Cancer Pathophysiology and Cachexia Flashcards
Primary tumor?
First tumour identified, then classified according to size and invasion of the surrounding tissues
Secondary tumors ?
Other tumors of the SAME histological origin as the primary tumor (primary has escaped, and has generated another tumor)
Regional lymph nodes?
Tumors may progress, malignant cells escape their tumors and release in the blood –> Activate lymph nodes which become activated, enlarged and inflamed
Are are regional lymph nodes classified ?
According to distance from primary tumor
Mestastasis?
Invasion of cancer into distal tissues and organ
(T/F) If there is a primary tumour in the left lung, and a secondary tumour in the right lung, this is NOT considered metastasis
FALSE, although within the same organ, still considered metastasis -> cancer has spread.
Effects of CA in digestive tract?
Obstruction (dysphagia, N/V, anorexia, malabsorption)and anemia from occult losses
Effects of CA in lung?
Obstructive of resp tract, SOB
Effects of CA in bone?
Pain
Effect of CA in gynaecological organs?
Intestinal obstruction, ascites, fertility
Diagnosis of cancers?
- Biochemical markers
- Tumour imaging techniques
- Invasive techniques
Example of biochemical marker?
PCA protein in prostate, allow for early detection
Examples of tumor imaging techniques?
MRI, CT, PET, Chest-xray, bone scans, mammographs
MRI?
Magnetic resonance imaging
CT?
Computed tomography, emits localized radiotherapy
PET?
Position emission tomography –> Glucose drink will produce fluorescence, and detect tumours as they avidly consume glucose.
Invasive techniques?
Biopsy, cytologic aspiration, laparoscopy
Carcinomas?
Epithelial tissue
Sarcomas?
Connective Tissue
Lymphomas?
Lymphatic system
Gliomas?
Glial cells of CNS
Adenocarcinomas?
Glands
Leukemias?
Bone marrow
For solid tumors, how is staging of cancer assessed?
TNM (Tumour-Node-Metastases) system
In the TNM system, how is the primary tumour classified?
T - from T1-T4 depending on size
In the TNM system, how are the lymph nodes classified?
N - from N0-N3 depending on how many lymph nodes are affected
In the TNM system, how is metastases classifies?
M - M0 or M1 (All or nothing)
Stage 0?
Carcinoma in situ (very early form)
Stage 1?
Localized
Stage II?
Early locally advanced
Stage III?
Late, locally advanced
Stage IV?
Metastasized
T2N0M1?
Stage 4 cancer, as there is metastases
6 main anti-cancer treatments?
1) Surgical removal
2) Radiotherapy
3) Chemotherapy
4) Biological therapies
5) Hematopoietic stem cell transplants
6) Gene therapies
What is the first choice in curative Tx of cancer? What is it appropriate for?
- Surgical removal
- May be palliative, meaning that in the case of metastases, will remove a certain tumour but not all
- Mostly for primary, local (stage I) cancers
Nutritional impact of surgery?
If within upper an lower GI –> Impact on feeding routes
Radiotherapy? Which cells are most susceptible?
An ionizing TARGETED radiation which will alter DNA to control growth/kill malignant cells
-Highly proliferating cells
is radiotherapy curative? When?
For smaller tumors, and may be targeted with other treatments, such as after surgical removal.
Advantages of radiotherapy?
Targeted, therefore relatively little damage to the surrounding tumors
Explain the dose/fractionation of radiotherapy
We will split up the amount of radiotherapy needed into separate treatments, meaning the side effects will follow the treatment schedule (less chronic)
Discuss the nutritional implications of radiotherapy treatment to head and neck
- Mucositis (inflammation of epithelia of mouth, larynx, esophagus)
- Dysgeusia
- Xerostomia (ry mouth)
- Dysphagia
- Odynophagia (disturbed smell)
- Severe esophagitis
Possible nutritional therapy for undergoing radiotherapy treatment to head and neck?
High risk of malnutrition, enteral feeding likely
Discuss the nutritional implications of radiotherapy treatment to abdomen and pelvis?
- Severe diarrhea
- malabsorption
- Radiation enteritis
Which kind of cells are highly effected in radiotherapy and chemotherapy ?
Highly proliferative cells which often cause nutritional consequences (Taste buds, epithelial cells)
What is chemotherapy? is it specific?
Cytotoxic drugs, which block DNA and RNA synthesis/cell division at different stages, but NOT specific and will target healthy cells as well
When is chemotherapy often used?
Stage 4, metastases
How is chemotherapy usually administered?
Orally, IV infusion or intra-muscular injection
Similar to radiotherapy, chemotherapy is administered on a dose/fractionation schedule. Discuss the nutritional implications
Patients will experience bouts of side effects, therefore we want to implement nutritional intervention between cycles - preventing malnutrition.Adopt to their chemotherapy schedules
Side effects of chemotherapy?
Systemic
What are biological therapies?
Will be used to treat the cancer itself, the progression OR side effects
Examples of biological therapies? (3)
1) Immunotherapy
2) Biological response modifiers
3) Targeted therapy
Immunotherapy?
-Use’s bodies own immune system to eradicate cancer cells –> May also administer cytokines, interferons and interleukins
Biological response modifiers?
Will induce apoptosis, growth factor inhibitors, block angiogenesis
Targeted therapy?
Monoclonal antibodies that will deliver toxic molecules to the cancer cells (type o immunotherapy)
When is hematopoietic stem cell transplantation used?
For blood cancers, uses the transplant of bone marrow from patient or someone else
Risks of hematopoietic stem cell transplantation
Rejection of the graft (graft vs. host disease)
What kind of gene therapy is undergoing testing in clinical trials?
If we know the genes that the tumours are expressing, we could develop and agent against it –> More customized, less systemic side effects
Examples of chemotherapy drugs (A I-TAA)
- Alkylating agents
- Indirect DNA agents
- Topoisomerase inhibitors
- Anti-tumour antibiotics
- Antimitotics
Common, systemic side effects of all chemotherapy drugs?
- Bone marrow suppression (less synthesis of WBC and RBC –> Anemia)
- Alopecia, Anorexia
- Renal, Cardiac and Hepatic toxicity
Biological and targeted therapy agents side effects?
Specific to the agent - but usually more tolerable than chemotherapy, but can still be severe.
Biological and targeted therapy agent examples (CHASMS)?
- Cytokines
- Hematopoietic growth factors
- Angiogenesis inhibitors
- Signal transduction inhibitors
- Monoclonal AB
- Selective estrogen receptor modulators
Cytokine, Monoclonal AB and Hematopoietic SE?
Flu-like symptoms, allergic rxn, low blood counts, organ damage
Angiogenesis inhibitor SE?
Dysgeusia, anorexia, diarrhea, weakness
Signal transduction inhibitor SE?
Anorexia, weight-loss, swelling
Selective estrogen receptor modulator SE?
Hot flashes, sweats
Effect of upper resp/digestive tract tumour?
Obstruction, dysphagia
Surgery effects of upper resp/digestive tract tumour?
Mastication and deglutition (swallowing) problems
Radiotherapy effect of upper resp/digestive tract tumour?
Dysgeusia, xerostomia, pain
What can exacerbate side effects of treatment of upper resp/digestive tract tumour?
Combination of tobacco, alcohol abuse and poor nutritional status w/ chemo Tx.
Nutritional intervention in upper resp/digestive tract tumour?
Enteral nutrition, sometimes permanent
Effect of esophagus tumour?
Obstruction, dysphagia, anorexia, anemia from occult losses
Surgery effect of esophagus tumour?
Early satiety, regurgitation, gastricstasis
Radiotherapy effect of esophagus tumour?
Esophagitis –> makes it hard to eat, dysphagia, odynophagia, fibrosis
Nutritional intervention of esophagus tumour?
Enteral nutrition
Effect of stomach tumour?
Obstruction, anorexia, anemia, water and electrolyte imbalances
Surgery effect of stomach tumour?
Early satiety, achlorydia, dumping syndrome, loss of intrinsic factor
Aclorydia?
When stomach surgery removes certain parts of the stomach, could affect pH, digestion an promote bacterial growth
Dumping syndrome?
Surgery to stomach- rapid passage of food into SI, creates acute hyperG, weakness, hot flashes and diarrhea
Radiotherapy effect of stomach tumour?
Fibrosis, ulcers
Nutritional intervention of stomach tumour?
Enteral nutrition by jujunostomia after Tx (bypassing the mouth)
Effect of pancreas, biliary tract tumour?
Weight loss, abdominal pain, anorexia, malabsorption, secondary diabetes
Surgery effect of pancreas, biliary tract tumour?
Pancreaticoduodenectomy, pancreatic insufficiency (Depending on location of cancer in pancreas, may have to remove large amounts, difficult surgery)
Effect of liver tumour?
Weight loss is frequency, anorexia
Surgery effect of liver tumour?
Usually partial hepatectomy with no specific effect
Radiotherapy effect of liver tumour?
Anorexia, nausea, risk of heptomegaly, risk of hepatitis if high does
Why is post-op nutritional support important in liver cancer?
As it has the capacity to regenerate itself
What is notable about liver cancer?
Primary liver Ca is rare, but metastases to liver is very common (especially from colorectal cancer)
Effect of SI, colon, rectum tumour?
Obstruction anemia from occult losses, malabsorption, steatorrhea
Surgery effect of SI, colon, rectum tumour –> Illeac resectons ?
Decr.B12, Ca, Mg, lipoprotiens, bile salt absorption
Surgery effect of SI, colon, rectum tumour –> Colectomy ?
Water and electrolyte losses
Radiation effect of SI, colon, rectum tumour?
Cramps, diarrhea, malabsorption, steatorrhea, fistula
What is fistula?
Perforation, where there is joining with another tissue but only in most severe cases
Effect of lung tumour?
Weight loss, cachexia
Radiotherapy effect of lung tumour?
Possible impact on esophagus
Effect of breast tumour?
Increased weight is considered with some breast cancers
Radiotherapy effect of breast tumour?
Possible impact on intestinal mucosa
Effect of gynaecological organ tumours?
Intestinal obstruction, enteropathy, ascites
radiotherapy effect of gynaecological organ tumours?
Possible impact on intestinal mucosa
Nutritional intervention of gynaecological organ tumours?
Diuretic or sodium restriction is NOT relevant
Effect of bone metastases?
Pain, anorexia
What is a common effect of drugs to control pain in bone metastases?
Slow down GI motility, leading to constipation
Define cachexia
A complex metabolic syndrome associated with underlying illness and characterized by loss of muscle, with or without the loss of fat mass
Prominent feature of cachexia?
Weight loss
What drives most complications of cachexia?
Muscle loss
Cancer is a ___ while cachexia is a _____
disease
syndrome
Ultimately, what does muscle wasting lead to?
Weakness, weight-loss, reduced strength, functionality, VO2 which will affect quality of life
What contributes to muscle wasting?
- Anorexia
- Inflammation
- Insulin Resistance
- Hypogonadism
- Anemia
What does muscle wasting predict?
Poor cancer-associated outcomes
Poor cancer associated outcomes with muscle wasting?
- Increase fatigue
- Increased treatment induced toxicity
- Decreased host response to tumour (much of the immune system lies in the muscle)
- Decreased performance, functionaliyty
Define sarcopenic obesity
Obesity with depleted muscle mass
Why are outcomes worse with obese/sarcopenia individuals?
Less responsive oto treatment
Which CA has more prevalence of SO?
Lung or GI tumours
Prevalence of cachexia in CA?
5-80%
Which cancers have a greater prevalence of cachexia?
Upper GI, Head/neck, lung (altered metabolism)
What are the two main components of the onset of cachexia?
- Metabolic changes
- Reduced Food intake
Metabolic changes?
- Hyper-catabolism (increased protein degradation)
- Hypo-anabolism (less response to anabolic stimuli)
What are metabolic changes driven by?
Systemic inflammation
What can systemic inflammation lead to?
Primary Anorexia (reduced food intake)
Primary anorexia?
Driven by the systemic inflammation (i.e. consequence by the physiological change of the illness itself)
Secondary anorexia?
Caused by the treatment of the disease, or complications of the disease (i.e. dysphagia in pharyngeal cancer)
Together, what do metabolic changes and reduced food intake lea to?
Negative energy and protein balance - and ultimately poor outcomes
What is the MAIN difference between starvation and cachexia?
Increase in REE and protein degradation (more active metabolism)
Which hormones change in cachexia vs starvation?
Serum insulin may increase or remain the same, cortisol increases
Precachexia?
- Weight loss <5%
- Anorexia and metabolic changes
Cachexia?
- Weight loss >5%
- BMI <20 and weight loss >2%
- Sarcopenia and weight loss >2%
- Often reduced food intake, systemic inflammation
Refractory cachexia?
-variable degree of cachexia, where cancer is pro-catabolic and not responsive to treatment
< 3 months expected survival
Why is it important to intervene early in cachexia?
Nutritional support in refractory cachexia is not effective
A the refractory stage of cachexia approaches, what are changes in body composition?
Muscle and adipose tissue rapidly drops off (even in overweight/obesity)
Inflammation leads to an ____
acute phase response
What is an acute phase response?
Coordinated adaptation of body to limit and clear tissue damage caused by hydrolyses released from inflammatory, injured, malignant cells
Where are acute-phase proteins synthesized?
In the liver
In acute-phase, positive acute-phase proteins (increase/decrease) by over 25% and negative-phase proteins (increase/decrease) by over 25%
- Increase
- Decrease
Does the synthesis of negative-acute phase proteins decrease during inflammation?
NO
Explain why albumin (NAP) is low during inflammation
Synthesis may increase, however inflammation promotes the permeability of vascular walls - albumin escapes to tissues and low albumin in blood
NAP examples?
- Albumin
- Transferine
- Transthyretin
- TBP
- IGF-1
- Alpha-fetoprtoeint
PAP examples?
- Complement system
- CRP
- Coagulation, fibrinolytic system
- Antiproteases
What is the acute-phase response modulated by? Where are they produced by?
- Cytokine
- Produces by tumour or host
Which inflammatory cytokine are often seen in cancer?
- TNF-alpha
- IL-1 and IL-6
- IFN-gamma
- Leukaemia inhibitory factor
Besides inflamation, what are other side effect of cytokines?
- Decrease in appetite (primary anorexia)
- Decrease GI function (early satiety, N/V)
- Inhibit LPL (less storage of dietary fat)
- Inhibit GH and IGF-1 signalling
Which cytokine may induce insulin resistance?
IL-6
Describe the host-tumour interactions between cytokines, protein degradation and nutritional status
- Cytokines directly or indirectly (by impacting appetite) will increase muscle protein breakdown
- Increase AAs in circulations are taken up by liver
- Liver synthesize glucose, APP an excess AA lost as nitrogen in urine
Cachexia is often accompanied by hyper-metabolism, which increases REE, but what happens to other component of energy expenditure? How is total energy expenditure compared to healthy individuals?
- TEF and PAL decrease
- Overall energy expenditure decreases
- Their overall caloric intake also tends to decrease
What are the two MAIN metabolic alterations in cachexia?
- Decreased concentration or responsiveness in anabolic factors
- Increased concentration of catabolic factors
What are anabolic factors?
-Insulin, IGF-1, GH, thyroid hormones, testosterone
What are catabolic factors?
-Glucagon, cortisol, pro-inflammatory cytokine, tumour-derived factors
Alterations in lipid metabolism in cachexia?
- Mobilization of lipids from adipose
- Increased lipolysis
- Decrease LPL (decreased storage of fat)
- HyperTG, but endogenous source
Alterations in glucose metabolism in cachexia?
- Glucose is preferred fuel of tumours, and tumours will produce lactate.
- Lactate can contribute to gluconeogenesis
- Gluconeogenesis is increased, as proteolysis increases
- Insulin resistance leads to more proteolysis
Alterations in protein metabolism in cachexia?
- Negative nitrogen balance (net protein catabolism)
- Increased basal protein turnover
- Increased hepatic protein synthesis of APP
What does the increase in muscle proteolysis allow for?
- AA for gluconeogenesis
- APP synthesis
- Tumour growth
What are the 3 pathways of intracellular protein defredation
- Lysosomal (caspases)
- Calcium-dependant (calpains
- Ubiquintin-proteosome pathway
What is the MOST important pathway in skeletal muscle proteolysis in cancer cachexia?
Ubiquintin proteosome
Describe the Ubiquintin proteosome pathways
Ubq-E3 ligase will link Ubq to a protein fragments, and will be destines for degradation with a proteosome
Which genes encode UbqE3 ligase? What are they associated with?
- Atrgenes: MAFbx and MuRF-1
- Greater muscles proteolysis
What may increase the expression of atrogenes?
-Inflammatory cytosines TNF-alpha, IL-1 and IFN-gamma
Why does the cori cycle increase in cancer?
The tumour feeds on glucose, produces lactate which participates in the cori cycle
Why does proteloysis increase in cancer?
Tumour secreted TNF-alpha and PIF (proteolysis inducing factor)
Why does gluconeogenesis increase in cancer?
Greater quantity of amino acids and lactate in circulation
Why does lipolysis increase in cancer?
Tumours secreting cytokines or catabolic factors –> Increase FFA, packages into VLDL and endogenous HyperTG
What does early satiety arise from?
- Reduced GI motility, Increase in GI emptying
- Dysregulation of metabolic signals of satiety
What are direct consequences of antineoplastic therapies?
- Diarrhea, Nausea
- Chemosensory abnormalities
What are some pharmacological agents to increase appetite?
- Pro-gestational agents
- Corticosteroids
- Cannabinoids
Pro-gestational agents?
-Birth control progesterone pills, increase appetite, weight gain but NOT lean mass
Nutritional implications of pro-gestational agents and corticiosteroids?
-Insulin resistance, muscle wasting and osteopenia
Corticosteroids?
Transient increase in appetite, but only for RESTRICTED periods (1-3 weeks)
Common drugs prescribed for symptom management in cancer?
- Antiemetics
- Antidepressants
- Corticosteroids
- Anti GI motility agents
- Narcotics, analgesic
What does thalidomide inhibit?
TNF-a, may attenuate weight-loss
What does pentoxifylline inhibit?
TNF-alpha, but no proven benefits
What are potential agents to treat cachexia?
- SARMS (incr. LBM and muscle function in elderly)
- Ghrelin receptor agonist (incr, appetite, weight gain, but NOT handgrip strength)
Conclusion surrounding cancer and cachexia?
A multi-modal approach, combining dietary, PA and pharmacological agents that must include individual nutritional counselling and early intervention has the best chances of success to treat cachexia
