Support Care Cancer DOI 10.1007/s00520-014-2317-x
REVIEW ARTICLE
What about Alice? Peripheral neuropathy from taxane-containing treatment for advanced nonsmall cell lung cancer Celia M. Bridges & Ellen M. Lavoie Smith
Received: 12 March 2014 / Accepted: 8 June 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose In this review, we discuss the plight of Alice, a patient with advanced nonsmall cell lung cancer (NSCLC) who struggles with taxane-related peripheral neuropathy (PN). Using this unique point of view helps us to appreciate the implications of PN on daily activities as well as the difficulty in decision-making regarding continuation of treatment. In addition, published reports of phase 3 trials are reviewed to identify the incidence and severity of chemotherapy-induced PN as well as the assessment tools used in these studies. Methods A literature review spanning the years 1998–2012 was performed. Phase 3 studies and a meta-analysis of taxanebased therapy in advanced NSCLC were selected for review for their findings regarding the incidence and severity of chemotherapy-induced PN. Results In total, 16 phase 3 studies and 1 meta-analysis were reviewed. Use of grading scales and PN assessment tools was inconsistent across the studies, and some studies did not report PN at all. Conclusions The true incidence and severity of chemotherapy-induced PN in clinical trials may be masked by nonstandardized reporting; thus, a more standardized approach to grading, assessing, and reporting PN in clinical trials is greatly needed to allow for appropriate comparisons across studies. Understanding chemotherapy-induced PN from the patient’s perspective as well as the development of PN at the clinical trial level will help health care providers anticipate the development of PN and improve their ability to manage it.
C. M. Bridges (*) : E. M. L. Smith University of Michigan School of Nursing, 400 N Ingalls St, Ann Arbor, MI 48109, USA e-mail: [email protected]
Keywords Peripheral neuropathy . Nonsmall cell lung cancer . Taxanes . Assessment tools
Alice’s plight After 69 years of considering herself quite healthy, Alice began to experience some shortness of breath but dismissed it as simply part of “getting on in years.” However, when she began coughing up blood, her concern prompted a visit to her primary care physician. Testing led to a diagnosis of stage IIIB nonsmall cell lung cancer (NSCLC), which is considered incurable. Nevertheless, she is now being treated with chemotherapy, deemed palliative, which has alleviated some of the symptoms of the disease but has caused adverse effects that she did not expect and about which she does not recall being forewarned. At each visit to her physicians, when they inquire about any side effects of the treatment, she has described the suffering she experiences, especially when she lies down at night: “restless leg-type symptoms with terrible shooting pain, numbness, and a creepy tingling” that keep her from being able to fall asleep and wake her up when she does manage to drift off. She mentioned how humiliating it is to have to ask strangers to help zip up her jacket when she ventures out, since she has trouble grabbing the pull tab. Despite these revelations to her providers, she received no new suggestions for symptom management. Desperate for relief, on her own she has tried nonprescription drugs, herbs, alcohol, marijuana, and other alternative treatments for her symptoms, to no avail. People like Alice, who are diagnosed with NSCLC at an advanced stage, often receive taxane-containing multidrug chemotherapy for palliation. While this treatment prolongs survival slightly and does improve symptoms, it also commonly causes toxic side effects, one of which is peripheral neuropathy. The results of most phase 3 trials assessing taxane-containing NSCLC therapy indicate that
Support Care Cancer
chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect—affecting up to 62 % of patients treated for advanced-stage disease. Common CIPN symptoms, such as numbness, tingling, and neuropathic pain in the extremities, often compromise ambulation, functional status, and quality of life (QOL) for patients with limited prospects for long-term survival. The focus of this article is to highlight what is known and unknown about CIPN based on data from phase 3 trials of taxane-based treatment for advanced NSCLC. The need for improved/standardized CIPN assessment in future trials is discussed. Lastly, suggestions are provided for how the nurse should care for Alice, a typical patient with advanced-stage NSCLC who is struggling with CIPN.
NSCLC Lung cancer is the leading cause of cancer deaths in the USA among both men and women, and the American Cancer Society projects that there will be approximately 224,210 new diagnoses and 159,260 deaths in 2014 [1]. Approximately 80 to 85 % of these cases will be NSCLC [2]. This disease has a poor prognosis because the rate of metastasis at diagnosis is high [3]. A systematic review found a median survival of 7.15 months from diagnosis for all stages of NSCLC [4]. However, even though advanced NSCLC— stages IIIB and IV—is not curable, chemotherapy is commonly administered in these cases, both for palliation and as part of clinical trials designed to uncover survival benefits by testing different drug combinations and treatment schedules. Randomized studies comparing chemotherapy with “best supportive care” provide evidence that, when effective, chemotherapy regimens cause tumor reduction or slow disease progression; reduce symptoms like shortness of breath, hemoptysis, pain, and fatigue; and help improve QOL [2]. The NSCLC Meta-Analyses Collaborative Group concurs with these findings and also found a modest increase in survival of 1.5 months (from 4.5 to 6 months) with supportive care plus chemotherapy versus supportive care alone [5].
CIPN During the past 15 to 20 years, since their discovery and addition to the armamentarium of chemotherapeutic agents, taxanes (docetaxel and paclitaxel) have been shown to prolong survival and have become a mainstay treatment for NSCLC [6]. Three taxanes, nab-paclitaxel, paclitaxel, and docetaxel, are currently approved for first-line treatment of locally advanced or metastatic NSCLC (all in combination with a platinum agent and in patients who are not candidates for curative surgery or radiotherapy for nab-paclitaxel and paclitaxel) [7]. While effective in treating cancer, taxanes are
neurotoxic, damaging the nerve cell axon, myelin sheath, and cell body in the dorsal root ganglion [8]. Therefore, peripheral neuropathy is a common side effect of taxane treatment and adds to the overall symptom burden experienced by patients with advanced-stage NSCLC. An early sign of CIPN is the decrease or absence of deep tendon reflexes, detectable through a clinical exam. Symptoms of CIPN may include both sensory and motor components. Numbness, tingling, burning or shock-like pain, and altered proprioception from decreased plantar sensation are common sensory symptoms [9–11]. These sensory alterations can affect activities of daily living, such as manipulating zippers or small buttons when dressing, and create instability with ambulation. Motor weakness, although less common, may affect grip strength, cause difficulty standing for extended periods and trouble rising from low positions (e.g., a bathtub), and contribute to trips and falls. Given these significant side effects, health care providers making treatment decisions must take into consideration the total symptom burden, both from the disease and its treatment.
Standard taxane-containing chemotherapy regimens for advanced NSCLC The American Society of Clinical Oncology guidelines for first-line treatment of stage IV NSCLC [6], all of which are “based on treatment strategies that improve overall survival,” recommend a combination of cytotoxic drugs for no more than 6 cycles. Platinum-based combinations, including carboplatin plus paclitaxel administered every 3 weeks, are the current standard of care for first-line treatment [7]; paclitaxel plus carboplatin usually improves survival by about 1.5 months [12]. Unfortunately, this drug combination contains two neurotoxic agents that often cause severe peripheral neuropathy. CIPN usually worsens over time with repeated chemotherapy treatments and may become permanent [6, 13, 14]. Phase 3 trials comparing various multidrug therapies and schedules have been conducted with the goal of improving outcomes for chemotherapy-naive patients with advanced NSCLC. Some of these studies have evaluated a taxane plus a platinum and/or other agent. A recent study evaluated combination treatment with nab-paclitaxel, a 130-nm albuminbound formulation of paclitaxel and carboplatin in patients with advanced NSCLC [15]. Improved survival and chemotherapy efficacy are the most common study endpoints, with secondary attention to various toxicities and QOL. In general, combination regimens provide a modest improvement in radiological response rates and survival, measured mostly in weeks, with a range of 0.1 to 2.5 months [3, 15–29]. However, their synergistic effects are often associated with
Support Care Cancer
adverse toxic effects greater than those of a single-drug therapy.
CIPN measurement in phase 3 NSCLC trials The PubMed database was searched using the terms “nonsmall cell lung cancer,” “phase,” and “paclitaxel or docetaxel or albumin-bound or nab-paclitaxel” (title only, English language only) using a data cutoff of January 1, 1998 through December 31, 2012. The time frame was chosen because 1998 was the first year that a taxane was approved for the treatment of advanced NSCLC (paclitaxel) and 2012 was the most recent year (nab-paclitaxel). Phase 3 trials that included a taxane in the first-line setting were examined for information on the incidence and severity of CIPN, and the findings of 16 phase 3 trials and 1 meta-analysis are described in this review [3, 12, 15–29]. The stated primary end point of 11 of these studies of different combinations and schedules of taxane-containing chemotherapy was survival; for the other 6, the primary aim was to assess efficacy and safety. QOL was listed as a secondary aim in 5 studies. Since these are drug trials, both hematologic and nonhematologic toxicities must be documented, and many of the trials listed specific grades of toxicity at which dose reductions or withdrawal from the study were to occur. However, attention to CIPN in these trials has been inconsistent. Even though CIPN may be severe and common and is a major factor in dose reductions or therapy cessation [12–14], 3 of the articles reported no data on it [23, 24, 29]. Another failed to specify which CIPN measurement approach was used, rendering the data unusable for our purposes [27]. Of the remaining 12 studies, 10 employed clinician-assessed toxicity grading scales: the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale (n=8) [3, 15, 16, 18, 19, 22, 26, 28], the World Health Organization (WHO) grading scale (n=1) [21], and the Eastern Cooperative Oncology Group Common Toxicity Criteria (ECOG CTC; n=1) [17] (Table 1). The remaining two studies [20, 25] used the European Organisation for Research and Treatment of Cancer’s Quality of Life Questionnaire—Lung Cancer module (EORTC QLQ-LC13), which is a patient-reported outcome measure (Table 1). This module includes one neuropathyspecific question: “In the past week—Have you had tingling hands or feet?” and is graded on a four-point Likert-type scale (not at all, a little, quite a bit, very much), leaving unassessed any numbness, neuropathic pain, or functional difficulties that might be treatment related. One study used a second scale in addition to the NCI CTCAE: the Functional Assessment of Cancer Therapy—Taxane (FACT-Taxane) self-report instrument [15]. This scale includes the FACT-General and a 16item taxane subscale [13]. Eleven of those items relate directly
to neurotoxicity, and seven specifically assess peripheral neuropathy. Altogether, 5 CIPN measurement tools were used in the 17 studies—3 that were clinician-rated grading scales and 2 that were patient-reported outcome measures (Table 1). Only one study reported sensory and motor neuropathy separately [3]. The 3 grading scales—WHO, NCI CTCAE, and ECOG CTC—facilitate clinician-graded evaluations of performance status based on assessments of paresthesia, deep tendon reflexes, instrumental and self-care activities of daily living, and weakness/paralysis. However, these scales present some difficulties due to the lack of accuracy and consistency of the language employed and the attendant subjectivity in scoring, leading to poor interrater reliability and lack of consistency between scales [30]. In one scale, for instance, a decrease in deep tendon reflexes is a criterion for grade 1, whereas the other two scales specify the loss of deep tendon reflexes. It is not clear if loss refers to a complete absence of deep tendon reflexes or a decrease in the reflex response and, therefore, is subject to variable evaluator interpretation. How many reflexes are affected is also not quantified, even though this is an important distinction, since a higher number of affected reflexes indicates more severe neuropathy. By not differentiating the degree of deep tendon reflex impairment, neuropathy grading scales contribute to inaccuracies in describing CIPN severity. Similarly, grade 2 CIPN is defined by the NCI CTCAE and the ECOG CTC grading scales as the presence of moderate paresthesia but by the WHO grading scale as severe paresthesia. Inconsistency also plagues the definition of grade 3 CIPN across the various scales: both intolerable and severe are used as grade 3 criteria. Furthermore, several studies provide evidence that the most commonly used grading scale (NCI CTCAE) is neither reliable nor sensitive due to floor effects (most scores cluster on the low end of the scale) [14, 31] and that it consistently indicates a lower incidence and severity of CIPN compared with several validated patient-reported outcome instruments [32]. Also, most studies suggest that the NCI CTCAE is a valid measure of sensory but not motor CIPN [14, 31]. Because of common reliance on these grading scales, CIPN is under recognized. Clinician bias may also be a factor in underreporting CIPN. Since grade 1 CIPN is not a trigger for either dose reductions or treatment cessation, it may barely register on a clinician’s radar, whereas any level of CIPN may be disturbing to someone experiencing it. Lack of attention to or concern about lowgrade symptoms may further obscure the incidence and severity of CIPN, as it may suggest to patients that the clinician discounts anything but severe symptoms. As a result, patients may hesitate to report CIPN as it worsens during treatment. Of the two patient-reported outcome measures, FACTTaxane more thoroughly explores the various symptoms of CIPN than does the EORTC QLQ-LC13 with its single
Support Care Cancer Table 1 Instruments used to measure CIPN Instrument Grading scales—clinician assessed WHO
NCI CTCAE sensory
NCI CTCAE motor
ECOG CTC sensory
ECOG CTC motor
Patient-reported outcome measures EORTC QLQ-LC13 (“In the past week: Have you had tingling hands or feet?”) FACT-Taxane: questions about numbness, tingling, discomfort in feet and hands (separately), pain in fingertips, ADL problems
Grade 1
Grade 2
Grade 3
Grade 4
Paresthesias and/or decreased tendon reflexes Asymptomatic; loss of deep tendon reflexes or paresthesia Asymptomatic; clinical or diagnostic observations only; intervention not indicated Mild paresthesias; loss of deep tendon reflexes
Severe paresthesias and/or mild weakness Moderate symptoms; limiting instrumental ADL Moderate symptoms; limiting instrumental ADLs
Intolerable paresthesias and/or marked motor loss Severe symptoms; limiting self-care ADL Severe symptoms; limiting self-care ADL; assistive device indicated
Paralysis
Mild or moderate objective sensory loss; moderate paresthesias Mild objective weakness without significant impairment of function
Severe objective sensory loss or paresthesias that interfere with function Objective weakness with impairment of function
Not at all
A little
Quite a bit
Very much
A little bit
Somewhat
Quite a bit
Very much
Subjective weakness; no objective findings
Life-threatening consequences; urgent intervention indicated Life-threatening consequences; urgent intervention indicated –
Paralysis
WHO from Postma and Heimans, 2000 [30]. NCI CTCAE from US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. ECOG from http://ecog.dfci.harvard.edu/general/common_tox.html. EORTC LC13 from http://www.eortc.be/qol/files/LC13/LC13% 20English.pdf. FACT-Taxane from http://www.facit.org/FACITOrg/Questionnaires (FACT-Tax_ENG_Final_Ver4_19Nov07.pdf). ADL activities of daily living, CIPN chemotherapy-induced peripheral neuropathy, ECOG CTC Eastern Cooperative Oncology Group Common Toxicity Criteria, EORTC QLQ-LC13 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire—Lung Cancer module, FACT Functional Assessment of Cancer Therapy, NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events, WHO World Health Organization
question about tingling. FACT-Taxane is not meant to reveal performance status changes in the way that the grading scales do; rather, it explores specific changes in sensory and motor CIPN by quantifying neuropathy-related discomfort, numbness, and tingling in hands and feet separately; sensation in and ability to manipulate a small object with the fingers; and ambulation. FACT-Taxane has been shown in one study to be reliable, valid, and responsive to change over time [13]. Besides relying on a single question, the EORTC QLQLC13 patient-reported outcomes measure is out of step with the other instruments in assigning grade 1 for no symptom of tingling, while the other scales—both provider- and patientreported—use grade 0 for a lack of neuropathy symptoms. This inconsistency in scoring definitions across CIPN measures makes it difficult to compare CIPN incidence and severity among studies.
CIPN incidence and severity as reported in phase 3 NSCLC trials Some level of sensory CIPN occurs in many people treated with taxanes. However, half of the reviewed studies that reported CIPN severity only specified grades ≥3—the level at which withholding of platinum and taxane combination chemotherapy is indicated. Grade 3 sensory neuropathy rates ranged from 0 [25] to 40 % [17]. For the studies reporting all grades, rates ranged from 13 [26] to 62 % [15]. In the four docetaxel studies presenting neuropathy data, reported rates of CIPN with docetaxel and cisplatin combinations ranged from 2 to 5 % for grade 3, 3.9 % for grades 3/4, and 4 % for grade 4. For docetaxel and carboplatin combinations, rates of 0.7 to 3 % for grades 3/4 and 30 % for grades 1 or 2 were reported (Table 2).
1c
1c 3 cycles (median), q 3 weeks 3 cycles (median), q 3–4 weeks 2 cycles (median), q 4 weeks
Cisplatin and gemcitabine Cisplatin and docetaxel
Stage IIIB, stage IV, or recurrent, no prior chemotherapy (301)
Stage IIIB, stage IV, or recurrent, no prior chemotherapy (304) Stage IIIB, stage IV, or recurrent, no prior chemotherapy (299) Carboplatin and paclitaxel
Cisplatin and paclitaxel
Vindesine plus cisplatin
Docetaxel plus cisplatin
Docetaxel
Stage IIIB, stage IV, or recurrent, no prior chemotherapy (303)
Advanced/metastatic, no prior chemotherapy (152) Stage IV, no prior chemotherapy(151) Stage IV, no prior chemotherapy (151)
4c
2c
4 cycles (median), q 3 weeks
Docetaxel 100 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 2 plus rhG-CSF 150 μg/m2/day on days 3–9 every 3 weeks Docetaxel 100 mg/m2 on day 1 (without rhG-CSF) every 3 weeks Docetaxel 60 mg/m2 plus cisplatin 80 mg/m2 every 3–4 weeks Vindesine 3 mg/m2 on days 1, 8, and 15 plus cisplatin 80 mg/m2 on day 1 of a 4-week cycle Paclitaxel 135 mg/m2 every 3 weeks on day 1 plus cisplatin 75 mg/m2 on day 2 every 3 weeks Gemcitabine 1,000 mg/m2 on days 1, 8, and 15 plus cisplatin 100 mg/m2 on day 1 every 4 weeks Docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 every 3 weeks Paclitaxel 225 mg/m2 plus carboplatin AUC 6 mg*mL/min every 3 weeks
Docetaxel/cisplatin
Not reported Not reported Not reported Not reported
5 (grade 3)d 9 (grade 3)d 5 (grade 3)d 10 (grade 3)d
Not reported, q 3 weeks Not reported, q 4 weeks Not reported, q 3 weeks Not reported, q 3 weeks
Not reported
Not reported
Not reported
Not reported
Not reported
Not reported
Not reported
Motor neuropathy grade, %
d
c
b
a
Grading scale not specified
World Health Organization (WHO) grading scale
NCI CTCAE
Sensory versus motor not delineated
AUC area under the curve, CIPN chemotherapy-induced peripheral neuropathy, MIC mitomycin + ifosfamide + cisplatin, MVP mitomycin + vinorelbine + cisplatin, NSCLC nonsmall cell lung cancer, q every, rhG-CSF recombinant human granulocyte colony-stimulating factor
Schiller (2002)
Kubota (2004)
Georgoulias (2004)
4 (grades 3–4)b
6 cycles, q 4 weeks
Vinorelbine 25 mg/m2/week plus cisplatin 100 mg/m2 every 4 weeks
Vinorelbine/cisplatin
REVIEW ARTICLE
What about Alice? Peripheral neuropathy from taxane-containing treatment for advanced nonsmall cell lung cancer Celia M. Bridges & Ellen M. Lavoie Smith
Received: 12 March 2014 / Accepted: 8 June 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose In this review, we discuss the plight of Alice, a patient with advanced nonsmall cell lung cancer (NSCLC) who struggles with taxane-related peripheral neuropathy (PN). Using this unique point of view helps us to appreciate the implications of PN on daily activities as well as the difficulty in decision-making regarding continuation of treatment. In addition, published reports of phase 3 trials are reviewed to identify the incidence and severity of chemotherapy-induced PN as well as the assessment tools used in these studies. Methods A literature review spanning the years 1998–2012 was performed. Phase 3 studies and a meta-analysis of taxanebased therapy in advanced NSCLC were selected for review for their findings regarding the incidence and severity of chemotherapy-induced PN. Results In total, 16 phase 3 studies and 1 meta-analysis were reviewed. Use of grading scales and PN assessment tools was inconsistent across the studies, and some studies did not report PN at all. Conclusions The true incidence and severity of chemotherapy-induced PN in clinical trials may be masked by nonstandardized reporting; thus, a more standardized approach to grading, assessing, and reporting PN in clinical trials is greatly needed to allow for appropriate comparisons across studies. Understanding chemotherapy-induced PN from the patient’s perspective as well as the development of PN at the clinical trial level will help health care providers anticipate the development of PN and improve their ability to manage it.
C. M. Bridges (*) : E. M. L. Smith University of Michigan School of Nursing, 400 N Ingalls St, Ann Arbor, MI 48109, USA e-mail: [email protected]
Keywords Peripheral neuropathy . Nonsmall cell lung cancer . Taxanes . Assessment tools
Alice’s plight After 69 years of considering herself quite healthy, Alice began to experience some shortness of breath but dismissed it as simply part of “getting on in years.” However, when she began coughing up blood, her concern prompted a visit to her primary care physician. Testing led to a diagnosis of stage IIIB nonsmall cell lung cancer (NSCLC), which is considered incurable. Nevertheless, she is now being treated with chemotherapy, deemed palliative, which has alleviated some of the symptoms of the disease but has caused adverse effects that she did not expect and about which she does not recall being forewarned. At each visit to her physicians, when they inquire about any side effects of the treatment, she has described the suffering she experiences, especially when she lies down at night: “restless leg-type symptoms with terrible shooting pain, numbness, and a creepy tingling” that keep her from being able to fall asleep and wake her up when she does manage to drift off. She mentioned how humiliating it is to have to ask strangers to help zip up her jacket when she ventures out, since she has trouble grabbing the pull tab. Despite these revelations to her providers, she received no new suggestions for symptom management. Desperate for relief, on her own she has tried nonprescription drugs, herbs, alcohol, marijuana, and other alternative treatments for her symptoms, to no avail. People like Alice, who are diagnosed with NSCLC at an advanced stage, often receive taxane-containing multidrug chemotherapy for palliation. While this treatment prolongs survival slightly and does improve symptoms, it also commonly causes toxic side effects, one of which is peripheral neuropathy. The results of most phase 3 trials assessing taxane-containing NSCLC therapy indicate that
Support Care Cancer
chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect—affecting up to 62 % of patients treated for advanced-stage disease. Common CIPN symptoms, such as numbness, tingling, and neuropathic pain in the extremities, often compromise ambulation, functional status, and quality of life (QOL) for patients with limited prospects for long-term survival. The focus of this article is to highlight what is known and unknown about CIPN based on data from phase 3 trials of taxane-based treatment for advanced NSCLC. The need for improved/standardized CIPN assessment in future trials is discussed. Lastly, suggestions are provided for how the nurse should care for Alice, a typical patient with advanced-stage NSCLC who is struggling with CIPN.
NSCLC Lung cancer is the leading cause of cancer deaths in the USA among both men and women, and the American Cancer Society projects that there will be approximately 224,210 new diagnoses and 159,260 deaths in 2014 [1]. Approximately 80 to 85 % of these cases will be NSCLC [2]. This disease has a poor prognosis because the rate of metastasis at diagnosis is high [3]. A systematic review found a median survival of 7.15 months from diagnosis for all stages of NSCLC [4]. However, even though advanced NSCLC— stages IIIB and IV—is not curable, chemotherapy is commonly administered in these cases, both for palliation and as part of clinical trials designed to uncover survival benefits by testing different drug combinations and treatment schedules. Randomized studies comparing chemotherapy with “best supportive care” provide evidence that, when effective, chemotherapy regimens cause tumor reduction or slow disease progression; reduce symptoms like shortness of breath, hemoptysis, pain, and fatigue; and help improve QOL [2]. The NSCLC Meta-Analyses Collaborative Group concurs with these findings and also found a modest increase in survival of 1.5 months (from 4.5 to 6 months) with supportive care plus chemotherapy versus supportive care alone [5].
CIPN During the past 15 to 20 years, since their discovery and addition to the armamentarium of chemotherapeutic agents, taxanes (docetaxel and paclitaxel) have been shown to prolong survival and have become a mainstay treatment for NSCLC [6]. Three taxanes, nab-paclitaxel, paclitaxel, and docetaxel, are currently approved for first-line treatment of locally advanced or metastatic NSCLC (all in combination with a platinum agent and in patients who are not candidates for curative surgery or radiotherapy for nab-paclitaxel and paclitaxel) [7]. While effective in treating cancer, taxanes are
neurotoxic, damaging the nerve cell axon, myelin sheath, and cell body in the dorsal root ganglion [8]. Therefore, peripheral neuropathy is a common side effect of taxane treatment and adds to the overall symptom burden experienced by patients with advanced-stage NSCLC. An early sign of CIPN is the decrease or absence of deep tendon reflexes, detectable through a clinical exam. Symptoms of CIPN may include both sensory and motor components. Numbness, tingling, burning or shock-like pain, and altered proprioception from decreased plantar sensation are common sensory symptoms [9–11]. These sensory alterations can affect activities of daily living, such as manipulating zippers or small buttons when dressing, and create instability with ambulation. Motor weakness, although less common, may affect grip strength, cause difficulty standing for extended periods and trouble rising from low positions (e.g., a bathtub), and contribute to trips and falls. Given these significant side effects, health care providers making treatment decisions must take into consideration the total symptom burden, both from the disease and its treatment.
Standard taxane-containing chemotherapy regimens for advanced NSCLC The American Society of Clinical Oncology guidelines for first-line treatment of stage IV NSCLC [6], all of which are “based on treatment strategies that improve overall survival,” recommend a combination of cytotoxic drugs for no more than 6 cycles. Platinum-based combinations, including carboplatin plus paclitaxel administered every 3 weeks, are the current standard of care for first-line treatment [7]; paclitaxel plus carboplatin usually improves survival by about 1.5 months [12]. Unfortunately, this drug combination contains two neurotoxic agents that often cause severe peripheral neuropathy. CIPN usually worsens over time with repeated chemotherapy treatments and may become permanent [6, 13, 14]. Phase 3 trials comparing various multidrug therapies and schedules have been conducted with the goal of improving outcomes for chemotherapy-naive patients with advanced NSCLC. Some of these studies have evaluated a taxane plus a platinum and/or other agent. A recent study evaluated combination treatment with nab-paclitaxel, a 130-nm albuminbound formulation of paclitaxel and carboplatin in patients with advanced NSCLC [15]. Improved survival and chemotherapy efficacy are the most common study endpoints, with secondary attention to various toxicities and QOL. In general, combination regimens provide a modest improvement in radiological response rates and survival, measured mostly in weeks, with a range of 0.1 to 2.5 months [3, 15–29]. However, their synergistic effects are often associated with
Support Care Cancer
adverse toxic effects greater than those of a single-drug therapy.
CIPN measurement in phase 3 NSCLC trials The PubMed database was searched using the terms “nonsmall cell lung cancer,” “phase,” and “paclitaxel or docetaxel or albumin-bound or nab-paclitaxel” (title only, English language only) using a data cutoff of January 1, 1998 through December 31, 2012. The time frame was chosen because 1998 was the first year that a taxane was approved for the treatment of advanced NSCLC (paclitaxel) and 2012 was the most recent year (nab-paclitaxel). Phase 3 trials that included a taxane in the first-line setting were examined for information on the incidence and severity of CIPN, and the findings of 16 phase 3 trials and 1 meta-analysis are described in this review [3, 12, 15–29]. The stated primary end point of 11 of these studies of different combinations and schedules of taxane-containing chemotherapy was survival; for the other 6, the primary aim was to assess efficacy and safety. QOL was listed as a secondary aim in 5 studies. Since these are drug trials, both hematologic and nonhematologic toxicities must be documented, and many of the trials listed specific grades of toxicity at which dose reductions or withdrawal from the study were to occur. However, attention to CIPN in these trials has been inconsistent. Even though CIPN may be severe and common and is a major factor in dose reductions or therapy cessation [12–14], 3 of the articles reported no data on it [23, 24, 29]. Another failed to specify which CIPN measurement approach was used, rendering the data unusable for our purposes [27]. Of the remaining 12 studies, 10 employed clinician-assessed toxicity grading scales: the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale (n=8) [3, 15, 16, 18, 19, 22, 26, 28], the World Health Organization (WHO) grading scale (n=1) [21], and the Eastern Cooperative Oncology Group Common Toxicity Criteria (ECOG CTC; n=1) [17] (Table 1). The remaining two studies [20, 25] used the European Organisation for Research and Treatment of Cancer’s Quality of Life Questionnaire—Lung Cancer module (EORTC QLQ-LC13), which is a patient-reported outcome measure (Table 1). This module includes one neuropathyspecific question: “In the past week—Have you had tingling hands or feet?” and is graded on a four-point Likert-type scale (not at all, a little, quite a bit, very much), leaving unassessed any numbness, neuropathic pain, or functional difficulties that might be treatment related. One study used a second scale in addition to the NCI CTCAE: the Functional Assessment of Cancer Therapy—Taxane (FACT-Taxane) self-report instrument [15]. This scale includes the FACT-General and a 16item taxane subscale [13]. Eleven of those items relate directly
to neurotoxicity, and seven specifically assess peripheral neuropathy. Altogether, 5 CIPN measurement tools were used in the 17 studies—3 that were clinician-rated grading scales and 2 that were patient-reported outcome measures (Table 1). Only one study reported sensory and motor neuropathy separately [3]. The 3 grading scales—WHO, NCI CTCAE, and ECOG CTC—facilitate clinician-graded evaluations of performance status based on assessments of paresthesia, deep tendon reflexes, instrumental and self-care activities of daily living, and weakness/paralysis. However, these scales present some difficulties due to the lack of accuracy and consistency of the language employed and the attendant subjectivity in scoring, leading to poor interrater reliability and lack of consistency between scales [30]. In one scale, for instance, a decrease in deep tendon reflexes is a criterion for grade 1, whereas the other two scales specify the loss of deep tendon reflexes. It is not clear if loss refers to a complete absence of deep tendon reflexes or a decrease in the reflex response and, therefore, is subject to variable evaluator interpretation. How many reflexes are affected is also not quantified, even though this is an important distinction, since a higher number of affected reflexes indicates more severe neuropathy. By not differentiating the degree of deep tendon reflex impairment, neuropathy grading scales contribute to inaccuracies in describing CIPN severity. Similarly, grade 2 CIPN is defined by the NCI CTCAE and the ECOG CTC grading scales as the presence of moderate paresthesia but by the WHO grading scale as severe paresthesia. Inconsistency also plagues the definition of grade 3 CIPN across the various scales: both intolerable and severe are used as grade 3 criteria. Furthermore, several studies provide evidence that the most commonly used grading scale (NCI CTCAE) is neither reliable nor sensitive due to floor effects (most scores cluster on the low end of the scale) [14, 31] and that it consistently indicates a lower incidence and severity of CIPN compared with several validated patient-reported outcome instruments [32]. Also, most studies suggest that the NCI CTCAE is a valid measure of sensory but not motor CIPN [14, 31]. Because of common reliance on these grading scales, CIPN is under recognized. Clinician bias may also be a factor in underreporting CIPN. Since grade 1 CIPN is not a trigger for either dose reductions or treatment cessation, it may barely register on a clinician’s radar, whereas any level of CIPN may be disturbing to someone experiencing it. Lack of attention to or concern about lowgrade symptoms may further obscure the incidence and severity of CIPN, as it may suggest to patients that the clinician discounts anything but severe symptoms. As a result, patients may hesitate to report CIPN as it worsens during treatment. Of the two patient-reported outcome measures, FACTTaxane more thoroughly explores the various symptoms of CIPN than does the EORTC QLQ-LC13 with its single
Support Care Cancer Table 1 Instruments used to measure CIPN Instrument Grading scales—clinician assessed WHO
NCI CTCAE sensory
NCI CTCAE motor
ECOG CTC sensory
ECOG CTC motor
Patient-reported outcome measures EORTC QLQ-LC13 (“In the past week: Have you had tingling hands or feet?”) FACT-Taxane: questions about numbness, tingling, discomfort in feet and hands (separately), pain in fingertips, ADL problems
Grade 1
Grade 2
Grade 3
Grade 4
Paresthesias and/or decreased tendon reflexes Asymptomatic; loss of deep tendon reflexes or paresthesia Asymptomatic; clinical or diagnostic observations only; intervention not indicated Mild paresthesias; loss of deep tendon reflexes
Severe paresthesias and/or mild weakness Moderate symptoms; limiting instrumental ADL Moderate symptoms; limiting instrumental ADLs
Intolerable paresthesias and/or marked motor loss Severe symptoms; limiting self-care ADL Severe symptoms; limiting self-care ADL; assistive device indicated
Paralysis
Mild or moderate objective sensory loss; moderate paresthesias Mild objective weakness without significant impairment of function
Severe objective sensory loss or paresthesias that interfere with function Objective weakness with impairment of function
Not at all
A little
Quite a bit
Very much
A little bit
Somewhat
Quite a bit
Very much
Subjective weakness; no objective findings
Life-threatening consequences; urgent intervention indicated Life-threatening consequences; urgent intervention indicated –
Paralysis
WHO from Postma and Heimans, 2000 [30]. NCI CTCAE from US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. ECOG from http://ecog.dfci.harvard.edu/general/common_tox.html. EORTC LC13 from http://www.eortc.be/qol/files/LC13/LC13% 20English.pdf. FACT-Taxane from http://www.facit.org/FACITOrg/Questionnaires (FACT-Tax_ENG_Final_Ver4_19Nov07.pdf). ADL activities of daily living, CIPN chemotherapy-induced peripheral neuropathy, ECOG CTC Eastern Cooperative Oncology Group Common Toxicity Criteria, EORTC QLQ-LC13 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire—Lung Cancer module, FACT Functional Assessment of Cancer Therapy, NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events, WHO World Health Organization
question about tingling. FACT-Taxane is not meant to reveal performance status changes in the way that the grading scales do; rather, it explores specific changes in sensory and motor CIPN by quantifying neuropathy-related discomfort, numbness, and tingling in hands and feet separately; sensation in and ability to manipulate a small object with the fingers; and ambulation. FACT-Taxane has been shown in one study to be reliable, valid, and responsive to change over time [13]. Besides relying on a single question, the EORTC QLQLC13 patient-reported outcomes measure is out of step with the other instruments in assigning grade 1 for no symptom of tingling, while the other scales—both provider- and patientreported—use grade 0 for a lack of neuropathy symptoms. This inconsistency in scoring definitions across CIPN measures makes it difficult to compare CIPN incidence and severity among studies.
CIPN incidence and severity as reported in phase 3 NSCLC trials Some level of sensory CIPN occurs in many people treated with taxanes. However, half of the reviewed studies that reported CIPN severity only specified grades ≥3—the level at which withholding of platinum and taxane combination chemotherapy is indicated. Grade 3 sensory neuropathy rates ranged from 0 [25] to 40 % [17]. For the studies reporting all grades, rates ranged from 13 [26] to 62 % [15]. In the four docetaxel studies presenting neuropathy data, reported rates of CIPN with docetaxel and cisplatin combinations ranged from 2 to 5 % for grade 3, 3.9 % for grades 3/4, and 4 % for grade 4. For docetaxel and carboplatin combinations, rates of 0.7 to 3 % for grades 3/4 and 30 % for grades 1 or 2 were reported (Table 2).
1c
1c 3 cycles (median), q 3 weeks 3 cycles (median), q 3–4 weeks 2 cycles (median), q 4 weeks
Cisplatin and gemcitabine Cisplatin and docetaxel
Stage IIIB, stage IV, or recurrent, no prior chemotherapy (301)
Stage IIIB, stage IV, or recurrent, no prior chemotherapy (304) Stage IIIB, stage IV, or recurrent, no prior chemotherapy (299) Carboplatin and paclitaxel
Cisplatin and paclitaxel
Vindesine plus cisplatin
Docetaxel plus cisplatin
Docetaxel
Stage IIIB, stage IV, or recurrent, no prior chemotherapy (303)
Advanced/metastatic, no prior chemotherapy (152) Stage IV, no prior chemotherapy(151) Stage IV, no prior chemotherapy (151)
4c
2c
4 cycles (median), q 3 weeks
Docetaxel 100 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 2 plus rhG-CSF 150 μg/m2/day on days 3–9 every 3 weeks Docetaxel 100 mg/m2 on day 1 (without rhG-CSF) every 3 weeks Docetaxel 60 mg/m2 plus cisplatin 80 mg/m2 every 3–4 weeks Vindesine 3 mg/m2 on days 1, 8, and 15 plus cisplatin 80 mg/m2 on day 1 of a 4-week cycle Paclitaxel 135 mg/m2 every 3 weeks on day 1 plus cisplatin 75 mg/m2 on day 2 every 3 weeks Gemcitabine 1,000 mg/m2 on days 1, 8, and 15 plus cisplatin 100 mg/m2 on day 1 every 4 weeks Docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 every 3 weeks Paclitaxel 225 mg/m2 plus carboplatin AUC 6 mg*mL/min every 3 weeks
Docetaxel/cisplatin
Not reported Not reported Not reported Not reported
5 (grade 3)d 9 (grade 3)d 5 (grade 3)d 10 (grade 3)d
Not reported, q 3 weeks Not reported, q 4 weeks Not reported, q 3 weeks Not reported, q 3 weeks
Not reported
Not reported
Not reported
Not reported
Not reported
Not reported
Not reported
Motor neuropathy grade, %
d
c
b
a
Grading scale not specified
World Health Organization (WHO) grading scale
NCI CTCAE
Sensory versus motor not delineated
AUC area under the curve, CIPN chemotherapy-induced peripheral neuropathy, MIC mitomycin + ifosfamide + cisplatin, MVP mitomycin + vinorelbine + cisplatin, NSCLC nonsmall cell lung cancer, q every, rhG-CSF recombinant human granulocyte colony-stimulating factor
Schiller (2002)
Kubota (2004)
Georgoulias (2004)
4 (grades 3–4)b
6 cycles, q 4 weeks
Vinorelbine 25 mg/m2/week plus cisplatin 100 mg/m2 every 4 weeks
Vinorelbine/cisplatin
