From the Guidelines
Chemotherapy drugs like carboplatin and etoposide cause persistent fatigue through a complex interplay of mechanisms affecting the body's energy production and regulation systems, including damage to rapidly dividing cells, inflammatory responses, mitochondrial damage, and disruption of hormone balance. The exact mechanism of fatigue caused by these drugs is not yet fully understood, but it is believed to involve multiple physiological and biochemical systems, including the skeletal muscles and the brain as a central regulator of fatigue perception [ 1 ].
Some of the key factors contributing to fatigue include:
- Damage to rapidly dividing cells, including healthy cells in bone marrow, leading to anemia and decreased oxygen delivery to tissues
- Inflammatory responses triggered by the body's response to cellular damage, releasing cytokines that alter brain chemistry and energy regulation [ 1 ]
- Mitochondrial damage in healthy cells, reducing the efficiency of cellular energy production
- Disruption of hormone balance, particularly thyroid and adrenal hormones that regulate energy levels
- Neurotoxicity affecting the central nervous system
- Muscle weakness developing from reduced physical activity and direct toxic effects on muscle tissue
- Sleep disturbances common during treatment, further compounding fatigue
- Psychological factors like anxiety and depression often accompanying treatment and contributing to energy depletion
The multifactorial impact of these mechanisms explains why fatigue often persists for months or even years after treatment ends, as the body slowly repairs these various systems [ 1 ]. It is essential to recognize that cancer-related fatigue is a distinct entity that affects almost 65% of patients with cancer, with up to 40% of patients reporting fatigue at cancer diagnosis, and 80%-90% during chemotherapy and/or radiotherapy [ 1 ].
From the FDA Drug Label
The following adverse reactions have been infrequently reported: abdominal pain, aftertaste, constipation, dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness, optic neuritis, interstitial pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associated with allergic reactions), Stevens-Johnson syndrome, and toxic epidermal necrolysis, pigmentation, and a single report of radiation recall dermatitis.
The mechanism for chemotherapy drugs like carboplatin and etoposide causing persistent fatigue is not directly stated in the provided drug labels. However, fatigue is listed as an infrequently reported adverse reaction in the etoposide label 2.
- Myelosuppression and anemia are reported in both labels, which could contribute to fatigue.
- The exact mechanism of fatigue caused by these drugs is not explicitly stated in the labels.
From the Research
Mechanism of Chemotherapy-Induced Fatigue
The mechanism of chemotherapy-induced fatigue is complex and multifactorial. Some studies suggest that chemotherapy drugs like carboplatin and etoposide can cause inflammation in the tumor microenvironment, which may lead to fatigue 3.
Role of Inflammation
Inflammation can play a key role in cancer development, metastasis, and exacerbation. Chemotherapy agents can induce systematic inflammation by provoking TLR4 signaling or triggering IL-1B secretion through the inflammasome pathway. NF-kB and MAPK are key signaling pathways of inflammation and could be activated by several chemotherapy drugs 3.
Anemia and Fatigue
Anemia is a common side effect of chemotherapy and can contribute to fatigue. Studies have shown that erythropoietin can reduce anemia and transfusions in patients receiving chemotherapy with paclitaxel and carboplatin 4.
Hematological Toxicity
High-dose carboplatin, etoposide, and melphalan can cause hematological toxicity, which can lead to fatigue. However, the administration of growth factors such as granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) can reduce hematological toxicity and improve hematopoietic recovery 5.
Tumor Vascularization and Perfusion
Erythropoietin can improve the accumulation and therapeutic effects of carboplatin by enhancing tumor vascularization and perfusion 6. This can lead to improved drug delivery and reduced tumor hypoxia.
Quality of Life
Erythropoietic stimulating agents can improve quality of life in patients with anemia by reducing symptoms of fatigue, poor energy, weakness, and shortness of breath 7. However, treatment of anemia should be directed toward improving patient-perceived quality of life rather than targeting specific hemoglobin levels.
- Key factors contributing to chemotherapy-induced fatigue include:
- Inflammation in the tumor microenvironment
- Anemia and hematological toxicity
- Tumor vascularization and perfusion
- Quality of life and patient-perceived symptoms
- Chemotherapy drugs like carboplatin and etoposide can cause inflammation and hematological toxicity, leading to fatigue 3, 4, 5.
- Erythropoietin can reduce anemia and improve quality of life in patients with chemotherapy-induced anemia 4, 6, 7.