In the name of God

1. In the name of God Presented by : F.Malek

2. 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

3. 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’sradiosensitivity and introduction of active chemotherapy agents in the 1960s improved survival rates to 90%.

4. Introduction • 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, actinomycinD,doxorubicin, radiation therapy or surgery.

5. 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.

6. Introduction • 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.

7. PIZZO

8. Introduction • 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

9. 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

10. 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

11. 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

12. 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%.

13. 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.

14. 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)

15. 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

16. objective • 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

17. 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

20. 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.

21. Individual patient data • 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

23. 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)

25. Discussion • 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-randomised comparisons of NoHDT versus HDT

26. Discussion • 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;

27. 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.

28. 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).

30. Future trial design implications • 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

31. 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.

33. 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.

36. Conclusion • 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 relapsed (or refractory) Wilms’ tumours

37. 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