Neurotoxicity Related to Radiotherapy and Chemotherapy for Nonsmall Cell and Small Cell Lung Cancer

Neurotoxicity Related to Radiotherapy and Chemotherapy for Nonsmall Cell and Small Cell Lung Cancer

43 43 Neurotoxicity Related to Radiotherapy and Chemotherapy for Nonsmall Cell and Small Cell Lung Cancer Thomas E. Stinchcombe and Elizabeth M. Gor...

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Neurotoxicity Related to Radiotherapy and Chemotherapy for Nonsmall Cell and Small Cell Lung Cancer Thomas E. Stinchcombe and Elizabeth M. Gore

SUMMARY OF KEY POINTS • Radiation-induced brachial plexopathy (RIBP) occurs with treatment of apical tumors and is frequently complicated by tumor-related brachial plexopathy (TRBP). Stereotactic ablative radiotherapy (SABR) of apical tumors, which employs a higher dose per fraction, can cause RIBP as well. • RIBP symptoms include upper extremity paresthesias, motor weakness, muscle atrophy, and neuropathic pain. The peak incidence is 1–2 years, and the onset is often insidious over months to years. • The most common side effect of radiation to the spinal cord is Lhermitte sign, which is caused by reversible demyelination of the ascending sensory neurons. Lhermitte sign is a shock-like sensation in the spine and extremities exacerbated by neck flexion, almost always symmetrical, and not associated with a dermatomal distribution. Radiation-induced Lhermitte sign begins 3 months and subsides within 6 months of the completion of radiotherapy. • Radiation myelopathy can be devastating, and the clinical presentation depends on the level of the spinal cord affected. In general it begins with paresthesia and muscle weakness, and as the syndrome progresses gait disturbance and paraparesis appear. Radiation myelopathy is a diagnosis of exclusion, and patients must be evaluated for tumor progression and paraneoplastic syndromes with magnetic resonance imaging (MRI) of the cord. • Assessment of the neurotoxic effects of radiation therapy can be confounded by the impact of brain metastases on neurologic function. Long-term outcome data are limited as a result of the short survival, and pretreatment and posttreatment neurologic testing has not been routine. • Chemotherapy induced peripheral neuropathy (CIPN) is associated with taxanes (e.g., paclitaxel, docetaxel, nanoparticle albumin-bound paclitaxel), platinum agents (e.g., cisplatin and carboplatin), and vinca alkaloids (vinorelbine). Neuropathy associated with microtubuletargeting agents (vinca alkaloids and taxanes) is dependent on the length of the nerves, and patients frequently present with numbness and paresthesias of the feet and fingertips. • The rate and severity of CIPN depends on the dose, duration and combination of chemotherapy agents used. Patients with a history of nerve damage from diabetes, alcohol use, and inherited neuropathy are at increased risk for the development of CIPN.

Chemotherapy and radiotherapy are routinely used for the treatment of nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Both types of treatment can cause acute and chronic neurotoxicities, which may affect the health-related quality of life of the patient and his or her ability to tolerate therapy. Management of the toxicities varies depending on the patient’s prognosis. In the palliative setting, acute toxicities may result in dose reduction, treatment delay, or treatment discontinuation, thus offsetting the potential benefits of palliative treatment. In the potentially curative setting, chronic treatment-related toxicities may be more clinically relevant. Unfortunately, the assessment of acute neurotoxicities has been variable, and the prospective collection of data on chronic neurotoxicities has been limited. Selected neurotoxicities are addressed in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Table 43.1);1 however, many of these toxicities are based on physician assessment, and the determination of a grade 2 or grade 3 toxicity can be patientand/or physician-dependent. When neurotoxicities do develop, management is often based on the patient’s symptoms. Current research is investigating methods of identifying patients who are at increased risk for neurotoxicity, as well as prevention strategies and improved treatment options.

NEUROTOXICITY FROM RADIOTHERAPY Neurotoxic effects of radiotherapy for lung cancer, predominantly to the brachial plexus, spinal cord, and brain, are important in the curative and palliative setting. Understanding the neurotoxic effects of radiotherapy is increasingly important, as patients with lung cancer are living longer and radiotherapy techniques are evolving. Intensity-modulated radiotherapy (IMRT) and imageguided radiotherapy (IGRT) allow for delivery of increasing total doses of radiation to the tumor while potentially resulting in a high total dose of radiation to small volumes of normal tissues and inhomogeneous doses across large volumes. SABR is a special consideration because it can potentially result in a very high dose per fraction to small volumes of the lung. As patients are living longer with more aggressive local treatment and more effective systemic therapy, the effects of late toxicity are more likely. It is imperative that current and future studies and clinical practice include long-term follow-up with appropriate documentation of dose, grading, and resulting toxicity.

Brachial Plexus Data regarding RIBP in patients with lung cancer are limited because of the perceived lack of clinical significance. High-dose radiation to the brachial plexus is limited to cases of apical tumors and is frequently complicated by TRBP. However, RIBP may increase in incidence because of improved therapy for advanced lung cancer and treatment of earlier-stage lung cancer, with SABR resulting in longer survival. The risk of RIBP is associated with increased radiation dose and higher dose per fraction,

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TABLE 43.1   National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0, Grades 1–4 Adverse Event

Grade 1

Grade 2

Brachial plexopathy

Grade 3

Asymptomatic; clinical or Moderate symptoms, limiting instrumental Severe symptoms; limiting diagnostic observations only; ADL self-care ADL intervention not indicated Cognitive Mild cognitive disability; not Moderate cognitive disability; interfering Severe cognitive disability; disturbance interfering with work, school, with work, school, life performance significant impairment life performance; specialized but capable of independent living; of work, school, life educational services, devices specialized resources on part-time performance not indicated basis indicated Concentration Mild inattention or decreased Moderate impairment in attention or Severe impairment in impairment level of concentration decreased level of concentration; attention or decreased limiting instrumental ADL level of concentration; limiting self-care ADL Memory Mild memory impairment Moderate memory impairment; limiting Severe memory impairment; impairment instrumental ADL limiting self-care ADL Neuralgia Mild pain Moderate pain; limiting instrumental ADL Severe pain; limiting self-care Paresthesia Mild symptoms Moderate symptoms; limiting instrumental Severe symptoms; limiting ADL self-ADL Peripheral motor Asymptomatic; clinical or Moderate symptoms; limiting instrumental Severe symptoms; limiting neuropathy diagnostic observations only; ADL self-care ADL; assistive intervention not indicated device indicated Peripheral Asymptomatic; loss of Asymptomatic; loss of deep tendon Severe symptoms; limiting sensory deep tendon reflexes or reflexes or paresthesia self-care ADL neuropathy paresthesia

  

Grade 4 NA NA

NA

NA NA NA Life-threatening consequences; urgent intervention indicated Life-threatening consequences; urgent intervention indicated

ADL, activities of daily living; NA, not applicable.   

as well as with the volume of the brachial plexus treated and the concomitant use of chemotherapy.2 Appropriate radiation dose to the brachial plexus and acceptable risk of RIBP ­varies depending on the stage of disease and intent of therapy. In many cases, avoiding high radiation dose to the brachial plexus results in undertreating the tumor. When disease is potentially curable or long-term survival is anticipated, the high risk of RIBP may be unavoidable and an understanding of the risks is important for counseling patients. The diagnosis of RIBP is often complicated by tumor involvement, surgery, and/or unrelated trauma or injury. Symptoms include upper extremity paresthesias, motor weakness, muscle atrophy, and neuropathic pain. The latency period for the onset of symptoms can be a few months to as many as 20 years; the peak incidence is around 1 to 2 years.3–5 The onset of RIBP is often insidious, occurring over 6 months to as long as 5 years and progressing in intensity, eventually resulting in paralysis of the upper extremity.3 RIBP is almost always chronic and progressive, although there are rare reports of early transient RIBP. Symptoms reported and attributed to early transient RIBP include pain, paresthesias, and weakness occurring in 2 to 14 months following therapy with regression and often complete resolution of symptoms.6 MRI and/or computed tomography (CT) are important diagnostic tools to rule out progressive or metastatic disease. Electromyography can be used to support a diagnosis of RIBP.7 Most information regarding the effects of radiation on the brachial plexus is from the literature on breast cancer. The brachial plexus is at least partially treated in almost all cases of breast or chest wall radiotherapy and is frequently involved in regions of matching fields, leading to high doses as a result of unintended field overlap. In addition, patients who receive radiotherapy for breast cancer tend to have relatively long follow-up, increasing the likelihood that late reactions will manifest. Over the past 50 years, different radiation techniques have been used to treat breast cancer, resulting in varying incidences of RIBP. In the 1950s and 1960s, RIBP was diagnosed in more than 50% of patients treated with 50 Gy to 60 Gy at 5 Gy per fraction; currently, RIBP develops in less than 1% to 2% of patients treated with less than 55 Gy at 1.8 Gy to 2 Gy per fraction.8

RIBP in patients with head and neck cancer is an increasing area of interest because of the use of IMRT for treatment of the disease. In an attempt to restrict radiation dose to organs at risk while maximizing dose to treatment target volumes with the use of IMRT, there is a relatively inhomogeneous dose distribution, and the implications may not be completely understood. If organs at risk are not appropriately contoured, these hot spots could be inadvertently in a high-risk area. Proper anatomic definition of the brachial plexus is necessary for understanding potential side effects and complying with dose–volume constraints. The development of a brachial plexus contouring atlas by the Radiation Therapy Oncology Group (RTOG) has facilitated and encouraged the consistent and routine evaluation and reporting of radiation effects to the brachial plexus in the treatment of head and neck cancers. RTOG guidelines recommend a maximum dose of 60 Gy to 66 Gy or less to the brachial plexus. Truong et al.9 retrospectively contoured and reviewed doses to the brachial plexus in 114 patients treated with IMRT for head and neck cancer with 69.3 Gy in 33 fractions. There were no reports of RIBP, despite a maximum dose of more than 66 Gy to the brachial plexus in 20% of patients, with a median follow-up of 16.2 months. Longer follow-up is needed to assess the true incidence of RIBP in patients with head and neck cancer. Chen et al.10 prospectively evaluated the incidence of clinically significant peripheral neuropathies in patients undergoing radiotherapy for head and neck malignancies and reported an incidence of 12% for all patients and 22% for patients who were followed for more than 5 years. The investigators also suggested that RIBP symptoms in patients with head and neck cancer are underreported. Their data suggested a threshold dose of more than 70 Gy to the brachial plexus, although RIBP was also reported in some patients treated with doses less than 60 Gy, suggesting other contributing factors. Prior neck dissection and higher maximum dose of radiotherapy were associated with an increased risk of RIBP.10 Eblan et al.2 evaluated RIBP in 80 patients treated to 50 Gy or more of conventionally fractionated radiotherapy for apical NSCLC; the median follow-up was 17.2 months. RIBP developed in five patients, which was more common among patients who had prior TRBP. The 3-year competing risk-adjusted rate of RIBP was 12%, whereas the 3-year estimated rate of TRBP as a

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result of treatment failure was 13%. The median onset of TRBP was 4 months compared with 11 months for RIBP, and symptom severity was greater for patients in whom TRBP developed. RIBP did not develop in any of the patients who received less than a maximum dose of 78 Gy to the brachial plexus, and for patients in whom RIBP did develop, considerable volumes were irradiated to doses above 66 Gy.2 Amini et al.11 identified 90 patients treated with definitive radiotherapy and concurrent chemotherapy and more than 55 Gy to the brachial plexus. The median dose to the brachial plexus was 70 Gy and the median follow-up was only 14 months; grade 1 to grade 3 RIBP developed in 16% of patients. The median time to symptoms was 6.5 months. Independent predictors of RIBP were a median dose to the brachial plexus of more than 69 Gy, a maximum dose of more than 75 Gy to 2 cm,3 and the presence of plexopathy before radiation. The brachial plexus receives a considerably higher dose per fraction with SABR and therefore is susceptible to greater risk of late complications. Maximum dose of SABR, as well as dose– volume tolerance and clinical presentation with high dose per fraction, is uncertain. Forquer et al.12 evaluated the risk of brachial plexopathy in 37 lesions treated with SABR for apical lung tumors; RIBP developed in 7 of 37 patients treated.12 Five patients had neuropathic pain alone, one patient had pain and weakness, and one patient had pain, numbness, and paralysis of the hand and wrist. At a median follow-up of 7 months, the absolute risk of RIBP was 32% with a dose to the brachial plexus of more than 26 Gy and 6% with a maximum dose of 26 Gy or less in three to four fractions. The median time to development of RIBP was 13 months. In contrast to RIBP reported in other series, symptoms improved in six of seven patients over 3 to 10 months, including improvement of neuropathic pain. One patient who had received a maximum dose of 76 Gy to the brachial plexus had onset of pain and tingling at 9 months of follow-up, with progression to muscle wasting and weakness at 42 months. Consistent contouring and dose–volume analyses in symptom reporting in the literature will continue to improve the c­linical understanding of radiation tolerance of the brachial plexus. C­urrently, for apical lung tumors adjacent to or contiguous with the brachial plexus, restricting the dose to the brachial plexus may not be possible without compromising tumor control. A better understanding of dose–volume constraints and symptoms will assist in determining the risk of RIBP and proper patient c­ounseling. 

Spinal Cord Radiation myelitis is a rare complication of radiotherapy for lung cancer because, in most cases, the spinal cord can be avoided without compromising disease coverage. This avoidance is particularly true for lung cancer in an era of smaller treatment fields directed at gross disease, three-dimensional conformal radiotherapy planning, IMRT, and IGRT. IMRT plans can shape the high-dose lines around the cord, and with IGRT, high doses adjacent to the spinal cord can be delivered with relative confidence that the set-up is reproducible and accurate. The most common side effect of radiation to the spinal cord is Lhermitte sign, which is caused by reversible demyelination of the ascending sensory neurons as a result of inhibition of oligodendrocyte proliferation.13 Lhermitte sign was first described in relation to injury to the cervical spinal cord; is associated with other demyelinating disorders, including multiple sclerosis; and can be induced by radiotherapy or chemotherapy.14–16 Lhermitte sign is a shock-like sensation in the spine and extremities exacerbated by neck flexion; it is almost always symmetrical, is not associated with a finite dermatomal distribution, and is transient, subsiding with oligodendrocyte recovery and remyelination. Radiation-induced Lhermitte sign begins at about 3 months and subsides within 6 months of the completion of

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radiotherapy. The incidence of Lhermitte sign is reported to be between 3.6% and 13% in large patient groups receiving radiotherapy for head and neck and thoracic malignancies. Risk factors associated with the development of Lhermitte sign are total radiation doses above 50 Gy to the cervical spinal cord and daily radiation fraction doses above 2 Gy.14 Pak et al.13 found a relatively high incidence of Lhermitte sign (21%) with IMRT for head and neck cancer and concurrent chemotherapy. The strongest predictors of Lhermitte sign were higher percentage and cord volumes receiving 40 Gy or more. The investigators suggested that the higher incidence of Lhermitte sign in their series might have been related to higher reporting in a prospective setting and the chemotherapeutic agents. Lhermitte sign appearing in the context of transient radiation myelopathy is not associated with chronic progressive myelitis; however, delayed radiation myelopathy, which is irreversible and results in paralysis, may be preceded by Lhermitte sign.16 Lhermitte sign that predates delayed radiation myelopathy is found later in onset than the usual latency period of Lhermitte sign found in transient radiation myelopathy. Because delayed radiation myelopathy can be a devastating side effect, radiation oncologists take every precaution to avoid it. Although glial cells and vascular endothelium are proposed to be the main targets for radiation and play a role in the pathogenesis of radiation myelopathy, experimental data support that radiation-induced vascular damage resulting in vascular hyperpermeability and venous exudation is a basic process.17 The clinical presentation of radiation myelopathy depends on the area of the affected spinal cord and the extent of the lesion. Generally, paresthesia and muscle weakness, which begins in the legs, are the main early symptoms. As the lesion progresses, various symptoms present, such as gait disturbance and paraparesis.17 Schultheiss and Stephens18 emphasized that radiation myelopathy is a diagnosis of exclusion, and patients should be evaluated for tumor progression and paraneoplasia. In almost all cases of radiation myelopathy, the latency period is longer than 6 months, and MRI may show tumor swelling or atrophy, and the level of protein in cerebrospinal fluid may be slightly elevated, with lymphocytes present.18 Radiation myelopathy is irreversible, although some interventions, including corticoster­ oids, heparin or warfarin, and hyperbaric oxygen, have been suggested to have benefit.19 The maximum dose considered safe for spinal cord tolerance and for the prevention of delayed radiation myelopathy is 45 Gy to 50 Gy delivered with conventional fractionation (1.8–2 Gy daily). Schultheiss20 combined reported data from the literature to establish the parameters of the dose–response function for clinical radiation myelopathy. He used data from 18 reported series that included the number of patients treated with a consistent dose regimen, dose, number of fractions, number of myelopathy cases resulting from the dose regimen, and information about the survival experience of patients at risk. At a 45-Gy dose, the probability of myelopathy is 0.03%; at 50 Gy, the probability is 0.2%. The dose for a 5% myelopathy rate is 59.3 Gy. Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) analysis demonstrated that, when conventional fractionation of 1.8–2 Gy/fraction is delivered to the full-thickness cord, the estimated risk of myelopathy is less than 1% at 54 Gy and less than 10% at 61 Gy.21 Data are limited regarding the risk of radiation myelopathy and repeat radiation to the spinal cord. Data on repeat radiation in animals and humans suggest partial repair of radiotherapyinduced subclinical damage becoming evident about 6 months after radiotherapy and improving over the next 2 years. Followup data for spinal cord injury after repeat radiation for recurrent disease is limited and few cases of radiation myelopathy are reported. In general, attempts should be made to avoid the spinal cord if repeat treatment is indicated.

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The understanding of spinal cord tolerance with SABR is evolving. The acceptable maximum dose is dependent on dose per fraction. Gibs et al.22 reported six cases of radiation myelopathy among 1075 patients treated for benign and malignant spinal cord tumors. They recommended limiting the volume of spinal cord treated above an 8-Gy equivalent dose in one fraction. Delayed radiation myelopathy developed at a mean of 6.2 months (range, 2 to 9 months). Saghal et al.23 evaluated five cases of radiation myelopathy following spine SABR and compared dosimetric data with those in a larger series of patients treated with spine SABR in which no radiation myelopathy occurred. The investigators concluded that the maximum point dose to the thecal sac should be respected for spine SABR. For single-fraction SABR, 10 Gy to a maximum point is safe, and up to five fractions and biologic estimated dose of 30 Gy to 35 Gy secondary to the thecal sac also poses a low risk of radiation myelopathy.23 This finding was supported by data reported by Macbeth et al.,24 showing no radiation myelopathy at 10 Gy in a single fraction. Based on extensive literature review, QUANTEC for spine radiosurgery demonstrated that a maximum cord dose of 13 Gy in a single fraction or 20 Gy in three fractions appeared to be associated with a less than 1% risk of injury.21 

Brain Neurotoxic effects of radiation to the brain are variably assessed in the setting of lung cancer. Data are available, primarily in the absence of controls, for patients with inoperable brain metastases treated palliatively with whole-brain radiation therapy (WBRT), local therapy with surgery or stereotactic radiosurgery for patients treated with and without WBRT, and with prophylactic cranial radiation for either SCLC or NSCLC. The neurotoxic effects of radiation therapy to the brain are difficult to assess because of several factors: most patients with lung cancer who are treated with WBRT have neurologic deficits from brain metastases, long-term follow-up is limited as a result of short survival, and neurologic testing has not been routine. Series that evaluated neurotoxic effects of radiation for brain metastases have consistently shown that the risk of neurocognitive deficits as a result of WBRT is outweighed by the benefits of treatment. In 1989, De Angelis et al.25 evaluated 12 patients with neurologic complications attributed to WBRT for brain metastases and reported an incidence of 1.9% to 5.1% for WBRTinduced dementia. All 12 patients, who were treated with total doses of 25 Gy to 39 Gy at 3 Gy to 6 Gy per fraction, had cortical atrophy and hypodense white matter on CT images. The authors concluded that more protracted schedules should be used for the safe and efficacious treatment of good-risk patients with brain metastases. In RTOG 91-04, a phase III trial designed to assess overall survival of patients with unresectable brain metastases treated with 54.4 Gy/1.6 Gy twice daily or 30 Gy/3 Gy once daily, no difference in overall survival was found between radiation doses; the median survival in both arms was only 4.5 months.26 A secondary analysis of this study was conducted to evaluate the importance of a Mini-Mental Status Exam (MMSE) before treatment on longterm survival and neurologic function of patients treated with 30 Gy/3 Gy once daily. Both pretreatment MMSE (p = 0.0002) and Karnofsky performance status (p = 0.02) were significant factors for survival. WBRT appeared to be associated with an improvement in MMSE score and a lack of decline to below 23 on the MMSE in long-term survivors.27 Additional analysis of both arms of this trial showed that the use of 30 Gy/3 Gy once daily as compared with 54.4 Gy/1.6 Gy twice daily was not associated with a significant difference in neurocognitive function as measured by MMSE. Control of brain metastases had a noticeable effect on the MMSE score.28

Neurocognitive function with a neuropsychometric battery before and after WBRT (30 Gy/3 Gy once daily) was assessed prospectively in a phase III trial of WBRT with or without motexafin gadolinium.29 Impairment was found in more than 90% of patients at baseline, and the results suggested that only tumor control correlated with neurocognitive function.30 Li et al.31 evaluated 135 of 208 patients in the control arm of the study who were available for evaluation at 2 months.31 The authors found that WBRT-induced tumor shrinkage correlated with better survival and preservation of neurocognitive function. Neurocognitive function was stable or improved in long-term survivors, and tumor progression adversely affected neurocognitive function more than WBRT. Studies in which patients treated with and without WBRT after local therapy for a limited number of brain metastases are evaluated have also routinely included assessment of neurotoxic effects. This setting provides an opportunity to review neurocognitive effects of radiotherapy in a patient population with a relatively good performance status and less extensive systemic disease. In general, these studies have shown that WBRT can be delivered safely without substantial changes in neurocognitive function and that it improves local control but not overall survival. Chang et al.32 conducted a phase III trial comparing stereotactic radiosurgery with and without WBRT for patients with one to three brain metastases, with the primary end point being a change in neurocognitive function at 4 months as measured by the Hopkins Verbal Learning Test (HVLT). The investigators found that patients treated with stereotactic surgery plus WBRT had noticeable impairment in learning and memory function by HVLT compared with the patients who were treated with stereotactic radiosurgery alone. This study, however, has been controversial because of unexpected survival differences favoring the stereotactic radiosurgery arm and for the timing of the neurocognitive assessment to one time point. The European Organisation for Research and Treatment of Cancer (EORTC) conducted a phase III trial assessing whether adjuvant WBRT (30 Gy/3 Gy once daily) increases the duration of functional independence after surgery or stereotactic radiosurgery for brain metastases.33 Adjuvant WBRT reduced intracranial relapses (surgery: 59% to 27%, p = 0.001; stereotactic radiosurgery: 31% to 19%; p = 0.040) and neurologic deaths. WBRT did not affect the rate of decline in performance status. The median time to World Health Organization performance status higher than 2 was 10.0 months after observation and 9.5 months after WBRT (p = 0.71). Aoyama et al.34 prospectively evaluated WBRT after local therapy for brain metastases and did not find a difference in survival or in neurocognitive function. Intracranial relapse occurred considerably more frequently among patients who did not receive WBRT and, consequently, as demonstrated in other studies, salvage treatment was frequently needed when upfront WBRT was not used. Neurocognitive function was scored 0 to 4 based on the degree of functional impairment and level of assistance required. Neurocognitive function assessment using the MMSE was optional. MMSE data for at least one time point were available for 28 of 44 patients who lived 12 months or longer (16 patients in the WBRT plus stereotactic radiosurgery group and 12 in the stereotactic radiosurgery-alone group) at a median follow-up of 30.5 months (range, 13.7 to 58.7 months). The median MMSE scores before and after treatment were 28 and 27, respectively, in the WBRT plus stereotactic radiosurgery group and 27 and 28 in the stereotactic radiosurgery-alone group. The investigators also evaluated MRI for leukoencephalopathy, and radiographic findings consistent with leukoencephalopathy were found in seven patients in the WBRT plus stereotactic radiosurgery group and in two patients in the stereotactic radiosurgery-alone group (p = 0.09). Three of these

CHAPTER 43  Neurotoxicity Related to Radiotherapy and Chemotherapy for Nonsmall Cell and Small Cell Lung Cancer

nine patients also had symptomatic leukoencephalopathy; the other six patients were asymptomatic. 

Prophylactic Cranial Radiation Prophylactic cranial radiation is a superior setting to assess the effects of radiotherapy on the whole brain, although it comes with some challenges. Even with the use of prophylactic cranial radiation, survival is limited for patients with lung cancer, routine use of neuropsychologic testing in this patient population is limited, and frequently, patients have baseline neuropsychologic deficits before prophylactic cranial radiation, partially as a result of prior chemotherapy and possibly also because of paraneoplastic effects from the underlying malignant process. Historically, high rates of toxicity with prophylactic cranial radiation were reported when it was given concurrently with chemotherapy or when it was given at high dose per fraction to patients with SCLC.35 After low-dose concurrent chemotherapy and prophylactic cranial radiation, 44% of patients with SCLC had abnormal neuropsychologic tests at a median follow-up of 6.2 years.35 Unexpected neurocognitive deficits have been detected in patients with SCLC after combination chemotherapy, with no noticeable change in those deficits after prophylactic cranial radiation.36 The authors suggest that neuropsychologic abnormalities associated with SCLC may be secondary to the disease itself (paraneoplasia) and systemic therapy. Le Péchoux et al.37 published the results of an international phase III study (PCI99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01) comparing 25-Gy and 36-Gy prophylactic cranial radiation for patients with limited-disease SCLC.37 Over 3 years, the authors found no significant difference between the two groups in any of the 17 selected items assessing quality of life and neurologic and cognitive functions. However, in both groups, there was mild deterioration in communication, memory, intellectual capacity, and leg strength (p < 0.005 for all). RTOG 0212 was a randomized phase II trial designed to evaluate the incidence of chronic neurotoxicity and changes in quality of life among patients who received prophylactic cranial radiation for limited-disease SCLC; some patients from this study were also involved in the international phase III prophylactic cranial radiation trial. Patients in RTOG 0212 were treated to 25 Gy/2.5 Gy once daily, 36 Gy/2 Gy once daily, or 36 Gy/1.2 Gy twice daily. There were no significant baseline differences among the treatment groups in terms of quality-of-life measures, and one of the neuropsychologic tests, namely the HVLT. However, at 12 months after prophylactic cranial radiation, there was a significant increase in the occurrence of chronic neurotoxity in the 36-Gy cohort (p = 0.02). According to logistic regression analysis, increasing age was found to be the most significant predictor of chronic neurotoxicity (p = 0.005). RTOG 0214 evaluated the use of prophylactic cranial radiation for patients with locally advanced NSCLC. Prophylactic cranial radiation was shown to considerably decrease the risk of brain metastasis from 18% to 7.7% at 1 year. However, there was no significant difference in overall survival or disease-free survival.38 A secondary end point of this study was to evaluate the neuropsychologic impact of prophylactic cranial radiation. There were no significant differences at 1 year between the two arms in any component of the EORTC Quality of Life Questionnaire (EORTC-QLQ) C30 or EORTC-QLQ BN20 studies, although a trend for greater decline in patient-reported cognitive functioning was noted with prophylactic cranial radiation. There were no significant differences in MMSE score or activities of daily living. However, for HVLT, there was a significantly greater decline in immediate recall (p = 0.03) and delayed recall (p = 0.008) in the prophylactic cranial radiation arm at 1 year. Gondi et al.39 reported a pooled secondary analysis of tested and self-reported cognitive functioning of patients treated with

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prophylactic cranial radiation in RTOG 0212 and RTOG 0214.39 Among patients with lung cancer in whom brain relapse did not develop, prophylactic cranial radiation was associated with decline in HVLT-tested and self-reported cognitive functioning; however, decline in HVLT and self-reported cognitive functioning were not closely correlated, suggesting that they may represent distinct elements of the cognitive spectrum. 

Radiographic Imaging Studies WBRT is one of the most effective modalities for the treatment and prevention of brain metastases, although it can result in neurocognitive deficits. WBRT is associated with the development of delayed white matter abnormalities or leukoencephalopathy and has been correlated with cognitive dysfunction. The effects of WBRT have been studied in the setting of treatment for intracranial disease and prophylactic cranial irradiation. Prophylactic cranial irradiation is ideal for studying the effect of WBRT, as patients do not have baseline neurologic effects from metastatic or primary tumors in the brain. Stuschke et al.40 studied neuropsychologic function and MRI of the brain in patients with locally advanced NSCLC after prophylactic cranial radiation. T2-weighted MR images demonstrated white matter abnormalities of higher grade in patients who received prophylactic cranial radiation than in those patients who did not. Two of nine patients treated with prophylactic cranial radiation and none of four patients not treated with prophylactic cranial radiation had grade 4 white matter abnormalities. A trend toward impaired neuropsychologic functioning was also found in patients with white matter abnormalities of higher degree. Impairments in attention and visual memory in longterm survivors were found among patients in both prophylactic cranial radiation and nonprophylactic cranial radiation groups. In prophylactic cranial radiation studies, MR images have not been prospectively evaluated before and after therapy for radiation effects and correlation with clinical toxicity. Johnson et al.35 evaluated CT and MR images of patients 6 to 13 years after receiving prophylactic cranial radiation for SCLC. Findings on CT were abnormal (i.e., demonstrated ventricular dilation, cerebral atrophy, and/or cerebral calcification) in 12 of 15 patients, and white matter abnormalities were present on MR images for seven of 15 patients. Anatomic abnormalities documented by CT and MRI were more frequent among patients with abnormal neuropsychologic function. Little is known about the factors that predispose patients to white matter changes that occur with WBRT. Sabsevitz et al.41 used MRI volumetrics to prospectively evaluate the effect of white matter health before treatment on the development of white matter changes after WBRT. Age at the time of treatment and volume of abnormal fluid-attenuated inversion recovery before treatment were significantly associated with white matter changes following WBRT; however, pretreatment fluid-attenuated inversion recovery volume was the strongest predictor of white matter changes after treatment. No significant relationships were found between dose of WBRT, total glucose, blood pressure, or body mass index and development of white matter changes. Szerlip et al.42 retrospectively reviewed serial MR images and measured volumetric white matter changes over time for patients treated with WBRT and who survived more than 1 year. Following WBRT, white matter changes accumulated at an average rate of 0.07% of total brain volume per month. On multivariate analysis, greater rates of accumulation were associated with older age, poor levels of glycemic control, and the diagnosis of hypertension. Routine use of MRI before and after therapy and correlation with neuropsychologic assessment are necessary to better understand the neurotoxic effects of brain radiation. Additionally, factors predicting neurologic change or faster rate of neurologic change are important to understand. Paying careful attention

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to mitigating risk, such as through control of hyperglycemia or hypertension or possibly avoiding or delaying WBRT for patients at high risk of complications, is vital for individualizing care. 

PREVENTION OF NEUROCOGNITIVE COMPLICATIONS Recent clinical efforts to minimize toxicity of radiotherapy have focused on modifying radiotherapy techniques and using neuroprotectants. Memantine is a clinically useful drug for many neurologic disorders, including Alzheimer disease. The principal mechanism of action of memantine is believed to be the blockade of current flow through channels of N-methyl-d-aspartate receptors. Memantine has been associated with a moderate decrease in clinical deterioration of cognition, mood, behavior, and the ability to perform daily activities in patients with Alzheimer disease. In RTOG 0614, a trial that studied the neuroprotective effects of memantine in patients treated with palliative WBRT,43 memantine was found to be well tolerated, with a toxicity profile very similar to placebo. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed of patients who received WBRT. The primary end point was delayed recall at 24 weeks; although less decline of delayed recall was found with the use of memantine, this decline lacked significance, possibly due to substantial patient loss. Follow up in this patient population is challenging secondary to death and noncompliance related to disease progression. According to emerging evidence, the pathogenesis of r­adiation-induced neurocognitive function deficit may involve radiation-induced injury to proliferating neuronal progenitor cells in the subgranular zone of the hippocampi.44 IMRT allows for sparing of the hippocampus while otherwise treating the whole brain with radiation therapy. In RTOG 0933, a single-arm phase II study, hippocampal avoidance WBRT for brain metastases with a p­rimary cognitive end point was evaluated in comparison to a h­istoric control of WBRT without h­ippocampal avoidance (RTOG 9801).45 Conformal avoidance of the h­ ippocampus d­uring WBRT was associated with memory preservation at 4 and 6 months of follow-up. These phase II results compared f­avorably with those in historic series.39

Chemotherapy-Induced Peripheral Neuropathy Agents commonly used in the treatment of NSCLC and SCLC that are associated with CIPN include the taxanes, (e.g., paclitaxel, docetaxel, nanoparticle albumin-bound paclitaxel [nabpaclitaxel]), platinum agents (e.g., cisplatin and carboplatin), and vinca alkaloids (e.g., vincristine, vinorelbine, vinblastine). The mechanism, incidence, and symptoms of CIPN vary with the class of agent. Neuropathy induced by microtubule-targeting agents (e.g., vinca alkaloids and taxanes) is dependent on the length of the nerves, and patients frequently present with symptoms in their fingertips and feet. The vinca alkaloids can cause autonomic neuropathy as well as peripheral neuropathy, symptoms of which can present as abdominal cramping, ileus and constipation, and, rarely, cranial nerve neuropathies.46 Cisplatin-related sensory neuropathy usually becomes clinically detectable after a cumulative dose of 300 mg/m2; carboplatin has a lower rate of neurotoxicity than does cisplatin.47 Oxaliplatin is associated with cold dysesthesias, paresthesias, and CIPN, but is not a standard agent used in the treatment of NSCLC or SCLC. The rate and severity of CIPN depends on the dose, duration, and combination of agents used. Patients with a history of nerve damage from diabetes, alcohol-use, or an inherited neuropathy are at increased risk for the development of CIPN, and symptomatic neuropathy may develop with lower doses or earlier in treatment.46 Initial symptoms of CIPN are often symmetric sensory and motor

impairment of the extremities causing tingling (paresthesias) or numbness (hypoesthesia) of the fingertips or feet. The loss of proprioception may cause unsteady gait, ataxia, or a tendency to fall. Other common symptoms are pain or motor neuropathy resulting in muscle weakness. In general, NCI-CTCAE grade 2 or grade 3 sensory neuropathy is thought to be clinically significant and requires an intervention such as dose delay and/or reduction or, potentially, discontinuation of the offending agent. Physicians often underestimate the frequency and severity of symptoms, and so patient-reported outcomes may be a more accurate assessment of the frequency and severity of this toxicity.48,49 

Chemotherapy Treatments Associated With CIPN The selection of chemotherapy combinations is frequently influenced by patients’ preexisting conditions and their risk for the development of CIPN. Patients with a preexisting neuropathy or with conditions that predispose them to CIPN often will receive a chemotherapy combination that is associated with a lower rate of CIPN (e.g., a platinum agent and pemetrexed or a platinum agent and gemcitabine). Cisplatin or carboplatin and paclitaxel, docetaxel, vinorelbine, and nab-paclitaxel are used in the treatment of NSCLC, and all are associated with CIPN. The combination of cisplatin and vincristine is a standard combination for adjuvant therapy and for metastatic disease. Two different schedules of cisplatin and vinorelbine have been investigated in phase III trials of adjuvant therapy, and the rate of CIPN was evaluated with the use of these agents (Table 43.2).50,51 The rate of all-grade constipation and grade 3 constipation—a symptom of autonomic neuropathy—found in these trials was approximately 45% and 5%, respectively. Given the significant improvement in overall survival and long-term survival in the adjuvant setting, the rate of neurotoxicities is acceptable, but diligent surveillance and symptom management are required. In a three-arm phase III trial, docetaxel plus cisplatin and docetaxel plus carboplatin were compared with vinorelbine plus cisplatin for advanced-stage NSCLC,52 and patients could receive a maximum of six cycles. The rate of grade 3 or grade 4 sensory neuropathy was numerically lower in the docetaxel plus carboplatin arm (Table 43.2). These trials provide an estimate of the rate of CIPN with commonly used chemotherapy combinations. The relationship between CIPN and single-agent paclitaxel and the combination of carboplatin and paclitaxel has been extensively studied in clinical trials. In a prospective study of patients receiving weekly paclitaxel (70–90 mg/m2) who completed the EORTC-CIPN instrument, 20% of patients had a clinically significant pain score with the first dose of paclitaxel.53 The rate of chronic neuropathy was higher among patients with higher paclitaxel-acute pain syndrome pain scores with the first dose of paclitaxel.53 Common symptoms of paclitaxel-acute pain syndrome include a diffuse aching of the legs, hips, and lower back 1 to 3 days after the paclitaxel administration. Numbness and tingling were more prominent chronic neuropathic symptoms than shooting or burning pain. Longer duration of treatment with carboplatin and paclitaxel has been associated with a higher rate of CIPN. A phase III trial of carboplatin and paclitaxel every 3 weeks for four cycles compared with carboplatin and paclitaxel until disease progression or unacceptable toxicity revealed similar efficacy.54 However, the rate of grade 2 to grade 4 sensory neuropathy increased from 19.9% (95% CI, 13.6–26.2%) at cycle 4 to 43% (95% CI, 28.6–57.4%) at cycle 8. An association between cumulative paclitaxel dose and development of sensory neuropathy has been demonstrated in other studies as well.55 In a phase III trial that compared cisplatin and paclitaxel every 3 weeks to carboplatin and paclitaxel every 3 weeks, patients continued therapy until disease progression or a maximum of 10 cycles.56 Rates for all-grade and grade 3 peripheral neuropathy were similar for the two combinations.

CHAPTER 43  Neurotoxicity Related to Radiotherapy and Chemotherapy for Nonsmall Cell and Small Cell Lung Cancer

415

TABLE 43.2   Rate of Chemotherapy-Induced Neuropathy Reported in Phase III Trials of Platinum Agent Doublets Author

Chemotherapy

No. of Patients

Rate of Sensory Neuropathy (all grades) (%)

Winton et al.50

Cisplatin 50 mg/m2 days 1 and 8 every 28 days Vinorelbine 25 mg/m2 weekly for 16 weeks Cisplatin 100 mg/m2 day 1 Vinorelbine 30 mg/m2 days 1, 8, & 15 (cycle: every 28 days) Cisplatin 75 mg/m2 & docetaxel 75 mg/m2 every 21 days Carboplatin AUC of 6 & docetaxel 75 mg/m2 every 21 days Cisplatin 100 mg/m2 day 1 every 28 days & vinorelbine 25 mg/m2 weekly Cisplatin 80 mg/m2 & paclitaxel 200 mg/m2 every 21 days Carboplatin AUC of 6 & paclitaxel 200 mg/m2 every 21 days Cisplatin 75 mg/m2 & paclitaxel 135 mg/m2 every 21 days Cisplatin 75 mg/m2 & paclitaxel 250 mg/m2 every 21 days Carboplatin AUC of 6 & paclitaxel 225 mg/m2 every 3 days Carboplatin AUC of 6 on day 1 & paclitaxel 100 mg/m2 on days 1, 8, & 15 every 28 days Carboplatin AUC of 6 on day 1 & nab-paclitaxel 100 mg/m2 on days 1, 8, & 15 every 21 days Carboplatin AUC of 6 & paclitaxel 200 mg/m2 every 21 days

242b

48

2a

367b

28

3

1218

NR

3.8

NR

3.9

NR

0.7

58

9

59

8

NR

23

NR

40

NR

18d

NR

12

46

3

62d

11e

Douillard et al.51 Fossella et al.52

Rosell et al.56

Bonomi et al.58c

Belani et al.59

Socinski et al.60

  

618

399

440

1052

Rate of Grade 3 or 4 Sensory Neuropathy (%)

aThe

rate of all-grade and grade 3 motor neuropathy observed was 15% and 3%, respectively. represent patients receiving cisplatin and vinorelbine. cThis trial included three arms, and the two arms containing paclitaxel are included in the table. The results are reported as grade 3 neurologic toxicity. dThe results represent the rate of grade 2 or grade 3 neuropathy, and the difference is significant (p = 0.05). eSignificant differences in the rates of all grades of sensory neuropathy (p < 0.001) and grade 3 or grade 4 sensory neuropathy (p < 0.05) were noted. AUC, area under the curve; NR, not reported. bNumbers

  

A lower-dose weekly schedule compared with every-3-week paclitaxel has been investigated in several trials to improve e­fficacy or reduce toxicity, and higher and lower doses of paclitaxel have been researched as well. Paclitaxel sensory neuropathy is also dose-related, and it rarely occurs below doses of 170 mg/m2.55,57 In a phase III trial of cisplatin and low-dose paclitaxel (135 mg/m2) every 3 weeks or high-dose paclitaxel (250 mg/m2) every 3 weeks, a significantly higher rate of grade 3 neurologic toxicity was found in the high-dose paclitaxel arm (40% vs. 23%);58 however, the low and high doses of paclitaxel investigated in this trial are not currently used in the treatment of NSCLC. In another phase III trial, carboplatin and paclitaxel every 3 weeks was compared with carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 4 weeks for four cycles; treatment was given for up to four cycles.59 The rate of grade 2 and grade 3 neuropathy was s­ignificantly lower in the weekly arm compared with the every-3-week arm (12% vs. 18%; p = 0.05). In a smaller phase II trial, c­arboplatin every 3 weeks was compared with either paclitaxel 225 mg/m2 every 3 weeks or 75 mg/m2 weekly for 12 weeks;60 the rate of sensory neuropathy was not significant between the two arms (p = 0.27). These data are suggestive of a lower rate of CIPN with a lower dose of paclitaxel used on a weekly schedule. Standard formulation paclitaxel uses a Cremophor-base, and nab-paclitaxel formulation does not. In a phase III trial, carboplatin and nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 every 3 weeks was compared with carboplatin and standard formulation paclitaxel 200 mg/m2 every 3 weeks.61 Treatment was continued for at least six cycles and was allowed to continue in the absence of disease progression or unacceptable toxicity. The median cumulative dose of paclitaxel in the nab-paclitaxel and standard paclitaxel formulation arms was 1325 mg/m2 and 1125 mg/m2, respectively.

The rate of all-grade sensory neuropathy in the nab-paclitaxel and standard paclitaxel formulation arms was 46% and 62% (p < 0.001) respectively, the rate of grade 3 or grade 4 sensory neuropathy was 3% and 11% (p < 0.05), respectively, and the median improvement of grade 3 or higher sensory neuropathy to grade 1 in the nabpaclitaxel and paclitaxel arms was 38 and 104 days, respectively. It is important to note that the dose, schedule, and formulation of paclitaxel were different between the two arms, and it is unclear if one or a combination of these factors contributed to the difference in CIPN found in this trial. Infusion of nab-paclitaxel over 2 hours instead of the standard 30 minutes was compared with nab-paclitaxel 125 mg/m2 on days 1, 8, and 15 every 4 weeks in a single-arm phase II trial.62 A significant decrease was found in the grade of the average peripheral neuropathy, as well as in the rate of grade 2 or higher peripheral neuropathy compared with historic controls, which suggests that a longer infusion time with nab-paclitaxel may reduce the rate of clinically significant CIPN. In summary, the rate of clinically relevant grade 2 or grade 3 sensory neuropathy found with platinum and taxane or vinorelbine combination therapy for the treatment of NSCLC is approximately 10% to 20%, and the rate of severe grade 3 sensory neuropathy is approximately 5%. Limiting the duration of carboplatin and paclitaxel to four cycles reduces the risk of clinically significant neuropathy, and the lower dose weekly schedule of paclitaxel may be associated with a lower rate of CIPN. 

Prevention of CIPN A number of agents have been investigated for the prevention of CIPN. Amifostine, an organic thiophosphate that acts as a scavenger of free radicals, was investigated as a cytoprotective agent for

43

416

SECTION VIII  Radiotherapeutic Management of Lung Cancer

chemotherapy-induced and radiotherapy-induced toxicities. This agent was investigated in several small trials of various chemotherapy regimens, and a definitive improvement in clinical symptoms of CIPN was not found.47 Glutathione is thought to prevent the accumulation of platinum adducts in the dorsal root ganglia, and to date, the trials in which glutathione is being researched for prevention of CIPN have been inconclusive.47 In a phase III placebo-controlled, double-blinded clinical trial glutathione was investigated for the prevention of CIPN in patients with ovarian cancer treated with carboplatin and paclitaxel (ClinicalTrials. gov identifier: NCT02311907). Acetyl-L-carnitine (ALC) is a natural compound involved in the acetylation of tubulin, a process that provides neuronal protection.63,64 ALC was investigated in a randomized, double-blind, placebo-controlled trial of 409 women treated with paclitaxel for breast cancer.65 CIPN was assessed using the Functional Assessment of Cancer Therapy-Taxane scale at 12 and 24 weeks (a lower score indicates worse CIPN); patients who were assigned to ALC compared with placebo had a 0.9-point lower score at 12 weeks than patients who received placebo (95% CI, –2.2 to 0.4; p = 0.17) and a 1.8-point lower score at 24 weeks (95% CI, –3.2 to –0.04; p = 0.01). Grade 3 or grade 4 neurotoxicity was more frequent in the ALC arm than in the placebo arm (8 vs. 1). The worsening of CIPN with this nutritional supplement is discouraging and illustrates the need to perform randomized controlled trials of nutritional supplements. Alpha-lipoic acid (ALA) may improve nerve blood flow by antioxidant action and has been investigated as a treatment of diabetic peripheral neuropathy.66,67 Accrual has been completed for a placebo-controlled phase III trial to evaluate alpha-lipoic acid (given for at least 24 weeks) for the prevention of CIPN in patients receiving cisplatin or oxaliplatin (ClinicalTrials.gov identifier: NCT00112996). 

Pharmacologic Therapy for CIPN When clinically significant CIPN develops, often defined as grade 2 or higher, treatment options are limited. The most problematic symptom for many patients is pain associated with the paresthesias, and a number of therapies have been investigated with variable success (Table 43.3). The primary end point for these trials is generally assessment of the grade of toxicity and patient-reported outcomes. In 2013, duloxetine was investigated in a randomized, double-blind, placebo-controlled, cross-over trial with the primary end point of reduction in average pain score.68 Patients were required to have at least grade 1 sensory pain based on the NCI-CTCAE version 3.0 (reported as 4 or higher on a 10-point pain scale) and have neuropathic pain for 3

months or longer after completing chemotherapy. To be considered eligible for the trial, patients could have received treatment with paclitaxel, oxali­platin, single-agent docetaxel, nab-paclitaxel, or cisplatin; however, none of the patients enrolled had received cisplatin. The majority of the patients enrolled had breast cancer (38%) or gastrointestinal cancer (56%). Eligible patients were randomly assigned to receive either duloxetine daily during the initial treatment period and placebo at cross-over period, or to receive placebo as initial treatment and duloxetine as cross-over treatment. The initial treatment period was week 1 to week 5, followed by a 2-week washout period, and cross-over (weeks 8 to 12); treatment consisted of either placebo or duloxetine 30 mg daily for the first week, and placebo or duloxetine 60 mg daily for 4 weeks. Patients reported the pain severity and functional interference weekly using the Brief Pain Inventory Short Form, in which 0 indicates no pain and 10 indicates pain “as bad as you can imagine.” The minimal clinically important difference in pain severity was determined to be a 0.98 difference in average pain score. CIPN was also assessed using the NCI-CTCAE version 3.0 on a weekly basis. Patients assigned to duloxetine as their initial 5-week treatment reported a decrease in average pain of 1.06 (95% CI, 0.72–1.40), and patients assigned to placebo reported a decrease in average pain of 0.34 (95% CI, 0.01–0.66; p = 0.003). The effect size was moderately large at 0.513, and the percentage of patients reporting a decrease in pain with duloxetine and placebo first was 59% and 38%, respectively. Patients treated with duloxetine reported a greater decrease in the amount of pain that interfered with daily function (p = 0.01) and greater improvement in pain related to quality of life using the Functional Assessment of Cancer treatment, Gynecological Oncology Group Neurotoxicity subscale (p = 0.03). The most common adverse events were fatigue (7%), insomnia (5%), and nausea (5%). In an exploratory analysis, patients who received oxaliplatin experienced more benefit from duloxetine than patients who received taxanes (p = 0.13). Other agents that have been investigated in double-blind, placebo-controlled trials for the treatment of CIPN include gabapentin and venlafaxine (Table 43.3).69,70 In a phase III trial of gabapentin (target dose of 2700 mg daily) compared with placebo, patients with either a numeric score of 4 or higher on the numeric rating scale or 1 or higher on the Eastern Cooperative Oncology Group neuropathy scale had a 2-week washout and then crossed over to the other therapy. Changes in symptom severity were similar between the two groups, and this study did not suggest any benefit for gabapentin for the treatment of CIPN. In a smaller study, venlafaxine 50 mg 1 hour before the oxaliplatin infusion and venlafaxine 37.5 mg twice a day from day 2 to

TABLE 43.3   Select Phase III Trials of Therapies for Treatment of Chemotherapy-Induced Peripheral Neuropathy Agent

No. of Patients

Trial Design

Primary End Point

Outcomea

Duloxetine

231

Average pain assessed using BPI-SF

Significant improvement (p = 0.003)

Rao et al.69

Gabapentin

115

Average pain assessed using NRS & ENS

No significant difference

Durand et al.70

Venlafaxine

48

Randomized, double-blind, placebo-controlled, crossover Randomized, double-blind, placebo-controlled, crossover Double-blind, placebocontrolled

NRS, NPSI, & oxaliplatinspecific neurotoxicity

Barton et al.71

Topical BAK-PLO

208

Double-blind, placebocontrolled

EORTC QLQ-CIPN20 at 4 weeks

Full relief according to NRS significantly more common in venlafaxine arm (31.3% vs. 5.3%, p = 0.03) Sensory neuropathy (p = 0.053); motor neuropathy (p = 0.021)

Author Smith

  

aA

et al.68

trend toward improvement in sensory neuropathy and a significant improvement in motor neuropathy was observed with BAK-PLO compared to placebo. BAK-PLO, baclofen 10 mg, amitriptyline 40 mg, ketamine 20 mg in a pluronic lecithin organogel; BPI-SF, Brief Pain Inventory-Short Form; ENS, Eastern Cooperative Oncology Group neuropathy scale; EORTC QLQ-CIPN20, European Organisation for Research and Treatment of Cancer 20-item quality-oflife chemotherapy-induced peripheral neuropathy questionnaire; NRS, numerical rating scale; NPSI, neuropathic pain symptom inventory.   

CHAPTER 43  Neurotoxicity Related to Radiotherapy and Chemotherapy for Nonsmall Cell and Small Cell Lung Cancer

day 11 or placebo was investigated. The primary end point was the percentage of patients reporting 100% relief while receiving treatment as assessed by a numeric rating scale; in the venlafaxine and placebo arms, this end point was reached in 31.3% and 5.3%, respectively (p = 0.03). In a double-blind, placebo-controlled trial a compounded gel containing 10 mg of baclofen, 40 mg of amitriptyline, and 20 mg of ketamine (BAK-PLO) was investigated compared with an identical-appearing placebo gel.71 The primary end point was change in sensory neuropathy subscale as measured by the EORTC QLQ-CIPN20 instrument, which includes sensory, motor, and autonomic subscales from baseline to 20 weeks. A trend toward improvement was found in the sensory subscale (p = 0.053) as well as in the motor subscale (p = 0.021). The improved symptoms included tingling and shooting or burning pain in the fingers and hands and the ability to a hold a pen. A significant difference between the two treatment arms in the Brief Pain Inventory score and the CTCAE grade was not found. 

CONCLUSION Historically the acute and chronic toxicities of radiotherapy and chemotherapy for patients with NSCLC and SCLC were not considered to be clinically relevant. Consequently the m­ajority of the data on the frequency and severity of n­eurotoxicity was retrospective. However, with improved s­urvival and an increased number of treatment options for lung cancer patients the impact of these toxicities has become more apparent and r­elevant. This has led to the development of clinical trials that p­rospectively assess neurologic toxicity. Many c­hemotherapy and r­adiotherapy trials are investigating t­reatment agents or r­adiotherapy techniques that may reduce the risk of neurologic toxicity. Several prospective studies have i­nvestigated preventive agents and assessed the efficacy of symptomatic treatments for neurologic toxicity.

417

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