Metastatic Cascade and Palliative care

Question 1

Metastatic Cascade

Answer 1

1. Primary Tumour
2. Local Invasion
3. Intravasation
4. Survival in the circulation
5. Arrest
6. Extravasion
7. Proliferation and angiogenesis

Question 2

Metastatic Cascade

Primary Tumour

Answer 2

There are two hypothesis regarding the development of metastatic cells from primary tumour

1. Early dissemination model - primary tumour microenvironment selects for malignant cells. A poor blood supply results in the tumour producing hypoxia-inducible transcription-factor and activation of RAS. This is associated with metastasis.
2. Late dissemination model - The primary tumour develops additional mutations that give tumour cells the ability to metastasize

Question 3

Local Invasion

Answer 3

1. Tumour cells that invade surrounding tissue have reduced intracellular adhesion due to loss of function in E-cadherin (a molecule that links cells)
2. Tumour cells cross the basement membrane, which is a barrier between epithelial tissues and stroma

Question 4

Intravasation

Answer 4

• Tumour cells enter the lumen of blood vessels or lymphatics by crossing the endothelium and associated pericytes (cells that wrap around endothelial cells that line the capillaries and venules).
• The blood vessels formed by tumour-mediated angiogenesis are more leaky and more permeable to intravasation of tumour cells.

Question 5

Survival in the circulation

Answer 5

• Cancer cells attach to platelets and from heterotypic clumps or attach to clotting factors like thrombin, forming emboli known as homotypic clumps. This helps the cancer cells evade immune attack, circulating shear force and anoikis (process where apoptosis occurs in cells that don’t undergo cell-to-cell adhesions).

Question 6

Arrest

Answer 6

• The organ where cancer cells arrest is determined by anatomical and molecular factors. Organ microvasculature and its relation to the primary tumour influences metastasis. As well, chemoattractants predispose arrest to circulating tumour cells.

Question 7

Extravastion

Answer 7

• Movement of cancer cells from blood vessels to distant sites. At distant sites the blood vessels are not leaky and thus, cancer cells will move through blood vessels that are naturally fenestrated (ex. liver and bone marrow) or they will move through small gaps created by the normal turnover in endothelial cells, or through damage in vessels wall to which the homotypic clumps are attracted. Finally, some cancer cells can produce proteins that can disrupt the endothelial barriers in distant organs.

Question 8

Proliferation and Angiogenesis

Answer 8

• Many disseminated tumour cells remain dormant or form microcolonies called micrometastases and don’t progress to gross metastases. In order for the cells to proliferate, the appropriate environment must be present.
• Angiogenesis is triggered by hypoxia in the developing tumour
• Both tumour angiogenesis and lymphangiogenesis occurs in a disorganized fashion an are promoted by various growth factors.

Question 9

Determination of Site of Metastasis

Answer 9

1. Seed and soil hypothesis - idea that certain organ tissues are predisposed to metastasis because their microenvironment is compatible with tumour cells. The tumour shapes the microenvironment to further stimulate tumour growth.
2. Route of dissemination - cancers can disseminate through hematogenous or lymphatic route
   
   • Hematogenous - tumour cells spread from primary tumour to distant site with few cells progressing to overt metastasis. Metastatic cells develop early in tumour progression and don’t pass through lymph. (Sarcoma)
   • Lymphatic - tumour cells spread through both the lymphatics and through the blood. In the lymph it is thought that the tumour cells gain the ability to form soild distant mets via selection. Lymph node mets can then form secondary metastasis to distant organ sites. (Carcinoma)
3. Pre-metastatic niche - bone marrow cells prime organ microenvirnoment via release of various factors that promote angiogenesis. I.e., migration of hematopoietic bone marrow cells expressing VEGFR 1 (vascular endothelial growth factor receptor 1) to microenvironment prior to arrival of primary tumour cells. Pre-metastic niche formation is influenced via the suppression of theimmune system and increased presence of cytokines and growth factors.

Question 10

Pain management Cancer Care

Answer 10

• WHO ladder - strength of analgesic chosen depends on severity of pain (not disease stage)
  
  • Adjuvant analgesic is chosen according to cause and type of pain
  • Opioids should generally be used in combination with non-opioids

Question 11

Adjuvants for Cancer Pain

Answer 11

• NSAIDs - Indications: bone mets, soft tissue infiltration, liver pain
• Steroids - Indications: Raised intracranial pressure, nerve compression, soft tissue infiltration, liver pain
• TCA - Indications: Nerve pain
• Carbamzepine - Indications: Nerve pain

Question 12

Nausea and vomiting cancer

Answer 12

• Nausea occurs in 40-70% of people with advanced cancer
• Appropriate management depends on establishing mechanism ex. raised intra-cranial pressure, renal failure, drugs, etc.
• Anti-emetic should be selected based on most likely cause and administed on best available route (avoiding oral if patient is vomiting)

Question 13

Breathlessness Cancer

Answer 13

• Commonly multifactorial in organ
• Simple reversible causes should be treated - ex. pleural effusion, anemia, fluid overload
• A consider non-pharmacologic strategies - breathing exercises, relaxation therapy, etc.
• Morphine can ease sense of breathlessness
• Benzodiazepines - sedative and muscle relaxation
• Oxygen therapy

Question 14

Constipation Cancer

Answer 14

• Goal should be to prevent constipation. It is usally caused by opioids, immobiliy, dehydration, hypercalcemia, spinal cord compression, pelvic or abdominal tumour
• Patients should be encouraged to increase fluid, fiber intake, and mobilize
• Laxative (softener and stimulant) should be given when patients are prescribed opioids
• If stool is hard = softener laxative
• If unable to expel stool = stimulate laxative

Question 15

Lymphedema cancer care

Answer 15

• Failure of lymph drainage is generally due to tumour infiltration of lymphatics or when the channels are compromised by surgery or radiation
• Treatment - daily skin care, self-massage, exercise, and use of compression garments

Question 16

Anorexia Cancer care

Answer 16

• Control of nausea, pain, and constipation
• Enternal feeding may be used during active anti-cancer therapy, but is less appropriate as disease progresses
• Corticosteroids can also help with appetite