Long-term neurotoxicity effects of oxaliplatin added to fluorouracil and leucovorin as adjuvant therapy for colon cancer: Results from National Surgical Adjuvant Breast and Bowel Project trials C-07 and LTS-01
Neurotoxicity from adjuvant treatment with oxaliplatin has been studied in patients with colorectal carcinoma in short-term studies, but, to the authors' knowledge, the current article is the first long-term assessment which reports the National Surgical Adjuvant Breast and Bowel Project (NSABP) investigation of whether excess neurotoxicity persists beyond 4 years.
As part of a colorectal cancer long-term survivor study (LTS-01), long-term neurotoxicity was assessed in 353 patients on NSABP Protocol C-07 (cross-sectional sample). Ninety-two of these patients from LTS-01 also had longitudinal data and were reassessed 5 to 8 years (median, 7 years) after random assignment (longitudinal sample). Contingency tables compared cohorts, a mixed model compared neurotoxicity between treatments over time, and a Wilcoxon rank-sum test compared neurotoxicity between treatments (cross-sectional sample).
In the cross-sectional sample, the increase in mean total neurotoxicity scores of 1.8 with oxaliplatin was statistically significant (P = .005), but not clinically significant (a minimally important difference of 4 was reported at the long-term assessment). Patients who received oxaliplatin had increased odds of numbness and tingling in hands (odds ratio, 2.00; P = .015) and feet (odds ratio, 2.78; P < .001) versus patients who did not receive oxaliplatin. The magnitude of the oxaliplatin effect varied with time (P < .001) in the longitudinal sample, such that the oxaliplatin-treated group did not have significantly greater total neurotoxicity scores by 7 years.
Although colorectal cancer (CRC) rates have decreased in the past 2 decades because of increased screening, CRC remains the third leading cause of cancer deaths among men and women.1 Surgery is the mainstay treatment for stage II and III colon cancer, although it has been demonstrated that the addition of adjuvant chemotherapy improves disease-free and overall survival.2-12 Because of the high incidence of CRC and improvements in its treatment, 10% of the estimated 11.7 million individuals living with cancer in the United States in 2007, were survivors of CRC.13 Almost half (4.7 million) of all cancer survivors were diagnosed at least 10 years earlier, requiring assessments of the long-term effects of cancer treatment. To address this need, the National Surgical Adjuvant Breast and Bowel Project (NSABP) designed a long-term survivorship study (LTS-01) in 2006 of CRC survivors from 5 completed NSABP trials (Protocols C-05, C-06, C-07, R-02, and R-03) to assess quality of life and late toxicity from adjuvant treatment >4 years after random assignment to the parent trial.
One of the specific objectives of this long-term follow-up study was to compare neurotoxicity between treatment groups from the C-07 trial. C-07 was a randomized, multicenter, phase III trial with the primary objective of comparing the efficacy of fluorouracil plus leucovorin (FULV) versus the same regimen plus oxaliplatin (FLOX) in prolonging disease-free survival for patients with stage II or III colon cancer. Initial results with a 4-year median follow-up reported an increase in disease-free survival in favor of FLOX (hazard ratio [HR], 0.80; P < .004).11 Updated results with an 8-year median follow-up further support the benefit of oxaliplatin, with a reported increase in disease-free survival in favor of FLOX (HR, 0.82; P = .002), and overall survival had a nonsignificant trend toward improved outcomes with FLOX (HR, 0.88; P = .08).14
Although oxaliplatin has been linked with improved disease-free survival, it has also been associated with important acute and chronic toxicities and, thus, the need for long-term neurotoxicity assessment. Oxaliplatin has been identified as safe with the exception of dose-limiting neurotoxicity characterized by peripheral sensory neuropathy, with dysesthesia and/or distal paresthesia often triggered or exacerbated by cold. Because of anticipated peripheral sensory neuropathy, the NSABP monitored self-reported neurotoxicity outcomes in a sample of C-07 patients at a long-term endpoint in the LTS-01 study. A subset of these LTS-01 patients also had longitudinal neurotoxicity data. To our knowledge, the current report provides the first long-term comparison of the severity and duration of neurotoxicity in patients who did and did not receive oxaliplatin.
The trials that were included in the current analyses are registered as National Clinical Trials (NCT) 00096278 (NSABP C-07) and NCT00410579 (NSABP LTS-01). Note that the work described in this article is original research and has not been previously published, although related work has been published.11, 15-17
MATERIALS AND METHODS
Selection of Participants
This report compares long-term neurotoxicity in 2 relevant groups of patients. The first group of patients is the cross-sectional sample, which consists of 353 patients from the C-07 trial who participated in the LTS-01 study. Within this group, 92 patients had longitudinal neurotoxicity information, composing the second group of interest: the longitudinal sample (for the patient flow diagram, see Fig. 1).
The cross-sectional sample consisted of 353 patients who previously participated in the NSABP C-07 trial and were reassessed in the LTS-01 study at a long-term endpoint (range, 4.2-8.6 years [median, 6.0 years] after random assignment). The LTS-01 study invited long-term survivors who previously participated in the NSABP C-05, C-06, C-07, R-02, and R-03 CRC trials from 65 institutions to enroll. Eligibility required that patients had survived at least 3 years after study entry and had been in contact with institutional staff within the prior 2 years. The institutional and patient recruitment process was reported previously (see Ganz et al.)18
This report is focused on patients in the LTS-01 who had participated in the C-07 trial. The C-07 trial accrued patients with stage II or stage III colon cancer from 2000 to 2002 who had undergone resection with curative intent. Patients were assigned randomly to receive FULV (1245 patients) or FLOX (1247 patients). Patients who had clinically significant (grade ≥2) peripheral sensory neuropathy according National Cancer Institute Common Toxicity Criteria, version 2.0,19 were excluded from the C-07 study. Informed consent was obtained from all participants for both the C-07 and LTS-01 studies. Protocols and consent forms were approved by the National Institutes of Health and by the institutional review boards of all participating institutions.
Of 65 institutions in the LTS-01 study, 60 institutions agreed to offer LTS-01 to their patients. Of 2408 eligible patients at participating institutions, 744 agreed to participate, of which, 708 patients completed the interview. The remaining patients either were not contacted successfully by institutional staff or did not agree to participate. The C-07 trial supplied 1038 of 2540 eligible LTS-01 patients (40.9%) and 372 of 744 LTS-01 patients (50%) who agreed to participate. Similar proportions of patients who were eligible to participate in the LTS-01 study by C-07 treatment arm actually participated. Interviews were completed by 354 of these patients, and 353 patients provided neurotoxicity information at the long-term endpoint (48% of patients who received FULV and 52% of patients who received FLOX).
The longitudinal sample consisted of 92 patients from the C-07 study who participated in the LTS-01 trial and had longitudinal neurotoxicity information from the Patient-Reported Outcomes (PRO) study. The PRO study was a substudy of NSABP C-07 that enrolled the first 400 patients from participating Clinical Community Oncology Programs. Of those 400 patients, 395 were eligible for neurotoxicity analysis over 18 months (for a description of this subset, see Land et al.),17 and 92 participated in the LTS-01 study. These 92 patients (46% of patients who received FULV and 54% of patients who received FLOX) reported neurotoxicity results at least at baseline and at the long-term endpoint, which, for this group, ranged from 5.5 to 8.1 years (median, 7.0 years) after random assignment.
The FULV regimen included weekly 500 mg/m2 as an intravenous bolus of fluorouracil for 6 weeks plus 500 mg/m2 of intravenous of leucovorin weekly for 6 weeks of each 8-week cycle for 3 cycles. The FLOX regimen added oxaliplatin to FULV at a dose of 85 mg/m2 administered intravenously in weeks 1, 3, and 5 of each 8-week cycle for 3 cycles.11 Oxaliplatin dose modifications were required by the protocol based on the National Cancer Institute-Sanofi grade. Dose modification was required for grade 2 toxicities that persisted between cycles or for any grade 3 toxicity. Grade 4 toxicities or persistent grade 3 toxicities required termination of oxaliplatin.
Assessment of Neurotoxicity
To evaluate patient-reported neurotoxicity, patients answered a 12-item neurotoxicity questionnaire (NTX-12) from the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Oxaliplatin-Specific Neurotoxicity questionnaire.15, 20, 21 Patients completed the questionnaire before random assignment (baseline); at week 4 of cycle 2; at 6-month, 12-month, and 18-month follow-up visits; and at the LTS-01 long-term assessment. Thus, the assessment of neurotoxicity was the same for the cross-sectional sample and for those who had longitudinal assessments. The NTX-12 questionnaire was comprised of statements intended to measure the severity and impact of peripheral sensory neuropathy on patients' lives, including numbness or tingling in hands or feet, discomfort in hands or feet, joint pain, general weakness, trouble hearing, ringing or buzzing in ears, trouble with buttons, trouble feeling shape of objects in hands, trouble walking, and pain in hands or feet when exposed to cold temperatures. Patients were instructed to choose the number corresponding to how true each statement was for them in the past week using a Likert-type scale, with 0 indicating not at all; 1, a little bit; 2, somewhat; 3, quite a bit; and 4, very much. The NTX-12 score at each evaluation refers to the sum of the ratings from the 12 items. This sum can range from 0 to 48, with lower scores indicating less neuropathy. We previously proposed that a difference of 4 points in the NTX-12 scale should be considered a minimal clinically important difference (proposed in the C-07 protocol based on historic data).17
Chi-square goodness-of-fit tests were used to compare characteristics of the LTS-01 cross-sectional and longitudinal samples with characteristics of the C-07 population to test the representativeness of the subsets to the C-07 population from which they originated. Differences in patient characteristics between treatment groups for patients in the LTS-01 longitudinal sample were computed using chi-square tests of independence. A Wilcoxon rank-sum test compared neurotoxicity scores between treatments for participants from the LTS-01 cross-sectional sample. The NTX-12 responses were dichotomized according to severity (higher severity included the categories somewhat, quite a bit, or very much; whereas lesser severity included not at all or a little bit) and were analyzed by logistic regression at the long-term endpoint. Comparisons of the distributions of severity level between treatment groups were computed using chi-square tests of independence. A mixed-effects longitudinal analysis compared long-term total neurotoxicity scores for patients in the longitudinal study between treatment groups from the second cycle of treatment out to the long-term endpoint controlling for baseline score and including continuously measured time from baseline to each evaluation for each patient, quadratic and cubic terms of time, and a term for the interaction of time and treatment. Computations were performed using the SAS statistical software package (version 9.2; SAS Institute, Cary, NC).
Patient Characteristics and Assessments
A full description of all patients who participated in the LTS-01 and C-07 trials have been reported elsewhere.11, 19, 22 The long-term endpoint for the 353 patients in the cross-sectional sample ranged from 4.2 to 8.6 years from random assignment (median, 6.0 years), whereas the long-term endpoint for the 92 patients in the longitudinal sample ranged from 5.5 to 8.1 years from random assignment (median, 7.0 years). In both the cross-sectional and longitudinal samples, the median time to long-term endpoint did not vary between treatment groups: For the cross-sectional sample, the median time to endpoint was 6.04 years for those who received FLOX and 6.07 years for those who received FULV (P = .60); whereas, for the longitudinal sample, the median time to endpoint was 6.92 years for those who received FLOX and 6.84 years for those who received FULV (P = .42). The subsets of C-07 patients in the cross-sectional and longitudinal LTS-01 samples were representative of the C-07 population in terms of age, sex, and site of colon cancer (Table 1). Both patient samples, however, differed significantly from the C-07 population with respect to the number of positive lymph nodes. In the full C-07 population, 26% had ≥4 positive lymph nodes, whereas this decreased to 20% and 13% of patients in the cross-sectional and longitudinal samples, respectively. Because more positive lymph nodes are associated with a poorer prognosis, a decreased representation of these patients is expected in studies of long-term survivors. There were no significant imbalances between treatment groups for patient characteristics among the 92 patients in the longitudinal sample (Table 2).
Table 1. Comparison of Characteristics Between Patients in National Surgical Adjuvant Breast and Bowel Project Trial C-07 and Patients in the Cross-Sectional and Longitudinal Long-Term Survivors Study (LTS-01) Samples
Abbreviations: FLOX, fluorouracil, leucovorin, plus oxaliplatin; FULV, fluorouracil and leucovorin.
P values were calculated with the chi-square test for independence.
No. of positive lymph nodes
Neurotoxicity submission rates were acceptable in the longitudinal sample. The lowest number of completed questionnaires occurred during week 4 of cycle 2, in which 76 of 92 patients, (83%) completed the questionnaire. There was no significant difference according to treatment received in the number of questionnaires completed over the 6 evaluation time points (P = .996), and the reasons given for missing forms were similar across treatments. In the FULV and FLOX groups, 72% and 67%, respectively, of missed assessments were because of staff oversight or for reasons unrelated to the patients' condition or choice. The median dose of oxaliplatin received for patients on the FLOX arm was 677 mg/m2 (interquartile range, 320-763 mg/m2).11
The NTX-12 scores for the 169 patients in the FULV group ranged from 0 to 33 (mean score, 5.7; median score, 4); whereas, for the 184 patients in the FLOX group, the score ranged from 0 to 28 (mean score, 7.5; median score, 6). Although there was a statistically significant difference in NTX-12 scores between treatment groups at the long-term endpoint (P = .005), the differences in the mean score of 1.8 and in the median score of 2 were not clinically significant, because the differences were less than the 4 points prospectively considered clinically important.
Dichotomized responses (at least somewhat severe vs lesser severity) to the individual neurotoxicity questions were examined to provide greater insight into specific long-term effects of adjuvant therapy. Odds ratios (ORs) for each of the 12 questions are presented in the forest plot in Figure 2 and depict the odds of greater severity for those who received FLOX compared with the odds for those who received FULV. There was no significant difference in the odds for all questions except for the 2 questions that asked about the severity of numbness or tingling in hands and feet.
Patients who received FLOX reported higher severity of numbness or tingling in hands and feet than those in the FULV group at the long-term endpoint. The OR of at least higher severity of numbness or tingling in hands for the FLOX group compared with the FULV group was 2.00 (95% confidence interval [CI], 1.15-3.48; P = .015). Whereas 24% of FLOX patients had at least somewhat severity of numbness or tingling in their hands, only 14% of FULV patients did so (Fig. 3, a). Differences in the distribution of the 5 levels of severity of numbness or tingling in hands between treatment groups illustrated in Figure 3 (a) were not significant at the P = .05 level (P = .07). The OR of higher severity of numbness or tingling in feet for the FLOX group compared with the FULV group was 2.78 (95% CI, 1.59-4.85; P < .001). Twenty-nine percent of FLOX patients had at least somewhat severe numbness or tingling in feet versus 13% of FULV patients. Differences in distribution across all 5 severity levels of numbness or tingling in feet illustrated in Figure 3 (b) were significant between treatments (P < .001; FLOX vs FULV: somewhat, 13% vs 8%, respectively, quite a bit, 10% vs 3%, respectively; very much, 6% vs 2%, respectively).
For the 92 patients who had baseline and long-term data available, there were a total of 498 neurotoxicity evaluations over 6 time points. For all patients at all evaluations, the total neurotoxicity score ranged from 0 to 33 (mean score, 4.66; median score, 3). Ninety percent of NTX-12 scores were <12, and only 6 observations reported very high neurotoxicity (scores >23).
Initially, the mean change from baseline in the NTX-12 score for patients who received FLOX was much greater than the mean change for patients who received FULV, but this difference dissipated by the long-term assessment. The median changes from baseline in the NTX-12 score followed a similar pattern but were lower than the mean changes from baseline for both treatment groups at each evaluation. The only difference in median scores deemed clinically important occurred at week 4 of cycle 2 with a difference of 5 (Fig. 4).
For the first 4 assessments after baseline, the 95% CIs of the mean changes from baseline for patients who received FULV straddled zero, indicating little or no change from baseline; whereas, for patients who received FLOX, the CIs were greater than zero. The mean changes from baseline and their CIs, however, were almost identical at the long-term assessment for both treatment groups. Also, the 95% CIs around the mean overlapped from the 12-month assessment to the long-term endpoint, illustrating no significant difference in the mean (median) change from baseline in the neurotoxicity scores between treatment groups (Fig. 4).
A mixed-effects model verified that the effect of oxaliplatin on the NTX-12 score changed significantly with time (P < .001). For patients with a zero baseline NTX-12 score in the FULV group, the mean NTX-12 score prediction was 0.77 at 6 months from baseline, 2.45 at 5 years from baseline, and 3.65 at 7 years. For similar patients with a zero baseline NTX-12 score in the FLOX group, the mean NTX-12 score prediction was 3.35 at 6 months from baseline, 3.63 at 5 years, and 3.92 at 7 years. Thus, the model suggests that, for patients with identical baseline neurotoxicity scores, the initial substantial difference in neurotoxicity scores during treatment dissipated by 7 years from baseline.
Neurotoxicity caused by oxaliplatin was reported previously by the C-07 and MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) trials. Land et al reported significant differences in neurotoxicity scores between treatments up to 18 months after treatment onset in the C-07 trial.17 The MOSAIC trial extended the time period analyzed by Land et al, reporting neurotoxic effects up to 48 months, but only for the treatment arm that included oxaliplatin, making a long-term treatment comparison impossible.12 Park et al also reported oxaliplatin-induced neuropathy results for 24 oxaliplatin-treated patients with follow-up at a median of 25 months post-treatment.23 At follow-up, 79.2% of those patients reported residual neuropathic symptoms, and the severity of their neurotoxicity scores correlated with cumulative dose. However, with a median follow-up of just over 2 years, Park et al only reported neurotoxicity information for a small sample of patients who received oxaliplatin, again making a treatment comparison impossible.
To our knowledge, the current study is the first long-term comparison of the severity and duration of neurotoxicity in patients treated with and without oxaliplatin, which indicates that, at the long-term assessment (median, 6 years), differences by treatment in mean and median neurotoxicity scores in the cross-sectional sample (n = 353) was half that deemed clinically important. Although there were differences in neurotoxicity scores between treatment groups in the first 18 months of the C-07 colon cancer trial, the longitudinal sample (n = 92) established that these differences dissipated by the long-term evaluation. At the long-term endpoint, the increase in the mean total neurotoxicity score for patients who received FULV most likely was because of the general increase in peripheral sensory neuropathy in an aging population.24
Findings from shorter term studies, like those by Haller et al25 and André et al,12 corroborate our findings that some neurotoxic effects from oxaliplatin are reversible. Haller et al25 reported grade 3 or 4 neurosensory toxicity in 11% of patients who received oxaliplatin (vs 8% of patients who were treated without oxaliplatin), and persistent symptoms in 5% of patients resolved a median of 1 month after completion of treatment. André et al12 reported that 92% of patients from the MOSAIC trial who received oxaliplatin experienced peripheral sensory neuropathy of any grade during treatment; however, 4 years after completion of therapy, only 15.5% reported peripheral sensory neuropathy, and only <1% had symptoms graded as severe.
In the 2007 report by Land et al, foot discomfort, foot numbness or tingling, and hand or foot pain in the cold were significantly more severe in the patients who received oxaliplatin at 18 months.17 From our long-term analysis, sensitivity to the cold as well as foot discomfort no longer differed significantly between the treatment groups, demonstrating that treatment-related differences in these effects disappear or at least decrease 6 years after random assignment. Hand and foot numbness or tingling appeared to be the longest lasting side effects for those who received oxaliplatin. The odds of hand numbness or tingling were significantly greater for the FLOX group during therapy and, although no longer significant at 18 months, were significantly greater at the long-term endpoint. The odds of foot numbness or tingling remained significantly greater for those in the FLOX group during therapy, both at 18 months and at the long-term assessment.
It is important to develop specific countermeasures to address these neurotoxic effects, which occur during and continue after treatment. Additional studies using a pharmacogenetic approach to assess toxicity and survival in patients with CRC who receive oxaliplatin may shed light on which patients are more susceptible to peripheral sensory neuropathy, provide early detection and supplemental treatment strategies for those who develop peripheral sensory neuropathy, and create specific medications to address the lingering effects of hand and foot numbness or tingling.26-29
We note that, because neurotoxicity scores correlate with cumulative oxaliplatin dose, the expected cumulative oxaliplatin exposure in the C-07 trial (765 mg/m2) was less than that from the trials reported by Haller et al (1040 mg/m2) and André et al (1020 mg/m2), as expected, based on the regimen. Thus, our findings may underestimate the long-term results in other long-term survivors who received regimens with different schedules of oxaliplatin. Along with the lower cumulative dose of oxaliplatin from the C-07 study, other limitations include the relatively small sample size of the longitudinal sample; the use of a relatively new patient-reported outcome measure to assess neurotoxicity; and a lack of comparison between the treatment groups of the longitudinal, cross-sectional, and original cohorts with respect to comorbidities that increase neuropathy.
The longitudinal sample provided adequate evidence, especially when combined with the comparison of mean scores from cross-sectional samples and other studies, that there was not a clinically significant difference in long-term NTX-12 scores for patients who did and did not receive oxaliplatin. Numbness or tingling of hands and feet persisted at an elevated incidence for oxaliplatin-treated patients 6 years from random assignment. This study enhances physicians' and patients' understanding of the severity and duration of neurotoxic effects of oxaliplatin. Efforts should be made to minimize peripheral sensory neuropathy during and after oxaliplatin treatment so that patients can benefit from extended disease-free survival while maintaining their quality of life.
This work was supported by National Institutes of Health Public Health Service grants U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974 from the National Cancer Institute, Department of Health and Human Services and by grant RSGPB-05-236-01-CPPB from the American Cancer Society.