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 HIGH-DOSE
RAPID AND STANDARD INDUCTION
CHEMOTHERAPY FOR PATIENTS AGED OVER 1
YEAR WITH STAGE 4 NEUROBLASTOMA: A
RANDOMISED TRIAL
† Lancet Oncol 2008; 9: 247–56
Neuroblastoma is one of the most common
childhood cancers.
 > 1 y/o + stage 4 disease→poor prognosis.
 Current standard treatment for HR
neuroblastoma:
♦ Initial induction chemotherapy,
♦ Attempted surgical resection of the primary
tumour,
♦ Myeloablation: consolidation tx
♦ local radiation to the primary tumour-site
♦ differentiation treatment with 13-cis retinoic
acid.

Rapid administration of max. tolerated doses of
drugs
>>> more rapid cell death, ↓drug resistance.
>>> some drugs will be given when the bone
marrow has been suppressed by a previous dose
of chemotherapy.
♣ Vincristine and cisplatin (ie, 80 mg/m2) are the
least myelotoxic.
♣ An intensive chemotherapy protocol was
designed that had a 10-day interval between
treatments, rather than the conventional 21-day
interval, and that used relatively non-myelotoxic
drugs alternated with myelotoxic drugs.

 rapid treatment
(cisplatin [C],
vincristine [O],
carboplatin [J],
etoposide [E], and
cyclophosphamide
[C], known as
COJEC)
 standard
treatment
(vincristine [O],
cisplatin [P],
etoposide [E], and
cyclophosphamide
[C], ie, OPEC,
alternated with
vincristine [O],
carboplatin [J],
etoposide [E], and
cyclophosphamide
[C], ie, OJEC).
 Oct
30, 1990 ↔ March 18, 1999.
 Patients >1 y/o and adults who fulfilled the
International Neuroblastoma Staging System
(INSS) criteria for stage 4 neuroblastoma and
who had not received previous C/T for their
disease were eligible.
 Patients with stage 4S neuroblastoma were
not eligible.
 Eligible
patients were randomly assigned to
receive standard(ST) or rapid treatment(RT).
 C/T was planned if neutrophils were
>1.0×10⁹/L and platelets >100×10⁹/L in
patients assigned to ST, or irrespective of
these counts as long as any infection was
controlled in patients assigned to RT.
 For both groups of patients, if GFR<80
mL/min / 1.73 m2 BSA, the subsequent
course of cisplatin should be omitted.
 Day
154 for ST >>> if there was CR, VGPR,
PR or mixed
response
 Day 100 for RT >>> (MR) with a CR of any
BM involvement
 >>> total surgical resection of the primary
tumour
 Gross total resection of the primary tumour
was assessed by CT or ultrasonography.

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All patients who had undergone resection were
scheduled to receive myeloablation as consolidation
treatment.
consisted of single-agent melphalan (200 mg/m2)
with haemopoieticstem-cell rescue.
After patients recovered from myeloablation, they
were randomised to receive 13-cis retinoic acid (0.75
mg/kg daily or 22.5 mg/m2 daily) or no 13-cis
retinoic acid.
better event-free survival with 13-cis retinoic acid
changed the protocol in November, 1999, so that all
patients received 6 months of treatment with 13-cis
retinoic acid (160 mg/m2 daily for 2 weeks in each
month).
Radiotherapy was not given.
Clinical assessments:
 history and physical assessment, measurements
of BW, BH, BP, CBC, BUN and electrolytes, serum
proteins, Mg, Ca and P, liver function tests, and
urine microscopy.
 GFR was measured :
◘ ST: before the courses 1, 3, and 6, and 4 wks
after completion of C/T,
◘ RT: days 1, 39, and 100
 High-tone audiometry :
♥ ST: at diagnosis, before course 6 and at the end
of C/T
♥ RT: at diagnosis, on days 39 and 100


At diagnosis and during treatment:
-measurement of urinary catecholamines,
-assessment of primary tumour(by CT or US),
-bone marrow assay
-bone metastases (by technetium-90 bone scan),
-CXR, and radiological visualisation of other
imageable disease were undertaken.
-MIBG: recommanded
-Assessment of tumours
◙ ST: before courses 3 and 6; at 4 weeks after
completion of C/T; and also immediately after
surgery.
◙ RT: on days 40 and 100, and after surgery.
 After
completion of induction treatment,
surgery, and myeloablation (if appropriate),
patients were followed up according to the
practice of the treating hospital.
 Primary
endpoints were 3-year, 5-year,
and10-year event-free survival (EFS).
 EFS was calculated from the date of
randomisation to date of relapse or
progression or death from any cause.
 Overall survival (OS)was calculated from the
date of randomisation to date of death
from any cause or to date of the last followup for those who were alive.
♣ Reasons for not attempting surgery after
induction treatment were:
 no detectable primary tumour
 surgical resection at diagnosis
 early death
 disease progression
 poor or no response
 complete response
 inoperable primary tumour
Two patients, both male, developed second
malignancies:
► One patient received ST and developed
rhabdomyosarcoma 27 months after diagnosis
and subsequently died at 34 months.
► The other patient received RT and developed
osteosarcoma 125 months after diagnosis; he is
currently alive a 10.9 years from diagnosis.
♫ High-tone hearing loss was his major long-term
side-effect, which did not progress.

 Hypothesis
>>> increasing dose-intensity of
induction chemotherapy by rapid drug
scheduling in patients aged over 1 year with
stage 4 neuroblastoma improved EFS.

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Current treatment for HR
Only myeloablation and the addition of
differentiation treatment with 13-cis retinoic acid for
6 months have been shown to be effective.
Although many different induction regimens for HR
neuroblastoma have been described, no regimen has
been shown to be better than the rest.
Comparison of EFS and OS is difficult between
different induction regimens.
EFS might be improved if induction treatment is
rapidly completed and followed by early
myeloablation (prevent drug resistance).
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In our randomised trial, the standard regimen was given every 21
days if patients had haematological recovery and the rapid
regimen was given every 10 days, irrespective of blood counts.
dose intensity of the rapid regimen was 1.8 times higher than
the standard regimen.
The total amount of C/T given compared with that prescribed in
the protocol was less in the rapid regimen (67% vs79%), but was
more often given on time.
10-year OS of the rapid regimen was 28.3%.
The patients in our trial were assigned only single-agent
melphalan for myeloablation, local treatment was not intensive
and most did not receive 13-cis retinoic acid at a therapeutic
dose ; 5-year EFS was lower
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A higher proportion of patients achieved overall CR or
VGPR (74%) compared with the SG (53%).
EFS and OS were consistent with these findings support to
the higher efficacy of the rapid regimen
Deaths due to toxicity were not different from previously
published regimens.
Patients assigned rapid treatment had a median neutrophil
count of below 1.0×10⁹/L for the duration of treatment.
had more episodes of febrile neutropenia and septicaemia,
with more patients receiving antibiotics and antifungal
treatment.
only two (2%) fungal infections were recorded in the RG
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The addition G-CSF »»» ↓ episodes of and numbers of
patients with febrile neutropenia, and resulted in
fewer days in hospital, fewer days with fever, and
shorter antibiotic use.
GI toxic effects were not significantly different
between the two treatment regimens.
Two potential concerns of the rapid regimen were
renal toxicity and ototoxicity that were induced by
platinum compounds.
rapid scheduling did not increase toxicity
In this trial, we noted second malignancies, but no
treatment-related myelodysplasia or leukaemia.
In conclusion, a rapid induction regimen
increases dose intensity in the treatment of
patients with high risk neuroblastoma.
 Although EFS and OS seem to be better with the
rapid than with the standard regimen, only EFS
at 5 years reached significance.
 Additionally, the rapid regimen produces a rapid
response in patients with high-risk
neuroblastoma and enables myeloablation to be
given much earlier, which could improve long
term survival.
