1. Oxaliplatin-Induced Peripheral Neuropathy’s Effects on Colorectal Cancer Survivors Cindy Tofthagen, PhD, ARNP, AOCNP Assistant Professor University of South Florida Postdoctoral Fellow University of Massachusetts Boston and Dana Farber Cancer Institute

2. Background over 1,000,000 survivors of colorectal 1 in 19 people will develop colorectal cancer during their lifetime (NCI, 2012) the risk of mortality from colorectal cancer has declined over the last twenty years because of early detection and new treatment alternatives like oxaliplatin (NCI, 2010). Oxaliplatin was approved by the Food and Drug Administration (FDA) for treatment of metastatic colorectal cancer in 2002 and approved for first-line adjuvant treatment of stage III colorectal cancer in 2004 (NCI, 2010).

3. Background Oxaliplatin is highly toxic to the peripheral nervous system Cause chronic neurotoxicity in up to 50% of patients that can persist for years following completion of chemotherapy. Neurotoxicities may not develop until after completion of chemotherapy Primarily effects sensory neurons

4. Purpose To examine severity of neuropathic symptoms and evaluate relationships between neuropathic symptoms, health- related quality of life, depressive symptoms and sleep in colorectal survivors who were treated with oxaliplatin.

5. Sample & Setting Men and women with a history of stage III – IV colorectal cancer treated with oxaliplatin at the Moffitt Cancer Center between 1 and 8 years previously. Eligibility criteria: at least 18 years of age; treated with oxaliplatin for stage III – IV colorectal cancer have no history of cancer other than colorectal cancer no other potentially neuropathy-inducing condition (e.g., diabetes) no documented or psychiatric or neurologic disorders that would interfere with study participation be able to speak and read standard English provide written informed consent.

6. Procedures The Institutional Review Board approved the study Patients were identified through the Moffitt Cancer Center Cancer Registry Potentially eligible survivors were contacted by telephone to confirm eligibility and obtain verbal informed consent Survivors who provided verbal consent were then mailed a study packet and postage paid return envelope Approximately 1 week later, those survivors who had not yet returned the packet were contacted by telephone and prompted to complete and return the material A total of 128 survivors agreed to participate. 111 (94%) survivors completed and returned the study packet

7. Instruments Chemotherapy Induced Peripheral Neuropathy Assessment Tool (CIPNAT) The Center for Epidemiological Studies-Depression Scale (CES-D) Insomnia Severity Index (ISI) Medical Outcomes Study Short Form- 36 (SF-36) Demographic Data Form

8. Power & Data Analysis A priori power analysis indicated that 108 subjects were needed, at 90% power and 2-sided type I error rate of 0.01, to detect a 10% or more change in R-square (percentage of variation explained) attributed independently to level of neuropathic symptoms. Correlation coefficients, simple regression and multiple linear regression analysis were used to examine relationships between neuropathy and depressive symptoms, sleep quality, and health-related quality of life (HRQOL).

9. Results-Demographics 51% male 88% Caucasian 71% stage 3 colon cancer 37% still employed (not retired or disabled) Mean of 3 years since oxaliplatin based chemotherapy

10. Prevalence of Symptoms

11. Severity of Symptoms

12. Symptom Distress

13. Frequency of Symptoms

14. Correlations Between CIPN, Depressive Symptoms and Sleep VariableSymptom ExperienceSymptom Interference Depressive Symptoms (CES-D).38 (p=.001).59 (p<.001) Sleep Disturbance (ISS).35 (p=.004).52 (p<.001)

15. Correlations Between CIPN and QOL Symptom experience r p Symptom interference r p Physical functioning-.22.03 -.55 <.0001 Role emotional-.36.0003 -.54 <.0001 Role physical-.32.001 -.59 <.0001 Bodily pain-.36.0002 -.51 <.0001 Vitality-.23.02 -.51 <.0001 General health-.003.98 -.06.57 Mental health-.26.01 -.43 <.0001 Social functioning-.36.0002 -.66 <.0001

16. Cluster Analysis VariableInstrument Cluster 1 (n=21) Mean (SD) Cluster 2 (n=56) Mean (SD) Cluster 3 (n=17) Neuro SymptomsCIPNAT 51.90 (37.73) 63.55 (49.93) 119.65 (58.43) Depressive symptomsCES-D 2.48 (3.14) 10.04 (7.07) 23.29 (14.47) InsomniaSSI 1.43 (1.54) 8.75 (5.32) 12.47 (6.79) AgeDemographic data 67.24 (7.52) 55.86 (11.66) 66.18 (9.32) General Health (norm based) SF-36 45.16 (3.11) 43.46 (4.90) 42.61 (4.71) Physical Functioning (norm based) SF-36 56.92 (13.54) 44.47 (11.58) 33.88 (12.98) Emotional Role Function (norm based) SF-3655.68 (0.00) 51.62 (6.08) 18.04 (15.80)

17. Discussion Colorectal cancer survivors continue to experience oxaliplatin-induced peripheral neuropathy that adversely affects emotional and physical well-being and quality of life for years following treatment There is a subset of colorectal cancer survivors who experience severe neuropathy that affects their ability to carry out usual activities, and is associated with increased depressive symptoms, sleep disturbance and reduced quality of life.

18. Limitations Relatively small sample, cross-sectional design, convenience sampling Lack of racial and ethnic diversity While our findings suggest that neuropathy contributes to depressive symptoms, insomnia, and reduced quality of life, it is possible that persons with a high degree of depressive symptoms and/or insomnia are more likely to report more severe neuropathic symptoms and neuropathic interference with activities.

19. Directions for Future Research and Practice Longitudinal studies using larger sample sizes and more diverse racial and ethnic groups Identification of possible modifiable and non-modifiable risk factors for severe neuropathy that may influence treatment decisions Interventions to relieve symptoms and improving physical performance Survivorship programs should include systematic assessment for neuropathy, provide rehabilitation when needed, and develop support programs for colorectal cancer survivors which emphasize the chronic nature of neuropathy, help maximize performance status,and assist patients in adjusting to and coping with physical and role limitations.

20. Acknowledgements Co-Investigators Kristine A. Donovan, PhD, MBA Moffitt Cancer Center & Research Institute Mary Ann Morgan, PhD, ARNP Moffitt Cancer Center & Research Institute David Shibata, MD FACS Moffitt Cancer Center and Research Institute

21. Acknowledgements Data analysis - Yating Yeh, PhD Dana-Farber Cancer Institute Funding – USF Nursing Faculty in Pilot Research Projects and the University of Massachusetts Boston - Dana Farber /Harvard Cancer Center U54 Cancer Research Partnership