Clinical manifestations, prevention, and treatment of radiation-induced fibrosis

INTRODUCTION — Radiation-induced fibrosis can develop as a late effect of radiation therapy (RT) in skin and subcutaneous tissue, the lungs, the gastrointestinal and genitourinary tracts, muscles, or other organs, depending upon the treatment site. Radiation-induced fibrosis may cause both cosmetic and functional impairment, which can lead to death or significant deterioration in quality of life.

The development of radiation-induced fibrosis is influenced by multiple factors, including radiation dose and volume, fractionation schedule, previous or concurrent treatments, genetic susceptibility, and comorbidities such as diabetes mellitus. Although radiation-induced fibrosis originally was assumed to be a slow, irreversible process, contemporary studies suggest that it is not necessarily a fixed process.

The prevention of radiation-induced fibrosis has focused on improvements in RT technique, which have resulted in higher doses to the tumor target and decreased doses to normal tissue, thus potentially preventing the development of radiation-induced fibrosis. Furthermore, established radiation-induced fibrosis may be treatable with novel therapeutic approaches, particularly the combination of pentoxifylline and vitamin E.

The pathogenesis, diagnosis, clinical manifestations, prevention, and treatment of radiation-induced fibrosis will be discussed here. Radiation-induced changes in the lungs and gastrointestinal tract are discussed separately. (See "Radiation-induced lung injury" and "Diagnosis and management of chronic radiation enteritis".)

PATHOGENESIS — Radiation-induced fibrosis is similar to inflammation, wound healing, and fibrosis of any origin. Typical histologic features include the presence of inflammatory infiltrates, particularly macrophages in the earlier stages of fibrosis, differentiation of fibroblasts into postmitotic fibrocytes, and changes in the vascular connective tissue with excessive production and deposition of extracellular matrix proteins and collagen [1,2].

The development of fibrosis is mediated by cytokine expression that probably begins immediately after radiation therapy (RT) and continues for months or years. Inflammatory mediators that have been implicated include tumor necrosis factor-alpha (TNF-alpha) and interleukins 6 and 1 (IL-6 and IL-1) [2-5]. Fibrogenic cytokines that modulate the proliferation and differentiation of fibroblasts and the synthesis of extracellular matrix proteins and matrix metalloproteinases include transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF). Other growth factors, such as the connective tissue growth factor (CTGF), which is secreted by fibroblasts and endothelial cells, also promote fibrosis [6,7].

Radiation-induced alterations of the vascular system, particularly damage to endothelial cells, appear to contribute significantly to late toxicity. Damage to the myocardium after RT for breast cancer has been associated with changes of the microvasculature, resulting in reduced perfusion and fibrosis [8]. Hyalinoid changes of the capillary wall and a rarefication of the capillary net are typically seen in fibrotic areas [9].

ETIOLOGIC FACTORS — A number of factors influence the response to radiation, thus increasing the incidence of complications.

RT parameters — The risk of radiation therapy (RT)-induced fibrosis is increased with higher radiation doses and larger treated volumes [10-13]. The radiation dose that causes fibrosis can vary substantially in different tissues, as is illustrated by the following examples:

●Fibrosis in both connective and vascular tissues is generally associated with total radiation doses of 60 Gy or higher.

●By contrast, the heart is relatively sensitive to radiation, and relatively low doses of radiation therapy (RT) can cause peri-, myo-, or endocardial fibrosis. Thus, incidental radiation to the heart should be minimized, and radiation doses to the whole heart should be kept small. Similarly, the lungs are relatively sensitive to radiation. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies" and "Radiation-induced lung injury".)

The technique of RT administration can have a major effect on the dose of radiation received by normal tissues. Examples of situations where the risk of radiation-induced fibrosis is influenced by the RT technique include the following:

●Skin induration is more frequent in women treated with overlapping tangential breast fields and internal mammary lymph node fields [14].

●The risk of radiation-induced fibrosis is increased with high single doses of RT (eg, intraoperative radiation treatment, single-fraction external beam RT, brachytherapy) [15].

●Fibrosis may be more common when different RT techniques are combined. As an example, the combination of external beam RT with interstitial and intracavitary brachytherapy for gynecological tumors can cause radiation-induced fibrosis of the ureter and vagina, as well as late toxicity to the large and small bowel [16,17].

●The use of multiple fractions per day increases the risk of radiation-induced fibrosis. In a randomized trial in patients with lung cancer, the risk of dysphagia was higher two years after treatment with hyperfractionated RT compared with conventional fractionation [18].

●Postoperative, as opposed to preoperative, administration of RT is associated with an increased risk of late radiation complications in sarcoma patients [10]. In men with prostate cancer, patients with a history of abdominal surgery or a transurethral resection of the prostate (TURP) had an increased risk for late RT complications [19].

●Higher doses of RT not only increase the incidence of fibrosis, but also shorten the latent period until late sequelae are apparent [9].

During RT planning, organ-specific guidelines are used to limit the dose to normal tissue. With this information, the risk for radiation-related sequelae can be estimated, and volume-dependent dose limits can be generated.

Genetic factors — Genetic variation in the response to radiation may be associated with an increased incidence of radiation-induced fibrosis.

As an example, there is a higher risk of subcutaneous fibrosis in patients with breast cancer who have specific modifications of the ATM gene [20]. Patients with other diseases associated with deficient DNA repair may also be more likely to develop symptoms of radiation-induced fibrosis. Fortunately, dramatic increases in the risk of radiation fibrosis are limited to the rare occurrence of these known genetic disorders.

Connective tissue diseases — Patients with connective tissue diseases, such as scleroderma, rheumatoid arthritis, or systemic lupus erythematosus, may have an increased incidence of toxicity from RT, but the magnitude of this risk is not clear [21-23]. In a review of eight observational studies that included 404 patients with connective tissue diseases who were treated with RT, there was a statistically significant association with late RT-induced complications in normal tissues (fibrosis, osteonecrosis, bone fractures) [21]. While not usually an absolute contraindication to RT, the severity of connective tissue disease should be taken into account when formulating the treatment plan.

Multiple factors may contribute to the association of RT complications with connective tissue diseases. The development of radiation-induced fibrosis may be affected by the concurrent use of medications such as corticosteroids and cytotoxic drugs. In addition to increasing RT toxicity, these drugs can cause osteopenia and bone fractures, which may be attributed to RT. Sequelae of connective tissue disorders, such as dry eye and dry mouth symptoms in Sjögren's disease, may mimic radiation-induced fibrosis.

Concurrent systemic therapy — Combining RT with systemic cancer treatment has been assumed to cause a higher risk of radiation-induced toxicities [24], but clinical studies have given conflicting results. The following illustrate the range of results that have been reported:

●In a randomized trial comparing sequential with concurrent chemotherapy in breast cancer patients receiving RT, the risk of late effects, including subcutaneous fibrosis, was significantly increased in those receiving concurrent chemotherapy [25].

●A review of eight studies of women with cervical cancer who were treated either with RT plus chemotherapy or with RT alone found that there were no significant differences in the rates of late complications in seven of eight trials [26].

●In women with breast cancer, the incidence of lung fibrosis was increased after combined RT and tamoxifen. In a trial of women receiving RT with or without tamoxifen following mastectomy, those receiving tamoxifen had a significant increase in the incidence of lung fibrosis (relative risk 2.0) [27]. Tamoxifen is thought to induce transforming growth factor beta (TGF-beta) secretion, which is a key factor in the signaling cascade leading to fibrosis. Tamoxifen may also increase the incidence of subcutaneous fibrosis when given concurrently with RT, but this has not been a consistent finding in all studies [28,29].

●In men, hormonal therapy given concurrently with RT for prostate cancer can increase the incidence of acute and late gastrointestinal and genitourinary toxicity [19,30-32].

●Targeted therapies are increasingly combined with RT for a wide variety of tumor entities. While often the combination was tolerated well, increased toxicities have repeatedly been reported [33] (eg, erlotinib [34,35], bevacizumab and erlotinib [36], bevacizumab and oxaliplatin [37], BRAF inhibitors [38]).

Immune-related pneumonitis from therapy with checkpoint inhibitors, such as pembrolizumab, was observed more frequently in lung cancer patients who had previous RT, particularly if treated with curative-intent RT [39,40].

Diabetes mellitus — Diabetes mellitus increases the risk of late RT complications in normal tissue. The increased risk has been attributed to changes in the micro- and macrovasculature, which result in decreased tissue perfusion and impaired normal tissue repair.

Several reports have described a higher risk for gastrointestinal and particularly genitourinary toxicity in diabetic patients [41,42]. Diabetes mellitus has also been identified as a risk factor for the development of ischemic heart disease following breast RT [43] and for radiation pneumonitis [44,45]. Patients with severe diabetes have even been reported to be excluded from stereotactic RT for lung cancer in one clinic, but this is not common practice [46].

CLINICAL MANIFESTATIONS — Radiation-induced fibrosis can cause a wide range of clinical manifestations, including cutaneous induration, lymphedema, restrictions in joint motion, strictures and stenoses in hollow organs, and ulcerations. An overview of common manifestations of radiation-induced fibrosis in various organ systems and the associated clinical symptoms is presented in the table (table 1). Other radiation-induced fibrosis-related symptoms exist but are less frequent.

Radiation-induced fibrosis typically presents 4 to 12 months after radiation therapy (RT) and progresses over several years. Although radiation-induced fibrosis can occur without acute symptoms during or immediately after RT, late toxicity often follows acute reactions in the same organ, either immediately or after a latency period.

Late toxicities following acute effects are termed consequential late effects and are directly dependent upon the degree and duration of acute toxicities. Consequential late effects are well described for bladder, bowel, lung, skin and mucosal membranes [47].

Skin and subcutaneous tissue — Radiation-induced fibrosis of the skin and subcutaneous tissue is seen most commonly in breast cancer patients in areas with overlapping treatment fields following breast-conserving surgery with postoperative RT or after mastectomy and RT. (See "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse", section on 'Chest wall and breast complications' and "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer".)

The risk for developing radiation-induced fibrosis after conventional RT for breast cancer is low, particularly with the use of modern skin-sparing megavoltage equipment. Signs and symptoms can include skin retraction and induration, pain, necrosis and ulceration, restricted arm and neck movement, lymphedema, and brachial or cervical plexopathy [48]. The risk for radiation-induced fibrosis and telangiectasia after brachytherapy alone seems to depend on the skin dose delivered [15,49,50]. Proton therapy also did not increase the risk for radiation fibrosis compared with accelerated partial breast irradiation with photons [51], although higher skin toxicity was observed. Adding a radiation boost to the tumor bed after whole breast RT improves local control, but also increases the rate of fibrosis in breast cancer patients [52]. (See "Overview of cancer pain syndromes".)

Radiation-induced fibrosis of the chest wall has also been reported following stereotactic body RT for lung lesions. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

Head and neck — Trismus is a frequent late effect that occurs in 8 to 35 percent of head and neck cancer patients following RT, which is caused by inflammation and fibrosis in the muscles of mastication [53]. Radiation-induced fibrosis results in a loss of the ability to fully open the mouth, which can progress over time. The risk of radiation-induced fibrosis in the head and neck region is increased in patients who have had surgery, and in those treated with RT for recurrent tumor. (See "Management of late complications of head and neck cancer and its treatment", section on 'Trismus'.)

In addition to trismus, RT can cause skin and subcutaneous fibrosis, resulting in induration and lymphedema. (See "Management of late complications of head and neck cancer and its treatment", section on 'Lymphedema and fibrosis'.)

Gastrointestinal tract — The radiation sensitivity of different parts of the gastrointestinal tract differs, with tolerance doses varying between 40 to 70 Gy. The manifestations of toxicity are dependent upon the area irradiated.

Radiation-induced fibrosis in the esophagus may lead to strictures, ulcerations, and fistula formation. The risk of complications may be increased when RT is combined with chemotherapy, with up to 20 percent of patients developing strictures after combined modality treatment [16]. (See "Overview of gastrointestinal toxicity of radiation therapy", section on 'Esophagitis'.)

Late small bowel toxicity is more common after pelvic RT, with its higher doses of RT, rather than after abdominal irradiation. The incidence of radiation-induced fibrosis is low after pelvic RT doses of 50 Gy, whereas a 5 percent incidence of small bowel toxicity has been reported with pelvic irradiation to doses >70 Gy for gynecologic tumors [54]. (See "Diagnosis and management of chronic radiation enteritis".)

Radiation-induced fibrosis of the rectum resulting in strictures occurs primarily in patients with cervix or prostate cancer when high curative doses of RT are used. (See "Radiation proctitis: Clinical manifestations, diagnosis, and management".)

Genitourinary tract — Radiation-induced changes can affect the bladder, ureters, urethra, or vagina depending upon the site and dose of RT. Examples include the following:

●Fibrotic constriction of the bladder can occur after doses of 65 to 70 Gy to small treatment volumes and after lower doses when the entire bladder is irradiated. Another potential late complication of bladder irradiation is hemorrhagic cystitis.

●Ureteral strictures are rare but occur in 1 to 3 percent of cases after gynecological treatment involving brachytherapy, which delivers high single doses to the distal ureters [17].

●In men treated with 60 to 70 Gy for prostate cancer, the incidence of urethral strictures is 0 to 5 percent for those without a prior transurethral resection of the prostate (TURP) and 5 to 15 percent with an antecedent TURP [17]. Interstitial brachytherapy for prostate cancer results in similar urethral stricture rates [55].

●External beam RT and brachytherapy for gynecologic tumors can cause radiation-induced fibrosis of the vulva and vagina, with symptomatic shortening and narrowing of the vagina, dryness, and dyspareunia in up to 70 percent of patients [56]. Symptoms may also be seen after RT for other pelvic tumors if the female reproductive tract is included in the RT treatment fields.

DIAGNOSIS AND ASSESSMENT — The diagnosis and assessment of severity of radiation-induced fibrosis depends upon the tissues involved.

●Fibrosis of the skin and subcutaneous tissue is usually diagnosed by palpation and inspection. Radiation-induced fibrosis is limited to the volume treated with radiation therapy (RT). To quantify the extent of radiation-induced fibrosis, the surface area and depth of involvement should be measured. This evaluation can be repeated to assess the potential effect of any therapeutic intervention.

●Endoscopy or imaging with contrast agents (eg, esophagograms) can be used to demonstrate the loss of elasticity of an organ wall as a result of radiation-induced fibrosis.

●Ultrasound may quantify the extent of radiation-induced fibrosis in the neck [57,58].

●In other anatomic regions, functional tests (eg, for salivary gland function or nerve function in plexus lesions associated with radiation-induced fibrosis) might be helpful, but are non-specific for the diagnosis of radiation-induced fibrosis.

The Radiation Therapy Oncology Group has developed organ-specific classification systems that can be used to describe the severity of RT side effects [59].

The differential diagnosis of radiation-induced fibrosis often includes recurrent tumor, and magnetic resonance imaging (MRI) may be useful in excluding this possibility [60,61]. Persistent parenchymal enhancement (late gadolinium enhancement) after MRI contrast application is associated with areas of local fibrosis. T1 mapping is being investigated to assess diffuse fibrosis [62].

Biopsies and other surgical interventions in areas with radiation fibrosis should be performed only when necessary to exclude tumor recurrence, eg, in situations with clinically unclear changes on repeated imaging or in the presence of ulcerations, since wound healing may be impaired in previously irradiated areas [9]. Furthermore, surgery may result in worsening of fibrosis.

PREVENTION

Radiation therapy techniques — The prevention of radiation-induced fibrosis depends upon minimizing the dose and volume of normal tissue irradiated.

With modern conformal radiation therapy (RT) techniques, high doses are delivered to the tumor while normal tissue should largely be spared [63,64]. Using intensity-modulated radiation therapy (IMRT), a long-term reduction in the incidence of radiation-induced late effects, such as breast induration [65] and telangiectasis [66] for breast cancer RT [67,68], and reduced xerostomia [69] for head and neck cancer were observed. In addition, low rates of lung fibrosis were observed following IMRT for lung cancer [70]. However, the effect of breast IMRT on quality of life has not yet been clearly demonstrated because of the important role of postsurgical cosmesis and breast volume. Using IMRT, a long-term reduction in the incidence of radiation-induced fibrosis should be expected particularly for breast [71] and has been shown for head and neck cancer patients [72,73].

Proton beam therapy is an increasingly available RT technique that potentially can spare neighboring critical structures better than RT using photons, eg, for patients with locally advanced lung cancer where toxicity of the heart and esophagus are critical [74]. Use of multiple fields and scanning techniques is expected to reduce the increased rates of skin toxicity seen with proton therapy use in breast cancer [51].

Supplemental techniques that are helpful to avoid complications of RT include the use of equipment such as belly boards that minimize intestinal irradiation and thereby avoid small bowel toxicity [75], treating patients with a full bladder to avoid intestinal sequelae [76], using shielded vaginal cylinders for gynecologic brachytherapy and rectal spacers for prostate cancer RT [77], and avoiding large single doses. Minimizing acute toxicity is thought to be important in reducing consequential late effects [47].

Pentoxifylline — Pentoxifylline is a xanthine derivative that inhibits platelet aggregation and enhances microvascular blood flow. It has been used alone and in combination with tocopherol, both to prevent and treat radiation-induced fibrosis. Pentoxifylline may also inhibit fibroblast proliferation and the production of extracellular matrix.

A randomized trial in which pentoxifylline alone was assessed for the prevention of radiation-induced fibrosis included 40 patients with either lung or breast cancer who were receiving RT that included normal lung in the treatment field [78]. Another study randomized 91 patients with thoracic RT to pentoxifylline and tocopherol during and for three months after RT versus no treatment and found decreased acute and long-term pulmonary toxicity [79]. A randomized trial testing pentoxifylline and vitamin E versus standard follow-up after breast cancer RT indicated a significant benefit for the prevention of radiation fibrosis [80]. (See "Radiation-induced lung injury", section on 'Prevention'.)

A randomized study in 78 postoperative head and neck cancer patients also identified a positive effect on late skin changes, fibrosis, and soft tissue necrosis with pentoxifylline alone [81].

Although statistically significant benefit associated with pentoxifylline treatment was observed and prophylactic treatment was recommended for high-risk patients, eg, those with poor pulmonary function, the activity of pentoxifylline to prevent pulmonary toxicity requires confirmation, and prophylactic use of pentoxifylline is currently not established as a routine management approach.

Amifostine — Amifostine may reduce the incidence and severity of acute side effects from RT at various treatment sites, although given the mixed results and its toxicity, it is not routinely used.

●Multiple randomized clinical trials have evaluated amifostine for the prevention of xerostomia in patients receiving RT or chemoradiotherapy for head and neck cancer. These trials have given conflicting results, and the role of amifostine in this setting remains uncertain. (See "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Amifostine'.)

●Although an initial randomized trial showed benefit from amifostine in patients receiving lung irradiation, a subsequent larger trial did not confirm these results. (See "Radiation-induced lung injury", section on 'Prevention'.)

●In one randomized trial, amifostine decreased the incidence of acute cystitis.

Amifostine requires intravenous or subcutaneous administration and is associated with significant side effects. Amifostine has not been assessed for the treatment of established radiation-induced fibrosis.

TREATMENT

Symptomatic treatment — The treatment of radiation-induced fibrosis depends upon the location and extent of the fibrosis, as well as the severity of symptoms. Therapeutic approaches include medical management of symptoms, conservative interventions such as dilatation and stent implantation for stenoses (eg esophagus, ureter), and surgical treatment of adhesions and strictures.

●In patients thought to be at high risk for radiation-induced fibrosis, early initiation of active and passive physical therapy measures is helpful.

●A special type of massage (Louis-Paul Guitay [LPG]) has been shown to reduce skin fibrosis after radiation therapy (RT) for breast cancer [82].

●In women receiving pelvic RT, regular vaginal dilatation and topical estrogen cream may be useful to prevent symptomatic shortening and narrowing of the vagina [83,84].

●For patients with early signs or symptoms of trismus, forced opening of the mouth is recommended. In a prospective study, a mouth-opening device was shown to reduce trismus compared with conventional approaches after 12 weeks of training and exercise [53,85].

●Preliminary results on the use of botulinum toxin type A for trismus, cervical dystonia, and neuralgias associated with radiation-induced fibrosis were encouraging [86].

●Lymph drainage for lymph edema and physical therapy to treat articular contractions are other conservative ways that may ameliorate manifestations of late radiation-induced fibrosis.

●In a small study on patients with severe radiation-induced fibrosis after breast-conserving therapy for breast cancer, partial mastectomy and latissimus dorsi reconstruction have been helpful to reduce symptoms [87].

●Adequate analgesic medication is important as well, since radiation-induced fibrosis can be painful.

Any surgical or mechanical intervention potentially can worsen the underlying fibrosis, thereby exacerbating symptoms. The risks of active interventions therefore need to be weighed against the possible benefits [9,16]. Although conservative approaches are favored, surgery may be required, particularly if a tumor recurrence cannot otherwise be excluded.

Pentoxifylline plus tocopherol — Pentoxifylline has been used alone and in combination with tocopherol, a scavenger of reactive oxygen, to treat radiation-induced fibrosis, as well as to prevent pulmonary toxicity. (See 'Pentoxifylline' above.)

The potential clinical utility of pentoxifylline, either alone or with tocopherol (vitamin E), to treat established radiation-induced fibrosis was initially suggested by case reports and observational series in a variety of settings, in which treatment resulted in healing or symptomatic improvement. These observations included:

●Partial reversal of soft tissue fibrosis following RT [48,88-90]

●Healing of radiation-induced soft tissue and bone necrosis [91-95]

●Improvement in symptoms of trismus [96]

●Reduction in pelvic fibrosis after childhood RT [97,98]

●Improvement of radiation-induced lumbosacral polyradiculopathy [99]

Multiple small randomized trials have suggested that pentoxifylline and or vitamin E may have a role in minimizing radiation fibrosis [14,80,100,101]. The two largest of these trials illustrate the range of results seen with this approach:

●In one trial, 83 women with breast cancer were randomly assigned to treatment with vitamin E plus pentoxifylline or vitamin E plus placebo for 12 months [100]. Increase in arm volume was significantly greater in patients receiving vitamin E plus placebo rather vitamin E plus pentoxifylline. Arm abduction, which was significantly impaired at baseline, improved significantly in both groups; the improvement was greater in those receiving pentoxifylline although the difference was not statistically significant.

●In a second trial, 68 women with long-standing lymphedema of the arm following axillary surgery and RT were randomly assigned to receive pentoxifylline plus tocopherol or matched placebos for six months [101]. No effect was observed at 6 or 12 months in arm volume, or in secondary parameters including fibrosis of the breast, chest wall, and regional lymph node areas was seen.

More prolonged therapy may be an important factor in reversing the effects of radiation-induced fibrosis. In a detailed longitudinal series, regression of superficial radiation-induced fibrosis following irradiation for breast cancer was assessed in 44 women with 55 areas of superficial radiation-induced fibrosis during and after treatment with pentoxifylline (800 mg/day) plus tocopherol (1000 units/day) [1]. Seven patients were treated for 6 to 12 months and therapy was then discontinued, while 37 patients remained on treatment for 24 to 48 months.

Overall, the mean estimated maximal regression in surface area of radiation-induced fibrosis was 68 percent, and this regression required an average of 24 months of treatment. The time to maximum regression of radiation-induced fibrosis was shorter in patients with fibrosis of less than six years duration (16 versus 28 months for those with fibrosis of longer duration). Among the seven patients who were treated for 6 to 12 months, a rebound increase in fibrotic area was observed after cessation of treatment.

For osteoradionecrosis in the mandible, a combination of pentoxifylline and tocopherol with clodronate (PENTOCLO) has been reported as a successful approach [95]. The PENTOCLO treatment is preceded by anti-inflammatory, antibacterial, and antimycotic therapy for four to six weeks, followed by PENTOCLO therapy until healing. Healing was achieved in 16 of 27 patients after a median of 82 days. Healing took longer in patients after radiochemotherapy (169 days) compared with surgery and radiotherapy (49 days). These results were confirmed in a prospective cohort study [102].

In summary, these data suggest that the combination of pentoxifylline plus tocopherol can reverse superficial radiation-induced fibrosis in some patients [103]. The optimal dose and duration of therapy and the role of tocopherol are unknown. However, some data suggest that a prolonged course of treatment may be necessary to induce maximal regression of radiation-induced fibrosis and to maintain any benefit. These results require additional confirmation. Furthermore, it is not clear whether these results can be extrapolated to radiation-induced fibrosis in other tissues, or whether treatment with pentoxifylline plus tocopherol needs to be continued indefinitely.

Hyperbaric oxygen — Hyperbaric oxygen has been evaluated as a treatment for late toxicities, including radiation-induced fibrosis, in multiple studies investigating the benefit for patients treated in the head and neck, breast, and pelvic area in particular. Small prospective studies identified some effect in reducing lymphedema and peripheral nerve damage.

Hyperbaric oxygen has been evaluated as a treatment for radiation-induced fibrosis in at least three small studies:

●Two observational studies, which together included a total of 31 women, found that hyperbaric oxygen decreased lymphedema following surgery plus RT for breast cancer [104,105]. The observed benefit persisted for at least one year.

●A double-blind trial in 34 women treated for radiation-induced brachial plexopathy did not demonstrate any benefit from hyperbaric oxygen [106]. However, two of the women who were treated with hyperbaric oxygen did have substantial improvement in their lymphedema. (See "Overview of cancer pain syndromes".)

However, a meta-analysis of 14 studies (753 patients) that randomized hyperbaric oxygen use versus no therapy found that hyperbaric oxygen can prevent osteoradionecrosis and proctitis, but it had no effect on other radiation-induced late effects [107].

SUMMARY AND RECOMMENDATIONS — Radiation-induced fibrosis can develop as a late effect in multiple tissues, as a function of the dose and volume of radiation as well as the radiation sensitivity of a given tissue. Radiation-induced fibrosis may cause both cosmetic and functional impairment, which can lead to a significant deterioration in quality of life or even death.

●The primary approach to prevention of radiation-induced fibrosis is through the use of appropriate radiation therapy doses and techniques that minimize the radiation exposure for normal tissue. (See 'Radiation therapy techniques' above.)

●For patients with established radiation-induced fibrosis, treatment is primarily symptomatic and depends upon the organ system involved. (See 'Symptomatic treatment' above.)

●For patients with established symptomatic subcutaneous fibrosis, we suggest a combination of pentoxifylline and tocopherol (Grade 2C). The optimal duration of therapy is unknown, but treatment may be required for two or more years to observe and maintain any benefit. (See 'Pentoxifylline plus tocopherol' above.)