The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy and Response Directed High Dose Myeloablative Chemotherapy or Maintenance Chemotherapy (Milan Strategy).
BACKGROUND
Historically, the 5-year overall survival (OS) for metastatic medulloblastoma (MMB) was less than 40%. The strategy of post-operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed high dose chemotherapy (HDC) was reported in a single center study to improve 5-year OS to 73%. We report outcomes of this strategy in UK.


METHODS
Questionnaires were sent to all 20 UK pediatric oncology primary treatment centers to collect retrospective data on delivered treatment, toxicity and survival with this strategy in children aged 3-19 years with MMB.


RESULTS
Between February 2009 and October 2011, 34 patients fulfilled the entry criteria of the original study. The median age was 7 years (range 3-15). Median interval from surgery to HART was 109 versus 85 days in the original series. The incidence of grade 3 or 4 hematological toxicities with IC and HDC was 83-100%. All 16 patients who achieved complete response by the end of the regimen remain in remission but only three of 18 patients with lesser responses are still alive (P < 0.0001). With a median follow-up of 45 months for survivors, the estimated 3-year OS is 56% (95% CI 38, 71). This result is outside the 95% CI of the original study results and encompasses the historical survival result of 40%.


CONCLUSIONS
Within the limits of statistical significance, we did not replicate the improved survival results reported in the original series. The reasons include differences in patient sub-groups and protocol administration. International randomized phase III studies are needed.
Clinical Oncology, Cambridge University Hospitals NHS Foundation Trust Addenbrooke's Hospital, Cambridge, UK.
Sindu
S
Vivekanandan
Paediatric Oncology, Cambridge University Hospitals NHS Foundation Trust Addenbrooke's Hospital, Cambridge, UK.
Richard
R
Breene
Paediatric Oncology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Ramya
R
Ramanujachar
Paediatric Oncology, Children's Hospital for Wales, Cardiff, UK.
Heidi
H
Traunecker
Paediatric Oncology, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK.
Barry
B
Pizer
Clinical Oncology, University College London Hospitals NHS Foundation Trust, London, UK.
Mark N
MN
Gaze
Clinical Oncology, The Royal Marsden NHS Foundation Trust, Surrey, UK.
Frank
F
Saran
Clinical Oncology, The Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK.
Nicky
N
Thorp
Paediatric Oncology, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
Martin
M
English
Paediatric Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Kate Ah
KA
Wheeler
Paediatric Oncology, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK.
Antony
A
Michalski
Paediatric Oncology, Nottingham Children's Hospital University of Nottingham, Nottingham, UK.
David A
DA
Walker
Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Daniel
D
Saunders
Clinical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK.
Fiona
F
Cowie
Clinical Oncology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Alison
A
Cameron
Paediatric Oncology, The Leeds Teaching Hospitals, Leeds, UK.
Susan V
SV
Picton
Cancer Research Unit, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
Deepak
D
Parashar
Clinical Oncology, Cambridge University Hospitals NHS Foundation Trust Addenbrooke's Hospital, Cambridge, UK.
Gail
G
Horan
Clinical Oncology, Cambridge University Hospitals NHS Foundation Trust Addenbrooke's Hospital, Cambridge, UK.
Michael V
MV
Williams
D000293:Adolescent; D000328:Adult; D002528:Cerebellar Neoplasms / Q000401:mortality* / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D060828:Induction Chemotherapy; D007223:Infant; D007231:Infant, Newborn; D060046:Maintenance Chemotherapy; D008297:Male; D008527:Medulloblastoma / Q000401:mortality* / Q000628:therapy*; D012189:Retrospective Studies; D011795:Surveys and Questionnaires; D015996:Survival Rate; D006113:United Kingdom / Q000453:epidemiology
HART; chemotherapy; induction; medulloblastoma; metastatic; myeloablative