1. CM923700-1 A Comparison of Simple Single-Item Measures and the Common Toxicity Criteria in Detecting the Onset of Oxaliplatin-Induced Peripheral Neuropathy in Patients with Colorectal Cancer R. F. Morton, J. A. Sloan, A. Grothey, D. J. Sargent, H. McLeod, E. M. Green, C. Fuchs, R. K. Ramanathan, S. K. Williamson, R. M. Goldberg

2. CM923700-2 Peripheral neuropathy (PN) is common during treatment with Oxaliplatin Assessment of PN is historically done via the Common Toxicity Criteria (CTC) We developed a single-item numerical analogue scale assessment to help measure PN We compared the two measures to look at the sensitivity of the CTC in detecting the onset of PN Peripheral neuropathy (PN) is common during treatment with Oxaliplatin Assessment of PN is historically done via the Common Toxicity Criteria (CTC) We developed a single-item numerical analogue scale assessment to help measure PN We compared the two measures to look at the sensitivity of the CTC in detecting the onset of PN Background

3. CM923700-3 696 patients randomized to FOLFOX4 PN assesed bi-weekly during treatment NAS filled out at baseline and every 12 weeks during treatment 696 patients randomized to FOLFOX4 PN assesed bi-weekly during treatment NAS filled out at baseline and every 12 weeks during treatment Methods

4. CM923700-4 IFL: Irinotecan + 5-FU/LV IFL: Irinotecan + 5-FU/LV IROX: Irinotecan + Oxaliplatin FOLFOX4: Oxaliplatin + 5-FU/LV RANDOMIRANDOMIZATZATIONIONRANDOMIRANDOMIZATZATIONION Goldberg et al, JCO 2004 NCCTG/Intergroup Trial N9741

5. CM923700-5 NAS Tools

6. CM923700-6 According to CTC only 20% of patients experienced serious PN Clinical knowledge suggested the incidence rate should be much higher (about 80%) According to CTC only 20% of patients experienced serious PN Clinical knowledge suggested the incidence rate should be much higher (about 80%) An Empirical Anomaly

7. CM923700-7 2 Point Change in QOL No (N=420) Yes (N=276) % Agreement Kappa Statistic Grade 2+ PN No (N=440) 30813265%0.25 Yes (N=256) 112144 Grade 3+ PN No (N=597) 38021763%0.13 Yes (N=99) 4059 The agreement of < 65% indicates CTC and NAS measure different aspects of PN. Agreement

8. CM923700-8 Dose to 2 Point QOL Change

9. CM923700-9 Time to 2 Point QOL Change

10. CM923700-10 Which Comes First?

11. CM923700-11 Which Comes First?

12. CM923700-12 Grade 2+ PN is found to be a significant problem according to the NAS Using CTC, PN is under-reported NAS may allow for earlier detection NAS should be used in conjunction with CTC Grade 2+ PN is found to be a significant problem according to the NAS Using CTC, PN is under-reported NAS may allow for earlier detection NAS should be used in conjunction with CTC Conclusions

13. CM923700-13 Background: Peripheral neuropathy (PN) is a common and intrusive side effect of chemotherapy. The assessment of PN is typically done via the common toxicity criteria (CTC). To date there is no optimal measure of peripheral neuropathy. We developed simple single-item numerical analogue scale (NAS) assessments for the unique oxaliplatin-induced PN. The purpose of this investigation was to asses the relative sensitivity of the CTC and NAS measures in detecting the onset and severity of PN in patients receiving oxaliplatin. Abstract

14. CM923700-14 Methods: 696 patients randomized to the FOLFOX4 arm of the practice-changing Intergroup/NCCTG study N9741 provided data on the incidence and severity of PN experienced via bi-weekly CTC assessments and NAS measurements taken every 12 weeks. The NAS is a simple measure from 0 representing no PN to 10 representing PN as bad as it can be. A change of 2 points from baseline on the NAS was used as a conservative estimate of a clinically meaningful change in PN. Methods: 696 patients randomized to the FOLFOX4 arm of the practice-changing Intergroup/NCCTG study N9741 provided data on the incidence and severity of PN experienced via bi-weekly CTC assessments and NAS measurements taken every 12 weeks. The NAS is a simple measure from 0 representing no PN to 10 representing PN as bad as it can be. A change of 2 points from baseline on the NAS was used as a conservative estimate of a clinically meaningful change in PN. Abstract

15. CM923700-15 Results: 276 patients (40%) reported a 2 point worsening from baseline in PN via NAS compared to 256 (37%) with a CTC reported grade 2+ PN and 99 (14%) with a CTC reported grade 3+ PN. For those ultimately reporting PN, median dose to onset of a clinically significant worsening of PN via NAS was 424 mg/m2 relative to a dose to grade 2+ (3+) PN of 765 (961) mg/m2 for CTC criteria. This means that patients notice an increase in PN about two or three months earlier via the NAS relative to the CTC. Agreement between CTC grade 2+ (3+) PN and NAS assessment was only 65% (63%) with a Cohen's Kappa of 0.26 (0.13). The majority of patients reported the 2 point decline in PN via NAS prior to their reported CTC PN event (53% for grade 2+, 83% for grade 3+). Results: 276 patients (40%) reported a 2 point worsening from baseline in PN via NAS compared to 256 (37%) with a CTC reported grade 2+ PN and 99 (14%) with a CTC reported grade 3+ PN. For those ultimately reporting PN, median dose to onset of a clinically significant worsening of PN via NAS was 424 mg/m2 relative to a dose to grade 2+ (3+) PN of 765 (961) mg/m2 for CTC criteria. This means that patients notice an increase in PN about two or three months earlier via the NAS relative to the CTC. Agreement between CTC grade 2+ (3+) PN and NAS assessment was only 65% (63%) with a Cohen's Kappa of 0.26 (0.13). The majority of patients reported the 2 point decline in PN via NAS prior to their reported CTC PN event (53% for grade 2+, 83% for grade 3+). Abstract

16. CM923700-16 Conclusions: The CTC measurement of PN under-reports the incidence and time to onset of PN relative to simple single-item NAS measures. Grade 2 PN via the CTC is a clinically significant problem according to patient ratings on the NAS. In future studies, it is recommended that the CTC be supplemented by patient-reported measures of PN. Conclusions: The CTC measurement of PN under-reports the incidence and time to onset of PN relative to simple single-item NAS measures. Grade 2 PN via the CTC is a clinically significant problem according to patient ratings on the NAS. In future studies, it is recommended that the CTC be supplemented by patient-reported measures of PN. Abstract