TREATMENT fTREATMENT ofEXPOSED PATIENTSEXPOSED PATIENTS

JACQUELINE WILLIAMS, Ph.D.,WILLIAM DICKERSON, M.D.

jackie williams@urmc.rochester.edujackie_williams@urmc.rochester.edudickersonwe@gmail.comASTRO September 2008

Disclosure Information

Opinions presented are those of the authors. Any “off-label” use of medications is at the discretion of a licensed medical provider.

Any use of trade or brand names is for illustration purposes only and does not imply endorsement by the authors (or the Department of Defense)the authors (or the Department of Defense).

This lecture does not constitute official policy of the United States Department of Defense.

2

ObjectivesObjectives

After this session, attendees should be able to:

• Describe the diagnosis and treatment of the Acute Radiation Syndrome (ARS)the Acute Radiation Syndrome (ARS)

• Understand the differences in diagnosis and treatment following external andand treatment following external and internal contamination

• Identify possible late effects and explainIdentify possible late effects and explain appropriate medical follow-up.

3

TopicsTopicsAcute Radiation Syndrome (ARS)y ( )• Definition and diagnosis• TreatmentTreatment

External and Internal ContaminationExternal and Internal Contamination• Definition and diagnosis• Treatment• Treatment

Examples Follow Up Care Research AreasExamples, Follow-Up Care, Research Areas

4

Acute Radiation SyndromeMedical Effects of Ionizing RadiationMedical Effects of Ionizing Radiation

Acute Radiation Syndrome

A combination of clinical signs andsymptoms occurring in stages over aperiod of hours to weeks due to asignificant partial body or wholeg ybody exposure of >1 Gy (100 cGy), asinjury to various tissues and organs isj y gexpressed

5

What Happens After WBI?What Happens After WBI?

What is the most fundamental event following irradiation?

CELL DEATH

As dose increases, which cells are most susceptible?

CELL DEATH

DIVIDING CELLS

Which dividing cells are most radiosensitive?

STEM / PRECURSOR CELLSSTEM / PRECURSOR CELLS

6

Tolerance Doses (TD5/5 - TD50/5)Tolerance Doses (TD5/5 TD50/5)Single Dose (Gy)

Ovary 2 - 6 Kidney 10 - 20Bone marrow 2 - 10 Liver 15 - 20Eye (lens) 2 - 10 Skin 15 - 20Eye (lens) 2 - 10 Skin 15 - 20Testes 2 - 10 Spinal cord 15 - 20Lymphoid 2 - 20 Peripheral nerve 15 - 20Gastrointestinal 5 - 10 Brain 15 - 25Mucosa 5 - 20 Heart 18 - 20Lung 7 10 Bone and cartilage >30Lung 7 - 10 Bone and cartilage >30Colorectal 10 - 20 Muscle >70

Microvasculature (endothelial cells) / epithelial cellsMicrovasculature (endothelial cells) / epithelial cells

J.M. Vaeth: Clinical Radiation Pathology, 1988. 7

The Human Lethal Dose - LD50/60The Human Lethal Dose LD50/60

100 • No medical intervention

80

100 • No medical intervention• Homogenous & total• 60 days - expression of

ff h i i

lity

in %

60

effects on hematopoiesis

Note: surviving to 60 days

Mor

tal

40

g ydoes not ensure long-termsurvival

0

20

Sources:• Japanese atomic bomb

Dose (Gy)0 2 4 6 8

0 Japanese atomic bomb• Accidents (e.g. Chernobyl)• Therapeutic exposures

LD50/60 Estimates (DS86): Atomic BombSource City # persons

(deaths)Source of

sampleLD50/60(Gy)

Comments

RERF Hiroshima 7593 Master sample 2 7 3 1 LD / based onRERF Survey

Hiroshima 7593(1095)

Master sample 2.7 -- 3.1 LD50/60 based on linear fit, excluding first day deaths

Special Hiroshima 53 Female students, Shi t k hi h

4.0 Dose estimates b dsurvey (27) Shintoku high

schoolbased on chromosomal aberrations in survivors

Hiroshima University survey

Hiroshima 1216(201)

Persons located 600-1300m from hypocenter

2.44 Survey by RINMB and city authorities

Oak Ridge-Dikewood Nuclear Def Agy

Nagasaki 97(79)

Young adult occupants of Chinzei and Shiroyama Schs

2.9 Extension of study for Nuclear Defense Agency

Def AgyTOTALS 8959

(1402)3.1

Considerations - LD50/60Sources:Sources:•• Japanese atomic bombJapanese atomic bomb

Additional injuries from the bombAdditional injuries from the bombAdditional injuries from the bombAdditional injuries from the bombTyphoon (typhoid fever)Typhoon (typhoid fever)Disturbed environmentDisturbed environmentPoor nutritionPoor nutritionUnderUnder--representation of middlerepresentation of middle--aged menaged menDosimetry (also accidents)Dosimetry (also accidents)

•• Therapeutic exposuresTherapeutic exposuresP h lth liP h lth liPoor health + malignancyPoor health + malignancy

•• Other factorsOther factorsAge gender medical care (supportive)Age gender medical care (supportive)Age, gender, medical care (supportive)Age, gender, medical care (supportive)

10

Best Estimates - LD 0/60Best Estimates - LD50/60

LD50/60

Acute TBI, no medical support = 2.5-3.5 Gy

Acute TBI + supportive care = 4.5 Gy

Acute TBI + supportive care + CSFs = 6-8 Gy

A t TBI + BMT 8 10 GAcute TBI + BMT = 8-10 Gy

11

Whole Body Irradiation (WBI)Whole Body Irradiation (WBI)io

nur

e

Latentperiod

Prodromalphase

Manifestillness

Recoveryor death

Rad

iati

Expo

su

Time

time of onset dosetime of onsetseverityduration

dosedose rate

quality12

Prodromal PhaseGastrointestinal• Anorexia

Neuromuscular• Easy fatigability

• Nausea• Vomiting

Easy fatigability• Apathy or

listlessnessg• Diarrhea• Intestinal cramps

listlessness• SweatingIntestinal cramps

• Salivation• Fluid loss

• Fever• HeadacheFluid loss

• Dehydration• Weight loss

• HypotensionWeight loss

13

Prodromal PhaseGastrointestinal• Anorexia

Neuromuscular• Easy fatigability

• Nausea• Vomiting

Easy fatigability• Apathy or

listlessnessg• Diarrhea• Intestinal cramps

listlessness• SweatingIntestinal cramps

• Salivation• Fluid loss

• Fever• HeadacheFluid loss

• Dehydration• Weight loss

• HypotensionWeight loss

50% lethal dose50% lethal dose14

Prodromal PhaseGastrointestinal• Anorexia

Neuromuscular• Easy fatigability

• Nausea• Vomiting

Easy fatigability• Apathy or

listlessnessg• Immediate diarrhea• Intestinal cramps

listlessness• SweatingIntestinal cramps

• Salivation• Fluid loss

• Fever• HeadacheFluid loss

• Dehydration• Weight loss

• HypotensionWeight loss

Supralethal doseSupralethal dose15

Prodromal Phase

Nausea, vomiting

Time of onset

Duration Lymphocyte count

CNS function

0 - 1 Gy None Minimally affected

No impairment

1- 2 Gy 5 - 50% 3 - 6 hr <24 hr Minimally No decreased impairment

2- 6 Gy 50 - 100% 2 - 4 hr <24 hr <1000 at 24 hr

Impairment for 6 - 20 hr

6 - 8 Gy 75 - 100% 1 - 2 hr <48 hr <500 at 24 hr

Impairment for >24 hr

10 30 90 100% <1 hr <48 hr Decreases Rapid10 - 30 Gy

90 - 100% <1 hr <48 hr Decreases in hrs

Rapid incapacitation

>30 Gy 100% Minutes N/A Decreases i h

Rapid i it tiin hrs incapacitation

Adapted from Burnham and Franco: Crit Care Clin, 2005.

Prodromal Phase

Nausea, vomiting

Time of onset

Duration Lymphocyte count

CNS function

0 - 1 Gy None Minimally affected

No impairment

1- 2 Gy 5 - 50% 3 - 6 hr <24 hr Minimally No impairmentdecreased

2- 6 Gy 50 - 100% 2 - 4 hr <24 hr <1000 at 24 hr

Impairment for 6 - 20 hr

6 - 8 Gy 75 - 100% 1 - 2 hr <48 hr <500 at 24 hr

Impairment for >24 hr

10 30 90 100% <1 hr <48 hr Decreases Rapid10 - 30 Gy

90 - 100% <1 hr <48 hr Decreases in hrs

Rapid incapacitation

>30 Gy 100% Minutes N/A Decreases i h

Rapid i it tiin hrs incapacitation

Adapted from Burnham and Franco: Crit Care Clin, 2005.

Prodromal Phase

Nausea, vomiting

Time of onset

Duration Lymphocyte count

CNS function

0 - 1 Gy None Minimally affected

No impairment

1- 2 Gy 5 - 50% 3 - 6 hr <24 hr Minimally No impairmentdecreased

2- 6 Gy 50 - 100% 2 - 4 hr <24 hr <1000 at 24 hr

Impairment for 6 - 20 hr

6 - 8 Gy 75 - 100% 1 - 2 hr <48 hr <500 at 24 hr

Impairment for >24 hr

10 30 90 100% <1 hr <48 hr Decreases Rapid10 - 30 Gy

90 - 100% <1 hr <48 hr Decreases in hrs

Rapid incapacitation

>30 Gy 100% Minutes N/A Decreases i h

Rapid i it tiin hrs incapacitation

Adapted from Burnham and Franco: Crit Care Clin, 2005.

Onset of Vomiting

19AFRRI

Whole Body Irradiation (WBI)io

nur

e

Latentperiod

Prodromalphase

Manifestillness

Recoveryor death

Rad

iati

Expo

su

Time

20

Latent Phase of Acute Radiation Syndrome (ARS)

Degree of ARS and approximate dose of acute WBE (Gy)Mild

(1–2 Gy)Moderate(2–4 Gy)

Severe(4–6 Gy)

Very Severe(6–8 Gy)

Lethal(>8 Gy)

L tLatency period (d) 21–35 18–28 8–18 7 or less None

Lymphocytes (G/L) 0.8–1.5 0.5–0.8 0.3–0.5 0.1–0.3 0.0–0.1(days 3–6)Granulocytes (G/L) >2.0 1.5–2.0 1.0–1.5 ≤ 0.5 ≤ 0.1

A ADiarrhea None None Rare Appears on days 6–9

Appears on days 4–5

Epilation NoneModerate,

beginning on Moderate or complete on

Complete earlier than

Complete earlier than p g g

day 15 or laterp

days 11–21 day 11 day 10

Medical response

Hospitalization not necessary

Hospitalization recommended

Hospitalization necessary

Hospitalization urgently

necessary

Symptomatic treatment

onlynecessary only

Adapted from IAEA: Diagnosis and treatment of radiation injuries; 1998.

Whole Body Irradiation (WBI)io

nur

e

Latentperiod

Prodromalphase

Manifestillness

Recoveryor death

Rad

iati

Expo

su

Time

22

Acute Radiation Syndromes (ARS)

• Hematopoietic• Gastrointestinal• Gastrointestinal • Multiple organ failure• Cardiovascular/CNS

23

Hematopoietic Syndrome

Critical cells: Hematopoietic precursorll

Dose: 1-5 GyH k t lit t 30 d

cells

Humans: peak mortality at 30 days, to 60 days

LD 2 5 3 5 GLD50/60: 2.5 - 3.5 GySymptoms:y pProdromal phase: nausea, vomiting,

anorexia, malaise, possible pdiarrhea (onset 3-16 hours)

24

Human 4.5 Gy15

10

3.1

4.4

5 6Lymphocytes

5.6

7.75

00 10 20 30 40 50

Time (days)Andrews et al., 1967.

Goans et al., 2005.

26

Human 4.5 Gy15

1 week = granulocytopenia

Granulocytesabortive rise

10

abortive rise

5

00 10 20 30 40 50

Time (days)Andrews et al., 1967.

15 Human 4.5 Gy

DeathDeath

2 weeks = thrombocytopenia

10300

DeathDeath

PlateletsPlatelets

200

Haemoglobin

5

100

00 10 20 30 40 50

Time (days)Andrews et al., 1967.

Hematopoietic SyndromeSymptoms:ARS: chills, fatigue, petechial (3 weeks) hemorrhages in skin,

ulceration of mouth,epilation (2 weeks >3 Gy)bone marrow atrophy, infections, fever, bleeding, anemia

Death: infection important causeChernobyl: 134 personnel >1 Gy; 37 -

severe bone marrow failure; 28 died in first 4 months 29

GI Syndrome

Critical cells: Epithelial lining of the g.i.tract

30

GI Syndrome

0 Gy0 Gy

10 Gy

14 Gy

Courtesy Hauer-Jensen. 31

GI Syndrome

Critical cells: Epithelial lining of the g.i.

Dose: ≥6 Gytract

ySymptoms:Prodromal phase: nausea and vomitingProdromal phase: nausea and vomiting,

prolonged (watery) diarrhea(onset 1-4 hours)(onset 1 4 hours)

Latent phase: malaise, weaknessARS: severe vomiting diarrheaARS: severe vomiting, diarrhea

(bloody) + fever, shock, death32

CV/CNS SyndromeDose: >20 GySymptoms: severe nausea and vomitingSymptoms: severe nausea and vomiting

disorientationloss of coordinationloss of coordinationrespiratory distressdiarrheadiarrheaconvulsive seizurescomacoma

Cause of death: ?

33

CV/CNS SyndromeDose: >20 GySymptoms: severe nausea and vomitingSymptoms: severe nausea and vomiting

disorientationloss of coordinationloss of coordinationrespiratory distressdiarrheadiarrheaconvulsive seizurescomacoma

Cause of death: increased brain fluid content d t ll l l kdue to small vessel leakage

34

Cutaneous Syndrome

• Erythema (skin reddening) occurs hours to days depending on dosey p g

• Duration of 1-2 days• Body locationy• Target cells reside in epidermis, dermis,

hair follicles, subcutaneous tissues,

• Symptoms: pruritus, blisters, hair loss, y p pmoist desquamation, ulceration

• Epilation: 10-20 days after >3-4 Gyp y y

35

Cutaneous Syndrome• Acute erythema can occur 1-2 days after 2-6 Gy• Erythema and epilation can occur 2-3 weeks after 5 - 10

GyGy• Desquamation can occur 2-3 weeks after 15 - 20 Gy• Re-epithelialization takes place after 6 - 8 weeksp p

Erythema Moist desquamationy

Courtesy W. McBride/Boreham.

Epilation

Combined Injury

Biomedical consequences of radiation exposure are exacerbated by trauma and/orexposure are exacerbated by trauma and/or disease, including burns and wounds.

Radiation + burn: 820

9799

95Radiation: LD50/30 - 963

Radiation + burn: 820

Radiation + wound: 761

90

70

50

erce

nt s

urvi

val

5

30

10

3

Pe

1500 700 900 1000

60Co Dose (cGy)Modified from Pellmar & Ledney, 2005.

Dosimetry (State of the Science)

BIOLOGICALDOSIMETRY

PHYSICALDOSIMETRY

CLINICALDOSIMETRY

DOSE SYMPTOMSDOSERECONSTRUCTION

Biophysics

SYMPTOMSType

Time of onset

OTHEROTHERBIOINDICATORS

Cytology,protein changes,

CYTOGENETICSDicentrics

PERIPHERALBLOOD

Lymphocyte novel biomarkers

EPR

y p ydepletion

38

TopicsTopicsAcute Radiation Syndrome (ARS)y ( )• Definition and diagnosis• TreatmentTreatment

External and Internal ContaminationExternal and Internal Contamination• Definition and diagnosis• Treatment• Treatment

Examples Follow Up Care and ResearchExamples, Follow-Up Care and Research

39

ARS - When Treatment is Too ARS - When Treatment is Too LateLate

HiroshimaHiroshimaARS VictimARS Victim

(~Day 20)(~Day 20)

40

Causes of death: Infection and bleedingPhoto: DOE, National Archives

First Action for Responders/First Action for Responders/Receivers – the ABCs

• Universal Precautions: Protect yourself with scrubs mask gloveswith scrubs, mask, gloves

• Standard medical emergency procedures

– Airway/ Breathing/ Circulation

• Decontaminate AFTER stabilized• Decontaminate AFTER stabilized

• Radiation injury NOT acutely life threatening

41AFRRI

ARS Treatment

• Supportive care

• Specific therapyy

42

Supportive Care

• Clean environment

• IV fluids, antiemetics, anti-di h ldiarrheals

P i di ti• Pain medication

43AFRRI

More on Supportive Care• Antiemetics

More on Supportive CareAntiemetics– KytrilTM (granisetron) and ZofranTM

(odansetron) Need should abate(odansetron). Need should abate within 48 hours

• Antidiarrheals– e.g. ImodiumTM (Ioperamide)

• Replace fluids, electrolytes, blood products and plateletsproducts, and platelets

44

ARS TreatmentARS TreatmentSpecific Therapyp py

A ti i bi l f t i f• Antimicrobials for neutropenic feverAnti-bacterial, anti-viral, anti-fungal

• Granulocyte Colony Stimulating FactorGranulocyte Colony Stimulating Factor

45

Antibiotics - Initial Management

Hughes WT. 2002 Guidelines for the Use of AntimicrobialAgents in Neutropenic Patients with Cancer Clin Infect Dis. 34:730-51, 2002. 46

Justification for Use of Colony Stimulating Factors (CSF) in

Radiation-Induced Neutropeniap

1. Oncology data with chemotherapy-Enhanced neutrophil recovery by 3-6 days

2. Pre-clinical animal data-Enhanced neutrophil recovery of radiationi d d t iinduced neutropenia

-Enhanced survival with early initiation

47

AFRRI / “Recommendations of the Strategic National Stockpile Radiation WorkingGroup”, Ann Intern Med 140: 1037-51, 2004.

Benefit of Supportive Care and G-CSF

LD 50/30 =260 cGy

LD 50/30 =260 cGy 338 cGy

LD 50/30 =LD 50/30 =488 cGy

MacVittie TJ, Health Phys, 2005. 48

FDA-Approved CSFsOnly 3 approved in USA for reducing neutropenia. None currently approved for radiation-induced neutropenia. y pp p

1. Granulocyte-colony stimulating factor, G-CSF, or filgrastim (Neupogen®)g ast ( eupoge )

2. Pegylated granulocyte-colony stimulating factor,PEG-G-CSF or pegfilgrastim (Neulasta®)PEG G CSF, or pegfilgrastim (Neulasta )

3. Granulocyte-macrophage-colony stimulating factor,GM CSF or sargramostim (Leukine®)GM-CSF, or sargramostim (Leukine®)

G-CSF is part of the US Strategic National Stockpile

49AFRRI

Granulocyte Colony Sti l ti F t (G CSF)Stimulating Factor (G-CSF)

• ASCO GUIDELINES* Includes• ASCO GUIDELINES*- Includes management of patients exposed to lethal doses of total body radiotherapy but notdoses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the j y g ,prompt administration of G-CSF or pegylated G-CSF

ASCO 2006 50

CSF Therapy for ARS

Cytokine Adults Pediatrics Pregnancy Precautions

G CSF or 5 µg/kg per 5 µg/kg per day Category C Sickle cell diseaseG-CSF orFilgrastim(Neupogen®)

5 µg/kg per day SQ injection started as early as

5 µg/kg per day SQ injection started as early as possible **

Category C Sickle cell disease,significant CAD,ARDS.

early as possible** Adverse reaction: bone

pain

C id di ti ti

Pegylated G-CSF or

6 mg SQ x 1 dose

For adolescents >45 kg: Give 6

Category C

Consider discontinuation if pulmonary infiltrates develop at neutrophil recovery

Pegfilgrastim(Neulasta®)

mg SQ x 1 dose

GM-CSF or 250 µg/m2 SQ 250 µg/m2 SQ Category C

**continued until ANC >1,000

Sargramostim(Leukine®)

per day started as early as possible**

per day started as early as possible**

AFRRI / “Recommendations of the Strategic National Stockpile Radiation Working Group”, Ann Intern Med 140: 1037-51, 2004. 51

Combined Effects of Whole Body Irradiation and Burns in Various

Animal ModelsCombined Injury

Animal Models

Model Injury Lethality20% Burn 12%Ref: AFRRI

SyndromeDog 100 cGy 0

Combined 73%10 15% B 0

Ref: AFRRI

Pig10-15% Burn 0

400 cGy 20%Combined 90%%

Rat31-35% Burn 50%

250 cGy 0Combined 95%

Guinea

1.5% Burn 9%250 cGy 11%Guinea

Pig250 cGy 11%

Combined 38%52

Combined Injury Patient Triage is Based on Traditional Triage MethodsBased on Traditional Triage Methods

Physical Expected changes in triage categories Physical injury without

irradiation

p g g gafter whole-body irradiation

<1.5 Gy 1.5~4.5 Gy 4.5~10 Gy5 Gy 5 5 Gy 5 0 Gy

Uninjured Ambulatory monitoring

Ambulatory monitoring, routine care and delayed

h it li timonitoring hospitalizationMinimal MinimalDelayed Delayed VariableDelayed Delayed

Immediate Immediate ExpectantExpectant

Variable

After: Ann Intern Med 2004;140:1037-1051Expectant

53

AFRRI / Recommendations of the Strategic National Stockpile Radiation Working Group, Ann Intern Med 140: 1037-51, 2004.

ARS TreatmentModerate Dose Exposure*Moderate-Dose Exposure

SyndromeEstimated Radiation Treatment

P iSyndrome RadiationDose (Gy) Summary

Fluids,

Prognosis

Excellent, Hematopoietic

syndrome(only)

1 - 4

,antimicrobials,

may require cytokines

continue therapy for 3-4 weeks

Hematopoietic (and GI?)

d4 - 7 Early cytokine Tx,

fluids, GI nutrition, Good with aggressive Tx,

syndromes, ,

antimicrobials, avoid infection

will require at least 4-5 weeks’ inpatient care

*Radiation injury only, no complicating trauma or chemical/biological weapons

54Modified from AFRRI

ARS TreatmentModerate Dose Exposure*Moderate-Dose Exposure

SyndromeEstimated Radiation Treatment Prognosisy

Severe

RadiationDose (Gy) Summary

Fluids,

Prognosis

Some survival with aggressiveSevere

Hematopoietic with GI

syndrome7 - 10

,symptomatic Tx,

cytokines, antimicrobials.

with aggressive Tx; will require weeks of inpatient Tx with

Hematopoietic GI and

Stem cell transplant?

inpatient Tx with barrier protection

GI and Cerebro-vascular

syndromes10 - 30

Aggressive treatment versus palliative care

Near 100% mortality

*Radiation injury only, no complicating trauma or chemical/biological weapons

55Modified from AFRRI