Management Strategies for Stage I germ cell tumours

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Management Strategies for Stage I germ cell
tumours
Professor Gordon J S Rustin Director of Medical
Oncology Mount Vernon Hospital Northwood,
Middlesex England
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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
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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?
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Initial management

• Widespread malignancy ? refer for immediate
  chemotherapy
• No 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 (lt12ml), and in patients
  lt 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 lt
  30
• Complete post op staging, CT chest/abdo/pelvis
• Post op tumour markers if raised pre-op. Should
  fall according to half life (4-6 days for AFP,
  24 hours for HCG)

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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.

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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 10s) to the testis
  eradicates CIS, relapses with lower doses
• Leydig cell function increasingly impaired at
  doses gt 17 Gy
• Long term hormone replacement therapy may be
  necessary

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Possible prognostic factors for stage 1 germ cell
tumours

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

• TERATOMAS
• Lymphovascular invasion
• Embryonal ca histology in primary tumour
• MIB- 1 monoclonal ab marker of proliferative
  activity
• Mitotic count

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Options for management of stage I Seminomas

• Adjuvant radiotherapy
• Adjuvant chemotherapy
• Surveillance

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1980s Management of stage I seminoma

• 20 will recur after orchidectomy
• 90 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)

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Late Morbidity from Radiotherapy

• Second Cancers
• Cardiac events
• Peptic ulceration
• Infertility

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Relative risks for second primary cancers(NB. RR
of contralateral testis ca is 35.7!)
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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
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MRC TE10 (Fossa et al 1999)
Survival at 3 years, 99 for PA vs 100 for
DL RFS 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. CONCL
USION 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.
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MRC TE 18 (Jones et al 2001 2005)
At median follow-up of 4 years 2 year relapse
free survival 97.7 after 30Gy 97
after 20Gy Better Quality of Life scores for
acute effects in lower dose arm Therefore Standa
rd radiotherapy for stage 1 seminoma should
be 20 Gy in 10 over 2 weeks to para-aortic
strip unless previous inguino/pelvic/scrotal
surgery when dog-leg field.
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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. carbo
platin n1447 30Gy/15s Radiothe
rapy 20Gy/10s
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TE 19 Radiotherapy vs carboplatin Relapse Free
Rate
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Results of TE19 / EORTC 30982
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Late Morbidity from Chemotherapy

• Infertility
• Second Tumours
• Cardiovascular damage

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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 lt4cm vs gt4cm,
hazard ratio 2 Invasion of the rete testis,
hazard ratio 1.7 5 year recurrence rate Both risk
factors 32 Single risk factor 16 No risk
factors 12
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Post orchidectomy surveillance vs carboplatin for
stage 1 seminoma Spanish germ cell cancer
cooperative group Ann oncol 2003

• N 203
• 60 pts with tumour gt4cm 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

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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 lt4cm and absence of
rete testis invasion RR 12 - surveillance.
Tumours gt4cm and presence of rete testis invasion
RR 35 ? offer adjuvant therapy
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Management Options for Stage 1 Non-seminomatous
germ cell tumours
Surveillance RPLND Adjuvant chemotherapy
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Surveillance for Non-seminomatous germ cell
tumours
relapse rate Overall 30 Lymphovascular
invasion lt40 No risk factors 10-15
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Surveillance programme MVH - NSGCTs
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 X
CXR X X X X X X X X X X X X X
Markers xx xx xx xx xx xx X X X X X X X X X
CT Chest/ abdo/ pelvis X X

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

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Advantages of Surveillance for Low risk NSGCT

• gt80 avoid any chemotherapy or RPLND
• gt80 avoid risk of 2nd tumours
• gt80 avoid risk of cardiovascular damage
• gt80 avoid risk of infertility

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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

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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

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Study Design
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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)

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183 stage 1 GCT on surveillance Initial
Presenting Factors among 52 relapses (Francis et
al EJC 2000)
Symptoms Tumour Markers Radiology (to
tal/no. NSGCT/no. seminoma)
4/3/1
24/21/3
3/2/1
3/3/0
15/8/7
3/3/0
18/12/6
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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 12 Reduces risk of relapse to lt3
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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 (90CI
gt80) 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
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Comparison of management policies for NSGCT
Surveillance Low risk RPLND Adjuvant BEP
Relapse rate lt20 5-23 lt3 Require
chemo lt20 5-23 100 Require RPLND lt 5
100 lt1
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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
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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

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Life insurance for patients treated for germ
cell tumours 
Temporary loading usually lasts 3-6
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Development Product Management Development -
Protection Direct line 01793 505736 (internal
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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

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STROMAL TUMOURS OF THE TESTIS

• Leydig, Sertoli cell, Granulosa cell or combined
  tumours
• 3 of testis tumours, 10 bilateral
• Derive from cells making hormones
• Mean age 36 years
• 10 metastasise cannot currently be predicted
  from histopathology of the primary tumour
• testosterone, oestradiol and androstenedione are
  markers (AFP and hCG are not)
• Resistant to conventional chemotherapy and
  radiotherapy.

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SURVIVAL FOLLOWING RPLND FOR STROMAL TUMOURS OF
THE TESTIS ACCORDING TO PATHOLOGICAL STAGE.
.
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Would surveillance alone be an option?
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• 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

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Surveillance programme MVH - seminomas
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

• 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.

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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

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Management of Stage IIA and B seminoma

• Radiotherapy 30Gy in 15 fractions

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Stage II NSGCT

• Ongoing debate ? ?PRLND alone vs neoadjuvant
  chemo followed by surgery. German trial n187. No
  difference in OS but in suregery alone group,
  significantly higher loss of ejaculation
• Oldenberg et al n87, stage II NSGCT undergoing
  RPLND 1990-2000. All patients had masses
  lt 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 lt
  2cm because of high rate of viable tumour found

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Testicular germ cell tumours Professor Rustin
MVH Cancer Centre
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Testicular germ cell tumoursProfessor Rustin
MVH Cancer Centre
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Testicular Germ Cell tumours

• Professor Rustin
• Mount Vernon Hospital Cancer Centre

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• 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

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Pathological classification of testicular cancers
Seminoma Seminoma
Spermatocytic 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
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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 lt2cm
• IIB- max diameter 2-5cm
• IIC max diameter 5-10cm
• IID max diameter gt10cm
• III Supra and infradiaphragmatic node
  involvement Abdominal nodes a,b,c, as above,
  Mediastinal nodes M, Neck nodes N
• IV Extralymphatic metastases. Lungs L1 - lt3
  mets, L2- multiple mets lt 2 cm, L3 multiple
  mets gt2cm. Liver involement H. Other sites
  specified.

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Prognostic Factors for seminomas on surveillance
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n638 (seminomas), F/U 7 years, 121 relapses 5
year RFR 82 On univariate analysis tumour
size RFR lt 4cm 87, gt4cm 76 (p0.003) Rete
testis invasion RFR 86 (absent), 77 (present)
p0.003 Presence of small vessel invasion RFR
86 (absent), 77 (present) p 0.038
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Prognostic factors investigated in seminomas
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