Brachial Plexopathy in Patients with Breast Cancer

Nathan I. Cherny

Pauline T. Truong

The brachial plexus is a somatic nerve plexus formed by intercommunications among the ventral rami of the lower four cervical nerves (C5-C8) and the first thoracic nerve (T1). The brachial plexus, which provides motor and sensory innervation of the upper extremity, is subdivided into roots, trunks, divisions, cords, and branches. Nerve roots exit through the vertebral interspaces joining to form the superior (C5-6), middle (C7), and inferior (C8-T1) trunk. The plexus trunks are located between the anterior and middle scalene muscles, bifurcating into anterior and posterior divisions within the supraclavicular fossa. These merge to form cords which pass over the first rib, coursing under the clavicle into the axilla. The terminal branches, located at the lateral border of the pectoralis minor muscle, include the axillary, musculocutaneous, radial, median, and ulnar nerves.

In patients with cancer, symptoms and signs of brachial plexus injury may be attributable to acute brachial neuritis, trauma to the plexus during surgery or anesthesia, metastatic spread of tumor, transient or permanent radiation injury, or radiation-induced tumors. In patients with breast cancer, metastatic spread of tumor, iatrogenic injury from radiation therapy and surgery, and second primary cancers are the most common causes of such signs. Careful evaluation of the clinical history, symptoms and signs, as well as electrodiagnostic and imaging studies are helpful in diagnosing the cause of a brachial plexopathy.

TUMOR INFILTRATION OF THE BRACHIAL PLEXUS (METASTATIC BRACHIAL PLEXOPATHY)

Despite the proximity to the draining axillary lymph nodes, tumor infiltration of the plexus is relatively uncommon. Even among specialist consultation services in a major cancer center, this diagnosis represented only 5% of the neurologic consultations evaluated by the neurology consultation service (1) and only 4% of patients referred to a cancer pain service (2). Early and accurate diagnosis is critical to prevent
irreversible nerve damage and chronic neuropathic pain and to determine the prognosis and treatment of the tumor.

Clinical Symptoms and Signs

Pain

Eighty-five percent of patients with tumor infiltration present with pain that is moderate to severe, often preceding neurologic signs or symptoms for up to 9 months (3, 4). The pain distribution depends on the site of plexus involvement. Typically, the pain radiates in the sensory distribution of the lower plexus, usually involving the shoulder girdle and radiating to the elbow, medial side to the forearm, and the fourth and fifth fingers (consistent with involvement of the lower plexus C7, C8, T1) (3, 4).

Other, less common clinical presentations are occasionally observed, including pain localized to the posterior aspect of the arm or to the elbow, a burning or freezing sensation and hypersensitivity of the skin along the ulnar aspect of the arm, or pain referred to either the shoulder girdle or the tip of either the index finger or thumb (consistent with infiltration of the upper plexus C5-6 by tumor rising in the supraclavicular nodes).

By the time of diagnosis of a brachial plexus lesion, 98% of patients have pain that is most often reported as severe. In Kori’s series (3), 2 of 78 patients with malignant brachial plexopathy had pain as the only symptom or sign of tumor recurrence and required exploration and biopsy of the plexus to establish the diagnosis.

Paresthesias

Paresthesias occur as a presenting symptom in 15% of patients with tumor, in an ulnar distribution from infiltration of the lower plexus, or with a median nerve distribution in lesions of the upper plexus.

Lymphedema

Lymphedema is rarely a presenting symptom of tumor infiltration of the brachial plexus (3, 4), but it does occur in about 10% of patients, most often in patients who received previous radiation therapy to the plexus and who subsequently develop recurrent tumor.

Weakness

Focal weakness, atrophy, and sensory changes in the distribution of the C7, C8, and T1 roots occur in more than 75% of patients. In one series of patients with brachial plexopathy arising from any tumor type, 25% of patients presented with whole-plexus motor weakness (panplexopathy) (3).

Horner’s Syndrome

Patients with a panplexopathy or a Horner’s syndrome have a higher likelihood of epidural extension and should undergo imaging of the epidural space as part of their evaluation.

Palpable Masses

Careful physical examination commonly reveals palpable supraclavicular or axillary lymphadenopathy. Occasionally, tumor infiltration in the distal plexus is associated with a palpable mass or fullness in the clavipectoral triangle. In all cases, these areas need careful evaluation.

Relationship to Natural History

In 12 of 78 patients with tumor infiltration of the brachial plexus included in the Kori series, the plexus lesion was the only evidence of tumor, and other metastases appeared only after several months (3). In two patients, the plexus lesion was the only sign of recurrence for 4 years. In one patient, surgical exploration after 2 years of plexopathy signs proved to be normal, but because of progressive worsening of neurologic signs, a second exploration was carried out, confirming tumor recurrence.

RADIATION INJURY TO THE BRACHIAL PLEXUS

Regional Nodal Radiation Therapy

Radiation therapy (RT) plays an important role in the curative treatment of women with early stage breast cancer. Randomized trials and meta-analyses have demonstrated that, in patients with node-positive disease, the addition of adjuvant radiation therapy to the regional lymph nodes improves locoregional control and survival compared to radiation to the breast or chest wall alone. Regional nodal radiation therapy generally includes the axillary and supraclavicular lymph nodes in patients with high risk disease. Late adverse effects from breast/chest wall RT, generally appearing months to years after treatment, may include skin and soft-tissue fibrosis, cardiac and lung injury, rib fracture, and secondary malignancies. Although very little of the plexus is usually exposed in radiation treatment of the breast or chest wall, the addition of radiation to the regional nodes can expose substantial portions of the plexus to the potential for radiation damage (5).

Pathophysiology of Radiation Injury

Factors that can contribute to radiation injury of the brachial plexus include age, total radiation dose, dose per fraction, radiation treatment volume, length and volume of the plexus receiving radiation, and combined chemotherapy (6, 7).

There are three possible types of peripheral nerve damage after radiation therapy:

A very high dose of radiation may cause severe vascular damage to the blood vessels supplying a segment of a nerve. This type of peripheral nerve damage occurs within months to years after irradiation.
Extensive fibrosis of the adjacent and overlying connective tissues may damage a peripheral nerve trunk situated within intact tissue. This tends to be a very late phenomenon, occurring many years after radiation.
Extensive fibrosis of the adjacent and overlying connective tissues may damage a peripheral nerve trunk situated within tissues previously subjected to surgical dissection. The microvascular disruption caused by the previous dissection makes these tissues more vulnerable, and, consequently, fibrosis may develop more rapidly, after a few months to years.

Fibrosis and decreased vascularity may destroy peripheral nerves and prevent the regeneration of their proximal normal portions. The degree of connective tissue injury at the time of or preceding radiation therapy may be important in influencing the subsequent development of connective tissue fibrosis.

Clinical Syndromes of Radiation-Induced Brachial Plexopathy

Three distinct clinical syndromes of brachial plexopathy related to radiation therapy have been reported in patients with breast cancer: (i) reversible or transient radiation injury, (ii) ischemic brachial plexopathy, and (iii) radiation fibrosis of the brachial plexus. All three are uncommon
clinical entities, each with a characteristic clinical presentation and course.

Transient Radiation Injury

Transient brachial plexopathy has been described in breast cancer patients immediately following radiotherapy to the chest wall and adjacent nodal areas. In retrospective studies, the incidence of this phenomenon has been variably estimated as 1% to 20% (8, 9 and 10).

In a retrospective study of 63 patients, Fulton et al. reported radiation-induced plexopathy in 19 cases, including 14 with transient and 5 with permanent injury (8). Transient plexopathy did not appear to predispose patients to the development of permanent plexopathy. In a review of 565 patients treated with adjuvant radiation doses of 50 Gy in 5 weeks using megavoltage radiation therapy, Salner et al. identified 8 (1.4%) cases of transient brachial plexopathy (9), with the onset of symptoms occurring 3 to 14 months (median 4.5 months) following irradiation. Seven of 8 patients received adjuvant chemotherapy; in 6 patients, symptoms began following drug treatment. There was a temporal clustering of these cases, suggesting a possible neurotropic viral component. The symptoms and signs of paresthesia and weakness did not conform to any anatomical pattern, but most commonly affected the distribution of the lower plexus. Weakness occurred in 5 of 8 patients, and was profound in two cases. All patients regained full strength. In 3 patients, residual paresthesias persisted.

In contrast to older series, clinical experience in the modern era suggests that lower estimates are more accurate. In a long-term follow-up study of 1,624 patients, Pierce et al. found that radiation-induced plexopathy was transient in 16 cases. Mild symptoms, with minimal pain and weakness, were predictive of resolution (11). Similarly, in a series of 419 patients who received radiation to the axillary nodal region, Galper et al. reported that 5 (1.2%) developed a transient brachial plexopathy (10).

Radiation-Induced Ischemic Brachial Plexopathy

Case reports during the era of extensive nodal surgery and outdated radiation techniques have described radiationinduced ischemic brachial plexopathy arising decades after treatment. Gerard et al. reported a case of subclavian artery occlusion occurring 19 years after radiation to the breast and axillary nodes following radical mastectomy (12). The patient’s symptoms occurred acutely after carrying a heavy object and holding her left arm outstretched above the shoulder. The syndrome was acute in onset, nonprogressive, and painless, in contrast to the typical progressive nature of radiation fibrosis. Rubin et al. described one case of radiation-induced arteritis of large vessels and brachial plexopathy occurring 21 years after local radiation for breast cancer. Arteriography revealed arteritis, with ulcerated plaque formation at the subclavian-axillary artery junction, consistent with radiation-induced disease, and diffuse irregularity of the axillary artery. The risk of this uncommon entity in contemporary practice is unclear but is likely rare with the use of less extensive nodal surgery and modern techniques in radiation therapy planning, which optimize dose homogeneity and limit normal tissue exposure.

Radiation Fibrosis

Radiation fibrosis of the brachial plexus is a well-described clinical entity characterized by progressive and irreversible neurologic dysfunction of the brachial plexus. The risk of developing chronic brachial plexopathy has been estimated as 0.6% to 14%, varying with study era, radiation therapy prescription and techniques, and other treatment factors, including extent of nodal surgery and the use of chemotherapy (3, 13, 14 and 15).

Symptoms and Signs: Symptoms of radiation fibrosis, including weakness, paresthesia, and pain, typically develop months to years after radiotherapy (13, 16, 17) though in many cases no latency is apparent (18). The natural history of brachial plexus fibrosis is variable. Motor dysfunction may be incomplete or may progress to a severe paresis (18). Even with advanced radiation fibrosis, severe pain is relatively uncommon at presentation and its presence should prompt evaluation for recurrent tumor (3).

Weakness Arm weakness is the dominant symptom of radiation fibrosis. Motor weakness typically involves the muscles innervated by the upper plexus alone or both the upper and lower plexus (3, 4, 16, 18). Weakness in a distribution of the lower plexus alone is uncommon (18).

Pain Although pain is a presenting symptom in less than 20% of patients with radiation injury to the brachial plexus, its prevalence increases with time (3, 18, 19). The pain is commonly described as mild discomfort associated with aching pain in the shoulder or hand. At the time of diagnosis, 65% of patients will report discomfort or pain in the arm; in 35%, it is severe (3).

Parasthesias In over 50% of affected patients, paresthesias are a prominent symptom (3). They are commonly reported to occur in the thumb and forefinger but often involve the entire hand. These symptoms are often confused with carpal tunnel syndrome but may be differentiated clinically and by electrodiagnostic studies.

Lymphedema Lymphedema of the ipsilateral arm was observed in 16 of 22 patients with radiation fibrosis in Kori’s series (3) and in a substantial proportion of those reported by others (4). Olsen et al. found that lymphedema is a common late consequence of radiation therapy that occurs in approximately 25% of patients, and that it was not predictive of brachial plexus fibrosis (20).

Radiation Skin Changes Radiation skin changes were noted in approximately one-third of the patients with radiation injury, but these changes were not predictive of an underlying plexopathy (3).

Uncommon Osteoradionecrosis of the ribs and, rarely, of the humeral head can be noted on plain radiographs (21). Horner’s syndrome is occasionally present (4, 18).

Radiobiology and Dose Fractionation Considerations

Tumors and normal tissues differ in their sensitivities to radiation therapy. The therapeutic ratio of radiation therapy, which represents the balance between maximizing tumor control versus minimizing normal tissue complication, is affected not only by the total radiation dose, but also by the fraction size or dose per fraction, overall treatment time, and volume of normal tissue exposure. Radiobiological models based on cell culture experiments and clinical studies have been developed to describe the sensitivities of tumor and normal tissues to different fractionation schedules (22). The most widely used model is the
linear-quadratic equation, in which the Biological Effective Dose (BED) = Total Dose (TD) × (1 + Dose per Fraction/α/β ratio). This model, which assumes dual mechanisms for cell kill resulting in nonrepairable (α) and repairable (β) damage, predicts that the biological effect of radiation will be directly proportional to the total dose and dose per fraction (22, 23). In the evaluation of different dose fractionation regimens, this equation can be used to calculate the biological effective dose and determine the isoeffective dose in tumors and normal tissues with similar kinetics.

Much of the data reporting high rates of radiationinduced brachial plexopathy in patients with breast cancer were from older eras that used techniques that result in field overlap, equipment such as orthovoltage and Cobalt units, and dosing schedules that would be considered suboptimal by modern standards.

The most commonly used fractionation schedules in North America for adjuvant radiation therapy for breast cancer deliver 1.8 to 2 Gy per fraction, 5 days a week to total dose of 45 to 50 Gy over 5 weeks. The risk of brachial plexopathy associated with conventional fractionation nodal irradiation using 2 Gy per fraction delivering a biological effective dose of 50 Gy or less to the plexus is approximately 1% (11, 24). In a series of 1,624 patients treated with breast conserving surgery and adjuvant radiation therapy with a median follow-up time of 79 months, Pierce et al. reported that nodal radiation therapy, chemotherapy use, and total radiation dose to the axilla were factors significantly associated with the development of brachial plexopathy. Among patients treated with nodal irradiation, the incidence of brachial plexopathy was 1.3% with total doses of 50 Gy or less to the axilla, compared to 5.6% with total doses greater than 50 Gy (11). In a study with 449 patients treated with postoperative radiation therapy to the breast and lymph nodes who were followed for 3 to 5.5 years, Powell et al. reported that the incidence of brachial plexopathy was 5.6% in 338 patients who received 45 Gy in 15 fractions (dose per fraction 3 Gy, BED 56 Gy in 2 Gy fractions) and 1% in 111 patients who received 54 Gy in 27 to 30 fractions (dose per fraction 1.8 Gy, BED 51 Gy in 2 Gy fractions) (24). Although the difference was not statistically significant (p = .09), the observation of a higher risk of brachial plexopathy in association with the use of both a higher dose per fraction and a higher biological effective dose is in keeping with radiobiological principles described by the linear-quadratic model.

The last decade has witnessed renewed interest and debates regarding the safety and efficacy of altered fractionation regimens, in particular hypofractionation or the delivery of a higher dose per fraction and smaller number of total fractions. Radiobiological modeling suggests that if the α/β ratio of a tumor is similar or less than that of the critical normal tissue, then hypofractionation with a concomitant reduction in total dose may confer similar tumor control and normal tissue effects compared to conventional fractionation (25). Hypofractionation is supported by data from randomized controlled trials compared to conventional fractionation radiation therapy in women with early breast cancer (26, 27, 28 and 29). In the Standardization of Breast Radiotherapy (START) B trial from the United Kingdom, 2,215 women with early-stage breast cancer were randomized between 1999 and 2001 after primary surgery to radiation therapy 50 Gy in 25 fractions with 2 Gy per fraction over 5 weeks versus 40 Gy in 15 fractions using 2.67 Gy per fraction over 3 weeks. Regional nodal radiation was delivered in 7% of enrolled subjects (29). Brachial plexopathy was prospectively evaluated and was reported if damage to the brachial plexus was suspected and the patient had symptoms of pain, paresthesia, numbness, or other sensory symptoms graded on a 4-point scale. Suspected cases of brachial plexopathy were subject to confirmation by neurophysiological assessment and MRI. At a median follow-up of 6 years, locoregional control was equivalent, and there were no cases of brachial plexopathy in 82 women who received 40 Gy in 15 fractions or in 79 women who received conventional fractionation 50 Gy in 25 fractions to the regional nodes (29).

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