Introduction
In its simplest form a peripheral nervous system injury is described as a lesion or damage to one or more of the nerves located outside of the brain and spinal cord. Causes are extensive and presentations may be highly variable. There are known congenital, nutritional, metabolic, and traumatic etiologies, among others. In the realm of oncology, peripheral nerve injuries are a widely recognized, but still likely underreported, complication of both the cancer itself and its treatment. Prompt diagnosis and subsequent management is of utmost importance, as these types of nerve injuries may have a detrimental effect on both function and quality of life. While no cancer type is necessarily exempt, this chapter will focus on nerve injuries as they relate to breast cancer and its treatment.
Patients with breast and gynecological cancers may experience damage to the nerves as a result of a number of different mechanisms. Direct neuromuscular effects may occur due to direct tumor compression or leptomeningeal disease (LMD). Paraneoplastic syndromes, such as stiff-person syndrome, occur as an immune response triggered by the cancer. Treatment may ultimately affect the nervous system as well. Chemotherapeutic treatments may cause length-dependent neuropathies. Radiation has the potential to cause an inflammatory state within the radiation field, which, in turn, may cause brachial or lumbosacral plexopathies depending on the location. Surgical procedures, including mastectomies and debulking surgeries, may also potentially cause some form of nerve damage.
Physicians specialized in cancer rehabilitation assist with the diagnosis and treatment of these types of injuries, among others. A detailed history along with a neurologic examination and further workup, including blood values, specialized neuroimaging, and electrodiagnostic studies, are warranted in the evaluation of nerve injuries. The importance of a clear diagnosis is twofold, both in providing a functional prognosis and subsequent management, including treatment and determining if oncologic management requires modification. In this vein, cancer rehabilitation specialists collaborate closely with oncologists, therapists, and other health-care professionals. Early intervention, including prevention, identification, and treatment, can reduce the occurrence of functional limitations.
Direct Neuromuscular Effects
Mononeuropathy
Focal mononeuropathies related to cancer may occur as a result of direct compression or infiltration from a primary tumor or metastases. Tumors arising from nerve components are typically benign, such as schwannomas and neurofibromas. Metastases to individual nerves are rare. Clinical presentation is dependent upon the individual nerves being affected. In patients with breast and gynecological cancers, mononeuropathies more commonly result as an indirect complication from the cancer or treatment, such as rapid weight loss resulting in a peroneal nerve compression neuropathy or median neuropathy arising from lymphedema.
Plexopathy
It has been estimated that neoplastic (tumor) brachial plexopathies occur with a frequency of approximately 0.43% in patients with cancer, most commonly occurring in those with lung (37%) and breast (32%) cancers. These types of plexopathies are divided into primary and secondary. Primary neoplastic plexopathies are rare and most commonly benign in nature. Of these, schwannomas are the most common (83%), followed by neurofibromas (9%). Less commonly, these tumors are malignant, such as malignant peripheral nerve sheath tumors (9%). Secondary neoplastic plexopathies are considered malignant and tend to occur as a late-stage complication of cancer. They occur as an extension and infiltration of either the primary tumor or metastases causing compression. Similarly, malignant lumbosacral plexopathies may also occur. While still rare, literature suggests that neoplastic lumbosacral plexopathies occur more frequently in patients with prostate cancer (through proliferation through the plexus) and less frequently in ovarian cancer (which tends to involve pressure on the lumbosacral plexus).
Clinically, pain is the most common presenting symptom (75%–98%), followed by the development of weakness and sensory deficits. Distribution of symptoms is dependent on the anatomic location of the lesion. MRI, CT, and positron emission tomography (PET) scans all serve diagnostic purposes, with MRI scans providing the best anatomic detail. While tumor plexopathies may involve the whole plexus, electrodiagnostic studies have shown involvement of the lower trunk and medial cord occurring more commonly. Treatment commonly involves local radiation therapy with improvement of pain in approximately 46%–86% of patients. Patients may benefit from early intervention utilizing a multimodal approach, including physical and occupational therapy, bracing evaluation, analgesics, and specialized procedures, such as regional nerve blocks.
Radiculopathy
Osseous metastatic disease in breast cancer may present as osteoblastic, osteolytic, or mixed lesions to the bone and can increase the risk for skeletal-related events, defined as pathological fractures, spinal cord or nerve root compression, and bone pain or impending fracture requiring radiation therapy or surgery. In patients with breast cancer, approximately 5% present with metastases at the time of their initial diagnosis, with bone being the most common site. Postmortem evaluation has demonstrated evidence of metastatic osseous disease in up to 70% of patients. There appears to be a predilection for the spine, accounting for two-thirds of osseous metastases in patients with breast cancer. Furthermore, one-third of these lesions to the spine become symptomatic, resulting in pain and neurologic deficits. While they may occur, osseous metastases are much less common in gynecologic cancers. Literature suggests the incidence of primary bone metastases in endometrial cancer is less than 1%. Complications may involve spinal cord compression and pathologic fractures. Prognosis is typically poor, and patients are usually treated with palliative radiation for pain control and improved quality of life.
Any patient with cancer presenting with new onset back or neck pain warrants a thorough, detailed evaluation. Pain in the thoracic spine is more suspicious for metastatic disease as symptomatic degenerative disease more commonly involves the cervical and lumbar regions. After spinal stenosis and disk disease, tumors involving the spine are the most common causes of radiculopathy and result in compression or irritation of individual nerve roots via tumor infiltration. Radicular pain is commonly described as shooting pain along the dermatomal distribution of a nerve root. As in nonmalignancy-related radiculopathies, weakness and sensory deficits may also occur. MRI of the spine is the gold-standard diagnostic modality, while PET and CT scans may also play a role depending on the type of osseous lesion. Treatment may consist of physical therapy with an emphasis on core and spine extensor strengthening, neuromodulators, radiation therapy, and surgical nerve root decompression.
Leptomeningeal Disease
LMD refers to the infiltration of the meninges surrounding the brain and spinal cord by malignant tumor cells. Along with lung and melanoma, breast cancer is among the most common types of cancers associated with LMD. It has been shown to occur in approximately 10%–25% of patients with breast cancer who have developed metastases to the central nervous system (CNS). Furthermore, an increased incidence has been found in patients with triple-negative breast cancer (approximately 30%–40% of breast LMD), suggesting the presence of tumor-specific biological risk factors. Dissemination is believed to be secondary to hematogenous spread through arterial or venous circulation or lymphatic system spread. Tumor cell extension into the cerebrospinal fluid (CSF) from adjacent CNS disease is also thought to play a role. As with osseous metastases, LMD in gynecologic malignancies is considered rare.
Diagnosis may be difficult as patients can present with a highly variable constellation of symptoms, including both radicular and focal pain, paresthesias, weakness, areflexia, upper motor neuron signs, and cranial nerve involvement (most commonly oculomotor, facial, and auditory nerves). Clinical symptoms are thought to be related to disease infiltration of neurologic tissue. Patients may also exhibit nausea, vomiting, positional headaches, and altered mental status secondary to obstructive hydrocephalus increasing intracranial pressure. Up to 80% of patients are symptomatic at the moment of diagnosis. Furthermore, patients may exhibit a rapidly progressive neurologic decline depending on disease burden.
There is currently no gold-standard diagnostic evaluation. If there is a clinical suspicion for LMD, MRI with gadolinium contrast of both brain and spine, CSF cytology, and a detailed neurologic evaluation are all warranted. MRI findings may include enhancing nodules of the leptomeninges and sulcal, linear ependymal, and cranial nerve root enhancement. Imaging abnormalities have been found in approximately 70%–80% of patients. CSF studies may reveal the presence of tumor cells. While the sensitivity of these studies is limited, repeating CSF cytology increases sensitivity to above 90%. In addition to a neurologic evaluation, electrodiagnostic studies serve as an extension to the physical examination and can reveal findings consistent with a polyradiculopathy.
Similar to diagnostic evaluation, there is no generally accepted standard of care in the treatment of LMD. Treatment is personalized and dependent on disease burden, functional status, and associated medical comorbidities. Both radiation therapy and chemotherapy (intrathecal and systemic) can be utilized; however, overall prognosis is poor, for which treatment often times is considered more palliative than curative.
Paraneoplastic Syndromes
Paraneoplastic neurological syndromes (PNS) are a group of nonmetastatic syndromes affecting any part of the central and peripheral nervous system occurring in patients with cancer. They are not caused by direct invasion, rather thought to be induced by antigens expressed by tumor cells, or as an immune response triggered by the cancer. PNS are extremely rare and are estimated to occur in 0.01% of all patients with cancer. Among the most common malignancies associated with PNS are small-cell lung cancer (associated with Lambert–Eaton myasthenic syndrome), thymoma (associated with myasthenia gravis), and breast cancer (which may be associated with stiff-person syndrome). Gynecologic malignancies may also be associated with paraneoplastic syndromes. For instance, the incidence paraneoplastic subacute sensory neuropathy may occur in up to 33.3% of patients with ovarian cancer. Lambert–Eaton myasthenic syndrome, although as above, is more commonly associated with small-cell lung cancer and has also been associated with uterine leiomyosarcoma and small-cell carcinoma of the cervix.
Given that any component of the neuraxial continuum may be affected, clinical presentation is highly variable, and diagnosis may be challenging. Patients usually present with symptoms occurring over weeks to months, producing significant and progressive functional disability. PNS usually present in patients with no known cancer history, for which early identification is crucial. It has been estimated that in up to 80% of patients, cancer is diagnosed within months to years. One study demonstrated that the median time from neurologic symptom onset to diagnosis of breast cancer was 4 weeks. Diagnostic workup, including MRI of the brain and spine, CSF cytology, serum paraneoplastic antibodies, and electrodiagnostic studies, is recommended in patients with clinical suspicion for PNS. Treatment is focused on effective control of the underlying malignancy.
Peripheral Neuropathy
While chemotherapy-induced peripheral neuropathy (CIPN) is a more common manifestation of peripheral neuropathy in breast cancer, paraneoplastic neuropathies have also been described. Paraneoplastic sensory neuronopathies usually present as an acute or subacute onset of asymmetric pain and sensory loss more common in the upper extremities. Sensory ataxia and pseudoathetoid movements have been described; however, motor deficits are typically absent. As opposed to platin-induced peripheral neuropathy that predominantly affects proprioception and spares small-fiber modalities, paraneoplastic sensory neuronopathy examination reveals sensory loss to all modalities. Subacute sensory neuronopathy is thought to occur secondary to destruction of the dorsal root ganglion by cytotoxic T lymphocytes. It is described as the classic paraneoplastic peripheral neuropathy and while it may occur in breast cancer, it is more commonly seen in small-cell lung cancer with evidence of anti-Hu antibodies.
Some of the earliest reports of paraneoplastic sensorimotor neuropathy as a presenting symptom in breast cancer date back to the 1990s. Sensorimotor polyneuropathies may be more difficult to diagnose as the pattern of involvement may mimic polyneuropathy seen as a result of chemotherapy and other underlying medical conditions, such as diabetes mellitus. Clinical presentation is consistent with paresthesias, numbness, pain, and weakness in a stocking–glove distribution. The only differentiating factor may be a more rapid progression of clinical signs and symptoms compared to nonparaneoplastic polyneuropathy. Paraneoplastic sensorimotor polyneuropathy occurs more commonly with plasma cell dyscrasia, such as multiple myeloma; however, it may also be seen in association with both breast and lung cancers. Antineuronal antibodies, most commonly anti-Hu, anti-Yo, and anti-Ri, have been detected in approximately 85% of cases.
Stiff-Person Syndrome
Previously known as stiff-man syndrome, this syndrome of hyperactivity has both nonparaneoplastic and paraneoplastic variants. The nonparaneoplastic variant is associated with glutamic acid decarboxylase antibodies and is seen in patients with autoimmune diseases, such as diabetes mellitus type 1. While also considered an autoimmune phenomenon, the paraneoplastic variant is most commonly associated with antibodies against amphiphysin and more commonly detected in patients with breast cancer, although cases in patients with lung carcinoma and Hodgkin’s lymphoma have also been described. Stiff-person syndrome is classically characterized by the gradual onset of painful axial and proximal lower extremity muscle stiffness and rigidity. Muscle contraction may be sustained, resulting in abnormal posturing. Symptoms may be precipitated by certain triggers, such as emotional upset or a loud noise. While not entirely understood, pathogenesis is thought to include a B cell–mediated process. Electrodiagnostic evaluation is normal, with the exception of continuous motor unit activity on needle electromyography. Treating the underlying malignancy is essential. Additional symptomatic treatment may also include antispasmodics.
Treatment Related
Chemotherapy
Chemotherapy-Induced Peripheral Neuropathy
CIPN is a common and often times disabling toxicity associated with the administration of chemotherapy. While CIPN is a well-recognized phenomenon, it is likely underreported. Understanding the epidemiology of CIPN is vital as the onset and progression of symptoms may ultimately require modification or discontinuation of chemotherapeutic protocols.
A wide variation of CIPN prevalence exists, owing largely to the utilization of numerous different measurement tools and scales. These may include the National Cancer Institute Common Terminology Criteria for Adverse Events, CIPN Assessment Tool, Total Neuropathy Scale, and the Patient Neurotoxicity Questionnaire. Despite this wide variability, literature has shown that both prevalence and incidence continue to be high. One study, utilizing the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 in patients with breast cancer, demonstrated CIPN prevalence of 73%. Other studies have shown prevalence ranging from 53% to 97%. Despite such high statistics, prevalence has been shown to decrease after completion of chemotherapy—approximately 68% 1 month after completion of treatment, decreasing to 60% at 3 months, and down to 30% at 6 months. In regard to incidence, literature has shown that both the percentage of patients exhibiting symptoms related to CIPN and the severity of the symptoms increases with cumulative dosing.
While nearly all chemotherapeutic agents have been associated with peripheral neuropathies, there are specific groups that are notorious for expressing neurotoxic effects. Among these are the platinum-based antineoplastics (such as cisplatin and oxaliplatin), the vinca alkaloids (vincristine, vinblastine, vinorelbine), the taxanes (paclitaxel, docetaxel), proteasome inhibitors (such as bortezomib), and immunomodulatory drugs (such as thalidomide). Patients with breast cancer commonly undergo neoadjuvant or adjuvant treatment with taxanes. Patients with gynecologic cancers, including ovarian, endometrial, cervical, and uterine cancers, typically receive both platinum-based and taxane treatments. The mechanism of neurotoxic action is diverse and includes DNA and microtubular targets, causing cell division arrest and, ultimately, apoptosis. Altered microtubule function may disrupt vesicular axonal transport, leading to axonal loss via Wallerian degeneration. In addition to this, neurotoxic chemotherapeutic agents may cause oxidative stress, altered calcium homeostasis, membrane remodeling, immune processes, and neuroinflammation.
CIPN commonly presents as a symmetric, length-dependent, sensory more than motor polyneuropathy. As such, a typical stocking–glove pattern is seen with the majority of agents. Alternatively, a glove–stocking pattern may be seen with platinum compounds in the setting of direct cytotoxic effects causing neurotmesis. Patients describe a wide range of predominantly sensory symptoms including paresthesias, numbness, allodynia, and hypersensitivity to temperature. Loss of proprioception and vibration may also occur, causing difficulty with fine motor tasks and gait. Symptom onset may be acute to subacute during chemotherapy. A phenomenon described as “coasting” has also been observed with vinca alkaloids and platinum-based compounds, in which symptoms either continue to progress despite completion of treatment or patients who were previously asymptomatic start to develop new symptoms. Risk factors include underlying or preexisting peripheral neuropathies, duration of treatment, dosing and frequency of treatment, and coadministration with other neurotoxic agents. Obesity, insomnia, and mood disorders (such as depression and anxiety) have also been described as risk factors.
There is currently no standardized approach for the diagnosis of CIPN. Evaluation should be tailored to each individual patient and should begin with a detailed neurologic examination with close attention to sensation, strength, proprioception, vibration, gait, and balance. A neuropathy panel is valuable to evaluate for reversible causes of peripheral neuropathy, including diabetes mellitus, thyroid abnormalities, and nutritional deficiencies. Although not strictly necessary, electrodiagnostic studies may provide further diagnostic insight if presentation is atypical. Neuroimaging of the peripheral nerves is typically not indicated; however, if a compounding central cause is suspected, an MRI of brain and spine may be warranted.
Similarly, there are no standard preventative measures for CIPN. Cryotherapy has shown promising results with patient reported outcomes demonstrating a statistically significant reduction in patient reported outcomes. Studies, however, have been limited. Trials studying the neuroprotective effect of anticonvulsants, such as pregabalin have been inconclusive. Vitamins, such as alpha-lipoic acid and vitamin E, have also been studied. The majority of trials to date have predominantly offered a small sample size and low statistical power and have not provided significant conclusive evidence for clinically preventative measures. As of 2014, the American Society of Clinical Oncology clinical practice guidelines have not recommended any agents for the prevention of CIPN.
The treatment approach for CIPN is multimodal. Physical and occupational therapy should focus on individual deficits and impairments but typically includes focus on fine motor skills, nerve gliding techniques, strengthening, proprioception, and gait and balance training. Medications may also be used. Duloxetine has been shown to result in greater reduction in pain compared to placebo for painful CIPN. It should be noted, however, that SSRIs, such as duloxetine, may reduce the concentration of Tamoxifen via the CYP2D6 pathway, for which concurrent use is generally avoided. Neuromodulators, such as gabapentin and pregabalin, have been used anecdotally; however, supporting studies are limited. These medications may provide relief for positive symptoms (i.e., painful paresthesias, burning, sharp pain); however, they may provide little to no relief for negative symptoms (i.e., numbness).
Radiation
Radiation-Induced Brachial Plexopathy
Radiation-induced brachial plexopathy (RIBP) is a delayed, nontraumatic brachial plexus injury following radiotherapy to adjacent areas, including the chest wall, axilla, and neck. Frequency has been estimated to be between 1.8% and 4.9% in treated patients. A percentage of 40 to 75 of reported cases have been found to be associated with radiation therapy for cancers of the breast, followed by lung cancer, and then lymphoma. There does appear to be a correlation between the total dose of radiation and the risk of developing RIBP, with higher doses increasing the risk. Literature has shown that RIBP incidence has ranged from 66% in the 1960s when 60 Gy in 5 Gy fractions was the preferred dosing regimen to less than 1% with 50 Gy in 2 Gy fractions today.
While RIBP is a well-recognized phenomenon, the pathophysiology remains less understood. Radiation may cause direct neurotoxic damage to the mature nerve, including the axon and vasa nervorum, from ionizing radiation with additional secondary and progressive microvascular injury. Nerve trunk fibrosis with components of demyelination and axon loss has been found during surgery and at postmortem evaluation. Risk factors may be either treatment-related or patient-related. Treatment-related factors include total dose of radiation, dose per fraction, and treatment schedule. Chemotherapy, especially when dosed concomitantly, has been suggested to increase the risk as well. Patient-related factors may include advanced age, obesity, and underlying medical conditions such as hypertension, dyslipidemia, diabetes mellitus, and peripheral neuropathy.
There appears to be a delayed onset of neurological symptoms with median time to onset typically described at 1.5 years, however, ranging from 6 months to 20 years after completion of radiation therapy. Patients classically present with symptoms of paresthesias, which may decrease as numbness develops. Distribution of symptoms depends on the level of injury. Pain is typically less common. Weakness may develop later on, tends to be progressive, and may eventually result in paralysis of the affected upper extremity. Lymphedema may also be present, however, may concurrently develop as a result of ipsilateral lymph node dissection. Neurologic deficits tend to progressively worsen over the span of several years to the point of significant functional impairment in approximately two-thirds of patients. Spontaneous neurologic recovery at this point is much less likely.
It may be challenging to clinically distinguish neoplastic versus RIBP. In fact, both conditions may occur simultaneously. Classically, neoplastic brachial plexopathy has been described as more painful and having a predilection for the lower trunk while RIBP has been described as less painful and typically affecting the upper portion of the plexus. Plexus involvement, however, may be more diffuse than previously thought. Electrodiagnostic studies demonstrate myokymia on electromyography in approximately 60% of patients. It should be noted that while myokymia by itself is not pathognomonic for radiation-induced injury, it is assumed that this is in fact the etiology when it is present in patients who have received radiotherapy. It should be noted, however, that the absence of myokymia on electrodiagnostic studies does not rule out the possibility of radiation-induced injury. MRI of the brachial plexus remains useful in further evaluation of compressive or infiltrative lesions. In cases of RIBP, brachial plexus MRI may demonstrate linear areas of high signal intensity suggesting fibrosis. More proximal imaging of the cervical spine should also be considered to rule out confounding involvement of the cervical nerve roots.
When developing a treatment plan, expectations should be set given the known clinical trajectory and depending on the patient’s individual severity of symptoms. Physical therapy should focus on cervical, shoulder, and scapular range of motion and stretching exercises, chest expansion exercises, shoulder girdle and spine extensor strengthening, and myofascial release. Occupational therapy may also be beneficial for neuromuscular reeducation and fine motor skills. Intermittent bracing may be necessary to prevent development or progression of glenohumeral joint subluxation. If the patient is experiencing pain, neuropathic agents or a short course of prednisone may be considered. In addition, if the patient is experiencing lymphedema, it is reasonable to start a course of complex decongestive therapy and evaluation for compression garments.
Radiation-Induced Lumbosacral Plexopathy
Lumbosacral plexopathy secondary to radiation may also occur in patients with gynecologic malignancies. While this phenomenon tends to be rare, it has been shown to occur from 0.8% to 3.0% of patients with cervical cancer. Similar to RIBP, risk increases with radiation fraction dose, concomitant chemotherapy, and individual risk factors. Symptom onset may occur acutely during the course of irradiation, subacutely within 6 months of completion of treatment, or even years later, with sources citing up to 30 years from completion of course. The exact pathophysiology remains unclear, again, thought to be related to a state of direct neurotoxic damage. Of the few cases described, Georgiou et al. noted the predominant neurologic symptom is deficits of strength in the lower extremities. Diagnosis and subsequent management parallels that of RIBP.
Surgery
Postmastectomy Pain Syndrome
Breast cancer surgery typically includes breast-conserving surgery (lumpectomy) or mastectomy. The overall rate of mastectomies is on the uptrend, with data suggesting a 21% increase between 2005 and 2013. Mastectomies, however, are only one type of breast surgery. Others surgical procedures include lumpectomies (or breast-conserving surgery), axillary/sentinel lymph node dissection, reconstruction, and augmentation. Postmastectomy pain syndrome (PMPS) is a misnomer, as this chronic pain syndrome may occur with these other types of breast surgeries as well. PMPS is essentially a diagnosis of exclusion and is defined as pain developing postoperatively at or near the surgical site and persisting more than 3 months after all other causes of pain, including recurrence, have been ruled out. Incidence has been shown to range from approximately 20% to 68% of patients. This wide variation of incidence rates may be in part due to the absence of a consensus for the definition or diagnostic criteria of PMPS.
The pathophysiology is still not entirely understood. PMPS has traditionally been thought to be a neuropathic condition, specifically due to surgical damage to the intercostobrachial, medial pectoral, lateral pectoral, thoracodorsal, or long thoracic nerves. Neuromas and phantom breast pain may also contribute. Risk factors may include pain in other parts of the body, young age, history of axillary lymph node dissection, and adjuvant radiation therapy. Psychosocial factors, including depression, anxiety, and insomnia, may also increase the risk of PMPS.
Patients present with pain most commonly in the axilla, shoulder, arm, and area of the scar. Symptoms may begin acutely in the postoperative period or several months after the surgery, lasting beyond the expected timeframe for surgical recovery. Patients may describe lancinating or burning pain and hypersensitivity around the operative site. The severity of PMPS has been described as moderate and studies have shown that approximately 22% of patients reported pain impacting daily life. Given PMPS is a diagnosis of exclusion, diagnostic studies include those that assist in ruling out other etiologies. PET/CT scans may be useful if tumor recurrence is suspected. MRI of the neck, shoulder, or brachial plexus may rule out cervical radiculopathy, musculoskeletal causes, or injury to the plexus, respectively. Furthermore, electrodiagnostic studies may assist with potential diagnosis of cervical radiculopathy, brachial plexopathy, or peripheral neuropathy. Diagnostic interventional procedures may also be considered, such as intercostobrachial nerve block under ultrasound guidance. Other etiologies, such as infection and rib/sternal fractures, should also be ruled out.
There is currently no standard preventative measure; however, one randomized control study suggested perioperative oral pregabalin starting at the morning of surgery and continued for 1 week significantly reduced neuropathic pain in patients undergoing elective breast cancer surgery. Treatment is multimodal and includes physical therapy with focus on myofascial mobilization, early desensitization techniques, range of motion (neck, shoulder, and scapula), stretching (notably the latissimus dorsi and pectoralis musculature), and strengthening of the shoulder girdle and spine extensors. Pharmacologic interventions may also be indicated, including nonsteroidal antiinflammatories (when medically indicated) and coanalgesics such as neuromodulators, including gabapentin or pregabalin, and selective serotonin reuptake inhibitors, such as duloxetine. Interventional procedures, including intercostobrachial nerve block, stellate ganglion block, paravertebral block, and serratus plane block, may be beneficial. Surgical resection for painful neuromas may also be considered.
Debulking Surgery
Surgical debulking is a surgical procedure in which a surgically incurable malignant tumor is partially removed without curative intent, but instead to make adjuvant treatment with chemotherapy or radiation therapy more effective. In patients who may not be surgical candidates to begin with, whether it be due to stage of gynecologic disease or other medical contraindications, neoadjuvant chemotherapy followed by interval debulking surgery (IDS) may be an option.
Women undergoing primary debulking or IDS may also be at risk for peripheral nerve injury. One large multiinstitutional cooperative group study comparing operative morbidity of primary and IDS for advanced stage ovarian cancer demonstrated that patients who received IDS with chemotherapy had a significantly higher risk of peripheral neuropathy than women who received chemotherapy alone. Mononeuropathy may also occur. One case report described a rare case of obturator nerve diagnosed ultimately by electrodiagnosis in a patient with left thigh weakness after primary debulking surgery for left-sided ovarian cancer.
Indirect Nerve Injuries
Patient with both breast and gynecologic malignancies may also experience indirect involvement of the peripheral nervous system. Preexisting medical conditions, such as diabetes mellitus and thyroid disease, may cause an underlying peripheral neuropathy. Patients with cancer are often times immunocompromised and, as such, are at higher risk for secondary infections. Herpes zoster may become reactivated and cause postherpetic neuralgia. Toxic neuropathy may also develop as a result of extended use of antibiotic treatment for infections. Fluoroquinolones, linezolid, metronidazole, and nitrofurantoin, among others, have been shown to cause peripheral neuropathy. Critical illness itself may also cause peripheral neuropathy. Usually presenting as flaccid and symmetric weakness, it has been estimated to occur in 25%–45% of patients admitted to the intensive care unit. Weight loss as a complication of malignancy may also cause neuropathy as seen in compression neuropathy of the peroneal nerve at the fibular head. Malnutrition, in turn, may cause vitamin B12 deficiency, ultimately causing demyelination of sensory nerve fibers.
Conclusion
With an estimated 3.1 million survivors in the United States alone, breast cancer is the most common noncutaneous cancer diagnosed in females. The American Cancer Society’s current estimates suggest that there will be approximately 270,000 new cases of breast cancer diagnosed in the United States in 2019. While gynecologic cancers are far less common than breast cancer, the CDC estimated that between 2012 and 2016, approximately 94,000 women were diagnosed with gynecologic cancers per year.
Given these and statistics for other types of cancer, it can easily be suggested that, regardless of subspecialty training, the majority of clinicians will treat patients who have or have had some form of cancer. It is crucial for clinicians to have at least a basic understanding of neurologic complications of both cancer and its treatment. As demonstrated with paraneoplastic neurologic syndromes, the majority of cases occur in patients without a prior diagnosis of cancer, thus making early recognition and intervention a pivotal component of the evaluation.
It is equally important for clinicians to educate their patients on potential neurologic complications related to their cancer and treatment. Patients should be aware that certain chemotherapeutic agents, such as taxanes and platins in breast and gynecologic cancers, may cause peripheral neuropathy. Clinicians should be able to manage expectations in regard to radiation therapy and educate their patients on potential lifelong complications related to radiation-induced injuries. Patients should also be educated on expectations in regard to pain management and early intervention after surgical treatments to minimize postoperative pain and dysfunction. Patient education, management of expectations, and reassurance are undoubtedly vital components of the treatment plan in patients with breast cancer.
References
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