Definition

  • Complications due to active malignancies or chemotherapy.
  • Metabolic, cardio-respiratory, neurological, structural, or mechanical in nature.
  • Requires active monitoring and immediate management.

Metabolic

Humoral hypercalcemia of malignancy (HHM)

Etiology and pathophysiology

Three major mechanisms lead to elevated serum calcium levels.

1)    Tumour secretion of parathyroid hormone-related protein (PTH-rp)

  • Most common cause of HHM in non-metastatic solid tumours; overall, cause of 80% cases of HHM.
  • PTH-rp shares homology of sequences with the parathyroid hormone (PTH).
  • This allows PTH-rp to have the same effects on the kidney that PTH has including increase in bone resorption and distal tubular calcium re-absorption.
  • PTH-rp is unable to activate calcitriol, and therefore does not affect calcium re-absorption at the intestinal level.
  • The increased bone resorption along with the reduced ability of the nephrons to clear calcium leads to high serum calcium levels.

2)    Osteolytic metastasis of the tumour with the local release of osteoclast activating factors

  • Common in metastatic tumours and multiple myeloma.
  • Cytokines from the malignant cancers lead to increased osteoclastic activity as well as increased bone marrow stromal cell differentiation into osteoclasts leading to bone resorption and release of calcium in the circulation.  Bone marrow differentiation into osteoblasts is inhibited as well as osteoblastic activity is reduced by these cytokines.

3)    Elevated 1,25 hydroxy Vitamin D (calcitriol) production

  • Cause of almost all causes of HHM in Hodgkin lymphoma and about one third of the cases of non-Hodgkin lymphoma.
  • Secretion of calcitriol leads to increased calcium uptake from the gastrointestinal tract resulting in hypercalcemia.

Explanation of signs and symptoms can be found in the Endocrinology chapter Hypercalcemia.

Tumour lysis syndrome (TLS)

  • Tumour cell lysis leading to the cellular contents expelling into the blood stream; common complication in non-Hodgkin lymphoma and acute leukemia.
  • Can be a complication of the cancer itself or can also be chemotherapy mediated.
  • Lysis of cells causes the release of intracellular potassium, phosphates, and nucleic acids (NA).

Four key electrolyte abnormalities

  1. Hyperkalemia
  2. Hyperuricemia: NAs are converted to xanthine and then uric acid, the final end product in humans, which is excreted through the kidneys.
  3. Hyperphosphatemia
  4. Hypocalcemia: secondary to hyperphosphatemia by binding and precipitating calcium.

Consequences of electrolyte imbalance

  • The potassium, phosphates, NAs and the cytokines released in the circulation are beyond the hemostatic mechanism to control.
  • Acute kidney injury (AKI)
    • AKI in TLS is mediated via a number of mechanisms:
      • Intra-tubular calcium phosphate and uric acid crystal deposition causes injury to the tubules and the collecting ducts. Uric acid precipitates more readily in the presence of calcium phosphate and vice versa.
      • Uric acid can also cause renal vasoconstriction and impaired auto-regulation of the GFR.
      • AKI is precipitated by dehydration and acidosis.
  • Multi-organ failure
    • Can be a complication of TLS; thought to be secondary to the cytokine storm, from the lysed tumour cells causing systemic inflammatory response syndrome leading to end organ damage.
  • Fatal dysrhythmias
    • Secondary to hyperkalemia and calcium phosphate crystal deposition in the cardiac conduction system.

Hyponatremia

  • Excess of water relative to sodium, in the body.
  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
    • Majority of cases of hyponatremia of malignancy are due to SIADH.
    • Commonly seen in small-cell lung cancers and CNS tumours.
    • Can also be iatrogenic: usually thought to be secondary to chemotherapeutic agents used.
    • Cisplatin, cyclophosphamide, and vincristine are common causative agents.
    • ADH promotes water uptake in the distal convoluted tubules; the problem is compounded by increased water intake due to lack of thirst inhibition (high levels ADH induce thirst).

Cardiovascular

Superior vena cava (SVC) syndrome

Etiology

  • Direct compression of the SVC by primary malignancies as well as metastatic tumours.
    • The thin walled vessel returns blood from the upper extremities as well as the head and the neck veins and sinuses.
    • Direct compression leads to elevated venous pressures causing edema.
  • Most common cancers associated with SVC syndrome include breast, right-sided lung cancers and mediastinal lymphomas.
  • Blockage is better tolerated if it develops overtime, rather than suddenly, due to the physiologic compensatory mechanisms.

Pathophysiology

  • Upper limb edema, periorbital edema, chemosis, stridor, hoarseness, dysphagia
    • Caused by edema of the respective organs: arms, periorbital area, ocular mucosal membranes, pharynx and larynx (reduced diameter of the organs), walls of the GI tract.
  • Pre-syncope, syncope
    • Reduction of cardiac output due to lack of compensation.
  • Headaches and confusion
    • Distention of cerebral vessels against the dura; and/or cerebral edema.

Pericardial effusion and tamponade

Etiology

  • Direct or metastatic involvement of the pericardial sac. Found in adjacent malignancies: breast, lung, mediastinal lymphomas.
  • Cancer treatment
    • Radiation therapy to the thoracic area can lead to transudative effusions.
    • Immunosuppression, from chemotherapy, can lead to potential infections developing in the pericardial space leading to effusions.

Respiratory

Cancer Imaging. 2009 Oct 2;9 Spec No A:S75-82.

Airway obstruction

Etiology

  • Can be caused by any tumour; however, the most common ones include bronchiogenic carcinomas, tumours of the tongue, oropharynx, thyroid, trachea and the lungs.
  • Can result from an external compression of the bronchi or trachea by the tumour or by an involved lymph node.
  • Tumour can also cause direct infiltration of the structure leading to significant narrowing.

Pathophysiology

  • Dyspnea
    • Obstruction causing “bronchoconstriction” limits the airflow to the lungs leading to the physiologic compensation to increase breathing rate.
  • Cough, hemoptysis, and wheeze
    • Direct irritation of the cough receptors in the airways causes cough.
    • Rupturing and edema from vascular tumours can manifest as hemoptysis.
    • Wheezing is due to the increased air velocity at the site of narrowing or obstruction.

Infectious

Febrile neutropenia (FN)

Definition: an absolute neutrophil count of <500 cells/μL with a fever >38.3°C.

Etiology

  • Cancer related
    • Cancer’s direct interference with hematopoiesis; leukemias or metastatic bone marrow replacement.
  • Chemotherapy related
    • Mucositis throughout the alimentary system; seeding the bloodstream with endogenous flora.
    • Cyclophosphamide, anthracyclines, topoisomerase inhibitors and taxanes are the most commonly associated chemotherapeutics.
    • Chemotherapeutic agents have also been shown to cause neutrophil chemotaxis and phagocytosis has also been found; along with a total decline in the number.
  • Infection
    • Known offending agents in FN have been found to be:
      • Gram positive: Staphylococcus aureas and epidermidis, Streptococcus pneumoniae, pyogenes and viridans.
      • Gram negative: E. coli, Klebsiella, and Pseudomonas.
      • Fungal infections: Candida is the most common fungal infection.
  • Other
    • Obstruction of lymphatics, biliary tract, bronchial, GI and urinary systems after surgery.

Pathophysiology

  • Fever
    • Elevated body temperature due to tissue inflammation (see Infectious disease unit for fever pathogenesis).
    • Sometimes fever might be the only presenting feature without any signs of infection due to the lack of pus and inflammation generating neutrophils.

Neurologic

CA Cancer J Clin. 2011 Aug 19. 61(5), 287-314.

Spinal cord compression

  • Compressive serration, displacement or the encasement of the thecal sac by cancer.
  • Most common location of metastasis occurs in the thoracic region, followed by lumbosacral and lastly cervical.

Etiology

  • Direct compression
    • Any primary tumour can metastasize to the vertebral bodies and erode into the spinal space.
    • Direct compression can also occur when a paravertebral lesion spreads into the spinal cord through the vertebral foramen.
  • Vertebral body collapse
    • Metastasis to the bone can lead to vertebral body collapse impinging nerves.
  • Spinal metastasis
    • Very rare; but direct metastasis to the spinal cord and the cauda equina can also occur.

Pathophysiology

  • Pain
    • Depends on the site of compression
      • Cervical: subscapular pain
      • Thoracic: lumbosacral or hip pain
      • Lumbosacral: thoracic pain
  • Motor weakness, sensory impairment and autonomic dysfunction
    • Compression of the nerves in the respective region causing muscle weak and loss of sensation.
  • Ataxia
    • Spinocerebellar tract dysfunction has been thought to cause gait ataxia.
  • Cauda equina syndrome
    • Clinical features: urinary retention, saddle anesthesia and loss of rectal tone.
    • Etiology: compression of the sacral nerves that control the respective functions including autonomic nervous system.

Increased ICP

Etiology

Primary brain malignancy or metastatic disease; most commonly from lung, breast, renal cancers and melanoma.

Pathophysiology

  • Mass effect of the tumour in the brain.
  • Cerebral edema secondary to the neoplastic disruption of the blood brain barrier.
    • Disruption can be secondary to mechanical compression as well as leaky tumour vasculature.
  • Headaches
    • Secondary to the elevated ICP causing meningeal irritation.
  • Seizures
    • Almost exclusively occur in supratentorial regions.
    • See Neurology unit for seizure pathogenesis.
  • Stroke
    • Sometimes with tumour embolization and bleeding.
    • Could occur if the tumour compresses a cerebral blood vessel.