Chapter 91 Radiotherapy of Nonmalignant Diseases

Chapter 91

Radiotherapy of Nonmalignant Diseases

Karen M. Winkfield, MD, PhD; Jose Bazan, MD; Iris C. Gibbs, MD; Tony Y. Eng, MD; Charles R. Thomas, MD

Karen M. Winkfield, MD, PhD

Harvard Medical School

Department of Radiation Oncology

Massachusetts General Hospital

100 Blossom Street, Cox 3

Boston, MA 02114

Email: [e-mail]

Ph: 617-724-1159

Fax: [phone]

Jose G. Bazan, MD, MS
Department of Radiation Oncology
Stanford University
875 Blake Wilbur Drive
Stanford, CA 94305-5847

Email: [e-mail]

Ph: 650-725-4021
Fax: [phone]
Iris C. Gibbs, MD

Associate Professor

Stanford University

875 Blake Wilbur Drive MC:5847

Stanford, CA 94305-5847

Email:  [e-mail]

Ph: 650-725-4021

Fax:  [phone]

Tony Y. Eng, MD
Professor and Vice Chair
The University of Texas Health Science Center at San Antonio
& Cancer Therapy and Research Center
Radiation Oncology Department
7979 Wurzbach Road
San Antonio, TX 78229

Email: [e-mail]

Charles R. Thomas, Jr., MD**
Professor and Chair

Department of Radiation Medicine

OHSU Knight Cancer Institute

Mail Code KPV4

3181 SW Sam Jackson Park Road
Portland, Oregon, USA 97239-3098

Email: [e-mail]

Ph 503-494-8758   

Fax [phone]

**Corresponding Author; will review proofs.

Benign diseases generally include a class of localized tumors or growths that have a low potential for progression, and do not invade surrounding tissue or metastasize to distant sites. Pathologically, they are composed of well differentiated cells that are considered non-malignant and usually do not require any treatment. However, clinically, not all benign diseases have benign consequences. Some untreated benign diseases can produce bothersome mass or secretory effects. Others can be locally aggressive and cause secondary debilitating symptoms.

For example, Grave’s ophthalmopathy can lead to local pain and visual impairment without therapeutic intervention;^1 a hormonally active pituitary adenoma may cause growth abnormality in addition to blindness;^2 desmoid tumors, can be locally persistent even after surgical resection and some desmoids therefore are managed aggressively, similar to their malignant counterparts and may require adjuvant radiation therapy after radical resection.^3

Documented empirical use of radiation in imaging and the treatment of benign diseases or conditions occurred soon after the discovery of x-rays by Wilhelm Röntgen in 1895.^4 An estimate of over a million Americans, mostly young adults and children, received x-ray treatments to the head and neck region for benign conditions between 1920 and 1960. The painless x-ray treatment and its visible efficacy led to many benign conditions being treated with radiation, such as acne, body hair, scalp ringworm, enlarged tonsils, enlarged thymus, enlarged lymph neck nodes, whooping cough, and others. Radiation therapy was used in some instances due to a lack of effective alternative therapies.^7

Over the past decades, advances in medical and surgical therapies have provided new treatment options for many diseases. With improved awareness of late radiation sequelae on normal tissue, particularly radiation carcinogenesis, there has been a gradual decline in the use of radiation therapy for treatment of benign conditions. However, with modern radiation therapy techniques and better understanding of radiobiology, judicial use of radiation still provides good local control in and relief of associated symptoms from a variety of benign diseases.
Radiobiological effects on benign diseases

The precise radiobiological mechanisms of radiation effects on benign diseases are not well defined. Radiation is believed to work through a complex of multicellular interactions that affect different cell types in our body system.^8 Specific cellular and functional mechanisms depend on the specific disease and site. While most benign lesions have no known stimuli or causes, some benign lesions may be triggered by trauma as seen in keloid formation after body piercing, or heteroptopic bone formation after surgery. In conditions that arise following trauma, local inflammation and repair occur, which is often characterized by stimulation of growth factors and accelerated cellular proliferation. For example, in the development of keloids, fibroblast proliferation is responsible for most of the hyperproliferative process. Even with the lower doses commonly used in benign diseases, radiotherapy is clinically effective in inhibiting cell proliferation and suppressing cell differentiation without inducing cell death as is typically seen with tumoricidal doses of radiation. Yet, radiation can induce apoptosis in selected target cells by influencing the expression of cytokines in macrophages, leukocytes, endothelial, and other cells, and thereby modulating the inflammatory cascade.

Among the major sites of radiation effects are the blood vessels; vascular endothelial cells respond rapidly to radiation damage by up-regulating the cytokine-mediated cellular reactions responsible for inflammatory tissue response. Low-dose irradiation (<12 Gy) exerts anti-inflammatory effects on the endothelial cells of capillaries and mononuclear cells of the immune system.^9

Cell adhesion molecules, selectins, are mobilized to the cell membrane and change the capillary permeability allowing the inflammatory cells (lymphocytes, macrophages, monocytes) to migrate into interstitial space. The anti-inflammatory effect is attributed to the modulation of cytokine and adhesion molecule expression on the activated endothelial cells and leukocytes. These cells are known to be radiosensitive. They express proinflammatory cytokines (e.g., interleukin-1, interleukin-6) or necrosis factors (e.g., tumor necrosis factor-α), which influence the complement cascade and enzymes of inflammatory reaction. Interleukin-1 stimulates the production and release of proinflammatory prostaglandins leading to a change in synthesis of inducible nitric oxide synthetase.

The radiation-induced modulation of nitric oxide production and oxidative burst in activated macrophages and native granulocytes lead to modification of the immune response and inflammatory process as well as clinical analgesic effects. Although endothelial cells possess a high proliferative potential and are sensitive to radiation damage at high doses, they are not prone to rapid mitotic radiation death at low doses.

Chronic inflammatory processes are triggered by antigen-antibody reactions and mediated by mononuclear peripheral blood cells in the immune system. Ionizing radiation helps suppress some of these cell populations, such as T lymphocytes, in the inflammation process or modulate their effects. While low doses of radiation can exert anti-inflammatory response in inflammatory tissue, high doses of radiation as used in malignant tumors can elicit pro-inflammatory effects and fibrotic change in normal tissue.^10 At higher single or total doses, endothelial cell damage can lead to sclerosis and obliteration of blood vessels. In vascular disorders such as hemangiomas or arteriovenous malformations, high radiation doses may induce occlusion of pathologic vessels. In addition to inhibition of cell proliferation, cell killing may play a part in the management of benign meningiomas, pituitary adenomas, or neuromas where higher, tumoricidal doses of radiation may be required.

Risk of second malignancies

The induction of cancer or genetic defects by radiation exposure is attributed to stochastic effects where there is no threshold level of radiation exposure below which cancer induction or genetic effects will not occur.  Increasing the radiation dose or the volume of exposure will increase the probability that a cancer or genetic effect will occur. Sometimes, the radiation effects are difficult to separate from inherent genetic effects. For example, in patients with retinoblastoma, the Rb1 gene plays an important role in the development of radiation-induced sarcomas. In a study of 384 retinoblastoma patients treated with radiation, the actuarial risk for developing a sarcoma in the treatment field 18 years after treatment was 6.6.^11 In another study of 693 patients, the cumulative risk for any sarcoma 50 years after radiotherapy was 13.1%.^12 Although most sarcomas were within the irradiated fields, 18 out 69 sarcomas developed outside of the treatment fields. The RB1 mutations appear to have a genetic pre-disposition to developing sarcoma especially after radiation exposure.

The risk of the induction of secondary tumors was overestimated in the past.^13 Trott and Kamprad used the epidemiological data from long-term follow-up studies on patients treated with radiotherapy for benign diseases to estimate the risk of cancer induction.^14 Taking all known modifying and organ-specific factors into account, including doses of radiation and volume irradiated, the estimated absolute lifetime risk for sarcoma induction was < 0.0001% for 1 Gy and a 100- cm² field. Table 1 lists the absolute lifetime risk for other malignancies.

Jansen et al. applied the effective dose concept and estimated the carcinogenic risk in patients after radiotherapy of benign diseases (heterotopic ossification, omarthritis, gonarthrosis, heel spurs and hidradenitis suppurativa).^15 Special risk modifying factors, including age at exposure and gender, were taken into account. For an average-aged population, the estimated number of radiation-induced fatal tumors was between 0.5 and 40 persons per 1000 patients treated. The range of effective doses was also found to be large (5–400 mSv). In addition to age and gender, the individual risk also depends on individual inherent sensitivity, anatomic site, type of disease, and treatment technique, such dose and fractionation.

Indication for Radiotherapy
The majority of benign diseases can be classified as inflammatory, degenerative, hyperproliferative, or functional. Therefore therapeutic approaches vary widely and are regionally customized, in part because of geographic traditions and differences in clinical training. Radiation treatment of benign diseases is less commonly used in the United States than in some other parts of the world where variation in indications and treatment schedules are institutionally based.^16 Within Germany, a pattern of care study revealed significant geographic and institutional differences.^17 Although most radiation treatments for benign disease are delivered in the low dose range (<10-15 Gy), the prescribed dose varied widely and inconsistently within geographic regions and between institutions.

Degenerative processes in tendons, ligaments, and joints can cause pain by chronic inflammation and trigger secondary functional impairment of the involved musculoskeletal system. Although radiation does not halt the degenerative process, it may reduce the inflammation and provide partial or complete pain relief. This clinical effect is well-established in reports of osteoarthritis, synovitis, and bursitis, where low-dose radiation therapy has improved the function of affected joints.

Benign diseases may have a significant effect on self-image and -esteem because of cosmetic appearance (e.g. facial keloids, juvenile angiofibroma) or lasting impact on quality of life because of chronic pain or other secondary symptoms (e.g. heterotopic bone, macular degeneration). When benign diseases become locally invasive with aggressive growth, therapeutic intervention can prevent or limit functional loss of organs. In rare cases of large hemangioma with associated thrombocytopenia and consumption coagulopathy (Kasabach-Merritt syndrome), potentially fatal complications can occur, and timely therapeutic intervention can be life-saving.^19

Although there is a lack of an international consensus, the German Working Group on Radiotherapy of Benign Diseases published their consensus guidelines for radiation therapy of nonmalignant diseases. The guidelines were to serve as a starting point for quality assessment, prospective clinical trials, and outcomes research.^18 In brief, treatment is indicated when benign diseases are symptomatic or potentially symptomatic. When other methods are unavailable or have failed, radiation therapy should be considered. As medical professionals, we remain mindful of therapeutic gain and potential treatment side effects and complications. A thorough risk-benefit analysis is always pertinent. Organ-specific acute and chronic toxicities including potential effects on fertility and induction of secondary tumors in the future must be explained to and discussed with patients, especially those who are young and have a long life expectancy. Informed consent that is required for all medical interventions is certainly required for treatment of benign diseases and should be obtained prior to the delivery of radiation therapy.

The current chapter covers some of the more common benign conditions that we still encounter in the practice of radiation oncology. Details on the therapeutic approaches and data on radiation dose regimens for different benign diseases are summarized in the individual corresponding sections.
Benign Neoplasms of the Brain, Head and Neck

Non-malignant tumors of the central nervous system (CNS) and neck can lead to severe, life-threatening symptoms due to pressure and mass effect on critical structures from tumor growth. However, depending on their growth rate and location, the surrounding tissue may also well adapt and lead to a delay in the clinical diagnosis.

Meningioma

Background and Clinical Aspects

Meningiomas are the most common benign tumors of the CNS. The incidence peaks in the 7^th decade of life with a 2:1 female-to-male predominance. The majority (>90%) of meningiomas are benign and classified by the World Health Organization (WHO) as grade I tumors.^20 WHO grade II meningiomas (atypical, clear cell or chordoid) have a higher tendency for local recurrence, and WHO grade III/malignant meningiomas (anaplastic, rhabdoid, papillary) are exceedingly rare.

The most common presenting symptom is headache, but patients may present with other localizing symptoms depending on the tumor location. The radiographic diagnosis of meningioma is often made on CT or MRI imaging based upon the appearance of a homogeneously and intensely enhancing extra-axial mass with or without the presence of a dural tail.

Surgical Management

Surgical resection is the treatment of choice for the majority of patients as this will relieve symptoms and also provide a pathologic diagnosis. The primary goal of surgery is to remove as much tumor burden as possible while minimizing the risk of neurologic deficits (maximal safe resection). Gross total resection (GTR) is generally attempted for patients with tumors in locations such as the convexity and olfactory groove. After GTR, the relapse rate is as low as 10%, but depends upon the Simpson classification, which grades tumors according to extent of resection and degree of dural involvement (Table 1).^23 Local recurrence rates are as high as 40% for patients with incomplete resection,^23 though these rates can be substantially reduced with the use of adjuvant radiotherapy.

Meningiomas tend to be highly vascularized tumors. In select patients, preoperative embolization is used to decrease blood loss and improve the extent of resection.

Active Surveillance

Asymptomatic patients with small meningiomas may be observed clinically. At the time of tumor growth or the development of symptoms, patients can be treated with surgery or radiation therapy. The safety and reasoning for this approach was established in a large retrospective series from Japan that demonstrated that the majority of patients do not require intervention in the short-term.^26

Systemic Therapy

Interest in the use of medical therapy to treat meningiomas stems from the observation that up to 67% of meningiomas express the progesterone receptor or androgen receptor, and approximately 10% express the estrogen receptor.^27 However, response rates to anti-hormonal agents are low. Overall, studies that have investigated the role of chemotherapy, such as hydroxyurea, in the management of recurrent disease have demonstrated little efficacy.^27

Radiotherapy

Primary radiotherapy (RT) is indicated for tumors in locations in which complete resection is not feasible (i.e. optic nerve, cavernous sinus, major venous sinus) or for patients who are poor surgical candidates. Adjuvant RT is indicated for patients with STR, recurrent disease, or for WHO grade II/III tumors. RT techniques include conventionally fractionated three-dimensional conformal radiotherapy (3DRT), conventionally fractionated intensity-modulated radiation therapy (IMRT), frame-based or linear accelerator-based fractionated stereotactic radiotherapy (FSRT), stereotactic radiosurgery (SRS), or protons and heavy ions.

The MRI sequences that best delineate the gross tumor volume (GTV) should be coregistered with the treatment-planning CT scan for optimal treatment planning and delivery. Particularly for patients receiving FSRT or SRS, it is important that a neuroradiologist and neurosurgeon be involved in assisting with GTV delineation, as enhancement from residual tumor versus postoperative change is often difficult to ascertain.

For 3DRT or IMRT treatments, the clinical target volume (CTV) is constructed by adding a 1-2 cm symmetric margin around the GTV, respecting normal tissue boundaries. An additional 3-5 mm is added for the final planning target volume (PTV). These margins may be modified based on institutional policy and other considerations, such as the availability of daily image guidance (i.e. kV imaging or cone-beam CT).

For benign meningiomas, the typical dose prescription to the PTV is 50-54 Gy given in 1.8-2 Gy daily fractions. Retrospective data suggests that local control is inferior for patients treated with doses of <52 Gy ^28. For patients with more aggressive histology (WHO grade II/ III tumors), the GTV is expanded by at least 2 cm with a higher dose prescription in the range of 59.4 – 63 Gy. Several modern series of radiotherapy show 5- year local control rates ranging approximately 89 – 98%, with 3-dimensional conformal therapy demonstrating local control rates greater than 95% (Table 2).^28-32

Since meningiomas are frequently well-circumscribed and non-invasive tumors, SRS and FSRT are increasingly being used in their treatment. The decision to fractionate depends largely upon tumor size and proximity to critical structures, such as the optic apparatus or brainstem. Typical dose prescriptions for frame-based SRS range from 12-16 Gy prescribed to the 50% isodose line (IDL) and 14-18 Gy prescribed to the 80% IDL for a frame-less robotic radiosurgery platform. In patients with tumors that require fractionated treatment, dose prescriptions vary and are dependent upon the individual case. For example, at our institution we often treat primary or residual meningiomas of the convexity and skull base to 15-18 Gy in 1-2 fractions. Additionally, we have treated a select group of perioptic tumors, including meningiomas, with a prescription of 24-30 Gy in 3-5 fractions (to the 80% IDL) with high rates of tumor control and visual preservation (Figure 1).^33 Recent non-randomized, prospective evidence indicates that FSRT should be the treatment of choice for optic nerve sheath meningiomas due to the high rate of preservation of visual acuity.^34

Reported results with SRS are excellent, with 5-year local control rates as high as 98-100% (Table 2).^35-44 DiBiase et al. demonstrated that male gender, conformality index <1.4 and size > 10 mL predict for worse outcome after SRS.^45 The DiBiase paper also showed improved disease free survival in patients in which the dural tail was covered as part of the target volume.^45 The benefit of including the dural tail has to be weighed against the risk of toxicity from increasing the target volume for each individual case.

Due to their physical properties, protons and heavy ions (i.e. carbon) are attractive choices for the treatment of meningiomas, particularly for those located near critical structures. Several studies have shown excellent local control rates with the combination of protons and photons or protons alone.^46-49 In the study by Weber, patients were treated to a median dose of 56 Cobalt Gray Equivalents (GyE) given in 1.8 – 2.0 GyE per day.^48

Pituitary Adenoma

Background and Clinical Aspects

Pituitary adenomas comprise 10-15% of all intracranial tumors. Approximately 75% of these tumors are functional (secretory) thereby producing increased amounts of hormones. Prolactinomas and growth-hormone (GH)-secreting adenomas are the most frequently encountered. Functional adenomas are more common in women, while non-functioning and GH-secreting adenomas are more common in men.

Adenomas are often classified by size with a picoadenoma < 0.3 cm, microadenoma < 1 cm and macroadenoma > 1cm. Macroadenomas may exert mass effect upon the optic chiasm leading to the classic sign of bitemporal hemianopsia. Headaches are seen in approximately 20% of patients. If the adenoma extends to the cavernous sinus, cranial nerve deficits may be present. Involvement of the hypothalamus by the adenoma results in hypopituitarism.

Patients with functional adenomas present with signs and symptoms that correspond to the excess hormone: galactorrhea, amenorrhea, diminished libido and infertility in patients with prolactinomas; acromegaly or gigantism in patients with GH-secreting adenomas; Cushing’s disease in ACTH-secreting adenomas; hyperthyroidism in patients with TSH-secreting adenomas. In patients who have had bilateral adrenalectomy, up to 40% will develop Nelson’s syndrome, which is characterized by an ACTH-secreting adenoma and increased skin pigmentation secondary to increased release of alpha-melanocyte-stimulating hormone.

In addition to history and detailed physical examination (H&P), workup of a pituitary tumor includes laboratory analysis of pituitary hormone levels, contrast enhanced MRI with thin slices through the pituitary (Figure 2A-B), and tissue diagnosis to rule out other causes of pituitary masses including craniopharyngioma, meningioma, suprasellar germ cell tumor, metastatic disease, or a benign lesion (i.e. cyst).

Surgical Management

Surgery is generally the treatment of choice for pituitary adenomas. Surgery provides immediate relief of compressive symptoms and helps to decrease hormone secretion. The most common surgical technique is through a transsphenoidal approach. In some cases, a more aggressive surgery (i.e. frontal craniotomy) may be indicated for patients with extensive intracranial and skull based involvement. Overall, local control rates range from 50-80% after surgery alone for both functioning and non-functioning adenomas.^50 In patients that continue to have abnormally elevated hormones after surgical resection, adjuvant treatment with pharmacotherapy and/or radiation therapy is pursued.

Pharmacotherapy

Pharmacotherapy, such as bromocriptine and cabergoline for prolactinomas, octreotide for GH-adenomas and TSH-adenomas, and ketoconazole for ACTH-adenomas, is often used as an adjunct to surgery for patients with functioning adenomas. With the exception of prolactinomas, the use of these drugs as monotherapy is generally not curative. Prolactinomas can often be managed with pharmacotherapy alone, but a high proportion of patients are unable to tolerate bromocriptine for long periods of time due to nausea, headache and fatigue.

Radiotherapy

Except for medically inoperable patients in which RT is used in the primary setting, the role of RT is generally in the adjuvant setting with the following indications: recurrent tumor after surgery; persistence of hormone elevation after surgery; residual disease after STR/debulking procedure. Tumor growth control is excellent, particularly for patients with non-functioning adenomas.^51-53 Endocrine control, as demonstrated by normalization of pituitary hormone levels, for functioning adenomas takes years to develop. Growth hormone levels stabilize quickest at a median of 2 years after radiation therapy and is slowest for TSH-secreting adenomas ^54. Pharmacologic therapy should be discontinued one to two months prior to the initiation of RT based on evidence demonstrating lower RT sensitivity with concurrent medical treatment ^55.

RT techniques include 3DRT, IMRT, single-fraction SRS and FSRT. Delineation of the GTV (or preoperative GTV in the case of GTR) should be performed by co-registration of the postoperative MRI to the treatment planning CT scan.

For 3DRT and IMRT, the CTV is constructed by adding 1-1.5 cm to the GTV; an additional 3-5 mm is added to the CTV to create the PTV. These margins may be modified based on institutional policy and other considerations, such as the availability of daily image guidance. Non-functional adenomas are typically prescribed a dose of 45-50.4 Gy given in 1.8-2.0 Gy daily fractions (Figure 2C-E). Higher doses in the range of 50.4-54 Gy are recommended for secretory adenomas.

SRS remains an attractive option for the treatment of pituitary adenomas. General principles apply in that FSRT is used over SRS for large lesions (i.e. > 3 cm) or lesions near critical structures (i.e. <1-2 mm from the chiasm). Similar to 3DRT/IMRT, higher doses are needed for functional adenomas compared to non-functional adenomas. Numerous retrospective studies have demonstrated excellent local control rates of 92-100% for non-functional adenomas using doses of 14-25 Gy (at the edge of the tumor) in a single fraction.^56 Commonly used prescriptions are 16-20 Gy in a single fraction for non-functional adenomas and 20-25 Gy in a single fraction for functional adenomas using a frameless robotic radiosurgery platform.