1. # 3564 Neurotoxicity with FULV versus FLOX in patients with stage II and III carcinoma of the colon: Results of NSABP Protocol C-07 S Land 1,2, J Kopec 3, R Cecchini 1, P A Ganz 4, HS Wieand 1,2, L Colangelo 1, S Sharif 5, JP Kuebler 6, JP Costantino 1,2, N Wolmark 5 1. NSABP Biostatistical Center, Pittsburgh, PA; 2. Department of Biostatistics, Univ of Pittsburgh; 3. University of British Columbia, Vancouver, BC, Canada; 4. Schools of Medicine and Public Health, and the Jonsson Comprehensive Cancer Center, University of California at Los Angeles, CA; 5. NSABP Operations Center, Pittsburgh, PA; 6CCOP - Columbus, OH

2. INTRODUCTION NSABP Phase III Protocol C-07 compared the efficacy of FULV versus FLOX in patients with stage II or III colon cancer. The definitive analysis revealed an increase in 4-year disease-free survival from 71.6% to 76.5% (HR=0.79, p=0.004) in favor of FLOX. The present study compares patient- reported neurotoxicity between the treatment groups.

3. METHODS Patients were randomized to FULV (5-fluorouracil, 500 mg/m2 iv bolus weekly x 6; leucovorin 500 mg/m2 iv weekly x 6, each 8-week cycle x 3) or FLOX (FULV with oxaliplatin 85 mg/m2 iv administered on weeks 1, 3 and 5 of each 8-week cycle x 3). N=400 were eligible for patient-reported outcomes (PRO) neurotoxicity sub-study.

5. Assessment of neurotoxicity 1. Patient-reported outcomes (PRO) * FACT/GOG Oxaliplatin-Specific Neurotoxicity (NTX) questionnaire (Likert 0-4). Summary scale NTX-12 * Baseline through 18 months 2. Staff-reported: NCI CTC v. 2.0 + NCI-Sanofi grade * After 12 months, Form NT was only required until resolution (no neurosensory toxicity exceeding the grade reported before treatment, no neuromotor toxicity exceeding the pre-treatment grade, and no episodes of pharyngo-laryngeal dysesthesias).

6. Statistical methods 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 model comparing all assessments longitudinally and a two- sample t-test using scores at 18 months (change from baseline). NTX-12 item responses were dichotomized as moderate (level “somewhat”) versus 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 based on the NCI-Sanofi criteria, including only subjects who had neurotoxicity reported at their first on-treatment assessment.

7. RESULTS Patients and assessments 2,492 patients enrolled in C-07 (2/2000-11/2002); 395 patients for PROs. Form submission rates were high (90-100% for staff-reported; 74- 100% for PRO). Discontinued therapy early due to toxicity: 77 (6.2%) FULV vs. 276 (22.1%) FLOX; about half of those patients remained on the other two agents.

8. N (%) AgeMean Range 57.6 22-83 Sex Male240 (60.8) Female155 (39.2) Pos. Node s 0135 (34.2) 1-3175 (44.3) 4+ 85 (21.5) Site L. Colon89 (22.5) R. Colon180 (45.6) Sigmoid124 (31.4) Multiple 2 (0.5) TABLE 1. PRO sub-study patient characteristics

9. Patient-reported neurotoxicity: total scores and individual items Mean NTX-12 was higher for FLOX throughout the 18-month period of study (p<0.0001) and remained higher at 18 months (p=0.009) The % who experienced a clinically important change (4 points) on NTX-12 from baseline to 6 months: 17% FULV vs. 40% FLOX (p<0.0001). At 18 months these percentages were 18% and 31% (p=0.016). During therapy, significantly more FLOX patients experienced hand/foot neuropathy and overall weakness; fewer reported trouble hearing during treatment. At 18 months, decreased hand neurotoxicity, but continued foot discomfort. Between baseline and 18 months, 10.4% of FULV vs. 20.2% FLOX had an increase of 3-4 points in at least one of the 12 items.

10. Mean Total NTX-12 Score (Change from Baseline)

11. TABLE 2.FULV (%) # FLOX (%) SYMPTOMS Cyc218moCyc 218 mo Trouble hearing10.36.52.416.7 Ringing ears7.444.38.6 Trouble walking4.532.46.7 Joint pain /muscle cramps11.21310.117.4 Weak all over16.26.927.48.7 Trouble feeling shapes1.91.5 5.6 Trouble w/ buttons3.11.54.52.5 Foot discomfort5.73.88.414.2 Feet numb /tingling3.84.611.422.1 Hand/foot pain in cold3.86.138.914.9 Hand discomfort5.25.417.610.7 Hand numb/tingling4.4636.711.9 Bold indicates statistically significant differences (p<.05) # % reporting “somewhat” or more severe symptoms

12. Observer-reported neurotoxicity Grade 3-4 toxicities were very rare (with point prevalence less than 5% in either treatment arm; Table 3). At cycle 2, grade 2-4 neurosensory toxicities were reported for 13.4% of patients assigned to FLOX. At their first on-treatment assessment, 98 (8%) of patients in the FULV group and 836 (68%) of patients in the FLOX group had neurotoxicity according to the NCI-Sanofi criteria. Time to resolution was 4.8 months FULV vs. 9.0 months FLOX (p<0.0001).

13. FULV (n=1245)FLOX (n=1247) 0123401234 Cycle 289.99.30.70.1028.757.910.42.80.2 12 months95.13.90.80.2070.125.04.40.50 TABLE 3. NCI-Sanofi Neurosensory Grade

14. months Time to resolution Time to resolution among patients whose first assessment indicated neurotoxicity (n=98 of patients assigned to FULV; n=837 of FLOX). Time is measured from start of treatment.

15. CONCLUSIONS FLOX causes significantly more neurotoxicity than FULV. The neurotoxicity is felt primarily in the hands during therapy and in the feet during follow-up. In a minority of patients the neurotoxicity is long-lasting.