Protocol Germ Cell

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The United Kingdom Children's Cancer Study Group
Germ Cell Working Group
PROTOCOL FOR THE TREATMENT OF

EXTRACRANIAL GERM CELL TUMOURS
IN CHILDREN AND ADOLESCENTS (GC III)
(GC 2005 04)
Chief Investigator:
Dr Juliet Hale
START DATE: 1st May 2005

MREC Approval date: 22nd February 2005
EUDRACT Number: 2004-002503-33
FINAL VERSION 1.0: SEPTEMBER 2004

PLEASE DESTROY ALL PREVIOUS DRAFTS
UKCCSG Data Centre
University of Leicester
Hearts of Oak House
9 Princess Road West
Leicester. LE1 6TH
Tel: 0116 249 4460

Fax: 0116 254 9504
GCIII/Final Version1.0/September 2004

CONTACT DETAILS
Chief Investigator Dr Juliet Hale

Sir James Spence Institute
Royal Victoria Infirmary
Newcastle upon Tyne NE1 4LP
Tel: 0191 202 3033
Fax: 0191 202 3060
e-mail: j.p.hale@ncl.ac.uk
Chemotherapy Dr James Nicholson

Dept of Paediatrics
Box 181
Addenbrooke’s NHS Trust
Hills Road
Cambridge CB2 2QQ
Tel: 01223 216959
Fax: 01223 586794
e-mail: james.nicholson@addenbrookes.nhs.uk
UKCCSG Data Centre
Trial Co-ordinator Janis Hayward

UKCCSG Data Centre
3rd Floor, Hearts of Oak House
9, Princess Road West
Leicester LE1 6TH
Tel: 0116 249 4468
Fax: 0116 254 9504
e-mail: jh106@le.ac.uk
Statistician David Machin

UKCCSG Data Centre
3rd Floor, Hearts of Oak House
9, Princess Road West
Leicester LE1 6TH
Tel: 0116 249 4460
Fax: 0116 254 9504
e-mail: dm113@le.ac.uk
1 GC III/Final Version1.0/September 2004

Pathology Dr Claire Thornton
Dept of Pathology
Royal Victoria Hospital
Grosvenor Road
Belfast BT12 6BA
Tel: 02890 892746
Fax: 02890 233643
e-mail: claire.thornton@bll.n-i.nhs.uk
Surgery Mr Simon Huddart

Dept of Paediatric Surgery
University College Hospital of Wales
Heath Park
Cardiff CF4 4XN
Tel: 01222 747747
e-mail: huddartsn@msn.com
Radiotherapy Dr Mike Sokal

Dept of Radiotherapy
The City Hospital
Hucknall Road
Nottingham NG5 1PB
Tel: 0115 969 1169
Fax: 0115 962 7923
e-mail: msokal@ncht.org.uk
Radiology Dr John Somers

The City Hospital
Hucknall Road
Nottingham NG5 1PB
Tel: 0115 969 1169
Fax: 0115 962 7776
e-mail: jsomers@ncht.org.uk

Contents
Page
Contact Details …………………………………………………………………………… 1
1. Objectives ………………………………………………………………………… 6
2. Background ……………………………………………………………………….. 6
Table 1 – Risk Groups ……………………………………………………. 10
Figure 1 – Flow Sheet – Overview of Management of Germ Cell Tumours 11
3. Patient Eligibility …………………………………………………………………. 12
3.1 Eligibility Criteria ………………………………………………………… 12
3.2 Exclusion Criteria ………………………………………………………… 12
4. Investigations at diagnosis ………………………………………………………… 12
5. Histopathology ……………………………………………………………………. 13
6. Staging ……………………………………………………………………………. 13
Table 2 – Histological Classification …………………………………….. 14
Table 3 – TNM Staging …………………………………………………… 15
7. Tumour Markers …………………………………………………………………... 16
8. Treatment Strategy ………………………………………………………………… 16
8.1 Overview ………………………………………………………………….. 16
8.2 Surgical guidelines ………………………………………………………… 17
8.2.1 Testicular Tumours ………………………………………………… 17
8.2.2 Ovarian Tumours …………………………………………………... 17
8.2.3 Sacrococcygeal Tumours …………………………………………... 18
8.2.4 Mediastinal/Thoracic Tumours ……………………………………. 18
8.2.5 Vagina/Uterus ……………………………………………………… 19
8.2.6 Other Sites …………………………………………………………. 19
8.2.7 Relapse …………………………………………………………….. 19
8.3 Management according to Risk Group ……………………………….……. 19
8.3.1 Low Risk …………………………………………………………… 19
8.3.2 Intermediate Risk ………………………………………………….. 20
8.3.3 High Risk …………………………………………………………... 20
8.3.4 Recommendations for adolescents …………………………………. 20
8.4 Chemotherapy Administration …………………………………………….. 21
8.4.1 Details of chemotherapy …………………………………………… 21

8.5 Measurement of GFR ……………………………………………………… 21
8.6 Patients with Renal Failure ………………………………………………… 22
8.7 Patients with Respiratory Compromise ……………………………………. 22
8.8 Infant Dose Adjustments ……………………………………………….….. 22
9. Investigations during treatment ……………………………………………………. 22
10. Investigations at end of, and following, treatment ………………………………… 23
11. Radiotherapy ………………………………………………………………………. 24
12. Statistical considerations …………………………………………………………... 24
12.1 Accrual …………………………………………………………………….. 24
12.2 Low Risk Patients …………………………..……………………………… 24
12.2.1 Stopping Rule ………………………………………………………. 24
12.3 Intermediate Risk Patients …………………………………………………. 25
12.3.1 Stopping Rule ……………………………………………………… 25
12.4 High Risk Patients …………………………………………………………. 26
12.4.1 Stopping Rule ……………………………………………………… 26
13. Recommendations for Relapsed/Progressive Disease …………………………….. 27
13.1 Overview of Treatment ……………………………………………………. 27
13.2 Investigations at Relapse ………………………………………………….. 27
13.3 Details of Chemotherapy ………………………………………………….. 28
13.3.1 Chemotherapy Administration …………………………………….. 28
13.4 Infant Dose Adjustments ………………………………………………….. 28
13.5 Investigations during Treatment …………………………………………… 29
13.6 Surgery …………………………………………………………………….. 29
13.7 Refractory Disease …………………………………………………………. 29
14. Toxicity Monitoring ...………………………………………………………….….. 29
14.1 Serious Adverse Events ……………………………………………………. 30
15. Recommendations for Immature Teratoma ……………………………………….. 30
16. Recommendations for Mature Teratoma ………………………………………….. 31
17. References …………………………………………………………………………. 32
Appendices
Appendix A: Serum AFP values in normal term babies …………………………………. 36
Appendix B: Carboplatin Dose Tables …………………………………………………... 37
Appendix C: Toxicity Grading + Brock ototoxicity grading ……………………….……. 40

Appendix D: Flow Sheets - JEB Chemotherapy and Recurrent MGCTs ……………... 49
Appendix E: Drug Information …………………………………………………………... 52
Appendix F: Patient Information sheets and Consent forms 62
Patient Information sheets: Parent/Guardian……………………………. 63
Patients 16+ years in Scotland …………….. 66
Patients 14+ years …………………………. 69
Patients 8 – 14 years ………………………. 72
Patients under the age of 8 ………………… 75
GP Information sheet ……………………… 76
Consent forms Parent/Child ………………………………... 79
Patients aged 16+ in Scotland ……………… 80

1. Objectives
- To stratify and reduce treatment for patients with extracranial germ cell tumours according to
prognostic factors derived from analysis of UKCCSG Study GC8901 (GCII) whilst maintaining
event free survival (EFS)
- To continue to treat newly diagnosed patients with extracranial germ cell tumours requiring
chemotherapy with a Carboplatin based strategy
- To develop a common strategy for the treatment of patients with recurrent or progressive
extracranial germ cell tumours
- To register all cases of mature and immature teratoma
- To develop a common strategy for the management of immature and mature teratoma including
follow-up strategies to permit early detection of yolk sac recurrence
2. Background
Germ cell tumours (GCTs) comprise a rare and highly varied group of tumours occurring at several
anatomical sites and with a histological spectrum ranging from mature and immature teratoma to
four different malignant sub-types. Nevertheless it has become possible to standardise a surgical
and chemotherapeutic strategy across the range of tumours.
Prior to the introduction of platinum based chemotherapy, survival of children with malignant germ
cell tumours (MGCTs) was poor. The combination of cisplatin, vinblastine and bleomycin(PVB)
used successfully in adult testicular MGCTs [1] was initially toxic when applied to children [2].
The introduction of hybrid cisplatin containing regimens in children improved survival rates to 47
– 87% [3–7]. More recently the French, German and North American groups have reported
survival from 75 – 100% in paediatric MGCTs using cisplatin, etoposide, bleomycin (BEP), BEP
with high dose cisplatin or cisplatin, etoposide and ifosfamide (PEI) [8–12].
In order to reduce the oto- and nephrotoxicity associated with cisplatin containing regimes the
UKCCSG has, since 1989, been using a carboplatin based strategy, GC8901(GCII), with
carboplatin 600mg/m2 (AUC 7.9), etoposide 360mg/m2 and bleomycin 15mg/m2 per course, for
paediatric MGCT. When GC8901 opened an early version of the Calvert formula was used to
calculate carboplatin dose based on uncorrected GFR and an anticipated AUC of 6. Subsequent
pharmacokinetic analysis has shown the actual AUC of 600mg/m2 to be 7.9. Approximately 75%
of patients treated on GCII had carboplatin prescribed according to surface area rather than GFR.
Patients were given the number of courses to achieve normalisation of tumour markers plus two
additional courses.
Previous studies have shown carboplatin to be less effective than cisplatin, including the French
TGM90 study which only gave 400mg/m2 every 6 weeks [13] and studies in adult MGCT [14-16]
which also used lower doses of carboplatin than GCII.
The UKCCSG Germ Cell Tumour Working Group has recently completed analysis of outcome in
patients with extracranial MGCTs treated on GCII between January 1989 and December 1997 [17].

A total of 184 patients with MGCT were eligible for analysis, of whom 47 were treated with
surgery alone and 137 with carboplatin, etoposide and bleomycin (JEB). The overall 5 year
survival was 93.2% and for the JEB treated patients was 90.9% with 5 year EFS 87.8%. At present
the UKCCSG is the main paediatric group using a carboplatin based strategy in MGCTs. These
results are comparable with the overall results of other international groups showing carboplatin in
appropriate doses to be as effective as cisplatin based strategies in children.
In preparation for the next UK Germ Cell Tumour Study the Working Group has held meetings
with SFOP and with the International Germ Cell Group (UK, France, Germany, USA, Italy,
Sweden). The focus of meetings with SFOP was to define risk groups for MGCTs based on prior
work by the French group [18]. Multivariate analysis of GCII has also shown alpha-fetoprotein
(AFP) level at diagnosis (< 10,000 or >10,000), tumour site and stage to be important prognostic
variables with AFP level being the most significant. Pure human chorionic gonadotropin (HCG)
secreting tumours are uncommon in childhood and HCG level at diagnosis does not emerge as a
prognostic variable. Furthermore patients with germinoma/seminoma do well regardless of stage.
These factors were combined to define three risk groups – see Table 1. Analysis of outcome for
GCII patients retrospectively allocated to one of these risk groups (under one year olds were
allocated ignoring AFP level) showed the following:
Risk group Number of Number of 3 year Number of 4 year

patients (%) events EFS deaths OS
Low 82 (45%) 20 73% 0 100%
Intermediate 35 (19%) 2 94% 1 97%
High 57 (32%) 16 70% 8 82%
Unknown 9 (5%) 2
The high number of events in the Low Risk group is accounted for by ‘surgery only’ Stage 1
patients relapsing. All of these patients were rescued with JEB.
The International Germ Cell Tumour Group hopes to develop a collaborative protocol that may
allow randomised questions to be answered. Until this is possible it is proposed that the UKCCSG
continues to use JEB for the treatment of MGCTs in view of its demonstrable efficacy. However,
although JEB has had relatively little toxicity in GCII, one child developed acute myeloid
leukaemia (without 11q23 abnormality) and in German MGCT Trials 6/616 developed AML [19].
Other toxicities involved Grade 3 deafness in one child, transient Grade 1/2 deafness in 5 and
pulmonary toxicity in 10 (transient in 9) [17]. The median number of courses of JEB given was 5
(5 for Intermediate Risk and 6 for High Risk). It would therefore seem appropriate to reduce
treatment for MGCTs if possible.
A strategy of reducing the length of therapy would also be in line with treatment given by other
paediatric and adult MGCT groups. Both in the USA and Germany paediatric “intermediate risk”
patients receive 3 courses of chemotherapy and “high risk” patients receive 4 courses of
chemotherapy [10,11]. Similarly adult patients with MGCT generally receive 3 or 4 courses of
BEP. Both paediatric groups use a cisplatin based strategy but analysis of GCII suggests JEB is
likely to be equivalent [17]. Any such reduction in therapy will need to be subject to ‘stopping
rules’.

In GCII pathology has been classified according to a modified version of Dehner’s classification
[20] and staging has been tumour site specific. At a meeting of the International Germ Cell Group
it was agreed that a TNM staging system should be adopted and a slightly revised histological
classification was agreed. Both changes will be used in this protocol.
Fortunately relapse is a rare event in childhood MGCTs. At present approximately 2 patients per
year treated on GCII relapse or develop progressive disease. We are unable to identify these
patients sufficiently well at diagnosis to intensify their first line therapy without also doing so for
many patients effectively treated by JEB. Currently these patients are treated with a mixture of
schedules containing cyclophosphamide, doxorubicin, actinomycin D, ifosfamide and cisplatin and
approximately 50% are salvaged. In this small group there is no particular pattern of treatment
associated with successful salvage. However, in order to establish tumour and treatment related
factors associated with successful second line therapy it is important to have a defined relapse
strategy. This protocol will develop such a strategy.
Cisplatin has been used successfully in salvage therapy for patients initially treated with
carboplatin in the SFOP study TGM 90 [8] and has also been used as part of retrieval therapy in
adult MGCTs initially treated with cisplatin [21]. Ifosfamide also has significant activity in
refractory MGCTs [22,23]. As etoposide forms part of first line therapy in the UK, its use in
second line treatment may increase the risk of secondary AML and vinblastine, which is also active
in MGCTs, will therefore be used instead.
High-dose therapy (HDT) has been used in both first line therapy of poor risk MGCTs and in
salvage therapy in adults [24-26] and appears to have a role in both these situations when remission
can be achieved prior to HDT. However no role has been defined in the paediatric setting and in
this protocol HDT will not be part of initial salvage therapy. In contrast the use of surgery to
achieve remission may well be important for MGCTs at some sites [27].
Immature teratoma is the sub-type of GCT where there has been most controversy about
management. Immature teratomas occur principally in ovarian and extragonadal sites. These
tumours include representative tissues from all three germ cell layers and, in addition, immature
tissues, usually neuroepithelium but immature ectoderm, mesoderm and endoderm can be present.
This can give these tumours an alarming appearance. Immature teratomas can occur in pure form,
can contain microfoci of yolk sac tumour [28] or can be part of mixed tumours containing MGCT
or non germ cell malignant elements such as PNET or Neuroblastoma [29-31]. The degree of
immaturity is generally graded according to one of several classifications [20,32-34]. In ovarian
primaries it is not uncommon to find peritoneal deposits of mature glial tissue, gliomatosis
peritonei [32,35], or of immature teratoma.
Due to the alarming appearance of these tumours and their tendency to peritoneal spread
chemotherapy has commonly been used in adults [32]. However several paediatric studies have
shown that initial surgery to remove all tumour, except for gliomatosis peritonei, and a ‘watch and
wait’ policy, is appropriate for most patients [29,36-38]. The significance of elevated AFP at
diagnosis is uncertain. Some tumours contain immature liver or intestine which stains positively for
AFP and may be responsible for raised serum levels. In the POG/CCG study only 45% of patients
with microfoci of yolk sac tumour had raised AFP for age (max 1045 ng/ml) and 26% of patients
with normal AFP had microfoci of yolk sac tumour. In addition 26% of patients with pure
immature teratoma had raised AFP (max 139ng/ml) [29]. This protocol will use a strategy of initial
complete surgery and ‘watch and wait’ for these tumours unless definite non germ cell malignancy
is present.

Although their appearance is less alarming, mature teratomas in extragonadal sites also require a
strategy of initial complete resection and follow-up. Recurrence of both mature teratoma, if initial
resection is incomplete, and of MGCT occurs, especially in sacrococcygeal primaries in infants. In
these patients the incidence of MGCT recurrence, usually yolk sac tumour, may be as high as 10%
[39]. Therefore this protocol will continue to register all cases of mature teratoma to learn about the
associated morbidity, and will recommend a surveillance policy.

Table 1
Risk groups for extracranial malignant germ cell tumours (MGCTs)
Low Risk
Gonadal Stage 1 tumours (regardless of AFP level if secreting).
Boys who have inadvertently had an initial trans-scrotal biopsy but are otherwise Stage 1 can be
included in this group with very close follow-up (See Surgical Guidelines 8.2.1)
In general extragonadal tumours cannot be completely resected without mutilation. If total

resection is achieved and serum markers fall to normal these patients will be Stage 1 and
considered low risk
Intermediate Risk
Testis <5yrs, any AFP, Stage 2, 3 + 4
Testis > 5yrs, AFP < 10,000 kU/L, Stage 2 + 3
All other sites, AFP < 10,000 kU/L, Stage 2+3 except thoracic tumours
Pure germinoma/seminoma, any site, Stage 2, 3 + 4
Pure HCG secreting tumours, any HCG, Stage 2 + 3
High Risk
All Stage 4 tumours except testis < 5yrs and germinoma/seminoma
AFP > 10,000 kU/L except all Stage 1 tumours and testis < 5yrs Stage 2,3 + 4
All thoracic tumours, Stage 2,3 + 4

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FIGURE 1 FLOW SHEET – OVERVIEW OF MANAGEMENT OF GERM CELL TUMOURS
Imaging of primary tumour

Serum AFP + HCG
Tumour resectable Tumour unresectable
Biopsy (unless AFP/HCG raised

Resection preserving & biopsy hazardous)
major organs
Complete staging
Mature/immature Malignant GCT

teratoma only Mature/immature
Malignant GCT
teratoma only
Complete staging Complete staging
Further surgery if
feasible
Monitor AFP/HCG
Stage 1 Stage 2/3 Rising AFP
AFP normal
Stage 1 Stage 2-4 Assign risk group
AFP/HCG
Further surgery fall to normal
Observe if feasible Chemotherapy
Monitor AFP
Observe
Monitor AFP/HCG
Observe
Monitor AFP Residual tumour
Rising AFP/HCG No residual tumour
Further surgery if
Restage feasible
Observe Observe
Monitor AFP/HCG Monitor AFP/HCG
3. Patient Eligibility
3.1 Eligibility Criteria
i) Newly diagnosed extracranial malignant germ cell tumour or mature/immature

teratoma. All tumours must be histologically proven with or without raised
AFP/HCG. Exceptional cases with unequivocally raised AFP/HCG and where the
risk of biopsy is felt to be high can be diagnosed on clinical grounds, imaging and
markers.
ii) Patients with relapsed or progressing extracranial MGCT if previously treated with
JEB chemotherapy
iii) Age 0 – 18 years (i.e. up to but not including 18th birthday - but see Guidelines for
Adolescents Section 8.3.4)
iv) Blood count with neutrophil count > 1 x 109/L and platelet count > 100 x 109/L
v) Liver function: Bilirubin < 2 x upper limit laboratory normal
ALT < 3 x upper limit laboratory normal
vi) National and local ethical approval
vii) Written and verbal informed patient/parent consent
3.2 Exclusion Criteria
i) Pregnant or lactating females

ii) Intracranial GCTs
iii) Patients receiving prior chemotherapy other than JEB. Patients relapsing following
JEB are eligible for the relapse strategy (see above).
4. Investigations at diagnosis
i) Imaging Ultrasound of primary site
Chest X-Ray (CXR)
MRI/CT scan of primary site and regional nodes
CT scan lungs and liver
Bone scan
ii) Blood tests AFP and HCG

Full blood count
Urea, creatinine and electrolytes
Liver function tests
Calcium, magnesium and phosphate
Lactate dehydrogenase
Constitutional chromosome analysis – mediastinal and ovarian
primaries only
2ml EDTA and 5ml serum for future biological studies according to
UKCCSG Tumour Banking Protocol (98 BS05) if consent has been given
iii) Bone marrow aspirate and trephine if other metastatic disease is present
iv) CT/MRI scan of brain if indicated by symptoms/signs or if HCG > 10,000 IU

v) Glomerular filtration rate (GFR) – by plasma clearance of 51Cr EDTA or 51Cr DTPA
vi) Audiometry
vii) Lung function – in children old enough to co-operate
5. Histopathology
Germ cell tumours have previously been classified according to Dehner 1986 [20]. A recent
international meeting of pathologists involved with paediatric GCTs has agreed a slightly revised
classification (Table 2). For this protocol all tumours will be reported according to this
classification.
The classification of immature teratoma will be according to Dehner’s modification [20] of earlier
classifications [32,33] rather than the classification devised by Gonzalez-Crussi, 1982 [34].
Grading is scored from the slide with the largest amount of aggregated immature tissue. It should
also be noted whether there are microfoci of yolk sac tumour present as described by Heifetz [28].
Central pathology review will be requested on all patients entered into the study. Please send one
H&E slide and four unstained slides from all blocks taken.
If rapid review of histology is required this can be provided by direct contact with the study
pathology co-ordinators.
Future progress in the management of GCTs depends on clearer understanding of their biological
behaviour. Banking of tumour material is therefore strongly encouraged as part of the study, and
should be carried out in accordance with the UKCCSG Tumour Banking Protocol (98 BS05).
Tumour tissue excess to diagnostic requirements, should be snap frozen in liquid nitrogen and
stored, ideally in several pieces, at less than -50°C. Since mixed GCTs are unlikely to be
homogeneous in appearance, particular care should be taken in selecting tissue for banking.
Features suggestive of malignancy within mixed tumours include the presence of mucoid or
encephaloid areas, and proximity to sites of haemorrhage. In cases of doubt, and where material
allows, multiple sampling is recommended.
6. Staging
In order to facilitate comparisons between studies, a TNM staging system (Table 3) will be used
rather than the site specific systems used in previous studies.
The clinical/radiological stage should only be used for tumours diagnosed on markers and
imaging alone. For all other tumours, whether biopsied or initially resected, the post-surgical
stage should be used.
For tumours designated pT1 (Clinical Stage 1) it is essential that complete staging imaging has
been undertaken and is negative.
Ovarian tumours with capsular breach (pre-operatively or at the time of surgery) are Stage 2.
Ovarian tumours with ascites detected on imaging or at surgery and not sent for cytology are
assumed to be Stage 3. Ascites sent for cytology and found to be negative for malignant cells can
be ignored for staging purposes. Bilateral ovarian tumours are staged according to the individual
stage of each tumour.

Table 2
Revised Histological Classification of Germ Cell Tumours
I Germinoma a. Intratubular
b. Invasive
II Teratoma:
A Mature
B Immature Grade 1 Immature tissue <1 Low Power(x 4)

Field(LPF)/slide
Grade 2 Immature tissue 1-3 LPF/slide
Grade 3 Immature tissue >4 LPF/slide
(Common to each of these: +/-microfoci of
probable yolk sac tumour (Heifetz lesion [28]))
C Malignant teratoma (Teratoma with non germ cell malignant component)
III Embryonal carcinoma
IV Yolk sac tumour
V Choriocarcinoma
VI Gonadoblastoma
VII Mixed malignant germ cell tumour (each component to be listed)
NB GCTs with mixed malignant germ cell elements are now VII and not IIc/IId
as previously

Table 3
Staging for MGCTs at all sites - TNM Classification

Clinical/Radiological Staging Post Surgical Staging
(use in patients with no initial surgery) (use in patients with biopsy/initial surgery)
T: Primary Tumour T0 No primary tumour pT0 No tumour on histology

T1 Localised T<5cm pT1 Complete resection of localised tumour
T2 Localised T>5cm and <10cm pT2 Complete resection of a T4 tumour
T3 Localised T>10cm pT3 Residual tumour
T4 T of any size with locoregional pT3a microscopic ( +ascites for
extension ovarian tumours)
pT3b macroscopic
T5 Bilateral pT3c biopsy alone
Tx Unknown pTx Unknown
N: Regional lymph node N0 No lymph node involved pN0 No regional nodes

N1 Clinical or imaging node pN1 Involvement of regional nodes
involvement pN1a completely removed
Nx Unknown pN1b incompletely removed
pNx Unknown
M: Metastasis M0 No metastasis pM0 No metastasis

M1 Metastases present M1 Metastases present including distant
Including distant nodes nodes
(lumbar-aortic are loco-regional
for testicular tumours)
Mx Unknown Mx Unknown
Stages: Clinical Postsurgical
Stage 1 CSI T1 N0Nx M0 pSI pT1 pN0pNx pM0

Stage2 CSII T2T3 N0Nx M0 pSII pT1 pN1a pM0
pT2 pN0pNxpN1a pM0
Stage 3 CSIII T1,2,3 N1 M0 pSIII pT3b+c all pN pM0
and T4 any N M0 pT2 pN1b pM0
pT3a pN0pNxpN1a pM0
Stage 4 CSIV all T any N M1 PSIV all pT all pN pM1

7. Tumour Markers
AFP is a glycoprotein which probably functions as a fetal serum binding protein. It is produced by
the yolk sac and later by the fetal liver and gastrointestinal tract. Fetal serum AFP is highest in the
14th gestational week and subsequently falls. There is a wide range of AFP values at birth in normal
infants (Appendix A). The initial half life of AFP is 5 – 7 days but the rate of fall later decreases
because of continuing AFP production from the infant liver and gut. Even at 12 months of age
normal infants often have serum AFP values above the adult norm of <10 kU/L [40].
There are various units of AFP measurement. Values used to be reported in ng/ml but are now
reported in IU/ml or kU/L. Values reported in ng/ml can be converted to kU/L by multiplying by
0.84. Conversely kU/L can be converted to ng/ml by multiplying by 1.2. For Risk Group
allocation AFP will be measured in kU/L.
As a tumour marker AFP is produced by yolk sac tumour (endodermal sinus tumour), by yolk sac
elements within mixed malignant germ cell tumours and by some embryonal carcinomas and
immature teratomas.
HCG is a glycoprotein composed of α and β subunits which is normally produced by

syncytiotrophoblasts. Assay of the β subunit avoids cross reactivity with other hormones. The half
life of βHCG is 24 – 36 hours and the upper limit of normal is 5mIU/ml. Elevation of βHCG
implies the presence of syncytiotrophoblasts as in choriocarcinoma or syncytiotrophoblastic giant
cells as in germinoma or occasionally in adult embryonal carcinoma.
8. Treatment Strategy
8.1 Overview
All patients with extracranial GCT should have measurement of AFP and HCG and staging
investigations. In the absence of metastases an assessment of resectability should be made. Most
resectable tumours will be gonadal primaries. Unresectable tumours should have an initial biopsy.
Avoidance of mutilating surgery is essential and there may be occasional cases where the clinical
situation dictates diagnosis on imaging and markers only, for example mediastinal primaries or
patients with renal failure.
Delayed surgery can be considered for residual masses at the end of chemotherapy but the
philosophy of avoiding surgery with significant morbidity is important. Only 2 of 45 children
having delayed surgery in GCII had any viable malignant tumour, the rest having necrosis/fibrosis
or mature/immature teratoma [17]. Consideration should be given as to whether a strategy of close
follow-up with serum markers and imaging is more appropriate. If in doubt discuss with Chief
Investigator.
Histopathology should be classified according to Table 2. Stage should be allocated according

to the TNM system (Table 3).
Chemotherapy strategy will then be determined by the patient’s allocated Risk Group (Table
1).

8.2 Surgical Guidelines
8.2.1 Testicular tumours
Pre-operative Investigations
(1) Scrotal and abdominal ultrasound
(2) Ideally the results of serum AFP/HCG should be available but it is
recognised that exploration may be urgent given the differential diagnosis of
testicular torsion.
Operation
(1) Orchidectomy through an inguinal incision with radical orchidectomy and
high ligation of the spermatic cord. Scrotal orchidectomy is inappropriate.
Control of testicular vessels and vas deferens should be gained prior to
testicular mobilisation. Incision should be extended if there is a risk of
tumour rupture.
(2) If scrotal biopsy has inadvertently occurred, the scrotum is assumed to be
contaminated and the tumour is at least Stage 2. An inguinal orchidectomy
should be performed but hemi-scrotectomy is probably unnecessary. In the
absence of metastatic disease, the boy requires very careful follow-up of
serum markers and chemotherapy only if markers remain elevated or rise.
(3) If scrotal orchidectomy has inadvertently occurred and the proximal
spermatic cord is histologically free of tumour the tumour remains Stage 1 if
other staging investigations are negative and serum markers return to normal
for age.
If the cut end of the cord is infiltrated consider high inguinal excision of the
remainder but the tumour is at least Stage 2 and requires chemotherapy.
Hemiscrotectomy is not required.
(4) Retroperitoneal lymph node biopsy is rarely necessary for non-secreting
MGCTs if there are enlarged nodes >1cm on imaging and serum markers are
normal. If markers remain elevated the nodes are assumed to contain
tumour and the tumour is at least Stage 3. There is no indication for
retroperitoneal lymph node dissection.
8.2.2 Ovarian tumours
(1) Abdominal ultrasound or CT scan and Chest X-ray with assessment of
resectability in the absence of visible metastases.
(2) The results of serum AFP/HCG should usually be available.
Operation
(1) Collect ascitic fluid or perform a peritoneal wash. Send washings/ascitic
fluid for cytology.
(2) Biopsy any enlarged para-aortic node - do not attempt lymph node
dissection.
(3) Any peritoneal or omental nodule should be biopsied.
(4) The tumour should not be aspirated - if it is the tumour is at least Stage 2.
(5) The tumour should be biopsied if it is unresectable or if the patient has
obvious Stage 3 or 4 disease. Otherwise unilateral oophorectomy should be
performed.

(6) If the contralateral ovary is normal do not biopsy. If there is a contralateral
nodule it should be biopsied.
(7) If there are obvious bilateral tumours an initial wedge biopsy of one tumour
should be performed. The patient should have second look surgery after
chemotherapy. At this stage conservative surgery may be possible -
specialist consultation is advised. If the patient is known to have XY gonadal
dysgenesis bilateral oophorectomy (gonadectomy) should be performed.
8.2.3 Sacrococcygeal tumours
(1) Serum AFP/HCG should be available. In neonates AFP is normally elevated
by adult standards - see Appendix A - and does not necessarily indicate
malignant histology. However a baseline level is useful for follow-up.
(2) MRI is the best imaging modality for tumours at this site but CT is
acceptable. Particular attention should be given to determining whether there
is intraspinal extension of the tumour.
Operation
(1) Neonates - the majority of tumours will be mature or immature teratomas.
Complete surgical excision with coccygectomy en-bloc is required. For very
large tumours consider laparotomy and early control of the median sacral
vessels, use of aprotinin or possible cardiopulmonary bypass support -
specialist advice is recommended.
Oncological follow-up with regular measurement of serum AFP at least 2/3
monthly for 3 years is essential, as approximately 14% tumours will recur as
a malignant GCT [39].
(2) Older children - the majority of these tumours will be malignant.
If serum markers are elevated at diagnosis an initial biopsy should be
performed and delayed resection with coccygectomy should take place at the
end of chemotherapy as long as marker levels fall appropriately. Mutilating
surgery should be avoided.
If serum markers are normal at diagnosis complete surgical excision with
coccygectomy en-bloc should be attempted. Before surgery the case should
be discussed with the Chief Investigator - initial biopsy may be appropriate.
8.2.4 Mediastinal/Thoracic tumours
(1) Serum AFP/HCG should be available
(2) CT scan of chest
Operation
(1) If serum markers are unequivocally elevated (see normal range in young
children – Appendix A) and clinical situation allows, give chemotherapy
without biopsy. If there are respiratory problems with O2 requirement
chemotherapy may be modified – see Prescribing in Respiratory
Compromise (Section 8.7). Delayed resection should take place at the end of
planned chemotherapy if serum markers are falling appropriately.
(2) If markers are normal at diagnosis surgical complete excision should be
performed if possible via lateral thoracotomy or median sternotomy,

otherwise biopsy should be performed. Enlarged regional nodes should be
biopsied.
8.2.5 Vagina/Uterus
(1) Serum AFP/HCG should be available
(2) MRI scan of pelvis
Operation
(1) Tumours in these sites are almost invariably yolk sac histology with elevated
AFP. Biopsy only should take place at diagnosis. Following chemotherapy,
if imaging reveals a residual mass still present, examination under
anaesthetic should be performed with non-mutilating surgery if feasible. If
resection would be mutilating a biopsy and strategy of close follow-up with
serum markers is appropriate if biopsy shows no viable tumour. If viable
tumour is present discuss with Chief Investigator.
8.2.6 Other sites
(1) Serum AFP/HCG
(2) Imaging of primary site
Operation
(1) Complete excision where feasible without damage to adjacent structures.
Otherwise biopsy and delayed resection following chemotherapy if possible.
8.2.7 Relapse
(1) Histological confirmation of relapse is necessary for non-secreting tumours.
8.3 Management according to Risk Group
Using histology, AFP level, stage, tumour site and age the patient should be allocated to one of the
three Risk Groups (see Table1).
Any patient without initial histology should be allocated a Risk Group on marker levels, site and
stage. Any patient where first AFP level is post initial surgery and < 10,000 should be allocated a
Risk Group according to site, histology and stage only.
8.3.1 Low risk
Patients in this group have Stage 1 fully resected MGCTs confirmed by histological examination.
Most patients will have gonadal primaries. Staging investigations will have revealed no residual or
metastatic disease. Ovarian primaries with unsampled ascites are Stage 3 and pre/intraoperative
rupture are Stage 2. Testicular tumours with inadvertent initial scrotal biopsy, which are otherwise
Stage 1, can be allocated to the Low Risk group.

Post-operatively serum markers (AFP/HCG) should be checked weekly until normal and then
every 4 weeks. Note that ‘normal’ AFP may be high for children under 2 years old (see Appendix
A for normal values <2yrs).
These patients receive no chemotherapy initially.
If serum markers subsequently rise and/or imageable tumour recurs patients should be treated
according to risk group at relapse.
Patients with rising serum markers only and no imageable disease should be treated as
Intermediate Risk.
It is important to be certain serum markers are definitely rising before starting chemotherapy,
particularly in younger children with AFP<100 where fluctuations can occur. If in doubt, discuss
with Chief Investigator.
8.3.2 Intermediate risk
These patients should receive a total of 4 courses of JEB at 21 day intervals. They should no
longer receive the number of courses to achieve normalisation of markers + 2.
Four courses of JEB will be sufficient to achieve ‘normal’ or ‘normal for age’ markers for levels
below approximately 900,000 kU/L at diagnosis when the rate of fall is appropriate (see Appendix
A for normal values <2yrs).
If AFP level has not quite returned to normal for age after 4 courses continue to monitor levels
weekly as it is likely they will continue to fall. If levels remain elevated, or do not fall
appropriately, discuss with Chief Investigator.
If a residual mass is present after 4 courses of JEB and marker levels are normal, second look
surgery should be considered if non-mutilating resection is thought to be possible.
8.3.3 High Risk
This group of patients should receive a total of 6 courses of JEB at 21 day intervals. They should
no longer receive the number of courses to achieve normalisation of markers + 2.
In the unlikely situation that AFP level has not quite returned to normal for age after 4 courses
continue to monitor levels weekly as it is likely they will continue to fall. If levels remain elevated
discuss with Chief Investigator.
If a residual mass is present at the end of chemotherapy, second look surgery should be considered
if non-mutilating resection is thought to be possible.
8.3.4 Recommendations for adolescents
Although carboplatin appears to be as effective as cisplatin in MGCTs in the paediatric population

there remains some doubt about its equivalence in adult MGCTs [14-16]. In the absence of a
randomised study using carboplatin AUC 7.9 in adults it is probably appropriate in adolescent
patients with more typically adult MGCTs eg pure choriocarcinoma, embryonal carcinoma or
seminoma to use established cisplatin strategies with BEP. Please discuss such patients with the
Chief Investigator.

8.4 Chemotherapy Administration
8.4.1 Details of Chemotherapy
Courses of chemotherapy will be given at 21 day intervals when neutrophils > 1 x 109/L and
platelets > 100 x 109/L.
In patients without haematological recovery at 21 days the next course should be delayed
until recovery, this will usually be less than a week.
Each course of JEB will be as follows (See Appendix D for Flow Sheet ):
Day 1 Etoposide 120mg/m2 IV over 4 hours at a concentration of 0.25 – 0.4 mg/ml

in 0.9% saline
Day 2 Etoposide as Day 1

Carboplatin IV over 1 hour in 50 – 100mls of 5% Dextrose
Dose calculated from body weight (kg) and t1/2 (half life) of 51CrEDTA or
51
CrDTPA clearance based on the modified Calvert formula [42] – see
Tables in Appendix B. These tables give the Day 2 dose of Carboplatin in
mg calculated to give an AUC of 7.9mg/ml.min
If GFR measurement not feasible use Carboplatin 600mg/m2 IV
Day 3 Etoposide as Day 1

Bleomycin 15mg/m2 IV infusion over 30mins
8.5 Measurement of GFR
An isotope method should be used for GFR estimation, either 51Cr EDTA or 51Cr DTPA clearance
with 3 sampling times. The half-life of isotope clearance is used to calculate the carboplatin dose
and is a more repeatable and direct measure than GFR as it does not involve the potential
inaccuracies in estimating volume of distribution. Oedema and dehydration may introduce errors in
assessing renal function.
EDTA clearance is preferred. The half life of DTPA clearance can be used and should be directly
equivalent to EDTA half life although it is important to check that the isotope formulation used by
the local Medical Physics department is designed for GFR estimation as some formulations are
protein bound and will underestimate clearance.
If there is any doubt about the accuracy of the GFR eg unexpectedly low (<60) or high (>180), the
result should be discussed with the local Medical Physics department. If the result is felt to be
unreliable carboplatin should be prescribed on surface area at 600mg/m2 and GFR reassessed prior
to the next course.
The use of creatinine clearance to calculate GFR is discouraged due to potential inaccuracies,
particularly in patients under 3 years old.

8.6 Patients with Renal Failure
Rare patients, especially those with pelvic germ cell tumours have significant renal impairment at
presentation due to ureteric obstruction. In this situation it is still appropriate to use carboplatin but
it is essential to use GFR based prescribing. If renal impairment is sufficiently severe to require
dialysis carboplatin can still be used with pharmacokinetic AUC monitoring (discuss with Chief
Investigator).
As renal impairment enhances bleomycin pulmonary toxicity, bleomycin should be omitted and
replaced by vincristine 1.5mg/m2 (max 2mg) IV bolus on Day 3 if GFR <60 ml/min/1.73m2. If
renal impairment recovers bleomycin can be reintroduced.
8.7 Patients with Respiratory Compromise
Occasional patients, particularly those with thoracic tumours, will have respiratory difficulty and
require O2 therapy. As there is a potential risk of enhanced bleomycin lung toxicity in patients with
respiratory problems, it is suggested that the dose of bleomycin on Day 3 is replaced by vincristine
1.5mg/m2 (max 2mg) IV bolus on Day 3 for the first course of JEB. Bleomycin should be given in
subsequent courses when the respiratory distress has resolved.
8.8 Infant Dose Adjustments
Doses for children <12 months of age
Carboplatin should be prescribed according to body weight and t1/2 EDTA clearance
according to Appendix B.
Etoposide and bleomycin doses should be adjusted according to the following guidelines:
Starting doses: For children <6 months of age 50% of calculated dose by body
surface area
For children 6 months - 1 year of age 75% of calculated dose by
body surface area
Under the age of 1 year doses can be increased (to a maximum of 100%) according to
tolerance at the treating clinician’s discretion.
Body surface area should be calculated using body weight as recommended by the
UKCCSG Chemotherapy Standardisation Group in 1998.
9. Investigations during treatment

i) FBC -before each course of chemotherapy and as clinically
indicated
ii) Electrolytes -before each course of treatment and as clinically

Liver function indicated
Bone chemistry
Magnesium
iii) AFP/HCG - if elevated at diagnosis monitor weekly until normal for age

and then before each course of JEB. Marker levels should be
plotted on a logarithmic plot (see Study Data Forms) and
monitored for appropriate rate of fall.
iv) GFR - for Intermediate Risk Group use baseline GFR to prescribe
all 4 courses of JEB unless renal impairment secondary to
tumour is present at diagnosis. In this case recheck GFR after
1 or 2 courses as indicated.
-for High Risk Group recheck GFR after 3 courses unless
renal impairment is present, when manage as above.
v) Audiology -for High Risk Group recheck hearing after 3 courses of JEB
-for Intermediate Risk Group recheck hearing at end of
chemotherapy.
vi) Imaging -on therapy imaging is usually only indicated for patients
with non-secreting tumours, when previous sites of tumour
should be assessed after every 2 courses of JEB. Imaging is
also indicated for patients with secreting tumours if marker
levels do not fall appropriately.
10. Investigations at end of, and following, treatment

i) AFP/HCG -at end of therapy then monthly for 1 year, 2 monthly for
2nd year and 3 monthly for 3rd year in secreting tumours
ii) Imaging -at end of therapy MRI or CT of primary site and all other sites
involved at diagnosis
-for non secreting MGCTs ultrasound of primary site and CXR 3
monthly for 2 years
-for tumours with mature/immature components appropriate imaging
6 monthly
iii) Bone Scan -if positive at diagnosis
iv) Bone marrow -if involved at diagnosis
v) GFR -at end of therapy. Repeat at 1 year and 5 years if abnormal for age at
end of therapy.
vi) Audiology -at end of therapy. For patients < 5 years at end of therapy repeat
when old enough for accurate assessment.
vii) Lung Function -at end of therapy and 5 years if able to co-operate
(usually > 8 yrs old)
viii) Blood pressure -at end of therapy and annually

11. Radiotherapy
Radiotherapy is not an integral part of the management of extracranial germ cell tumours of
childhood. It may however be useful for the occasional patient with relapsed tumour.
Dysgerminoma of the ovary and seminoma of the testis are exquisitely radio-sensitive and large
tumours would be expected to regress with only modest doses of radiation (20 - 40 Gy). This may
allow radiotherapy to sites that are usually considered unsuitable for radiotherapy, eg lungs and
liver.
Those tumours with secreting or teratomatous elements are more radio-resistant (40 – 45 Gy), but
in the rare patient who has end stage disease radiotherapy may help painful bone metastases or
spinal cord compression.
Discussion about individual patients should be directed to the Study Radiotherapy Co-ordinator.
12. Statistical considerations

12.1 Accrual
On the basis of the accrual rate onto GC II it is anticipated 20 patients per year would be included
in the study. In 5 years, 100 patients in all could be treated according to GC III. More patients may
be recruited from non-UKCCSG centres.
As with GC II, this would enable overall survival and event free survival rates to be estimated to
within 6% (95% confidence interval).
In order to ensure that event free survival is maintained at the level of GC II interim monitoring is
to take place for the stratified patient risk groups.
12.2 Low risk patients
On the basis of the accrual rate onto GC II it is anticipated 10 patients per year would be included
in the low risk group of patients. In 5 years, 50 patients could be treated according to this protocol.
12.2.1 Stopping rule
The protocol treatment for low risk patients is the same as before, but the relapse rate will be
monitored, with a stopping rule to prevent an excess of relapses or progressions in these patients.
The rule is based on monitoring the 12-month event rate - an event being defined as relapse,
progression or death. The observed rate in the previous study is considered to be an acceptable one.
Five interim analyses will take place at intervals when 20%, 40%, 60%, 80% and 100% of the
patients will potentially have 1 year of follow up. The rule is based on the Fleming multi-stage
procedure [41].
The boundaries have been set taking a 12 month event rate ≤ 25% to be acceptable and requiring a
power of 84% to detect a 12 month event rate of ≥ 40%. The α error risk i.e. the probability of
stopping the trial with a true event rate ≤ 25% is 0.10.

After the first 10 patients are included in the study with a minimum of 12 months’ follow up,
analysis will be carried out. The stopping boundary will be crossed if 7 or more than 7 events are
observed (observed event rate 70%).
If 6 or fewer than 6 events are observed accrual will continue and a second analysis will be carried
out when a further 10 patients are included in the study and have a minimum of 12 months’ follow
up. The stopping boundary will be crossed if 10 or more than 10 events are observed (observed
event rate 50%).
If 9 or fewer than 9 events are observed accrual will continue and a third analysis will be carried
event rate 40%).
If 11 or fewer than 11 events are observed accrual will continue and a fourth analysis will be
carried out when a further 10 patients are included in the study and have a minimum of 12 months’
follow up. The stopping boundary will be crossed if 15 or more than 15 events are observed
(observed event rate 38%).
If 14 or fewer than 14 events are observed accrual will continue and a final analysis will be carried
out when the 50 patients are included in the study and have a minimum of 12 months’ follow up.
The relapse rate would be significantly higher than before if 17 or more than 17 events are
12.3 Intermediate risk patients
On the basis of the accrual rate onto GC II it is anticipated 4 patients per year would be included in
the intermediate risk group of patients. In 5 years, 20 patients could be treated according to the
protocol.
The reduction in the number of courses of chemotherapy may lead to a higher relapse rate and so a
stopping rule to prevent an excess of relapses or progressions in patients entering the study will be
used. The rule, as for low risk patients, is based on monitoring the 12-month event rate. The
observed rate, or less, in the previous study is considered to be an acceptable one.
Five interim analyses will take place as before. The boundaries have been set taking a 12 month
event rate ≤ 6% to be acceptable and requiring a power of 80% to detect a 12 month event rate of ≥
26%. The α error risk i.e. the probability of stopping the trial with a true event rate ≤ 6% is 0.03.
analysis will be carried out. The stopping boundary will be crossed if 3 or more than 3 events are
up. The stopping boundary will be crossed if 3 or more than 3 events are observed (observed event
rate 38%)

rate 25%).
If 2 or fewer than 2 events are observed accrual will continue and a fourth analysis will be carried
rate 19%).
The relapse rate would be significantly higher than before if 4 or more than 4 events are observed
12.4 High risk patients
On the basis of the accrual rate onto GC II it is anticipated 7 patients per year would be included in
the high-risk group of patients. In 5 years, 35 patients could be treated according to the protocol.
The protocol treatment for high-risk patients is similar to before, but the relapse rate will be
monitored, with a stopping rule to prevent an excess of relapses or progressions in these patients.
The rule is based on monitoring the 12-month event rate. The observed rate in the previous study is
considered to be acceptable.
The boundaries have been set taking a 12 month event rate ≤ 30% to be acceptable and requiring a
power of 84% to detect a 12 month event rate of ≥ 50%. The α error risk i.e. the probability of
stopping the trial with a true event rate ≤ 30% is 0.07
analysis will be carried out. The stopping boundary will be crossed if 7 events are observed
rate 64%).
event rate 52%).
If 10 or fewer than 10 events are observed accrual will continue and a fourth analysis will be
carried out when a further 7 patients are included in the study and have a minimum of 12 months’
follow up. The stopping boundary will be crossed if 13 or more than 13 events are observed

The relapse rate would be significantly higher than before if 15 or more than 15 events are
13. Recommendations for Relapsed and Refractory Tumours

13.1 Overview of Treatment Strategy
There is currently no defined second line chemotherapy strategy for relapsed paediatric MGCTs.
The aim of this protocol is to develop appropriate relapse chemotherapy in the context of first line
JEB chemotherapy. It is recommended that patients are treated with vinblastine, ifosfamide and
cisplatin for a total of 6 courses. It also seems to be important in relapse patients to attempt
resection of residual masses where possible [27]. With a unified chemotherapy strategy it is hoped
to learn more about the factors that contribute to successful salvage.
These recommendations do not apply to patients with MGCTs who relapse having had initial
surgery only and a ‘watch and wait’ strategy. These patients should be treated with JEB according
to their Risk Group at relapse.
13.2 Investigations at relapse

1) Histological confirmation of relapse should be obtained and is mandatory for non-
secreting tumours.
2) AFP/HCG when relapse is suspected from rising serum markers care should be taken to
confirm that markers continue to rise rather than fluctuating - this is particularly true for
AFP<100 and young children. If in doubt discuss with Chief Investigator.
3) Radiology MRI or CT of all sites of recurrence

CT chest
Bone scan
4) Bone marrow aspirate and trephine
5) A relapse stage should be allocated according to (3) and (4)
6) Audiometry
7) Glomerular filtration rate (GFR) – by plasma clearance of 51Cr EDTA or

51
Cr DTPA. Baseline GFR should be >60ml/min/1.73m2 at start of relapse therapy - if not
discuss with Chief Investigator.
8) Renal tubular function using paired plasma and urine samples for phosphate and creatinine
to calculate Tmp/GFR
Tmp/GFR(µmol/ml.min) = Plasma PO4 – [Urine PO4 x Plasma creatinine]

Urine creatinine
9) FBC
10) Biochemical screen including magnesium

13.3 Details of Chemotherapy
Patients with relapsed MGCT will be treated with courses of vinblastine, ifosfamide and cisplatin
(VeIP) given at 21 day intervals with G-CSF support at clinician’s discretion. Because this
chemotherapy is potentially ototoxic and nephrotoxic in patients who have already received JEB
the drugs will be given over 5 days to minimise toxicity. Patients will be given 6 courses of VeIP.
Chemotherapy will be given when neutrophils > 1 and platelets > 100. If haematological recovery
has not occurred delay chemotherapy until FBC is satisfactory, usually less than a week.
13.3.1 Chemotherapy Administration (see Appendix D for Flow Sheet )
Ve Vinblastine 3mg/m2 Day 1 + 2

I Ifosfamide 1.5gm/m2 Day 1 - 5
P Cisplatin 20mg/m2 Day 1 - 5
A double lumen central venous line is necessary for administration of this chemotherapy.
Day 1 Line 1 T0 Vinblastine 3mg/m2 IV bolus

Commence hydration with 0.45% saline/2.5% dextrose at
200ml/m2 with Mesna 250mg/m2 for 3 hours
T+3 Ifosfamide 1.5gm/m2 over 1 hour Y-connected to

Mesna hydration
Change hydration to 0.45% saline/2.5% dextrose + 20mmol
KCl/L at 1L/m2/24hrs with Mesna 1.8gm/m2/24hrs and run
continuously until a minimum of 12hrs after final dose of
Ifosfamide
Line 2 T+3 Commence Cisplatin infusion

Cisplatin 20mg/m2/24hrs in 0.45% saline/2.5% dextrose at
2L/m2/24hrs with KCl 20mmol/L, magnesium sulphate
5mmol/L and Ca gluconate 0.6mmol/L
Day 2 As Day 1
Day 3 As Day 2 No Vinblastine
Day 4 As Day 3
Day 5 As Day 4
Day 6 Line 2 T+123 Commence Cisplatin post-hydration for 24hrs

With 0.45% saline/2.5% dextrose at 2L/m2/24hrs with KCL
20mmol/L, magnesium sulphate 5mmol/L, Ca gluconate
0.6mmol/L, 6gm mannitol/L
13.4 Infant dose adjustments
Infants <1 year are unlikely to require relapse chemotherapy.

However in this event doses should be adjusted:
Starting doses: For infants <6 months of age 50% of calculated dose by body
surface area

For infants 6 months - 1 year of age 75% of calculated dose
by body surface area
Under the age of 1 year these doses can be increased (to a maximum of 100%) according to
tolerance at the discretion of the treating clinician.
13.5 Investigations during treatment
1) FBC -before each course of chemotherapy and as clinically indicated
2) Electrolytes -prior to each course of chemotherapy and as indicated

Liver function
Bone chemistry
Magnesium
3) AFP/HCG -weekly until normal for age then pre each course of chemotherapy
4) Tmp/GFR -before each course of chemotherapy
5) GFR -after 3 courses of VeIP and at end of therapy,

if < 60ml/min/1.73m2 discuss with Chief Investigator
6) Audiometry -after 3 courses and at end of therapy
7) Radiology -all sites of tumour should be imaged after 2 courses and at end of
therapy for non-secreting tumours
-if AFP/HCG are not falling as expected all sites of disease should be
imaged
-for secreting tumours with appropriately falling AFP/HCG all sites of
tumour at relapse should be imaged at end of therapy
8) Bone marrow -re-assess after 2 courses and at end of therapy if involved at relapse
13.6 Surgery
If a residual tumour mass remains at the end of chemotherapy, surgical resection should be
considered. Although it is important not to undertake surgery that will result in significant
morbidity it is possible that surgery to improve local control has an important role in relapsed
patients particularly in some sites e.g. sacrococcygeal [27].
13.7 Refractory Disease
Patients with refractory disease, i.e. failure of serum markers to fall appropriately on relapse
therapy, should be discussed with Chief Investigator – use of paclitaxel, dose intensification of
cisplatin and/or high dose chemotherapy with stem cell support may be indicated. There may also
be a role for radiotherapy in some cases.
14. Toxicity Monitoring

Toxicity will be graded according to the Common Toxicity Criteria (CTC V2.0) with the exception
of ototoxicity which will be reported according to Brock grading (Appendix C). Some Grade 3/4
CTC toxicity is expected eg myelosuppression and possibly mucositis on relapse chemotherapy.
However any unexpected Grade 3/4 CTC toxicity or other Serious Adverse Event should be
immediately (i.e. within 24 hours of knowledge of the event) reported by fax to the UKCCSG
Data Centre and it will then be relayed to the Chief Investigator.
14.1 Serious Adverse Events
A Serious Adverse Event is any untoward medical occurrence that, at any dose:
1) Is fatal (results in death, except tumour progression/relapse)

2) Is life-threatening
3) Requires unexpected in-patient hospitalisation or prolongation of existing
hospitalisation
4) Results in persistent or significant disability/incapacity or congenital anomaly/birth
defect
5) Any Grade 3 or 4 renal, pulmonary or ototoxicity.
6) Any other unexpected Grade 3 or 4 CTC toxicity.
7) Any second malignant neoplasm
15. Recommendations for Immature Teratoma

Surgery is the mainstay of treatment for immature teratoma. Studies from Germany, USA and Italy
[29,36,38] and the recent publication from GC II [37] have shown immature teratoma is almost
always cured with surgery alone. For patients with ovarian primaries, a common site for this
histology, there may be secondary deposits of immature teratoma around the abdominal cavity
which are often not suspected pre-operatively. These deposits should also be removed at initial
surgery if possible or at least biopsied. Second look surgery with the aim of resecting any deposits
of immature teratoma may be necessary once the histology has been confirmed. Associated
gliomatosis peritonei does not need resecting.
The significance of moderately elevated AFP levels in immature teratoma is controversial. AFP
staining can be associated with immature endodermal elements within these tumours and may not
indicate a malignant element [29]. At present it is probably reasonable to recommend that if AFP at
diagnosis is less than 1000 kU/L in a patient with immature teratoma, AFP levels should be
followed weekly until normal following surgery. This strategy includes patients with Clinical Stage
>1 although second look surgery may be necessary if imaging shows a progressing deposit or
rising AFP.
Following surgery patients should be followed closely with appropriate imaging, ideally ultrasound
3 monthly and monitoring of AFP and HCG 4-6 weekly. If tumour regrowth is detected further
resection should be attempted unless tumour markers are significantly elevated when initial JEB
chemotherapy is appropriate.
Patients with immature teratoma and AFP > 1000 at diagnosis should be treated as MGCT with
JEB chemotherapy according to their Risk Group. Patients with non germ cell malignant elements
should receive chemotherapy directed to the type of non germ cell malignancy eg Ewings
chemotherapy for PNET.
Difficult problems can be discussed with the Chief Investigator.

16. Recommendations for Mature Teratoma
Mature teratoma is the commonest sub-type of childhood GCT and occurs at gonadal and
extragonadal sites. Typically mature teratoma is seen in neonates in the sacrococcygeal region, in
infant boys in the testis, in the head and neck region in young children then in the ovary of
peripubertal girls and the mediastinum of older children and adolescents. Because not all cases of
mature teratoma are registered the true incidence and risk of recurrence is not completely known
but is probably site dependent.
The risk of recurrence seems to be highest for sacrococcygeal tumours resected in the neonatal
period where the risk is of the order of 10-14% [39]. The recurrent tumour is generally yolk sac.
Recurrence also occurs at other sites where complete resection is difficult e.g. head and neck. The
timing of recurrence can be as late as 3 years after original resection. Recurrence can be of
teratoma locally or occasionally in draining nodes or it can be MGCT.
The Germ Cell Working Group would like to establish the natural history of mature teratoma and
the true risk of recurrence. Encouragement is given to registration of all cases of mature teratoma.
Mature teratoma requires complete surgical resection. Ideally AFP and HCG should be measured
prior to resection. If marker levels are elevated prior to surgery then the patient should be managed
and followed as MGCT even if mature teratoma is the only histology seen at resection. In neonatal
tumours in the sacrococcygeal region where AFP levels are physiologically elevated and difficult
to interpret, MGCT at presentation is extremely unlikely. For immature teratoma see Section 15.
Follow up should consist of measurement of AFP levels 6 – 8 weekly for the first year, 2 monthly
for the second year and 3 monthly for the third year. The exception to this is completely resected
gonadal mature teratomas where AFP/HCG were known to be normal prior to or immediately
following surgery. In this case early postoperative follow-up only is appropriate. Teratomas known
to be incompletely resected should be imaged every 3 months for 3 years.
If a mature teratoma recurs management should be as MGCT if markers are raised for age or
should be further resection if markers are normal.

17. References
1. Einhorn L, Donohue J. Cisdiamminedichloroplatinum, vinblastine and bleomycin
combination chemotherapy in disseminated testicular cancer. Ann Intern Med 1977; 87:
293-298
2 Exelby PR. Testicular cancer in children. Cancer 1980; 45: 1803-1809
3 Ablin A, Krailo M, Ramsay NK. Results of treatment of malignant germ cell tumours in 93
children: A report from the Children’s Cancer Study Group. J Clin Oncol 1991; 9: 1782-
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14 Bajorin DF, Sarosdy MF, Pfister DG et al. Randomised trial of etoposide and cisplatin
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17 Mann JR, Raafat F, Robinson K et al. The United Kingdom Children’s Cancer Study
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cyclophosphamide for patients with refractory germ cell tumours: Treatment results and
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29 Marina NM, Cushing B, Giller R et al. Complete surgical excision is effective treatment for
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237-246
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Oncol 1998; 31: 8-15
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323

Appendix A:
Serum AFP values in normal term babies

(from Blohm et al: Klinische Padiatre 1991; 203: 246)
Age (days) Mean AFP (ng/ml) AFP 95.5% range(ng/ml)

0 41,687 9,120 – 190,546
1 36,391 7,943 – 165,959
2 31,769 6,950 – 144,544
3 27,733 6,026 – 125,893
4 24,210 5,297 – 109,648
5 21,135 4,624 – 96,605
6 18,450 4,037 – 84,334
7 16,107 3,524 – 73,621
8-14 9,333 1,480 – 58,887
15-21 3,631 575 – 22,910
22-28 1,396 316 – 6,310
29-45 417 30 – 5,754
46-60 178 16 – 1,995
61-90 80 6 – 1,045
91-120 36 3 – 417
121-150 20 2 – 216
151-180 13 1.25 – 129
181-720 8 0.8 – 87
Note: AFP values in this table are in ng/ml. Most AFP values are now reported in kU/L. To
convert ng/ml to kU/L multiply by 0.84. To convert kU/L to ng/ml multiply by 1.2.

Appendix B:
Carboplatin Dose Tables
The tables on the following two pages give the dose of carboplatin in mgs to be administered on
Day 2 of JEB chemotherapy. The dose is calculated using the patient’s weight in kg and the t1/2
(mins) of the EDTA GFR by the following formula [42]:
Dose(mg) = AUC (mg/ml.min) x { [ 0.693 / t ½ (min)] x [ 0.52 x ( 843 x body weight (kg)0.891)] +
( 0.36 x body weight (kg)) }

AUC 7.9 mg/ml.min Dose of Carboplatin in mg. Appendix B
Half life EDTA (min)

Body Wt (kg) 40 45 50 55 60 65 70 75 80 85 90 95 100 110 120 130 140 150 160
5 266 238 216 197 182 169 158 148 140 133 126 120 115 106 98 92 86 81 77
5.5 290 259 235 215 198 184 172 162 153 145 137 131 125 115 107 100 94 89 84
6 313 280 254 232 214 199 186 175 165 156 149 142 136 125 116 108 102 96 91
6.5 336 301 273 250 230 214 200 188 177 168 160 152 146 134 124 116 109 103 98
7 360 322 292 267 246 229 214 201 190 180 171 163 156 143 133 124 117 110 105
7.5 383 342 310 284 262 244 228 214 202 191 182 173 166 153 142 132 125 118 112
8 405 363 329 301 278 258 241 227 214 203 193 184 176 162 150 140 132 125 118
8.5 428 383 347 318 293 273 255 240 226 214 204 194 186 171 159 148 140 132 125
9 451 403 366 335 309 287 268 252 238 226 214 205 196 180 167 156 147 139 132
9.5 473 423 384 351 324 301 282 265 250 237 225 215 205 189 176 164 154 146 139
10 495 443 402 368 340 316 295 277 262 248 236 225 215 198 184 172 162 153 145
11 539 483 438 401 370 344 322 302 285 270 257 245 235 216 201 188 176 167 158
12 583 522 473 434 400 372 348 327 309 293 278 265 254 234 217 203 191 181 171
13 627 561 509 466 430 400 374 351 332 314 299 285 273 251 234 218 205 194 184
14 670 600 544 498 460 428 400 376 355 336 320 305 292 269 250 234 220 208 197
15 713 638 579 530 489 455 425 400 378 358 340 325 311 286 266 249 234 221 210
16 755 676 613 562 519 482 451 424 400 379 361 344 329 304 282 264 248 235 223
17 797 714 648 593 548 509 476 448 423 401 381 364 348 321 298 279 262 248 236
18 839 752 682 624 577 536 502 472 445 422 401 383 366 338 314 294 276 261 248
19 881 789 716 655 605 563 527 495 468 443 422 402 385 355 330 308 290 275 261
20 923 826 749 686 634 590 552 519 490 464 442 421 403 372 345 323 304 288 273
21 964 863 783 717 662 616 576 542 512 485 462 440 421 388 361 338 318 301 286
22 1005 900 816 748 691 642 601 565 534 506 481 459 440 405 377 353 332 314 298
23 1046 937 850 778 719 669 626 588 556 527 501 478 458 422 392 367 346 327 311
24 1087 973 883 809 747 695 650 611 577 547 521 497 476 439 408 382 359 340 323
25 1127 1010 916 839 775 721 675 634 599 568 540 516 494 455 423 396 373 353 335
26 1168 1046 949 869 803 747 699 657 621 589 560 534 511 472 438 410 386 366 347
27 1208 1082 982 899 831 773 723 680 642 609 579 553 529 488 454 425 400 378 360
28 1248 1118 1014 929 858 799 747 703 664 629 599 572 547 504 469 439 413 391 372
29 1288 1154 1047 959 886 824 771 725 685 650 618 590 565 521 484 453 427 404 384
30 1328 1190 1079 989 914 850 795 748 706 670 637 608 582 537 499 468 440 417 396
31 1367 1225 1112 1018 941 875 819 770 728 690 657 627 600 553 515 482 454 429 408
32 1407 1261 1144 1048 968 901 843 793 749 710 676 645 617 570 530 496 467 442 420
33 1446 1296 1176 1077 995 926 867 815 770 730 695 663 635 586 545 510 480 455 432
34 1486 1331 1208 1107 1023 951 890 837 791 750 714 682 652 602 560 524 494 467 444
AUC 7.9 mg/ml.min

Half life EDTA (min)
Body Wt (kg) 40 45 50 55 60 65 70 75 80 85 90 95 100 110 120 130 140 150 160
35 1525 1366 1240 1136 1050 977 914 860 812 770 733 700 670 618 575 538 507 480 456
36 1564 1401 1272 1165 1077 1002 938 882 833 790 752 718 687 634 590 552 520 492 468
37 1603 1436 1303 1194 1104 1027 961 904 854 810 771 736 704 650 604 566 533 505 480
38 1642 1471 1335 1223 1130 1052 984 926 875 830 790 754 722 666 619 580 546 517 491
39 1680 1506 1367 1252 1157 1077 1008 948 896 850 808 772 739 682 634 594 559 529 503
40 1719 1541 1398 1281 1184 1102 1031 970 916 869 827 790 756 698 649 608 572 542 515
41 1758 1575 1429 1310 1211 1126 1054 992 937 889 846 808 773 713 664 622 585 554 527
42 1796 1610 1461 1339 1237 1151 1078 1014 958 908 865 825 790 729 678 635 598 567 539
43 1834 1644 1492 1368 1264 1176 1101 1035 978 928 883 843 807 745 693 649 611 579 550
44 1873 1679 1523 1396 1290 1201 1124 1057 999 948 902 861 824 761 708 663 624 591 562
45 1911 1713 1554 1425 1317 1225 1147 1079 1019 967 920 879 841 776 722 677 637 603 574
46 1949 1747 1585 1453 1343 1250 1170 1101 1040 986 939 896 858 792 737 690 650 616 585
47 1987 1781 1616 1482 1369 1274 1193 1122 1060 1006 957 914 875 808 751 704 663 628 597
48 2025 1815 1647 1510 1396 1299 1216 1144 1081 1025 976 932 892 823 766 718 676 640 609
49 2063 1849 1678 1538 1422 1323 1239 1165 1101 1045 994 949 909 839 781 731 689 652 620
50 2101 1883 1709 1567 1448 1347 1261 1187 1121 1064 1013 967 926 854 795 745 702 664 632
51 2138 1917 1740 1595 1474 1372 1284 1208 1142 1083 1031 984 942 870 809 758 715 677 643
52 2176 1951 1770 1623 1500 1396 1307 1230 1162 1102 1049 1002 959 885 824 772 727 689 655
53 2214 1984 1801 1651 1526 1420 1329 1251 1182 1121 1068 1019 976 901 838 785 740 701 666
54 2251 2018 1832 1679 1552 1444 1352 1272 1202 1141 1086 1037 993 916 853 799 753 713 678
55 2288 2052 1862 1707 1578 1468 1375 1294 1222 1160 1104 1054 1009 932 867 812 766 725 689
56 2326 2085 1892 1735 1604 1493 1397 1315 1243 1179 1122 1071 1026 947 881 826 778 737 701
57 2363 2119 1923 1763 1629 1517 1420 1336 1263 1198 1140 1089 1042 962 896 839 791 749 712
58 2400 2152 1953 1791 1655 1541 1442 1357 1283 1217 1158 1106 1059 978 910 853 804 761 724
59 2437 2185 1984 1818 1681 1565 1465 1378 1303 1236 1177 1123 1076 993 924 866 816 773 735
60 2475 2219 2014 1846 1707 1588 1487 1399 1323 1255 1195 1141 1092 1008 939 880 829 785 747
61 2512 2252 2044 1874 1732 1612 1510 1420 1343 1274 1213 1158 1109 1024 953 893 842 797 758
62 2549 2285 2074 1902 1758 1636 1532 1442 1362 1293 1231 1175 1125 1039 967 906 854 809 769
63 2585 2318 2104 1929 1783 1660 1554 1463 1382 1312 1249 1192 1142 1054 981 920 867 821 781
64 2622 2351 2134 1957 1809 1684 1576 1483 1402 1330 1267 1209 1158 1069 995 933 879 833 792
65 2659 2384 2164 1984 1834 1707 1599 1504 1422 1349 1285 1227 1175 1085 1010 946 892 845 803
66 2696 2417 2194 2012 1860 1731 1621 1525 1442 1368 1302 1244 1191 1100 1024 959 904 857 815
67 2732 2450 2224 2039 1885 1755 1643 1546 1462 1387 1320 1261 1207 1115 1038 973 917 868 826
68 2769 2483 2254 2067 1911 1778 1665 1567 1481 1405 1338 1278 1224 1130 1052 986 929 880 837
69 2806 2516 2284 2094 1936 1802 1687 1588 1501 1424 1356 1295 1240 1145 1066 999 942 892 849
70 2842 2549 2314 2121 1961 1826 1709 1609 1521 1443 1374 1312 1256 1160 1080 1012 954 904 860

Appendix C:
Common Toxicity Criteria and Brock ototoxicity grading
BILATERAL HEARING LOSS GRADE Designation

< 40 dB at all frequencies 0 None
=/> 40 dB at 8,000 Hz only 1 Mild
=/> 40 db at 4,000 Hz and above 2 Moderate
=/> 40 dB at 2,000 Hz and above 3 Marked
=/> 40 dB at 1,000 Hz and above 4 Severe

UKCCSG Shortened listing of National Cancer Institute Common Toxicity Criteria (CTC), Version 2.0
Created October 2001

This abbreviated version of the NCI Common Toxicity Criteria catalogues the most usual problems seen during treatment for childhood cancers. However it is not exhaustive and if you
suspect a drug toxicity that is not listed the full listing can be obtained via the CTEP Home Page (http://ctep.info.nih.gov). This site also carries a manual for using the coding system.
Two categories of toxicities should be separately recorded when reporting the toxicity results of the treatment: acute or subacute, and chronic or long-term toxic effects.
Separate criteria are available for coding of late radiation effects – RTOG/EORTC Late Radiation Morbidity Scoring Scheme, Appendix IV of CTC Version 2.0 – contact UKCCSG Data
Centre for information.
WNL = within normal limits
LLN = Lower limit of normal values.
ULN = Upper limit of normal values.
GENERAL PERFORMANCE
CRITERIA Grade 0 Grade I Grade II Grade III Grade IV
Lansky or Karnofsky > 90 - 100 90 to > 70 70 to > 50 50 to > 30 < 30
WHO Scale Capable of all normal activities Capable of light activities except Ambulant and capable of self-care Capable of some personal Confined totally to a bed or chair,
all laborious physical activities but incapable of all other activities but confined to a bed or incapable of all activities, even
activities. Not resting or sitting chair more than 50% of waking essential activities such as eating
more than 50% of waking hours hours
BODY WEIGHT
(Loss or gain from baseline) < 5.0 % 5.0 - 9.9% 10.0 - 19.9% > 20% -
HEMATOLOGICAL
TOXICITY Grade 0 Grade I Grade II Grade III Grade IV
Haemoglobin WNL <LLN - 100 g /l 80 to 100 g /l 65 to 79 g /l < 65 g /l

<LLN – 10.0 g/dl 8.0 to 10.0 g/dl 6.5 to 7.9 g/dl < 6.5 g/dl
<LLN – 6.2 mmol /l 4.9 – 6.2 mmol /l 4.0 – 4.9 mmol /l < 4.0 mmol /l
WBC x10 9 /l >4.0 3.0 - 3.9 2.0 - 2.9 1.0 - 1.9 < 1.0
Granulocytes / Neutrophils: > 2.0 1.5 - 1.9 1.0 - 1.4 0.5 - 0.9 < 0.5
x10 9 /l
Platelets: x10 9 /l WNL <LLN - 75 > 50 to 74.9 > 10 to 49.9 < 10
Haemorrhage NONE Mild no transfusion - Requiring transfusion Catastrophic bleeding requiring

major non-elective intervention.

COAGULATION Note: See the HEMORRHAGE category for grading the severity of bleeding events.
Partial thromboplastin time (PTT) WNL >ULN - <1.5 x ULN >1.5 - <2 x ULN >2 x ULN -
Prothrombin time (PT) WNL >ULN -<1.5 x ULN >1.5 - <2 x ULN >2 x ULN -
Fibrinogen WNL > 0.75 - < 1.0 x LLN >0.5 - < 0.75 x LLN >0.25 - < 0.5 x LLN <0.25 x LLN
For leukemia studies or bone <20% decrease from pretreatment >20 - <40% decrease from
marrow infiltrative/ value or LLN pretreatment value or LLN
myelophthisic process, if >40 - <70% decrease from <50 mg
specified in the protocol. pretreatment value or LLN
WNL
Disseminated Intravascular Absent - - Laboratory findings present with Laboratory findings and bleeding
Coagulation (DIC) no bleeding
Also consider Platelets.
Note: Must have increased fibrin split products or D-dimer in order to grade as DIC.
Thrombotic Microangiopathy Absent - - Laboratory findings present Laboratory findings and clinical
(e.g., thrombotic without clinical consequences consequences, (e.g., CNS
thrombocytopenic purpura/TTP hemorrhage/ bleeding or
or hemolytic uremic thrombosis/ embolism or renal
syndrome/HUS) failure) requiring therapeutic
intervention
Note: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments)
CARDIAC
(DYS) Rhythm None Asymptomatic, transient, Symptomatic, but requiring no Symptomatic and requires Life threatening
requiring no therapy therapy treatment
(E.g. arrhythmia associated with
CHF, hypotension, syncope,
shock)
Cardiac Left Ventricular Function No change Asymptomatic, decline of resting Asymptomatic, decline of resting Mild CHF responsive to therapy Severe or refractory CHF
LVEF < 20% of baseline LVEF > 20% of baseline (congestive heart failure)
Cardiac Echography: Normal >25% to ≤ 30% >20% to ≤ 25% > 15% to ≤ 20% ≤ 15 %
Fractional Shortening
Mild CHF responsive to therapy Severe or refractory CHF
(congestive heart failure)

Cardiac Ischaemia None Non specific T- wave flattening or Asymptomatic, ST and T - wave Angina without evidence for Acute myocardial infarction
changes. changes suggesting ischaemia infarction.
Pericardial Effusion / Pericarditis None Asymptomatic, effusion, no Pericarditis (rub, chest pain, ECG Symptomatic effusion, drainage Tamponade; drainage urgently
intervention required changes) required required
Hypotension None or No change Changes requiring no Requiring brief fluid replacement Requiring therapy and sustained Shock
therapy(including transient or other therapy but not medical attention, but resolves (associated with acidemia and
orthostatic hypotension) hospitalisation: no physiological without persisting physiological impairing vital organ function due
consequences consequences to tissue hypoperfusion)
Hypertension* None or no change Asymptomatic, transient increase Recurrent/persistent increase > Requires therapy or more Hypertensive crisis
> 95th percentile of ULN 95th percentile of ULN intensive therapy than previously
Not requiring treatment
* For paediatric patients use age & sex appropriate normal values to give >95th percentile of Upper Normal Limit (ULN)
Acute Vascular Leak Syndrome Absent - Symptomatic, but not requiring Respiratory compromise, Life threatening; requiring pressor
fluid support. or requiring fluids. support and/or ventilatory support.
CONSTITUTIONAL SYMPTOMS
Fatigue None Increased fatigue over baseline, Moderate (e.g., decrease in Severe (e.g., decrease in Bedridden or disabling
(lethargy, malaise, asthenia) but not altering normal activities performance status by 1 performance status by > 2 ECOG
Note: See page 1 for performance WHO/ECOG level or 20% levels or 40% Karnofsky or
status scales. Karnofsky or Lansky) or causing Lansky) or loss of ability to
difficulty performing some perform some activities
activities
Rigors, chills None Mild, requiring symptomatic Severe and/or prolonged, Not responsive to narcotic -
treatment (e.g., blanket) requiring narcotic medication medication
or non- narcotic medication
Sweating (diaphoresis) Normal Mild and occasional Frequent or drenching - -
INFECTIONS / FEVER
Infection None Mild, Moderate, Severe, Life Threatening Sepsis

no active treatment loacised infection requiring local systemic infection, requiring IV (e.g. septic shock)
or oral treatment. antibiotic or antifungal teatment,
or hospitalisation
Fever in absence of infection None 38.0 – 39.0 oC 39.1 – 40.0 oC > 40.0 oC for < 24 hours > 40.0 oC for > 24 hours
or with hypotension

DERMATOLOGY / SKIN
Allergy None Transient rash, Urticaria, Symptomatic bronchospasm Anaphylaxis

drug fever < 38°C drug fever > 38°C requiring parenteral medication,
Asymptomatic bronchospasm +/- urticaria; allergy-related
oedema/angioedema
Injection site reaction None Pain or itching or erythema Pain or swelling, with Ulceration or necrosis that is -
inflammation or phlebitis severe or prolonged, or requiring
surgery
Rash / Desquamation None or no change Scattered macular or papular Scattered macular or papular Generalized symptomatic macular, Generalised exfoliative or
eruption or erythema: eruption with pruritus or other papular or vesicular eruption ulcerative dermatitis
asymptomatic. associated symptoms covering
less than 50% of body surface. Or desquamation covering > 50%
of body surface.
Or localised desquamation or
other lesions covering < 50% of
body surface.
Erythema Multiforme Absent - Scattered, but not generalized Severe or requiring IV fluids (e.g., Life-threatening (e.g., exfoliative
(e.g.,Stevens-Johnson syndrome, eruption generalized rash or painful or ulcerating dermatitis or
Toxic epidermal necrolysis) stomatitis) requiring enteral or parenteral
nutritional support)
Alopecia No loss Mild hair loss Pronounced or total hair loss - -
GASTROINTESTINAL
Stomatitis None Painless ulcers, erythema, Painful erythema, oedema, or Painful erythema, oedema, or Requires parenteral or enteral
or mild soreness ulcers, but can eat or swallow ulcers requiring IV hydration. support or prophylactic intubation
Nausea None Able to eat reasonable intake Intake significantly decreased No significant intake, -
but can eat requiring IV fluids.
Vomiting None 1 episode in 24 hours 2 - 5 episodes in 24hrs > 6 episodes in 24 hrs; or need for Requires parenteral nutrition; or
IV fluids physiologic consequences
requiring intensive care: or
haemodynamic collapse.
Diarrhoea None Increase <4 stools/day over Increase 4 - 6 stools/day or Increase ≥7 stools/day or Physiologic consequences
pre-treatment nocturnal stools. incontinence or need for requiring intensive care: or
parenteral support for dehydration haemodynamic collapse.
Anorexia None Loss of appetite Oral intake significantly Requiring IV fluids Requiring feeding tube or
decreased parenteral nutrition

Colitis None - Abdominal pain with mucus Abdominal pain, fever, change in Perforation or requiring surgery or
and/or blood in stool bowel habits with ileus or toxic megacolon
peritoneal signs, and radiographic
or biopsy documentation
Pancreatitis None - - Abdominal pain with pancreatic Complicated by shock

enzyme elevation (acute circulatory failure)
Constipation – see also None Requiring stool softener or dietary Requiring laxatives Intractable constipation requiring Obstruction or toxic megacolon
NEUROLOGICAL modification manual evacuation or enema
Ileus (or neuroconstipation)
HEPATIC
Bilirubin WNL < 1.5 x ULN 1.6 to 3.0 x ULN 3.1 to 10.0 x ULN > 10.0 x ULN
Transaminase WNL ≤ 2.5 x ULN 2.6 to 5.0 x ULN 5.1 to 20.0 x ULN > 20.0 x ULN
SGOT/SGPT, ALT/AST
Alkaline phosphatase WNL ≤ 2.5 x ULN 2.6 to 5.0 x ULN 5.1 to 20.0 x ULN > 20.0 x ULN
Portal vein flow Normal - Decreased portal vein flow Reversal/retrograde -

(Veno-occlusive Disease) portal vein flow
PULMONARY
Cough Absent Mild, relieved by non-prescription Requiring narcotic antitussive Severe cough or coughing spasms, -
medication poorly controlled or unresponsive
to treatment.
Pulmonary Function, Dyspnoea None or no change Asymptomatic, abnormal PFT’s Dyspnoea on significant exertion Dyspnoea at normal level of Dyspnoea at rest
activity
PA 02 – change from pre- > 90% >75 - <90% >50 - <75% >25 - <50% <25%
treatment normal value
Carbon Monoxide Diffusion 100 - 75% 74 - 65% 64 - 55% 54 - 40% < 40%
Capacity (DLCO)
Vital Capacity (VC) 100 - 75% 74 - 65% 64 - 55% 54 - 40% < 40%

RENAL
Proteinuria Normal 1 + or 2 - 3 + or 4 + or Nephrotic syndrome

< 3 g /l 3 - 10 g /l > 10 g /l
Haematuria Negative Microscopic only Intermittent gross bleeding, no Persistent gross bleeding or clots. Open surgery or necrosis or deep
clots May require catheterisation or bladder ulceration.
instrumentation, or transfusion
Serum Creatinine WNL < 1.5 x N 1.5 - 3.0 x N 3.1 - 6.0 x N > 6.0 x N
Note: adjust to age-appropriate
levels for paediatric patients
Glomerular filtration rate (GFR)

ml/min/1.73m2 ≥ 90 60 - 89 40 - 59 20 - 39 ≥ 19
Note: not listed in CTC Criteria
Tubular Toxicity (Overall*) Increase of 2 microglobulin and Decrease of phosphate Debre de Toni-Franconi Prolonged (≥ 5 years) or definitive
or lysozyme in urine. Mild reabsorption (TRP 75 - 85%) Syndrome, Hypophosphataemic substitution required, or
None hyperamino-aciduria (HAA) glucosuria < 10 mol /l. Moderate rickets, tetany. Hyperchloraemic progressive renal failure
HAA metabolic acidosis, polyuria,
dehydration
Distal Tubular Toxicity ≥ 600 or normal response to 500 - 599 400 - 449 No symptom BUT 300 - 399 with Nephrogenic diabetes insipidus or
Early morning urine osmolality DDAVP no response to DDAVP
< 300 with no response to
EMUO - (mOsm/kg) DDAVP
* For more details concerning tubular and glomerular toxicity after drugs such as ifosfamide or platinum compounds a separate precise grading of nephrotoxicity should be used as described by SKINNER et al.
(J Clin Oncol. 1993 Jan;11(1):173-90)
BLOOD ELECTROLYTES
Hypernatremia WNL >ULN - 150 >150 - 155 >155 - 160 > 160
(High Sodium, Na+) mmol /l
Hyponatremia WNL <LLN - 130 - 120- <130 < 120

+
(Low Sodium, Na ) mmol /l
Hyperkalemia WNL >ULN - 5.5 >5.5 – 6.0 >6.0 – 7.0 > 7.0
(High Potassium, K+) mmol /l
Hypokalemia WNL <LLN – 3.0 - 2.5 - <3.0 < 2.5

(Low Potassium, K+) mmol /l
Hypercalcemia WNL >ULN – 11.5 mg/dl >11.5 – 12.5 mg/dl >12.5 – 13.5 mg/dl >13.5 mg/dl
(High Calcium, Ca++ )
>ULN – 2.9 mmol /l >2.9 – 3.1 mmol /l >3.1 – 3.4 mmol /l >3.4 mmol /l
Hypermagnesemia WNL >ULN -3.0mg/dl - >3.0-8.0mg/dl >8.0mg/dl

(High Magnesium, Mg++)
>ULN -1.23mmol /l >1.23-3.30mmol /l >3.30mmol /l
Hypomagnesemia WNL <LLN-1.2mg/dl 0.9-<1.2mg/dl 0.7-<0.9mg/dl <0.7mg/dl

(Low Magnesium, Mg++)
<LLN - 0.5mmol /l 0.4-<0.5mmol /l 0.3-<0.4mmol /l <0.3mmol /l
NEUROLOGICAL
Cortical None Mild somnolence or agitation, not Moderate somnolence or agitation Severe somnolence, agitation, Coma, seizures, toxic psychosis
interfering with function interfering with function, but not with confusion, disorientation or
activities of daily living hallucinations
Ataxia (incoordination) None Asymptomatic but abnormal on Mild symptoms interfering with Moderate symptoms interfering Bedridden or disabling
physical exam, not interfering with function, but not interfering with with activities of daily living
function activities of daily living
Confusion Normal Confusion or disorientation or Confusion or disorientation or attention Confusion or delirium interfering Harmful to others or self;
attention deficit of brief duration; deficit interfering with function, but with activities of daily living requiring hospitalization
resolves spontaneously with no not interfering with activities of daily
sequelae living
Irritability (children <3 years of Normal Mild; easily consolable Moderate; requiring increased attention Severe; inconsolable -
age)
Leukoencephalopathy associated None Mild increase in SAS (subarachnoid Moderate increase in SAS; and/or Severe increase in SAS; severe Severe increase in SAS; severe
radiological findings space) and/or mild ventriculomegaly; moderate ventriculomegaly; and/or ventriculomegaly; near total ventriculomegaly; diffuse low
and/or small (+/- multiple) focal T2 focal T2 hyperintensities extending white matter T2 hyperintensities attenuation with calcification
hyperintensities, involving into centrum ovale; or involving 1/3 to or diffuse low attenuation (CT); (CT); diffuse white matter
periventricular white matter or <1/3 of 2/3 of susceptible areas of cerebrum focal white matter necrosis necrosis (MRI)
susceptible areas of cerebrum (cystic)
Seizure(s) None - Seizure(s) self-limited and Seizure(s) in which Seizures of any type which are
consciousness is preserved consciousness is altered prolonged, repetitive, or difficult
to control (e.g., status epilepticus,
intractable epilepsy)
Mood No change Mild anxiety or depression Moderate anxiety or depression Severe anxiety or depression Suicidal ideation or danger to
interfering with function, but not interfering with activities of daily self.
interfering with activities of daily living
living
Sensory None or No change Mild paresthesia or loss of deep Objective sensory loss or paresthesia Sensory loss or paresthesia Permanent sensory loss that
tendon reflexes – not interfering with interfering with function, but not interfering with activities of daily interferes with function
function. interfering with activities of daily living
living
Motor None or No change Subjective weakness; no objective Mild objective weakness without Objective weakness with Paralysis
findings significant impairment impairment of function

Headache None Mild Moderate or severe but transient Unrelenting and severe -
Ileus (or neuroconstipation) None - Intermittent, not requiring intervention Requiring non-surgical Requiring surgery
intervention
Vision None or No change - - Symptomatic subtotal loss of Blindness

vision
Hearing None or no change Asymptomatic, hearing loss, Tinnitus Hearing loss interfering with Deafness not correctable
audiometry only function, correctable with hearing
aid
Audiometry Loss < 40 db on all Loss at least 40 db at 8000HZ Loss at least 40db at 4000HZ Loss at least 40 db at 2000 HZ Loss at least 40 db at 1000 HZ
frequencies
PAIN
Treatment Related Pain None Mild Moderate Severe Resistant to treatment
Headache None Mild Moderate or severe but transient Unrelenting and severe -

Appendix D:
FLOW SHEETS
-
-
49
RECURRENT MGCTS
JEB CHEMOTHERAPY
GC III/Final Version1.0/September 2004

FLOW SHEET – JEB CHEMOTHERAPY
ETOPOSIDE 120mg/m2 day 1,2,3

CARBOPLATIN AUC 7.9 day 2
(or 600mg/m2)
BLEOMYCIN 15,000 IU/m2 day 3
(Note infant dose adjustments)
Week 0 1 2 3 6 9 12 15 18
STOP STOP
‘INTERMEDIATE RISK’ ‘HIGH
RISK’
GFR High Risk * * *

Intermediate Risk * *
(+ according to clinical needs)
AUDIOMETRY High Risk * * *
LUNG FUNCTION High Risk * *
AFP/HCG – weekly until normal then pre-chemo
IMAGING - At diagnosis + end of therapy for secreting tumours

- At diagnosis + alt. courses for non-secreting tumours
- As indicated if tumour markers not falling appropriately

FLOW SHEET – RECURRENT MGCTs
VINBLASTINE 3mg/m2 day 1,2

IFOSFAMIDE 1.5gm/m2 day 1-5
CISPLATIN 20mg/m2 day 1-5
(Note infant dose adjustments)
Week 0 1 2 3 6 9 12 15 18
GFR * * *
(+ if clinical need)
RENAL TUBULAR FUNCTION * * * * * * *
AUDIOMETRY * * *
AFP/HCG - weekly until normal and then before each chemotherapy
IMAGING - secreting * * *
- non-secreting * * * *

Appendix E:
Drug Information
BLEOMYCIN
Alternative names
None
Mechanism of action
DNA strand cleavage via free radicals produced by activated bleomycin complexes.
DNA intercalator, resulting in base excision and strand breakage.
Considerations prior to administration

·Pulmonary Function
·Adequate renal function
Adverse events
Early
Common
·Fevers (25%)
Occasional
·Skin (erythema, hyperkeratosis, peeling, pigmentation, bullae, ulceration.)
Rare
·Alopecia
·Nail Changes
·Anaphylaxis
Late
Occasional
·Pulmonary Fibrosis
Recommended routes
·Intravenous bolus or 12 hr infusion
·IM with lignocaine
·Intrapleural or intralesional
CAUTION
Dose should be reduced if renal function is impaired.
Administration
Bolus administration - inject slowly or via a fast running drip.
Intravenous administration - dilute in up to 100 mls 0.9% sodium chloride and administer slowly

Dose/Schedule
Every 21 days as part of combined chemotherapy for germ cell tumour 15 - 30mg stat or per m2
Interactions
Oxygen enhances pulmonary toxicity - even years after exposure.
Cisplatin increases risk of pulmonary toxicity.
Dilution specification and stability

• 0.9% sodium chloride only.
• Protect from light.
• Stable for up to 7 days after reconstitution provided it is protected from light and store in a
refrigerator.
CARBOPLATIN
Alternative names
• JM8
• Paraplatin (Proprietary Name)
• CBCDA
Mechanism of action
Produces interstrand and intrastrand DNA crosslinks

• Renal function
• FBC
Adverse effects
Common
• Nausea + vomiting
• Myelosuppression
• Persisting thrombocytopenia
Occasional
• Ototoxicity
• Raised LFT's (Alk Phos)
• Nephrotoxicity
Rare
• Neurotoxicity
• Rash
• Anaphylaxis + anaphylactoid reactions
• Ocular, transient visual disturbances
• Alopecia
Recommended routes
Intravenous

Administration:
Administered as a intravenous infusion over 1 hour or greater if dictated by fluid volume
Dose/schedule
If renal function is poor, dose should be calculated according to GFR.
In some cases it may be desirable to calculate the dose to deliver a specific AUC.
Paediatric regimens aim to deliver a carboplatin AUC 6 - 10mg/ml.min.
Interactions
Co administration with potentially nephrotoxic agents should be avoided due to the risk of acute
reductions in GFR and hence decreased drug clearance.
Overdose
• Full supportive measures, including the use of growth factors should be considered.
• Carboplatin is removed by haemodialysis. Although there are no publications on its use
following overdosage, haemodialysis would be a reasonable management option.
Dilution specification & stability
• Dextrose 5%
• Concentration is not critical and should be adjusted to the child’s fluid requirements
• Carboplatin can be diluted as low as 500 micrograms/ml
• Hydration is not required
• Once reconstituted, carboplatin is stable for 8 hours at room temperature, or 24 hours if
refrigerated
CISPLATIN
Alternative Names:
• Cis DDP
• Cis diamminedichloro-platinum
Mechanisms of action:
• Produces interstrand and intrastrand DNA crosslinks.
Considerations prior to chemotherapy

• Renal function
• Audiology
• Adequate hydration and diuresis must be established prior to administration
• FBC
Adverse Effects
Common
• Nausea/vomiting (may be delayed)
• Nephrotoxicity (dose limiting)
• Hypokalaemia

• Hypomagnesaemia
• Hyperuricaemia
• Alopecia
Occasional
• Peripheral neuropathy
• Taste disturbance
Rare
• Anaphylaxis
• Other neurotoxicity
• Ototoxicity
• Ocular
Recommended schedule of administration:

Intravenous
CAUTION:
• Must establish adequate hydration and diuresis prior to administration
• Prolonged electrolyte losses are seen in some cases (especially magnesium & potassium)
Administration
• Hydration is necessary to ameliorate the renal damage caused by cisplatin.
• All protocols require hydration, and an adequate urine output to be established before
administration of cisplatin.
• Mannitol is also used and has advantages over frusemide (which can itself cause renal damage).
• Mannitol should be given during the cisplatin infusion, and in some cases after the infusion.
• Hydration needs to continue for at least 24 hours after the end of the cisplatin infusion
• Cisplatin should be given as a continuous infusion over 24 hours as dose rate can effect both acute
and late toxicities.
• There is some evidence to suggest that a continuous infusion may be as/or more effective with
decreased emesis.
Interactions
• Co-administration with potentially nephrotoxic agents should be avoided due to the risk of acute
reductions in GFR and hence decreased clearance, as well as additive renal toxicity.
• Concomitant administration of cisplatin and etoposide may reduce etoposide clearance.
Overdosage
• Full supportive measures should be considered
• Plasmapheresis may be of use in cisplatin overdosage
Dilution specification and stability:

• Cisplatin is stable in Sodium Chloride 0.9% for 7 days
• It remains stable in Sodium Chloride 0.9% in the presence of magnesium sulphate & potassium
chloride for up to 24 hours
• Do not refrigerate
• No need to protect from light

NB. The minimum concentration of sodium chloride providing an acceptable level of stability is
approximately 0.3% w/v
ETOPOSIDE
Alternative names
• VP16
• VEPESID
Mechanisms of action:
Acts by inhibition of Topoisomerase II which results in DNA strand breakage

• FBC
• Renal function
• Liver function
Adverse Effects
Common
• Alopecia
Occasional
• Nausea/vomiting
Rare
• Anaphylactic reactions
• Fever
• Hypotensive reactions
• Headache
• Pruritus
• Pigmentation
• Mucositis
• Second tumours
Recommended route
Intravenous
Administration
• Ampoules 100mg in 5ml
• Dilute to a concentration of 0.4mg/ml in 0.9% Sodium Chloride Injection, give as an IV infusion
over 1 to 4 hours2. One hour infusion is recommended in order to avoid problems with “line time”
during complex chemotherapy regimens.
• Data sheet recommends administration over at least 30 minutes, to avoid hypotensive reaction
• Due to potential solubility problems care should be taken when mixing with other agents.

Dose/schedule
Daily administration has greater anti-tumour efficacy than an equivalent dose given over 24 hours
with comparable toxicity + AUC e.g. 100mg/m2/day for 5 days versus 500mg/m2 over 24 hours,
although this is the subject of some debate.
Drug is undetectable (< 0.2microgram/ml) in plasma by 48 hours post administration in the majority
of patients (important for protocols with marrow reinfusion).
Interactions (IV and Oral preparations)

• No major interactions with the possible exception of warfarin, where etoposide may displace
protein bound warfarin or alter it's metabolism, leading to increased prothrombin times
• Cisplatin may reduce the clearance of etoposide.
• For the related drug tenopiside and possibly for etoposide as well, co-administration of
anticonvulsants (Phenytoin or Phenobarbitone) can also result in increase clearance.
Overdosage (IV and Oral preparations)

• Full supportive measures, including the use of growth factors should be considered.
• Dialysis and haemofiltration are not effective as etoposide is highly plasma protein bound.
Dilution specification & stability

Intravenous
• Manufacturers recommend diluting to 0.25mg/ml, however a dilution of 0.4mg/ml is stable at
room temperature for 96 hours (may precipitate if refrigerated).
• Only licensed in UK for administration in Normal Saline.
• Poor water solubility therefore formulated in polyethylene glycol solubilising agent which
dissolves plastics.
• Use nylon filters + PVC bags or glass bottles
IFOSFAMIDE
Alternative names
• Mitoxana (Proprietary Name)
Mechanism of action
Ifosfamide is a pro-drug which is activated by microsomal enzymes, mainly in the liver, producing
a series of metabolites. The primary anti-tumour metabolite, ifosphosphoramide mustard is thought
to exert its cytotoxic effect by producing interstrand and interstrand DNA crosslinks

• Low serum albumin associated with increased risk of encephalopathy
• Presence of large pelvic tumour ( ureteric obstruction )
• FBC.
• Impaired renal function
• Impaired liver function
• Prior cisplatin treatment may enhance renal toxicity
• Urothelial damage following radiation or previous chemotherapy

Adverse Effects
Common
• Renal toxicity, particularly tubular dysfunction
• Emesis
• Alopecia
Occasional
• Liver dysfunction
• Haemorrhagic cystitis if inadequate mesna prophylaxis
Rare
• Encephalopathy
Late
• Sub-fertility/infertility
• Second malignant tumours
Recommended route
Intravenous infusion over 1 hour.
Dose/schedule
Courses given approximately 3 weeks apart to allow haematological recovery.
In order to prevent urothelial toxicity, hydration and prophylactic mesna are essential with this
drug.
Administration
Give over 1 hour. Intravenous hydration (with glucose/saline + potassium chloride 20 mmol/l.),
containing mesna at 120% ( mg/mg) of the prescribed daily ifosfamide dose. Infuse this solution at
a rate of 3L / m2 / 24 hours, commencing 3 hours before the first ifosfamide dose and continuing
for a minimum of 12 hours after completion of the last ifosfamide infusion. Recommendations are
of 24 hours post hydration.
Interactions
The concomitant use of ifosfamide with anticoagulants, especially warfarin, may result in an
increased anti-coagulant effect.
Ifosfamide metabolism may be inhibited by antifungal azole agents and nifedipine. Carbamazepine,
phenytoin and prolonged steroids may increase clearance.
Overdosage
The most serious consequences are haemorrhagic cystitis, and myelosuppression. If the overdose
is recognised early, intravenous hydration and diuresis, together with mesna may be beneficial in
ameliorating damage to the urinary tract. Methylene blue and diazepam have shown some activity
in reversing ifosfamide encephalopathy
Dilution specification and stability

Supplied in 1 g and 2 g vials. Reconstitute with Water for Injection. Dilute to < 4% w/v for
peripheral infusion.
Ifosfamide is stable in glucose/saline with added potassium and mesna (1mg/ml) for 24 hours at
room temperature and 72 hours at 4°C.
VINBLASTINE
Alternative names:
• Velbe
Mechanisms of Action
Tubulin binding agent producing mitotic arrest.

Ensure good, robust, venous access
Hepatic function.
Adverse effects
Common
• Abdominal pain
• Constipation
• Leucopenia
Occasional
• Peripheral neuropathy (mild)
• Thrombocytopenia and Anaemia
Rare
• Nausea and vomiting
• Alopecia
• Paralytic ileus
Recommended routes
By bolus injection or into the tubing of a fast running intravenous infusion.
Hydration not required.
CAUTION
Vinblastine is a highly vesicant drug, and great care must be taken to avoid extravasation
Dose/schedule
Concentration for administration 1 mg/ml.
Recommended dose: 6mg/m2 no more frequently than every 7 days.
Maximum single dose: 10mg.
Interactions
Nil known

VINCRISTINE
Alternative names
• Oncovin
Mechanisms of action
Tubulin binding agent producing mitotic arrest.
• Well established, robust, venous access.

• Hepatic function.
• Neurotoxicity
• Avoid administration at the same time as intrathecal methotrexate.
Adverse effects
Common
• Alopecia
• Abdominal pain - cramps
• Pain in jaw, bones and joints
• Constipation
Occasional
• Peripheral neuropathy (loss of deep tendon reflexes)
• Autonomic neuropathy (paralytic ileus, urinary retention)
Rare
• Leucopenia, Thrombocytopenia, Anaemia
• Nausea and vomiting
• Raised LFTs (mild and transient)
• Convulsions
• Diplopia and Photophobia
Toxicity related to individual and cumulative dose of Vincristine
Recommended routes
By bolus injection or into the tubing of a fast running intravenous infusion.
Hydration not required.
CAUTION
Vincristine is a highly vesicant drug, and great care must be taken to avoid extravasation.
DO NOT GIVE INTRATHECALLY

Dose /schedule
• Variable
• Dose reduction may be necessary if toxicity unacceptable
• The need to limit the total vincristine dose per administration to 2mg is not supported by clinical
experience in adults.
Interactions
Vincristine plasma clearance can be reduced by nifedipine, cimetidine or ranitidine, and
increased by phenobarbitone. The clinical relevance of these interactions in not clear.
Overdose
Plasmapheresis and phenobarbitone have been reported to be of value in cases of systemic vincristine
overdose.
Dilution specification
• Dextrose 5%, Sodium Chloride 0.9%

• Undiluted at 1 mg/ml but at this concentration there would be increased toxicity with extravasation,
therefore can be administered at lower concentrations, e.g. 0.2 mg/ml.
Stability
• Solution 1 mg/ml - 2 years in vial at 2 to 8 oC

• Lyophilised powder - 3 years at 2 to 8 oC. Chemically stable for 30 days after reconstitution when
stored at 2 - 8 oC.
Pharmacokinetics
Vincristine is eliminated by hepatic metabolism and biliary excretion. Clearance is variable and may
be age dependent.
Mean (±SD) pharmacokinetic parameters:
Clearance 431±238, 482±342 ml/min/m2

t½b 1122±1128, 823±390 min
AUC 3.2±1.8, 2.9±2.1 mg/ml.min per 1.4mg/m2
In adults, but not children, vincristine neurotoxicity has been related to AUC. Also in adults, impaired
liver function has been related to reduced clearance and predisposition to neurotoxicity. A dose
reduction has been recommended for patients with a raised serum bilirubin.

Appendix F:
Parent/Patient Information Sheets and Consent Forms
Parent/Guardian Information Sheet

Patient Information Sheet (aged 16+ years Scotland)
Patient Information Sheet (14+ years)
Patient Information Sheet (8-14 years)
Information Sheet (under 8 years)
GP Information Sheet
Parent/Child Consent Form
Patient Consent Form (aged 16+ Scotland)

To be printed on hospital headed paper
Protocol for the Treatment of Extracranial Germ Cell Tumours in

children and adolescents (GC 2005 04)
Chief Investigator: Dr J Hale, Royal Victoria Infirmary, Newcastle upon Tyne

Local Investigator: to be inserted
PARENT/GUARDIAN INFORMATION SHEET (Version 2.0, January 2005)
Your child has been diagnosed with a type of tumour known as a germ cell tumour. Your child’s
doctor will already have explained about the tumour and where it is in his/her body. It is possible
your child has already had an operation to remove the tumour.
This leaflet sets out the way it is proposed to treat your child’s germ cell tumour. Because this
treatment involves some changes from the way we have previously treated germ cell tumours in
children in the United Kingdom (UK) it is a research study. Before you decide whether to give
your consent for your child to be treated in this way you should read this leaflet and discuss it with
your child’s doctor, nurses and others. Please take your time to decide whether to give your consent
or not.
1. What is the purpose of the study?
The aim of this study is to continue to reduce the amount of treatment some children with germ cell
tumours need without affecting the chance of being cured.
In the UK doctors have treated children’s germ cell tumours with surgery only or with surgery plus
chemotherapy using etoposide, carboplatin and bleomycin. Overall about 9 out of 10 children are
cured.
Germ cell tumours usually produce substances (AFP or HCG) that can be measured in the blood.
This is useful for telling how the tumour is responding to treatment. In the past we have given as
many courses of chemotherapy as it took to reduce the level of AFP or HCG to normal plus 2
additional courses. On average this was about 5-6 courses.
Analysis of the last UK germ cell tumour study shows that some germ cell tumours are more
responsive to treatment than others. In fact some tumours, usually in the ovary or testis, can be
cured with surgery without any chemotherapy at all.
We propose to decide how much treatment your child needs based on where the tumour started,
whether it has spread or not and how high the level of AFP is in the blood. For some children this
will mean no chemotherapy at all initially. Some children will receive 4 courses and some will
receive 6 courses of chemotherapy. This means some children will receive less treatment than in
the past.
The aim is to reduce the treatment as much as we can but maintain the good cure rates. To prove
this is possible will take about 5 years.
Documents approved with GC III Protocol/Final Version1.0/September 2004
63
2. Why is my child being chosen?
Your child has a germ cell tumour. All children with germ cell tumours in the UK are being asked
to be part of this study.
3. Does my child have to take part?
You can decide whether your child takes part or not. You will be asked to sign a consent form
before starting treatment. You can change your mind at any time without affecting the standard of
treatment your child receives.
4. What alternatives are there?
If you decide you do not want your child to take part your doctor will discuss alternatives. It is
likely that he/she will suggest using the same chemotherapy but the number of courses will be
decided by the time it takes the blood AFP to reduce to normal as was used in the past.
5. What will happen to my child if he/she takes part?
There are no extra tests or treatment involved if your child takes part in this research study. Your
child will already have had scans, blood tests and probably an operation to make the diagnosis.
Your child’s doctor will have explained about having chemotherapy and what it involves. The
study uses a different way of deciding how much treatment your child needs. For some children
this will mean they receive fewer courses of chemotherapy than in the past. The chemotherapy is
the same as has been used for germ cell tumours for some years in the UK.
6. What are the side effects of treatment?
Unfortunately all chemotherapy has some side effects. The 3 drugs used to treat germ cell tumours
(etoposide, carboplatin, bleomycin) will cause hair loss, some sickness and temporary decrease in
the numbers of white cells and platelets in the blood, which can make your child at risk of infection
and bruising and bleeding. In addition etoposide can cause a sore mouth. Carboplatin can cause
kidney damage and affect hearing. Your child will be checked for these side effects. In general they
are mild. Bleomycin is used in a fairly low dose but can rarely cause lung damage. Anyone at risk
of pregnancy must use effective contraception until their treatment is finished.
7. What are the possible disadvantages and risks of taking part?
There is a small possibility that reducing treatment for some children might increase the risk of the
tumour recurring. Because of this risk the results of this study will be monitored closely and it will
be stopped if there is any sign of the results not being as good as in the past.
8. What are the possible benefits of taking part?
It is hoped that some children with germ cell tumours can be cured with less chemotherapy and
therefore fewer side effects. However this cannot be guaranteed. The information we get from this
study may help us to treat future patients with germ cell tumours better.
64
9. What if new information becomes available?
Sometimes during a research study new information becomes available about the treatment. If this
happens your child’s doctor will discuss whether your child continues in the study. If you or your
child’s doctor decide your child should be withdrawn his/her care will be continued. If your child
continues in the study you may be asked to sign a new consent form.
10. What if something goes wrong?
If taking part in this study causes harm to your child there are no special compensation
arrangements. However if your child is harmed due to someone’s negligence, then you may have
grounds for legal action but you may have to pay for this. Regardless of this, if you wish to
complain or have any concerns about the way you have been treated during this study, the normal
National Health Service complaints procedure should be available to you.
11. Will my child’s participation in the study be kept confidential?
We would like your permission to collect information from your child’s medical records during the
study. All information collected will be kept strictly confidential. Information on all patients in this
study will be sent to the UKCCSG (United Kingdom Children’s Cancer Study Group) Data Centre
in Leicester, UK where it will be kept. All the information that could be traced to your child will be
kept confidential.
When the results of the study are analysed, your child’s tumour sample will be reviewed by a panel
of pathologists. This review is for research purposes only and will not affect your child’s treatment.
12. What will happen to the results of this study?
When the study is complete the results will be published in medical journals. If you would like to
know when the results are available please let your doctor know. Your child will not be identified
in any publication.
13. Who is organising this research?
The UKCCSG is organising this study. This group organises most children’s tumour treatment in
the UK. There is no payment for taking part in this research and there is no payment to the doctors
organising this study.
14. What if I have any concerns?
If you have any concerns about this study or the way it has been carried out you should contact the
local investigator (name, tel, etc) or the hospital (name) complaints department or the UKCCSG
(UKCCSG Data Centre, University of Leicester, Hearts of Oak House, 9 Princess Road West,
Leicester, LE1 6TH).
If you agree to your child taking part you will need to sign a consent form. You will be given a
copy to keep. With your permission, we will let your GP know your child is taking part in this
study.
Contact details: (Name of doctor in centre and telephone number)

Thank you for taking the time to read this leaflet.
65

children and adolescents (GC2005 04)

INFORMATION SHEET FOR PATIENTS 16+ YEARS IN SCOTLAND (Version 2.0,

January 2005)
You have been diagnosed with a type of tumour known as a germ cell tumour. Your doctor will
already have explained about the tumour and where it is in your body. It is possible you have
already had an operation to remove the tumour.
This leaflet sets out the way it is proposed to treat your germ cell tumour. Because this treatment
involves some changes from the way we have previously treated germ cell tumours in children in
the United Kingdom (UK) it is a research study. Before you decide whether to give your consent to
be treated in this way you should read this leaflet and discuss it with your parents, your doctor,
your nurse and others. Please take your time to decide whether to give your consent or not.
cured.
We propose to decide how much treatment you need based on where the tumour started, whether it
has spread or not and how high the level of AFP is in the blood. For some patients this will mean
no chemotherapy at all initially. Some patients will receive 4 courses and some will receive 6
courses of chemotherapy. This means some patients will receive less treatment than in the past.
66
2. Why am I being chosen?
You have a germ cell tumour. All children and young people with germ cell tumours in the UK are
being asked to be part of this study.
3. Do I have to take part?
You can decide whether to take part or not. If you decide to take part you will be asked to sign a
consent form before starting treatment. You can change your mind at any time without affecting
the standard of treatment you receive.
If you decide you do not want to take part your doctor will discuss alternatives. It is likely that
he/she will suggest using the same chemotherapy but the number of courses will be decided by the
time it takes the blood AFP to reduce to normal as was used in the past.
5. What will happen to me if I take part?
There are no extra tests or treatment involved if you take part in this research study. You will
already have had scans, blood tests and probably an operation to make the diagnosis. Your doctor
will have explained about having chemotherapy and what it involves. The study uses a different
way of deciding how much treatment you need. For some patients this will mean they receive
fewer courses of chemotherapy than in the past. The chemotherapy is the same as has been used for
germ cell tumours for some years in the UK.
Unfortunately all chemotherapy has some side effects. The three drugs used to treat germ cell
tumours (etoposide, carboplatin, bleomycin) will cause hair loss, some sickness and temporary
decrease in the numbers of white cells and platelets in the blood, which can make you at risk of
infection and bruising and bleeding. In addition etoposide can cause a sore mouth. Carboplatin can
cause kidney damage and affect hearing. You will be checked for these side effects. In general they
are mild. Bleomycin is used in a fairly low dose but can rarely cause lung damage. Anyone who
might get pregnant must use contraception until their treatment is finished.
There is a small possibility that reducing treatment for some patients might increase the risk of
their tumour recurring. Because of this risk the results of this study will be monitored closely and it
will be stopped if there is any sign of the results not being as good as in the past.
It is hoped that some children with germ cell tumours can be cured with no, or less chemotherapy
and therefore fewer side effects. However this cannot be guaranteed. The information we get from
this study may help us to treat future patients with germ cell tumours better.
67
happens your doctor will discuss with you and your parents whether you continue in the study. If
you or your doctor decides you should be withdrawn, your care will be continued. If you continue
in the study you may be asked to sign a new consent form.
If taking part in this study causes you harm there are no special compensation arrangements.
However if you are harmed due to someone’s negligence, then you may have grounds for legal
action but your family may have to pay for this. Regardless of this, if you wish to complain or have
any concerns about the way you have been treated during this study, the normal National Health
Service complaints procedure should be available to you.
11. Will my participation in the study be kept confidential?
We would like your permission to collect information from your medical records during the study.
All information collected will be kept strictly confidential. Information on all patients in this study
will be sent to the UKCCSG (United Kingdom Children’s Cancer Study Group) Data Centre in
Leicester, UK where it will be kept. All the information that could be traced to you will be kept
confidential.
When the results of the study are analysed, your tumour sample will be reviewed by a panel of
pathologists. This review is for research purposes only and will not affect your treatment.
know when the results are available please let your doctor know. You will not be identified in any
publication.
If you agree to take part you will need to sign a consent form. You will be given a copy to keep.
With your permission, we will let your GP know you are taking part in this study.
68

children and adolescents (GC2005 04)

INFORMATION SHEET FOR PATIENTS 14+ YEARS (Version 2.0, January 2005)
You have been diagnosed with a type of tumour known as a germ cell tumour. Your doctor will
already have explained about the tumour and where it is in your body. It is possible you have
already had an operation to remove the tumour.
This leaflet sets out the way it is proposed to treat your germ cell tumour. Because this treatment
involves some changes from the way we have previously treated germ cell tumours in children in
the United Kingdom (UK) it is a research study. Before you decide whether to give your consent to
be treated in this way you should read this leaflet and discuss it with your mum or dad, your doctor,
your nurse and others. Please take your time to decide whether to give your consent or not.
cured.
We propose to decide how much treatment you need based on where the tumour started, whether it
has spread or not and how high the level of AFP is in the blood. For some patients this will mean
no chemotherapy at all initially. Some patients will receive 4 courses and some will receive 6
courses of chemotherapy. This means some patients will receive less treatment than in the past.
69
You have a germ cell tumour. All children and young people with germ cell tumours in the UK are
being asked to be part of this study.
You and your parents can decide whether to take part or not. If you decide to take part you and
your parents will be asked to sign a consent form before starting treatment. You can change your
mind at any time without affecting the standard of treatment you receive.
If you decide you do not want to take part your doctor will discuss alternatives. It is likely that
he/she will suggest using the same chemotherapy but the number of courses will be decided by the
time it takes the blood AFP to reduce to normal as was used in the past.
There are no extra tests or treatment involved if you take part in this research study. You will
already have had scans, blood tests and probably an operation to make the diagnosis. Your doctor
will have explained about having chemotherapy and what it involves. The study uses a different
way of deciding how much treatment you need. For some patients this will mean they receive
fewer courses of chemotherapy than in the past. The chemotherapy is the same as has been used for
germ cell tumours for some years in the UK.
Unfortunately all chemotherapy has some side effects. The 3 drugs used to treat germ cell tumours
(etoposide, carboplatin, bleomycin) will cause hair loss, some sickness and temporary decrease in
the numbers of white cells and platelets in the blood, which can make you at risk of infection and
bruising and bleeding. In addition etoposide can cause a sore mouth. Carboplatin can cause kidney
damage and affect hearing. You will be checked for these side effects. In general they are mild.
Bleomycin is used in a fairly low dose but can rarely cause lung damage. Anyone who might get
pregnant must use contraception until their treatment is finished.
There is a small possibility that reducing treatment for some patients might increase the chance of
their tumour recurring. Because of this risk the results of this study will be monitored closely and it
will be stopped if there is any sign of the results not being as good as in the past.
70
happens your doctor will discuss with you and your mum or dad whether you continue in the study.
If you or your doctor decides you should be withdrawn, your care will be continued. If you
continue in the study you may be asked to sign a new consent form.
If taking part in this study causes you harm there are no special compensation arrangements.
However if you are harmed due to someone’s negligence, then you may have grounds for legal
action but your family may have to pay for this. Regardless of this, if you wish to complain or have
any concerns about the way you have been treated during this study, the normal National Health
Service complaints procedure should be available to you.
11. Will my participation in the study be kept confidential?
We would like your permission to collect information from your medical records during the study.
All information collected will be kept strictly confidential. Information on all patients in this study
will be sent to the UKCCSG (United Kingdom Children’s Cancer Study Group) Data Centre in
Leicester, UK where it will be kept. All the information that could be traced to you will be kept
confidential.
When the results of the study are analysed, your tumour sample will be reviewed by a panel of
pathologists. This review is for research purposes only and will not affect your treatment.
know when the results are available please let your doctor know. You will not be identified in any
publication.
If you agree to take part you and your parents will need to sign a consent form. You will be given a
copy to keep. With your permission, we will let your GP know you are taking part in this study.

71


INFORMATION SHEET FOR PATIENTS 8 – 14 YEARS (Version 2.0, January 2005)
Your doctor has found out that you have a kind of tumour (lump) called a germ cell tumour. Your
doctor will tell you about the tumour and where it is in your body. You might already have had an
operation to take out the tumour.
This leaflet is to help you understand how we would like to treat your germ cell tumour. Because
this treatment is a bit different from the way we used to treat germ cell tumours in children in the
United Kingdom (UK) it is called a research study. In this study doctors are trying to find ways to
make the treatment for germ cell tumours better but they need your mum or dad’s permission to do
this. Before you all decide whether to give your permission for you to be treated in this way, you
should read this leaflet and discuss it with your mum or dad, your doctor and your nurse. Take your
time to decide whether to give your permission or not.
1. Why are we doing this study?
Most people with germ cell tumours need some medicines called chemotherapy as well as an
operation to get better. We are pretty good at getting children with germ cell tumours better. We
think we might be able pick out some children who don’t need as much chemotherapy to get better
as we used to give. In fact some germ cell tumours can be treated without any chemotherapy at all.
We will decide how much treatment you need from where the tumour is in your body and from the
results of a special blood test. For some children this will mean no chemotherapy at all at first.
Some children will get 4 doses of chemotherapy and some will get 6 doses.
The aim is to reduce the treatment as much as we can but still make people better. To prove this is
possible will take about 5 years.
You have a germ cell tumour. All children who get germ cell tumours in the UK are being asked to
be part of this study.
You and your parents can decide if you should be treated this way. If you decide to take part your
parents will be asked to sign a consent form before starting treatment. You can change your mind
at any time, it will not change the way we look after you.
72
4. What other treatment could I have?
If you decide you do not want to take part your doctor will use another way of deciding how much
chemotherapy you need to make you better.
There are no extra tests or treatment if you take part in this study. You will already have had scans,
blood tests and probably an operation. Your doctor will have explained about having chemotherapy
and what it is like. The study uses a new way of deciding how much treatment you need. For some
children this will mean they get less chemotherapy than in the past. The chemotherapy is the same
drugs we have used to treat germ cell tumours for quite a long time.
6. How will the treatment make me feel?
Unfortunately all chemotherapy does some things we don’t want it to do. The medicines used to
treat germ cell tumours will make you lose your hair (it will come back again when the treatment is
finished), you might feel sick and you might get infections and bruises. Your doctor will give you
treatment to make you better if these things happen.
7. What are the bad things about taking part?
It is possible that giving less chemotherapy might not get as many people with germ cell tumours
better. If this seems to be happening the study will be stopped.
8. What are the good things about taking part?
We hope that some children with germ cell tumours get better with no, or less chemotherapy and
therefore fewer side effects. However we don’t know this yet. The information we get from this
study may help us to treat children with your type of tumour better in the future.
9. What if we find out more about the treatment?
Sometimes while we are doing a study we learn new things about the treatment. If this happens
your doctor will discuss with you and your mum or dad whether you stay in the study. If your mum
or dad or your doctor decides you should stop being in the study, they will decide what treatment
you should get then. If you stay in the study your mum or dad may be asked to sign a new consent
form.
10. Will my taking part be kept secret?
We would like your permission to collect information from your medical notes while you are on
the study. All information collected will be kept secret from anyone not working on this study.
When the results of the study are worked out, your tumour sample will be looked at again by a
panel of pathology doctors. This is for the study only and will not change your treatment.
73
When the study is finished the results will be written about in medical journals. If you would like
to know the results when they are available please let your doctor know. Your name will not be in
any report.
12. What if I have any questions or worries?
If you agree to take part your parents will be asked to sign a consent form. You will be given a
copy to keep. With your permission, we will let your GP know you are taking part in this study.
74


INFORMATION SHEET TO BE READ TO PATIENTS UNDER THE AGE OF 8

(Version 1.0, September 2004)
Your doctor has found out that you are poorly because you have a lump (tumour).
Your doctor will tell you about the lump and where it is in your body. You might
already have had an operation to take out the lump.
Most children with your kind of lump need to have some special medicines called
chemotherapy as well as an operation to make them better. Your doctor will tell you
more about chemotherapy. Chemotherapy medicines are strong medicines and
sometimes they make you feel poorly before they make you well again. If this
happens your doctor will give you some other medicines to make you feel better.
Your doctor will explain to your mum or dad about a new way of deciding exactly how
much chemotherapy you need. If your mum or dad says yes we will use this new way
to decide about your medicines.
We want to find the best way of knowing how much chemotherapy to give children
with your kind of lump to make them better. Your mum or dad will decide if you can
help us learn this.
75


GP INFORMATION SHEET (Version 2.0, January 2005)
Your patient (insert name) has been diagnosed with a germ cell tumour. You will receive a separate
letter about the site and stage of the tumour.
This information sheet is about a research study that has been discussed with your patient and their
family.
In the UK children’s germ cell tumours are treated with chemotherapy using etoposide, carboplatin
and bleomycin. In other countries cisplatin is substituted for carboplatin. Analysis of the results of
treatment in the UK has shown the chance of curing children’s germ cell tumours using carboplatin
to be comparable to the chance of being cured when cisplatin is used. Overall about 9 out of 10
children are cured. Carboplatin has fewer side effects than cisplatin, particularly nephrotoxicity and
ototoxicity.
Most childhood germ cell tumours secrete AFP or HCG. In the past we have given as many courses
of chemotherapy as it took to reduce the level of AFP or HCG to normal plus 2 additional courses.
This was usually about 5-6 courses. When cisplatin is used most patients require 4-6 courses.
Analysis of the last UK germ cell tumour study defined ‘risk groups’ based on site of origin of the
tumour, AFP level at diagnosis and stage. We propose to use these risk groups to determine the
amount of chemotherapy given. For some children this will mean no chemotherapy at all initially.
Some children will receive 4 courses and some will receive 6 courses of chemotherapy. This is a
small change from the way we have treated children’s germ cell tumours in the UK for over 10
years.
The aim is to reduce the treatment as much as we can but maintain the good cure rates. We
anticipate the study will run for about 5 years.
2. Why is my patient being chosen?
All children with germ cell tumours in the UK are being approached about taking part in the study.
76
3. Does my patient have to take part?
Your patient and their family will decide whether to give consent or not. They will be asked to sign
a consent form before starting treatment. They can withdraw at any time without affecting the
standard of treatment they will receive.
If your patient/their family decide they do not want to take part it is likely that they will be offered
treatment using the same chemotherapy but the number of courses will be decided by the time it
takes the blood AFP to reduce to normal as was used in the past.
5. What will happen to my patient if he/she takes part?
There are no extra tests or treatment involved if your patient takes part in this research study. Your
patient will already have had scans, blood tests and probably an operation to make the diagnosis.
Their consultant will explain about having chemotherapy and what it involves. Your patient will be
allocated a ‘risk group’ based on diagnostic features of their tumour and this will determine the
amount of chemotherapy given. For some children this will mean they receive fewer courses of
chemotherapy than in the past.
Unfortunately all chemotherapy has some side effects. The drugs used to treat germ cell tumours
(etoposide, carboplatin, bleomycin) will cause hair loss, nausea and myelosuppression with
associated risk of infection and bruising and bleeding. In addition etoposide can cause a sore
mouth. Carboplatin can cause nephrotoxicity and affect hearing. These side effects will be
monitored. In general they are mild. Bleomycin is used in a fairly low dose but can rarely cause
lung damage. Any patient at risk of pregnancy should use effective contraception.
There is a small possibility that reducing treatment for some children might increase the chance of
relapse. Because of this risk the results of this study will be monitored closely and it will be
stopped if there is any sign of survival being reduced.
happens we will discuss whether your patient continues in the study. If your patient, their family or
their consultant decide your patient should be withdrawn his/her care will be continued. If your
patient continues in the study they/their parents may be asked to sign a new consent form.
77
If taking part in this study causes harm to your patient there are no special compensation
arrangements. However if your patient is harmed due to someone’s negligence, then the family
may have grounds for legal action but they may have to pay for this. Regardless of this, if they
wish to complain or have any concerns about the way they have been treated during this study, the
normal National Health Service complaints procedure should be available to them.
11. Will my patient’s participation in the study be kept confidential?
We will obtain permission to collect information from your patient’s medical records during the
study. All information collected will be kept strictly confidential. Information on all patients in this
study will be sent to the UKCCSG (United Kingdom Children’s Cancer Study Group) Data Centre
in Leicester, UK where it will be kept. All the information that could be traced to your patient will
be kept confidential.
When the results of the study are analysed, your patient’s tumour sample will be reviewed by a
panel of pathologists. This review is for research purposes only and will not affect your patient’s
treatment.
know when the results are available please let us know. Your patient will not be identified in any
publication.
local investigator (name,tel, etc) or the UKCCSG (UKCCSG Data Centre, University of Leicester,
Hearts of Oak House, 9 Princess Road West, Leicester, LE1 6TH).
78
Centre Number:
Study Number:
Patient Identification Number for this trial:
PARENT/CHILD CONSENT FORM

Title of Project: Protocol for the treatment of Extracranial Germ Cell Tumours in children
and adolescents (GC 2005 04)
Name of Researcher:
Please initial box

1. I confirm that I have read and understand the information sheet(s) dated
(version ) for the above study and have had the
opportunity to ask questions.
2. I understand that my/my child’s participation is voluntary and that I

am/he/she is free to withdraw at any time, without giving any reason,
without my/his/her medical care or legal rights being affected.
3. I understand that sections of any of my/my child’s medical notes may be

looked at by responsible individuals from UKCCSG or from regulatory
authorities where it is relevant to my/my child’s taking part in research. I
give permission for these individuals to have access to my/my child’s
records
4. I agree/agree for my child to take part in the above study.
________________________ ________________ _______________________

Name of patient Date Signature
________________________ ________________ _______________________

Name of parent/guardian Date Signature
_________________________ ________________ _______________________

Name of person taking consent Date Signature
(if different from researcher)
_________________________ ________________ _______________________

Researcher Date Signature
1 for patient; 1 for researcher; 1 to be kept with hospital notes
79
Centre Number:
Study Number:
Patient Identification Number for this trial:
PATIENT CONSENT FORM

(Patients aged 16+ in Scotland)
Title of Project: Protocol for the treatment of Extracranial Germ Cell Tumours in children
and adolescents (GC 2005 04)
Name of Researcher:
Please initial box
1. I confirm that I have read and understand the information sheet(s)

dated (version ) for the above study and have
had the opportunity to ask questions.
2. I understand that my participation is voluntary and that I am free to

withdraw at any time, without giving any reason, without my medical
care or legal rights being affected.
3. I understand that sections of any of my medical notes may be looked at

by responsible individuals from [company name] or from regulatory
authorities where it is relevant to my taking part in research. I give
permission for these individuals to have access to my records
4. I agree to take part in the above study.
________________________ ________________ _______________________

Name of patient Date Signature
_________________________ ________________ _______________________

Name of person taking consent Date Signature
(if different from researcher)
_________________________ ________________ _______________________

Researcher Date Signature
1 for patient; 1 for researcher; 1 to be kept with hospital note
80

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PLEASE REFER TO THE CCLG WEBPAGE FOR LATEST VERSION OR TO THE DATA CENTRE BEFORE TREATING PATIENTS.

PROTOCOL FOR THE TREATMENT OF

START DATE: 1st May 2005

FINAL VERSION 1.0: SEPTEMBER 2004

Tel: 0116 249 4460

GCIII/Final Version1.0/September 2004

Chief Investigator Dr Juliet Hale

Chemotherapy Dr James Nicholson

UKCCSG Data Centre

Trial Co-ordinator Janis Hayward

Statistician David Machin

1 GC III/Final Version1.0/September 2004

Surgery Mr Simon Huddart

Radiotherapy Dr Mike Sokal

Radiology Dr John Somers

2 GC III/Final Version1.0/September 2004

3 GC III/Final Version1.0/September 2004

4 GC III/Final Version1.0/September 2004

5 GC III/Final Version1.0/September 2004

- To register all cases of mature and immature teratoma

6 GC III/Final Version1.0/September 2004

Risk group Number of Number of 3 year Number of 4 year

7 GC III/Final Version1.0/September 2004

8 GC III/Final Version1.0/September 2004

9 GC III/Final Version1.0/September 2004

Gonadal Stage 1 tumours (regardless of AFP level if secreting).

In general extragonadal tumours cannot be completely resected without mutilation. If total

Testis <5yrs, any AFP, Stage 2, 3 + 4

Testis > 5yrs, AFP < 10,000 kU/L, Stage 2 + 3

Pure germinoma/seminoma, any site, Stage 2, 3 + 4

Pure HCG secreting tumours, any HCG, Stage 2 + 3

All Stage 4 tumours except testis < 5yrs and germinoma/seminoma

All thoracic tumours, Stage 2,3 + 4

10 GC III/Final Version1.0/September 2004

Imaging of primary tumour

Tumour resectable Tumour unresectable

Biopsy (unless AFP/HCG raised

Mature/immature Malignant GCT

3.1 Eligibility Criteria

i) Newly diagnosed extracranial malignant germ cell tumour or mature/immature

3.2 Exclusion Criteria

i) Pregnant or lactating females

ii) Blood tests AFP and HCG

iv) CT/MRI scan of brain if indicated by symptoms/signs or if HCG > 10,000 IU

12 GC III/Final Version1.0/September 2004

vii) Lung function – in children old enough to co-operate

13 GC III/Final Version1.0/September 2004

Revised Histological Classification of Germ Cell Tumours

B Immature Grade 1 Immature tissue <1 Low Power(x 4)

C Malignant teratoma (Teratoma with non germ cell malignant component)

III Embryonal carcinoma

IV Yolk sac tumour

VII Mixed malignant germ cell tumour (each component to be listed)

14 GC III/Final Version1.0/September 2004

Staging for MGCTs at all sites - TNM Classification

T: Primary Tumour T0 No primary tumour pT0 No tumour on histology

N: Regional lymph node N0 No lymph node involved pN0 No regional nodes

M: Metastasis M0 No metastasis pM0 No metastasis

Stages: Clinical Postsurgical

Stage 1 CSI T1 N0Nx M0 pSI pT1 pN0pNx pM0

15 GC III/Final Version1.0/September 2004

HCG is a glycoprotein composed of α and β subunits which is normally produced by

Histopathology should be classified according to Table 2. Stage should be allocated according