renal cancers rationale

Renal tumours

Andrew PotterRegistrar

Radiation OncologyRoyal Adelaide Hospital

2004 WHO classification - kidney tumours

Renal cell tumours Metanephric tumours Nephroblastic tumours Mesenchymal tumours

Children Adults

Mixed mesenchymal and epithelial Neuroendocrine Haematopoietic/lymphoid

Renal cell carcinoma

(Renal adenocarcinoma)

Renal cell tumours

Malignant Clear cell RCC - 70% Multilocular & papillary RCC 10-15% Chromophobe RCC - 5%

Benign (5%) Oncocytoma Papillary adenoma

Familial RCC Von Hippel Lindau VHL gene 3p25-26

Multiple bilateral clear cell RCC Hereditary papillary RCC MET oncogene 7q31

Multiple bilateral papillary RCC Hered leiomyomatosis and RCC FH gene 1q42

Solitary unilateral tumours Birt Hogg Dube syndrome BHD gene 17p11

Multiple oncocytoma, chromophobe RCC Tuberous sclerosis TSC1 gene 9q34 TSC2 gene 16p13

Multiple bilateral AML

Clear cell RCC <5% multicentric or bilateral 50% stage I & II at

presentation <5% stage IV Organ involvement with

metastases 40% bone 22% adrenals 15% brain 14% kidney

Late mets up to 10+ years

Papillary RCC

70% stage I More commonly

bilateral and multifocal

Oncocytoma

Benign tumours when accurately defined 33% appear to have central stellate scar Acceptable features

Mitoses Necrosis Small foci of clear cell change

EM - numerous mitochondria “Oncocytosis”

Fuhrman Grade Assigned a Grade 1 - 4 Based on nuclear size, shape and prominence of

nucleoli Tumour is given the highest pattern present Nuclear grade 5 yr survival

1 65% 2 35% 3 30% 4 10%

TNM stagingT - primary tumourT - primary tumour

TXTX Primary tumour cannot be assessedPrimary tumour cannot be assessed

T0T0 No evidence of primary tumourNo evidence of primary tumour

T1T1 Tumour confined to kidney, <7cmTumour confined to kidney, <7cm

T1aT1a ≤≤4cm, confined to kidney4cm, confined to kidney

T1bT1b >4cm but <7cm, confined to kidney>4cm but <7cm, confined to kidney

T2T2 Tumour >7cm, confined to kidneyTumour >7cm, confined to kidney

T3T3 Tumour extends into major veins or adrenal or perinephric tissue but not Tumour extends into major veins or adrenal or perinephric tissue but not beyond Gerota’s fasciabeyond Gerota’s fascia

T3aT3a Direct invasion of adrenal gland, perirenal and/or sinus fatDirect invasion of adrenal gland, perirenal and/or sinus fat

T3bT3b Gross extension into renal vein or IVCGross extension into renal vein or IVC

T3cT3c Extends into IVC above diaphragm or wall of IVCExtends into IVC above diaphragm or wall of IVC

T4T4 Invasion beyond Gerota’s fasciaInvasion beyond Gerota’s fascia

TNM stagingN - regional lymph nodesN - regional lymph nodes

NXNX Nodes cannot be assessedNodes cannot be assessed

N0N0 Regional lymph nodes not involvedRegional lymph nodes not involved

N1N1 Metastasis in a single regional lymph nodeMetastasis in a single regional lymph node

N2N2 Metastases in >1 regional lymph nodeMetastases in >1 regional lymph node

M - distant metastasesM - distant metastases

MXMX Metastases cannot be assessedMetastases cannot be assessed

M0M0 No distant metastasesNo distant metastases

M1M1 Distant metastasesDistant metastases

Stage groupingsII T1T1 N0N0 M0M0IIII T2T2 N0N0 M0M0

IIIIIIT3T3 N0N0 M0M0T1T1 N1N1 M0M0T2T2 N1N1 M0M0

IVIV

T4T4 N0N0 M0M0T4T4 N1N1 M0M0Any TAny T N2N2 M0M0Any TAny T Any NAny N M1M1

Prognostic factors for RCC Pathologic stage 5 yr survival

T1 - 2 organ confined 70-90% T3 50-70% N+, M1 5-30%

Tumour size < 4 cm > 90% 4 - 10 cm 50% > 10 cm 0%

Histological type Clear cell 70% Papillary, Chromophobe 85% Multilocular cystic 100% Medullary, Collecting duct 0%

Surgery

Role of renal biopsy Organ confined Locally Advanced Metastatic

Indeterminate lesions Small or indeterminate renal lesions present a

management dilemma Traditional teaching was to avoid biopsy in

fear of “seeding” biopsy tract We now know that;

Tumour seeding from biopsy is rare Tumours < 4cm 25% are benign, < 1cm 50% Core biopsy has higher PPV than FNA Need experienced Pathologist to interpret

Role of renal biopsy Definite role

Lesion may relate to a systemic disease Possible metastatic disease ie. when a +’ve result excludes surgery

Suggested role When active surveillance is considered To identify benign lesions which need no

treatment When MIT is considered, and for follow up

Organ confined disease

Active surveillance Radical nephrectomy

Open Laparoscopic Da Vinci

Nephron sparing surgery (NSS) Partial nephrectomy - open or lap Minimally invasive therapies (MIT)

Cryotherapy, RFA, HIFU, interstitial LASER

Natural history of small lesions Volpe et al, Cancer 2004

32 solid lesions < 4 cm Followed median 27.9 mths with US/CT Mean growth rate 0.2 cm/yr 9 surgically removed after average 3 yrs 8 RCC, 1 oncocytoma No mets during followup

Excision is an option, but must accept risks of surgery and possibility lesion is benign or clinically insignificant

Active surveillance Contrast CT each 3-6 mths for 2 yrs to determine

baseline kinetics, increase interval Advantages

May avoid unnecessary surgery and complications Disadvantages

Burden of follow up Small but definite risk of metastases Need dedicated radiologist to compare studies

Clinical decision must balance the risks and likely benefits of both intervention and observation in an individual patient

Nephrectomy complications

Death Adjacent organ injury

Bowel, spleen, liver, pancreas, major vessels Infection Bleeding Renal impairment

Indications fornephron-sparing surgery (NSS) Absolute

nephrectomy would render patient anephric bilat tumours, solitary kidney, familial RCC

Relative Future threat to contralateral kidney

Elective Small, exophytic, polar location Benign disease

Issues with NSS Open partial remains the gold standard Recent enthusiasm for less invasive

techniques Growing awareness of natural history

30% of small lesions are benign or indolent Metastatic potential increases > 3cm

Better imaging technology available Up to 10% risk of contralateral disease

Partial nephrectomy technique Flank incision, extraperitoneal approach Mobilise within Gerota’s fascia Access to renal vessels, control with loops Mannitol Clamp renal artery Renal hypothermia Excise tumour Close vessels and collecting system Insert drain +/- stent

Outcomes Long-term outcomes approach radical nephrectomy

5y survival 90-95% Local recurrence 4-6%

Complications Mortality <1% Adjacent organ injury <1% Infection 3% Fistula/urine leak 5-10% ARF 5-10% 2 Haemorrhage 2-3%

Complications

Mortality <1% Re-operation <3% Adjacent organ injury <1% Infection/collections 3% Fistula/urine leak 5-10% ARF 5-10% 2 Haemorrhage 2-3%

Laparoscopic partial nephrectomy Technically demanding “Softer” indications to the OPN Importance of imaging

CT with 3D reconstruction Angiography Intraoperative US

Clamping, cooling, warm ischaemic time (WIT) Difficult to reproduce open technique, often omitted Acceptable WIT 30min and longer can have

detrimental effect

3D CT reconstruction

Outcomes Similar complications, plus conversion Double the warm ischaemic time With careful selection it may approach open

technique Advantages

Decrease length of stay (2 vs 5 days) Decrease analgesia requirement

Disadvantages Increased costs and “laparoscopic” risks

Radiotherapy

Radiosensitivity of RCC is variable Animal experiments suggest a theoretical benefit

to preoperative RT (? Reduce intra-operative seeding)

Historically several series suggested clinical benefit to adjuvant (post-op) RT Limited applicability because of long time span,

improvements in staging, surgery, changing RT technology

Neo-adjuvant radiotherapy

Rotterdam study Radical nephrectomy vs neo-adjuvant RT (30Gy/15#

APPA) plus nephrectomy No overall survival or metastasis-free survival

advantage (both 50% 5-year survival) No improvement in resectability Further study to 40Gy - still no advantage

Swedish study Poorer 5-year survival with pre-op RT (47% vs 63%)!

Adjuvant radiotherapy Some early studies suggested advantage to post-op

RT but poorly designed and reported Newcastle (UK) study

Poorer survival with adjuvant RT (55Gy) vs surgery alone Not stratified by grade or stage

Copenhagen study Stage II/III disease No difference in RCC relapse Significantly more GI complications (44%) in RT group 19% of deaths attributed to RT complications

So what is the role for RT? MSKCC and Kao retrospective series

Potential benefit of RT in selected cases where there is a high risk of local failure, ie: Pre-op RT in unresectable, locally-advanced tumours

(“downstaging”), including T3a/T3c T3b (vena cava invasion) doesn’t necessarily increase risk of local

failure Incomplete resection with positive margins Lymph node involvement

RT in these cases may improve local control but probably not overall survival

Clear role in palliation

RT techniques Pre-op RT 40-50Gy to kidney + lymphatics for

unresectable lesions may improve resectability 45-50Gy post-op

10-15Gy boost (ie. ~60Gy total) to gross residual disease Include scar to reduce chance of scar recurrence

CT-planned, multifield technique Dose limitations (fully fractionated)

Liver D30 <36-40Gy Contralateral kidney <20Gy max Spinal cord <45Gy max

Cryotherapy Cryoprobes use liquid argon/nitrogen to form an

ice ball at the probes’ tip (-180C) Shown to produce predictable and reproducible

tissue destruction Tumour necrosis at -40C Double freeze-thaw cycle

Rapid freeze and slow thaw Aim to extend ice ball 1cm beyond tumour Monitor visually and with intra-operative US Percutaneous, laparoscopic, open techniques

Outcomes

Complications Pain at probe site - Ileus Collecting system injury - Fistula Adjacent organ injury - Haemorrhage

Harmon et al J Urol 2003;169:229 76 patients with mean follow up 17 mths 3 failures Considered success if -’ve biopsy, no gad

enhancement on MRI or tumour shrinkage

Radio Frequency Ablation high frequency AC causes heat-based tissue damage T 60-100ºC

denaturation of cellular protein, melting of lipids, coagulative necrosis

2 zone of damage due to vascular thrombosis Open, laparoscopic or percutaneous Difficult to monitor procedure with imaging Exophytic lesions are most suitable

“heat sink” effect of renal hilum Impedance monitoring required

Disadvantages

Incomplete ablation Need for multiple treatments Lack of real-time monitoring Serious histological concerns about

viable tumour

Minimally invasive therapy High Intensity Focussed Ultrasound (HIFU)

Extracorporeal US focused on lesion Temperature at site increases thermal injury Nonthermal injury by cavitation and cellular oscillation ablation volumes are controlled by adjusting power, duration and

location of ultrasound pulses LASER Interstitial therapy

fibre placed directly into lesion under CT/MRI heat and tissue injury using Nd:YAG 25W, 10 - 30 min

Metastatic disease Role of nephrectomy

Palliative Therapeutic

Spontaneous regression of met’s < 1 % of cases 1969 - 2000 35 papers describing 65 cases < 50% associated with nephrectomy

Role of metastectomy ? Bisphosphonates

RT techniques

Palliation Long survival is possible, even with distant

metastases, where performance status is good Encompass metastatic deposit (or local

recurrence) with 2-3cm margins Higher doses (up to 35-40Gy) may be required

to overcome radioresistance Symptomatic relief in 64-84% of patients

Chemotherapy

Metastatic RCC remains one to the most resistant cancers

Conventional therapy has little to offer ? More effective in non-clear cell tumours

Platinum, gemcitabine, doxorubicin RCT’s < 10% response, including

vinblastine Hormonal treatment is ineffective

Cytokines

15-30% response rate for clear cell tumours Small % experience a durable, complete

remission RCT’s vs placebo or observation

IL 2 - Clark et al JCO 2003 IFN - Messing et al JCO 2003 Observation superior in both No advantage to combination IL2 + IFN

SWOG 8949 241 patients randomised Received IFN 2b - 3% response 106 of 120 pt’s underwent nephrectomy Improved survival 11.1 vs 8.1 mths (p<0.05)

EORTC 30 947 85 patients IFN 2b nephrectomy 29/42 completed surgical arm vs 40/42 Improved survival 17 vs 7 mths (p<0.05)

Tyrosine kinase receptor inhibitors

Sunitinib TK receptor inhibitor Interferes with tumour angiogenesis Partial responses up to 40% Up to 10% complete response Median time to progression ~8 months

Renal pelvis/ureteric carcinoma

Renal pelvis/ureteric carcinoma

Transitional cell (“urothelial”) carcinoma 7% of renal neoplasms 1.5-2% bilateral (synchronous) 6-8% bilateral (asynchronous) M:F = 2-3:1 Most common age 50-70 years Increased risk of other urinary tract malignancies

(eg. Bladder)

Natural history and presentation

Frequently multi-focal Haematogenous and lymphatic metastases Metastasis relates to histologic grade Presents with

Haematuria (70-95%) Pain (8-40%) Flank mass (10-20%) Bladder irritation(5-10%)

TNM stagingT - primary tumourT - primary tumourTXTX Primary tumour cannot be assessedPrimary tumour cannot be assessedT0T0 No evidence of primary tumourNo evidence of primary tumourTaTa Papillary, non-invasive carcinomaPapillary, non-invasive carcinomaTisTis Carcinoma Carcinoma in situin situT1T1 Tumour invades subepithelian connective tissueTumour invades subepithelian connective tissueT2T2 Tumour invades muscularisTumour invades muscularisT3T3 (For renal pelvis only) tumour invades into peripelvic fat or into (For renal pelvis only) tumour invades into peripelvic fat or into

renal parenchymarenal parenchymaT3T3 (For ureter only) tumour invades into periureteric fat(For ureter only) tumour invades into periureteric fatT4T4 Tumour invades adjacent organs or through kidney into Tumour invades adjacent organs or through kidney into

perinephric fatperinephric fat

TNM stagingN - regional lymph nodesN - regional lymph nodes

NXNX Nodes cannot be assessedNodes cannot be assessed

N0N0 Regional lymph nodes not involvedRegional lymph nodes not involved

N1N1 Metastasis in a single regional lymph node (≤2cm max)Metastasis in a single regional lymph node (≤2cm max)

N2N2 Metastases in a single regional lymph node (>2 but ≤5cm max), Metastases in a single regional lymph node (>2 but ≤5cm max), or multiple nodes (≤5cm max)or multiple nodes (≤5cm max)

M - distant metastasesM - distant metastases

MXMX Metastases cannot be assessedMetastases cannot be assessed

M0M0 No distant metastasesNo distant metastases

M1M1 Distant metastasesDistant metastases

Stage groupings0a0a TaTa N0N0 M0M00is0is TisTis N0N0 M0M0II T1T1 N0N0 M0M0IIII T2T2 N0N0 M0M0IIIIII T3T3 N0N0 M0M0

IVIVT4T4 N0N0 M0M0Any TAny T N1-N3N1-N3 M0M0Any TAny T Any NAny N M1M1

Prognostic factors

5-year survival By stage

Ta - 80% T1 - 83% T2 - 72% T3 - 51% T4 - 16%

By grade G1 - 83% G2 - 75% G3 - 52% G4 - 0%

Management

Radical nephroureterectomy Removal of contents of kidney, Gerota’s fascia,

ureter and cuff of bladder at the distal extent High loco-regional recurrence rates (30%)

with less extensive surgery Only consider local excision with small,

localised, low grade lesions or where kidney preservation is important

Adjuvant therapy Little data to support routine adjuvant RT Small series suggest improved local control with

post-op RT (40-60Gy) for T3-T4 tumours 11% vs 46% recurrence 27% vs 17% survival …in a series of 20 patients

Chemotherapy, eg. MVAC, as used in bladder protocols Again, no clear role for routine adjuvant chemo

RT techniques

For elective adjuvant RT, CTV includes renal fossa and course of ureter to bladder

CT-based planning 45-50Gy in 25# for microscopic disease 5-10Gy boost for positive nodes or gross

residual disease ? Concurrent chemotherapy

Wilms’ tumour

(Nephroblastoma)

Wilms’ tumour

Highly curable Most common renal malignancy of

childhood 7 cases per million children (<15 years) Peak incidence 3-4 years of age Sporadic or hereditary, or in the context of

genetic disorders

Associations WAGR syndrome

Wilms’ tumour, aniridia, GU malformations, mental retardation

Denys-Drash syndrome Pseudohermaphroditism, mesangial sclerosis, renal

failure, Wilms’ tumour Beckwith-Weidemann syndrome

Somatic gigantism, omphalocele, macroglossia, GU abnormalities, ear creases, hypoglycaemia, hemihypertrophy

Genetics

WT1 gene Tumour suppressor gene on chromosome 11p13 Probably has a role in glomerular and gonadal

development Seen in 82% of Wilms’ patients

WT2 Beckwith-Weidemann syndrome Maps to chromosome 11p15.5

Pathology Most are solitary, unilateral

lesions 7% bilateral 12% multifocal in single

kidney Uniform pale grey/tan

appearance, often with cysts, haemorrhage and necrosis

Pseudocaspule Extension into renal

vein/IVC

Histology

Classically 3 cell types Epithelial (tubular) (A) Blasternal

(undifferentiated, small blue cells) (B)

Stromal (C) Anaplasia is an

unfavourable histologic feature

AA

BBCC

Staging and treatment Different approaches with similar results

National Wilms’ Tumor Study Group (NWTSG), USA Nephrectomy adjuvant chemotherapy

International Society for Paediatric Oncology (SIOP) Neo-adjuvant chemotherapy nephrectomy

NWTSG staging

I - confined to kidney, completely excised II - extension beyond kidney, completely

excised III - residual tumour, confined to abdomen IV - haematogenous metastases/involved

nodes beyond abdomen/pelvis V - bilateral

NWTSG I-IV conclusions Routine post-op RT not necessary for

Stage I favourable histology Stage I anaplastic Stage II favourable histology

10 weeks vincristine + actinomycin-D sufficient Stage III favourable histology best treated with VCR/Act-

D/ADR* + 10Gy RT to flank (or 20Gy without ADR) Addition of cyclophosphamide did not improve stage IV

disease Pulse intensive actinomycin-D decreased toxicity with

equivalent efficacy

*VCR = vincristine, Act-D = actinomycin-D, ADR = doxorubicin (Adriamycin),VP16 = etoposide (don’t ask me!), CPA = cyclophosphamide

NWTSG V regimensStageStage HistologyHistology RTRT ChemoChemo DurationDuration

I-III-II FavourableFavourableNoNo VCR + ActDVCR + ActD 18 weeks18 weeks

II AnaplasticAnaplastic

III-IVIII-IV FavourableFavourableYesYes VCR + ActD + VCR + ActD +

ADRADR 24 weeks24 weeksII-IVII-IV Focal anaplasiaFocal anaplasia

II-IVII-IV AnaplasticAnaplastic YesYes VCR + CPA + VCR + CPA + VP16 + ADRVP16 + ADR 24 weeks24 weeks

I-IVI-IV Clear cell sarcoma Clear cell sarcoma of kidneyof kidney

YesYes Carboplatin + Carboplatin + VP16 + CPAVP16 + CPA 24 weeks24 weeks

I-IVI-IV Rhabdoid tumour Rhabdoid tumour of kidneyof kidney

NWTSG V radiotherapy

StageStage Favourable Favourable histologyhistology AnaplasticAnaplastic Clear cell or Clear cell or

rhabdoidrhabdoid

II No RTNo RT 10Gy to flank10Gy to flank

IIII No RTNo RT 10Gy to flank10Gy to flank 10Gy to flank10Gy to flank

IIIIII 10Gy to flank or abdomen10Gy to flank or abdomen**

IVIV12Gy whole lung12Gy whole lung##

Abdo RT if Abdo RT if operative stage IIIoperative stage III

12Gy whole lung,12Gy whole lung,Abdo RT if Abdo RT if operative stage operative stage II/IIIII/III

12Gy whole lung,12Gy whole lung,Abdo RTAbdo RT

# if lung mets on CXR * 10.8Gy/6# flank or 10.5Gy/7# abdomen

SIOP staging (at time of surgery) I - confined to kidney, completely excised II - extending beyond kidney, completely excised

Invasion beyond capsule (perirenal/perihilar fat) Invasion of regional lymph nodes (N+) Invasion of external vessels Invasion of ureter

III - incomplete excision, without haematogenous metastases Preoperative biopsy Preoperative or perioperative rupture Invasion of extra-regional lymph nodes

IV - distant metastases V - bilateral renal tumours

SIOP studies

Staging and histological diagnosis delayed until after neoadjuvant chemo and surgery completed

SIOP-1 - pre-operative RT reduces intra-operative tumour rupture

SIOP-2 - 6 months post-op chemo produced same DFS and OS as 15 months chemo

SIOP-5 - pre-op chemo gave similar results to pre-op RT (in terms of tumour spill and staging)

SIOP studies

SIOP-6 - no difference in OS for stage I receiving 17 vs 38 weeks post-op chemo, post-op RT prevents local recurrence where nodes are involved

SIOP-9 - optimum pre-operative chemo 4 weeks (no advantage to 8 weeks). Epirubicin overcame local recurrence in stage II disease

SIOP 93-01

Pre-operative chemo: vincristine weekly for 4 weeks, 2 courses of Act-D (days 1,2,3 and 14,15,16)

Post-op chemo based on stage and pathological response to chemo - tumour graded as low, intermediate or high risk

SIOP 93-01

Stage I intermediate or stage I high risk - all received Further weekly vincristine for 4 weeks Act-D days 8-12 Randomised to further chemo (weeks 10,17) or

no therapy No difference in survival at 2 years (88.8% vs

91.4%)

SIOP radiotherapy

RT limited to post-op only Indications

Favourable histology stage II (N+) and stage III receive 15Gy

Anaplastic stage II/III and clear cell sarcoma stages I-III receive 30Gy

Stage IV receive whole lung RT only where lung mets still seen on post-op CXR

Important RT considerations Open lines of communication with paediatric oncologists,

surgeons, pathologists Book planning session & machine time (can always cancel)

prior to surgery Is an anaesthetic required?

(<4-5yo, but individualise) Allow time for discussion with parents Child must be stable post-op, free of ileus or diarrhoea,

ANC >1000, Hb >10, plats.>75,000 Interaction with chemotherapy agents (Act-D &

doxorubicin)

Flank RT (1)AT PRESENTATION

Favourable Histology (stage III) residual disease postop (micro/macroscopic) confined to flank* Hilar nodes Para-aortic nodes

Anaplastic Wilms tumour Indications as above , but also include Stage II

*Boost 10.8Gy to macro disease >3cm in max. diameter

Flank RT

Clear Cell Sarcoma of the Kidney All stages when abdominal disease confined to flank

Rhabdoid Tumour of the kidney As above Stage III (gross residual disease) Stage IV…+/- RT week 6 after assessment of response

to CT

Flank RT

(2) AT RELAPSE Localised intra-abdominal relapse

Flank RT TIMING

Start no later than day 9

VOLUME Determined by pre-op CT outline of the kidney and any

associated tumour with a 1cm margin (PTV) (include nodes if positive)

cross midline to cover full width of vertebral bodies at levels concerned (avoid contralateral kidney)

4-6 MV photons AP:PA

Flank RT

DOSE 10.8Gy/6fractions

Whole Abdominal RT (WART) INDICATIONS

Peritoneal seeding

Gross residual abdominal disease*

Preoperative intraperitoneal rupture

Diffuse/major operative spill

*Local 10.8Gy supplements to volumes > 3cm or more in max. diameter.

WART TIMING

NO later than day 9 VOLUME

To cover the whole intraperitoneal cavity

Diaphragmatic domes to the bottoms of the obturator foramina. Exclude femoral heads

4-6 MV photons AP:PA

DOSE 10.5Gy/7 fractions

Whole lung RT INDICATIONS

Pulmonary metastases at diagnosis(Stage IV) Pulmonary mets. at relapse.

ISSUES Remains controversial CXR detected vs “CT only” mets Pathologically confirmed solitary nodule At relapse give at end of CT Localised foci of disease persisting 2 weeks after 12Gy can be either

excised or be given additional 7.5Gy <18 months, give trial of CT alone.

Whole lung RT VOLUME From apex of lung to

posteroinferior recess of costophrenic angles (~level of L1), block shoulders

Simulate in quiet respiration (image intensifier)

AP:PA 6 MV photons Dose: 12Gy/1.5Gy per

fraction

Metastases BONE

field includes obvious disease with a 3cm margin 30.6Gy

BRAIN Whole brain 30.6Gy (1.8Gy/#)

LIVER RT only if unresectable 2cm margin if localised Dose 19.8-30.6Gy, depending on volume

Criticisms

NWTSG Higher intra-operative

tumour spillage (reduced DFS but equivalent OS)

SIOP No up-front

histological diagnosis (5% incorrect)

“True” pre-op staging not known

? Under-treatment by down-staging

OutcomesSIOP-9SIOP-9 NWTSG VNWTSG V

DFSDFS OSOS DFSDFS OSOS

2 years2 years

I-IIII-III 89%89% 93%93% 86%86% 96%96%

IVIV 70%70% 85%85% 72%72% 86%86%

4 years4 years

I-IIII-III 87%87% 90%90% 86%86% 95%95%

IVIV 65%65% 81%81% 69%69% 81%81%