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

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).

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

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.

Sample & SettingMen 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.

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

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

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).

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

Prevalence of Symptoms

Numbness or tingling in hands

Numbness or tingling in feet

Discomfort in hands

Discomfort in feet

Sensitivity to cold

Muscle or joint aches

Arms or legs weak

Trouble with balance

0 10 20 30 40 50 60 70 80

Percentage

Severity of Symptoms

Numbness/tingling hands

Numbness/tingling feet

Discomfort Hands

Discomfort Feet

Cold Sensitivity

Muscle/joint aches

Muscle Weakness

Balance Trouble

0 1 2 3 4 5 6 7 8 9

Mean

Mean

Symptom Distress

Numbness/tingling hands

Numbness/tingling feet

Discomfort Hands

Discomfort Feet

Cold Sensitivity

Muscle/joint aches

Muscle Weakness

Balance Trouble

0 1 2 3 4 5 6 7 8 9

Mean

Frequency of Symptoms

Numbness/tingling hands

Numbness/tingling feet

Discomfort Hands

Discomfort Feet

Cold Sensitivity

Muscle/joint aches

Muscle Weakness

Balance Trouble

0 1 2 3 4 5 6 7 8 9

Mean

Mean

Correlations Between CIPN, Depressive Symptoms and Sleep

Variable Symptom Experience Symptom Interference

Depressive Symptoms (CES-D)

.38 (p=.001) .59 (p<.001)

Sleep Disturbance (ISS) .35 (p=.004) .52 (p<.001)

Correlations Between CIPN and QOL

  Symptom experiencerp

Symptom interferencerp

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

Cluster Analysis

Variable Instrument Cluster 1 (n=21) Mean(SD)

Cluster 2 (n=56)Mean(SD)

Cluster 3(n=17)

Neuro Symptoms CIPNAT 51.90(37.73)

63.55(49.93)

119.65(58.43)

Depressive symptoms CES-D 2.48(3.14)

10.04(7.07)

23.29(14.47)

Insomnia SSI 1.43(1.54)

8.75(5.32)

12.47(6.79)

Age Demographic 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-36 55.68(0.00)

51.62(6.08)

18.04(15.80)

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.

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.

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.

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

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