Recruitment strategies and design considerations in a trial of resistance training to prevent dose-limiting toxicities in colon cancer patients undergoing chemotherapy

Abstract

Low muscle is associated with an increased risk of chemotherapy-related dose limiting toxicities (DLT) in cancer patients. Resistance training (RT) improves muscle mass; however, the effects of RT on preventing DLTs and dose reductions in colon cancer patients has not been investigated.

FOcus on Reducing dose-limiting toxicities in Colon cancer with resistance Exercise (FORCE) is a multicenter, randomized clinical trial examining the effects of RT on relative dose intensity (RDI; primary outcome) and moderate and severe chemotoxicities (primary outcome) in non-metastatic colon cancer patients receiving adjuvant chemotherapy. Patients (N=180) will be recruited from Kaiser Permanente Northern California, Dana-Farber Cancer Institute, and Penn State Cancer Institute. This paper describes recruitment strategies and design considerations.

Patients will be randomized in equal numbers to RT intervention or control. Patients have baseline and post completion of chemotherapy visits where information on anthropometry, physical function, body composition, quality of life, physical activity and dietary behaviors, and inflammatory blood markers will be collected. Patient-reported outcomes of chemotherapy side effects will be collected around the time of chemotherapy throughout the duration of the trial. Intervention participants will be prescribed a progressive RT program consisting of 4–6 visits with a certified exercise trainer, delivered either in-person or remotely by video conference, and will be asked to engage twice weekly in-home training sessions. Control patients at the end of the study receive a consult with a FORCE exercise trainer, an online exercise RT training program and a set of resistance bands.

Results of this trial will provide information on the benefit of resistance exercise as a treatment to increase RDI.

Introduction

Colorectal cancer (CRC) is the 4^th most common type of cancer in the United States with an estimated 147,950 individuals diagnosed in 2020 [1]. While surgery is the primary modality of management for colon cancer in patients with non-metastatic disease (stages I-III), adjuvant therapy is offered to a subset of those with stage II disease and the majority of stage III patients [2]. Dose limiting toxicity (DLT) leading to dose delays, dose reductions and a lower relative dose intensity (RDI) is common among those receiving chemotherapy for colon cancer.

Sarcopenia (low muscle mass), an established risk factor for CRC mortality, is prevalent in up to 45% of early stage CRC patients at diagnosis [3]. Those with sarcopenia who receive chemotherapy are at a higher risk of dose delays and reductions [4], which are associated with poorer survival outcomes [5]. Given the large number of CRC diagnoses, the high prevalence of sarcopenia among those diagnosed with CRC and the increased risk of DLT among those with sarcopenia, research on interventions to decrease the risk of these toxicities is of high clinical importance.

Cytotoxic agents used in the treatment of CRC, such as fluorouracil (5-FU) and oxaliplatin, are considered narrow therapeutic index drugs, where small changes in drug exposure can greatly impact clinical efficacy and toxicity [6]. 5-FU is hydrophilic, but widely distributed through active transport [7]. It undergoes extensive metabolism, primarily through dihydropyrimidine dehydrogenase, variants of which have been associated with increased risk of toxicity to 5-FU [8]. Based on these considerations, 5-FU clearance and volume of distribution are likely related to hydrophilic compartments of body composition: skeletal muscle mass (MM). Studies have shown that clearance of 5-FU is increased (i.e., exposure decrease and less toxicity) in individuals with higher MM [9].

Body composition is known to impact the pharmacokinetics of oxaliplatin. Oxaliplatin is eliminated renally, with clearance similar to glomerular filtration rate [10] and is highly lipophilic. Thus, distribution may be increased in individuals with higher fat mass/muscle mass ratios, resulting in higher drug exposure in sarcopenic obese individuals than in nonsarcopenic individuals. It has been hypothesized that low MM may result in a smaller tissue volume for distribution of cancer therapies with potentially lower capacity for metabolism and clearance of drugs, leading to enhanced toxicity.

Resistance training (RT) can result in increased MM [11]. In a meta-analysis of six trials that evaluated RT on lean body mass, resistance training was associated with a statistically significant increase of 1.07 kg (p<0.0001) in cancer survivors [12]. However, only a limited number of studies [13–16] have examined the effect of RT on chemotherapy completion rates or in preventing dose reductions, with inconsistent results. Thus, large scale studies, especially in colon cancer, are warranted.

FOcus on Reducing dose-limiting toxicities in Colon cancer with resistance Exercise (FORCE) is a 6-month randomized trial designed to investigate the effects of building MM through RT on preventing DLT, dose delays and dose reductions. This study will fill many existing gaps in our understanding of body composition, RT, DLT and RDI.

METHODS

Research Design

Overview of FORCE –

FORCE is a randomized trial comparing study participants in a home-based resistance training intervention to a usual care (UC) group in recently diagnosed stage II and III colon cancer patients, following surgery, being treated with adjuvant chemotherapy. The goal of the trial is to increase muscle mass by at least one kilogram thereby reducing DLTs. Eligible participants will be recruited within the first 6 weeks of chemotherapy from Kaiser Permanente Northern California (KPNC) and Dana Farber Cancer Institute (DFCI), over a period of 42 months and Penn State Cancer Institute (PSCI), over a period of 16 months. Participants will be randomized on a 1:1 basis between intervention and control. We will examine differences between intervention and control groups in measures of average relative dose intensity (ARDI), RDI and severe toxicities; body composition; and inflammatory markers.

Recruitment Strategies –

FORCE is a multi-site study across three different medical institutions: KPNC, DFCI, and PSCI. The study was approved by the KPNC (CN-17–2877), DFCI (18–063) and PSCI (STUDY00008634) institutional review boards and informed consent was required. At all sites, study staff obtain approval from the treating providers, typically oncologists, before recruiting participants into the study.

KPNC recruitment:

Preliminary eligibility of participants will be assessed using the electronic medical record (EMR). After confirmation of chemotherapy prescription at the time of first oncology visit, and permission to contact is received, study staff will send invitation letters via USPS mail and/or secure email. Five days later participants will be called to invite them to the study and to screen for full eligibility.

DFCI recruitment:

Participants will be recruited from the patient populations of the Gastrointestinal Cancer Center clinics at Dana-Farber Cancer Institute. Study staff will utilize multiple active recruitment techniques to maximize participation including: review of clinic schedules for medical oncologists to identify patients with stage II and III colon cancer (partial HIPAA waiver was obtained to review these patient lists); education of oncology providers about the FORCE study to encourage referrals; tumor registries; and advertisements in patient areas. Once potential participants are identified, and oncologist approval is obtained, they will be contacted to gauge interest and screened by study staff and if eligible, the individuals will be scheduled to meet with a member of the study staff to review the protocol and sign informed consent.

PSCI recruitment:

On a weekly basis, study staff will review the EMR to identify potentially eligible patients. Once oncologist approval is received study staff will contact participants by phone to gauge interest and ask a series of brief eligibility screening questions. Patients who are provisionally eligible based on the phone screening and interested will meet with study staff in person for further eligibility and to consent.

Participant Screening and Eligibility –

Eligible participants are men and women, 18 years or older, with newly diagnosed stage II or III colon cancer who recently completed curative-intent surgical resection and are prescribed one of the following adjuvant chemotherapy regimens: FOLFOX (5-FU/leucovorin [LV] and oxaliplatin), 5-fluorouracil and leucovorin (5-FU/LV), CAPOX (capecitabine and oxaliplatin), or capecitabine.

Patients will be excluded if they have concurrent actively treated other cancer (except non-melanoma skin cancer, in situ cervical cancer or localized prostate cancer treated with surveillance only); untreated hypertension; creatinine values less than 2 mg/dL; metastatic disease; a current strength training regimen; or are enrolled in other behavioral health clinical trials.

Pre-Randomization Screening –

Recruiters will conduct eligibility screenings with participants to ask additional questions that cannot be answered by EMR review. Items include the Physical Activity Readiness Questionnaire (PAR-Q) [17]; questions about regular participation in RT exercises during the past year; whether they have any major surgeries planned during the intervention period; and whether they are enrolled in other clinical trials for weight loss, physical activity, or dietary interventions. All participants must be able to understand English and be willing to be randomized.

Baseline Clinic Visit –

Prior to the start of the baseline visit, written informed consent for participation in the FORCE study will be reviewed and signed. The first clinic visit includes the following assessments: anthropometric measures (i.e., height, weight, hip and waist circumference); the short physical performance battery (SPPB) [18] and grip strength; questionnaires including the EORTC Quality of Life Questionnaire [19], SF-36 [20], demographic information, Paffenbarger Physical Activity Questionnaire [21], 2014 Block Food Frequency Questionnaire [22, 23]; non-fasting blood specimen; and a whole body composition dual-energy x-ray absorptiometry (DXA) scan.

Follow-up Clinic visit –

All baseline assessments will be repeated within 4 weeks of when participants finish with their last cycle of chemotherapy at 3 or 6 months, depending on prescribed regimen. In addition, participants complete an injury history questionnaire [24].

Field interviewers will be trained and certified on administration of all clinic visit study measures. Further, all interviewers will have access to the FORCE data collection manual, a resource that outlines standard operating procedures for each measure.

Randomization

After completion of the baseline visit, participants will be randomized to either the RT group or the waitlist control. A covariate adaptive randomization procedure [25] (minimization) will be used to ensure that the two treatment groups are balanced on site, gender (male, female), stage (II or III), treatment regimen (FOLFOX, 5-FU/LV, CAPOX, capecitabine), and treatment duration (3-months, 6-months). After randomization, study staff will inform participants of their group assignment and provide instructions on how to proceed for the remainder of their involvement in the study.

Intervention Groups

Resistance Training Group –

The RT intervention will begin, ideally, around the first treatment of chemotherapy, must start before the third chemotherapy cycle and will continue through the completion of chemotherapy treatment. The intervention program is presented in face-to-face sessions between an exercise trainer and the participant typically right before or during chemotherapy sessions. Then participants are instructed to train at home twice weekly, performing prescribed resistance exercises using equipment (i.e., Power Blocks), that is specifically designed for home-based RT and that will be shipped directly to their homes. The intervention also includes a recommended daily consumption of a protein supplement. Exercise trainers, delivering the intervention are nationally certified, trained and approved to deliver the FORCE intervention protocol.

Each person in the intervention group will be asked to consume daily 40 grams of whey protein in the form of a powdered supplement. Protein supplements will be recommended to make sure each intervention participant has adequate protein intake to optimize their anabolic response to the resistance training. They will be given or mailed (coinciding with initial trainer visit) 20 gm packets (unflavored or vanilla flavored) of BiPro whey protein (Agropur, Eden Praire, MN) and instructed to consume them at two out of their three meals per day. They will be instructed to consume the protein supplement approximately 30 minutes into the meal, so the extra protein does not interfere with their current or subsequent meal protein intake. For patients who are lactose intolerant, they will be offered a pea protein supplement as an alternative (Garden of Life Raw Organic Protein, unflavored or vanilla flavored). Participants will be given a packet of weekly protein logs, instructed on how to use the protein and how to complete the logs. Logs will be reviewed with the exercise trainer each time they meet in-person or by phone with recommendations to encourage use or modify as needed.

FORCE exercise trainers will meet with participants in-person four to six times, depending on chemotherapy duration, for supervised and individualized instruction sessions. At the first exercise session, the exercise trainers will test the participants’ current strength capacity using estimated one repetition maximum for each exercise to create an individualized exercise prescription; teach participants the specific series of RT exercises and how to use the exercise equipment; instruct and motivate them to complete the exercises at home two times each week for the duration of their treatment and to consume the protein supplement; and teach them how to document adherence using the exercise and protein logs.

At all following in-person sessions, the exercise trainers will review exercise and protein logs, evaluate the participants’ ability to increase weights with proper lifting form and adjust the exercise prescriptions depending on how the participants are feeling. Weeks when there is no in-person meeting, the exercise trainers will call participants to check in and troubleshoot and provide ongoing motivation to continue the RT intervention. Tracking for adherence for the remote based intervention that was instituted after COVID-19 will be the same as tracking for the protocol that had initial-in person visits. Weekly exercise logs will be kept throughout the duration of the trial and sent to the trainer, and weekly check-in calls from the trainer to the participant will be continued. Exercise trainers will document all interactions with participants in a REDCap database. An in-depth description of the exercise intervention will be summarized in a subsequent exercise protocol paper.

Due to COVID-19, beginning March 16, 2020, all study visits for patients already enrolled in the trial were delivered by videoconference remotely. When in-person recruitment resumed in June and July 2020, the decision was made in most cases to continue with an in-person visit for the first exercise session for new participants randomized to the intervention arm so that the exercise trainer could test the participants’ current strength and safety doing exercises. All subsequent in-person exercise sessions for participants randomized to the intervention arm after June 2020 (approximately one-third of the sample) will be delivered by videoconference remotely. The exercise trainers and participants will meet through a secure remote platform such as MS Teams or Zoom. Like the in-person visits, online sessions will last between 30 and 45 minutes. During these sessions they will discuss how the participant is feeling, review the past weeks exercise and protein logs, and perform exercises with increased weights. If requested, once a week the trainer will also be available to complete a full exercise session online with the participant to provide motivation and guidance.

Fidelity of Intervention:

All exercise trainers participated in a standardized FORCE training and were approved to deliver the intervention as designed. Initial certification involved exercise trainers completing mock training sessions while being observed by an exercise supervisor who used quality control checklists to evaluate competencies in delivery of the intervention. Following the initial certification process, exercise trainers will be recertified annually during study site visits. Like the initial certification, an exercise supervisor observes the exercise trainers delivering one in-person training session and one phone check-in. At the end of the site visit, the exercise supervisor debriefs with the exercise trainer and develops a corrective action plan for any problems or deviations from the study’s protocol. In addition to trainings, the exercise trainers participate in cross-site conference calls every other week with the exercise supervisors to troubleshoot any issues or challenges that participants are experiencing while completing the RT program during chemotherapy. Study staff document these issues in a frequently asked questions document so exercise trainers can consistently respond to subsequent participant challenges and deliver the intervention in a standardized manner.

Usual Care Group –

Participants randomized to the UC group will be instructed to speak with their physician regarding what forms of exercise are safe for them, given their specific medical history. The UC group will be told to continue whatever exercise program they are currently doing at the time of enrolling in the study, but not to increase exercise or begin resistance training over the period of study participation. At the conclusion of participation in the study, these participants will be offered: an online exercise RT routine; a set of resistance bands; a 30-minute consult with FORCE exercise trainer; and samples of protein powder.

Measurements

Anthropometric Measurements –

Field interviewers will measure participants’ height, weight, hip circumference and waist circumference at the clinic visits. Procedures are based upon the National Health and Nutrition Examination Survey (NHANES) Anthropometry Procedures Manual (waist circumference, height and weight) [26], and the World Health Organization’s STEPS Surveillance Guide to Physical Measurements (hip circumference) [27].

Computerized Tomography –

Muscle mass, muscle radiodensity, and visceral and subcutaneous adipose tissue will be assessed at diagnosis for all participants utilizing computed tomography (CT) scans from the abdominal region collected as part of routine clinical care for diagnostic purposes. Co-PIs Drs. Caan and Meyerhardt have co-published study results utilizing CT scans to assess skeletal muscle index amongst patients with colon and breast cancer [28, 29].

Physical Function –

Physical function status will be measured by having participants complete the SPPB[18]. This is an objective assessment tool developed by the National Institute on Aging to measure lower extremity functioning. Additionally, participants will complete the grip strength test following a standardized procedure.

Quality of Life –

Participants will answer the 36-Item Short Form Health Survey (SF-36) to assess quality of life. The SF-36 was developed by RAND Health Care as part of the Medical Outcomes Study and includes a set of generic, coherent, and easily administered quality-of-life measures that are widely utilized by managed care organizations and Medicare for routine monitoring and assessment of care outcomes in adult patients [20].

Physical Activity and Dietary Behaviors –

Participants will complete an abbreviated Paffenbarger Physical Activity questionnaire [30] to provide a measure of physical activity, other than resistance training, summarized as Metabolic Equivalents (MET)-min/week.

Participants will complete the 2014 Block Food Frequency Questionnaire (FFQ) [23], which is a full-length dietary assessment developed from analysis of two waves of NHANES dietary recall data, 2007–2008 and 2009–2010 [22].

Additional Measures –

Participants will be asked to complete a brief demographics questionnaire, and an injury history questionnaire, which was developed by Co-PI Dr. Schmitz’s research group at Penn State Cancer Institute [24].

See Table 1 for a summary of the baseline and follow-up study measurements.

Table 1.

Baseline and Follow-up Study Measurements

Category and name	Criterion and remarks
Anthropometric Measurements
Height	Baseline only; Will be conducted using a stadiometer; May be extracted from medical record from same day as study visit
Weight	Will be measured using digital scales; May be extracted from medical record from same day as study visit
Hip circumference	Will be measured using a flexible, non-stretchable measuring tape with a tension device
Waist circumference
Medical Imaging
Computerized tomography scan	Baseline only; Will not be used to assess intervention effects
Physical Function
Short physical performance battery	Includes the balance, gait speed, and sit/stand tests
Grip strength	Will measure upper extremity muscular strength, using a calibrated Jamar hydraulic hand dynamometer
Quality of Life
36-Item short form health survey (SF-36)	Includes 8 scales: physical functioning; role limitations due to physical health; role limitations due to emotional problems; energy/fatigue; emotional well-being; social functioning; pain; general health; perceived change in health
Physical Activity and Dietary Behaviors
Paffenbarger physical activity questionnaire	3 variables from this questionnaire (type of sport/exercise, frequency and duration) will be used
2014 Block food frequency questionnaire	Estimates usual and customary diet from a list of 127 food and beverage items
Additional Measures
Demographics questionnaire	Baseline only; Includes variables on gender, marital status, household size, race and ethnicity, educational level, and occupational status
Injury history questionnaire	Follow-up only; Includes variables on recent emergency room visits and physical injuries since participating in the study

Study Outcomes

Primary Outcome Measures

Chemotherapy Completion Rates –

Chemotherapy completion rates will be assessed as relative dose intensity for each agent and then average relative dose intensity, which considers all chemotherapy agents in a regimen. We will examine differences in RDI for each chemotherapy agent and the ARDI across all agents between the RT group and the UC group.

Considerations for Calculating Relative Dose Intensity:

There are several considerations for calculating RDI for exercise intervention trials. Formulas used in clinical research for RDI vary, but all include a ratio of some measure of delivered to standard dose. One consideration is whether to impute missed cycles due to early stoppage [31] or to only consider dose reductions and dose delays for actual cycles [32]. Since our hypothesis is that RT will reduce chemotoxicity and offer patients a higher likelihood of not only receiving the standard dose in the time frame intended but also complete all cycles of chemotherapy, we opted to use the Weycker method [31] which accounts for missing cycles in the calculation of the dose delivered intensity (DDI).

Another consideration is whether standard dose intended (SDI) should be calculated based on the first dose of chemotherapy or the dose given in the cycle after randomization into the intervention. Patients were eligible to be included in FORCE up until initiation of their third chemotherapy cycle, and some patients may have already been dose reduced before randomization. But since those dose reductions could not be attributed to the intervention, we calculated standard dose based on the dose given in the cycle immediately after randomization and included only treatment cycles received between randomization and the follow-up visit. Thus, in our study, the SDI will be calculated as the dose/m² multiplied by number of planned cycles during the timeframe between randomization and anticipated end of adjuvant chemotherapy divided by total number of days from day 1 of first cycle after randomization to last planned dose of that drug. DDI will be calculated as the sum total of dose/m² for each of the cycles that occur between randomization and last dose of adjuvant chemotherapy divided by total number of days from day 1 of first cycle after randomization to last actual dose of that drug. Calculation of DDI will include missed cycles similar to Weycker’s method. Thus, our measure of RDI incorporates dose reduction/modification, treatment delay, and early stoppage.

Chemotherapy-Associated Toxicities –

We will examine differences in chemotherapy tolerance through patient-reported outcomes. The NCI Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of symptomatic treatment toxicities [33]. Participants complete a customized 9-item PRO-CTCAE questionnaire around the initiation of each chemotherapy cycle reporting on the following symptomatic toxicities: nausea, vomiting, diarrhea, shortness of breath, hand-foot syndrome, numbness in hands and feet, pain, aching muscles, and fatigue.

Secondary Outcome Measures

Dual Energy X-ray Absorptiometry (DXA) –

We will examine differences in change in body composition (i.e., lean mass, lean mass /fat mass ratio) between the RT group and the UC group. DXA scans provide measurement of fat mass and lean body mass, which is similar to muscle mass. Certified technicians conduct DXA scans at baseline and after the completion of chemotherapy to examine pre to post changes. All scans are conducted on either a Hologic Discovery, Hologic Horizon, GE Lunar Prodigy or GE Lunar I-DXA and are performed in the total body scanning mode. These machines are calibrated regularly to meet research standards. Participants are scanned on the same model DXA machine at both time points.

Inflammatory Blood Markers –

We will examine specific inflammatory blood markers (e.g., CRP, IL-6 and TNF-RII) as potential biomarkers of baseline muscle mass and determine how they change in response to RT. Serum blood cell samples are obtained from 8.5 mL of whole blood specimen collected at the baseline and follow-up clinic visits. Samples are centrifuged within 2 hours of collection, aliquoted and labeled into 4 cryovials and frozen at −80°C. The following assays will be conducted in the laboratory of Dr. Nader Rafai at Boston Children’s Hospital and are highly reproducible. High Sensitivity C-Reactive Protein (hsCRP): The concentration of CRP will be determined using an immunoturbidimetric assay on the Roche P Modular system (Roche Diagnostics - Indianapolis, IN). This high-sensitivity assay has a limit of detection of 0.03 mg/L. The day-to-day variabilities of the assay at concentrations of 0.91, 1.60 and 18.40 mg/L are 3.8, 3.3 and 1.9%, respectively. Interleukin-6 (IL-6): IL-6 is measured by an ultra-sensitive ELISA assay from R & D Systems, Minneapolis, MN. The assay has a sensitivity of 0.094 pg/mL, and the day-to-day variabilities of the assay at concentrations of 0.49, 2.78 and 5.65 pg/mL are 9.6, 7.2 and 6.5%, respectively. TNFα-receptor II (TNF-RII): TNF-RII is measured by an ELISA assay from R & D Systems. The assay has a sensitivity of 0.6 pg/mL. The day-to-day variabilities of the assay at concentrations of 89.9, 197, and 444 pg/mL are 5.1, 3.5, and 3.6%, respectively.

Other Chemotoxicities Measures –

We will also use an objective measure of chemotoxicity derived from the EMR, specifically absolute neutrophil and platelet counts. In addition, at baseline and follow-up, participants answer the 19-item EORTC CIPN20 questionnaire, which was developed by the European Organization for Research and Treatment of Cancer to assess chemotherapy-induced peripheral neuropathy, a common phenomenon, often resulting in serious limitations in daily functioning and compromised quality of life [19].

Data Analyses

All data analyses will be by intent-to-treat. Multiple linear regression will be used to assess the difference between the RT and UC groups in mean RDI for each agent, ARDI across all agents, change in body composition (MM, MM/FM ratio), change in inflammatory markers (hsCRP, IL-6, TNF-RII), and absolute neutrophil and platelet counts. Analysis of number of grade 3 and 4 toxicities in relation to randomization arm will utilize Poisson regression given that this outcome is characterized as a count. In addition to treatment arm, model covariates will include those used in the covariate adaptive randomization procedure (study site, treatment duration, treatment regimen, gender, stage). In analyses of change (body composition, inflammatory markers), baseline level will be additionally included as a covariate. Exploratory analyses will examine the impact of including additional (not pre-specified) covariates in estimation of treatment effect, with a focus on variables with chance imbalance in distributions by treatment group. Analyses resulting in an appreciable change in the estimate of between-group differences or increase in precision of the treatment effect will be noted. Additional exploratory analyses will assess heterogeneity in treatment effect on primary outcomes (RDI, ARDI and chemotoxicity) by gender, baseline muscle mass (sarcopenic yes vs. no) and exercise adherence (<60% vs > 60%) in stratified analyses and by inclusion of appropriate cross product terms in regression models. Similarly, we will examine heterogeneity in treatment effect on changes in body composition and on changes in inflammatory markers by gender, baseline muscle mass and intervention adherence.

Sample Size and Study Power

This study will randomize 180 colon cancer patients, with 90 in the RT group, and 90 in the UC group. We expect chemotherapy dosing and completion rates (RDI, ARDI) to be assessed on the full sample given measurement via the EMR. Given the number of grade 3 and 4 chemotoxicities will be assessed with the NCI PRO CTCAE survey, analyses will be based on expected on approximately 81 patients in each arm (10% loss). We have sufficient power (.80) to detect a between arm difference in means of at least .42 standard deviation (SD) units in analyses of RDI and ARDI (two-sided t-test, α=.05). The minimum detectable reduction in mean number of chemotoxicities is 56%, given an expected mean of .45 in the UC group (two-sided likelihood ratio test of ratio of Poisson means, α=.05). With an expected RDI SD of 17.3, the minimum detectable difference in mean RDI is 7.3%, a clinically meaningful effect that has been seen in other similar trials [13].

Data Safety and Monitoring

The trial is monitored by an independent Data and Safety Monitoring Board (DSMB). The DSMB meets annually with the study investigators, receiving annual reports and has the option to request additional reports due to unforeseen problems.

Anticipated Results

Results from this clinical trial will allow us to determine whether RT among early stage colon cancer patients builds muscle and lowers the risk of DLT and affects RDI. Results are expected to be available by June 2022 and will inform the recommendation and prescription of RT as an adjunct to chemotherapy in this population.

Strengths and Limitations

The strengths of this study are several. It is an application of a rigorous progressive RT intervention tailored to each patient’s individual strength level. It is administered by certified exercise trainers; and it is primarily a home-based exercise program. With COVID-19 modification, it is a remotely delivered intervention for some patients. Advantages of this modification include the increased likelihood of translation and dissemination. Furthermore, this intervention is evidenced-based and has been adapted from other successful RT interventions used in breast cancer with favorable results. Several limitations exist. This is not a double-blind study, however, participants are offered a modified version of the intervention at the end of the study. While it is impossible to blind participants to the fact that they did not receive the exercise intervention arm of the trial, it is highly unlikely that contamination of the control group will occur and that participants in the control group will successfully achieve the level of resistance exercise required without the directed efforts of a dedicated trainer. In a systematic review of oncology trials where they studied control group contamination, they found extremely low contamination rates (7.1% of studies) in control groups that offered an intervention after the exercise intervention period [34].

Additionally, this study includes bringing the participant to their maximum weight and repetition progression at a time that may coincide with a point in time when side effects of treatment are at their greatest. An additional limitation is the challenge of getting chemotherapy patients to adhere to a relatively rigorous RT program while dealing with toxicities. COVID-19 restrictions prompted us to deliver the intervention remotely for approximately one-third of our sample. While the primary analyses will include all patients enrolled in the trial, we will plan to conduct sensitivity analyses to determine the potential impact post-COVID-19 study adjustments on final analyses.

In 2017, new data suggested a choice of therapy-based determination of duration of chemotherapy, in which 3 months of chemotherapy (particularly capecitabine + oxaliplatin) was noninferior to 6 months of therapy in patients with T1–3 (tumor up to but not through pericolonic tissues), and N1 tumors (1–3 positive regional lymph nodes) [35]. As such, patients now get variable number of months of chemotherapy, which results in some patients only having approximately 3 months of RT. Our analyses will consider the impact of only 3 months of chemotherapy versus 6 months on efficacy of the intervention. Nevertheless, we will learn valuable information of use to clinicians about the ability of colon cancer patients to embark on an ambitious progressive RT program during chemotherapy and if that varies by age, gender or initial physical fitness.

Summary and Conclusions

The FOcus on Reducing dose-limiting toxicities in Colon cancer with resistance Exercise (FORCE) study is designed to investigate whether progressive resistance training with a twice daily protein supplement can, as the primary aim, reduce DLT and increase RDI, and as secondary aims, build muscle mass, alter biomarkers of inflammation, and affect the pharmacokinetics of fluorouracil (5-FU) and oxaliplatin in patient undergoing adjuvant chemotherapy for stage II and III colon cancer. This will be the first study in the literature to investigate the utility of a progressive RT intervention on RDI in men and women with colon cancer being treated with 5-FU, capecitabine and oxaliplatin. Although these chemotherapy drugs improve progression-free survival and overall survival in patients with colon cancer [36] DLT associated with these drugs may cause dose delays and reductions leading to lower than expected benefit on survival. If an effective intervention is identified to mitigate the adverse effects associated with chemotherapy regimens prescribed for colon cancer, it could be incorporated into clinical guidelines as an adjunct to chemotherapy. In addition, it could be used to support a paradigm shift to encourage using lean body mass instead of body surface area as a metric for chemotherapy dosing. These data are critical in developing future clinical trials in this group of patients. Additionally, the findings hold potential to open new avenues of research such as the impact of resistance training on survival and other cancer outcomes.

Table 2.

Study Outcome Measures

Assessment	Measurement Instrument
Primary Outcomes
Chemotherapy dosing and completion rates (RDI)	Medical record
Patient-reported chemotherapy-associated toxicities	NCI PRO CTCAE survey
Secondary Outcomes
Body composition	DXA
Inflammatory blood markers	Serum blood samples
Chemotherapy-associated toxicities	Medical record
Patient-reported chemotherapy-associated toxicities	EORTC CIPN20 questionnaire

• Impact of resistance training on chemotherapy completion and chemotoxicities

• Exercise and Protein Interventions in Colon Cancer patients

• Relative dose intensity calculation includes dose reductions, delays and stoppage

Abbreviations

5-FU/LV

5-fluorouracil/leucovorin

ARDI

average relative dose intensity

CAPOX

capecitabine and oxaliplatin

CRC

colorectal cancer

CT

computed tomography

DDI

dose delivered intensity

DLT

dose limiting toxicities

DXA

dual energy x-ray absorptiometry

FFQ

food frequency questionnaire

FOLFOX

5-fluorouracil/leucovorin and oxaliplatin

MET

metabolic equivalents

MM

muscle mass

RDI

relative dose intensity

RT

resistance training

SDI

standard dose intended

UC

usual care