Abbreviations

and Acronyms

ADT ¼ androgen deprivationtherapy

CSS ¼ cancer specific survival

PLND ¼ pelvic lymph nodedissection

PSA ¼ prostate specific antigen

Accepted for publication November 13, 2013.* Correspondence: Department of Urology,

University of Bern, CH-3010 Bern, Switzerland(telephone: þ41 31 632 3641; FAX: þ41 31 6322180; e-mail: fiona.burkhard@insel.ch).

For another article on a relatedtopic see page 1439.

1280 j www.jurology.com

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Removal of Limited Nodal Disease in Patients UndergoingRadical Prostatectomy: Long-Term Results Confirm a Chancefor Cure

Roland Seiler, Urs E. Studer, Konrad Tschan, Pia Bader and Fiona C. Burkhard*

From the Department of Urology, University of Bern, Bern, Switzerland

Purpose: In 2003 we reported on the outcomes of 88 patients with node positivedisease who underwent radical prostatectomy and pelvic lymph node dissection(median 21 nodes) between 1989 and 1999. Patients with limited nodal diseaseappeared to have a good chance of long-term survival, even without immediateadjuvant therapy (androgen deprivation therapy and/or radiotherapy). In thisstudy we update the followup in these patients and verify the reported projectedprobability of survival.

Materials and Methods: The projected 10-year cancer specific survival proba-bility after the initially reported followup of 3.2 years was 60% for these patientswith node positive disease. The outcome has been updated after a medianfollowup of 15.6 years.

Results: Of the 39 patients with 1 positive node 7 (18%) remained biochemicallyrelapse-free, 11 (28%) showed biochemical relapse only and 21 (54%) experiencedclinical progression. Of these 39 patients 22 (57%) never required deferredandrogen deprivation therapy and 12 (31%) died of prostate cancer. All patientswith 2 (20) or more than 2 (29) positive nodes experienced biochemical relapseand only 5 (10%) of these 49 experienced no clinical progression. Of these49 patients 39 (80%) received deferred androgen deprivation therapy.

Conclusions: Biochemical relapse is likely in patients with limited nodal diseaseafter radical prostatectomy and pelvic lymph node dissection, but for 46% ofpatients this does not imply death from prostate cancer. Patients with 1 positivenode have a good (75%) 10-year cancer specific survival probability and a 20%chance of remaining biochemical relapse-free even without immediate adjuvanttherapy.

Key Words: prostatic neoplasms, lymphatic metastasis,

prostatectomy, treatment outcome

PELVIC lymph node dissection inpatients with prostate cancer re-mains the most accurate and reliablestaging procedure for the detection oflymph node metastases. Despite exten-sive research, neither imaging tech-niques1,2 nor lymphoscintigraphy3e5

are yet able to replace PLND forprostate cancer due to their lowsensitivity. In fact, technetium based

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lymphoscintigraphy can miss up to30% of diseased nodes.4

The incidence of nodal metastasisafter radical prostatectomy andPLNDin patients with presumed clinicallylocalized prostate cancer was 20%to 40% in the 1970s and 1980s6,7 andhas decreased more recently to 4%to 10%, depending on patient selec-tion and PLND technique.8,9 There is

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SURVIVAL OF PATIENTS WITH NODE POSITIVE DISEASE AFTER RADICAL PROSTATECTOMY 1281

increasing evidence that a subset of patients mayhave a survival benefit from surgery alone whileothers may profit from multimodal therapy. How-ever, the majority of studies evaluating these ques-tions had a limited followup10,11 and have mainlyincluded patients on immediate ADT.12e15 There-fore, we updated the followup in 88 patients whounderwent radical prostatectomy with PLND be-tween 1989 and 1999, and were diagnosed withlymph nodemetastases at histological evaluation butdid not receive immediate adjuvant therapy (ADTand/or radiotherapy).16

PATIENTS AND METHODS

PatientsThe clinicopathological characteristics of the 88 patients(median age 64 years, range 44 to 76) who underwentradical retropubic prostatectomy and PLND between 1989and 1999 are shown in table 1. Despite clinically organconfined prostate cancer as well as negative preoperativeabdominopelvic computerized tomography, bone scan andchest x-ray, all 88 patients had positive lymph nodes onhistopathological evaluation. Overall 39 of these patients(44%) had 1 positive node, 20 (23%) had 2 positive nodesand 29 (33%) had more than 2 positive nodes. More thantwo-thirds of the patients had primary tumors withextraprostatic extension. Median preoperative PSA was11.9 ng/ml (range 0.4 to 172). None of the patients receivedpreoperative treatment for prostate cancer such as ADT orradiotherapy. Patients with pathologically enlargedlymph nodes at preoperative staging or with incompletepreoperative diagnostic evaluation (no computerized to-mography or bone scan) were excluded from this study.The 88 patients were prospectively followed for biochem-ical relapse, clinical progression (defined as documentedbone metastases, visceral metastases, lymphatic progres-sion or local recurrence) and cancer specific survival.

Surgical Technique and PathologyAll patients underwent open PLND followed by radicalretropubic prostatectomy. Preserving the lymphatics

Table 1. Clinicopathological characteristics of patients

Median age at surgery (range) 62 (35e78)Median yrs followup (range, 95% CI) 15.6 (1.1e22.4, 14.7e16.5)No. death from prostate Ca (%) 47 (53)No. death from any cause (%) 14 (16)No. pT stage (%):Organ confined (pT2c or less) 27 (31)Extracapsular extension (pT3a) 14 (16)Invasion of seminal vesicles (pT3b) 45 (51)Invasion of bladder neck, external

sphincter (pT4)2 (2)

No. Gleason score (%):6 or Less 24 (27)7 38 (43)8e10 26 (30)

Median evaluated nodes/pt (range) 21 (6e41)No. pos nodes (%):1 39 (44)2 20 (23)More than 2 29 (33)

overlying the anterolateral aspect of the external iliacartery, lymph node dissection was performed along theexternal iliac vein, with the caudal limit being the deepcircumflex iliac vein and the femoral canal. All lymphaticvessels from the lower extremities were ligated. Theproximal border was the bifurcation of the common iliacartery. All tissue in the angle between the external andinternal iliac artery was removed. All fatty, connectiveand lymphatic tissue of the obturator fossa along theobturator muscle was removed, leaving only the obturatornerve and vessels. The internal iliac artery and, as far aspossible, the internal iliac vein, were skeletonized. Threedifferent tissue samples on each side, labeled externaliliac, obturator fossa and internal iliac, were sent sepa-rately for histological evaluation. No frozen sections weredone. In 2 patients surgery was aborted after lymph nodedissection because of large palpable lymph node metas-tases and these patients were not included in the study.

All lymph node specimens removed during surgerywere fixed in neutral buffered 4% formaldehyde for24 hours and placed in acetone to dissolve the fatty tissue.Lymph nodes were meticulously searched for and countedmanually. Each node was cut in 3 mm slices which wereseparately embedded in paraffin, stained with hematox-ylin and eosin, and examined microscopically for thepresence of cancer by pathologists. No immunohisto-chemical staining for keratin or PSA or reversetranscriptase-polymerase chain reaction technology wasused. All tumors and lymph node metastases were stagedaccording to the 6th edition TNM classification.17

Adjuvant TreatmentNo adjuvant therapy such as hormonal treatment orradiotherapy was recommended in these patients withlymph node positive disease but 4 patients received ADTwithin 6 months after surgery. ADT or radiotherapy wasonly recommended and initiated at the appearance ofsymptoms or if clinically life threatening progressionoccurred (eg bladder outlet obstruction, gross hematuriaor hydronephrosis due to local progression, pain, visceralor bone metastases, or lymphedema caused by lymph nodemetastasis).

Statistical AnalysesTo estimate biochemical relapse-free, clinical progression-free and cancer specific survival, Kaplan-Meier estimateswere used for all 88 patients. Patients alive at the lastevaluation or relapse-free at the time of death werecensored. The log rank test was used to evaluate differ-ences among the subgroups. Cox proportional hazardsregression models were applied to determine the effect ofthe number of diseased lymph nodes on outcome inmultivariate setting. A significance level of 0.05 was usedfor all tests and all statistical analyses were performedusing SPSS� 20.0 software.

RESULTSAfter a median followup of 15.6 years 81 of the88 patients (92%) had biochemical relapse and65 (74%) showed clinical progression, 90% of whomwithin 5 years after the diagnosis of biochemical

Table 2. Outcome of patients with lymph node metastasesfrom prostate cancer after a median followup of 15.6 years

No. pos nodes 1 2 Greater than 2 TotalsNo. pts 39 20 29 88No. biochemical relapse-free (%) 7 (18) 0 (0) 0 (0) 7 (8)No. biochemical relapse only (%) 11 (28) 3 (15) 2 (7) 16 (18)No. clinical progression (%) 21 (54) 17 (85) 27 (93) 65 (74)No. Ca related deaths (%) 12 (31) 14 (70) 21 (72) 47 (53)

1282 SURVIVAL OF PATIENTS WITH NODE POSITIVE DISEASE AFTER RADICAL PROSTATECTOMY

relapse. Of the 88 patients 56 (64%) required ADTdue to clinical progression observed a median of2.9 years (range 0.3 to 14.6) after surgery. Overall61 of the 88 patients (69%) died, including 47 (53%)of prostate cancer and 14 (16%) of noncancer specificcauses, with 1 man dying of cardiac failure 1.1 yearsafter surgery.

Clinical progression, as local recurrence, inlymph nodes, hematogenous (eg bones, visceral etc)and combined was observed in 7 of 65 (11%), 5 of65 (8%), 22 of 65 (34%) and 31 of 65 (47%) patients,respectively. The distribution of these metastaticsites was virtually the same when compared withthe number of positive lymph nodes (p ¼ 0.1).

Patients with 1 positive lymph node had thebest outcome. Of 39 patients 7 (18%) remained PSArelapse-free after a median followup of 15.6 yearsand 11 (28%) had biochemical relapse only. Of these39 patients 21 (54%) showed clinical progressionand less than half of the patients (17, 43%) requireddeferred ADT. Of the 39 patients 12 (31%) died ofprostate cancer (table 2).

All 49 patients with 2 or more positive lymphnodes experienced biochemical relapse within thefirst 10 years of followup and only 5 (10%) haveremained clinically progression-free. Of these 49patients 39 (80%) received deferred ADT and two-thirds died of prostate cancer (table 2).

After a median followup of 15.6 years the Kaplan-Meier estimates for 10-year cancer specific andoverall survival probabilities were 58% (95% CI47e69) and 51% (95% CI 41e61), respectively, forthe entire cohort of 88 patients (fig. 1). Thebiochemical relapse-free, clinical progression-free

Figure 1. Ten-year cancer specific and overall survival probabili

and cancer specific survival probabilities stratifiedaccording to number of positive nodes show asignificantly better outcome for all parameters inpatients with 1 positive lymph node (fig. 2). Thedifferences in CSS in patients with 1 positive nodevs those with 2 or more positive lymph nodes lie inthe same range as predicted in 2003 (fig. 3).

The number of positive nodes was the strongestprognosticator for CSS in a multivariate Coxregression model that included the number of lymphnode metastases, pT stage and Gleason score. Pa-tients with 2 or more positive nodes had a threefoldgreater risk of dying of cancer compared to thosewith 1 positive node (table 3).

DISCUSSIONIn 2003 we reported on the short-term outcome of88 surgically treated patients with prostate cancerclinically staged N0, but revealed by histopatho-logical evaluation to have lymph node metastases.16

Our initial results after a median followup of3.2 years suggested that radical prostatectomycombined with extended PLND not limited to theobturator fossa alone may benefit some patientswith minimal metastatic disease. These findingscalled into question the widely used algorithm forsubmitting suspicious nodes for frozen sectioningand, if positive, to abort the procedure in view of anexpected poor prognosis for apparently incurablesystemic disease. Indeed, the present update withthe median followup extended to more than 15 yearsshows a good long-term CSS probability (58% at10 years) and confirms our earlier projected survivalprobabilities surprisingly well. The fact that thesepatients did not receive immediate adjuvant ther-apy (ADT and/or radiotherapy) is also noteworthy.

Precise staging in malignant disease is aprecondition of adequate prognosis and treatment.In prostate cancer representative lymph nodedissection remains superior to imaging techniquesfor achieving correct lymph node staging.1,2 How-ever, due to variations in PLND templates, the

ties of entire study group were 57% and 51%, respectively

Figure 2. Biochemical relapse-free (A), clinical progression-free (B) and cancer specific (C ) survival after median followup of 15.6 years

in relation to number of positive lymph nodes (1 vs 2 vs more than 2 positive nodes). Outcome of patients with only 1 positive lymph

node is significantly better than in patients with 2 or more than 2 positive nodes.

SURVIVAL OF PATIENTS WITH NODE POSITIVE DISEASE AFTER RADICAL PROSTATECTOMY 1283

number of lymph nodes detected and metastasesidentified varied considerably.18e20 At the time thepatients reported in this study underwent surgery,we routinely performed PLND, including tissuealong the external iliac vein, in the obturator fossaand along the internal iliac artery up to the bifur-cation of the common iliac artery. The location of theprimary lymphatic sites had not been established atthat time and since PLND was not known to have apossible benefit in patients with prostate cancer, therisk of adverse side effects had to be kept low. Nowthe template for PLND has been extended morecephalad around the bifurcation and both sides ofthe common iliac vessels up to the ureters, andalong both sides of the internal and external iliacvessels. It is likely that the PLND template weapplied in the 88 patients may have missed someadditional positive nodes. Thus, we cannot rule outthe possibility that the patients in whom we found 1positive node in fact harbored additional positive

Figure 3. CSS after median followup of 3.2 (gray lines) and 15.6

(black lines) years according to number of positive lymph

nodes. Kaplan-Meier based predicted probability of survival

after median followup of 3.2 years corresponds surprisingly

well with observed survival more than 10 years later.

nodes outside the PLND template used at that time.Thus, with the larger template the outcome mayimprove in more contemporary series.

Our findings are in line with those of severalother retrospective analyses showing that thenumber of positive lymph nodes correlates withsurvival probability. Interestingly the number ofdiseased lymph nodes seems to have a greaterimpact on clinical course than Gleason score or pTstage has.12,13,21e23 The significant differences inclinical progression in our patients with 1 vs 2 vsmore than 2 positive lymph nodes may reflect themetastatic tumor burden or ultimately the biolog-ical aggressiveness of the metastatic cancer. Un-fortunately the current TNM classification does notinclude any node positive substages for prostatecancer.24 It also does not discriminate according tonumber of positive nodes, nor does it specify otherparameters of metastatic tumor burden such asvolume of metastases, which also correlates withpatient outcome.23 Furthermore, the differentiationinto regional and juxta regional lymph nodes hasnot been adjusted,24 despite convincing evidence inthe meantime that primary lymphatic landing sitesmay be found, although rarely, up to the origin ofthe internal mesenteric artery.25 Therefore, thecurrent TNM classification is challenged by previ-ous and present findings.12,13,21e23,25

The optimal timing of androgen deprivation inpatients with prostate cancer and regional lymphnode involvement is still a matter of debate.12e14

Messing et al showed that immediate ADT afterradical prostatectomy and PLND improves thesurvival of patients with node positive prostatecancer.14 Shortcomings of this study were thelimited PLND template and the inclusion of pa-tients with locally advanced disease such as seminal

Table 3. Multivariate Cox regression models for CSS

HR 95% CI p Value

No. pos nodes (2 or more vs 1) 3.2 1.6e6.3 0.001pT stage (pT3/4 vs pT2) 0.3 0.8e2.5 0.6Gleason score (8e10 vs 7 or less) 0.6 0.6e2.2 0.3

1284 SURVIVAL OF PATIENTS WITH NODE POSITIVE DISEASE AFTER RADICAL PROSTATECTOMY

vesical invasion in 60%. Therefore, limited PLNDin patients with locally advanced disease involves arisk of under staging. Importantly there were alsolong-term survivors among the patients in thecontrol arm, which calls into question whetherall patients with lymph node positive disease needADT and who profits most from immediate ADT.

Indeed, data from other studies confirm thatradical prostatectomy combined with PLNDwithout immediate ADT can be curative forsome patients with lymph node positive prostatecancer.12,22,26 Pound et al reported a 10-year clinicalprogression-free survival rate of 68% in patientswith lymph node micrometastases without adjuvanttherapy.26 Steinberg et al followed 64 patients withnode positive disease treated with radical prosta-tectomy and found that 68% were still clinicallyprogression-free after a median observation timeof 80 months.22 Of the patients in the study byBoorjian et al who did not receive ADT 88% wereasymptomatic at 10 years and the clinical coursewas virtually the same as in those who did receiveADT.12 The conclusion was that the value of ADTis poorly defined and that the timing of ADT shouldbe adapted according to the metastatic tumorburden. Our previous findings and this update morethan 10 years later confirm a good survival proba-bility for patients with only 1 positive node (75% at10 years), importantly without immediate ADT.16

Almost half of these patients remained withoutclinical evidence of tumor progression.

Our results are in line with those of other cen-ters12,22,26 and suggest that immediate ADT shouldnot be routinely offered to patients with a minimalmetastatic burden, provided PLND was represen-tative, especially in light of the negative sideeffects.27 The patients most likely to benefit fromimmediate adjuvant ADT are those with multiple

positive nodes and a rapidly progressing PSA (PSAdoubling time less than 12 months).28

The PLND template used in this limited andretrospectively evaluated cohort is less extensivethan that of more recent series. It is likely thatadditional positive nodes might be found withmore extended templates and it may be expected(although it remains to be proven) that the prog-nosis for patients with a single positive node maybecome even better than our present long-term re-sults show. However, our results again underscorethat a PSA relapse, especially if it occurs late, doesnot require immediate treatment and that many ofthese patients will not necessarily die of prostatecancer. A minimally longer surgical time seems asmall price to pay for a potential survival advantageand delay of additional treatments which are notwithout side effects. Therefore, we believe thatif radical prostatectomy is deemed necessary,extended PLND should be performed at least up towhere the ureters cross the common iliac vessels inaccordance with the newly defined template.25

CONCLUSIONSBiochemical relapse is likely in surgically treatedpatients with prostate cancer and lymph nodemetastases, but does not necessarily imply cancerrelated death. This update confirms that patientswith 1 positive node have a good survival probabil-ity and a 20% chance of remaining biochemicalrelapse-free after a median followup of 15.6 yearseven without immediate adjuvant therapy. There-fore, observation can be recommended for thesepatients. In contrast, patients with multiple positivenodes are likely to experience rapid progressionand, thus, may benefit from early adjuvanttherapies.

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