II-30. Secondary disorders caused by tumors (1): organ disorders in cancer

腫瘍による二次的障害（1）：癌患者の他臓器障害

Heart Damage

Very common in cancer patients, often the cause of death; main cause = cancer therapy (may require dose reduction)
Causes: cardiotoxic chemo (inhibits DNA replication → harms dividing cells incl. cardiac stem cells); immunotherapy (checkpoint inhibitors → autoimmunity → myocardial attack); cachexia (muscle wasting); hypercalcemia (arrhythmogenic); thoracic radiotherapy
Cardiotoxicity types: Type 1 irreversible (chemotherapy); Type 2 reversible (biological/targeted, receptor TK antibodies)
Consequences: heart failure, infarction, arrhythmia (may co-occur & worsen each other)
Mechanism: ROS central — toxic ROS → membrane/DNA damage + apoptosis (heart has low antioxidant capacity); dead cardiomyocytes → scar (Type 1)
TKIs: block VEGF-R (anti-angiogenesis) → bleeding, ↓wound healing, coronary issues/MI, ↑BP; block HER-2/EGFR/PDGF-R on cardiomyocytes → atrophy, ↓afterload adaptation

GI Tract Damage

Chemo mucosal damage → peripheral nausea; stimulation of central vomiting center
CINV (chemo-induced nausea/vomiting), teeth disorders, oral mucosal lesions
Phase 1 (acute, peripheral, <24 h): serotonin-driven → 5-HT₃ antagonists
Phase 2 (late, central, 2–5 days): substance P → NK1 receptors

Musculoskeletal — Malignant Osteolysis

Osteoporosis, rheumatic symptoms (immunotherapy), Ca²⁺ release → arrhythmias, muscle weakness, renal failure
Mechanism: the tumor (not therapy) → PTH-related peptide → ↑renal Ca²⁺ reabsorption + osteoclast activation → osteolysis, fractures, bone pain, ↑serum Ca²⁺
Treatment: bisphosphonates (but halt bone turnover → slow fracture healing)

Bone Marrow Damage

Causes: chemo (↓proliferation), radiotherapy, BM involvement (metastasis; leukemia/myeloid/lymphoma)
Anemia: BM depression, malnutrition (Fe/B12/folate), bleeding (tumor hypoxia/erosion — iron deficiency may be first sign), EPO deficiency, hemolysis/hemophagocytosis, ↑hepcidin (IL-6) → ↓duodenal Fe absorption
Leukopenia: BM depression, splenectomy, immunosuppression → febrile neutropenia (temp >38.5 °C, ANC <0.5×10⁹/L; infection 50%, bacteremia 20%); prevent with G-CSF (filgrastim — but induces MDSC); treat with antibiotics/hospitalization/dose reduction
Thrombocytopenia: symptoms <50,000; cerebral hemorrhage risk <10,000; but thrombosis risk is more important — cancer-associated thrombosis (80% venous, 20% arterial) via Virchow triad (stasis, hypercoagulability, endothelial damage)

Lymphatic System Damage

Causes: irradiation/lymphadenectomy, tumor blockage → secondary lymphedema
Treatment: decongestive therapy (compression bandage, intermittent pneumatic compression), surgery

一問一答

▶What is the main cause of heart damage in cancer patients?

Cancer therapy (cardiotoxic chemo, immunotherapy, radiotherapy), which is very common and often a cause of death.

▶Why is the heart vulnerable to ROS-mediated cardiotoxicity?

The heart has low antioxidant capacity, so toxic ROS readily cause membrane/DNA damage and apoptosis; dead cardiomyocytes form scar (Type 1).

▶Distinguish Type 1 and Type 2 cardiotoxicity.

Type 1 is irreversible (chemotherapy); Type 2 is reversible (biological/targeted agents, receptor tyrosine kinase antibodies).

▶How do VEGF-R-blocking TKIs cause cardiovascular harm?

Anti-angiogenesis from VEGF-R blockade causes bleeding, reduced wound healing, coronary issues/MI, and increased BP.

▶What are the two phases of chemotherapy-induced nausea/vomiting (CINV) and their treatments?

Phase 1 (acute, peripheral, <24h) is serotonin-driven, treated with 5-HT₃ antagonists; Phase 2 (late, central, 2–5 days) is substance P-driven, treated with NK1 receptor antagonists.

▶What is the mechanism of malignant osteolysis?

The tumor (not therapy) produces PTH-related peptide → ↑renal Ca²⁺ reabsorption + osteoclast activation → osteolysis, fractures, bone pain, and ↑serum Ca²⁺.

▶What is a drawback of bisphosphonate treatment for malignant osteolysis?

They halt bone turnover, which slows fracture healing.

▶What are the causes of bone marrow damage in cancer?

Chemotherapy (reduced proliferation), radiotherapy, and bone marrow involvement (metastasis; leukemia/myeloid/lymphoma).

▶What are the mechanisms of anemia in cancer?

Bone marrow depression, malnutrition (Fe/B12/folate), bleeding (iron deficiency may be the first sign), EPO deficiency, hemolysis/hemophagocytosis, and ↑hepcidin (IL-6) reducing duodenal Fe absorption.

▶What defines febrile neutropenia and how is it prevented?

Temp >38.5°C with ANC <0.5×10⁹/L (infection ~50%, bacteremia ~20%); prevented with G-CSF (filgrastim, though it induces MDSC).

▶In cancer thrombocytopenia, which is the more important concern — bleeding or thrombosis?

Thrombosis is more important; cancer-associated thrombosis (80% venous, 20% arterial) arises via the Virchow triad.

▶What are the components of the Virchow triad driving cancer-associated thrombosis?

Stasis, hypercoagulability, and endothelial damage.

▶At what platelet counts do thrombocytopenia symptoms and cerebral hemorrhage risk appear?

Symptoms below 50,000; cerebral hemorrhage risk below 10,000.

▶What causes secondary lymphedema in cancer and how is it treated?

Irradiation/lymphadenectomy or tumor blockage of lymphatics; treated with decongestive therapy (compression bandage, intermittent pneumatic compression) and surgery.

▶How does cardiotoxic chemotherapy damage the heart at the cellular level?

It inhibits DNA replication, harming dividing cells including cardiac stem cells.

▶How does immunotherapy cause cardiac damage?

Checkpoint inhibitors trigger autoimmunity that attacks the myocardium.

▶How do TKIs blocking HER-2/EGFR/PDGF-R affect cardiomyocytes?

They cause cardiomyocyte atrophy and reduced afterload adaptation.

▶What cardiac consequences can co-occur and worsen each other in cancer patients?

Heart failure, infarction, and arrhythmia.

▶How does febrile neutropenia get treated?

Antibiotics, hospitalization, and dose reduction.

▶Why may iron-deficiency anemia be an early clue to malignancy?

Occult bleeding from tumor hypoxia/erosion can cause iron deficiency, which may be the first sign of the cancer.