Ten-year outcomes of high-dose, intensity-modulated radiotherapy for localized prostate cancer

Ten-Year Outcomes of High-Dose, Intensity-Modulated Radiotherapy for LocalizedProstate CancerZumre A. Alicikus, MD1; Yoshiya Yamada, MD1; Zhigang Zhang, PhD2; Xin Pei, PhD1; Margie Hunt, MA3;

Marisa Kollmeier, MD1; Brett Cox, MD1; and Michael J. Zelefsky, MD1

BACKGROUND. The authors investigated long-term tumor control and toxicity outcomes after high-dose, intensity-

modulated radiation therapy (IMRT) in patients who had clinically localized prostate cancer. METHODS. Between

April 1996 and January 1998, 170 patients received 81 gray (Gy) using a 5-field IMRT technique. Patients were classi-

fied according to the National Comprehensive Cancer Network-defined risk groups. Toxicity data were scored accord-

ing to the Common Terminology Criteria for Adverse Events Version 3.0. Freedom from biochemical relapse, distant

metastases, and cause-specific survival outcomes were calculated. The median follow-up was 99 months. RESULTS.

The 10-year actuarial prostate-specific antigen relapse-free survival rates were 81% for the low-risk group, 78% for the

intermediate-risk group, and 62% for the high-risk group; the 10-year distant metastases–free rates were 100%, 94%,

and 90%, respectively; and the 10-year cause-specific mortality rates were 0%, 3%, and 14%, respectively. The 10-year

likelihood of developing grade 2 and 3 late genitourinary toxicity was 11% and 5%, respectively; and the 10-year likeli-

hood of developing grade 2 and 3 late gastrointestinal toxicity was 2% and 1%, respectively. No grade 4 toxicities

were observed. CONCLUSIONS. To the authors’ knowledge, this report represents the longest followed cohort of

patients who received high-dose radiation levels of 81 Gy using IMRT for localized prostate cancer. The findings indi-

cated that high-dose IMRT is well tolerated and is associated with excellent long-term tumor-control outcomes in

patients with localized prostate cancer Cancer 2011;117:1429–37. VC 2010 American Cancer Society.

KEYWORDS: high-dose, intensity-modulated radiotherapy, prostate cancer, prostate-specific antigen.

Recent randomized controlled trials and several single-institution studies have confirmed the advantage of deliveringhigh doses of external beam radiotherapy to achieve optimal tumor-control outcomes in patients with localized prostatecancer.1-9 Several studies have demonstrated an association between high-dose radiotherapy that is delivered using conven-tional treatment planning and elevated risks of late urinary and rectal toxicities.5,10,11 An advanced form of 3-dimensional,conformal radiation therapy is intensity-modulated radiotherapy (IMRT), which delivers nonuniform beam intensities toan irregular target volume to create a highly sculpted dose distribution. These techniques have facilitated the safe deliveryof increased doses of radiation to the prostate and seminal vesicles with concurrent dose reductions to adjacent normaltissues.

At Memorial Sloan-Kettering Cancer Center, IMRT was introduced as a dose-escalation tool in 1996 to allow forthe delivery of higher dose radiation levels of 81 grays (Gy) to 86.4 Gy and for the delivery of as much as 91 Gy to signifi-cant portions of the target. These ultrahigh dose levels have been possible and are well tolerated.6 We previously reportedthe long-term results from 81 Gy delivered with IMRT, which has been associated with a low risk for treatment-relatedcomplications. In this report, we summarize the 10-year results of IMRT. To our knowledge, the current study representsthe longest followed cohort of patients to date who have received high-dose IMRT for localized prostate cancer. Our find-ings indicate that delivery of high-dose IMRT continues to be associated with excellent long-term tolerance outcomes anddisease-control rates.

DOI: 10.1002/cncr.25467, Received: September 4, 2009; Revised: December 24, 2009; Accepted: January 4, 2010, Published online November 8, 2010 in Wiley

Online Library (wileyonlinelibrary.com)

Corresponding author: Michael J. Zelefsky, MD, Department of Radiation Oncology, 1275 York Avenue, New York, NY 10065; Fax: (212) 639-8876;

[email protected]

1Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York; 2Department of Epidemiology and Biostatistics, Memorial

Sloan-Kettering Cancer Center, New York, New York; 3Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York

Cancer April 1, 2011 1429

Original Article

MATERIALS AND METHODSBetween April 1996 and January 1998, 170 patients withhistologically proven prostate cancer received IMRT upto a prescribed dose of 81 Gy at Memorial Sloan-Ketter-ing Cancer Center. The median patient age was 69 years(range, 51-82 years). The characteristics of these patientsare listed in Table 1. Ninety-one patients (54%) received3 months of neoadjuvant androgen deprivation therapy(N-ADT) before radiotherapy. In general, short-courseN-ADT was given to decrease the size of the enlargedprostate before radiotherapy or to patients who had high-grade, unfavorable-risk disease. ADT routinely was con-tinued during the course of IMRT and then was discon-tinued at the completion of therapy. On-treatmentevaluations were performed at least weekly during thetreatment course, and follow-up evaluations were per-formed at intervals of 3 to 6 months for 5 years and yearlythereafter. The median follow-up was 99 months and wascalculated from the completion of radiation therapy.

Detailed IMRT techniques for treatment planningand delivery as well as quality assurance have been reportedelsewhere.12-15 Briefly, all patients were treated in the proneposition within a thermoplastic mold and were instructedto empty their bladders immediately before treatment toensure reproducibility of the daily setup and to minimize

organ motion, as described previously.16 Patients werescanned in the treatment position from the L5-S1 levels to10 cm caudal to the ischial tuberosities on a computerizedtomography (CT) simulator. CT slices were reconstructedat 0.3-cm increments to produce high-resolution, 3-dimensional images and digitally reconstructed radio-graphs. The CT images were downloaded into the Memo-rial Sloan-Kettering treatment-planning system.Permanent localizationmarks were placed at a standardizedtreatment isocenter: a midline point near the center of theprostate located 1 cm inferior to and 6 cm posterior to thesymphysis pubis. The clinical target volume included theprostate and seminal vesicles. A margin of 1.0 cm wasadded to the clinical target volume except at the prostator-ectal interface, where a 0.6-cm margin was used. An addi-tional 0.5-cm margin was added around the planningtarget volume (PTV) (except superiorly and inferiorly,where 1.0 cm was used) to account for penumbra. The rec-tum, bladder, bowel, and femora were contoured as criticalnormal tissue structures. An isocentric, 5-field techniquecomprising a posterior field (0�), a right posterior obliquefield (75�), a right anterior oblique field (135�), a left-ante-rior oblique field (225�), and a left posterior oblique field(285�) was used. Treatment plans then were optimizedwith an inverse optimization algorithm,17,18 which is usedto minimize the sum of quadratic differences between thedesired and computed dose distributions. Optimizationwas performed using dose or dose-volume constraints andpenalties to control the PTV dose, homogeneity within thePTV, and doses to critical structures. The parameters thatwere used to produce the desired dose distribution includeddose uniformity (100%) to the PTV, and limits that nogreater than 30% of the rectal wall volume should receive>75.6 Gy (V75.6 <30) and that no greater than 53% ofthe rectal and bladder walls should receive >47 Gy (V47<53). In the overlap region between the PTV and thesecritical organs, the constraint was set at 88% of the pre-scription dose for the rectum and at 98% for the bladder.Once the intensity profiles of the 5 IMRT beams weredetermined, leaf-motion files were created, and dose distri-butions were generated. Beam’s-eye-view, digitally recon-structed radiographs were generated, onto which fluenceapertures were projected. The fluence apertures of each in-tensity-modulated field were specified to encompass thearea with an intensity >1% of the maximum. The desiredbeam-intensity profiles were delivered by dynamic multi-leaf collimation using the sliding window technique.15

All patients were treated to a prescribed dose of 81Gy in daily fractions of 1.8 Gy in 45 fractions using 15-

Table 1. Patient Characteristics

Characteristic No. of Patients %

AJCC tumor classificationT1c 71 42

T2a 37 22

T2b 33 19

T2c 21 12

T3a 2 1.5

T3c 2 3

T4 1 0.5

Gleason scoreMedian (range) 6 (5-9)

£6 97 57

7 60 35

‡8 13 8

PSA, ng/mLMedian (range) 8 (47-95)

£10 110 65

>10 60 35

NCCN risk groupLow risk 49 29

Intermediate risk 89 52

High risk 32 19

AJCC indicates American Joint Committee on Cancer; PSA, prostate-spe-

cific antigen; NCCN, National Comprehensive Cancer Network.

Original Article

1430 Cancer April 1, 2011

megavolt photons. The prescribed dose represented theminimum dose to the PTV, but portions of the target vol-ume, including the isocenter (International Commissionon Radiation Units and Measurements prescriptionpoint), received up to 10% higher doses. During the treat-ment period for patients in this study, the patient positionwas verified with weekly port films. More recently, weinstituted a policy of routine fiducial marker placementand daily, 2-dimensional-kV imaging for prostate local-ization for all patients who receive prostate IMRT.

Late gastrointestinal (GI) and genitourinary (GU)toxicities were graded according to the National CancerInstitute Common Terminology Criteria for AdverseEvents, version 3.0, on the following 4-point scale: grade1, minimal side effects not requiring medications; grade2, side effects requiring medications for symptom man-

agement (or an increase in the dose of pre-existing medi-cation); grade 3, side effects requiring minor procedures(ie, cauterization, catheterization, transfusions) to controlor affect activities of daily living; or grade 4, life-threaten-ing toxicity requiring major surgery and hospitalization.Erectile function was evaluated according to patientreports at the time of each follow-up and was definedas the inability to achieve an erection sufficient forpenetration.

Patients were classified into groups according totheir risk of recurrence as defined by National Compre-hensive Cancer Network (NCCN) guidelines (www.nccn.org; accessed May 14, 2009). Patients were classifiedwith low-risk disease if they had clinical T1 to T2atumors, a Gleason score �6, and a pretreatment prostate-specific antigen (PSA) level <10 ng/mL. Patients with

Figure 1. The planned dose distribution for a patient with prostate cancer is illustrated. cGy indicate centigrays.

High-Dose IMRT for Prostate Cancer/Alicikus et al


clinical T2b or T2c tumors, a Gleason score of 7, or a pre-treatment PSA level between 10 ng/mL and 20 ng/mLwere classified with intermediate-risk disease. Patientswho had T3a or higher tumors, a Gleason score �8, or apretreatment PSA level >20 ng/mL were classified withhaving high-risk disease.

Disease status was determined according to an anal-ysis in October 2008. The date patients completed radio-therapy was used as the starting time for all survivalendpoints in this analysis. PSA relapse was defined accord-ing to the Phoenix consensus definition as an absolute na-dir PSA level plus 2 ng/mL dated at the call.19 None ofthe patients received postirradiation ADT or other anti-cancer therapy before documentation of a PSA relapse.For cause-specific survival (CSS) analysis, patients withdocumentation of biochemical or metastatic, relapsingdisease who subsequently died were scored as deaths fromprostate cancer. Death from other causes was considered acompeting risk. Distributions of PSA relapse-free survivaland distant metastases-free survival (DMFS) were calcu-lated using the Kaplan-Meier method. Cause-specificmortality rates were calculated using competing-risksanalysis tools. The log-rank test was used to assess whethersubgroups had nonparametrically and univariately identi-cal distributions of the survival endpoints. When multi-

variate analysis was applicable or continuous covariateswere involved, the Cox proportional hazards regressionmodel was used to determine the effect of covariates, anda stepwise model selection tool was used to construct thefinal multivariate model. Statistical significance wasachieved when P� .05.

RESULTSA typical dose distribution depicting improved tumorcoverage with 81 Gy and reduced volume of critical nor-mal structures using IMRT is shown in Figure 1.

Biochemical Tumor Control

PSA relapse-free survival rates according to NCCN prog-nostic risk groups are shown in Figure 2. The 10-yearactuarial PSA relapse-free survival was 81% (95% confi-dence interval [CI], 64%-97%), 78% (95% CI, 66%-91%), and 62% (95%CI, 44%-80%) for the low-risk, in-termediate-risk, and high-risk groups, respectively (P ¼.013). Clinical tumor classification (P¼ .0002) and a pre-treatment PSA level >10 ng/mL (P ¼ .008) were identi-fied as significant predictors of biochemical relapse onmultivariate analysis (Table 2). Gleason score, receipt of

Figure 2. These Kaplan-Meier curves illustrate the actuarial probability of achieving prostate-specific antigen relapse-free survivalbased on the prostate-specific antigen (PSA) nadir plus 2 ng/mL definition according to National Comprehensive Cancer Net-work risk group. Int indicates intermediate.

Original Article


short-term N-ADT, and patient age had no demonstrableimpact on the biochemical relapse rate in these patients.

Distant Disease Control and SurvivalOutcomes

Distant metastasis developed in 8 patients (5%) at a me-dian of 20 months (range, 7-70 months) after the comple-tion of therapy. The 10-year DMFS rate was 95% (95%CI, 91%-98%) (Fig. 3). The 10-year DMFS outcomeswere 100%, 94%, and 90% for low-risk, intermediate-risk, and high-risk patients, respectively (P ¼ .12). Uni-variate analysis demonstrated that clinical tumor classifi-cation (P¼ .0002) and a pretreatment PSA level>10 ng/mL (P ¼ .014) were predictors of long-term DMFS.Because of the limited number of events, a multivariateanalysis could not be performed (Table 3).

The overall 10-year cause-specific mortality rate was3.8%. The 10-year cause-specific mortality rates were 0%,3%, and 14% for low-risk, intermediate-risk, and high-risk patients, respectively (P¼ .0012).

Toxicity

The incidence of late GU and GI toxicities is shown inTable 4. The median time to the development of lategrade 2 GU and grade 3 GU toxicities were 31 monthsand 42 months, respectively. No late grade 4 GU toxici-ties were observed. The 10-year actuarial risk of develop-ing late grade �2 GU toxicity was 17% (Fig. 4). Lategrade 2 GI toxicity occurred in 4 patients (2%), and lategrade 3 GI toxicity occurred in 2 patients (1%). Amongpatients who developed late grade 2 GI toxicity, 2 patientsdeveloped grade 2 rectal bleeding at a median of 24.5

Table 2. Cox Regression Model Results for Prostate-Specific Antigen Relapse-Free Survival Analysis

Univariate Analysis Multivariate Analysis

Variable HR (95% CI) P HR (95% CI) P

NCCN risk group 1.99 (1.18-3.34) .009 NS NS

Age, continuous 1.02 (0.96-1.08) .51

Age, >69 y vs �69 y 1.09 (0.54-2.22) .80

HT, 1 vs 0 0.89 (0.44-1.81) .75

Pre-PSA, >10 ng/mL vs �10 ng/mL 2.41 (1.19-4.88) .015 2.64 (1.29-5.43) .008

Tumor classification 1.42 (1.17-1.71) .0003 1.47 (1.20-1.80) .0002

Gleason score 1.44 (0.92-2.24) .11 NS NS

HR indicates hazard ratio; CI, confidence interval; NCCN, National Comprehensive Cancer Network; NS, nonsignificant; HT, hormone therapy; PSA, prostate-

specific antigen.

Figure 3. This Kaplan-Meier curve illustrates the actuarial probability of achieving distant metastasis-free survival.



months after the completion of therapy. Among thepatients who developed late grade 3 GI toxicity, 2 patientsdeveloped grade 3 rectal bleeding that required 1 or moretransfusions or a laser cauterization procedure at a median17 months after the completion of IMRT. No grade 4 rec-tal toxicities were noted. The 10-year incidence of lategrade �2 GI toxicity was 3.7% (Fig. 5). On multivariateanalyses, the presence of acute grade �2 GU toxicity waspredictive for the development of late grade�2 GU toxic-ity (P ¼ .001). The receipt of ADT and patient age werenot associated with developing late grade�2 GU toxicity.The presence of acute grade �2 GI toxicity was the onlypredictor on multivariate analyses of late grade �2 GItoxicity (P¼ .0025).

Erectile Dysfunction

Forty-one patients were impotent before they receivedradiotherapy. Of the 105 patients who were potent (ie,had erections sufficient for penetration) before IMRT, 44patients (42%) became impotent. The 10-year actuarialincidence of developing postradiation erectile dysfunctionwas 44%. The 10-year actuarial incidence of developingpostradiation erectile dysfunction in patients who did and

did not receive N-ADT was 54% and 35%, respectively.The receipt of N-ADTwas predictive for the developmentof erectile dysfunction on multivariate analyses (P¼ .02).

DISCUSSIONThe current results demonstrate that radiation dose levelsof 81 Gy with IMRT are tolerated well in these patients,who have been followed for many years after treatment.The limitations of current reports on IMRT includedsmaller numbers of patients who were followed for �5years, which did not allow adequate time to observe clini-cal failures or treatment-related toxicities. We observedrelatively low failure rates 10 years after IMRT. The 10-year biochemical control rates were 81%, 78%, and 62%in patients with low-risk, intermediate-risk, and high-riskfeatures, respectively.

It is now well established that conventional doses forexternal beam radiotherapy in the range of 70 Gy are notsufficient for the eradication of local prostatic disease.Three-dimensional, conformal radiotherapy and IMRTrepresent improvements in radiation planning and deliv-ery that make it possible to deliver higher doses of radia-tion to the prostate, which can lead to improved outcomesfor biochemical tumor control in patients with clinicallylocalized prostate cancer.2,3,5,7,8,20 The improvements in

Table 4. Late Toxicity From Intensity-ModulatedRadiotherapy (n¼170)

No. of Patients (%)

Toxicity Grade Genitourinary Gastrointestinal

None 108 (63) 132 (78)

1 39 (23 32 (19)

2 15 (9) 4 (2)

3 8 (5) 2 (1)

4 0 (0) 0 (0)

Figure 4. This Kaplan-Meier curve illustrates the actuarialprobability of grade �2 late genitourinary (GU) toxicity andindicates that 130 patients will be at risk at 5 years and that8 patients will be at risk at 10 years.

Table 3. Competing Risks Analysis Results for Cause-SpecificMortality Rates

Univariate Analysisa

Variable HR (95% CI) P

NCCN risk group 5.95 (1.48-24.03) .012

Age

Continuous 1.12 (1.00-1.24) .05

Ages >69 y vs �69 y 1.66 (0.28-9.98) .58

HT, 1 vs 0 1.43 (0.24-8.57) .70

Pre-PSA, >10 ng/mL vs �10 ng/mL 8.58 (1.00-73.74) .05

Tumor classification 2.16 (1.40-3.34) .0005

Gleason score 1.19 (0.54-2.59) .67

HR indicates hazard ratio; CI, confidence interval; NCCN, National Compre-

hensive Cancer Network; HT, hormone therapy; PSA, prostate-specific

antigen.aMultivariate analysis was not applicable because there were only 5

events.

Original Article


biochemical tumor-control rates with the use of higherradiation doses have been correlated not only with supe-rior local control but also with improved distant metasta-ses-free and CSS outcomes.21-25 The significant doseeffect was demonstrated for improved DMFS in patientswho received �81 Gy compared with patients whoreceived 75.6 Gy.24 In the current report, we observedthat a pretreatment PSA level �10 ng/mL and advancedclinical tumor classification were significant predictors ofbiochemical control, distant disease control, and CSSrates. The lack of a benefit from ADT in high-risk patientsprobably is related to the relatively short course of only 5to 6 months of ADT that was received by patients at thattime. Currently, we advocate the use of longer courses ofADT, and particularly for high-risk patients.

The effectiveness of high-dose radiation therapy islimited by possible increased risks to normal tissues forlong-term morbidity. The incidence of late grade �2 GUand GI toxicity reportedly ranges from 13% to 40% andfrom 26% to 30%, respectively, in high-dose (78 Gy)radiotherapy arms of recent studies10,26,27 More recently,Cahlon et al reported our results using ultrahigh dose(86.4 Gy) radiotherapy.6 The 5-year incidence of lategrade �2 GU and GI toxicity was 16% and 4%, respec-tively, in the study. In the current report, using an 81-Gy

dose level with IMRT, the risks of developing late grade�2 GU and GI toxicities were 17% and 3.7%, respec-tively, at 10 years, and the 10-year incidence of developinggrade �2 rectal bleeding was 2%. Taken together, thesedata demonstrate that IMRT is the safest way to deliverhigh doses of external beam radiotherapy and that ourroutinely used normal tissue margins are sufficient tocover the PTV.

Grade 2 and greater acute GU symptoms and GIsymptoms developed in 5 patients (3%) and 2 patients(1%), respectively, during the course of radiotherapy.Fifty-four percent of our patients received short-courseN-ADT, and we did not observe more toxicity in thosepatients. Similarly, Zelefsky et al reported that the receiptof ADT did not have a demonstrable influence on theincidence of acute symptoms.28 In contrast to our report,other studies have suggested higher toxicities when longercourses of hormone therapy were used.8,29 We also couldnot demonstrate any predictive effect of ADT for develop-ing higher GU or GI toxicity in our multivariate analyses.Similarly, the Radiation Therapy Oncology Group 94-06trial has demonstrated no effect of neoadjuvant hormonetherapy on late GI or GU toxicity.30 That group notedthat only patients with poor pretreatment urinary func-tion who were receiving hormone therapy had increasedacute toxicity. Conversely, a relation between acute andlate GI toxicities was reported. In a study by Heemsbergenet al, the authors observed that late effects were a directconsequence of the initial tissue injury.31 In that study,the presence of diarrhea during treatment predicted anincreased risk of late grade �2 rectal toxicity. Zelefsky etal recently reported that the presence of acute GI and GUsymptoms during treatment conferred a 5-fold and 3-foldincreased risk of late GI and GU toxicities, respectively, in1571 patients with prostate cancer who had a long follow-up after receiving 3-dimensional, conformal radiotherapyor IMRT.28 Similarly, in our current multivariate analy-ses, we observed that the presence of acute grade �2 GIand GU toxicity was a significant predictor of late grade�2 GI and GU toxicity. The other important finding inour report is the relatively high incidence at 10 years oferectile dysfunction in men with prostate cancer. Theactuarial incidence of developing postradiation erectiledysfunction was 44% at 10 years. Certainly the multitudeof factors that affect the likelihood of developing erectiledysfunction are well known and include pretreatment sta-tus; the presence of comorbidities, such as diabetes andheart disease; medications; and patient age. With a me-dian age of 69 years at the time of treatment, it is expected

Figure 5. This Kaplan-Meier curve illustrates the actuarialprobability of grade �2 late gastrointestinal (GI) toxicity andindicates that 141 patients will be at risk at 5 years and that 8patients will be at risk at 10 years.



that a significant number of patients would have devel-oped a decline in erectile function with normal aging overthe 10 years of follow-up. Although IMRT would allowfor the delivery of lower doses to erectile tissues andpotentially lead to improved potency rates,32 we couldnot demonstrate that the use of this modality was associ-ated with a lower incidence of erectile dysfunction in thesepatients compared with other treatment techniques, suchas 3-dimensional, conformal radiotherapy. In our report,the use of short-course N-ADT played a significant role inthe development of erectile dysfunction, as noted in ourmultivariate analyses. Similar findings have been reportedby others.14,33,34

In conclusion, the current data indicate that IMRTis associated with excellent clinical outcomes in patientswith localized prostate cancer who were followed for 10years. IMRT requires more time and effort from physi-cians and physicists, but much of the planning and deliv-ery have become automated. Computer algorithms areavailable to support treatment-planning optimization andtreatment delivery with dynamic multileaf collimation.Using dynamic multileaf collimation and inverse-plan-ning treatment software, IMRT can deliver a highly con-formal and targeted radiation dose to the prostate whilealso lowering the concomitant dose to the rectum andbladder. Our findings indicate that high-dose IMRT istolerated well and is associated with excellent long-termtumor-control outcomes in patients with localized pros-tate cancer.

CONFLICT OF INTEREST DISCLOSURESSupported by Program 2219 of the Scientific and TechnicalResearch Council of Turkey (TUBITAK).

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Ten-year outcomes of high-dose, intensity-modulated radiotherapy for localized prostate cancer