basic clinical radiobiology · 2018. 5. 9. · basic clinical radiobiology alfredo polo md, phd...

BASIC CLINICAL RADIOBIOLOGYAlfredo Polo MD, PhD

INT6062: Strengthening Capacity for Cervical Cancer Control through Improvement of Diagnosis and Treatment

Radiotherapy in the treatment of locally advanced cervical cancer. Rabat (Morocco), 9-11th May 2018

Applied Radiation Biology and Radiotherapy Section Division of Human health

BASIC RADIATION DAMAGE

REPOPULATION

REPAIR REOXYGENATION

RADIO- SENSITIVITYREDISTRIBUTION

THE FIVE R IN RADIOBIOLOGY

Valu

e (%

)

0

20

40

60

80

100

Fraction time (%)0 20 40 60 80 100

DOSELinear.(DOSE)DAMAGELog.(DAMAGE)REPAIRExpon.(REPAIR)

INSIDE A FRACTION

LINEAR QUADRATIC MODEL

NSD: Nominal standard dose (Ellis, 1969)

TDF: time-dose-fractionation (Orton & Ellis, 1973)

ERD: extrapolated response dose (Barendsen, 1982)

LQ: linear-quadratic (Orton & Cohen, 1988)

Modelo LinealModelo Lineal--QuadrQuadrááticotico•• αααααααα:: Parámetro que expresa la muerte

celular por impacto único/daño letal (parte lineal). Valor en Gy-1

•• ββββββββ: : Parámetro que expresa la muerte celular por impacto doble/daño subletal (parte cuadrática). Valor en Gy-2

•• αααααααα//ββββββββ: : proporción entre el daño letal respecto al subletal de un tejido. Valor en Gy.

♦♦αααααααα//ββββββββ alto: alto: Tejidos en los que predomina el componente α, la muerte por daño letal, en los que, por lo tanto, predomina el efecto de la dosis total. Dosis por fracción de 1-2 Gy (y dosis total altas, > 60 Gy) son adecuadas para esterilizar sus células (a estas dosis predomina la muerte por impacto único). Corresponde a tejidos de respuesta rápida, con valores de α/β entre 6-20 en su mayoría.

♦♦αααααααα//ββββββββ bajo: bajo: Tejidos en los que predomina el componente β, la muerte por daño subletal, en los que, por lo tanto, predomina el efecto de la dosis por fracción. Dosis por fracción altas (>3-4) y dosis totales reducidas (< 50-60 Gy) son adecuadas. Corresponde a tejidos de respuesta lenta, con valores de α/β < 6 en su mayoría.

α: Parameter that express single-hit/lethal (linear component). Value in Gy-1 β: Parameter that express multiple-hit/sublethal damage (quadratic component). Value in Gy-2 α/β: Proportion between lethal and sublethal damage. Value in Gy

The dose-response relationship for late responding tissues is more curved than for early responding tissues. In the linear-quadratic formulation this translates into a larger α/β for early than for late effects. The ratio α/β is the dose at which the linear component (α) and the quadratic (β) components of cell killing are equal.

The much smaller proportion at 2 Gy than 8 Gy per fraction is showed

Only the red proportion is altered by α/β, T1/2 and dose per fraction

Keeping low the dose per fraction guarantees minimal risk of excess damage in late tissues

INSIDE A FRACTION

Adapted from Fowler 1999

FRACTION FRACTION FRACTIONGAP GAP

Creation of SLD

Repair of SLD

Δ no repair of SLD

Time

Dose

rate

per

pul

se

BETWEEN FRACTIONS

1. Conventional EBRT/HDR daily fractions (>24h) permit enough time between fractions for full repair to occur.

2. If interfraction time is reduced to less than aprox 8h, repair between fraction may be incomplete and cell survival decreased.

3. A potential for therapeutic gain exists when the fractionation sensitivity α/β for the host dose limiting late reacting normal tissues is greater than a tumor lying within such tissue.

Thames HD et al. Incomplete repair model for survival after fractionated and continuous irradiation. IJRO 1985; 47: 319

Dale RG et al. The application of the LQ formula dose-effect equation to fractionated and protracted radiotherapy. B J Radiol 1985; 58: 515

SUBLETHAL DAMAGE REPAIR: incomplete repair

Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell. 2005;8:89-91.

ENDOTELIAL MEDIATED CELL DAMAGE

BASIC MODEL FORISOEFFECT CALCULATION

PII S0360-3016(99)00330-2

PHYSICS CONTRIBUTION

A SIMPLE METHOD OF OBTAINING EQUIVALENT DOSES FOR USE INHDR BRACHYTHERAPY

SUBIR NAG, M.D., AND NILENDU GUPTA, PH.D.Division of Radiation Oncology, Arthur G. James Cancer Hospital and Research Institute, Ohio State University, Columbus, OH

Purpose: To develop a simple program that can be easily used by clinicians to calculate the tumor and late tissueequivalent doses (as if given in 2 Gy/day fractions) for different high-dose-rate (HDR) brachytherapy regimens.The program should take into account the normal tissue sparing effect of brachytherapy.Methods and Materials: Using Microsoft Excel, a program was developed incorporating the linear-quadratic(LQ) formula to calculate the biologically equivalent dose (BED). To express the BED in terms more familiar toall clinicians, it was reconverted to equivalent doses as if given as fractionated irradiation at 2 Gy/fraction. Sincedoses given to normal tissues in HDR brachytherapy treatments are different from those given to tumor, anormal tissue dose modifying factor (DMF) was applied in this spreadsheet (depending on the anticipated doseto normal tissue) to obtain more realistic equivalent normal tissue effects.Results: The spreadsheet program created requires the clinician to enter only the external beam total dose anddose/fraction, HDR dose, and the number of HDR fractions. It automatically calculates the equivalent doses fortumor and normal tissue effects, respectively. Generally, the DMF applied is< 1 since the doses to normal tissuesare less than the doses to the tumor. However, in certain circumstances, a DMF of > 1 may need to be appliedif the dose to critical normal tissues is higher than the dose to tumor. Additionally, the !/" ratios for tumor andnormal tissues can be changed from their default values of 10 Gy and 3 Gy, respectively. This program has beenused to determine HDR doses needed for treatment of cancers of the cervix, prostate, and other organs. It canalso been used to predict the late normal tissue effects, alerting the clinician to the possibility of undue morbidityof a new HDR regimen.Conclusion: A simple Excel spreadsheet program has been developed to assist clinicians to easily calculateequivalent doses to be used in HDR brachytherapy regimens. The novelty of this program is that the equivalentdoses are expressed as if given at 2 Gy per fraction rather than as BED values and a more realistic equivalentnormal tissue effect is obtained by applying a DMF. Its ease of use should promote the use of LQ radiobiologicalmodeling to determine doses to be used for HDR brachytherapy. The program is to be used judiciously as a guideonly and should be correlated with clinical outcome. © 2000 Elsevier Science Inc.

HDR brachytherapy, Time–dose-effect, Linear-quadratic, Biologically equivalent dose.

INTRODUCTION

Most radiation oncologists are familiar with low-dose-rate(LDR) brachytherapy. Recently, there has been a trendtowards increased use of high-dose-rate (HDR) brachyther-apy due to its advantages, namely that it eliminates radiationexposure to caregivers, requires only short treatment times,and that its dose distribution can be optimized by varyingthe dwell times. HDR is generally given as fractionatedtreatments to decrease normal tissue toxicity. The doseeffect relationship in radiation therapy is not linear, but maybe assumed to follow a linear-quadratic (LQ) function (1).Hence, doses from different treatment modalities cannot beadded linearly to determine the combined effect. Manyradiation oncologists are not very familiar with the fraction-

ation schemes to be used in HDR brachytherapy. Further,there is a marked difference between the biological effectsin the tumor and those in late reacting normal tissue (1).Besides, patients are often treated with external beam ra-diotherapy combined with HDR brachytherapy, whichposes the added challenge of determining the combinedeffect of the two treatments.One way to calculate the biologically equivalent doses

(BEDs) of different dose fractionation schemes is to use theLQ equation (eq. 1 in Appendix 1). In this equation, the !/"ratio is usually taken to be 10 Gy for tumor/early effects and3 Gy for late effects (2). The concept of LQ modeling isfamiliar to most radiation oncologists. However, this calcu-lation is cumbersome, and the resultant BED values are notfamiliar to the clinicians. Further, it does not take into

Reprint requests to: Subir Nag, M.D., Chief of Brachytherapy,The Arthur G. James Cancer Hospital, Ohio State University,300 West Tenth Avenue, Columbus, OH 43210. E-mail:[email protected]—The authors wish to express their gratitude to

David Carpenter for editorial assistance. This study was supportedin part by Grant 5P30CS16058 from the National Cancer Institute,Bethesda, MD.Accepted for publication 29 July 1999.

Int. J. Radiation Oncology Biol. Phys., Vol. 46, No. 2, pp. 507–513, 2000Copyright © 2000 Elsevier Science Inc.Printed in the USA. All rights reserved

0360-3016/00/$–see front matter

507

SUMMARY

A simple Excel spreadsheet program has been developedto assist clinicians to easily calculate equivalent doses to beused in HDR brachytherapy regimens. The novelty of thisprogram is that the equivalent doses are expressed as ifgiven at 2 Gy per fraction rather than as BED values, and a

more realistic equivalent normal tissue effect is obtained byapplying a DMF. Its ease of use should promote the use ofLQ radiobiological modeling to determine HDR brachyther-apy doses. The program is to be used judiciously as a guideonly and should be correlated with clinical outcome.

REFERENCES

1. Hall EJ. Time, dose, and fractionation in radiotherapy. In: HallEJ, editor. Radiobiology for the radiobiologist. 4th ed. Phila-delphia: J.B. Lippincott; 1994. 211–229.

2. Dale RG. The application of the linear quadratic dose-effectequation to fractionated and protracted radiotherapy. Br JRadiol 1985;58:515–528.

3. Nag S, Young D, Orton C, Erickson B. Survey of the Brachy-therapy Practice for Carcinoma of the Cervix: A Report of theClinical Research Committee of the American BrachytherapySociety. Gynecol Oncol 1999;73:111–118.

4. Gaspar LE, Qian C, Kocha WI, Coia LR, Herskovic A, Gra-ham M. A phase I/II study of external beam radiation, brachy-therapy and concurrent chemotherapy in localized cancer ofthe esophagus (RTOG 92-07): Preliminary toxicity report. IntJ Radiat Oncol Biol Phys 1997;37:593–599.

5. Ellis F. Is NSD-TDF useful to radiotherapy? Int J RadiatOncol Biol Phys 1985;11:1685–1697.

6. Barendsen GW. Dose fractionation, dose-rate and iso-effectrelationships for normal tissue responses. Int J Radiat OncolBiol Phys 1982;8:1981–1997.

7. Fowler JF. The linear-quadratic formula and progress in frac-tionation. Br J Radiol 1985;58:515–528.

8. Thames HD. An “incomplete-repair” model for survival afterfractionated and continuous irradiation. Int J Radiat Biol1985;47:319–339.

9. Brenner DJ, Hall EJ. The origins and basis of the linear-quadratic model. Int J Radiat Oncol Biol Phys 1992;23:252.

10. Brenner DJ, Hlatky LR, Hahnfedlt PJ, Huang Y, Sachs RK.The linear-quadratic model and most other common radiobi-ological models result in similar predictions of time–doserelationships. Radiat Res 1998;150:83–91.

11. Dale RJ, Jones B. The clinical radiobiology of brachytherapy.Br J Radiol 1998;71:465–483.

12. Orton C. Radiobiology. In: Nag S, editor. Principles andpractice of brachytherapy. Armonk, NY: Futura; 1997. 27–45.

13. Barton M. Tables of equivalent dose in 2 Gy fractions: Asimple application of the linear quadratic formula. Int J RadiatOncol Biol Phys 1995;31:371–78.

14. Brenner DJ, Hall EJ. Fractionation and protraction for radio-therapy of prostate carcinoma. Int J Radiat Oncol Biol Phys1999;43:1095–1101.

APPENDIX 1:BIO-EQUIVALENCE CALCULATIONS FOR

MULTIPLE MODALITY RADIATION TREATMENTS

The dose effect relationship in radiation therapy is not alinear relationship, but follows a LQ function. Hence, dosesdelivered by different modalities cannot be added to eachother to predict the effect of the combined modality treat-ment. One way to calculate the BEDs of different dosefractionation schemes is to use the LQ equation, using theformula

BED! nd !1 "d(!/"" (1)

where n ! the number of fractions and d ! the dose perfraction. To express the results in terms more familiar toclinicians, the BED was converted back to equivalent doses(DEq) as though given as conventionally fractionated irra-diation given at 2 Gy/day for tumor and late effects respec-tively using the formula

DEq !BED

#1" dREF(!/")$

(2)

where dREF ! the reference dose per fraction for a conven-tionally fractionated external beam treatment to be used for

calculating the equivalent dose (which for the purposes ofthis paper has been assumed to be 2 Gy/fraction).If the equivalent dose for late effects is calculated using

eq. 2 above, the implicit assumption in this calculation isthat doses delivered to the normal tissues were equal todoses delivered to the tumor (which is true for externalbeam radiotherapy). However, under certain circumstances(e.g., with HDR brachytherapy), this assumption may not betrue, because the dose given to normal tissues is reduced dueto the fall-off in dose with distance. For example, if the doseto normal tissue is estimated to be 70% of the prescribeddose to the tumor in HDR brachytherapy, a dose reductionfactor (DMF) of 0.7 would need to be applied to obtain themodified, more realistic late normal tissue effects using theformulas

BEDHDR ! n*d*DMF*#1"#d*DMF!/" $$ (3)

DEq!BEDHDR

#1"dREF!/"$#

n*d*DMF*#"1#d*DMF!/" $$#1"dREF!/"$

(4)

512 I. J. Radiation Oncology ● Biology ● Physics Volume 46, Number 2, 2000

SUMMARY

A simple Excel spreadsheet program has been developedto assist clinicians to easily calculate equivalent doses to beused in HDR brachytherapy regimens. The novelty of thisprogram is that the equivalent doses are expressed as ifgiven at 2 Gy per fraction rather than as BED values, and a

more realistic equivalent normal tissue effect is obtained byapplying a DMF. Its ease of use should promote the use ofLQ radiobiological modeling to determine HDR brachyther-apy doses. The program is to be used judiciously as a guideonly and should be correlated with clinical outcome.

REFERENCES

1. Hall EJ. Time, dose, and fractionation in radiotherapy. In: HallEJ, editor. Radiobiology for the radiobiologist. 4th ed. Phila-delphia: J.B. Lippincott; 1994. 211–229.

2. Dale RG. The application of the linear quadratic dose-effectequation to fractionated and protracted radiotherapy. Br JRadiol 1985;58:515–528.

3. Nag S, Young D, Orton C, Erickson B. Survey of the Brachy-therapy Practice for Carcinoma of the Cervix: A Report of theClinical Research Committee of the American BrachytherapySociety. Gynecol Oncol 1999;73:111–118.

4. Gaspar LE, Qian C, Kocha WI, Coia LR, Herskovic A, Gra-ham M. A phase I/II study of external beam radiation, brachy-therapy and concurrent chemotherapy in localized cancer ofthe esophagus (RTOG 92-07): Preliminary toxicity report. IntJ Radiat Oncol Biol Phys 1997;37:593–599.

5. Ellis F. Is NSD-TDF useful to radiotherapy? Int J RadiatOncol Biol Phys 1985;11:1685–1697.

6. Barendsen GW. Dose fractionation, dose-rate and iso-effectrelationships for normal tissue responses. Int J Radiat OncolBiol Phys 1982;8:1981–1997.

7. Fowler JF. The linear-quadratic formula and progress in frac-tionation. Br J Radiol 1985;58:515–528.

8. Thames HD. An “incomplete-repair” model for survival afterfractionated and continuous irradiation. Int J Radiat Biol1985;47:319–339.

9. Brenner DJ, Hall EJ. The origins and basis of the linear-quadratic model. Int J Radiat Oncol Biol Phys 1992;23:252.

10. Brenner DJ, Hlatky LR, Hahnfedlt PJ, Huang Y, Sachs RK.The linear-quadratic model and most other common radiobi-ological models result in similar predictions of time–doserelationships. Radiat Res 1998;150:83–91.

11. Dale RJ, Jones B. The clinical radiobiology of brachytherapy.Br J Radiol 1998;71:465–483.

12. Orton C. Radiobiology. In: Nag S, editor. Principles andpractice of brachytherapy. Armonk, NY: Futura; 1997. 27–45.

13. Barton M. Tables of equivalent dose in 2 Gy fractions: Asimple application of the linear quadratic formula. Int J RadiatOncol Biol Phys 1995;31:371–78.

14. Brenner DJ, Hall EJ. Fractionation and protraction for radio-therapy of prostate carcinoma. Int J Radiat Oncol Biol Phys1999;43:1095–1101.

APPENDIX 1:BIO-EQUIVALENCE CALCULATIONS FOR

MULTIPLE MODALITY RADIATION TREATMENTS

The dose effect relationship in radiation therapy is not alinear relationship, but follows a LQ function. Hence, dosesdelivered by different modalities cannot be added to eachother to predict the effect of the combined modality treat-ment. One way to calculate the BEDs of different dosefractionation schemes is to use the LQ equation, using theformula

BED! nd !1 "d(!/"" (1)

where n ! the number of fractions and d ! the dose perfraction. To express the results in terms more familiar toclinicians, the BED was converted back to equivalent doses(DEq) as though given as conventionally fractionated irra-diation given at 2 Gy/day for tumor and late effects respec-tively using the formula

DEq !BED

#1" dREF(!/")$

(2)

where dREF ! the reference dose per fraction for a conven-tionally fractionated external beam treatment to be used for

calculating the equivalent dose (which for the purposes ofthis paper has been assumed to be 2 Gy/fraction).If the equivalent dose for late effects is calculated using

eq. 2 above, the implicit assumption in this calculation isthat doses delivered to the normal tissues were equal todoses delivered to the tumor (which is true for externalbeam radiotherapy). However, under certain circumstances(e.g., with HDR brachytherapy), this assumption may not betrue, because the dose given to normal tissues is reduced dueto the fall-off in dose with distance. For example, if the doseto normal tissue is estimated to be 70% of the prescribeddose to the tumor in HDR brachytherapy, a dose reductionfactor (DMF) of 0.7 would need to be applied to obtain themodified, more realistic late normal tissue effects using theformulas

BEDHDR ! n*d*DMF*#1"#d*DMF!/" $$ (3)

DEq!BEDHDR

#1"dREF!/"$#

n*d*DMF*#"1#d*DMF!/" $$#1"dREF!/"$

(4)

512 I. J. Radiation Oncology ● Biology ● Physics Volume 46, Number 2, 2000

The�Linear-Quadratic�Model�Is�anAppropriate�Methodology�for�DeterminingIsoeffective�Doses�at�Large�Doses�Per�FractionDavid�J.�Brenner,�PhD,�DSc

The�tool�most�commonly�used�for�quantitative�predictions�of�dose/fractionation�dependen-cies� in� radiotherapy� is� the� mechanistically� based� linear-quadratic� (LQ)� model.� The� LQformalism�is�now�almost�universally�used�for�calculating�radiotherapeutic�isoeffect�dosesfor�different�fractionation/protraction�schemes.�In�summary,�the�LQ�model�has�the�follow-ing� useful� properties� for� predicting� isoeffect� doses:� (1)� it� is� a� mechanistic,� biologicallybased�model;�(2)�it�has�sufficiently�few�parameters�to�be�practical;�(3)�most�other�mecha-nistic�models�of�cell�killing�predict�the�same�fractionation�dependencies�as�does�the�LQmodel;�(4)�it�has�well-documented�predictive�properties�for�fractionation/dose-rate�effectsin�the�laboratory;�and�(5)�it�is�reasonably�well�validated,�experimentally�and�theoretically,�upto�about�10�Gy/fraction�and�would�be�reasonable�for�use�up�to�about�18�Gy�per�fraction.�Todate,�there�is�no�evidence�of�problems�when�the�LQ�model�has�been�applied�in�the�clinic.Semin�Radiat�Oncol�18:234-239�©�2008�Elsevier�Inc.�All�rights�reserved.

L�et�us�start�from�the�premise�that�we�need�some�model�forcalculating� isoeffect� doses�when� alternate� fractionation

schemes�are�considered.�In�addition,�apart�from�increasinginterest�in�alternative�fractionation/protraction�schemes,�it�isessential�that�we�know�how�to�compensate�appropriately�formissed�radiotherapy�treatments.

The�tool�most�commonly�used�for�quantitative�predic-tions�of�dose/fractionation�dependencies�is�the�linear-qua-dratic�(LQ)�formalism.1-5�In�radiotherapeutic�applications,the�LQ�formalism�is�now�almost�universally�used�for�cal-culating�isoeffect�doses�for�different�fractionation/protrac-tion�schemes.

In�contrast�to�earlier�methodologies,�such�as�cumulativeradiation�effect,�nominal�standard�dose,�and�time-dose�fac-tor,6,7� which�were�essentially�empirical�descriptions�of�pastclinical�data,�the�LQ�formalism�has�become�the�preferred�toollargely�because�it�has�a�somewhat�more�biological�basis,�withtumor�control�and�normal�tissue�complications�specificallyattributed� to�cell�killing.�By�contrast,�descriptive�empiricalmodels�can�go�disastrously�wrong�if�used�outside�the�dose/

fractionation�range�from�which�they�were�derived,�as�whenNSD�was�applied�to�large�doses�per�fraction.8,9

MechanisticBackground�to�the�LQ�ModelIt� is� clear� that� radiotherapeutic� response,� both� for� tumorcontrol� and� for� complications,� is� dominated� by� cell� kill-ing,2,10,11� and�LQ�is�a�mechanistic�model�of�cell�killing.�Un-derlying� the� application�of� LQ� to� fractionation/protractioneffects�is�pairwise�misrepair�of�primary�lesions�such�as�dou-ble-strand�breaks�(DSBs)�or�base�damage�(hereon�in�we�shallrefer�to�DSB�as�the�primary�lesion,�but�base�damage�sites�maywell�also�be�relevant�here12).�As�schematized�in�Figure�1,�cellkilling�occurs�via�chromosome�aberrations�such�as�dicentricaberrations,13� which�are�formed�when�pairs�of�nearby�DSBwrongly� rejoin� to� one� another.14� Protracting� the� exposuretime�potentially�allows�the�first�DSB�to�be�repaired�before�thesecond� is� produced,� and� the� LQ� approach� quantifies� thiseffect.5� Nowadays,� this�binary�DSB�misrepair�model� is� themost�usual�way�to�motivate�the�standard�LQ�approach,�butdifferent�biological�rationales�for�the�same�mathematical�for-malism�have�also�been�given,�as�we�will�discuss.

It�is�important�to�stress�here�that�the�standard�LQ�formal-ism, as applied to time-dose relationships, is not merely atruncated power series in dose. Its key feature here is a spe-cific mechanistically based functional form for the protrac-

Center for Radiological Research, Columbia University Medical Center, 630West 168th Street, New York, NY.

Supported by NIH grants U19 AI-067773 and P41 RR-11623.Address reprint requests to David J. Brenner, PhD, Center for Radiological

Research, Columbia University Medical Center, 630 West 168th Street,New�York,�NY�10032.�E-mail:�[email protected]

234 1053-4296/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.semradonc.2008.04.004

AAPM REPORT NO. 166

The Use and QA of Biologically RelatedModels for Treatment Planning

Report of AAPM Task Group 166of the Therapy Physics Committee

March 2012

© 2012 by American Association of Physicists in Medicine

DISCLAIMER: This publication is based on sourcesand information believed to be reliable, but theAAPM, the authors, and the editors disclaim any war-ranty or liability based on or relating to the contents ofthis publication.

The AAPM does not endorse any products, manufac-turers, or suppliers. Nothing in this publication shouldbe interpreted as implying such endorsement.

EXAMPLE: HDR BRACHYTHERAPY FOR CERVICAL CANCER

TUMOR Point A(Physical dose)

Point A(Equivalent dose)

EBRT 25fr x 1.8Gy(45 Gy) 44 Gy EQD2 (α/β=10)

BT 4fr x 7Gy(28 Gy) 40 Gy EQD2 (α/β=10)

Total 73 Gy 84 Gy EQD (α/β=10)

EXAMPLE: HDR BRACHYTHERAPY FOR CERVICAL CANCER

TUMOR Point A(Physical dose)

Point A(Equivalent dose)


BT 4fr x 7Gy(28 Gy) 40 Gy EQD2 (α/β=10)


OAR Dose to OAR(Physical dose)

Dose to OAR(Equivalent dose)


BT 4fr x 4.9Gy (70% of PtA)(20 Gy) 31 Gy EQD2 (α/β=3)


Com

plic

atio

ns (%

)

0,0

20,0

40,0

60,0

80,0

100,0

BED (Gy3)100 120 140 160 180 200

G1-G4G3-G4

Ogino I, et al. Late rectal complication following high dose rate intracavitary brachytherapy in cancer of the cervix. IJRO 1995; 31: 725

BED < 119 keeps rectal G3-4 < 5%BED < 124 keeps rectal G3-4 < 10%

Num

ber o

f pat

ients

0 %

25 %

50 %

75 %

100 %

BED (Gy3)125 175 225 275 325 375

CDDP - No tox CDDP - Tox

Clark B, et al. The prediction of late rectal complications in patients treated with high dose-rate brachytherapy for carcinoma of the cervix. IJRO 1997; 38: 989-993

D0.1cc (Tables 1 and 2). Figure 1 shows the dose effect for G2to G4 rectal side effects; with a threshold of around 60 Gy forD2cc, a dose of 78 Gy results in a 10% probability of $G2side effects.

Bladder toxicityTwenty patients experienced cystitis with hematuria, dys-

uria, and incontinence (G1–G2). One patient experiencedurinary incontinence with 1- to 2-h intervals (G3). Two pa-tients developed a severe late adverse effect 4 years aftertreatment, consisting of refractory cystitis and excruciatingdysuria. Both patients underwent cystectomy (G4). Grades3 and 4 side effects were verified by cystoscopy. No signif-icant dose response was observed for G1 to G4 side effects.However, for complications $G2, dose effect curves couldbe generated for all DVH parameters with p values of<0.05 (Tables 1 and 2). The best defined curve was forD1cc and D2cc (Fig. 2).

Sigmoid toxicityComplete obstruction of the rectosigmoidal junction

occurred in 2 patients, who required surgical intervention

(G4). One patient presented with alternating diarrhea andconstipation caused by a stricture of the lower sigmoid, butno surgical treatment was needed (G2). The mean D2cc,D1cc , and D01.cc doses given to these 3 patients were 77 !11 Gy, 84 !14 Gy, and 104 ! 24 Gy. No reliable doseresponse effect could be analyzed due to insufficient data.

DISCUSSION

Following the DVH parameters recommended by GEC-ESTRO, the D2cc, D1cc, and D0.1cc values are systematicallyand routinely used in centers where MR IGBT for cervicalcancer has been implemented. The clinical results of the firstlarge single-institution report show excellent local controlrates through dose-volume adaptation and dose escalation(2). Two recently published studies analyzing the samepatient population showed strong evidence for the clinicalrelevance of the GEC/ESTRO target volumes and the prog-nostic value of target-related DVH parameters for local con-trol. Based on a previous analysis (12, 19), clinical cut-offvalues for various DVH parameters have been recommen-ded. The aim of the present study with the same patientpopulation was to establish complete dose response relation-ships for various DVH parameters for the rectum and theurinary bladder.

RectumFor rectal morbidity, D2cc and D1cc show a well-defined

dose response for either G1 to G4 or G2 to G4 toxicity.The 5% incidence dose is in the range from 60 to 80 Gydue to the shallow gradient of the curve. In contrast, thedoses for an incidence of 10% or 20% increase with decreas-ing volume.

In a previous analysis (17), the ED10 and ED5 of the D2cc

for clinical changes according to the LENT SOMA scalevalues $2 was 65 Gy for both EDs, compared to 67 Gyand 78 Gy in the present work. This slight discrepancymust be attributed to the negative patient selection in theprevious study.

Table 2. Probability of G2–G4 side effects according to doselevels

Dose volume

Probability of EQD2 for G2–G4 side effects (Gy)for the incidence rates shown (95% CI)

5% 10% 20% p value

RectumD2cc 67 (30–79) 78 (66–110) 90 (78–171) 0.0178D1cc 71 (0"89) 87 (69–209) 104 (87–443) 0.0352D0.1cc 83 132 186 0.1364

BladderD2cc 70 (0"95) 101 (29–137) 134 (110–371) 0.0274D1cc 71 (0–107) 116 (17–169) 164 (129–498) 0.0268D0.1cc 61*(0–155) 178 (0–368) 305 (213–2126) 0.0369

Abbreviation: CI = confidence interval.Probability analyses for G2–G4 side effects according to dose

levels for D2cc, D1cc, and D0.1cc using probit.* lower level due to broad CI.

D2cc [Gy]

20 40 60 80 100 120 140 160 180 200

4-2G

stceffeedis

mutcerfoytilibaborP

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Fig. 1. Relationship between D2cc and late side effects in the rec-tum.

D2cc [Gy]

50 100 150 200 250 300 350 400

eddalbfoytilibaborP

4-2G

stceffeedisr

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Fig. 2. Relationship between D2cc and late side effects in the uri-nary bladder.

Dose effect for late pelvic complications d P. GEORG et al. 655







DISCUSSION







Dose volume


5% 10% 20% p value





D2cc [Gy]

20 40 60 80 100 120 140 160 180 200

4-2G

stceffeedis

mutcerfoytilibaborP

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


D2cc [Gy]

50 100 150 200 250 300 350 400

eddalbfoytilibaborP

4-2G

stceffeedisr

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0









DISCUSSION







Dose volume


5% 10% 20% p value





D2cc [Gy]

20 40 60 80 100 120 140 160 180 2004-2

Gstceffe

edismutcerfo

ytilibaborP0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


D2cc [Gy]

50 100 150 200 250 300 350 400

eddalbfoytilibaborP

4-2G

stceffeedisr

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0



Georg P, Potter R, Georg D et al. Dose effect relationship for late side effects of the rectum and urinary bladder in magnetic resonance image-guided adaptive cervix cancer brachytherapy. Int J Radiat Oncol Biol Phys. 2012;82:653-657.

Dimopoulos JC, Potter R, Lang S et al. Dose-effect relationship for local control of cervical cancer by magnetic resonance image-guided brachytherapy. Radiother

Oncol. 2009;93:311-315.

Acknowledgements

The Department of Radiotherapy at the Medical University ofVienna receives financial and/or equipment support for researchand educational purposes from Nucletron B.V., Varian Medical Sys-tems, Inc., and Isodose Control B.V. This study has been in part sup-ported by the following grant: ‘‘Jubilaeumsfonds deroesterreichischen Nationalbank, Nr. 10937”.

References

[1] Lindegaard JC, Tanderup K, Nielsen SK, Haack S, Gelineck J. MRI-guided 3Doptimization significantly improves DVH parameters of pulsed-dose-ratebrachytherapy in locally advanced cervical cancer. Int J Radiat Oncol BiolPhys 2008;71:756–64.

[2] De Brabandere M, Mousa AG, Nulens A, Swinnen A, Van Limbergen E. Potentialof dose optimisation in MRI-based PDR brachytherapy of cervix carcinoma.Radiother Oncol 2008;88:217–26.

[3] Kirisits C, Pötter R, Lang S, Dimopoulos J, Wachter-Gerstner N, Georg D. Doseand volume parameters for MRI based treatment planning in intracavitarybrachytherapy of cervix cancer. Int. J Radiat Oncol Biol Phys 2005;62:901–11.

[4] Pötter R, Dimopoulos J, Georg P, et al. Clinical impact of MRI assisted dose–volume adaptation and dose escalation in brachytherapy of locally advancedcervix cancer. Radiother Oncol 2007;83:148–55.

[5] Weitmann HD, Pötter R, Waldhäusl C, et al. Pilot study in the treatment ofendometrial carcinoma with 3D image-based high-dose-rate brachytherapyusing modified Heyman packing: clinical experience and dose–volumehistogram analysis. Int J Radiat Oncol Biol Phys 2005;62:468–78.

[6] Gerbaulet A, Pötter R, Haie-Meder C. Cervix cancer. In: Gerbaulet A, Pötter R,Mazeron JJ, Meertens H, Van Limbergen E, editors. GEC ESTRO handbook ofbrachytherapy. Brussels: ESTRO; 2002. p. 301–63.

[7] Shin K, Kim T, Cho J, et al. CT-guided intracavitary radiotherapy for cervicalcancer: comparison of conventional point A plan with clinical target volume-based three-dimensional plan using dose–volume parameters. Int J RadiatOncol Biol Phys 2006;64:197–204.

[8] Haie-Meder C, Pötter R, van Limbergen E, et al. Recommendations from thegynaecological (GYN) GEC ESTRO working group: concepts and terms in 3Dimage based 3D treatment planning in cervix cancer brachytherapy withemphasis on MRI assessment of GTV and CTV. Radiother Oncol2004;74:235–45.

[9] Pötter R, Haie-Meder C, van Limbergen E, et al. Recommendations fromgynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3Dimage-based treatment planning in cervix cancer brachytherapy-3D dose–volume parameters and aspects of 3D image-based anatomy, radiation physics,radiobiology. Radiother Oncol 2006;78:67–77.

[10] Dimopoulos JCA, Lang S, Kirisits C, et al. Dose–volume histogram parametersand local tumor control in MR image guided cervical cancer brachytherapy. IntJ Radiat Oncol Biol Phys 2009;75:56–63.

[11] Chargari C, Magné N, Dumas I, et al. Physics contributions and clinical outcomewith 3D-MRI-based pulsed-dose-rate intracavitary brachytherapy in cervicalcancer patients. Int J Radiat Oncol Biol Phys 2009;74:133–9.

Table 3Dose–response parameter for D90 and D100 of the HR CTV and the IR CTV for the tumour categories for which a significant dose–effect was observed.

Tumour group ED50 [95% CI] ED70 [95% CI] ED80 [95% CI] ED90 [95% CI] c-value

D90 HR CTV2 61 [22;70] 72 [57;82] 80 [71;97] 92 [82;131] 1.12b 68 [30;78] 77 [67;118] 83 [74;137] 91 [80;228] 2.0

Total 45 [<0;60] 61 [21;72] 71 [50;81] 86 [77;113] 0.6

D100 HR CTV2 54 [41;58] 59 [53;64] 63 [59;70] 68 [64;83] 0.52b 56 [<0;63] 62 [55;123] 66 [60;197] 72 [64;314] 1.9

Total 33 [<0;47] 46 [<0;55] 55 [17;63] 67 [59;103] 1.9

D90 IR CTV2 53 [21;59] 60 [48;66] 65 [59;76] 71 [66;102] 1.6

D100 IR CTV2 47 [21;51] 52 [42;55] 55 [51;62] 59 [56;81] 2.1

Dose effect parameters have been calculated by probit analyses (EDxx: dose, at which cure can be expected in xx % of the patients; CI, confidence interval; c, normalized dose–response gradient [20]).

Fig. 1. Dose–response relationships (D90 in the HR CTV) for local control in the total patient population (left panel), for group 2 (large tumours, middle panel) and for group2b (large, non-responding tumours, right panel). Particular values of the curves are presented in Table 3.

314 Dose–effect relationship in cervical cancer

Acknowledgements

The Department of Radiotherapy at the Medical University ofVienna receives financial and/or equipment support for researchand educational purposes from Nucletron B.V., Varian Medical Sys-tems, Inc., and Isodose Control B.V. This study has been in part sup-ported by the following grant: ‘‘Jubilaeumsfonds deroesterreichischen Nationalbank, Nr. 10937”.

References

[1] Lindegaard JC, Tanderup K, Nielsen SK, Haack S, Gelineck J. MRI-guided 3Doptimization significantly improves DVH parameters of pulsed-dose-ratebrachytherapy in locally advanced cervical cancer. Int J Radiat Oncol BiolPhys 2008;71:756–64.

[2] De Brabandere M, Mousa AG, Nulens A, Swinnen A, Van Limbergen E. Potentialof dose optimisation in MRI-based PDR brachytherapy of cervix carcinoma.Radiother Oncol 2008;88:217–26.

[3] Kirisits C, Pötter R, Lang S, Dimopoulos J, Wachter-Gerstner N, Georg D. Doseand volume parameters for MRI based treatment planning in intracavitarybrachytherapy of cervix cancer. Int. J Radiat Oncol Biol Phys 2005;62:901–11.

[4] Pötter R, Dimopoulos J, Georg P, et al. Clinical impact of MRI assisted dose–volume adaptation and dose escalation in brachytherapy of locally advancedcervix cancer. Radiother Oncol 2007;83:148–55.

[5] Weitmann HD, Pötter R, Waldhäusl C, et al. Pilot study in the treatment ofendometrial carcinoma with 3D image-based high-dose-rate brachytherapyusing modified Heyman packing: clinical experience and dose–volumehistogram analysis. Int J Radiat Oncol Biol Phys 2005;62:468–78.

[6] Gerbaulet A, Pötter R, Haie-Meder C. Cervix cancer. In: Gerbaulet A, Pötter R,Mazeron JJ, Meertens H, Van Limbergen E, editors. GEC ESTRO handbook ofbrachytherapy. Brussels: ESTRO; 2002. p. 301–63.

[7] Shin K, Kim T, Cho J, et al. CT-guided intracavitary radiotherapy for cervicalcancer: comparison of conventional point A plan with clinical target volume-based three-dimensional plan using dose–volume parameters. Int J RadiatOncol Biol Phys 2006;64:197–204.

[8] Haie-Meder C, Pötter R, van Limbergen E, et al. Recommendations from thegynaecological (GYN) GEC ESTRO working group: concepts and terms in 3Dimage based 3D treatment planning in cervix cancer brachytherapy withemphasis on MRI assessment of GTV and CTV. Radiother Oncol2004;74:235–45.

[9] Pötter R, Haie-Meder C, van Limbergen E, et al. Recommendations fromgynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3Dimage-based treatment planning in cervix cancer brachytherapy-3D dose–volume parameters and aspects of 3D image-based anatomy, radiation physics,radiobiology. Radiother Oncol 2006;78:67–77.

[10] Dimopoulos JCA, Lang S, Kirisits C, et al. Dose–volume histogram parametersand local tumor control in MR image guided cervical cancer brachytherapy. IntJ Radiat Oncol Biol Phys 2009;75:56–63.

[11] Chargari C, Magné N, Dumas I, et al. Physics contributions and clinical outcomewith 3D-MRI-based pulsed-dose-rate intracavitary brachytherapy in cervicalcancer patients. Int J Radiat Oncol Biol Phys 2009;74:133–9.

Table 3Dose–response parameter for D90 and D100 of the HR CTV and the IR CTV for the tumour categories for which a significant dose–effect was observed.

Tumour group ED50 [95% CI] ED70 [95% CI] ED80 [95% CI] ED90 [95% CI] c-value

D90 HR CTV2 61 [22;70] 72 [57;82] 80 [71;97] 92 [82;131] 1.12b 68 [30;78] 77 [67;118] 83 [74;137] 91 [80;228] 2.0

Total 45 [<0;60] 61 [21;72] 71 [50;81] 86 [77;113] 0.6

D100 HR CTV2 54 [41;58] 59 [53;64] 63 [59;70] 68 [64;83] 0.52b 56 [<0;63] 62 [55;123] 66 [60;197] 72 [64;314] 1.9

Total 33 [<0;47] 46 [<0;55] 55 [17;63] 67 [59;103] 1.9

D90 IR CTV2 53 [21;59] 60 [48;66] 65 [59;76] 71 [66;102] 1.6

D100 IR CTV2 47 [21;51] 52 [42;55] 55 [51;62] 59 [56;81] 2.1

Dose effect parameters have been calculated by probit analyses (EDxx: dose, at which cure can be expected in xx % of the patients; CI, confidence interval; c, normalized dose–response gradient [20]).

Fig. 1. Dose–response relationships (D90 in the HR CTV) for local control in the total patient population (left panel), for group 2 (large tumours, middle panel) and for group2b (large, non-responding tumours, right panel). Particular values of the curves are presented in Table 3.

314 Dose–effect relationship in cervical cancer

CONCLUSIONS

Dopt

Effect

TCPNTCP

UTCP

TCPNTCP

UTCP

Effect

Dopt

basic clinical radiobiology · 2018. 5. 9. · basic clinical radiobiology alfredo polo md, phd...

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