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PaediatricPaediatric Radiation Radiation Oncology: Balancing Cure and Oncology: Balancing Cure and

Quality of LifeQuality of Life

John A. John A. KalapurakalKalapurakalAssociate Professor, Radiation OncologyAssociate Professor, Radiation Oncology

Northwestern University Feinberg School of MedicineNorthwestern University Feinberg School of Medicine

3939thth Congress of the International Congress of the International Society of Society of PaediatricPaediatric OncologyOncology31 October 31 October -- 3 November, 20073 November, 2007

http://www.siop.nl/

Pediatric Radiation Therapy Balancing cure and quality of life

John A. Kalapurakal MDAssociate Professor, Radiation Oncology

Northwestern UniversityChicago, Illinois

Current pediatric oncology stats in the US

• Most pediatric cancers curable >75% • >90% cooperative group clinical trial• 5 yr survival ~ 80%• 270,000 childhood cancer survivors;1 in 810

and among adults (20-34 yrs) 1 in 640• Price of success: need to reduce late sequelae

and improve QOL

Cancer Incidence & Death Rates* in Children 0-14 Years,

1975-2003

0

2

4

6

8

10

12

14

16

18

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002

Incidence

Mortality

Rate Per 100,000

*Age-adjusted to the 2000 Standard population.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006.

Trends in Survival, Children,1975-2002

*5-year relative survival rates, based on follow up of patients through 2003.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control andPopulation Sciences, National Cancer Institute, 2006.

79.7

77.9

80.1

58.8

58.2

57.3

5 - Year Relative Survival Rates *Age Year ofDiagnosis

• 1975 - 19771996 - 2002

•1975 - 19771996 - 2002

•

• 0 - 4 Years

• 1975 - 19771996 - 2002

•

• 5 - 9 Years

• 10 - 14 Years

Multidisciplinary Oncology Team

Radiation Oncology

PathologyGenetics

Radiology

Social Work

OT, PT, Psychology Specialists

Long-term Follow-up

clinic

Endocrinology

Surgery

Neurosurgery

Oncology

Patient

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Guiding Principles of Cancer Therapy

• Survival - success of therapy in the past• Good-quality survival - modern era • Risk-based treatment approach

• Low- risk tumors: Minimize therapy, maintain high cure rates, minimize toxicity

• High- risk tumors: Intensify therapy, increase cure rates,‘acceptable’ toxicity

Evolution of RT Planning

• 1D planning: surface anatomy and point dosecalculations

• 2D planning: radiographic anatomy (simulator), dose calculations isodose lines single CAX slice

• 3D planning: tumor images on CT/MRI, computerized dosimetry all along target/NT

• 4D planning: 3D imaging + organ movement

ICRU 50 Target volume definitions

• GTV- macroscopic tumor (imaging)• CTV- GTV+ area at risk for microscopic

extension• PTV- Volume to be treated to ensure that

CTV is always treated (systematic and random daily setup errors, and intertreatment and intratreatment motion)

• NT: Organs At Risk (OARs) and Planning Organs at Risk values (PRVs) (ICRU 62)

Modern Radiation therapy

• 3DCRT• IMRT• Proton therapy• IORT• Brachytherapy: LDR, HDR• Radiosurgery: Brain• Radiosurgery: Body

IMRT• One of the important advances in RT since the advent

of the linear accelerator- advanced form of conformal RT- sculpts high dose areas around tumor- and low dose areas around normal tissue

(conformal avoidance)- with great precision never achieved in the past- using multiple small beamlets of different

radiation intensity

3

Huang IJROBP 20020

102030405060708090

100

0102030405060708090

100

Percentage of Radiation Dose Delivered to the Inner Ear

Incidence of Grade 3 or 4 Ototoxicity

Radiation Dose and Ototoxicity

Huang IJROBP 2002

Ewing’s sarcoma spine-6 yr old

Re-RT (40Gy/27fr, 54Gy/27fr) Protons vs Photons

• Bragg peak: targets tumor and spares NT• Treatment comes at a greater cost• Protons reduce SMN risk by factor of > 2 and 8-

15 for medulloblastoma• Medulloblastoma: protons save € 23,600 and 0.68

quality-adjusted life-yrs (due ↓IQ, ↓GHD)• Further studies required to prove its efficacy and

cost-effectiveness

4

Wilson, J Ped Hem Oncol, 2005

3D CRT

IMRT

Protons

Electrons

Photons

Protons

Electrons

Photons

Protons

Lee, IJROBP, 2005

Hall, IJROBP 2006

SMNs after IMRT/Proton therapy

IGRT

• Improve precision - daily imaging target/NT (↓geometric variation in patient set up and organ motion - ↓PTV)

• Kv xrays, markers, u/s, MV CT (tomotherapy), kv or MV cone beam CT

• Rapid image acquisition- registration- method of correction (table shifts)- replanning

• Higher integral dose (ultrasound, EM markers)

Functional Imaging and RT

• Improve accuracy of target definition (CT/MRI)• Tumor anatomic and metabolic definition• MRS, Functional MRI, SPECT, PET (CT-PET)• (18F) FDG PET (lymphomas, sarcomas), (11C)

MET PET and (18F) FET PET (CNS tumors)• biochemical expression, angiogenesis, NT DFH,

gene expression

Prognostic value of metabolic imaging

• ~ 25% change in chemotherapy (PET)• Change in surgery volume (CNS tumors)• Change in RT fields (CNS, lymphomas,

sarcomas)• Improve local tumor control (RT)?• ↓metabolic activity-impact on prognosis/dose?

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MET-PET scan shows tumor infiltration in areas (arrows) located beyond CE area on CT and MRI scans

Univ Munich, IJROBP 2005

MEDULLOBLASTOMA

Balancing cure and quality of life

McGregor Oncology, 2007

POG-8631/CCG-923 Reduced doseRT alone N=46

ACNS0331 Average-risk MB• Reduce neurotoxicity and maintain EFS/OS• 25% reduction in CSI in 3-7 yr age group (18Gy)• moderate intensification of chemotherapy• Only 4 week interval between S-RT, RT-C• Reduce boost volume from entire PCF to tumor

bed+margins?• Audiologic, Endocrine, Neuropsych. testing• Develop an optimal gene expression predictor

ACNS0332 – Phase III study

• Determine if daily carboplatin + RT improves RFS in high-risk MB/PNET (Randomized)

• Isoretinoin maintenance therapy improves EFS? (Randomized)

• CSI: 36Gy PCF 55.8Gy (M0,M1)• HRQOL and Neuropsychological testing

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HODGKIN’S LYMPHOMA

Balancing cure and quality of life

Donaldson, Ca J Sc Am 1999

SMN after HD therapy

• Host factors (age, gender, genetics)• Therapy (RT, chemotherapy, splenectomy)• Behavioral risk factors (smoking, drugs etc)• AML (LESG) SIR: 174.8, 14 yr risk-2.1%

(alkylators, etoposide, nitrosoureas)• NHL SIR:11.1, 20 yr risk-1.5%• Solid tumor: SIR 18.5 (breast, thyroid, skin,

bone, colon/rectum, stomach, lung)

Cardiovascular sequelae

• CHF (DOX >350-400mg/m2 with RT/other agents), CAD, pericarditis, conduction/valvular dysfunction

• RT dose (>40Gy), > heart, fraction size, equally weighted beams, 1 field/day, young age

• Dox 150-200mg/m2, ↓ RT(20 Gy), 1.5Gy/fr, IF-RT, subcarinal blocking, 3D plan

• Stanford series: no death from MI with modern CMT

RT – Modern era

• Evolved from classic mantle fields/TNI to IFRT • IF-RT includes involved nodes + LN region• Immobilization (aquaplast mask, vacloc)• CT simulation, CT and PET fusion• 36-40 Gy: Local control > 95%• > 30Gy: subclinical disease (>95%)• CMT: > 20 Gy (~ 97%)

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Combination chemotherapy

• Non-cross resistant agents with individual activity and non-overlapping toxicities

• MOPP, ABVD, OPPA, OEPA, COPP/ABV, VAMP (no alkylators-etoposide-bleomycin), DBVE, DBVE-PC

100/100100/95100/94

97/9187/8390/81

21 +/-21 +/-21 +/-

I- IIAI/II,IIIIV

(CCG)

4 COPP/ABV6 COPP/ABVAraC/E/COPP/ABV/CHOP

94/9792/7891/80

20- 35 +/-20- 35 +/-20- 35 +/-

I- IIAIIB- IIIAIIIB- IV

(German/Austrian HD-95)

2 OEPA/OPPA2 ”+2COPP2 ”+4COPP

826815- 25.5 Bulky I/II, III- IV

6 VEPA (Stanford)

96 (10 yr)

90 (10 yr)

15- CRs 25.5- PR

I/II4 VAMP (Stanford)

%OS%EFSRT (IF) GyStg (CS)Chemotherapy

Hodgkin’s Lymphoma

• Low risk: To investigate response-based therapy-eliminating RT CR 3 cycles of AV-PC (RER)

• IM risk: Determine if IF RT can be eliminated:- RER to 2 cycles of ABVE-PC AND CR after 2 more cycles

• Role of augmented therapy in SER after 2 cycles ABVE-PC (2xDECA) + IFRT (21Gy)

• Prognostic value of PET scans

Response Criteria (QARC)

• CR – > 80% reduction in product of perpendicular

diameters (PPD)– resolution of FDG uptake

• VGPR (CT/MRI only, Ga/PET may +’ve)– >60% reduction in PPD

• RER: CR or VGPR after 2 cycles• SER: < VGPR after 2 cycles

WILM’S TUMOR

Balancing cure and quality of life

Wilms Tumor

• Uniformly fatal disease beginning of last century• NWTS: RT not required in stage I, II FH tumors• NWTS-3: RT dose ↓ from age-adjusted (18-40

Gy) to 10Gy (3 drugs)• RT and ADR eliminated in > 60% • NWTS 3-5: superior border need not extend

to dome of the diaphragm (CT)• NWTS-5: significant prognostic value (LOH 1p

and 16q) for RFS and OS

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M,WLIAREN0533HigherNoNoneIVAnyAny

DD4A, noWLI

AREN0533StandardYesNoneIVAnyAny

MAREN0533HigherAnyYesIVAnyAny

MAREN0533HigherAnyYesIIIAnyAny

DD4AAREN0532StandardAnyNoneIIIAnyAny

DD4AAREN0532StandardN/AYesIIAnyAny

DD4AAREN0532StandardN/AYesI≥ 550 gAny

DD4AAREN0532StandardN/AYesIAny> 2yrs

EE4AAREN0532LowN/ANoneIIAnyAny

EE4AAREN0532LowN/ANoneIAny>2yrs

EE4AAREN0532LowN/ANoneI≥ 550 gAny

Surgery only

AREN0532Very Low

N/AAnyI< 550 g< 2 yrs

RegimenCOG StudyRisk Group

Rapid Response#

LOH(both 1p

16q)StageTumor

WeightAge

COG Risk Group Classification: FH WT

19.8 Gy (Infants 10.8 Gy) Flank* RTStage III DAStage I-III RTK

10.8 Gy Flank* RTStage III FHStage I-III FAStage I-II DAStage II-III CCSK

No RTStage I/II FHStage I CCSK

RT dose (Gy) and fieldsTumor Stage/histology

COG protocol- RT guidelines

12.6 -18 Gy (< 12 months of age)21.6 Gy in older children9 Gy boost to gross residual tumor

Relapsed WT (Flank/Abdomen)

19.8 GyUnresected LN metastases

25.2 Gy (Tumor + 3 cm margin)Stage IV (Bone)

25.2 Gy (Whole brain) + 10 Gy (local boost)Stage IV (Brain)

12 Gy WLIStage IV (lung, UH)

12 Gy WLI if no CR at week 6 of DD4AStage IV (Lung, FH)

RHABDOMYOSARCOMA

Balancing cure and quality of life

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IRS I 1972-’78 51/55%

IRS II 1978-’84 55/63%

IRS III 1984-’91 65/71%

IRS IV 1991-’97 77/86%

Evolution of RT guidelines

• Whole compartment RT not required• Gp I FH no RT• Margins of 1-2 cm around GTV sufficient• IRS III: 41.4 - 50.4Gy• IRS IV: no value to HFRT• Role of SLS at wk 12 (IRS V)• Clear margins 36 Gy, microscopic 41.4 Gy, gross

residual 50.4 Gy (Orbit 45 Gy)

RMS risk stratification(IRS V,COG)

High (25- 35%)All4IVALVIM (55- 60%)All1,2,3I, II, IIIALVHigh (25- 35%)> 10 yrs4IVEMBIM (70- 85%)< 10 yrs4IVEMBIM (70- 85%)All2,3IIIEMBLow (90- 95%)All2,3I, IIEMBLow (90- 95%)All1I, II, IIIEMBRisk GroupAgeStageGroupHistology

ARST0331/0531RMS

• Low risk- Reduce dose of CTX in VAC and duration of

therapy- ↓RT Gp II/III: M + N 0/1 36 Gy-41.4Gy,

gross residual 50.4 Gy, orbital tumors 45Gy• Intermediate risk

- Compare VAC or VAC alternating with VI- Compare LC early RT (wk 4)- RT+ concurrent irinotecan

Parameningeal RMS

• Eliminated the need for craniospinal RT, WB RT in high-risk PM tumors (1-2 cm margin)

• IRS I (3yr DFS 33%, meningeal extension fatal)• IRS II-IV 5 yr EFS/OS 69/73%, LF (17%)• CT/MRI ↑detection of ICE and ↑outcomes• Early RT (<2wks) reduce LF in pts with ICE (16%

vs 37%)

SIOP study: Omission of RT?• No RT/SLS for CR after chemotherapy• RT (> 5yrs-PM tumors, all >12 yrs) • Survival- isolated LR (44%), distant (18%)• 50-60% avoided local therapy (Rt/S)• Orbital trs - LF: No RT (10/22) vs (1/9) with RT• DM in 3 pts with LF and 2 died• No difference in survival + RT ~62%• EFS/OS 53/85% vs (3 drugs/RT) 94/100% IRS IV

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CHILDHOOD CANCER SURVIVORS

Balancing cure and quality of life

Issues: Care for cancer survivors

• Medical issues (organ dysfunction, SMN)• Delivery of care to survivors (STAR): screening,

counseling, management• Preventive research Strategies (therapy)• Future directions:

- Study of late effects beyond first decade- identify genetic predisposition- identify role of lifestyle choices- develop effective intervention strategies

ALTE03N1 – childhood cancer survivors

• Treatment-related and demographic risk factors (case-groups and controls)

• Compare frequency of mutations/ polymorphisms in specific candidate genes

• Gene-environment interactions for late toxicity• Foundation for studying molecular mechanisms• Contribute to primary and secondary

prevention of these events in cancer survivors (individualize treatments)

Risk for sub fertility after cancer therapy

Brain tr, <24Gy

Brain tr, Sy

Retinoblastoma

Germ cell tr

WT

ALL

Low < 20%

Brain tr, >24GyHodgkin'sEwing’s (localized)OsteosarcomaNHLAML

Medium

Metastatic tumorsSarcomasHodgkin’sBMT/SCT- CTRT: Pelvis, testesTBI

High (>80%)

Fertility preservation

• Reproductive Medicine / Endocrinology /Urology consultation at diagnosis and follow-up

- Cryopreservation: embryos, oocytes, ovarian tissue and transplantation

- Oophoropexy: lateral/midline open/laparoscopy- Testicular transposition - Sperm banking

IORT for pediatric brain tumors Photon Radiosurgery System (PRS)

Phase I dose- escalation studyChicago Children’s Memorial Hospital

Phase I studies → Balancing cure and quality of life

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Group 1—RT recurrent tumors

Tumor sites not adjacent to brain stem10 Gy; 12 Gy; 14 Gy; 16 Gy

Tumor sites adjacent to brain stem10 Gy; 12 Gy; 14 Gy

Group 2— Unirradiated tumors

Tumor sites not adjacent to brain stem10 Gy; 13 Gy; 16 Gy;

Tumor sites adjacent to brain stem10 Gy; 12 Gy; 14 Gy

Results

• Between 2001 and 2007 23 patients, 25 sites• 19 had ependymoma, 1 astroblastoma, 2

malignant glioma, 1 fibrosarcoma• Gp 1 : prior RT (ependymoma 14, glioma 1)• Gp 2 (ependymoma 6, glioma 1, astroblastoma 1)• IORT dose: 10 Gy to 2 mm in 15, 10 Gy to 5mm

in 4,12 Gy to 2 mm in 5, 14Gy to 2mm in 1

A B

Pre IORT

9m post

29m post Kalapurakal, JROBP,2006

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Pre IORT

4m later

5,5m later

IORT- Conclusions

• IORT (10 Gy to 5mm) and use of 2 applicators: high incidence of necrosis and should not be used

• Phase I study: established safety of 10Gy, 12 Gy to 2mm

• Accrual continues on the next dose level 14 Gy to 2mm

Role of Radiobiology

Balancing cure and quality of life

RT: Present and Future

• Novel RT technologies ↑ TR by NT sparing• Radiobiological approach to ↑ TR by ↑ intrinsic

radiosensitivity• RT activates a complex network of cellular signal

transduction pathways stress response• Novel therapeutic targets in experimental models for

radiosensitization of tumors

FDA approved Biologic modifiers*

Myelosupp.CMLBCR- ABL TKIGleevec

NeutropeniaMyelomaProteosome inhibitor

VelcadeBleedingColonVEGFR MabAvastin*Rash, GINSCLCEGFR TKITarceva*Rash, GINSCLCEGFR TKIIressa*AnaphylaxisColon, HN*EGFR MabErbitux*CardiacBreastHER2 MabHerceptin*ToxicityIndicationClassAgent

Promising molecular targets forradiosensitization

• NF-ĸB inhibitors (velcade, thalidomide etc)• PKC inhibitors• Apoptosis inducing death-ligands: TNFα

(local, gene therapy), TRAIL (Lung/prostate)• COX-2 inhibitors• RAS inhibitors (Farnesyl transferase): LY-

778,123 (Lung/HN)

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Ling IJROBP 2000McGregor Oncology, 2007

Conclusions

• ↑ QOL: Reduce RT dose/volumes (Low risk) • ↑ Cure: Augment therapy (Higher risk)• ↑ QOL: Cancer survivors: Long-term follow up

clinics and screening guidelines• ↑ Cure ↑ QOL: Technologic and biologic advances• Improve survival and QOL: Phase I studies in

patients with recurrent tumors

John A. John A. KalapurakalKalapurakal

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