Peripheral Neuropathy from Taxane-Containing Treatment for Advanced Nonsmall Cell Lung Cancer

Support Care Cancer (2014) 22:2581–2592 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 /Published online: 21 June 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Keywords Peripheral neuropathy . Nonsmall cell lung Purpose In this review, we discuss the plight of Alice, a cancer . Taxanes . Assessment tools patientwithadvancednonsmallcelllungcancer(NSCLC) who struggles with taxane-related peripheral neuropathy (PN). Using this unique point of view helps us to appreciate Alice’splight the implications of PN on daily activities as well as the difficulty in decision-making regarding continuation of treat- After 69 years of considering herself quite healthy, Alice ment. In addition, published reports of phase 3 trials are began to experience some shortness of breath but dismissed reviewed to identify the incidence and severity of it as simply part of “getting on in years.” However, when she chemotherapy-induced PN as well as the assessment tools began coughing up blood, her concern prompted a visit to her used in these studies. primary care physician. Testing led to a diagnosis of stage IIIB Methods A literature review spanning the years 1998–2012 nonsmall cell lung cancer (NSCLC), which is considered was performed. Phase 3 studies and a meta-analysis of taxane- incurable. Nevertheless, she is now being treated with chemo- based therapy in advanced NSCLC were selected for review therapy, deemed palliative, which has alleviated some of the for their findings regarding the incidence and severity of symptoms of the disease but has caused adverse effects that chemotherapy-induced PN. she did not expect and about which she does not recall being Results In total, 16 phase 3 studies and 1 meta-analysis were forewarned. At each visit to her physicians, when they inquire reviewed. Use of grading scales and PN assessment tools was about any side effects of the treatment, she has described the inconsistent across the studies, and some studies did not report suffering she experiences, especially when she lies down at PN at all. night: “restless leg-type symptoms with terrible shooting pain, Conclusions The true incidence and severity of numbness, and a creepy tingling” that keep her from being chemotherapy-induced PN in clinical trials may be masked able to fall asleep and wake her up when she does manage to by nonstandardized reporting; thus, a more standardized ap- drift off. She mentioned how humiliating it is to have to ask proach to grading, assessing, and reporting PN in clinical trials strangers to help zip up her jacket when she ventures out, since is greatly needed to allow for appropriate comparisons across she has trouble grabbing the pull tab. Despite these revelations studies. Understanding chemotherapy-induced PN from the to her providers, she received no new suggestions for symp- patient’s perspective as well as the development of PN at the tom management. Desperate for relief, on her own she has clinical trial level will help health care providers anticipate the tried nonprescription drugs, herbs, alcohol, marijuana, and development of PN and improve their ability to manage it. 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 com- * : C. M. Bridges ( ) E. M. L. Smith monly causes toxic side effects, one of which is peripheral University of Michigan School of Nursing, 400 N Ingalls St, Ann Arbor, MI 48109, USA neuropathy. The results of most phase 3 trials assessing e-mail: [email protected] taxane-containing NSCLC therapy indicate that 2582 Support Care Cancer (2014) 22:2581–2592 chemotherapy-induced peripheral neuropathy (CIPN) is a neurotoxic, damaging the nerve cell axon, myelin sheath, and common side effect—affecting up to 62 % of patients treated cell body in the dorsal root ganglion [8]. Therefore, peripheral for advanced-stage disease. Common CIPN symptoms, such neuropathy is a common side effect of taxane treatment and as numbness, tingling, and neuropathic pain in the extremities, adds to the overall symptom burden experienced by patients often compromise ambulation, functional status, and quality with advanced-stage NSCLC. of life (QOL) for patients with limited prospects for long-term An early sign of CIPN is the decrease or absence of deep survival. The focus of this article is to highlight what is known tendon reflexes, detectable through a clinical exam. and unknown about CIPN based on data from phase 3 trials of Symptoms of CIPN may include both sensory and motor taxane-based treatment for advanced NSCLC. The need for components. Numbness, tingling, burning or shock-like pain, improved/standardized CIPN assessment in future trials is and altered proprioception from decreased plantar sensation discussed. Lastly, suggestions are provided for how the nurse are common sensory symptoms [9–11]. These sensory alter- should care for Alice, a typical patient with advanced-stage ations can affect activities of daily living, such as manipulat- NSCLC who is struggling with CIPN. ing zippers or small buttons when dressing, and create insta- bility with ambulation. Motor weakness, although less common, may affect grip strength, cause difficulty standing for NSCLC extended periods and trouble rising from low positions (e.g., a bathtub), and contribute to trips and falls. Given these signif- Lung cancer is the leading cause of cancer deaths in the USA icant side effects, health care providers making treatment among both men and women, and the American Cancer decisions must take into consideration the total symptom Society projects that there will be approximately 224,210 burden, both from the disease and its treatment. 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 Standard taxane-containing chemotherapy regimens a median survival of 7.15 months from diagnosis for all stages for advanced NSCLC of NSCLC [4]. However, even though advanced NSCLC— stages IIIB and IV—is not curable, chemotherapy is common- The American Society of Clinical Oncology guidelines for ly administered in these cases, both for palliation and as part of first-line treatment of stage IV NSCLC [6], all of which are clinical trials designed to uncover survival benefits by testing “based on treatment strategies that improve overall survival,” different drug combinations and treatment schedules. recommend a combination of cytotoxic drugs for no more Randomized studies comparing chemotherapy with “best sup- than 6 cycles. Platinum-based combinations, including portive care” provide evidence that, when effective, chemo- carboplatin plus paclitaxel administered every 3 weeks, are therapy regimens cause tumor reduction or slow disease pro- the current standard of care for first-line treatment [7]; pacli- gression; reduce symptoms like shortness of breath, hemop- taxel plus carboplatin usually improves survival by about tysis, pain, and fatigue; and help improve QOL [2]. The 1.5 months [12]. Unfortunately, this drug combination con- NSCLC Meta-Analyses Collaborative Group concurs with tains two neurotoxic agents that often cause severe peripheral these findings and also found a modest increase in survival neuropathy. CIPN usually worsens over time with repeated of 1.5 months (from 4.5 to 6 months) with supportive care plus chemotherapy treatments and may become permanent [6, 13, chemotherapy versus supportive care alone [5]. 14]. Phase 3 trials comparing various multidrug therapies and schedules have been conducted with the goal of improving CIPN outcomes for chemotherapy-naive patients with advanced NSCLC. Some of these studies have evaluated a taxane plus During the past 15 to 20 years, since their discovery and a platinum and/or other agent. A recent study evaluated com- addition to the armamentarium of chemotherapeutic agents, bination treatment with nab-paclitaxel, a 130-nm albumin- taxanes (docetaxel and paclitaxel) have been shown to pro- bound formulation of paclitaxel and carboplatin in patients long survival and have become a mainstay treatment for with advanced NSCLC [15]. Improved survival and chemo- NSCLC [6]. Three taxanes, nab-paclitaxel, paclitaxel, and therapy efficacy are the most common study endpoints, with docetaxel, are currently approved for first-line treatment of secondary attention to various toxicities and QOL. In general, locally advanced or metastatic NSCLC (all in combination combination regimens provide a modest improvement in ra- with a platinum agent and in patients who are not candidates diological response rates and survival, measured mostly in for curative surgery or radiotherapy for nab-paclitaxel and weeks, with a range of 0.1 to 2.5 months [3, 15–29]. paclitaxel) [7]. While effective in treating cancer, taxanes are However, their synergistic effects are often associated with Support Care Cancer (2014) 22:2581–2592 2583 adverse toxic effects greater than those of a single-drug to neurotoxicity, and seven specifically assess peripheral neu- therapy. ropathy. 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 CIPN measurement in phase 3 NSCLC trials one study reported sensory and motor neuropathy separately [3]. The PubMed database was searched using the terms The 3 grading scales—WHO, NCI CTCAE, and ECOG “nonsmall cell lung cancer,”“phase,” and “paclitaxel or do- CTC—facilitate clinician-graded evaluations of performance cetaxel or albumin-bound or nab-paclitaxel” (title only, status based on assessments of paresthesia, deep tendon re- English language only) using a data cutoff of January 1, flexes, instrumental and self-care activities of daily living, and 1998 through December 31, 2012. The time frame was chosen weakness/paralysis. However, these scales present some dif- because 1998 was the first year that a taxane was approved for ficulties due to the lack of accuracy and consistency of the the treatment of advanced NSCLC (paclitaxel) and 2012 was language employed and the attendant subjectivity in scoring, the most recent year (nab-paclitaxel). Phase 3 trials that in- leading to poor interrater reliability and lack of consistency cluded a taxane in the first-line setting were examined for between scales [30]. In one scale, for instance, a decrease in information on the incidence and severity of CIPN, and the deep tendon reflexes is a criterion for grade 1, whereas the findings of 16 phase 3 trials and 1 meta-analysis are described other two scales specify the loss of deep tendon reflexes. It is in this review [3, 12, 15–29]. The stated primary end point of not clear if loss refers to a complete absence of deep tendon 11 of these studies of different combinations and schedules of reflexes or a decrease in the reflex response and, therefore, is taxane-containing chemotherapy was survival; for the other 6, subject to variable evaluator interpretation. How many re- the primary aim was to assess efficacy and safety. QOL was flexes are affected is also not quantified, even though this is listed as a secondary aim in 5 studies. Since these are drug an important distinction, since a higher number of affected trials, both hematologic and nonhematologic toxicities must reflexes indicates more severe neuropathy. By not differenti- be documented, and many of the trials listed specific grades of ating the degree of deep tendon reflex impairment, neuropathy toxicity at which dose reductions or withdrawal from the study grading scales contribute to inaccuracies in describing CIPN were to occur. However, attention to CIPN in these trials has severity. Similarly, grade 2 CIPN is defined by the NCI been inconsistent. CTCAE and the ECOG CTC grading scales as the presence Even though CIPN may be severe and common and is a of moderate paresthesia but by the WHO grading scale as major factor in dose reductions or therapy cessation [12–14], 3 severe paresthesia. Inconsistency also plagues the definition of of the articles reported no data on it [23, 24, 29]. Another grade 3 CIPN across the various scales: both intolerable and failed to specify which CIPN measurement approach was severe are used as grade 3 criteria. used, rendering the data unusable for our purposes [27]. Of Furthermore, several studies provide evidence that the most the remaining 12 studies, 10 employed clinician-assessed commonly used grading scale (NCI CTCAE) is neither reli- toxicity grading scales: the National Cancer Institute’s able nor sensitive due to floor effects (most scores cluster on Common Terminology Criteria for Adverse Events (NCI the low end of the scale) [14, 31] and that it consistently CTCAE) grading scale (n=8) [3, 15, 16, 18, 19, 22, 26, 28], indicates a lower incidence and severity of CIPN compared the World Health Organization (WHO) grading scale (n=1) with several validated patient-reported outcome instruments [21], and the Eastern Cooperative Oncology Group Common [32]. Also, most studies suggest that the NCI CTCAE is a Toxicity Criteria (ECOG CTC; n=1) [17](Table1). valid measure of sensory but not motor CIPN [14, 31]. The remaining two studies [20, 25] used the European Because of common reliance on these grading scales, CIPN Organisation for Research and Treatment of Cancer’s is under recognized. Quality of Life Questionnaire—Lung Cancer module Clinician bias may also be a factor in underreporting CIPN. (EORTC QLQ-LC13), which is a patient-reported outcome Since grade 1 CIPN is not a trigger for either dose reductions measure (Table 1). This module includes one neuropathy- or treatment cessation, it may barely register on a clinician’s specific question: “In the past week—Have you had tingling radar, whereas any level of CIPN may be disturbing to some- hands or feet?” and is graded on a four-point Likert-type scale one experiencing it. Lack of attention to or concern about low- (not at all, a little, quite a bit, very much), leaving unassessed grade symptoms may further obscure the incidence and sever- any numbness, neuropathic pain, or functional difficulties that ity of CIPN, as it may suggest to patients that the clinician might be treatment related. One study used a second scale in discounts anything but severe symptoms. As a result, patients addition to the NCI CTCAE: the Functional Assessment of may hesitate to report CIPN as it worsens during treatment. Cancer Therapy—Taxane (FACT-Taxane) self-report instru- Of the two patient-reported outcome measures, FACT- ment [15]. This scale includes the FACT-General and a 16- Taxane more thoroughly explores the various symptoms of item taxane subscale [13]. Eleven of those items relate directly CIPN than does the EORTC QLQ-LC13 with its single 2584 Support Care Cancer (2014) 22:2581–2592

Table 1 Instruments used to measure CIPN

Instrument Grade 1 Grade 2 Grade 3 Grade 4

Grading scales—clinician assessed WHO Paresthesias and/or Severe paresthesias Intolerable paresthesias Paralysis decreased tendon and/or mild and/or marked reflexes weakness motor loss NCI CTCAE sensory Asymptomatic; loss Moderate symptoms; Severe symptoms; Life-threatening of deep tendon limiting instrumental limiting self-care consequences; urgent reflexes or paresthesia ADL ADL intervention indicated NCI CTCAE motor Asymptomatic; clinical Moderate symptoms; Severe symptoms; limiting Life-threatening or diagnostic limiting instrumental self-care ADL; assistive consequences; urgent observations only; ADLs device indicated intervention indicated intervention not indicated ECOG CTC sensory Mild paresthesias; loss Mild or moderate Severe objective sensory – of deep tendon objective sensory loss or paresthesias reflexes loss; moderate that interfere with paresthesias function ECOG CTC motor Subjective weakness; Mild objective Objective weakness with Paralysis no objective findings weakness without impairment of function significant impairment of function Patient-reported outcome measures EORTC QLQ-LC13 (“In the Not at all A little Quite a bit Very much past week: Have you had tingling hands or feet?”) FACT-Taxane: questions about A little bit Somewhat Quite a bit Very much numbness, tingling, discomfort in feet and hands (separately), pain in fingertips, ADL problems

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, FAC T 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 CIPN incidence and severity as reported in phase 3 performance status changes in the way that the grading scales NSCLC trials do; rather, it explores specific changes in sensory and motor CIPN by quantifying neuropathy-related discomfort, numb- Some level of sensory CIPN occurs in many people treated ness, and tingling in hands and feet separately; sensation in with taxanes. However, half of the reviewed studies that and ability to manipulate a small object with the fingers; and reported CIPN severity only specified grades ≥3—the level ambulation. FACT-Taxane has been shown in one study to be at which withholding of platinum and taxane combination reliable, valid, and responsive to change over time [13]. chemotherapy is indicated. Grade 3 sensory neuropathy rates Besides relying on a single question, the EORTC QLQ- ranged from 0 [25]to40%[17]. For the studies reporting all LC13 patient-reported outcomes measure is out of step with grades, rates ranged from 13 [26]to62%[15]. the other instruments in assigning grade 1 for no symptom of In the four docetaxel studies presenting neuropathy data, tingling, while the other scales—both provider- and patient- reported rates of CIPN with docetaxel and cisplatin combina- reported—use grade 0 for a lack of neuropathy symptoms. tions ranged from 2 to 5 % for grade 3, 3.9 % for grades 3/4, This inconsistency in scoring definitions across CIPN mea- and 4 % for grade 4. For docetaxel and carboplatin combina- sures makes it difficult to compare CIPN incidence and sever- tions, rates of 0.7 to 3 % for grades 3/4 and 30 % for grades 1 ity among studies. or 2 were reported (Table 2). upr aeCne 21)22:2581 (2014) Cancer Care Support Table 2 CIPN incidence and severity in phase 3 clinical trials in NSCLC—Docetaxel [18, 19, 21, 23, 27]

Lead author Overall population (N) Taxane Dosage and schedule Treatment duration Sensory neuropathy grade, % Motor neuropathy grade, % Grade 3 Grade 4

Booton (2006) Inoperable (stage III/IV), no prior MIC/MVP Mitomycin 6 mg/m2 plus ifosfamide 4 cycles, q 3 weeks 1 (grades 3–4)a,b chemotherapy (216) 3g/m2 plus cisplatin 50 mg/m2 or mitomycin 6 mg/m2 plus vinblastine 6mg/m2 plus cisplatin 50 mg/m2 every 3 weeks Inoperable (stage III/IV), no prior Docetaxel/carboplatin Docetaxel 75 mg/m2 plus carboplatin 4 cycles, q 3 weeks 3 (grades 3–4)a,b chemotherapy (217) AUC 6, every 3 weeks 2 b Fossella (2003) Locally advanced or recurrent Docetaxel/cisplatin Docetaxel 75 mg/m plus cisplatin 6 cycles, q 3 weeks 4 (grades 3–4) Not reported – (stage IIIB) or metastatic (stage IV), 75 mg/m2 every 3 weeks 2592 no prior chemotherapy (408) Locally advanced or recurrent (stage IIIB) Docetaxel/carboplatin Docetaxel 75 mg/m2 plus carboplatin 6 cycles, q 3 weeks <1 (grades 3–4)b Not reported or metastatic (stage IV), no prior AUC 6 mg*mL/min every 3 weeks chemotherapy (406) Locally advanced or recurrent Vinorelbine/cisplatin Vinorelbine 25 mg/m2/week plus 6 cycles, q 4 weeks 4 (grades 3–4)b Not reported (stage IIIB) or metastatic (stage IV), cisplatin 100 mg/m2 every 4 weeks no prior chemotherapy (404) Georgoulias (2004) Advanced/metastatic, no prior Docetaxel/cisplatin Docetaxel 100 mg/m2 on day 1 plus 4cycles(median), 2c 4c Not reported chemotherapy (167) cisplatin 80 mg/m2 on day 2 plus q3weeks rhG-CSF 150 μg/m2/day on days 3–9 every 3 weeks Advanced/metastatic, no prior Docetaxel Docetaxel 100 mg/m2 on day 1 3cycles(median), 1c 1c Not reported chemotherapy (152) (without rhG-CSF) every 3 weeks q3weeks Kubota (2004) Stage IV, no prior Docetaxel plus cisplatin Docetaxel 60 mg/m2 plus cisplatin 3cycles(median), Not reported chemotherapy(151) 80 mg/m2 every 3–4weeks q3–4weeks Stage IV, no prior Vindesine plus cisplatin Vindesine 3 mg/m2 on days 1, 8, 2cycles(median), Not reported chemotherapy (151) and 15 plus cisplatin 80 mg/m2 q4weeks on day 1 of a 4-week cycle Schiller (2002) Stage IIIB, stage IV, or recurrent, Cisplatin and paclitaxel Paclitaxel 135 mg/m2 every Not reported, 5(grade3)d Not reported no prior chemotherapy (303) 3 weeks on day 1 plus cisplatin q3weeks 75 mg/m2 on day 2 every 3 weeks Stage IIIB, stage IV, or recurrent, Cisplatin and gemcitabine Gemcitabine 1,000 mg/m2 on days 1, Not reported, 9(grade3)d Not reported no prior chemotherapy (301) 8,and15pluscisplatin q4weeks 100 mg/m2 on day 1 every 4 weeks Stage IIIB, stage IV, or recurrent, Cisplatin and docetaxel Docetaxel 75 mg/m2 plus cisplatin Not reported, 5(grade3)d Not reported no prior chemotherapy (304) 75 mg/m2 every 3 weeks q3weeks Stage IIIB, stage IV, or recurrent, Carboplatin and Paclitaxel 225 mg/m2 plus carboplatin Not reported, 10 (grade 3)d Not reported no prior chemotherapy (299) paclitaxel AUC 6 mg*mL/min every 3 weeks q3weeks

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 a Sensory versus motor not delineated b NCI CTCAE c World Health Organization (WHO) grading scale d Grading scale not specified 2585 2586 Support Care Cancer (2014) 22:2581–2592

In comparison, CIPN incidence and severity due to com- Nonstandardized reporting hinders comparison among bination treatment with paclitaxel and cisplatin were found to studies and may blur the picture of the incidence and severity be somewhat higher: 54 % for grades 1 through 4 and ranging of CIPN for those receiving taxanes. For example, comparison from 4 to 40 % for grade 3. Paclitaxel and carboplatin com- of grade 3 with grades 1 through 4 CIPN incidences, when all bination regimens were reported to be associated with 22.8 % grades are collapsed into one category, is difficult if not of grade 1 CIPN, 7 % of grade 2 CIPN, 0 to 13 % of grade 3 impossible. Many of the studies report ranges of grades 1 CIPN, and 0 % of grade 4 CIPN. When grades were com- through 3 or 1 through 4, which obscures the important bined, grades 2/3 occurred in 12 to 18 %, grades 3/4 in 4.4 to distribution of scores. If only grade 3 is reported, it may seem 9.1 %, and grades 1 to 4 in 13 to 62 % (Tables 3 and 4). as though only moderate rates of CIPN are occurring, but there Only one study allows direct CIPN rate comparisons be- may be high levels of grades 1 and 2 that remain unreported. tween paclitaxel and nab-paclitaxel because patients were In one study that reported total CIPN rates of 46 and 62 % in randomized to either paclitaxel and carboplatin or nab-pacli- two taxane-containing treatment arms [15], for example, taxel and carboplatin treatment [15]. The authors used both grades 1 and 2 made up 43 and 51 %, respectively, of the the FACT-Taxane and NCI CTCAE to quantify CIPN. Using total, raising the question of possible widespread under the NCI CTCAE scale, they reported grades 3 and 4 separately reporting. Also, although one study reported grade 3 motor as well as all grades combined. For nab-paclitaxel-treated CIPN (8 %) and sensory CIPN (13 %) separately [3], approx- patients, CIPN rates for grades 3, 4, and total, respectively, imately half reported sensory CIPN only; the rest reported were 3, 0, and 46 %; for paclitaxel-treated patients, the rates sensory and motor conflated or did not specify which was were 11, <1, and 62 %, respectively (Table 4). This study is assessed. also the only one that reports a result that may greatly affect patients’ QOL: the mean time to improvement of neuropathy. In the nab-paclitaxel and paclitaxel arms, the median time to improvement to grade 1 from grade ≥3 sensory neuropathy Consequences of CIPN was 38 and 104 days, respectively. The effect of schedule on the incidence and severity of CIPN causes significant distress and suffering, negatively CIPN is somewhat difficult to ascertain based on data from affecting functioning and QOL and compromising patient phase 3 trials. While development of CIPN was greater in safety. Sensory deficits contribute to accidental injuries such those receiving chemotherapy every 3 weeks versus weekly, it as burns and cuts, since individuals do not feel heat or pain is unclear whether the effect was due to schedule or drug dose. adequately to respond appropriately. Motor or sensory neu- One study found grade 3 or greater CIPN in 4.4 % of patients ropathy can be contributing factors in falls; indeed, evidence in the weekly group and 9.1 % in the every 3 weeks group indicates that those who receive taxanes may be at higher risk [28]. Another study reported grade 2/3 rates of 12 and 18 % of falls [33]. This is not an insignificant concern for the for weekly and every 3 weeks administration, respectively elderly, who constitute the majority of those diagnosed with (see Table 3 for regimen) [16]. The meta-analysis found rates NSCLC [34]. Also, those who are trying to maintain indepen- to be 10 % (weekly) and 17.9 % (every 3 weeks) [12]. dence through activities that require driving may be unable to manage the foot controls. Patient education prior to and during treatment, including recommendations for injury-avoiding precautions, is necessary to mitigate the problems caused by Comparing CIPN across studies reduction in sensation and function. Since the median improvement in survival for patients In order to discern with clarity the effects of different taxane- with NSCLC is a mere month and a half, and is bought containing regimens on the incidence and severity of CIPN with taxane-including chemotherapy regimens at the price and to ascertain the true scope of the problem, standardization of substantial CIPN, it is crucial that patients understand of grading scales, reporting, and assessment scheduling is the trade-offs. Unfortunately, many—69 % of patients with necessary. However, very little standardization exists across advanced lung cancer—who receive these treatments do these phase 3 trials. In the 14 studies reporting CIPN, grades not understand that chemotherapy is not curative, even were categorized in 11 different ways (Table 5). Direct com- after the first course of chemotherapy has “failed” [35], parison across studies was possible with only one pair of and do not fully comprehend either its benefits, such as studies that used the same grading scale and reported the same abatement of some symptoms, or its risks, such as CIPN. grade categorical groupings [19, 28]. Furthermore, most stud- This misunderstanding may represent a barrier to appro- ies do not report the frequency or scheduling of neuropathy priate end of life planning and raises the question of assessments. The seven studies that did report this variable whether patients are being appropriately informed that, in differed regarding when neuropathy was assessed (Table 5). advanced NSCLC, chemotherapy is palliative. upr aeCne 21)22:2581 (2014) Cancer Care Support Table 3 CIPN incidence and severity in phase 3 clinical trials in NSCLC—paclitaxel [3, 12, 16, 17, 20, 22, 24–29]

Lead author Overall population (N) Taxane Dosage and schedule Treatment duration Sensory neuropathy Motor neuropathy grade, % grade, %

Grade 3 Grade 4 Grade 3 Grade 4

Belani (2008) Stage IIIB/IV, previously Paclitaxel/carboplatin Paclitaxel 100 mg/m2 weekly for 3 of 4 weeks 3 cycles paclitaxel/4 cycles 12 (grade 2–3), 0 (grade 4)a,b untreated (223) plus carboplatin AUC 6 mg*mL/min on day 1 carboplatin (median), of each 4-week cycle (after 4 cycles, qweek paclitaxel 70 mg/m2 weekly for 3 of 4 weeks as maintenance therapy) Stage IIIB/IV, previously Paclitaxel/carboplatin Paclitaxel 225 mg/m2 plus carboplatin AUC 4 cycles paclitaxel/4 cycles 18 (grade 2–3), 0 (grade 4)a,b

untreated (221) 6 mg*mL/min every 3 weeks (after 4 cycles, carboplatin (median), – paclitaxel 70 mg/m2 weekly for 3 of 4 weeks q3weeks 2592 as maintenance therapy) Bonomi (2000) Stage IIIB or IV disease, previously Etoposide/cisplatin Etoposide 100 mg/m2 on days 1, 2, and 3 plus Not reported, q 3 weeks 21 (grade 3)a,c untreated (200) cisplatin 75 mg/m2 on day 1 every 3 weeks Stage IIIB or IV disease, previously Paclitaxel/cisplatin Paclitaxel 250 mg/m2 on day 1 plus cisplatin Not reported, q 3 weeks 40 (grade 3)a,c untreated (201) 75 mg/m2 on day 2 every 3 weeks Stage IIIB or IV disease, previously Paclitaxel/cisplatin Paclitaxel 135 mg/m2 on day 1 plus cisplatin Not reported, q 3 weeks 23 (grade 3)a,c untreated (198) 75 mg/m2 on day 2 every 3 weeks Gao (2012) Stage IIIB or IV disease, previously Paclitaxel-based Various, weekly Not reported, q week 10 (grades 2–4)a,b meta-analysis untreated Stage IIIB or IV disease, previously Paclitaxel-based Various, every 3 weeks Not reported, q 3 weeks 18 (grades 2–4)a,b untreated Gatzemeier (2000) Stage IIIB or IV disease, previously Cisplatin Cisplatin 100 mg/m2 every 3 weeks 3 cycles (median), q 3 weeks 1 (grade 3), 0 (grade 4)a,d untreated (207) Stage IIIB or IV disease, previously Paclitaxel/cisplatin Paclitaxel 175 mg/m2 plus cisplatin 80 mg/m2 5 cycles (median), q 3 weeks 4 (grade 3), 0 (grade 4)a,d untreated (207) every 3 weeks Giaccone (1998) Locally advanced or metastatic, Paclitaxel/cisplatin Teniposide 100 mg/m2 on days 1, 3, and 5 plus 5 cycles (median), q 3 weeks 1 (grade 3)a,b no previous chemotherapy (116) cisplatin 80 mg/m2 on day 1 every 3 weeks Locally advanced or metastatic, Cisplatin/teniposide Paclitaxel 175 mg/m2 plus cisplatin 80 mg/m2 6 cycles (median), q 3 weeks 9 (grade 3)a,b no previous chemotherapy (116) on day 1 every 3 weeks Kelly (2001) Selected stage IIIB or stage IV, Vinorelbine/cisplatin Vinorelbine 25 mg/m2/week plus cisplatin 3 cycles (median), q 4 weeks 3b 0b 7b 0b no previous chemotherapy (202) 100 mg/m2 every 4 weeks Selected stage IIIB or stage IV, Paclitaxel/carboplatin Paclitaxel 225 mg/m2 plus carboplatin AUC 4 cycles (median), q 3 weeks 13b 0b 8b 0b no previous chemotherapy (206) 6 mg*mL/min every 3 weeks Sandler (2006) Stage IIIB/IV, no previous Paclitaxel/carboplatin Paclitaxel 200 mg/m2 plus carboplatin AUC 5 cycles (median), q 3 weeks Not reported chemotherapy (444) 6mgevery3weeks Stage IIIB/IV, no previous Paclitaxel/carboplatin+ Paclitaxel 200 mg/m2 plus carboplatin AUC 7 cycles (median), q 3 weeks Not reported chemotherapy (434) bevacizumab 6 mg*mL/min plus bevacizumab 15 mg/kg every 3 weeks Scagliotti (2002) Stage IIIB, recurrent, and/or stage Gemcitabine/cisplatin Gemcitabine 1,250 mg/m2 on days 1 and 8 plus 4 cycles (mean), q 3 weeks 0 (grade 3)a,d IV disease, no previous cisplatin 75 mg/m2 on day 2 every 3 weeks chemotherapy (205) Stage IIIB, recurrent, and/or stage Paclitaxel/carboplatin Paclitaxel 225 mg/m2 plus carboplatin AUC 4.2 cycles (mean), q 3 weeks 0 (grade 3)a,d IV disease, no previous 6 mg*mL/min every 3 weeks chemotherapy (204) Stage IIIB, recurrent, and/or stage Vinorelbine/cisplatin Vinorelbine 25 mg/m2/week for 12 weeks, then 3.2 cycles (mean), various <1 (grade 3)a,d IV disease, no previous every other week plus cisplatin 100 mg/m2 chemotherapy (203) every 4 weeks Scagliotti (2010) Stage IIIB/IV, no previous Paclitaxel/carboplatin + Paclitaxel 200 mg/m2 plus carboplatin AUC 4 cycles (median), q 3 weeks 3b 0b Not reported chemotherapy (464) sorafenib 6 mg*mL/min plus sorafenib 400 mg twice daily on days 2–19 every 3 weeks Stage IIIB/IV, no previous Paclitaxel/carboplatin+ 5 cycles (median), q 3 weeks 2b 0b Not reported 2587 chemotherapy (462) placebo 2588 Table 3 (continued) Lead author Overall population (N) Taxane Dosage and schedule Treatment duration Sensory neuropathy Motor neuropathy grade, % grade, %

Grade 3 Grade 4 Grade 3 Grade 4

Paclitaxel 200 mg/m2 plus carboplatin AUC 6 mg*mL/min plus placebo on days 2–19 every 3 weeks Schiller (2002) Stage IIIB, recurrent, and/or stage Paclitaxel/cisplatin Paclitaxel 135 mg/m2 on day 1 plus cisplatin Not reported, q 3 weeks 5 (grade 3)e IV disease, no previous 75 mg/m2 on day 2 every 3 weeks chemotherapy (303) Stage IIIB, recurrent, and/or Gemcitabine/cisplatin Gemcitabine 1,000 mg/m2 on days 1, 8, and Not reported, q 4 weeks 9 (grade 3)e stage IV disease, no previous 15 plus cisplatin 100 mg/m2 on day chemotherapy (301) 1 every 4 weeks Stage IIIB, recurrent, and/or stage Docetaxel/cisplatin Docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 Not reported, q 3 weeks 5 (grade 3)e IV disease, no previous every 3 weeks chemotherapy (304) Stage IIIB, recurrent, and/or stage Paclitaxel/carboplatin Paclitaxel 225 mg/m2 plus carboplatin AUC Not reported, q 3 weeks 10 (grade 3)e IV disease, no previous 6 mg*mL/min every 3 weeks chemotherapy (299) Schuette (2006) Stage IIIB/IV, no previous Paclitaxel/carboplatin Paclitaxel 100 mg/m2 plus carboplatin AUC 2 cycles, q week 4 (grade 3–4)b Not reported chemotherapy (457) 2 mg*mL/min once a week for 6 to 8 weeks Stage IIIB/IV, no previous Paclitaxel/carboplatin Paclitaxel 200 mg/m2 plus carboplatin AUC 6 cycles, q 3 weeks 9 (grade 3–4)b Not reported chemotherapy (464) 6 mg*mL/min every 3 weeks Smit (2003) Stage IIIB/IV, no previous Paclitaxel/cisplatin Paclitaxel 175 mg/m2 plus cisplatin 80 mg/m2 5 cycles (median), q 3 weeks Not reported chemotherapy (159) every 3 weeks Stage IIIB/IV, no previous Gemcitabine/cisplatin Gemcitabine 1,250 mg/m2 on days 1 and 8 plus 5 cycles (median), q 3 weeks Not reported chemotherapy (160) cisplatin 80 mg/m2 on day 1 every 3 weeks Stage IIIB/IV, no previous Paclitaxel/gemcitabine Paclitaxel 175 mg/m2 on day 1 plus gemcitabine 4 cycles (median), q 3 weeks Not reported chemotherapy (161) 1,250 mg/m2 on days 1 and 8 every 3 weeks

AUC area under the curve, CIPN chemotherapy-induced peripheral neuropathy, NSCLC nonsmall cell lung cancer, q every a Sensory versus motor not delineated b NCI CTCAE c ECOG CTC d EORTC QLQ-LC13 upr aeCne 21)22:2581 (2014) Cancer Care Support e Grading scale not specified – 2592 Support Care Cancer (2014) 22:2581–2592 2589

Implications for practice

Phase 3 trials focus on survival, efficacy, and tolerability. Trials of taxane-containing multidrug regimens for NSCLC Motor neuropathy grade, % have shown a modest prolongation of survival but also new, a potentially disabling CIPN. Although the limitations in current measurement blur its incidence, severity, onset, duration,

<1 Not reported and patient experience, CIPN appears to affect a substantial percentage of patients treated with taxanes. When considering the tolerability of treatment side effects, it is important to understand that what can be borne by someone hoping for a cure may not be acceptable to someone clearly understanding 62 (all grades) 46 (all grades) Grade 3 Grade 4 that advanced NSCLC is incurable. Informed decision- making requires clear communication between clinicians and patients, including a full and balanced disclosure of the risks and benefits in language that the patient is capable of understanding [6]. Given the development of new treatment regimens that improve survival, the known increase in severity of CIPN with cumulative doses, and the continuing neurotoxic effects cce(ein,3ek 11 6cycles(median),q3weeks 6 cycles (median), q 3 weeks 3 0 Not reported even after cessation of therapy, thorough and precise evalua- 2

every tion of CIPN is crucial. Although physicians rely on phase 3 q trials to guide patient management, these studies fall short in on days

2 helping manage other very important aspects of the patient experience. All clinicians—physicians, mid-level providers, and RNs—have an important role in the care of patients being treated with taxane-containing chemotherapy, including

] assessing CIPN using reliable, valid, and sensitive instru- 15 ments; educating patients about their options; eliciting patient -paclitaxel 100 mg/m nonsmall cell lung cancer, plus carboplatin AUC 6min mg*mL/ every 3 weeks 1, 8, and 15of6mg*mL/minonday1every plus carboplatin AUC 3weeks preferences; and assisting patients in making choices that are Solvent-based paclitaxel 200 mg/m nab in harmony with their unique situations. Teaching patients NSCLC -paclitaxel [ about CIPN—that it is likely to occur, what the symptoms

nab may be and that there are strategies to compensate for alter- — — ’ ent-based) + ations in sensation or strength is within all clinicians scope of practice. CIPN can be assessed through clinical exams and patients’ reports using reliable, valid, and sensitive instru- -paclitaxel + carboplatin

carboplatin ments such as the Total Neuropathy Score and FACT-Taxane ripheral neuropathy, Paclitaxel (solv nab [14]. Clinicians can also help patients weigh the pros and cons of treatment and articulate their treatment preferences. For example, hospice could be the optimal choice for a patient whose goal is to be as comfortable as possible during the last stage of life, but it might not be available to someone receiving chemotherapy. More than 60 % of hospices will not iously untreated

chemotherapy-induced pe admit a patient who is receiving chemotherapy, even if it is

) Taxane Dosage and schedule Treatment durationconsidered Sensory neuropathy grade, % palliative, since the chemotherapy regimens are N CIPN exponentially more expensive than the meager $140 per day that Medicare will reimburse for hospice care [36]. for metastatic disease (adjuvant OK if >1 year prior) (531) metastatic disease (adjuvant OK if > 1 year prior) (521) Stage IIIb or IV, prev

So, what about Alice? CIPN incidence and severity in phase 3 clinical trials in NSCLC

area under the curve, Alice (A) has come in for her 3-month check-up. Her nephew NCI CTCAE Socinski (2012) Stage IIIb or IV, previously untreated for Table 4 Lead author Population ( AUC a has brought her since her CIPN makes it difficult to drive and 2590 Support Care Cancer (2014) 22:2581–2592

Table 5 CIPN grades reported, instruments used to measure CIPN, and assessment schedule [3, 12, 15–29]

Lead author CIPN grade(s) reported Instrument Assessment schedule

Kubota, Sandler, Smit No report NA NA Scagliotti (2002) 1–3 specified EORTC QLQ-LC13 End of each cycle Gatzemeier 1–3 combined EORTC QLQ-LC13 Baseline, within 3 days before each cycle, off study q 2 months until progression Scagliotti (2010) 1–4 combined, 3–5 specified NCI CTCAE Unspecified Booton 1–4 combined with 3 and 4 specified NCI CTCAE q 3 weeks on day 14 Socinski 1–4 combined with 3 and 4 specified NCI CTCAE and FACT-Taxane Baseline, day 1 of each cycle, at completion Giaccone 2 and 3 NCI CTCAE Unspecified Gao (meta-analysis) 2–4 combined Various Unspecified Fossella 3 and 4 combined NCI CTCAE End of each cycle Schuette 3 and 4 combined NCI CTCAE Unspecified Belani 2–4 specified NCI CTCAE Unspecified Bonomi 3 ECOG CTC Unspecified Schiller 3 Unspecified Unspecified Georgoulias 3 and 4 WHO Before each course of treatment Kelly 3 and 4 NCI CTCAE Unspecified

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-Taxane Functional Assessment of Cancer Therapy—Taxane, NA not applicable, NCI CTCAE National Cancer Institute’s Common Terminology Criteria for Adverse Events, WHO World Health Organization she is fearful of walking by herself, as she has fallen a few what I can tell from the exam, you’re having some of times. those side effects, like the pain, numbness, and tingling.” A: “Ijusthate to ask for help…I’ve always been so A: “Yes. I am.” independent…it just makes me want to cry…this weak- The nurse hands Alice the FACT-Taxane questionnaire ness and these weird feelings in my hands and feet are to complete while she prepares the chemotherapy driving me crazy—Ican’t do the things I used to.” premedications. She then reviews the questionnaire with Nurse (N): “I can tell you’re frustrated and it’s not easy Alice, noting the reported difficulty with ambulation and for you. You’re fortunate to have such a responsive discomfort in the hands. She advises Alice how to be support person. Unfortunately, these side effects from safe: remove any throw rugs from her house, keep the chemotherapy are fairly common. Let me just ask clutter at a minimum, etc. She also tells Alice that there you a few questions about it and do a quick exam.” are treatments, such as duloxetine [39], that might alle- A: “OK.” viate the pain she’s experiencing. The nurse completes a brief neuropathy exam using an N: “May I discuss these symptoms with your doctor? It abbreviated version of the Total Neuropathy Score [37, may be time to make decisions about adjusting the 38]. chemotherapy, or possibly stopping it altogether, to N: “Alice, did the cancer doctor make it clear to you that make you more comfortable.” the chemotherapy you’re getting is palliative?” A: “Yes. Would you ask my nephew to come in? I want A: “What’sthat?” himtobeinvolvedinthisdecision.” N: “It means that it won’tcureyourcancer,butitmight slow the growth of your tumor and could help your symptoms—like the breathing trouble you were having.” Conclusion A: “Idon’t think they told me that. I don’tremember that.” Taxane-containing chemotherapy, recommended as first-line N: “Well, basically, it’s supposed to make you a little treatment for advanced NSCLC, frequently causes CIPN. This more comfortable, but it has some side effects that can may result in symptoms such as numbness, tingling, and make you less comfortable. From what you’ve said and neuropathic pain and often causes substantial suffering. Support Care Cancer (2014) 22:2581–2592 2591

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