the role of surgery in the management of recurrent or persistent non-seminomatous germ cell

e a u - e b u u p d a t e s e r i e s 5 ( 2 0 0 7 ) 1 6 3 – 1 7 6

The Role of Surgery in the Management of Recurrent orPersistent Non-seminomatous Germ Cell Tumors

Niels-Erik B. Jacobsen *, Richard S. Foster 1

Department of Urology, Indiana University, Indiana Cancer Pavilion, 535 N Barnhill Dr, Suite 420, Indianapolis, IN 46202, USA

avai lab le at www.sciencedi rect .com

journa l homepage: www.europeanurology.com

Article info Abstract

Keywords:Non-seminomatous germcell tumorRelapseRetroperitoneal lymph nodedissection

Objective: To review the management of patients with non-seminoma-tous germ cell tumors (NSGCTs) with persistent or recurrent diseasefollowing primary or secondary therapy, with particular attentiondevoted to the role of surgery.Methods: A non-structured review of the literature until January 2007was performed using the PubMed database.Results: The management of persistent or recurrent disease amongpatients with NSGCT depends on stage at presentation and relapse,serum tumor marker levels at relapse, prior therapy, and timing ofrelapse. Clinical stage I patients who relapse following active surveil-lance are usually treated with induction chemotherapy. Likewise,patients who relapse following primary retroperitoneal lymph nodedissection (RPLND) are treated with induction chemotherapy based onthe systemic pattern of recurrence. Advanced cases with residual radio-graphic disease >1 cm and normal tumor markers following inductionchemotherapy are generally recommended for postchemotherapy sur-gical resection, whereas those with persistently elevated markersundergo salvage chemotherapy. Select patients with resectable diseaseand elevated serum tumor markers may be appropriate candidates forsurgery. Based on intrinsic chemoresistance, the treatment of patientswith advanced disease who relapse >2 yr (late relapse) following suc-cessful chemotherapy is primarily surgery.Conclusion: Patients with NSGCTs with persistent disease or recur-rence within 2 yr of initial therapy remain highly curable. The prog-nosis of patients with late relapse is compromised based on tumorchemoresistance. The role of surgery in the management of recurrentdisease is primarily limited to the postchemotherapy setting; how-ever, in the context of late relapse it often represents the primarytreatment.

# 2007 European Association of Urology and European Board of Urology.

Published by Elsevier B.V. All rights reserved.

* Corresponding author. Tel. +1 317 274 7076; Fax: +1 317 274 0174.E-mail address: [email protected] (N.-E.B. Jacobsen), [email protected] (R.S. Foster).1 Tel. +1 317 274 3458; Fax: +1 317 274 0174.

1871-2592/$ – see front matter # 2007 European Association of Urology and European Board of Urology.Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eeus.2007.03.003

mailto:[email protected]

mailto:[email protected]

http://dx.doi.org/10.1016/j.eeus.2007.03.003


1. Introduction

Germ cell cancer of the testis is the most commonsolid tumor in men aged 20–35 years [1]. Over 8000new cases are expected in the United States in 2006,of which non-seminomatous germ cell tumors(NSGCTs) will account for more than half. Withthe introduction of effective cisplatin-based che-motherapy, long-term survival now exceeds 85%.Although the role of chemotherapy cannot beoverstated, surgery, particularly retroperitoneallymph node dissection (RPLND), retains criticalimportance in the contemporary management ofpatients with both early and advanced stage disease.

This article reviews the management of NSGCTpatients with persistent or recurrent disease follow-ing primary or secondary therapy, with particularattention devoted to the role of surgery. Early andlate relapse will be discussed as will be role andtechnique of postchemotherapy RPLND (PC-RPLND).

2. Relapse following active surveillance forclinical stage I NSGCT

2.1. Rationale for active surveillance

Roughly 50% of non-seminoma patients presentwith clinical stage I (CS I) disease based on negativeradiographic evaluation and normalization of serumtumor markers (STMs) after orchiectomy (Table 1)[2,3]. Management options include primary RPLND,two cycles of BEP (bleomycin, etoposide, cisplatin)and active surveillance. Although one third of suchpatients harbor subclinical metastases at presenta-tion, cure rates approach 100% regardless of initialchosen therapy. This reflects the early detection ofrecurrence through STM analysis or computedtomography (CT) imaging, coupled with the avail-ability of efficacious salvage treatment.

Table 1 – American Joint Committee on Cancer TNM staging s

Group Regional (retrope

Clinical stage (CS)

I cN0 No regional lymph node metastases

IIA cN1 Metastases with a lymph node mass �2 cm;

or multiple lymph nodes, none >2 cm

IIB cN2 Metastases with a lymph node mass

>2 cm but <5 cm; or multiple lymph

nodes, any one mass >2 cm but <5 cm

IIC cN3 Metastases with a lymph node mass >5 cm

Distant met

III Distant metastases (including non-regional lymph node me

Seventy percent of CS I non-seminoma patientswill never develop a recurrence following orchiec-tomy if managed by surveillance. Recognizing thisfact, a significant proportion of patients chooseactive surveillance as primary therapy, rather thanRPLND or chemotherapy. Thirty percent of patientson surveillance will subsequently relapse, the vastmajority of whom are cured with chemotherapy.Whereas the role of primary RPLND at relapse isunknown, PC-RPLND is integral to the managementof patients with an incomplete response to che-motherapy. It is estimated that 5–10% of patients onsurveillance will eventually require PC-RPLND forresidual disease [4].

2.2. Predictors of recurrence on active surveillance

Established predictors of recurrence in CS I non-seminoma patients on surveillance include lym-phovascular invasion (LVI) and embryonal carci-noma predominance (EC-pred) in the primary tumor[5–8]. Depending on the number of risk factorspresent, patients can be stratified into low- (no riskfactors) and high-risk (LVI or EC-pred or both) groupswith predicted relapse rates of 10% and 50%,respectively [2,4,6]. Risk-adapted managementguidelines recommend primary RPLND or two cyclesof BEP for patients considered to be at high risk forrecurrence, whereas those at low risk are appro-priate for active surveillance [9].

2.3. Pattern, timing, and evaluation of recurrence on active

surveillance

The pooled relapse rate for CS I non-seminomapatients on active surveillance is 29% (23–36%) basedon the accepted diagnostic criteria of a radiographicmass �1 cm or larger or an elevation of one or bothSTMs [2]. The vast majority of recurrences occurwithin 2 yr of initial diagnosis at a median time of

ystem, 2002 [3]

ritoneal) lymph nodes

Pathologic stage (PS)

pN0 No regional lymph node metastases

pN1 Metastases with a lymph node mass

�2 cm or smaller and �5 nodes positive, none >2 cm

pN2 Metastases with a lymph node mass

>2 cm but <5 cm; or >5 nodes positive, none >5 cm;

or evidence of extranodal extension

pN3 Metastases with a lymph node mass >5 cm

astases

tastases)

Table 2 – Evaluation of relapse

Modality Indication

History Routine

Physical examination

(including contralateral testis)

AFP, b-HCG

CT chest, abdomen, pelvis

CT brain If clinically indicated

Bone scan

AFP = a-fetoprotein; b-HCG = b-human chorionic gonadotropin;

CT = computed tomography.

e a u - e b u u p d a t e s e r i e s 5 ( 2 0 0 7 ) 1 6 3 – 1 7 6 165

6 mo [2,4,6,8,10,11]. Recurrence beyond 2 yr is veryuncommon (<3%).

Lymphatic spread, common to all GCTs, usuallyfollows a predictable and systematic pattern fromthe testis to the retroperitoneum and subsequentlyto distant sites, most notably the lungs and media-stinum. Indeed, recurrence among CS I patients onactive surveillance is most common in the retro-peritoneum (65–80%) followed by the chest (15–30%)[2,4,6]. STM levels are elevated in 65–85% of patientsand constitute the only sign of recurrence in 10–15%.Because surveillance strategies involve frequentclinical evaluation, most patients are asymptomaticat relapse and disease burden is typically smaller incomparison to patients who initially present with CSII/III disease. Retroperitoneal tumor volume usuallydoes not exceed 5 cm in greatest dimension (50–94%)and very few patients are categorized as poor riskby International Germ Cell Cancer CollaborativeGroup (IGCCCG) criteria [6,12–14]. The completeevaluation for confirmed or suspected relapse isoutlined in table format (Table 2). In addition toroutine staging of the chest and abdomen it isimportant to rule out the presence of a secondprimary GCT in the contralateral testis, which maydevelop in 1–2% of patients on surveillance [12,13].Likewise, patients with only biochemical recurrencemust be evaluated for other conditions known toelevate a-fetoprotein (AFP; liver disease) or b-humanchorionic gonadotropin (b-HCG; hypogonadism,marijuana use) levels.

Surveillance strategies vary among institutionsand no one schedule appears to be superior toanother with regard to overall survival (97–100%) [2].Based on the predictable pattern of GCT recurrence,all protocols concentrate follow-up during thefirst 2 yr after which evaluation is less frequent.

2.4. Management of recurrence on active surveillance

The standard treatment for recurrent GCT followingactive surveillance is cisplatin-based chemother-

apy. RPLND is an option for patients with low-volume retroperitoneal recurrence (CS II); however,it does not retain the same diagnostic and ther-apeutic value as demonstrated in CS I/II patientswho undergo RPLND at diagnosis. Whereas 23–40%of patients who present with CS II NSGCT have noactive disease identified at RPLND, the vast majorityof patients with an enlarging retroperitoneal masson surveillance harbor teratoma or viable GCT[15,16]. Up to 26% of CS II patients with pathologicstage IIA (PS IIA) disease and 55% with PS IIB diseasewill relapse following RPLND monotherapy versusonly 2% with the addition of adjuvant chemotherapy[16,17]. As a result, two cycles of adjuvant BEP issometimes recommended in patients who undergoprimary RPLND for isolated retroperitoneal recur-rence. Rather than commit patients to dual-modality therapy, induction chemotherapy isrecommended as first-line treatment in the vastmajority who relapse on surveillance, includingthose with isolated retroperitoneal recurrence andnormal STM levels. Patients with teratoma in theorchiectomy specimen may represent one caveat tothis recommendation because 27% with CS IIA and57% with CS IIB disease are also found to haveretroperitoneal teratoma [18]. RPLND may be moreappropriate in these patients because teratoma isnot sensitive to chemotherapy.

Surgery in non-seminoma patients who recur onsurveillance is limited primarily to the postche-motherapy setting. Approximately one third ofpatients with advanced NSGCT will not achieve acomplete response to induction chemotherapy asindicated by residual radiographic disease (>1 cm)[19–21]. Response rates are slightly better amongsurveillance patients because recurrence is typicallydiagnosed at an early stage in this cohort. Post-chemotherapy surgery is recommended in allpatients with normal STM levels and residualradiographic disease >1 cm because >50% of suchmasses harbor persistent active disease (teratoma orviable GCT) [20,22,23]. Unfortunately, there exist nosufficiently accurate criteria by which to predict thepresence of benign histology (necrosis) and avoidPC-RPLND in this setting. The management ofpatients with little or no radiographic abnormality(�1 cm) is a matter of some controversy. Mostcenters, including ours, consider this to representa radiographic complete response and recommendobservation in lieu of surgery [24]. A low rate ofrelapse (5%) with long-term follow-up providesjustification for such an approach [25]. Still, othercenters continue to perform PC-RPLND in patientswith normal STMs and minimal or no radiographiclesions, particularly in those with bulky (�3 cm)


retroperitoneal disease at original diagnosis [26,27].Motivation for this comes from series that demon-strate a 20–30% incidence of active disease (teratomaor viable GCT) in residual masses �1 cm [26–28].Interestingly, the rate of relapse among series withan aggressive surgical policy is 6%, similar to seriesin which residual masses �1 cm are observed (5%)[25,26,29]. The indications, rationale, technique, andresults of PC-RPLND are discussed at a later point inthis article.

3. Relapse following primary RPLND forclinical stage I and II NSGCT

3.1. Rationale for primary RPLND for clinical stage I and II

NSGCT

RPLND is an important diagnostic and therapeuticmodality for patients with early stage testis cancerincluding those with normal STM levels andevidence of low-volume retroperitoneal disease(< CS IIB). Despite technological improvements,20–37% of CS I patients remain under-staged bymodern CT imaging [6,7,16,30–32]. Conversely,23–40% of CS IIA/IIB patients are found to have noevidence of retroperitoneal disease at the time ofsurgery [15,16]. In this regard, RPLND directs appro-priate stage-specific treatment and follow-up stra-tegies. Patients with proven lymph node metastasesmay be selected for adjuvant chemotherapy on arisk-adjusted basis, whereas those with negativelymph nodes are spared the potential long-termtoxicity associated with primary chemotherapy andare subjected to less intensive follow-up than isotherwise required by active surveillance protocols.

The therapeutic value of primary RPLND derivesfrom the orderly spread of GCT from the testis firstto the retroperitoneum. The majority of CS I patients(70%) have no evidence of retroperitoneal metas-tases (PS I) at RPLND [15,32]. Although retroperito-neal recurrence is exceedingly rare in these patients,7–10% will recur at a distant location [7,33]. Thirtypercent of CS I patients have active retroperitonealdisease, three fourths of which are low volume(pN1). Surgery alone is curative in 66–92% of CS Ipatients with pN1 disease and 50% with largervolume disease (pN2, pN3) [16,17,33,34].

Although patients who present with low-volumeretroperitoneal disease (CS IIA, IIB) are more com-monly treated with induction chemotherapy, theycan also derive therapeutic benefit from primaryRPLND. Surgery alone provides cure in approxi-mately two thirds of CS II patients with confirmedretroperitoneal metastases (PS II), whereas the

remaining one third will relapse if adjuvantchemotherapy is withheld [16]. The individual riskof relapse depends on the volume of retroperitonealdisease (pN1 26%,� pN2 55%). Two cycles of adjuvantchemotherapy reduce the risk of relapse below 2%andissometimes chosen forpatients with pN2 or pN3disease (>2 cm) [16,17,35]. By excluding patients withCS IIB disease or elevated STMs from RPLND (ie, onlyCS I or IIA and normal STM levels), investigators atMemorial Sloan-Kettering Cancer Center (New York,NY, USA) have reduced the rate of subsequentrelapse (4% vs. 17%) as well as the need for adjuvantchemotherapy [15]. Even among high-risk patientswith EC-pred or LVI (or both), 5-yr progression-freesurvival rates of 90% can be expected followingRPLND for CS I or IIA NSGCT [36].

3.2. Pattern, timing, and management of recurrence

following primary RPLND

The risk of recurrence following primary RPLNDranges from 10% to 50%, depending on the volume ofretroperitoneal disease [16,17,33,34]. In the absenceof adjuvant chemotherapy, the pattern and timingof recurrence is similar regardless of pathologicstage. The vast majority of failures occur within 2 yrof surgery and are most commonly diagnosed in thechest (lungs, mediastinum) or serologically. Basedon this systemic pattern, induction chemotherapyrepresents the standard treatment for postsurgicalrelapse. The combination of surgery and chemo-therapy in this manner provides long-term survivalin>96% of patients who undergo RPLND for CS I andII disease [16,33].

Retroperitoneal recurrence, particularly withinthe template of dissection, is distinctly uncommon(<2%) after RPLND and reflects inadequate surgicaltechnique [37]. Most patients are treated initiallywith systemic chemotherapy followed by PC-RPLNDfor residual radiographic disease. If retroperitonealteratoma is suspected on the basis of negative STM,imaging characteristics (cystic), and presence ofteratoma in the orchiectomy specimen, repeatRPLND is sometimes performed in lieu of chemo-therapy. Reoperative surgery in the primary andpostchemotherapy settings is a formidable task.Adjunctive procedures such as thoracotomy,nephrectomy, and vascular reconstruction are oftenrequired (59–71%) and major morbidity is common(21–27%) [37–39]. Following reoperation after pri-mary RPLND, the overall 5-yr disease-specificsurvival rate is 86% [38].

Recurrence following RPLND and adjuvant che-motherapy is very uncommon (<2%) and typicallydevelops outside the retroperitoneum [16,17,33].


Unless the suspicion for teratoma is high, standardtreatment is systemic chemotherapy. Second-line(ifosfamide and cisplatin plus etoposide [VIP] orvinblastine [VeIP] or paclitaxel [TIP]) or third-line(high-dose chemotherapy) salvage regimens arecommonly used in this circumstance [40–42].

4. Persistent or recurrent disease followingchemotherapy for advanced NSGCT

The standard treatment for patients with advancedNSGCT (CS IIC/III) is cisplatin-based chemotherapy.Approximately 70% will achieve a complete responseas demonstrated by a normalization of STMs and acomplete resolution of radiographic disease (�1 cm)[19–21]. The policy at Indiana University is to observethese patients because the risk of subsequent relapseis 5% [25]. Patients in whom STMs remain elevatedfollowing induction chemotherapy usually receivesalvage chemotherapy, although surgery for isolatedretroperitoneal disease may be curative. In contrast,surgical resection is recommended in patients withresidual postchemotherapy masses >1 cm, providedthat STM levels are normal, since 50–60% of suchmasses harbor persistent active disease (teratoma orcancer) [20,22,23]. Select patients with resectabledisease and elevated STM levels who demonstratechemoresistance may be appropriate candidates for‘‘desperation’’ surgery rather than second- or third-line chemotherapy. The rationale and results ofdesperation PC-RPLND are discussed elsewhere inthis article.

5. PC-RPLND

5.1. Indications and rationale for PC-RPLND

Thirty percent of patients with advanced NSGCT willfail to achieve a complete response to inductionchemotherapy as indicated by a persistent elevationof STM or persistent radiographic tumor [21,43].Most centers, including Indiana University, recom-mend postchemotherapy surgery in all patientswith normal STMs and residual radiographic disease>1 cm because >50% of residual masses harborteratoma (40–50%) or viable cancer (10–20%) or both[20,22,23]. Resection of residual teratoma or viableGCT is rational and well accepted. Unfortunately,there exist no clinical criteria by which to accuratelypredict the presence of necrosis (45%) and obviatethe need for surgery in such patients [44,45].Teratoma warrants surgical resection by reason ofchemoresistance, disposition for progressive local

growth, risk of malignant transformation, and riskof late relapse, whereas persistent viable GCTreflects some element of intrinsic chemoresistanceand will progress if left untreated [46–48]. Patients inwhom necrosis or teratoma is resected require nofurther therapy because the risk of relapse is low(necrosis <5%, teratoma 7–14%) [48–50]. In contrast,48–100% of patients with viable GCT will relapseafter surgery, indicating that the provision of twocycles of adjuvant chemotherapy may be appro-priate [51,52]. Adverse predictors of progression-freeand overall survival in patients with persistent GCTat PC-RPLND include incomplete resection, propor-tion of viable malignant cells >10%, and intermedi-ate or poor risk disease by IGCCCG criteria [52]. Riskstratification by such parameters may guide theprovision of adjuvant chemotherapy (Table 3). Theintegration of surgery and chemotherapy in patientswith advanced NSGCT is well established andprovides long-term survival in 70–80% [14,42,53].

Some centers also perform PC-RPLND in patientswith minimal or no radiographic disease (�1 cm)provided that retroperitoneal disease was present atdiagnosis and STMs have normalized followingchemotherapy. The basis for this practice comesfrom reports of a 20–30% incidence of active disease(teratoma or viable GCT) in residual masses �1 cm[26–28]. Although such an observation would appearto support routine postchemotherapy surgery in allpatients with retroperitoneal disease at diagnosis, alack of benefit in terms of disease-free survivalargues against such a policy. Indeed, the recurrencerate among patients with little or no radiographicdisease (�1 cm) is 6% following PC-RPLND and 5%with long-term (5 yr) observation [25,26,29]. Thisdisconnect in clinical and pathologic outcomesuggests that the biologic behavior of residual tumormay, in fact, be variable. Although persistent viableGCT will almost certainly progress, microscopicmature teratoma may represent biologically inertdisease with a low risk of growth and late relapse.Such a hypothesis remains purely speculative,however. Alternate explanations include pathologicmisdiagnosis of tumor viability, staging error, anddifferences in chemotherapeutic efficacy amongothers.

Regardless of size criteria, a substantial propor-tion of patients (�45%) harbor necrotic tissue onlyand gain no therapeutic benefit from postche-motherapy surgery. Absence of teratoma in theprimary tumor, normal prechemotherapy STM (AFP,b-HCG, lactate dehydrogenase), residual mass size<2 cm, and >90% volume reduction after che-motherapy have all been shown to be predictive ofresidual necrosis; however, no single criterion, or

Table 3 – Results of adjuvant chemotherapy in patients with viable cancer at PC-RPLND according to risk stratification

Risk group No. RF 5-yr PFS (%) p 5-yr OS (%) p

Adj CTx Observe Adj CTx Observe

Favorable 0 94 84 0.41 100 100 —

Intermediate 1 84 42 0.0005 88 56 0.02

Poor �2 45 45 0.43 55 60 0.69

Risk factors include incomplete resection of tumor, proportion of viable malignant cells >10% and intermediate- or poor-risk disease by

International Germ Cell Cancer Collaborative Group criteria.

RF = risk factors; PFS = progression-free survival; OS = overall survival; Adj CTx = adjuvant chemotherapy.


combination thereof, is sufficiently accurate toobviate the need for surgery [44]. It was previouslysuggested that postchemotherapy surgery could beavoided in patients with teratoma-negative primarytumors, normal STM levels, and a�90% reduction inthe volume of retroperitoneal disease. This wasbased on the results of an early series in which 15 of15 patients who met such criteria were found tohave necrosis only at PC-RPLND [54]. A follow-upstudy, however, found that only 74% of a similarcohort of patients remained continuously free ofdisease without the addition of surgery [25].Although the presence of teratoma in the primarytumor is indeed predictive of similar retroperitonealhistology, 33–58% of patients without teratoma inthe primary tumor are found to have teratoma in thePC-RPLND specimen. This underscores the limita-tions of primary histology as a predictive tool [27,55].In an attempt to improve on the predictive accuracyof individual clinicopathologic factors, statisticalmodels have been developed that incorporateseveral recognized histologic predictors, as listedabove. Even the most accurate predictive model,however, maintains a false-negative rate of 20% [28].Furthermore, contemporary predictive models suf-fer from a lack of clinical relevance. This point washighlighted by a recent external validation study ofthe residual histology in testicular cancer (ReHiT)prediction rule, which found that only 4% of residualmasses were classified as benign and could beoffered surveillance in lieu of surgery [45].

Based on a composite of the aforementioned data,it is the policy of Indiana University to observepatients with normal STM levels and residualmasses �1 cm after chemotherapy, regardless ofprimary tumor histology, IGCCCG risk stratification,and volume of retroperitoneal disease at diagnosis.In turn, PC-RPLND is recommended for thosepatients with normal STMs and residual radio-graphic disease >1 cm. This management strategymaintains a low rate of relapse (5%) among patientsentered into surveillance while at the same timeminimizes the number of patients with necrosis

who undergo postchemotherapy surgery unneces-sarily.

5.2. Surgical considerations

RPLND is an advanced surgical procedure thatrequires a detailed knowledge of retroperitonealanatomy, familiarity with vascular surgery tech-niques, and a full understanding of the naturalhistory of testis cancer. Only then can surgery beperformed in a safe, efficient, and efficaciousmanner. This becomes even more apparent duringPC-RPLND on account of a larger tumor volume, theinevitable desmoplastic reaction associated withchemotherapy as well as its adverse effects on renal,hematologic, and pulmonary function. Although themorbidity of PC-RPLND exceeds that of primaryRPLND, modifications in surgical technique com-bined with improvements in chemotherapeuticdelivery and perioperative care have reduced theincidence of severe or long-term complications to anacceptable level without compromising cure [56]. Tothis end, postchemotherapy surgery should beperformed in tertiary referral centers specializingin the management of testis cancer.

5.3. Preoperative preparation

PC-RPLND is usually performed 4–6 wk after thecompletion of chemotherapy to allow for physicaland hematologic recuperation. A complete meta-static evaluation, including CT chest/abdomen/pelvis and STM analysis should be performed inthe month before RPLND and STM analysis repeated1–2 d prior. Bleomycin-related pulmonary toxicity israre in good-risk patients who receive three cycles(9 wk) of BEP; therefore, pulmonary function testingis not routinely performed. Indications for pulmon-ary evaluation include prolonged administration ofbleomycin (�10 wk or >300 U), age >40 yr, historyof smoking, advanced disease, renal insufficiency,and signs or symptoms of pulmonary compromise[57,58].

Fig. 1 – Full bilateral retroperitoneal lymph node dissection

template.


5.4. Evolution of the surgical technique and template of

RPLND

Over the past three decades, considerable modifica-tions in the technique and template of RPLND haveoccurred. Most notably, these include the modifiedunilateral template and nerve-sparing RPLND.Founded on improvements made in clinical staging,chemotherapeutic efficacy and our understandingof lymphatic drainage patterns and the neuroana-tomy of antegrade ejaculation, these modificationswere originally intended to minimize the morbidityof primary RPLND. In fact, such techniques havesince found application in select patients under-going PC-RPLND as well.

Surgical and anatomic mapping studies havedetailed the most common sites of retroperitonealmetastases and form the basis for surgical templatesin contemporary use. Lymphatic spread follows apredictable and systematic pattern that correspondsto the site of testicular origin and path of embry-ologic descent. The primary drainage zone for right-sided testicular tumors is the infrahilar precaval andinteraortocaval lymph nodes, whereas that for theleft is the lateral para-aortic lymph nodes [59–61].Although not common in the absence of bulkyretroperitoneal disease, the potential for contral-ateral spread does exist, particularly from right toleft [62]. For this reason, full bilateral RPLNDrepresents the standard surgical template used inthe postchemotherapy setting. The limits of dissec-tion include the crura of the diaphragm (superior),the bifurcation of the common iliac arteries (infer-ior), and the ureters (lateral). Within these bound-aries lie the primary and secondary lymphaticdrainage zones of both the right (interaortocaval,paracaval lymph nodes) and left testes (periaortic,preaortic lymph nodes; Fig. 1).

In times past, RPLND was routinely performedusing the extended bilateral template, which alsoincludes resection of the suprahilar lymphaticregion. Although this procedure was historicallymorbid, the rationale for its wide extent came fromthe inaccuracy of clinical staging and the suboptimalefficacy of chemotherapy available at the time.Studies have since demonstrated that suprahilarlymphatic metastases are rare in the absence ofbulky retroperitoneal disease (CS IIB, IIC) and, whenpresent, are most commonly found in the retro-crural space [59,61,63]. In conjunction with improve-ments in imaging and chemotherapy, it becamedifficult to justify such radical surgery and, as such,suprarenal resection was omitted from routine use.Without evidence of retrocrural disease, the tem-plate of resection used at Indiana University does

not extend above the origin of the diaphragmaticcrura.

Loss of antegrade ejaculation, the most consistentlong-term complication of RPLND, is almost inevi-table with full bilateral RPLND and represents theimpetus for two important modifications [64,65].Previous series had demonstrated that retroperito-neal metastases in the setting of low-volume PS IIdisease is almost always unilateral and confined tothe infrarenal zone of primary spread [59,60,63].Recognizing that the postganglionic sympatheticnerves critical to antegrade ejaculation join thehypogastric plexus in the para-aortic tissue justbelow the inferior mesenteric artery (IMA), it wasproposed to omit contralateral dissection (Fig. 2) [66].Dubbed the modified unilateral RPLND, this proce-dure has since been shown to preserve ejaculation inup to 90% of patients undergoing primary RPLNDwithout compromising cure [67]. Although it isconsidered the standard template for primary RPLNDat most centers, intraoperative evidence of high-volume or contralateral retroperitoneal diseaseremains an indication for full bilateral dissection.

Fig. 2 – Modified unilateral retroperitoneal lymph node dissec template. (A) Right. (B) Left.


Application of the modified unilateral templateto PC-RPLND remains controversial. Many centersroutinely perform bilateral dissection based on a 3–8% reported incidence of active disease (teratoma/cancer) in the contralateral landing zone [68,69]. It isimportant to note, however, that such reports comefrom studies involving a large proportion of patientswith bulky disease at presentation. The risk ofcontralateral disease in the patient with small-volume disease clinically limited to the ipsilaterallanding zone (CS IIA, IIB) is likely much less. Becausemost patients who completely respond to che-motherapy are observed based on a low risk ofsubsequent relapse (5%), the necessity of contral-ateral resection in patients with low-volume ipsi-lateral disease comes into question [25]. This issuebecomes even more relevant as the number ofpatients with small volume disease treated withprimary chemotherapy continues to rise, a scenariothat accurately describes most patients with retro-peritoneal relapse while on surveillance. Investi-gators at Indiana University recently reported theoutcome of 100 patients who underwent modi-fied unilateral template PC-RPLND [70]. Selection

criteria included low-volume retroperitoneal dis-ease (<5 cm), both before and after chemotherapy,confined to the ipsilateral primary landing zone.Updated results at a median 32-mo follow-up foundthat only four patients had a relapse (median, 8 mo),all outside the confines of a full bilateral template(unpubl. data, S.D.W. Beck, Indianapolis, Indiana,USA). The 2- and 5-yr disease-free survival was95%. Based on these data it appears that modi-fied unilateral resection is appropriate in selectpatients after chemotherapy. We currently performmodified unilateral PC-RPLND in patients withlow-volume residual disease who meet the afore-mentioned criteria.

Up to 40% of patients who undergo modifiedunilateral template RPLND will develop retrogradeejaculation secondary to sympathetic denervation.The sympathetic nerves that mediate seminalemission and antegrade ejaculation arise from theT12 to L3 nerve roots. Postganglionic fibers from theparavertebral sympathetic chains converge towardthe midline forming the hypogastric plexus belowthe IMA and travel thereafter to the pelvis wherethey innervate the seminal vesicles and bladder


neck (Fig. 3). The prospective identification andpreservation of these postganglionic nerves wasdescribed and popularized by both Jewett andDonohue [71,72]. Although the nerve-sparing tech-nique is used more commonly in the primarysetting, it may be appropriate in select patientsundergoing PC-RPLND for low-volume residualdisease. Of 472 PC-RPLND procedures performedat Indiana University between 1988 and 1995, 93patients (20%) were deemed appropriate candidatesfor nerve-sparing procedures. Antegrade ejaculationwas preserved in 77% of patients (62 of 81) withadequate follow-up, none of whom developed aretroperitoneal recurrence [67]. It must be remem-bered, however, that fertility issues should nevertake precedence over cancer control. Evidence ofviable tumor warrants full bilateral RPLND withresection of nerves en bloc if preservation provesdifficult.

6. Complicated postchemotherapy surgery

Certain groups of patients undergoing PC-RPLND areseverely disadvantaged in terms of relapse-free andoverall survival. These include patients who havereceived salvage chemotherapy, have undergoneprior RPLND (reoperative RPLND), or have demon-

Fig. 3 – Retroperitoneal neuroanatomy.

strated disease progression prior to surgery (des-peration RPLND). Review of the Indiana UniversityPC-RPLND experience has shown that the presenceof any one high-risk feature portends a 45% risk ofrelapse versus only 12% in patients without anycomplicating risk factors [22]. A fourth group ofpatients with especially poor prognosis are thosejudged to have unresectable disease. In this settingthe relapse rate following surgery is 90% and overallsurvival is only 21% [22].

Residual radiographic disease after second-line orsalvage chemotherapy is associated with a higherincidence of viable GCT (50% vs. 10%) and higher rateof incomplete surgical resection (39% vs. 16%),defined as gross residual disease, persistent post-operative STM elevation, or relapse within 1 mo ofsurgery, relative to patients who have only receivedinduction chemotherapy [51]. Long-term survivalafter PC-RPLND is also lower in salvage chemother-apy patients (50–60%) and, unlike their inductionchemotherapy counterparts, adjuvant chemother-apy appears to provide no survival benefit.

Reoperative surgery is an independent risk factorfor poor outcome among patients with testis cancerand likely represents the only prognostic variablenot absolutely dictated by the disease process itself[22,37,38,73]. The mean overall survival amongpatients who undergo repeat PC-RPLND is 56–63%versus 86% of primary PC-RPLND patients, andvaries according to tumor histology and type ofinitial surgery. The prognosis with residual teratomais intermediate between that of necrosis and viablecancer, whereas the prognosis following reopera-tion after primary RPLND is superior to thatfollowing reoperation after PC-RPLND [22,37,38].Teratoma is the most commonly identified histolo-gic subtype at secondary surgery and most patientshave received chemotherapy between the surgicalprocedures. Repeat PC-RPLND is a formidable taskthat should be performed only at centers withextensive experience in the surgical management oftestis cancer. Adjunctive procedures including thor-acotomy, nephrectomy, and vascular reconstruc-tion are often necessary (59–71%) and majormorbidity is common (21–27%) [37–39]. Takentogether, these data highlight the importance ofcomplete surgical resection, for which adjuvantchemotherapy is no substitute.

The final high-risk PC-RPLND patient groupincludes those with rising STM levels ascribed tochemotherapy-resistant disease (desperation PC-RPLND). Although all such patients were tradition-ally considered to be poor surgical candidates, arecent review from Indiana University has shownthat a select group of patients with elevated STMs


after chemotherapy may benefit from surgery [74].Of 114 desperation PC-RPLND procedures performedbetween 1977 and 2000, the mean 5-yr overallsurvival was 54%. Survival was superior in patientswith teratoma or necrosis only; however, one thirdof the 54% of patients with resected viable canceralso achieved long-term survival. Poor prognosticfactors included a rising b-HCG concentration,serum AFP level (continuous variable), repeatRPLND, and viable cancer in the resected specimen.Patient selection guidelines provided by this reviewinclude declining or plateau STMs after chemother-apy, rising STMs after initial complete response tochemotherapy, resectable radiographic disease inone or two locations, and increasing STMs withresectable disease after exhausting all chemother-apeutic options. It has become our policy to proceedwith postchemotherapy surgery in patients withelevated STM levels and resectable chemoresistantdisease rather than proceed with second- or third-line chemotherapy.

Among high-risk patients, adjuvant or concomi-tant procedures such as nephrectomy, aortic resec-tion, and vena cava resection are not uncommon.Although such procedures potentially add to mor-bidity, en bloc resection of adjacent organs is oftennecessary to ensure complete resection of residualtumor. An aggressive surgical approach is justifiedbecause many high-risk cases involve chemother-apy-resistant disease.

7. Late relapse

Late relapse is defined as the recurrence of tumorfollowing a disease-free interval of �2 yr from thetime of initial treatment. The diagnosis rests onbiopsy-proven GCT, STM elevation, or the growth ofradiographic disease in the absence of a secondprimary tumor. Although only a small percentage oftestis cancer patients will experience late relapse(2–4%), the incidence appears to be rising [75]. Thismay reflect the extended disease-free survivalbrought on through improvements in systemicchemotherapy [46,76]. The behavior, treatment,and prognosis of late relapse GCT differs from thatof typical or early relapse and deserves individualconsideration.

The median time to late relapse is 5–7 yr with areported range of 2–32 yr [75–77]. The latest relapseobserved at Indiana University is 35 yr, whichcertainly points to the importance of lifelongfollow-up in the testis cancer population. Mostcases of late relapse are diagnosed through STMelevation, predominantly AFP, which is elevated in

50–76%. Up to two thirds of patients are sympto-matic with back or abdominal pain representing themost frequent complaints [75,76]. Consistent withthe systematic pattern of metastatic spread, themost common site for late relapse is the retro-peritoneum (47–80%) followed by the lungs (7–25%).A single site of radiographic disease is identified in57% of patients and 8–10% present with elevatedSTM levels only. Those with marker-only relapsemanifest radiographic disease within a median of19 mo following initial STM elevation.

Although late relapse has been reported inpatients of all clinical stages, it develops morecommonly in those with advanced disease at initialdiagnosis. Likewise, late relapse is more commonlydescribed among NSGCT patients. Established riskfactors include early relapse (<2 yr), poor-riskdisease by IGCCCG criteria, postchemotherapyteratoma, and an inadequately controlled retro-peritoneum at initial or postchemotherapy treat-ment [75–77]. Among 35 CS I patients with laterelapse referred to Indiana University from 1979 to1992, 31 (89%) had undergone prior RPLND, 19 (61%)of whom recurred within the retroperitoneum [78].Interestingly, 10 of these 19 patients with retro-peritoneal recurrence received immediate adjuvantchemotherapy following RPLND. Conversely, areview of all primary RPLNDs performed at ourinstitution for CS I disease between 1965 and 1989found that no patients with PS I disease developedlate recurrence and only three patients with PS IIdisease did so, all outside the retroperitoneum.Taken together, this would indicate that incompleteresection may be a major predisposing factor for laterelapse and adjuvant chemotherapy is no substitutefor proper surgical technique.

Teratoma (60%) and yolk sac tumor (47%) are themost common histologic subtypes identified[76,79,80]. Most tumors consist of mixed histologybut when categorized according to most aggressivecomponent, viable GCT is most frequent (54–71%)followed by teratoma (19–28%). In contrast toprimary and postchemotherapy RPLND series, ter-atoma with malignant transformation (sarcoma oradenocarcinoma) is not uncommon in cases of laterelapse (10–18%) [76].

Whereas the standard treatment for early relapseis chemotherapy, that for late relapse is surgery.Most cases of late relapse demonstrate inherentchemoresistance such that cure with standard oreven high-dose chemotherapy is rare [76]. The highprevalence of teratoma reported in available seriesechoes this point. In the largest single-institutionalseries of late relapse to date, a complete responsewas observed in only 6 (19%) of 32 patients treated


with primary chemotherapy, 4 of whom werechemotherapy naı̈ve [76]. In contrast, 45 (92%) of49 patients who underwent primary surgery wererendered disease-free and 21 (43%) remained con-tinuously disease-free. The addition of postche-motherapy surgery to patients who failed initialtreatment with chemotherapy rendered an addi-tional 18 or 25 patients (72%) disease-free, 12 (48%) ofwhom were long-term. On the basis of this studyand similar reports, primary surgical resection is thepreferred treatment for late relapse at our institu-tion [77]. Primary chemotherapy is usually reservedfor patients with ‘‘unresectable’’ disease but mayalso be considered in chemotherapy-naı̈ve patientswherein chemosensitivity is often maintained. Like-wise, late relapse among seminoma patients typi-cally responds to chemotherapy. Patients withmarker-only relapse and a history of prior che-motherapy are typically observed until radiographicdisease is manifest at which time surgical resectionis recommended. En bloc resection of adjacentorgans or vascular structures (kidney, inferior venacava, aorta) may be required to ensure surgical cure.Likewise, distant sites of late relapse warrantresection if technically feasible.

The prognosis of late relapse is poor in compar-ison to that of early relapse. Continuous disease-freesurvival at 2 and 4 yr is reported in only 47% and 26%of patients, respectively [76]. Factors associated withimproved prognosis include pure teratoma histol-ogy, single site of radiographic recurrence, serumAFP <100 U/L and chemotherapy-naı̈ve status[75–77]. Although treatment is generally deliveredin a multidisciplinary fashion, most patientscannot expect long-term survival without surgicalresection.

8. Conclusion

The management of persistent or recurrent diseaseamong patients with NSGCT depends on stage atpresentation and relapse, STM levels at relapse,prior therapy, and timing of relapse. Patients withpersistent disease or recurrence within 2 yr of initialtherapy remain highly curable. Most patients withearly-stage disease who relapse following activesurveillance or primary RPLND are treated withinduction chemotherapy. In this context, surgery forrecurrent disease is primarily limited to the post-chemotherapy setting. Similarly, postchemotherapysurgery is commonly recommended in patients withadvanced disease at presentation who demonstrateresidual radiographic disease and normal tumormarkers following induction chemotherapy. In

contrast, most advanced cases with persistentlyelevated markers after chemotherapy receive sal-vage chemotherapy. However, select patients withresectable disease and elevated STMs who aredeemed refractory to chemotherapy may be appro-priate candidates for ‘‘desperation’’ surgery. In thesetting of late relapse, surgery often represents theprimary treatment modality based on relative tumorchemoresistance.

Over the past three decades, considerable mod-ifications in the technique and template of RPLNDhave occurred, most notably, the modified unilat-eral template and nerve-sparing RPLND. Originallyintended to minimize the morbidity of primaryRPLND, such techniques have since found applica-tion in select patients undergoing PC-RPLND as well.Although the morbidity of PC-RPLND continues toexceed that of primary RPLND, modifications insurgical technique combined with improvements inchemotherapeutic delivery and perioperative carehave reduced the incidence of severe or long-termcomplications to an acceptable level without com-promising cure.

Conflicts of interest

The authors have nothing to disclose.

References

[1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA

Cancer J Clin 2006;56:106–30.

[2] Segal R. Surveillance programs for stage I nonseminoma-

tous germ cell tumors of the testis. Urol Oncol 2006;24:

68–74.

[3] American Joint Committee on Cancer. AJCC cancer sta-

ging manual, ed. 6. New York: Springer; 2002.

[4] Heidenreich A. Clinical stage I nonseminomatous testi-

cular germ-cell tumors: surgery or watchful waiting, still

an issue? Curr Opin Urol 2002;12:427–30.

[5] Witjes JA, Spermon JR. Prognostic factors in clinical stage

1 non-seminomatous testicular tumours. Curr Opin Urol

2001;11:531–4.

[6] Sogani PC, Perrotti M, Herr HW, Fair WR, Thaler HT, Bosl G.

Clinical stage I testis cancer: long-term outcome of

patients on surveillance. J Urol 1998;159:855–8.

[7] Albers P, Siener R, Kliesch S, et al. Risk factors for relapse

in clinical stage I nonseminomatous testicular germ cell

tumors: results of the German Testicular Cancer Study

Group Trial. J Clin Oncol 2003;21:1505–12.

[8] Gels ME, Hoekstra HJ, Sleijfer DT, et al. Detection of

recurrence in patients with clinical stage I nonsemino-

matous testicular germ cell tumors and consequences for

further follow-up: a single-center 10-year experience.

J Clin Oncol 1995;13:1188–94.


[9] Albers P, Albrecht W, Algaba F, et al. Guidelines on testi-

cular cancer. Eur Urol 2005;48:885–94.

[10] Spermon JR, Roeleveld TA, van der Poel HG, et al. Com-

parison of surveillance and retroperitoneal lymph node

dissection in stage I nonseminomatous germ cell tumors.

Urology 2002;59:923–9.

[11] Read G, Stenning SP, Cullen MH, et al. Medical Research

Council prospective study of surveillance for stage I tes-

ticular teratoma. J Clin Oncol 1992;10:1762–8.

[12] Nicolai N, Pizzocaro G. A surveillance study of clinical

stage I non-seminomatous germ cell tumors of the testis:

10-year follow-up. J Urol 1995;154:1045–9.

[13] Francis R, Bower M, Brunstrom G, et al. Surveillance for

stage I testicular germ cell tumors: results and cost benefit

analysis of management options. Eur J Cancer 2000;36:

1925–32.

[14] The International Germ Cell Cancer Collaborative Group.

International germ cell consensus classification: a prog-

nostic factor-based staging system for metastatic germ

cell cancers. J Clin Oncol 1997;15:594–603.

[15] Stephenson AJ, Bosl GJ, Motzer RJ, et al. Retroperitoneal

lymph node dissection for nonseminomatous germ cell

testicular cancer: impact of patient selection factors on

outcome. J Clin Oncol 2005;23:2781–8.

[16] Donohue JP, Thornhill JA, Foster RS, Rowland RG, Bihrle R.

Clinical stage B non-seminomatous germ cell testis can-

cer: the Indiana University experience (1965–1989) using

routine primary retroperitoneal lymph node dissection.

Eur J Cancer 1995;31A:1599–604.

[17] Williams SD, Stablein DM, Einhorn LH, et al. Immediate

adjuvant chemotherapy versus observation with treat-

ment at relapse in pathological stage II testicular cancer.

N Engl J Med 1987;317:1433–8.

[18] Foster RS, Baniel J, Leibovitch I, et al. Teratoma in the

orchiectomy specimen and volume of metastasis are

predictors of retroperitoneal teratoma in low stage non-

seminomatous testis cancer. J Urol 1996;155:1943–5.

[19] de Wit R, Stoter F, Sleiger DT, et al. Four cycles of BEP vs

four cycles of VIP in patients with intermediate-prognosis

metastatic testicular non-seminoma: a randomized study

of the EORTC Genitourinary Tract Cancer Cooperative

Group. European Organization for Research and Treat-

ment of Cancer. Br J Cancer 1998;78:828–32.

[20] de Wit R, Toberts JT, Wilkinson PM, et al. Equivalence of

three or four cycles of bleomycin, etoposide, and cisplatin

chemotherapy and of a 3- or 5-day schedule in good-prog-

nosis germ cell cancer: a randomized study of theEuropean

Organization for Research and Treatment of Cancer Geni-

tourinary Tract Cancer Cooperative Group and the Medical

Research Council. J Clin Oncol 2001;19:1629–40.

[21] Einhorn LH, Williams SD, Loehrer PJ, et al. Evaluation of

optimal duration of chemotherapy in favourable-prog-

nosis disseminated germ cell tumors: a Southeastern

Cancer Study Group protocol. J Clin Oncol 1989;7:387–91.

[22] Donohue JP, Leviovitch I, Foster RS, Baniel J, Tognoni P.

Integration of surgery and systemic therapy: results and

principles of integration. Semin Urol Oncol 1998;16:65–71.

[23] Albers P, Weissbach L, Krege S, et al. Prediction of necrosis

after chemotherapy of advanced germ cell tumors: results

of a prospective multicenter trial of the German Testicular

Cancer Study Group. J Urol 2004;171:1835–8.

[24] Schmoll HJ, Souchon R, Krege S, Albers P, Beyer J, et al.

European consensus on diagnosis and treatment of germ

cell cancer: a report of the European Germ Cell Cancer

Consensus Group (EGCCCG). Ann Oncol 2004;15:1377–99.

[25] Debono DJ, Heilman DK, Einhorn LH, Donohue JP. Deci-

sion analysis for avoiding postchemotherapy surgery in

patients with disseminated nonseminomatous germ cell

tumors. J Clin Oncol 1997;15:1455–64.

[26] Oldenburg J, Alfsen GC, Lien HH, Aass N, Waehre H, Fossa

SD. Postchemotherapy retroperitoneal surgery remains

necessary in patients with nonseminomatous testicular

cancer and minimal residual tumor masses. J Clin Oncol

2003;21:3310–7.

[27] Toner GC, Panicek DM, Heelan RT, et al. Adjunctive sur-

gery after chemotherapy for nonseminomatous germ cell

tumors: recommendations for patient selection. J Clin

Oncol 1990;8:1683–94.

[28] Vergouwe Y, Steyerberg EW, Foster RS, et al. Predicting

retroperitoneal histology in postchemotherapy testicular

germ cell cancer: a model update and multicentre valida-

tion with more than 1000 patients. Eur Urol 2007;51:

424–32.

[29] Kondagunta GV, Bacik J, Bajorin D, et al. Etoposide and

cisplatin chemotherapy for metastatic good-risk germ

cell tumors. J Clin Oncol 2005;23:9290–4.

[30] Hilton S, Herr HW, Teitcher JB, Begg CB, Castellino RA. CT

detection of retroperitoneal lymph node metastases in

patients with clinical stage I testicular nonseminomatous

germ cell cancer: assessment of size and distribution

criteria. AJR Am J Roentgenol 1997;169:521–5.

[31] Leibovitch L, Foster RS, Kopecky KK, Donohue JP.

Improved accuracy of computerized tomography based

clinical staging in low stage nonseminomatous germ cell

cancer using size criteria of retroperitoneal lymph nodes.

J Urol 1995;154:1759–63.


Retroperitoneal lymphadenectomy for clinical stage A

testis cancer (1965 to 1989): modifications of technique

and impact on ejaculation. J Urol 1993;149:237–43.


Primary retroperitoneal lymph node dissection in clinical

stage A non-seminomatous germ cell testis cancer.

Review of the Indiana University experience 1965–1989.

Br J Urol 1993;71:326–35.

[34] Richie JP, Kantoff PW. Is adjuvant chemotherapy neces-

sary for patients with stage B1 testicular cancer? J Clin

Oncol 1991;9:1393–6.

[35] Kondagunta GV, Sheinfeld J, Mazumdar M, et al. Relapse-

free and overall survival in patients with pathologic stage

ii nonseminomatous germ cell cancer treated with etopo-

side and cisplatin adjuvant chemotherapy. J Clin Oncol

2004;22:464–7.

[36] Stephenson AJ, Bosl GJ, Bajorin DF, Stasi J, Motzer RJ,

Sheinfeld J. Retroperitoneal lymph node dissection in

patients with low stage testicular cancer with embryonal

carcinoma predominance and/or lymphovascular inva-

sion. J Urol 2005;174:557–60.


[37] Heidenreich A, Ohlmann C, Hegele A, Beyer J. Repeat

retroperitoneal lymphadenectomy in advanced testicular

cancer. Eur Urol 2005;47:64–71.

[38] McKiernan JM, Motzer RJ, Bajorin DF, Bacik J, Bosl GJ,

Sheinfeld J. Reoperative retroperitoneal surgery for non-

seminomatous germ cell tumor: clinical presentation,

patterns of recurrence and outcome. Urology 2003;62:

732–6.

[39] Baniel J, Foster RS, Rowland RG, Bihrle R, Donohue JP.

Complications of post-chemotherapy retroperitoneal

lymph node dissection. J Urol 1995;153:976–80.

[40] Loehrer Sr PJ, Gonin R, Nichols CR, Weathers T, Einhorn

LH. Vinblastine plus ifosfamide plus cisplatin as initial

salvage therapy in recurrent germ cell tumor. J Clin Oncol

1998;16:2500–4.

[41] Kondagunta GV, Bacik J, Donadio A, et al. Combination of

paclitaxel, ifosfamide, and cisplatin is an effective sec-

ond-line therapy for patients with relapsed testicular

germ cell tumors. J Clin Oncol 2005;23:6549–55.

[42] Bosl GJ, Bajorin DF, Sheinfeld J, Motzer RJ, Chaganti RSK. In

Chp Cancer of the testis. In: DeVita Jr VT, Hellman S,

Rosenberg AS, editors. Cancer: principles and practice of

oncology. ed. 7. Philadelphia: Lippincott Williams and

Wilkins; 2005. p. 1269–93.

[43] de Wit R, Stoter G, Kaye SB, et al. Importance of bleomycin

in combination chemotherapy for good-prognosis testi-

cular nonseminoma: a randomized study of the European

Organization for Research and Treatment of Cancer Gen-

itourinary Tract Cancer Cooperative Group. J Clin Oncol

1997;15:1837–43.

[44] Steyerberg EW, Keizer HJ, Fossa SD, et al. Prediction of

residual retroperitoneal mass histology after chemother-

apy for metastatic nonseminomatous germ cell tumor:

multivariate analysis of individual patient data from six

study groups. J Clin Oncol 1995;13:1177–87.

[45] Vergouwe Y, Steyerberg EW, de Wit R, et al. External

validity of a prediction rule for residual mass histology

in testicular cancer: an evaluation for good prognosis

patients. Br J Cancer 2003;88:843–7.

[46] Gerl A, Clemm C, Schmeller N, et al. Late relapse of germ

cell tumors after cisplatin-based chemotherapy. Ann

Oncol 1997;8:41–7.

[47] Shahidi M, Norman AR, Dearnaley DP, Nicholls J, Horwich

A, Huddart RA. Late recurrence in 1263 men with testi-

cular germ cell tumors. Multivariate analysis of risk fac-

tors and implications for management. Cancer 2002;95:

520–30.

[48] Donohue JP, Foster RS. Management of retroperitoneal

recurrences. Seminoma and nonseminoma. Urol Clin

North Am 1994;21:761–72.

[49] Loehrer Sr PJ, Hui S, Clark S, et al. Teratoma following

cisplatin-based combination chemotherapy for nonsemi-

nomatous germ cell tumors: a clinicopathological corre-

lation. J Urol 1986;135:1183–9.

[50] Stenning SP, Parkinson MC, Fisher C, et al. Postche-

motherapy residual masses in germ cell tumor patients:

content, clinical features, and prognosis. Medical

Research Council Testicular Tumour Working Party. Can-

cer 1998;83:1409–19.

[51] Fox EP, Weathers TD, Williams SD, et al. Outcome ana-

lysis for patients with persistent nonteratomatous germ

cell tumor in postchemotherapy retroperitoneal lymph

node dissections. J Clin Oncol 1993;11:1294–9.

[52] Fizazi K, Tjulandin S, Salvioni R, et al. Viable malignant

cells after primary chemotherapy for disseminated non-

seminomatous germ cell tumors: prognostic factors and

role of postsurgery chemotherapy—results from an inter-

national study group. J Clin Oncol 2001;19:2647–57.

[53] Einhorn LH. Testicular cancer as a model for a curable

neoplasm. The Richard and Hinda Rosenthal Foundation

Award Lecture. Cancer Res 1981;41:3275–80.

[54] Donohue J, Rowland R, Kopecky K, et al. Correlation of

computerized tomographic changes and histological find-

ings in 80 patients having radical retroperitoneal lymph

node dissection after chemotherapy for testes cancer.

J Urol 1987;137:1176–9.

[55] Beck SDW, Foster RS, Bihrle R, et al. Teratoma in the

orchiectomy specimen and volume of metastasis are

predictors of retroperitoneal teratoma in post-che-

motherapy nonseminomatous testis cancer. J Urol

2002;168:1402–4.

[56] Mosharafa AA, Foster RS, Koch MO, Bihrle R, Donohue JP.

Complications of post-chemotherapy retroperitoneal

lymph node dissection for testis cancer. J Urol 2004;171:

1839–41.

[57] Einhorn LH, Foster RS. Bleomycin, etoposide, and cispla-

tin for three cycles compared with etoposide and cisplatin

for four cycles in good-risk germ cell tumors: is there a

preferred regimen? J Clin Oncol 2006;24:2597–8.

[58] O’Sullivan JM, Huddart RA, Norman AR, Nicholls J, Dear-

naley DP, Horwich A. Predicting the risk of bleomycin lung

toxicity in patients with germ-cell tumours. Ann Oncol

2003;14:91–6.

[59] Ray B, Hajdu SI, Whitmore Jr WF. Distribution of retro-

peritoneal lymph node metastases in testicular germinal

tumors. Cancer 1974;33:340–8.

[60] Weissbach L, Boedefeld E. Localization of solitary and

multiple metastases in stage II non seminomatous testis

tumors as a basis for a modified staging lymph node

dissection in stage I. J Urol 1982;138:77–82.

[61] Schmeller NT, Siegelman SS, Walsh PC. Anatomical con-

siderations in suprahilar lymph node dissection for tes-

ticular tumors. Urol Int 1981;36:341–5.

[62] Sogani PC. Evolution of the management of stage I non-

seminomatous germ-cell tumors of the testis. Urol Clin

North Am 1991;18:561–73.

[63] Donohue JP, Zachary JM, Maynard BR. Distribution of

nodal metastases in nonseminomatous testis cancer.

J Urol 1982;128:315–20.

[64] Narayan P, Lang PH, Fraley EE. Ejaculation and fertility

after extended retroperitoneal lymph node dissection for

testicular cancer. World J Urol 1982;127:685–8.

[65] Donohue JP, Rowland RG. Complications of retroperito-

neal lymph node dissection. J Urol 1981;125:338–40.

[66] Richie JP, Socinsky MA, Fung CY, Brodsky GL, Kalish LA,

Garnick MB. Management of patients with clinical stage I

or II nonseminomatous germ cell tumors of the testis.

Evolving therapeutic options. Arch Surg 1987;122:1443–5.


[67] Donohue JP, Foster RS. Retroperitoneal lymphadenec-

tomy in staging and treatment: the development of

nerve-sparing techniques. Urol Clin North Am 1998;25:

461–8.

[68] Wood Jr DP, Herr HW, Heller G, et al. Distribution of

retroperitoneal metastases after chemotherapy in

patients with nonseminomatous germ cell tumors. J Urol

1992;148:1812–5.

[69] Rabbani F, Goldenberg SL, Gleave ME, Paterson RF, Murray

N, Sullivan LD. Retroperitoneal lymphadenectomy for

post-chemotherapy residual masses: is a modified dis-

section and resection of residual masses sufficient? Br J

Urol 1998;81:295–300.

[70] Beck SDW, Foster RS, Bihrle R, Donohue JP. Is full bilateral

retroperitoneal lymph node dissection (RPLND) always

necessary for post chemotherapy residual tumor? J Urol

2005;173:117 (abstract no. 430A).

[71] Donohue JP, Foster RS, Rowland RG, Bihrle R, Jones J, Geier

G. Nerve-sparing retroperitoneal lymphadenectomy with

preservation of ejaculation. J Urol 1990;144:287–92.

[72] Jewett MA, Kong YS, Goldberg SD, et al. Retroperitoneal

lymphadenectomy for testis tumor with nerve sparing for

ejaculation. J Urol 1988;139:1220–4.

[73] Beck SD, Foster RS. Long-term outcome of retroperitoneal

lymph node dissection in the management of testis can-

cer. World J Urol 2006;24:267–72.

[74] Beck SD, Foster RS, Bihrle R, Einhorn LH, Donohue JP.

Outcome analysis for patients with elevated serum tumor

markers at postchemotherapy retroperitoneal lymph

node dissection. J Clin Oncol 2005;23:6149–56.

[75] Carver BS, Motzer RJ, Kondagunta GV, Sogani PG, Shein-

feld J. Late relapse of testicular germ cell tumors. Urol

Oncol 2005;23:441–5.

[76] George DW, Foster RS, Hromas RA, et al. Update on late

relapse of germ cell tumor: a clinical and molecular ana-

lysis. J Clin Oncol 2003;21:113–22.

[77] Dieckmann KP, Albers P, Classen J, et al. Late relapse of

testicular germ cell neoplasms: a descriptive analysis of

122 cases. J Urol 2005;173:824–9.

[78] Baniel J, Foster RS, Gonin R, et al. Late relapse of testicular

cancer. J Clin Oncol 1995;13:1170–6.

[79] Sheinfeld J, Herr HW. Role of surgery in management of

germ cell tumor. Semin Oncol 1998;25:203–9.

[80] Michael H, Lucia J, Foster RS, Ulbright TM. The pathology

of late recurrence of testicular germ cell tumors. Am J Surg

Pathol 2000;24:257–73.

CME questions

Please visit www.eu-acme.org/europeanurologyto answer these CME questions on-line. The CMEcredits will then be attributed automatically.

1. T
he median time to recurrence in patients withclinical stage I non-seminomatous germ celltumors on active surveillance is?A. 3 moB. 6 moC. 12 moD. 18 mo
2. T
he primary treatment for marker-negative iso-lated retroperitoneal recurrence in patients withclinical stage I non-seminomatous germ celltumors on active surveillance is?A. Induction chemotherapy (3 cycles BEP or 4
cycles EP)B. Second-line salvage chemotherapyC. Primary retroperitoneal lymph node dissec-

tionD. Radiotherapy

3. W
hat percentage of pathologic stage I NSGCTpatients will relapse following primaryRPLND?
A. <10%B. 20–30%C. 40–50%D. 60–70%

4. F
ollowing induction chemotherapy, what per-centage of residual retroperitoneal masses harborteratoma or viable germ cell cancer?A. 10–20%B. 30–40%C. 50–60%D. 80–90%
5. T
he standard surgical template for postche-motherapy RPLND is:A. Bilateral suprahilar RPLNDB. Bilateral infrahilar RPLNDC. Modified unilateral RPLNDD. None of the above
6. T
he single most effective treatment for laterelapse in non-seminoma patients is:A. Induction chemotherapyB. Second-line salvage chemotherapyC. SurgeryD. None of the above
http://www.eu-acme.org/europeanurology

the role of surgery in the management of recurrent or persistent non-seminomatous germ cell

Documents