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North Central Cancer Treatment Group/Alliance trial N08CA—the use of glutathione for prevention of paclitaxel/carboplatin-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled study
Alexis D. Leal MD,
Department of Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota
Additional participating institutions include: Siouxland Hematology-Oncology Associates, Sioux City, Iowa (Donald Wender, MD); Medical College of Georgia, Augusta, Ga (Anand P. Jillella, MD); Colorado Cancer Research Program, Denver, Colo (Eduardo R. Pajon, Jr, MD); Mayo Clinic Arizona, Scottsdale, Ariz (Michele Y. Halyard, MD); Medcenter One Health Systems, Bismarck, ND (Keren Sturtz, MD); Carle Cancer Center Community Clinical Oncology Program (CCOP), Urbana, Ill (Kendrith M. Rowland, Jr, MD); Essentia Duluth CCOP, Duluth, Minn (Daniel A. Nikcevich, MD); Metro-Minnesota CCOP, St. Louis Park, Minn (Daniel M. Anderson, MD); Missouri Valley Cancer Consortium, Omaha, Neb (Gamini S. Soori, MD); St. Vincent Regional Cancer Center CCOP, Green Bay, Wis (Anthony J. Jaslowski, MD); Hematology & Oncology of Dayton, Inc., Dayton, Ohio (Howard M. Gross, MD); Wichita CCOP, Wichita, Kan (Shaker R. Dakhil, MD); Edward Comprehensive Cancer Center, Huntington, WVa (Maria Rosalia B. Tri Tirona, MD); Ochsner CCOP, New Orleans, La (Jyotsna Fuloria, MD); Sioux Community Cancer Consortium, Sioux Falls, SD (Miroslaw Mazurczak, MD); Virginia Mason CCOP, Seattle, Wash (Craig R. Nichols, MD); Hawaii Minority-Based CCOP, Honolulu, Hawaii (Jeffrey L. Berenberg, MD); Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa (Deborah Weil Wilbur, MD); and Geisinger Clinic and Medical Center CCOP, Danville, Pa (Maged Khalil, MD).
Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of taxane and platinum-based chemotherapy. Several studies have supported the potential benefit of glutathione for the prevention of platinum-induced CIPN. The current trial was designed to determine whether glutathione would prevent CIPN as a result of carboplatin/paclitaxel therapy.
In total, 185 patients who received treatment with paclitaxel and carboplatin were accrued between December 4, 2009 and December 19, 2011. Patients were randomized to receive either placebo (n = 91) or 1.5 g/m2 glutathione (n = 94) over 15 minutes immediately before chemotherapy. CIPN was assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life (EORTC-QLQ) 20-item, CIPN-specific (CIPN20) sensory subscale and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
There were no statistically significant differences between the 2 study arms with regard to: 1) peripheral neurotoxicity, as assessed using both the EORTC-QLQ-CIPN20 (P = .21) and the CTCAE scales (P = .449 for grade ≥2 neurotoxicity; P = .039 for time to development of grade ≥2 neuropathy, in favor of the placebo); 2) the degree of paclitaxel acute pain syndrome (P = .30 for patients who received paclitaxel every 3-4 weeks and P = .002, in favor of the placebo, for patients who received weekly paclitaxel); 3) the time to disease progression (P = .63); or 4) apparent toxicities. Subgroup analyses did not reveal any evidence of benefit in any particular subgroup.
Chemotherapy-induced peripheral neuropathy (CIPN) is a significant chemotherapy side effect that manifests as numbness, tingling, and/or pain, generally beginning in the hands and/or feet with proximal progression in a “stocking-and-glove” manner.[1, 2] It is common with platinum-based agents (eg, cisplatin, oxaliplatin, and carboplatin [CBDCA]), vinca alkaloids, taxanes, and other agents, with an estimated incidence of 30% to 40%.[2-6] CIPN can significantly impact patient quality of life; it may lead to dose reductions, dose delays, and/or early termination of chemotherapy. Because there are limited options available to effectively treat CIPN once it is established, efforts have been made to study means to prevent the development of CIPN.
Glutathione is a naturally occurring compound consisting of 3 amino acids: glutamic acid, cysteine, and glycine; it is an important scavenger molecule that participates in many detoxification reactions to protect the body from intracellular oxidants such as free radicals and reactive oxygen species. It is believed that platinum-induced neurotoxicity is secondary to the accumulation of platinum within the dorsal root ganglion.[7, 8] Glutathione is a nontoxic agent that has been shown to reduce the accumulation of platinum within the dorsal root ganglion, supporting the possibility that this may provide an underlying mechanism to prevent neurotoxicity.
Multiple previous studies have investigated the efficacy of glutathione for the prevention of CIPN. One small, placebo-controlled, randomized trial involving 33 patients reported that the regimen was safe, although there were minimal changes in sensory neuropathy. Another placebo-controlled, randomized trial involving 33 patients with relapsed ovarian cancer reported that higher cisplatin doses could be administered with glutathione. Cascinu et al performed a double-blind, placebo-controlled, randomized trial evaluating the ability of glutathione to prevent CIPN in a cohort of 50 patients with gastric cancer who were receiving a cisplatin-based regimen and reported a decreased incidence of neuropathy in the glutathione arm. Cascinu et al performed a second small (n = 52), randomized, double-blind, placebo-controlled trial to evaluate the efficacy of glutathione for the prevention of oxaliplatin-induced peripheral neuropathy in a cohort of patients with colorectal cancer; that trial also produced results that appeared to be promising. Similar findings were observed by Milla et al (n = 27) in patients who were receiving combined oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX4). Smyth et al conducted a randomized, double-blind, placebo-controlled study in 151 patients who were receiving cisplatin and reported numerically reduced neurotoxicity among those who received glutathione (P = .22). Lin et al reported a small trial in 14 patients who were receiving adjuvant FOLFOX and were randomized to receive either 1200 mg of oral N-acetylcysteine, a glutathione precursor, or placebo; and a reduced incidence of oxaliplatin-induced neuropathy was observed among those who received N-acetylcysteine. Further evidence to support the role of glutathione in the reduction of neurotoxicity was reported by Periera et al, who observed that neuronal glutamate toxicity was secondary to the inhibition of cysteine uptake and, thus, depletion of glutathione stores and resulting oxidative stress/damage. Pursuant to this extensive body of preliminary data, the current study was developed to evaluate the efficacy of glutathione for preventing CIPN in a cohort of patients who were receiving paclitaxel/CBDCA chemotherapy.
MATERIALS AND METHODS
Patients who were considered for this trial were adults scheduled to receive paclitaxel at doses from 150 to 200 mg/m2 and CBDCA at an area under the receiver operating curve (AUC) from 5 to 7 every 21 or 28 days for at least 12 weeks. Alternatively, paclitaxel could be prescribed at 80 mg/m2 weekly for at least 12 weeks with the same CBDCA dose and schedule. Patients had to have an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2 and a life expectancy of at least 6 months. Baseline laboratory values (including a white blood cell count ≥3.4 × 109/L, an absolute neutrophil count ≥1500/μL, platelets ≥100 × 109/L, hemoglobin ≥10.0 g/dL, and creatinine ≤1.5 times the upper normal limit) were required. Each participant signed an institutional review board-approved, protocol-specific informed consent in accordance with US federal and institutional guidelines.
Patients were excluded from study participation for 1) a pre-existing history of peripheral neuropathy greater than grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.0) from any cause (chemotherapy, diabetes, alcohol, toxin, hereditary, etc); 2) other medical conditions that would make study participation unreasonably hazardous; 3) prior receipt of paclitaxel and/or CBDCA chemotherapy treatment; or 4) concurrent use of any agents to try to prevent or treat neuropathy, including gabapentin, glutamine, vitamin B6, and vitamin E.
At study baseline and before each cycle of chemotherapy, patients were required to undergo a history and physical examination with laboratory evaluation (including a complete blood count and creatinine, aspartate aminotransferase, and bilirubin levels). Procedures for measuring CIPN were performed at baseline and 1 week after each dose of chemotherapy. The European Organization for Research and Treatment of Cancer Quality-of-Life (EORTC-QLQ) CIPN20, which was used to measure the primary endpoint in this clinical trial, is a 20-item, CIPN-specific, patient-reported outcome questionnaire that includes 3 subscales to assess sensory, motor, and autonomic symptoms and functioning, with each item measured on a scale from 1 (not at all) to 4 (very much). This questionnaire can be completed in 5 minutes or less and has been well received in previous clinical trials. In addition, NCI CTCAE version 4.0 was used to quantify the chronic neurotoxicity associated with chemotherapy using standardized questions regarding neurotoxic symptoms and examples of answers (Table 1) to allow a more accurate classification of patient symptoms as grade 1, 2, or 3. Symptoms of paclitaxel-associated acute pain syndrome were measured by asking patients to keep a daily symptom log on days 2 through 7 after each paclitaxel dose with a tool used to define this syndrome.[18, 19]
Table 1. Neurotoxicity Evaluation
NCI-CTCAE v4.0: Sample Answers for Each Toxicity Grade
Grade 1: Mild Symptoms
Grade 2: Moderate Symptoms Limiting Instrumental Activities of Daily Living
Grade 3: Severe Symptoms Limiting Self-Care Activities of Daily Living
Abbreviations: NCI-CTCAE v4.0, National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
Do you have problems tying your shoelaces, buttoning your shirts, fastening buckles, or pulling up zippers?
“No, I might feel some tingling in my hands, but I have no problems tying laces, buttoning shirts, fastening buckles, or pulling up zippers”
“It is a bit harder than before, but I can still tie laces, button shirts, fasten buckles, or pull up zippers”
“I have severe difficulties tying shoe laces, buttoning shirts, fastening buckles, or pulling up zippers” or “I cannot tie laces, button shirts, fasten buckles, or pull up zippers anymore”
Do you have problems writing?
“No, I might feel some tingling in my hands, but I have no problems writing”
“It is a bit harder than before, but I can still write”
“I have severe difficulties writing” or “I cannot write anymore”
Do you have problems putting on your jewelry or your watch?
“No, I might feel some tingling in my hands, but I have no problems putting on my jewelry or my watch”
“It is a bit harder than before, but I can still put on my jewelry or my watch”
“I have severe difficulties putting on my jewelry or my watch” or “I cannot put on my jewelry or my watch anymore”
Do you have problems walking?
“No, I might feel some tingling in my feet, but I have no problems walking”
“It is a bit harder than before, but I can still walk”
“I have severe difficulties walking” or “I cannot walk anymore”
Functional Assessment of Cancer Therapy for Patients with Ovarian Cancer (FACT-O) assessments were obtained at baseline and 1 week after each dose of chemotherapy. The FACT-O is a questionnaire used to assess quality of life in patients, with a particular emphasis on patients with ovarian cancer.
Patients received glutathione 1.5g/m2 or placebo (100 mL of 0.9% NaCl) intravenously over 15 minutes immediately before chemotherapy. Ideally, patients were to begin glutathione before their first dose of this chemotherapy, but they were required to begin before their second dose of chemotherapy. Glutathione was obtained from Biomedica Foscarna (Ferentino, Italy), a company that makes the product that was used in the positive studies conducted by Cascinu et al.[12, 13] It was reconstituted from glutathione sodium salt (equivalent to 600 mg glutathione) with sterile water.
In the event that a patient developed a CTCAE neurotoxicity grade ≥3, paclitaxel was held until the patient recovered to a CTCAE toxicity grade ≤2, then treatment was resumed at a 10% dose reduction. Modification or discontinuation of CBDCA because of neurotoxicity was at the discretion of the clinician. If CBDCA was discontinued but paclitaxel was continued, then the patient continued glutathione/placebo therapy. If a patient developed any clinically significant adverse event (AE) attributed to glutathione/placebo, then the glutathione/placebo was stopped. In the event that glutathione/placebo was stopped for an AE, the patient continued to be followed according to protocol criteria. If the patient required additional chemotherapeutic agents because of chemotherapy toxicity and/or disease progression, then the patient was taken off study treatment.
For this clinical trial, a single-stage, parallel group design was used. The dynamic allocation procedure to balance the marginal distributions of baseline neuropathy, debulked status, and cancer type was adopted for randomization.
The primary endpoint was sensory chemotherapy-induced peripheral neuropathy as measured repeatedly by the sensory subscale of the EORTC QLQ-CIPN20 during the first 6 cycles of chemotherapy. The EORTC QLQ-CIPN20 sensory subscale score was computed by using a standard scoring algorithm and then converting scores to a scale from 0 to 100, in which higher scores indicated less symptoms and better quality of life. A repeated-measures model was used to compare the primary endpoint between the glutathione and placebo arms for the primary statistical analysis. Descriptive statistics—such as mean (standard deviation), median (range), and frequency (percentage)—were used to summarize all clinical data including the AE profile. Two-sample t tests and Wilcoxon rank-sum tests were used to compare continuous secondary endpoints, and Kaplan-Meier[23, 24] methodology and the log-rank test were adopted for time-to-event secondary endpoints.
On the basis of a 2-sided test of the time-averaged QLQ-CIPN20 sensory subscale scores with an assumption of moderate correlation (rho = 0.5), we calculated that a sample size of 154 patients (77 patients per arm) would be required to provide 90% power to detect a difference of 6 points in the QLQ-CIPN20 sensory subscale score (standard deviation = 15 points) between the glutathione and placebo arms. This sample size was further inflated by 20% to account for patient ineligibility, cancellation, or major violations.
This trial was monitored at least twice annually by a Data and Safety Monitoring Board, which was composed of individuals from within and outside the Alliance for Clinical Trials in Oncology. Data collection and statistical analyses were conducted by the Alliance Statistics and Data Center. Data quality was ensured through a review of data by the Alliance Statistics and Data Center and by the study chairperson, according to Alliance policies. All analyses were based on the study database, which was frozen on January 22, 2013.
This study accrued 195 patients between December 4, 2009 and December 19, 2011 from over 50 individual sites. Baseline patient characteristics, as detailed in Table 2, were similar in the 2 treatment groups. Patient study flow is illustrated in Figure 1.
Table 2. Patient Demographics and Clinical Characteristics
Data on patient-reported acute pain syndrome, which has been described as primarily a manifestation of acute paclitaxel neuropathy[18, 19] but commonly has been labeled as paclitaxel-induced arthralgia/myalgia, are illustrated in Figure 2. The figure illustrates that, for 7 days after each chemotherapy dose, there was no significant advantage for glutathione between the 2 study arms (P = .30 for the every-3-week subset vs P = .002 for the weekly subset, in favor of the placebo arm).
Cumulative peripheral neurotoxicity
The data presented regarding peripheral neuropathy include the patients who received paclitaxel weekly and those who received it every 3 weeks, because the data were quite similar in these 2 subsets. Peripheral neuropathy data for the 2 study arms, as scored using the QLQ-CIPN20 sensory neuropathy scale (primary endpoint) (Fig. 3), illustrate that there were no statistically significant differences in the AUC between the 2 study arms (P = .21). The median follow-up for these patients was 326 days.
In addition, no significant benefits for glutathione were observed when neurotoxicity was assessed by physicians using the CTCAE scale for determining grade ≥2 neurotoxicity (P = .449) or the time to the development of grade ≥2 neurotoxicity (P = .039, in favor of the placebo arm) (Table 3, Fig. 4). FACT-O data evaluating changes from baseline values did not reveal any substantial difference between the 2 study arms.
Table 3. Percentage of Patients With Grade ≥2 and Grade ≥3 Paclitaxel/Carboplatin-Induced Peripheral Neuropathy According to National Cancer Institute Common Terminology Criteria for Adverse Events
There were no significant differences between the 2 study arms with regard to the time to disease progression in the gynecologic patients according to carbohydrate antigen 125 (CA 125)-determined disease progression, defined as a CA 125 elevation >2 times the upper limit of normal on 2 occasions, separated by at least 1 week, when the level had normalized during therapy or upon completion of therapy.
Evaluation of Glutathione Toxicity
There were no statistically significant or clinically apparent differences in toxicity between the 2 study arms with regard to multiple evaluated toxicities (including fatigue, nausea, vomiting, diarrhea, rash, anaphylaxis, anemia, and leukopenia).
Subgroup analyses by age, sex, tumor type, and specific paclitaxel regimens revealed no compelling evidence of benefit in any subgroup.
The negative findings from the current trial contrast with the positive pilot findings[10-17] that led to its development. Of the data available to investigate the efficacy of glutathione as a CIPN-preventative agent, most studies were conducted in patients who were receiving either oxaliplatin-based or cisplatin-based therapy. In comparing the neurotoxicity of the agents involved in the current trial, CBDCA is the least neurotoxic of the platinum agents and is less neurotoxic than paclitaxel. Although the current results support the finding that glutathione is not an effective agent in the prevention of taxane-induced CIPN when given in combination with CBDCA, these results may not be applicable for cisplatin-induced or oxaliplatin-induced neurotoxicity.
A recently published study by Smith et al supports the view that therapies for chemotherapy-induced neuropathy may be different for different chemotherapy agents. Their report included data from a randomized, double-blind, placebo-controlled, crossover trial that investigated the efficacy of duloxetine for the treatment of established CIPN in a cohort of patients with either taxane-induced or oxaliplatin-induced CIPN. Those authors observed a significant decrease in patient-reported average pain among those who received duloxetine compared with those who received placebo. However, in a subgroup analysis, it appeared that duloxetine was efficacious in patients with oxaliplatin-induced CIPN but not in those with taxane-induced CIPN. This may explain the differences between our current findings and the findings reported previously in other pilot trials that examined oxaliplatin-based or cisplatin-based therapies.
Despite substantial efforts, currently, there are no recommended agents for preventing chemotherapy-induced neuropathy. A recent large trial illustrated that intravenous calcium/magnesium was not helpful for oxaliplatin-induced neuropathy despite substantial previous enthusiasm for this approach. Similarly, despite pilot reports suggesting the utility of vitamin E, a larger, placebo-controlled, double-blind, randomized trial was not able to substantiate a benefit. Acetyl-L-carnitine, despite preliminary reports and supporting animal tumor data, actually appeared to worsen CIPN in patients who were receiving paclitaxel-based therapy. Two reasonably sized, placebo-controlled, double-blinded clinical trials demonstrated no benefit for an adrenocorticotropic hormone derivative[30, 31] despite 4 smaller pilot trials that suggested a benefit.[32-35]
Although this series of negative trials is disappointing, so is the substantial neuropathy caused by commonly used neurotoxic chemotherapy agents. This calls for ongoing scientific methods to identify ways of using these agents for their antitumor activity while preventing unwanted neuropathy.
Along this line, we are excited about the potential utility of minocycline[36-53] and selective serotonin norepinephrine reuptake inhibitors, such as venlafaxine and duloxetine. Efforts are ongoing to address the potential utility of these agents. In addition, work is being done to address the role of genetic factors as a means of identifying which patients are at increased risk for developing CIPN.
In conclusion, the results from this study do not support the use of glutathione for the prevention of taxane-induced CIPN. There was no suggestion of glutathione-associated toxicity or interference with antitumor activity. Further inquiries into the efficacy of this drug in patients who are receiving oxaliplatin-based or cisplatin-based therapy would be of interest.
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group/Alliance and Mayo Clinic and was supported in part by Public Health Service grants CA-25,224, CA-37,404, CA-63,848, CA-35,090, CA-35,431, CA-63,849, CA-35,272, CA-35,195, CA-35,103, CA-35,267, CA-35,269, CA-63,844, CA-52,352, and CA-35,448. The study was also supported, in part, by grants from the National Cancer Institute (CA31946) to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, Md, Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, PhD; CA33601). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.