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2011 Vaeth Lecture2011 Vaeth Lecture

Sarah S. Donaldson, MDSarah S. Donaldson, MDStanford UniversityStanford University

Jerome M. Vaeth, MDJerome M. Vaeth, MD1925 1925 -- 19981998

Lessons in Radiation Therapy Lessons in Radiation Therapy from the Clinical Trials in from the Clinical Trials in

Pediatric Sarcoma ManagementPediatric Sarcoma Management

2011 Vaeth Lecture 2011 Vaeth Lecture Sarah S. Donaldson, MDSarah S. Donaldson, MD

Stanford UniversityStanford University

Clinical Trials Clinical Trials ––A challenge in pediatric cancerA challenge in pediatric cancer

•• cchildhood cancers are rare; need large hildhood cancers are rare; need large numbers, long follownumbers, long follow--upup

•• risk of late effects, often unknownrisk of late effects, often unknown•• barriers to overcomebarriers to overcome•• nneed to collaborate and participate in eed to collaborate and participate in

clinical trialsclinical trials

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Participation in Clinical Trials by Age Ewing's Sarcoma – Chemotherapy + RadiotherapyPOG 8346 – Radiotherapy randomization

Standard whole boneStandard whole bone Experimental involved fieldExperimental involved field

Ewing's SarcomaProblemProblem

-- Many primary tumors are smallMany primary tumors are small-- IF same as whole bone IF same as whole bone -- No difference in 2 study groupsNo difference in 2 study groups

SolutionSolution-- Administer Rx to IF Administer Rx to IF -- Study patterns of failureStudy patterns of failure

OutcomeOutcome-- Local failures are centralLocal failures are central-- IF + chemotherapy became IF + chemotherapy became

standard of carestandard of care

Localized Ewing's Sarcoma – Treatment: Chemotherapy + Local Therapy

Radiotherapy or Surgery?

Induction chemotherapy 12 wks Randomize Rx Induction chemotherapy 12 wks Randomize Rx

Randomize to RT or ResectionRandomize to RT or Resection

Problem: Problem: Local therapy can not be predicted up front. Local therapy can not be predicted up front. Patients, families + physicians want to choose Patients, families + physicians want to choose their therapy.their therapy.

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No randomized study comparing XRT vs SurgeryNo randomized study comparing XRT vs Surgery

Bias in selection factorsBias in selection factors

Resectable lesions are likely to be:Resectable lesions are likely to be:Smaller tumorsSmaller tumorsPeripheral rather than centralPeripheral rather than centralFollowing good response to induction chemotherapyFollowing good response to induction chemotherapyand may require postoperative, supplemental XRTand may require postoperative, supplemental XRT

Irradiated lesions are likely to be:Irradiated lesions are likely to be:NonNon--resectableresectableLarger tumorsLarger tumorsCentral (axial skeleton)Central (axial skeleton)Following poor response to induction chemotherapyFollowing poor response to induction chemotherapy

OSOS 69%69%

RFSRFS 69%69% 70%70% 7474%% 66%66%

LCLC 86%86% 100100%% 95%95%

CESS-86 Outcome @ 5 years

XRTXRT SurgSurg Surg + XRTSurg + XRT

Summary: Considering the selection criteria forSummary: Considering the selection criteria forlocal therapy, XRT yielded RFS & OS local therapy, XRT yielded RFS & OS comparable to radical surgerycomparable to radical surgery

Protocol DevelopmentProtocol Development

Look at what’s been doneLook at what’s been done

To know what to do nextTo know what to do next

Rewards from clinical trials ...Rewards from clinical trials ...CChildhood hildhood RRhabdomyosarcoma habdomyosarcoma -- IRSGIRSG

Grouping SystemGrouping System

I. Localized disease completely resected;

(Regional nodes not involved)

II. Grossly resected, microscopic residual (with or without regional nodal disease)

III. Incomplete resection, biopsy only, gross residual disease

IV. Metastatic disease

4

0

25

50

75

100

I II III IV

Clinical Grouping SystemClinical Grouping SystemIRS IIIRS II

1313 1717

5353

1717

%%

FFS by Group FFS by Group -- IRS IVIRS IV

0.0

0.2

0.4

0.6

0.8

1.0

YearsYears0 2 4 6 8 10

Group II

Group IGroup I

Group IIIGroup III

Group IV Group IV

P < 0.001P < 0.001

Group I Localized disease, completely resected

•• IRS I: Patients randomized to postoperative RT vs no RT

• Dose: 40 - 60 Gy in 1.5 – 2 Gy fractions

• Time: Immediately after surgery, week 0

• Conclusion: 5 yr DFS not improved by RT;RT for Grp I patients omitted

p < 0.001p < 0.001

IRS IRS –– I / II, with RTI / II, with RT

IRS IRS –– I / II, no RTI / II, no RT

IRS IRS -- III, with RTIII, with RT

IRS IRS -- III, no RTIII, no RT

Grp I Grp I -- Failure Free SurvivalFailure Free SurvivalAlveolar and Undifferentiated Sarcoma HistologyAlveolar and Undifferentiated Sarcoma Histology

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

00 22 44 66 88 1010

Wolden et al. JCO 17: 3468, 1999Wolden et al. JCO 17: 3468, 1999

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Group II Group II

a a -- Microscopic residual diseaseMicroscopic residual disease

b b -- Regional lymphatic spread, resectedRegional lymphatic spread, resected

c c -- BothBoth

Gross Total ResectionGross Total Resection

5 yr FFS Group II patients5 yr FFS Group II patients

IRS IV IRS IV 87 %87 %

Prognostic FactorsPrognostic Factors

-- EmbryonalEmbryonal histology vs otherhistology vs other

-- Subgroup II a / II b Subgroup II a / II b

-- IRS III / IV IRS III / IV

Local failure Local failure -- 8 %8 %

Regional Regional -- 4 %4 %

Distant Distant -- 14 %14 %

Smith et al. JCO 19:4058, 2001Smith et al. JCO 19:4058, 2001

Group IIIGroup III

Incomplete resection with Incomplete resection with gross residual diseasegross residual disease

5 Year Data, IRS5 Year Data, IRS--III, Group IIIIII, Group III

ENDPOINTENDPOINT

FFS 70 %FFS 70 %Survival 78 %Survival 78 %

FAILURE SITE FAILURE SITE

Local 19 % Local 19 % Regional 2 %Regional 2 %Distant 11 %Distant 11 %

Wharam et al. JCO 22:1902, 2004Wharam et al. JCO 22:1902, 2004

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Factors Affecting Failure Factors Affecting Failure at 5 yrs: IRSat 5 yrs: IRS--III, Group IIIIII, Group III

FACTORFACTOR LOCAL (%)LOCAL (%) DISTANT (%)DISTANT (%)

All PatientsAll Patients 1919 1111

NNOO / N/ N11 16 / 3216 / 32 9 / 279 / 27

< 5 / ≥ 5 cm< 5 / ≥ 5 cm 16 / 2116 / 21 8 / 178 / 17

TT11 / T/ T22 14 / 1914 / 19 8 / 148 / 14

Wharam et al. JCO 22:1902, 2004Wharam et al. JCO 22:1902, 2004

Radiotherapy DoseRadiotherapy DoseIRS IRS -- III, Group IIIIII, Group III

AGEAGE < 5 cm< 5 cm ≥≥ 5 cm5 cm

< 6 yrs.< 6 yrs. 41.4 Gy 45 Gy41.4 Gy 45 Gy

≥≥ 6 yrs.6 yrs. 45 Gy45 Gy 50.4 Gy50.4 Gy

Local FailureLocal FailureAge, Tumor Size, and RT DoseAge, Tumor Size, and RT Dose

Age / SizeAge / Size Dose Dose Local Failure Local Failure

< 6 yr, < 5cm< 6 yr, < 5cm 41.4 Gy41.4 Gy 14 %14 %

< 6 yr, ≥ 5cm< 6 yr, ≥ 5cm≥ 6 yr, < 5cm≥ 6 yr, < 5cm

45 Gy45 Gy 23 %23 %

≥ 6 yr, ≥ 5cm≥ 6 yr, ≥ 5cm 50.4 Gy50.4 Gy 16 %16 %

p = .20p = .20 Wharam et al. JCO 22:1902, 2004Wharam et al. JCO 22:1902, 2004

RT Volume GuidelinesRT Volume Guidelines

IRS I Involved muscle compartmentIRS II Initial tumor volume + 5 cmIRS III Initial tumor volume + 5 cmIRS IV Initial tumor volume + 2 cmIRS V 3D – CRT to GTV + 1.5 cm CTV + 0.5 cm PTV*IRS VI IMRT – GTV + 1.5 cm CTV + 0.5 cm PTV*

* Volume reduction @36 Gy

Group IIIGroup III

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Appropriate AppropriateAppropriate

Cumulative Incidence of Local Failure by Cumulative Incidence of Local Failure by QARC Guidelines and Quality ControlQARC Guidelines and Quality Control

Major or Minor DeviationMajor or Minor Deviation

6655 77 88 99 1010 1111 1212 1313 141444332211000055

10101515

20202525

30303535

4040

4545

5050

YearsYearsp = .012p = .012 Wharam et al. JCO 22:1902, 2004Wharam et al. JCO 22:1902, 2004

24 %24 %

15 %15 %

Conclusions / ChallengesConclusions / Challenges

•• IRS III, Group III local failure rate was IRS III, Group III local failure rate was unacceptably high for all primary sites, especially unacceptably high for all primary sites, especially NN1 1 patients.patients.

•• Optimal radiotherapy dose has not been Optimal radiotherapy dose has not been determined. determined.

•• Optimal radiotherapy volume has not been Optimal radiotherapy volume has not been defined.defined.

•• Role of delayed surgery has not been defined.Role of delayed surgery has not been defined.

•• Risk of local failure exceeds distant failure.Risk of local failure exceeds distant failure.

IRS IV Radiation GuidelinesIRS IV Radiation Guidelines

–– Group I Group I -- No RTNo RT–– Group II Group II -- 41.4 Gy (1.8 Gy / day)41.4 Gy (1.8 Gy / day)

–– Group IIIGroup III

–– Volume Volume -- GTV + 2 cmGTV + 2 cm–– Timing Timing -- Week 9 for all exceptWeek 9 for all except

PM with high risk features, day 0PM with high risk features, day 0

Conv Conv -- 50.4 Gy (1.8 Gy/ day)50.4 Gy (1.8 Gy/ day)HF HF -- 59.4 Gy (1.1 Gy bid)59.4 Gy (1.1 Gy bid)

Crist et al. JCO 19:3091, 2001Crist et al. JCO 19:3091, 2001

FFS by Type of RadiationFFS by Type of RadiationGroup III Group III

P = 0.76P = 0.760.0

0.2

0.4

0.6

0.8

1.0

Years0 5

ConventionalConventional

Hyperfractionated

Donaldson et al. IJROBP 51: 718, 2001Donaldson et al. IJROBP 51: 718, 2001

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Response Driven Therapy Response Driven Therapy –– IRS IVIRS IV

RateRate FFSFFS

CR CR 22%22% 81%81%

PRPR 59%59% 72%72%

NRNR 19%19% 84%84%

P = 0.34P = 0.34 Burke M. JCO 25:4909, 2007Burke M. JCO 25:4909, 2007

End of Rx ResponseEnd of Rx Response 5yr FFS5yr FFS

CRCR 81%81% 80%80%PR/NR (residual mass)PR/NR (residual mass) 19%19% 78% 78% p = 0.4p = 0.4

Rodeberg, D, JCO 27:2009Rodeberg, D, JCO 27:2009

Rhabdomyosarcoma IRS IV, Group IIIRhabdomyosarcoma IRS IV, Group IIIResponse to therapy by imaging (CT / MR)Response to therapy by imaging (CT / MR)

•• Response to Rx does not predict outcome Response to Rx does not predict outcome (FFS / OS)(FFS / OS)

•• CR at end of Rx does not improve outcomeCR at end of Rx does not improve outcome

PR/NR (residual mass)PR/NR (residual mass) 8/16 (50%) have viable tumor8/16 (50%) have viable tumor

of whom only 3/8 with viable of whom only 3/8 with viable tumor obtain atumor obtain acomplete resectioncomplete resection

Rodeberg, D, JCO 27:2009Rodeberg, D, JCO 27:2009

Rhabdomyosarcoma IRS IV, Group IIIRhabdomyosarcoma IRS IV, Group IIIPathologic response after resection of residual mas sPathologic response after resection of residual mas s

•• Only 50% of residual masses represent viable tumorOnly 50% of residual masses represent viable tumor•• Resection of residual mass does not improve outcome Resection of residual mass does not improve outcome

(FFS or OS)(FFS or OS)

Rhabdomyosarcoma IRS IV, Group IIIRhabdomyosarcoma IRS IV, Group III

•• High risk of morbidity High risk of morbidity -- loss of organ function 5 8%loss of organ function 58%

•• Low likelihood of complete resection Low likelihood of complete resection 29%29%

•• Given the small benefit and the morbidity, there is no Given the small benefit and the morbidity, there is no justification for attempted resection of a residual mass justification for attempted resection of a residual mass at the end of therapyat the end of therapy

•• It is not necessary to extend treatment (surgery, It is not necessary to extend treatment (surgery, radiotherapy, or chemotherapy) of a residual mass a t radiotherapy, or chemotherapy) of a residual mass a t the end of planned therapythe end of planned therapy

Rodeberg, D, JCO 27:2009Rodeberg, D, JCO 27:2009

Resection of residual massResection of residual mass

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IRS IV, Group IIIIRS IV, Group III5 yr Local Control5 yr Local Control

–– Orbit Orbit 98 %98 %–– Head and neck Head and neck 88 %88 %–– Parameningeal Parameningeal 84 %84 %–– Bladder/prostateBladder/prostate 81 %81 %–– ExtremityExtremity 93 % 93 % –– Other Other 86 %86 %–– All sitesAll sites 87 %87 %

Donaldson et al. IJROBP 51:718, 2001Donaldson et al. IJROBP 51:718, 2001

Timing of RadiotherapyTiming of Radiotherapy

Grp II Grp III PM / High risk

IRS - I week 0 week 6 week 0, 6 / 0IRS - II week 0, 6 week 6 week 6, 9 / 0IRS - III week 2 week 6 week 6, 9 / 0 IRS - IV week 9 week 9 week 9 / 0

IRSIRS V V -- Risk Group AssignmentRisk Group Assignment

•• LowLow : ~ 35% of RMS: ~ 35% of RMS–– EmbryonalEmbryonal–– Favorable site, Group IFavorable site, Group I--IIIIII–– Unfavorable site, Group Unfavorable site, Group

I/III/II•• IntermediateIntermediate : ~ 50%: ~ 50%

–– Groups IGroups I--III AlveolarIII Alveolar–– Unfavorable site, Group Unfavorable site, Group

III III EmbryonalEmbryonal•• HighHigh : ~ 15% of RMS: ~ 15% of RMS

–– Metastatic diseaseMetastatic disease

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

YearsYears

00 22 44 66

Pro

port

ion

FF

SP

ropo

rtio

n F

FS

88 1010

LowLow

IntermediateIntermediate

HighHigh

Timing of Timing of RadiotherapyRadiotherapyRisk based protocols Risk based protocols

Low Risk Low Risk Intermediate Risk Intermediate Risk

Grp II Grp III All PM / High risk

D9602 Week 3Week 3 Week 12Week 12 D9803D9803 WeekWeek 1212 Week 12/0Week 12/0

ARST0331

Week 13Week 13 Week 13Week 13 ARST0531

Week 4Week 4 Week 4Week 4

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IRS V IRS V -- Local Control IssuesLocal Control Issues•• SurgerySurgery -- PreopPreop vsvs post op RT with post op RT with SLOSLO

•• XRTXRT -- Dose reductionsDose reductions for select patientsfor select patients–– Group I alveolar/undifferentiatedGroup I alveolar/undifferentiated 36 Gy36 Gy–– Group II NGroup II N 00 36 Gy36 Gy–– Group III orbit/eyelidGroup III orbit/eyelid 45 Gy45 Gy–– Group III second look operationGroup III second look operation

negative margins negative margins 36 Gy36 Gymicroscopically + marginsmicroscopically + margins 41.4 Gy41.4 Gy

Volume ReductionVolume Reduction , Group III @ , Group III @ 36 36 -- 41.4 Gy41.4 Gy

Timing Timing –– week 12week 12

LowLow -- 35%35%

Intermediate Intermediate -- 50%50%

High High -- 15%15%

35%35%

55%55%

10%10%

IRS V IRS V -- Risk Group Assignment / ResultRisk Group Assignment / Result

ExpectedExpected EnrolledEnrolled

Outcome Outcome –– 5 5 yryr survival 78%survival 78%

What’s new for COG RMS studies?What’s new for COG RMS studies?•• LowLow-- RiskRisk RMS (ARST 0331)RMS (ARST 0331)

–– Shorter treatment (subset 1) Shorter treatment (subset 1) –– Lower cyclophosphamide cumulative doseLower cyclophosphamide cumulative dose

(subset 2)(subset 2)•• Intermediate Intermediate -- RiskRisk RMS (ARST 0531) RMS (ARST 0531)

–– Randomized addition of irinotecanRandomized addition of irinotecan–– Early (week 4) radiotherapy for allEarly (week 4) radiotherapy for all–– Optional FDG PET imaging at weeks 1, 4, and 15Optional FDG PET imaging at weeks 1, 4, and 15

•• High High -- RiskRisk RMS (ARST 0431)RMS (ARST 0431)–– Most active drug pairs usedMost active drug pairs used–– Interval compression of VDC/IEInterval compression of VDC/IE

•• Goal Goal –– cure without late effectscure without late effects•• Strategy Strategy –– customize therapycustomize therapy

-- For radiation oncology For radiation oncology -- minimize minimize dose / dose / volume to achieve local volume to achieve local --regional controlregional control

-- For others For others -- omitting radiation?omitting radiation?

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OrbitOrbit Chemotherapy Alone Chemotherapy Alone –– Orbital RMSOrbital RMS

MMT 84MMT 84 Rx: 3 Rx: 3 –– 10 c 10 c -- IfosIfos, VCR, Act, VCR, Act--DDif PR, 3c if PR, 3c CisplatinCisplatin, , AdriaAdriaif NR/PD, 45 Gyif NR/PD, 45 Gy

Results: Results: LF LF –– 37 %37 %4 4 yryr EFS 62 %, OS 86 %EFS 62 %, OS 86 %

Toxicity: 5 Toxicity: 5 ExenterationsExenterations, , I Cardiomyopathy, 1 RTAI Cardiomyopathy, 1 RTA

COG D 9602COG D 9602 Rx: VA + 45 GyRx: VA + 45 GyResults: Results: 3 3 yryr FFS 88 %, OS 99 %FFS 88 %, OS 99 %

GYN SitesGYN Sites

Uterus Uterus –– CervixCervixVulvaVulva

-- XRT XRT administrateredadministratered as as a function of Groupa function of Group

VaginaVagina - ““special”special”

Vaginal RMS Vaginal RMS –– Unique ApproachUnique Approach

- Favorable site & histologyFavorable site & histologyExcellent prognosis, high survivalExcellent prognosis, high survival

-- Goal: Avoid loss of organ function, Goal: Avoid loss of organ function, Avoid radical resection & XRTAvoid radical resection & XRT

-- Emphasis: Primary Emphasis: Primary chemoRchemoR xx x 12, 20, 24, 28 wks. x 12, 20, 24, 28 wks. Evaluate by: Imaging, EUA, Evaluate by: Imaging, EUA, BB xx

-- Plan: Delay resection & RT. Plan: Delay resection & RT. Omit RT if CROmit RT if CR

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7 local recurrences – 26% 7 local recurrences – 43%

D 9602 1997 D 9602 1997 –– 20042004n = 25, Group II, IIIn = 25, Group II, IIIResults @ Results @ 55 yearsyears

ARST 0331 2004 ARST 0331 2004 –– 20082008n = 16, Group IIIn = 16, Group III@ @ 22 yearsyears

None of patients with local recurrences received XR T

IRSG Protocols for Vaginal RMSIRSG Protocols for Vaginal RMS

OS OS –– 88%88%

FFS FFS –– 42%42%

YearsYearsP

roba

bilit

yP

roba

bilit

yYearsYears

Pro

babi

lity

Pro

babi

lity

FFS FFS –– 70%70%

OS OS –– 100%100%

ConclusionsConclusions•• Higher rates of local failure in Group II / III vag inal Higher rates of local failure in Group II / III vag inal

patients related to attempt to delay /avoid RTpatients related to attempt to delay /avoid RT•• Goal of achieving good FFS while delaying / avoidin g Goal of achieving good FFS while delaying / avoidin g

RT was not achievedRT was not achieved•• Plan Plan –– modify recommendations for local therapy for modify recommendations for local therapy for

vaginal RMS to follow guidelines for other pelvic s itesvaginal RMS to follow guidelines for other pelvic s ites

Group I Group I -- no RTno RTII a II a -- 36 Gy @ week 1336 Gy @ week 13II b/c II b/c -- 41.4 Gy @ week 1341.4 Gy @ week 13IIIIII -- 50.4 Gy @ week 1350.4 Gy @ week 13

ProblemsProblems

•• Making the diagnosisMaking the diagnosis

Need Need H and EH and E plusplusImmunohistochemistryImmunohistochemistry plusplusMolecular geneticsMolecular genetics

Alveolar RMS PAXAlveolar RMS PAX--FKHR Fusions FKHR Fusions

FKHR ActivationFD FKHR (13q14)FKHR (13q14)

PAX3PAX3--FKHR FKHR t(2;13)t(2;13)

PB HD

PB HDPAX7PAX7--FKHR FKHR

t(1;13)t(1;13)

PAX3 (2q35)PAX3 (2q35)PB HD

PAX7 (1p36)PAX7 (1p36)PB HD

BreakpointBreakpoint

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Future Future 1. Rhabdomyosarcoma 1. Rhabdomyosarcoma –– 2 distinct diseases2 distinct diseases

2. 2. Need large data sets of clinical outcome Need large data sets of clinical outcome and large tissue banksand large tissue banks

3. 3. Need more clinical trialsNeed more clinical trials

Survival in RhabdomyosarcomaFour Decades of Progress

0

10

20

30

40

50

60

70

80

90

1960s Early1970s

Late1970s

Mid 1980s 1990s Early2000s

Era

5-yr

sur

viva

l (%

)

IRSIRS--IIIRSIRS--IIII

IRSIRS--IIIIIIIRSIRS--IVIV

PrePreCooperativeCooperative

GroupGroup

IRSIRS--VV

NCI Clinical Trials ProgramNCI Clinical Trials Program

“The system for conducting cancer clinical trials in “The system for conducting cancer clinical trials in the United States is approaching a state of crisis. ”the United States is approaching a state of crisis. ”

John Mendelsohn, Committee ChairJohn Mendelsohn, Committee Chair

“Adult cooperative groups are highly inefficient; “Adult cooperative groups are highly inefficient; CChange is clearly necessary”.hange is clearly necessary”.

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NCI Cooperative Group ProgramNCI Cooperative Group Program

“… too slow, unwieldy, and fragmented, unable “… too slow, unwieldy, and fragmented, unable to deal with the increasingly complex to deal with the increasingly complex

molecularlymolecularly-- driven therapeutics research” driven therapeutics research”

especially in rare cancers such as sarcomasespecially in rare cancers such as sarcomas

Federal Funding for Cooperative Groups is Flat

1950 1960 1970 1980 1990

22

44

66

88

( )( )

Annual USA Cancer Mortality Rate Annual USA Cancer Mortality Rate Children < 15 YearsChildren < 15 Years

CCG

NWTSGIRSG

CALGB Pediatric DivisionCALGB Pediatric Division

SWOG Pediatric DivisionSWOG Pediatric Division POG

Pediatric Cooperative GroupsPediatric Cooperative Groups

2000

Mortality Mortality per per

100,000, 100,000, AgeAge--

AdjustedAdjusted

2005

CCOOGG

New NCI Clinical Trials ProgramNew NCI Clinical Trials Program

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New Clinical Trials NetworkNew Clinical Trials Network

GoalGoal -- Promote scientific collaboration Promote scientific collaboration -- Improve therapeutic outcomes Improve therapeutic outcomes -- Improve efficiencyImprove efficiency

FacilitateFacilitate -- Study rare malignanciesStudy rare malignancies-- Use sophisticated imaging modalitiesUse sophisticated imaging modalities-- Promote molecular characterization of Promote molecular characterization of

tumorstumors-- Provide access to national tissue banksProvide access to national tissue banks

Be Optimistic…. Be Optimistic….

“ It is imperative to preserve and “ It is imperative to preserve and strengthen the unique capabilities of strengthen the unique capabilities of the cooperative group program”. the cooperative group program”.

-- All important lessons from the ChildrenAll important lessons from the Children