Neuropathic pain associated with the administration of chemotherapy agents has been widely reported in both controlled and uncontrolled studies. On the one hand, more patients are experiencing excellent outcomes of chemotherapy with prolonged survival. On the other hand, increasing numbers of patients are unable to complete full treatment because of the development of chemotherapy-induced neuropathy. Long-term management of pain is therefore becoming one of the most challenging aspects of treatment for neurologists and oncologists. The medical and nursing issues related to recognizing and managing the symptoms of disabling pain and loss of function, while minimizing neuropathy and maintaining quality of life are the focus of this issue of Cancer Pain Release.

--Sophie M. Colleau, PhD

An interview with Dr. Charles Loprinzi & Dr. Judy Paice*

* Charles L. Loprinzi, MD, is Professor of Oncology at the Mayo Clinic College of Medicine and Director of Cancer Control for the North Central Cancer Treatment Group, Rochester, Minnesota.

Judith A. Paice, PhD, RN, FAAN is Director of the Cancer Pain Program in the Division of Hematology-Oncology and Research Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Q: Are painful peripheral neuropathies common among patients undergoing chemotherapy?
Paice: Peripheral neuropathy is a widespread side effect of treatment with certain chemotherapeutic agents. The pain associated with these neurotoxic effects can be prolonged, severe and relatively resistant to intervention. The overall incidence of chemotherapy-induced peripheral neuropathy [CIPN] and associated neuropathic pain is not clearly delineated, although it is documented frequently with vincristine, taxanes and platinum-based agents.

The impact of vincristine on peripheral nerves

Q: Vincristine, used predominantly to treat leukemia and lymphoma, has been considered an essential medicine by the World Health Organization since 1977. To what extent does it cause peripheral neuropathies?
Loprinzi: Vincristine is indeed a front-line plant-derived anti-cancer agent that is very effective in a number of lymphoid malignancies. However its use can be limited by the onset of peripheral neuropathy which is sometimes severe enough to require a lesser dose and a less effective treatment or the termination of chemotherapy altogether.

Q: What type of symptoms do patients report with vincristine?
Loprinzi: Pain in the hands and feet, muscle cramps, numbness and tingling in the fingertips and toes have been reported in over 50% of patients receiving vincristine therapy; affected patients may have changes in their ability to feel things, to detect sharpness and to sense temperature. These sensory complaints may be associated with atrophy of the peripheral nerve fibers [see Dougherty abstract].

Q: What is the time course of these painful sensory side effects with vincristine?
Loprinzi: Onset of pain often occurs approximately 3-4 months into treatment, and may be related to small nerve fibers damage. Recovery from the neuropathy may take up to 2 years, may worsen after vincristine is stopped, and it is not always reversible.

Q: Can symptoms be improved by reducing the dose or the frequency of the treatment?
Loprinzi: Decreasing the vincristine dose may minimize toxicity. However there is no other known effective prevention of peripheral neuropathy caused by vincristine.

Cisplatin-induced neuropathy

Q: Cisplatin is also on WHO's Essential Medicines list for the treatment of various cancers, including ovarian cancer, testicular cancer, cervical cancer and for palliative therapy in many advanced cancers. To what extent is it neurotoxic?
Loprinzi: Since the introduction of cisplatin treatment, mortality from testicular cancer has been drastically reduced with a cure rate of more than 80%. Significant peripheral neuropathy occurs in patients who receive more than 400-500 mg/m2, generally 3-6 months into treatment.

Q: Is the severity of the nerve damage related to the cumulative dose of cisplatin?
Loprinzi: Yes, the minimum cumulative dose of cisplatin that usually causes peripheral neuropathy is 200 mg/m2, and it is almost always neurotoxic when the dose goes over 400 mg/m2. Neuropathy affects predominantly the large sensory fibers with patients complaining of paresthesias in the extremities and loss of large fiber sensory function is common. Symptoms may continue for months after therapy has stopped.

Q: Do patients continue to experience residual pain from the treatment?
Loprinzi: Neuropathic pain may in some patients last for several years after discontinuation of therapy.

Q: A wide variety of adjuvant analgesics have been employed to relieve cancer-related neuropathic pain [see Cancer Pain Release, Vol. 15, No. 2]. Has any drug been identified to relieve patients from chemotherapy-related nerve pain due to agents like cisplatin?
Loprinzi: A recent randomized, placebo-controlled double-blind study has reported that vitamin E (400mg/day) has a beneficial neuroprotective effects in patients treated with cisplatin [see Pace abstract]. This work should be replicated and the safety of vitamin E needs to be better established in patients receiving cytotoxic chemotherapy before this treatment is established in clinical practice.

Oxaliplatin causes acute and chronic neurotoxicities

Q: What is known about the toxicity of oxaliplatin?
Loprinzi: Oxaliplatin --a newer platinum compound effective in advanced colon cancer, as well as in gastric, ovarian, breast and lung cancers-- causes two types of neurotoxicity: an early acute reaction of dysesthesia within hours of treatment in up to 90% of patients, and a chronic sensory neuropathy similar to that seen with cisplatin [see Binder abstract].

Q: Which acute symptoms are reported by patients immediately after oxaliplatin infusion?
Loprinzi: Pain in hands and feet when exposed to cold is a troubling acute symptom with oxaliplatin; it can also be accompanied by paresthesias of the throat, difficulty swallowing and jaw pain. These latter symptoms can be more prominent in patients drinking cold liquids.

Q: Which chronic symptoms are reported by patients after oxaliplatin therapy?
Loprinzi: It is apparent that oxaliplatin can produce significant, long-lasting neurotoxicity and when the cumulative dose reaches 1000 mg/m2, neuropathic pain may persist for long periods. Signs of chronic neuropathy with oxaliplatin consist of changes in proprioception that do not disappear between treatments. If severe, this problem can make daily activities (such as writing, buttoning shirts or picking up objects) difficult.

Q: Clearly many of these patients have a very limited quality of life. Is there any way to prevent oxaliplatin neuropathy and decrease the associated pain?
Loprinzi: Several agents have been investigated for prevention and the only approach that appears effective is the use of a calcium and magnesium infusion, 1 g of each, before and after oxaliplatin infusion. The minerals are an inexpensive treatment and do not interfere with chemotherapy. However, they do require time to administer (30 minutes, both before and after chemotherapy) and this is less than ideal. A recent trial of calcium and magnesium infusion reported that this therapy significantly decreased oxaliplatin-induced neuropathy and that it was associated with significantly improved patient-reported quality of life with regards to muscle cramps, numbness in fingers and toes and swallowing discomfort [see Nikcevich abstract] . Since more than half of patients with metastatic colon cancer discontinue oxaliplatin because of neurotoxicity, we need strategies to allow patients to remain on therapy longer. One option that has been studied is to give the patient oxaliplatin intermittently, as opposed to continuously. This procedure does appear to decrease neuropathy and allow similar survival probabilities.

Paclitaxel-induced paresthesias

Q: Taxanes are also widely used against various types of cancer either alone or in combination with other chemotherapy agents. Do taxanes cause pain?
Loprinzi: Taxanes are indicated for the treatment of lung, breast and ovarian cancer to prolong remissions and improve survival. We know that taxanes affect many sensory neurons especially the nerve fibers that conduct vibration sensation and proprioception reducing the quality of life of patients with cancer. Paclitaxel induces paresthesias, loss of sensation and dysesthetic pain in the feet and hands. This neurotoxicity is dose-related and nearly 95% of patients exposed to 500-800 mg/m2 will develop paclitaxel-associated neuropathy and/or pain following the termination of paclitaxel therapy. Pre-existing neuropathy and co-administration of other chemotherapy agents also enhance the risk of neuropathic pain.

Q: Using detailed patient interviews, you have recently identified an acute transient pain occurring a few days after paclitaxel administration [see Loprinzi abstract] . Is this syndrome different from the painful neuropathy occurring with long-term paclitaxel therapy?
Loprinzi: We studied patients' reports regarding an acute pain syndrome that commonly occurs following paclitaxel therapy. Classically this syndrome has been labeled as paclitaxel-induced arthralgias/myalgias. Our study indicated that the pain symptoms began 1-2 days after the patients received paclitaxel and lasted for 4-5 days. Pain was described as radiating, shooting, aching, stabbing, and pulsating and it was mostly located in the back, hips, shoulders, legs and feet. Most of the patients specifically reported that the pain was not in the joints or muscles. We believe this syndrome is not related to joint or muscle pathology but rather is related to a direct nerve injury induced by paclitaxel.

Similarities in clinical presentation

Q: Since patients now live longer with cancer, is the incidence of CIPN likely to increase?
Loprinzi: The incidence of CIPN is increasing because more neurotoxic agents have been developed and because patients are living longer and receive multiple chemotherapy drugs. The severity of peripheral neuropathy varies with the type of agent used, the cumulative dose, and the duration of treatment. Serious painful sensory disturbances tend to occur in patients who are more vulnerable because of a pre-existing nerve disorder associated for example with diabetes mellitus or alcoholism.

Q: Which nerve fibers are affected?
Loprinzi: Chemotherapy induced peripheral neuropathy can affect large and small nerve fibers. Symptoms of neuropathy in large fibers include decreases in vibratory sensation, proprioception, deep tendon reflexes and muscle strength. Symptoms in small peripheral nerves include tingling, prickling, burning and decreased temperature and light-touch sensations.

Q: What is the clinical presentation?
Loprinzi: Patients experience sensory symptoms that are quite similar regardless of the chemotherapeutic agent, ranging from tingling to painful burning paresthesias, hyperesthesias, and dysesthesias in the toes and feet, and also involvement of the fingers and hands, often described as a stocking-and-glove pattern. The onset of CIPN is progressive, although some patients have rapid onset following administration of chemotherapy. Some patients are unable to complete the optimal treatment regimen because of the distress caused by neuropathic pain.

Painful CIPN: a diagnostic dilemma

Q: Are tools available to identify the presence of neuropathy and the severity of pain in patients undergoing chemotherapy?
Paice: Scales are available to measure toxicity and neuropathy. However there are no instruments specifically designed to assess pain severity associated with chemotherapy. Current approaches to assessment are inadequate and contribute to the lack of knowledge regarding the true prevalence of CIPN and its long-term consequences.

Q: Can you comment on the scales currently used to measure both toxicity and neuropathy?
Paice: Oncologists interested in assessing the toxicity of new chemotherapy agents introduced in clinical trials use scales developed by the World Health Organization, the Eastern Cooperative Oncology Group (ECOG) and the National Cancer Institute. Because the scales are not consistent in measuring toxicity, it is difficult to aggregate data across studies. Neurologists assessing individual patients for the presence of neuropathy following a chemotherapy regimen have used more specific neuropathy-focused scales such as the Total Neuropathy Score (TNS) [see Screening Tools] .

Q: Are these scales able to differentiate the neuropathy symptoms caused by chemotherapy from the neuropathic pain caused by the underlying cancer, or from symptoms unrelated to either?
Paice: No. These physician-based instruments are inadequate because they are used without a standardized approach that is consistently or precisely implemented. In addition, these scales are not sufficiently sensitive or reliable. For example, current instruments do not capture properly the degree of pain resulting from the toxicity. As a result chemotherapy-induced painful neuropathy is under-recognized and underreported.

Q: Do you mean that CIPN symptoms are underreported by physicians or by patients?
Paice: CIPN symptoms are under-recognized by physicians in part because they are difficult to diagnose; they are also under-reported by patients. Some CIPN symptoms are related to but distinct from pain. In addition, cancer patients often experience several different types of pain simultaneously, making neuropathic pain difficult to distinguish from other pains. Another barrier to assessment is that many oncologists believe that treatment-induced pain will improve over time so pain tends to be discounted as a non-issue. When assessment does take place, the current grading system is too broad to adequately detect changes in neuropathy. In addition, tools to measure painful peripheral neuropathy have been validated in patients with diabetic or post-herpetic neuropathy, but rarely in patients with CIPN.

Q: To what extent do patients underreport pain from CIPN?
Paice: Patients often struggle to describe painful neuropathy during initial screening, in part because it is difficult to describe uncomfortable sensations including pain without being prompted. Clinicians have to work through these verbal descriptions without a reference standard for "what is a symptom of neuropathic pain." In addition many do not have adequate time for a thorough neurological examination. As a result, analgesics for neuropathic pain are not initiated. We have found that patients are sometimes reluctant to report symptoms because they realize that -if they do-- a potentially life-saving chemotherapy treatment may have to be stopped.

Q: In your opinion, what is needed to improve the assessment of CIPN?
Paice: We need tools that are sensitive enough to monitor clinically significant changes as patients go through the chemo regimen so one can tailor drug dosages to individual patients. In theory, assessing patients prior to each chemotherapy cycle, as well as during the progression of chemotherapy treatments would be good. In fact, no consensus exists in the US as to when assessments should be taken. Assessments should directly ask patients about specific activities of daily living, which are highly clinically relevant as they relate to the adequate functioning of the peripheral nervous system. Thus, asking a woman if she has difficulty putting on her earrings in the morning or buttoning her blouse, or inquiring of patients if they have trouble writing their names when holding a pen or pencil will offer a more meaningful assessment of the effect of the neuropathy on the individual's quality of life.

Q: How would you assess painful CIPN if the patient has coexisting diabetes or a neuropathy from another etiology?
Paice: The clinician must carefully evaluate and record the patient's baseline neurologic findings and symptoms prior to the initiation of chemotherapy. Clearly we need to be able to identify patients who may be candidates for severe side effects.

Q: What is the role of the oncologist in assessing CIPN?
Paice: It is important that oncologists communicate to patients the importance of providing accurate descriptions of their symptoms in spite of the potential effects such information may have on the physician's decision to modify the treatment program. The most important clinical objective is to determine the level of functional impairment involving activities of daily living since this finding is critical to determine the need to modify, interrupt or discontinue the chemotherapy.

Q: In your own practice have you found a tool that properly captures the patient's experience of pain?
Paice: We have used the Brief Pain Inventory (BPI) along with the Neuropathic Pain Scale (NPS) and the FACT-taxane scale to examine pain, neuropathy and quality of life among women treated with paclitaxel for breast cancer [see Screening Tools] . Other clinicians have used questionnaires such as the Pain Quality Assessment Scale (PQAS) that attempts to measure pain and peripheral neuropathy. Although there is interest in developing better tools [see Kuroi abstract, Smith abstract], there is no patient-based questionnaire to-date that adequately assesses pain severity related to CIPN. We believe that the patient's stated subjective discomfort must be used to evaluate the magnitude of the nerve damage and guide future management.

Treatment strategies: prevention or palliation?

Q: What is the current understanding for treating patients with CIPN?
Loprinzi: First, treatment should focus on ways to eliminate or reduce CIPN. After CIPN is established, palliative management and supportive care are indicated.

Q: Is any strategy known to minimize the risk of neuropathy from chemotherapy?
Loprinzi: Modifying the chemotherapy regimen can reduce toxicity. One strategy consists of stopping the infusion at a predetermined dose and resuming the infusion when symptoms lessen. This stop-and-go approach to medical management is being evaluated in clinical trials for various agents as a method to manage the toxicity while still controlling the disease long-term.

Q: Of the agents evaluated to prevent neuropathy and associated symptoms which ones are the most promising to-date?
Loprinzi: Evidence strongly suggests that intravenous calcium and magnesium therapy can attenuate the development of oxaliplatin-induced CIPN without reducing treatment response. We do not know if this therapy will be effective to reduce CIPN from other agents and we need more data on efficacy and safety before this approach can be generalized.

Q: Why are treatment strategies for CIPN still tentative?
Loprinzi: A major challenge regarding treatment is that we have an incomplete understanding of the origin of the neuropathy and the cause of the pain produced by chemotherapy agents remains unknown. Neuropathic pain from chemotherapy is believed to come from aberrant somato-sensory processing in the peripheral nervous system which is more sensitive than the central nervous system to the effects of chemotherapy. Another problem is that controlled trials for the treatment of chemotherapy-induced neuropathic pain are lacking.

Q: After CIPN is established, are the pharmacological strategies used to manage chemotherapy-related neuropathic pain similar to the principles used to manage cancer-related neuropathic pain?
Paice: We need controlled trials to test the efficacy of analgesics to relieve pain associated with CIPN. The current consensus is that pain management for CIPN should be guided by the same principles as other types of neuropathic pain, and should include opioid analgesics, anti-depressants and anti-convulsants. As with disease-dependent painful neuropathies, treatment needs to be individualized with the practitioner searching for the best analgesic for each patient. Opioids are effective, usually at higher doses as they block the release of neurotransmitters in the spinal cord. An important recommendation in initiating pharmacologic therapy for neuropathic pain is to introduce one drug at a time, with gradual upward titration, based on the patient's response. However, adjuvant analgesics that work for cancer-dependent painful neuropathies do not necessarily work for CIPN.

Q: Have any randomized studies been conducted to evaluate the usefulness of anti-depressants in relieving the pain of CIPN once it is established?
Paice: One trial evaluated nortriptyline for CIPN because this adjuvant is effective in treating diabetic neuropathies. Another randomized double-blind study evaluated amitriptyline (an anti-depressant on WHO's Essential Medicines list) as treatment for CIPN. These trials were unable to demonstrate any benefit to improve the pain of CIPN [see Kautio abstract] .

Q: Among the anti-convulsants, gabapentin has been shown to be effective in treating neuropathic pain from diabetes, postherpetic neuralgia, and the phantom pain syndrome. Is gabapentin equally effective to relieve neuropathic pain from chemotherapy?
Loprinzi: We conducted a multi-center randomized, double-blinded, placebo-controlled crossover trial that failed to demonstrate any benefit of using gabapentin to ameliorate the pain caused by CIPN [see Rao, Michalak abstract] . Another anticonvulsant, lamotrigine, was evaluated in a randomized double-blind trial and showed no improvement over placebo for CIPN symptoms [see Rao, Flynn abstract] .

Q: Is there any evidence that preventing chemotherapy-related pain might be more effective than managing chemotherapy-related pain after it has set in?
Paice: A recent report that examined patients with chronic chemo-neuropathy one year or more after initial treatment using pain diagrams, pain descriptors, and pain medication histories shows that chemotherapy-related neuropathy is both very persistent and also refractory to therapy once the transition to chronicity is crossed. The author suggests that therapies would therefore best be directed at protection as opposed to palliation [see Dougherty abstract] .

Q: Where will progress come from to improve the patients' experience of this debilitating condition?
Loprinzi: We need to identify better neuroprotective agents so patients can enjoy longer life expectancies without a reduction in quality of life. We also need to better understand the peripheral mechanisms of neuropathic pain to improve therapeutic options.

Table 1. Neuropathic pain syndromes

Peripheral neuropathy:
a disease or degenerative state (as polyneuropathy) of the peripheral nerves in which motor, sensory, or vasomotor nerve fibers may be affected and which is marked by muscle weakness and atrophy, pain, and numbness.

loss or lack of sensation; often burning, tingling or prickling, which happens without warning and is usually associated with injury or irritation of a sensory nerve or nerve root.

abnormal impairment of sensitivity especially to touch.

abnormally increased pain sensitivity to nonpainful stimuli.

severe joint pain.

diffuse and non-specific muscular pain.