Chapter 91 Radiotherapy of Nonmalignant Diseases

Keloids and Hypertrophic Scars

Background and Clinical Aspects

Keloids are an excessive tissue proliferation about scars after skin injury from surgery, heat, chemical burns, inflammation (e.g., acne), or even spontaneous proliferation. They differ from hypertrophic scars by their typical infiltrative growth pattern, causing local pain and inflammatory reactions, and sometimes long-term progression; hypertrophic scars show thickening without surrounding reaction and can flatten spontaneously. Keloids appear mostly in the upper body and in regions with high skin tension (e.g., sternum, earlobes). The cause is still unknown, although there is a genetic and race-specific predisposition that is already noted during adolescence. Keloids at the earlobe after piercing are typical. In some patients the resulting lesions are severely disfiguring and painful (Fig. 9). Recurrence is common after treatment

Nonradiotherapeutic Treatment

Silicone bandages, pressure dressings, and cryosurgery have all been used to treat for keloids with varying efficacy.^232-234 Intralesional injections remain the first-line therapy for most keloids. Corticosteroids, 5FU, and verapamil have all been directly injected into keloid lesions with symptom improvement. Up to 70% of patients respond to intralesional corticosteroid injection with flattening of keloids, although the recurrence rate is high in some studies (up to 50 percent at five years).^235

Surgical excision may be indicated if injection therapy alone does not result in improvement. In patients treated with excision alone, recurrence rates range from 45-100%,^236 therefore excision is typically combined with peri-operative postoperative injections of either triamcinolone or interferon.^235
Radiotherapeutic Options

Radiotherapy should be considered in cases of repeat recurrences postoperatively or where there is a high-risk of recurrence (e.g., marginal resection, large lesion, unfavorable location). Primary RT can be considered in instances where resection would result in functional impairment and in actively proliferating disorders within about 6 months after the triggering trauma. Because proliferating fibroblasts and mesenchymal and inflammatory cells are the target cells for RT, fully matured keloids have minimal response to RT alone. Prophylactic RT immediately following excision is most effective and reduces the risk of recurrence to 20% to 25% in most series.

RT is initiated 24 hours after surgery. The target volume is limited to the scar plus a 1-cm margin; lead shielding can be constructed to protect normal tissue. An analysis of multicenter data on the use of post-operative RT for earlobe keloids show that higher dose per fraction and use of deeper penetrating electrons is preferable to standard 2 Gy fractionation schemes or use of brachytherapy techniques that have rapid dose fall off.^237 Radiation dose is typically 12 to 20 Gy, delivered in 3 or 4 fractions within 1 week.^238 Single-fraction RT with 7.5 to 10 Gy is also effective.^239 Clinical end points are long-term control, low relapse rate, and good cosmesis.
Diseases of Bone

Gorham-Stout Syndrome

Gorham-Stout Syndrome, also known as disappearing bone disease or essential osteolysis, is a rare bone disorder of unknown etiology. It is characterized by painless bone destruction due to progressive proliferation of small blood or lymph vessels. There may also be significant osteoclast activation. The symptoms are nonspecific, but include muscular weakness, limb tenderness, and pathologic fracture occurring minimal trauma. Involvement of the cervical spine or skull base could be fatal. Case reports indicate limited efficacy of systemic therapies such as zoledronic acid and interferon-alpha. Radiation therapy has also been used. Heyd, et al. completed a national patterns-of-care study and literature review that summarizes the scant data available for this rare disorder.^244 The 38 articles listed therein provide evidence from treatment of 44 patients that conventionally fractionated external beam RT (total dose of 36 to 45 Gy) may prevent disease progression in 77% to 80% of cases.

Pigmented villonodularsynovitis

Pigmented villonodular synovitis or tenosynovial giant cell tumor is a rare proliferative disorder of synovial tissue. Symptoms include sudden onset, unexplained joint swelling and pain that frequentlyinvolves a single joint. The knee and foot are most commonly affected, but there are reports of shoulder, hand, and hip involvement.^245 Decreased motion, joint stiffness, and increased pain occur as the disorder progresses. Surgical resection with either synovectomy or joint replacement is the treatment of choice.

Radiation therapy is indicated in cases of diffuse disease, bulky disease resulting in bone destruction, or in the rare instance of multiple recurrences after resection. Although intra-synovial injection of radioactive isotopes post-operatively has been used in the past for high-risk patients,^248 most institutions use external beam radiation therapy. RT to a dose of 35 to 50 Gy has been effective. MRI is essential for delineating disease pre- and post-operatively. Final dose of RT should be tailored to amount of residual disease.^251

Vertebral Hemangiomas

Hemangiomas are benign proliferations of blood vessels that can affect any tissue and are typically asymptomatic. About 50% of hemangiomas involving the vertebral body are associated with pain and therefore may require treatment. Treatment options include surgical resection or more conservative interventions such as vetebroplasty or intralesional injections.^252 Radiation therapy either alone or post-operatively has been successful in reducing pain caused by vertebral hemangiomas.^253 In this study, a total of 84 patients with 96 symptomatic lesions were irradiated for a symptomatic vertebral hemangioma. At a median 68 months follow-up, 90% of patients had either complete or partial pain relief. Radiation doses ≥34 Gy resulted in significantly improved pain relief. A total radiation dose of 36-40 Gy delivered in 2 Gy per fraction has been recommended.^254

Heterotopic Ossification

Background and Clinical Aspects

Heterotopic ossification (HO) is a common complication of total hip arthroplasty, hip trauma, or acetabular fracture. HO occurs when the soft tissues around the hip become ossified. Following trauma, primitive mesenchymal cells in the surrounding soft tissues are transformed into osteoblastic tissue that then forms mature bone. The hip is the most common joint affected; HO typically occurs around the femoral neck and adjacent to the greater trochanter. The risk factors for development of HO are unknown, but the incidence is greater in men and occurs in more than 80% in patients who have a history of ipsilateral or contralateral HO. It is also more common in patients with a known history of osteoarthritis, ankylosing spondylitis, diffuse and Paget’s disease.^255 Hip stiffness is the primary symptom and the diagnosis is made radiographically. Pain is typically not associated with HO.

Nonradiotherapeutic Treatment

The treatment for HO is surgical excision followed by some form of HO prophylaxis. Prophylaxis is only applied to patients at high risk for developing HO. A meta-analysis showed that NSAIDs are effective in reducing the risk of post-operative HO.^256 Indomethacin is the most commonly used NSAID for HO prophylaxis. Indomethacin is a prostaglandin synthase inhibitor that also suppresses mesenchymal cells. The limited data available have not shown a clear benefit to the use of selective cyclooxygenase-2 inhibitors in HO prophylaxis. Bisphosphonates have been used for prophylaxis because they delay mineralization of osteoid and appear to have some efficacy in preventing HO if used at the appropriate time. In one study, the cost of bisophosphonate use was prohibitive for routine use when compared to indomethacin.^259
Radiotherapeutic Options

External-beam radiation is an effective method for prevention of HO after total hip arthroplasty. Prophylactic radiation therapy for the prevention of HO has been used sine the 1970s. A single fraction of 700 or 800 cGy to the at-risk region (Figure 17) is recommended and should be delivered in the peri-operative period, either preoperatively (within 24 hours) or postoperatively (within 72 hours).^260-262 When comparing radiation therapy and NSAIDs, there is no clear benefit for use of one modality over another. A prospective, randomized study demonstrated that radiation therapy and indomethacin are both effective in the prevention of postoperative HO.^263 Although one meta-analysis of seven randomized studies concluded that radiotherapy is more effective than NSAIDs for HO prophylaxis,^264 a more recent analysis of 9 studies involving 1295 patients found no statistically significant difference between the two.^265 An economic analysis using the same 9 studies and the meta-analysis suggest that radiation therapy is not cost effective when compared to use of NSAIDs.^266 This analysis has yet to be validated.
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