Cancer Pathophysiology and Cachexia Flashcards
What is primary tumor?
first tumor identified, classified according to size and invasion of surrounding tissues
What is secondary tumor?
other tumors of the same histological origin as the primary, located nearby
How are the regional lymph nodes classified?
classified according to distance from primary tumor
What is metastasis?
invasion of distal tissues and organs
How is cancer diagnosed?
§ Biochemical: detect biomarkers
§ Tumor imaging techniques:
- MRI: magnetic resonance imaging
- CT: computed tomography
- PET: positron emission tomography
- Chest X-ray, ultrasound, mammogram, bone scans
§ Invasive techniques: biopsy, cytologic aspiration, laparoscopy
How are solid tumors classified?
For solid tumors: based on TNM system
§ Primary tumor (T: T1 to T4), lymph nodes (N: N0 to N3), metastasis (M: M0 or M1)
§ With some specificities according to each cancer type
What are the stages of cancer? Describe
Stage 0 --> Carcinoma in situ (early form) Stage 1 --> Localized Stage 2 --> Early locally advanced Stage 3 --> Late locally advanced Stage 4 --> Metastasized
What are anti-cancer treatments?
- Surgical removal
- Radiotherapy
- Chemotherapy
- Immunotherapy or biological response modifiers
- Hematopoietic stem cell transplantation
- Gene therapy
Explain surgical removal of cancerous tissue
§ first choice for curative Tx (may be palliative, e.g. to alleviate pain)
§ mostly for primary, local tumors (Stage I) and pre-cancerous lesions
§ may be more or less invasive depending on site
What is radiotherapy?
ionizing radiation altering DNA to control growth or kill malignant cells (continuously proliferating cells are most susceptible)
§ For curative Tx, or adjuvant with other treatment regimens
§ Targeted to tumors with relatively limited damage to surrounding tissues
§ Dose/fractionation vary according to type and size of tumors
What are some side effects of radiotherapy and nutrition concerns?
§ head and neck: mucositis, dysgeusia, xerostomia, dysphagia, odynophagia, severe esophagitis –> hisk risk of malnutrition, may need tube feeding
§ abdomen and pelvis: severe diarrhea, malabsorption, radiation enterotitis
What is chemotherapy?
cytotoxic drugs that block DNA and RNA synthesis or cell division at different stages (next slide)
§ Administered orally, IV infusion or intra-muscular injections, dose given in cycles
§ Many systemic side effects (also affects healthy cells replicating rapidly)
What are Immunotherapy or biological response modifiers? Side effects?
use body’s own immune system to eradicate cancer cells
§ Synthesized interferons, interleukins, cytokines
§ Side effects: bone pain, fatigue, fever, anorexia, rashes, flu-like symptoms
What is Hematopoietic stem cell transplantation?
for blood cancers
§ May lead to graft vs. host disease
What are the classes of chemotherapy agents?
• Alkylating agents
– Cisplatin, carboplatin
• Indirect DNA agents
– 5-fluorouracil, gemcitabine
• Topoisomerase inhibitors
– Irinotecan, topotecan
• Antitumor antibiotics
– Doxorubicin
• Antimitotics
– Vincristine, vinblastine, paclitaxel
What are the common side effects of chemotherapy agents?
• Bone marrow suppression – Anemia, neutropenia, thrombocytopenia • N/V, stomatitis, diarrhea • Alopecia • Anorexia • Renal toxicity (cisplatin) • Hepatotoxicity (5-FU) • Cardiotoxicity (doxorubicin)
What is cancer cachexia?
A complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature is weight loss…
What are some consequences of cancer cachexia due to muscle wasting?
§ Muscle wasting predicts poor cancer-associated outcomes: § ↑ fatigue § ↑treatment-induced toxicity § ↓host response to tumor § ↓ performance status § ↓ survival
What is the prevalence of cancer cachexia?
Overall prevalence: 50-80%
Cachexia occurs more frequently in certain types of cancer:
§ Upper gastro-intestinal cancer : ≅ 80% § upper gastric and pancreatic: 83-87%
§ Lung cancer: ≅ 60%
What is the main pathophysiology of cachexia?
Dual contribution of metabolic change (Systemic inflammation Catabolic factors) and reduced food intake to cachexia
Define undernutrition
insufficient food intake
Define malnutriton
insufficient intake in one or more nutrients (can also refer to over- or undernutrition)
Define starvation
food deprivation (all nutrients)
Define Sarcopenia
decreased muscle mass in the absence of weight loss
What are the stages of cachexia?
- precachexia
- cachexia
- refectory cachexia
How does the body composition change in cachexia?
It has been traditionally thought that weight loss results from roughly equal proportions of:
§ Fat mass
§ Fat-free mass: mainly from skeletal muscle
(visceral proteins are better preserved)
§ The trajectory of losses of both compartments is currently being investigated…
What are some decrease concentration or responsiveness in anabolic factors?
– Insulin – IGF-1 – Growth hormone – Thyroid hormone – Testosterone
What are some increase concentration of catabolic factors
– Glucagon – Cortisol – Pro-inflammatory cytokines – Eicosanoids – Tumor-derived factors
What is acute phase response?
§ Coordinated adaptations of the body to limit and clear the tissue damage caused by hydrolases released from inflammatory, injured or malignant cells.
§ Hepatic synthesis of acute-phase proteins:
their plasma concentrations (positive) or (negative) by >25%
Give examples for positive acute phase proteins
§ Complement system § Coagulation and fibrinolytic system § Antiproteases § Participants in inflammatory responses § Others: C-reactive protein, fibronectin, ferritin, ceruloplasmin, haptoglobin
Give examples for negative acute phase proteins
§ Albumin § Transferrin § Transthyretin § Thyroxin-binding globulin § IGF-1 § Factor XII § Alpha-fetoprotein
The acute phase response is modulated by _____
cytokines
Where are cyokines produced and secreted?
§ Cytokines are produced by the tumor and/or the host:
§ Secreted from immunocompetent cells: lymphocytes, macrophages
§ They act locally (paracrine and autocrine) and systemically (endocrine)
Give examples for Pro-inflammatory cytokines
§ High serum levels of these cytokines have been found in some, but not all types of cancer: – Tumor-necrosis factor alpha (TNF-α) – Interleukins 1 and 6 (IL-1, IL-6) – Interferon gamma (IFN-γ) – Leukemia inhibitory factor (LIF)
What are some other effects of cytokines
§ decreased appetite and food intake, resulting from both central and peripheral elements
§ decreased GI functions: decreased gastric emptying , intestine mobility
§ decreased blood flow
§ Inhibit lipoprotein lipase (LPL)
§ Inhibit growth hormone and IGF-1 signaling
§ Induce insulin resistance (IL-6)
How is lipid metabolism altered in case of cancer?
§ Mobilization of lipids and increased turnover of fatty acids
§ increased lipolysis, FFA, VLDL
§ decreased LPL activity
§ Hypertriglyceridemia
How is glucose metabolism altered in case of cancer?
§ Glucose is the preferred fuel for tumors
§ Tumors produce lactate –> Cori cycle (uses ATP)
§ increased gluconeogenesis –> increased proteolysis (muscle)
§ Insulin resistance
How is protein metabolism altered in case of cancer?
§ Negative N balance § ↑ protein turnover § ↑ or ↔ muscle proteolysis: provides AA for GNG, acute-phase protein synthesis and tumor growth § ↓ or ↔ in muscle protein synthesis § ↑ hepatic protein synthesis (APPs)
What are the 3 pathways that involve intracellular protein degradation?
- Lysosomal (caspases)
- Ca++-dependent (calpains)
- ATP-dependent ubiquitin-proteasome pathway
—> The most important in skeletal muscle proteolysis in many wasting conditions, including cancer cachexia
How is anorexia related to cancer?
§ Associated with >50% cases of cachexia
§ decrease in food intake may result from:
- Obstruction of the GI tract
- Malabsorption
- Pain
- Depression/anxiety
- Constipation
- Radio- and chemo-therapy
- Inflammation
§ Many patients with no obvious clinical reason
How is appetite and food intake regulated?
Controlled by a complex of hormones and neuropeptides in the hypothalamus
§ Homeostasis: energy repletion or depletion
Hypothalamic orexigenic signals (NPY)
- Stimulate feeding
- Decrease Energy expenditure
Anorexigenic signals (POMC)
- Inhibit feeding
- IncreaseEnergy expenditure
What is the cause of early satiety happen in cancer patients?
§ Results from: § Reduced GI motility § decreased gastric emptying time § May be caused by autonomic dysfunction and opioid analgesics § Metabolic signals of satiety?
What are the problems that arise from nausea and chemosensory abnormalities?
§ Both are direct consequences of antineoplastic therapies, but also very frequent in untreated patients
§ Nausea may occur as:
- Side effect of drugs
- Abdominal disease, intracranial metastases, metabolic derangements, GI stasis
§ Distortion of taste and smell:
- Includes: hypersensitivity to odors and flavors, persistent bad tastes, phantom smells, food aversions
- Apart from treatment, may result from chronic nutritional deficiencies
What are additional assessment to diagnosis of cachexia?
To define severity and phenotype and target appropriate treatment:
§ Anorexia or reduced food intake
§ Questionnaires or <70% of usual food intake
§ Catabolic drive
§ serum CRP levels
§ Muscle mass and strength (next lecture)
§ Functional and psychosocial effects
What are the therapeutic agents to improve appetite in cancer?
- Progestational agents (megestrol acetate): ↑ appetite and weight gain but not lean mass. Serious side effects: oedema, thromboembolism.
- Corticosteroids: transient increase in appetite and well-being. Side effects: insulin resistance, muscle wasting, osteopenia. Should be used for restricted periods (1-3 weeks).
- Cannabicoids: dronabinol may have potential but inconsistent evidence
What are the types of drugs that can be used for symptom management of cachexia?
§ Antiemetics § Antidepressants § Corticosteroids § Anti GI motility agents § Narcotics and other analgesics
What are some hormones that can be used for cachexia?
§ Growth hormone +/- IGF-1: no proven benefits
§ Melatonin: no proven benefits
§ Anabolic agents and steroids: adverse effects
What are some anti-inflammatory agents (cytokine directed) that can be used for cachexia?
§ Thalidomide: inhibits TNF-α, may attenuate weight loss
§ Pentoxifylline: inhibits TNF-α, no proven benefits
§ Proteasome inhibitors: no proven benefits
What are the pharmacologic agents under investigation
to treat cachexia?
§ Selective androgen receptor modulators (SARMs, Enobosarm):
increased lean body mass and muscle function in elderly. Phase II RCT in NSCLC patients treated with chemotherapy (POWER trial): ↑ LBM, muscle power, +/- stair climbing.
§ Ghrelin receptor agonist (Anamorelin):
2 phase III trials in NSCLC with cachexia (ROMANA 1&2): significant increase in appertite, weight gain and lean mass but not handgrip strength (Temel et al. Lancet Oncol 2016)
§ Anti-IL-6 antibody:
average muscle gain of 2.3 kg in one trial, improved lung symptoms and reverse fatigue in another.
§ Anti-myostatin monoclonal antibody:
trials in pancreatic and lung cancer completed, not published.
What is carcinoma?
cancer in epithelial tissue
What is sarcoma?
cancer in connective tissue
What is lymphoma?
cancer in lymphatic system
What are gliomas?
cancer in glial cells of CNS
What are leukemias?
cancer in bone marrow
What are adenocarcinomas?
cancer in glands
How do upper respiratory tract and digestive tract tumors affect nutrition status?
- Obstruction, dysphagia
- mastication and deglutition problems
How does esophagus tumor affect nutrition status?
- Obstruction, dysphagia, anorexia, anemia from occult losses
- Early satiety, regurgitation, gastric stasis
- Enteral nutrition often necessary, sometimes permanent
How does stomach tumor affect nutrition status?
- Obstruction, anorexia, anemia, water and electrolyte losses
- Early satiety, achlorydria, dumping syndrome, loss of intrinsic factor
- Enteral nutrition by jejunostomia after Tx
How do pancreas and biliary tract tumors affect nutrition status?
- Weight loss, abdominal pain, anorexia, nausea, malabsorption, secondary diabetes (due to pancreatitis)
How does liver tumor affect nutrition status?
- Weight loss is frequent, anorexia
- Anorexia, nausea, hepatomegaly, risk of hepatitis if high dose
- Post-op nutritional support important, capacity to regenerate
How do small intestine, colon, rectum tumors affect nutrition status?
- Obstruction, anemia from occult losses, malabsorption, steatorrhea
- Ileal resection: ̄ B12, Ca, Mg, lipo vit. bile salt absorption,; Colectomy: water and electrolyte losses
- cramps, diarrhea, N&V, malabsoption (Ca, Mg, Fe, B12), steatorrhea; fistula, perforation
- TPN may by indicated
How does breast tumor affect nutrition status?
- Weight gain with some forms
- Possible impact on esophagus
How does lungs tumor affect nutrition status?
Weight loss is frequent
How does gynecological organs tumor affect nutrition status?
- Intest. obstruction (by pressure), enteropathy, ascites
- Possible impact on intestinal mucosa
- Diuretics or sodium restriction are not relevant
How does bone metastases tumor affect nutrition status?
- Pain (anorexia)
- Constipation secondary to analgesia
What is sarcopenic obesity?
- obesity with depleted muscle mass
- ≈15% of patients with lung or gastro-intestinal tumors
- worse outcomes than obese or sarcopenic patients
How is precachexia diagnosed?
weight loss <5%, anorexia and metabolic change
How is cachexia diagnosed?
weight loss >5% or BMI <20 and weight loss >2% or sarcopenia and weight loss >2% Often reduced food intake/ systemic inflammation
What is refractory cachexia?
- end-stage
- variable degree of cachexia, cancer disease both procatabolic and not responsive to anticancer treatment,
- low performance score,
- less than 3 months expected survival
