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