Clinical Oncology (2005) 17: 435–440

doi:10.1016/j.clon.2005.03.011

Original Article

The Management and Outcome of Patients withGerm-cell Tumours Treated in the Edinburgh

Cancer Centre Between 1988 and 2002

G. C. W. Howard, D. S. Conkey, S. Peoples, D. B. McLaren, T. B. Hargreave,D. N. Tulloch, W. Walker, G. R. Kerr

Urological Oncology Section, Edinburgh Cancer Centre, Western General Hospital,

Crewe Road South, Edinburgh, UK

ABSTRACT:Aims: The aim of this retrospective analysis was to review the outcome of patients with germ-cell tumours treated in the Edinburgh CancerCentre over the past 15 years, and to see whether there had been any changes over three 5-year cohorts.Materials and methods: Patients referred with gonadal and extra-gonadal primary germ-cell tumours, between 1988 and 2002, wereidentified from the departmental database, and survival by stage and prognostic group was analysed.Results and conclusions: The proportion of patients with stage I seminoma has significantly increased. The good prognosis of patients withearly stage disease is confirmed, with the outcome for some groups of patients being better than expected. There is a non-significant trend toimproved results over the three 5-year cohorts. The outcome for patients with stage IV seminoma is worse than would be expected, butnumbers are small. The poor prognosis of patients with non-seminomatous germ-cell tumours who fall into the International Germ CellConsensus Classification (IGCCC) poor-prognostic group is confirmed. Failure of patients with metastatic non-seminomatous germ-celltumours to achieve a complete response to initial therapy is shown to be a poor prognostic indicator. Howard, G. C. W. et al. (2005).Clinical Oncology 17, 435–440

� 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Key words: Germ-cell tumours, prognostic group, testicular cancer

Received: 19 July 2004 Revised: 16 March 2005 Accepted: 17 March 2005

Introduction

Over the past 30 years, the use of cisplatin-basedchemotherapy has transformed the outlook for patientswith metastatic testicular cancer from being fatal to curablein most cases. It is a cancer in which response and cure isdependent on the appropriateness and timing of chemo-therapy. An earlier audit [1] showed that the results for mentreated with a low bleomycin-dose regimen were satisfac-tory overall, but identified a sub-group of men in whom itwas felt the outcome could have been better. A ScottishNational audit has also shown variation in the managementof, and the outcome for, men with this disease [2]. Furtheraudits have, therefore, been carried out, and the basicchemotherapy regimen used has reverted to a standardhigher dose bleomycin schedule.

Author for correspondence: Grahame Howard, Urological Oncology

Section, Edinburgh Cancer Centre, Western General Hospital, Crewe Road

South, Edinburgh EH4 2XU, UK. Tel: C44-131-537-2211; E-mail:

grahame.howard@luht.scot.nhs.uk

0936-6555/05/000000C06 $35.00/0 � 2005 The Roy

This paper brings together 15 years’ experience oftreating this disease. It presents overall results anda comparison between the three 5-year cohorts.

Materials and Methods

From the departmental database, we identified 742 newpatients with testicular tumours referred to the EdinburghCancer Centre between 1988 and 2002. Eight men withnon-Hodgkin’s lymphoma were excluded from furtheranalysis, as was one man with an adenocarcinoma, onewith an adenomatoid tumour, four with spermatocyticseminoma and two with in-situ disease only. Themanagement of, and outcome for, two men with Sertoli-cell tumours and 16 with Leydig-cell tumours are addressedelsewhere [in press]. Of the 708 men with germ-celltumours of the testicle, five were excluded because theywere managed elsewhere, leaving 703 men suitable foranalysis.

In addition, 25 men were identified with primaryretroperitoneal or mediastinal disease. These men were

al College of Radiologists. Published by Elsevier Ltd. All rights reserved.

436 CLINICAL ONCOLOGY

analysed both separately and in combination with thetesticular primaries, stratified according to their prognosticgroup.

Case notes were reviewed if additional information notroutinely held on the database was required. End pointsincluded response to chemotherapy, relapse rates onsurveillance, salvage rates and survival. Patients werecategorised according to the Royal Marsden staging and byprognostic group according to the International Germ CellConsensus Classification (IGCCC) [3]. Results were pooledand analysed together, and also analysed separately bycohort.

The policy at the Edinburgh Cancer Centre was tofollow-up the patients for 10 years, but this is not alwayspossible when dealing with a young, mobile population,some of whom are poor attenders. Ten men (1.4%) havebeen lost to follow-up at less than 5 years: at 2 weeks(nZ 1), 3 months (nZ 1), 6 months (nZ 1), 16 months(nZ 1), 2 years (nZ 2), 3 years (nZ 2), and 4 years(nZ 2). It is appreciated that, for the final cohort, follow-up is shorter, and that further events may occur in thisgroup.

These data were analysed using SAS software. Actuarialsurvival and relapse rates were estimated using the Kaplan–Meier technique [4], and compared using the Log-rank test.Proportional hazards analysis [5] was carried out to identifyany independent prognostic factors for survival or relapse.

Results

Of the 703 men with germ-cell tumours of the testisincluded in this audit, 446 had a seminoma and 257 hada non-seminomatous germ-cell tumour. Thirteen of theextra-gonadal primaries were seminoma and 12 were non-seminomatous germ-cell tumours.

Testicular Seminoma

Table 1 shows the breakdown by cohort, stage and age forthe 446 men presenting with seminoma of the testis.

The incidence of seminoma has increased over the 15years, with a significant increase in the proportion of menwith stage I disease, which was 92% in the final cohort(P! 0.001). All men with seminoma of the testis fell into

Table 1 – Stage and age of patients with testicular seminoma

1988–1992 1993–1997 1998–2002 Total

Number 114 147 185 446

Mean age (years) 38.4 38.5 39.0 38.7

Range (years) 22–69 21–75 18–74 18–75

Stage

I 87 (76%) 129 (88%) 170 (92%) 386 (86%)

II 24 15 11 50

III 1 1 4 6

IV 2 2 0 4

the IGCCC good prognosis group. The treatment policy forstage I seminoma was either adjuvant radiotherapy, usinga para-aortic strip or dogleg field, or surveillance. For stageII disease, it was either radiotherapy or chemotherapy, andfor stages III and IV it was chemotherapy. The first-linechemotherapy regimen used in most cases was a 3-day BEP(bleomycin 30 mg days 3, 10 and 17; etoposide 120 mg/M2days 1, 2,and 3; and cisplatin 50 mg/M2 days 1 and 2),regimen with the bleomycin omitted in older men.

Stage I Disease

Overall, 334 of the 386 men (86.5%) with stage I diseasewere treated with adjuvant radiotherapy. Five of these men(1.5%) relapsed and were treated with chemotherapy. Onedied of progressive disease. Four were salvaged, two ofwhom also had residual nodal masses excised.

Five men received chemotherapy, as there were specificcontra-indications to radiotherapy, and none have relapsed.Forty-seven men were managed on a surveillance protocol.Five of them relapsed, but all have been salvaged bysystemic chemotherapy. The actuarial relapse rate of menwith seminoma of the testis on surveillance was 9.8%. Allmen relapsed within 3 years, except one who relapsed 11years after orchidectomy.

Metastatic Disease

Eighteen men with small-bulk disease (stage IIa) weretreated with radiotherapy, and none have subsequentlyrelapsed. The other 32 men, with more bulky disease, weretreated with chemotherapy. One died without achievinga complete response and three others relapsed. Of the 32men treated with chemotherapy, three men died of theirdisease (9%).

All six men with stage III disease received chemother-apy. One died without achieving a complete response andone died of acute bleomycin pneumonitis. Of the four menwith stage IV disease, three received chemotherapy and onedied before starting treatment. Two of the treated men didnot achieve a complete response and subsequently died,leaving one man cured of his disease.

Overall Survival

Table 2 and Fig. 1 show survival by stage in the threecohorts. Overall, the survival by Royal Marsden Hospitalstage was 99.7%, 93.9%, 66.7% and 25.0%.

Increasing stage (P! 0.0001) and increasing age(PZ 0.0214) were significant prognostic factors forcause-specific survival on proportional hazard analysis;however, only eight out 446 men died from seminoma(98.2% cause-specific survival).

Testicular Non-seminomatous Germ-cell Tumour

Table 3 shows the breakdown by stage, age and prognosticgroup for the 257 men presenting with testicular non-seminomatous germ-cell tumour.

437THE MANAGEMENT AND OUTCOME OF PATIENTS WITH GERM-CELL TUMOURS

For stage I disease, the treatment policy was eithersurveillance or adjuvant chemotherapy. Men with moreadvanced disease received chemotherapy.

Stage I Disease

The policy for patients with stage I disease was either closemonitoring and treatment on relapse, if it occurred(surveillance), or adjuvant BEP chemotherapy for menwith lympho-vascular invasion who were deemed to be athigher risk of relapse. Of the 134 men with stage I disease,111 received no adjuvant treatment. One was terminally illfrom another cancer, and 110 were put on activesurveillance.

The actuarial relapse rate on surveillance was 22.9%(nZ 25). All of these men were salvaged using chemo-therapy. Twenty-two men with lympho-vascular invasionreceived two courses of adjuvant chemotherapy. None haverelapsed. One man received adjuvant radiotherapy becauseof an initial diagnosis of seminoma. He relapsed but wassubsequently salvaged with chemotherapy.

Stage IM Disease

Twenty-one men had no evidence of metastatic disease onscanning, but one or more serum markers remained raisedafter orchidectomy. They were, therefore, treated as thoughthey had metastatic disease, with either three or four

Fig. 1 – Seminoma, survival by cohort.

Table 2 – Actuarial cause-specific survival by stage and cohort for

seminoma testis

1988–1992 1993–1997 1998–2002 Total

Stage

I 100.0 99.2 100.0 99.7

II 91.7 93.3 100.0 93.9

III 100.0 100.0 50.0 66.7

IV 0.0 50.0 25.0

Total 96.5 98.0 98.7 97.9

courses of BEP chemotherapy. Three men subsequentlyrelapsed, but were all salvaged with further treatment.

Stages II, III and IV Disease

All men in these groups were treated with chemotherapy.Fifty-nine men had stage II disease. Two men died withoutachieving a complete response. Another three men re-lapsed, but were successfully salvaged.

Of six men with stage III disease, one died withoutachieving a complete response and one is alive witha residual mass that has not been resected. Thirty-sevenmen had stage IV disease, of whom eight died withoutachieving a complete response. One man achieveda complete response but later relapsed and died, and oneis alive with residual disease.

Survival

Cause-specific actuarial survival rates for men withtesticular non-seminomatous germ-cell tumour are shownin Table 4 and Fig. 2. Survival for men with stages I and IMdisease is 100%. For stages II, III and IV disease, it is96.6%, 83.3% and 75.2%, respectively. Survival by IGCCCprognostic group is 96.0%, 100.0% and 50% for good,intermediate and poor prognosis, respectively, with thepoor prognosis patients doing significantly worse(P! 0.0001). The improvement in survival by 5-yearcohort (PZ 0.0514) just failed to reach significance.

Relapse

All relapses occurred within 4 years of treatment. Theoverall relapse rates were 19.8%, 8.8%, 14.3%, 33.3% and27.0% for stages I, IM, II, III and IV, respectively. Fig. 3shows relapse rates by cohort. These relapse rates aresignificantly different (PZ 0.0237), with the middle cohortfaring worst and the most recent doing best.

Table 3 – Stage, age and IGCCC prognostic group for patients

with non-seminomatous germ-cell tumour testis

1988–1992 1993–1997 1998–2002 Total

Number 79 86 92 257

Mean age (years) 31.2 30.6 32.1 31.3

Range (years) 14–63 14–67 17–62 14–67

Stage

I 39 42 53 134

IM 7 12 2 21

II 24 17 18 60

III 1 2 3 6

IV 8 13 16 36

IGCCC group

Good 33 26 20 79

Intermediate 5 9 12 26

Poor 2 9 7 18

IGCCC, International Germ Cell Consensus Classification.

438 CLINICAL ONCOLOGY

Primary chemotherapy failed in 20 men (13.8%). Sevenmen relapsed after achieving a complete response, eitherwith chemotherapy alone or with resection of a residualmass. Of these, six (85.7%) were salvaged and one died. Ofthe 13 men who did not achieve a complete response afterprimary chemotherapy, 11 have died and two have residualdisease. This gives an overall salvage rate of 33.3%.

Extra-gonadal Germ-cell Tumours

Thirteen men presented with extra-gonadal seminoma, twowith mediastinal and 11 with retroperitoneal primaries.Both men with mediastinal disease are alive and well afterchemotherapy. Two men with retroperitoneal primarieshave died from their disease, one died from intercurrentdisease after being successfully treated for a relapse andeight (73%) are alive and well. The overall survival of allmen with extra-gonadal seminoma is 85%.

Twelve men presented with extra-gonadal non-semi-nomatous germ-cell tumours, five in the mediastinum andseven retroperitoneal. Eight men were in the IGCCC poorprognosis group, three intermediate and one good.

Table 4 – Actuarial cause-specific survival by cohort, stage and

prognostic group

1988–1992 1993–1997 1998–2002 Overall

Stage

I 100.0 100.0 100.0 100.0

IM 100.0 100.0 100.0 100.0

II 95.8 94.1 100.0 96.6

III 100.0 50.0 100.0 83.3

IV 62.5 69.2 87.1 75.2

Total 94.9 93.0 97.8 95.3

Stage IM–IV

Good 90.9 100.0 100.0 96.0

Intermediate 100.0 100.0 100.0 100.0

Poor 50.0 33.3 71.4 50.0

Total 90.0 86.3 94.6 90.0

Fig. 2 – Non-seminomatous germ-cell tumour, survival by cohort.

Of the men with mediastinal disease, two (40%) havedied and three (60%) are alive and well. In men withretroperitoneal disease, three men have died (43%) and fourmen (57%) are alive and well. Cause-specific survival inthe whole group is 56% at 5 years.

Analysis of Patients with Metastatic TesticularGerm-cell Tumour by Prognostic Group

The proportion of men in the different prognostic groupshas changed a little over time, with a trend towards a higherproportion of men in the intermediate or poor-prognosticgroups in the later cohorts. Of the 123 men with metastaticdisease, 64% are in the good prognosis group. For men withtesticular primaries, the survival for the good, intermediateand poor-prognostic groups are 96.0%, 100.0% and 50.0%,respectively (Table 4). If the men with mediastinal andretroperitoneal primaries are included, the figures aresimilar at 96.2%, 96.6% and 49.5%, respectively (Fig. 4).Three men in the good prognostic group died. These wereall in the first cohort. Two were treated in 1988 with thelow-dose bleomycin regimen before it was changed from3-weekly to weekly. The third man was treated withcarboplatin in the MRC carboplatin vs cisplatin study in

Fig. 3 – Non-seminomatous germ-cell tumour, relapse by cohort.

Fig. 4 – Non-seminomatous germ-cell tumour, survival byprognostic group.

439THE MANAGEMENT AND OUTCOME OF PATIENTS WITH GERM-CELL TUMOURS

1991. He achieved a complete response, but subsequentlyrelapsed and could not be salvaged.

Discussion

Seminoma

The number of men presenting with seminoma has almostdoubled between the first and last cohorts. Epidemiologicalstudies have shown a marked increase in the incidence oftesticular cancer over time in Scotland [6], England andWales [7], Europe [8], North America [9] and Australia[10]. In this series, although there has been an increase inNSGCT, this is much less marked than for seminomas.Such disparity is lacking in other studies that have reportedthe histological subtypes separately [10,11]. The percent-age of men with stage I disease has significantly increasedfrom 76% to 92% (P! 0.001). The reasons for earlierpresentation are unclear. It could be due to earlier diagnosisor increased public awareness of this disease. This is anencouraging trend but, interestingly, it is not reflected inmen with non-seminomatous germ-cell tumour, in whichonly a small increase in early stage disease was seen in themost recent cohort.

The actuarial survival for men with stage I disease ishigh at 99.7% at 5 years. At 1.5%, the relapse rate afterradiotherapy compares favourably with other publishedseries, which record relapse rates between 2% and 4%[12–14]. Four of the five men who relapsed were salvagedwith chemotherapy. Those men put on a surveillance policyfor specific clinical reasons had a relapse rate of 10.6%.The outcome for these men was excellent, with all patientsbeing successfully salvaged. With such a low relapse rate,we should consider the necessity of adjuvant treatmentfor this group of patients. The concerns about surveillanceare the potential for late relapse, the lack of reliable tumourmarkers and the significant radiation dose associated withregular computed tomography scanning. In this series,whether on surveillance or after primary treatment, allrelapses occurred within 3 years, except for one at 11 years.

The results of patients treated for stage II disease are ofinterest. In the earliest cohort, half the men receivedradiotherapy and half chemotherapy. In the two latercohorts, over 70% of men received chemotherapy. Therewere no relapses among the men receiving radiotherapy,which is reassuring in terms of treatment selection. Theactuarial relapse rate after chemotherapy was 12.5%, withonly one man being salvaged with further treatment. Theoverall survival at 5 years for this group was 94%. A recentCanadian study [15] describing the outcome of treatment ina large cohort of patients with stage II seminoma obtainedan almost identical survival rate. The treatment strategywas broadly similar to our own, and the authors alsonoted a trend over time towards an increasing use ofchemotherapy.

The outcome for men with stages III and IV disease ispoor, with five out of 10 men dying of their disease, andonly one out of four men with stage IV disease surviving. Ifthose men with stage II disease who were treated with

chemotherapy are included, of whom only three out of 32died, then the overall 5-year survival for the men treatedwith chemotherapy is 82.8%. These men all fell into thegood prognostic group, as defined by the IGCCC. Asa cohort, these results are satisfactory, but the results forstages III and IV disease are poor. However, the numbersare so small as to make interpretation difficult.

It is worth noting that the IGCCC prognostic factor-based staging system for seminomas is relatively lessrobust than for NSGCT. The system is derived from 660men pooled from various centres, with 127 men progress-ing and 102 deaths. The comparative figures for NSGCTare 5202 men, 1313 with progression and 1056 deaths.The IGCCC aim ‘to generate a unifying staging classifi-cation which incorporates both seminomas and NSGCT’ iscommendable, facilitating collaboration between trialgroups and allowing meaningful comparison betweenreported series. For seminoma, however, the attractivesimplicity of the system may render it a rather blunt toolin separating good risk from poor risk patients. TheIGCCC note the prognostic importance of other factorssuch as a raised LDH (O2 times ULN). Other authorshave highlighted the adverse effect of increasing age onoutcome [16]. We found that, of those over 50 years ofage, a greater proportion presented with metastatic diseasecompared with those under 50 years (22.4% vs 11.9%).Five-year survival is better in the younger group (98.6%vs 93.9%), although this is not significant.

One chemotherapy-related death occurred in this group,which was due to bleomycin pneumonitis. This was a managed over 40 years who now would probably not havereceived this drug.

Non-seminomatous Germ-cell Tumours

In the more recent cohorts, there is a trend towards bettersurvival (Fig. 2), and the relapse rate for the most recentcohort is significantly lower than for the previous two(Fig. 3). It should be remembered that the most recentcohort has shorter follow-up. The reason for this improve-ment in outcome with time is unclear. This does, however,highlight the well-recognised danger of using historicalcontrols.

The relapse rate for men on surveillance has not changedsignificantly over the 15 years. This was 24.9% in theearliest cohort and 16.2% in the latest. Recent large seriesfrom Australia (26.5%) [17] and Spain (22%) [18] quotesimilar rates of relapse. Over this period, computedtomography techniques have improved, and we haveconsistently treated men considered at high risk of relapsebecause of lympho-vascular invasion with adjuvant che-motherapy. These factors do not seem to have resulted ina significant reduction in relapse rate, but it is encouragingthat those men who did relapse on surveillance were allsalvaged with chemotherapy.

Of those men who presented with stage IM disease, 15out of the 18 men who received three or four courses oftreatment were cured with primary treatment. Thethree men who relapsed have been successfully salvaged.

440 CLINICAL ONCOLOGY

The relapse rate after primary chemotherapy for stage IIdisease and above was 16.4%. Of these, 30% were salvaged.All but one of those who initially achieved a completeresponse were salvaged. Not achieving a complete responsewas a poor prognostic indicator, with 11 men dying, and theremaining two alive with residual disease. Similar resultshave been published by Fossa et al. [19], who also reporteda salvage rate of 30% and noted that not achievinga complete response to initial chemotherapy was one ofthree factors that defined a sub-group with an especiallypoor survival. The other risk factors were a progression-freeinterval of less than 2 years, and high tumour markers atprogression (alpha-fetoproteinO 100 kU/L and/or humanchorionic gonadotrophin 100 U/L). No men progressingwith all three factors survived beyond 3 years. Those withone or two factors had a 5-year survival of 47%.

Survival by prognostic group is of interest, with nosignificant difference between the good and intermediategroup, with 96.1% and 100.0% 5-year survival, anda survival in the poor-prognostic group of 50.0% (Fig. 4).These compare favourably with the IGCCC results, whichfor the three groups are reported as 92%, 80% and 48%.

If the prognostic group is taken into account, theoutcome for non-gonadal primaries is not significantlydifferent to those with testicular primaries. If all men withtesticular and non-testicular primaries are analysedtogether, the survival does not significantly change at96.2%, 96.6% and 49.5% for the good, intermediate andpoor-prognostic groups, respectively.

Conclusions

Over the 15-year period of analysis, the proportion of menwith seminoma has increased, and those with stage Idisease has significantly increased (92% in the most recentcohort). A similar trend for earlier presentation for thosewith NSGCT was not significant. There has been a non-significant trend to improved results with time.

Survival for early stage disease for seminoma andNSGCT is good, with results comparing favourably withother published series. A higher proportion of menwith NSGCT are in the good prognostic group comparedwith the intermediate and poor groups that one mightexpect (78%, 14% and 7%, respectively). Men in the goodand intermediate prognostic groups did particularly well,with no difference between them. The survival of men inthe poor-prognostic group was significantly worse. Al-though, overall, men with metastatic seminoma fared asexpected, the outcome for those with stages III and IVdisease is poor, but the numbers are extremely small.

Chemotherapy toxicity has not been assessed in detail,but there has been one death from bleomycin in 176 mentreated with bleomycin-containing regimens, an incidenceof 0.56%.

The authors feel that the results, as published, support thecurrent management of these patients within a multi-disciplinary setting, with close co-operation between allpractitioners involved with this disease.

Acknowledgements. The successful management of patients withthis disease requires the highest level of skills from all those involved withtheir care. The authors would like to acknowledge the support of all thoseinvolved in the management of these patients, where multi-disciplinarymanagement is of paramount importance. Special thanks to Mrs SusanHunter for typing the manuscript.

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