Mitochondrial dysfUnction: a Key Player in Doxorubicin-induced Skeletal and Cardiac muscLE Damage
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- UMC Utrecht
- 入组人数
- 12
- 试验地点
- 6
- 主要终点
- Changes in skeletal and cardiac muscle mitochondrial function
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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-
- •Patients with sufficient Dutch writing and reading skills.
- •Written informed consent.
排除标准
- •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.
结局指标
主要结局
Changes in skeletal and cardiac muscle mitochondrial function
时间窗: Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Assessed through 31P-MRS imaging. Parameters include: * PCr recovery rate (in seconds) * PCr/ATP ratio
次要结局
- Adherence rates to the study protocol(Baseline to 18 weeks.)
- Changes in physical fitness (Maximum short exercise capacity (Watt))(Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks))
- Changes in hand grip strength (kg)(Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks))
- Changes in leg strength (kg)(Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks))
- Changes in skeletal muscle area in cm2(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)(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)(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(Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks))
- Changes in lymphoma specific symptoms(Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks))
- Changes in fatigue(Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks))
- Changes in skeletal muscle end-exercise pH(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(Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks))