the evolving role of pelvic radiation therapy

The Evolving Role of Pelvic Radiation TherapyTerence Roberts and Mack Roach IIIWhole pelvic radiotherapy (WPRT) is controversial in

the management of prostate cancer. The estimation of

the risk of pelvic lymph node involvement in prostate

cancer patients will identify those who will potentially

benefit from WPRT. Nomograms and equations based

on pretreatment prostate-specific antigen (PSA), Glea-

son score, and/or clinical stage allow clinicians to

quickly estimate nodal risk. Most of the studies analyz-

ing WPRT, including a randomized trial from the Radi-

ation Therapy Oncology Group (RTOG), were con-

ducted in the pre-PSA era and did not necessarily

include patients at high risk for nodal involvement. The

addition of hormonal therapy to WPRT has been shown

in 4 major prospective randomized trials to improve

survival for some subsets of patients. The preliminary

results of RTOG 94-13 show the superiority of WPRT

over prostate-only radiotherapy (PORT) in high-risk

prostate cancer patients receiving hormonal therapy.

For most other solid tumors, the regional lymph nodes

are routinely treated by some modality, so it is not

surprising that WPRT might benefit a subset of high-

risk patients.

© 2003 Elsevier Inc. All rights reserved.

The role of whole pelvic radiotherapy (WPRT)is one of the many controversies in prostate

cancer management. Whether used in an electivefashion for patients who are at high risk foroccult pelvic lymph node metastases or in thesetting of patients with proven involvement ofthe regional lymph nodes, treatment of the nodescontinues to be hotly debated.

Arguments exist for and against the use ofWPRT. A high percentage of patients with locallyadvanced prostate cancer will harbor occult pel-vic lymph node metastases. If prostate cancerspreads in an orderly pattern from the prostate,to the pelvic lymph nodes, and finally to distantsites, then treating the pelvic lymph nodes withelective nodal radiation therapy can potentiallyimpact disease-free survival and/or overall sur-vival in some subsets of these patients. Similarly,the treatment of node-positive patients with ther-apeutic nodal radiation therapy may sterilizeknown sites of disease, again theoretically pro-longing disease-free survival and perhaps sur-vival.

Alternatively, patients may not benefit fromWPRT if the treatment is not effective in steril-izing occult or demonstrable regional lymph nodemetastases or if lymph node disease is a harbin-ger of distant metastatic spread. Also, the benefit

of WPRT may not be apparent if it impacts theoutcome of treatment in only a very small subsetof patients.

In this review, we will discuss: the lymph nodedrainage of the prostate, methods of identifyingpatients at high risk for regional lymph nodemetastases, both retrospective and prospectiverandomized studies comparing WPRT with pros-tate-only radiation therapy (PORT), the impor-tance of radiation technique in maximizing thebenefit from WPRT, and the role of androgensuppression before and/or in conjunction withWPRT.

Lymphatic Drainage of the Prostate

The lymphatics of the prostate drain into a sub-capsular system, then into a periprostatic lym-phatic network and finally into 4 major collectingtrunks.1 The 4 trunks are (1) the external iliacpedicle, which terminates in the external iliacnodes; (2) the hypogastric pedicle, which termi-nates in one of the hypogastric nodes; (3) theposterior pedicle, which extends to nodes alongthe medial aspect of the second sacral foramen orto other nodes in the region of the sacral prom-ontory; and (4) the inferior pedicle which termi-nates in a hypogastric node near the origin of theinternal pudendal artery. Therefore, coverage ofthe primary drainage areas must include the ob-turator, external iliac, hypogastric, and presacrallymph nodes. Figure 1 shows these drainage ar-eas. The seminal vesicle lymphatics drain intothe superficial and deep plexuses, which termi-nate in the hypogastric and external iliac lymphnodes.2

From the Department of Radiation Oncology, University of Cali-fornia, San Francisco, San Francisco, CA.

Address reprint requests to Mack Roach III, MD, Department ofRadiation Oncology, University of California, San Francisco, 1600Divisadero Street, H1031, San Francisco, CA 94143-1708.

© 2003 Elsevier Inc. All rights reserved.1053-4296/03/1302-0004$30.00/0doi:10.1053/srao.2003.50014

Seminars in Radiation Oncology, Vol 13, No 2 (April), 2003: pp 109-120 109

Incidence of Lymph Node Metastasis

Knowledge of the incidence of positive nodesfound in the lymphatic drainage areas and theclinical predictors of lymph node involvement willidentify those patients who are most likely tohave a favorable outcome from WPRT.

Because of increased screening efforts in thepost–prostate-specific antigen (PSA) era, therehas been a shift to earlier stages at patient pre-sentation and a decrease in the overall incidenceof pelvic lymph node metastases. In the pre-PSAera, Fowler and Whitmore3 reported that 40% of300 patients with apparently localized prostatecancer had pelvic lymph node metastases uponsurgery. Other surgical series during this eradescribed approximately the same percentage ofnode-positive patients.4,5 In contrast, the inci-dence of pelvic metastases reported in more mod-ern surgical series is less than 10%.6,7

Partin et al8 analyzed surgical data from 3major academic institutions to develop internallyand externally validated nomograms that predict

lymph node involvement based on clinical stage,preoperative PSA and Gleason score (GS). Re-cently, the staging nomograms were updated toreflect the contemporary migration to earlierstages at presentation.9

However, these contemporary surgical seriesmay underestimate the risk of lymph node in-volvement because of the false-negative rate oflymph node dissections. Golimbu et al10 reportedthe results of extended pelvic lymphadenectomy(EPL) performed on 30 patients with clinicallylocalized prostate cancer. Table 1 indicates thedistribution of node metastasis in the node-posi-tive patients. It is of note that in this pre-PSA eraseries, the presacral-presciatic nodes were in-volved almost as often as the more superficialexternal iliac-obturator lymph nodes. A more re-cent study by Heidenreich et al11 reviewed 103patients who underwent EPL and compared theresults with those of 100 patients who had astandard pelvic lymphadenectomy. There wereno significant differences between the groups inclinical stage, preoperative PSA, or preoperativeGS. However, the group undergoing EPL had asignificantly higher incidence of lymph node me-tastasis. The overwhelming majority of node-positive EPL patients had metastases outsideof areas dissected in a standard pelvic lymph-adenectomy and of all metastases, 42% were out-side of these regions. Despite negative obturatornodes, metastases were shown in the internaliliac and presacral nodes. In contrast to theGolimbu series, the presacral nodes were in-volved only 4% of the time and only when multi-ple other sites were involved.

Using the Partin nomograms, Roach et al12

derived a simple equation that uses pretreatment

Table 1. Distribution of Node Metastasis inClinically Localized Prostate Cancer

Nodal Sites Involved % Single %

#1 External iliac 60 0#2 Obturator 53 20#3 Presacral 53 7#4 Presciatic 47 7#5 Common iliac 27 0#6 Hypogastric 14 0#1 � 2 External iliac/obturator 86 NA#3 � 4 Presacral/presciatic 80 NA

Abbreviation: NA, not available.Data from Golimbu et al.10

Reprinted with permission.38

Figure 1. Distribution and localization of 9 selectivefields for extended pelvic lymphadenectomy, includingright external iliac (1), common iliac (2), obturatorfossa (3) and internal iliac (4) lymph nodes, presacrallymph nodes (5), and left external iliac (6), commoniliac (7), obturator fossa (8) and internal iliac (9)lymph nodes. (Reprinted with permission.11)

110 Roberts and Roach

PSA and GS to estimate the risk of lymph nodeinvolvement (�N). The equation is as follows: %� LN � (2/3) PSA � ([GS � 6] � 10). Otherinvestigators have validated this equation.13

To effectively estimate the risk of lymph nodeinvolvement, physicians must appreciate thegrading error of prostate biopsies. Undergradingis more common than overgrading. Table 2 showsthat approximately 50% of low-grade tumors areundergraded. There is a 15% chance of under-grading and a 10% chance of overgrading forintermediate grade tumors. For high-grade tu-mors, there is an approximately 25% chance ofundergrading. A Radiation Therapy OncologyGroup (RTOG) analysis shows the importance ofthe pathologist’s experience in reviewing biop-sies. This study showed that the concordance ratebetween centrally reviewed pathology and out-side institutions is only 36% for GS 2 to 5 tumorsbut rises to approximately 70% for tumors with aGS of 6 to 10.14

Occult lymph node metastases may be missedwhen lymph node specimens are reviewed by con-ventional pathologic methods. Freeman et al15

showed that 16% of patients with pT3N0 prostatecancer had occult lymph node metastases whenevaluated by immunohistochemistry and PSA ex-pression. As one would expect, occult metastaseswere more common in patients with high Glea-son grade tumors and seminal vesicle invasion.Investigators have used molecular staging of pel-vic lymph nodes to more accurately assess thestatus of pelvic lymph nodes. Using a reversetranscription-polymerase chain reaction (RT-PCR) assay that amplified PSA messenger RNA,Edelstein et al16 tested pelvic lymphadenectomyspecimens from 57 patients who had no evidence

of metastasis by conventional pathologic meth-ods. Forty-four percent of the evaluable speci-mens had a positive assay. Disease recurrencesubsequently occurred in 88% of the patientswith a positive assay compared with 30% of pa-tients with negative nodes.

Ferrari et al17 also used PSA expression andRT-PCR to examine lymph node specimens of 29patients with clinically localized, high-risk pros-tate cancer who had negative bone scans, com-puterized tomographic scans of the pelvis, and noevidence of metastases by conventional patho-logic methods. Approximately 80% of these pa-tients had positive RT-PCR results. As more ef-fective methods of detecting occult lymph nodemetastases are developed, researchers will beable to better distinguish high-risk patients be-fore treatment.

Elective Nodal Radiation Therapy

Most prostate cancer patients will present withclinically localized disease. A central question inthe management of these patients is whetherthere are subgroups that will benefit from theaddition of WPRT to their treatment regimen.

Positive Retrospective StudiesTo our knowledge, 3 published retrospectivestudies show a disease-free survival and/or sur-vival benefit for subsets of patients treated withWPRT when compared with PORT. A summaryof the 3 studies is presented in Table 3. The 2reports by Seaward et al18,19 from the Universityof California, San Francisco were conducted inthe PSA era and included only patients with ahigh estimated risk of lymph node involvement.One study compared WPRT with PORT in pa-tients with an estimated lymph node risk greaterthan or equal to 15%. In this patient group,WPRT significantly increased the PSA failure-free survival. The other study divided patientsinto 2 subgroups: intermediate risk patients (de-fined as an estimated lymph node risk of greaterthan or equal to 15% but less than 35%) andhighest risk patients (defined as an estimatedlymph node risk of greater than or equal to 35%).Intermediate risk patients treated with WPRThad significantly improved PSA failure-free sur-vival compared with those treated with PORT,but no significant difference was seen in highest-risk patients. This report suggests that WPRT

Table 2. Relationship Between Biopsy Stage andFinal Pathologic Stage

Biopsy Grade

Pathologic Gleason Score No. ofPatients†2-4* (%) 5-7* (%) 8-10* (%)

Well (2-4) 50 48 2 122Moderate (5-7) 10 74 15 258Poor (8-10) 1� 25 74 81

NOTE. Underlined numbers reflect understaging, and bold-face numbers reflect overstaging.†Number of patients in series by Benson and review of 5 seriesby Johnstone.Data from Johnstone et al and Benson.31,32

Reprinted with permission.38

Pelvic Radiation Therapy 111

alone may not benefit patients with a very highrisk of nodal disease.

Other studies show increased local controlwhen adequate pelvic dose and field size are em-ployed. Rangala et al20 reported increased localfailures when the pelvic portal was less than 15 �15 cm. In the study by Perez et al,21 patients withstage C poorly differentiated tumors weretreated with WPRT. Patients who received wholepelvic doses of 50 to 55 Gy had significantly fewerpelvic failures compared with those who received40 to 45 Gy (P � .01). In addition, PSA levelswere available for 317 patients. For these pa-tients, there was a suggestion that receivingWPRT increased disease-free survival (althoughnot a statistically significant improvement).

Negative Retrospective StudiesSeveral other studies have failed to show a dis-ease-free survival or survival benefit from WPRT.

Table 4 summarizes 4 representative series. In alater report by Zagars et al,22 treatment withWPRT also failed to improve disease-free survivalor overall survival in patients with stages A2 andB prostate cancer. It is of note that in the PSA eraonly the study by Rasp et al,23 reported in ab-stract form, fails to show a benefit from WPRT.This report evaluated patients with an estimatedrisk of lymph node involvement of greater than orequal to 15%. Although the 2 groups had nosignificant differences in clinical tumor and nodalstage, GS, and pretreatment PSA, there was asignificant difference in the prostate radiationdose delivered (median 68.4 Gy dose in theWPRT group v 63.0 Gy in the PORT group).However, the variation in clinical tumor stagesbetween the groups approached statistical signif-icance (P � .07). One possible reason for the lackof benefit from WPRT is that WPRT patientstended to have more advanced tumors with a

Table 3. Retrospective Studies Showing a Benefit From WPRT

Study Population FieldNo. of

Patients DFS (%) P Value Survival (%) P Value

McGowan et al33 Stages B2-C WPRT 91 63 (5 yr) �.01 NA NAPORT 44 35 (5 yr)

Ploysongsang et al72 Stage B WPRT 32 68 (5 yr) NA 92 (5 yr) �.025PORT 60 NA 70 (5 yr)

Stage C WPRT 82 63 (3 yr) �.0004 72 (5 yr) �.0004PORT 41 30 (3 yr) 40 (5 yr)

Seward et al18 �15% risk of pelvic WPRT 117 34.3* �.0001 NA NALN involvement PORT 84 21.0*

Abbreviations: WPRT, whole-pelvis radiation therapy; PORT, prostate-only radiation therapy; DFS, disease-free survival; NA, notavailable.*Progression-free survival interval (in months).

Table 4. Retrospective Studies Failing to Show a Benefit from WPRT

Study Population Field SizeNo. of

PatientsLocal-RegionalRecurrence (%) P Value DFS (%) P Value

Aristizabal et al73 Stages A-D1 �12 � 12 cm 58 12 NA NA�10 � 10 cm 160 7.5 NA

Rosen et al74 Stage B �150 cm2 29 10 NS �60 (5 yr) NS�150 cm2 48 12.5 �60 (5 yr)

Stage C �150 cm2 49 14 NS �45 (5 yr) NS�150 cm2 38 21 �65 (5 yr)

Zagars et al75 Stage C* �11 cm W 202 54 (10 yr) NS�11 cm W 233 43 (10 yr)

Rasp et al23 �15% risk of pelvic NA 52 35 (5 yr)† NSLN involvement NA 52 29 (5 yr)†

Abbreviations: WPRT, whole-pelvis radiation therapy with a prostate-only boost; PORT, prostate-only radiation therapy; DFS,disease-free survival; NA, not available; NS, not statistically significant; W, width.*Without tumor fixation to the pelvic sidewall.†Includes biochemical relapses.


poorer prognosis as implied by them beingtreated to a higher prostate dose. Other possibleexplanations include different methods of esti-mating lymph node risk, a delay in the time ofPSA failure secondary to institutional definition,a failure to analyze patients with an intermediatehigh risk of nodal involvement separately fromthose with the highest risk of involvement, vari-ability in clinical staging among the patients, orthe lack of sufficient sample size to show a sig-nificant survival benefit.

Randomized TrialsWe are aware of 3 published prospective random-ized trials that have compared WPRT withPORT. In the Stanford series, the lymph nodes of57 patients were surgically evaluated before ran-domization to WPRT or PORT.24 Patients withpathologically negative lymph nodes were eligiblefor this trial. In those randomized to receiveWPRT, the pelvis was treated with 4 MV photonsvia a 4-field arrangement (with some variation)to a dose of 5,000 cGy in 200 cGy fractions.Approximately half of the pelvic dose was initiallygiven, followed by an interruption of 2 weekswhile the prostate bed was treated, with the re-mainder of the pelvic dose delivered after theboost (a “sandwich technique”). The prostate wastreated to a total dose of 7,000 cGy in 200 cGyfractions. The disease-free survival was 70% forpatients who received WPRT compared with 53%for those who did not receive pelvic radiation.This was not a statistically significant result, butthe sample size may have been too small to showa difference.

The RTOG conducted a prospective random-ized study (RTOG 77-06) evaluating WPRT ver-sus PORT for clinical staged A2 and B patients.25

The pelvic lymph nodes were evaluated via astaging lymphadenectomy or lymphangiogrambefore treatment. The pelvis was treated witheither rotational, 4-field, or parallel opposed (forenergies greater than 10 mV) field arrangementsto 4,500 to 5,000 cGy in 180 to 200 cGy fractions.The doses delivered to the prostate ranged from6,500 to 7,200 cGy in 180 to 200 cGy fractions.The protocol allowed use of the sandwich tech-nique. With a median follow-up of 12 years, therewas no significant difference in disease-free oroverall survival between the 227 patients ran-domized to receive WPRT and the 222 PORTpatients. However, the patients enrolled in the

protocol were a favorable group of patients whohad surgically staged lymph nodes, early stagedisease, and lower-grade tumors. These patientswould be expected to have a low risk of nodalinvolvement. In addition, PSA was not availablefor use in assessing failure.

The third randomized trial, RTOG 94-13,compared WPRT with PORT in patients receiv-ing hormonal therapy and will be discussed later.

Radiation TechniqueAs summarized in Table 5, the radiation tech-nique in the older literature varies considerably.There is evidence in the literature that optimallocal control of prostate cancer is correlated withimproved local-regional control, a lower inci-dence of pelvic failure, a lower incidence of dis-tant metastases, and improved survival.26-28 Animportant factor in local control is tumor dose:higher doses to the tumor volume are associatedwith improved local control rates but are alsoassociated with higher complication rates. In con-trast, although some investigators found signifi-cantly increased morbidity with the use of largertreatment fields, most studies, including an anal-ysis of RTOG study 77-06, report no associationof larger treatment volumes with increased mor-bidity.21,29,30-33

Over the past decade, more accurate methodsof radiation delivery to the tumor volume thatreduce normal tissue exposure have becomewidely available in the radiation oncology com-munity.34 Replacement of the conventional tech-niques that were used in older studies by 3-di-mensional treatment planning and conformalradiotherapy (3D-CRT) techniques have allowedhigher doses to be safely delivered to the pros-tate. For example, Pollack et al35 reported a sig-nificant improvement in the freedom from clini-cal and/or biochemical failure among thosepatients randomized to treatment with 78 Gy(3D-CRT prostate boost) rather than 70 Gy con-ventional treatment. However, with a median fol-low-up of 60 months, the 78-Gy group had signif-icantly increased rectal, but not bladder, toxicity.Rectal morbidity was greatly decreased if lessthan 25% of the rectal volume received �70 Gy,confirming an earlier report.36 If greater localcontrol can be achieved by delivering higherdoses to the prostate, greater benefits may berealized from WPRT.


Geographic miss can also result in inferiorlocal control rates. Using electronic portal imag-ing devices improves the accuracy of isocenterpositioning during radiation treatment. Thesedevices use the treatment beam to acquire adigital image of the target area. Radiopaque fi-ducial markers (eg, gold or titanium seeds) arealso sometimes implanted within the prostate toallow for localization in the image and to adjustfor organ movement.37 Figure 2 shows on-lineportal imaging with gold seeds used as fiducial

markers. These methods help to reduce dailysetup error, which should be kept to a minimum,especially for conformal treatment.

Figure 3 shows an example of standard simu-lation films for whole pelvis radiotherapy. Thesetup and simulation of a standard whole pelvisfield is as follows. The patient is simulated in thesupine position with a full bladder and emptyrectum. An immobilization device is used for re-producible patient positioning daily. A urethro-gram is performed to identify the inferior extent

Table 5. Radiation Technique Used in Retrospective WPRT Studies

StudyPelvic FieldArrangement Photon Energy

Pelvic Dose(cGy)

DPF(cGy)

Boost Dose(cGy)

DPF(cGy)

PORT Dose(cGy)

DPF(cGy)

McGowan et al33 PO Co60, 6 MV 2,500 250 3,500 175 6,000 2008 MV 3,250 217 2,750 183

Rangala et al20 PO, FF Co60, 4 MV, 8 MV,25 MV

4,000-5,000 180-200 2,000 180-200 — —

Aristizabal et al73 PO 4 MV, 10 MV 4,000-5,000 180-200 1,500-2,500 180-200 6,500-7,000 180-200Rosen et al76 PO, RF 4 MV, 8 MV 3,800-4,600 180-200 6,000-7,100* 180-200 6,000-7,100 180-200Zagars et al77 FF 18 to 25 MV 5,000† 200 1,000-2,000† 200 6,000-7,000† 200Ploysongsang

et al74FF Co60, 4 MV, 20 MV 4,600-5,000 180-200 2,000‡ 200 7,000-7,500 180

Perez et al21 PO 20 to 35 MV 4,500-5,500 180-200 6,500-7,100* 180-200 6,500-7,100 180-200Rasp et al23 NA NA 5,040 NA 6,840 NA 6,300 NASeward et al18 FF NA NA 180 6,100-8,120§ 180 6,000-8,730§ 180

NOTE. Except as noted, doses are calculated either at the tumor minimum or the midplane (for PO fields).Abbreviations: DPR, dose per fraction; CCR, chronic complication rate; WPRT, whole-pelvis radiation therapy; PORT, prostate-only radiation therapy; PO, parallel opposed; FF, 4 fields; RF, rotational fields; NA, not available.*Total dose to the prostate.†Dose calculated at the central axis of the beam.‡In 71% of the patients, the initial 2,400 to 2,600 cGy was delivered to the pelvis, followed by an interruption of 2 weeks whilethe boost was given, with the remainder of the pelvic dose delivered after the boost (“sandwich technique”).§Three-dimensional conformal radiotherapy was used in some patients.

Figure 2. (A) Anterior-posterior and (B) lateral on-line portal images showing gold seed fiducial markers in theprostate.


of the prostatic apex. The superior border of thefield is placed at the L5-S1 junction and theinferior border is placed 1 cm below the area inwhich the contrast narrows to a point on theurethrogram. To include the iliac lymph nodes,the lateral margins of the anterior-posterior por-tal are approximately 1.5 to 2 cm lateral to thebony margin of the pelvic inlet at the widestpoint. Appropriate corner blocking is used to de-crease dose to the femoral heads, bowel, and bonemarrow. The anterior margin of the lateral portalis placed at the anterior portion of the pubicsymphysis. Posteriorly, the lateral portal is placedat approximately the S2-3 interspace to includethe upper presacral lymph nodes. Blocking ante-riorly decreases dose to the small bowel and pos-teriorly spares the posterior wall of the rectum.The position of the rectum is obtained from atreatment planning computerized tomography.38

Interestingly, the standard 4-field pelvic radi-ation portal has been shown through lym-phangiography, treatment planning computedtomography, and beam’s eye view display to ex-clude a portion of either the internal iliac orexternal iliac lymph node volume in 19 of the 20patients studied by Forman et al.39 In addition,dose-volume histograms showed that up to 30%of the lymph node volume received only 56% ofthe prescribed dose. However, it is not knownwhether altering the treatment volume wouldresult in increased local-regional control, disease-free survival, or overall survival.

Androgen Deprivation Plus RadiationTherapy

In an effort to improve the results of radiationtherapy in the treatment of prostate cancer, hor-monal therapy has been added to WPRT in theneoadjuvant or adjuvant setting. Four major pro-spective randomized trials conducted by theRTOG and European Organization for Researchand Treatment of Cancer have shown increasedsurvival for at least some subsets of patients andall have used WPRT.40-43 One could argue that abenefit of hormonal therapy has not been shownin the absence of WPRT. One rationale for neo-adjuvant androgen suppression is to induce cy-toreduction of androgen-dependent tumor cells.Therefore, the final prostate boost volume maybe reduced, potentially sparing portions of adja-cent structures (such as the bladder and rectum).Several studies have described a reduction inprostate volume secondary to neoadjuvant andro-gen suppression.44,45 However, some investigatorshave reported that neoadjuvant or adjuvant an-drogen deprivation (AD) increases late toxicity.For example, data from Bolla et al42 showed asignificantly higher incidence of incontinence inpatients who received adjuvant hormonal treat-ment when compared with those who receivedradiotherapy alone. Also, Sanguineti et al46 foundthat the use of adjuvant hormonal therapy was anindependent predictor of late rectal toxicity onmultivariate analysis.

Figure 3. Anterior-posteriorand lateral simulation filmsillustrate the portals used forwhole pelvis irradiation. Ar-rows show the positions of theseed markers.


A second rationale for androgen ablation is toincrease the effectiveness of radiation therapy byenhancing radiation-induced cellular damageand/or by treating radiation-resistant cells.Mechanisms for these effects may include syner-gistic interactions between radiation therapy andthe antiandrogen agent, independent inductionof apoptosis in tumor cells, and the shift of thecell cycle from an active to a resting phase result-ing in enhanced killing effect.47

The antiangiogenic effects of androgen abla-tion may also be a basis for the improved resultswith combined therapy. There is considerableevidence in the literature that tumor growth andmetastasis are angiogenesis dependent.48,49 Maz-zucchelli et al50 showed that patients who under-went 3 months of complete androgen blockadebefore prostatectomy had downregulation of vas-cular endothelial growth factor and decreasedvascularization compared with those who had notreceived preoperative hormonal therapy. The an-tiangiogenic effects of AD may also extend tolymph node metastases.

RTOG 94-13 compared WPRT with PORTand neoadjuvant to adjuvant androgen suppres-sion. 1,295 patients with an estimated risk oflymph node involvement of greater than 15%(using the Roach equation) were randomized to 4treatment arms: (1) neoadjuvant hormonal ther-apy (NHT) 2 months before and during WPRT,(2) NHT 2 months before and during PORT, (3)WPRT followed by 4 months of adjuvant hor-monal therapy (AHT), or (4) PORT followed by 4months of AHT. Hormonal therapy consisted ofgoserelin acetate administered subcutaneously indepot form (3.6 mg/mo or 10.8 mg/3 mo) andflutamide 250 mg taken 3 times daily by mouthfor 4 months. WPRT consisted of 50.4 Gy to thepelvis followed by a 19.8 Gy boost, whereas PORTpatients received 70.2 Gy to the prostate. A pre-liminary analysis of the trial showed a significant4-year progression-free survival advantage for pa-tients treated with WPRT, but no significant dif-ference in overall survival.51 There was also nosignificant difference in 4-year progression-freesurvival or overall survival when patients treatedwith NHT were compared with those treatedwith AHT. When all 4 arms of treatment werecompared, there was a progression-free survivaladvantage, but not an overall survival advantage,for patients in the WPRT � NHT group com-pared with the other treatment groups.

This trial suggests a biologic interaction be-tween radiotherapy and hormonal therapy thatoccurs in the pelvic lymph nodes that is depen-dent on the timing of hormonal therapy in rela-tion to radiotherapy. The study also supports an-imal data that the dose required to control 50%of in vivo tumors (TCD50) is significantly less ifAD occurs before radiation therapy.52 In contrastto these radiation therapy series, to our knowl-edge, published randomized studies of neoadju-vant hormonal therapy plus radical prostatec-tomy in node-negative patients have not shown asignificant improvement in biochemical and/orclinical disease-free survival.53-56 These negativestudies further support a biologic interaction be-tween radiotherapy and hormonal therapy. In-deed, if, as has been shown in animal models, ADleads to the outgrowth selection and proliferationof androgen-independent clones, it is not surpris-ing that neoadjuvant hormonal therapy does notalter disease-free survival in surgical series.57

Therapeutic Nodal Radiation Therapy

The finding of lymph node metastasis is a poorprognostic factor. It is clear that both the numberof involved nodes and the extent of metastaticinvolvement predict the subsequent course of dis-ease.58 Nearly all patients will develop metastaticdisease if untreated and the long-term disease-free survival of patients with even minimal mi-croscopic involvement is poor.59

Radiation AloneThe impact of radiation alone on the naturalhistory of node-positive patients is minimal. Avery high percentage of patients will still developdistant metastases.

Spaas et al60 reported the results of 241 pa-tients who underwent staging lymphadenectomyat Stanford. A subset of 91 patients were enteredinto a prospective randomized trial in whichnode-negative patients received WPRT or PORTand node-positive patients received WPRT or pel-vic plus para-aortic irradiation (extended-fieldradiation therapy or EFRT). Among the nonran-domized patients, most node-negative patientsreceived prostate irradiation (either externalbeam radiotherapy or brachytherapy) and node-positive patients all received EFRT. At 10 years,the node-positive patients had an overall survivalof 25%, disease-free survival of 3%, and local


control rate of 30%. Only 8% of the patients werefree of distant metastases.

Hanks et al61 described the 10-year results ofpathologic node-positive patients treated on theRTOG 75-06 protocol. Patients were assignedrandomly to WPRT or pelvis plus para-aortic ir-radiation. At 10 years, the overall survival of the90 node-positive patients was 29%, and the dis-ease-free survival was 7%. The PSA levels ob-tained in 2 of the 5 disease-free patients were lessthan 0.8 ng/mL.

Therefore, it is possible to cure only a smallfraction of node-positive patients with radiationtherapy alone. This is not surprising given thefindings of Wood et al,62 who used RT-PCR andimmunohistochemistry using a PSA antibody toevaluate the bone marrow of prostate cancer pa-tients with pelvic lymph node metastases and anegative bone scan. Over 70% of these patientshad involvement of the marrow by RT-PCR.

Androgen Deprivation Plus RadiationTherapy

The results of AD combined with radiation ther-apy have been more promising.

In the series described by Robnett et al,63 79patients with pathologically proven node-positivedisease were treated with radiotherapy and, atthe patient’s election, either DES, orchiectomy,LHRH agonist, or combined androgen blockade.The radiation therapy consisted of whole pelvisirradiation to 45 Gy with an additional 9Gy to theprostate and unresected grossly involved lymphnodes. A final boost was then delivered to treatthe prostate to 65 to 69 Gy for T2 lesions and 65 to72 Gy for T3 and T4 lesions. The disease-free sur-vival at 5, 8, and 12 years was 86%, 72%, and 53%,and the overall survival was 90%, 87%, and 81%.

Zagars et al64 reported the outcome of 255node-positive patients treated at the MD Ander-son Cancer Center. The nodal status of patientswas established by staging lymphadenectomy,and treatment consisted of either AD alone orcombined AD and radiotherapy. Usually, radio-therapy was delivered through 11 � 11 cm ante-rior-posterior fields and 11 � 9 cm lateral fieldsfor 46 Gy.65 Reduced fields were then used toboost the prostate to a median dose of 68 Gy. TheAD alone group had a longer median follow-upthan the combined therapy group (9.4 years com-pared with 6.2 years). The freedom from clinicaland/or biochemical relapse rate for the 183 pa-

tients treated with AD alone at 5, 10, and 13years was 41%, 25%, and 19%, whereas the rate at5 and 10 years for the 72 patients who receivedcombined treatment was 91% and 80%. The over-all survival rate for the AD alone group was 83%,46%, and 21% at 5, 10, and 13 years. In contrast,the combined therapy group had a 5- and 10-yearoverall survival rate of 92% and 67%. The supe-rior results in the combined AD and radiotherapygroup were statistically significant in univariateand multivariate analyses.

Lawton et al66 described the results of 173biopsy-proven node-positive patients enrolled inRTOG 85-31 (described earlier). Ninety-eight pa-tients received immediate hormonal therapy(arm I) and 75 received hormonal therapy only atthe time of relapse (arm II). Although the pa-tients in arm I had a significantly higher pre-treatment PSA values (60% of the patients hadpretreatment PSA values), there was a significantdifference in disease-free survival with a PSA of1.5 ng/mL or less and metastatic failure rate infavor of these patients at 5 years. However, nosignificant difference was seen between the armsin disease-specific failure and overall survival,including a subset analysis of patients with GS 8to 10 tumors.

A Swedish trial randomized surgically stagedT1-4, pN0-3, M0 patients to radiation therapyalone or radiation therapy and orchiectomy.67

The pelvis received a dose of 50 Gy followed by aboost to the prostate for a total mean dose of 64.9Gy. There were 39 patients with node-positivedisease. Among node-positive patients, the com-bined treatment group had a significantly higherprogression-free survival, disease-specific sur-vival, and overall survival.

The treatment of patients with lymph nodemetastasis is discussed in more detail by Pollacket al68 in this issue.

Summary

The literature from the post-PSA era shows thatthere may be a benefit from WPRT for patientsestimated to be at high risk (�15%) for pelviclymph node involvement. Unfortunately, manyWPRT reports evaluate patients treated in thepre-PSA era, and problems arise when one at-tempts to reconcile the literature. First, becauseof screening-induced stage migration, the patientpopulation is not the same. Contemporary pa-tients present with lower tumor volumes and


fewer lymph node metastases. Second, withoutPSA testing and contemporary imaging methods,the selection of high-risk patients and the detec-tion of disease recurrence are suboptimal. Third,radiation treatment technique has greatly im-proved, allowing greater doses of radiation to thetumor volume with decreased morbidity. In-creased doses are associated with greater localcontrol, which should theoretically increase thebeneficial effects of WPRT. Study comparisonsmay be difficult even for studies conducted in thePSA era because the definition of PSA failure mayvary from institution to institution and may alterthe time to failure. This alteration will result inthe shift of patient groups.

We find it is somewhat surprising that WPRTremains controversial in the treatment of high-risk prostate cancer. For many solid tumors, theregional lymph nodes are routinely treated inhigh-risk patients by surgery, radiotherapy, orcombined therapy. Also, clear precedent existsfrom other cancer sites that the use of regionalnodal irradiation can impact disease-free and/oroverall survival. For example, one study includedpremenopausal breast cancer patients who hadundergone mastectomy and had a high risk oflocal recurrence. These patients were randomlyassigned to receive chemotherapy alone or che-motherapy plus irradiation to the chest wall andregional lymph nodes.69 The 10-year disease-freesurvival and overall survival were significantlyimproved for patients who received chemother-apy plus irradiation. Another trial randomizingnode-positive premenopausal women to postmas-tectomy chemotherapy alone or chemotherapyplus irradiation to the chest wall and regionallymph nodes also showed significantly increasedcontrol rate and overall survival in womentreated with combined therapy.70 A prospectiverandomized RTOG trial found that bulky stageIB and IIA cervical cancer patients had a signif-icantly better 5-year survival rate when treatedwith para-aortic plus pelvic irradiation ratherthan pelvic irradiation alone.71 The traditionalmanagement of stage I, IIA, and IIB seminomapatients is postorchiectomy nodal irradiation. Fi-nally, the standard treatment for resectable lo-cally advanced squamous cell carcinomas of thehead and neck is surgery followed by radiationtherapy to the tumor bed and regional lymphnodes.

We may never know definitively if WPRTalone is more beneficial for high-risk patients

since the combination of WPRT and hormonaltherapy appears to improve treatment results.The preliminary results of RTOG 94-13 show thesuperiority of WPRT over PORT when combinedwith neoadjuvant AD. The data also show thatneoadjuvant hormonal therapy is superior to ad-juvant hormonal therapy. Even if overall survivalis not improved, patients will benefit from in-creased disease-free survival. Fewer treatmentfailures result in decreased need for salvage hor-monal therapy. Patients do not have to experi-ence the psychologic and physical pain from dis-ease recurrence and the side effects of salvagetherapy. In addition, patients (and society) avoidthe cost of salvage therapy.

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the evolving role of pelvic radiation therapy

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