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Pathophysiology: Neoplasia

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

Pathophysiology of Cancer: Basic Principles

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)

Natural history of cancer


1. Formation of the primary tumor
a. Cross-talk between
cancer cells & host Cell type Promotion of metastasis Inhibition of metastasis
stromal cells (up or Tumor Activation of growth factor pathways Antigenicity
down-regulated Angiogenic factors Angiogenesis inhibitors
Motility/invasiveness Cohesion (E-cadherin)
gene expression in
Aggregation/deformability Tissue inhibitors of proteolysis
both)
Host Paracrine/endocrine growth factors Tissue barriers
b. Nutrients supplied
Neovascularization Endothelial cells/blood turbulence
by simple diffusion Platelets Tissue inhibitors of proteolysis
(avascular tumor) Immune cells Immune cells
c. Balanced rate of Antiproliferative factors
tumor cell Inhibitors of angiogenesis
proliferation &
death (until “switch” to pro-angiogenic phenotype) – see table
2. Progressive growth & angiogenesis
a. Tumor cells can either directly secrete angiogeneic substances or release / activate them from ECM
i. Can also recruit lymphocytes, macrophages (release angiogenic substances too)
ii. Leads to activation of endothelial cells & neovascularization
b. Process of angiogenesis
i. Capillary basement membrane degraded (vascular deformity in existing vessel)
ii. Endothelial cells migrate out (pro-angiogenic stimulus)
iii. Proliferation @ leading edge of endothelial cell column
iv. Reorganization and canalization of endothelial cell tube
v. Anastamosis to establish blood flow
c. Proangiogenic substances include fibroblast growth factors, epidermal growth factors, vascular
endothelial growth factor (VEGF)
d. Antiangiogenic factors include the statins (angiostatin, endostatin, etc).
e. Tumor angiogenesis is different from physiological angiogenesis
i. Aberrant vasculature & blood flow formed
ii. Altered endothelial cell-pericite interactions
iii. Increased permeability
3. Invasion
a. Tumor cells & invading mononuclear cells from host produce degradative enzymes which facilitate
invasion of stroma
b. Host response: lay down fibrous ECM (desmoplasmic response)
c. Tumor cell downregulates adhesion molecules (e.g. E-cadherin) which normally need to be stimulated
to promote cell survival
d. Invasion: thin-walled vessels (lymphatics, capillaries, venules) – easily penetrated
4. Embolization & transport
a. Single cells or aggregates
b. Blood stream is hostile environment (shear forces, host hematopoetic defenses, etc.)
i. Most die & those that survive rarely produce metastases
ii. Aggregates more likely to survive & become trapped in microvasculature of distant organs
(“safety in numbers”)
c. Not always a simple picture (e.g. malignant ascites from ovarian cancer treated with peritoneavenous
shunts, dumping tons of cancer cells into jugular vein, but no increase in lung metastases).
5. Arrest, adhesion, extravasation
a. Adhere to capillary endothelial cells or subendothelial basement membrane if exposed – primarily a
mechanical process
b. Extravasate & invade stroma
c. Metastasis often but not always explained by drainage patterns to areas of microvasculature (via blood
or lymph drainage)
i. Colon cancer  liver metastases (portal circ)
ii. Breast cancer  lung metastases (systemic circ)
6. Subsequent growth
a. Inefficient & dependent on suitability of “soil” organ (not all observed metastasis sites are compatible
with simple drainage hypothesis)
i. E.g. melanoma to brain, liver, bowel; prostate carcinoma to bone, testicular carcinoma to liver
b. Factors at play:
i. “Seed” = tumor cell: growth factor expression, specific chemokine receptors, cell adhesion
molecules
ii. “Soil” = target organ: chemokine milieu (match of chemokine receptors), etc.
1. Example: breast cancer cells express CXCR4, CCR7 receptors; their normal target organs
express the conjugate chemokine ligands
iii. Certain tumor cell subsets may be genetically predisposed to metastatic phenotype
1. Inactivation of metastasis suppressor genes may be key (genes which prevent
metastasis without impacting growth of the primary tumor)
7. Progressive growth
a. Cancer cells need to grow further to actually establish a metastasis:
i. Establish a microenvironment
ii. Proliferate
iii. Begin angiogenesis (tpo grow beyond 1-2 mm in diameter)
iv. Evade host immune system

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

How does cancer make people sick?


1. local effects (compression of vital structures, replacement of tissues)
a. Headaches, seizures, change in personality: brain involvement?
b. Hematuria: urinary tract?
c. Productive cough – postobstructive pneumonia?
d. Bone pain: bone metastases?
2. systemic effects (humoral factors)
3. metastasis

Oncologic emergencies:

1. Spinal cord compression


a. 10-40% pts presenting with acute SCC have undiagnosed cancer
b. Most important: status @ presentation (80% ambulatory pts will retain ability to walk vs 25% non-
ambulatory)
c. Motor function & sphincter control are two big issues
d. Pathophysiology: compression of anterior spinal cord / nerve roots from vertebral body collapse = most
common. Can also have invasion of paraspinous tumor through vertebral foramen
e. Thoracic = 70%; lumbrosacral (20%); cervical (10%)
f. Most from prostate, breast, lung cancer.
g. Back pain is initial symptom in 95% of pts. RESPECT ANY COMPLAINT OF BACK PAIN IN KNOWN
CANCER PTS. THINK SCC!
h. MRI with gadolinium contrast is imaging modality of choice. Plain films can be abnormal if SCC present,
but do not exclude SCC if normal
i. Treatment: steroids, local radiation; anterior decompression & rod placement if unstable

2. Superior Vena Cava Syndrome


a. 80% pts with SVC syndrome have underlying cancer (most frequently small cell lung cancer).
b. Pathophysiology: obstruction of blood flow in SVC from thrombosis or external compression. Both can
occur simultaneously.
c. Symptoms: dyspnea, facial puffiness, fullness in head / dusky complexion, cough
d. Findings: engorgement of neck veins, development of collaterals over chest wall, facial edema (50%),
plethora / peripheral cyanosis (25%)
e. Evaluate with chest radiograph and/or CT to look for chest mass. If chemosensitive; give chemotherapy;
if not, give radiotherapy. If thrombosis, give blood thinners
f. Only use emergency radiotherapy empirically if symptoms are rapidly progressive and there’s no time
for a tissue diagnosis.

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).

Endocrine paraneoplastic syndromes:


 Ectopic ACTH syndrome (most common)
o Results in Cushing’s-type manifestation (weight gain in trunk/face, “buffalo hump”, weight loss
elsewhere, hypertension, hyperpigmentation, hypokalemia, metabolic alkalosis, excess sweating,
hirstutism, etc) with a pulmonary mass usually
o ½ due to small cell lung cancer, remainder pheochromocytoma, thymoma, medullary thyroid cacner,
carcinoid tumors

Neurologic paraneoplastic syndromes:


 Cerebellar and neuropsychiatric are most common; subacute but progressive
 Eaton Lambert myasthenic syndrome: rare manifestation of small cell lung cancer (<1% pts)
o Proximal mm weakness (pelvic girdle, thighs)
o Muscle strength improves with repeated activity; response to edrophonium chloride poor (opposite of
real myasthenia gravis)

Hematologic manifestations of cancer: erythrocytosis, anemia, granulocytosis, granulocytopenia, thrombocytopenia,


eosinophilia, basophilia, thrombocytopenia, thrombo-phlebitis, coagulopathies

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

Gastronintestinal manifestations of cancer: anorexia, cachexia, protein-losing enteropathy


 Significant weight loss associated with shorter survival
 Can result from neurologic dysfunction, GI dysfunction, alterations in taste, depression

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)

Screening: classification of healthy (asymptomatic) individuals who


probably have a disease from those who probably do not. (vs.
diagnostic test: already have signs & symptoms; surveillance: follow-
up in those already diagnosed)
 Sensitivity: correctly determine patients with the disease;
specificity: correctly identify pts without the disease
 Type I error: false positive; Type II error: false negative
 Validity (accuracy): identification of correct results,
Reliability (precision): reproducibility of results
 Positive predictive value: likelihood that an individual has a
disease if test comes back positive. Depends on prevalence
and specificity

Study types & designs from cancer screening:


 Randomized clinical trial is gold standard (esp. double-blind
& matched experimental / control groups) but expensive &
difficult
 Cohort study: good for more common conditions; groups
unified by a characteristic & entered into study before
appearance of disease in question; control from general
population
 Case-control: compare pts with disease to group of healthy patients; less expensive & difficult (but not as good)
 Cross-sectional study: observing a subset of population at a specific time

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.

Biases in cancer screening trials


 Volunteer bias: people who volunteer can be different from general pop (those who choose screening = better
health behaviors: screening looks beneficial, or poorer risk profiles so more worried: screening looks worse)
 Lead time bias:
o Lead time: period between early detection of disease from screening program & normal detection time
o Screening catches disease earlier, so survival appears longer even if it’s not: need to correct for lead
time using natural history information & compare age-specific mortality rates instead of 5yr survivals
 Length bias:
o DPCP = detectable pre-clinical phase
o Screening can catch more cases with longer DPCP which can be less aggressive disease
o Better prognosis, so screening appears too beneficial
o Affects case-fatality rate (CFR)
 Over-diagnosis bias:
o Diagnose cases with screening that would normally be undetected in normal lifetime (would not
progress / regress over time)
b. Can cause extra psychological stress, unneeded interventions / treatments

Where should we focus our resources?


 Non-aggressive cancers
 More prevalent cancers
 Effective current treatments

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)

Example: PSA & prostate cancer. Multiple studies:


 no difference in mortality in US study but maybe the PSA cut-off was too high, PSA screening was common in
control group, improvements in Tx masked difference, longer-follow-up needed?
 European study showed some benefit: maybe better control because PSA screening isn’t as common?
Breast Cancer Symposium
Breast cancer: 15% of cancer-related deaths; most common Dx & second most common cause of cancer death in women
1:100 Male:Female; 1 in 50 women by age 50 (1:8 lifetime)

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)

o Progestins, estrogens, androgens are bad


o Note: pre-menopausal women have ovarian estrogen as primary source, so ovarian ablation is good
therapy. Post-menopausal women have androgens as primary source of e, so aromatase inhibitors are
indicated.
 Growth-factor-receptor targeted (trastuzumab & lapatinib)
o trastuzumab
 For HER-2 positive tumors (15-20%)
 Blocks the mutated, constitutive activation of epidermal growth factor receptor on tumor cells
 Cytotoxic & inhibitory (host immune response, promotes other chemotherapies, etc.)
o lapatinib
 small molecule inhibitor; prevents phosphorylation of HER-2 and EGFR receptors & blocks
signaling in that way
 Anti-angiogenesis (bevacizumab)
o Targets VEGF (vascular endothelial growth factor)

Treating metastatic breast cancer (Stage IV)


 Want to relieve / prevent symptoms from tumor (usually can’t cure)
 Chronic therapy – balance side effects of disease & therapy
 Common sites: lung, liver, bone, soft tissue

Treating locally advanced breast cancer (Stage III)


 Note: swelling of nipple (lymph blocked), peau d’orange (like skin of orange)
 Want to control local disease & eradicate micrometasteses
 Surgery, radiation, chemotherapy – want to be aggressive (eg neoadjuvant therapy - shrink & then surgery)

Treating early breast cancer (Stage I & II)


 Eradicate micrometastatic disease
 Give drugs around time of surgery
 Need effective drugs & high risk population
 Intent: cure (tolerate toxicity because you can beat it)

ER (-) pts don’t’ usually benefit from endocrine therapy


Post-menopausal patients with ER (+) usually don’t give chemo (less aggressive dz; may not respond as well)
Adjuvant chemotherapy: important to keep to dose schedule; short duration (months)
Adjuvant endocrine therapy: need steroid receptor (+) patients; long duration of therapy (years)

Toxicities of adjuvant therapy:


 Acute: nausea, vomiting, hair loss, bone marrow suppression, weight gain, mucositis, fatigue
 Chronic: ovarian failure, late end organ damage, second malignancy, cognitive dysfunction (“chemo brain”)
Radiobiology as applied to the clinic

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

 Indirect action on DNA:


o Tissues are mostly water, so electron hits usually hits water and generates a hydroxyl radical
o Hydroxyl radical leads to base damage, breakage of phosphodiester backbone
 Direct action on DNA also possible: hits DNA, protein, etc. directly (less frequent)

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

Cell survival curves:


 Low doses: less radiation; unlikely to get DSB (two breaks near each
other in time and space). Lethal events caused by single hit (varies
with Dose=D)
 High doses: more likely to get DSB; two events will interact (varies
with Dose2 = D2)
 Curve can therefore be defined by “linear-quadratic formula”.

Four “R’s” of Radiobiology


Most clinical radiation is delivered in a fractionated scheme where total dose is delivered in many small doses instead of
several large doses: why?
Early experiment: try to sterilize a French goat. Big doses hurt the scrotum; smaller doses achieve same sterilization but
without all the agony.

1. Sublethal damage Repair:


a. Increase in cell survival if you split a dose into two fractions with a time interval (the normal cells can
repair themselves)
b. Tumor cells repair less well, with less fidelity (part of why they become tumors in the first place) but still
repair themselves somewhat.
2. Reassortment
a. Cells redistribute into radiosensitive phases of the cell cycle after DNA-damaging events (e.g. G2/M
checkpoint – highly radiosensitive & also arrest checkpoint)
b. If you hit cells with more radiation after they redistribute, they’ll mostly be at the G2/M checkpoint and
will be more vulnerable (killing increases).
3. Repopulation
a. Cells can divide after doses of radiation, increasing
their apparent survival (tumor & normal)
b. See graph on right: first three R’s
i. Survival increases if you deliver the first
dose after a little break (repair)
ii. Then survival decreases if you wait until
reassortment happens
iii. “Survival” increases if you wait until later
(repopulated)
4. Reoxygenation
a. Cells that are hypoxic at time of radiation become
oxygenated afterwards
b. Oxygen is required to make DNA damage permanent
c. Some solid tumors have hypoxic/anoxic areas in the center (farther away from vasculature; tumor cells
are using increased amounts of oxygen)
d. As you hit the cells with radiation, the oxygenated outer cells die & tumor shrinks, allowing oxygenation
of formerly hypoxic cells (ready to be killed with next round)

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.

Why is exposure to radiation different in tumors vs. normal tissue?


 Early-responding tissue: tumor or normal tissue that when irradiated shows reactions early during the course of
treatment (e.g. skin, mucosa)
 Late-responding tissue: normal tissue where proliferative
rate is low (peripheral nerves, spinal cord)

For early-responding tissue, there’s a beginning of repopulation early


on in treatment. If your time of treatment is lengthy, you would
theoretically have to increase the dose to get the same effect. For
late-responding tissues, that point is much later.

So longer treatment time spares some of the early-responding


tissue (skin, tumor) but has no significant difference in late-
responding tissue (brain spinal cord).

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).

At higher doses per day, though, effect on late-responding tissues is


proportionally greater, since it has a more curved dose-response curve
(hurts therapeutic index).

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.

A few new radiation treatment designs:


 Hyperfractionation: use twice the number of fractions & same
amount of time).
o Dose per fraction decreased; total dose increased to give same overall tumor killing.
o Decreases side effects in late-responding normal tissue (not to increase tumor killing significantly)
 Accelerated treatment: get the treatment time done ASAP (avoid repopulation in tumor)
o Increased killing of early-responding tissue but also more side effects in early-responding normal tissue
o Study: use accelerated in pts with high doubling times for tumors: showed much better amount of local
control for pts with fast-dividing tumors
 Trade-off: decreased late side effects (hyperfractionation) vs. increased tumor control with increased acute side
effects (accelerated)