Definition

Radiation-induced toxicity after cancer treatment may result in significant long-term disability. Radiation fibrosis describes the insidious pathologic fibrotic tissue sclerosis that occurs in response to radiation exposure. Radiation fibrosis syndrome (RFS) is the term used to describe the myriad clinical manifestations of progressive fibrotic tissue sclerosis that can result from radiation treatment. It is estimated that about half of the approximately 14 million cancer survivors in the United States will receive radiation treatment during the course of their disease [1]. The incidence of RFS is unknown, and its severity is affected by multiple factors (see later). Radiotherapy is typically combined with surgery or chemotherapy; therefore the toxicities of these modalities may be cumulative and difficult to separate clinically.

The therapeutic goal of radiation therapy is to kill rapidly proliferating tumor cells by inducing apoptosis or mitotic cell death through free radical–mediated DNA damage [2]. Various dose-sculpting techniques have been developed to minimize exposure to normal tissues; however, radiation exposure to normal body cells cannot be completely eliminated [3]. The effects of radiation can be acute (occurring during or immediately after treatment), early-delayed (up to 3 months after completion of treatment), or late-delayed (occurring more than 3 months after completion of treatment) [4]. Radiation fibrosis is generally a late complication of radiation therapy and may become clinically apparent many years after treatment. Its progression can be insidious or rapid, but it is invariably irreversible [5,6]. It can damage any tissue type, including skin, muscle, ligament, tendon, nerve, viscera, and bone [7]. The underlying mechanism of radiation fibrosis is complex and not completely understood. It has been postulated that radiation-induced vascular endothelial injury causes thrombomodulin deficiency, resulting in its inability to scavenge locally formed thrombin, which in turn leads to abnormal accumulation of proliferative fibrin in the intravascular, perivascular, and extravascular compartments [2].

The long-term morbidity due to RFS is largely determined by the size of the radiation field, the type and susceptibility of underlying tissues to radiation, and the patient’s individual resistance to the effects of radiation. Other factors include the patient’s age, overall health, and medical and degenerative disorders, particularly degenerative spine disease; cancer status; exposure to neurotoxic, cardiotoxic, and other chemotherapy types; and time since radiation was administered [8]. For signs or symptoms to be considered referable to RFS, either the structures generating them must be within the radiation field or the neural, vascular, lymphatic, muscular, tendinous, or other structures important in their genesis must traverse the field. It is therefore necessary to understand which type of radiation field was used to treat a given patient to determine whether the signs, symptoms, or functional deficits can be attributable to RFS. The common radiation fields used in Hodgkin lymphoma (HL) are depicted in Figure 111.1. Extensive radiation fields, such as mantle field used to treat HL, can result in widespread sequelae of RFS. Patients with head and neck cancer (HNC) treated with radiation are also likely to develop RFS because of the high dose of radiation required for tumor control as well as the proximity of many vital tissues to the radiation field [9].

Symptoms

Patients with RFS can present with a variety of symptoms as virtually every organ system can be affected. Symptoms should be anatomically congruent to the radiation field and involved tissues. HL survivors frequently present with neck extensor weakness (dropped head syndrome), pain and limited range of motion of the neck and shoulders, weakness, fatigue, gait and dexterity problems, neuropathic symptoms, and difficulty in performing activities of daily living. Spasms are frequently described as tight, pulling, or cramping sensations. Neuropathic pain is usually described as burning, stabbing, or searing. HNC patients commonly have trismus, cervical dystonia, facial lymphedema, dysphagia, and dysarthria. Radiation-induced trigeminal neuralgia (commonly in the V2-V3 distribution on the affected side, but bilateral involvement is possible) and anterior cervical neuralgia are also common complications. Neuropathic pain in patients with RFS can be severe and markedly out of proportion to the perceived pathologic process. If the spinal cord was in the radiation field, patients may present with spastic paraparesis or quadriparesis, depending on the level of the spinal cord affected by radiation. Early-delayed radiation-induced myelopathy is almost always reversible, whereas late-delayed is almost always progressive and permanent [10]. If autonomic nerves are affected, patients can present with orthostatic hypotension, baroreceptor failure, bowel and bladder dysfunction, and sexual dysfunction. Shortness of breath in HL patients treated with mantle field radiation may be due to pulmonary insufficiency from bilateral phrenic nerve dysfunction [11].

Physical Examination

Comprehensive examination, including detailed neuromuscular and musculoskeletal evaluation, is of paramount importance. Physical examination findings will vary greatly from patient to patient; however, a full account of physical examination findings is beyond the scope of this chapter.

Examination of patients treated for HL commonly demonstrates cervicothoracic paraspinal, shoulder girdle, and rhomboid muscle atrophy and often a C-shaped posture due to forwardly positioned neck and shoulders secondary to relatively strong pectoral muscles (Fig. 111.2). HNC patients commonly present with asymmetric positioning of the head and neck due to severe neck tightness, pain, and spasms of trapezius, sternocleidomastoid, and scalene muscles, among others. This radiation-induced cervical dystonia may progress to fixed contracture of the anterior cervical musculature [12]. Trismus seen in HNC patients is commonly associated with spasms in the masseter and pterygoid muscles (Fig. 111.3). Marked loss of range of motion and function may be seen if joints were involved in the radiation field. Rotator cuff tendinitis and adhesive capsulitis may develop because of perturbation of normal shoulder motion secondary to C5 and C6 radiculopathy or upper brachial plexopathy [13]. Neurologic testing may reveal sensory loss, including light touch, pain, temperature, vibration, and proprioception. Weakness and gait dysfunction may be secondary to damage of neural tissue (spinal cord, plexus, cauda equina, peripheral nerves) or muscle itself. Not infrequently, the clinical picture fits that of myelo-radiculo-plexo-neuro-myopathy, with some or all components of the neuromuscular axis affected to varying degrees. The upper brachial plexus, frequently included in the radiation field of head and neck radiation ports, may be more susceptible to radiation injury because of its apical location in the neck and the long course traversed by its fibers relative to the middle and lower trunk. The pyramidal shape of the thorax and the clavicle may provide less protective tissue around the upper plexus, but the clinical validity of this phenomenon is unclear [14].