Optimizing Integrative Oncology Approaches to Address Chemotherapy-induced Peripheral Neuropathy in Gastrointestinal (GI) Cancer Patients: A SMART Pilot Study

This study explores the combined effects of Tai Chi/Qi Gong and Alpha-Lipoic Acid (ALA) on participants over time, with adjustments to treatment based on individual responses. Participants begin the study at baseline and are assessed for their response to either Tai Chi/Qi Gong or ALA at multiple time points-week 8 and week 16, which is the study's conclusion.

At each evaluation point, participants are categorized as having either a sufficient response (≥2-point reduction on the CIPN scale) or an insufficient response (<2-point reduction on the CIPN scale) to the intervention they are receiving (Tai Chi/Qi Gong or ALA). For those who demonstrate a sufficient response to their assigned treatment, they continue with their original intervention throughout the study. However, participants showing insufficient response undergo adjustments in their treatment regimen.

If a participant's response is deemed insufficient, they are assigned to combination treatments aimed at improving outcomes. The possible combinations include:

* Tai Chi/Qi Gong combined with acupuncture
* Tai Chi/Qi Gong and ALA
* ALA combined with acupuncture This dynamic approach allows the study to test not only the individual effects of Tai Chi/Qi Gong and ALA but also their combined impact with acupuncture when participants do not respond adequately to the primary interventions.

The study follows this response-adjusted intervention protocol over the course of 16 weeks, with final assessments made at the end of the study to evaluate the overall efficacy of each treatment pathway.

Tai Chi/Qi Gong arm: Participants will undertake an 8-week virtual Tai Chi/Qi Gong program consisting of online classes for 1 hour, twice a week. Using a manualized approach, each class will provide objectives and learning activities related to sequentially learning a specific set of Tai Chi/Qi Gong movements, with weekly verification of skills attainment. Six key elements will be emphasized: 1) Mindfulness; 2) Postural alignment; 3) Natural breathing; 4) Active relaxation, 5) Slow movement, and 6) Integrated movement.

ALA arm: Participants will have daily intake of 600 mg of ALA supplement, with instructions with food.

Acupuncture arm: Participants will receive acupuncture treatments for 8 weeks. After disinfecting the skin with an alcohol swab, acupuncturists will insert filiform 0.16 mm × 15 mm (or 30 mm) sterilized, disposable acupuncture needles in the ear and Ba Feng points. Additionally, 0.20 mm × 30 mm (or 40 mm) sterilized, disposable acupuncture needles will be inserted at body points. Needles for body points will be inserted 0.5 inches into the skin and left for 30 minutes after achieving de qi, a sensation of achiness, soreness, and heaviness.

• Tai Chi/Qi Gong (Behavioral): Participants will be asked to attend Tai Chi/Qi Gong classes for one hour twice a week for 8 weeks over Zoom video conferencing or in person. Using a manualized approach, each class will provide objectives and learning activities related to sequentially learning a specific set of Tai Chi/Qi Gong movements with verification of skills attainment weekly24. Six key elements will be emphasized: 1) Mindfulness; 2) Postural alignment; 3) Natural breathing; 4) Active relaxation, 5) Slow movement, and 6) Integrated movement.
• α- Lipoic acid (Dietary supplement), also known as ALA: Participants will be provided with Lipoic Acid Supplement (300 mg) bottles, with instructions to take two tablets daily, 30 minutes before breakfast.
• Acupuncture (Procedure): participants will receive acupuncture treatments for 8 weeks. After disinfecting the skin with an alcohol swab, acupuncturists inserted filiform 0.16 mm × 15 mm (or 30 mm) sterilized, disposable acupuncture needles in the ear and Ba Feng points; 0.20 mm × 30 mm (or 40 mm) sterilized, disposable acupuncture needles will be inserted at body points. Needles for body points will be inserted 0.5 inches into the skin and left for 30 min after achieving de qi, a sensation of achiness, soreness and heaviness.

Primary outcomes

• Consent Rate [Up to 2 years]: Proportion of eligible participants who provide informed consent.
• Treatment Adherence [16 weeks]: Proportion of prescribed intervention activities completed, including attendance at Tai Chi/Qi Gong or acupuncture sessions and adherence to alpha-lipoic acid (ALA) supplementation.
• Retention Rate [16 weeks]: Proportion of enrolled participants who complete the final follow-up assessment at the end of the study
• Progression to Stage II [8 weeks]: Proportion of participants who do not respond to Stage I treatment and undergo re-randomization to Stage II treatment within the SMART design.

Secondary outcomes

• Participant Satisfaction [16 weeks]: The Client Satisfaction Questionnaire - 8 item version (CSQ-8) is an 8-item standardized measure of global satisfaction with services. Each item is rated on a 4-point Likert scale, and the responses are summed to produce a total score ranging from 8 to 32, where 8 represents the lowest possible satisfaction and 32 represents the highest. Higher CSQ-8 scores indicate greater (better) satisfaction with services received.

Other outcomes

• Change in Chemotherapy-Induced Peripheral Neuropathy (CIPN) [From Baseline to Week 16 (about 4 months)]: Change in numbness and tingling severity assessed using the relevant items from the European Organization for Research and Treatment of Cancer Quality of Life - CIPN20 (QLQ-CIPN20) sensory subscale. The QLQ-CIPN20 sensory subscale uses a 1-4 response scale (1 = Not at all, 4 = Very much) for each item, which is then converted to a 0-100 score, where higher values indicate worse sensory neuropathy symptoms. The total sensory score is calculated by averaging the sensory-item responses and applying the standard EORTC symptom-scale transformation, resulting in a score where lower = better outcomes and higher = worse outcomes. A 2.5-5.9-point increase represents a clinically meaningful worsening (MCID) in sensory symptoms.
• Change in Falls Efficacy [Baseline to Week 16]: Short Falls Efficacy Scale-International consists of 7 items covering indoor and outdoor activities. Respondents indicate their level of concern about falling during each activity on a 4-point scale. The Short Falls Efficacy Scale-International is a 7-item self-report measure assessing an individual's concern about falling while performing everyday activities. Each item is rated on a 4-point scale, and responses are summed to produce a total score ranging from 7 to 28, where 7 indicates no concern about falling and 28 indicates severe concern about falling. Higher scores represent a worse outcome, reflecting greater fear of falling and lower falls-related self-efficacy.
• Upper Body Physical Function [Baseline to Week 17]: Upper-body physical function will be assessed using the Grip Strength Test measured with a Jamar Hand Dynamometer, a standardized and widely accepted measure of maximal isometric hand-grip force. Grip strength is recorded in kilograms (kg) or pounds (lb), with a minimum value of 0 (no measurable force) and a maximum measurable value of approximately 90 kg (200 lb) based on the device's calibrated range. Higher grip-strength values indicate a better outcome, reflecting greater upper-extremity muscle strength and functional capacity.
• Lower Body Physical Function [Baseline to Week 18]: physical function will be measured by Chair to Stand (CTS). The Chair-to-Stand (CTS) test is a functional performance measure of lower-body strength and mobility, most commonly administered as the 30-Second Chair Stand Test or the Five-Times Sit-to-Stand Test. In the 30-second version, the score is the number of complete stands performed in 30 seconds, with a minimum value of 0 (unable to rise without arm support) and no fixed maximum, although higher counts reflect better function; higher scores indicate a better outcome, representing greater lower-extremity strength and functional capacity.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Individuals must meet all the following inclusion criteria in order to be eligible to participate in the study:

  * Age 18 years or older,
  * Self-reported moderate (≥ 2/4) numbness and tingling on the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Numbness and Tingling Severity Item in the previous week,
  * At least three months since the last receipt of neurotoxic chemotherapy,
  * Prior receipt of paclitaxel, docetaxel, cisplatin, oxaliplatin, nab-paclitaxel, or carboplatin for the treatment of stage I-III Gastrointestinal (GI) cancers,
  * Speaking/reading English.

Exclusion Criteria:

* An individual who meets any of the following criteria will be excluded from participation in this study:

  * Prognosis of ≤ 3 months,
  * Documented neuropathy attributed to other causes (e.g., diabetic neuropathy),
  * Intention to initiate a new prescription of duloxetine or other pain medications (i.e., first-line treatment for CIPN pain) during the study period; however, participants may continue on duloxetine or other pain medications if initiated at least 8 weeks before study enrollment, with no change in dose, and reporting unmanaged CIPN (i.e., ≥ 2/4) PRO-CTCAE numbness/tingling severity in the last week,
  * Currently using alcohol (ethyl), which means regular alcohol consumption (defined as ≥7 drinks/week for women, ≥14 drinks/week for men, or binge drinking >3 drinks per occasion at least weekly) within the past 3 months, or current alcohol use disorder or inability/unwillingness to abstain from alcohol during the study intervention period,
  * Currently using calcium salts, iron preparations or magnesium salts orally,
  * With thyroid disorders, particularly those with hypo- or hyperthyroidism,
  * With thiamine deficiency, as assessed and verified by the physician.

• Kuang-Yi Wen, PhD, Principal investigator, Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University