MASTERCLASS: BRACHYTHERAPY in PARTIAL BREAST … · BED Gy 10 BED Gy 2 BED Gy 3 BED Gy 4 8 x 4Gy 4-5 32 45 96 74.8 64 10x3.4Gy 5 (7) 34 46 92 72.8 63 EQD2 8 x 4Gy 32 37.5 57.5 44.8

MASTERCLASS: BRACHYTHERAPY in PARTIAL BREAST IRRADIATION

Euro-Asian Breast Brachytherapy School

October 8-9th, 2015

Singapore

BRACHYTHERAPY IN PARTIAL BREAST IRRADIATION

Fractionation concepts, radiobiologic considerations

Dr. José Luis Guinot

Foundation Instituto Valenciano de Oncologia (I.V.O.) Spain.

- A 1cc tumour has 109 clonogenic cells,one billion cells.

- The objective of radiation is to kill allresidual cells in the tumour bed afterbreast surgery, therefore the number ofclonogenic cells is low.

- Partial breast irradiation is treating bothresidual cells and normal breast tissue,not the tumour itself.

The sensitivity of a tissue or tumour toradiation is measured by the a/b value

- a/b is very similar for breast tumorsand breast tissue.

- Hypofractionated treatments are moreadequate for slow growing breast tumors

- There is no standard protocol for APBI,but shorter schedules should be better…

The goal with APBI

http://www.google.es/url?sa=i&rct=j&q=axillar%20radiation&source=images&cd=&cad=rja&docid=_RZE10sraraZXM&tbnid=UrXUUPbZxrG3jM:&ved=0CAUQjRw&url=http%3A%2F%2Frtnotes.wikidot.com%2Fbreast-cancer-anatomy&ei=kkAGUqfnNbPK0AWnyICoBw&bvm=bv.50500085,d.ZGU&psig=AFQjCNFCT0DkN6tvUVcE25AEmQFCHwzUxg&ust=1376225881544721

http://www.google.es/url?sa=i&rct=j&q=axillar%20radiation&source=images&cd=&cad=rja&docid=_RZE10sraraZXM&tbnid=UrXUUPbZxrG3jM:&ved=0CAUQjRw&url=http%3A%2F%2Frtnotes.wikidot.com%2Fbreast-cancer-anatomy&ei=kkAGUqfnNbPK0AWnyICoBw&bvm=bv.50500085,d.ZGU&psig=AFQjCNFCT0DkN6tvUVcE25AEmQFCHwzUxg&ust=1376225881544721

Presence of tumoral cells at a

distance from the primary tumour

What do we need to treat with APBI?

In APBI we are treating residual cells, not the tumour. Margin should be free.

We cannot compare breast brachytherapy with other locations as cervix.

Veronesi U. Radiotherapy after breast-conserving surgery in small breast carci-

noma. Long-term results ps a randomized trial. Ann Oncol 12; 2001:997-1003.

What do we control with radiation?

•We treat 100% BCS cases

•RT control ¼ cases

•RT failures due to unsufficient dose

(total dose)•Some failures due to missing PTV

(technique)

What can we learn about radiobiology?

1.0

0.1

0.01

0.001

Accumulation ofsub-lethal

damage

single lethal hits

n

dose

Surviving Fraction depends on the dose of radiation

Puck and Marcus, J.E.M.103, 563, 1956

First in vitro mammalian survival curve

Two component model:

Eukaryotic survival curves are

exponential but have a shoulder

From William McBride. Dept. Radiation Oncology.

David Geffen School Medicine. UCLA, Los Angeles, Ca

Cell kill is the result of single lethal hits

plus accumulated damage from 2

independent sublethal events

E = aD + bD2

For a fractionated regimen

E= nd(a + bd) = D (a + bd)

Where d = dose per fraction and D = total dose

a/b is dose at which death due tosingle lethal lesions = death due toaccumulation of sublethal lesions

aD = bD2

S.F. = e-aD

Single lethal hits

S.F. = e-(aD+bD2)

Single lethal hits plus

accumulated damage

Survivinigfraction.

1.0

0.1

0.01

0.001

DOSE Gy

a/b in Gy

aD

bD2

Linear Quadratic Model



From Pravin U.

Dugel, Jeffrey

Nau, Ram Palanki

242016128400

.01

.1

1

Dose (Gy)

S.F.

Single dose

limiting slope/

low dose rate

3 fractions

5 fractions

Multi-fraction survival curves can be considered linear if sublethal damage is repaired between fractions

Multi-fraction survival curves



Response to Fractionation Varies With Tissue

Modified from William McBride. Dept. Radiation Oncology.


a/b is high (>6Gy) when survival

curve is almost exponential and low

(1-4Gy) when shoulder is wide

Fractionation has small influence

on acute effects and tumours. But

it spares late responding tissues

Response to Fractionation Varies With Tissue (a/b)

The advantage of using more fractions with a/b 10 is that when all

clonogenic cells are killed, enough normal cells remain to recover tissues

To kill all clonogenic cells with a/b low, fewer fractions are better

Redistribution

Repair

Repopulation

700R 1500R

What is happening between fractions?4Rs of dose fractionation

• Assessed by varying the

time between 2 or more

doses of radiation

• With HDR BT six hours

between fractions allow the

recovery of normal tissues.

• Repopulation requires

longer times: Avoid

weekends

Reoxygenation


David Geffen School Medicine UCLA, Los Angeles, Ca

Response with different dose rates.

• With HDR brachytherapy, doses are higher in a short time , and SF is lower

Response with different dose rates.

• With LDR brachytherapy, surviving fraction is lower with higher dose rates

• Both a and b vary with the cell cycle. At high doses, S phase and hypoxic cells become more important.

• The a/b ratio varies depending upon whether a cell is proliferative or quiescent (breast?)

• The LQ model best describes data in the range of 1 - 6Gy and should not be used outside this range

(what to do with HDR in few fx.?)

Problems with a/b

The a/b value quantifies the sensitivity of a tissue/tumor to fractionated radiation. But…

Dose

oxic

hypoxicS.F



What are a/b ratios for breast cancers?

a/b ratios may be moderately low

– Owen JR et al. Lancet Oncol 2006; 7: 467-471,

– Dewar et al. JCO 2007 , ASCO Proceedings Part I. Vol 25, No. 18S: LBA518

• UK START Trial

– 50Gy (2x25), compared with

39Gy (3x13) 41.6Gy (3.2x13) 40Gy (2.67 x15)

• Breast Cancer a/b = 4.0Gy (1.0-7.8)

• Breast appearance a/b = 3.6Gy;

• Breast induration a/b = 3.1Gy

If fractionation sensitivity of a cancer is similar to dose-limiting healthy

tissues, it may be possible to give fewer, larger fractions without

compromising effectiveness or safety



How to compare different doses?

What total dose (D) to give if the dose/fx (d) is changed

New Old

Dnew (dnew + a/b) = Dold (dold +a/b)

What total dose in 4Gy fractions is equivalent to 50Gy in 2Gy fractions?

for acute responding tissue a/b:10

Dnew (4+10) = 50 (2 + 10) Dnew = 42.8Gy

for late responding tissue a/b:3

Dnew (4+3) = 50 (2 + 3) Dnew = 35.7Gy

for breast tissue a/b:4

Dnew (4+4) = 50 (2 + 4) Dnew = 37.5Gy

Small differences in a/b for late responding tissues can make a big

difference in estimated total dose D

Modified from William McBride. Dept. Radiation

Oncology. David Geffen School Medicine UCLA, Los

Angeles, Ca

Late responding tissues respond badly to increased dose/fraction

When increasing dose/fraction, total dose must be decreased.



The effect on late responding tissues varies with dose/fx

Looking for a common language

Biologically Effective

Dose (BED) Total dose

RE: Relative

Effectiveness

S.F. = e-E = e-(aD+bD2)

E = nd(a + bd)

E/a = nd (1+d/a/b)

25 x 2Gy = 50 Gy B.E.D. of 60Gy10 75Gy4 83.5Gy3

Dose equivalent to 2Gy EQD2 = Normalized total dose2Gy = BED/RE

for a/b of 10Gy = BED / 1.2

for a/bof 4Gy = BED / 1.5

for a/bof 3Gy = BED / 1.67



(EQD2) Biologically Effective Dose (BED)

LDR brachytherapy BED values

EBRT and HDR brachytherapy BED values

α / β : 10 7

x

4.3

10

x

3.4

8

x

4

7

x

5.2

8

x

5

10

x

3.8

5

x

6

Rosenstein BS et al, IJROBP 2004;60:1393-1404

α / β : 2

Late effects7

x

4.3

10

x

3.4

8

x

4

7

x

5.2

8

x

5

10

x

3.8

5

x

6


α / β : 4

Breast

10

x

3.4

7

x

4.3

8

x

4

7

x

5.2

5

x

6

8

x

5

10

x

3.8


daysTotaldose

BED Gy10

BED Gy2

BED Gy3

BED Gy4

8 x 4Gy 4-5 32 45 96 74.8 64

10x3.4Gy 5 (7) 34 46 92 72.8 63

EQD2

8 x 4Gy 32 37.5 57.5 44.8 42.7

10x3.4Gy 34 38 55 43.6 42

Comparison of BED and EQD2 in standard APBI protocols with brachytherapy

The selected total dose chosen in current schedules is low compared with EBRT

BED and repopulation with EBRT

• The standard schedule is 60 Gy in 2-Gy fractions.

• Assuming tumor parameters α / β= 4 Gy, if repopulation effects are neglected, 60 Gy/30 fractions delivers a tumor BED of 90 Gy4.

• Wyatt et al. have reviewed postoperative repopulation parameters relevant to breast cancer and used a K factor of 0.1 Gy/day.

• A 30-fraction treatment lasts around 39 days, thus the calculated BED is reduced by 39 x 0.1 = 3.9 Gy, that is, the reference tumor BED, corrected for repopulation, is

BED 90 - 3.9 = 86 Gy4.

Khan AJ et al. Ultrashort courses of adjuvant breast radiotherapy. Wave of the future or a

fool’s errand? Cancer 2012;118:1962-70.

Study PatientsTotal dose

Numberfx

Fx size(Gy)

weeksAsumedα/β

START A 223641.6Gy 13 3.2 5 4 Gy

39Gy 13 3.0 5 3 Gy

START B 40Gy 15 2.67 3

Ontario 1234 42.7Gy 16 2.67 3

FAST 91530Gy 5 6.0 5 4Gy

28.5Gy 5 5.7 5 3Gy

FAST forward

4000 prev27Gy 5 5.4 1 3Gy

26Gy 5 5.2 1

Hypofractionated protocols in breast EBRT

Schedules of hypofractionated WBI similar to HDR brachytherapy

are under investigation

Altered fractionations

Rationale of Proposed Fractionation Schemes

• The primary rationale for APBI is the enhanced convenience for patients, which may result in increased access to BCT.

• The fractionation schemes for APBI were devised empirically.

• With the low α / β ratio for breast cancer, the fraction sensitivity of breast cancer can be exploited with higher fraction sizes, resulting in even more compressed treatment times.

• Not to exceed the tolerance of normal tissues.



HDR APBI over two days

• The William Beaumont Hospital (Michigan)

• 45 patients, phase 1-2 protocol , single-lumen MammoSite RTS applicator.

• 7 Gy x 4 fractions over 2 days ,

• Median age 66 years (48-83), median tumor size 0.6 cm (0.2-2.3 cm) 5% N+, 73% ER +. Median FU 3.7 years (2.4-7).

• Only G 1-2 chronic toxicities were noted: fat necrosis (18%), asymptomatic seromas (42%), 7% rib fractures (n=3)

• 98% good or excellent cosmetic outcome.

• No ipsilateral breast tumor recurrences or regional nodal failures; 2 M+.

• CONCLUSIONS: acceptable chronic toxicity and similar clinical outcomes as standard 5-day fractionation.

Wilkinson JB et al. Four-year results using balloon-based brachytherapy to deliver

accelerated partial breastirradiation with a 2-day dose fractionation schedule.

Brachytherapy. 2012 Mar-Apr;11(2):97-104.

Prospective trial of ultrashort-course APBI using a multi-lumen balloon brachytherapy device

• A prospective phase II trial that sequentially treats 3 cohorts of women (each n = 30) with 3 progressively hypofractionatedschedules.

• Age ≥50 years, unifocal invasive or in situ tumors ≤3.0 cm, negative margins, N -hormone receptors +.

• 30 patients enrolled at the 7 Gy × 4 fractions followed 6 m.

• Median skin dose 84% (40-100), median rib dose 71% (16-119).

• 1 breast infection; 2 symptomatic fat necrosis ; 2 symptomatic seromas.

• CONCLUSION: Short-course APBI is dosimetrically feasible using the Contura MLB and appears to be tolerable in terms of acute toxicities.

• We have opened enrollment to the next schedule of 8.25 Gy x 3

Khan AJ, et al. Dosimetric feasibility and acute toxicity in a prospective trial of ultrashort-course

accelerated partial breast irradiation (APBI) using a multi-lumen balloon brachytherapy device. Ann Surg

Oncol. 2013; 20(4):1295-301

Radiobiological influence of gradient with balloon applicators

• Dale et al calculate a multiplication factor (MF) to multiply theprescribed BED to take account of the dose gradient effect, theradiosensitivity parameters, the fractional dose, and thenumber of fractions.

Dale R, et al. Calculation of integrated biological response in brachytherapy. IJROBP

1997;38:633-642.

• Dose is prescribed 1 cm from the balloon surface. (Diameter 4.5cm, radius 2.25, prescription point 3.25cm)• There is a large dose gradient. The surface dose is 44% higher than the prescription dose.



α / β : 4

Breast

10

x

3.4

7

x

4.3

8

x

4

7

x

5.2

5

x

6

8

x

5

10

x

3.8


• Intraoperative HDR technique using a Silastic applicator (Harrison-Anderson-Mick or HAM applicator)

• Single fraction of 20 Gy at 1 cm from the surface of the

applicator.

• This was modified to 18 Gy at the lateral aspects of the applicator, because 5 of the first 18 patients developed significant fibrosis and retraction at the 6-month interval.

• 90 Gy delivered in 2-Gy fractions, (α/β:3) for normal tissue effects.

• the investigators do not report accounting for the steep gradient of inhomogeneity within the prescription volume.

• After the modest dose reduction, fewer complications were noted, although the reported follow-up is short.

Sacchini V, et al. Study of quadrant high-dose intraoperative radiation therapy for early-stage

breast cancer. Br J Surg. 2008;95:1105-1110.

HDR single fraction

SIFEBI

• 16 Gy in one fraction. Age >=70 years, pT1pN0, margins-

• This dose is calculated with α/β for the breast, on the order of 3.4 Gy for late toxicity and 4.6 Gy for local control.

• Applying the linear-quadratic model with α/β = 4, 16 Gy x1 is equivalent to 53 Gy in conventional fractionation.

• BED is between the dose in the protocols IPAS intraoperative electron or X-ray photons of 50 kV (21 Gy in one fraction, 87 Gy EQD2 α/β= 4.6) and the post-operative irradiation of 34-38 Gy in 10 fractions, 5 days (42 Gy EQD2 α/β= 4.6)

• (First results in ESTRO…)

Single Fraction Elderly Breast Irradiation (SiFEBI)

J.M. Hannoun-Levi. Centre Antoine Lacassagne. Nice. France.

Dose

Therapeutic window: To choose the right dose

100%

0%

Wide

therapeutic

window

100%

0%

Narrow

therapeutic

window

Tumor control

Late responding tissue

complications

Complication-free cure

α / β : 4

Breast

Inhomogeneity of HDR brachytherapy

Local relapse 3.9% CosmesisExcellent-good 38%Moderate 55%Bad 7%

HDR: 9.7 Gy (7 – 12 Gy)

LDR: 20 Gy (9.9 - 27 Gy)

Resch A. Long-term results (10 years) of intensive breast conserving therapy including a high-dose and large-volume interstitial brachytherapy boost (LDR/HDR) for T1/T2 breast cancer. Radiother Oncol 2002;63:47-58

410 patients (Viena)

Importance of the prescription: Boost HDR to 10mm

↑25%↑31%

ROIDose(%)

Dose(cGy)

Volume(ccm)

DNRV150/V100

External 100 400 970.31

External 150 600 30

External 100 400 970.5

External 150 600 49

Importance of hot spots on HDR brachytherapy

Prescription is 4Gy but one half of the

volume receives 6Gy

In brachytherapy the dose inside the treated volume is far higher than the prescribed dose

J Contemp Brachyther 2012; 4,1:12-20

The inevitable dose gradient in BT ensures non-uniform dosage within the target volume and this extra-dose has its own biological effect

Importance of gradient on HDR brachytherapy

10 x 3.4 Gy

α/β 10: 13.5 Gy

Single fraction 8 Gy

α/β 4: 17 Gy

α/β 4: 20-25 Gy

Taking into account the dose gradient

Conclusions

CURRENT MODEL OF FRACTIONATION

BREAST CANCER: HYPOFRACTIONATION

α/β4,5

Radiobiological justification: Tumour α/β <10 will response better

to higher doses than standard 2Gy fractionation

α/β10

© Manuel Algara

• The Swedish Insurance Company

• Fractions from 2.5-6Gy

• BED up to 146 EQD2 (6Gy x 13fx).

• >95% had stiff shoulder, paralysis, pain, oedema, atrophy.

• Latency as long as 30years

• CONCLUSION: HFX can cause injuries if the target volume is not

exact or the total dose is not adjusted to a tolerable level as

compared to conventional 2Gy/day fractions.

© Manuel Algara

Smith GI, Xu Y, Buchholz TA, et al.

JAMA 2012;307:1827-37

•Retrospective

study

•APBI

hazard ratio 2.2

(95%CI) vs

mastectomy

•Balloon

technique

Conclusions I• Breast tumours have an a/b=4-4.5 very similar to

late responding tissues. Maybe because the tumour is removed and radiation acts on the residual cells.

• Hypofractionation should be more useful, but the therapeutic window is narrow.

• If the selected schedule is overtreating, the complications rate will be unacceptable.

• If it is undertreating, we cannot appreciate it because the cases treated with APBI have a low rate of relapse and the outcome must be evaluated at least at ten years of FU.

Conclusions II

• When the dose per fraction increases moderately, toxicity is similar if the total dose is decreased.

• Accelerated protocols have the same efficacy if the total duration is decreased.

• Doses of HDR APBI schedules are very variable.

• The standard schedules are 3.4Gy x10 or 4Gy x8

• More hypofractionated protocols are under investigation.

• Probably in the future shorter schedules will be recommended.

Thank you for your attention

Documents

MASTERCLASS: BRACHYTHERAPY in PARTIAL BREAST … · BED Gy 10 BED Gy 2 BED Gy 3 BED Gy 4 8 x 4Gy 4-5 32 45 96 74.8 64 10x3.4Gy 5 (7) 34 46 92 72.8 63 EQD2 8 x 4Gy 32 37.5 57.5 44.8