Cancer Pathophysiology and Cachexia Flashcards Preview

6-Clinical Nutrition 1 > Cancer Pathophysiology and Cachexia > Flashcards

Flashcards in Cancer Pathophysiology and Cachexia Deck (69)
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1
Q

What is primary tumor?

A

first tumor identified, classified according to size and invasion of surrounding tissues

2
Q

What is secondary tumor?

A

other tumors of the same histological origin as the primary, located nearby

3
Q

How are the regional lymph nodes classified?

A

classified according to distance from primary tumor

4
Q

What is metastasis?

A

invasion of distal tissues and organs

5
Q

How is cancer diagnosed?

A

§ 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

6
Q

How are solid tumors classified?

A

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

7
Q

What are the stages of cancer? Describe

A
Stage 0 --> Carcinoma in situ (early form)
Stage 1 --> Localized 
Stage 2 --> Early locally advanced
Stage 3 --> Late locally advanced 
Stage 4 --> Metastasized
8
Q

What are anti-cancer treatments?

A
  • Surgical removal
  • Radiotherapy
  • Chemotherapy
  • Immunotherapy or biological response modifiers
  • Hematopoietic stem cell transplantation
  • Gene therapy
9
Q

Explain surgical removal of cancerous tissue

A

§ 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

10
Q

What is radiotherapy?

A

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

11
Q

What are some side effects of radiotherapy and nutrition concerns?

A

§ 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

12
Q

What is chemotherapy?

A

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)

13
Q

What are Immunotherapy or biological response modifiers? Side effects?

A

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

14
Q

What is Hematopoietic stem cell transplantation?

A

for blood cancers

§ May lead to graft vs. host disease

15
Q

What are the classes of chemotherapy agents?

A

• Alkylating agents
– Cisplatin, carboplatin

• Indirect DNA agents
– 5-fluorouracil, gemcitabine

• Topoisomerase inhibitors
– Irinotecan, topotecan

• Antitumor antibiotics
– Doxorubicin

• Antimitotics
– Vincristine, vinblastine, paclitaxel

16
Q

What are the common side effects of chemotherapy agents?

A
• Bone marrow suppression 
– Anemia, neutropenia, thrombocytopenia
• N/V, stomatitis, diarrhea
• Alopecia
• Anorexia
• Renal toxicity (cisplatin)
• Hepatotoxicity (5-FU)
• Cardiotoxicity (doxorubicin)
17
Q

What is cancer cachexia?

A

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…

18
Q

What are some consequences of cancer cachexia due to muscle wasting?

A
§ Muscle wasting predicts poor cancer-associated outcomes: 
§ ↑ fatigue
§ ↑treatment-induced toxicity 
§ ↓host response to tumor
§ ↓ performance status
§ ↓ survival
19
Q

What is the prevalence of cancer cachexia?

A

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%

20
Q

What is the main pathophysiology of cachexia?

A

Dual contribution of metabolic change (Systemic inflammation Catabolic factors) and reduced food intake to cachexia

21
Q

Define undernutrition

A

insufficient food intake

22
Q

Define malnutriton

A

insufficient intake in one or more nutrients (can also refer to over- or undernutrition)

23
Q

Define starvation

A

food deprivation (all nutrients)

24
Q

Define Sarcopenia

A

decreased muscle mass in the absence of weight loss

25
Q

What are the stages of cachexia?

A
  • precachexia
  • cachexia
  • refectory cachexia
26
Q

How does the body composition change in cachexia?

A

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…

27
Q

What are some decrease concentration or responsiveness in anabolic factors?

A
– Insulin
– IGF-1
– Growth hormone 
– Thyroid hormone 
– Testosterone
28
Q

What are some ­increase concentration of catabolic factors

A
– Glucagon
– Cortisol
– Pro-inflammatory cytokines
– Eicosanoids
– Tumor-derived factors
29
Q

What is acute phase response?

A

§ 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%

30
Q

Give examples for positive acute phase proteins

A
§ Complement system
§ Coagulation and fibrinolytic system
§ Antiproteases
§ Participants in inflammatory responses
§ Others: C-reactive protein, fibronectin, ferritin, ceruloplasmin, haptoglobin
31
Q

Give examples for negative acute phase proteins

A
§ Albumin
§ Transferrin
§ Transthyretin
§ Thyroxin-binding globulin
§ IGF-1
§ Factor XII
§ Alpha-fetoprotein
32
Q

The acute phase response is modulated by _____

A

cytokines

33
Q

Where are cyokines produced and secreted?

A

§ 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)

34
Q

Give examples for Pro-inflammatory cytokines

A
§ 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)
35
Q

What are some other effects of cytokines

A

§ 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)

36
Q

How is lipid metabolism altered in case of cancer?

A

§ Mobilization of lipids and ­increased turnover of fatty acids
§ ­increased lipolysis, FFA, VLDL
§ decreased LPL activity
§ Hypertriglyceridemia

37
Q

How is glucose metabolism altered in case of cancer?

A

§ Glucose is the preferred fuel for tumors
§ Tumors produce lactate –> Cori cycle (uses ATP)
§ ­increased gluconeogenesis –> increased proteolysis (muscle)
§ Insulin resistance

38
Q

How is protein metabolism altered in case of cancer?

A
§ 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)
39
Q

What are the 3 pathways that involve intracellular protein degradation?

A
  1. Lysosomal (caspases)
  2. Ca++-dependent (calpains)
  3. ATP-dependent ubiquitin-proteasome pathway

—> The most important in skeletal muscle proteolysis in many wasting conditions, including cancer cachexia

40
Q

How is anorexia related to cancer?

A

§ 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

41
Q

How is appetite and food intake regulated?

A

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

42
Q

What is the cause of early satiety happen in cancer patients?

A
§ Results from:
§ Reduced GI motility
§ ­decreased gastric emptying time
§ May be caused by autonomic dysfunction and opioid analgesics
§ Metabolic signals of satiety?
43
Q

What are the problems that arise from nausea and chemosensory abnormalities?

A

§ 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
44
Q

What are additional assessment to diagnosis of cachexia?

A

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

45
Q

What are the therapeutic agents to improve appetite in cancer?

A
  • 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
46
Q

What are the types of drugs that can be used for symptom management of cachexia?

A
§ Antiemetics
§ Antidepressants
§ Corticosteroids
§ Anti GI motility agents
§ Narcotics and other analgesics
47
Q

What are some hormones that can be used for cachexia?

A

§ Growth hormone +/- IGF-1: no proven benefits
§ Melatonin: no proven benefits
§ Anabolic agents and steroids: adverse effects

48
Q

What are some anti-inflammatory agents (cytokine directed) that can be used for cachexia?

A

§ Thalidomide: inhibits TNF-α, may attenuate weight loss
§ Pentoxifylline: inhibits TNF-α, no proven benefits
§ Proteasome inhibitors: no proven benefits

49
Q

What are the pharmacologic agents under investigation

to treat cachexia?

A

§ 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.

50
Q

What is carcinoma?

A

cancer in epithelial tissue

51
Q

What is sarcoma?

A

cancer in connective tissue

52
Q

What is lymphoma?

A

cancer in lymphatic system

53
Q

What are gliomas?

A

cancer in glial cells of CNS

54
Q

What are leukemias?

A

cancer in bone marrow

55
Q

What are adenocarcinomas?

A

cancer in glands

56
Q

How do upper respiratory tract and digestive tract tumors affect nutrition status?

A
  • Obstruction, dysphagia

- mastication and deglutition problems

57
Q

How does esophagus tumor affect nutrition status?

A
  • Obstruction, dysphagia, anorexia, anemia from occult losses
  • Early satiety, regurgitation, gastric stasis
  • Enteral nutrition often necessary, sometimes permanent
58
Q

How does stomach tumor affect nutrition status?

A
  • Obstruction, anorexia, anemia, water and electrolyte losses
  • Early satiety, achlorydria, dumping syndrome, loss of intrinsic factor
  • Enteral nutrition by jejunostomia after Tx
59
Q

How do pancreas and biliary tract tumors affect nutrition status?

A
  • Weight loss, abdominal pain, anorexia, nausea, malabsorption, secondary diabetes (due to pancreatitis)
60
Q

How does liver tumor affect nutrition status?

A
  • Weight loss is frequent, anorexia
  • Anorexia, nausea, hepatomegaly, risk of hepatitis if high dose
  • Post-op nutritional support important, capacity to regenerate
61
Q

How do small intestine, colon, rectum tumors affect nutrition status?

A
  • 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
62
Q

How does breast tumor affect nutrition status?

A
  • Weight gain with some forms

- Possible impact on esophagus

63
Q

How does lungs tumor affect nutrition status?

A

Weight loss is frequent

64
Q

How does gynecological organs tumor affect nutrition status?

A
  • Intest. obstruction (by pressure), enteropathy, ascites
  • Possible impact on intestinal mucosa
  • Diuretics or sodium restriction are not relevant
65
Q

How does bone metastases tumor affect nutrition status?

A
  • Pain (anorexia)

- Constipation secondary to analgesia

66
Q

What is sarcopenic obesity?

A
  • obesity with depleted muscle mass
  • ≈15% of patients with lung or gastro-intestinal tumors
  • worse outcomes than obese or sarcopenic patients
67
Q

How is precachexia diagnosed?

A

weight loss <5%, anorexia and metabolic change

68
Q

How is cachexia diagnosed?

A

weight loss >5% or BMI <20 and weight loss >2% or sarcopenia and weight loss >2% Often reduced food intake/ systemic inflammation

69
Q

What is refractory cachexia?

A
  • 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