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Int. J. Radiation Oncology Biol. Phys.. Vol. 34, No. 3. pp. 555-564. 1996Copyright 0 1996 Elsevier Science I nc.

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l Clinical Original Contribution

CONVENTIONAL VS. CONFORMAL RADIOTHERAPY FOR PROSTATE CANCER:PRELIMINARY RESULTS OF DOSIMETRY AND ACUTE TOXICITYALAN POLLACK, M.D., PH.D.,* GUNAR K. ZAGARS, M.D.,* GEORGE STARKSCHALL, PH.D.+

CONSTANCE H. CHILDMSS, B.S., C.M.D., R.T.(R)(T),t SUSAN KOPPLIN, R.N., B.S.N.,*ARTHUR L. BOYER, PH.D.+ AND ISAAC I. ROSEN, PH.D.+

Departments of *Radiotherapy and Radiation Physics, The University of Texas M. D. Anderson Cancer Center.15 15 Holcombe Boulevard, Houston, TXPurpose: To compare conformat radiotherapy using three dimensional treatment planning (3D-CRT) toconventional radiotherapy (Convert-RT) for patients with Stages T2-T4 adenocarc inoma of the prostate.Methods and Materials: A Phase III randomized study was activated in May 1993, to compare treatmenttoxicity and patient outcome after 78 Gy in 39 fractions using 3D-CRT to that after 70 Gy in 35 fractionsusing Convert-RT. The first 46 Gy were administered using the same nonconform field arrangement (four-field) in both arms. The boost was given nonconformalty usiug four fields in the Conven-RT arm andconformally using six fields in the 3D-CRT arm. The dose was specifkd to the isocenter. The hrst 60patients, 29 in the 3D-CRT arm and 31 in the Conven-RT arm, are the subject of this pretimtnary analysis.Results: The two treatment arms were tirst compared in terms of dosimetry by dose-volume histogramanafys~s. Using a subgroup of patients in the 3D-CRT arm (n = U), both Conven-RT and 3D-CRT planswere generated and the dose-volume histogram data compared. The mean volumes treated to doses above60 Gy for the bladder and rectmn were 28 and 36% for the 3D-CRT plans, and 43 and 38% for theConven-RT plans, respectively @ < 0.05 for the bladder volumes). The mean clinicat target volume (prostateand seminal vesicles) treated to 95% of the prescribed dose was 97.5% for the 3D-CRT arm, and 95.6%for the Convert-RT arm (p < 0.05). There were no signiticant differences in the acute reactions betweenthe two arms, with the major ity experiencing Grade 2 or less toxicity (92%). Moreover, no relationshipwas seen between acute tox icity and the volume of bladder and rectum receiving in excess of 60 Gy forthose in the 3D-CRT arm. There was also no difference between the groups in terms of early biochemicalresponse. Prostate-specific antigen levels at 3 and 6 months after completion of radiotherapy were similarin the two treatment arms. There was only one biochemica l failure in the study population at the time ofthe analysis.Conclusions: Comparison of the Conven-RT and 3D-CRT treatment plans revealed that signiticantty lessbladder was in the high dose volume iu the 3D-CRT plans, white the volume of rectum receiving dosesover 60 Gy was equivalent. There were no differences between the two treatment arms in terms of acutetoxicity or early biochemical response. Longer follow-up is needed to determine the impact of 3D-CRT onlong-term patient outcome and late reactions.Conformal radiotherapy, Dosimetry, Acute toxicity, Prostate specific antigen.

INTRODUCTIONConformal radiotherapy using three dimensional treat-ment planning (3D-CRT) allows for more precise deliveryof treatment, and hence, the potential for sparing more ofthe surrounding normal tissues from the higher doses,as compared to conventional radiotherapy (Conven-RT).

Although the feasibility of dose escalation is being ad-dressed (9, 15), to our knowledge no direct comparisonsof 3D-CRT and Conven-RT in the setting of a randomizedtrial have been made. We initiated such a trial in May1993 with the goal of accruing 150 patients per treatmentarm over a 3-year period. As of this writing, over 100patients have been entered and treated. A preliminary

Reprint requests to: Alan Pollack, M.D., Ph.D., Departmentof Radiotherapy (Box 97), M. D. Anderson Cancer Center, 1515 man Services, and an American Cancer Society Career Develop-ment Award (A.P.). The authors thank Ms. Joan Day, Adminis-Holcombe Boulevard, Houston, TX 77030. trative Assistant, for typing tbe manuscript, and tbe residentsAcknowledgements-This work was supported n part byGrantsCA 06294, CA 43840, and CA 16672awardedby tbe in tbe Departmentof Radiotherapy or their supportive ole inNational Cancer nstitute, U.S. Departmentof Health and Hu- the implementation f the protocol.Accepted for publication21 August 1995.555


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556 I. J. Radiation Oncology 0 Biology 0 Physics

analysis of the dosimetry using dose-volume histogramsand acute toxicity for the first 60 patients is describedherein.

METHODS AND MATERIALSProtocol eligibility and pretreatment evaluationPatients with Stages T2-T4 adenocarcinoma of theprostate were eligible if they met the following criteria:(a) no clinical or radiographic evidence of metastases; (b)Zubrod performance status < 2 (33); (c) adequate bonemarrow function (hemoglobin 2 10 mg/ml, white bloodcells z 35OO/mm, and platelets 2 75,000; (d) no priorpelvic radiotherapy; (e) no prior or planned radical pros-tate surgery; (f) no prior or planned androgen ablationtherapy; and (g) no recent ( 4 and I 10, and > 10 rig/ml.

Volume 34, Number 3, 1996Approximately 6 months into the study we instituted a policychange whereby patients at high risk of biochemical failure,with pretreatment PSA levels 2 30 @ml, were no longerentered into the study. These patients are now being treatedwith androgen ablation and radiotherapy (11) and, therefore,are not candidates for the protocol.Protocol violationsThere were two protocol violations in the Conven-RTarm, including one patient who refused radiotherapy alto-gether and opted for watchful waiting after consenting totreatment, and one patient who received androgen abla-tion after radiotherapy for persistent postradiotberapy uri-nary outlet obstruction in the setting of a suprapubic cath-eter (placed during radiotherapy and removed soon afterandrogen ablation was initiated). The patient on the Con-ven-RT arm who refused treatment was not included inthe analyses of acute toxicity or early biochemical re-sponse. There was one protocol violation in the 3D-CRTarm because of an inability to obtain complete CT-scanimages secondary to obesity-he was treated with Con-ven-RT.RadiotherapyThe initial treatment fields were the same for both treat-ment arms and were used to deliver 46 Gy at 2 Gy perfraction to the isocenter using 18 MV photons. The pros-tate and periprostatic tissues were treated using a four-field technique. The anterior-posterior:posterior-ante-rior (AP:PA) fields were typically 11 X 11 cm, with theinferior border at the ischial tuberosities as described pre-viously (30). The lateral fields extended from the tip ofthe pubis anteriorly and split the rectum posteriorly. Therectal block was shaped to follow the curvature of therectum such that the seminal vesicles were included inthe treatment field. The anterior-superior portion o f thebladder was usually blocked as well. Planning CT scanswere performed on all patients to confirm prostate andseminal vesicle position. Although these initial fields weresometimes enlarged based on the CT scan findings, theydid not conform precisely to the prostate and seminalvesicles. The fields were designed to cover a minimumof 1.5 cm of periprostatic soft tissue in all directions,except posteriorly, where the field edge was defined bythe rectum.The cone-down boost fields for those in the Conven-RT arm were typically 9 X 9 cm, with the inferior borderremaining at the ischial tuberosities (30). However, largerfield sizes were used when necessary to include the semi-nal vesicles in the boost fields for all Conven-RT patients.The simulation for the conventional technique involvedplacement of Foley catheters and contrast into the bladderand rectum. A planning CT scan (1 cm cuts, 3-5 mm

The Tandem-E, Hybritech, Inc. , San Diego, CA. AIA-Pack PA, TOSOH Medics, San Francisco, CA.


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thick) to confirm prostate and seminal vesicle positionwas obtained during the first week of treatment, with thepatient in treatment position, supine, with the bladder full.In some cases the lateral fields were adjusted based onthe CT scan findings to ensure inclusion of the seminalvesicles. The final prescribed dose to the prostate andseminal vesicles fo r the Conven-RT treatment was 70 Gyin 35 fractions to the isocenter. The fields were weightedapproximately equally.The cone-down boost fields for those in the 3D-CRTarm conformed to the shape of prostate and seminal vesi-cles. The region just below the prostatic apex was local-ized on CT scan (0.5 cm cuts, 3-5 mm thick) using theslice in which the crura of the corpora cavemosa and thebulbospongiosis muscle were seen simultaneously. Theplanned target volume (PTV) included a margin of 0.75cm posteriorly, 1.00 cm superiorly and inferiorly, and1JO- 1.25 cm anteriorly around the clinical target vol-ume. The PTV defined the treatment volume; margin forpenumbra was not added. These relatively small PTVmargins were necessary to avoid the inclusion of exces-sive bladder and rectum. It should be emphasized that therectal margins for patients in the 3D-CRT arm were notmuch tighter than those used for patients in the Conven-RT arm. A six-field technique was used, consisting of leftlateral, left anterior oblique, right anterior oblique, rightlateral, right posterior oblique, and left posterior oblique.The obliques were at 30 degrees above and below thetrue laterals.Simulation of the 3D-CRT fields involved selection ofthe isocenter without catheters or contrast in the bladderand rectum. The planning CT scan was done immediatelyfollowing simulation, and the patients were encouragedto have a full bladder during this procedure. The shapingof all fields was performed on the treatment-planningcomputer and transposed to film for documentation. Thepatients were resimulated prior to beginning the confor-mal boost to place the isocenter lines on the skin and tocompare the simulation films with the digitally recon-structed radiographs generated from the 3D-CRT plan.The majority of patients were treated without immobiliza-tion. The final dose for the 3D-CRT treatment was 78 Gyin 39 fractions to the isocenter. The fields were equallyweighted until 46 Gy, and thereafter the boost lateralfields were weighted slightly heavier than the obliques(37% of the dose from the laterals). Tissue inhomogeneitycorrections were included in the 3D-CRT plans. Theconventional treatments were administered without in-homogeneity correction. The isocenter dose difference,assuming homogeneity, between the monitor units from3D-CRT plans run with and without inhomogeneity cor-rections was an average of 1.33 + 0.15% (+ SE) or 1Gy (78 to 79 Gy).SD-CRT p lan evaluationThe dose distributions were examined on three trans-verse CT images and a sagittal reconstruction. The distri-

butions were calculated using a photon convolution algo-rithm as described previously (32). Dose-volume histo-gram analyses (3) were routinely performed for theprostate and seminal vesicles, bladder, rectum, and eachfemoral head. Only the normal tissues included withinthe superior and inferior aspects of the initial anterior:pos-terior field were included. This was done to prevent theinclusion of bowel above the field, which would lowerthe dose-volume results. The volume of the organ treatedto doses above the marker doses (75 Gy for prostate andseminal vesicles, 60 Gy for bladder and rectum, and 45Gy for the femoral heads) was used to compare plans.Follow-upFollow-up per the protocol is at 3-month intervals dur-ing the first 2 years and at 6-month intervals thereafter.A routine history and physical examination and PSA areobtained at each visit. Ultrasound of the prostate is sched-uled for every 6-month visit over the first 2 years, andthe prostate wil l be biopsied in all patients who haveremained without biochemical or clinical evidence of dis-ease at 2 years. Biopsy at 2 years postradiotherapy waschosen as an endpoint to assess whether the 3D-CRTtreatment resulted in an enhancement in tumor eradicationas compared to the Conven-RT arm treatment.Grading of acute toxicityAcute reactions were graded on a l-4 scale in accor-dance with the RTOG system (25). For lower gastrointes-tinal (GI) symptoms, the following scale was adhered to:Grade 1, increased frequency of bowel movements orrectal discomfort not requiring medication; Grade 2, fre-quent stools requiring parasympatholytic drugs, mucousdischarge not requiring sanitary pads or rectal/abdominalpain requiring analgesics; Grade 3, diarrhea requiring par-enteral support, severe mucous or blood discharge neces-sitating pads or abdominal distention (distended bowelloops on radiograph); and Grade 4, acute or subacuteobstruction, fistula or perforation, GI bleeding requiringtransfusion, or abdominal pain or tenesmus requiring tubedecompression or bowel diversion. For genitourinarysymptoms, the following scale was adhered to: Grade 1,frequency of urination or nocturia twice pretreatmenthabit, or dysuria or urgency not requiring medication;Grade 2, frequency of urination or nocturia less frequentthan every hour, or dysuria, urgency, or bladder spasmrequiring local anesthetic (e.g., Pyridium); Grade 3, fre-quency with urgency and nocturia hourly or more fre-quently, or dysuria, pelvic pain or bladder spasm requiringregular, frequent narcotic, or gross hematuria with/with-out clot passage; Grade 4, hematuria requiring transfu-sion, acute bladder obstruction not secondary to clot pas-sage, ulceration, or necrosis.Dejinitions of failureLocal failure was defined as enlarging palpable prostateabnormalities or a rising PSA profile when confirmed


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558 I. J. Radiat ion Oncology 0 Biology Physics Volume 34, Number 3, 1996

Fig. 1. Isodose distributions from a representative 3D-CRT plan. (a) CT-scan slice through seminal vesicles; (b)through midprostate; (c) through prostate above the apex. The 78, 77; 70, 55, 45, and 25 Gy lines are shown.

by biopsy o f the prostate. Regional failure was definedradiographically as pelvic lymph node relapse. Distantfailure w as defined radiographically as hematogenousspread or lymph nodal involvement outside of the pelvis.Biopsy confirmation of lymph nodal or distant spread wasnot required. Biochemical failure was defined as two ormore successive increases in PSA, or a greater than 1.5@ml increase in a single measurement.Statistics

The significance of differences between proportions wastested using the &i-square test (1). The differences betweenpaired samples was tested for significance using the nonpara-metric Wilcoxon matched-pairs Signed-Ranks Test.

RESULTSComparison of dosimetry

Figure 1 shows the isodose lines of representative CTscan cuts through the prostate and seminal vesicles from a3D-CRT plan. A similar example from a Conven-RT planis shown in Fig. 2. As described above, treatment was tothe isocenter; therefore, the prostate and seminal vesicleswere usually encased by the 76-77 Gy lines for the 3D-CRT plans and the 68-69 Gy lines for the Conven-RTplans. Also noteworthy, a greater proportion of the posterior

bladder appeared to receive somewhat higher doses (above60 Gy) in the Conven-RT plans. This is reflected in therepresentative dose-volume histograms in Fig. 3 and in thesummary calculations in Table 1. The representative dose-volume histograms in Fig. 3 also indicate that the volumeof rectum treated to doses above 60 Gy, and the volume ofthe femoral head that received doses above 45 Gy, wereslightly greater for the 3D-CRT plan.

Table 1 displays the dose-volume histogram resultsfor the prostate and seminal vesicles, bladder, and rectum.The percent volume of the bladder and rectum above themarker doses of 60 and 70 Gy were used to assess the3D-CRT plans. The data show that, on average, less than30% of the bladder and rectum received over 60 Gy andless than 18% of the bladder and rectum received over70 Gy, while 97% of the prostate and seminal vesiclesreceived over 75 Gy (95% of the prescribed dose). The60 Gy marker dose for the bladder and rectum, and the95% prescription doses (75 Gy for 3D-CRT and 67 Gyfor Conven-RT) for the prostate and seminal vesicles,were used to compare 3D-CRT and Conven-RT plansdone on a subset (n = 15) of randomly chosen patientsin the 3D-CRT arm. The comparison revealed that thepercent volume of bladder that received over 60 Gy wassignificantly lower, while the percent volume of prostateand seminal vesicles that received over 95% of the pre-

Fig. 2. Isodose distributions from a representative Conven-RT plan . (a) CT-scan slice through seminal vesicles;(b), through midprostate; (c), through prostate above the apex. The 70, 69,65, 55,40, and 25 Gy lines are shown.

SPSS Statistical Package for Windows, Release 6.0, Chi-cago, IL.


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Conventional vs. conform al radiotherapy for prostate cancer l A. POLLACK et al. 559

a b

Dose WY )

, 2ooa 4ow 6ooa eoooDose WY)

d

Dose (SY)Fig. 3. Dose-volume histograms from a patient wherein 3D-CRT (solid lines) and Conven-RT (dashed lines)plans were compared. (a) prostate; (b) bladder; (c) rectum; (d) one femoral head.

scribed dose was significantly higher for the 3D-CRTplans as compared to that for the Conven-RT plans. Thepercent volume of rectum that received above 60 Gy wasthe same for the 3D-CRT and Conven-RT plans.

The relationships between the volume of bladder andrectum receiving greater than 60 Gy for the 3D-CRTand Conven-RT plans are further illustrated in Fig. 4.Significan t linear correlations were observed with theslope greater than one for the bladder volumes andslightly less than one for rectal volumes. Although consis-tently more bladder was treated to doses above 60 Gyin the Conven-RT plan, very similar volumes of rectumreceived doses above 60 Gy in the 3D-CRT and Conven-

RT plans. Linear regression analysis of the prostate andseminal vesicle volumes receiving greater than 95% ofthe prescribed dose also revealed a significant correlationbetween the 3D-CRT and Conven-RT plans with a slopeof 1.39 and R2 = 0.771 (data not shown). The linearregression slopes were not significantly different from 1 .Ostatistically for any of these relationships.Comparison of acute toxicity

Bladder and rectal acute toxicities are shown in Fig. 5.There were no differences between the two treatmentarms (p > 0.4 for both bladder and rectal toxic ities, chi-square). For those in the 3D-CRT arm, 97% and 100%

Table 1. Dose-volume histogram resultsPercent of volume above specified dose (MN + SE)

Group PrescribeddoseProstate* Bladder Rectum

n 75167 Gy 60 Gy 70 Gy 60 Gy 70 Gy3D-CRT 78 Gy 28 96.9 -t 0.8 27.6 2 2.5 16.0 + 1.5 29.5 i- 2.6 17.9 + 2.13D-CRT 78 Gy 15 97.5 -t 0.9 28.4 2 4.0 - 36.4 ? 3.7 -Conven-RT 70 Gy 15 95.6 z 1.4 43.3 -+ 5.9* - 36.8 k 3.9 -

MN = Mean.SE = Standarderror.* Percentvolume of prostateand seminal esicles eceiving over 75 Gy (3D-CRT group) or 67 Gy (Conven-RT group). p < 0.05, Wilcoxon matchedpairs.


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560 I. J. Radiat ion Oncology Biology 0 Physics Volume 34, Number 3, 1996

a Bladder b RectumY = 6.46166 + 1.26663XF = u6.363= 6.762

00

80-

% Volume>60 GyConven-RT

IOO-

80-

80-

40-

20- 100 0010 20 30 40 50 80 70 10 20 30 40 50 80

% Volume >60 Gy 3D-CRTFig. 4. Linear regression analysis of tbe percent volume of bladder (a) and rectum (b) that received doses above60 Gy in the dose-volume histogram analyses of the 3D-CRT vs. Conven-RT plans.

had Grade 2 or less bladder and rectal reactions, as com- grade was chosen. The breakdown of those in the Conven-pared to 90% and 97% for those in the Conven-RT arm. RT arm was: Grade 3, one patient with hematuria; andThere were a total of five Grade 3 or four reactions, with Grade 4, two patients with acute urinary retention not duefour of the five in the Conven-RT arm. The RTOG grad- to clots and one patient with rectal bleeding requiringing scheme was strictly adhered to, and when there was hospital admission and fresh frozen plasma (this patientany question concerning the appropriate grade, the higher was taking coumadin for an unrelated problem). One pa-

20

15

3a 10

Ei

5

0

am Conven-RTI

Bladder20

15

0 1 2 3 4

Grade

b Rectumm Conven-RTm SD-CRT

Fig. 5. Acute toxicity, as graded using the RTGG system, for patients in the 3D-CRT (black) and Conven-RT(gray) treatment arms. Bladder reactions (a), and rectal reactions (b).


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%Volume>60 Gy

a Bladder0

00

0 1 I I I I I0 1 2 3 4

b Rectum7060

08

4O- 0 830- J + 020- d000O- 0 8o- , I , I I0 1 2 3 4

GradeFig. 6. Relationship f percentvolume of bladder a) or rectum (b) receiving greater han 60 Gy to acute oxicitygrade or patients n the SD-CRT arm. Each open circle represents patient and eachplus sign representshemean.

tient in the 3D-CRT arm had a Grade 3 reaction consistingof urinary retention due to clots. This was an unusuallyhigh number considering our prior experience (5), andwe expect the percentages of Grades 3 and 4 reactions todrop over time. The only treatment interruption was inthe patient with Grade 4 rectal reaction, and it was onlyfor 2 treatment days.The relationship of acute reactions to the volume ofbladder or rectum receiving greater than 60 Gy for thosein the 3D-CRT arm is shown in Fig. 6. No relationshipwas seen between these two parameters.Distribution of prognostic factors and early PSAresponseTable 2 shows the distribution of potential prognosticfactors between the two treatment arms. There were nosignificant differences in terms of stage, grade, pretreat-ment PSA, pretreatment PAP, or transurethral resectionof the prostate TURP in Stage T3. Pretreatment PSA was15.8 2 3.0 rig/ml (2 SE, median = 10.0, range 3.4-86.1)in the 3D-CRT arm and 10.8 t 1.5 r&ml (median = 9.5,range 1.3-34.9) in the Conven-RT arm Cp > 0.05, Mann-Whitney). Pretreatment PAP was 0.4 mu/ml in both armsand PAP was < 0.8 mu/ml in all patients. The two groupswere evenly matched for known prognostic factors.A comparison of 3-month and 6-month posttreatmentPSA levels is shown in Table 3. Although slightly greaterpercentages of patients in the Conven-RT arm had post-treatment PSA levels 5 4 @ml and > 4 5 10 rig/ml,and a lower percentage > 10 rig/ml, the differences werenot significant. The same trend wa s seen at 6 monthsposttreatment.

DISCUSSIONNumerous reports involving patients treated with Con-ven-RT in the PSA era (17, 21) have documented

alarming rates of biochemical failure, showing that curerates are substantially lower than once believed. Whileinvestigators have suggested that distant failure is themechanism responsible (31), our data (26) strongly pointto an inability of Conven-RT to effectively eradicate localdisease as the principal reason. The evidence in support ofthis mechanism is considerable, including that (a) hiopsy-proven residual prostate cancer has been consistentlyidentified in significant numbers of patients who are clini-Table 2. Distribution of potentialprognostic actors betweenthe two treatmentarms

Percent n)Prognostic actor Conven-RT 3D-CRT P*

StageT2 61 (19) 69 (20)T3 39 (12) 31 (9) 0.53Gleason core2-4 7 (2) 3 (1)S&6 40 (12) 45 (13)7 27 (8) 31 (9)8-10 27 (8) 21 (6) 0.87PretreatmentPSA54 13 (4) 3 (1)>4 510 42 (13) 48 (14)>lO 45 (14) 48 (14) 0.41PretreatmentPAP10.4 70 (21) 59 (17)>0.4 50.8 30 (9) 41 (12) 0.36TURP in StageT3No 92 (11) 100 (9) -Yes 8 (1) 0 (0) 0.37PSA = prostatespecificantigen &ml).PAP = prostatic acid phosphatase (mu/ml).TURP = transurethral esectionof the prostate.* Chi-square.


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562 I. J. Radiation Oncology 0 Biology 0 Physics Volume 34, Number 3, 1996Table 3. PSA values at 3 and 6 months after conformal orconventional radiotherapy

Percent (n)~2 &ml >2 5 4 rig/ml >4 nglml p*

3 Months3D-CRT 31 (9) 35 (10) 35 (7)Conven-RT 45 (13) 41 (12) 14 (4) 0.18

6 Months3D-CRT 53 (10) 37 (7) 11 (2)Conven-RT 72 (13) 22 (4) 6 (1) 0.47* Chi-square.

tally and biochemically free of disease after Conven-RT(4,6,8, 16); (b) the greatest fall in PSA after radiotherapyis seen in patients with high pretreatment PSA levels (7,26, 27); and (c) in patients with evidence of biochemicalfailure, the only site of active disease is the prostate, asconfirmed by biopsy, in over 70% of cases (7,29). Furtherevidence that PSA is a marker of local disease comesfrom the surgical literature where undetectable postpros-tatectomy PSA levels are seen in the overwhelming ma-jority. Clearly, we must, above all else, strive to improvelocal control and 3D-CRT offers a straightforward meanswith which to achieve this end.The Phase III randomized study described here wasdesigned to address whether higher doses to the prostateand seminal vesicles will result in improved freedom frombiochemical and/or clinical failure. Moreover, at 2 yearspostradiotherapy the prostate will be biopsied in all pa-tients who remain free of disease to determine the effectof dose on disease eradication. Our treatment approachwas to build on our prior experience consisting of morethan 2000 patients treated since 1975 with definitive ra-diotherapy for prostate cancer. Over the last 10 yearswe have increased the dose from 60-64 to 70 Gy, withtreatment prescribed to the isocenter. The 70 Gy dosehas been used for the last 2.5 years with no severe latecomplications seen yet. Thus, the prostate and seminalvesicles in the Conven-RT arm were treated to 70 Gy tothe isocenter.The 3D-CRT technique used in the protocol involveda mixture of nonconformal four-field treatment to 46 Gy,and conformal treatment, given as the boost, to 78 Gy.This schema necessitated tight margins on the prostateand seminal vesicles during the conformal treatment tominimize bladder and rectum in the high dose volume.As a consequence, our conformal PTV margins of 0.75cm posteriorly and 1 OO- 1.25 cm anteriorly are somewhatless than that described by those who use conformal ther-apy throughout treatment (9). We observed (not shown),as have others (12), that a small increase in the conformalmargins translated into significantly more bladder andrectum in the high dose volume, which we considered anunacceptable risk for late complications. There is alsosome debate regarding the selection of patients for inclu-

sion of the seminal vesicles in the target volume using3D-CRT (2, 10). In the protocol described, the seminalvesicles were purposefully included in all patients toavoid discrepancies between the two treatment tech-niques, since the seminal vesicles would be included inad-vertently in most of those in the Conven-RT arm. Thedose-volume histogram analyses described here showthat despite treating these volumes to 78 Gy using 3D-CRT, significantly less bladder and similar amounts ofrectum were included in the high dose volume above 60Gy, as compared to that in matched Conven-RT plans.

Daily setup variability and target organ movement havereceived much attention in the arena of prostate cancertreatment. There are now mixed reports concerning thebenefit of immobilization on setup variability (13, 19,24).We have chosen to avoid costly immobilization tech-niques until the benefit has been documented and, to thisend, we are conducting such a comparison using a subsetof patients in the 3D-CRT arm. Long laser lines are placedon the skin in those treated without immobilization, andthe setup has been reproducible.In considering the degree of prostate movement in theselection of appropriate margins for conformal radiotherapy,the available data may be misleading. Artificial distensionof the bladder and rectum may result in prostate shifts ofup to 0.9 cm (18, 22) but may not reflect day-to-day shif tswhen the patient is instructed to come for treatment withthe bladder full. We are examining prostate movement viafour serial CT scans at different times during treatment tomore accurately assess day-to-day shifts. The preliminaryresults suggest that prostate movement may be substantiallyless than that seen under different conditions of artificialfilling/emptying of the bladder and rectum.The data from University of Michigan (15) and Memo-rial Sloan-Kettering (9) showed minimal acute toxicity atdoses of 76 Gy or above. In a retrospective comparisonby Soffen et ~1. (20) of patients treated to 68 Gy with3D-CRT vs. Conven-RT, the percentages of patients withurinary or rectal symptoms was similar, although fewerpatients treated with 3D-CRT required medication. Simi-lar findings were reported by Vijayakumar et al. (23)in that fewer acute Grade 2 reactions were seen whenconformal radiotherapy was used. Our data show thatthe acute toxicity from 78 Gy using 3D-CRT is virtuallyidentical to that seen from 70 Gy using Conven-RT. Theacute toxicities were the same even though the first 46Gy was administered using the same nonconformal fieldarrangement in both study arms and the patients in theconformal arm received a higher dose. In addition, therewas no correlation between the volume of bladder orrectum treated to over 60 Gy and acute toxicity for thosein the 3D-CRT arm. The data were not suffic iently matureto investigate late effects, although no severe reactionshave been observed thus far.In the study described, the response to radiotherapy wasevaluated using the early biochemical endpoints of 3 and 6month postradiotherapy PSA values. We reported previously


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Conventional vs. conformal radiotherapy for prostate cancer 0 A. POLLACK et al. 563

that a PSA of less than 2 q/ml connotes a good prognosis; whether the higher dose administered using 3D-CRT hadthe incidence of a rising PSA profile was 20% in these any impact on failure rates.patients as opposed to > 60% for those with 3 month values In summary, the preliminary results of a Phase III ran-above 2 q/ml (28). In a subsequent analysis we found domized trial comparing 3D-CRT to 78 Gy vs. Conven-RTthat postradiotherapy PSA values at 6 months were more to 70 Gy for the treatment of clinically localized prostatesignificant than those at 3 months. Likewise, nadir PSA were presented. There were no differences between thevalues, which are typically seen between 9 and 12 months groups in terms of acute toxicity or early biochemical re-after radiotherapy, are even more significant than 3 or 6 sponse. A comparison of the dosimetry for 3D-CRT andmonth values (7). No significant differences were seen be- Conven-RT plans using dose-volume histogram analysistween the 3D-CRT and Conven-RT groups using 3- and 6- showed minimal differences, with somewhat less bladdermonth postradiotherapy PSA values. It should be empha- treated to doses above 60 Gy in the 3D-CRT plans. Longersized that these are preliminary data. Nadir values, or later follow-up and further patient accrual is needed to fully eval-endpoints such as a rising PSA or local control, in addition uate whether 3D-CRT will result in lower failure rates andto the accmal of more patients are necessary to fully evaluate acceptable late toxicity.

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prostata conformal versus convencional

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