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Introduction and Neoplasia - Pathophysiology
Introduction and Neoplasia - Pathophysiology
Introduction and Neoplasia - Pathophysiology
Table of Contents
Pathophysiology of Cancer: Basic Principles ........................................................................................................................... 1
Cancer screening and prevention ........................................................................................................................................... 6
Breast Cancer Symposium ...................................................................................................................................................... 8
Radiobiology as applied to the clinic .................................................................................................................................... 11
Cancer: 2nd leading cause of mortality in US (23% all deaths). More cancer survivors now than ever.
Women: lung, breast, colon, rectum = 50% cancers; Men: lung, prostate, colorectal
Metastasis: set of host-tumor interactions involved. A failure in any step will halt metastasis.
(proliferation, angiogenesis of primary tumor detatchment, invasion of lymphatics or blood embolism &
circulation transport & survival arrest in organs adherence & extravasation survival in new tissue,
proliferation, angiogenesis)
Dormancy: can have a relapse decades after primary treatment (e.g. breast cancer, melanoma) – not well understood
Possible mechanisms: persistent pre-angiogenic micrometastases (dividing & apoptosing @ same rate) and then
undergo angiogenic shift; or maybe persistence of solitary tumor cells in secondary organs
Oncologic emergencies:
3. Leukostasis
a. True oncologic emergency (requires expert management by oncologist with significant experience
b. Most common in AML (acute myelogenous leukemia) or accelerated / blast phases of chronic myelocytic
leukemia (CML)
c. Pathophysiology: plugging of capillaries with immature leukocytes (organ dysfunction results)
i. Not just simple obstruction: white cell thrombi also compete for oxygen, causing further hypoxia
ii. Endothelial injury invasion of surrounding tissue pulmonary edema, hypoemia in lung /
risk for hemorrhage in brain
d. Symptoms: dyspnea, tachypnea, cough, chest pain, progressive hypoxemia, fever, headache, dizziness,
visual change, tinnitus, ataxia, lethargy, stupor, somnolence, seizure, coma. Think: microvasculature
(lungs, brain, retina)
e. Findings: tachypnea, bilateral crackles, papilledema, retinal vein distension
f. Treatment: hydration, urine alkalinization & allopurinal (prevent tumor lysis syndrome & uric acid
buildup), chemotherapy. May need leukapheresis to reduce WBC count quickly
4. Hypercalcemia of malignancy
a. Most common life-threatening metabolic disorder in cancer patients
b. Most common causes of hypercalcemia: hyperparathyroidism (45%), malignancy (45%)
i. Multiple myeloma and breast cancer are big two cancers
c. Pathophysiology: direct involvement of cancer metastatic to bone, or humoral secretion at distant cyte.
d. Humoral mediators:
i. 1,25-dihydroxyvitamin D in hypercalcemia associated with melanoma, multiple myeloma,
Hodgkins / Non-Hodgkin’s lymphoma
ii. PTHrP (parathyroid hormone-related peptide) associated with squamous cell carcinoma of
lung, small cell / anaplastic lung carcinoma, melanoma, prostate cancer, breast cancer, renal
carcinoma
e. Immobilization can also play a role in some pts with advanced cancer (bone loss)
f. Symptoms: fatigue, weakness, confusion, lethargy, constipation, nausea, vomiting, polyurea.
g. Normal Ca = 8.4-10.5
h. Therapy: IV fluids, diuretics (lasix), bisphosphonates to inhibit Ca relase from bone (interfere with
osteoclasts). Steroids used too – but need to treat the underlying tumor.
Paraneoplastic syndromes: systemic effects of cancer that are not related to direct invasion or compression from tumor
or to metastatic spread (endocrine, neurologic, hematologic derangements).
Trousseau’s syndrome: thrombophlebitis (venous blood clots) with cancer – Trousseau diagnosed himself.
Risk is highest for migratory thrombophlebitis in pancreatic cancer but can also be present in other
adenocarcinomas (breast, prostate, ovarian cancers)
Manage with anticoagulation & tx of underlying malignancy
Cancer pain
Grossly undertreated: 90% can be well controlled
Most due to direct tumor infiltration
Three types of pain
o Somatic pain: dull, aching, well-localized. E.g. metastatic bone pain
o Visceral pain: deep, squeezing, pressure-like, poorly localized. Infiltration / compression of viscera. Can
be associated with nausea/vomiting if acute (e.g. pancreatic cancer)
o Neuropathic pain: direct injury to PNS/CNS from direct tumor infiltration or compression, or therapy-
related injury.
Assessment: believe the patient (esp. in cancer); do Hx & physical exam, use pain assessment tools as fifth vital
sign, individualize approach, educate patient
Treatment: assess & treat underlying cause (including palliative treatment of tumors), match medications to
type of pain, titrate medication to patient response, give on schedule rather than prn basis, use oral meds if
possible, anticipate side effects and treat, be aware of tolerance
o Tolerance: ability to take large dose of drug without ill effect (reduction of desired effects from
continued use)
o Dependence: physical, biological need for a drug to prevent withdrawal syndrome
o Addiction: psychological craving for drug; rare result in appropriate cancer pain management
Performance status: global assessment of ability to conduct activities of daily living (not QOL).
o Major prognostic factor for pts with cancer, predictor of toxicity of treatment, indicator of comorbid
disease and other host factors.
o Two major scales: Karnofsky performance status (0-100), Eastern Cooperative Oncology Group (0-4)
Cancer screening and prevention
Fundamental assumptions:
1. Disease can be identified in pre-clinical phase
2. Treatment is more effective at earlier rather than usual time of Dx
3. In absence of intervention, all cases proceed to clinical disease
and eventual mortality
4. Disease follows a natural history course
a. DPCP = detectable pre-clinical period (1st point detectable
by screening to first onset of symptoms)
More frequent screening is not always better (more false positives = more $$, more unnecessary procedures, etc.)
Should be determined from rate of disease progression and sensitivity of test
Also need to determine when to stop screening – balance benefits of screening vs. decreasing life expectancy
from other causes in the aging population
Screening may not be good in cancers where there’s a good prognosis for disease, in people with a limited life
expectancy, or if you can’t detect disease during a preclinical phase (or short pre-clinical phase)
Identifying high-risk populations (fam Hx, BRCA mutations, exposure to carcinogen like smoking or afalotoxin) causes a
higher “prevalence” in your screened population and therefore increases positive predictive value.
When should we screen? Need to consider the properties of the test & the population effectiveness
Burden (mortality/morbidity)
Good detectable clinical phase, early detection beneficial & effective
Screening test is safe & effective
Prevalent in population
Feasible & acceptable to patient and physician
Want a high precision, high PPV, high accuracy (specificity is especially important because most cancers are rare)
Risk factors
Reproductive: prolonged estrogen exposure
o early menarche, late menopause, nulliparity / late first pregnancy, lactation (?)
Environmental: radiation=yes (not pesticides or electromagnetic fields
Lifestyle: Diet, alcohol, physical activity, tobacco use (big cancer risk)
Endogenous hormones: high hormone levels, post menopausal obesity (metabolic syndrome), increased bone
density (may be marker for high E instead of risk factor)
Exogenous hormones: hormone replacement therapy=yes (estrogen replacement therapy = ?, oral
contraceptives = no)
Pathology: atypical ductal or lobular hyperplasia; lobular carcinoma in situ are risk factors
Inheritance: family history important; major inherited susceptibility (DNA repair defects are key)
About 75% breast cancer has no family influence
15-20% “clustered” (no clear inheritance); 5-10% directly inheritable
BRCA1 (20-40%), BRCA2 (10-30%) are two big players in heritability (% of heritability attributable)
Undiscovered genes (30-70%) are still very important
BRCA MUTATIONS
BRCA-1
Increased likelihood of having BRCA mutation:
o 50-80% lifetime risk of BC; often early age at onset; o Multiple cases of early onset BC in family
40-60% chance of having second primary BC o Ovarian cancer with FHx of breast/ovarian cancer
o Ovarian cancer 15-45% risk o Breast & ovarian cancer in same woman
o Possible increase in risk of other cancers o Bilateral breast cancer
BRCA-2 o Ashkenazi Jewish heritage
o 50-85% lifetime risk of BC; 6% male breast cancer o Male breast cancer
o Ovarian cancer 10-20% risk
o Increased risk prostate, laryngeal, pancreatic cancers
Management: test other relatives; increase surveillance & institute lifestyle changes, chemoprevention
(tamoxifen), possibly prophylaxic surgery if lots of risk
Risk assessment:
o Gail model (age, repro history, benign breast disease history, FHx in first degree). Doesn’t incorporate
age @ Dx, other cancers, other relatives
o Claus tables: only considers FHx of breast cancer
Prevention:
Lifestyle changes (exercise, alcohol, tobacco) Signs & Symptoms of Breast Cancer
Chemoprevention (tamoxifen, raloxifene) Breast lump or thickening
Skin or nipple changes
Screening: Nipple discharge
Breast self exam (beginning in 20s; some negative RCT) Regional adenopathy
Clinical breast exam (annual) Abnormal mammogram
Mammography: (good evidence for 50-69, uncertain in 40-
49yo, no data 70+)
o Looking for calcification
New approaches: ductoscopy (endoscope in duct); ductal lavage (inject fluid, aspirate to get some cells)
Diagnostic tests: bilateral mammography, ultrasound/MRI, biopsy
Pathophysiology & Treatment
Ductal epithelial cells are site of origin for 95% BC
Classification:
o Invasive vs non-invasive
o Ductal vs lobular (“origin”)
o Histiologic grade
o Special stains (ER = estrogen receptor, PR = progesterone receptor, HER-2 = human epidermal growth
factor receptor 2 = more aggressive cancer)
Staging: establish prognosis & guide therapy Staging Breast Cancer
o Use: hx, physical exam; mammorgraphy, CBC/chemistry,
I: T < 2 cm, N0
X-rays/scans if symptoms, pathological exam on axillary
II: T > 2 cm – 5 cm or N1
nodes after surgery, analysis of tumor for ER/PR/HER-2
III: locally advanced breast cancer
Prognostic factors: predict natural history for individual dz.
IV: metastases
Nodal status, tumor size, steroid receptors, grade/subtype,
proliferation, age.
Predictive factors: predict how well tumor will respond to specific therapies. Steroid receptors, HER-2 presence
Tumor subtypes: different natural histories, different types of responses to therapy
o Best is “luminal A”
o Worst is “basal” & “HER-2+”
Good example of personalized medicine: “Oncotype dx” – figure out what therapy in combination will work best
for patient’s tumor algorithmically & then apply.
Surgery & radiation with adjuvant systemic chemo is generally how treatment works.
Surgery
Halsted pioneered the radical mastectomy
Less surgery causes less lymphedema, less mobility problems, etc.
RCTs: mastectomy vs. lumpectomy & radiation showed no survival difference.
Breast conserving therapy (BCT) is now preferred unless contraindicated (multifocal, poor cosmetic outcome,
patient preference, previous radiation, etc.)
Systemic treatment
Chemotherapy:
o Alkylators (cyclophosphamide, etc.)
o Antimetabolites (MTX, 5-FU, etc)
o Topoisomerase inhibitors (doxorubicin)
o Antimitotics too
Hormonal: endocrine therapy
o Ovarian ablation (surgery/radiation or LHRH agonists)
o SERMs like tamoxifen antagonize ER gene products in breast tissue
o Aromatase inhibitors (if post-menopausal)
Basic physics:
X-ray is a stream of photos with energy inversely proportional to wave length. Ionizing if it can knock an orbital
election out from an atom that it encounters (electron cloud is big, so most likely to hit an electron)
Electron flies out and deposits energy distant to site of ejection
o Energy reaches a maximum at some distance from site of ejection (distance to maximum depends on
energy)
o this is “sparing” of high dose to tissue right under surface (so for instance skin not always harmed
because it’s closer than the maximum distance
DNA strand breaks / chromosomal aberrations (what happens after DNA gets damaged)
Single strand break = easily repaired (use complementary strand)
Double strand break = irreparable
o Need two breaks close to each other in time and space
o Chromosomal aberrations: sticky ends at each broken part
Common formations: dicentrics, rings (sticky ends stick together – lethal)
May fail to rejoin: deletion(lethal)
Rate of aberrations (and resultant cell death) increases with
amount of radiation
So in summary: Fractionated irradiation spares normal tissue by allowing repair of sublethal damage and repopulation
of cells. Fractionation increases tumor damage by allowing reassortment of cells into more radiosensitive cell cycle
phases and permits reoxygenation to occur in order to make DNA damage permanent.
You might think that you’d want to get the treatment done ASAP then
(bigger dose per day to decrease # fractions) to avoid sparing the early
responding tissue (including the tumor).
If you multifractionate your regimen, you can reduce this problem (top
graph shows that your killing of early-responding tissue is slightly less, but
bottom graph shows that your killing of late-responding tissue is much
less) – improving your therapeutic ratio.