Exercise to Reduce Chemotherapy-Induced Peripheral Neuropathy

Background: Over 190,000 men and women will be diagnosed in 2018 with invasive
gastrointestinal (GI) cancers (e.g, colorectal and gastric cancer) for which oxaliplatin is a
standard chemotherapy treatment. However, 85-95% of these patients develop
oxaliplatin-induced peripheral neuropathy (OIPN). Currently, OIPN is the primary
dose-limiting factor of oxaliplatin-based regimens, because persistent OIPN can impair
physical function and quality of life (QOL) years after treatment completion. There are no
effective treatments for OIPN. Four randomized controlled trials and two quasi-experiments
have reported positive effects of at least 10 minutes/day of moderate-intensity aerobic
exercise, 2-5 days/week over at least 6-8 weeks on chemotherapy-induced peripheral
neuropathy. Exercise-enhanced circulation could re-distribute neurotoxic drugs away from
vulnerable neurons, reduce oxidative stress, and help to prevent OIPN. However, all the prior
trials had critical study limitations and all but two studies evaluated OIPN as a secondary
outcome. Thus, this prospective, randomized, controlled, pilot experiment will evaluate the
efficacy of an aerobic walking intervention for OIPN in GI cancer patients who are already
prescribed oxaliplatin (85 mg/m2 every other week for at least six cycles) by their
oncologists. The "MI-Walk intervention"— an 8-week motivational enhancement therapy (MET)-
and home-based aerobic walking intervention—will be tested in this study.

Specific aims: The specific aims and hypotheses are to:

Aim 1: Evaluate the effect of the MI-Walk Intervention on OIPN severity at 8 weeks (T6)
compared to physical activity (PA) education alone.

Hypothesis: Participants who receive the MI-Walk intervention will exhibit less severe OIPN
at T6 than participants who receive PA education alone.

Aim 2: Explore the effect of the MI-Walk intervention on total oxaliplatin received, and QOL
at T6 compared to PA education alone.

Hypothesis: Participants who receive the MI-Walk intervention will receive higher total doses
of oxaliplatin and report higher QOL at T6 than participants who receive PA education alone.

Aim 3: Evaluate the feasibility of the MI-Walk intervention. Research Questions: Among
patients receiving oxaliplatin, 1) how acceptable is the intervention? 2) what percent of
patients will enroll in, complete, and adhere to the walking intervention? 3) what
participant characteristics are associated with study compliance, adherence, completion, and
acceptability? 4) What, if any, adverse events will result from the MI-Walk intervention?

Study design: Sixty GI cancer patients will be recruited at multiple cancer clinics within
the week before their second oxaliplatin cycle. All participants will receive a PA education
pamphlet. Half (n=30) will receive the MI-Walk Intervention. These patients will receive a
tailored progressive walking plan, supplemental cancer treatment & exercise education,
patient testimony, HR-enabled pedometer and PA-tracking app, exercise diary, and
semi-scripted brief MET (motivational interviewing, SMAART goals, and if-then statements)
from research staff before practicing the intervention at home for 8 weeks. Additional brief
MET sessions at 2 (T3) and 4 weeks (T4), progress summaries at T3, T4, and T6, a private
email group, weekly group walking events, and peer accountability phone calls/email will be
used to engage and support participants. To level attention, both groups will receive regular
phone assessments of intervention-related adverse events at 1 week (T2), T3, T4, and 6 weeks
(T5). Outcomes will be measured at (T1) and 8 weeks after (T6) intervention initiation. The
outcome measures include the 0-10 NRS of OIPN symptom severity (primary outcome measure); and
EORTC QLQ-CIPN20 self-report survey, cumulative oxaliplatin dose, and EORTC QLQ-C30. The
study will also record feasibility, adherence, acceptability, and intervention fidelity data.
Multiple linear regression will be used to evaluate the inter-group differences in the T1 to
T6 change in mean NRS scores (OIPNΔ), controlling for T6 total oxaliplatin received
(OXALIT6), and the interaction between the intervention and OXALIT6. Mediation analysis will
be used to explore the secondary outcomes.

Future Directions: This study will be among the first to provide efficacy and feasibility
data for an 8-week home-based aerobic walking intervention to reduce OIPN - a common
chemotherapy side effect, for which there are no good treatments. This pilot study will
inform the design of larger phase III trials to evaluate the efficacy of aerobic walking for
OIPN, and potential mediators (e.g., vascular biomarkers) in this relationship.

Inclusion Criteria:

- Diagnosed GI cancer (e.g, colorectal, gastric, pancreatic, esophageal, bowel);

- Scheduled to receive at least 6 cycles of oxaliplatin (85 mg/m2);

- Receiving care at the University of Michigan or St. Joseph Cancer Clinics;

- A Karnofsky Performance Status ≥ 80% or an Eastern Cooperative Oncology Group Status 0
to 1;

- Voluntarily consented to participate in all intervention components.

Exclusion Criteria:

- Exercise- or mobility-limiting cardiovascular, pulmonary, musculoskeletal, or
psychological disease, based on the EMR (electronic medical record) past medical
history and consultation with the medical oncologist;

- Scheduled major surgery during the study time period;

- Pre-existing peripheral neuropathy prior to chemotherapy (potentially due to diabetes,
central nervous system malignancy, vitamin deficiency, heredity, nerve compression
injury, non-surgically corrected carpal tunnel disease, or alcohol dependence) per
patient self-report in response to brief screening questions noted in the
pre-screening section;

- Prior receipt of neurotoxic chemotherapy - taxanes (paclitaxel and docetaxel),
platinums (cisplatin, oxaliplatin, and carboplatin), vinca alkaloids (vincristine and
vinblastine), proteasome inhibitors (bortezomib), and thalidomide;

- Pregnancy;

- Inability to read or speak English;

- Prognosis of less than three months.