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Seminar articleSurveillance in stage I testicular seminoma

Peter Chung, M.B., M.R.C.P., F.R.C.R., Padraig Warde, M.B., M.R.C.P.I., F.R.C.P.C.*Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

bstract

Treatment options in patients with stage I testicular seminoma include adjuvant radiotherapy (RT), surveillance, and adjuvant chemo-herapy. RT was the treatment of choice for the past 50 years, but there has been increasing concern in the past decade regarding lateomplications. Surveillance, reserving treatment for patients who relapse, has been shown to be a safe and effective strategy. It allows �80%f patients to avoid any post-orchidectomy treatment and is the recommended approach for these patients. The possible role of adjuvanthemotherapy is currently being assessed in clinical trials and should not be used outside of a study setting. © 2006 Elsevier Inc. All rightseserved.

Urologic Oncology: Seminars and Original Investigations 24 (2006) 75–79

eywords: Seminoma; Surveillance; Radiotherapy; Prognostic factors

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ntroduction

Testicular tumors are uncommon but constitute anmportant group of malignancies in young men. World-ide it is estimated that there were more than 48,500 new

ases and 8900 deaths from disease in 2002 [1]. The vastajority are primary germ cell tumors (GCT), and they

re the most common solid malignancies in males be-ween 20 and 35 years of age. It is estimated that in 2005,here will be 8010 new cases and 390 deaths from tes-icular cancer in the United States [2]. The incidence ofCT has doubled during the last 30 years, and althoughost patients present with early-stage, highly curable

isease, the continued increase in incidence of theseumors presents a major challenge.

Approximately 60% of GCT are pure seminoma, 30%re NSGCT, and 10% are mixed tumors (both seminomand NSGCT elements present) [3]. In patients who presentith no evidence of metastasis, a diagnostic and therapeutic

adical orchidectomy is usually performed after a solid masss detected on physical examination or by ultrasonography.he majority of patients (70% to 80%) with seminomaresent with clinical stage I disease; 15% to 20% havenfradiaphragmatic lymph node involvement on radiologic

* Corresponding author. Tel.: �1-416-946-2122-; fax: �1-416-946-568.

6E-mail address: padraig.warde@rmp.uhn.on.ca (P. Warde).

078-1439/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.urolonc.2005.07.007

nvestigation (stage II disease), and less than 5% presentith distant disease.Treatment options in patients with stage I seminoma

nclude radiotherapy, surveillance, and adjuvant chemother-py. Although adjuvant retroperitoneal radiotherapy was thetandard of care for the last 50�60 years, it is now acceptedhat a policy of surveillance provides the optimal outcome,inimizing the burden of treatment while maintaining the

ure rate at virtually 100% [4-6]. Adjuvant radiotherapyemains a viable treatment option for those patients who arenable to follow a surveillance protocol. Adjuvant chemo-herapy using carboplatin has been investigated as an alter-ative strategy to radiation therapy or surveillance in stageseminoma [7–9]. The long-term safety and toxicity of thistrategy is unknown, and it should only be used in a studyetting.

urveillance

The data on seminoma surveillance are now mature, andelapse rates have consistently been reported to be approx-mately 15% in unselected populations of patients withtage I disease. The results of prospective nonrandomizedtudies of surveillance are shown in Table 1 [4,6,10–14].he 2 largest reported series are from the Rigshospitalet inopenhagen and the Princess Margaret Hospital (PMH) inoronto [6,14]. In the Rigshospitalet series of 394 patients,

he crude relapse rate was 17%, with a median follow-up of

0 months. In the PMH series of 345 patients, with a median

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76 P. Chung, P. Warde / Urologic Oncology: Seminars and Original Investigations 24 (2006) 75–79

ollow-up of 9.4 years, the actuarial 5-year relapse-free rateas 85% (Fig. 1). The other studies with adequate fol-

ow-up (�36 months) have reported similar relapse rates.he predominant site of relapse in all studies was in theara-aortic lymph nodes, 41 of 49 (82%) of relapses in theanish Testicular Cancer Study Group (DATECA) study

nd 47 of 55 (85%) in the PMH series [5,6]. Median time toelapse ranged from 12 to 18 months, but late relapses (�4ears) have also been reported [15].

rognostic factors for relapse

Prognostic factors for relapse have been studied in aumber of the surveillance studies [5,16,17]. In the PMHeries on multivariate analysis, age and tumor size wereredictive of relapse, while small vessel invasion ap-roached statistical significance [17]. In the DATECA re-ort, tumor size was the only significant predictive factor forelapse on multivariate analysis [5]. In the Royal Marsdenospital series of 103 patients treated with surveillance, thenly significant factor predicting for relapse was the pres-nce of lymphatic and/or vascular invasion (9% vs. 17%elapse rate) [16]. To determine more accurately prognosticactors for relapse in patients with stage I testicular semi-oma treated by surveillance, a pooled analysis of 4 largeurveillance series using individual patient data was per-

able 1esults of surveillance in stage I seminoma

nvestigators Number of patients M(

llhoff et al. [10] 33 —erma Lluch et al. [11] 45orwich et al. [4] 103liver et al. [12] 67amakrishnan et al. [13] 72augaard et al. [14] 394arde et al. [6] 345 1

Fig. 1. Relapse-free rate on surveillance PMH 1981�1999. S

ormed [18]. Data on 638 patients were obtained from 4enters, including Royal Marsden Hospital, DATECA,MH, and the Royal London Hospital. On multivariatenalysis, tumor size and rete testis invasion predicted forelapse. The effect of the number of prognostic factorsresent is shown in Fig. 2. The hazard ratio for relapse withtumor size �4 cm was 2.0 (95% confidence interval [CI].3, 3.2) relative to baseline (tumor size �4 cm and no reteestis invasion). The hazard ratio for rete testis involvementas 1.7 (95% CI 1.1, 2.6), and with both adverse prognostic

actors present, the hazard ratio for relapse was 3.4 (95% CI.0, 6.1). A cross-Canada study is underway to validate thisrognostic model.

reatment at relapse

At relapse, most patients have been treated with retro-eritoneal radiotherapy. The incidence of a second relapsefter radiotherapy was 12.5% in the PMH series and 11% inhe DATECA series. The likelihood of detecting progres-ion in the retroperitoneal lymph nodes early (nodes �5 cm)nd, therefore, suitable for radiotherapy, depends on the

ig. 2. Pooled analysis. Relapse-free rate. Effect of both 0, 1, or 2 adverserognostic factors. (Reprinted with permission [18]. © 2002 American

follow-up Number of patientswith relapse

Cause-specificsurvival (%)

3 1005 100

17 10016 9713 10069 10055 99.7

edianmos)

3462614460

ociety of Clinical Oncology.)

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77P. Chung, P. Warde / Urologic Oncology: Seminars and Original Investigations 24 (2006) 75–79

requency of follow-up computerized tomography (CT) ofhe abdomen and pelvis. One concern regarding the routinese of surveillance is the potential for an increased use ofhemotherapy, which involves a more prolonged and toxicreatment. However, at PMH, a similar proportion of pa-ients treated between 1981 and 1999 required chemother-py as part of their treatment, whether initially treated withurveillance (5.1%) or adjuvant radiotherapy (3.5%). Thisoncern is difficult to address because some centers usehemotherapy electively at relapse, and some patients haveontraindications to radiotherapy.

ollow-up policy

The optimal follow-up strategy for patients on surveillanceas not been determined. The current policy at PMH (Table 2)as evolved during the last 20 years, and consists of 20 am-ulatory care visits over 10 years with CT of the abdomen andelvis at each visit. This is similar to the follow-up schedulesed for patients treated with adjuvant radiotherapy, excepthat no follow-up CT is performed in these patients.

adiation therapy

The overall survival rate in most series in the modern eraanges between 92% and 99% at 5�10, years with cause-pecific survival approaching 100%. Most deaths are causedy intercurrent illness, but concern exists that prematureeath may be occurring from radiation-induced cancers orardiac disease [19,20]. In large single or multi-institutionaleries in the modern era, the relapse rate has varied from.5% to 5% (Table 3) [6,21–23]. In-field relapse is rare and,hen suspected, biopsy should be performed to excludeonseminomatous disease. The most common sites of re-apse after adjuvant radiotherapy are the mediastinum,ungs, and left supraclavicular fossa. A small proportion ofatients, usually with predisposing factors, have relapse inhe inguinal nodes. For supradiaphragmatic relapse, chemo-herapy is the treatment of choice and gives close to 100%ure. Inguinal relapse can often be treated successfully withadiotherapy to the involved area [24]. Most relapses occur

able 2ollow-up policy in stage I seminoma

Months Years

1–3 4–7 8–10

4 Markers � CT � CXR6 CT8 Markers � CT2 Markers � CT � CXR CT � CXR CT � CXR

CT not performed in patients receiving adjuvant radiotherapy.Abbreviation: CXR � chest x-ray.

ithin 2 years of radiotherapy. In the PMH series of 282W

atients treated between 1981 and 1999, median time toelapse was 18 months, with the latest relapse occurring atyears. Therefore, follow-up efforts should concentrate on

he 2 years after radiotherapy, and the current PMH fol-ow-up policy is similar to that used for surveillance, excepthat CT of the abdomen/pelvis is not routinely performed.

oxicity

With the low-dose radiotherapy used in seminoma, acuteomplications are minor in most patients, but late toxicity,specially increased cardiac mortality and induction of sec-nd nontesticular cancers, is a major concern.

ate gonadal toxicity

Testicular germinal epithelium is exquisitely sensitive toonizing radiation. Although the contralateral testis is notocated directly in the radiation field, scatter dose can beignificant, and may cause profound depression of spermat-genesis and compromise future fertility. A radiation doseetween 20 and 50 cGy may produce temporary aspermia,nd doses higher than 50 cGy may preclude recovery ofpermatogenesis [25]. The use of scrotal shielding reduceshe scattered radiation dose to the testis but cannot ensurerotection of spermatogenesis in all patients. Limiting ra-iotherapy target volume to the para-aortic and commonliac area does not eliminate concerns regarding radiother-py induced infertility [26].

ardiovascular toxicity

Recent data from MD Anderson and the Royal Marsdenospital suggest that long-term survivors of testicular sem-

noma treated with radiotherapy after orchiectomy are atignificant excess risk for death as a result of cardiac disease19,20]. In the MD Anderson series of 453 patients treatedetween 1951 and 1999, the standardized cardiac mortalityatio for patients (infradiaphragmatic radiotherapy, no me-iastinal radiotherapy) �15 years after radiotherapy was.80 (95% CI 1.01�2.98) [19]. Huddart et al. [20] reportedsimilar increase in cardiac events in a cohort of 992

atients treated at the Royal Marsden Hospital, with a riskatio of 2.4 (95% CI 1.04�5.45). Although the relevance ofhese data to the modern practice of radiotherapy has been

able 3esults of retroperitoneal radiotherapy in stage I seminoma

nvestigators Number ofpatients

Relapse(%)

Cause-specificsurvival (%)

ayens et al. [21] 132 4.5 99ultenschmidt et al. [22] 188 1 100antoni et al. [23] 487 4.3 99.4

arde et al. [24] 282 5 100

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78 P. Chung, P. Warde / Urologic Oncology: Seminars and Original Investigations 24 (2006) 75–79

uestioned, patients should be informed of this increasedisk in cardiac death when deciding whether to have radio-herapy or surveillance [27].

econd malignancy

An increased risk of second nontesticular cancers haseen documented in a number of studies, and because thisncreased risk is expressed more than 10�15 years afteradiotherapy, it is often not apparent in a series with shorterollow-up [28,29]. Zagars et al. [19] have reported an in-reased cancer specific standardized mortality ratio in 453ong-term survivors of radiation treatment for testiculareminoma. The cancer specific standardized mortality ratioas 1.91 (99% CI 1.14�2.98), and this increased mortalityas detected only after 15 years of follow-up. Travis et al.

30,31] conducted the largest study of second cancers inong-term survivors of testicular cancer. More than 28,000atients with testis cancer, including more than 15,000 witheminoma from 16 population-based registries worldwide,ere evaluated. Overall, 1406 second nontesticular cancersccurred against 981 expected (observed/expected � 1.43).he actuarial risk of a second nontesticular malignancyeveloping increased with time from diagnosis of testicularancer and was 18.2% at 25 years. Secondary leukemia wasinked with radiotherapy and chemotherapy, while an ex-ess of the stomach, bladder, and possibly, pancreas tumorsas associated with prior radiotherapy.

hemotherapy

Adjuvant chemotherapy using carboplatin has been in-estigated as an alternative strategy to radiation therapy orurveillance in stage I seminoma. The Medical Researchouncil (United Kingdom) has conducted a randomizedhase III study of 1447 patients comparing adjuvant radio-herapy and a single course of carboplatin [7]. The relapseate in both arms of the study was similar at 3 years (3.4%adiotherapy vs. 4.6% carboplatin), with most of the recur-ences in the carboplatin arm occurring in the retroperito-eal lymph nodes. Data from other series indicate that ifdjuvant carboplatin is given in this setting, then 2 coursesf treatment are necessary [9,32,33]. Even with 2 cycles ofarboplatin, a small but significant percentage of patientsave recurrence in the retroperitoneum, and, therefore, con-inued surveillance of the retroperitoneal lymph nodes isequired. In addition, the long-term toxicity of this strategys unknown, and, except in high select cases (e.g., patientsith coincidental inflammatory bowel disease), it shouldnly be used in a study setting.

onclusion

The available data from surveillance and adjuvant radio-

herapy series suggest that almost 100% of patients with

tage I testicular seminoma are cured whichever approach ishosen as treatment after orchidectomy. However, there isncreasingly persuasive data that adjuvant radiotherapy inhis setting is associated with a small but definite increasedisk of second malignancy and cardiovascular death. Inddition, the long-term data from surveillance series haveocumented the safety of this approach. In a compliantatient, surveillance should be considered the treatmentption of choice. It is disturbing to note that a considerableroportion of urologists and radiation oncologists do notiscuss the option of surveillance with their patients [34,35].djuvant chemotherapy should be restricted to study set-

ings.

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