The Translation of Biodosimetry: Animal Models and Human Absorbed Dose Brian R. Moyer Sr. Science...

The Translation of Biodosimetry:Animal Models and Human Absorbed

Dose

Brian R. MoyerSr. Science Advisor, Contractor, HHS/BARDA

[email protected]

mailto:[email protected]

ASPR: Resilient People. Healthy Communities. A Nation Prepared.

Radiation Can and Will Impact All of Us and the Dose MattersAccidents - Environment Contamination – Medical Procedures – Radon

• Guarapari Beach, Brazil, has an extremely high level of background radiation in the sand

• readings of 175 mSv per year (20μSv/h)• Radon exposures in air and water in New England:

• Water upper limit of 4 pCi/L (Air limit: per cubic meter)• lung cancer risk at >4.0 pCi/L - 7 cancer deaths per 1000 persons• A picocurie is one-trillionth of a Curie; diagnostic lung scan = 20 mCi• Acute versus chronic lifetime (aka. fractionated?) doses

Normal Environment:

Fukushima Chernobyl


Estimating the Absorbed Dose What are the Permutations?

In a nuclear/IND event we will have a single finite fluence from the epicenter with added dose from fallout and beta exposures (internal oral/inhalation and skin) • The exposures will be complicated by:

• Variable absorbed doses due to fluence, distance, shielding, and genetics• Exposure will be assumed to be unilateral• There may be a partial shielding effects from the environment





• Animal Models “normalize” to “constant” conditions:• We use uniform sources and exposure fields• We do 5% bone marrow shielding to benefit survival responses• We “harmonize” our groups to minimize their differences• All of these are “out the window” for the IND “event” re. people





• Animal Models “normalize” to “constant” conditions:• We use uniform sources and exposure fields• We do 5% bone marrow shielding to benefit survival responses• We “harmonize” our groups to minimize their differences• All of these are “out the window” for the IND “event” re. people

• Non-Clinical Assumptions of the IND problem: • Energy fluence is of low LET; High LET radiation is assumed to be absent • We test efficacy at the high LDx under minimal supportive care

• 260,000 may be “exposed” – a fraction of these are in the high LD range• Testing is done under “Worst-case” evaluations of an MCM

• Desired survival response: >30% for a MCM under minimal supportive care• This is a compromise of statistical power and animal use


What are the CONOPs Assumptions?What is important and what can we ignore?

• In the event of an IND detonation we will act on the following:

• For a 10KT - Modeling predicts 260,000 “prompt” exposed individuals

• First order distribution of dose with distance but increasing population from the epicenter

• A fraction are burn and blast trauma (combined injury) • The detonation has resource “rings” of “Expectant”, “Immediate” and

“Minimal”• Without high throughput screening, dosimetry may be limited to geography –

>24 hrs for lymphocyte depletion


What are the CONOPs Assumptions?What is important and what can we ignore?

The focus of the CONOPs will be delivery of medicine and allocation of medical support• infrastructure loss and destruction• 10 KT event:

• Outermost region of >4 Km will have low prompt exposures (possible fallout) – “worried well” – “Minimal” Exposure range

• Risk: Likely to insist received “exposure” and will demand medications • Mid region 4 Km 1.5 Km: will have midrange doses with onset of infrastructure loss• The model of 260,000 victims begins in this region – “Immediate” range• Proximate to epicenter ( to 1 Km): “Expectant” range, burn/trauma (pink region below)

Expectant Minimal range


Why Does Radiation have a Heterogeneous Outcome in Tissues?

• Dose Distribution is Not Uniform• Can’t deliver a homogeneous dose across a heterogeneous density• Tumor Rx: Can’t give enough radiation to kill every tumor stem cell

without intolerable damage to normal tissue• Must use fractionation, or,• Tumor sensitization (chemotherapeutics), or, • normal tissue protection (shielding)

• Genetics plays a large role in radiation resistance• and may affect tumor sensitization

• Tissue and Tumor Physiology Matters• Hypoxic cells are relatively resistant to radiation• Poor perfusion (i.e. center of tumors) may affect radiation effects• May need fractionation with radiation sensitizers (mesonidazole, others)• Mitotically stable vs active regenerations = sensitive

• Rapidity of tumor cell growth – use accelerated fractionation; tumor sensitization]


Animal Model Dosimetry and the Human Correlate

•We set the study limits (assumptions) using three likely inconsistent points to study efficacy of MCMs off an IND event. We assume:• 1) uniformity of dose and dose distribution; • 2) a single high lethal dose, and,• 3) uniformity of the host injury responses over time (by the population)

NONE OF THESE WILL BE COMPLETELY TRUE

Animal Models assume these 3 points in order to “do the science”

In the Human Case we have a problem: We cannot study lethal radiation exposure

We must rely on the Animal Rule to extrapolate MCM Efficacy and Biomarkers

Testable human radiation exposure is limited to cancer therapies and skin therapies• Human exposure is:

• Generally targeted exposures (lung, prostate, abdomen, brain, etc) - not total body • Fractionated doses (lower doses given over defined time and schedule)• IR is given with other compromising agents with coincident toxicities and often similar

biomarker expressions• Designed targeting for minimal exposures to “normal” surrounding tissues• Biomarker expressions are “noisy” due to genetic diversity of subjects


Animal Models: Institutional Lethality Profile and Dose Confidence

Models to Mimic the IND Scenario

The Probit Plot provides a working dose range confidence limit for the ~LD20 to ~LD80)

•In general, animal models use a single TBI dose (or two bilateral exposures) over a set time at a set dose selected off the lethality profile standard curve (the Institutional Lethality Profile; ILP; PROBIT plot)

• The ILP has an inherent “noise” in dose assignment of about 10-15%

• Noise increases out from the LD50 value

•The inherent “noise” of Animal Models is reduced through:•Selection of the LD50 as the most predictive lethality (LD30 and LD70 are “noisy” and LD90 and LD10 are not definable statistically. •Minimal supportive care (antibiotics and fluids), •Bone marrow shielding (0, 5% and up to 50% for GI models•Minimal or Full Supportive Care including blood products (based on CBC status)•Single sex studies


GOAL: “Biomarker expression” ≡ “Energy depot”

Dosimetry is an Absorbed Energy Translation

Energy Terms• Erg vs Joule delivered per gm or Kg• Erg = 1 x 10-7 joules = 100 nJ• Erg = 624.15 GeV = 6.2415×1011 eV

• N = Newton = 1 kg*m/s2

• Joule = 1 m*N = 1 kg*m2/s2

METHODS: • Calorimetry –

• transition of heat energy• i.e. TLDs (thermoluminescence)

• Fricke – • EPR change • i.e. alanine

• Ion Chamber – • Measures the charge (induced current)

resulting from ionization • needs corrections applied as in

AAPM Protocols (TG51, TG 61)

• Radiation sensitizers• Hypoxic cell sensitizers• Chemotherapeutic agents• Molecularly targeted therapies

• Radiation protectors• Free radical scavengers• Prevent cytokine induced damage through

anti-inflammatory Rx• Shifts in biomarker expression must be

quantifiable, Emax, EC50, etc.• GOAL: A “Rosetta Stone” “Biomarker expression ≡ Energy depot”

Chemical Modifiers used in Radiotherapy alter Biomarker Responses

Physical Change Measurements:


The Radiation Problem: Energy Heterogeneity and the Absorbed Fraction

Direct + Indirect

The Mars Mission as an “Integrated Dose”

Astronauts on a 3 year mission to Mars will likely accumulate a dose of 0.66 Sv (~0.66 Gy)The lifetime dose for an astronaut is 1 Sv (~1 Gy) This is however, a dose rate of 1 Gy over 3 years or ~900 µSv/day (~0.1 cGy/day)

High LET radiation is a problem in space but not necessarily for our IND scenarios

“Model” IND scenario assumptions: •no inhalation of radioactive isotopes, i,e., transuranics (alpha emitters; high LET)•Through-and-through photons (MeV)•Uniform field (solid angle away) •Standardized dose rate @ 60-100 cGy/min•Repair and repopulation are ON

The IND as an “Instantaneous Dose”


Energy Deposition is a Permutation – Combination Problem

The linear quadratic model is now most often used to describe the cell survival curve, assuming that there are two mechanisms to cell death by irradiation (IR):• single lethal event, slope D1; plus, • an accumulation of harmful but non-lethal events, slope D0

• D0 and D1 are shown as alpha and a beta contributions – the ratio depicts the IR content

Random energy fluence leads to single lethal “hits” (D1 slope; α) and multiple “hits” leading to lethality (D0 slope; β) and most photons simply pass through with limited impedance

β

α


How Can We Study Human Radiation Injury When it is So Rare?

Human cancer therapy is very different from TBI Animal Models:• 1) “fractionation” (total dose is administered as fractions over a time period)• 2) the irradiation is generally “local” (limited)

• TBI is done for blood cancers, but again, fractionated • 3) the combination of cytotoxic chemicals (esp., DNA acting agents) complicates

the adjudication of what was caused by radiation alone

• Fractionation: The Total Dose and Dose Spacing based upon cancer behavior

The Four “R”s of Radiotherapy : • 1: Repair of sub-lethal damage (earliest event)• 2. Redistribution of the cell cycle (more M and G1) in irradiated cells (recovery)• 3. Repopulation of the tumor mass (later event; ~spread of hypoxic cells) • 4. Reoxygenation (late effect; ↑pO2; ↑ neovascular, and ↑ blood flow)

• And a 5th “R” – “Radiosensitivity” (patient genetics)

Most important reason for radiation tumor therapy failure: Hypoxia Low oxygen leads to a decreased radiosensitivity to IR

Use the Clinical Experience - Extrapolate Fractionation Therapy in Animal Models BUT…..


The Four “R’s” Help Define Biomarker Appearance

When we irradiate in an animal model we set up a cascade of events in each tissue where a unique time line occurs for:

Repair (R1) Redistribution of the Cell Cycle (R2) Reoxygenation (R3) Repopulation (R4)

Biomarkers (BM) of Repair are generated in hours For human tumor cells, the characteristic repair half-time ranges from a few minutes to several hours.

BM of Reoxygenation (expansion of a tumor’s hypoxic core) occurs in hours to days,

BM of cell cycle Redistribution in hours to days

BM of Repopulation over several days/weeks

In Single Dose TBI we have a single starting point for Biomarker cascades to appear and decay

Fractionation sets a new schedule , T2, etc.• Each Tx has a new “zero” for each of the

“R’s” to begin anew• The timing of T1 T2 (etc) catches

“Repair”, and each of the other R’s, at some new intermediary activity Fractionation may lead to Biomarker

expressions, potentially a steady state


Single Dose (Single “Fraction” Vs Fractionation

• Small tumors not abutting critical structures can be treated with a single fraction (closer to animal models)

• Usually 10-20 Gy -- Concept is targetted ablation• Metastases to certain brain regions, lung regions, liver – others.

• Larger tumors or tumors that contain normal tissues are treated using fractionated approaches

• Concept is employ a narrow therapeutic index • Maximize tumor killing dose vs “acceptable” normal tissue kill • treatment causes at least slightly more tumor kill than normal tissue damage

• 20-40 treatments @ 1.8 to 2 Gy each, will multiply the effect • hits the “Repair and Repopulate” “R’s” by arresting Repair and genetic

Redistribution• Together they support minimizing the regrowth of the hypoxic tumor core

which in turn reduces tumor radiation resistance, and improves local tissue “R” - Reoxygenation

Why is Fractionation selected over single fraction?


Impact of Fractionation on Biomarker Expression

• Parallel organs • Examples: lung and liver- Damage to small fraction has no clinical

toxicity- Compensatory capacity- Clinical toxicity can occur when a threshold

injury level is passed for a fraction of the parallel organ

- Loss of compensatory capacity• Serial organs

• Example: esophagus and spinal cord- Damage to a small fraction produces toxicity as there is no allowance for compensation

• Kidney - 20 Gy in daily 2 Gy fractions• Liver - 30 Gy• Spinal cord - 46 Gy• Parenchyma / vasculature of the organ

• Vasculature of each tissue may be different as well as the anatomy leading to and away from an organ

• Brain – radioresistant, esp. Glioblastoma

Radiation tolerance is organ dependent:Normal Tissue Responses:

Radiosensitive Adult Body Cells and Tissues :• Lymphoid tissue, particularly lymphocytes (most radiosensitive) • Immature blood cells found in bone marrow • Cells lining gastro-intestinal canal • Cells of the gonads-testes more sensitive than ovaries • Skin, particularly the portion around hair follicles • Lining of blood vessels • Lining of liver and adrenal glands • Other tissues – incl. bone, muscle and nerves, (least radiosensitive)


Measuring Biomarkers in Animal Models for In-Vivo Human Absorbed Dose Correlates

• “Biomarker” is a term we loosely define as: “…a deviation of a measurable physiologic parameter from normal expression (baseline)

following a dose(s) of irradiation”• We already can name a few that indicate absorbed dose-dependency:

• γH2AX; Citrulline; IL-8; IL-6; INF-γ; stem cell markers (i.e. CD34, or the Lgr5-R which is enriched in crypts in GI syndrome), and many other markers

• Lymphocyte depletion; apoptosis markers; mitotic markers; • DNA Destructive markers (p53, p21, PARP1, others); • DNA protective markers (apoptosis suppression; PUMA deficiency; TLR-4/5/9 agonists/ NF-

κB)• Proportional energy change as EPR signal from teeth/bone

Many more…..• Now we have many new approaches – many involving array algorithms:

• Proteomic mapping: capable of spatial /temporal resolution of endogenous proteins

Genomics: altered gene expression represents a central component of radiation injury

Metabolomics: changes in metabolic fates as well as increases and decreases in normal metabolites

• Other non-conventional approaches include:• Imaging (PET/SPECT: blood flow, alterations in tracer kinetics, MR: apparent diffusion

coefficient (ADC) of water distribution, sodium-23; and thermography)• Many novel imaging tracers/contrasts/platforms to choose form and they may be

complimentary to define an outcome

Cautious Optimism that the Measures in Animals will Parallel Change in Humans


Considerations in Use of Imaging Biomarkers as Dosimetry Tools

From: Smith, JJ, Sorensen, AG and Thrall, JH, Opinion: Biomarkers in Imaging: Realizing Radiology’s Future Radiology 2003; 227:633–638


Imaging Changes with Fractionated Dosing Example: Quantifying in-vivo changes using PET and MRI

REF: Oborski, et al., Challenges and approaches to quantitative therapy response assessment in Glioblastoma Multiforme (GBM) using the novel apoptosis PET tracer F-18 ML-10, Translational Oncology 7(1): 111-119, 2014

Clinical Goal: Fractionated radiotherapy can induce an apoptotic response in human GBM• Theory: Apoptosis rate changes occur on a fast time scale post IR

• We can measure apoptosis in real time using imaging to rapidly assess the clinical value of a selected IR fractionated therapy

• PET and MR imaging together can provide a wide array of rapid reporting biomarkers

• Methods: • IR Injury: Brain tumors (GBM); fractionated IR therapy @200 cGy per day for 30 days

• plus an alkylating agent prodrug; temozolamide; @75 mg/m2 (caveat for interpretation)

• PET and MRI scanning: Baseline (BL) scan; ~1 - 2 weeks before therapy, followed by a therapy assessment (TA) scan at ~14 ± 3 days after therapy initiation

• Measure changes in sugar metabolism and blood/oxygen perfusion • PET: O-15, F-18 FDG, Rb-82; • MRI: T1, ADC and BOLD

• Apoptosis Imaging: dynamic imaging over a short period of time• F-18 ML-10 (a malonic acid tracer; 206 D for PET) and Tc-99m-Annexin V (for SPECT)

• Fractionated Tx changes the Pharmacodynamic modeling K1 (input function)

• MRI sodium (Na-23) images (a proliferation marker) quantify therapy-induced changes of intracellular sodium concentration (>60% of bound sodium is from the intracellular compartment; IR ↓ intracellualar Na)

• cell death (apoptosis) lowers the repopulation and lowers the Na-23 content

Representative BL (A and E) and TA (B and F) contrast-enhanced MRI as well as BL (C and G) and TA (D and H) F-18 ML-10 PET scans. In this study, assessment of response based on qualitative visual interpretation or even by a semi-quantitative index was ambiguous.

EXAMPLE 1: Imaging Biomarker Changes with Fractionated Dosing MRI images (anatomical) PET tracer apoptosis images

Conclusion: quantitative assessment was ambiguous - apoptotic gradient insufficient; MR volume assessments showed increases over the therapeutic period; therapy is not working

Baseline (BL) post therapy Baseline (BL) post therapy

Oborski, et al., Challenges and approaches……

Representative BL (A and E) and TA (B and F) contrast-enhanced MRI as well as BL (C and G) and TA (D and H) F-18 ML-10 PET scans. In this study, assessment of response based on qualitative visual interpretation or even by a semi-quantitative index was ambiguous.

EXAMPLE 1: Imaging Biomarker Changes with Fractionated Dosing MRI images (anatomical) PET tracer apoptosis images

Conclusion: quantitative assessment was ambiguous - apoptotic gradient insufficient; MR volume assessments showed increases over the therapeutic period; therapy is not working

Baseline (BL) post therapy Baseline (BL) post therapy


EXAMPLE 1 (con’t): Imaging GBM Biomarkers After Fractionated Dosing

Subject #4 was a POS Outcome: Same-day F-18 ML-10 PET and Na-23 MR scans at “Baseline” versus “Therapeutic day” from subject 4.

Contrast MRI at post therapy window: • decreased volume of tumorNeeds Correcting for geometry changes post-IR:

PET F-18 ML-10 uptake: • apoptosis imaging shows an increase in tracer

uptake

MRI Total Na image: • decrease in Na

MRI intracellular (bound) Na image: • a significant decrease (absence) of Na is evident

Findings: F-18 ML-10 (apoptosis) is observed to increase at the same location that intracellular sodium (proliferation marker) is seen to decrease ( WHITE arrow).

• These results show decreased proliferation at the same brain location as increased apoptosis

(also from Ref: Oborski, et. al.,Translational Oncology, 2014)



Subject #4 was a POS Outcome: Same-day F-18 ML-10 PET and Na-23 MR scans at “Baseline” versus “Therapeutic day” from subject 4.

Contrast MRI at post therapy window: • decreased volume of tumorNeeds Correcting for geometry changes post-IR:

PET F-18 ML-10 uptake: • apoptosis imaging shows an increase in tracer

uptake

MRI Total Na image: • decrease in Na

MRI intracellular (bound) Na image: • a significant decrease (absence) of Na is evident

Findings: F-18 ML-10 (apoptosis) is observed to increase at the same location that intracellular sodium (proliferation marker) is seen to decrease ( WHITE arrow).

• These results show decreased proliferation at the same brain location as increased apoptosis Conclusion: Fractionated therapy is working for this patient

(also from Ref: Oborski, et. al.,Translational Oncology, 2014)



Patient #4

also from Ref: Oborski, et al., Translational Oncology 7(1): 111-119, 2014)

CONCLUSION: Fractionated therapy is working for this patient

Scatterplot of the parametric data to show regional and total apoptosis and Na gradient changes

2-D MRI (subject 4) Parametric Voxel Scatterplot PET-MRI fusion ROI magnified

Scatterplot for multi-parametric display of changes overlaid on the contract MRI:A. Up/Down PET or Na changes represented four-quadrants by assignment of each voxel in the

tumor ROI B. Colors correspond to four scatterplot outcomes of:

A. [apoptosis ↑] [Na ↑] purple B. [apoptosis ↓] [Na ↑] green C. [apoptosis ↓] [Na ↓] yellow D. [apoptosis ↑ ] [Na ↓] red desired outcome/ Tx is Working


Example 2: Cell Population Changes Following

Single and Fractionated IR

One dose1 x 7 Gy

Frac5 x 2 Gy

Non-IR

How does radiation schedule affect the appearance rate of cells and bone formation?

Esenwein, et.al., Arch Orthop Trauma Surg (2000) 120 :575–581 Table 1: Histologic Scoring

MODEL: Rat: Heterotopic implantation of demineralized bone matrix into the thigh muscle of rats can mimick the induction cascade of heterotopic ossification (HO) after total endoprosthesis of the hip.

Matrix-induced osteogenesis was examined histologically and enzymatically over time.

MOA: Bone stems from pluripotent mesenchymal cells that have the ability to transform into osteogenetic stem cells. Rapid differentiation of these stem cells into chondroblasts and osteoblasts leads to the formation of HO.

Right shift

Largerright shift


Example 2: Cell Population Changes Following

Single and Fractionated IR

One dose1 x 7 Gy

Frac5 x 2 Gy (10Gy)

Non-IR

How does radiation schedule affect the appearance rate of cells and bone formation?

Esenwein, et.al., Arch Orthop Trauma Surg (2000) 120 :575–581 Table 1: Histologic Scoring

MODEL: Rat: Heterotopic implantation of demineralized bone matrix into the thigh muscle of rats can mimick the induction cascade of heterotopic ossification (HO) after total endoprosthesis of the hip.

Matrix-induced osteogenesis was examined histologically and enzymatically over time.

MOA: Bone stems from pluripotent mesenchymal cells that have the ability to transform into osteogenetic stem cells. Rapid differentiation of these stem cells into chondroblasts and osteoblasts leads to the formation of HO.

Right shift

Largerright shift

Early fractionated IR therapy can arrest HO formation by blocking repopulation/transformation

TIME, days


Biomarker EXAMPLE 2: Fractionated IR Extends Redistribution and Repopulation

Acid Phosphatase (AcP)

Alk Phosphatase (AlkP)

Fractionated IR ~20 days of damped expression in heterotopic ossification (HO)

OUTCOME: • Fractionated dosing delays the differentiation

(genetic redistribution) of chondrocytes and chondroblasts enzymatic suppression

• Arrest of HO by damping AcP and AlkP

• Single dose IR was less effective in this model

In this Rat HO Model Fractionated Tx damped the AcP and AlkP responses

▲ = Non-IR □ = single dose 7 Gy ♦ = fractionated 5 x 2 Gy

▲

□

♦

♦

□

▲

▲ = Non-IR □ = single dose 7 Gy ♦ = fractionated 5 x 2 Gy


EXAMPLE 3: Fractionated Radiotherapy-Induced Alimentary Mucositis

Novel rat model using fractionated radiotherapy to induce mucositis

Yeoh, A. et.al., Mol Cancer Ther 2007; 6(8):2319

Fractionated abdominal radiotherapy: 45 Gy @18 x 2.5 Gy fractions/ 3X/wk over 6 wks

Endpoints: • Histomorphology - to assess mucin distribution and apoptosis (dUTP nick end labeling assay) • Intestinal morphometry - to assess villus length, crypt length, and mitotic crypt count • Immunohistochemistry - p53, nuclear factor-KB, (COX)-1, and (COX)-2

All BW↓15-25% n.s. n.s.

All crypts↑119%-152%No trend

Wk 4Nadir↓~15%

All ↓20%-50%Wk 3-4 Nadir


EXAMPLE 3: Tissue Histology Biomarker Expression over Time

H&E TUNEL ABPASHistology Markers: p53, NF-

Note reduction of mucin in Goblet cells by radiation

Note the absence of the p53 signal in Controls

Yeoh, A. et.al., Mol Cancer Ther 2007; 6(8):2319

Anatomy Apoptosis Mucin


Summary

What do we know about estimating human dosimetry from animal model?or vice versa………..We wish we knew more!

• The lymphocyte depletion scale works – however, Day 1 only and animals are NOT human • Challenge: Subject variability (age, sex, depth dose distribution, tissue sensitivities, etc.) all

are non-homogeneous and biomarkers will have varying expression• Fractionation is a tool for cancer therapy to tighten a therapeutic index

• Caution in use of Fractionation outcomes in Human to Animal Dosimetry translation• Consider The Four R’s as critical to understanding the biomarker expressions

• R1=Repair ; R2= Reoxygenation; R3 = Redistribution; R4 = Repopulation• Fractionation will mainly change R1 and R2 events creating a “steady state” • Impact is thus arresting the R3 (Redistribution) and R4 (Repopulation) rates

• Biomarkers of interest in dosimetry includes non-invasive tools for Biomarkers• We will use lymphocyte depletion (Andrews plot) and neutrophil nadirs • Blood / urine biomarkers: metabolomics, proteomics, p53, citrulline, IL-6, G-CSF, RNA SNPs, choline,

N-acetylaspartate, creatine, lipids, and lactate, and metabolite ratios, more….• Imaging: Adapt methodologies from cancer fractionation

• Proliferation/active metabolism: Na-23 T1 imaging (MR); F-18-FDG PET (proliferation); energy metabolism SUV measures of F-18-FDG PET (glucose use)

• Apoptosis: F-18 ML-10 PET ; Tc-99m Annexin V SPECT• Blood flow change (i.e. cutaneous erythema): Thermography ; BOLD – blood flow imaging; ADC

measures (apparent diffusion/water mobility maps, (water movement in the intra and extracellular compartments); tracer surrogates: O-15 (oxygenation), Rb-82 (extracellular K), Tc-99m RBCs


Thank You!

I wish to thank the BARDA and NIAID teams for their suggestions and edits

• And to the Organizers of this Workshop for the invitation to discuss these points

• Contact info:

Brian R. MoyerSr. Science Advisor, Contractor to BARDAPhone: 202-420-1976E-mail: [email protected]

mailto:[email protected]

BACK-UP SLIDES


Human Tumor Dose Fractionation as a Study Model vs Single Dose Animal Models

Fractionation Does NOT make the same Biomarker Response

Response to fractionation varies with tissue:

Fractionation spares late responding elements• Keeps “hitting” Repair and Reoxygenation

and Redistribution• Repopulation eventually affected

High dose IR affects a limited set of “R”s • Repair and Reoxygenation are highly

degraded – some mitotic activity remains• Redistribution ↓/ Repopulation “likely”

• Depending on the fractionation schedule, the four R’s can attain a steady state expression assuming metabolic resources are intact

• We must understand the SPECTRA of Dosesin an IND event

• < 2Gy and > 2 Gy sorting will be important• Prompt alone vs prompt with fallout


Human Cancer Radiotherapy: Hyper vs Accelerated Fractionation

• Standard Dose: • 1.8 to 2 Gy per day• Hyperfractionation:

• Two treatments per day• Daily doses at 1.1-1.2 Gy • less than single standard dose

• Overall treatment time about the same as standard

• Used for:• Rapidly proliferating cancers (i.e., head

and neck)• Normal cells repair damage of many

fractions better than the tumor (hypoxic radioresistance)

• Clinical result: same anti-tumor effect as

single dose Tx but with less late toxicity

Hyperfractionation Accelerated fractionation

• Standard Dose: • 1.8 to 2 Gy per day X 2• Accelerated fractionation

• Two treatments a day• Each treatment at same dose as

standard dose (1.8-2 Gy) • Administered twice a day

• more dose per day than standard Tx• Overall treatment time is shorter

• Goal: Prevent tumor from growing during treatment

repeatedly deplete R1(Repair)result = decrease R4

(Repopulation)

Entry dose

Exit dose

Using Co-60 as a model for the 6 MV LINAC:

Target midline dose

“NHP”

IR #1 IR #2

There is a small but finite addition to the absorbed dose AUC for the larger animals

Given the tissue heterogeneity can we assume no difference due to Girth size?

Girth 2

Girth 1

Ideal (per phantom)

Actual

Depth

Dos

e

Hrs Days

Time

Cell Killing

IR Doset1=0

Reoxygenation

Repair

Repopulation

Redistribution

Imaging Biomarkers as Dosimetry Tools

From: Smith, JJ, Sorensen, AG and Thrall, JH, Opinion: Biomarkers in Imaging: Realizing Radiology’s Future Radiology 2003; 227:633–638

Definition: Selectivity of radiation for killing the cancercompared to the normal cells

• The therapeutic index for a single radiation treatment (i.e., TBI) is small

• How can we increase the Therapeutic Index?• Multiple fractions (1.230 = 36)• Drugs that selectively sensitize tumor cells• Drugs that selectively protect normal cells

Radiation and the Therapeutic Index of Radiotherapy

Summers RM, Joseph PM, Kundel HL. Sodium nuclear magnetic resonance imagingof neuroblastoma in the nude mouse. Invest Radiol 1991; 26:233–241. Thulborn KR, Davis D, Adams H, Gindin T, Zhou J. Quantitative tissue sodium concentration mapping of the growth of focal cerebral tumors with sodium magnetic resonance imaging. Magn Reson Med 1999; 41: 351–359.

The Translation of Biodosimetry: Animal Models and Human Absorbed Dose Brian R. Moyer Sr. Science...

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