Management Strategies for Stage I germ cell tumours

Professor Gordon J S Rustin

Director of Medical Oncology

Mount Vernon Hospital

Northwood, Middlesex

England

Testicular Germ Cell Tumours

Approximately 2000 new cases per year in UK (population 60.000000)

70% of seminomas and 50% of NSGCTs are diagnosed at stage I

Considerations in initial management

Is a testicular cancer present?

Are there metastatses?

Is there carcinoma in situ in contralateral testis?

If there are bilateral tumours is partial orchidectomy an option?

Initial managementWidespread malignancy refer for immediate chemotherapyNo evidence of spread inguinal orchidectomy. Biopsy of contralateral testicle should be considered if there is

a high risk of carcinoma in situ eg. small testis (<12ml), and in patients < 30 years.

SJ Harland. Eur Urol 1993 n= 89. 13% pts had CIS in contralateral testis. Increased risk of CIS in clinically atrophic testes, but NOT in maldescent. Pts found to have CIS were younger < 30

Complete post – op staging, CT chest/abdo/pelvisPost –op tumour markers if raised pre-op. Should fall

according to half life – (4-6 days for AFP, 24 hours for HCG)

Points to consider in managing stage 1 germ cell tumours

• Seminomas spread predictably, firstly to the para-aortic lymph nodes and subsequently to the supra-diaphragmatic LNs and on to other metastatic sites.

• NSGCT spread more randomly with blood borne mets occuring earlier than with seminoma

• NSGCT produce AFP and/or HCG in 75% of cases• Seminomas produce HCG in only 25% of cases• LDH is non-specific. In our series of 494 patients

who relapsed on surveillance over a 10 year period, the LDH alone did not identify any of these.

Management of carcinoma in situ

• 50% of patients with CIS will develop invasive tumours within 5 years from diagnosis.

• Low dose XRT (20 Gy in 10#s) to the testis eradicates CIS, relapses with lower doses

• Leydig cell function increasingly impaired at doses > 17 Gy

• Long term hormone replacement therapy may be necessary

Possible prognostic factors for stage 1 germ cell tumours

SEMINOMAS1. Size of tumour (J Clin Onc 2002,

Warde et al)2. Invasion into the rete testis3. Age4. Small vessel invasion5. Histological subtype – classical vs

anaplastic6. DNA ploidy status7. Mitotic count8. DNA S-phase %9. Syncitiotrophoblasts10. Degree of lymphocytic infiltration of

primary tumour11. Expression of HCG and low MW

keratin on immunohistochemistry

TERATOMAS1. Lymphovascular invasion

2. Embryonal ca histology in primary tumour

3. MIB- 1 monoclonal ab – marker of proliferative activity

4. Mitotic count

Options for management of stage I Seminomas

• Adjuvant radiotherapy

• Adjuvant chemotherapy

• Surveillance

1980’s Management of stage I seminoma

20% will recur after orchidectomy90% relapse in para-aortic nodes

Traditionally adjuvant treatment with radiotherapy to para-aortic and ipsilateral iliac nodes in a “dog leg” field. (28-30 Gy)

Late Morbidity from Radiotherapy

• Second Cancers

• Cardiac events

• Peptic ulceration

• Infertility

Relative risks for second primary cancers(NB. RR of contralateral testis ca is 35.7!)

1.725Colon

1.316Rectum

2.216Kidney

1.847Other skin

1.35Melanoma

1.042Lung

1.121Prostate

2.137Bladder

2.115Pancreas

1.924Stomach

2.313Leukaemia

1.5337All sites

RRn

Impaired spermatogenesis

• Azospermia or oligospermia persists in approx 50% after dog leg radiotherapy

• 22-53% of all men after unilateral orchidectomy and 25% of all patients with testicular tumours remain subfertile regardless of therapy

Strategies to reduce radiotherapy morbidity

Reduction of radiation field size

MRC TE10 478 patients randomised to traditional dog-leg

or para-aortic radiotherapy

Reduction in dose

MRC TE18 625 patients randomised to 30 Gray in 15 # over 3 weeks or 20 Gray in 10 # over 2 weeks

MRC TE10 (Fossa et al 1999)

Survival at 3 years, 99% for PA vs 100% for DLRFS 96% PA vs 96.6% DL

Acute toxicity ( nausea, vomiting, leukopaenia) was less frequent and less severe in PA group

Within the first 18/12 of F/U the sperm counts were significantly higher after PA than after DL radiotherapy.

CONCLUSION: Adjuvant radiotherapy confined to the paraaortic LNs is associated with decreased haematologic, GI and gonadal toxicity, but with a higher risk of pelvic recurrence compared with dog-leg radiotherapy.

MRC TE 18 (Jones et al 2001 & 2005)

At median follow-up of 4 years2 year relapse free survival 97.7% after 30Gy

97% after 20GyBetter Quality of Life scores for acute effects in lower dose arm

Therefore:Standard radiotherapy for stage 1 seminoma should be:20 Gy in 10 # over 2 weeks to para-aortic stripunless previous inguino/pelvic/scrotal surgery when “dog-leg” field.

Can chemotherapy replace radiotherapy for stage 1 seminoma ?TE19 / EORTC 30982

Randomised comparison of single agent carboplatin AUC 7 with radiotherapy in adjuvant treatment of stage 1 seminoma following orchidectomy.

carboplatinn=1447 30Gy/15#s

Radiotherapy20Gy/10#s

TE 19 Radiotherapy vs carboplatin : Relapse Free Rate

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0R

ela

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ate

0 12 24 36 48 60 72 84

Months from randomisation

Carboplatin

Radiotherapy

Relapse-free rates - all patients

Numbers at riskRadiotherapy 904 873 823 694 448 209 45 12Carboplatin 573 552 523 425 288 124 31 6

RFR at 2 years at 3 yearsR96.7% (95%, 98%)95.9% (94%, 97%)C97.7% (96%, 99%)94.8% (93%, 96%)

Absolute difference R - C =-1.0% (-2.5%, 0.5%)1.1% (-1.0%, 3.2%)

HR based CI for differenceR – C =0.9% (-0.5%, 3.0%)1.1% (-0.6%, 3.7%)

Results of TE19 / EORTC 30982

Carboplatin Radiotherapy2 year RFS 97.2 98.13 year RFS 96.6 95.4PA recurrences 70% 7%Pelvic recurrences 4% 28%2nd GCT malignancies 1 72nd non-GCT malignancies 2 4

Late Morbidity from Chemotherapy

• Infertility

• Second Tumours

• Cardiovascular damage

Prognostic Factors for seminomas on surveillance ( Warde et al 2002)

121 of 638 patients relapsed at a median follow up of 7 years (Relapse free survival 82%)

On multivariate analysis:Tumour size <4cm vs >4cm, hazard ratio 2 Invasion of the rete testis, hazard ratio 1.7

5 year recurrence rateBoth risk factors 32%Single risk factor 16%No risk factors 12%

Post orchidectomy surveillance vs carboplatin for stage 1 seminoma – Spanish germ

cell cancer cooperative group; Ann oncol 2003

• N = 203• 60 pts with tumour >4cm or lymphovascular

invasion given 2 x carboplatin• 143 pts with no risk factors put on surveillance• 5 yr DFS 83.5% in surveillance pts and 96.6% in

carbo grp. All salvaged with 3 or 4 cycles of BEP• 5 year OS 96.7%. Cause specific survival 100%

Conclusion on management of stage 1 seminomas

Almost 100 % of patients with stage 1 seminoma are cured regardless of approach chosen as post orchidectomy therapy.Adjuvant radiotherapy or chemotherapy are both as effective at reducing relapse rates.However with a relapse rate of 15-20%, and a 5 year survival of 97.7%, surveillance may be considered an alternative “treatment” option.Identification of prognostic factors for relapse on surveillance will allow clinicians to recommend the most appropriate therapy for individual patients.

Current recommendations – tumours <4cm and absence of rete testis invasion – RR 12% - surveillance. Tumours >4cm and presence of rete testis invasion – RR 35% offer adjuvant therapy

Management Options for Stage 1 Non-seminomatous germ cell tumours

Surveillance

RPLND

Adjuvant chemotherapy

Surveillance for Non-seminomatous germ cell tumours

relapse rate

Overall 30%

Lymphovascular invasion <40%

No risk factors 10-15%

Surveillance programme MVH - NSGCTs

• Markers currently HCG, AFP and LDH • Follow up for 10 years

Month 1 2 3 4 5 6 7 8 9 10 11 12 18 24 36

OPD X X X X X X X X X X X X X X XCXR X X X X X X X X X X X X XMarkers xx xx xx xx xx xx X X X X X X X X XCT Chest/ abdo/ pelvis

X X

Advantages of Surveillance for Low risk NSGCT

• >80% avoid any chemotherapy or RPLND

• >80% avoid risk of 2nd tumours

• >80% avoid risk of cardiovascular damage

• >80% avoid risk of infertility

Disadvantages of surveillance for NSGCT

• More frequent clinic visits and blood tests

• Greater diagnostic radiation (10 body CT scans induces 1% 2nd tumours)

• Anxiety of follow -up

• Concern about non-attendance

MRC TE08 trial of surveillance intensities

• Currently a wide variation in the intensity of surveillance programs between hospitals

• Concern about high levels of radiation produced by CT scans

• Alternative methods need to be found to determine relapse during surveillance

• Frequency of CT scans needs to be kept to a minimum

Study DesignHistologically confirmed

Stage I NSGCT

Randomise

5 CT scans

Chest and abdomen CT at 3 monthsChest and abdomen CT at 6 monthsChest and abdomen CT at 9 monthsChest and abdomen CT at 12 months Chest and abdomen CT at 24 months

2 CT scans

Chest and abdomen CT at 3 months

Chest and abdomen CT at 12 months

3:2 randomisation in favour of 2 CT arm

Lack of value of chest CT scans in surveillance of Stage I NSGCT

168 patients 42 (25%) relapsed

8/42 (19%) intrathoracic relapse

All 8 had abnormal CXR at relapse

7/8 also had elevated AFP and or HCG

(Harvey et al Annals Oncol 13: 237-42, 2002)

183 stage 1 GCT on surveillance: Initial Presenting Factors among 52

relapses (Francis et al EJC 2000)

Symptoms Tumour Markers

Radiology (total/no. NSGCT/no. seminoma)

3/2/1

24/21/3

18/12/6

15/8/7 3/3/0

4/3/1

3/3/0

Adjuvant BEP chemotherapy for high risk NSGCT (Cullen et al 1996)

2 courses Bleomycin 30,000 units day 2, 8, 15, Etoposide 120 mg/m2 days 1-2, Cisplatin 50 mg/m2 day 1&2

Reduces risk of relapse to <3%

MRC Trial TE22: Study of FDG PET in the prediction of relapse in patients

with high risk stage 1 NSGCT

108 patients registered by 13.12.2004

78/96 (81%) PET scans negative, 77/78 chose surveillance

Expected relapse free rate for high risk ~60% at 2 years

Anticipated relapse free rate for PET –ve patients ~90% at 2 years (90%CI >80%)

Interim analysis 12 month relapse free rate in 77 PET –ve patients 65% (90% CI 53-74%) at 2 years at best 70%

Trial closed 18.1.05

Comparison of management policies for NSGCT

Surveillance Low risk RPLND Adjuvant BEP

Relapse rate <20% 5-23% <3%

Require chemo <20% 5-23% 100%

Require RPLND < 5% 100% <1%

Comparison of costs per life saved for managing stage 1 germ cell tumours (Francis et al EJC 2000)

Surveillance RPLND Adjuvant chemotherapy

£6126 £7672 £5851

Management of Stage 1 Testicualr Germ Cell tumours

• Many surgeons do orchidectomies,

• Only a few oncologists should specialise in managing GCT patients

• Patients should be made aware of the different management options

• Deciding which option depends upon histology, prognosis, geography, personality, reliability, bias of the doctor, but most importantly the patient

Life insurance for patients treated for germ cell tumours

   Time without Time to standard Extra/£1000 yr3-4 Extra year 5-6

Seminoma stage1 1 year 4 years £5  

Non-seminoma stage 1

1 year 6 years £10 £5

Stage 2 A/B 2-3 years 9 years £10 £5

Stage 2 B, stage 3 3 years 9 years £15 £10

Stage 4, intermediate and poor risk

3-4 years 9 years £20 £15

Temporary loading usually lasts 3-6 years Provided by Graham JonesUnderwriting Development Product Management & Development - ProtectionDirect line: 01793 505736 (internal: 5736)Email: graham.jones@uk.zurich.com

Factors for Research

• Prognostic factors to more accurately define those requiring treatment : eg. Compare by comparative genomic hybridization and

expression micoarray analysis relapses versus non relapses

• Reduce diagnostic radiation by comparing MRI with CT scans

• To better understand factors increasing incidence of germ cell tumours

• To better understand relationship of 12p isochromosome and Kit with germ cell tumours

STROMAL TUMOURS OF THE TESTIS STROMAL TUMOURS OF THE TESTIS

• Leydig, Sertoli cell, Granulosa cell or combined tumoursLeydig, Sertoli cell, Granulosa cell or combined tumours• 3% of testis tumours, 10% bilateral3% of testis tumours, 10% bilateral• Derive from cells making hormonesDerive from cells making hormones• Mean age 36 yearsMean age 36 years• 10% metastasise – cannot currently be predicted from 10% metastasise – cannot currently be predicted from

histopathology of the primary tumourhistopathology of the primary tumour• testosterone, oestradiol and androstenedione are markers testosterone, oestradiol and androstenedione are markers

(AFP and hCG are not)(AFP and hCG are not)• Resistant to conventional chemotherapy and Resistant to conventional chemotherapy and

radiotherapy.radiotherapy.

SURVIVAL FOLLOWING RPLND FOR STROMAL TUMOURS OF THE TESTIS ACCORDING TO

PATHOLOGICAL STAGE.

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Time (months)

Su

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Stage I

Stage II

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• A substantial proportion of patients would not need further treatment and could therefore avoid the side-effects of chemo/radiotherapy.

• This supposition was based partly on a series of retroperitoneal LN disections in stage 1 seminoma which revealed microscopic nodal involvement in only 8% of patients ( Maier et al 1968), and partly on the success of a surveillance policy in stage 1 NSGCTs (Freeman et al 1987, Horwick & Peckham1998, and Cullen 1991)

Would surveillance alone be an option?

• Curr opin oncol 2004 n= 394 stage I seminomas, 301 stage I NSGCTs, post orchidectomy 1984-2002. 22% relapse rate – 17% seminomas, 29% NSGCTs.

• Median time to relapse 13 months for seminomas with 49% relapsing in first year, 5 months for NSGCT, 80% relapsing in first year.

• 54% of NSGCTs with vascular invasion relapsed and 38% of the seminomas

• 32% of NSGCTs with embryonal ca relapsed. • 90% of relapses detected as routine examination,

remaining 10% at patients initiative – treated appropriately with surgery/chemo/radiation

• 10 deaths in F/u, not related to GCT• Os 98.6%, cause specific survival 100%

Surveillance - disadvantages

• Patients lost to f/u• Requires patient compliance with routine blood

tests and CTs• Psychological stress of “watching and waiting”• Lack of reliable tumour marker compared with the

sensitivity and specificity of HCG and AFP in NSGCTs. PLAP is raised in 50-90% of pts with active disease, but still the sensitivity of this test is lower than required for reliable f/u

• Indolent natural history of seminoma, therefore requirement for prolonged surveillance

Surveillance programs – RMH -Seminoma

• Yr 2 OPD, CXR and markers every 2/12, Year 3 every 3/12, year 4 every 4/12 and year 5 and 6 every 6/12. Yearly thereafter to 10 years

XXUS Abdo

XXXCT chest/ abdo/ pelvis

XXXXXXXXXXXAXR

XXXXXXXXXXXCXR

XXXXXXXXXXXXXXXXMarkers

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36302418121110987654321Month

Surveillance program – Middlesex Hospital - seminomas

Follow-up after year 3 is annually to 10 years. CT scan often done at 5 years to pick up late recurrence

XXXXCT abdo/ pelvis

XXXXXXXXCXR

XXXXXXXXMarkers

XXXXXXXXOPD

36302418121110987654321Month

Surveillance programme MVH - seminomas

• CXR & markers performed at each clinic visit. Year 2 OPD every 2/12, Year 3 every 3/12, year 4 every 4/12, years 5 and 6 every 6/12. Yearly thereafter to 10 years. Lifetime follow-up if had XRT.

Month 1 2 3 4 5 6 7 8 9 10 12 18 24 36

OPD X X X X X X X X X X X X X X

CXR X X X X X X X X X X X X X X

Markers X X X X X X X X X X X X X X

CT

abdo/ pelvis

X X X X

Management of stage I NSGCT

• Relapse rate after orchidectomy alone – 25%• Vascular or lymphatic invasion relapse rate – 40%• Surveillance – low risk patients (85% cure rate surgery alone)• 2 x BEP – in high risk patients with vascular or lymphatic

invasion reduces relapse rate to 1%• Prophylactic RPLND J Urol 2000 – group of high risk stage I teratomas, relapse risk

35-40% - RPLND reduced relapse risk to 23%. Comparable group given BEP x 2 – risk of relapse 3-4%. Good risk patients on surveillance with a 15-20% risk of relapse -RPLND reduces relapse risk to 5%

Adjuvant chemotherapy

Single agent Carboplatin

JCO 2001, Werner et al, n=107, 2 courses of carboplatin given post op (400mg/m2)

pT1 = 84 pts, pT2 = 18 pts, pT3 = 5 pts

• 6 pts died (unrelated causes)

• 101 pts alive and disease free after 6.1 yrs f/u.

Management of Stage IIA and B seminoma

• Radiotherapy 30Gy in 15 fractions

Stage II NSGCT

• Ongoing debate ?PRLND alone vs neoadjuvant chemo followed by surgery. German trial n=187. No difference in OS but in suregery alone group, significantly higher loss of ejaculation

• Oldenberg et al n=87, stage II NSGCT undergoing RPLND 1990-2000. All patients had masses < 2cm on imaging. Viable tumour found in 33% (26% mature teratoma, 7% malignant tumour), 67% fibrosis/necrosis. – No clinical/serological parameters were predictive of

histopath findings. CONCLUSION: RPLND recommended for all patients with masses < 2cm because of high rate of viable tumour found

Testicular germ cell tumours – Professor Rustin – MVH Cancer

Centre

Testicular germ cell tumoursProfessor Rustin – MVH Cancer

Centre

Testicular Germ Cell tumours

Professor Rustin

Mount Vernon Hospital Cancer Centre

• 1-1.5% of male neoplasms

• Most common tumour in men aged 20-35 yrs.

• Incidence has doubled in last 20 years

• One of the few solid tumours which is completely curable even after it has metastasized with an overall survival of 90%

• 70% of seminomas and 50% of NSGCTs are diagnosed at stage I

Pathological classification of testicular cancers

Seminoma SeminomaSpermatocytic seminoma Spermatocytic seminoma

Teratoma Non-seminomatous germ cell tumour

Teratoma Differentiated (TD) Mature teratoma

Malignant teratoma intermediate (MTI)

Embryonal carcinoma with teratoma (teratocarcinoma)

Malignant teratoma undiffrentiated (MTU)

Yolk sac tumour, embryonal carcinoma

Malignant teratoma trophoblastic (MTT)

Yolk sac tumour; choriocarcinoma

Second malignanciesEur J Cancer 1993, Moller et al, 6187 Danish patients,

f/u 44 years• 459 second cancers occurred • Relative risks significantly increased for leukaemia

(within first 10 years), gastric, colonic and pancreatic cancer( between 10 &19 years), bladder, non-melanoma skin and renal cell cancer.

• Increased incidence was suggested for ca rectum, lung and prostate.

• This may reflect the differences in growth rates of tumours originating in different tissues.

RMH Staging• I – No evidence of disease outside the testis• IM – As above but persistently raised tumour markers• II – Infradiaphragmatic nodal involvement• IIA – max diameter <2cm• IIB- max diameter 2-5cm• IIC – max diameter 5-10cm• IID – max diameter >10cm• III – Supra and infradiaphragmatic node involvement

Abdominal nodes a,b,c, as above, Mediastinal nodes M+, Neck nodes N+

• IV – Extralymphatic metastases. Lungs: L1 - <3 mets, L2- multiple mets < 2 cm, L3 – multiple mets >2cm. Liver involement H+. Other sites specified.

JCO, 2002 – Warde et al

• n=638 (seminomas), F/U 7 years, 121 relapses– 5 year RFR 82%

• On univariate analysis:– tumour size – RFR < 4cm 87%, >4cm 76%

(p=0.003)– Rete testis invasion – RFR 86% (absent), 77%

(present) p=0.003– Presence of small vessel invasion – RFR 86%

(absent), 77% (present) p= 0.038

Prognostic Factors for seminomas on surveillance

n=638 (seminomas), F/U 7 years, 121 relapses – 5 year RFR 82%

On univariate analysis: tumour size – RFR < 4cm 87%, >4cm 76% (p=0.003)Rete testis invasion – RFR 86% (absent), 77% (present) p=0.003Presence of small vessel invasion – RFR 86% (absent), 77% (present) p= 0.038

• Size of tumour (J Clin Onc 2002, Warde et al)• Invasion into the rete testis• Age• Small vessel invasion• Histological subtype – classical vs anaplastic.

Embryonal carcinoma in primary tumour• DNA ploidy status• Mitotic count• DNA S-phase %• Syncitiotrophoblasts• Degree of lymphocytic infiltration of primary tumour• Expression of HCG and low MW keratin on

immunohistochemistry• MIB- 1 monoclonal ab – marker of proliferative activity

Prognostic factors investigated in seminomas

Toxicities

• Grade 1 cytopaenia in 10.7% of all cycles• Grade 2 cytopaenia in 2.1% of all cycles

ie; No tumour recurrence with minimal toxicity. 2 courses of carboplatin may be equivalent to radiotherapy.

Compared with cisplatin, carboplatin doesn’t cause renal damage, neuropathy, or ototoxicity. Myelosuppression, esp thrombocytopaenia is therefore the dose limiting toxicity.