf, Waldorf, MD.

Address reprint requests to Paul Okunieff, MD, University of Rochester School of Medicine, 601 Elmwood Ave, Box 647, Rochester, NY 14642; e-mail: Paul_Okunieff{at}urmc.rochester.edu

	ABSTRACT

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PURPOSE: Fibrotic sequelae remain the most important dose-limiting toxicity of radiation therapy to soft tissue. Functionally, this is reflected in loss of range of motion and muscle strength and the development of limb edema and pain. Tumor necrosis factor alpha and fibroblast growth factor 2 (FGF2), which are abnormally elevated in irradiated tissues, may mediate radiation fibrovascular injury.

PATIENTS AND METHODS: In an open label drug trial, we studied the effects of pentoxifylline (400 mg orally tid for 8 weeks) on 30 patients who displayed late, radiation-induced fibrosis at 1 to 29 years posttreatment (40 to 84 Gy). The primary outcome measurement was change in physical impairments thought to be secondary to radiation, including active and passive range of motion (AROM and PROM), muscle strength, limb edema, and pain. Plasma levels of cytokines (tumor necrosis factor alpha and FGF2) also were measured. Twenty-seven patients completed baseline and 8-week assessments, and 24 patients completed baseline, 8-week, and 16-week assessments.

RESULTS: After 8 weeks of pentoxifylline intervention, 20 of 23 patients with impaired AROM and 19 of 22 with impaired PROM improved; 11 of 19 patients with muscle weakness showed improved motor strength; five of seven patients with edema had decreased limb girth; and nine of 20 patients had decreased pain. Pretreatment FGF2 levels dropped from an average of 44.9 pg/mL to 24.0 pg/mL after 8 weeks of treatment.

CONCLUSION: Patients receiving pentoxifylline demonstrated improved AROM, PROM, and muscle strength and decreased limb edema and pain. Reversal of these delayed radiation effects was associated with a decrease in circulating FGF2.

	INTRODUCTION

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The severity of radiation fibrosis is dependent on the total radiation dose, fraction size, and volume treated. Classic theories of radiation effects not only indicate DNA double-strand breaks as the early lethal event, but also assert that tissues that are prone to late radiation fibrosis (eg, skin and soft tissue) have slow reproductive rates that delay depopulating cell death and obligate late reactions.¹ However, few tissues have cell cycle rates measured in years, and most of the cells involved in late effects (eg, capillary endothelium, cutaneous epithelium, fibroblasts) have turnover rates measured in days or weeks. Therefore, late radiation toxicity, commonly seen a decade after irradiation, is not likely to be solely as a result of delayed cell death and slow cell turnover.

It has long been observed that inflammation worsens delayed radiation fibrosis. Inflammation is mediated largely by proinflammatory cytokines, including tumor necrosis factor alpha (TNF). Administration of TNF has been shown to cause neovascular necrosis at low doses and mature vascular necrosis at higher doses; necrosis has a demonstrated association with the later development of fibrosis.² In addition, TNF expression has been shown to be involved in the recruitment and activation of macrophages into injured tissue, which leads to the release of downstream fibrogenic cytokines. These cytokines include fibroblast growth factor 2 (FGF2) and transforming growth factor beta 1 (TGFß1).^3,4 FGF2 is chemotactic and mitotic for fibroblasts,⁵ whereas TGFß1 stimulates fibroblast proliferation and premature end-differentiation, leading to excessive extracellular matrix glycoprotein production.^6-10

These observations have led to speculation that fibrosis after irradiation may be due to the aberrant production of proinflammatory and fibrogenic cytokines,^3,4,11-13 and that treatment directed at the reduction of cytokine release might reduce the clinical sequelae of radiation fibrosis. Since radiation-induced fibrosis is often progressive, does not spontaneously regress, and is difficult to manage, the economic and personal costs of this disease motivate the search for preventive measures. Pentoxifylline is known to suppress the synthesis of TNF,¹⁴ thus we explored the role that pentoxifylline may play as an anticytokine therapy in the alleviation of late-radiation fibrovascular toxicity.

	PATIENTS AND METHODS

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Patient Eligibility Criteria and Profile
Patients were eligible for the study if they had regional advanced postirradiation fibrosis of the neck, chest wall, pelvis, or extremities causing measurable impairments, including decreased range of motion, weakness, limb edema, and pain requiring narcotics. Table 1 presents the distribution of patient injury sites. The fibrosis and related disability had to be documented in the patient's clinical chart in the postradiation period of follow-up. Patients were excluded if their fibrosis and related disability predated completion of their radiation therapy (present before or during radiation treatment). Patients with a history of surgical treatment and chemotherapy were eligible, as long as surgery or chemotherapy could not have caused any of their measurable functional deficits. Other exclusion criteria included: a previously demonstrated intolerance to pentoxifylline or other xanthines; pentoxifylline use within 3 months before study; a Karnofsky performance status of < 70 because of reasons unrelated to postirradiation fibrosis; recurrent, metastatic cancer, or concurrent second cancer; age < 18 years; and current pregnancy or lactation. The combination of high-dose vitamin E with pentoxifylline has been used in other studies.¹⁵ Vitamin E was neither prescribed nor limited in the present study.

Treatment Schedule
After the initial assessment, patients were treated with pentoxifylline (Trental, Hoechst Marion Roussel, Kansas City, MO), 400 mg controlled release tablets given orally tid for 8 weeks, followed by 8 weeks off-drug. Patients underwent a second assessment after 8 weeks (while still on the drug), and a third assessment at 16 weeks (after being off-drug for 8 weeks). Patients were evaluated for toxicity to digestive system and CNS, based on National Cancer Institute Common Toxicity Criteria (Version 1). The first patient report of grade 1 side effects that persisted for at least 1 week triggered a dose reduction to 400 mg orally bid. Upon first patient report of side effects following the dose reduction, the drug was discontinued. Patient compliance to the administered drug dosage was assessed by pill count.

Primary Outcome Measurements
General scoring. Standard measures of physical impairments included: 1) active and passive range of motion (ROM) of the upper and lower extremities, cervical, thoracic, and lumbar spine; 2) manual muscle testing (MMT) for strength/weakness; 3) circumferential girth measurements for limb edema; and 4) visual analog for pain. All impairments were rated on a 4-point severity scale (normal = 4; mild = 3; moderate = 2; severe = 1); the criterion for improvement of ROM, MMT, and edema was a deficit decrease by one level (eg, severe to moderate, moderate to mild, or mild to normal). Likewise, the criterion for pain improvement was pain diminution by one level. Net improvement of an entire evaluation area was considered the more strict criterion for improvement and was therefore used for the final analysis.

Range of motion. Both passive and active ROM of the involved and uninvolved extremities were measured by goniometry.¹⁶ Active ROM of the cervical, thoracic, and lumbar spine was measured with an inclinometer. Values for full ROM were obtained from the American Academy of Orthopedic Surgery.¹⁷ Rotation was assessed by a modified NIH scale. Function was expressed using the American Medical Association scale for regional impairment. There were a total of 65 separate ROM measurements for each subject: 40 for the extremities and 25 for the cervical, thoracic, and lumbar spine.

As an example of scoring, the specific grading scale for ROM for shoulder flexion was: 0% to 5% deficit from full ROM = normal; 6% to 15% = mild; 16% to 40% = moderate; 40% = severe. If, at baseline, a subject's involved shoulder flexion measured 151 degrees of a full 180 degrees ROM (graded as a 16% deficit: moderate), then that subject's ROM deficit was rated as moderate on the 4-point severity scale (score of 2 on the scale of severity). If, after 8 weeks of receiving pentoxifylline, that subject's involved shoulder flexion ROM improved to 175 degrees (graded as a 3% deficit: normal), then that subject's ROM deficit would be rated as normal (score of 4 on the scale of severity). Such a patient would show a net improvement of two levels of severity.

Muscle motor strength. Measurement of muscle motor strength of the neck and upper and lower extremities used an adapted standard MMT technique.¹⁸ This technique grades muscle strength on a 5-point scale: 5 = normal strength; 4 = good; 3 = fair; 2 = poor; 1 = trace muscle contraction; 0 = no strength). For use in this study, the MMT results were converted to a 4-point severity scale for strength: normal (4) = grade 5 MMT; mild (3) = grade 4 MMT; moderate (2) = grade 2 to 3 MMT; severe (1) = grade 0 to 1 MMT.

Edema. Assessment of each subject's edema was dictated by the location of their initial radiation treatment field (either the upper or the lower extremities): extremities were assessed with a tape measure (cm) by girth measurements at three predetermined points on each extremity. A 4-point scale from normal to severe was used to determine degree of edema based on girth difference between affected and unaffected sides¹⁹: a difference of 0 to 2.9 cm = normal; 3 to 3.9 cm = mild; 4 to 5.9 cm = moderate; 6 cm = severe.

Pain. Pain intensity was measured by the patient using the Visual Pain Analog scale (0 [no pain] to 10 [intolerable pain]); the patient rated the perceived pain level by making a mark on a 10 cm line.²⁰ The severity scale for pain was rated on the 4-point system: 0 to 1 cm = normal; 2 to 4 cm = mild; 5 to 7 cm = moderate; 8 to 10 cm = severe pain.

Cytokine Measurements
Blood samples were kept on ice and processed within 3 hours. Processing consisted of centrifugation, plasma removal, division into aliquots, and storing at –20°C. Quantitative cytokine assay of TNF and FGF2 plasma levels were performed using enzyme-linked immunosorbent assay kits (R & D Systems Inc, Minneapolis, MN), following protocol recommendations of the manufacturer.

Data Analysis
Objective clinical success was considered met if 25% of patients improved 1 rank on any of the 4-point severity scales (normal, mild, moderate, severe), or if 10% of patients improved two levels on the 4-point severity scale. Cytokine levels were correlated with clinical outcome using a paired t-test analysis.

	RESULTS

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Out of the initially registered 30 patients, 27 patients completed the 8-week evaluation and were assessable. One patient discontinued drug because of persistent moderate nausea and was taken off-study; two patients declined further study participation during the first 8 weeks. Twenty-four of the 27 assessable patients returned for their 16-week evaluation and were assessable for status change off-drug. The remaining three patients declined to discontinue the drug, and were thus off-study. Pentoxifylline was generally well tolerated with mild or moderate (grade 1 or 2) gastrointestinal or CNS toxicities. One patient had severe (grade 3) nausea, and was the only patient with any toxicity greater than level 2. Seven patients had mild or moderate nausea, three patients had dyspepsia, and one patient complained of anorexia. Two patients experienced jitteriness, six experienced insomnia, three reported mild headaches, one reported migraines, and two patients complained of dizziness.

Twenty-two patients responded to pentoxifylline with improvement of at least one level on a 4-point severity scale in at least one evaluation area. Of 23 patients who had an initial deficit in active range of motion (AROM), 20 improved (Fig 1), while two patients worsened. Nineteen of 22 patients had improved passive range of motion (PROM), while two worsened. Eleven of 19 patients with measurable weakness had improved motor strength, while one worsened. Five of seven patients with initial edema improved, while two worsened. Nine of 20 patients with initial pain improved, while two worsened. Thirteen patients had dramatic ( 2 of 4 levels) improvement in at least one ROM deficit, and two patients had complete resolution of their pain. No patients worsened more than one level. As shown in Figure 2, when all patient data for the 8-week time-point were combined, there was a total of 346 measured deficits for AROM; 107 of these 346 deficits improved (31%). In addition, of 167 measured PROM deficits, 57 improved (34%), and of 88 measured MMT (strength) deficits, 17 improved (19%). The patient physical impairment data yielded few discernable patterns—no particular sites were more responsive to treatment than others. Furthermore, response did not differ depending on years postradiation or the dose.

View larger version (22K): [in this window] [in a new window]   Fig 1. The total number of patients with initial deficit is represented by the entire bar length, and shaded areas include: gray, improvement after 8 weeks of pentoxifylline (PTX) treatment; black, net improvement at 16 weeks, after 8 weeks of PTX treatment followed by 8 weeks off-drug.

View larger version (16K): [in this window] [in a new window]   Fig 2. Of a total of 346 active range of motion (ROM) deficits, 107 (31%) improved, 225 (65%) were unchanged, and 14 (4%) worsened. Of a total of 167 measured passive range of motion deficits, 57 (34%) improved, 103 (62%) were unchanged, and seven (4%) worsened.

Analysis of the plasma cytokine levels of TNF and FGF2 demonstrated large variability between patients. Complete data on TNF plasma levels for the pretreatment, 8-week, and 16-week time-points were available for 16 of 27 patients, and complete data on FGF2 plasma levels for the pretreatment, 8-week, and 16-week time-points were available for 20 of 24 patients. Mean TNF plasma levels (pg/mL ± 1 standard deviation) were 1.95 ± 6.73 pretreatment, 0.13 ± 0.31 at week 8, and 0.20 ± 0.34 at week 16. Normal controls rarely have detectable levels of circulating TNF. Mean FGF2 plasma levels (pg/mL) were 44.9 ± 84.9 pretreatment, 24.0 ± 48.7 at week 8, and 24.2 ± 43.5 at week 16. Normal controls rarely have circulating FGF2 levels greater than 15 pg/mL. Pentoxifylline caused FGF2 levels to decrease in 15 patients, but failed to decrease circulating FGF2 levels in five patients (Fig 3). Using a paired t-test to analyze a log distribution of the data, we found these data to be statistically significant (P = .04). Among the five patients who had no decrease in circulating FGF2 levels, all five improved at least one level in an area of impairment, including two with pain, two with weakness, and four with ROM deficits. In addition, all patients whose circulating FGF2 levels decreased from high to normal also experienced net improvement of at least one impairment.

View larger version (20K): [in this window] [in a new window]   Fig 3. Scatterplot diagram of plasma levels of fibroblast growth factor 2 (FGF2; pg/ml). Each line represents one patient. For most patients, FGF2 levels normalized or became undetectable after 8 weeks on pentoxifylline (PTX); however, levels rose again after discontinuation of the drug (A). PTX failed to reduce FGF2 levels in five patients (B).

	DISCUSSION

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Since pentoxifylline may alter late radiation injury by several mechanisms, we are unable to conclude that the clinical improvements in radiation-induced fibrosis demonstrated in this study were as a result of the anticytokine properties of pentoxifylline. Although pentoxifylline has previously been shown to decrease TNF levels in peripheral monocytes at the dose used in this study,²¹ the pretreatment circulating plasma levels of TNF in our study participants were not significantly elevated, so that any decrease was difficult to assess. However, it also must be noted that circulating levels of TNF may not reflect tissue levels, and prior reports also have demonstrated that circulating TNF levels might only be detected in peripheral monocytes, perhaps because of short TNF plasma half-life (approximately 6 minutes) and soluble TNF receptors that bind circulating TNF.²¹

The most important pentoxifylline mechanism for altering radiation damage may be its ability to increase locoregional blood flow. Pentoxifylline improves blood flow by a multi-tiered process. Firstly, it inhibits cAMP phosphodiesterase and thereby increases cAMP and ATP in RBCs, improving their deformability. Pentoxifylline also can promote streamlined blood flow by inhibiting ICAM expression, minimizing leukocyte adherence to endothelial cells, and increasing prostacycline production, inhibiting platelet aggregation. By increasing prostacycline levels and decreasing thromboxane effect, pentoxifylline dilates capillaries. Finally, it decreases plasma fibrinogen concentrations and increases fibrinolytic activity. Each of these effects alone could improve vascular blood flow. In concert, these effects decrease both whole blood viscosity, and systemic vascular resistance. The alleviation of tissue hypoxia in turn may reduce angiogenic stimuli and thus could account for the reduced FGF2 level.

Another mechanism by which pentoxifylline may alter late radiation injury is through the inhibition of Interleukin-1ß (IL-1ß) and platelet derived growth factor (PDGF) activity. In preclinical studies, pentoxifylline inhibited serum- and IL-1ß-driven fibroblast proliferation in vitro, as well as fibroblast collagen, glycosaminoglycan, and fibronectin production, while it enhanced collagenase activity.²² IL-1ß causes fibroblast proliferation by inducing PDGF-AA synthesis and secretion,²³ and pentoxifylline may act as a reversible, competitive antagonist for the PDGF receptor.²⁴ IL-1 is known to promote pulmonary radiation fibrosis.^25-28 Pentoxifylline has been shown to inhibit PDGF-driven fibroblast proliferation in vitro.²⁴ In animal studies, pentoxifylline lowered liver collagen concentration in a pig model for liver cirrhosis,²⁴ prevented TNF induced lung injury in guinea pigs,²⁹ and diminished severity of late radiation injury in mouse hind limbs.³⁰

Two independent abstract reports have been published on pentoxifylline for the treatment of radiation-induced soft tissue fibrosis. In one report,³¹ six patients with soft tissue fibrosis were treated with oral pentoxifylline 400 mg tid for 3 to 8 months duration. Four of six patients showed clinical improvement and the injury completely resolved in one patient. Pentoxifylline has also been used to treat radiation-induced soft tissue necrosis. In 1990, Dion et al³² showed improved healing of chronic radiation-induced ulcers and necrosis in 12 patients taking oral pentoxifylline 400 mg tid for 6 months.

Randomized clinical trials of pentoxifylline for bone marrow transplant-induced toxicity have shown equivocal results. Bianco et al,³³ in their initial phase I-II trial in 30 consecutive bone marrow transplant patients, did show that pentoxifylline (1,200 to 2,000 mg/d) reduced transplant-related toxicities. In their follow-up placebo controlled trial of 88 randomized allogeneic bone marrow transplant patients, pentoxifylline had no significant effect on graft-versus-host disease (GVHD) incidence, veno-occlusive liver disease, infection rate, oxygen need, posttransplant survival, or duration of hospital stay.³⁴ However, the administered pentoxifylline dose was higher in the randomized study (600 mg orally qid) and was poorly tolerated, causing significantly more vomiting than the placebo, which could have resulted in incomplete pentoxifylline dosing. Further, subsequent vomiting-induced dehydration could have worsened transplant-related toxicities. A second prospective randomized trial of 140 patients failed to show prophylactic effect of a more moderate pentoxifylline dose (1,600 mg/d) in transplant-related toxicities.³⁵ There were no observed differences in incidence of severe mucositis, GVHD incidence, hematologic toxicity, transfusion requirements, fever duration, or hepatic toxicity. Most transplant-related morbidity was due to acute infection or inflammation. The transplant studies differ substantially from ours in that there is no opportunity for GVHD and any autoimmune toxicity is minor. Perhaps, more importantly, radiation-induced fibrosis occurs months and years after irradiation, making it a late fibrovascular phenomenon.

Any improvement in the clinical manifestations of established radiation-induced fibrosis is propitious for it indicates that fibrosis may be alterable and that postirradiation intervention may be effective. In the present study,^36,37 85% of patients had decreased impairment and improved function. These preliminary results with pentoxifylline are encouraging, and they indicate that postirradiation cytokine cascade intervention may alleviate or even reverse some late effects of radiation. Both the positive patient result and the theoretical shortcomings of the present study necessitate a larger study—such a study is currently in development and will feature serial cytokine measurements and a blinded, placebo-controlled group.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicate no potential conflicts of interest.

	NOTES

 
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

 
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Submitted September 22, 2003; accepted March 15, 2004.

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