Unforeseen complications due to COVID-19 and funding

This pilot study aims to evaluate the feasibility to conduct a study of acupuncture treatment (AT) for Chemotherapy-Induced Peripheral Neuropathy (CIPN) at Huntsman Cancer Institute and to investigate changes in physiological biomarkers when using acupuncture to treat CIPN.

This pilot feasibility study aims to determine if conducting a trial of AT for CIPN is feasible at Huntsman Cancer Institute (HCI). The investigators aim to enroll and retain twenty participants who will undergo fMRI during the baseline visit, receive 10 sessions of AT, and undergo fMRI after completion of AT. The investigators will examine fMRI for potential neurologic mechanisms of action of AT in CIPN management. The ultimate objective of this pilot project is to lay the foundation for a future randomized controlled clinical trial of AT for CIPN. Specifically, the investigators will be able to demonstrate that the investigators have the team and location in place to conduct a successful trial.

The participant will receive 10 acupuncture treatments over the course of 8 weeks with a baseline fMRI done prior to receiving acupuncture treatments and a final fMRI done after the completion of acupuncture treatments. Participant will receive questionnaires before fMRI, acupuncture treatments following final fMRI and at a 3 month follow up time point. (See below for more detail.)

1.1 Primary Objectives and Endpoints

To evaluate the feasibility to conduct a trial of AT for CIPN + standard of care therapy. Primary feasibility objectives will be evaluated in terms of recruitment (enrollment of 20 women, average of 2 eligible women per month to participate in the trial, identification of appropriate recruitment strategies, the appropriateness of eligibility criteria), retention (70% or more participants comply with 8 or more AT sessions and complete both fMRI scans), safety (zero serious adverse events directly related to AT) and questionnaire completion (70% or more enrolled participants comply with all data collection).

1.1.1 Primary outcome measures: Mean enrollment, completion rate of AT, fMRI, rate of serious adverse events, rate of questionnaire completion.

1.2 Secondary Objectives and Endpoints To evaluate the impact of AT on the reported experience of CIPN. 1.2.1 To evaluate central pain processing and cortical connectivity in patients with CIPN treated by acupuncture by analyzing fMRI of all participants.

1.2.2 To evaluate if there is any change in patient-reported measures from before AT to after study completion.

This study will enroll female patients who have completed treatment with paclitaxel or docetaxel at least three months prior. Paclitaxel and docetaxel are neurotoxic chemotherapies known to cause CIPN. Patients must have experienced at least one month of altered sensation and/or pain with a score of greater than or equal to 20 for CIPN on the sensory subscale of the CIPN-20. The investigators will commence recruitment 3 months after patients have completed their last paclitaxel or docetaxel dose. Patients will be recruited from the Huntsman Cancer Center Oncology Clinics in collaboration with their oncologists.

For this study, enrollment will be limited to patients with breast, ovarian, cervical, endometrial, or uterine cancer with CIPN and completed paclitaxel or docetaxel treatments.

Visits:

Screening Visit:

Potentially eligible subjects will be scheduled for a screening visit. After informed consent is obtained, the Study Coordinator (SC) will review and confirm inclusion/exclusion criteria. The SC will take a brief medical and neurological history and administer the CIPN-20 questionnaire. If all inclusion and exclusion criteria are fulfilled, the subject will proceed to baseline visit. This visit may occur on the same day as screening, but must occur within 2 weeks of study screening visit.

Baseline Visit:

Patients diagnosed with breast, ovarian, cervical, endometrial, or uterine cancer who were treated with paclitaxel or docetaxel chemotherapy associated with CIPN will undergo a number of questionnaires/exam scales designed to assess neuropathic symptoms and the effect of neuropathy on quality of life. The patient will then be enrolled in the study and scheduled in the Wellness Center for acupuncture therapy (AT). All participants will be scheduled for fMRI , which must occur within nine days after baseline.

Participants will undergo study interview and fMRI within 9 days after baseline following enrollment.

Demographic data and clinical data including current medications and medical history and fall rates will be gathered during the baseline visit. Questionnaires (BPI, CIPN-20, CIPN- Rasch-built Overall Disability Scale (R-ODS), MAIA-2) will be completed in person or emailed to patients via REDCap at baseline. Reminder calls and AT appointments will be scheduled by HCI Wellness and Integrative Health Center personnel in conjunction with a SC. The SC will aid participants in scheduling fMRI appointments online. AT treatments will occur within 7 days/4 business days in general.

Follow up Visits:

Participants will receive 10 sessions of AT: twice per week for 2 weeks, thereafter once per week for six weeks, with a total of 10 treatments during a two-month course. Each session will last 45-60 minutes, with acupuncture needles retained 30-40 minutes. A minimum of 8 treatments must be received by each participant with no more than 9 days' gap between weekly treatments permitted (sessions 5-10). Concurrent medications are allowed as prescribed and will be tracked in the study and analyzed as potential confounders.

Final Visit:

Participants will undergo examination within one week of AT completion. This will include the fMRI scan and questionnaires. Compensation for participation will be offered following the completion of questionnaires.

Measures:

Questionnaires will be completed in person or emailed to patients via REDCap at baseline and study conclusion, as well as at a 3-month follow-up. Primary Endpoints: Mean enrollment, percentage completion rate of all study procedures, frequency count of serious adverse events, and percentage of enrolled participants completing questionnaires will be calculated. Data will be collected via REDCap and analyzed with Statistical Package for the Social Sciences (SPSS).

Additional measures to be collected: CIPN-20: This measure includes questions about tingling, numbness, painful numbness, cramps, balance, temperature intolerance, grasping items, ankle flexion weakness and leg weakness. CIPN-R-ODS (a validated measure of quality of life specific to CIPN), will be used to assess impact on function, BPI to assess pain and Multidimensional Assessment of Interoceptive Awareness (MAIA-2) to assess mind-body awareness. The investigators will also collect demographic information including age, marital status, race and ethnicity, current medications and medical history.

Acupuncture therapy (AT): AT will be delivered onsite at HCI in the Linda B. and Robert B. Wiggins Wellness & Integrative Health Center. AT will be delivered twice per week for two weeks and then weekly for six weeks by Annie Budhathoki, Doctor of Acupuncture and Oriental Medicine (DAOM), a Licensed Acupuncturist who has over five years' clinical experience treating persons with cancer, or another Licensed Acupuncturist in the Wellness & Integrative Health Center. Each session will last 45-60 minutes, with acupuncture needles retained 30-40 minutes. A minimum of 8 treatments must be received by each participant with no more than 9 days' gap between weekly treatments permitted (sessions 5-10). .

Functional MRI (fMRI) to be conducted within 9 days after baseline and within 1 week of final AT session. fMRI scans will be conducted at Imaging and Neuroscience Center (INC) in Research Park. Imaging will consist of structural brain imaging (MP2RAGE), task fMRI, and resting-state fMRI connectivity. Task fMRI will consist of a mental imagery task with a 20-second block design wherein patients will alternate between concentration on a part of their body where they experience pain and a part of their body where they do not experience pain, prompted by visual cues. The investigators will provide gift cards for $25 after the completion of the second fMRI and questionnaires associated with this visit.

Clinical evaluations: Demographic data, clinical data including current medications and medical history and fall rates will be gathered.

Inclusion Criteria:

Female age 18 or older.

• Histologically proven breast, uterine, cervical or ovarian cancer of any stage.
• Received either (1) a Paclitaxel treatment dose of at least 480 mg/m2 paclitaxel as a single or combination agent or (2) a Docetaxel treatment dose of at least 150 mg/m2 docetaxel as a single or combination agent. Treatment must be completed at least 3 months prior to enrollment.
• Eligible participants report at least 1 month of altered sensation and/or pain in the feet (with or without presence in one or both hands) with a score of greater than or equal to 20 for CIPN on the sensory subscale of the CIPN-20 (scale 0-100).
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
• Eastern Cooperative Oncology Group (ECOG) status of 0 (asymptomatic), 1 (symptomatic but completely ambulatory) or 2 (symptomatic, <50% in bed during the day).

Exclusion Criteria:

• Preexisting neuropathy due to other identified etiologies includes diabetes, vitamin B12 deficiency, or alcoholism.
• Having received more than 6 acupuncture treatments for any condition in the last six months.
• Participants with claustrophobia, pacemakers, non-MRI compatible breast expanders or port-a-caths, neurostimulator devices, current pregnancy, exposure to shrapnel, left-handedness, or otherwise unsafe for MRI scanning.

From start of acupuncture treatment (AT) to 12 weeks following discontinuation of AT (approximately 22 weeks per patient)

The COVID-19 pandemic forced recruitment and enrollment to stop in March 2020 leading to small numbers of participants analyzed.