Original Article
Patient-Reported Neuropathy and Taxane-Associated Symptoms in a Phase 3 Trial of nab-Paclitaxel Plus Carboplatin versus Solvent-Based Paclitaxel Plus Carboplatin for Advanced Non–Small-Cell Lung Cancer Vera Hirsh, MD, FRCPC,* Isamu Okamoto, MD, PhD,† Jeremy K. Hon, MD,‡ Ray D. Page, DO, PhD,§ James Orsini, MD,║ Hiroshi Sakai, MD,¶ Hui Zhang, MS,# Markus F. Renschler, MD,# and Mark A. Socinski, MD**
Introduction: nab-Paclitaxel (nab-P) is approved, in the United States, in combination with carboplatin for the first-line treatment of advanced non–small-cell lung cancer, based on a randomized phase 3 trial of nab-P plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C). This trial revealed a higher overall response rate (33% versus 25%; p = 0.005) and longer, but not statistically significant, overall and progression-free survival for nabP/C versus sb-P/C. In addition, nab-P/C demonstrated lower rates of grade 3 or higher peripheral neuropathy, myalgia, arthralgia, and neutropenia but higher rates of anemia and thrombocytopenia. This report analyzes patient and physician assessment of symptoms within this trial. Methods: Patients completed the taxane subscale of the Functional Assessment of Cancer Therapy questionnaire, which focuses on taxane toxicity, including peripheral neuropathy and neurotoxicity. Mean baseline scores and changes from baseline are reported. Physicians also graded the severity of neuropathy at each patient visit using National Cancer Institute Common Toxicity Criteria. Results: Patients receiving nab-P/C reported significantly less worsening of peripheral neuropathy (p < 0.001), pain (p < 0.001), and hearing loss (p = 0.002). Patient-reported edema was similar between the two treatment arms. In agreement with patient-reported symptoms, *McGill University, Montreal, Quebec, Canada; †Kinki University Faculty of Medicine, Osaka-Sayama, Japan; ‡Clearview Cancer Institute, Huntsville, Alabama; §The Center for Cancer and Blood Disorders, Fort Worth, Texas; ║Essex Oncology of New Jersey, Belleville, New Jersey; ¶Saitama Cancer Center, Saitama, Japan; #Celgene Corporation, Summit, New Jersey; and **University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Disclosure: Dr. Hirsh is a consultant for Celgene Corporation. Dr. Hon received research funding from Celgene Corporation. Dr. Orsini is employed in a leadership role for Essex Oncology. Ms. Zhang was an employee of Celgene Corporation. Dr. Renschler is an employee in a leadership position of and owns stock in Celgene Corporation. Dr. Socinski is a consultant for and received research funding from Celgene Corporation. The remaining authors declare no conflict of interest. Address for correspondence: Vera Hirsh, MD, McGill University, 1650 Cedar Avenue, Montreal, Quebec H3A 1A1, Canada. E-mail: vera.hirsh@muhc. mcgill.ca Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0901-0083
the results of a per-treatment cycle physician assessment of peripheral neuropathy also favored nab-P/C over sb-P/C (p < 0.001). Conclusion: In this trial of patients receiving first-line treatment for advanced non–small-cell lung cancer, nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C. Key Words: nab-Paclitaxel, Solvent-based paclitaxel, Functional Assessment of Cancer Therapy-Taxane, Non–small-cell lung cancer, Peripheral neuropathy. (J Thorac Oncol. 2014;9: 83–90)
T
he goals of therapy for advanced non–small-cell lung cancer (NSCLC) are to prolong survival and manage symptoms associated with the disease.1 Because survival times for patients with advanced NSCLC are relatively short, symptom control is an important consideration.2 Treatment can affect a patient’s well-being through both symptom control and treatment-related toxicity.3 Therefore, treatments that can help limit tumor growth (achieve a tumor response)4 while limiting toxicity are of paramount importance in this population.3 Underscoring the value of symptom control to patients, an analysis of patient preference with respect to chemotherapy for advanced NSCLC found that 68% of those interviewed would accept chemotherapy if it would substantially reduce symptoms, even in the absence of a survival benefit.5 Worsening symptoms may decrease a patient’s independence, rendering him or her more dependent on caregivers, including family. A number of reports have revealed that many patients with terminal cancer are concerned about becoming a burden to loved ones at the end of life.6–8 This phenomenon, known as self-perceived burden, may be experienced at minimal to mild levels by 35% of patients and at moderate to extreme levels by another 28% of patients according to one study.6 This perception of being a burden to loved ones may affect a patient’s preference of treatment.8 Symptom management is an important component of care in advanced NSCLC because the majority of patients
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present with disease-related symptoms.2 Symptom control can be achieved with tumor response, but it can also be achieved in the absence of an objective response, possibly through tumor shrinkage that does not meet the criteria to be considered a partial response.2 The effect of tumor response on disease-related symptoms is an area of active research, with some but not all studies suggesting a link between tumor response and symptoms such as cough, dyspnea, chest pain, and systemic symptoms (fever, anorexia, and weight loss).9–11 Therefore, tumor shrinkage is an important consideration because it may relate to both the goals of treatment and the patient’s well-being. Platinum-based regimens are recommended therapy for advanced NSCLC in patients with good performance status (PS).1,12 Different platinum doublets offer similar overall response rates (ORRs) and overall survival values; therefore, the selection of the proper combination partner should be individually tailored by clinicians to their patients.12 Solvent-based paclitaxel (sb-paclitaxel) is among the recommended platinum combination partners.1,12 However, toxicities such as peripheral neuropathy, arthralgia, and myalgia are known taxane-associated side effects.3,13 nab-Paclitaxel was developed to improve the therapeutic index of paclitaxel therapy.14 Compared with sb-paclitaxel, nab-paclitaxel reaches a 10-fold higher peak concentration of free paclitaxel in patients, delivers 33% more drug to tumors in preclinical models, and crosses endothelial cells more efficiently.15,16 Furthermore, nab-paclitaxel has shown superior ORR and time to progression/progression-free survival and favorable safety versus sb-paclitaxel and docetaxel in trials of metastatic breast cancer (MBC).14,17 nab-Paclitaxel, either as monotherapy or in combination with carboplatin (nab-P/C) has demonstrated promising efficacy in NSCLC in a number of clinical trials.18–20 These findings were recently confirmed in a phase 3 trial in which nab-P/C was compared with sb-paclitaxel plus carboplatin (sb-P/C) as first-line treatment for patients with advanced NSCLC.21 The dose and schedule of nab-P/C was chosen based on the findings of a phase 2 dose-finding study,20 whereas the sb-P/C regimen was selected because it represents an established standard against which to compare nab-P/C.22,23 Compared with sb-P/C, nab-P/C produced a significantly higher ORR (33% versus 25%, respectively; p = 0.005) and a nonsignificant 1-month longer median overall survival versus sb-P/C (12.1 versus 11.2 months, respectively; p = 0.271).21 In addition, the safety profile revealed lower rates of physicianassessed grade 3 or higher sensory neuropathy, neutropenia, myalgia, and arthralgia for nab-P/C but lower rates of grade 3 or higher anemia and thrombocytopenia for sb-P/C. On the basis of these findings, the U.S. Food and Drug Administration approved nab-P/C for locally advanced or metastatic NSCLC as first-line treatment in patients who are not candidates for curative surgery or radiation therapy.24 The Functional Assessment of Cancer Therapy (FACT)-General questionnaire is a reliable and validated tool to measure symptoms and quality of life (QoL) from the perspective of a patient with cancer.25 The tool consists of subscales that measure physical well-being, social/family well-being, emotional well-being, functional well-being, and patient perception of his or her relationship with the physician.25 Subsequently, the developers of the FACT-General
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questionnaire created FACT-Taxane, a more specific tool to assess QoL in patients receiving taxanes.3 FACT-Taxane consists of both FACT-General and an added taxane subscale. The subscale has 16 items (Table 1), including an 11-item neurotoxicity subscale and five additional taxane-specific questions related to the effects of arthralgia, myalgia, and skin changes. The tool was found to be reliable and sensitive to changes in symptoms over time.3 In a study of patients with NSCLC receiving treatment with sb-P/C, the impact on QoL of lung cancer symptom improvement because of treatment equaled the impact of treatment-related toxicities on total QoL, as measured by the FACT-Taxane tool. However, with respect to patients’ global rating of QoL by using the single item “I am content with the quality of my life right now,” improvements in disease-related symptoms outweighed concerns about treatment-related toxicity.3 In the trial of nab-P/C versus sb-P/C described above, the taxane subscale of the FACT-Taxane questionnaire was selected as a methodical instrument to gauge patient perception of how treatment-related symptoms affected QoL.3,21 In addition to assessing sensory neuropathy during study treatment by established grading criteria, the investigators also evaluated the degree of sensory neuropathy on a visit-by-visit basis. This analysis explores patient- and physician-assessed symptoms related to treatment with nab-P/C versus sb-P/C in patients with advanced NSCLC who participated in the phase 3 study.
PATIENTS AND METHODS This international, multicenter, randomized phase 3 study in patients with advanced NSCLC compared the efficacy and safety of nab-P/C versus sb-P/C.21 Patients in the nab-P/C arm received nab-paclitaxel 100 mg/m2 on days 1, 8, and 15, administered as a 30-minute infusion, followed by TABLE 1. The 16-Item Taxane Subscale of FACT-Taxane (Adapted from the Study by Cella et al., 2003)3 Category Neurotoxicity component
Taxane component
Statement I have numbness or tingling in my hands I have numbness or tingling in my feet I feel discomfort in my hands I feel discomfort in my feet I have joint pain or muscle cramps I feel weak all over I have trouble hearing I get a ringing or buzzing in my ears I have trouble buttoning buttons I have trouble feeling the shape of small objects when they are in my hand I have trouble walking I feel bloated My hands are swollen My legs or feet are swollen I have pain in my fingertips I feel discomfort in my feet
FACT, Functional Assessment of Cancer Therapy.
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carboplatin area under the concentration curve = 6 mg*min/ mL (per Calvert formula)26 given on day 1 every 21 days. Patients in the sb-P/C arm received sb-paclitaxel 200 mg/m2, infused over 3 hours, plus carboplatin area under the concentration curve = 6 mg*min/mL, both given on day 1 every 21 days. Patients were randomized 1:1 to nab-P/C or sb-P/C and stratified by age (< 70 years versus ≥ 70 years), disease stage (IIIB versus IV), sex (male versus female), histology (squamous versus adenocarcinoma versus other), and geographic region (Canada/United States versus Russia/Ukraine versus Japan versus Australia). Six cycles of therapy were encouraged, and treatment beyond six cycles was permissible at the investigators’ discretion in the absence of progressive disease or unacceptable toxicity. Eligible adults had histologically or cytologically confirmed stage IIIB (with or without pleural effusion) or IV NSCLC, measurable by Response Evaluation Criteria In Solid Tumors version 1.0,4 an Eastern Cooperative Oncology Group PS of 0 to 1, and a life expectancy of more than 12 weeks. Patients were previously untreated for metastatic disease and received no radiotherapy within 4 weeks of enrollment. Prior adjuvant chemotherapy was permitted if it had been completed 12 months or more before study enrollment. Patients were excluded from the study if they had untreated or symptomatic brain metastases. This study was approved by the independent ethics committees of the participating medical institutions and was conducted in compliance with the World Medical Association Declaration of Helsinki and Good Clinical Practice and Guidelines of the International Conference on Harmonization.27 Written informed consent was obtained from all patients before study initiation. Physician-assessed toxicities in this trial were classified by both the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and by Medical Dictionary of Regulatory Activities (MedDRA) criteria. Patient-reported symptoms were assessed using the 16-item taxane subscale of the FACT-Taxane instrument (Table 1), which includes a neurotoxicity subscale comprising 11 questions and five more questions on additional taxane-related symptoms, such as myalgia, arthralgia, and skin changes.3 All 16 questions from the taxane subscale were completed at baseline and on day 1 of each treatment cycle. Patients gave each statement a score of 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit), or 4 (very much). Selected questions from the neurotoxicity and taxane components of the FACT-Taxane were grouped into predefined subscores for peripheral neuropathy, pain, hearing, and edema as defined in Table 2. Responses to all questions were analyzed in total, individually, and as the following groups: peripheral neuropathy, pain, hearing, and edema. Descriptive statistics were used to summarize patientassessed responses from the FACT-Taxane scale, including mean change from baseline at each cycle; differences between treatment arms were assessed using the two-sample t test by visit or repeated measurement across all visits. In all charts of FACT-Taxane data, the values for cycles 2 to 8 and final evaluation are mean changes from the baseline score.
Neuropathy and Taxane-Associated Symptoms
TABLE 2. FACT-Taxane Subscores Category Peripheral neuropathy
Pain Hearing Edema
Statement I have numbness or tingling in my hands I have numbness or tingling in my feet I have trouble buttoning buttons I have trouble feeling the shape of small objects when they are in my hands I have pain in my fingertips I feel discomfort in my hands I feel discomfort in my feet I have trouble hearing I get ringing or buzzing in my ears I feel bloated My hands are swollen My legs or feet are swollen
FACT, Functional Assessment of Cancer Therapy.
Physicians conducted a detailed analysis of sensory neuropathy by evaluating patients at every cycle and coding severity over the course of treatment using the five-grade NCI CTCAE version 3.0 scale: grade 1—asymptomatic, loss of deep tendon reflexes or paresthesia, including tingling but not interfering with function; grade 2—sensory alteration or paresthesia, including tingling and interfering with function but not interfering with activities of daily living; grade 3—sensory alteration or paresthesia interfering with activities of daily living; grade 4—disabling; and grade 5—death.
RESULTS Of the 1038 patients in the treated population, 1031 (99%) completed the FACT-Taxane questionnaire at baseline. Compliance with the questionnaire through eight cycles was also 99% (completed in 4278 of 4335 cycles). Baseline scores of all individual items, the total score of all 16 items, and each subscore were balanced between the treatment arms. There was a significant treatment effect favoring nab-P/C over sbP/C over the entire course of treatment for the total score of all 16 items (Fig. 1; p < 0.001) as well as for the 11-item neurotoxicity subscore (p < 0.001). Figure 2 shows the results of the FACT-Taxane peripheral neuropathy subscore through cycle 8 of treatment. Figure 2A reflects the composite results of the five peripheral neuropathy questions, whereas Figure 2B–F shows the graph for each individual question. The composite score and each individual question subscore revealed a lesser change over the course of treatment for the nab-P/C group versus the sbP/C group (p < 0.001 for all comparisons), suggesting less development of treatment-related symptoms with nab-P/C. Furthermore, the composite score revealed statistically significant differences from baseline to each of cycles 2 to 8 (p ≤ 0.002 for each). These values were consistent with the physician assessment of peripheral neuropathy by cycle (Fig. 3) and the number of patients who experienced at least one peripheral neuropathy adverse event of grade 3 or higher by MedDRA criteria (3% versus 12%; p < 0.001).21
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FIGURE 1. Composite change from baseline for the 16-item taxane subscale. Symptoms were reported prior to dosing on day 1 of each cycle. Note that larger bars represent greater deteriorations from baseline as perceived by patients. BL, baseline; nab-P/C, nab-paclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. aP value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
Of note, deterioration in the patient-reported peripheral neuropathy subscore at or after the development of grade 3 or higher peripheral neuropathy was substantially less for nabP/C versus sb-P/C (median change from baseline 4.5 versus 10). The median time to improvement to MedDRA grade 1 or lower peripheral neuropathy was shorter for nab-P/C versus sb-P/C (38 versus 104 days), although this difference was not statistically significant (p = 0.326). The composite scores for pain and the subscores for individual questions are shown in Figure 4. The change over the course of treatment for the composite score significantly favored the nab-P/C arm over the sb-P/C arm (p < 0.001). The changes over the course of treatment for each individual question also significantly favored nab-P/C versus sb-P/C (p < 0.001 for each). In addition, patient-reported deterioration in the pain subscore at or after the onset of grade 3 or higher peripheral neuropathy was less for nab-P/C versus sb-P/C (median change from baseline 1.0 versus 4.0). These patient-reported results were consistent with those from an earlier report of adverse event grading for grade 3 myalgia (< 1% for nab-P/C versus 2% for sb-P/C; p = 0.011) and arthralgia (0% for nab-P/C versus 2% for sb-P/C; p = 0.008).21 Figures 5 and 6 show the composite scores for the hearing and edema categories, respectively. The hearing subscore over the course of treatment favored nab-P/C versus sb-P/C (p = 0.002); however, the edema subscore change over the course of treatment did not differ significantly between nabP/C and sb-P/C (p = 0.437), suggesting that patient perception of edema was similar between the two groups.
DISCUSSION This is the largest study in NSCLC that evaluated the impact of taxane-related toxicity on QoL as reported by patients using the taxane subscore module of the FACT-Taxane instrument. The robustness of this analysis is underscored by the more
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than 99% completion rate of this QoL instrument by patients in the study at baseline, through treatment, and during follow-up. In addition to patients reporting the impact of sensory neuropathy on QoL, physicians graded sensory neuropathy during the same office visits. The results of patient and physician reports showed a striking similarity. By both FACT-Taxane and physician assessment, nab-P/C seemed superior to sb-P/C with respect to neurotoxic effects. Specifically, patients in the nabP/C arm noted less severe peripheral neuropathy, neuropathic pain in the hands and feet, and hearing loss. Patient-reported edema subscores seemed to be similar between the two treatment groups. Taken together, these findings demonstrated an advantage for nab-P/C with respect to patient-reported treatment-related symptoms in this trial of patients being treated for advanced NSCLC. Importantly, patient-reported assessment of neuropathy mirrored the physician-evaluated degree of neuropathy with respect to both the cumulative change over time and visit-by-visit differences between the treatment arms, further validating the FACT-Taxane tool. The patient-reported peripheral neuropathy data in this report are consistent with adverse event data collected separately and previously reported.21 Notably, the MedDRA assessment of neuropathy revealed that 3% of patients in the nab-P/C arm experienced a peripheral neuropathy event of grade 3 or higher versus 12% of patients in the sb-P/C arm (p < 0.001). Assessments of peripheral neuropathy by using NCI CTCAE criteria for nab-P/C and sb-P/C were also 3% and 12%, respectively (p < 0.001).21 In addition, the median time to improvement of peripheral neuropathy from MedDRA grade 3 to grade 1 or lower was 38 days for nab-P/C versus 104 days for sb-P/C. The consistent findings of three different methods for assessing peripheral neuropathy (adverse event data, physician assessment by cycle of treatment, and FACT-Taxane) confirm that nab-P/C resulted in a lower incidence of neuropathy-associated symptoms versus sb-P/C. In addition, the changes from baseline in the FACT-Taxane peripheral neuropathy and pain subscale scores were lower in the nab-P/C arm versus the sb-P/C arm at or after the onset of peripheral neuropathy of grade 3 or higher. The rate and severity of peripheral neuropathy are partly dependent on the maximum plasma concentration (Cmax) of the taxane administered as well as the schedule of administration and taxane used.17,20,28–31 A phase 3 MBC trial reported a higher rate of peripheral neuropathy for nab-P 260 mg/m2 versus sb-P 175 mg/m2, each administered on an every-3-week schedule (q3w; 10% versus 2%; p < 0.001).14 However, the time to improvement of grade 3 peripheral neuropathy by 1 grade or higher was 22 days for nab-P versus 79 days for sb-P.14,32 A pharmacokinetic study demonstrated that nab-P administered at 260 mg/m2 over 30 minutes resulted in an approximate fourfold higher Cmax of total paclitaxel and an approximate 10-fold higher Cmax of unbound paclitaxel compared with sb-P administered at 175 mg/m2 over 3 hours.15 In this trial, the infusion time was maintained at 30 minutes but the dose was reduced from 260 mg/m2 to 100 mg/m2 for the weekly schedule, which would have resulted in a substantially reduced Cmax and, possibly as a consequence, a lower rate of peripheral neuropathy in the nab-P/C arm of this trial versus the nab-P arm of the phase 3 MBC trial.
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FIGURE 2. Peripheral neuropathy subscore and individual statements. Symptoms were reported prior to dosing on day 1 of each cycle. A, composite peripheral neuropathy subscore, (B) subscore for the statement “I have numbness or tingling in my hands,” (C) subscore for the statement “I have numbness or tingling in my feet,” (D) subscore for the statement “I have trouble buttoning buttons,” (E) subscore for the statement “I have pain in my fingertips,” and (F) subscore for the statement “I have trouble feeling the shape of small objects when they are in my hands.” BL, baseline; nab-P/C, nab-paclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. a = *P value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
A previous phase 3 trial in advanced NSCLC reported a higher rate of grade 2/3 neuropathy in patients who received q3w versus weekly sb-P/C (18% versus 12%).22 However, the weekly regimen did not demonstrate superior efficacy in that trial, and q3w remains the standard schedule for sb-P/C.22,23 In addition, in the current trial, the cumulative paclitaxel dose
of nab-P/C was higher than that of sb-P/C (1325 mg/m2 with nab-P/C versus 1125 mg/m2 with sb-P/C), as was the median paclitaxel dose intensity (82 versus 65 mg/m2/week), suggesting that even though patients were able to receive more paclitaxel with nab-P/C, this did not result in more neuropathy.21 However, the median cumulative carboplatin dose (3140 versus
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Grade 3
on peripheral neuropathy or other components of the FACTTaxane questionnaire is difficult to estimate, especially as peripheral neuropathy and ototoxicity caused by carboplatin (unlike cisplatin) are known to be infrequent.33 Taxane use has been shown to be associated with a triad of pain related to sensory neuropathy, myalgia, and arthralgia.13,24,34 Results from the pain subscore derived from the FACT-Taxane survey in this trial revealed that patients receiving nab-P/C perceived less pain in the hands and feet compared with patients receiving sb-P/C. The FACT-Taxane tool does not directly assess the impact of myalgia and arthralgia on patient perception of QoL. We have previously reported significantly less grade 3 myalgia (< 1% for nab-P/C versus 2% for sb-P/C; p = 0.011) and arthralgia (0% for nab-P/C versus 2% for sb-P/C; p = 0.008) using the adverse event data from this study.21 Thus, nab-P/C has a favorable profile in all three of these areas of pain, which may be of great importance to patients. One of the more intriguing findings in this study was the effect of treatment on patient-reported hearing loss. Few reports have indicated taxane-related effects on hearing.35 The initial publication of this phase 3 trial did not list hearing loss as a common physician-assessed adverse event in either treatment arm.21 Similarly, the low raw FACT-Taxane hearing subscores for both arms of this trial indicated that difficulties with hearing were not a major concern. However, the difference in change from baseline between the nab-P/C and sb-P/C
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FIGURE 3. Physician assessment of peripheral neuropathy by cycle. BL, baseline; nab-P/C, nab-paclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin. a At the final evaluation, 1 patient in the sb-P/C arm reported grade 4 peripheral neuropathy (none in the nab-P/C arm).
3315 mg) and median carboplatin dose intensity (166 versus 204 mg/week) were both lower for nab-P/C versus sb-P/C. The exact impact of this marginal difference in carboplatin dose
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FIGURE 4. Pain subscore and individual statements. Symptoms were reported prior to dosing on day 1 of each cycle. A, composite pain subscore. B, subscore for the statement “I feel discomfort in my hands.” C, subscore for the statement “I feel discomfort in my feet.” BL, baseline; nab-P/C, nab-paclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. aP value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
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Mean Baseline Score or Mean Change From Baseline to Day 1 of Each Cycle or Final Evaluation
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FIGURE 5. Composite hearing subscore. Symptoms were reported prior to dosing on day 1 of each cycle. BL, baseline; nab-P/C, nabpaclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. aP value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
arms was statistically significant (p = 0.002), suggesting that patients receiving sb-P/C reported more severe hearing loss during treatment versus those receiving nab-P/C. Future study would be required to explain this subtle but interesting finding. Taken together, the data from this analysis revealed a robust agreement between patient- and physician-assessed tolerability profiles for nab-P/C versus sb-P/C in patients with advanced NSCLC. The high rates of compliance with the questionnaire suggest that these results are indeed representative of the trial population. In addition to the favorable results for nab-P/C over sb-P/C with respect to treatment-related symptoms in this study, some patients may have derived symptom relief through the shrinkage of their tumors.2,21 Notably, a higher proportion of patients in the nab-P/C arm versus the sb-P/C arm achieved an objective response (33% versus 25%; p = 0.005).21 Taken together, these data suggest that for patients
Mean Baseline Score or Mean Change From Baseline to Day 1 of Each Cycle or Final Evaluation
1 0.8 0.6 0.5 0.4 0.3 0.2 0.1 0
ACKNOWLEDGMENTS
This study was funded by Celgene Corporation. The authors thank all participating sites and investigators for their support with the clinical study. Medical writing assistance was provided by John McGuire, PhD, MediTech Media, funded by Celgene Corporation. The authors were fully responsible for all content and editorial decisions for this manuscript. REFERENCES
p = 0.437a
0.7
who receive a taxane and a platinum for their first-line treatment of advanced NSCLC, nab-P/C is the preferred choice. Because the survival time of patients with advanced NSCLC is relatively short, patient perception of treatmentrelated symptoms becomes especially important.2 Treatment for advanced NSCLC is entering an age of personalized medicine dependent on tumor-specific biomarkers.12 However, many patients, especially those with squamous tumors, are given chemotherapy, often platinum-based doublets, because targeted agents are deemed inappropriate or have shown little benefit in particular patient populations.36 Because more lines of treatment are now available for advanced NSCLC,37 it is of utmost importance that treatment-related side effects are minimized, preserving patients’ QoL and PS, one of the most important criteria for receiving treatment.12 Neuropathy, myalgia, and arthralgia can severely decrease patients’ PS to the point that they can no longer take care of their own needs. Thus, nab-P/C represents a regimen for the first-line treatment of advanced NSCLC that has a favorable tolerability profile, potentially preserving PS and enabling patients in the era of personalized medicine to benefit from new agents either in combination with this regimen or as a sequential therapy. The population of elderly patients with NSCLC is growing, and tolerance of progressively more palliative treatments is becoming an important factor in treatment decision making. This is particularly relevant in light of the side effects of novel targeted agents, including possible drug interactions that cause unfavorable toxicities, such as worsening of peripheral neuropathy.
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512 519
482 471
414 405
378 373
309 310
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162 165
128 139
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FIGURE 6. Composite edema subscore. Each timepoint represents day 1 of the corresponding cycle, prior to administration of treatment in that cycle. BL, baseline; nab-P/C, nabpaclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. a = *P value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
1. The Stage IV NSCLC treatment [National Cancer Institute Web site]. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/nonsmall-cell-lung/healthprofessional/page11. Accessed March 2, 2012. 2. Socinski MA. The role of chemotherapy in the treatment of unresectable stage III and IV nonsmall cell lung cancer. Respir Care Clin N Am 2003;9:207–236. 3. Cella D, Peterman A, Hudgens S, Webster K, Socinski MA. Measuring the side effects of taxane therapy in oncology: the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane). Cancer 2003;98:822–831. 4. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216. 5. Silvestri G, Pritchard R, Welch HG. Preferences for chemotherapy in patients with advanced non-small cell lung cancer: descriptive study based on scripted interviews. BMJ 1998;317:771–775. 6. McPherson CJ, Wilson KG, Lobchuk MM, Brajtman S. Self-perceived burden to others: patient and family caregiver correlates. J Palliat Care 2007;23:135–142. 7. McPherson CJ, Wilson KG, Murray MA. Feeling like a burden: exploring the perspectives of patients at the end of life. Soc Sci Med 2007;64:417–427.
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8. Johnson JO, Sulmasy DP, Nolan MT. Patients’ experiences of being a burden on family in terminal illness. J Hosp Palliat Nurs 2007;9:264–269. 9. de Marinis F, Pereira JR, Fossella F, et al. Lung cancer symptom scale outcomes in relation to standard efficacy measures: an analysis of the phase III study of pemetrexed versus docetaxel in advanced non-small cell lung cancer. J Thorac Oncol 2008;3:30–36. 10. Mohan A, Singh P, Kumar S, et al. Effect of change in symptoms, respiratory status, nutritional profile and quality of life on response to treatment for advanced non-small cell lung cancer. Asian Pac J Cancer Prev 2008;9:557–562. 11. Tanvetyanon T, Soares HP, Djulbegovic B, Jacobsen PB, Bepler G. A systematic review of quality of life associated with standard chemotherapy regimens for advanced non-small cell lung cancer. J Thorac Oncol 2007;2:1091–1097. 12. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 2.2014. Available at: http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed December 23, 2012. 13. Taxol (paclitaxel) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2011. 14. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005;23:7794–7803. 15. Gardner ER, Dahut WL, Scripture CD, et al. Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel. Clin Cancer Res 2008;14:4200–4205. 16. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of Cremophorfree, albumin-bound paclitaxel, ABI-007, compared with Cremophorbased paclitaxel. Clin Cancer Res 2006;12:1317–1324. 17. Gradishar WJ, Krasnojon D, Cheporov S, et al. Significantly lon ger progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 2009;27:3611–3619. 18. Green MR, Manikhas GM, Orlov S, et al. Abraxane, a novel Cremophorfree, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol 2006;17:1263–1268. 19. Rizvi NA, Riely GJ, Azzoli CG, et al. Phase I/II trial of weekly intravenous 130-nm albumin-bound paclitaxel as initial chemotherapy in patients with stage IV non-small-cell lung cancer. J Clin Oncol 2008;26: 639–643. 20. Socinski MA, Manikhas GM, Stroyakovsky DL, et al. A dose finding study of weekly and every-3-week nab-paclitaxel followed by carboplatin as first-line therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol 2010;5:852–861. 21. Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced
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non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol 2012;30:2055–2062. 22. Belani CP, Ramalingam S, Perry MC, et al. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 2008;26:468–473. 23. Gao G, Chu H, Zhao L, Gui T, Xu Q, Shi J. A meta-analysis of paclitaxelbased chemotherapies administered once every week compared with once every 3 weeks first-line treatment of advanced non-small-cell lung cancer. Lung Cancer 2012;76:380–386. 24. Abraxane for Injectable Suspension (paclitaxel particles for injectable suspension) (albumin-bound) [package insert]. Summit, NJ: Celgene Corporation; 2012. 25. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993;11:570–579. 26. van Warmerdam LJ, Rodenhuis S, ten Bokkel Huinink WW, Maes RA, Beijnen JH. The use of the Calvert formula to determine the optimal carboplatin dosage. J Cancer Res Clin Oncol 1995;121:478–486. 27. Good clinical practice research guidelines reviewed, emphasis given to responsibilities of investigators: second article in a series. J Oncol Pract 2008;4:233–235. 28. Gradishar WJ, Krasnojon D, Cheporov S, et al. Phase II trial of nab-paclitaxel compared with docetaxel as first-line chemotherapy in patients with metastatic breast cancer: final analysis of overall survival. Clin Breast Cancer 2012;12:313–321. 29. Pachman DR, Barton DL, Watson JC, Loprinzi CL. Chemotherapy induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther 2011;90:377–387. 30. Rowinsky EK, Chaudhry V, Cornblath DR, et al. Neurotoxicity of Taxol. J Natl Cancer Inst Monogr 1993;(15):107–115. 31. Rivera E, Mejia JA, Arun BK, et al. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer 2008;112:1455–1461. 32. Cortes J, Saura C. Nanoparticle albumin-bound (nab)-paclitaxel: improving efficacy and tolerability by targeted drug delivery in metastatic breast cancer. EJC Supplements. 2010;8(1):1–10.33. 33. Bristol-Myers Squibb Company (Ed). Paraplatin (carboplatin) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2004. 34. Taxotere (docetaxel) [package insert]. Bridgewater, NJ: Sanofi-Aventis US LLC; 2010. 35. Sarafraz M, Ahmadi K. Paraclinical evaluation of side-effects of taxanes on auditory system. Acta Otorhinolaryngol Ital 2008;28:239–242. 36. Pennell NA. Selection of chemotherapy for patients with advanced non-small cell lung cancer. Cleve Clin J Med. 2012;79(suppl 1): eS46–eS50. 37. Hirsh V. Review of the treatment of metastatic non small cell lung carcinoma: a practical approach. World J Clin Oncol 2011;2:262–271.
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Patient-Reported Neuropathy and Taxane-Associated Symptoms in a Phase 3 Trial of nab-Paclitaxel Plus Carboplatin versus Solvent-Based Paclitaxel Plus Carboplatin for Advanced Non–Small-Cell Lung Cancer Vera Hirsh, MD, FRCPC,* Isamu Okamoto, MD, PhD,† Jeremy K. Hon, MD,‡ Ray D. Page, DO, PhD,§ James Orsini, MD,║ Hiroshi Sakai, MD,¶ Hui Zhang, MS,# Markus F. Renschler, MD,# and Mark A. Socinski, MD**
Introduction: nab-Paclitaxel (nab-P) is approved, in the United States, in combination with carboplatin for the first-line treatment of advanced non–small-cell lung cancer, based on a randomized phase 3 trial of nab-P plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C). This trial revealed a higher overall response rate (33% versus 25%; p = 0.005) and longer, but not statistically significant, overall and progression-free survival for nabP/C versus sb-P/C. In addition, nab-P/C demonstrated lower rates of grade 3 or higher peripheral neuropathy, myalgia, arthralgia, and neutropenia but higher rates of anemia and thrombocytopenia. This report analyzes patient and physician assessment of symptoms within this trial. Methods: Patients completed the taxane subscale of the Functional Assessment of Cancer Therapy questionnaire, which focuses on taxane toxicity, including peripheral neuropathy and neurotoxicity. Mean baseline scores and changes from baseline are reported. Physicians also graded the severity of neuropathy at each patient visit using National Cancer Institute Common Toxicity Criteria. Results: Patients receiving nab-P/C reported significantly less worsening of peripheral neuropathy (p < 0.001), pain (p < 0.001), and hearing loss (p = 0.002). Patient-reported edema was similar between the two treatment arms. In agreement with patient-reported symptoms, *McGill University, Montreal, Quebec, Canada; †Kinki University Faculty of Medicine, Osaka-Sayama, Japan; ‡Clearview Cancer Institute, Huntsville, Alabama; §The Center for Cancer and Blood Disorders, Fort Worth, Texas; ║Essex Oncology of New Jersey, Belleville, New Jersey; ¶Saitama Cancer Center, Saitama, Japan; #Celgene Corporation, Summit, New Jersey; and **University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Disclosure: Dr. Hirsh is a consultant for Celgene Corporation. Dr. Hon received research funding from Celgene Corporation. Dr. Orsini is employed in a leadership role for Essex Oncology. Ms. Zhang was an employee of Celgene Corporation. Dr. Renschler is an employee in a leadership position of and owns stock in Celgene Corporation. Dr. Socinski is a consultant for and received research funding from Celgene Corporation. The remaining authors declare no conflict of interest. Address for correspondence: Vera Hirsh, MD, McGill University, 1650 Cedar Avenue, Montreal, Quebec H3A 1A1, Canada. E-mail: vera.hirsh@muhc. mcgill.ca Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0901-0083
the results of a per-treatment cycle physician assessment of peripheral neuropathy also favored nab-P/C over sb-P/C (p < 0.001). Conclusion: In this trial of patients receiving first-line treatment for advanced non–small-cell lung cancer, nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C. Key Words: nab-Paclitaxel, Solvent-based paclitaxel, Functional Assessment of Cancer Therapy-Taxane, Non–small-cell lung cancer, Peripheral neuropathy. (J Thorac Oncol. 2014;9: 83–90)
T
he goals of therapy for advanced non–small-cell lung cancer (NSCLC) are to prolong survival and manage symptoms associated with the disease.1 Because survival times for patients with advanced NSCLC are relatively short, symptom control is an important consideration.2 Treatment can affect a patient’s well-being through both symptom control and treatment-related toxicity.3 Therefore, treatments that can help limit tumor growth (achieve a tumor response)4 while limiting toxicity are of paramount importance in this population.3 Underscoring the value of symptom control to patients, an analysis of patient preference with respect to chemotherapy for advanced NSCLC found that 68% of those interviewed would accept chemotherapy if it would substantially reduce symptoms, even in the absence of a survival benefit.5 Worsening symptoms may decrease a patient’s independence, rendering him or her more dependent on caregivers, including family. A number of reports have revealed that many patients with terminal cancer are concerned about becoming a burden to loved ones at the end of life.6–8 This phenomenon, known as self-perceived burden, may be experienced at minimal to mild levels by 35% of patients and at moderate to extreme levels by another 28% of patients according to one study.6 This perception of being a burden to loved ones may affect a patient’s preference of treatment.8 Symptom management is an important component of care in advanced NSCLC because the majority of patients
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present with disease-related symptoms.2 Symptom control can be achieved with tumor response, but it can also be achieved in the absence of an objective response, possibly through tumor shrinkage that does not meet the criteria to be considered a partial response.2 The effect of tumor response on disease-related symptoms is an area of active research, with some but not all studies suggesting a link between tumor response and symptoms such as cough, dyspnea, chest pain, and systemic symptoms (fever, anorexia, and weight loss).9–11 Therefore, tumor shrinkage is an important consideration because it may relate to both the goals of treatment and the patient’s well-being. Platinum-based regimens are recommended therapy for advanced NSCLC in patients with good performance status (PS).1,12 Different platinum doublets offer similar overall response rates (ORRs) and overall survival values; therefore, the selection of the proper combination partner should be individually tailored by clinicians to their patients.12 Solvent-based paclitaxel (sb-paclitaxel) is among the recommended platinum combination partners.1,12 However, toxicities such as peripheral neuropathy, arthralgia, and myalgia are known taxane-associated side effects.3,13 nab-Paclitaxel was developed to improve the therapeutic index of paclitaxel therapy.14 Compared with sb-paclitaxel, nab-paclitaxel reaches a 10-fold higher peak concentration of free paclitaxel in patients, delivers 33% more drug to tumors in preclinical models, and crosses endothelial cells more efficiently.15,16 Furthermore, nab-paclitaxel has shown superior ORR and time to progression/progression-free survival and favorable safety versus sb-paclitaxel and docetaxel in trials of metastatic breast cancer (MBC).14,17 nab-Paclitaxel, either as monotherapy or in combination with carboplatin (nab-P/C) has demonstrated promising efficacy in NSCLC in a number of clinical trials.18–20 These findings were recently confirmed in a phase 3 trial in which nab-P/C was compared with sb-paclitaxel plus carboplatin (sb-P/C) as first-line treatment for patients with advanced NSCLC.21 The dose and schedule of nab-P/C was chosen based on the findings of a phase 2 dose-finding study,20 whereas the sb-P/C regimen was selected because it represents an established standard against which to compare nab-P/C.22,23 Compared with sb-P/C, nab-P/C produced a significantly higher ORR (33% versus 25%, respectively; p = 0.005) and a nonsignificant 1-month longer median overall survival versus sb-P/C (12.1 versus 11.2 months, respectively; p = 0.271).21 In addition, the safety profile revealed lower rates of physicianassessed grade 3 or higher sensory neuropathy, neutropenia, myalgia, and arthralgia for nab-P/C but lower rates of grade 3 or higher anemia and thrombocytopenia for sb-P/C. On the basis of these findings, the U.S. Food and Drug Administration approved nab-P/C for locally advanced or metastatic NSCLC as first-line treatment in patients who are not candidates for curative surgery or radiation therapy.24 The Functional Assessment of Cancer Therapy (FACT)-General questionnaire is a reliable and validated tool to measure symptoms and quality of life (QoL) from the perspective of a patient with cancer.25 The tool consists of subscales that measure physical well-being, social/family well-being, emotional well-being, functional well-being, and patient perception of his or her relationship with the physician.25 Subsequently, the developers of the FACT-General
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questionnaire created FACT-Taxane, a more specific tool to assess QoL in patients receiving taxanes.3 FACT-Taxane consists of both FACT-General and an added taxane subscale. The subscale has 16 items (Table 1), including an 11-item neurotoxicity subscale and five additional taxane-specific questions related to the effects of arthralgia, myalgia, and skin changes. The tool was found to be reliable and sensitive to changes in symptoms over time.3 In a study of patients with NSCLC receiving treatment with sb-P/C, the impact on QoL of lung cancer symptom improvement because of treatment equaled the impact of treatment-related toxicities on total QoL, as measured by the FACT-Taxane tool. However, with respect to patients’ global rating of QoL by using the single item “I am content with the quality of my life right now,” improvements in disease-related symptoms outweighed concerns about treatment-related toxicity.3 In the trial of nab-P/C versus sb-P/C described above, the taxane subscale of the FACT-Taxane questionnaire was selected as a methodical instrument to gauge patient perception of how treatment-related symptoms affected QoL.3,21 In addition to assessing sensory neuropathy during study treatment by established grading criteria, the investigators also evaluated the degree of sensory neuropathy on a visit-by-visit basis. This analysis explores patient- and physician-assessed symptoms related to treatment with nab-P/C versus sb-P/C in patients with advanced NSCLC who participated in the phase 3 study.
PATIENTS AND METHODS This international, multicenter, randomized phase 3 study in patients with advanced NSCLC compared the efficacy and safety of nab-P/C versus sb-P/C.21 Patients in the nab-P/C arm received nab-paclitaxel 100 mg/m2 on days 1, 8, and 15, administered as a 30-minute infusion, followed by TABLE 1. The 16-Item Taxane Subscale of FACT-Taxane (Adapted from the Study by Cella et al., 2003)3 Category Neurotoxicity component
Taxane component
Statement I have numbness or tingling in my hands I have numbness or tingling in my feet I feel discomfort in my hands I feel discomfort in my feet I have joint pain or muscle cramps I feel weak all over I have trouble hearing I get a ringing or buzzing in my ears I have trouble buttoning buttons I have trouble feeling the shape of small objects when they are in my hand I have trouble walking I feel bloated My hands are swollen My legs or feet are swollen I have pain in my fingertips I feel discomfort in my feet
FACT, Functional Assessment of Cancer Therapy.
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carboplatin area under the concentration curve = 6 mg*min/ mL (per Calvert formula)26 given on day 1 every 21 days. Patients in the sb-P/C arm received sb-paclitaxel 200 mg/m2, infused over 3 hours, plus carboplatin area under the concentration curve = 6 mg*min/mL, both given on day 1 every 21 days. Patients were randomized 1:1 to nab-P/C or sb-P/C and stratified by age (< 70 years versus ≥ 70 years), disease stage (IIIB versus IV), sex (male versus female), histology (squamous versus adenocarcinoma versus other), and geographic region (Canada/United States versus Russia/Ukraine versus Japan versus Australia). Six cycles of therapy were encouraged, and treatment beyond six cycles was permissible at the investigators’ discretion in the absence of progressive disease or unacceptable toxicity. Eligible adults had histologically or cytologically confirmed stage IIIB (with or without pleural effusion) or IV NSCLC, measurable by Response Evaluation Criteria In Solid Tumors version 1.0,4 an Eastern Cooperative Oncology Group PS of 0 to 1, and a life expectancy of more than 12 weeks. Patients were previously untreated for metastatic disease and received no radiotherapy within 4 weeks of enrollment. Prior adjuvant chemotherapy was permitted if it had been completed 12 months or more before study enrollment. Patients were excluded from the study if they had untreated or symptomatic brain metastases. This study was approved by the independent ethics committees of the participating medical institutions and was conducted in compliance with the World Medical Association Declaration of Helsinki and Good Clinical Practice and Guidelines of the International Conference on Harmonization.27 Written informed consent was obtained from all patients before study initiation. Physician-assessed toxicities in this trial were classified by both the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and by Medical Dictionary of Regulatory Activities (MedDRA) criteria. Patient-reported symptoms were assessed using the 16-item taxane subscale of the FACT-Taxane instrument (Table 1), which includes a neurotoxicity subscale comprising 11 questions and five more questions on additional taxane-related symptoms, such as myalgia, arthralgia, and skin changes.3 All 16 questions from the taxane subscale were completed at baseline and on day 1 of each treatment cycle. Patients gave each statement a score of 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit), or 4 (very much). Selected questions from the neurotoxicity and taxane components of the FACT-Taxane were grouped into predefined subscores for peripheral neuropathy, pain, hearing, and edema as defined in Table 2. Responses to all questions were analyzed in total, individually, and as the following groups: peripheral neuropathy, pain, hearing, and edema. Descriptive statistics were used to summarize patientassessed responses from the FACT-Taxane scale, including mean change from baseline at each cycle; differences between treatment arms were assessed using the two-sample t test by visit or repeated measurement across all visits. In all charts of FACT-Taxane data, the values for cycles 2 to 8 and final evaluation are mean changes from the baseline score.
Neuropathy and Taxane-Associated Symptoms
TABLE 2. FACT-Taxane Subscores Category Peripheral neuropathy
Pain Hearing Edema
Statement I have numbness or tingling in my hands I have numbness or tingling in my feet I have trouble buttoning buttons I have trouble feeling the shape of small objects when they are in my hands I have pain in my fingertips I feel discomfort in my hands I feel discomfort in my feet I have trouble hearing I get ringing or buzzing in my ears I feel bloated My hands are swollen My legs or feet are swollen
FACT, Functional Assessment of Cancer Therapy.
Physicians conducted a detailed analysis of sensory neuropathy by evaluating patients at every cycle and coding severity over the course of treatment using the five-grade NCI CTCAE version 3.0 scale: grade 1—asymptomatic, loss of deep tendon reflexes or paresthesia, including tingling but not interfering with function; grade 2—sensory alteration or paresthesia, including tingling and interfering with function but not interfering with activities of daily living; grade 3—sensory alteration or paresthesia interfering with activities of daily living; grade 4—disabling; and grade 5—death.
RESULTS Of the 1038 patients in the treated population, 1031 (99%) completed the FACT-Taxane questionnaire at baseline. Compliance with the questionnaire through eight cycles was also 99% (completed in 4278 of 4335 cycles). Baseline scores of all individual items, the total score of all 16 items, and each subscore were balanced between the treatment arms. There was a significant treatment effect favoring nab-P/C over sbP/C over the entire course of treatment for the total score of all 16 items (Fig. 1; p < 0.001) as well as for the 11-item neurotoxicity subscore (p < 0.001). Figure 2 shows the results of the FACT-Taxane peripheral neuropathy subscore through cycle 8 of treatment. Figure 2A reflects the composite results of the five peripheral neuropathy questions, whereas Figure 2B–F shows the graph for each individual question. The composite score and each individual question subscore revealed a lesser change over the course of treatment for the nab-P/C group versus the sbP/C group (p < 0.001 for all comparisons), suggesting less development of treatment-related symptoms with nab-P/C. Furthermore, the composite score revealed statistically significant differences from baseline to each of cycles 2 to 8 (p ≤ 0.002 for each). These values were consistent with the physician assessment of peripheral neuropathy by cycle (Fig. 3) and the number of patients who experienced at least one peripheral neuropathy adverse event of grade 3 or higher by MedDRA criteria (3% versus 12%; p < 0.001).21
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FIGURE 1. Composite change from baseline for the 16-item taxane subscale. Symptoms were reported prior to dosing on day 1 of each cycle. Note that larger bars represent greater deteriorations from baseline as perceived by patients. BL, baseline; nab-P/C, nab-paclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. aP value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
Of note, deterioration in the patient-reported peripheral neuropathy subscore at or after the development of grade 3 or higher peripheral neuropathy was substantially less for nabP/C versus sb-P/C (median change from baseline 4.5 versus 10). The median time to improvement to MedDRA grade 1 or lower peripheral neuropathy was shorter for nab-P/C versus sb-P/C (38 versus 104 days), although this difference was not statistically significant (p = 0.326). The composite scores for pain and the subscores for individual questions are shown in Figure 4. The change over the course of treatment for the composite score significantly favored the nab-P/C arm over the sb-P/C arm (p < 0.001). The changes over the course of treatment for each individual question also significantly favored nab-P/C versus sb-P/C (p < 0.001 for each). In addition, patient-reported deterioration in the pain subscore at or after the onset of grade 3 or higher peripheral neuropathy was less for nab-P/C versus sb-P/C (median change from baseline 1.0 versus 4.0). These patient-reported results were consistent with those from an earlier report of adverse event grading for grade 3 myalgia (< 1% for nab-P/C versus 2% for sb-P/C; p = 0.011) and arthralgia (0% for nab-P/C versus 2% for sb-P/C; p = 0.008).21 Figures 5 and 6 show the composite scores for the hearing and edema categories, respectively. The hearing subscore over the course of treatment favored nab-P/C versus sb-P/C (p = 0.002); however, the edema subscore change over the course of treatment did not differ significantly between nabP/C and sb-P/C (p = 0.437), suggesting that patient perception of edema was similar between the two groups.
DISCUSSION This is the largest study in NSCLC that evaluated the impact of taxane-related toxicity on QoL as reported by patients using the taxane subscore module of the FACT-Taxane instrument. The robustness of this analysis is underscored by the more
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than 99% completion rate of this QoL instrument by patients in the study at baseline, through treatment, and during follow-up. In addition to patients reporting the impact of sensory neuropathy on QoL, physicians graded sensory neuropathy during the same office visits. The results of patient and physician reports showed a striking similarity. By both FACT-Taxane and physician assessment, nab-P/C seemed superior to sb-P/C with respect to neurotoxic effects. Specifically, patients in the nabP/C arm noted less severe peripheral neuropathy, neuropathic pain in the hands and feet, and hearing loss. Patient-reported edema subscores seemed to be similar between the two treatment groups. Taken together, these findings demonstrated an advantage for nab-P/C with respect to patient-reported treatment-related symptoms in this trial of patients being treated for advanced NSCLC. Importantly, patient-reported assessment of neuropathy mirrored the physician-evaluated degree of neuropathy with respect to both the cumulative change over time and visit-by-visit differences between the treatment arms, further validating the FACT-Taxane tool. The patient-reported peripheral neuropathy data in this report are consistent with adverse event data collected separately and previously reported.21 Notably, the MedDRA assessment of neuropathy revealed that 3% of patients in the nab-P/C arm experienced a peripheral neuropathy event of grade 3 or higher versus 12% of patients in the sb-P/C arm (p < 0.001). Assessments of peripheral neuropathy by using NCI CTCAE criteria for nab-P/C and sb-P/C were also 3% and 12%, respectively (p < 0.001).21 In addition, the median time to improvement of peripheral neuropathy from MedDRA grade 3 to grade 1 or lower was 38 days for nab-P/C versus 104 days for sb-P/C. The consistent findings of three different methods for assessing peripheral neuropathy (adverse event data, physician assessment by cycle of treatment, and FACT-Taxane) confirm that nab-P/C resulted in a lower incidence of neuropathy-associated symptoms versus sb-P/C. In addition, the changes from baseline in the FACT-Taxane peripheral neuropathy and pain subscale scores were lower in the nab-P/C arm versus the sb-P/C arm at or after the onset of peripheral neuropathy of grade 3 or higher. The rate and severity of peripheral neuropathy are partly dependent on the maximum plasma concentration (Cmax) of the taxane administered as well as the schedule of administration and taxane used.17,20,28–31 A phase 3 MBC trial reported a higher rate of peripheral neuropathy for nab-P 260 mg/m2 versus sb-P 175 mg/m2, each administered on an every-3-week schedule (q3w; 10% versus 2%; p < 0.001).14 However, the time to improvement of grade 3 peripheral neuropathy by 1 grade or higher was 22 days for nab-P versus 79 days for sb-P.14,32 A pharmacokinetic study demonstrated that nab-P administered at 260 mg/m2 over 30 minutes resulted in an approximate fourfold higher Cmax of total paclitaxel and an approximate 10-fold higher Cmax of unbound paclitaxel compared with sb-P administered at 175 mg/m2 over 3 hours.15 In this trial, the infusion time was maintained at 30 minutes but the dose was reduced from 260 mg/m2 to 100 mg/m2 for the weekly schedule, which would have resulted in a substantially reduced Cmax and, possibly as a consequence, a lower rate of peripheral neuropathy in the nab-P/C arm of this trial versus the nab-P arm of the phase 3 MBC trial.
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A
B sb-P/C
nab-P/C
5 p < 0.001a
4 3 2 1
Cycle
BL
2
3
4
5
6
nab-P/C, n sb-P/C, n
512
482
414
378
309
262
162
128
494
519
471
406
373
310
279
165
139
493
Mean Baseline Score or Mean Change From Baseline to Day 1 of Each Cycle or Final Evaluation
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1.4
0.8 0.6 0.4 0.2
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BL
2
nab-P/C, n sb-P/C, n
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482 471
4
5
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414 406
378 373
309 309
262 280
162 165
128 139
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p < 0.001a
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512 519
482 471
413 404
377 371
308 310
260 278
162 165
127 139
494 493
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512 519
482 470
414 406
378 373
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0.8 sb-P/C
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0.7 0.6
p < 0.001a
0.5 0.4 0.3 0.2 0.1 Cycle
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0
494 493
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p < 0.001a
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Neuropathy and Taxane-Associated Symptoms
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FIGURE 2. Peripheral neuropathy subscore and individual statements. Symptoms were reported prior to dosing on day 1 of each cycle. A, composite peripheral neuropathy subscore, (B) subscore for the statement “I have numbness or tingling in my hands,” (C) subscore for the statement “I have numbness or tingling in my feet,” (D) subscore for the statement “I have trouble buttoning buttons,” (E) subscore for the statement “I have pain in my fingertips,” and (F) subscore for the statement “I have trouble feeling the shape of small objects when they are in my hands.” BL, baseline; nab-P/C, nab-paclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. a = *P value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
A previous phase 3 trial in advanced NSCLC reported a higher rate of grade 2/3 neuropathy in patients who received q3w versus weekly sb-P/C (18% versus 12%).22 However, the weekly regimen did not demonstrate superior efficacy in that trial, and q3w remains the standard schedule for sb-P/C.22,23 In addition, in the current trial, the cumulative paclitaxel dose
of nab-P/C was higher than that of sb-P/C (1325 mg/m2 with nab-P/C versus 1125 mg/m2 with sb-P/C), as was the median paclitaxel dose intensity (82 versus 65 mg/m2/week), suggesting that even though patients were able to receive more paclitaxel with nab-P/C, this did not result in more neuropathy.21 However, the median cumulative carboplatin dose (3140 versus
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Grade 3
on peripheral neuropathy or other components of the FACTTaxane questionnaire is difficult to estimate, especially as peripheral neuropathy and ototoxicity caused by carboplatin (unlike cisplatin) are known to be infrequent.33 Taxane use has been shown to be associated with a triad of pain related to sensory neuropathy, myalgia, and arthralgia.13,24,34 Results from the pain subscore derived from the FACT-Taxane survey in this trial revealed that patients receiving nab-P/C perceived less pain in the hands and feet compared with patients receiving sb-P/C. The FACT-Taxane tool does not directly assess the impact of myalgia and arthralgia on patient perception of QoL. We have previously reported significantly less grade 3 myalgia (< 1% for nab-P/C versus 2% for sb-P/C; p = 0.011) and arthralgia (0% for nab-P/C versus 2% for sb-P/C; p = 0.008) using the adverse event data from this study.21 Thus, nab-P/C has a favorable profile in all three of these areas of pain, which may be of great importance to patients. One of the more intriguing findings in this study was the effect of treatment on patient-reported hearing loss. Few reports have indicated taxane-related effects on hearing.35 The initial publication of this phase 3 trial did not list hearing loss as a common physician-assessed adverse event in either treatment arm.21 Similarly, the low raw FACT-Taxane hearing subscores for both arms of this trial indicated that difficulties with hearing were not a major concern. However, the difference in change from baseline between the nab-P/C and sb-P/C
P < .001
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nab-P/C, n 513 sb-P/C, n 523
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Physician Assessment of Peripheral Neuropathy by Grade at Day 1 of Each Cycle (%)
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FIGURE 3. Physician assessment of peripheral neuropathy by cycle. BL, baseline; nab-P/C, nab-paclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin. a At the final evaluation, 1 patient in the sb-P/C arm reported grade 4 peripheral neuropathy (none in the nab-P/C arm).
3315 mg) and median carboplatin dose intensity (166 versus 204 mg/week) were both lower for nab-P/C versus sb-P/C. The exact impact of this marginal difference in carboplatin dose
B
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FIGURE 4. Pain subscore and individual statements. Symptoms were reported prior to dosing on day 1 of each cycle. A, composite pain subscore. B, subscore for the statement “I feel discomfort in my hands.” C, subscore for the statement “I feel discomfort in my feet.” BL, baseline; nab-P/C, nab-paclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. aP value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
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Journal of Thoracic Oncology ® • Volume 9, Number 1, January 2014
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FIGURE 5. Composite hearing subscore. Symptoms were reported prior to dosing on day 1 of each cycle. BL, baseline; nab-P/C, nabpaclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. aP value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
arms was statistically significant (p = 0.002), suggesting that patients receiving sb-P/C reported more severe hearing loss during treatment versus those receiving nab-P/C. Future study would be required to explain this subtle but interesting finding. Taken together, the data from this analysis revealed a robust agreement between patient- and physician-assessed tolerability profiles for nab-P/C versus sb-P/C in patients with advanced NSCLC. The high rates of compliance with the questionnaire suggest that these results are indeed representative of the trial population. In addition to the favorable results for nab-P/C over sb-P/C with respect to treatment-related symptoms in this study, some patients may have derived symptom relief through the shrinkage of their tumors.2,21 Notably, a higher proportion of patients in the nab-P/C arm versus the sb-P/C arm achieved an objective response (33% versus 25%; p = 0.005).21 Taken together, these data suggest that for patients
Mean Baseline Score or Mean Change From Baseline to Day 1 of Each Cycle or Final Evaluation
1 0.8 0.6 0.5 0.4 0.3 0.2 0.1 0
ACKNOWLEDGMENTS
This study was funded by Celgene Corporation. The authors thank all participating sites and investigators for their support with the clinical study. Medical writing assistance was provided by John McGuire, PhD, MediTech Media, funded by Celgene Corporation. The authors were fully responsible for all content and editorial decisions for this manuscript. REFERENCES
p = 0.437a
0.7
who receive a taxane and a platinum for their first-line treatment of advanced NSCLC, nab-P/C is the preferred choice. Because the survival time of patients with advanced NSCLC is relatively short, patient perception of treatmentrelated symptoms becomes especially important.2 Treatment for advanced NSCLC is entering an age of personalized medicine dependent on tumor-specific biomarkers.12 However, many patients, especially those with squamous tumors, are given chemotherapy, often platinum-based doublets, because targeted agents are deemed inappropriate or have shown little benefit in particular patient populations.36 Because more lines of treatment are now available for advanced NSCLC,37 it is of utmost importance that treatment-related side effects are minimized, preserving patients’ QoL and PS, one of the most important criteria for receiving treatment.12 Neuropathy, myalgia, and arthralgia can severely decrease patients’ PS to the point that they can no longer take care of their own needs. Thus, nab-P/C represents a regimen for the first-line treatment of advanced NSCLC that has a favorable tolerability profile, potentially preserving PS and enabling patients in the era of personalized medicine to benefit from new agents either in combination with this regimen or as a sequential therapy. The population of elderly patients with NSCLC is growing, and tolerance of progressively more palliative treatments is becoming an important factor in treatment decision making. This is particularly relevant in light of the side effects of novel targeted agents, including possible drug interactions that cause unfavorable toxicities, such as worsening of peripheral neuropathy.
sb-P/C
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Neuropathy and Taxane-Associated Symptoms
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FIGURE 6. Composite edema subscore. Each timepoint represents day 1 of the corresponding cycle, prior to administration of treatment in that cycle. BL, baseline; nab-P/C, nabpaclitaxel + carboplatin; sb-P/C, solvent-based paclitaxel + carboplatin; SEM, standard error of the mean. a = *P value for treatment effect based on repeated measures over treatment period (cycle 2 through end of treatment).
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