In the name of God
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Transcript of In the name of God
IN THE NAME OF GOD
Presented by : F.Malek
EUROPEAN JOURNAL OF CANCER (2013)
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
INTRODUCTION 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%.
INTRODUCTION The success of treatment of newly
diagnosed WTpresents challenges in determining optimum
therapyfor 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.
INTRODUCTION 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.
INTRODUCTION Due to poor long-term survival rates,
severalgroups 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.
PIZZO
INTRODUCTION The application of risk-adapted intensive
retreatmentstrategies has improved survival after
relapse of WT tonearly 80% for the subgroup who relapse
after minimalfirst line therapy consisting of only
vincristine and actinomycin
INTRODUCTION 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
INTRODUCTION 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 non-myeloablative
chemotherapy would theoretically lower the risk of morbidity and mortality and long-term renal dysfunction
OBJECTIVE The objectives of this paper are to
review historicalevidence for anticipated 3-year EFS and
OS rates afterrelapse in WT, to quantify how outcome
depends onintensity 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
MATERIALS AND METHODS
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
INDIVIDUAL PATIENT DATA 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.
INDIVIDUAL PATIENT DATA A total of 13 NoHDT regimens were
utilised amongst134 of 137 patients. Regimens including
Cb and Etopwere 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 +
Etop, 46)
DISCUSSION We have summarised event free survival
(EFS) andoverall survival (OS) experience of
patients withrelapsed or refractory Wilms’ tumour (WT)
with theobjective of comparing patients who
received high dosetherapy (HDT) with those who did not
(NoHDT). In our situation, there are no
randomised trials to review so that information from non-randomised comparisons of NoHDT versus HDT
DISCUSSION and from single arm studies of either
NoHDT or HDTalone 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).
FUTURE TRIAL DESIGN IMPLICATIONS As is clear from the preceding sections,
patients withrecurrent (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 for randomised trials to resolve therapeutic issues.
TRIAL SIZE 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.
CONCLUSION It is important to review all available evidence
whenascertaining whether a randomised trial to
address aclinically important therapeutic question is
requiredand 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
relapsed (or refractory) Wilms’ tumours
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 of patients