1. Childhood Cancers: A Review Haruna Baba Jibril MB,BS; FCMPaed; MSc (Haem) Department of Pediatrics Princess Marina Hospital

2. OUTLINE Introduction Review of common cancers - ALL - ALL - Lymphoma - Lymphoma - Solid tumors: Non-CNS - Solid tumors: Non-CNS CNS CNS Princess Marina Hospital experience The Future

3. Introduction Infectious diseases have continued to be the leading causes of death in children in developing countries HIV/AIDS has changed the grossly distorted mortality/morbidity trends in many developing countries Competition for resource allocation has intensified in the past two decades

4. M

5. Deaths Under Five Years of Age Attributable to HIV/AIDS

6. Introduction In the US cancer is the second leading cause of death in children (after accidents) Overall survival rates have improved over decades(80%) Significant advancement in diagnosis and treatment

9. Introduction These significant changes are due to: - Better understanding of tumor biology - Better understanding of tumor biology - Multidisciplinary approach to care - Multidisciplinary approach to care - Improvement in therapy - Improvement in therapy - Establishment of specialized research centres - Establishment of specialized research centres - Cooperation between study groups - Cooperation between study groups

10. Survival Factors Improved critical care Infectious disease management Nutritional support Widespread use of central venous catheters By 2010: 1 in 250 adults will be a childhood cancer survivor!!! By 2010: 1 in 250 adults will be a childhood cancer survivor!!!

11. Acute Lymphoblastic Leukemia Survival: - In the ’70s 50% - In the ’70s 50% - Currently 90% - Currently 90%Factors: - Improved supportive care - Improved supportive care - Better understanding of immunology - Better understanding of immunology - Different chemo agents and intensity - Different chemo agents and intensity needed for different disease burden needed for different disease burden

12. Progress Refinement of therapy through continued clinical trial: Refinement of therapy through continued clinical trial: - streamlining prognostic factors (host & - streamlining prognostic factors (host & leukemic cell) leukemic cell) - generation of complex protocols - generation of complex protocols - better understanding of pharmacodynamics/pharmacogenetics - better understanding of pharmacodynamics/pharmacogenetics

13. Progress - Global gene expression profiling of leukemic cells: Identify specific gene expression patterns in leukemia subtypes e.g. - Epo receptor overexposed in e.g. - Epo receptor overexposed in TEL-AML1+ ALL ( affect prolif & survival) TEL-AML1+ ALL ( affect prolif & survival) - H0X11+ ALL, expression of anti- apoptotic genes (good outcome) - H0X11+ ALL, expression of anti- apoptotic genes (good outcome)

15. Progress Drugs: - Very few new drugs - Very few new drugs - Optimization of the current ones - Optimization of the current ones - Understanding selective roles of various agents - Understanding selective roles of various agents Alternative approaches to CNS prophylaxis Consistent use of the principles of: induction intensification (or consolidation) induction intensification (or consolidation) continuation therapy re-induction for risk groups continuation therapy re-induction for risk groups

16. Progress CNS Prophylaxis: - Early prophylaxis prevents CNS & BM - Early prophylaxis prevents CNS & BM relapses more effectively relapses more effectively - Intra-thecal chemo now favored - Intra-thecal chemo now favored - CNS DXT has more complications: - CNS DXT has more complications: acute and long-term neuro-cognitive acute and long-term neuro-cognitive impact impact risk of 2 o brain tumors risk of 2 o brain tumors

17. Progress Response to therapy: - most important independent predictor of treatment success - most important independent predictor of treatment success - measured by minimal residual disease: - measured by minimal residual disease: (MRD of < 0.01% favorable) (MRD of < 0.01% favorable)

18. Progress Supportive therapy: Supportive therapy: - Routine empiric antibiotics (neutropenia) - Routine empiric antibiotics (neutropenia) - PCP prophylaxis( Cotrimoxazole) - PCP prophylaxis( Cotrimoxazole) - Use of uricolytics - Use of uricolytics

19. Hodgkin’ Lymphoma Combined modality therapy (chemo and DXT)10yr survival rate of up to 90% DXT)10yr survival rate of up to 90% Response to initial therapy determines subsequent therapy Diagnostic imaging obviates invasive staging procedures: - High resolution CT and MRI - High resolution CT and MRI FDG-PET helps assess tumor response to therapy

20. Hodgkin’ Lymphoma

21. Recurrent or refractory tumor remains a challenge - 5-year DF survival <20% - 5-year DF survival <20% - relapse >1yr 20-50% - relapse >1yr 20-50% 40-50% with high dose 40-50% with high dose chemo chemo

22. Hodgkin’ Lymphoma Novel modalities of therapy: - Nuclear factor kappa B pathway - Nuclear factor kappa B pathway - Monoclonal antibody to HL-associated - Monoclonal antibody to HL-associated receptors(CD30, CD20, CD40) receptors(CD30, CD20, CD40) - Proteasome inhibitors - Proteasome inhibitors - Radio-labeled immunoglobulin therapy - Radio-labeled immunoglobulin therapy

23. Non Hodgkin Lymphoma More diverse Mostly intermediate to high grade in children Combination chemo and supportive care:70% to 80% cure rate Etiology: remains unknown Immune deficiency: risk Role of EBV and tumor-specific fusion product (NPM-ALK)

24. Non Hodgkin Lymphoma Therapy: Systemic combination chemo Limited use of primary surgery No DXT except for emergencies Use of IV high dose Methotrexate (T-cell) Cure rate of >85% achievable Cure rate of >85% achievable

25. Non Hodgkin Lymphoma Complication of therapy: - Anthracycline-induced cardiomyopathy - Anthracycline-induced cardiomyopathy - Secondary AML - Secondary AML Novel modalities: - MoAb-based immunotherapy - MoAb-based immunotherapy - Cellular approaches (targeted cytotoxic - Cellular approaches (targeted cytotoxic T cell) T cell)

26. SOLID TUMORS:NON-CNS Neuroblastoma Biologic tumor features now allow risk-directed therapy Biologic tumor features now allow risk-directed therapy - DNA ploidy - DNA ploidy - MYCN amplification - MYCN amplification ( POG & CCG ) ( POG & CCG ) Age remains of prime consideration <1yr disseminated disease: good <1yr disseminated disease: good chance of cure with chemo and surgery chance of cure with chemo and surgery

27. SOLID TUMORS:NON-CNS Neuroblastoma >1yr with disseminated disease :suboptimal survival Local/regional disease with MYCN amp and diploidy: Poor prognosis Progression-free survival improved by intense chemo with stem cell rescue (Children Cancer Group)

28. SOLID TUMORS:NON-CNS Neuroblastoma New approaches: New approaches: - Immunotherapy - Immunotherapy - Multiple autologous stem cell transplant - Multiple autologous stem cell transplant - Newer agents: camptothecins - Newer agents: camptothecins - Anti-angiogenic agents - Anti-angiogenic agents - Targeted DXT with MIBG (an Iodine - Targeted DXT with MIBG (an Iodine 131compound) 131compound)

29. SOLID TUMORS:NON-CNS Wilms Tumor Improved outcome with a balanced use of surgery, chemo and DXT (NWTSG/CCG) Survival now 85%(30% in the ’30s) Approaches differ: US: surgery at Dx EU: Pre-chemo EU: Pre-chemo

30. SOLID TUMORS:NON-CNS Major challenges: Poorer outcome with anaplasia Poorer outcome with anaplasia - Cyclophosphamide improves survival - Cyclophosphamide improves survival 27% to 55% Stages II-IV 27% to 55% Stages II-IV Late effects of therapy vis-à-vis high cure rate - Organ damage from DXT - Organ damage from DXT - Cardiac effect of doxorubicin - Cardiac effect of doxorubicin (NWTSG trails 1 to 3) (NWTSG trails 1 to 3)

31. SOLID TUMORS:NON-CNS Rhabdomyosarcoma Cure rates now 70% in the US. Favorable histology (ERMS): 80% Unfavorable histology (ARMS); 30% DXT reduced or removed for low risk ERMS ERMS Surgery modified to preserve organ

32. SOLID TUMORS:NON-CNS Advances: - Cyclophos added to a sub set of low risk patients for a better outcome - Cyclophos added to a sub set of low risk patients for a better outcome - Ifosfamide/etoposide:no improved outcome for intermediate risk patients - Ifosfamide/etoposide:no improved outcome for intermediate risk patients (IGRMSG) (IGRMSG) 20% continue to have poor prognosis:5yr survival <25%:experimental drugs being tried on them

33. CNS TUMORS Therapeutic Challenges: - anatomic constraint on resection - anatomic constraint on resection - blood-brain &blood-CSF barriers - blood-brain &blood-CSF barriers - sensitivity of developing brain to toxic insult - sensitivity of developing brain to toxic insult Germinoma remains the most responsive tumor to chemo and DXT Survival rate increases unimpressive except for some: low-grade glioma, epedymoma, medulloblastoma

34. List of Cancers seen in children at Princess Marina Hospital from June 2001-June 2007 S/N Cancer Type Total No. Alive Lost to follow-up 1 Leukemia ALL AML AML553300 2 Lymphomas NHL(+BL) HL HL641420 3 Wilms Tumor 310 4Neuroblastoma210 5Retinoblastoma520 6Rhabdomyosarcoma440 7 Kaposi Sarcoma 420 8Ganglioneuroblastoma110 9 Mesoblastic Nephroma 110 10Osteosarcoma1-1 11Hepatosarcoma100 12Medulloblastoma(Cerebellar)100 13Teratoma110 14Unknown100

35. Princess Marina Hospital The Pluses: Availability of most chemo agents Availability of antibiotics Pathology services including post mortem Imaging services: X-ray, US, CT scan IV infusions Blood products Growth factors: G-CSF, Epo, ICU facilities Relatively easy referral to RSA

36. Princess Marina Hospital Challenges: Late presentation Inadequate investigative facilities (cytogenetics) Blood products:- red cell-packed/whole - platelets - platelets Restrictions in antibiotic use Stock outs of chemotherapy Lack of trained personnel

37. Princess Marina Hospital RECOMMENDATION A comprehensive oncology unit Training of staff Oncology Group - Protocols - Protocols - Registry - Registry - Studies and Publications - Studies and Publications - Collaboration - Collaboration - Policies on supportive and palliative care - Policies on supportive and palliative care

38. Thank You Thank You Kealeboga Kealeboga Nagode Nagode