Assessment of Neuropathic Pain in Cancer Patients Deborah T. Blumenthal, MD
Corresponding author Deborah T. Blumenthal, MD Oncology Division, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, 64239 Tel-Aviv, Israel. E-mail:
[email protected] Current Pain & Headache Reports 2009, 13:282–287 Current Medicine Group LLC ISSN 1531-3433 Copyright © 2009 by Current Medicine Group LLC
Neuropathic pain is an increasingly common problem facing the cancer patient. Painful neuropathy can come from various sources and significantly impact quality of life. The most commonly observed scenario is paraesthesia and dysesthesia as a result of toxic effects of chemotherapies on the distal peripheral nerves. Neuropathic pain should be addressed ideally with the help of a neuro-oncologist, and it usually can be successfully treated with a variety of agents, including atypical analgesics such as antidepressants, newer drugs with analgesic benefit, and opioids for more refractory cases. Direct and indirect effects of the primary neoplasm need to be considered in the etiology of specific syndromes of mononeuropathies and plexopathies.
burning, needle-like pain, or electric sensations. However, some cases are refractory to most agents and require a more aggressive approach with opioids. The element of hypoesthesia (numbness) is not effectively treated symptomatically and recovers only with nerve regeneration, which occurs slowly and not always completely, and is dependent upon the cumulative magnitude of the exposure to the toxic agent and the individual’s inherent sensitivity [1•]. Patients with underlying disorders such as diabetes may have enhanced sensitivity and lowered threshold to the effects of neurotoxic agents. In addition to neurotoxic chemotherapeutic agents, cancer patients may suffer from painful neuropathies due to direct involvement of their neoplasm in the form of mononeuropathies, radiculopathies, or plexopathies, or from paraneoplastic syndromes such as sensory ganglionopathy or vasculitic neuropathy. Adequate treatment of these syndromes usually demands control of the cancer.
Toxic Neuropathy From Chemotherapy Painful neuropathy is being seen with increasing frequency with the growing use of regimens with neurotoxic chemotherapy agents. The most common neuropathic scenarios seen in the clinic involve patients treated with platinum analogs (cisplatin, oxaliplatin), taxanes, and less commonly, fluorouracil (5-FU).
Introduction Neuropathic pain is a problem seen with increasing incidence in oncology clinics. With the increasing use of chemotherapy regimens, including neurotoxic agents, the clinician is commonly faced with the dilemma of assessing the etiology and degree of neuropathic pain and deciding what the threshold is to discontinue causative toxic treatment that may be important in controlling the primary neoplasm. The Common Toxicity Criteria (CTC) scale may be useful for assessing and grading the neuropathic injury, but there are no defi nitively established guidelines for when to discontinue therapy and how to predict irreversible or intolerable neuropathic toxicity. Elements of neuropathy and neuropathic pain may differ depending on the etiologic agent. Components of nonpainful paraesthesia, which can affect daily function, also need to be considered in the assessment. A number of typical and atypical analgesic agents can be helpful in ameliorating dysesthesias (unpleasant sensations),
Causative agents Most chemotoxic neuropathies are purely sensory and often involve an element of pain. Small and/or large sensory fibers may be involved. Cisplatin is a heavy metal platinum agent used largely in head and neck and gynecologic cancer regimens, usually in combination with other agents or radiation. It can cause a distal sensory neuropathy that involves the large myelinated sensory fibers, characterized by symmetric loss of distal sensory axons with proprioception deficit. Loss of vibratory sense may be proportionately large compared with other sensory modalities. The peripheral neuropathy associated with cisplatin may be associated with dorsal column spinal cord involvement and damage to the dorsal root ganglion, with clinical Lhermitte’s sign (an electric shock–like sensation involving the limbs or trunk, produced by neck flexion). Cisplatin causes selective damage to the hair cells in the organ of Corti, resulting in high-frequency
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hearing loss in 60% of patients treated with doses greater than 600 mg/m 2 . Neuropathy usually develops when cumulative doses exceed 400 mg/m 2 [2]. Long-term toxicity after a median of 15 years was studied in a cohort of patients treated with cisplatin for testicular cancer. Of these patients, 38% were found to have nonsymptomatic neuropathy, 28% had symptomatic neuropathy, and 6% had disabling polyneuropathy [3]. Oxaliplatin is a newer platinum derivative used as a standard agent in regimens for colorectal malignancies [4]. Although it has an improved toxicity profi le compared with older platinum agents, its dose-limiting toxicity is typically neurologic. Oxaliplatin may cause two distinct forms of neuropathy that can be disturbing for the patient. One form is a temperature-sensitive, (cold)-induced, acute, painful neuropathic syndrome that is usually time-limited to the day of treatment and several days thereafter. It manifests in perioral dysesthesias, tingling, and laryngopharyngeal spasms. This acute neuropathy occurs in a majority of patients to some degree early in their course of treatment; it is not cumulative and is reversible. The possible underlying mechanism may be a disturbance in voltage-gated sodium channels, which may be related to calcium levels, leading to hyperexcitability [5]. As such, administration of calcium and magnesium has been given to lessen the severity of the hyperexcitability symptoms [6,7]. The serotonin-noradrenaline reuptake inhibitor, venlafaxine, and the neuroprotective amifostine have been used, but no defi nitive randomized trials of these agents have been performed [8]. Avoidance of offending cold agents is helpful during the transient period after treatment. The second form of oxaliplatin-induced neuropathy involves the distal (sensory) nerves. This sensory axonal and demyelinating neuropathy can lead to a debilitating sensory ataxia. It intensifies with the degree of treatment exposure. Less than 15% of patients will suffer from neuropathy when exposed to doses of 780 mg/m 2 , whereas 50% will manifest symptoms at doses of 1200 mg/m 2 . More than 75% of patients will ultimately have improvement of their neuropathy following discontinuation, but a subset may have irreversible symptoms. Most sequelae of neuropathy from oxaliplatin reverse in 4 to 6 months and completely resolve in 40% of patients by 6 to 8 months. Patients may suffer from hypersensitivity or dysesthesia, but most commonly they are bothered by numbness, which can often affect activities of daily life involving fine coordination (eg, buttoning, sewing, and handling coins). There is increasing information regarding mechanism-based biomarkers that may be able to identify patients at increased risk of neurotoxicity from treatment with single-agent or combination platinum chemotherapy regimens [9•]. Taxanes, namely paclitaxel, are antimicrotubule agents—commonly used in gynecologic malignancies and lung cancer—that have broad activity for a variety of other cancers. Paclitaxel is much more commonly implicated in neuropathy compared with docetaxel. Both taxanes can
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affect small- and large-fiber sensory nerves resulting in a painful sensory neuropathy with a dysesthetic, hypersensitive component. The underlying toxic mechanism is thought to be damage to the axonal mitochondria of C fibers [10]. In as many as 17% of cases, paclitaxel can cause a motor neuropathy that can present with disabling, but usually reversible, proximal weakness that is likely due to proximal denervation [11]. Transient visual scotomas have been described with taxane infusions in about 20% of cases, with a minority of these patients showing subclinical optic neuropathy and decreased visual acuity [12]. Taxane-platinum combined regimen neurotoxicity may be ameliorated by substituting docetaxel for the more neurotoxic paclitaxel [13]. Prophylactic treatment with acetyl-L-carnitine has been proposed to prevent neuropathic pain associated with paclitaxel. Animal models show a possibly protective effect via protection of C-fiber mitochondria [14]. A randomized study of 86 colorectal patients treated with a regimen of oxaliplatin and 5-FU showed significantly less neurotoxicity in the group treated with oral glutamine [15]; studies of oral glutamine with high-dose paclitaxel also suggest a neuroprotective effect [16]. Vinca alkaloids (vincristine) are microtubule inhibitors that are often used in leukemic malignancies and cause an axonal sensory-motor neuropathy. A mild to moderate sensory neuropathy is seen in 7% to 31% of treated patients. This is typically distal in distribution, presenting with paresthesias. Doses above the usual cap of 2 mg may result in a motor neuropathy with weakness, drop foot/feet, and (less commonly) wrist drop. Patients with hereditary neuropathies, such as Charcot-Marie-Tooth [17], are particularly susceptible to these toxic motor neuropathies. Constipation, ileus, and bowel pain can occur from involvement of autonomic nerves. Symptoms are usually reversible, but the motor-sensory deficits can be permanent. A small percentage (< 5%) of patients may suffer severe pan-neurotoxicity, which can be fatal [18]. Focal cranial nerves also can be involved, including facial pain, jaw pain, optic atrophy, and extraocular muscle enervating nerves. Thalidomide, used as an antineoplastic agent for multiple myeloma and Kaposi’s sarcoma, causes an axonal sensory neuropathy in up to 30% of cases, presenting with distal paresthesias and loss of sensation [19]. Less commonly, antimetabolites such as 5-FU (used for treatment of colorectal cancers) can cause a sensorimotor neuropathy. This is usually a painless hypoparaesthesia. Oral capecitabine (used in breast and colorectal cancer) can also elicit such symptoms [20]. Cytarabine, used most commonly in hematologic malignancies, can be associated with a peripheral neuropathy, but more commonly causes cerebellar toxicity when given in high doses [21].
Characteristics of Painful Neuropathy The characteristics of toxic neuropathy depend upon the fibers injured from the causative chemotherapy. Small-fiber
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Table 1. NCI common terminology criteria for adverse events Grade I Neuropathy (motor)
Grade II
Grade III
Asymptomatic; Symptomatic weakness Weakness interfering weakness on exami- interfering with function, with ADL; bracing or nation/testing only but not ADL assistance to walk
Neuropathy (sensory) Asymptomatic; loss of DTRs or paraesthesia (tingling) not interfering with function
Grade IV Life-threatening; disabling (paralysis)
Sensory alteration or Sensory alteration or Disabling paraesthesia (tingling) paraesthesia interfering interfering with function, with ADL but not ADL
Pain (peripheral nerve) Mild pain not inter- Moderate pain; pain or Severe pain; pain or fering with function analgesics interfering with analgesics severely function, but not ADL interfering with ADL
Disabling
ADL—activities of daily living; DTR—deep tendon reflexes; NCI—National Cancer Institute. (Data from the National Cancer Institute [33].)
involvement, as seen from taxane toxicity, results in burning, lancinating dysesthesias, and hyperesthesia/pressure sensitivity, with loss of pain and temperature sensation. Large-fiber involvement from cisplatin results in vibration and proprioception loss. Autonomic neuropathy (taxanes and vinca alkaloids) results in orthostatic hypotension and gastrointestinal dysfunction. Patients with chemotherapy-induced neuropathy most commonly complain of a loss of sensation or numbness in a stocking-glove distribution or “thickness” of the extremity that involves the most distal aspects of the toes and fi ngers, but spreads proximally with worsening. The patient may wake from sleep because of dysesthesias. Such complaints justify initiation of palliative symptomatic treatment. Neuropathy symptoms can begin early in the course of treatment and worsen with increased exposure to the toxic agent. They may initially abate between treatments, but tend to accumulate and become constant after repeated exposures. Neuropathic symptoms can worsen for more than a month after the discontinuation of the offending agent, take months to plateau, and up to a year or years (in some cases) to lessen in severity. There may be worsening of the grade of neuropathy severity for weeks to months after stopping the therapy. In some cases, the symptoms do not reverse and the patient is left with irreversible disability from neuropathy. Such cases are thought to involve injury to the dorsal root ganglion and lead to actual neuronal death [22]. Although there are no clear guidelines as to when a toxic agent should be stopped, when the patient approaches a degree of disability or pain that cannot be tolerated long-term, discontinuation of the causative chemotherapy drug or change to a less neuropathic agent needs to be considered. The degree of importance of the chemotherapy for the individual patient (ie, adjuvant treatment of a low-stage cancer vs essential therapy for residual or recurrent active and responding disease) needs to be considered in regard to changing therapy. Sensory and motor neuropathy is graded by the CTC scale, labelled as grades I through V (grade V being death). Pain is classifi ed separately (Table 1). No
reliable data in the literature currently exist regarding reversibility of the toxicity. Hence, caution should be taken to stop chemotherapy before the patient reaches an intolerable grade of damage.
Treatment Neuropathic pain can be treated with typical analgesics such as acetaminophen and NSAIDs, but these are often not helpful for the aspects of burning dysesthesia, lancinating electric pain, or hypoesthesia. Although there are no defi nitive trials to provide level I evidence, adjuvant analgesics such as tricyclic antidepressants (TCAs; eg, amitriptyline), antiepileptics, and newer agents mentioned below may be useful in the treatment of neuropathic pain. The therapeutic effect of these agents needs to be balanced with side effects that often include sedation and anticholinergic phenomena in the TCAs: dry mouth and orthostasis. In general, an analgesic agent should not be discounted as ineffective until it has been tested adequately (typically for several weeks to a month) at a maximally tolerated, side effect–limited dose. Antiepileptics, such as carbamazepine and gabapentin, may be effective and remain fi rst-line agents for treatment of neuropathic pain in trigeminal neuralgia [23]. The agents used with increasing success include gabapentin, pregabalin, and duloxetine. Gabapentin was developed as an antiepileptic and has been found to be effective for the treatment of atypical and neuropathic pain. Starting doses begin at 100 to 300 mg twice or three times daily, and it can be increased up to 3000 mg a day in split doses. Pregabalin is an antiepileptic agent thought to work via reduction of neuronal hyperexcitability. Treatment starts at 75 mg twice daily, and it can be increased gradually to 150 mg twice daily. Duloxetine is approved by the US Food and Drug Administration for the treatment of diabetic painful neuropathy, at a oncea-day dose of 60 mg. Occasionally, adequate trials of numerous atypical agents are unsuccessful, and the patient continues to suffer from debilitating neuropathic pain. Opioids,
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component, how to prevent this common toxicity, and how to treat painful symptoms.
Mononeuropathies in Cancer Patients
Figure 1. Infiltration (arrow pointing to enhancing lesion) of proximal radial nerve by systemic non-Hodgkin’s lymphoma.
beginning with short-acting agents and usually titrated to longer-acting oral agents or transdermal forms, may be appropriate in the treatment of such refractory painful neuropathy. Individuals with underlying metabolic diseases such as diabetes or hereditary neuropathies may have a much lower threshold for developing neuropathy after exposure to toxic chemotherapy drugs [24]. These patients can present with symptoms of paresthesias after a much less cumulative exposure than other patients without underlying disease. Many patients ask about preventive or helpful measures other than medications. There is no evidence that massage, exercise, or alternative therapies have an effect on painful neuropathy, either damaging or helpful. Patients should be advised to use protective gloves if exposed to dishwashing or caustic cleaning materials. In general, once the offending chemotherapy agent has been discontinued, nerve recovery is time-dependent. Nerve regeneration occurs at the rate of approximately 3 mm per year. Nerve conduction study and electromyogram (NCS/EMG) may be helpful in prognosis and in gauging the rate of nerve regeneration during recovery. Electrophysiologic tests may be useful in detecting unexpected patterns of neuropathy in patients treated with toxic agents that may be caused by a differential of rarer pathologies (eg, amyloid or sarcoid infi ltration [25] or globulinopathies [26]) but will typically not add to the clinically based diagnostic suspicion. These rarer causes of neuropathy should be considered if the patient’s symptoms continue to worsen more than several months after stopping treatment. There is clearly a need for better delineation of painful neuropathy caused by chemotherapy agents to better understand how to predict the degree of irreversible
Cancer patients may suffer from pain or paresthesias related to involvement of single nerves, typically related to direct infiltration or compression by tumor. Any peripheral or cranial nerve may be affected (Fig. 1). Systemic lymphoma may have a predilection for nerve infiltration [27]. The “numb chin syndrome” is a relatively common scenario involving paraesthesias or dysesthesias involving the distribution of the mental nerve or V3 branch of the trigeminal nerve. It is caused by either direct nerve infiltration at the mental nerve, a bone lesion involving the jaw at the mental foramen, or at the base of skull (foramen ovale or cavernous sinus, along the trigeminal nerve’s route) at the exit of the V3 branch. Cancers that create lytic lesions of bone, such as prostate and breast, can commonly cause such symptoms. Treatment includes systemic treatment of the underlying tumor. If the local symptom is progressive or painful and spreads to other neurologic structures, then radiation (typically whole-brain) is recommended. The other etiology of “numb chin syndrome” is leptomeningeal involvement. Cerebrospinal fluid (CSF) involvement with cancer usually presents with multiple symptoms, including cranial nerve symptoms, headache, nausea/vomiting, or confusion, as well as radicular extremity or sphincter symptomatology [28]. However, CSF cancer can present with mononeuropathy or with a multiple, scattered radicular pattern (mononeuritis multiplex); lumbar puncture should be considered in such a patient if a focal cause is not apparent. Successful palliative treatment of carcinomatous meningitis depends largely upon the underlying neoplasm. Lymphoma, germ cell, and breast cancers are more amenable to palliative intrathecal treatments, whereas most solid tumors are refractory to therapy.
Plexopathy Cancer patients can suffer from painful neuropathy from disease of the plexus caused by direct infi ltration of the plexus (breast, lung), and head and neck cancers and lymphoma (involving the cervical lymph nodes). Colorectal, prostate, chordoma, lymphoma, and gynecologic cancers may involve the lumbo-sacral plexus. Pain is a primary component of plexopathy from direct cancer infi ltration [29]. Depending on the level of the plexus involved (typically the lower trunk of the brachial plexus if breast or lung cancer), the distal hand is involved fi rst, with symptoms ascending proximally. Pain is followed subacutely by sensory change, weakness, and eventually trophic changes. The main differential in cancer plexopathy from direct invasion of the neoplasm or compression from involvement of regional lymph nodes is radiation-induced plexopathy if the patient has undergone radiation treatments. Pain may be a somewhat less prominent component
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in radiation-induced plexopathy, and fibrosis and surface skin changes may be supportive of such a diagnosis. Contrast fat-saturated CT scan, gadolinium MRI, or axillary ultrasound can be helpful in differentiating between active disease and treatment-related effect. NCS/EMG can be helpful if myokymia is identified. Myokymia is a specific electrophysiologic phenomenon related to cell membrane instability seen in radiation plexopathy but not seen in plexopathy due to cancer infiltration [30]. Cancer involving the plexus may be palliated by radiation; radiation-induced plexopathy is unfortunately fairly refractory to treatments. There have been case reports and some laboratory-based rationale of therapies, including anticoagulation and neuroprotection with vitamin E, but they have not been proven helpful. Palliative therapy is based on pain management and physical therapy.
prolonged more than several months, or if the condition worsens months after treatment or has atypical features. Better measures and documented clinical data are needed for assessing the severity and reversibility of toxic damage from chemotherapy agents.
Paraneoplastic Neuropathy
1.•
Painful sensory neuronopathy, or ganglionopathy, is one of the common manifestations of the uncommon paraneoplastic disorders. Paraneoplastic disorders are thought to occur as a result of dysregulation of autoimmunity in misdirection of antibodies targeted against the foreign agent (neoplasm), which are targeted to specific neurons—in the case of neuronopathy, the dorsal ganglion cells. The resultant neuropathy presents with burning, severe dysesthesias. As the ganglion cells are targeted, the syndrome is not typically reversible, as is the distal sensory neuropathy seen from toxic chemotherapy exposure, in which the distal-most nerve is affected. This syndrome is seen most commonly in the setting of small cell lung cancer and typically involves the anti-Hu antibody [31]. Paraneoplastic microvasculitis also can present with a less symmetric distal painful neuropathy [32]. If suspected clinically and supported by electrophysiologic testing, this diagnosis can be made defi nitively by nerve biopsy, with the appearance of perivascular infi ltrate of inflammatory and plasma cells. Immune-modulating therapy (steroids, plasma exchange, or immunoglobulins) and treatment of the underlying cancer may be helpful.
Conclusions Painful neuropathy is a problem that can adversely affect the quality of life and functional status of the cancer patient. The most common cause of painful neuropathy is toxic chemotherapy exposure, and the degree of neuropathy may be the dose-limiting factor in deciding further oncologic treatment. The clinician should have a low threshold for increasing the strength of analgesic agents and narcotics if adequate trials with fi rst-line and atypical medications are not palliative. Less commonly, other etiologies need be considered as the source of painful neuropathy in the cancer patient. Clinicians should consider other causes if recovery is
Disclosure No potential confl ict of interest relevant to this article was reported.
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