As the understanding of cancer therapies has evolved, the use of radiation therapy has increased. The treatment paradigm for solid cancers increasingly relies on radiation therapies, but currently the chronic effects associated with these treatments are poorly characterized. In fact, the use of radiation therapy has increased significantly in the past 2 decades — meaning that the recognition and understanding of radiation-specific chronic pain is now critical.
In a narrative review published in Advances in Therapy, researchers considered the epidemiology of radiation-therapy specific pain, then characterized the various pain syndromes.1
Burden of Chronic Pain
“Post-treatment chronic pain syndromes in patients with cancer are associated with a plethora of quality of life detriments, including psychological distress, immobility, and even disability,” the review authors wrote. “These pain syndromes can also manifest during cancer treatment and affect ongoing treatment candidacy. Therefore, early recognition and goal-directed treatment strategies addressing these conditions are essential to optimize ongoing and future physical and functional well-being.”
Incidence Outpaces Information
According to the review authors, an increase in cancer survivorship is at least partially responsible for the increase in chronic pain prevalence among people with cancer. Tumor type, tumor severity, and cancer treatment strategies all factor into the pathogenesis of chronic pain, with estimates indicating chronic pain in 50% of those with early cancer and 75% of those with advanced disease.
In general, the prevalence of patients treated with radiation therapy is increasing; one study estimated that within the next 10 years, there will be more than 4 million cancer survivors who received radiation therapy, while half of all people with new cancer diagnoses will be eligible for radiation therapy.2 Despite this, the literature on chronic pain sequelae following radiation therapy is significantly lacking compared with the literature on chronic peripheral neuropathies associated with cytotoxic chemotherapies.
The study authors point out that the multiple challenges in classifying radiation therapy-associated pain syndromes include the heterogeneous nature of the conditions, when the patient presents with the condition, and the concomitant use of chemotherapies and surgical procedures in these patients. Radiation-specific pain syndromes can manifest in a various organ systems and can become apparent either early or late in the treatment course.
Specific chronic pain patterns manifest in certain cancers. For example, people with breast cancer — the cancer with the highest number of survivors who have undergone radiation therapy — are vulnerable to conditions like brachial plexopathy or upper extremity lymphedema. In contrast, people with gynecologic cancers are more likely to develop radiation enteritis.
Understanding Radiation Therapy Toxicity
Damage to DNA is the driving mechanism behind the biological effects of radiation therapy. Radiation therapy-induced inflammatory cytokines, then, are responsible for the acute systemic effects. Cellular sensitivity to radiation therapy varies and is inherent, per the review authors, to tissue type, respective kinetics, and cellular organization.
It is critical to consider clinical and temporal factors when determining radiation therapy-related toxicity. When determining the probability of late radiation effects, important factors include the radiation therapy dose, tissue type targeted, tissue volume irradiated, and the time since treatment.
“Improvements in [radiation therapy] planning, image guidance, and delivery have greatly reduced [radiation therapy] dose[s] to structures such as the brain stem, spinal cord, and brachial plexus, making severe events rare and not particularly well described,” the researchers wrote.
Overview of Radiation Therapy-Specific Pain Syndromes
The following 7 pain syndromes must be given individual examination: dermatitis, oral mucositis, acute radiation enteritis, chronic abdominal pain, local connective tissue fibrosis, lymphedema, and neuropathic pain syndromes.
Posttreatment dermatitis occurs in roughly 95% of people who undergo radiation therapy. Early symptoms include erythema, pigment color changes, edema, depilation, and radiation burns. While most symptoms typically occur within 90 days of treatment, transient erythema can occur as soon as 2 hours posttherapy.
Chronic radiation dermatitis symptoms include scaly skin, hyperkeratosis, pigment changes, telangiectasia, alopecia, nail changes, slow-healing erosions or ulcers, and soft tissue, bone, and cartilage necrosis, among others. Patients with head and neck cancers or breast cancers are most susceptible to the late complications of primary dermatitis, according to the review authors, due to the radiation-specific skin sensitivity of the face, neck, and chest. Because the mechanism of radiation therapy induces DNA damage, and cutaneous tissue and skin cells are among “the most regenerative,” these areas are highly vulnerable to experiencing radiation injury.
Prevention and treatment options are varied. Superficially, proton therapy can more accurately direct high-dose radiation therapy to target structures, sparing the critical structures below. Other prevention options include good skin hygiene, moisturizers, and decreased sun exposure. But, the review authors caution, emollients must be compatible with radiation therapy, and should not be applied in the hours before treatment.
Acute radiation dermatitis severity is graded on a 1-to-4 scale by the National Cancer Institute. 3 Grade 1 is described as faint erythema, while grade 4 is described as skin necrosis or ulceration and may include spontaneous bleeding in the affected area.
Treatments, then, vary based on dermatitis grade: for grades 2 and 3, hydrocolloid and hydrogel dressings can be used, while for grade 4, lesions may require surgical debridement with skin flaps. Evidence for the use of vitamins C and E and beta-carotene antioxidants is limited. Studies have reported supportive evidence for the use of pentoxifylline which, in combination with vitamin E, may increase tissue vascularity.3,4
For radiation-induced cutaneous fibrosis, deep-friction massage, therapy, and orthotics have been proposed as possible treatments.5,6 Gabapentin, pregabalin, duloxetine, and tricyclic antidepressants may be used in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs) for nociceptive and neuropathic pain.6,7
Between 80% and 100% of patients who receive radiation therapy for head and neck cancers will develop oral mucositis. Patients undergoing concurrent chemotherapy are the most susceptible for this development, but other risk factors include being older than 65 years of age or having poor oral hygiene, salivary dysfunction, poor nutrition, or diabetes. Symptoms can include oral pain, odynophagia, and dysphagia. Patients with secondary bacterial infections or decreased oral intake may need feeding tube placement.
A multistep process has been proposed to clarify the pathophysiology of oral mucositis.8,9 Radiation therapy breaks down DNA, causing subsequent cell damage. Transcription factors then lead to a pro-inflammatory cascade and dysregulated inflammation, followed by ulceration — and an increased risk for secondary infections — and the healing stage. When radiation therapy ends, cells can regenerate and heal. Symptoms and stages are further described by the National Cancer Institute.10,11
Management focuses heavily on prevention and early goal-directed treatment. Mouthwash is often used, but chlorhexidine mouthwash, which is commonly used in chemotherapy-induced mucositis, may have a limited role in preventing radiation-induced disease. For patients undergoing concomitant chemotherapy, preventive strategies include cryotherapy, pentoxifylline, beta carotene, and prostaglandin E2 as well as low-level laser therapy, antibiotics, antivirals, and antifungal medications.
Opioids can be used to manage oral mucositis-related pain; however, the review authors recommend a judicious approach due to the adverse effect profiles. Topical doxepin, tricyclic antidepressants, NSAIDs, and gabapentin have also been used to manage pain. Nonmedication alternatives such low-level laser therapy and transcutaneous electrical nerve stimulation may also help, but evidence is still emerging.
In abdominal and pelvic cancers, gastrointestinal mucosa is severely affected by radiation therapy. Roughly 10% to 15% of patients with pelvic cancers who receive radiation therapy will experience chronic abdominal pain that impacts their quality of life.
Acute radiation enteritis occurs within hours to days of exposure, resolves after a few weeks, and is characterized by nausea, vomiting, diarrhea, abdominal pain, and tenesmus. According to the review authors, signs and symptoms are “likely caused by direct radiation-induced cytotoxicity and inflammatory storm.” Microvasculature damage also likely plays a role.
Conversely, chronic radiation enteritis can appear from 2 months to several years after radiation therapy. Signs and symptoms include chronic abdominal pain, ulcers, fistulas, ischemia due to vascular sclerosis, abscesses, perforation, bleeding, and fibrosis. Conservative radiotherapy strategies might not be a practical solution in people with malignant tumors.
Radiation enteritis-associated pain can be difficult to treat. Current measures to improve tissue perfusion have been used to increase both vascularity and oxygen supply to the damaged tissues. Opioids can be used but on a limited basis due to the risks of opiate-induced gut dysmotility and constipation.
Chronic Abdominal Pain
Patients with refractory chronic pain associated with radiation enteritis may be able to be treated with one of several interventional management measures. One study reported success with splanchnic nerve neurolysis.12 A second study demonstrated analgesic benefit with radiofrequency ablation of the splanchnic nerves in people with abdominal cancer pain.13 A third study reported on the positive benefit associated with sympathetic blockade of the ganglion impar in a patient with postradiation therapy chronic proctitis and anorectal pain for prostate cancer.14
Ongoing research is exploring the utility of botulinum in addressing acute proctitis pain15 and the efficacy of direct radiofrequency ablation of intra-abdominal tumors in alleviating chronic pain.16 However, the review authors note, these interventions have been associated with higher complication rates.
Connective Tissue Fibrosis
Local connective tissue fibrosis is assumed to underlie the late effects of radiation therapy, but the pathophysiology is uncertain. Three phases are suggested for radiation-induced fibrosis: endothelial cell dysfunction associated with chronic, nonspecific inflammation at the radiation site, fibroblast activation to secrete disorganized extracellular matrix, and further remodeling of the extracellular matrix leading to dense sclerotic tissue and poor vascularization.
Many patients who have radiation fibrosis syndrome experience debilitating chronic pain. Clinical presentations vary depending on which anatomic structures radiation therapy targets as well as on the use of concomitant treatments such as surgery or chemotherapy.
Any person who receives radiation therapy at any site that contains “critical neuromuscular structures” can be at risk for radiation fibrosis syndrome. Patients with head and neck cancers are among the most at risk, with from 20% to 60% of these patients experiencing radiation fibrosis syndrome, while 30% of breast cancer patients experience it. Complications such as radiculopathy and plexopathy may occur and manifest as weakness or sensory changes in the nerves. Myopathy due to muscle fiber fibrosis may cause contractures in head, neck, and shoulder girdle muscles.
The primary treatment for radiation fibrosis syndrome is comprehensive physical and rehabilitative therapy. Neuromuscular re-education can correct movement and postural problems, and myofascial release has improved pain, range of motion, and motor functionality. Medications such as pregabalin, gabapentin, duloxetine, and tricyclic antidepressants can be used to manage both neuropathic and muscular pain, while opioids can be “cautiously considered” if appropriate. Combination pentoxifylline and vitamin E is hypothesized to have anticytokine activity, and some evidence suggests this combination is helpful as both a preventive and therapeutic measure.17,18
Lymphedema can predispose patients to multiple sequelae, including skin changes, infection, and joint immobility. Though the condition itself may not be painful, it can sometimes progress to painful musculoskeletal conditions such as rotator cuff disease and adhesive capsulitis.
Studies of lymphedema are most commonly undertaken in patients with breast cancer treated with radiation therapy and/or surgery, especially patients whose treatment involves axillary lymph node dissection. When these therapies are paired, the risk for lymphedema increases substantially. Pelvic and head and neck cancers are also associated with lymphedema, as well as other cancers that require treatment of regional lymph nodes.
Complex decongestive therapy is a mainstay of lymphedema treatment, regardless of cancer type, and includes 4 primary components: manual lymphatic drainage, compression therapy, lymph-reducing exercises, and skincare. Studies of manual lymph drainage have demonstrated mixed results, and no significant benefit was noted in improving pain and function.19 Low-level laser therapy has been suggested for severe or refractory lymphedema due to the proposed anti-inflammatory and antifibrotic properties.20
Other intervention strategies for refractory cases include stellate ganglion blocks using local anesthetics and corticosteroids with local anesthetic.
The most severe cases may require surgical intervention, including lymphaticovenular anastomosis and vascular lymph node transfer. One trial has demonstrated the safety of human vascular endothelial growth factor C gene therapy in combination with vascularized lymph node transfer, but its efficacy is unclear.21
Neuropathic Pain Syndromes
Radiation therapy is associated with a host of neurotoxic adverse effects and radiation-specific peripheral neuropathies, resulting in gradual and irreparable nerve damage over the course of several years. Pathophysiology of these processes is not fully understood, but 3 key factors have been identified: indirect compressional damage from radiation-induced fibrosis, direct axonal damage and demyelination, and neural ischemia from microvascular injury.
Radiation-induced brachial plexopathy is, according to the review authors, one of the most feared complications. The condition typically results in mild paresthesia, numbness, swelling, weakness, and debilitating pain in distal upper extremities. These symptoms can, in some patients with severe presentations, progress to paralysis. Pain occurs in half of all patients but is generally mild to moderate. Severe pain is representative of new or increased tumor burden.
Radiation-induced lumbosacral plexopathy is another debilitating condition, often occurring after pelvic, colon, and testicular cancers or para-aortic lymph node tumors. Onset is typically within 1 year of treatment but can be delayed up to 31 years. Disease progression is slow and classified by sensory changes, muscle atrophy, fasciculations, and abnormal deep tendon reflexes. Pain is an uncommon presenting symptom.
For both conditions, radiographic imaging is required to rule out tumor-based etiology. However, treatment options are mostly symptomatic, and the goal is managing pain and improving function and quality of life. Prevention strategies include using the minimum effective radiation dose.
For radiation-specific peripheral neuropathies secondary to radiation-induced fibrosis, early physical therapy can slow progression of muscular atrophy and sensory and motor defects. Medication management includes corticosteroids, anti-inflammatory agents, pentoxifylline, and hyperbaric oxygen vascular therapy. Studies, though, are inconsistent and suggest an “unpredictable patient response.” Neurolysis with omentoplasty for revascularization provides short-term pain relief, but long-term prognosis is unclear.22,23
Pregabalin and botulinum neurotoxins improve pain, mood, and quality of life in symptomatic treatment for both radiation-induced peripheral neuropathy and postsurgical pain. Evidence suggests that botulinum neurotoxins have direct analgesic properties, decreasing the release of noxious neurotransmitters including substance P and calcitonin gene-related peptide.23,24 Other medication options include nonopioid analgesics, muscle relaxants, benzodiazepines, tricyclic antidepressants, and antiepileptics.
Delayed-onset radiation-induced myelopathy is observed in patients who receive radiation therapy in the cervical and upper thoracic region. Pathogenesis is hypothesized to stem from glial cell and microvascular damage; glial cells are stimulated by direct radiation damage to produce vascular endothelial growth factor, leading to increased vascular permeability, edema, and damage. Radiation-induced myelopathy typically occurs around 6 months after radiation therapy but can present up to 10 years afterwards; 75% of patients present with symptoms within 2.5 years.
No evidence-based guidelines for treating radiation-induced myelopathy currently exist, and it has no specific signs or symptoms. Corticosteroids, due to their anti-inflammatory properties, have demonstrated promise in mitigating disease progression; other treatments include anticoagulation therapy, hyperbaric oxygen, and vascular endothelial growth factor antibody bevacizumab.
“Understanding these unique pain syndromes is paramount, given that the diagnosis and management of these conditions can serve to present long-standing functional impairments, optimize quality of life, and even allow for continued [radiation therapy] candidacy,” the researchers concluded. “It is necessary to maintain a low threshold of suspicion for appropriately diagnosing these conditions, as there exists a variance in when these symptoms arise after radiation.”
Disclosure: Some review authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
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