The Role of Botulinum Toxin Type A in the Radiation Fibrosis Syndrome: A Preliminary Report

Methods 

An institutional review board−approved retrospective chart review, spanning the period of January 1, 2003, to February 14, 2005, was performed. We searched billing records at the Memorial Sloan-Kettering Cancer Center (MSKCC) to identify all patients who had received botulinum toxin injections in treatment by a rehabilitation medicine physician at MSKCC. This search identified 45 patients who had collectively undergone 135 botulinum toxin injection procedures. Of the 45 patients who had received botulinum toxin injections, 23 had undergone a total of 73 procedures to treat a complication of radiation therapy.

All patients were evaluated and treated by one of 2 board-certified physiatrists. Determination of the patient’s musculoskeletal or neuromuscular diagnosis was made on clinical grounds and documented in the medical record. The diagnoses that were considered for botulinum toxin injections included the following. One, cervical dystonia was defined clinically as involuntary spasm and/or tightness, with or without pain, in the cervical musculature (especially the sternocleidomastoid, trapezius, and cervical paraspinal muscles). Because radiation-induced cervical dystonia usually affects muscles symmetrically, torticollis, laterocollis, retrocollis, or anterocollis need not be present. Two, trigeminal and cervical plexus neuralgia was defined clinically as constant or intermittent paresthesias, dysesthesias, allodynia, hyperalgesia, and/or hyperpathia in the distribution of one or more branches of the trigeminal nerve and/or cervical plexus. Three, trismus was defined clinically as involuntary spasms and/or tightness in the masseter muscle, with or without associated pain and/or contracture of jaw opening. Four, thoracic pain was defined clinically as neuropathic and/or somatic pain in the thoracic paraspinal muscles. Five, migraine was defined clinically as a severe and recurring headache, usually affecting only 1 side of the head, characterized by sharp pain and often accompanied by nausea, vomiting, and visual disturbances. To be considered radiation-induced, the migraine must have started with, or been significantly worsened after, radiation therapy; botulinum toxin injections were considered if the patient had failed traditional conservative treatments. These treatments varied by indication but included anti-inflammatories, opioids, muscle relaxants, nerve stabilizing (tricyclics antidepressants and gabapentin), physical or occupational therapy, and conventional trigger point injections.

Decisions on injection sites and dosage of botulinum toxin were made empirically based on the clinicians’ clinical experience and were not rigorously standardized. Injections were generally given at approximately 6-week intervals and were sub- or intradermal for migraines and trigeminal and cervical plexus neuralgia and intramuscular for all other disorders. Only BTX-A (Botox) was used. Assessment of efficacy of botulinum toxin injections as well as adverse events were based on the patient’s self report and physician’s assessment of symptom (pain, spasms) relief as documented in the medical record and were not rigorously standardized. Descriptive statistics are reported.

Results 

Table 1 provides patient demographics and table 2 injection details. Of the 23 patients included in the series, 12 (52%) were men and 11 (48%) were women, with a mean age of 54. All patients had undergone surgical resection of primary or metastatic tumors and had received radiation therapy locally with involvement of the region subject to botulinum toxin injection. Eighteen months after closure of the study, 6 (26%) patients were deceased. All but 1 tumor, a meningioma, was considered malignant. The majority (91%) of the tumors were primary with head and neck (61%) cancers being the most common, followed by sarcoma (13%). Radiation-treated metastatic tumor at the symptomatic location was present in 2 (9%) of patients. Tumor involved the head or neck in 17 (74%), the cervical spine in 3 (13%), the cervical and thoracic spine in 2 (9%), and the thoracic spine in 1 (4%) of patients.

Table 1. Patient Demographics (N=23)

	Variable	n	%
	Sex
	Men	12	52
	Women	11	48
	Mean age (range), y	54 (20–85)
	Current status
	Alive	17	74
	Dead	6	26
	Tumor type
	Primary tumors	21	91
	Head and neck	14	61
	Lymphoma	2	9
	Meningioma	1	4
	Merkel cell carcinoma	1	4
	Sarcoma	3	13
	Metastatic tumors	2	9
	Adenocarcinoma of unknown primary	1	4
	Leiomyosarcoma	1	4
	Tumor location
	Head or neck	17	74
	Cervical spine	3	13
	Cervical and thoracic spine	2	9
	Thoracic spine	1	4
	Indication for injection
	Cervical dystonia	18	78
	Migraine	3	13
	Trigeminal or cervical plexus neuralgia	10	43
	Trismus	7	30
	Thoracic pain	1	4
	No. of procedure visits
	1	5	22
	2	7	30
	3	4	17
	4	4	17
	≥5	3	13

Table 2. Injection Details

	Variable	n	%
	Botulinum toxin injection site
	Trigeminal nerve/cervical plexus	9	39
	Frontal/temporal	4	17
	Masseter	3	13
	Sternocleidomastoid	10	43
	Cervical and/or thoracic paraspinals	12	52
	Trapezius	9	39
	Total amount botulinum toxin used (U)
	50	1	4
	100	8	35
	200	14	61
	Electromyographic guidance used
	Yes	6	26
	No	17	74
	Improved
	Yes	20	87
	No	1	4
	Unknown	2	9
	Complication
	Bleeding	0	0
	Dysphagia	2	9
	Dysarthria	1	4
	Increased pain	0	0
	Increased tightness	0	0
	Infection	0	0
	Neck weakness	0	0

The indication for botulinum toxin injection as documented by the treating physiatrist included cervical dystonia in 18 (78%), trigeminal nerve or cervical plexus neuralgia in 10 (43%), trismus in 7 (30%), migraine in 3 (13%), and thoracic pain in 1 (4%) patient. Injections were subcutaneous in the distribution of one or more branches of the trigeminal nerve and/or cervical plexus in 9 (39%), subcutaneous in the frontal and temporal region in 4 (17%), into the masseter in 3 (13%), into the sternocleidomastoid in 10 (43%), into the cervical and/or thoracic paraspinal muscles in 12 (52%), and into the trapezius muscle in 9 (39%) of patients. Eleven (48%) patients were treated for more than 1 indication thought to be a complication of RFS. The total amount of BTX-A used per visit ranged from 50 to 200U and electromyographic guidance was used in 6 (26%) of patients. The range of botulinum toxin used per injection site is detailed in table 3.

Table 3. Dose of Botulinum Toxin Injected per Site or Muscle

	Site or Muscle	Range (U)
	Trigeminal nerve distribution	70–200
	Frontal and temporal forehead	100
	Masseter	25–100
	Sternocleidomastoid	12.5–50
	Paraspinals	25–100
	Trapezius	25–200

Most (87%) patients self-reported benefit from the injections. One patient did not benefit and 2 patients were lost to follow-up. Five patients underwent only 1 injection procedure (22%), 7 underwent 2 injection procedures (30%), 4 underwent 3 injection procedures (17%), 4 underwent 4 injection procedures (17%), and 3 underwent 5 or more injection procedures (13%) by the time of closure of the series. Complications included dysphagia in 2 patients and dysarthria in 1 patient, which lasted approximately 2 weeks and resolved completely. Subsequent injections were performed in these patients with either a lower dose of medication and/or a change in the muscles injected. There were no bleeding or infection complications and no patients reported increased pain, increased tightness, or neck weakness.

Discussion 

Botulinum toxin has a potential adjunctive role in the alleviation of cancer- and cancer treatment–related musculoskeletal and neuromuscular complications. However, this study is severely limited by its retrospective and descriptive nature, with the most significant shortcomings being lack of rigorous, standard, and objective outcome measures including a lack of standardization of inclusion criteria, botulinum toxin injection technique, and outcomes. The data are derived from a heterogeneous cohort of cancer survivors who vary widely in their radiation fibrosis-related complications. As such, any conclusions derived from the present data should be taken as only preliminary and in need of validation in future prospective studies that should be more focused in terms of the study population, specific disorder addressed, and outcome measures.

Despite these significant limitations, this preliminary report on the use of botulinum toxins in RFS is encouraging because the majority of patients encountered in our initial clinical experience as reported in this series are those who had been treated aggressively with traditional first-line modalities such as high-dose opioids and muscle relaxants and were thought to be refractory. It is also important to note that many of the procedures were considered palliative (26% of patients were deceased at 18mo) when they were performed but nearly all were deemed to be beneficial to the patient clinically. Most of the patients underwent the procedure several times and reported a marked worsening of their symptoms as the botulinum toxin wore off. Injections were usually repeated at 6-week intervals, which was the approximate duration of effect in most patients in our study. Injection location and dosage were usually modified from procedure to procedure to optimize the beneficial effects or to minimize complications such as dysphagia. Complications were rare but usually occurred within 3 to 7 days of the procedure and all resolved spontaneously. It should be noted that we are extremely careful in terms of dose and dose escalation when injecting the anterior neck of patients with pre-existing swallowing difficulties and the posterior cervical musculature of patients with cervical weakness, so as not to worsen these conditions.

Elucidation of the components of RFS has been instrumental in targeting botulinum toxin therapy. We consider musculoskeletal and neuromuscular complications of RFS amenable to botulinum toxin injection to fall into one of 2 general categories. These broadly include painful muscle spasm (cervical dystonia, trismus) and neuropathic pain (trigeminal neuralgia, cervical plexus neuralgia, migraine), although overlap of pathogenic mechanisms likely exists.

Muscle spasm in RFS is thought to be due to spontaneous activity originating at one or more levels of the motor nerve including the anterior horn cell, nerve root, plexus, or peripheral nerve. Peripheral nervous system dysfunction in RFS results from ischemia due to progressive fibrosis and stenosis of the vaso vasorum, external compressive fibrosis of the skin and soft tissues, or both.16, 17 Motor nerve ectopy then results from focal demyelination, instability of the nerve membrane, and/or ephaptic cross-talk of neurons. Muscle spasms arise when these spontaneous motor nerve discharges cross the neuromuscular junction in sufficient numbers to activate the muscle.18 Persistent muscle spasms cause compression of the muscle’s blood vessels and tissue ischemia. This results in the release of factors such as bradykinin as well as a lowering of pH, which activates nociceptors and generates pain.19 Ectopic activity in the spinal accessory nerve may be causally related to the spasms of the sternocleidomastoid muscle and trapezius that often characterize cervical dystonia. The spinal accessory nerve is involved in the radiation field of many head and neck cancers because it receives a large contribution of fibers from upper cervical nerve roots and the cervical plexus.20

Progressive fibrosis in muscle fibers within the radiation field can cause a focal myopathy that is associated with nemaline rods.11 Myopathic muscles are weak relative to normal muscle and prone to spasm and pain. Cervical myopathy, cervical radiculopathy, and brachial plexopathy are commonly seen together in patients with RFS and may result in severe neck weakness and neck drop.

Our experience with needle electromyography in patients with RFS supports the contention that both peripheral motor nerve ectopy and focal myopathy can cause painful muscle spasms. Electromyography of muscles that lie predominantly outside the radiation field usually reveals copious fibrillation potentials and positive sharp waves as well as marked cramp potentials. The patient is often unable to fully relax the muscle of interest and motor units are usually neuropathic. Myokymia is only occasionally seen and complex repetitive discharges or rare. On physical examination, myopathic motor units with marked spontaneous activity can be seen in muscles within the radiation field, particularly if they are severely wasted. Neuropathic and myopathic motor units can coexist in the same muscle, and are commonly seen in severely wasted posterior cervical musculature. We rarely subject weak or predominantly myopathic muscles to botulinum toxin injection for fear of worsening weakness.

Pain in RFS can be caused directly by muscle spasms or damage to cutaneous sensory nerves, or can be referred in the distribution of an affected nervous structure such as the root or plexus. Similarly, pain may be indirectly caused by RFS as in the case of rotator cuff tendonitis wherein damage to upper cervical nerve roots or the upper brachial plexus causes weakness of the rotator cuff with subsequent perturbation of normal shoulder motion and the development of rotator cuff tendonitis.21 A tertiary adhesive capsulitis may also develop. More than 1 pain mechanism is commonly encountered in a given patient with RFS.

Our use of botulinum toxin to treat radiation-induced focal neuropathic pain disorders is based on the premise that ectopic activity in the sensory nerve is responsible for the generation of neuropathic pain via mechanisms similar to those that generate muscle spasms. Botulinum toxin has been postulated to inhibit the release of substances that subtend neural inflammation and thus peripheral sensitization. Early studies showed that botulinum toxin can inhibit the release of substance P from cultured rat dorsal root ganglion cells and regulate calcitonin gene-related peptide (CGRP) secretion from cultured rat trigeminal nerve cells.22, 23 These findings initially led to speculation that botulinum toxin injected peripherally would somehow be transported centrally to inhibit the release of pain neurotransmitters in the central nervous system. This speculation has not been supported experimentally because intact botulinum toxin cannot be detected centrally after peripheral injection. Other evidence suggests that the anti-nociceptive effects of botulinum toxin are in fact peripheral and are related to a dose-dependent decrease in the release of glutamate and most likely other pain neurotransmitters (substance P and CGRP) at the site of peripheral inflammation.24 Botulinum toxin-induced block of peripheral pain neurotransmitter release would inhibit nociceptor sensitization and thus pain. Indirect central effects likely result from the secondary inhibition of central sensitization that occurs as a result of hyperexcitability in the peripheral nervous system.25 The mechanism of inhibition of release of the peripheral neurotransmitters is most likely, as at the neuromuscular junction, related to the cleavage of synaptosome-associated protein with a molecular mass 25,000d and the resultant inhibition of vesicle release.26

Conclusions 

Our initial clinical experience with the use of botulinum toxin as adjunctive treatment for select neuromuscular and musculoskeletal complications of RFS in a variety of cancer patients has been encouraging with 87% of our initially treated patients reporting benefit. Many of the patients included in this series were only partially treated with conventional modalities such as opioids and muscle relaxants. Botulinum toxin injections were instituted on a compassionate basis and resulted in tremendous self-reported benefit in many of the patients. We have continued to modify our technique and targeting of injections and have progressed to using botulinum toxin as primary therapy in conditions such as radiation-induced cervical dystonia. Clearly, the need for a large, randomized, double-blind, placebo-controlled trial is indicated to compare botulinum toxin injection with placebo in several of the conditions included in this series. First among these conditions would be radiation-induced cervical dystonia, trismus, and trigeminal and cervical plexus neuralgia. Objective measures would vary among the indications but should include a standard pain assessment tool such as the visual analog scale, a quality of life instrument, and range of motion measurements for cervical dystonia and trismus if the botulinum toxin injections are studied in combination with physical therapy or a jaw opening device for cervical dystonia and trismus, respectively.