Abstract & Commentary
Synopsis: Investigators in Paris performed a follow-up phase III randomized trial to confirm the efficacy and synergism of pentoxifylline and alpha-tocopherol as an antifibrotic treatment in women who had received previous breast radiotherapy. Results of their earlier phase II trial indicated that the 2 drugs act via complementary mechanisms to break the self-perpetuating cycle of tissue damage, with continued improvement over time. The earlier trial results were confirmed in the randomized trial, and the investigators have suggested larger trials to establish their regimen as the standard approach for treatment of this "orphan disease." Source: Delanian S, et al. J Clin Oncol. 2003;21:2545-2550.
Radiation-induced fibrosis (RIF) is most often considered to be an irreversible process involving nonspecific changes in the connective tissue and has been associated with extracellular matrix deposition and hyperactive fibroblasts. The process generally stabilizes or progresses, with sporadic acute inflammatory periods. It is felt to involve a dynamic process combining atrophy/contraction and connective tissue hypertrophy/fibrosis. Although there is no effective treatment for this condition, it has been reported in the literature that the use of pentoxifylline1 and superoxide dismutase2 can promote healing of radiation-induced tissue damage. On that basis, Delanian and colleagues hypothesized that alpha-tocopherol might offer an antioxidant benefit similar to that shown for superoxide dismutase since the latter is not readily available. Since their unpublished results with either agent alone showed little effect on RIF, they conducted a Phase II trial to explore possible synergies between the 2 agents and found that 66% RIF regression occurred at 1 year.3 Given these results, Delanian et al embarked on a phase III double-blind randomized trial using a 2 ´ 2 factorial design. The main end point was relative regression of the fibrotic surface area at 6 months.
Between 1998 and 2000, 31 women with postradiotherapy breast fibrosis were enrolled in a 4-arm trial. Seven were excluded because they did not have measurable fibrosis or their fibrosis was shorter than 6 months’ duration. The etiology of the fibrosis was attributed to either prior breast brachytherapy or the junction of breast and nodal external beam fields. The mean time to development of RIF was 7 ± 4 years. The mean initial diameter of RIF was 6.5 cm, depth was 2.1 centimeters, and surface area was 41 square centimeters. Fifteen patients had received "combined chemotherapy." The 24 study patients were randomized to Group A: pentoxifylline 800 mg q.d. and Vitamin E 1000 IU q.d.; Group B: pentoxifylline + Vitamin E placebo; Group C: pentoxifylline placebo + Vitamin E; and Group D: double placebo. The study drugs were given for 6 months. Patients were then evaluated for RIF surface area and volume changes using palpation, ultrasound, and the Subjective Objective Medical management and Analytic evaluation of injury (SOMA) scale. The latter grades scaliness, pruritus, pain, local edema, alterations in pigmentation, ulceration, necrosis, fibrotic scarring, atrophy, and tissue contraction.
There were 22 evaluable patients. One patient withdrew at the outset and another withdrew during the trial because of intercurrent psoriasis. Both drugs were well tolerated. Clinical regression of RIF was defined as centripetal reduction of the edges of the fibrotic block without contraction. The combined pentoxifylline/Vitamin E patients demonstrated significantly better regression of RIF measured by surface area at 6 months than did the double placebo group (60% vs 43%; P = .038) and a trend toward better RIF volume regression (73% vs 51%; P = .054).
Delanian et al concluded that, despite the small sample size, their randomized trial confirmed the results of their earlier phase II trial, as well as previous animal studies. They felt that 6 months was almost too short to observe a significant improvement but that a reversal of the fibroatrophic process was achieved. The precise mechanism of chronic radiotherapy damage reduction is unknown, but pentoxifylline is a methyl xanthine derivative that seems to effect dermal fibroblast proliferation and extracellular matrix production, while vitamin E scavenges reactive oxygen species. The TGF beta-1 pathway has been implicated in the overall process. Given that long-term follow-up of their phase II patients showed progressive improvement that peaked at 18-36 months, Delanian et al speculated that the current study patients may have further RIF regression. Larger trials are needed to confirm their findings.
Comment by Edward J. Kaplan, MD
In my opinion, Delanian et al are to be commended for their innovative approach and tenacity in their mission to evaluate an antifibrotic regimen in patients suffering from postradiation soft-tissue toxicity. Their work has spanned more than 10 years and consisted of animal studies right on through to a randomized trial. Delanian et al appear to be mostly alone in the quest for treatment of a fairly common but neglected problem. As Moulder pointed out in a recent article about pharmacological intervention for radiation injuries, the behavior of parenchymal and vascular cells can be modulated such that deleterious responses to radiation are not necessarily inevitable. "Unfortunately, assessment of the utility of these agents for clinical use has been minimal, and there are no established mechanisms for any of the experimental or clinical successes."4 Aside from a couple of case reports, there is almost nothing published about the pentoxifylline/vitamin E regimen by authors other than Delanian et al. Gottlober from Germany presented a 58-year-old woman who was treated with pentoxifylline 1200 mg + vitamin E 400 mg q.d. following surgery in an area of postradiation fibrosis. Skin thickness was measured via ultrasound, and improvement was noted beginning at 4 months. Continued improvement was seen beyond 6 months.5 Another German group reported on a breast cancer patient treated with pentoxifylline 1200 mg + Vitamin E 400 mg q.d. for ulcerating RIF. The ulcers were nearly healed by 18 months.6 Neither case report found any side effects from treatment.
I was somewhat dismayed at the low patient numbers in the Delanian trial, but I am confident that the regimen has activity that can reverse postradiation fibrotic changes. I have used the regimen on my own patients since the phase II data were published, and I have seen excellent outcomes with it. Hot, swollen, or firm tissue can regain its natural texture and contour with continued use of these agents. I am hopeful that this line of study will be explored further by a cooperative group or large institution with the resources to enroll sufficient numbers of patients so that compelling data may be generated.
Dr. Kaplan is Acting Chairman, Department of Radiation Oncology, Cleveland Clinic Florida Ft. Lauderdale, FL; Medical Director, Boca Raton Radiation Therapy Regional Center, Deerfield Beach, FL.
1. Dion M, et al. Int J Radiat Oncol Biol Phys. 1990;19: 401-407.
2. Delanian S, et al. Radiother Oncol. 1994;32:12-20.
3. Delanian S, et al. J Clin Oncol. 1999;17:3283-3290.
4. Moulder JE. Semin Radiat Oncol. 2003;13:73-84.
5. Gottlober P, et al. Strahlenther Onkol. 1996;172:34-38.
6. Fischer M, et al. Eur J Dermatol. 2001;11:38-40.