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**Author(s): John T. Lyman
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Source: Radiation Research Supplement, Vol. 8, Heavy Charged Particles in Research and

Medicine. Proceedings of a Symposium Held at the Lawrence Berkeley Laboratory, University

of California, Berkeley, California, May 1-3, 1985 (Nov., 1985), pp. S13-S19

Published by: Radiation Research Society

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154. Sophisticated treatment planning. a method is needed to determine the complication probabilities for the different normal tissues which will be affected by the treatment. To fully optimize a treatment plan (maximize the tumor dose without exceeding an acceptable complication probability).3. the degree of uniformity or nonuniformity of the irradiation may be S-13 This content downloaded from 200. Suppl. INTRODUCTION Treatment planning optimization involves selection of an acceptable plan that controls the local and regional spread of cancer without causing normal tissue complications (1). Thesevaluesarethe bestguidelinesforestimatingcomplicationprobabilitiesin tissuesthat receivea uniformdose to a fractionof the tissue and no dose to the remainder.Frequentlythe normaltissuesarenot uniformlyirradiatedas is demonstrated by dose-volumehistogramsfor differenttreatmentplans. must be examined to ascertain that the target is adequately treated and the normal tissues are adequately spared. particularly for particle beam therapy. 104. To evaluate a given plan.California94720 as AssessedfromDose-VolumeHistograms. LYMAN LawrenceBerkeleyLaboratory. S-13-S-19(1985). Decisions to maximally spare normal structures must be tempered by the possibility of not adequately treating normal tissues bearing occult disease.RADIATION RESEARCH 104. the radiotherapistmust integrate the information presented by series of isodose distributions superimposed on the CT images.Thetolerancedosevaluesavailableforvarious normaltissuesare usuallyassumedto applyto partialor full volumesof the tissuewhichhave beenuniformlyirradiated. T.goodtreatmentplansdelivera highuniformdose to the targetvolume andlowerdosesto thesurrounding normaltissues. which demonstrate the target volume and the critical tissues. Optimizationof a treatmentplan for radiationtherapywill producea plan with the highest probabilityfortumorcontrolwithoutexceedingan acceptablecomplicationrate. LYMAN. If dose-volume histograms are calculated from the data presented in the isodose distributions. S-13-S-19 (1985) ComplicationProbabilityas Assessed from Dose-Volume Histograms JOHN T. ComplicationProbability Res..Berkeley. All the slices.202 on Fri.A recursivealgorithmwhichuses these dose-volumehistogramsto tolerancedosedatahasbeenwrittenand can be appliedto arbitrary estimatethe complicationprobability. Dose-volumehistograms areone meansof evaluatingthe uniformityof the irradiation on the tissues.8.J.In general. 20 Feb 2015 13:02:23 PM All use subject to JSTOR Terms and Conditions 0033-7587/85$3.00 .To achievethis goal it is necessaryto havea meansto estimateprobabilitiesof localcontroland normaltissue complication.Radiat. involves three-dimensional calculations or a series of two-dimensional calculations using adjacent slices of CT data (2). Heavy charged-particlebeams offer a means for sparing normal tissues from irradiation that is not available with conventional radiations.

The bestexampleof the tolerancedose (in Gy) is forthe heart(TableI). The isodose distributions are needed to determine the location of the high-dose regions. The identification of the optimal plan is also subject to clinical judgment of the acceptability of the plan and the risk/ benefit for each individual patient. M.J.S-14 JOHN T. Y. H. Therefore the dose-volume histogramsdo not substitutefor the isodose distributionsin the evaluation of a treatment plan.Thereare manyotherfactorsthat are involved.3.This surfacewasdeterminedby assumingthat the volumedependencecouldbe represented by a power-lawrelationship(7. R.or fractionof the organtreated. G. arefor treatmentwith low-LETradiationsand a conventionalfractionschedule. Chen. whilethe remainingpointrepresents thecollectivejudgmentof several experiencedtherapistswho are participatingin an NCI-sponsored projectto evaluateparticletreatment plans. 8). An evaluation of several representative cases has led to some generalized conclusions which may provide guidance to the radiotherapist in assessing appropriate treatment plans.and W. which are the best available. Kessler. 2 M.G. Pitluck. Phys. This approach is being explored in the optimization of heavy-charged-particle treatment plans. T. 1). R. Zink.however.Treatment withphotonsforcarcinomaof the esophagus. (5).respectively. Castro.and M. The purpose of this study is to develop a method to estimate the complication probability of a normal tissue structure from a dose-volume histogram and data from a population of radiation therapy patients.are not as completeor as firmas desirable.Thereforeit mustbe assumedthattherecouldbe significanterrorsin the estimationof theportionof theorganortissue which receivedthe irradiationand in the uniformityof the irradiation. 20 Feb 2015 13:02:23 PM All use subject to JSTOR Terms and Conditions .Biol.and representtwo points on what is assumedto be a sigmoid-shaped dose-response curve.1'2 The histograms give another way to look at the plan and may give some additional information that is not readily apparent when using the isodose distributions. T.Oncol. J.Thesevalueswerederivedfrom observationof patientswho weretreatedbeforethe daysof sophisticatedtreatmentplanning.Biol. R. M. 'S. The estimates of the complication probability can then be used to optimize a treatment plan. METHODS Datafromthe literaturewhichmightaid in thisrankingarevaluesof the tolerancedoseof varioustissues (4-6).J. A fullsetof datacanbe represented surfacethatrepresents theprobability of complication by a three-dimensional as a functionof both the volumeand the dose (Fig.Oncol.Manuscriptsubmittedto Int.S.Thesedata. Saunders. Tolerancedosesare usuallygivenas a functionof beamarea. Chen. Castro. LYMAN quickly assessed because a single histogram can present dose uniformity information which is contained in a number of sets of isodose distributions (3). Woodruff. Saunders. T. The techniques developed in this work are equally applicable to optimization of treatment plans for other radiations. but augment them. Collier. Lyman. A high-dose region in the histogram may represent a high-dose region that is related to a single CT slice or may represent a contiguous region related to adjacent CT slices or even a number of isolated high-dose regions related to the same or different slices. Datafor otherpartialvolumesand tolerancelevelscan be obtainedby interpolationor extrapolation.J.154.or lengthof the irradiatedportionof structure.forthe momentthisand all theseotherfactorswill be heldconstant. Radiat. Austin-Seymour. The dataforthe partial-volume irradiations arefromRubinet al.The TD50and TD5are the dosesthat wouldresultin 50 and 5%complicationprobabilitiesafter5 years.J. M.W.Manuscript planningstudycomparesheavyion radiotherapy submittedto Int. This content downloaded from 200.J.K. Phys. M.Dose volumehistogramanalysisof liverradiationtolerance. Y.These data.whicharepartof the folkloreof radiotherapy.These data imply that the complicationprobabilityis a functionof both the percentagevolume irradiatedand the absorbeddose receivedby the volume. Radiat.202 on Fri. most noticeablythe fractionationscheme.

betweenthehistograms.carbon. (1) whereTD(V) is the tolerancedose for a givenpartialvolume(V). tolerancedoses for the heart(in Gy) calculatedwith Eqs.Forthe two-fieldarrangements arrangements samehistogram.However. n.an estimateof the probabilityfor complicationcan also be obtained. Calculatedvaluesfor pointsthat correspondto valuesin TableI are underlined. TD5o(). ranking being andeventherelativerankingof thesehistograms It is notdifficultto determinethe mostdesirabledistribution by visualinspection. studiesusingthree-dimensional Cumulativedose-volumehistogramsfora kidneyfor severalpossibletreatmentplansareshownin Fig.5 Volume v \D 20 v 4U ose (Gray) Dose (Gray) of the probabilityof complicationfor the heartas a surfacerepresentation FIG. of thedifferences thesemethodsdo notprovidean estimateof theclinicalsignificance Providedthereare sufficientdatato obtainan estimateof the three-dimensional complicationsurface.S-15 COMPLICATION PROBABILITY TABLEI ToleranceDosesfor Heart % Volume TDso TD5 25 60 80 55 70 45 35 100 TD(V) TD(I)/j".Thethree-dimensional surfacecan then be completelydefinedby the threeparameters.andn is a fittedparameter. - (2) where t = (D .Thefour-fieldarrangement givesthe lowestdoseswithhelium withthethree-field occurs This same neon. A three-dimensional function of the dose and the partial volume which is uniformily irradiated.154. 20 Feb 2015 13:02:23 PM All use subject to JSTOR Terms and Conditions .3. which is lower than lower than carbon arrangements.The histogramswerederivedfromtreatmentplansusinghelium. This content downloaded from 200.as such. TD( ) is the tolerancedose for the full is represented Thedosedependence volume. three.the one withthe largestdose.The averagedoseor the integraldosecan alsobe usedto aid in the rankings. 2. bytheintegralof a normaldistribution of a sigmoidcurve). and m.theyshouldbe usedwithcaution.sincethesehistogramsrepresenta fairly PC0.TD5o(V))/a( V)).1.0 Partial 0. Thesehistogramsshowthe fractionof the organwhichreceivesa dose equalto or greaterthana given value.Thesevaluesare preliminaryestimatesbasedon publishedand unpublisheddata and willemergefrom opinions. and m for a selectedlist of organsand tissuesare given in TableIII.It is anticipatedthatbetterparameters treatmentplanningsystemsanddose-volumehistograms.or neon beamswith field all beamsproducedessentiallythe of two. (one of severalpossiblerepresentations PC = e-'2/2dt.5- 0 1.(1) Table II is an exampleof partial-volume and (2) and parametersderivedfromthe data in TableI.202 on Fri. This curve is completely defined by the mean (TD50(V)) and the standard deviation(a(V))whichforthecurrentworkhasbeenapproximated by m X TD5( V).or fourfields.Valuesof TD5o(1).n.

Thedifferences uniformpartial-volume give a measureof the clinicallyimportantdifferencesbetweenthe histograms.3 70.1 0.8 66.900 0.600 0.0 of complication betweenthe estimatesof the probability irradiation.05 0.05 0.1 0.2 62.1 0.10 0.750 0.7 83.1 0.10 0.05 0.0 0.154.550 0.000 93.5 70.5 56.0 55.1 0.0 50.250 0.0 62.450 0. LYMAN TABLEII DerivedToleranceDosesfor Heart V TDso(V) TD5(V) 0.1 0.05 0.40 0.0 60.1 0.4 39.1 0.2 43.1 0.0 35.1 0.9 45.10 0.9 59.1 0.2 49.9 35.0 41.5 47.0 22.400 0.5 59.5 66.1 This content downloaded from 200.05 0.4 46.0 72.20 0.2 43.S-16 JOHN T.15 0.2 55.0 64.8 76.05 0.15 0.1 0.350 0.1 0.1 0.650 0.9 78.1 0.35 0.950 1.1 0.500 0.Incidentally.0 36.the comparisonof the dose-volumehistogramsof the sameorgan TABLEIII Factorsfor DerivingToleranceDoses Organ/tissue TDso n m Bladder Bone Brain Brainstem Caudaequina Esophagus Eye Femoralhead Heart Intestine Kidney Liver Lung Mandible Opticnerve Parotid Pituitary Rectum Spinalcord Stomach 72.1 0.5 44.0 41.50 0.1 52.0 65.3.05 0.1 0.10 0.0 63.1 48.9 55.0 57.8 40.65 0.850 0.800 0.10 0.202 on Fri.200 0.0 77.with a target will yielda clinicallysignificant the two-fieldarrangements dose of 66 Gy.0 29.300 0. 20 Feb 2015 13:02:23 PM All use subject to JSTOR Terms and Conditions .5 54.0 64.0 70.9 35.1 0.0 50. only the histogramrepresenting probabilityof complication.4 41.700 0.In general.0 54.2 45.10 0.1 38.0 75.4 52.

whichis the numberof standarddeviationsbetweenthe mean(TD50(V))and the dose for the dose-volumestep in question(t = (D(V) .2Regionsof tissuesor organs with differentradiosensitivities can be handledin separatehistogramswith differenttoleranceparameters(8). B.Differencesare relatedto the numberof treatmentfieldsandthe typeof radiationemployed.hasbeenimplemented.fc.P. N Pc= - ( - Pc()).3 The algorithmis usedto determinean estimateof the complicationprobabilityfromthe two highestdose stepsof the histogram. This probability PIc. This content downloaded from 200. 20 Feb 2015 13:02:23 PM All use subject to JSTOR Terms and Conditions . When thereis more than one normalstructureat riskfor a severecomplication.3).4 0.havethesameradiosensitivity. Wolbarst. forbeingcomplicationfree.3. of tworivalplansmaynotbeas simpleastheseinitialconsiderations maysuggestbecausethetwodistributions mayhavedissimilarshapes(Fig. Implicitin this procedureis theassumptionthatall regionsof an organ. Thedifferencebetweenthesehistogramsis thatone histogramrepresents a treatmentplanthattakesa smallvolumeto a higherdose whileminimizingthe dose to a largervolume whilethe otherplan does the converse. (3) i=l Failureto controlthe tumorcan alsobe consideredas a treatmentcomplication. (1) and (2).6 0.the estimatesof the complicationscan be combinedto determinethe probabilityforany complication(9).a recursivehistogram-reduction algorithmhas beendeveloped.andthenthe algorithmis recursivelyusedto sumthe partialcontributionsfromthe remainingstepsof the histogram.A generalmethodof assessingcomplicationsfrom dose-volume histograms.To estimatecomplicationprobabilities forthe generalcase(one whichcannotbe approximated by a single-stephistogram). T. If the treatment plan is 3J. Cumulativedose-volumehistogramsfor the incidentalirradiationof a kidney.it is possibleto estimatethe probabilityof complication-free. forlocalcontrol. RESULTS There are some important deductions that can be made from the estimates of the complication probability as represented by Eqs. is then usedto obtainan optimizedtreatmentplan.Sometissueswillbe moretolerantof small-volumehighdose regionsthanothers.P.154.The measureof the complicationusedforthe histogramreductionis the standardized normaldeviate.(11).whichusesthedose-volumehistogramforthetargetvolume.S-17 COMPLICATION PROBABILITY (D E E 0 0.2..Pf = 1 .TD5o(V))/a(V))). andtheprobability Bycombiningtheprobabilities localcontrol.202 on Fri.Manuscriptsubmittedforpublication.The clinicalsignificanceof the dose distributionsrepresentedby thesehistogramsdependsuponthe typeof tissue. Lymanand A.A probabilityof tumorcontrolalgorithm(10). andno portionof the organis morecriticalthananotherfornormalfunction.represented in a singlehistogram.2 - 0 0 10 30 20 40 50 60 Percent Target Dose FIG.

better (lower likelihood of complications) plans may result. For the more general histograms (Fig. Assuming 50% of the heart was irradiatedwhen it was really 60% will result in a 10%errorin the tolerance dose (Table II). Factors such as fractionation scheme or adjuvant chemotherapy can also result in changes to the tolerance dose.2 02 0 10 20 30 40 50 60 Dose (Gray) FIG. Similarly. if the tolerance dose is 5% lower than expected the complication probability will also be doubled. LYMAN 0. This may result in deviating from standard protocols by using a lower tumor dose for some patients and a higher dose for other patients with similar type tumors.40. where there are no known tolerance dose data.S-18 JOHN T.Theseare more thanthoseof Fig. The result is the identification of the combination of patient and treatment plan which have high or low likelihood for complications. then an error which would result in a 5% overdose will double the complication probability. Cumulativedose-volumehistogramsfor the incidentalirradiationof a kidney. The algorithm used to determine the tolerance doses includes corrections for fraction sizes other than 2 Gy (12). 2). The expected result is the estimate calculated by Eqs. Errors in the estimation of the tolerance dose can result from the estimation of the volume irradiated. The estimates in these cases appear reasonable when one considers the dose-volume dependence of the tissue (Table III). there are no data for comparison. 3). If these individual variations are taken into consideration during the treatment planning process.3. This approachto optimization of treatment plans is being tested in an NCI-supported project on the evaluation of particletreatment plans. (1) and (2) when the histogram is approximated by a single step.2 andthebetterdistribution is notobvious.8 - E 06- 0. 3. This can be considered to be a predictive assay based on patient anatomy and the treatment plan. The histogram-reduction algorithm gives the expected result for simple histograms (Fig.Estimates of thecomplication complexhistograms probabilitycan aid in the selectionof the betterplan.202 on Fri.154. The estimates of the complication probabilities are also being compared with the clinical observations following heavy- This content downloaded from 200. DISCUSSION Individual variations in size and location of tumors can result in higher or lower estimates of complications. 20 Feb 2015 13:02:23 PM All use subject to JSTOR Terms and Conditions . designed to have a 5% complication probability.

J. Vaeth.Treatmentplansarenot optimizedunlesstheyhave takeninto accountthe individualvariationsin size. W. (Eds. 1975. R.Oncol. P. PITLUCK. 75-83 (1984). RUBINand G.1984.U.and locationof the normal criticalstructuresrelativeto the targetvolume.5. SVENSSON. doserateandiso-effectrelationships Dosefractionation. L.From the dose-volume histogramsand the tolerancedoses.8. CHEN. IEEE. L. J.8. 12. : Radiation Oncology. pp. pp.PROBABILITY COMPLICATION S-19 Thesecomparisonswill be helpfulin establishingthe irradiations.Comparisonsof the observedand the expectedcomplicationprobabilitieswould resultin betterpredictionsof the complicationsarisingfromthe nonuniformirradiationof the normaltissues. Phys. 11. ABRAMS. 264-268. R.Since the complicationprobabilitycan be verysensitiveto the dose and the tolerancedose. W.8.EighthInternational Conference in RadiationTherapy. P. Med. G.9. Delineationof anatomy.J. Phys. 10.Baltimore. and G. 385-395 (1982). The utility of computed tomography in radiation therapy: An estimate of outcome.and fractionationareimportantfactors. 1981-1997(1982). BARENDSEN.Biol. 9.pp.154. Phys. Radiat. PETERS.3.Oncol. SCHULTHEISS. M.202 on Fri.Int. Vol. G. COHEN. RadiationBiologyand RadiationPathology Syllabus. WOLBARST. REFERENCES of and preventability and F. ACKNOWLEDGMENTS Thisworkwassupportedin partby the NationalCancerInstitute.S. Cancer Treat.Phys. 1. H. 1-16.Models in radiotherapy: Volume effects.NationalInstitutesof Health. ZINK. J.). Set R. GIBBS. J. volume.Biol.Biol. CASTRO.The tissue factor in radiation oncology. 10. K. Phys. Departmentof EnergyunderContractDE-AC03-76SF00098.Oncol. PECK. 1983.Med. Frontiers of Radiation Therapy and Oncology (J. 3. University Park Press.Rev. D. Boca Raton. Y. AUSTIN-SEYMOUR. J. THAMES. M. fornormaltissueresponses.Dose volumehistogramsin treatmentplanningevaluationof on Usesof Computers carcinomaof the pancreas. RUBIN.Annu.This necessitatestreatmentplanningthe entirevolume containingthe structuresof interest. SAUNDERS. S. 2-7. Optimization of radiation therapy: Integral- responseof a modelbiologicalsystem. R. 410-415 (1983).Int. H. L. A.and R.In Proceedings. In 4. B. accurateestimatesof the dose-volume distributionswithin organsand tissues are needed. 777-787 (1983). Radiat. This content downloaded from 200. COHEN. treatmentplanning:I. 1771-1774 (1982). GOITEIN. M. 8.BiophysicalModelingin RadiationOncology. ORTON. LYMAN. M. 1799-1807(1979). Officeof EnergyResearch.33. PHILLIPS. 6.J. A. M. 7. validity histogram-reduction Whiletherearea numberof factorsthatcontributeto theprobability of complication.Biol.1972. J. American College of Radiology. 1761-1769(1982). 20 Feb 2015 13:02:23 PM All use subject to JSTOR Terms and Conditions .J. WITHERS. Int. Int. W.1'2 charged-particle of the algorithmand the data in TableIII.Biol. and L. STEWART complicationof radiationinjury.Public HealthServiceunderAgreementNo. Y01-CM-20211andtheOfficeof HealthandEnvironmental Research.Preventionof radiationinjury:Predictability 1. A. 6. Symp. L. shape. CASARETT. M. Int. T. CHIN. COOPER.R. Chicago. E. A direction for clinical radiation pathology: The tolerance dose. G.Oncol. R.and S.These estimatescan be usedto optimizetreatmentplans. 5. T.). Ed. it is well establishedthatdose. Radiat. T.CRC Press. 2. Radiat. Radiat. GOITEINand M. it is a simpleprocedureto estimatethe complicationprobabilities. Dose fractionation and volume effects in normal tissues and tumors. C.and T. A.Phys. COLLIER. M. T.Oncol.Multi-dimensional J.

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