Guidelines for children with renal tumours aged less than 7 months

(Addendum to SIOP 2001 protocol)

IKA

February 2005

M.M. van den Heuvel-Eibrink,

On behalf of the SIOP working group for renal tumours

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These guidelines are based on information of a retrospective collaborative study of SIOP, NWTSG,
GPOH and UKWTSG.(By M.M. van den Heuvel-Eibrink, C. Bergeron, C. Patte, N. Graf, J. de
Kraker, E. Peter, H. van Tinteren, A. Rey (SIOP/GPOH/SFOP), K. Pritchard-Jones, C. Hutton
(UKWTSG), P. Grundy, J. Anderson (NWTSG))

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 Page

Legends 3

1) Introduction 4

2) Rationale and background 5

3) Aims of this protocol amendement 7

4) Staging 8

5) Histology 8

6) Diagnostic proposal and stratification. 9

7) Therapy recommendations for WT cases aged less than 7 months 11

8) Therapy recommendation for Non-Wilms tumours 12

A. CMN 12
B. MRTK 13
C. CCSK 14

9) Chemotherapy dose adjustments for renal tumour patients 15

aged less than 7 months

10) Radiotherapeutic considerations in children with renal tumours less 16

than 7 months of age

11) Registration Forms 17

References 18

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1. INTRODUCTION

Nephroblastoma or Wilms Tumour (WT) is the most frequently occuring renal tumour in
childhood. In infancy, especially under the age of 7 months, the exact epidemiology and incidence
of WT and of other renal tumours, like congenital mesoblastic nephroma (CMN) and malignant
rhabdoid tumor of the kidney (MRTK) is not known.
From retrospective studies it has become clear that evidence based guidelines for the management
of these young patients are difficult to retrieve, and that general recommendations are not easy to
make due to incompleteness of datasets. Especially data on incidence of non-Wilms tumours, data
on dosages of radiotherapy and chemotherapy and information about short and long term toxicity
are difficult to retrieve. In the past, the evaluation of patients with renal tumours under the age of 7
months has been hampered by incomplete registration as most study groups considered very young
patients as study patients and not as protocol patients. Also, a selection biass may have occured in
the registration as less-malignant diseases like CMN, which may have been registered relatively
less frequently as compared to the relatively more malignant renal tumours.
In order to get insight into the disease characteristics, treatment, toxicity and outcome of very
young children with renal tumours it was therefore decided within the SIOP Renal Tumour Study
Group to start a prospective registration and evaluation of patients under the age of 7 months based
on general guidelines for diagnostic and therapeutic approach. The aim for the future would be to
design a SIOP study for these patients with the ultimate goal to improve the outcome meanwhile
limiting the toxic side effects of treatment in this young infant group.

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 2. RATIONALE AND BACKGROUND

Recently, a retrospective collaborative study was conducted among patients registered in the most
recent protocols from SIOP, NWTSG, GPOH and UKCCSG. In the registry of SIOP9, SIOP93-01,
NWTSG 4 and 5 and UKWT3, which altogether included 10.238 renal tumour patients, 750 renal
tumour patients were identified under the age of 7 months. The incidence of the several
histological subtypes of renal tumours is shown in Figure 1.

The distribution of histologic subtypes

Renal tumours < 7

months
N=750

WT CMN CCSK MRTK Unknown

n=432 n=133 n=15 n=59 n=111
58% 18% 2% 8% 14%

n= n= n= n=

Stage I/II 355 98 11 15

Stage III 36 17 4 22

Stage IV 2 0 0 10

Stage V 36 1 0 3

Missing 3 17 0 9

Figure 1. The distribution of renal tumours in children aged less than 7 months in the retrospective cohort from
NWTSG 3&4, SIOP 9, SIOP 93-01 and UKCCSG-WT3.

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The distribution of histologic subtypes according to age group

It also appeared from this study that in very young patients the incidence of CMN is high whereas
the incidence of WT increases as age rises (Figure 2).

Histology ~ age (% per age group)

80

70

60
WT
50
CMN
40 MRTK
CCSK
30
NWT-unknown/other
20 Missing

10

0
0 1 2 3 4 5 6
--> months

Figure 2. The distribution of histologic subtypes in children with renal tumours aged less than 7 months

In the cohort of 750 patients, 523 patients were treated with primary surgery, 103 patients received
pre-operative chemotherapy, and in 124 cases it was unknown what treatment was given upfront.

The overall survival in this retrospective cohort was 87% (WT:94%, CMN:96%, CCSK:51% and
MRTK:16%).

In patients treated with pre-operative chemotherapy only, of the minority of the cases the
information on dosage schedules was available. In general, SIOP patients received 66% of the
advised doses, and the NWTSG patients received 50% of the dose. Also, data on the toxicity were
scarce. The only comparison that could be made is the group of 77 WT patients, younger than 7
months treated according to SIOP93-01. In this group, 30% grade III and IV hematologic toxicity,
no severe infections, no cardiologic, renal, gastrointestinal and neurological toxicity was reported,
whereas 4% of the patients developed VOD. In comparion, the older WT children treated
according to SIOP 93-01 revealed 35% hematological toxicity, 6% severe infections, less than 1%
cardiological and renal toxicity, 3 % neurological toxicity and 5 % VOD. A very prudent
conclusion may be that the toxicity did not exceed the toxicity in the older age group however
again a registration biass restrains from drawing strong conclusions. Finding general
recommendations for effective dosages of chemotherapeutic drugs with a limited toxicity in this
very young infantsgroup is a challenge.

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3. AIM OF THE PROTOCOL FOR PATIENTS WITH RENAL TUMOURS LESS THAN 7
MONTHS

To investigate prospectively, the incidence of the various renal tumours in patients less than 7
months by registration of all patients with a renal tumour in this age group.

To investigate the outcome of the various subtypes after following the general guidelines
according to this protocol.

To investigate the toxicity of chemotherapy and radiotherapy in very young children treated
according to this protocol.

The aim for the future would be to improve the outcome of children with renal tumours in very
young infancy where possible, meanwhile limiting the toxic side effects of treatment.

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4. STAGING of the renal tumour
Follow the guidelines for staging according to protocol SIOP 2001
(page 33, section 5.5)

5. HISTOLOGY of the renal tumour

Follow the guidelines for histology according to protocol SIOP 2001
(page 35, section 5.6 and page 140, appendix 3))

It is important to ask for urgent histopathological review by (the national) reference

pathologist in renal tumours under the age of 7 months, due to the likelihood of non-Wilms
and particularly benign diagnosis.

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6. DIAGNOSTIC PROPOSAL AND STRATIFICATION

Minimal diagnostic procedures/tests

Follow the guidelines for histology according to protocol SIOP 2001

(page 27, section 4.6).

Ultrasound of the abdomen

Chest X-ray
Urine analysis for VMA/HVA

Stratification at diagnosis

Stage I-III patients

In patients with localised disease, primary surgery is the first choice treatment (Figure 3). In case
of a large in-operable tumour, pre-treatment with chemotherapy is recomended. In these patients
the doses of chemotherapy according to age is mandatory (section 9,Table 2). In patients in which
pre-operative chemotherapy is considered, percutaneous true-cut biopsy (PTCB) is recommended
(max 0.9 mm).

Stage IV patients

Patients with metastatic disease are not likely to be Wilms tumour or CMN patients. It is
recommended to perform percutaneous true-cut biopsy (PTCB) of the primary tumour or of a
metastasis and treat the patient based on the histological diagnosis, with dose adjustment for age
(Table 2).

Stage V patients

It is not recommended to perform percutaneous true-cut biopsy (PTCB). The guidelines for stage V
disease according to the SIOP 2001 protocol with dose adjustment according to age (page 147-151)
can be followed.

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 GUIDELINES for CHILDREN WITH A RENAL TUMOUR AGED < 7 MONTHS

Renal tumour < 7 months

Non-metastatic Stage V
Stage IV, Metastatic disease
Irresectable/
large tumours

Protocol for bilateral

WT/nephroblastomatosis
(SIOP2001)

Pre-operative Immediate PTCB tumor/metastasis

Chemo (WT) tumornephrectomy

surgery

WT/CMN Non-WT

Follow SIOP 2001 protocol for WT (adjust dose). Follow disease related protocol
*)**)***) (adjust dose)*)

Figure 3. Strategy for children less than 7 months of age with a renal tumour.

*)If radiotherapy is considered always discuss indication (and dose) with national coordinator.
**)Stage II and stage III WT patients under the age of 7 months are not eligiable for
randomisation.
***) With exception of Stage I , IR histology, they can go on to a wait and see policy after surgery

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7. Therapy recommendations for Wilms tumour patients aged less than 7 months.

It is advised to follow the SIOP 2001 protocol for nephroblastoma guidelines, with some
adjustments:

1. If radiotherapy is considered this should be discussed with the national coordinator and the
radiotherapist for the indication and the dose.

2. WT patients less than 7 months of age are not eligible for randomization

3. Stage II high risk patients :discuss with national coordinator

4. Stage I intermediate risk patients can go to a wait and see policy in stead of receiving
postoperative chemotherapy.

Classification of the tumours into low intermediate and high risk tumours is different for
patients who received pre-operative chemotherapy (page 30, section 5.2) and for those cases
that were treated with immediate surgery (page 140. appendix 3). This is important to notice
as a higher proportion of children aged < 7 months will be treated with surgery first as
compared to with the age group > 7 months.

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8. Guidelines for the treatment of non-Wilms tumors aged < 7 months.

A. Guidelines for the treatment of Congenital Mesoblastic Nephroma, age < 7

months

General advise: radical resection (including perirenal fat)

Recommended: cytogenetic analysis
After surgery:

CMN cellular type CMN classic type

Wait and see Wait and see

Stage I

Wait and see Wait and see

Stage II

Second surgery first to get Second surgery first to get

Stage III lower stage, if not possible: lower stage, if not possible: wait
wait and see and see

Stage IV Extremely rare, be sure Extremely rare, be sure

histology is revised by panel
pathologists
Extremely rare, be sure
Stage V histology is revised by panel
pathologists
histology is revised by panel
pathologists
Extremely rare, be sure
histology is revised by panel
pathologists

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B. Guidelines for the treatment of Malignant Rhabdoid tumour of the kidney (MRTK), age <
7 months

Follow the guidelines of the (inter-)national protocol for MRTK

With adjustment of the dose for age (see section 9)

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 C. Guidelines for the treatment of Clear cell sarcoma in patients age < 7
months.

Follow the SIOP 2001 HR protocol (page 30 and page 140)

Treatment proposal

Stage I Surgery and AVD

Stage II Surgery and high risk WT protocol

Stage III Surgery and high risk WT protocol

RT? *)

*) Discuss the indication for RT (postponed>age of 6 months, < 15 Gy) of each individual case with the national
coordinator.

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9. Chemotherapy dose adjustments for infants aged less than 7 months of age.

Chemotherapy

Full dose >7 months, >12 kg < 5 kg 5-12 kg

Vincristine 1,5 mg/m2 0.025 mg/kg (50%) 0.034 mg/kg (66%)
Actinomycine 45 mcg/kg omit 30 mcg/kg (66%)
Doxorubicin 50 mg/m2 0,8 mg/kg (50%) 1,1 mg/kg (66%)
Carboplatin 200 mg/m2 (x3) 3,5 mg/kg (50%) 4,5 mg/kg (66%)
Cyclophosphamide 450 mg/m2(x3) 7,5 mg/kg (50%) 10 mg/kg (66%)
VP16 150/m2(x3) omit 3,3 mg/kg (66%)

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10. Radiotherapy

If possible radiotherapy should be avoided in these young infants, because of the increased risk of
serious long term toxivcity. In case of very high risk patients (aggressive histology together with
stage 3 disease) it is advised to discuss the indication and dose with the national coordinator before
radiotherapy is administered.

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11. Registration forms.

Forms from SIOP 2001 can be used, with exception of form 5 and 11, as patients < 7 months are
not eligible for randomisation.
Form 1 page 2 ": the words under 6 months can be removed at registration as the young infants will
not be study patients anymore.

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References

1. Charles, A.K., G.M. Vujanic, and P.J. Berry, Renal tumours of childhood. Histopathology, 1998. 32: p. 293-
309.
2. Isaacs Hart, J., Congenital and neonatal malignant tumors. The American Journal of Pediatric
Hematology/Oncology, 1987. 9: p. 121-129.
3. Van den Heuvel-Eibrink M.M., Grundy P., Graf N., Patte C., Pritchard-Jones, K, Bergeron C., Peter E.,Van
Tinteren H., Andreson J.R., Hutton C., Rey A., J. de Kraker. Characteristics and survival of children with a
renal tumour in infancy (0-6 months), a collaborative retrospective study of the SIOP, NWTSG, AND UK-
CCSG.Ped Blood and Cancer, 2004,43:331:0018a.
4. Pritchard-Jones, K., Biology of Wims' tumour. Lancet, 1997. 349: p. 663-664.
5. Lowe, L.H., Pediatric renal masses: Wilms' tumor and beyond. Radiographics, 2000. 20: p. 1585-1603.
6. Lonergan, G.J., et al., Nephrogenic rests, nephroblastomatosis, and associated lesions of the kidney.
Radiographics, 1998. 18: p. 947-968.
7. McLorie, G.A., Wilms' tumor (nephroblastoma). Current opinion in urology, 2001. 11(6): p. 567-570.
8. Vujanic, G.M., et al., New definitions of focal and diffuse anaplasia in Wilms tumor: the International Society
of Paediatric Oncology (SIOP) experience. Medical and Pediatric Oncology, 1999. 32: p. 317-323.
9. Bonadio, J.F., et al., Anaplastic Wilms' tumor: clinical and pathologic studies. Journal of Clinical Oncology,
1985. 3: p. 513-520.
10. Boccon-Gibod, L., et al., Complete necrosis induced by preoperative chemotherapy in Wilms tumor as an
indicator of low risk: report from the International Society of Pediatric Oncology (SIOP) Nephroblastoma
trial and study 9. Medical and Pediatric Oncology, 2000. 34: p. 183-190.
11. Pritchard-Jones, K., Controversies and advances in the management of Wilms' tumour. Archives of Disease in
Childhood, 2002. 87: p. 241-244.
12. Trbs, R.B., et al., A 23-year experience with malignant renal tumors in infancy and childhood. European
Journal of Pediatric Surgery, 2001. 11: p. 92-98.
13. Aslam, A., A.B.M. Foot, and R.D. Spicer, Needle track seeding after percutaneous biopsy of Wilms' tumour.
International Pediatric Surgery, 1996. 11: p. 416-417.
14. Tsuchida, Y., et al., Renin production in comparison with that in Wilms' tumor. Pediatric Pathology, 1993.
13(2): p. 155-164.
15. Bisceglia, M., et al., Congenital mesoblastic nephroma: a report of a case with review of the most significant
literature. Pathol Res Pract, 2000. 196(3): p. 199-204.
16. Loeb, D.M., D.A. Hill, and J.S. Dome, Complete respons of recurrent cellular congenital mesoblastic
nephroma to chemotherapy. Journal of Pediatric Hematology/Oncology, 2002. 24(6): p. 478-481.
17. Amar, A.M., et al., Clinical Presentation of Rhabdoid Tumors of the Kidney. Journal of Pediatric
Hematology/Oncology, 2001. 23(2): p. 105-108.
18. Chung, C.J., et al., Rhabdoid tumours of the kidney in children: CT findings. American Journal of
Roentgenology, 1995. 164: p. 697-700.
19. Palmer, N.F. and W.W. Sutow, Clinical aspects of the rhabdoid tumor of the kidney: a report from the
National Wilms' tumor Study Group. Medical Pediatric Oncology, 1983. 11: p. 242-245.
20. Murphy, J.M., J.B. Beckwith, and G.M. Farrow, Tumors of the kidney, bladder and related urinary structures,
ed. AFIP. 1994, Washington.
21. Fernbach, D.J. and T.J. Vietti, Clinical pediatric oncology. 1991, Missouri: Mosby Year Book.
22. Argani, P., et al., Clear cell sarcoma of the kidney: a review of 351 cases from the national Wilms' tumor
study group pathology center. The American Journal of Surgical Pathology, 2000. 24(1): p. 4-18.
23. Pizzo, P.A. and D.G. Poplack, Principles and practice of pediatric oncology, ed. J.B.L. Company. 1999,
Philadelphia.
24. Agrons, G.A., et al., Multilocular cystic renal tumor in children: radiologic-pathologic correlation.
Radiographics, 1995. 136(3): p. 653-669.
25. Chen, F., et al., Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations
with phenotype. Hum Mutat, 1995. 5: p. 66-75.
26. Jost, L., Das nierenzellkarzinom. Schweiz Med Forum, 2003. 26.
27. Glick, R.D., et al., Renal tumors in infants less than 6 months of age. Journal of Pediatric Surgery, 2004.
39(4).
28. Skotnicka-Klonowicz, G., Nephroblastoma in children ages less than 6 months at diagnosis. Med Wieku
Rozwoj., 2003. 7(3): p. 347-357.
29. Corn, B.W., et al., Outcomes in Low-Risk Babies with half-dose chemotherapy according to the third national
Wilms' tumor study. Journal of Clinical Oncology, 1992. 8: p. 1305-1309.

18
30. Kullendorff, C.M. and T. Wiebe, Wilms' tumour in infancy. Acta Paediatrica, 1998. 87: p. 747-750.
31. Pritchard-Jones, K., et al., Older age is an adverse prognostic factor in stage 1, favourable histology Wilms'
tumor treated with vincristine monotherapy: a study by the United Kingdom Children's Cancer Study Group,
Wilms' tumor working group. Journal of Clinical Oncology, 2003. 21: p. 3269-3275.
32. Larsen, E., et al., Surgery only for the treatment of patients with stage I (Cassady) Wilms' tumor. Cancer,
1990. 66: p. 264-266.
33. Ritchey, M.L., et al., Neonatal Wilms tumor. Journal of Pediatric Surgery, 1995. 6: p. 856-859.
34. Green, D.M., et al., Treatment outcomes in patients less than 2 years of age with small, stage I, favorable-
histology Wilms' tumors: a report from the national Wilms' tumor study. Journal of Clinical Oncology, 1993.
11: p. 91-95.
35. Morgan, E., et al., Chemotherapy-related toxicity in infants treated according to the second National Wilms'
Tumor Study. Journal of Clinical Oncology, 1988. 6(1): p. 51-55.
36. Beckwith J.B. National Wilms Tumor Study : An update for pathologists. Ped and Dev Pathology. 1998,
1:79-84.

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