Childhood Cancers: A Childhood Cancers: A ReviewReview

Haruna Baba Jibril Haruna Baba Jibril MB,BS; FCMPaed; MSc (Haem)MB,BS; FCMPaed; MSc (Haem)

Department of PediatricsDepartment of PediatricsPrincess Marina HospitalPrincess Marina Hospital

OUTLINEOUTLINE

IntroductionIntroductionReview of common cancersReview of common cancers

- ALL- ALL - Lymphoma- Lymphoma - Solid tumors: Non-CNS- Solid tumors: Non-CNS CNSCNS

Princess Marina Hospital experiencePrincess Marina Hospital experienceThe FutureThe Future

IntroductionIntroduction

Infectious diseases have continued to be Infectious diseases have continued to be the leading causes of death in children in the leading causes of death in children in developing countriesdeveloping countries

HIV/AIDS has changed the grossly HIV/AIDS has changed the grossly distorted mortality/morbidity trends in distorted mortality/morbidity trends in many developing countriesmany developing countries

Competition for resource allocation has Competition for resource allocation has intensified in the past two decadesintensified in the past two decades

MM

Deaths Under Five Years of Deaths Under Five Years of Age Attributable to HIV/AIDSAge Attributable to HIV/AIDS

33.6%

36.5%

40.6%

42.2%

57.7%

4.0%

0% 10% 20% 30% 40% 50% 60%

Zambia

Namibia

Swaziland

Zimbabwe

Botswana

Global

Introduction Introduction

In the US cancer is the second leading In the US cancer is the second leading cause of death in children (after accidents)cause of death in children (after accidents)

Overall survival rates have improved over Overall survival rates have improved over decades(80%)decades(80%)

Significant advancement in diagnosis and Significant advancement in diagnosis and treatmenttreatment

IntroductionIntroduction

These significant changes are due to: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 - Establishment of specialized research centrescentres

- Cooperation between study groups- Cooperation between study groups

Survival FactorsSurvival Factors

Improved critical careImproved critical care

Infectious disease managementInfectious disease management

Nutritional supportNutritional support

Widespread use of central venous Widespread use of central venous catheterscatheters

By 2010: 1 in 250 adults will be a By 2010: 1 in 250 adults will be a childhood cancer survivor!!!childhood cancer survivor!!!

Acute Lymphoblastic LeukemiaAcute Lymphoblastic Leukemia

Survival:Survival: - In the ’70s 50%- In the ’70s 50% - Currently 90%- Currently 90%Factors: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

ProgressProgress

Refinement of therapy through Refinement of therapy through continued clinical trial: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 - better understanding of pharmacodynamics/pharmacogeneticspharmacodynamics/pharmacogenetics

ProgressProgress

- Global gene expression profiling of leukemic - Global gene expression profiling of leukemic cells:cells:

Identify specific gene expression patterns in Identify specific gene expression patterns in leukemia subtypesleukemia 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-- H0X11+ ALL, expression of anti-apoptotic genes (good outcome)apoptotic genes (good outcome)

ProgressProgress

Drugs: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 prophylaxisAlternative approaches to CNS prophylaxisConsistent use of the principles of:Consistent use of the principles of:

induction intensification (or consolidation) induction intensification (or consolidation)

continuation therapy re-induction for risk continuation therapy re-induction for risk groupsgroups

ProgressProgress

CNS Prophylaxis:CNS Prophylaxis: - Early prophylaxis prevents CNS & BM - Early prophylaxis prevents CNS & BM relapses more effectivelyrelapses 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 impactimpact risk of 2risk of 2oo brain tumors brain tumors

ProgressProgress

Response to therapy:Response to therapy:

- most important independent predictor of - most important independent predictor of treatment successtreatment success

- measured by minimal residual disease:- measured by minimal residual disease:

(MRD of < 0.01% favorable)(MRD of < 0.01% favorable)

ProgressProgress

Supportive therapy:Supportive therapy:

- Routine empiric antibiotics (neutropenia)- Routine empiric antibiotics (neutropenia)

- PCP prophylaxis( Cotrimoxazole)- PCP prophylaxis( Cotrimoxazole)

- Use of uricolytics- Use of uricolytics

Hodgkin’ LymphomaHodgkin’ Lymphoma

Combined modality therapy (chemo and 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 Response to initial therapy determines subsequent therapysubsequent therapyDiagnostic imaging obviates invasive Diagnostic imaging obviates invasive staging procedures:staging procedures:

- High resolution CT and MRI- High resolution CT and MRIFDG-PET helps assess tumor response to FDG-PET helps assess tumor response to therapytherapy

Hodgkin’ LymphomaHodgkin’ Lymphoma

Hodgkin’ LymphomaHodgkin’ Lymphoma

Recurrent or refractory tumor remains a Recurrent or refractory tumor remains a challengechallenge

- 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

chemochemo

Hodgkin’ LymphomaHodgkin’ Lymphoma

Novel modalities of therapy: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

Non Hodgkin LymphomaNon Hodgkin Lymphoma

More diverseMore diverseMostly intermediate to high grade in Mostly intermediate to high grade in childrenchildrenCombination chemo and supportive Combination chemo and supportive care:70% to 80% cure ratecare:70% to 80% cure rateEtiology: remains unknownEtiology: remains unknownImmune deficiency: riskImmune deficiency: riskRole of EBV and tumor-specific fusion Role of EBV and tumor-specific fusion product (NPM-ALK)product (NPM-ALK)

Non Hodgkin LymphomaNon Hodgkin Lymphoma

Therapy:Therapy:

Systemic combination chemoSystemic combination chemo

Limited use of primary surgeryLimited use of primary surgery

No DXT except for emergenciesNo DXT except for emergencies

Use of IV high dose Methotrexate (T-cell)Use of IV high dose Methotrexate (T-cell)

Cure rate of >85% achievableCure rate of >85% achievable

Non Hodgkin LymphomaNon Hodgkin Lymphoma

Complication of therapy:Complication of therapy: - Anthracycline-induced cardiomyopathy - Anthracycline-induced cardiomyopathy - Secondary AML- Secondary AML

Novel modalities:Novel modalities: - MoAb-based immunotherapy- MoAb-based immunotherapy - Cellular approaches (targeted cytotoxic - Cellular approaches (targeted cytotoxic T cell)T cell)

SOLID TUMORS:NON-CNSSOLID TUMORS:NON-CNS

NeuroblastomaNeuroblastoma Biologic tumor features now allow risk-directed Biologic tumor features now allow risk-directed therapytherapy

- DNA ploidy- DNA ploidy - MYCN amplification- MYCN amplification ( POG & CCG )( POG & CCG )

Age remains of prime considerationAge remains of prime consideration <1yr disseminated disease: good <1yr disseminated disease: good chance of cure with chemo and surgerychance of cure with chemo and surgery

SOLID TUMORS:NON-CNSSOLID TUMORS:NON-CNS

NeuroblastomaNeuroblastoma

>1yr with disseminated >1yr with disseminated disease :suboptimal survivaldisease :suboptimal survival

Local/regional disease with MYCN amp Local/regional disease with MYCN amp and diploidy: Poor prognosisand diploidy: Poor prognosis

Progression-free survival improved by Progression-free survival improved by intense chemo with stem cell rescue intense chemo with stem cell rescue (Children Cancer Group)(Children Cancer Group)

SOLID TUMORS:NON-CNSSOLID TUMORS:NON-CNS

NeuroblastomaNeuroblastoma 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)

SOLID TUMORS:NON-CNSSOLID TUMORS:NON-CNS

Wilms TumorWilms Tumor

Improved outcome with a balanced use of Improved outcome with a balanced use of surgery, chemo and DXT (NWTSG/CCG)surgery, chemo and DXT (NWTSG/CCG)

Survival now 85%(30% in the ’30s)Survival now 85%(30% in the ’30s)

Approaches differ: US: surgery at Dx Approaches differ: US: surgery at Dx

EU: Pre-chemoEU: Pre-chemo

SOLID TUMORS:NON-CNSSOLID TUMORS:NON-CNS

Major challenges:Major challenges:

Poorer outcome with anaplasiaPoorer outcome with anaplasia

- Cyclophosphamide improves survival- Cyclophosphamide improves survival

27% to 55% Stages II-IV27% to 55% Stages II-IV

Late effects of therapy Late effects of therapy vis-à-visvis-à-vis high cure rate 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)

SOLID TUMORS:NON-CNSSOLID TUMORS:NON-CNS

RhabdomyosarcomaRhabdomyosarcoma

Cure rates now 70% in the US.Cure rates now 70% in the US.

Favorable histology (ERMS): 80%Favorable histology (ERMS): 80%

Unfavorable histology (ARMS); 30% Unfavorable histology (ARMS); 30%

DXT reduced or removed for low risk DXT reduced or removed for low risk

ERMSERMS

Surgery modified to preserve organSurgery modified to preserve organ

SOLID TUMORS:NON-CNSSOLID TUMORS:NON-CNS

Advances:Advances: - Cyclophos added to a sub set of low risk - Cyclophos added to a sub set of low risk

patients for a better outcomepatients for a better outcome - Ifosfamide/etoposide:no improved - Ifosfamide/etoposide:no improved

outcome for intermediate risk patientsoutcome for intermediate risk patients (IGRMSG)(IGRMSG)

20% continue to have poor prognosis:5yr 20% continue to have poor prognosis:5yr survival <25%:experimental drugs being survival <25%:experimental drugs being tried on themtried on them

CNS TUMORSCNS TUMORS

Therapeutic Challenges: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 Germinoma remains the most responsive tumor to chemo and DXTto chemo and DXT

Survival rate increases unimpressive except for Survival rate increases unimpressive except for some: low-grade glioma, epedymoma, some: low-grade glioma, epedymoma, medulloblastomamedulloblastoma

List of Cancers seen in children at Princess Marina HospitalList of Cancers seen in children at Princess Marina Hospitalfrom June 2001-June 2007from June 2001-June 2007

S/NS/N Cancer TypeCancer Type TotalTotal No. AliveNo. Alive Lost to follow-upLost to follow-up

11 Leukemia ALLLeukemia ALL

AMLAML

55

55

33

33

00

00

22 Lymphomas NHL(+BL)Lymphomas NHL(+BL)

HLHL

66

44

11

44

22

00

33 Wilms TumorWilms Tumor 33 11 00

44 NeuroblastomaNeuroblastoma 22 11 00

55 RetinoblastomaRetinoblastoma 55 22 00

66 RhabdomyosarcomaRhabdomyosarcoma 44 44 00

77 Kaposi SarcomaKaposi Sarcoma 44 22 00

88 GanglioneuroblastomaGanglioneuroblastoma 11 11 00

99 Mesoblastic NephromaMesoblastic Nephroma 11 11 00

1010 OsteosarcomaOsteosarcoma 11 -- 11

1111 HepatosarcomaHepatosarcoma 11 00 00

1212 Medulloblastoma(Cerebellar)Medulloblastoma(Cerebellar) 11 00 00

1313 TeratomaTeratoma 11 11 00

1414 UnknownUnknown 11 00 00

Princess Marina HospitalPrincess Marina Hospital

The Pluses:The Pluses:Availability of most chemo agentsAvailability of most chemo agentsAvailability of antibioticsAvailability of antibioticsPathology services including post mortemPathology services including post mortemImaging services: X-ray, US, CT scanImaging services: X-ray, US, CT scanIV infusionsIV infusionsBlood productsBlood productsGrowth factors: G-CSF, Epo,Growth factors: G-CSF, Epo,ICU facilitiesICU facilitiesRelatively Relatively easyeasy referral to RSA referral to RSA

Princess Marina HospitalPrincess Marina Hospital

Challenges:Challenges:

Late presentationLate presentation

Inadequate investigative facilities (cytogenetics)Inadequate investigative facilities (cytogenetics)

Blood products:- red cell-packed/wholeBlood products:- red cell-packed/whole

- platelets- platelets

Restrictions in antibiotic useRestrictions in antibiotic use

Stock outs of chemotherapyStock outs of chemotherapy

Lack of trained personnelLack of trained personnel

Princess Marina HospitalPrincess Marina Hospital

RECOMMENDATIONRECOMMENDATIONA comprehensive oncology unitA comprehensive oncology unitTraining of staffTraining of staffOncology GroupOncology 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

Thank YouThank You KealebogaKealeboga

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