Ovarian Germ Cell Tumors

Report
MANAGEMENT OF OVARIAN GERM CELL
AND STROMAL TUMOURS- An update
Michael Friedlander
Ovarian Germ Cell Tumours
 1-2% of all ovarian malignancies
 Usually in adolescents but 42% of 614
patients were over 30!
 60-70% STAGE 1 at diagnosis
 No randomized trials in OGCT
 Guided by results of large body of data
from randomized trials in testis cancer
Ovarian Germ Cell Tumours
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Dysgerminoma
Endodermal sinus tumour
Embryonal Carcinoma
Choriocarcinoma
Teratoma-Mature/Immature
Immature – low grade/high grade
Surgical Principles
Suspect diagnosis
Pre-operative markers
Conservative- fertility preserving surgery
Staging-controversial- careful inspection of
peritoneum, omentum, contralateral ovary
and nodes with washings and biopsies of
suspicious areas adequate
 Unilateral oophorectomy with debulking if
advanced stage
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Management Principles
 Monitoring tumour markers
b hcg AFP LDH
t ½ b HCG 24- 48 hrs AFP 5-7 days
 Switch to salvage therapy if markers not
falling adequately or rising during
treatment
 Radiological re-staging following therapy
 Resection of residual masses particularly if
teratoma elements in primary
IGCCCG Prognostic classification
Testis cancer
Prognosis
Proportion
survival
Non-seminoma
seminoma
Good
56%
90%
AFP<1000
& BHCG<1000
& LDH<1.5 N
Any marker
level
& no visceral
mets
Intermediate
28%
80%
AFP 1000-10,000
& BHCG 100010,000
& LDH 1.5-10 ULN
Non
pulmonary
mets
Poor
16%
50%
Non pulmonary
mets
AFP >10,000
BHCG>10,000
LDH> 10 ULN
Staging System-POG
 Stage 1-limited to ovary. Washings –ve.
Markers fall within T ½
 Stage 2-microscopic residual/positive
nodes<2cm.-ve washings
 Stage 3->2cm nodes;gross
residual,contiguous visceral
involvement;+ve washings
 Stage 4-distant metastases
Malignant Germ Cell Tumors in Children
and Adolescents-POG Study
J Paed.Surg 39;424:2004
Stage
1
2
3
4
No.
41
16
58
16
6yr EFS%
95
87.5
96.6
86.7
6yr S%
95.1
93.8
97.3
93.3
BEP B 15mg/m2 D1 E 100mg/m2 1-5 P 20/m2 1-5
4 cycles at 3 weekly intervals
Management of Dysgerminomas
 Most patients Stage 1a- surveillance
appropriate.
 15% will relapse and salvaged with
chemotherapy
 Rare-therefore not clear if BEP X 3 is essentialin advanced or recurrent disease
 GOG STUDY- 39 patients with stage 1b-3
completely resected-treated with Carboplatin
400mg/m2 and etoposide 120mg/m2 x3 every
4 weeks x 3 No recurrences
Management of Good Prognosis Subset
 BEP x 3
 If Bleomycin contraindicated or dropped- EP
X4
 5 day BEP less toxic and optimal regimen
B 30 U d1,8,15
E 100mg/m2 1-5
Cisplatin 20mg/m21-5
Australian Germ Cell Study
Lancet 357;739;2001
Indiana BEP vs. 4 Cycles
Cisplatin 100mg/m2 day1
Etoposide 120mg/m2 d1-3
Bleomycin 30 u q21
166 randomized
Trial stopped as 1 vs. 9 deaths from cancer in
the 2 regimens
5 day BEP-Indiana superior regimen
Toxicity of BEP
 Pulmonary toxicity 3%; decreased DLCO
20%
 AML 0.2- 1%
 Neuropathy 20%
 Raynauds 20%
 Tinnitus 24%
 High tone hearing loss 70%
 Gonadal dysfunction 16 -30%
 Cardiovascular disease/Hypertension
How important is Bleomycin
 Bleomycin should only be omitted if
contra-indications when 4 cycles of EP
can be used
 Inconsistent findings from trials of 4
EP vs 3 BEP
Management of Intermediate to Poor
Risk Subgroup
 BEP X 4- represents standard of care
 Multiple studies using various combinations
and permutations do not appear superior
 VeIP appropriate if compromised lung
function
 High dose therapy not demonstrated to be
superior first line treatment
Accelerated BEP
Intermediate-high risknew Australian study
Administer every 14 days with
pegylated GCF support day 6
Cisplatin 20 mg/m2 day1-5
Etoposide 100mg/m2 d1-5
Bleomycin 30 u weekly x 12
Role of Second Look Surgery
 Not necessary in patients with
completely resected disease at primary
surgery
 Resection of residual masses-particularly
if teratomatous elements in primary
tumour
 Resection of residual masses in nondysgerminoma – 50% necrosis;35%
mature teratoma; 15% residual cancer
Second look surgery
Matthew et al J Postgrad Med 2006
 68 patients with germ cell tumors
 35 residual mass post chemo
 29 laparotomy
3 patients had viable tumor, 7 immature
teratoma, 3 mature teratoma and 16
necrosis or fibrosis
no cases of viable tumour if dysgerminoma,
embryonal carcinoma
/absence of teratoma in primary
Salvage therapy TIP
Journal of Clinical Oncology 18; 2000: 2413-2418
 Treatment consisted of four cycles of TIP given
21 days apart.
 Paclitaxel 250/m2 by 24-hour infusion on day
1, followed by an ifosfamide 1.2 g/m2 infusion
given over 4 hours, and cisplatin 20 mg/m2 on
days 2 through 6.
 80% of 30 achieved a favorable response.
 22 (73%) of the favorable responses
remain durable at a median follow-up
duration of 33 months
Survival for patients with relapsed testicular GCTs treated
with TIP therapy (n = 30; 25 alive)
Motzer, R. J. et al. J Clin Oncol; 18:2413-2418 2000
Copyright © American Society of Clinical Oncology
Stem Cell Transplant ?
European Bone Marrow Transplant GroupRandomized 280 relapsed patients to
VIP/VeIP X4 vs VIP/VeIP X3 followed by
High Dose Chemo and stem cell support
No advantage to High dose and stem cell
support
53% 3 year survival in both arms
Stem Cell Transplant
 Results of 2 randomized trials EORTC
and an intergroup study do not
support role in first line therapy for
high risk disease
 Still contentious for salvage therapy
Ovarian Germ Cell Tumors
Can stage 1 be managed with close surveillance?
 Surveillance successful in male germ cell
tumours20-30% relapse but salvaged
2 cycles of BEP in “high risk”
 What about ovarian germ cell tumours
Surveillance for Stage 1 tumors
Study
No.
Pathology
Relapse
Survival
Cushing et
al 1999
POG/CCG
44
Immature
teratoma-stage1
1
97.7%
Dark et al
1997
24
9 dysgerminoma
9 immature
teratoma
6 yolk sac
8
95%
Barazelli
2000
12
6
95%
patient
Surveillance program
Charing Cross /Mount Vernon
Pre-op markers and scans
3 months post surgery CT Chest/abd-pelvis
If clear2nd look laparoscopy if inadequate
staging/immature teratoma
Surveillance
Markers HCG AFP LDH CA125
1st year every 2 weeks x 6 m and then
monthly x 6
2nd year monthly
3rd year every 3/12
4th year every 4/12
Subsequent years 6/12
Surveillance
Clinical exam
1st year monthly
2nd year every 2 months
3rd year every 3 months
4th year every 4 months
5-10 every 6 months
Imaging
 Chest X ray alternate visits
 Abdo-pelvic US every 3rd visit for first
2 years followed by annual abdopelvic ultrasound subsequent years
Surveillance in stage 1
 Relapses occur within 1 year in
almost all cases
 Salvage high
 Advantages- reduced toxicty
leukemia 0.9%
hypertension 15%
neuropathy 15%
Conclusions
 Paradigm of a curable malignancy
 Can not be complacent- still needs expert
treatment rather than “recipe –based’’
 Good evidence base for treatment
 Focus on reduction of toxicity in low risk
and improving outcomes in intermediate to
poor risk
 Surveillance has not been standard of care
in ovarian germ cell tumors but should be
considered for 1A
Sex cord stromal tumours
Sex Cord Stromal Tumors
 5-8% of ovarian malignancies
 Derive from sex cords and ovarian
stroma
 Granulosa Cell;Sertoli Leydig
 Adult granulosa cell tumors are the
most common of the group
Granulosa Cell Tumors(GCT)
Median Age 54
2-5% of ovarian cancers
5% juvenile-prepubertal age group
Usually unilateral
70% secrete estrogen- concurrent
endometrial cancer in 5-10%
 Increased risk of breast cancer
 Most stage 1 at diagnosis
 Late recurrences 10-30 years post
diagnosis can occur
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GCT-Survival by Stage
FIGO Stage
5year survival 10 year
survival
1
90-100%
85-95%
2
55-75%
50-65%
3
25-50%
20-30%
GCT- Natural History
 Indolent
 Late relapses in up to 30% Stage 1 –but
data not robust
 90% 5 year survival
 Recurrences can occur many decades later
10 year survival after recurrence-56%
Median Survival after recurrence 2 yrs
GCT –Prognostic Factors
 Stage
 Poorly differentiated or sarcomatoid
variant-worse prognosis
 Mitotic count 4/10HPF 100% @ 5yrs
5-9 –80% 5yr survival
>10-no long term survivors
 Ploidy- better prognosis in diploid tumors
 Residual disease post surgery
Management
 Unilateral oophorectomy in children or
women of reproductive age group
 Bilateral tumours uncommon
 TAHBSO in post menopausal women
 No evidence to support adjuvant radiation
 No evidence that adjuvant chemotherapy
prevents recurrence-but no studies !
Recurrent Disease management
 Median time to relapse 4-6 years
 Repeat debulking surgery should be
considered in all patients
 Localised recurrence-consider
radiation
 Hormonal therapy
 Chemotherapy
Compilation of Results of
Chemotherapy
Regimen No.
RR %
Duration Toxic
death
months
CAP
30
73
5-73
0
BEP
63
72
5-80+
2
PVB
56
70
2-81+
3
Chemotherapy of GCT
Homesley et al Gynecol Oncol 1999;72:131
 GOG study- 55 women with Stage 2-4 or
recurrent GCT- BEP
 RR 40% CR 24%
 14/38 women had negative second look
surgery
 50% of patients with recurrent disease
progression free at 3 years
 69% of patients with advanced tumors
progression free at 3 years
 Significant toxicity with 2 bleomycin related
deaths
Taxanes in Sex Cord Stromal Tumours
MD Anderson Experience-JCO 22;3517;2004
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Non-randomized
44 patients-both adjuvant and recurrent
Taxane +/- platinum
42% response rate in measurable disease
Median PFS 20 months in recurrent disease
Less toxic than BEP in this older population
Hormone Receptors
Hardy et al Gyn Oncol 2005
ER + 32%
PR + 100%
Hormonal Therapy
Agent
number
Response%
LHRH agonist
13
50
Progestin-MPA
5
90
Tamoxifen-progestin
1
100
Conclusions
 Good prognosis for most
 Rare –no strong evidence base for
treatment decisions
 Adjuvant therapy controversial-? In
high risk
 Surveillance-long term

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