Optimal Timing of a tailored Physical Activity program during chemotherapeutic Cancer Treatment to reduce long-term cardiovascular morbidity.

The number of long-term cancer survivors is growing. As a result,
treatment-related morbidity * such as cardiovascular disease, metabolic
syndrome, functional decline and fatigue * is impacting quality of life and
impairing survival. The development of metabolic syndrome and other
cardiovascular risk factors can be observed even during the first years of
follow-up of cancer survivors.
Due to high cure rates in recent decades, testicular cancer survivorship is a
paradigm for survivorship-related issues in young adult cancer survivors. Our
research group found a 25% prevalence (a striking 2-fold increased risk
compared to the age-matched controls) of metabolic syndrome in long-term
testicular cancer survivors treated with platinum-based chemotherapy. Moreover,
current data have also shown this association between cancer treatment and
metabolic syndrome in other cancer survivors. Metabolic syndrome in the general
population is currently treated with lifestyle advice to increase physical
activity and reduce caloric intake. However, this approach is still underused
as standard care for cancer survivors, even though recent meta-analyses have
shown the beneficial effects of physical fitness.
Previous studies focused primarily on physical fitness, but did not provide
evidence for the best starting point of the physical activity programs and did
not focus on sustainable effects or prevention of cardiovascular risk factors
clustered in metabolic syndrome. Investigating these aspects with large
randomized clinical trials using cardiovascular events as a primary endpoint
would delay the implementation of potential lifestyle-changing programs. We
have chosen a novel approach and investigate the effects of an early starting
point for a tailored PA program for cancer survivors during chemotherapeutic
treatment compared with a late starting point (post-treatment).

To investigate whether a tailored physical activity program that starts early
(during curative chemotherapy with cardiovascular toxic potential) is superior
in terms of reducing long-term cancer-treatment-related metabolic syndrome and
cardiovascular morbidity to a program that starts late (after completion of
chemotherapy).

A multi center study, to propectively evaluate the application of a tailored
physical activity program in patients treated with curative intent with
chemotherapy. Patients treated with curative systemic chemotherapeutic
treatment for testicular cancer, early colon cancer, early breast cancer or
B-cell non-Hodgkin lymphoma (B-NHL) will be randomized at the start of
treatment in two groups: early or late. The early group will start the PA
program during chemotherapy for 3 months, and after completion of chemotherapy
for 3 months (total 6 months). The late group will start the PA program after
completion of the chemotherapy for 6 months. In both groups the program will be
performed in the UMCG trainings facility, the Martini Hospital Groningen or in
a hospital of the Ommelander Ziekenhuis Groep (Delfzicht in Delfzijl, Lucas in
Winschoten) for the first 3 months and at home for the next 3 months. During
this last 3 months patients will be coached by telephone/email and during
regular follow up visits. There will be a stratification for diagnosis.

The exercise program will consist of two components: improvement of physical
fitness and empowerment to adopt a healthy lifestyle. Improvement of physical
fitness will be divided into an aerobic exercise program and a muscle exercise
circuit focused on physical performance and muscle strength, respectively, and
both will be personalized based on patients* individual exercise capacity. The
intensity of aerobic exercise program will be prescribed on the basis of the
VO2 max and the 1 Repetition Maximum (1-RM) in line with the ACSM guidelines.
The aerobic training, three times per week will consist of aerobic exercises
that are performed for 30 minutes per session. Exercises can be performed on
bicycle ergometers or treadmills and rowergometers. The training will be based
on the training heart rate (THR), which can be computed using the Karvonen
formulae: THR=HRrest+40 to 75% (HRmax-HRrest). During weeks 1-6, exercise
training will be performed at a THR of HRrest+40 to 60%(HRmax-HRrest) and
during weeks 7-24 at a THR of HRrest+60 to 70-75 %(HRmax-HRrest). This aerobic
exercise training will include a warm-up before and a cool-down after the
training.
General muscle strength training of the trunk and the lower and upper
extremities will be performed twice per week during 20-30 minutes in accordance
with the recommendations of the ACSM . Before training, the individual 1-RM
will be defined. Individual intensity of muscle strength training will start at
50% of the 1-RM during the first week, and will be increased by 5-10% over the
ensuing weeks with a frequency of 12 repetitions during three series. The
resistance program consists of several exercises targeting the following large
muscle groups (exercises): 1) m. longissimus, m. biceps brachii, m. rhomboideus
(vertical row), 2) m. quadriceps, m. glutei, m. gastrocnemius (leg press), m.
pectoralis major, m. triceps (bench press); 4) m. pectoralis, m. triceps
brachii, m. deltoideus, m. trapezius (pul over) 5) m. rectus abdominis
(abdominal crunch); 6) m. quadriceps, m. glutei, hamstring muscles (lunge).
In addition to the aerobic and muscle strength training once a week (in the
first 12 weeks of the program, when all activities take place in the UMCG
training facilities) there will be an additional session (around 1 h per week)
to empower patients to adopt a healthy lifestyle. This part of the program is
aimed at both increasing physical activity during daily life and at reducing
sedentary behavior. In addition to self-monitoring by patients, the
physiotherapist will use behavioral practices proven to be effective to keep
patients motivated to be active.

The risks that are associated with physical activity during cancer treatment
are anticipated to be low with the proposed physical activity program. The
physical burden for the patients consists of several measurements including
physical examination (5 or 6 times), VO2 max (5 or 6 times), muscle strength (5
or 6 times), ECG (5 or 6 times), blood samples (5 or 6 times), assessment of
intima-media thickness (3 or 4 times), oral glucose tolerance test (5 or 6
times), 24 hours urine collection (5 or 6 times), skin auto fluorescence (5 or
6 times) and in the testicular patient group a skin- and fat biopsy will be
assessed once. In addition, patients have to fill in four questionnaires at 5
or 6 time points which will take approximately 30 minutes to complete. Patients
have to perform a training programme for 12 weeks, 3 times a week, under
supervision of a physiotherapist in the hospital and 12 weeks at home.