The effect of (chemo- or bio)radiation on functional capacity, fatigue and quality of life in patients with head and neck cancer: a trial within cohorts, the VITAL study.

In 2018 the incidence of Head and Neck Cancer (HNC) was 3.195 and the
prevalence was 10.655 in the Netherlands1. In the south of the Netherlands, per
year 100 patients with HNC are treated with radiotherapy (RT) and
chemoradiation (CRT) or bioradiation (BRT) at the Instituut Verbeeten hospital
in Tilburg. HNC includes tumours located in four anatomical sites: pharynx,
larynx, oral and sinonasal cavity2. The most prevalent causes of HNC are heavy
consumption of tobacco and/or alcohol and the human papilloma virus (HPV)2.
Treatment of HNC by surgery, RT or C/BRT can cause unintentional weight loss,
loss of muscle mass, loss of muscle strength, increased fatigue and a decreased
health related quality of life (HR-QoL)3. (C/B)RT can also cause acute and late
side effects like osteoradionecrosis, prolonged enteral nutrition, soft tissue
necrosis and fibrosis, vascular stenosis, thromboembolic events, and neurologic
damage4.

During the last nine years, ten studies are published investigating exercise
interventions for patients with HNC during or after (C/B)RT
treatment5,6,7,8,9,10,11,12,13,14,15,. When compared to 874 Randomized
Controlled Trials (RCT) (comparing *breastcancer* with *physical activity* on
PubMed) investigating the effects of an exercise intervention in patients with
breast cancer, there is less evidence. The overall conclusion is clear,
exercise interventions for patients with HNC are safe and feasible6,9,10,
11,13. Exercising during or after (C/B)RT may maintain or improve both physical
function and HR-QoL. It is, however, necessary to do more research to underpin
the found effects, because research about the effect of such interventions in
the Dutch population is still missing. Above that, HNC is hard to compare with
other types of cancer because HNC and treatment by (C/B)RT for HNC is
characterised by heavy weight loss caused by malnutrition. Therefore, there is
no cost-effectiveness analysis of exercise interventions for patients with HNC.

Primary Objective:
- To determine and compare physical performance in patients with HNC with and
without an exercise intervention.

Secondary Objective(s):
- To determine and compare muscle strength in patients with HNC with and
without an exercise intervention.
- To determine and compare fatigue in patients with HNC with and without an
exercise intervention.
- To determine and compare HR-QoL in patients with HNC with and without an
exercise intervention.
- To determine and compare body composition in patients with HNC with and
without an exercise intervention.
- To determine and compare nutritional status in patients with HNC with and
without an exercise intervention.
- To determine and compare physical activity in patients with HNC with and
without an exercise intervention.
- To determine and compare treatment tolerability of (C/B)RT treatment in
patients with HNC with and without an exercise intervention.
- To determine and compare the healthcare related costs in patients with HNC
with and without an exercise intervention.

Normally, to investigate and compare an experimental intervention with a
control group, a randomized controlled trial (RCT) design is used. A common
problem of this design is the lack of participants. Participants can refuse
because of the preference for an exercise intervention or not, they therefor
probably dislike the concept of randomization which can result in low
recruitment numbers17.

For this study, a TwiCs design, also known as a cohort multiple randomized
controlled trial (cmRCT) design will be used. Aiming to improve recruitment.
For this design, patients will sign a first informed consent (IC) to
participate in a prospective cohort and have several measurements. Patients are
informed about the design of this study including the likelihood that an
experimental intervention may be offered, or not, during participation. After
joining the prospective cohort, the patients will be randomized for the cohort
+ intervention group or staying in the cohort group. The cohort + intervention
group will receive an exercise intervention and the cohort group usual exercise
care. Usual exercise care consists of advice to exercise. The patients who are
randomized in the cohort + intervention group will be informed about the
exercise intervention and asked to participate. When agreed, patients sign a
second IC. The patients who are randomized to stay in the cohort group will not
be informed about the exercise intervention. After one year ,the patients who
are not randomized to receive an exercise intervention will be informed about
this intervention. They will be offered a similar exercise intervention.

The cohort + intervention group receives an exercise intervention for 10 weeks:
1 week before the start, 7 weeks during and 2 weeks after (C/B)RT. The
experimental intervention consists of twice a week 60 minutes exercise
intervention at the department of physiotherapy. Executing exercises will be
supervised by a physiotherapist. The physiotherapist will registrate every
intervention which aerobic or muscle strength exercise is done and how many
sets, repetitions and the resistance of the exercise.

Every exercise intervention starts and stops with a 10 minute aerobic exercise
by using the home trainer or treadmill. The purpose of the aerobic exercise is
to reach an heartrate of 60% of the heartrate max (HRmax). HRmax will be
calculated by the maximum heartrate (220) minus the age of the patient. To
reach 60% of the HRmax, resistance and/or speed will be improved.

Exercise for muscle strength contains exercises for lower and upper extremity:
calf raises, leg press, lunges, squat, seated row, lateral pull down, bicep
curl and triceps extension. Before starting the intervention, muscle power is
measured by an one rapid maximum (1RM). At the start of this program, patients
will start at 60% of their 1RM and perform 2 sets of 8 to 12 repetitions. By
trying to maintain muscle strength during (C/B)RT, resistance will presumably
not increase a lot. But, when the exercise is too easy, resistance can increase
by 5 to 10% of the 1RM. On the other hand, when it is too hard for a patient to
maintain 60% of their 1RM because of the adverse events, it is permissible to
do exercises based on a lower base of 60%. It is more important to continue
doing exercises than the level of resistance. To preserve an exercise stimulus,
patients are asked to rate the perceived exertion of the exercises by using the
BORG Rating of Perceived Exertion (BORG RPE). A 0 to 10 scale is used aiming a
score between 5 and 8 which means hard of really hard.

Patients who will receive the experimental intervention also have to do
home-based aerobic and muscle strength exercises three times a week.
Instructions will be at the first appointment with the physiotherapist. Aerobic
exercises contains a walking schedule to walk 30 minutes. Muscle strength
exercises are based on the exercises that patients can perform without
instruments: calf raises, squats, lunges and wall sits for lower extremity,
push-ups against the wall, side raises and front raises for upper extremity.
The home based muscle strength exercises also have the objective to maintain
muscle strength during (C/B)RT. patients start with 2 sets of 8 to 12
repetitions. To register these exercises, patients need to fill in an exercise
dairy and use a pedometer application for smartphones. Self-efficacy has shown
to impact on health practices and adaptation to cancer and treatment. By
supervised exercises followed by the patient performing these exercises at home
we hope to increase self-efficacy.

Potential benefits for participants of the physical exercise intervention are
reduce in symptoms, such as fatigue, increase of physical fitness leading to
prosperous recovery and better HR-QoL. Risks related to the exercise
intervention are estimated low or negligible.