Presented by : F.Malek
 An
international strategy to determine
the role of high dose therapy in recurrent
Wilms’ tumour

Tam C. Ha a,k, Filippo Spreafico b, Norbert Graf c, Sandro
Dallorso d, Jeffrey S. Dome e,Fondazione

Istituto Nazionale Tumori, Via G Venezian 1, 20133 Milano, Italy
Department of Paediatric Oncology and Haematology, Saarland
University Hospital, Homburg/Saar, Germany
Outpatient and Home Care Service, Department of Haematology
and Oncology, G Gaslini Children’s Hospital, Genoa, Italy
Division of Oncology, Children’s National Medical Center,
Washington, DC, USA
Department of Pediatrics, Medical College of Wisconsin, USA
Institute of Child Health, Royal Victoria Hospital, Newcastle
upon Tyne NE1 4LP, UK
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 Wilms’
tumour (WT) is the most common
genitourinary tract cancer in childhood, with
an annual incidence of 1 per 100,000
children.

Early recognition of the tumour’s
radiosensitivity and introduction of active
chemotherapy agents in the 1960s improved
survival rates to 90%.
 The
success of treatment of newly diagnosed
WT
presents challenges in determining optimum
therapy
for the small number of patients who suffer a
recurrence.
 Before
the mid 1980s, recurrent WT was
treated with
combinations of vincristine, actinomycin
D,doxorubicin,
radiation therapy or surgery.
 In
many cases, identical chemotherapy
agents were used for treatment of both
primary and recurrent disease and long term
overall survival (OS) rates for recurrent cases
were poor at 24–43%.
 More dose intensive second line
combination regimens incorporating drugs
such as CPM, ifex, platiniums and Vp16 have
been shown to be efficacious, but their
impact on long-term survival remains poorly
defined.
 Due
to poor long-term survival rates, several
groups have incorporated myeloablative high
dose chemotherapy into relapse regimens.
 However, no randomised comparison of the
potential additional benefit of such an
approach over systematically intensifying
non-myeloablative chemotherapy has been
concluded.
 The
application of risk-adapted intensive
retreatment
strategies has improved survival after relapse
of WT to
nearly 80% for the subgroup who relapse after
minimal
first line therapy consisting of only vincristine
and actinomycin
 However,
nearly two thirds of relapses fall
into
 higher risk groups that have received prior
treatment with doxorubicin and, sometimes,
with radiotherapy and additional
chemotherapeutic agents.
 Nevertheless approximately half of these
‘high risk’ relapses can be salvaged with a
combination of intensive multiagent
chemotherapy, together with surgery and
radiotherapy where feasible
 An
international consensus is forming on the
approach to risk stratification of relapsed
WT.
 There
is recognition of three groups:
standard, high and very high risk; according
to initial treatment received, which in turn is
largely dictated by tumour stage and
histology


Clinical relevance of other putative
prognostic factors such as time to relapse
and site of recurrence is less certain.
The standard risk group, who relapse after
vincristine and actinomycin D in first line
therapy, are generally salvageable
 Current
approaches using fairly intensive
dose and scheduling of different
chemotherapy agents to those used first line
( combinations of doxorubicin, ifex/CPM,
etoposide and sometimes carboplatin)
combined with routine use of radiotherapy
and surgery of relapse site where feasible,
achieve second 3-year event free survival
(EFS) of approximately 80%.
 However,
high- and very-high-risk relapse
groups present two areas of specific clinical
need.
 The first need is to define the role of
myeloablative high dose chemotherapy in
treatment of relapse occurring after therapy
including doxorubicin
and/or radiotherapy (high-risk) where survival
rates
of approximately 50% are reported with
systemic use of
intensive chemotherapy.
 Second
is to identify more efficacious
treatments for tumours with initial high risk
histology (anaplastic or pre-treated
blastemal type) or adverse molecular
characteristics that recur or progress after
first line intensive multiagent therapies and
have very poor outcomes (very-high-risk
group)
 there
is an important clinical question
 about whether high dose chemotherapy
requiring ASCR (autologous stem-cell rescue)
is able to increase overall survival.
 Retreatment with intensive but nonmyeloablative
chemotherapy would theoretically lower the
risk of morbidity and mortality and long-term
renal dysfunction
 The
objectives of this paper are to review
historical
evidence for anticipated 3-year EFS and OS
rates after
relapse in WT, to quantify how outcome
depends on
intensity of pre-relapse treatment received
and to investigate whether a retreatment
approach using high dose therapy with ASCR
should be tested in those of poor prognosis
following their relapse
 All
studies that investigated treatment of
relapsed
 WT using intensive chemotherapy with or
without high dose chemotherapy and ASCR,
and provided individual patient, graphical or
summary data, on EFS and/or OS
 median
age at initial diagnosis of 57 months,
majority (54.4%) female, numbers in Stages I,
II and III were similar 25%
 First line therapy included VA in 94.3%
(199/211)of patients of whom in 23.7%
(50/211) combination
was given alone and 69.7% (147/211) with one
other
agent.
A
total of 13 NoHDT regimens were utilised
amongst
134 of 137 patients. Regimens including Cb and
Etop
were used alone (15 and 1 patients) and
together (10)
 Etop was also used in combination with one
(13/83), three (10) and four (10) other
agents
A
total of 26 HDT regimens were utilised
amongst
155 of the 168 patients. Regimens including
Mel were
given to 81.5% (137/168) either alone (1
patient), in
combination with one other agent in 11.3%
(19/168),
of whom 14 received Vcr, and 35.7% (60/168)
with
two (MEC, 53) and 33.9% (57/168) three (Cb +
Cyc +
 We
have summarised event free survival
(EFS) and
overall survival (OS) experience of patients
with
relapsed or refractory Wilms’ tumour (WT)
with the
objective of comparing patients who received
high dose
therapy (HDT) with those who did not
(NoHDT).
 In our situation, there are no randomised
trials to review so that information from non-
 and
from single arm studies of either NoHDT
or HDT
alone had to be synthesised. Thus, at best
interpretation of all our findings must be
taken with caution
 The situation is compounded by some studies
reporting only summary information
describing type of patients included, not
clearly indicating when survival time
measure begins: for example, date of first
recurrence of WT or date of post recurrence
therapy started;
 Despite
these difficulties we attempted a
synthesis
of relevant information but remain conscious
of constraints this imposes on conclusions
drawn.
 Thus
our analysis provides biased estimates
of, for example the hazard ratio, to an
extent that is not possible to quantify.
Pooling all studies that provided individual
patient data suggested an advantage to
HDT,HREFS = 0.87 andHROS = 0.94
However, incorporating a subjective assessment of
the quality of evidence provided by each study
 suggested HREFS = 1.18 and HROS = 0.87.
Nevertheless,a stratified analysis of those
studies which provided individual patient data on
both HDT and NoHDT gave HREFS = 0.83 (Table 5)
and HROS = 0.92.
 Further, there was a suggestion that benefit
from HDT was greatest in those of the highest
risk groups: Risk II,
HREFS = 0.90 and for Risk III, 0.50 (Fig. 5).

 As
is clear from the preceding sections,
patients with
recurrent (or refractory) unilateral Wilms’
tumour have
 experienced a range of treatments prior to
relapse and their subsequent outcome
following post relapse treatment may depend
critically on this prior therapy. Review of all
studies (Table 5 and Appendix 3) suggests a
possible improvement in 3-year EFS and OS
for patients receivingHDTwith HRs of 0.87
and 0.94 respectively
 In
summary, we have some evidence that
defined risk
groups have a differing prognosis (Fig. 4), and
Risk III
group is most likely to benefit from more
intensive treatment.
 We also conclude that, despite information
from
studies describing 1226 patients (NoHDT 992,
HDT
234), much uncertainty remains This
uncertainty indicates very clearly the need
 Assuming
3-year EFS of 25% (Fig. 4) for Risk III
 patients on Standard, then if this is improved to
50%with Test this implies a HREFS = 0.5, a major but
unlikely improvement.
 Using a two-sided test size of 5% and power 80%
implies a randomised trial of 120 patients would be
required to establish convincingly such an effect.
 It
is important to review all available
evidence when
ascertaining whether a randomised trial to
address a
clinically important therapeutic question is
required
and whether there are clinically relevant
subgroups with differing levels of potential
benefit.
 We have collated information from the
published literature on patients less than 21
years old treated for
 We
conclude that the evidence is suggestive
of the value of a high dose option,
particularly in the highest risk relapse group
 We outline a proposal for a multicentre
multinational
worldwide randomised trial to compare
standard and
more intensive options, which by incorporating
results
of this analysis, should lead to an improved
level of certainty in the evidence base within
an achievable time frame for this rare group