Mitochondrial dysfUnction: a Key Player in Doxorubicin-induced Skeletal and Cardiac muscLE Damage

Rationale: Anthracyclines and platinum-based drugs are widely used chemotherapeutic agents, offering a favorable approach to treating solid and hematological cancers. However, treatment with these drugs can lead to severe toxicities, which last for many years. These chemotherapeutic agents are known to have detrimental effects on skeletal and cardiac muscles. Loss of skeletal muscle mass is associated with treatment modifications (i.e., dose delay/reduction/discontinuation), increased levels of fatigue, decreased quality of life (QoL) and shorter survival. Cardiomyopathy might lead to chronic heart failure in the long-term, which negatively affects prognosis as well. Preclinical studies investigating underlying mechanisms of these detrimental effects suggest that mitochondrial dysfunction plays a key role. However, human data is lacking due to the need of invasive repeated muscle biopsies. Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS) is an innovative, non-invasive technique, which enables repeated measures of skeletal and cardiac muscle mitochondrial energy metabolism.

Hypothesis:

In this study we hypothesize that patients treated with anthracyclines and/or platinum-based agents will show decreased mitochondrial function in skeletal and cardiac muscle tissue following chemotherapy treatment.

Objective:

To demonstrate the ability of using non-invasive 31P-MRS to monitor changes of in vivo markers of mitochondrial function in skeletal and cardiac muscles (i.e., skeletal muscle PCr recovery rate constant and cardiac PCr/ATP ratio) in patients treated with anthracyclines and/or platinum-based agents. Furthermore, we will assess the feasibility of undergoing the study measurements for patients during intensive cancer treatment and explore the association between changes in in vivo measured mitochondrial function in skeletal and cardiac muscle tissue and changes in muscle mass, physical fitness, muscle strength, physical activity levels measured by Fitbit, chemotherapy completion rate and patient-reported outcomes, including physical activity, fatigue and quality of life.

Study design: Cohort study.

Study population: Patients scheduled for cancer treatment with anthracyclines and/or platinum-based agents.

Main study parameters/endpoints:

The main study parameters are differences in skeletal muscle PCr recovery rate constant and cardiac PCr/ATP ratio. These parameters will be compared within-patients before, halfway during and after completion of chemotherapy treatment.

Nature and extent of the burden and risks associated with participation and benefit:

Included patients will visit the UMC Utrecht 3 times (i.e., before, halfway during and after completion of chemotherapy treatment). During these visits, participants will undergo 31P-MRS imaging of the calf muscles and of the heart at 7 Tesla. During the calf muscle scan, patients will be asked to perform a mild exercise challenge (i.e., dynamic plantar flexions). 7T 31P-MRS is a safe and reliable technique for subjects without contra-indications for undergoing MRI. Possible side-effects are limited to short-term vertigo and nausea. In addition, anthropometrics will be measured and small tests to evaluate muscle strength and physical performance will be performed. Participants will be asked to complete questionnaires regarding physical activity, quality of life and fatigue. Finally, patients will be asked to wear a Fitbit, provided by the study team, to objectively assess their levels of physical activity.

Subjects will not experience direct benefits by participating in this study. By the end of the study, the investigators will demonstrate the ability to non-invasively monitor skeletal and cardiac muscle mitochondrial damage using 31P-MRS, which is a pre-requisite to assess the efficacy of (non-)pharmacological interventions.

Inclusion criteria

• Age ≥ 18 years
• Patients diagnosed with any type of cancer, who are scheduled to receive chemotherapy treatment containing at least anthracyclines and/or platinum-based drugs.
• WHO-performance score 0-2.
• Patients with sufficient Dutch writing and reading skills.
• Written informed consent.

Exclusion criteria

• Contra-indications for 7T MR scanning, including patients with a non-MRI compatible pacemaker, cochlear implant or neurostimulator; patients with non-MR compatible metallic implants in their eye, spine, thorax or abdomen; patients with a non-MR compatible aneurysm clip in their brain; patients with claustrophobia, and/or severe obesity.
• Any circumstances that would impede adherence to study requirements or ability to give informed consent.
• Medical disorders affecting mitochondrial function; e.g., spinal muscular atrophy.
• (Other) relevant medical disorders; e.g., comorbidities affecting exercise tolerance.
• Being under examination for non-diagnosed disease at the time of investigation.