Virtual Personalized Exercise Program for Lung Cancer Patients

This is a prospective study providing lung cancer subjects at R.J. Zuckerberg Cancer Center with a customized exercise program provided by Salaso, with the goal of improving functional status and outcomes. This study will assess the feasibility and usability of a virtual exercise platform designed for lung cancer subjects. Subjects will be referred to physical therapy and rehabilitation medicine doctors for evaluation and enrolment in a virtual exercise program tailored specifically to their needs. The virtual exercise program will be available on a digital platform accessible through a personal device. Subjects will undergo a pulmonary function test if not previously completed within 3 months of signing consent, a Six minute walk test (6MWT) and the Sit to Stand Test (STS) at the start and end of the 12- month program. Subjects will also be asked to complete quality of life FACT-L and the Patient Satisfaction questionnaires at 1 month, 3-months, 6-months, and 12-months. Patient satisfactions questionnaires include the System Usability Scale, Net Promotor Score (NPS), and the Technology Acceptance Model. Physicians will also complete a provider satisfaction questionnaire at 1 month, 6 months, 12 months, and 24 months from the time their first patient is enrolled. Subject participation in the trial will last 12 months from the time the subject starts utilizing the platform. If we find that the platform is accepted by subjects and is found to be feasible, a future randomized study will be developed to follow.

Eligibility criteria (note that subjects will be allowed to be enrolled in the program as long as it is within 3 weeks of starting treatment):

i. Subjects with Non-small cell lung cancer who belong to any of the three cohorts below ii. Have an ECOG PS of 0-2 iii. Can provide informed consent iv. Can engage in a virtual exercise platform v. Commit to all study procedures as per protocol vi. Are deemed appropriate for virtual exercise program by the PM\&R team

The following three cohorts of subjects will be eligible for this feasibility study:

1. Cohort A: Peri-operative (subjects starting neoadjuvant chemotherapy or within 4-8 weeks after curative-intent thoracic surgery which could be segmentectomy, lobectomy of pneumonectomy), irrespective of adjuvant treatment).

1. Expected recruitment - 15 subjects
2. Cohort B: Subjects starting definitive chemotherapy and radiation for locally advanced lung cancer.

1. Expected recruitment - 15 subjects

3. 3. Cohort C; Subjects with stage IV metastatic non-small cell lung cancer irrespective of type of treatment.

1. Expected recruitment - 30 subjects

Cancer as a chronic disease: Cancer is now considered a chronic disease and the number of cancer survivors is estimated to be more than 22 million individuals in the United States by 2030.\[1\]

Cancer and exercise: As opposed to chronic conditions such as heart disease, diabetes, and pulmonary disease where exercise has been recommended for decades, exercise recommendations for oncologists has been slow to evolve. However, exercise and rehabilitation interventions are known to benefit cancer survivors. Interestingly, research has been shown that the risk of developing cancer can be reduced by exercising a minimum of 3 - 5 hours per week, reducing the risk of breast cancer by 15 to 20%, decreasing the risk of colorectal cancer by 19-24%, gastric cancer by 19%, kidney cancer by 23%, and esophageal cancer by 21%.\[2, 3\] While we know a lot about exercise beneficial effects on the heart and skeletal muscle, studies are emerging on its effects on other organs where cancer cells grow including breast, prostate, colon, pancreas, kidney, liver and lung. Exercise can also play a role in cancer treatment by reducing treatment-related toxic and side effects and enhancing the curative effects of other treatments.\[2\] For those undergoing active cancer treatment, exercise has proven benefits. For example, breast cancer subjects treated with aromatase inhibitors develop decreased cognitive ability and lower bone mass.\[2\] Exercise is thought to prevent cognitive impairments caused by estrogen deficiency. Similarly, for prostate cancer, physical exercise can improve androgen-deprivation therapy. The most reported issues for cancer survivors are physical problems (muscle mass reduction, pain, and fatigue) and psychosocial problems (depression, cognitive decline, and fear of recurrence) and increased risk of developing secondary comorbidities such as cardiovascular disease.\[4\] Physical exercise has been shown to improve fatigue related to cancer treatment, likely by mitigating oxidative stress and reducing hormone stimulation. Additionally, those who exercise post-colon resection have a 50% reduction in disease-free survival when comparing 18 to 27 metabolic equivalent task (MET)-hours per week versus less than three MET-hours per week.\[5\] Observational cohort studies show that subjects who have high physical activity after diagnosis have lower risk of disease recurrence and cancer mortality.\[6\] Randomized clinical trials have also validated that physical activity interventions both mitigate cancer-impaired quality of life and improve outcomes for cancer survivors. One in ten cancer deaths have been attributed to lack of physical activity.\[7\] And, a recent meta-analysis of 38,560 cancer survivors demonstrated a 37% lower relative risk of dying from cancer for the most active compared with the least active subjects (HR: 0.63; 95% CI: 0.54-0.73).\[8\] There are a number of clinical trials focused on the impact of physical activity and/or dietary modifications on ovarian cancer (LIVES - The Lifestyle Intervention for Ovarian Cancer Enhanced Survival), colon cancer (CHALLENGE - The Colon Health and Life-Long Exercise Change), prostate cancer (INTERVAL-GAP4 - Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer), and breast cancer (BWEL - The Breast Cancer Weight Loss).\[12-15\] A meta-analysis estimated that each 15 metabolic equivalent task-hour per week increase in physical activity after colorectal cancer diagnosis was associated with a 38% lower risk of mortality.\[9\]

The science behind beneficial effect of exercise in cancer subjects: There are multiple mechanisms cited for how exercise produces its beneficial effects, including through hormones, dopamine, transforming growth factor-B1 (TGF-B1), insulin-like growth factors (IGFs), microphthalmia/transcription factor E (MiT/TFE), mammalian target of rapamycin (mTOR), and secreted protein and rich in cysteine (SPARC). It has been shown in in-vitro and mice models that exercise inhibits cancer cell proliferation (for moderate- and high-intensity exercise, not low-intensity exercise) and induces apoptosis. One such mechanism involves dopamine release in the prefrontal cortex, serum, and cancer tissues. Dopamine binds to the dopamine receptor 2 (D2) upregulating the kinase phosphorylation and TGF-B1 to inhibit cancer cell proliferation.\[10\] Another mechanism involves IGFs which regulate mitosis and anti-apoptosis and affect proliferation and differentiation of cancer cells. Studies have shown that postmenopausal women have decreased IGF-1 and IGF-3 after walking training for 6 months, which inhibits IGF's anti-apoptosis effect in breast cancer, for example. Weight loss also reduces levels of IGF-1. Exercise induces skeletal muscle to produce SPARC, which promotes cleavage of caspase-3 and caspace-8, promoting cell apoptosis and inhibiting colon cancer. AMP activated protein kinase (AMPK) is an important center of homeostasis and regulator of mTOR kinase activity. In a mouse study involving hepatocarcinoma, exercise reduced the activity of mTOR kinase by stimulating AMPK, thereby reducing cancer cell proliferation. Finally, exercise can regulate cancer metabolism by inhibiting Warburg anaerobic glycolysis and weakening the hypoxia microenvironment of cancer. Lactic acid is the most important metabolite of glycolysis and cancer cells produce lots of lactic acid, creating a low-pH environment. Lactic acid suppresses the immune response, inhibiting T cells. Therefore, by inhibiting anaerobic glycolysis, exercise suppresses lactic acid production, improving the immune response to target cancer cells.\[11\] Additionally, exercise stimulates the activity of NK cell function, decreasing inflammation, enhancing antigen presentation, and mitigating the accumulation of aging cells in the elderly.\[12\]

Guidelines regarding exercise in cancer subjects and survivors: Both the American Cancer Society (ACS) and National Comprehensive Cancer Network (NCCN) have recommendations for cancer survivors regarding maintaining healthy weight and exercise among cancer survivors. \[13,14\].

The NCCN recommends:

* Be physically active every day - routine activities, recreation, or exercise
* Avoid being inactive for long periods each day
* Increase your heart rate each week: moderate-intensity activity for at least 150 to 300 minutes a week or vigorous-intensity activity for 75 minutes a week or a mix of moderate and vigorous-intensity activity
* Strengthen major muscles with resistance training 2 to 3 times a week
* Stretch major muscles on at least 2 of the days of high-intensity activity
* Healthy eating: focus on plant-based diet and limiting animal proteins such as red meat. Limiting processed foods.

The ACS recommends:

* Getting 150-300 minutes of moderate intensity or 75-150 minutes of vigorous intensity activity each week. Getting to or exceeding the upper limit of 300 minutes is ideal.
* Limit sedentary behavior such as sitting, lying down, watching TV, and other forms of screen-based entertainment.
* Healthy eating patterns
* Foods that are high in nutrients in amounts that help you get to and stay at a healthy body weight
* A variety of vegetables - dark green, red and orange, fiber-rich legumes and others
* Fruits, especially whole fruits in a variety of colors
* Whole grains
* Limiting red and processed meats, sugar-sweetened beverages, highly processed foods and refined grain products.

However, no clinical trials were found in our literature search that involve lung cancer subjects. There have been many articles describing the benefits of exercise for lung cancer survivors. Physical fitness, such as cardiorespiratory endurance and muscular strength have been independent predictors of survival.\[15\] However, the potential impact of exercise in lung cancer has not been fully explored and there are no guidelines for specific exercise programs. Avancini et al. proposed that a collaboration of exercise specialists is urgently needed to develop tailored programs based on subjects' needs, preferences and physical and psychological status.

It is becoming generally agreed that exercise improves oncological outcomes in cancer survivors. However, implementing programs for oncology rehabilitation have not been fully delineated. It has been proposed for oncology rehabilitation to piggy-back onto widely available exercise programs, such as cardiac rehabilitation.\[16\] It has also been proposed to use LIVESTRONG programs at the YMCA.\[5\] In a systematic review of sixteen randomized controlled trials including 2,684 participants, it was shown that the exercise programs that are most effective use technology-supported self-guided interventions.\[17\] Additionally, in a meta-analysis of 34 RCTs, exercise effects on quality of life and physical function were significantly improved with supervised rather than unsupervised exercise interventions.\[18\] Despite clear benefits, compliance with exercise program amongst cancer survivors has been an obstacle. In a systematic review of breast cancer subjects, only 6 of 17 trials demonstrated that significant intervention effects were maintained.\[19\] The study recommended greater transparency in reporting interventions to help maintain exercise programs. It will be important to determine when to start an exercise program, whether at diagnosis, during treatment or sometime after treatment, with the understanding that exercise can be considered another form of treatment and prevention. As the survivorship pool increases, it will be important to educate subjects that exercise is an essential component of treatment and secondary prevention.

Physical fitness, such as cardiorespiratory endurance and muscular strength have been independent predictors of survival.\[20\] However, no clinical trials were found in our literature search that specifically targeted lung cancer subjects on active treatment. As such, the potential impact of exercise in lung cancer subjects has not been fully explored and there are no guidelines for specific exercise programs. Furthermore, optimal timing, assessment for readiness, exercise specifics, and mode of administration of programs for oncology rehabilitation have not been fully delineated.

Lung cancer as focus: Subjects with lung cancer have a high symptom burden, due to their underlying disease and comorbidities. Surgical resection (segmentectomy, lobectomy or pneumonectomy), thoracic radiation and systemic cancer treatment can further add to deconditioning and low exercise capacity. It can be theorized that physical and pulmonary rehabilitation can potentially benefit these subjects and improve outcomes. A metanalysis which included 6 clinical trials and 221 participants showed that exercise training may improve or delay the decline in exercise capacity and disease specific global (Health Related Quality of Life) HRQoL for adults with advanced lung cancer.\[21\] However, there was no significant effects of exercise training on dyspnea, fatigue, feelings of anxiety and depression, or lung function. As the authors noted, there was significant heterogeneity between the trials, all of which had too small a sample size to derive any definitive conclusions.

Small randomized controlled studies have shown that pulmonary pre-habilitation and rehabilitation improve post-operative outcomes, post-operative pulmonary function and HRQoL.\[22\] Similarly, subjects who are undergoing chemotherapy were shown to benefit from an exercise program.\[23\] Despite multiple studies showing benefit, exercise program is not typically included in the treatment plan of lung cancer subjects. This is because this intervention has several challenges. Some of these issues are listed below.

1. Lostistic issues related to creating a multidisciplinary team of physiatrists, pulmonologist, oncologists, and other specialists for every subject
2. Creating a tailored regimen that is appropriate for each subject
3. Creating and maintaining enthusiasm amongst to participate in an exercise program
4. Time constraints of a busy oncology practice
5. Barriers related to number of visits to outsubject rehab facility, especially for subjects who live far from the rehab center.
6. Physical and emotional stress resulting from cancer diagnosis and treatment.
7. Comorbidities

Rationale for Northwell Health: Northwell Health is the largest health care system in the region, caring for over 300 lung cancer subjects every year. With a cohesive multidisciplinary team, accrual for this study will not be difficult. The virtual platform and the hands-on support from the PM\&R and Salaso team will make it easier for subjects to participate regardless of their ability to travel frequently to the cancer center, and level of comfort with virtual platform.

Northwell is collaborating with Salaso for this project. Salaso is a digital health technology company that has online, mobile and telehealth solutions enabling providers to 'prescribe' evidence-based exercise programs for patients to complete virtually. The ExerciseRx project has two components:

* Platform Feasibility: Evaluating the feasibility of incorporating the Salaso platform into clinician workflow and understanding overall utilization of the platform by subjects (e.g., frequency of use, user satisfaction). Salaso will provide access to their ExerciseRx virtual exercise platform to Northwell providers and subjects and provide the necessary technical support to facilitate training and onboarding to the platform.
* Clinical Outcomes: In addition to feasibility of the platform the Northwell oncology team seeks to evaluate clinical impact for lung cancer subjects. For example, this will include evaluating pulmonary function and conducting the Six minute walk test (6MWT) and Sit to Stand Test (STS) at baseline and at the 12 month end of the study.

  * The additional clinical components of the study are Investigator Initiated and are funded by Northwell's Cancer Institute.

The Salaso digital technology is already integrated with Northwell's EMR. Platform satisfaction and FACT-L quality of life questionnaires will be directly administered to subjects via RedCap or on paper.

The following measures have been taken to protect HIPAA compliance

1. Despite Salaso's integration with Northwell EMR, Salaso will not have access to identifiable subject data. Although data will be collected via the ExerciseRx application, Salaso will only retain de-identified aggregate information and they will share the aggregate information directly with AstraZeneca. Questionnaires will be collected via RedCap. Biostatistician will be able to access RedCap data without PHI for statistical analysis.
2. Salaso will also passively collect data on the utilization of ExerciseRx, such as time spent in the platform and number of video views, to be shared with Northwell and Astrazeneca quarterly.

Disclosure:

Northwell Holdings, the investment arm of Northwell Health has invested in Salaso. Salaso's platform is already being used through Northwell's employee benefits portal (myHealthBody) and by the neurology department at Northwell (ExerciseRx). Salaso's platform is currently integrated with Allscripts.

In addition, AstraZeneca, is funding the use of the Salaso platform with Northwell and lung cancer patients. AstraZeneca funding will be used by Salaso to support the following:

* Development of the evidence-based exercises for the lung cancer patient population
* Salaso on the ground resource to support the training and onboarding of providers and patients to the Salaso ExerciseRx platform
* Collecting de-identified data on patient use of the platform, e.g. how many patients downloaded the ExerciseRx app, how often the patients used the app etc. (there will be no sharing of patient identifiable data).

The following measures are being taken to mitigate any perceived or potential conflict of interest (COI) related to Northwell Holding's investment in Salaso:

1. This study is investigator initiated. None of the investigators have any financial interests in Salaso.
2. Salaso's exercise program will be provided with no direct cost to subjects or providers.
3. Disclosure of Northwell's holding in Salaso will be made in the subject consent forms as well as in the final publication of study results.
4. Updates regarding the study, whether positive of negative will be provided to IRB as per Northwell IRB policies.
5. All investigators will engage in good clinical practices (GCP) and follow Human Subjects Research Protection guidelines per their Collaborative Institutional Training Initiative (CITI) training.

Eligibility Criteria:
Inclusion Criteria:

(1) Adults aged 18 and older (2) Have an ECOG PS of 0-2 (3) Have the ability to provide informed consent (4) Have the ability to engage in a virtual exercise platform (5) Commit to all study procedures as per protocol (6) Are deemed appropriate for virtual exercise program by the PM\&R team (7) English speaking (8) Subjects with non-small cell lung cancer who belong to any of the three cohorts: (i) Cohort A: Peri-operative (subjects starting neoadjuvant chemotherapy or within 4-8 weeks after curative-intent thoracic surgery which could be segmentectomy, lobectomy of pneumonectomy), irrespective of adjuvant treatment - expected recruitment: 15 subjects (ii) Cohort B: Subjects starting definitive chemotherapy and radiation for locally advanced cancer - expected recruitment: 15 subjects (iii) Cohort C: Subjects with stage IV metastatic non-small cell lung cancer irrespective of type of treatment- expected recruitment: 30 subjects

Exclusion Criteria:

1. Unable to render informed consent
2. No other current active malignancy (beside lung cancer) at time of enrollment
3. Any contraindication to participating physically in an exercise program
4. Pregnant or breastfeeding at the time of screening visit
5. Any of the following contraindications to exercise use: acute post-operative subjects (within 8 weeks of operation; subjects with extreme fatigue, anemia, or ataxia; and general cardiovascular and respiratory contraindications for an exercise regimen.
6. Lack of proficiency in English sufficient for comprehension of trial source documents including the protocol, consent, and questionnaires.