EQD2 & BED

EQD2 & BED:Practical Application for a Radiation Oncologist

MAYUR MAYANK04.03.2016

OVERVIEW◦ INTRODUCTION◦ BIOLOGICALLY EFFECTIVE DOSE (BED)◦ EQUIVALENT DOSE (EQD)◦ USES AND LIMITATIONS◦ SITE SPECIFIC EXAMPLES

◦ Head and Neck Cancers◦ Cervical Cancers

◦ CONCLUSIONS

INTRODUCTION Linear Quadratic Model

Proposed by Fowler – 1989

INTRODUCTION Effective dose response curve for a multi fraction regimen approaches an exponential function of dose for many doses

Effective dose-response relationship is a straight line from the origin through the point on the single-dose survival curve corresponding to the daily dose fraction

INTRODUCTION For n well separated fractions of dose d, the biologic effect is given by

E = α(total dose) (relative effectiveness)

1 + [d/(α/β)] is called relative effectiveness

INTRODUCTION

BIOLOGICALLY EFFECTIVE DOSE BED

◦ Measure of true Biological dose◦ Used for isoeffective dose calculations

◦ Based on ◦ Dose per fraction◦ Total dose to a particular tissue◦ α/β ratio of that tissue

BIOLOGICALLY EFFECTIVE DOSE◦ A simple way to compare different fractionation regimens

◦ Use of the linear-quadratic model, with appropriate values for the parameters α and β, emphasizes the difference between early and late responding tissues

◦ It is never possible to match two different fractionation regimens to be equivalent for both

Differences between Early and Late Responding Tissues

Early responding tissues and Tumors◦ α/β = 10

Late responding tissues◦ α/β = 3

70 Gy in 35 fractions ◦ 1 fraction / day◦ 5 days a week◦ Total time : 7 weeks

BED10 = 70 [1+(2/10)] = 84 Gy10 – For early responding tissues BED3 = 70 [1+(2/3)] = 116.67 Gy3 – For late responding tissues

Comparison of two Fractionation schedules


BED10 = 70 [1+(2/10)] = 84 (Acute)

BED3 = 70 [1+(2/3)] = 116.67 (Late)

80.5 Gy in 70 fractions ◦ 2 fractions / day ◦ 5 days a week◦ Total time : 7 weeks

BED10 = 80.5 [1+(1.15/10)] = 89.8 (Acute)

BED3 = 80.5 [1+(1.15/3)] = 111.4 (Late)

BIOLOGICALLY EFFECTIVE DOSE For combined schedules, calculate the total BED

This general BED expression does not take into account the proliferation during treatment could decrease as much as about 1 Gy/day

BED with proliferation during treatment

The effect of proliferation - supplementary term subtracted from BEDtot

Ttreat is the overall treatment time,

Tk is the time for the onset of proliferation

Tp is the effective doubling time during proliferation

α is the linear parameter of LQ model

BIOLOGICALLY EFFECTIVE DOSE

BED is often confused with ‘‘biologically equivalent dose’’

Which it definitely is not

EQUIVALENT DOSE (EQD) EQD2

◦ Equivalent total dose in 2-Gy fraction.◦ The total dose in 2-Gy fractions that would give the same log cell kill as the given

schedule. ◦ It is this that is the biologically equivalent dose, which should not be abbreviated to

BED.

Older literature - EQD has been called NTD (normalised total dose at 2-Gy fractions)

EQD2 EDQ2 can be found for any BED by dividing the BED by the RE for 2 Gy fractions, using the appropriate α/β ratio

For tumour and acute reactions : EQD2 = BED / 1.2 [α/β = 10] For late reactions : EQD2 = BED / 1.67 (for all except CNS) [α/β = 3] EQD2 = BED / 2 (for CNS) [α/β = 2]

BED to EQD2◦ More practical alternative is to convert the BED values to equivalent total

doses delivered in 2 Gy fractions– more practical to clinical practice– more familiar to clinicians– interpreted according to clinical experience

◦ Easier to understand than BED

BED & EQD2

Uses of BED and EQD2◦ Comparison between two fractionation schedules◦ Formulation of new fractionation schedules

Comparison between two fractionation schedules

n1d1 = n2d2 1 + d1 α/β

1 + d2α/β

For equivalent BED

Comparison of two Fractionation schedules


BED10 = 70 [1+(2/10)] = 84

BED3 = 70 [1+(2/3)] = 116.67

80.5 Gy in 70 fractions ◦ 2 fractions / day ◦ 5 days a week◦ Total time : 7 weeks

BED10 = 80.5 [1+(1.15/10)] = 89.8

BED3 = 80.5 [1+(1.15/3)] = 111.4

EQD10/2 = 89.8 / [1+(2/10)] = 74.83

EQD3/2 = 111.4 / [1+(2/3)] = 66.71

Formulation of a new fractionation schedule

The three sets of biologically effective dose (BED) calculations to analyse any schedule

1. Ensure late complication constraints are not overdosed (unless volume reduced)◦ No overall time factor normally assumed

2. Tumour BED10=nd(1+d/[α/β]) - 0.693 (T-Tk)/0.35 Tp ◦ Tk=21–32 days and Tp=3 days for lung or head and neck cancer◦ For most tumours a/b=10 Gy, but prostate cancer a/b=1.5 to 2 Gy, breast cancer a/b=4 Gy, malignant

melanoma a/b=0.6 Gy, non-small-cell lung cancer a/b=20 Gy.

3. Acute mucosal BED10=nd(1+d/10)-0.693 (T-7d)/0.35x2.5d ◦ (EQD10/2 = 49–52.5 : derived from oropharyngeal data; possibly applies to rectal mucosa too)

Fowler, Br Jour Radiology 83; 2010

Limitations of BED • Need to know α/β ratio

• LQ model fails at extremes of low dose rate and large fraction sizes

• Hot spots of treatment

• Previous cytotoxic chemotherapy

• Previous surgery

• Extremes of age

• Vascular pathology

• Breaks in treatment, compensation for accelerated proliferation

• Generic values of 10 Gy for tumors and 3 Gy for normal

HEAD AND NECK CANCERS

RTOG 9003 Largest randomized study of fractionation ever conducted

Designed to answer the question whether each of 3 experimental altered fractionation arms would improve loco regional control (LRC) for patients with locally advanced squamous cell cancer of the head and neck

Standard Fractionation 70 Gy/35 fractions/ 7 weeks

Hyperfractionation81.6 Gy/68 fractions/7 weeks

Accelerated Fractionation – Continuous72 Gy/42 fractions/6 weeks

Accelerated Fractionation – Split67.2 Gy/42 fractions/6 weeks with 2-week rest after 38.4 Gy

SFX

HFX

AFX-C

AFX-S

RTOG 9003

Bietler et al, IJROBP 89 ; 2014

Radiobiology of RTOG 9003 arms


Other Fractionation Studies in Head and Neck Cancers


CERVICAL CANCER

BED of Radiation Treatment – Cervical Cancer

In Cervical cancer

BEDtotal = BEDEBRT + BEDbrachy

Low Dose Rate (LDR) Brachytherapy

Significant repair of damage during delivery

D - Radiation dose, T - duration of the BT session μ - a parameter characterizing the repair of sublethal damage in the irradiated tissuesμ = ln(2)/T1/2, where T1/2 is half-life of sublethal damage repair

High Dose Rate (HDR) Brachytherapy

BED is calculated same as that for EBRT

Calculation of BED for Cervical cancer

EBRT : 50 Gy / 25 # over 5 weeks followed by HDR Brachytherapy : 15 Gy / 3 # Assuming α/β = 2

BEDEBRT = 50[1+(2/2)] = 100Gy2

BEDBT = 15[1+(5/2)] = 52.5Gy2

BEDtotal = BEDEBRT + BEDBT = 152.5Gy2

EQD2 = BED / [1+(2/α/β)] = 152.5 / [1+(2/2)] = 76.25 Gy (38 fractions of 2 Gy/fraction)

Recommended EQD2 for Cervical Cancers

The recommended mean combined EBRT plus brachytherapy, EQD2 :◦ 78.9 Gy [SD=10.7] for Stage IB–IIA patients◦ 83.3 Gy [SD=11.2] for Stage IIB–IVA patients

For all stages, EBRT plus brachytherapy◦ 80.9 Gy [SD=10.14]

Viswanathan et al., IJROBP 82; 2012

CONCLUSIONS◦ BED and EQD2 are important tools for Radiation Oncologists to decide the fractionation

patterns

◦ They help in predicting the tumour control and the acute and late reactions to an extent

◦ EQD2 is a better tool than BED as most clinicians are more used to data with doses in conventional fractionation of 2Gy/fraction

◦ Although not perfect, they are integral tools and should be used in all fractionation related studies and for predicting toxicities

THANK YOU….

EQD2 & BED

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