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

The goal of this observational study is to demonstrate the ability of using non-invasive Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS) to monitor changes of in-vivo markers of mitochondrial function in skeletal and cardiac muscles in muscles in patients with cancer treated with anthracyclines and/or platinum-derivates. The main question it aims to answer is:

• Can 31P-MRS be used to monitor changes of in vivo markers of mitochondrial function in skeletal and cardiac muscles in patients with cancer undergoing treatment with anthracyclines and or platinum derivates?

To be able to answer this main question, participants will undergo 31P-MRS imaging of the calf muscles and of the heart 3 times during the study period.

Study Overview

• Status: Completed
• Conditions: Anthracyclines; Chemotherapeutic Toxicity; Doxorubicin Induced Cardiomyopathy
• Intervention / Treatment: Diagnostic test: 31-MRS at 7 Tesla (T)

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 12

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Ede, Gelderland, Netherlands, 6716 RP
      • Ziekenhuis Gelderse Vallei
  • Utrecht
    • Amersfoort, Utrecht, Netherlands, 3813 TZ
      • Meander Medisch Centrum
    • Utrecht, Utrecht, Netherlands, 3584CX
      • UMC Utrecht
    • Utrecht, Utrecht, Netherlands, 3582 KE
      • Diakonessenhuis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients will be recruited at UMC Utrecht, Diakonessenhuis Utrecht and possibly other hospitals in the vincity of the UMC Utrecht. The aim is to include 12 patients with with any type of cancer scheduled to receive treatment with anthracyclines and/or platinum-based drugs at any of the recruiting hospitals.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Study population; Patients scheduled for cancer treatment with anthracyclines and/or platinum-based agents.	Diagnostic test: 31-MRS at 7 Tesla (T); 31-MRS imaging at 7T to evaluate mitochondrial function in skeletal and cardiac muscles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in skeletal and cardiac muscle mitochondrial function	Assessed through 31P-MRS imaging. Parameters include: PCr recovery rate (in seconds); PCr/ATP ratio	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherence rates to the study protocol	Measured as: recruitment/retention rates; completion of study measurements within timeframes	Baseline to 18 weeks.
Changes in physical fitness (Maximum short exercise capacity (Watt))	Assessed through Steep Ramp test	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Changes in hand grip strength (kg)	Assessed through Hand Grip Strength Test	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Changes in leg strength (kg)	Assessed through hypothetical 1-repetition max leg press	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Changes in skeletal muscle area in cm2	Assessed through routine CT-scans	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Changes in subjective physical activity levels (min/week moderate-to-vigorous physical activity)	Physical activity levels will be assessed subjectively using the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH)	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Changes in objective physical activity levels (min/week moderate-to-vigorous physical activity)	Participants are provided with a Fitbit Inspire HR and are asked to wear these as much as possible during the whole study period. The Fitbit continuously registers the heart rate. Based on this, physical activity levels will be calculated.	Throughout the whole study, but of particular interest are the 9th week after baseline and 18th week post-baseline
Changes in health-related Quality of Life	Measured using the core EORTC Quality of life questionnaire (QLQ-C30). The results of the questionnaire can be used to calculate a summary score, global health status, functional subscales and symptom subscales. For the summary score, global health status and functional subscales, a higher score is a better outcome, whilst for the symptom subscales, a lower score is a better outcome. All scores range from 0 to 100.; Global health status; Summary score Functional scales: Physical functioning; Role functioning; Emotional functioning; Cognitive functioning; Social functioning Symptom scales: Fatigue; Nausea and vomiting; Pain; Dyspnoea; Insomnia; Appetite loss; Constipation; Diarrhoea; Financial difficulties	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Changes in lymphoma specific symptoms	Measured using the add-on of the abovementioned EORTC QLQ-C30, which is specifically developed for non-Hodgkin lymphoma patients (EORTC QLQ-NHL-HG29). A higher score depicts worse outcomes. All scores range from 0 to 100.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Changes in fatigue	The EORTC provides several questionnaires to asses the quality of life of cancer patients. To assess fatigue the EORTC developed a specific fatigue questionnaire (QLQ-FA12). This questionnaire can be used to assess different dimensions of fatigue. A lower score depicts a better outcome. All scores range from 0 to 100. Fatigue dimensions: Physical fatigue; Emotional fatigue; Cognitive fatigue	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Changes in skeletal muscle end-exercise pH	Assessed through 31P-MRS imaging.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Changes in skeletal muscle delta PCr during recovery after exercise in mM	Assessed through 31P-MRS imaging.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in weight (kg)	As measured by investigator during study visit.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Height (cm)	As measured by investigator during study visit.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: Julius Clinical

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2023
• Primary Completion (Actual): March 20, 2026
• Study Completion (Actual): March 20, 2026

Study Registration Dates

• First Submitted: January 25, 2023
• First Submitted That Met QC Criteria: February 7, 2023
• First Posted (Actual): February 16, 2023

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Cardiomyopathies
• Other Study ID Numbers: NL83538.041

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: As the data is privacy-sensitive, the investigators will publish the descriptive metadata in the data repository with a description of how a data request can be made (by sending an email to the corresponding author). In the event that peers like to reuse our data this can only be granted if the research question is in line with the original informed consent signed by the study participants. Every application therefore wille be screened for this requirement. If granted, a data usage agreement is signed by the receiving party.
• IPD Sharing Time Frame: Data and documentation needed to reproduce findings from this study will be stored for at least 15 years.
• IPD Sharing Access Criteria: Data access can only be granted for research with a research question in line with the original informed consent signed by the study participants.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No