Pentoxyphylline (Trental) is a member of the methylxanthine class of drugs as are caffeine and theophylline.  Pentoxyphylline is able to increase the flexibility of red blood cells, reduce blood viscosity, and increase the blood’s ability to break down blood clots. The overall effect is to make blood more liquid and to enable the red blood cells to travel deeper into tissues than they would normally be able to. This enables better oxygen delivery to tissues and improved microcirculation.

The usual dosage of Trental in controlled-release tablets is one 400-milligram tablet 3 times a day with meals. While the effect of Trental may be seen within 2 to 4 weeks, it is recommended that treatment be continued for at least 8 weeks.    See studies below

Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial.

Delanian  Head Neck. 2005 Feb;27(2):114-23.

 Paris, France.

Osteoradionecrosis (ORN) is a nonhealing wound of the bone that is difficult to manage. Is a treatment combining pentoxifylline (PTX) and tocopherol (vitamin E) boosted by clodronate effective in reversing this fibronecrotic process? Eighteen consecutive patients previously irradiated for head and neck cancer had exteriorized mandible ORN. Length of exposed bone (L) was 13.4 +/- 8 mm, and the mean subjective objective medical management and analytic evaluation of injury (SOMA) score was 12.6 +/- 4.9. Between June 1995 and January 2002, all 18 were given a daily oral combination of 800 mg of PTX and 1000 IU of vitamin E for 6 to 24 months. In addition, the last eight patients who were the worst cases were given 1600 mg/day clodronate 5 days a week. RESULTS: The treatment was well tolerated. All patients improved at 6 months, with 84% mean L and 67% mean SOMA score reductions. Sixteen (89%) of 18 patients achieved complete recovery, 14 in 5 +/- 2.6 months. The remaining two patients exhibited a 75% response at 6 months. CONCLUSION: PTX-vitamin E boosted by clodronate is an effective treatment of mandibular ORN that induces mucosal and bone healing in a median period of 6 months.

Pentoxifylline in the treatment of radiation-related soft tissue injury: preliminary observations.

Futran ND, Trotti A, Laryngoscope. 1997 Mar;107(3):391-5.

Division of Otolaryngology-Head and Neck Surgery, University of South Florida, Tampa, U.S.A.

Soft tissue or mucosal injuries following radiotherapy of head and neck cancer include ulceration (necrosis), fibrosis, pain, and atrophy. Current management includes analgesics, wound debridement, antibiotics, and physical therapy depending on the type of injury. Pentoxifylline is a methylxanthine derivative that produces dose-related hemorrheologic effects, lower blood viscosity, improved erythrocyte flexibility, and increased tissue oxygen levels. Twenty-six patients with late radiation complications (occurring more than two months after x-ray therapy) were given treatment with oral pentoxifylline: 15 for soft tissue necrosis (STN), six for fibrosis, and five for mucosal pain. Nine of 12 patients with STN completely healed. In all three failures osteoradionecrosis developed. Mucosal pain resolved in all five patients. Fibrosis improved in 67% of those patients. Pentoxifylline appears to accelerate healing of STN and reverse some late radiation injuries. This is the first series to our knowledge that documents activity of this agent in moderate radiotherapy complications such as fibrosis, pain, or mucosal fragility.

Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer: a double-blind randomized trial.

Ozturk Int J Radiat Oncol Biol Phys. 2004 Jan 1;58(1):213-9.

 Gazi University Medical Faculty, Ankara, Turkey. b

Pentoxifylline (Ptx) is thought to be helpful in preventing radiotoxicity by inhibiting platelet aggregation and tumor necrosis factor. We assessed whether prophylactic use of Ptx could prevent early and late normal lung tissue damage due to radiotherapy in a double-blind, randomized trial. METHODS AND MATERIALS: A total of 40 patients with lung or breast cancer were randomized to receive Ptx (400 mg) or a placebo, 3 times daily, during the entire period of radiotherapy. We used the late effects normal tissue-subjective, objective, management, and analytic (LENT-SOMA) scale to evaluate and compare toxicity, including the findings of pulmonary function tests and radiologic and scintigraphic evaluations performed before and at 3 and 6 months of follow-up. RESULTS: According to the LENT score, a statistically significant difference was found between the two groups in favor of Ptx (p = 0.016). The difference in diffusing capacity of the lung for carbon monoxide and regional perfusion scan results were found to be statistically significant between the groups at 3 and 6 months (p <0.05). The use of Ptx resulted in a noticeable reduction in the higher degrees of lung injury detected radiologically. CONCLUSION: Our study showed a significant protective effect of Ptx for both early and late lung radiotoxicity. We recommend the prophylactic use of Ptx, finding it to be safe and effective.

Pentoxifylline in the treatment of radiation-related pelvic insufficiency fractures of bone.

Bese NS,   Radiat Med. 2003 Sep-Oct;21(5):223-7.

Cerrahpasa Medical School, Istanbul University, Turkey.

The reported incidence of bone complications after radiation therapy is quite low. The most commonly seen bone complication is insufficiency fractures of the pubis and sacrum. Treatment of insufficiency fractures consists of conservative care, and mineral replacement may be useful. The resolution of symptoms takes at least one year with these treatments. Vascular damage has an important role in the etiology of late radiation injury in normal tissues. Progressive ischemic changes further weaken the bone structure, which can cause fractures, and healing is also delayed. Pentoxifylline is a methylxanthine derivative that is shown to increase tissue blood flow. Here, we present a 63-year-old male patient with pelvic insufficiency fractures due to postoperative pelvic irradiation for rectal adenocarcinoma. The patient received pelvic radiotherapy to a total dose of 50.4 Gy with concomitant 5-FU. Six months after the completion of radiotherapy, the patient presented with severe pelvic pain. Pelvic magnetic resonance imaging (MRI) demonstrated abnormal signal intensity with insufficiency fractures at the sacrum and bone marrow edema near the fractures, but not an abnormal intensity that revealed bone metastases. Neither distant nor locoregional recurrence was observed at his work-up. The final diagnosis was insufficiency fractures of the pelvic bones owing to irradiation, and pentoxifylline (400 mg, 3 times daily, peroral, 1,200 mg/day) was used for eight months as treatment. Dramatic clinical improvement was obtained in six months, and objective healing was revealed

Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis.

Delanian  J Clin Oncol. 2003 Jul 1;21(13):2545-50.

Service d'Oncologie-Radiotherapie, Hopital Saint Louis 1, Paris, France

Radiation-induced fibrosis (RIF) is a rare morbid complication of radiotherapy, without an established method of management. RIF treatment with a combination of pentoxifylline (PTX) and alpha-tocopherol (vitamin E; Vit E) was recently prompted by the good results of a clinical trial and an animal study. The present double-blind, placebo-controlled, monocentric study was designed to assess the efficacy of this combination in treating RIF sequelae. PATIENTS AND METHODS: Twenty-four eligible women with 29 RIF areas involving the skin and underlying tissues were enrolled from December 1998 to April 2000. These patients, previously irradiated for breast cancer, were randomly assigned to four balanced treatment groups: (A) 800 mg/d of PTX and 1,000 U/d of Vit E; (B) PTX plus placebo; (C) placebo plus Vit E; and (D) placebo-placebo. The main end point measure was the relative regression of measurable RIF surface after 6 months of treatment. Assessment was completed by depth (with ultrasonography) and associated symptom measures. RESULTS: Twenty-two patients with 27 RIF areas were analyzed at 6 months. Mean RIF surface regression was significant with combined PTX/Vit E versus double placebo (60% +/- 10% v 43% +/- 17%; P =.038). The median slope for the speed of RIF surface area and volume regression was significantly higher for group A than groups B, C, and D. All treatments were well tolerated. CONCLUSION: Six months' treatment of combined PTX/Vit E can significantly reduce superficial RIF. Synergism between PTX and Vit E is likely, as treatment with each drug alone is ineffective, but these results require confirmation in larger series.

Role of pentoxifylline and vitamin E in attenuation of radiation-induced fibrosis.

Chiao TB, Lee AJ.  Ann Pharmacother. 2005 Mar;39(3):516-22. Epub 2005 Feb 8.

Veterans Affairs (VA) Medical Center, San Francisco, CA

To evaluate the use of pentoxifylline and vitamin E as monotherapy and in combination for the treatment of radiation-induced fibrosis (RIF). DATA SOURCES: Literature retrieval was performed through MEDLINE (1966-March 2004) using the terms vitamin E, alpha-tocopherol, pentoxifylline, radiation-induced fibrosis, and radiation injury. DATA SYNTHESIS: Few treatments exist for managing RIF of soft tissues. Due to its antioxidant properties, vitamin E may reduce the oxidative damage induced by radiation. The precise mechanism of action for pentoxifylline in management of RIF remains unclear. Uncontrolled studies evaluating vitamin E or pentoxifylline as monotherapy in RIF have shown modest improvement in clinical regression of fibrosis. However, controlled data are needed to verify these benefits. Studies involving pentoxifylline plus vitamin E demonstrated regression in RIF. The combination was more effective than placebo and may be superior to monotherapy with either agent. Adverse effects were rarely reported in the studies and consisted mainly of gastrointestinal and nervous system effects. CONCLUSIONS: Overall, pentoxifylline is well tolerated and is one of the few commercially available drugs with clinical data for management of RIF. Despite a lack of large, well-designed clinical trials, pentoxifylline plus vitamin E should be considered as an option in patients with symptomatic RIF.

Pentoxifylline in the treatment of radiation-induced fibrosis.

Okunieff P,  J Clin Oncol. 2004 Jun 1;22(11):2207-13.

University of Rochester School of Medicine

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.

Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate.

Delanian S, Lefaix JL.  Br J Radiol. 2002 May;75(893):467-9.

Service d'Oncologie-Radiotherapie, Hopital Saint-Louis APHP, 1 Ave Claude Vellefaux, 75010 Paris, France.

Osteoradionecrosis (ORN) is a late terminal sequela of irradiation that does not resolve spontaneously. In a preliminary study, a combination of pentoxifylline (PTX), tocopherol (Vit-E) and clodonate has been shown to be of clinical benefit with more than 50% regression of progressive ORN observed at 6 months in 12 patients. A 68-year-old woman presenting with severe exteriorized osteoradionecrosis had received radiotherapy for breast cancer 29 years previously. She had palpable breast fibrosis, including the sternum (15 cm x 11 cm) and a painful fistulous track in the upper part of the bone (orifice diameter 10 mm) surrounded by local inflammatory signs, and chronic osteitis with sequestra extrusion. MRI showed deep radiation-induced fibrosis below this area without cancer recurrence, and complete bone destruction over an area of 7 cm x 4 cm. Oral PTX (800 mg day(-1)), Vit.E (1000 IU day(-1)) and clodronate (1600 mg day(-1)) were administered daily for 3 years and were well tolerated. The patient exhibited regular clinical improvement until complete closure of the fistula and total regression of the clinical fibrosis. MRI confirmed the good response and showed heterogeneous restoration of the sternum, which was filled with new tissue. This is the first time that antifibrotic treatment with combined PTX-Vit.E plus clodronate has been shown to have a significant effect on necrosis, by completely reversing severe progressive ORN and the associated radiation-induced fibrosis.