FOcus on Reducing Dose-limiting Toxicities in Colon Cancer With Resistance Exercise Study
Phase: NA
Conditions: Resistance Training, Colon Cancer, Chemotherapy Effect
Sponsor: Kaiser Permanente

 
 
 
 
FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer 
with Resistance Exercise 
Study Protocol 
NCT03291951 
 
2-11-2022 
 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
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Contents 
PROTOCOL SUMMARY ............................................................................................................. 3 
1.1 
Colon cancer epidemiology and prognosis by stage: ........................................... 4 
1.2 
Adjuvant chemotherapy and dosing: .................................................................... 4 
1.3 
Toxicities of adjuvant therapy: .............................................................................. 4 
1.4 
Pharmacokinetics of 5-FU and oxaliplatin are altered by body 
composition: ......................................................................................................... 5 
1.5 
Low muscle mass increases dose limiting toxicity: ............................................... 5 
1.6 
Dose limiting toxicities are associated with poorer prognosis: .............................. 6 
1.7 
Previous exercise interventions were successful in preventing dose 
reductions and improving chemotherapy completion rates: .................................. 7 
1.8 
Inflammation, muscle mass and exercise: ............................................................ 7 
1.9 
Summary: ............................................................................................................ 8 
2. 
OBJECTIVE .................................................................................................................... 9 
2.1 
Primary Objective: ................................................................................................ 9 
2.2 
Secondary Objectives: ......................................................................................... 9 
2.3 
d3 Creatine Objectives: ........................................................................................ 9 
3. 
INTERVENTION .............................................................................................................. 9 
3.1 
Rationale for home-based resistance training: ..................................................... 9 
3.2 
Target population: .............................................................................................. 10 
3.3 
Key inclusion criteria: ......................................................................................... 10 
3.4 
Exclusion criteria: ............................................................................................... 10 
3.5 
Inclusion of women and minorities: .................................................................... 10 
3.6 
Patient recruitment, registration and randomization requirements: ..................... 11 
3.7 
Enrollment and baseline testing: ........................................................................ 12 
3.8 
Interventions for experimental group: ................................................................. 14 
3.9 
Enhanced safety procedures due to COVID-19: ................................................ 17 
3.10 
Intervention for the waitlist controls: ................................................................... 17 
3.11 
Pharmacokinetics study: .................................................................................... 17 
3.12 
Compensation: ................................................................................................... 17 
3.13 
Photographs of study subjects: .......................................................................... 17 
3.14 
Sharing of results with subjects: ......................................................................... 17 
4. 
STUDY MEASUREMENTS ........................................................................................... 18 
4.1 
Screening questionnaire: ................................................................................... 19 
4.2 
Demographic and health information: ................................................................. 19 
4.3 
Medical outcomes study 36-Item, short form (SF-36): ........................................ 19 
4.4 
Physical activity and diet assessment: ............................................................... 19 
4.5 
Balance test: ...................................................................................................... 19 
4.6 
Gait speed: ........................................................................................................ 20 
4.7 
Sit and stand: ..................................................................................................... 20 
4.8 
Grip strength: ..................................................................................................... 20 
4.9 
Medical record review: ....................................................................................... 20 
4.10 
Body composition and body size: ....................................................................... 20 
4.11 
Dose reductions/delays and early discontinuation of treatment: ......................... 21 
4.12 
Chemotoxicity: ................................................................................................... 21 
4.13 
Inflammatory blood measures: ........................................................................... 21 
4.14 
Pharmacokinetic (PK) measurements: ............................................................... 22 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
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4.15 
Injury history questionnaire: ............................................................................... 23 
4.16 
Intervention follow-up survey: ............................................................................ 23 
4.17 
Enhanced safety procedures due to COVID-19: ................................................ 23 
5. 
POTENTIAL RISKS AND CHARACTERISTICS ............................................................ 24 
6. 
ADVERSE EVENTS ...................................................................................................... 25 
6.1 
Chemotherapy toxicity ....................................................................................... 25 
6.2 
Adverse events and serious adverse events ...................................................... 25 
6.3  
Expectedness .................................................................................................... 25 
6.4 
Reporting requirements: ..................................................................................... 27 
7. 
CRITERIA FOR REMOVAL FROM STUDY................................................................... 28 
8. 
DATA REPORTING / REGULATORY REQUIREMENTS .............................................. 29 
9. 
STATISTICAL CONSIDERATIONS ............................................................................... 30 
9.1 
Study design: ..................................................................................................... 30 
9.2 
Sample size, accrual time and study duration: ................................................... 30 
9.3 
Statistical analysis: ............................................................................................. 31 
10. 
STUDY INVESTIGATORS ............................................................................................ 32 
11. 
DATA PRIVACY AND SECURITY ................................................................................. 32 
12. 
REFERENCE LIST ........................................................................................................ 34 
13. 
APPENDIX .................................................................................................................... 38 
13.1 
Recruitment Communications ............................................................................ 38 
13.2 
Phone Screening Forms and Questionnaires ..................................................... 38 
13.3 
Consent Form .................................................................................................... 38 
13.4 
Baseline and Post-Intervention Questionnaires .................................................. 38 
13.5 
Physical Activity Assessments and Exercise Intervention Materials ................... 38 
13.6 
Nutrition Assessments and Intervention Materials .............................................. 38 
13.7 
Chemotherapy Toxicity, Side Effects, and Injury History Forms and Email......... 38 
13.8 
Anthropometric Measurements and Blood Draw Procedures ............................. 38 
13.9 
Usual Care Handout .......................................................................................... 38 
13.10 Thank You Card Text ......................................................................................... 38 
 
 
 
 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
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PROTOCOL SUMMARY 
 
Protocol Version Date: 2/11/2022 
 
Principal Investigators: Multiple PI: Bette Caan DrPH, Kaiser Permanente of Northern 
California (Corresponding PI); Kathryn Schmitz, Pennsylvania State University; Jeffrey 
Meyerhardt, Dana-Farber Cancer Institute  
 
PROTOCOL TITLE 
 
1. Full Title: FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with 
Resistance Exercise 
 
STUDY SPONSORSHIP 
 
1. Funding Sponsor: NATIONAL CANCER INSTITUTE/NIH 
2. Primary Sponsor: Kaiser Permanente of Northern California – Bette J Caan 
 
PROTOCOL ABSTRACT 
 
FORCE is a randomized home-based resistance training/strength training (RT) intervention 
study for Stage II and III colon cancer patients undergoing chemotherapy. 
 
Participants will be 180 newly diagnosed Stage II and III colon cancer patients from Kaiser 
Permanente of Northern California (KPNC), the Penn State Cancer Institute (PSCI), and the 
Dana Farber Cancer Institute (DFCI). The intervention will begin by the third visit for adjuvant 
chemotherapy and continue exercise through the completion of post-operative chemotherapy. 
Specifically, we will examine between group differences for RT versus waitlist control for 
chemotherapy outcomes including dose delays, dose reductions, early stoppage and Grade 3 
and 4 toxicities. We will also study changes in muscle mass (MM) and changes in specific 
inflammatory markers (e.g. CRP, IL-6 and TNF-RII) as potential markers of change in response 
to RT. To determine effects of change of MM on chemotherapy-specific drug clearance, we will 
examine the impact body composition changes on the pharmacokinetics (PK) of 5-FU and 
oxaliplatin, two of the most commonly used drugs for colon cancer.  
 
OBJECTIVES 
 
1. Primary Objective:  
To examine differences in dose reductions, dose delays and early stoppage for chemotherapy 
and the total combined number of moderate and severe chemotherapy-associated toxicities 
between intervention group and waitlist controls. 
2. Secondary Objectives:  
a. To examine specific inflammatory markers (e.g. CRP, IL-6, TNF-α receptor II [TNF-RII]) 
in relation to baseline MM and fat mass (FM) and examine differences in changes in 
inflammatory markers between intervention group and waitlist controls. Inflammatory 
markers and body composition will be measured pre and post intervention. 
b. To examine the impact of RT induced body composition changes on the 
pharmacokinetics (PK) of 5-FU and oxaliplatin between baseline and 4 months of RT. 
3. d3 Creatine Objectives 
a. To test whether resistance training during chemotherapy (v. control) increases d3 
creatine muscle mass at 6 months.  

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
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b. To evaluate the association of d3 creatine muscle mass with changes in functional 
status and strength during chemotherapy.  
c. To evaluate the association of d3 creatine muscle mass with chemotherapy toxicity and 
relative dose intensity.  
d. To evaluate the association of d3 creatine muscle mass with cancer-related biomarkers, 
including inflammation, CEA levels and cardiometabolic risk factors. 
 
BACKGROUND 
 
1.1 
Colon cancer epidemiology and prognosis by stage:  
Colorectal cancer is the 4th most common in the United States, with an estimated 134,490 
individuals being diagnosed in 2016, 71% located in the colon (versus rectum)2. Unfortunately, 
more than 49,190 individuals die from the disease annually, making colorectal cancer the 
second leading cause of cancer death in the United States. Surgery is the primary modality of 
management for colon cancer, and a ‘curative intent’ resection occurs in 80-85% of patients with 
non-metastatic disease (stages I-III). The benefit of adjuvant therapy has been consistently 
shown in multiple clinical trials, although the 5-year disease free survival for stage III disease is 
only 70%3.   
 
1.2 
Adjuvant chemotherapy and dosing:  
Beginning in 1990, an NCI expert panel recommended 5-fluorouracil (5-FU) and leucovorin (LV) 
as adjuvant therapy for patients with stage III colon cancer5.  While initial studies tested a longer 
duration of treatment, the current standard is 6 months of therapy.  An oral form of 5-FU, called 
capecitabine, has also demonstrated noninferiority as an alternative to IV 5-FU6. Select stage II 
patients, based on recurrence risk, are considered for adjuvant therapy as well. Further trials 
demonstrated a modest, but statistically significant, benefit to adding oxaliplatin to 5-FU/LV. The 
most common regimen is a 3 drug infusional combination called FOLFOX (5-FU/LV and 
oxaliplatin), now standard treatment for most stage III patients, considered in some stage II 
patients4 as well as in stage IV/metastatic disease patients. Substitution of capecitabine for 
infusion 5-FU and leucovorin is another treatment regimen (CAPOX).  Dosing of 5-FU/LV, 
capecitabine or FOLFOX is based on a standard formula that incorporates a patient’s height 
and weight into a metric called, body surface area (BSA)7. Recommended milligrams per BSA 
were derived from trials testing for dose limiting toxicities (DLT), typically defined as severe 
(grade III or IV based on the NCI Common Toxicity Criteria [CTC] scale). While a standard 
starting dose is defined for each treatment 
option, many patients will still derive 
significant toxicities (Table 1). Issues with 
BSA dosing include the use of absolute 
weight without consideration of body 
composition or physiologic measures relevant 
for drug metabolism and disposition, such as 
renal and hepatic function. Dosing based on 
BSA is limited in ability to reduce inter-
patient variability in a drug’s volume of 
distribution8. Various drug elimination 
processes (e.g. metabolic breakdown or excretion) account for inter-patient variability in 
pharmacokinetics to a large degree8. Body composition (i.e. adipose tissue and muscle mass)9 
is another factor influencing pharmacokinetics and may predict toxic reactions to certain 
chemotherapy regimens10;11. 
 
1.3 
Toxicities of adjuvant therapy:  
All 4 adjuvant therapy regimens have potential for multiple toxicities, including but not limited to 
gastrointestinal (e.g. nausea, emesis, diarrhea, abdominal cramping or discomfort), bone 
Table 1. Select Toxicities associated with adjuvant 
therapy4 
Toxicity 
5-FU/LV 
FOLFOX 
Any 
Grade 
Grade  
3/4 
Any  
Grade 
Grade  
3/4 
Neutropenia 
40% 
5% 
79% 
41% 
Low platelets 
19% 
<1% 
77% 
2% 
Nausea 
61% 
2% 
74% 
5% 
Diarrhea 
48% 
7% 
56% 
11% 
Neuropathy 
16% 
<1% 
92% 
12% 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
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marrow suppression (i.e. lowering white blood cells and thus immune system or platelets 
increasing bleeding risk), and fatigue and anorexia symptoms (Table 1). Oxaliplatin can lead to 
cold-induced and/or cumulative peripheral neuropathy, manifested as numbness, pins and 
needles, or pain in hands and feet, which can impact function.  
 
1.4 
Pharmacokinetics of 5-FU and oxaliplatin are altered by body composition:  
Cytotoxic agents, such as fluoropyrimidine and oxaliplatin, are considered narrow therapeutic 
index drugs, where small changes in drug exposure can greatly impact clinical efficacy and 
toxicity. 5-FU is hydrophilic, but widely distributed through active transport12. It undergoes 
extensive metabolism, primarily through dihydropyrimidine dehydrogenase (DPYD), variants of 
which have been associated with increased risk of toxicity to 5-FU13. On the basis of these 
considerations, 5-FU clearance (CL) and volume of distribution (V) are likely related to body 
composition. Gusella et al. studied the PK of adjuvant 5-FU (425 mg/m2 IV bolus) in 34 
colorectal cancer patients14 and determined that CL was significantly correlated with sex and fat 
free mass (FFM), while V was correlated with sex and Total Body Water (TBW). Overall, they 
concluded that CL of 5-FU was better predicted by FFM and TBW than by Body Surface Area 
(BSA)14. Thus, clearance of 5-FU is expected to increase (i.e. exposure decrease) in individuals 
with a higher FFM.  
 
Body composition is also known to impact the PK of oxaliplatin. Oxaliplatin is eliminated renally, 
with clearance similar to glomerular filtration rate15. Quinney et al.16 have previously reported 
that obesity is associated with an increased GFR as measured by clearance of iohexol. Thus, it 
is expected that oxaliplatin clearance may be increased in individuals with more adiposity and 
because it is also highly lipophilic, may lead to increased distribution in individuals with higher 
FM/MM ratios. In a population PK analysis of ultrafilterable oxaliplatin in 56 adults with 
metastatic disease, both CL and V were associated with bodyweight and individuals with higher 
body weights had larger exposure (AUC) to oxaliplatin17. To our knowledge, the effect of MM 
measured by DXA and change in body composition over time on PK of these drugs has not 
been examined. 
 
1.5 
Low muscle mass increases dose limiting toxicity:  
The effect of low MM on chemotherapy treatment in several individual studies of different 
chemotherapy drugs and different cancer types have been explored. Cancer patients with 
identical BSA (i.e. 2.00 m2) are highly variable in MM (range 30–70 kg)18 and 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. 
 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
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Figure 1 demonstrates 
among different cancer 
types, that patients with 
low MM behaved as if 
overdosed and had dose-
limiting toxicity (i.e. of 
sufficient magnitude to 
require dose reductions, 
treatment delays or 
definitive termination of 
treatment). Relevant to 
this study, doses of 5-
fluorouracil (5-FU) per 
kilogram of lean body 
mass (LBM) was 
associated with dose-
limiting toxicity in stage 
II/III colon cancer patients 
and demonstrated that 
low LBM is a significant 
predictor of toxicity in 
patients administered 5-FU but only in females concluding 
that variation in toxicity between 
females and males may be partially 
explained by their differences in MM. 
Several other studies support LBM as 
an important determinant of 
chemotoxicity. In a study of French 
cancer survivors treated with FOLFOX 
regimens (Figure 2)19, estimated mg 
oxaliplatin/kg lean body mass for this 
population cohort (n=58) varied from 
2.5 to more than 6.0 mg/kg. A value of 
3.09 mg/kg LBM was determined to be 
the cut point for dose-limiting toxicity 
(area under ROC curve=0.708). Toxicity 
rates were 0/17 (0.0%) and 18/41 
(44.0%) using this cut point to separate 
the data into two groups (p=0.005; 
Fisher’s Exact Test). In a retrospective 
analysis of 229 patients receiving 
FOLFOX4 for adjuvant chemotherapy 
following surgical resection of colon 
cancer, low psoas muscle cross-sectional area/height2 (psoas index) was associated with an 
increased rate of grade 3-4 toxicity20. These combined results offer evidence that MM at 
initiation of chemotherapy may be an indicator of DLT and MM maybe be useful to individualize 
chemotherapy dosing.  
 
1.6 
Dose limiting toxicities are associated with poorer prognosis: 
Several studies across different cancers have demonstrated that either dose reductions or dose 
delays are associated with poorer overall survival (OS) or progression-free survival (PFS). Most 
relevant to this current study is a study that was designed to evaluate the impact of relative dose 
intensity (RDI), dose reduction, and schedule modification on outcomes in patients with 
Table 2. Rates and reasons for chemotherapy dose 
reduction in breast cancer patients 
Characteristic 
OnTrack 
 (n=76) 
Usual Care 
 (n=77) 
Patients requiring dose 
adjustments, No. (%) 
9(12) 
26(34) 
Mean prescribed length of 
chemotherapy, days 
119.2 
116.7 
Reasons for chemotherapy adjustment, No. (%) 
Neuropathy 
3 
6 
Myelosuppression 
2 
3 
Febrile neutropenia 
0 
6 
Nausea and vomiting 
2 
3 
Pain 
1 
3 
Infection 
0 
3 
Dyspnea 
0 
2 
Obstipation/diarrhea 
1 
0 
Average % dose reduction* 
9.8 
25.2 
*Average dose reductions per group among participants 
needing a dose adjustment. 
Figure 1: Synopsis of results from 
several studies relating treatment 
toxicity related to muscle mass 
during antineoplastic therapies1 
 
Figure 2: Distribution of the estimated 
oxaliplatin dose/kg lean body mass in 
French patients, from lowest to highest 
value.  

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
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metastatic colorectal cancer (mCRC). Pooled datasets from two previous phase II trials of 
FOLFIRI (CCOG-0502; n=36) and mFOLFOX6 (CCOG-0704; n=30) in patients with mCRC 
were analyzed retrospectively. The median RDIs of irinotecan in FOLFIRI and oxaliplatin in 
mFOLFOX6 were 80 and 79%, respectively. Higher RDI of irinotecan in FOLFIRI was 
associated with significant improvements in PFS (9.9 vs. 5.6 months, P <0.01) and OS (26.7 vs. 
12.9 months, p=0.01) and was the only independent factor associated with PFS (hazard ratio 
[HR] 8.48, p<0.01). Time delays of oxaliplatin was the only independent factor associated with 
PFS (HR 2.74, p=0.04)21. Numerous studies of women receiving chemotherapy treatment for 
ovarian cancer have also demonstrated that RDI, dose delays and dose reductions in 
chemotherapy regimens impact PFS and OS. In one of the largest multi-center retrospective 
studies of 325 women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively 
with multi-agent intravenous chemotherapy between 1995 and 200922, delivered RDI <85% 
(hazard ratio [HR]=1.71; p=0.003) was associated with reduced OS. 
 
1.7 
Previous exercise interventions were successful in preventing dose reductions 
and improving chemotherapy completion rates:  
To our knowledge, only a few previous studies have examined the effect of exercise on 
chemotherapy completion rates or in preventing dose reductions. In the most recent large study, 
a moderate to high-intensity, combined supervised resistance and aerobic exercise program 
(OnTrack) was compared to usual care (UC) in 230 breast cancer patients scheduled to 
undergo chemotherapy. Performance-based and self-reported outcomes were assessed before 
random assignment, at the end of chemotherapy, and at the 6-month follow-up. Those 
randomized to OnTrack required less chemotherapy dose adjustments (p=.002) had less 
nausea and vomiting (p=.031) compared with UC. Table 2 shows rates and reasons for 
chemotherapy dose reductions23. Similar non-significant results were observed in another small 
(n=33) study of CRC patients in Europe24, however the sample size was too small for definitive 
results. In a second study of 242 breast cancer patients25 those randomized to supervised 
resistance training during chemotherapy compared to usual care resulted in improved 
chemotherapy completion rate (p=.033). In a third trial of 30 women with recurrent ovarian 
cancer26, a 12 week combined supervised and home-based exercise intervention during 
chemotherapy demonstrated that participants who completed the intervention had a higher 
relative dose intensity than non-completers (p=0.03)25;26. While three of the studies collectively 
demonstrate positive effects of exercise training during chemotherapy on completion rates 
and/or prevention of dose reductions in other cancers, only one small trial with inadequate 
power studied these effects in colon cancer patients, demonstrating a need to examine this in a 
group who experience significant DLT and a high prevalence of sarcopenia at diagnosis.  
 
1.8 
Inflammation, muscle mass and exercise: 
Although the development of muscle wasting involves multiple contributors including 
neuropeptides, hormonal mediators, tumor- or pathogen-derived compounds, as well as various 
cytokines, the presence of inflammatory processes represents the primary requirement for the 
alterations in muscle protein synthesis and breakdown27. Recently, this observation was 
confirmed in a CRC cohort. Richard et al. reported an association between low skeletal MM 
index measured on CT scans and increased acute inflammatory response (i.e. high C-reactive 
protein and low albumin)28. In another study of 763 patients diagnosed with CRC undergoing 
elective surgical resection, multivariate logistic regression analysis showed that high 
neutrophil/lymphocyte ratio (NLR) (odds ratio [OR]=1.78 (95% confidence interval [CI]: 1.29-
2.45), p <0.001) and low albumin (OR=1.80 [95% CI: 1.17-2.74], p=0.007) were independent 
predictors of reduced muscle mass29. A plethora of studies have investigated the role of the 
main inflammatory players in muscle wasting, such as tumor necrosis factor-a (TNF-a), 
interleukin-6 (IL-6), interleukin-1 (IL-1) and interferon-r (IFNr). These pro-inflammatory cytokines 
act directly or potentiate each other’s actions at two key metabolic control points: the activation 
of ubiquitin-proteasome system30 and inhibition of Akt/mTOR pathways31, promoting protein 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
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degradation as well as resistance to the anabolic actions, and ultimately leading to muscle loss. 
Several studies have now demonstrated that exercise reduces inflammation, through multiple 
mechanisms32. Specific to RT, an acute transient local increase in IL-6 is observed, which in 
turn results in a rise in anti-inflammatory markers locally to combat this rise, such as IL-10 and 
IL-1A, blunting the release of further inflammatory factors. This local effect then stimulates pro- 
and anti-inflammatory molecule secretion by other tissues, thus augmenting levels of systemic 
inflammation33 . In cancer survivors the 12-week RT intervention in breast cancer survivors 
compared to relaxation control (n=103), blunted the marked rise in systemic levels of 
inflammation observed in the control group (IL-6, p=0.01 and IL6: IL-1ra ratio, p=0.02)34. 
 
1.9 
Summary:  
Since reductions in dose intensity of chemotherapy (both dose reductions and/or not completing 
planned number of treatments) are associated with lower survival in many cancers, identifying 
ways to maintain dose intensity are of tremendous clinical significance. Sarcopenia or low MM is 
a highly prevalent and an occult problem among newly diagnosed colon cancer patients and is 
associated with DLT. RT is known to increase MM, and increases in MM could reduce DLT with 
a potential impact on survival. This study may also provide evidence for consideration of dosing 
based on body composition. This study will fill many existing gaps in our understanding of body 
composition, RT and DLT.  
 
 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
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2. OBJECTIVE 
 
2.1 
Primary Objective:  
 
To examine differences in dose reductions, dose delays and early stoppage for chemotherapy 
and the total combined number of moderate and severe chemotherapy-associated toxicities 
between intervention group and waitlist controls. 
 
2.2 
Secondary Objectives:  
 
2.2.1 Examine specific inflammatory markers (CRP, IL-6, TNF-α receptor II [TNF-RII]) in relation 
to baseline MM and FM and examine differences in changes in inflammatory markers between 
intervention group and waitlist controls.  
2.2.2 Examine the impact of intervention versus control and RT-induced body composition 
changes on the pharmacokinetics [PK] of 5-FU and oxaliplatin between baseline and 4 months 
of RT. 
 
2.3 
d3 Creatine Objectives:  
 
2.3.1 Test whether resistance training during chemotherapy (FORCE intervention group v. 
control) increases d3 creatine muscle mass at 6 months. 
2.3.2 Evaluate the association of d3 creatine muscle mass with changes in functional status and 
strength during chemotherapy. 
2.3.3 Evaluate the association of d3 creatine muscle mass with chemotherapy toxicity and 
relative dose intensity. 
2.3.4 Evaluate the association of d3 creatine muscle mass with cancer-related biomarkers, 
including inflammation, CEA levels and cardiometabolic risk factors. 
 
 
3. INTERVENTION 
 
3.1 
Rationale for home-based resistance training: 
Resistance training increases muscle mass through hypertrophy of muscle cells35. A recent 
meta-analysis identified 11 resistance training intervention trials conducted within individuals 
with cancer36. In the six trials that evaluated intervention effects on MM, the weighted mean 
effect size was a statistically significant increase of 1.07 kg MM (p<0.0001). The interventions 
ranged from 12 to 52 weeks in length, 2 to 4 exercise sessions per week, with intensity 
described by percent of maximal (25-80% of 1 repetition maximum (RM)), or according to rate of 
increase (gradually, with the smallest available increment of resistance). The meta-analysis did 
not see further benefit of more than 2 sessions per week, and low to moderate intensity netted 
as much benefit as high intensity programs. Both women (n=818) and men (n=313) were 
represented in these trials and the beneficial effects were observed in both genders. Finally, 
more pertinent to the proposed work, a post-hoc analysis of data from a large resistance training 
trial in breast cancer survivors conducted by Co-PI Schmitz indicates that appendicular skeletal 
mass was better maintained in the intervention group who did twice weekly strength training 
when compared to usual care controls37. There have been fewer home-based resistance 
training studies than supervised or facility-based studies among cancer survivors. However, a 
systematic review on home based resistance training specifically for older adults demonstrated 
that home based resistance training programs can improve strength and functional ability38. 
Additionally, home based resistance exercise is generally well tolerated by cancer survivors and 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
10 
has demonstrated benefits in physical function, strength and/or quality of life in patients with 
prostate cancer39;40 and breast cancer41-43. 
 
3.2 
Target population:  
All newly diagnosed, Stage II and III, colon cancer patients within the first weeks of 
chemotherapy will be selected for participation in the study. Recruitment strategies will vary at 
each site (KPNC, PSCI, and DFCI).  
 
3.3 
Key inclusion criteria:  
• 
Men and women ≥18 years 
• 
Newly diagnosed with histologically confirmed stage II-Ill colon cancer  
• 
Completed curative-intent surgical resection  
• 
Currently prescribed one of the following adjuvant chemotherapy regimens: (IV 5-fluorouracil 
[5-FU] / leucovorin [LV], capecitabine, FOLFOX [5-FU, LV, oxaliplatin], CAPOX 
[capecitabine and oxaliplatin] 
o Patients must have started chemotherapy or plan to start, with planned receipt of the 
first exercise visit by the third infusion visit.  
o Patients receiving FOLFOX chemotherapy are eligible to enroll in the 
pharmacokinetics sub-study (see section 3.10). 
• 
No planned major surgery anticipated in the intervention period  
• 
Sufficient time to heal from any major surgery to start of intervention, including colostomy 
reversal (port-a-cath removal excluded) 
• 
Creatinine value <2 mg/dL 
• 
Approval by either oncologist or surgeon to participate in trial 
• 
Readiness (as determined by the Physical Activity Readiness Questionnaire (PAR-Q) – see 
Appendix 13.2.2) 
o If there are any indications that home based exercise would be unsafe based on 
PAR-Q the patient will not be enrolled until confirmation from the patient’s treating 
provider is received via email and/or phone that they are safe to exercise. Provider 
does not need to be contacted if patient answers ‘yes’ to ‘Is your doctor currently 
prescribing any medication for your blood pressure or for a heart condition?’ 
• 
Ability to understand and the willingness to sign a written informed consent document in 
English 
• 
Willingness to be randomized 
 
3.4 
Exclusion criteria: 
• 
Concurrent actively treated other cancer (except non-melanoma skin cancer, in situ cervical 
cancer or localized prostate cancer treated with surveillance only) 
• 
Patients with untreated hypertension (>180 mm Hg systolic or >100 mm Hg diastolic) 
appearing in the patient’s medical record in the two weeks prior to screening will not be 
enrolled until confirmation from the patient’s treating provider is received via email and/or 
phone that they are safe to exercise.  
• 
Presence of metastatic disease 
• 
Current strength training >2x week for the past 3 or more months  
• 
Patients enrolled in other clinical trials of weight loss, physical activity or dietary 
interventions are ineligible. 
 
3.5 
Inclusion of women and minorities:  
We seek to recruit 180 participants with a diagnosis of colon cancer. We will not exclude any 
participants due to their race and ethnicity. All races are accepted. The distribution of 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
11 
participants by race and ethnicity is expected to mirror that of the institution’s colon cancer 
patient population. 
 
3.6 
Patient recruitment, registration and randomization requirements:  
Prior to initiating recruitment, each study site will obtain separate IRB approval from their 
respective institutions. Each collaborating site is under their own IRB’s purview. Patient 
recruitment will be specific to each site. At all sites, participants must have the approval of a 
treating provider in order to participate in the study. 
 
 
Kaiser Permanente Northern California recruitment: 
At KPNC, potentially eligible study participants will be identified using the Electronic Medical 
Record (EMR) and a pathology database which is updated daily with newly diagnosed cancer 
cases. Additionally, oncology providers will be made aware of the study and will be asked for 
patient referrals at each Kaiser facility. Through the EMR, each stage II-Ill colon cancer patient 
will be identified close to the time of diagnosis and passively followed through surgery. After 
confirmation of chemotherapy prescription at the time of first oncology visit, the oncologist will 
be emailed through our secure internal email system to request approval for study participation 
for their patient and permission to contact the patient (see Appendix 13.1.1). Once permission is 
received from the oncologist, we will contact the patient through our secure internal email 
system and USPS mail, and then by phone to invite them to the study and to screen for 
eligibility using the above criteria. Contact information (i.e., email, address, phone number) will 
be identified using the EMR. The MD recruitment email, the participant recruitment email/letter 
and the recruitment phone script can be found in the Appendix 13.1. 
 
Dana-Farber Cancer Institute recruitment: 
Patients will be recruited from the patient populations of the Gastrointestinal Cancer Center 
clinics at Dana-Farber Cancer Institute. We will utilize multiple active recruitment techniques to 
maximize participation and generalizability. We will use the following strategies to identify 
potential participants 
• 
Review of clinic schedules and patient lists for medical oncologists at Dana-Farber to 
identify patients with Stage II-III colon cancer. HIPAA waiver will be obtained to review 
these patient lists. 
• 
Education of oncology providers of availability of protocol to encourage oncology providers 
to identify patients for study staff. 
• 
Tumor registries at Dana-Farber 
• 
Advertisements in patient areas 
 
For potential participants identified through patient lists, we will contact provider and request 
permission to contact their patients. Providers will be asked to indicate any patients who should 
not be approached regarding participation in this study. Patients whose provider either provided 
permission to contact or who did not respond to email request will be assumed to be appropriate 
to approach. Once potential participants are identified, they will be contacted during next clinic 
visit or through mailing (see Appendix 13.1.2). 
 
Interested subjects at Dana-Farber identified through these recruitment strategies will be 
screened by study staff either in person or by phone initially and if potentially eligible, he or she 
will schedule a visit with a member of the study staff to review the protocol and sign informed 
consent. All participants must have the approval of a treating provider in order to participate in 
the study.  
 

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12 
Penn State Cancer Institute recruitment: 
At PCSI, we will recruit by having a staff person review the EMR to identify potentially eligible 
patients. The study staff will approach the treating oncologist for permission to contact 
potentially eligible patients. Upon written (email) confirmation of permission to contact, the 
research coordinator will contact him/her by phone. During this phone call, the study will be 
briefly described, and study staff will ask if the patient would be willing to allow study staff to visit 
in person at the next clinic visit. Brief screening will also take place during this initial phone call 
(see Appendix 13.2). Patients found to be provisionally eligible based on this initial screening 
who are interested in hearing more will be visited in person by a study staff person to further 
discuss the trial and to proceed with the consent process if appropriate. Prior to starting 
recruitment, Co-PI Schmitz will visit the GI research conference and the GI tumor board 
meetings to describe the trial to the medical oncologists who treat colon cancer at PSCI and 
answer any questions they may have. 
 
3.6.1 From Section D. Study overview of the original KPNC application 
approved 2017 
 
3. How many participants will be enrolled in this study, or how many 
electronic records or medical records will be used? Provide your best 
estimate if you are not sure 
Number of KPNC 
participants or records: 
Approximately 115 participants to be enrolled 
Records used: 
Approximately 7500 KPNC records used 
Number of non-KPNC 
participants or records: 
Approximately 65 participants enrolled 
Total number of 
participants or records: 
Approximately 180* participants enrolled  
 
*Due to the impact of the COVID-19 pandemic on 
the study, we estimate that the total number of 
participants will be within the range of 10% above 
the original total of 180 participants.   
 
3.7 
Enrollment and baseline testing:  
Eligible participants who agree to participate will be scheduled for their first intervention visit at 
the earliest possible chemotherapy visit but by the third infusion visit. See Table 3 for details 
regarding the enrollment window based on the specific chemotherapy regimen 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13 
Table 3. Chemotherapy Regimens and Timeline 
 
Regimen name 
& drugs  
Cycle 
# 
cycles 
  1    2   3 
4 
5 
 6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 
 
14 
days 
6 
cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 
days 
12 
cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
days 
8 
cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
days 
4 
cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
days 
8 
cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 days 
4 
cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 days 
12 
cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A research assistant will either conduct eConsent over the phone or by video conference or 
meet the participant in person to complete the consent forms. The baseline visit will most likely 
occur as an add-on to the first or second chemotherapy infusion session or another clinical 
appointment, so as to avoid the need for additional visits to the clinic or cancer center for the 
study. If scheduling of the baseline or follow-up visits at the clinic is not convenient for the 
participant, the research assistant will also be available to conduct these study visits at the 
participant’s home. 
 
After the participant consents to be in the study (see Appendix 13.3), we will complete 
questionnaires with the participant as part of the baseline visit (e.g. physical activity assessment 
and physical function testing, see Appendix 13.5, FFQ, see Appendix 13.6.1, SF-36, and 
demographics, see Appendix 13.4), as well as a patient-completed side effects questionnaire 
mFOLFOX 6 - 3 months 
Oxaliplatin, Leucovorin, 5FU 
mFOLFOX 6 - 6 months 
Oxaliplatin, Leucovorin, 5FU 
sLV5FU2 
Leucovorin, followed by 2 
day continuous infusion 
5FU, repeated every 2 
weeks 
Capecitabine only 
oral Capecitabline 2x daily 
for 14 days, then 1 week off 
CAPEOX - 3 months 
Oxaliplatin infusion, day 1; 
oral Capecitabine 2x daily for 
14 days, then 1 week off 
CAPEOX - 6 months 
Oxaliplatin infusion, day 1; 
oral Capecitabine 2x daily for 
14 days, then 1 week off 
5FU/Leucovorin 
Leucovorin and 5FU 
repeated weekly X 4-6, rest 
2 weeks, start again 
20 Weeks 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
IV 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
8 Weeks 
8 Weeks 
18 Weeks 
20 Weeks 
18 Weeks 
28 Weeks  
WEEK 
Oral 
Oral 
Oral 
Oral 
Oral 
Oral 
Oral 
Oral 
INTERVENTION 
DRUG 
VISIT 

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14 
(see Appendix 13.7.3). In addition, body composition will be assessed using anthropometrics 
collected at the baseline visit, a DXA (see Appendix 13.8) to be scheduled as soon as possible, 
prior to initial intervention, and creatine dilution (see Appendix 13.8.3). Also, at the baseline visit, 
we will arrange for research blood draw, when possible to be coordinated with clinical blood 
draw that the patient receives as part of clinical care (either that visit or next chemotherapy visit 
but prior to starting intervention).  
 
3.8 
Interventions for experimental group: 
 
Table 4. Intervention Terminology 
Chemotherapy Cycle  
A cycle of chemotherapy from infusion visit to the next 
infusion visit, usually this will be 2-3 weeks 
Chemotherapy Infusion Visit  Date on which the participant receives chemotherapy 
infusion at the cancer/medical center. 
Exercise Session  
A virtual meeting (except for one in person safety check) or 
in rare cases if patient does not have video access meeting 
in person between the exercise professional and the 
patient. In person will be scheduled on a day when 
participant has another clinical appointment. In rare 
instances, an appointment may need to be scheduled on a 
date and time other than an existing appointment. 
Home Exercise Session 
Exercise performed by the participant, at home with or 
without supervision by the cancer exercise professional 
 
Exercise professionals are nationally certified, with expertise working with oncology patients.  
Pre-In Person Training Visit Phone Call 
1. The intervention begins with a telephone call between the trainer and the participant.  
The purpose of the call is to: 
a. Begin to build rapport with the participant 
b. Give them an overview of what to expect from the exercise training 
c. Begin behavioral counseling for motivating the participant to adhere to the 
training regimen 
d. Provide an opportunity for the trainer to ask about past experience with weight 
training, any injuries, surgeries or medical conditions that might impact the 
participant’s ability to perform specific exercises.   
At Exercise Session 1, the exercise professional will:  
1. Teach the participant a warm-up and cool down routine.  
a. Teach the study specific exercises of the protocol (see Appendix 13.5.3). At the first 
exercise session, patients will be provided with the handouts for this session using the 
software SimpleSet Pro that will show pictures and explanations of the movements. 
Patients will also receive a simple exercise log and protein tracker for the duration of 
the study. 
b. A set of adjustable dumbbells and an aerobic step will be shipped to the participant’s 
home. The FORCE Study will cover the cost of purchasing and shipping this 
equipment. 
c. Adapt the intensity of the exercises so that the load will fit with the individual physical 
ability of the patient and will follow the progression scheme in the table below.  
d. Patients will be instructed to consume one scoop of protein powder, with water, yogurt 
or milk or other foods about 30 minutes into their meal at 2 meals each day (see 

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15 
Appendix 13.6.2). The FORCE Study will cover the cost of purchasing and shipping 
the protein powder. 
e. Participants will receive a supply of the protein powder. The remainder will be shipped 
to their homes. 
f. For exercise safety purposes, the first exercise session will happen in person, when 
possible. If not possible, the exercise professional may complete this session virtually 
by video conferencing. All study supplies (e.g., weights, handouts, exercise logs, 
protein logs, and protein powder) will be mailed to the participant’s home.   
2. The exercise and protein log will be used to track the adherence of the patient to the 
protocol. Patients will be taught to complete the exercise log on the days they perform 
the exercises at home, along with making any pertinent notes about the exercises and/or 
how they are feeling. Patients will be taught to complete the protein log daily. 
3. Explain to patients that they should do in-home exercise sessions 2 times weekly until 
the next Exercise Session with the exercise professional. Patients will complete these 
exercises alone twice a week. After COVID-19, exercise professionals can offer to work-
out virtually with participants once a week. 
 
Table 5. Summary of exercise progression  
 
Exercise** 
Session 1 
Exercise** 
Session 2 
Exercise** 
Session 3 
Exercise** 
Session 4 
Exercise** 
Session 5 
Exercise** 
Session 6 
SETS 
3 
3 
4 
4 
5 
5 
REPS 
6 
8 
8 
10 
10 
10 
LOAD* 
65% 
65% 
75% 
75% 
80% 
80%- 85% 
REST 
30-60 secs 
30-60 secs 
30-60 secs 
30-60 secs 
30-60 secs 
30-60 secs 
*individualized to the patient’s strength; **Prior to COVID-19, exercise sessions 1-6 are all in person. After 
COVID-19, exercise session 1 is in person and sessions 2-6 are virtual. 
 
The exercise professional will meet with the patient for 4-6 Exercise Sessions that will coincide 
to the degree feasible with their regular infusion sessions. Prior to COVID-19, if scheduling of 
the Sessions at the clinic is not convenient for the participant, the exercise professional will also 
be available to conduct these visits at the participant’s home. After COVID-19, only Exercise 
Session 1 is scheduled in person on a day when the participant a clinical appointment, and 
Sessions 2-6 are conducted virtually via video conferencing. If a participant is not capable of 
meeting virtually (e.g., lack of technology, internet access or tech skills), the exercise 
professional will meet the participant in person on the same day as a clinical appointment.   
 
During each follow-up Exercise Session, the exercise professional will:  
1. Collect and review the phone/visit log (these are the same questions asked during the 
weekly phone call) and exercise log to see what the participant did during the past 
weeks, discuss barriers, successes, and problem solve if needed. Participants can 
return logs either in person, over email or by text.   
2. Collect and review the protein tracker to ensure that the participant is consuming 
adequate protein to build lean mass through resistance exercise. Participants can return 
logs either in person, over email or by text.    
3. Visually evaluate the participant’s ability to increase weight and adjust the amount of 
weight appropriately.  
In between Exercise Sessions and after the initial 4-6 Sessions, the exercise professional will 
contact each participant 1 time per week either by phone or video and ask a series of questions 

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16 
(see Appendix 13.5.5). These calls may be completed through the centralized calling center, by 
an exercise professional from one of the three study sites. Questions will assess adherence of 
the patient to the exercise regimen and the pattern of sessions with regard to time between 
sessions; protein supplement adherence; and any medical complications that prevented 
exercise sessions from occurring. A contact card will be mailed to participants when they are 
halfway through the intervention.   
 
Table 6. Intervention Contacts 
What 
Number of times* 
Aim 
Time per session 
Pre-In Person Training 
Visit Phone Call 
1 time prior to 1st Exercise 
Session 
Make introductions, 
orient participant to 
intervention, obtain 
health information on 
participant 
20-30 min 
Exercise Sessions 
4-6 times, every 2-3 weeks 
during first 3 months of 
intervention  
Learn and progress with 
exercise protocol 
60 min 
Home Exercise Sessions 
2 times per week 
Resistance exercise 
45 min 
Log Exercise  
At-home exercise sessions 
Log adherence 
5 min 
Log Protein Intake 
Daily 
Log adherence 
5 min 
Phone or Video Call 
Weekly 
Track adherence 
5 min 
Contact Card 
1 time 
Encourage participation, 
remind participants to 
return logs 
n/a 
*Each cycle is administered every 2-3 weeks 
 
1. The exercise professional will speak with participants to review these exercise and 
protein logs each week, by phone or video conference, until the intervention is complete 
at approximately 6 months post initiation (corresponding to completion of adjuvant 
chemotherapy).  
 
2. Study staff will then record the adherence of the patients to the exercise regimen and the 
pattern of sessions with regard to time between sessions, as well as any medical 
complications that prevent sessions from happening. 
 
Intervention Goals: 
Progressively higher weights for resistance training exercises conducted twice weekly 
throughout intervention) to achieve a 1-kg increase in lean body mass by the end of the 
intervention.  
 
 
Intervention Standardization: 
All exercise professionals will participate in a multi-day workshop. During this workshop, 
procedures of the intervention will be explained, and case studies will be presented and 
practiced. There will be monthly conference calls including all exercise professionals across 
sites, to monitor and discuss progress, problems and to monitor fidelity of the protocol. 
Telephone calls to intervention participants to encourage adherence will be scripted.  
 
 

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17 
3.9 
Enhanced safety procedures due to COVID-19: 
As a result of COVID-19, exercise professionals will adhere to strict safety procedures when 
meeting with participants for the in person exercise sessions. Enhanced safety procedures 
include: 
• 
phone screening before visits with COVID-19 script (Appendix 13.2.6),  
• 
temperature checking when entering a clinical facility (KP only),  
• 
both exercise professional and participant wearing face masks,  
• 
frequent hand washing and hand sanitizing,  
• 
maintaining a 6 ft distance when possible,  
• 
frequently wiping down surfaces and equipment with disinfectant wipes, and 
• 
any other appropriate precautions as required by local clinic and hospital procedures. 
DFCI exercise professionals will be following DFCI COVID-19 policy for patients and staff while 
in the building. 
 
3.10 
Intervention for the waitlist controls: 
Participants randomized to the usual care (U) group will be instructed to refer to their physician 
regarding what forms of exercise are safe for them, given their specific medical history. The U 
group will be told to continue whatever exercise program they have been undertaking up to 
enrolling in the study, but not to increase exercise or begin weight-lifting over the period of study 
participation (See Appendix 13.9). Participants will be sent a contact card halfway through the 
intervention reminding them of the follow-up visit. At the conclusion of participation, they will be 
offered: Emailed link to WebExercise routine; a set of resistance bands; a 30-minute interview 
with FORCE exercise professional; and a sample of protein powder. 
 
3.11 
Pharmacokinetics study:  
Up to 30 individuals, who are scheduled to receive 6 months of 5-FU, leucovorin and oxaliplatin 
(FOLFOX), will be given the option to participate in pharmacokinetic (PK) testing (see Section 
4.14), in addition to the randomized intervention.  
 
3.12 
Compensation: 
All participants participating at Kaiser Permanente, Penn State and Dana-Farber who are not 
participating in the PK study will receive a gift card either in person or by USPS as a thank you 
for completing the baseline visit ($25) and the follow-up visit ($25). See Appendix 13.10 for 
example language to be included in thank card for those gift cards sent by mail. Patients 
participating in the PK study will receive a total of $225 in gift cards by study completion- $100 
for each day that PKs are drawn and $25 for the follow-up visit (total 3 cards). In addition, 
parking will be validated on the 2 days that PKs are drawn.  
 
3.13 
Photographs of study subjects: 
Participants will be asked if they would be willing to have their photograph taken. If they are 
interested, they will be asked to complete the Media Consent form. For those who consent, 
photographs of study participants will be taken during clinic visits (completing questionnaires, 
physical assessment testing, talking with study staff), to use in research presentations, for 
conferences and workshops, where the Investigator(s) present the study. Dana Farber Cancer 
Institute is excluded from this as they will not ask their participants if they are willing to be 
photographed. 
 
3.14 
Sharing of results with subjects: 
All participants will be provided with whole body DXA results, both Baseline and Post-
Intervention, after the conclusion of participation (See Appendix 13.8.5). 

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18 
4. STUDY MEASUREMENTS 
Initial screening will take place via telephone. At the in-person baseline visit, after the patient 
signs the consent form, s/he will undergo a series of baseline assessments, questionnaires and 
blood draws as described above. Many of the data collection instruments will be either data 
entered by a researcher or self-administered by participants into REDCap, which is a secure 
web application for managing online surveys and databases. The table below provides an 
overview of the measurements that participants will undergo over the course of the protocol and 
the timing of these measurements: 
 
Table 7. Measurement Schedule 
Measure 
Screening 
Baseline 
Weekly 
PK Cohort 
Only 
Post-Intervention 
Visit3 
Phone screening 
questions- PA screening 
and additional questions 
X 
 
 
 
 
PAR-Q 
X 
 
 
 
 
SF-364 
 
X 
 
 
X 
Demographics4 
 
X 
 
 
 
Paffenbarger 
questionnaire 
 
X 
 
 
X 
Physical function tests 
(balance, gait speed, sit 
and stand, grip strength) 
 
X 
 
 
X 
Food frequency 
questionnaire4 
 
X 
 
 
X 
Height, weight, waist 
and hip circumference 
 
X 
 
 
X 
Whole body DXA 
 
X 
 
X2 
X 
Patient-completed side 
effects questionnaires4 
 
X 
 
 
X 
D3- creatine dilution 
 
X 
 
 
X 
NCI PRO CTCAE 
 
 
X1 
 
 
Medical record review 
for chemotherapy 
dosing and toxicities 
 
 
X 
 
 
Physical activity and 
nutrition logs 
 
 
X 
 
 
Inflammatory markers 
 
X 
 
 
X 
Pharmacokinetics (PK) 
 
 
 
See section 
4.14 
 
Injury history 
questionnaire4 
 
 
 
 
X 
Intervention follow-up 
survey 
 
 
 
 
X 
1 At each scheduled intervention visit (for intervention arm) and thereafter by phone or secure web-link every time chemotherapy appointment 
is scheduled. For U group controls, an RA will administer by phone or secure web-link every time a chemotherapy appointment is scheduled. 
2 For PK cohort, a DXA scan will also occur at time of 2nd PK draw, at approximately 4 months after initiation of the intervention 
3 To be conducted within 2 weeks after last cycle of chemotherapy and end of intervention 
4 As a result of COVID-19, to reduce in person time participants will complete baseline and post-intervention questionnaires virtually. Study staff 
will email participants a secure web-link, send them home with paper copies to be mailed back within 3 days, or administer questionnaires over 
the phone. 
 

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19 
4.1 
Screening questionnaire: 
Through a screening phone call, we will assess interest in and eligibility for the intervention. This 
will occur as soon as possible after the patient is scheduled for chemotherapy, ideally before 
initiation of chemotherapy. We will assess baseline physical activity eligibility by asking a series 
of physical activity screening questions (see Appendix 13.2.3) in order to ensure eligibility with 
regard to minutes of physical activity per week (eligibility= not engaging in current strength 
training >2x week for >3 months). Readiness will be determined using the Physical Activity 
Readiness Questionnaire (PAR-Q) (see Appendix 13.2.2). This latter survey was specifically 
designed to screen individuals for whom such unsupervised home-based exercise would be 
unsafe. These questions will be administered by a trained interviewer and those not meeting the 
eligibility qualifications (either already exercise too much or unsafe to exercise without 
supervision) will be reviewed by their treating oncologist and/or the study oncologist for advice 
on suitability of exercise intervention participation. We will also ask whether the individual has 
any planned major surgeries or is currently enrolled in other weight loss, physical activity or 
dietary studies (see Appendix 13.2.4). A researcher will record all screening question responses 
in an online REDCap form. 
  
4.2 
Demographic and health information:  
Participants will be asked to complete a brief standardized survey regarding gender, marital 
status, household size, race and ethnicity, educational level, occupational status. In addition, 
cancer registry data and EMR will be reviewed for information on prognostic factors, including 
disease stage, nodal status, histologic grade, surgical procedures, and treatment medical 
history/comorbidities, cardiometabolic risk factors, including blood pressure. See Appendix 
13.4.1. A researcher will record all relevant health information in an online REDCap form. 
Participants will complete an online REDCap survey about demographic information. 
 
4.3 
Medical outcomes study 36-Item, short form (SF-36): 
 A self-reported questionnaire consisting of 8 subscales that measure perceptions of general 
health, physical functioning, mobility limitations, pain, general mental health or emotional 
distress, and general social functionality. Response options allow participants to indicate the 
degree to which they feel healthy or impaired, with a score range of 0-100. Higher scores 
indicate a self-perception of better health than lower scores. See Appendix 13.4.2. Participants 
will complete the SF-36 in an online REDCap survey. 
 
4.4 
Physical activity and diet assessment: 
We will use an abbreviated Paffenbarger Physical Activity (PA) Questionnaire to assess usual 
physical activity (See Appendix 13.5.1) and the 2014 Block food frequency questionnaire to 
assess usual diet (see Appendix 13.6.1). Participants will complete these questionnaires either 
on paper or via research assistant interview. Participants will fill out the PA assessment on 
paper, and then a researcher will enter their responses into an online REDCap form. 
Participants will complete the food frequency questionnaire on a paper scantron form.  
 
Physical function tests include 4.5 to 4.8: 
 
4.5 
Balance test:  
This test is conducted to measure participant’s balance. Participants will be instructed to stand 
and maintain 3 different foot positions- side-by-side, semi-tandem and tandem- for 10 seconds 
each. (see Appendix 13.5.2). A researcher will use a stopwatch to keep time and record results 
from this physical function test in an online REDCap form. 
 
 

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20 
4.6 
Gait speed:  
To measure locomotion, participants walk a short distance (4 meters) at their usual pace, 
completing one practice and two-timed trials. Scores are recorded as time in seconds required 
to walk 4 meters on each of two trials, with the better trial used for scoring. Tests will be 
administered by research staff trained in administering the test and in safety precautions. See 
Appendix 13.5.2. A researcher will record results from this physical function test in an online 
REDCap form. 
 
4.7 
Sit and stand:  
To measure lower extremity muscular strength and endurance, the time required to complete 5 
full stands from a seated position will be recorded using a stopwatch. One practice stand will be 
performed for positioning and learning of the task49. Tests will be administered by research staff 
trained in administering the test and in safety precautions. See Appendix 13.5.2. A researcher 
will record results from this physical function test in an online REDCap form. 
 
4.8 
Grip strength:  
Grip strength is measured in both hands using a hydraulic grip strength dynamometer at baseline 
and at the post-intervention visit. If the participant reports current flare-up of pain in one wrist or 
hand, or has undergone fusion, arthroplasty, tendon repair, synovectomy, or other related 
surgery in the past 3 months, only the other hand should be tested. Other possible temporary 
discomfort during the test itself, there are no known risks for the participant. To measure upper 
extremity muscular strength, a Jamar hand grip will be held at the side of the body in a handing 
position with the elbows slightly bent. The dynamometer will be squeezed with as much force as 
possible over three trials with 20 seconds rest in between trials. Tests will be administered by 
research staff trained in administering the test and in safety precautions. Patients will complete 
the test 3 times with each hand, and the research staff will record the test results and note the 
patient’s dominant hand. See Appendix 13.5.2. A researcher will record results from this 
physical function test in an online REDCap form. 
 
4.9 
Medical record review:  
Details of each patient’s health history, including medical imaging, comorbidities and colon 
cancer diagnosis and treatment details will be extracted from the EMR. In addition, laboratory 
and clinical data about the colon cancer tumor marker Carcinoembryonic Antigen (CEA) and 
cardiometabolic risk factors blood glucose, lipids, blood pressure and medication usage 
conditions will be extracted from the EMR. See Appendix 13.2.1. A researcher will record all 
relevant medical variables in an online REDCap form. In addition, CT scans will be obtained 
from the participant’s medical record. KP scans will be stripped of PHI and analyzed at DOR. 
Penn State and DFCI scans will be stripped of PHI and transmitted directly to DOR via SFT. CT 
scan closest to the date of diagnosis but before chemotherapy will be colored using TomoVision 
sliceOmatic software to determine body composition, including muscle attenuation.   
 
4.10 
Body composition and body size:  
At the baseline visit and at the follow-up visit, a DXA scan to assess body composition will be 
performed (see Appendix 13.8.2). All DXA scans will be performed in the total body scanning 
mode. A third scan will take place after 4 months for the subset of people participating in the PK 
study to correspond to timing of the 2nd PK blood draws.  
 
At the baseline visit and at the follow-up visit, d3-creatine dilution will be used to accurately 
assess total body skeletal muscle mass (see Appendix 13.8.3).  
 
Height and weight will be assessed using a scale mounted stadiometer and digital scale (or per 
institutional clinic standards) to the nearest 0.1 cm and 0.1 kg. Waist circumference and hip 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
21 
circumferences will be measured at standardized landmark with participants dressed in light 
indoor clothing without shoes. Height will be assessed at baseline only. A researcher will record 
anthropometric measurements in an online REDCap form. See Appendix 13.8.1. 
 
Because of COVID-19, if a participant doesn’t feel comfortable with study staff touching him/her 
for waist or hip circumference measures, the study staff can teach the participant how to self-
measure while observing and recording results in REDCap. 
 
4.11 
Dose reductions/delays and early discontinuation of treatment: 
At the initiation of adjuvant chemotherapy, we will ascertain planned treatment course for 
participants, including planned cumulative dose and planned treatment duration. We will then 
examine the EMR for changes in chemotherapy dose and timing. The following variables will be 
defined for each drug administered: 
• Planned dose intensity (mg/week) = planned total dose / planned duration of therapy 
(weeks) 
• Actual dose intensity (mg/week) = actual total dose (mg) / actual duration of therapy 
(weeks) 
• Relative dose intensity (RDI) (%) = actual total dose intensity / planned total dose intensity 
• Average relative dose intensity (ARDI) (%) = the average across all regimens of the 
relative dose intensity  
• Number of cycles of chemotherapy and date of initiation of each cycle 
 
In addition, we will report on early stoppage by calculating actual number of cycles / planned 
number of cycles of adjuvant therapy. We will only consider dose reductions that occur after 
start of intervention. Chemotherapy treatment forms will be used to capture data from the EMR 
on chemotherapy administration (see Appendix 13.7.4). A researcher will record all relevant 
chemotherapy treatment variables in an online REDCap form. 
 
4.12 Chemotoxicity:  
Total combined number of moderate and severe chemotherapy-associated toxicities, assessed 
via medical record review, patient-completed NCI PRO-CTCAE and patient-completed side 
effects questionnaires. As shown in the Appendix, we will use a series of validated 
questionnaires for chemotherapy-associated side effects including NCI PRO-CTCAE and a 
questionnaire on neurotoxicity utilized in a recent phase III trial with oxalipatin48. See Appendix 
13.7. Throughout the intervention, the research manager or assistant will email a secure web-
link to the patient requesting completion of the NCI PRO-CTCAE questionnaire in advance of 
his/her next chemotherapy infusion visit. A researcher will record all relevant chemotoxicity 
variables in an online REDCap form. Participants will complete the patient-completed side 
effects questionnaire and NCI PRO-CTCAE questionnaire in online REDCap surveys. 
 
4.13 
Inflammatory blood measures: 
All participants will undergo measurements of inflammatory markers around the time of the 
baseline clinic visit and the follow-up clinic visit. Blood will be drawn at each time point in a 
standardized fashion. A total of three tubes of blood (one 8.5 ml SST red-top tube for serum and 
two 6 ml EDTA purple-top tubes for whole blood and plasma) will be collected from all 
participating patients.   
 
Tubes will be prepared and stored at local sites until completion of study.  Each site will 
maintain a log of all collected specimens. At the completion of the study, the participating 
institutions will submit that log to the coordinating center for verification that each participant had 
required samples. Upon completion of the study, samples will be shipped to the laboratory of Dr. 
Jeffrey Meyerhardt, a FORCE PI at Dana Farber Cancer Institute, where his staff will inventory, 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
22 
aggregate, and freeze samples until samples required for assays are shipped to Dr. Nader 
Rifai’s laboratory at Boston Children’s Hospital. The combined log (with deidentified study ID 
and sample numbers only) will be submitted to respective testing labs to ensure all samples are 
received. Any additional or unused samples will be returned to and collectively stored at Dana 
Farber Cancer Institute until needed for future studies.   
 
Collection and Processing 
1 x 8.5 ml SST red-top tube will be collected at baseline and follow-up visit. 
•         Invert tubes 5 times to initiate clotting 
•         Allow blood to clot for a minimum of 30 minutes, but no longer than 2 hours. 
•         Centrifuge 15-20 min at 3000 RPM (1100-2000 x g) at room temperature or 
4°C. 
•         Aliquot the serum (top layer) into 4 cryovials (800 ul aliquots) per tube of 
blood. Label as serum. 
•         Freeze samples at -70°C 
•         Batch ship on dry ice. 
 
2 x 6 ml EDTA purple-top tubes will be collected at baseline and follow-up visit. 
•         Gently invert the tube 8-10 times to mix the EDTA. 
•         Centrifuge 1100-1300g for 10 min (swing-bucket) or 15 min (fixed-angle) at 
room temperature or 4°C. 
•         Aliquot the top layer (plasma) into 4 cryovials (800 ul aliquots). Label as 
plasma. 
•         Aliquot the bottom layer into 2 cryovials (800 ul aliquots). Label as buffy coat. 
•         Freeze samples at -80°C. 
•         Batch ship on dry ice. 
 
Assays for inflammation markers will be conducted in the laboratory of Dr. Nader Rifai at Boston 
Children’s Hospital. 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), using reagents and calibrators from Roche. Interleukin-6 (IL-6): 
IL-6 is measured by an ultra-sensitive ELISA assay from R & D Systems, Minneapolis, MN. The 
assay employs the quantitative sandwich enzyme immunoassay technique. TNF-receptor II: 
TNF-RII is measured by an ELISA assay from R & D Systems. The assay employs the 
quantitative sandwich enzyme immunoassay technique. 
 
4.14 
Pharmacokinetic (PK) measurements: 
5-FU and oxaliplatin plasma PK will be determined during the first cycle of FOLFOX following 
study enrollment and during the FOLFOX cycle at approximately 4 months post enrollment 
Blood samples (5 mL, EDTA treated tubes) will be obtained from each patient at the following 
seven time points on each study day: prior to OX infusion; at the end of OX infusion (before 5-
FU); after 5-FU loading dose (but before 5-FU infusion); approximately 0.5, 1, 2 hours after the 
start of the 5-FU infusion; and at the end of the 5-FU infusion (approximately 46 hours). For 
samples obtained up to 4 hours after the start of 5-FU infusion, an intravenous saline lock 
catheter will be placed in the participant’s forearm. A minimal waste sample (<2 mL) will be 
obtained prior to each study sample. Less than 60 mL (about ¼ cup) total of blood will be 
withdrawn during each of the two phases. 
 
Samples will be immediately processed to plasma, labeled with the study ID and sample ID (i.e., 
PK1 and collection time) and stored at -80°C until analysis. Samples will be shipped on dry ice 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
23 
to the Clinical Pharmacology Analytical Core (CPAC) at the Indiana University Melvin and Bren 
Simon Cancer Center (IUSCC). Each site will maintain a log of all collected specimens. When 
the site is ready to ship samples, they will submit that log (with anonymized study ID numbers 
and time point only) to the CPAC for verification that each participant had the required samples. 
See Appendix 13.8.6 for a summary of the KP PK blood draw protocol.  
 
Samples will be analyzed for oxaliplatin and 5-FU (and metabolite) concentrations in plasma 
using validated LC/MS/MS assays. A qualified analytical method will be developed by CPAC 
using internal standardization, liquid-liquid extraction, and UPLC-MS/MS (e.g. API 5500 QTrap, 
Applied Biosystems). The method development includes the infusion of the compound of 
interest (COI, i.e. OX, 5-FU and metabolites) with multiple mobile phases to identify a Q1 and 
Q3 that will maximize detection, chromatography in the selected mobile phases to maximize 
separation, selection of an appropriate internal standard, stability testing, the extraction of the 
COI from plasma by testing multiple acids/base and solvents, and linearity of an extracted 
standard curve and quality controls of the COI prepared in human plasma. The targeted lower 
limit of quantification is 1ng/ml using 20 µl of sample. CPAC has successfully used this 
sequence of studies to develop methods to quantify 57 new chemical entities and 75 clinically 
approved drugs.  
 
A researcher will record all relevant PK variables in an online REDCap form. 
 
4.15 
Injury history questionnaire: 
 
During the post-intervention visit, participants will be asked to complete a one-time 
questionnaire in REDCap detailing any recent emergency room visits or injuries since the start 
of the FORCE study. Injuries specifically focus on those that might be related to physical activity 
such as joint pain, soft tissue pain, chest pain, headaches, dizziness, nausea and abdominal 
pain (see Appendix 13.7.6).  
 
4.16 
Intervention follow-up survey:  
 
During the post-intervention visit, intervention participants only will be asked to complete a one-
time questionnaire in REDCap detailing their experience engaging with the exercise 
professional virtually (Appendix 13.4.3). This survey will only be collected with participants who 
enrolled in the study after the start of the COVID-19 pandemic.  
 
4.17 
Enhanced safety procedures due to COVID-19: 
As a result of COVID-19, study staff will adhere to strict safety procedures when meeting with 
participants in person for the baseline and follow-up clinic visits. Enhanced safety procedures 
include: 
• 
phone screening before visit with COVID-19 script (Appendix 13.2.6),  
• 
temperature checking when entering a clinical facility (KP only),  
• 
both study staff and participants wearing face masks,  
• 
frequent hand washing and hand sanitizing,  
• 
maintaining a 6 ft distance when possible,  
• 
frequently wiping down surfaces and equipment with disinfectant wipes,   
• 
allowing the option for participants to self-administer measurements that require 
touching with staff observing and recording results, and 
• 
any other appropriate precautions as required by local clinic and hospital procedures. 
 

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24 
DFCI study staff will be following DFCI COVID-19 policy for patient and staff while in the 
building. 
 
5. POTENTIAL RISKS AND CHARACTERISTICS 
 
5.1 
Exercise: 
There is the possibility of muscle soreness and injury from the exercise training program. The 
muscle soreness may last several days after the testing and after each exercise training 
session, but it is not likely to be severe enough to limit any usual daily activities. There is also a 
risk of muscle injury from the exercise training program. Muscle injuries may require medical 
attention, may take several months to heal, and may limit usual daily activities for a period of 
days, weeks, or months. It is expected that all study participants will incur at least minor muscle 
soreness over the course of the entire intervention.  
                                                                
5.2 
DXA scan: 
The cumulative radiation exposure from this test is considered small and is not likely to 
adversely affect disease status.  
 
5.3 
D3-creatine dilution test: 
There are no known risks. 
 
5.4 
Blood draw: 
Local pain, bruising, and, in rare instances, an infection might occur at the site where blood is 
drawn. There is also the possibility of dizziness or fainting while blood is being drawn. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
25 
6. ADVERSE EVENTS 
 
6.1 
Chemotherapy toxicity  
As differences in chemotherapy-associated toxicities are part of objectives of the study, 
chemotherapy-associated toxicities will be monitored and recorded throughout chemotherapy 
period. However, severity and grading will not require reporting to IRB as those would be 
expected with standard of care treatment.   
 
6.2 
Adverse events and serious adverse events 
Any unfavorable or unintended medical or psychological event experienced by a study 
participant during clinical research, sometimes referred to as an adverse experience or adverse 
effect. An AE can represent a new symptom or an exacerbation or worsening of an existing 
condition. It is not necessarily causally related to or associated with the investigational agent or 
protocol.   
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that: 
 
• 
Results in death 
• 
Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• 
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-
hour hospitalization or prolonged a hospitalization beyond the expected length of 
stay). Hospitalization admissions and/or surgical operations scheduled to occur 
during the study period but planned prior to study entry are not considered SAEs if 
the illness or disease existed before the person was enrolled in the trial, provided 
that it did not deteriorate in an unexpected manner during the trial (e.g., surgery 
performed earlier than planned). 
• 
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• 
Is an important medical event when, based upon appropriate medical judgment, it 
may jeopardize the participant and require medical or surgical intervention to prevent 
one of the outcomes listed above.  
 
Events not considered to be serious adverse events are hospitalizations for: 
 
• 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures; 
• 
Elective or pre-planned treatment for a pre-existing condition that did not worsen; 
• 
Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission; and 
• 
Respite care. 
 
6.3  
Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.' 
 
6.3.1 
Expected adverse event: 
 

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26 
Expected adverse events are those that have been previously identified as resulting 
from the intervention. For the purposes of this study, an adverse event is considered 
expected when it appears in the informed consent document as a potential risk. 
 
6.3.2 
Unanticipated problem (UP): 
 
Any incident, experience, or outcome that meets all of the following reporting criteria: 
 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
Related or possibly related to participation in the research where possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures or interventions involved in the research); 
and 
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
PIs must report UPs involving risk to subjects or others to the IRB. 
 
6.3.3  
Attribution: 
 
Attribution is the relationship between an adverse event or serious adverse event and 
the study intervention. Attribution will be assigned as follows: 
• 
Definite – The AE is clearly related to the study intervention. 
• 
Probable – The AE is likely related to the study intervention. 
• 
Possible – The AE may be related to the study intervention. 
• 
Unlikely - The AE is doubtfully related to the study intervention. 
• 
Unrelated - The AE is clearly NOT related to the study intervention. 
 
6.3.4  
Procedures for AE and SAE recording and reporting: 
 
6.3.4.1 The PI or designee will investigate and analyze any event or incident 
to determine whether it is reportable to the IRB. 
 
To determine whether an event or incident is a reportable UP, the PI 
or designee must answer and comment on the following three 
questions: 
 
1. Is the event or incident unexpected in nature, severity, or 
frequency? 
Evaluate whether the event or incident is described as a risk in the 
research application, investigators’ brochure, or informed consent 
document and outside the expected severity or frequency. 
 
2. Is the event or incident related or possibly related to participation 
in the research? 

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27 
Evaluate whether the event or incident could reasonably have 
been caused by participation in the research. 
 
3. Does the unanticipated incident, experience, event, and/or 
outcome suggest, in the PI’s opinion, that either: 
a. The research places subjects or others at a greater risk 
(including physical, psychological, economic, or social 
harm) than was previously known or recognized; or 
b. This incident has more than a minimal effect on the 
integrity of the study or research results? 
 
Determination 1: If the answer to all three questions above is 
“Yes,” the event or incident is a UP and must be reported to 
the IRB. See PI Reportable Event and Incident Requirements 
SOP KPNC-502 for timeframe to report upon discovery. 
 
Determination 2: If any answer is “No,” the event or incident is 
not a UP and does not have to be reported as a UP; however, 
analysis is required to determine if reporting should be made 
as a different type of reportable event or incident (e.g., 
noncompliance). 
 
6.3.4.2 All AEs and SAEs whether reported by the participant, discovered 
during questioning, directly observed, or detected by physical 
examination, laboratory test or other means, will be recorded in the 
appropriate study-specific case report forms. 
 
6.3.4.3 The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of 
the CTCAE version 4.0 can be downloaded from the CTEP website. 
 
6.4 
Reporting requirements: 
 
6.4.1 
Each participating investigator is required to abide by the reporting 
requirements set at their individual sites.  
 
6.4.2 
Each investigative site will be responsible to report SAEs that occur at that 
institution to their respective IRB. It is the responsibility of each participating 
investigator to report serious adverse events to the Kaiser overall principal 
investigator. 
 
6.4.3 
Serious adverse event reporting: 
All serious adverse events that occur after the initiation of study intervention, during 
intervention or within 30 days after completion of intervention must be reported to the 
Kaiser Permanente overall principal investigator using the individual site’s SAE form. 
This includes events meeting the criteria outlined in Section 6.2, as well as the 
following: 
• 
Grade 3 (severe) Events – Only events that are unexpected and possibly, 
probably or definitely related/associated with the intervention. 

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28 
• 
All Grade 4 (life-threatening or disabling) events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
• 
All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the last 
study intervention. 
 
Participating investigators must report each serious adverse event to the Kaiser 
Permanente Overall Principal Investigator within 24 business hours of learning of the 
occurrence. In the event that the participating investigator does not become aware of the 
serious adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 business hours after learning of 
it and document the time of his or her first awareness of the adverse event. Report 
serious adverse events by telephone, email or facsimile to: 
Bette Caan, DrPH 
Division of Research 
Kaiser Permanente 
2000 Broadway 
Oakland, CA 94612 
510-891-3719 
Bette.caan@kp.org 
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information should 
describe whether the event has resolved or continues, if and how the event was treated, 
and whether the participant will continue or discontinue study participation. 
 
6.4.4 
Reporting to the Institutional Review Board (IRB): 
All unanticipated serious adverse events should be reported to the Kaiser Permanente 
IRB as defined by the PI Reportable Event and Incident Requirements SOP KPNC-502.  
Other investigative sites should report serious adverse events to their respective IRB 
according to the local IRB’s policies and procedures in reporting adverse events.  
 
6.4.5       Reporting to Hospital Risk Management: 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
 
 
7. CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will be removed from study when any of following criteria occur: new invasive cancer 
diagnosis or recurrence; decision of the participant to stop receiving chemotherapy treatment; 
request of the patient to withdraw; illness that prevents further administration of the intervention; 
or study team or treating clinicians deem continued participation not safe for patient.  Patients 
who are removed from study will be asked to complete follow-up assessments if clinically 
feasible and patients are agreeable. Reason for removal from study will be recorded in patient’s 
study record. 
 
 
 

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29 
8. DATA REPORTING / REGULATORY REQUIREMENTS 
 
The Kaiser Permanente of Northern California study team will oversee all adverse events with a 
designated Data and Safety Monitoring Board. This board will include Dennis Black 
(biostatistician), Kerri Winters Stone (exercise interventionist), Kathleen Van Loon (gastro 
oncologist) and study liaison.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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30 
9. STATISTICAL CONSIDERATIONS 
 
9.1 
Study design: 
This randomized controlled trial of resistance training intervention in colon cancer patients 
receiving chemotherapy consists of two arms: an in-person and telephone-based intervention to 
promote home-based resistance training, and a wait-list, control group. After consent and 
baseline visit measurements, randomization assignment will utilize a covariate adaptive 
randomization procedure which ensures that equal numbers of patients are assigned to each 
study arm and that the two arms remain balanced on five key characteristics: site of 
participation [Kaiser Permanente vs Penn State vs Dana-Farber]; gender [male vs female]; 
cancer stage [stage II vs stage III], and duration of chemotherapy [3 months vs 6 months]; 
planned chemotherapy regimen [FOLFOX vs CAPOX vs capecitabine vs 5-FU/LV]. This 
randomization method (also known as the minimization method) has been demonstrated to 
outperform simple randomization or stratified randomization in terms of achieving balanced 
groups, particularly in smaller trials with multiple important prognostic factors.  
 
The primary objective of this trial is to compare the effect of a RT intervention versus a wait-list 
control on chemotherapy dose reductions, dose delays, early discontinuation of chemotherapy 
and treatment-related toxicity. The secondary objective is to compare the effect of the 
intervention versus wait-list control on changes in inflammatory biomarkers, and the tertiary 
objective is to compare pre and post intervention pharmacokinetics of 5-FU and oxaliplatin. The 
d3 Creatine objective is to compare the effect of a RT intervention versus a wait-list control on 
d3 creatine muscle mass at 6 months. 
  
9.2 
Sample size, accrual time and study duration: 
One hundred and eighty (180) participants will be recruited and randomized over a total of 3.5 
years. Patient involvement and data collection will last approximately 6 months.  
 
9.2.1 From Section D. Study overview of the original KPNC application 
approved 2017 
 
3. How many participants will be enrolled in this study, or how many 
electronic records or medical records will be used? Provide your best 
estimate if you are not sure 
Number of KPNC 
participants or records: 
Approximately 115 participants to be 
enrolled 
Records used: 
Approximately 7500 KPNC records 
used 
Number of non-KPNC 
participants or records: 
Approximately 65 participants enrolled 
Total number of 
participants or records: 
Approximately 180* participants 
enrolled 
 
*Due to the impact of the COVID-19 
pandemic on the study, we estimate that 
the total number of participants will be 
within the range of 10% above the original 
total of 180 participants 
 
 

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31 
9.3 
Statistical analysis:  
 
9.3.1 
Primary endpoints:  
All data analyses will be by intent-to-treat, though in exploratory analyses we will 
consider compliance to intervention (defined as >75% of planned sessions) and changes 
in MM. We will use multiple linear regressions to assess the difference between the 
intervention and wait-list control groups in mean relative dose intensity (RDI) for each 
agent and in mean average RDI (ARDI) across all agents. Continuous model covariates 
will be categorized either as quartiles or into clinically relevant categories (e.g. WHO BMI 
classification).  
 
Analysis of number of grade 3 and 4 toxicities in relation to randomization arm will utilize 
Poisson regression given that this outcome can be characterized as a count. These 
regression models will provide point and interval estimates of adjusted proportional 
differences in rates of toxicities (expressed as rate ratios) between the control and 
intervention groups. 
 
9.3.2 
Secondary endpoints:  
Analyses of inflammatory markers in relation to baseline body composition will utilize 
multiple linear regression techniques These analyses of associations at baseline will be 
conducted in each randomization arm separately, followed by an analysis in the full 
sample (differences in associations at baseline across arms are not expected).  
 
Pharmacokinetics: As 5-FU is known to undergo nonlinear disposition, compartmental 
modeling will be conducted using nonlinear mixed effects analysis with NONMEM (Icon 
Development Solutions, Hanover MD).  NONMEM allows for simultaneous estimation of 
fixed-effects values (e.g. CL and V) and random-effects values (e.g. inter-individual, 
inter-occasional, and residual unexplained variability). Previous models of 5-FU and 
oxaliplatin28 have been reported and will serve as a basis for development of the 
structural model. The final structural (e.g. 1- vs. 2-compartment) and error models (e.g. 
additive or proportional) will be chosen based on minimization of the objective function 
value (OFV, -2 log likelihood) and evaluation of diagnostic plots generated in R. During 
the covariate selection process, various measures of body composition (e.g.MM, MM/FM 
ratio) will be compared to identify the contribution of these parameters to PK variability in 
colon cancer patients. Pre- and post-intervention PK parameters (e.g. CL, V) will be 
compared using a paired t-test.   
 
9.3.3 
d3 creatine endpoints:  
We will first assess the distribution of the baseline covariates by FORCE randomization 
arm. Most outcomes will be treated as continuous variables and we will fit linear 
regression models (e.g., for the continuous outcomes such as change in d3 creatine 
muscle mass, SPPB and SF-36 score, grip strength, relative dose intensity, and values 
of inflammatory markers, CEA and cardiometabolic risk factors). We will assess 
departures from regression model assumptions primarily by diagnostic plots of residuals, 
with attention to detection of non-constant variance of errors and detection of outliers 
that may indicate the need for a variance stabilizing transformation of the dependent 
variable. In secondary analyses, when considering outcomes dichotomously, we will fit 
logistic regression models (e.g., for abnormal CEA values). 
 
Aim 1 is a randomized comparison of the FORCE resistance training intervention to the 
waitlist control. Analyses in Aims 2-4, however, are subject to confounding. Our a priori 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
32 
set of potential confounders for cross-sectional analyses at baseline includes age, sex, 
body mass index or weight, race/ethnicity and tumor stage. For longitudinal analyses, 
potential confounders also include chemotherapy type, intervention assignment and time 
from surgery and/or chemotherapy start to assessment. We will include those covariates 
resulting in a 10% or more change in the d3 creatine muscle mass regression 
coefficient. The change-in-estimate approach to confounder selection performs well with 
regard to power, bias, mean squared error and confidence interval coverage. 
 
 
9.3.4 
Power:  
Given previous exercise studies in cancer patients, we assume approximately 10% drop 
out with no follow-up DXA and blood draw for biomarker assessment. We expect 
chemotoxicity metrics (RDI, # toxicities) to be assessed on the full sample. We have 
sufficient power (.80) to detect a between arm difference in means of at least .42 
standard deviation (s.d.) units (two-sided t-test, α=.05) in Aim 1 analyses of 
chemotoxicity. With an expected RDI s.d. of 17.345, the minimum detectable difference in 
mean RDI is 7.3%, which is clinically meaningful and similar to effects found with a study 
of exercise among breast cancer patients receiving adjuvant chemotherapy45. With the 
expected loss to follow-up and reduced sample size of 81 per group, the minimum 
detectable between arm difference in mean change is .44 units, which is considered in 
the “small” to “medium” range in effect size using the terminology and classification of 
Cohen.  Relevant to Aim 4, on pharmacokinetics, a sample size of 30 subjects will 
provide sufficient power (.80) to detect a mean change of at least 0.5 s.d. units (two-
sided t-test, α=.05). Given previous data26, the minimum detectable change in clearance 
of oxaliplatin or 5-FU due to RT is 15%. 
 
 
10. STUDY INVESTIGATORS  
 
The study’s Principal Investigators include:  
• 
Bette Caan, DrPH, Kaiser Permanente, Division of Research 
• 
Jeffrey Meyerhardt, MD, MPH, Dana-Farber Cancer Institute 
• 
Kathryn Schmitz. PhD, Penn State Cancer Institute 
Co-Investigators include: 
• 
Justin Brown, PhD, Pennington Biomedical Research Center, Louisiana State University 
• 
Kristin Campbell, PT, MSc, PhD, University of British Columbia 
• 
Elizabeth Feliciano, Kaiser Permanente, Division of Research 
• 
Raymond Liu, MD, The Permanente Medical Group 
• 
Charles Quesenberry, PhD, Kaiser Permanente, Division of Research 
• 
Sara Quinney, PhD, Indiana University 
• 
Renate Winkels, PhD, Penn State Cancer Institute 
 
11. DATA PRIVACY AND SECURITY 
 
Disclosure of PHI to non-KPNC workforce 
PHI will be disclosed to members of the Data Safety and Monitoring Board (DSMB) as well as 
an independent contractor, Dr. Barbara Sternfeld. The DSMB members will oversee and 
monitor the study to ensure participant safety and the validity and integrity of the data. Dr. 
Sternfeld will act as exercise intervention liaison, including overseeing exercise sessions, case 
review with trainer, and contact with DSMB. Types of PHI that will be disclosed include dates. 

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33 
Disclosure of deidentified datasets to non-KPNC workforce 
The following investigators and research staff from collaborating institutions will receive 
deidentified datasets (i.e., contains no PHI identifiers): 
• 
Jeffrey Meyerhardt, MD, MPH, Dana Farber Cancer Institute 
• 
Kathryn H. Schmitz, PhD, MPH, FACSM, FTOS, The Pennsylvania State University, 
Hershey Medical Center 
• 
Kristin Campbell, BSc PT, PhD, University of British Columbia 
• 
Justin Brown, PhD, Pennington Biomedical Research Center, Louisiana State University 
• 
Sara Quinney, PhD, Pharm. D., Indiana University 
• 
Barbara Sternfeld, PhD, independent contractor, Kensington, CA  
 
Deidentified datasets will include intervention data such as exercise adherence; study measure 
and questionnaire data from baseline and follow-up data collection; chemotherapy data and 
demographic data. 
 
Data transfer 
All data will be shared securely with investigators and staff via KPNC secure file transfer. 
 
Data storage 
All study data including data with PHI will be stored electronically on a secure, password 
protected KP server behind a firewall and in an online, secure, password protected REDCap 
database. Only approved research study staff have REDCap access. REDCap data will be 
archived off the server within 12 months after data collection ends. No PHI data will be stored 
for any part of the study on an endpoint computing device or removeable media (i.e., 
workstation, laptop, flash drive, CD). 
 
Blood biospecimen samples will be stored at Kaiser Permanente Northern California and Dana 
Farber Cancer Institute. Samples will be kept until they are used up for future studies or the 
Principal Investigators decide to destroy them. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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34 
12. REFERENCE LIST  
 
 
(1)  Prado CM, Antoun S, Sawyer MB, Baracos VE. Two faces of drug therapy in cancer: 
drug-related lean tissue loss and its adverse consequences to survival and toxicity. Curr 
Opin Clin Nutr Metab Care 2011;14:250-254.PM:21415735 
 
(2)  Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-
30.PM:26742998 
 
(3)  Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ. Adjuvant treatment of colorectal 
cancer. CA Cancer J Clin 2007;57:168-185.PM:17507442 
 
(4)  Andre T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, 
and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J 
Clin Oncol 2009;27:3109-3116.PM:19451431 
 
(5)  NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. 
JAMA 1990;264:1444-1450.PM:2202842 
 
(6)  J.Cassidy, W.Scheithauer, J.McKendrick et al. Capecitabine (X) vs bolus 5-
FU/leucovorin (LV) as adjuvant therapy for colon cancer (the X-ACT study): positive 
efficacy results of a phase III trial [abstract]J.Cassidy, W.Scheithauer, J.McKendrick et 
al. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings 2004;22:3509 
 
(7)  Sawyer M, Ratain MJ. Body surface area as a determinant of pharmacokinetics and 
drug dosing. Invest New Drugs 2001;19:171-177.PM:11392451 
 
(8)  Baker SD, Verweij J, Rowinsky EK et al. Role of body surface area in dosing of 
investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 2002;94:1883-
1888.PM:12488482 
 
(9)  Baker SD, Sparreboom A, Verweij J. Clinical pharmacokinetics of docetaxel : recent 
developments. Clin Pharmacokinet 2006;45:235-252.PM:16509758 
 (10)  Prado CM, Baracos VE, McCargar LJ et al. Body composition as an independent 
determinant of 5-fluorouracil-based chemotherapy toxicity. Clin Cancer Res 
2007;13:3264-3268.PM:17545532 
 (11)  Prado CM, Baracos VE, McCargar LJ et al. Sarcopenia as a determinant of 
chemotherapy toxicity and time to tumor progression in metastatic breast cancer patients 
receiving capecitabine treatment. Clin Cancer Res 2009;15:2920-2926.PM:19351764 
 (12)  Nies AT, Magdy T, Schwab M, Zanger UM. Role of ABC transporters in fluoropyrimidine-
based chemotherapy response. Adv Cancer Res 2015;125:217-243.PM:25640272 
 (13)  Caudle KE, Thorn CF, Klein TE et al. Clinical Pharmacogenetics Implementation 
Consortium guidelines for dihydropyrimidine dehydrogenase genotype and 
fluoropyrimidine dosing. Clin Pharmacol Ther 2013;94:640-645.PM:23988873 
 (14)  Gusella M, Toso S, Ferrazzi E, Ferrari M, Padrini R. Relationships between body 
composition parameters and fluorouracil pharmacokinetics. Br J Clin Pharmacol 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
35 
2002;54:131-139.PM:12207632 
 (15)  Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas M, Gamelin E. Clinical 
pharmacokinetics of oxaliplatin: a critical review. Clin Cancer Res 2000;6:1205-
1218.PM:10778943 
 (16)  Friedman AN, Strother M, Quinney SK et al. Measuring the glomerular filtration rate in 
obese individuals without overt kidney disease. Nephron Clin Pract 2010;116:c224-
c234.PM:20606483 
 (17)  Bastian G, Barrail A, Urien S. Population pharmacokinetics of oxaliplatin in patients with 
metastatic cancer. Anticancer Drugs 2003;14:817-824.PM:14597876 
 (18)  Prado CM, Lieffers JR, McCargar LJ et al. Prevalence and clinical implications of 
sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal 
tracts: a population-based study. Lancet Oncol 2008;9:629-635.PM:18539529 
 (19)  Ali R, Baracos VE, Sawyer MB et al. Lean body mass as an independent determinant of 
dose-limiting toxicity and neuropathy in patients with colon cancer treated with FOLFOX 
regimens. Cancer Med 2016;5:607-616.PM:26814378 
 (20)  Jung HW, Kim JW, Kim JY et al. Effect of muscle mass on toxicity and survival in 
patients with colon cancer undergoing adjuvant chemotherapy. Support Care Cancer 
2015;23:687-694.PM:25163434 
 (21)  Nakayama G, Tanaka C, Uehara K et al. The impact of dose/time modification in 
irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal 
cancer. Cancer Chemother Pharmacol 2014;73:847-855.PM:24577566 
 (22)  Hanna RK, Poniewierski MS, Laskey RA et al. Predictors of reduced relative dose 
intensity and its relationship to mortality in women receiving multi-agent chemotherapy 
for epithelial ovarian cancer. Gynecol Oncol 2013;129:74-80.PM:23262376 
 (23)  van WH, Stuiver MM, van Harten WH et al. Effect of Low-Intensity Physical Activity and 
Moderate- to High-Intensity Physical Exercise During Adjuvant Chemotherapy on 
Physical Fitness, Fatigue, and Chemotherapy Completion Rates: Results of the PACES 
Randomized Clinical Trial. J Clin Oncol 2015;33:1918-1927.PM:25918291 
 (24)  van Vulpen JK, Velthuis MJ, Steins Bisschop CN et al. Effects of an Exercise Program in 
Colon Cancer Patients undergoing Chemotherapy. Med Sci Sports Exerc 2016;48:767-
775.PM:26694846 
 (25)  Courneya KS, Segal RJ, Mackey JR et al. Effects of aerobic and resistance exercise in 
breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized 
controlled trial. J Clin Oncol 2007;25:4396-4404.PM:17785708 
 (26)  Mizrahi D, Broderick C, Friedlander M et al. An Exercise Intervention During 
Chemotherapy for Women With Recurrent Ovarian Cancer: A Feasibility Study. Int J 
Gynecol Cancer 2015;25:985-992.PM:25914961 
 (27)  Delano MJ, Moldawer LL. The origins of cachexia in acute and chronic inflammatory 

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
36 
diseases. Nutr Clin Pract 2006;21:68-81.PM:16439772 
 (28)  Richards CH, Roxburgh CS, MacMillan MT et al. The relationships between body 
composition and the systemic inflammatory response in patients with primary operable 
colorectal cancer. PLoS ONE 2012;7:e41883.PM:22870258 
 (29)  Malietzis G, Johns N, Al-Hassi HO et al. Low Muscularity and Myosteatosis Is Related to 
the Host Systemic Inflammatory Response in Patients Undergoing Surgery for 
Colorectal Cancer. Ann Surg 2016;263:320-325.PM:25643288 
 (30)  Khal J, Wyke SM, Russell ST, Hine AV, Tisdale MJ. Expression of the ubiquitin-
proteasome pathway and muscle loss in experimental cancer cachexia. Br J Cancer 
2005;93:774-780.PM:16160695 
 (31)  Frost RA, Lang CH. Protein kinase B/Akt: a nexus of growth factor and cytokine 
signaling in determining muscle mass. J Appl Physiol (1985 ) 2007;103:378-
387.PM:17332274 
 (32)  Goh J, Niksirat N, Campbell KL. Exercise training and immune crosstalk in breast cancer 
microenvironment: exploring the paradigms of exercise-induced immune modulation and 
exercise-induced myokines. Am J Transl Res 2014;6:422-438.PM:25360210 
 (33)  You T, Arsenis NC, Disanzo BL, Lamonte MJ. Effects of exercise training on chronic 
inflammation in obesity : current evidence and potential mechanisms. Sports Med 
2013;43:243-256.PM:23494259 
 (34)  Schmidt ME, Meynkohn A, Habermann N et al. Resistance Exercise and Inflammation in 
Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis 
From a Randomized, Controlled Intervention Trial. Int J Radiat Oncol Biol Phys 
2016;94:329-337.PM:26853341 
 (35)  Phillips SM. A brief review of critical processes in exercise-induced muscular 
hypertrophy. Sports Med 2014;44 Suppl 1:S71-S77.PM:24791918 
 (36)  Strasser B, Steindorf K, Wiskemann J, Ulrich CM. Impact of resistance training in cancer 
survivors: a meta-analysis. Med Sci Sports Exerc 2013;45:2080-2090.PM:23669878 
 (37)  Brown JC, Schmitz KH. Weight lifting and appendicular skeletal muscle mass among 
breast cancer survivors: a randomized controlled trial. Breast Cancer Res Treat 
2015;151:385-392.PM:25935584 
 (38)  Thiebaud RS, Funk MD, Abe T. Home-based resistance training for older adults: a 
systematic review. Geriatr Gerontol Int 2014;14:750-757.PM:25109883 
 (39)  Galvao DA, Spry N, Denham J et al. A multicentre year-long randomised controlled trial 
of exercise training targeting physical functioning in men with prostate cancer previously 
treated with androgen suppression and radiation from TROG 03.04 RADAR. Eur Urol 
2014;65:856-864.PM:24113319 
 (40)  Santa MD, Alibhai S MH, Matthew AG et al. A randomized trial of aerobic versus 
resistance exercise in prostate cancer survivors. J Aging Phys Act 2013;21:455-

FORCE: Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise 
 
37 
478.PM:23238110 
 (41)  Musanti R. A study of exercise modality and physical self-esteem in breast cancer 
survivors. Med Sci Sports Exerc 2012;44:352-361.PM:21796050 
 (42)  Yuen HK, Sword D. Home-based exercise to alleviate fatigue and improve functional 
capacity among breast cancer survivors. J Allied Health 2007;36:e257-
e275.PM:19759996 
 (43)  Beidas RS, Paciotti B, Barg F et al. A hybrid effectiveness-implementation trial of an 
evidence-based exercise intervention for breast cancer survivors. J Natl Cancer Inst 
Monogr 2014;2014:338-345.PM:25749601 
 (44)  L.S.Pescatello, R.Arena, D.Riebe, P.D.Thompson. ACSM's Guidelines for Exercise 
Testing and Prescription.  2013. Philadelphia, PA, Lippincott Williams & Wilkins. 
 
 Ref Type: Generic 
 (45)  Ainsworth BE, Leon AS, Richardson MT, Jacobs DR, Paffenbarger RS, Jr. Accuracy of 
the College Alumnus Physical Activity Questionnaire. J Clin Epidemiol 1993;46:1403-
1411.PM:8263567 
 (46)  Sallis JF, Haskell WL, Wood PD et al. Physical activity assessment methodology in the 
Five-City Project. Am J Epidemiol 1985;121:91-106.PM:3964995 
 (47)  Hayden-Wade HA, Coleman KJ, Sallis JF, Armstrong C. Validation of the telephone and 
in-person interview versions of the 7-day PAR. Med Sci Sports Exerc 2003;35:801-
809.PM:12750590 
 (48)  Loprinzi CL, Qin R, Dakhil SR et al. Phase III randomized, placebo-controlled, double-
blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced 
sensory neurotoxicity (N08CB/Alliance). J Clin Oncol 2014;32:997-1005.PM:24297951 
 (49)  Csuka M, McCarty DJ. Simple method for measurement of lower extremity muscle 
strength. Am J Med 1985;78:77-81.PM:3966492 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13. APPENDIX  
 
 
13.1 
Recruitment Communications 
13.1.1 Email to Oncology Provider 
13.1.2 DFCI Recruitment Letter 
13.1.3 Recruitment Phone Script 
13.1.4 Recruitment Email/Letter to Participant 
13.2 
Phone Screening Forms and Questionnaires 
13.2.1 Screening Eligibility Form 
13.2.2 Physical Activity Readiness Questionnaire (PAR-Q)  
13.2.3 Physical Activity Screening Questions 
12.2.4  Additional Screening Questions 
13.2.5 Participant Information Form 
13.2.6 COVID-19 Phone Script- Staff Screening of In Person Visits 
13.3 
Consent Form 
13.3.1 Consent Form 
13.3.2 eConsent and HIPPA Authorization Forms 
13.3.3 REDCap eConsent and HIPPA Signature Sections  
13.3.4 FORCE Invite and eConsent REDCap Email 
13.4 
Baseline and Post-Intervention Questionnaires 
13.4.1 Demographic Information 
13.4.2 Medical Outcomes Study 36-Item Short Form (SF-36) 
13.4.3 Intervention Follow-up Survey  
13.5 
Physical Activity Assessments and Exercise Intervention Materials 
13.5.1 Abbreviated Paffenbarger Physical Activity Questionnaire 
13.5.2 Physical Function Tests Protocol and Assessment Sheets  
13.5.3 Exercise Protocol 
13.5.4 Participant Exercise Log  
13.5.5 Exercise Trainer Phone Call/Clinic Visit Questions 
13.6 
Nutrition Assessments and Intervention Materials 
13.6.1 Food Frequency Questionnaire (FFQ) Block 2014 
13.6.2 Nutrition Protocol 
13.6.3 Participant Protein Log 
 
12.6.4  Usual Care Protein Handout 
13.7 
Chemotherapy Toxicity, Side Effects, and Injury History Forms and Email  
13.7.1 Patient-completed NCI- PRO-CTCAE 
13.7.2 Email regarding NCI-PRO-CTCAE 
13.7.3 Patient-completed Side Effect Questionnaire 
13.7.4 Chemotherapy Treatment Form 
13.7.5 Chemotherapy-associated Toxicity Form 
13.7.6 Injury History Form 
13.8 
Anthropometric Measurements and Blood Draw Procedures 
13.8.1 Waist and Hip Circumference, Height and Weight 
13.8.2 Dual X-Ray Absorptiometry Protocol 
13.8.3 D3 Creatine Dilution Protocol 
13.8.4 Blood Draw and DXA Instruction Cards 
13.8.5 DXA Cover Sheets 
13.8.6 KP PK Blood Draw Protocol 
13.9 
Usual Care Handout 
13.10 Thank You Card Text