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Originally published as JCO Early Release 10.1200/JCO.2006.08.6652 on April 30 2007 © 2007 American Society of Clinical Oncology. Neurotoxicity From Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: NSABP C-07
From the National Surgical Adjuvant Breast and Bowel Project Operations Office and Biostatistical Center; University of Pittsburgh Graduate School of Public Health, Department of Biostatistics, Pittsburgh; The Regional Cancer Center, Erie; and Allegheny General Hospital, Pittsburgh, PA; Department of Health Care and Epidemiology, University of British Columbia, Vancouver, BC, Canada; University of California, Los Angeles, Schools of Medicine and Public Health, and the Jonsson Comprehensive Cancer Center, Los Angeles, CA; Colorectal Cancer Coalition, Skaneateles, NY; Clinical Community Oncology Program, Columbus, OH; Atlanta Regional Community Clinical Oncology Program (CCOP), Atlanta, GA; St John's Mercy Medical Center, St Louis, MO; Upstate Carolina CCOP, Spartanburg, SC; Northwest CCOP, Tacoma, WA; Columbia River Oncology Program, Portland, OR; Colorado Cancer Research Program, Denver Veterans Medical Center, Denver, CO; and the Evanston Northwestern Healthcare, Evanston, IL Address reprint requests to Stephanie R. Land, PhD, NSABP Biostatistical Center, 201 N Craig St, Suite 350, Pittsburgh, PA 15213; e-mail: land{at}pitt.edu
Purpose: The randomized, multicenter, phase III protocol C-07 compared the efficacy of adjuvant bolus fluorouracil and leucovorin (FULV) versus FULV with oxaliplatin (FLOX) in stage II or III colon cancer. Definitive analysis revealed an increase in 4-year disease-free survival from 67.0% to 73.2% in favor of FLOX. This study compares neurotoxicity between the treatments. Patients and Methods: Neurotoxicity was recorded for all patients using standard adverse event reporting. Patients at select institutions completed a neurotoxicity questionnaire through 18 months of follow-up. Results: A total of 2,492 patients enrolled onto C-07 and 400 patients enrolled onto the patient-reported substudy. Mean patient-reported neurotoxicity was higher with oxaliplatin throughout the 18 months of study (P < .0001). During therapy, patients receiving oxaliplatin experienced significantly more hand/foot toxicity (eg, "quite a bit" of cold-induced hand/foot pain 26% FLOX v 2.6% FULV) and overall weakness (eg, moderate weakness in 27.4% FLOX v 16.2% FULV). At 18 months, hand neuropathy had diminished, but patients who received oxaliplatin experienced continued foot discomfort (eg, moderate foot numbness and tingling for 22.1% FLOX v 4.6% FULV). Observer-reported neurotoxicity was low grade and primarily neurosensory rather than neuromotor. Sixty-eight percent in the FLOX group v 8% in the FULV group had neurotoxicity at their first on-treatment assessment. Time to resolution was significantly longer for those receiving oxaliplatin, and continued beyond 2 years for more than 10% in the oxaliplatin group. Conclusion: Oxaliplatin causes significant neurotoxicity. It is experienced primarily in the hands during therapy and in the feet during follow-up. In a minority of patients the neurotoxicity is long lasting.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-07 was a randomized phase III clinical trial comparing the efficacy of fluorouracil plus leucovorin (FULV) with that of fluorouracil plus leucovorin and oxaliplatin (FLOX) among patients who had completed a potentially curative resection of a stage II or III carcinoma of the colon. At the time of protocol initiation, FULV was the standard of care. Oxaliplatin (a platinum derivative) was novel in the adjuvant setting, although it had demonstrated effectiveness in advanced disease. The definitive analysis revealed an increase in 4-year disease-free survival from 67.0% to 73.2% (hazard ratio, 0.80; P < .004) in favor of FLOX. The absolute survival at 4 years was 81.9% for FULV and 82.6% for FLOX.1 Oxaliplatin has been found to be tolerable, with the exception of dose-limiting neurotoxicity in some patients. At the time the C-07 protocol was developed, previous studies with oxaliplatin had demonstrated a cumulative, dose-related peripheral sensory neuropathy characterized by dysesthesia and/or distal paresthesia, which was dose limiting in some patients. In addition, acute neuropathy (oral-facial and peripheral), which in some cases was induced or exacerbated by exposure to cold, was observed.2-9 In a combined analysis of 682 patients from nine phase II to III studies using oxaliplatin, approximately 25% of patients withdrew from treatment early due to neurologic toxicity.10 However, although neurotoxicity had been a well-known adverse effect of oxaliplatin, investigations about the duration of neurotoxicity were limited, and we found no published studies presenting the patient's perspective. This study compares the C-07 treatments in terms of patient-reported and clinician-reported neurotoxicity. The patient-reported assessment provides easily understood information about the discomfort and functional limitations of the treatments. A goal of this report is to characterize the neurotoxicity associated with oxaliplatin to enable treatment providers and patients to make informed decisions and to anticipate the need for symptom management.
Patients Patients with operable (stage II to III) colon cancer were randomly assigned to either FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus LV 500 mg/m2 IV weekly for 6 weeks of each 8-week cycle for three cycles (FULV), or FULV with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). Patients with clinically significant peripheral neuropathy (National Cancer Institute [NCI] Common Toxicity Criteria version 2.015 [CTCv2.0] grade 2 or higher) were excluded. The first 400 patients from the NSABP centers designated as Clinical Community Oncology Programs were eligible for participation in the patient-reported outcomes (PROs) neurotoxicity substudy. Informed consent was obtained from all participants. The protocol and consent forms were approved by the National Institutes of Health and the institutional review boards of all participating institutions.
Assessment of Neurotoxicity Questionnaires were completed at office visits, or via phone or postal administration when necessary. The clinical staff was instructed to allow the patient to complete the questionnaires independently. Patients were expected to complete the questionnaires through 18 months unless they withdrew consent for C-07, died, or experienced a recurrence or second primary cancer. When a questionnaire was not completed for a given assessment, the clinical staff was to complete a missing-data form to indicate the reason for the missed assessment. Neurotoxicity was also assessed for all C-07 participants by the clinicians or their designees. The neurotoxicity adverse event form included relevant toxicities from the CTCv2.0 as well as items developed in collaboration with the manufacturer of oxaliplatin. The new items included a global measure of neurosensory toxicity, the NCI-Sanofi grade: 0, no symptoms; 1, paresthesias or dysesthesias of short duration that resolve and do not interfere with function; 2, paresthesias or dysesthesias interfering with function but not activities of daily living; 3, paresthesias or dysesthesias with pain or functional impairment that also interfere with activities of daily living; 4, persistent paresthesias or dysesthesias that are disabling or life threatening. A second new item captured pharyngolaryngeal dysesthesias. The neurotoxicity adverse event form was completed at baseline, at the end of each cycle of chemotherapy, and at 6, 9, and 12 months. After 12 months, continued reporting was only required until resolution of neurotoxicity according to the following criteria (NCI-Sanofi criteria): no neurosensory toxicity (using either the NCI-Sanofi or CTC grade) exceeding the grade reported before treatment, no neuromotor toxicity exceeding the pretreatment grade, and no episodes of pharyngolaryngeal dysesthesias. Oxaliplatin dose modifications were required by the protocol based on the NCI-Sanofi grade. Dose modification was required for grade 2 toxicities that persisted between cycles or any grade 3 toxicities. Grade 4 toxicities or persistent grade 3 toxicities required termination of oxaliplatin.
Statistical Methods
Patients and Assessments Between February 1, 2000, and November 15, 2002, 2,492 patients were enrolled onto the C-07 study. Patient characteristics by treatment group for the full C-07 population are reported elsewhere.1 Submission rates of neurotoxicity adverse event forms were high and comparable between treatment groups (eg, 89% to 90% at 12 months). Accrual to the PRO substudy was closed in July 2001, when it had enrolled the intended 400 patients. However, three participants did not complete the baseline questionnaire and two withdrew consent to participate in C-07 either before or during therapy. The analysis cohort for the PRO substudy therefore includes 395 patients (206 FULV, 189 FLOX). There was no significant imbalance by treatment arm, substudy participation, or patient characteristics (Table 1). Neurotoxicity questionnaire submission rates were acceptable (eg, 78% at 18 months), and although the rate of missing forms was somewhat higher in the FLOX arm, the difference was not significant (P = .08). Missing-data forms were submitted for all but three of the missed assessments. The reasons given were comparable across treatment arms (data not shown). In the FULV and FLOX groups, respectively, 74% and 63% of missed assessments were attributed to staff oversight or other reasons unrelated to the patient's condition or choice. Because of high compliance and ignorable missingness, we did not perform specialized analyses for missing data. A few missed assessments (11 assessments among FULV patients v 22 assessments among FLOX patients) were related to treatment discontinuation, although patients were expected to continue neurotoxicity assessments after discontinuation. In the FULV group, 77 patients (6.2%) discontinued therapy early due to toxicity. In the FLOX group, 276 (22.1%) discontinued therapy early due to toxicity; about half of those patients continued to receive FULV. The median dose of oxaliplatin received was 677 mg/m2 (interquartile range, 320 to 763 mg/m2).
Patient-Reported Neurotoxicity: Total Scores and Individual Items Mean NTX-12 scale values were worse in the oxaliplatin arm throughout the 18-month period of study (P < .0001) and remained worse at 18 months (P = .009; Fig 1). The percentages of patients who experienced a worsening that exceeded the MCID on the NTX-12 from baseline to 6 months was 17% in the FULV group v 40% in the FLOX group (P < .0001). At 18 months these percentages were 18% and 31% (P = .016), respectively.
During therapy, significantly more oxaliplatin patients experienced hand/foot neuropathy (with odds ratio [OR] for at least "somewhat" v lesser severity ranging from 4.0 to 17.6), and overall weakness (OR, 1.8). Surprisingly, significantly fewer patients in the oxaliplatin group reported trouble hearing during treatment (OR, 0.34; Table 2). At 18 months, hand neurotoxicity was reduced, but patients who received oxaliplatin experienced continued foot discomfort (OR, 4.2 for foot discomfort; OR, 5.0 for foot numbness/tingling). Secondary analyses including age and sex revealed that neurotoxicity was worse with FLOX than with FULV for every subgroup of patients, although there were sex differences in the rates (Appendix Table A1, online only).
To describe the patient-reported neurotoxicity further, we present three analyses of the NTX-12 items. First, in graphical analysis of the mean severity of individual items, differences were greatest in hand/foot pain with cold (Appendix Fig A1, online only) and hand numbness/tingling (Appendix Fig A2, online only). During therapy, the mean differences in treatment arms were roughly one unit, the same magnitude as a difference between "not at all" and "a little bit." Second, Table 3 lists the distribution of symptom severity by treatment group and time point. Among patients in the PRO substudy receiving oxaliplatin, the most common symptoms reported during treatment were cold-induced pain in the hands and feet (with severity "quite a bit" or "very much" among 26.0% FLOX v 2.6% FULV patients, among patients without the symptom at baseline) and hand numbness/tingling (19.5% FLOX v 1.3% FULV patients). By 6 months after the start of therapy, cold-induced hand/foot pain among oxaliplatin patients had diminished (7.8%), but hand numbness/tingling remained high (17.3%), and increases were seen in foot discomfort (10.0%) and foot numbness/tingling (16.7%). The same symptoms were quite severe for only 1% to 3% of FULV patients. At month 18, foot numbness/tingling remained high (13.9% FLOX v 1.5% FULV patients). Third, focusing on the 18-month assessment in terms of the worst symptom for each patient, 10.4% of patients in the FULV group had an increase of 3 to 4 points in at least one of the 12 items between baseline and 18 months, whereas 20.2% in the oxaliplatin group experienced a change of that magnitude. This is comparable to an increase from "not at all" to "quite a bit."
Observer-Reported Neurotoxicity: Grade Distributions and Time to Resolution Grade 3 to 4 observer-reported neurologic toxicities were rare (point prevalence < 5%; Table 4). At cycle 2, grade 2 to 4 neurosensory toxicities were reported for 13.1% of patients assigned to oxaliplatin. All other neurologic toxicities from the CTCv2.0 (eg, ataxia) were rare (fewer than 5% of patients at grade 3 or above).
At their first on-treatment assessment, 98 patients (8%) in the FULV group and 836 patients (68%) in the oxaliplatin group had neurotoxicity according to the NCI-Sanofi criteria. Among those patients, the median time from the start of treatment to resolution of neurotoxicity was 4.8 months for FULV v 9.0 months for FLOX (P < .0001; Fig 2). At 6 months, 36% of the FULV group versus 70% of the FLOX group had unresolved neurotoxicity. In the FLOX group, among those whose initial assessment indicated neurotoxicity, 10% of patients still had unresolved neurotoxicity at 27.2 months.
Some episodes of neurotoxicity may have been due to other medical conditions (eg, diabetes). One hundred three patients (8%) in the FULV arm and 112 patients (9%) in the FLOX arm were reported to have such conditions. All analyses were repeated without these patients, with no major differences in the results (data not shown).
This article provides the first review of the severity and persistence of neurotoxicity associated with oxaliplatin in NSABP C-07. As expected, greater neurotoxicity was experienced during therapy by patients receiving oxaliplatin, primarily numbness/tingling in the hands and feet, hand discomfort, cold-induced hand and foot pain, and general weakness. For some patients, oxaliplatin caused neurotoxicity that continued to be more severe than that in FULV patients for at least 18 months after the start of treatment. In these later months, neurotoxicity was primarily in the feet. Observer-reported neurotoxicity was almost exclusively neurosensory rather than neuromotor, and most reports were at grade 1 to 2: as reported elsewhere, only 0.7% of patients were ever reported to have had a grade 3 to 4 neurosensory toxicity in the FULV arm, versus 8.4% in the FLOX arm.1 Furthermore, only 8% in the FULV group versus 68% in the FLOX group had any neurotoxicity at their first on-treatment assessment (according to the NCI-Sanofi criteria). Of those patients, the time to resolution was significantly longer for oxaliplatin, in some cases continuing beyond 2 years. The peripheral sensory neuropathy observed in the FULV arm was unlikely to be attributable to FU and leucovorin.16-19 This does occur in the general elderly population for many different reasons, and the rates seen among the patients age 65 or older in the FULV arm were below those reported for the general population (data not shown).20 The differences in neurotoxicity between treatments were of clinical significance. We found that at both of the time points we tested (6 and 18 months), significantly more patients in the oxaliplatin arm had experienced an increase from baseline greater than the MCID (4 points) in the NTX-12. That definition of the MCID was based on a psychometric analysis of data from C-07, but a mean treatment group difference of the same magnitude was discussed in the C-07 protocol based on historical data. Future studies with this scale may validate this MCID. For individual items, we have addressed clinical significance by dichotomizing items so that the responses can be interpreted directly as a change from little or no severity to moderate or greater severity. The PROs in C-07 suggest higher levels of neurotoxicity than are indicated by clinical reporting, although the two measurements were significantly associated (as we reported previously).13 At cycle 2, merely 10% of patients had grade 2 and 3% had a grade 3 NCI-Sanofi neurosensory toxicity in the oxaliplatin group, but 26% of patients experienced cold-induced hand/foot pain "quite a bit" or "very much." One explanation might be timing: the PRO was assessed at week 4 of cycle 2 but the observer-reported form generally was completed at the end of each cycle, after the rest period. The difference might also relate to the distinction between acute toxicity of short duration and more chronic toxicity. In the observer-reported measure, toxicity of short duration not interfering with function was considered grade 1. The PRO instrument did not make this distinction, and we cannot presume that a short duration of toxicity would be rated as less severe than a chronic condition. It has also been observed in other studies that symptoms are reported at higher rates in PROs than in institutional reporting.21,22 Observer reports might reflect lower severity in part because dose-modification rules take effect when patients report severe neuropathy to the clinical staff, whereas bothersome symptoms reported only on a patient questionnaire could persist without requiring a dose reduction. Using standard adverse event reporting, several phase III trials have confirmed neurotoxicity as the major adverse effect of oxaliplatin (Appendix Table A2, online only).23-26 In a European trial in advanced colorectal cancer, 18% of patients assigned to an oxaliplatin-containing regimen had grade 3 neurosensory toxicity at some time during treatment.24 The same rate was observed in a North Central Cancer Treatment Group study in metastatic colorectal cancer.25 In the Multicenter International Study of Oxaliplatin/5-Fluorouracil, Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC), 12.4% of patients treated with oxaliplatin developed grade 3 paresthesia during therapy.26 The rates of grade 3 neurotoxicity in those studies are higher than the 8.4% incidence reported for patients in C-07, in part because in those studies the oxaliplatin regimen did not include the 2-week rest. Treatment also continued longer for many patients in the advanced setting. Results from previous trials regarding the reversibility of oxaliplatin-induced neurotoxicity have been inconsistent. In the European trial, with median potential follow-up to 27.7 months, grade 3 neurosensory toxicity was reversible in 74% of patients.24 In contrast, in the oxaliplatin arm of the MOSAIC study, 0.5% of patients had grade 3 neurosensory toxicity at 18 months.26 Based on the MOSAIC results, one review article concluded that neurotoxicity is completely reversible.27 However, as in C-07, lower grade neurotoxicity in MOSAIC continued for some patients throughout follow-up, with 40% continuing to have neurologic symptoms at 12 months. In recent years, some have drawn a distinction between acute and cumulative neuropathy.27-31 The former is attributed to peripheral sensory and motor nerve hyperexcitability, and often is related to exposure to cold, whereas the latter is dose related, persistent, and primarily sensory. These observations have been central to the development of agents to prevent and manage oxaliplatin-induced neuropathy. The present results together with the clinical findings from C-07 describe an agent that improves disease-free survival at the cost of toxicity, not only neurotoxicity but also diarrhea, dehydration, and vomiting.1 The neurotoxicity is long lasting in a minority of patients. The duration of neurotoxicity will be explored further in an ongoing NSABP study of long-term colorectal cancer survivors. The extent that neurotoxicity influences quality of life is unclear, given inconsistent conclusions in other studies.11,12,20,24 Perhaps for patients already undertaking a chemotherapy regimen, the toxicity of oxaliplatin will seem minor. The choice rests with the patient and physician; the present study will provide the information to inform that choice and to manage the sequelae of the chosen treatment.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: J. Philip Kuebler, Sanofi-aventis; Michael J. O'Connell, Sanofi-aventis Stock: N/A Honoraria: J. Philip Kuebler, Sanofi-aventis; Michael J. O'Connell, Sanofi-aventis; Norman Wolmark, Sanofi-aventis- Research Funds: Norman Wolmark, Sanofi-aventis Testimony: N/A Other: N/A
Conception and design: Jacek A. Kopec, Patricia A. Ganz, H. Samuel Wieand, Kate Murphy, Roy E. Smith, Norman Wolmark Administrative support: Eduardo R. Pajon Jr, Roy E. Smith, Joseph P. Costantino, Norman Wolmark Provision of study materials or patients: J. Philip Kuebler, Burton M. Needles, James D. Bearden III, Keith S. Lanier, Eduardo R. Pajon Jr Collection and assembly of data: Stephanie R. Land, H. Samuel Wieand, Linda H. Colangelo, Keith S. Lanier, Eduardo R. Pajon Jr, Joseph P. Costantino Data analysis and interpretation: Stephanie R. Land, Reena S. Cecchini, Patricia A. Ganz, H. Samuel Wieand, Linda H. Colangelo, J. Philip Kuebler, David Cella, Roy E. Smith, Michael J. O'Connell Manuscript writing: Stephanie R. Land, Patricia A. Ganz, H. Samuel Wieand, Kate Murphy, J. Philip Kuebler, Eduardo R. Pajon Jr, Michael J. O'Connell, Norman Wolmark Final approval of manuscript: Stephanie R. Land, Jacek A. Kopec, Reena S. Cecchini, Patricia A. Ganz, H. Samuel Wieand, Linda H. Colangelo, Kate Murphy, J. Philip Kuebler, Thomas E. Seay, Burton M. Needles, James D. Bearden III, Lauren K. Colman, Keith S. Lanier, Eduardo R. Pajon Jr, David Cella, Roy E. Smith, Michael J. O'Connell, Joseph P. Costantino, Norman Wolmark
We thank the courageous participants. We also thank Barbara C. Good, PhD, Director of Scientific Publications for the NSABP, Wendy L. Rea for editorial assistance, and Martha Duncan, RN, MSN, for technical advice. Dr Good, Ms Rea, and Ms Duncan are NSABP employees and were not compensated beyond their normal salaries for this work.
published online ahead of print at www.jco.org on April 30, 2007. Supported by Grants No. U10-CA-69951 and U10-CA-12027 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and Michael Smith Foundation for Health Research (J.A.K.). Trial Registry: ClinicalTrials.gov ID#: NCT00004931; url: http://clinicaltrial.gov/ct/shows/NCT00004931?order=1. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Kuebler JP, Wieand HS, O'Connell, et al: Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol 25:10.1200/JCO.2006.08.2974 2. Mathe G, Kidani Y, Triana K, et al: A phase I trial of trans-1-diaminocyclohexane oxalato-platinum (l-OHP). Biomed Pharmacother 40:372-376, 1986[Medline] 3. Caussanel JP, Levi F, Brienza S, et al: Phase I trial of 5-day continuous venous infusion of oxaliplatin at circadian rhythm-modulated rate compared with constant rate. J Natl Cancer Inst 82:1046-1050, 1990 4. Chevallier B: L-OHP-pilot study clinical results. Lausanne, Switzerland, Debiopharm Internal Report, 1992 5. Marty M: L-OHP-phase I study. Lausanne, Switzerland, Debiopharm Internal Report, 1992 6. Taguchi T: Oxaliplatin phase I study. Toyko, Japan, Asahi Internal Report, 1992 7. Armand J: Early clinical study of oxaliplatin in patients with malignant solid tumor. Lausanne, Switzerland, Debiopharm Internal Report, 1993 8. Becouarn Y, Ychou M, Ducreux M. Oxaliplatin (L-HOP) as first-line chemotherapy in metastatic colorectal cancer (MCRC) patients: Preliminary activity/toxicity report. Proc Am Soc Clin Oncol 16:229a, 1997 (abstr 804) 9. Diaz-Rubio E, Sastre J, Zaniboni A, et al: Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study. Ann Oncol 9:105-108, 1998 10. Wolmark N, Kuebler JP: NSABP Protocol C-07: A clinical trial comparing 5-fluorouracil (5-FU) plus leucovorin (LV) and oxaliplatin with 5-FU plus LV for the treatment of patients with stages II and III carcinoma of the colon. NSABP internal document. Pittsburgh, PA, NSABP 11. Kuroi K, Shimozuma K. Neurotoxicity of taxanes: Symptoms and quality of life assessment. Breast Cancer 11:92-99, 2004[Medline] 12. Cella D, Peterman A, Hudgens S, et al: Measuring the side effects of taxane therapy in oncology: The functional assessment of cancer therapy-taxane (FACT-taxane). Cancer 98:822-831, 2003[CrossRef][Medline] 13. Kopec JA, Land SR, Cecchini RS, et al: Validation of a self-reported neurotoxicity scale in patients with operable colon cancer receiving oxaliplatin. J Support Oncol 4:W1-W8, 2006 14. Cella D: Manual for the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: Version 4. Evanston, IL, Evanston Northwestern Healthcare and Northwestern University, 1997 15. National Cancer Institute: NCI Cancer Therapy Evaluation Program: Common Toxicity Criteria, Version 2.0. http://ctep.cancer.gov/reporting/ctc.html 16. Saif MW, Hashmi S, Mattison L, et al: Peripheral neuropathy exacerbation associated with topical 5-fluorouracil. Anticancer Drugs 17:1095-1098, 2006[CrossRef][Medline] 17. Saif MW, Wilson RH, Harold N, et al: Peripheral neuropathy associated with weekly oral 5-fluorouracil, leucovorin and eniluracil. Anticancer Drugs 12:525-531, 2001[CrossRef][Medline] 18. Stein ME, Drumea K, Yarnitsky D, et al: A rare event of 5-fluorouracil-associated peripheral neuropathy: A report of two patients. Am J Clin Oncol 21:248-249, 1998[CrossRef][Medline] 19. van Laarhoven HW, Verstappen CC, Beex LV, et al: 5-FU-induced peripheral neuropathy: A rare complication of a well-known drug. Anticancer Res 23:647-648, 2003[Medline] 20. Mold JW, Vesely SK, Keyl BA, et al: The prevalence, predictors, and consequences of peripheral sensory neuropathy in older patients. J Am Board Fam Pract 17:309-318, 2004[Medline] 21. Goldberg RM, Sargent DJ, Morton RF, et al: Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: A North American Intergroup Trial. J Clin Oncol 24:3347-3353, 2006 22. Land SR, Kopec JA, Yothers G, et al: Health-related quality of life in axillary node-negative, estrogen receptor-negative breast cancer patients undergoing AC versus CMF chemotherapy: Findings from the National Surgical Adjuvant Breast and Bowel Project B-23. Breast Cancer Res Treat 86:153-164, 2004[CrossRef][Medline] 23. Jensen K, Bonde Jensen A, Grau C: The relationship between observer-based toxicity scoring and patient assessed symptom severity after treatment for head and neck cancer: A correlative cross sectional study of the DAHANCA toxicity scoring system and the EORTC quality of life questionnaires. Radiother Oncol 78:298-305, 2006[CrossRef][Medline] 24. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 25. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 26. Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004 27. Grothey A: Oxaliplatin-safety profile: Neurotoxicity. Semin Oncol 30:5-13, 2003 (4 suppl 15)[Medline] 28. Leonard GD, Wright MA, Quinn MG, et al: Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer. BMC Cancer 5:116, 2005[CrossRef][Medline] 29. Gamelin E, Gamelin L, Bossi L, et al: Clinical aspects and molecular basis of oxaliplatin neurotoxicity: Current management and development of preventive measures. Semin Oncol 29:21-33, 2002 (5 suppl 15)[Medline] 30. Wilson RH, Lehky T, Thomas RR, et al: Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 20:1767-1774, 2002 31. Lehky TJ, Leonard GD, Wilson RH, et al: Oxaliplatin-induced neurotoxicity: Acute hyperexcitability and chronic neuropathy. Muscle Nerve 29:387-392, 2004[CrossRef][Medline] Submitted August 25, 2006; accepted January 31, 2007. Related Editorial
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests and two-sample t tests, characteristics of PRO substudy participants were compared with contemporaneously enrolled C-07 patients not in the substudy. Form submission rates were compared across treatments with repeated-measures logistic regression. Two analyses compared mean NTX-12 scores between treatment arms: a mixed-effects longitudinal analysis and a two-sample t test using scores at 18 months (change from baseline). NTX-12 item responses were dichotomized (severity at least "somewhat" v lesser severity) and analyzed with logistic regression during treatment and at 18 months. All analyses of NTX-12 scores and items controlled for baseline symptoms. Kaplan-Meier and log-rank methods were used to compare the time to resolution of neurotoxicity. Analyses were performed with SAS version 9.1 (SAS Institute, Cary, NC). 
