Brachial plexopathy after breast cancer: A persistent late effect of radiotherapy

Radiation‐induced brachial plexopathy (RIBP) is an iatrogenic, progressively disabling, and often very late effect of adjuvant radiotherapy most commonly seen in breast cancer survivors but also in those treated for lymphoma, lung, and head and neck cancers. In late‐onset RIBP following breast cancer, the nerve injury is chronic and irreversible, occurring more commonly when axillary and/or supraclavicular nodes have been irradiated, as well as the breast/chest wall. RIBP is manifested initially by paresthesia, hypoesthesia, dysesthesia, and later by weakness in the ipsilateral hand with those symptoms progressing distally to proximally up through the shoulder. Depressed/absent deep tendon reflexes in the upper extremity and muscle fasciculations occur also. Neither patients nor their health care providers tend to associate these unusual neurological symptoms with cancer treatments received ≥20 years prior, often failing to link these sensory‐motor symptoms with radiotherapy decades before. Because long‐term follow‐up of these patients now typically falls to general practitioners, many cases may be missed or misdiagnosed because of the rarity of this disorder. Physiatrists and allied rehabilitation professionals must be aware of this progressively disabling, incurable condition to provide appropriate diagnoses and compensatory rehabilitation therapies. Additionally, professional oncology organizations should include RIBP in their long‐term, survivorship guidelines for breast cancer. Researchers examining the iatrogenic late effects of radiotherapy should extend their follow‐up periods well beyond the current 5–6 years to ascertain the true incidence of RIBP today. Rehabilitation providers must continue to advocate for awareness, diagnosis, and management of iatrogenic outcomes experienced by long‐term cancer survivors.


INTRODUCTION
][5] Whereas chemotherapy-induced peripheral neuropathy (CIPN) has gained increasing research attention, especially since the introduction of taxanes for adjuvant treatment of breast cancer more than 2 decades ago, 6 the interest appears to have waned in RIBPdue, perhaps, to declining rates of this disorder secondary to lower and more targeted doses of adjuvant radiation. 7or example, changes in radiotherapy delivery over the past couple of decades (eg, hypofractionation, imageguided radiotherapy, intensity-modulated radiation, prone positioning radiotherapy, proton beam therapy), [8][9][10][11] could possibly reduce the incidence and severity of RIBP.
The purpose of this narrative review is to focus primarily on RIBP following treatments for breast cancer, based mainly on research articles, case reports, and case series published within the past 20 years.This article first describes the clinical characteristics of RIBP and risk factors for its development, how to differentiate RIBP from axillary recurrence, clinical and electrodiagnostic strategies for identifying RIBP, the historical and current estimated incidence of the disorder and its therapeutic management.Finally, it is postulated that RIBP continues to occureven todayas a very late effect of treatment, despite advances made in reducing radiation doses and improving beam targeting.Because long-term follow-up of breast cancer patients typically falls now to general practitioners and other primary care providers, it is imperative that both generalist and specialist physicians (eg, oncologists, physiatrists, and neurologists), as well as nurse practitioners and allied rehabilitation professionals (eg, physical and occupational therapists), be aware of this rare but disabling condition sometimes appearing as late as 20-30 years after treatment.

Search strategy
A PubMed search in February 2023 of "radiationinduced brachial plexopathy" yielded 60 citations.When "AND breast cancer" was added, there were only 33 PubMed references (1984-2022): eight clinical studies (including one randomized controlled trial), 16 case reports or case series, eight narrative reviews, and one quantitative analysis of an RIBP questionnaire.The preponderance of case reports and case series (and predominantly small-n clinical trials) is not surprising given the rarity of identified cases of RIBP.

Clinical characteristics of radiation-induced brachial plexopathy
In late-onset RIBP, radiation-induced fibrosis leads to compression of the nerves, further complicated by direct nerve injury via axonal damage and demyelination as well as ischemic blood vessel injury. 12The nerve injury is chronic, progressive, and irreversible, occurring more commonly when axillary and/or supraclavicular nodes have been irradiated, 13 as well as the breast or chest wall.Based on brachial plexus anatomy, radiation to the axillary lymph nodes will result predominantly in lower trunk plexus involvement (C8-T1) whereas radiation to the supraclavicular nodes will lead to upper trunk plexopathy (C5-C6).The entire plexus will be involved in about 25% of cases of RIBP. 74][15] Depressed or absent deep tendon reflexes in the involved upper extremity are common also, 14 as are muscle fasciculations or involuntary twitches in the hand and arm. 13Muscle atrophy also occurs in a distal to proximal fashion, resulting ultimately in a flail upper extremity (see Table 1). 7he initial clinical examination should include also the contralateral upper extremity to rule out CIPN, which typically occurs bilaterally as a result of systemic treatment (eg, taxanes or vinca alkaloids). 16ased on my own clinical experience, neither patients nor their health care providers, even medical oncologists in some cases, tend to associate these unusual neurological symptoms with cancer treatments received as long as 20 years before.In addition, former breast cancer patients often fail to link these sensory-motor symptoms with radiotherapy occurring often decades before.Because longer-term follow-up of these patients now typically falls to general practitioners/primary care physicians, many cases may be missed or misdiagnosed because of the rarity of this disorder. 17lthough RIBP can occur within months of receiving radiation treatment, that manifestation is less common, mild and usually short termwhereas late or very late versions tend to be more severe with progressive distal to T A B L E 1 Differential diagnosis of RIBP and axillary recurrence.proximal weakness in the involved upper extremity, including significant loss of strength and dexterity in the fingers and hand, a factor that is especially functionally disabling if the dominant upper extremity is the one affected. 18ecause there are several disorders that have symptoms mimicking those of RIBP (eg, carpal tunnel syndrome, thoracic outlet syndrome, amyotrophic lateral sclerosis), 13 immediate referral to a neurologist or physiatrist for electrodiagnostic testing is paramount. 19In addition, it is critically important to differentiate RIBP from cancer recurrence in the axilla as soon as possible because treatments for the two conditions are very different.

Risk factors for developing RIBP
Clearly the greatest risk factor for developing RIBP is the overall radiation dosage, with total doses >55 gray (Gy) increasing the risk. 20,21Research has shown that a posterior axillary radiation boost contributes further to increasing this risk. 22The number of axillary lymph nodes removed is also significantly related to developing RIBP, 22,23 as is concurrent chemotherapy. 20,21In a 2017 study, smoking, diabetes mellitus, and irradiation of supraclavicular nodes were significantly associated with later RIBP as was the number of axillary lymph nodes removed, with a greater number of lymph nodes removed increasing that risk. 24

Differentiating RIBP from axillary recurrence
Both sensory and motor nerve conduction studies, as well as electromyography (EMG), are needed to reliably diagnose RIBP and to aid in differentiating late radiation plexopathy from metastatic axillary recurrence. 25hereas severe pain typically accompanies recurrence, there is little pain associated with radiation-induced plexopathy. 20As well as employing nerve conduction studies and EMG to assist in confirming a diagnosis of RIBP, additional investigative procedures are needed to rule out metastatic recurrence in the brachial plexus as an even more serious potential cause of muscle weakness and other neurological symptoms in the involved upper extremity.Magnetic resonance imaging (MRI) of the axilla can reveal relatively large tumors, whereas positron emission tomography (PET) scan is preferable for smaller lesions. 26MRI findings specific to RIPB include thickening of the involved plexus nerves and absence of a discrete mass representing metastasis. 27luorodeoxyglucose PET/computed tomography (CT) has been recommended as an adjunctive modality to MRI in differentiating RIBP from neoplastic plexopathy. 26,27According to a case report by Soydal et al., 28 18F-fluorodeoxyglucose PET/CT was especially helpful in differentiating metastatic plexopathy from RIBP.
Distinguishing between these two entities at their outset is critical to informing treatment planning (see Table 1).

Diagnosis of RIBP
Nerve conduction studies show segmental slowing in RIPB 17 whereas, during EMG assessment, myokymia (repetitive firing of nerve units due to nerve hyperexcitability) is frequently pathognomonic for the condition (although the absence of myokymia does not exclude an RIBP diagnosis). 25,26Furthermore, in lower trunk brachial plexopathies, sensory nerve action potentials (SNAP) amplitudes will be normal in the median sensory nerve but reduced in the ulnar and medial antebrachial sensory nerves. 19,23The presence of clinical symptoms such as muscle fasciculations, weakness, paresthesia, and diminished or absent deep tendon reflexes in the involved upper extremity contribute also to the diagnosis of RIBP (see Table 2).

Historical and current estimated incidence of RIBP
According to the results of a seminal 2000 study by Johansson et al. 29 examining the postoperative effects of radiotherapy in breast cancer patients treated in the mid-1960s, the cumulative incidence of RIBP was a staggering 63% at 34 years of follow-up, leading the authors to conclude: "Only long-term follow-up can determine the ultimate risks of radiotherapy."Another report provided examples of RIBP presenting as late as 20 years after radiation treatment for breast cancer, 30 as did a recent case report. 18n a 2019 systematic review of radiation dose tolerance of the brachial plexus, 22 of the 37 cohorts (59.5%) in studies published between 1966 and 2017 reported an RIBP incidence of ≤5%; however, the median length of follow-up for all of the cohorts was only 2.5 years. 4thers have suggested rates of plexopathy as low as 1%-2%. 12,22,35][33][34] Over the years, several groups of researchers have postulated that the incidence of chronic RIBP could be on the rise due to the increased length of survival of persons with breast cancer. 17,29,31In fact, the U.S. death rate from breast cancer declined by 40% between 1989 and 2017, 36 thus supporting increased longevity from the disease with a greater opportunity for developing very late effects of treatment.Recently published case reports support the finding that very late effects of radiation therapy (after 15-20 years) continue to result in RIBP in survivors of breast cancer, 18,[37][38][39] as well as in a patient with nasopharyngeal cancer. 5As Bajrovic et al. 40 noted in their study of RIBP after supraclavicular lymph node radiotherapy: "a follow-up period of 5 years … is too short a time a time interval for recording the majority of lesions occurring in total."

Therapeutic interventions for RIBP
A review article on RIBP published in 2004 was subtitled "complication without a cure." 41Sadly, that description is still valid nearly 2 decades later.Treatments such as hyperbaric oxygen therapy have been shown to be ineffective for late breast cancer-related RIBP 18,42 and successful surgeries (eg, omentoplasty and nerve or muscle transfers) have been limited to case reports only. 38,43,44lthough phase II trials had shown promise for a combination of pentoxifylline and vitamin E in reducing symptoms of late RIBP, 45 a 2020 randomized controlled trial of pentoxifylline combined with tocopherol and clodronate in patients with very late radiation-induced brachial or lumbar plexopathy showed no differences in pain, paresthesia, or motor disability. 46Physical therapy, occupational therapy, and hand therapy may be beneficial in developing compensatory strategies for the loss of arm and hand function in activities of daily living. 7,18

DISCUSSION
2][33][34] Furthermore, the fact that a major clinical practice guideline on survivorship care (within the section devoted to management of long-term and late effects of treatment) failed to include this debilitating disorder as a late iatrogenic effect reinforces the suspicion that RIBP has essentially been "forgotten" by the medical community. 47rimary care practitioners as well as oncologists and physiatrists need to be aware that this irreversible condition persists and must refer suspected patients for neurological follow-up testing as well as MRI and PET/CT scans to diagnose or rule out metastatic plexopathy.Researchers conducting studies examining the iatrogenic late effects of radiotherapy should extend their follow-up period well beyond the current 5-6 years to ascertain the true incidence of RIBP in today's world.Although a 2014 meta-analysis reported the long-term benefits of postmastectomy radiotherapy (ie, after up to 20 years of follow-up), the authors failed to examine the disabling long-term side effects, such as RIBP. 48urthermore, influential professional groups, such as the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology, and others, must include RIBP as a potential late outcome of breast cancer treatment.A PubMed search (February 2023) of "breast cancer AND long-term survivorship guidelines" resulted in 64 articles.However, when "AND brachial plexopathy" was added to the foregoing search terms, there were zero results.
As Stout et al., 49, p 1 noted in their 2021 systematic review of rehabilitation and exercise recommendations found within oncology guidelines: "Guidelines promote high quality cancer care."Although there was no mention of RIBP specifically, the ASCO breast cancer guideline at least recommended rehabilitation interventions to improve functional limitations and other late effects of cancer and its treatments. 47p 21 A recently published editorial on the American Academy of Physical Medicine and Rehabilitation's (AAPM&R) cancer rehabilitation medicine core services included three symptom-specific, global impairments that relate directly to RIBP: musculoskeletal/neuromuscular disorders in cancer, radiation fibrosis syndrome, and cancer-related neuropathies. 50As well, one of the core procedures listed that is crucial to identifying RIBP was electrodiagnosis, encompassing EMG and nerve conduction velocity. 50

CONCLUSIONS
Although changes in the delivery of radiation therapy (eg, image-guided radiotherapy, intensity-modulated radiation, proton beam therapy) have advanced in order to minimize radiation toxicity, we continue to see patients newly diagnosed with RIBP, and there remains a dearth of long-term follow-up studies (ie, >5 years) involving these patient cohorts.Primary care providers, physiatrists, neurologists, and oncologists all need to be aware of this progressively disabling, incurable condition in order to refer patients for appropriate diagnosis and compensatory rehabilitation therapies.As well, professional oncology societies would be prudent to include RIBP in their long-term survivorship guidelines for breast cancer as well as including those for lymphoma and head and neck cancers.It is encouraging that AAPM&R has highlighted radiation fibrosis syndrome (which includes RIBP) under its core services impairments. 50inally, all of us who provide rehabilitative care must continue to advocate for awareness, diagnosis, and management of both the common and rare iatrogenic outcomes experienced by long-term cancer survivors.As Rudra et al. 23 concluded in their recent retrospective review of RIBP in 498 survivors of breast cancer, this disorder remains "a rare but devastating consequence" of adjuvant radiation therapy that appears to largely have been forgotten.

RECOMMENDATIONS
Based on this narrative review of the rare but complex condition known as RIBP, the author proposes the following recommendations: (1) physiatrists, neurologists, medical residents (eg, neurology, physiatry, internal medicine, family medicine residents) and other neurorehabilitation professionals (eg, nurse practitioners) should be educated about the fact that RIBP continues to occur in patients with breast cancer who received radiotherapy as long as 20 years ago (eg, via curriculum content additions for medical residents and educational materials developed for primary care practitioners); (2) professional oncology and rehabilitation societies would be prudent to include RIBP diagnosis and management within their clinical practice guidelines on longterm survivorship in breast cancer; (3) neurorehabilitation clinicians should be aware that physical therapy, occupational therapy, and hand therapy may be beneficial in developing compensatory strategies for the loss of arm and hand function in activities of daily living for patients with RIBP; and (4) researchers who examine the iatrogenic very late effects of radiotherapy must extend their follow-up periods well beyond the current 5-6 years to ascertain the true incidence of RIBP in today's world.This journal-based CME activity is designated for 1.0 AMA PRA Category 1 Credit™.Effective January 2024, learners are no longer required to correctly answer a multiple-choice question to receive CME credit.Completion of an evaluation is required, which can be accessed using this link, https://onlinelearning.aapmr.org/.This activity is FREE to AAPM&R members and available to nonmembers for a nominal fee.CME is available for 3 years after publication date.For assistance with claiming CME for this activity, please contact (847) 737-6000.All financial disclosures and CME information related to this article can be found on the Online Learning Portal (https://onlinelearning.aapmr.org/) prior to accessing the activity.
, and prognostic characteristics of RIBP.