7/1/2015. Objectives. Host Factors LATE EFFECTS OF RADIOTHERAPY IN CHILDHOOD CANCER. Chronic Conditions in Adult Survivors

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1 LATE EFFECTS OF RADIOTHERAPY IN CHILDHOOD CANCER ARNOLD C. PAULINO, M.D. PROFESSOR DEPARTMENT OF RADIATION ONCOLOGY MD ANDERSON CANCER CENTER Objectives At the end of the presentation, the participant should be able to Gain an appreciation for the impact of treatmentrelated late effects on mortality and morbidity of long-term childhood cancer survivors Gain an understanding of host, tumor and treatment parameters which can impact on late effects of treatment Gain an understanding of trends in pediatric oncology on how late effects can be minimized or avoided Cause of Mortality in 5-Year Survivors of Childhood Cancer Recurrent Cancer Second Malignancy/ Neoplasm Cardiac Toxicity Pulmonary Disease Other Sequelae Non- Treatment Related Childhood Cancer Survivor Study N = 2823 Piedmont Region, Italy N = 143 British Columbia, Canada N = % 15% 7% 2% 4% 15% 62.2% 12.6% 1.4% NA 8.4% 15.4% 69.1% 7.7% 4.4% 2.2% 5.5% 11.1% Chronic Conditions in Adult Survivors Host Factors Condition Relative Risk of Grade 3 or 4 Complication as Compared to Siblings Major Joint Replacement Congestive Heart Failure 15.1 Second malignant neoplasm 14.8 Cognitive dysfunction, severe 10.5 Coronary artery disease 10.4 Age of the Child Gender Genetic Predisposition Comorbid Disease Cerebrovascular Accident 9.3 Renal failure or dialysis 8.9 Hearing loss not corrected by aid 6.3 Legally blind or loss of eye 5.8 Ovarian failure 3.5 Oeffinger KC et al. N Engl J Med 2006; 355:

2 Tumor Parameters Treatment Parameters Direct tissue effects (extent of organ invasion) examples: parameningeal rhabdomyosarcoma with unilateral hearing loss, bone and soft tissue sarcomas causing cord compression Indirect mechanical effects examples: brain tumors causing hydocephalus, abdominal sarcomas causing renal failure by compression of ureters Volume Irradiated Total Dose Fraction Size Use of Concurrent Chemotherapy Timing of Chemotherapy and Radiotherapy (methotrexate and cisplatin) Use of Surgery AGE GENDER HEREDITY Different organs are maturing at different times during childhood Host Parameters ECONOMIC STATUS RACE Brain Most sensitive during fetal period but postnatally during first few years of life Most neurons present at birth but brain is still in an unfinished state Increase in axonal growth, dendritic arborization and synaptogenesis 2

3 Brain Impact of Age in Ependymoma Myelin formation well developed at the second year of life and continues in some tracts until years By age 6, most children have attained adult brain size Neurogenesis still occurs in adults mainly in hippocampus von Hoff K et al. BMC Cancer 2008; 8:15 Impact of Age in Low Grade Glioma Reduced Craniospinal Dose in Medulloblastoma Rate of IQ Change -4.3 FSIQ points/year -4.2 VIQ points/year -4.0 NVIQ points/year Females (p=0.008) were more subject to have a VIQ decline Younger children (< 7 years) were more likely to have NVIQ decline Merchant TE et al. J Clin Oncol 2009; 27: Ris MD et al. J Clin Oncol 2001; 19: Musculoskeletal Bone Accelerated growth at birth to 5 years and during puberty Bone density is at a maximum at 18 to 20 years 10% of bone is remodeled annually With age, activity of osteoclasts increase and of osteoblast decrease Radiation injury depends on portion of bone irradiated Epiphysis arrested chondrogenesis Metaphysis deficient absorptive process in calcified bone and cartilage Diaphysis alteration in periosteal activity causing abnormal bone modeling 3

4 Height Deficit from Radiotherapy Gonadal Age at treatment (years) Height deficit (cm) after 10 Gy Height deficit (cm) after 20 Gy Height deficit (cm) after 30 Gy Hogeboom CJ et al. Med Pediatr Oncol 2001; 36: Secondary Breast Cancer Ovarian Failure 9.2% incidence of breast cancer at 20 years after radiotherapy for Hodgkin lymphoma Higher incidence of breast cancer in those treated from years compared to < 12 years (Constine et al.) Higher incidence of breast cancer in those treated with RT from years compared to < 10 years (Bhatia et al., Late Effects Study Group) Adults are more susceptible to sterility than children because of limited number of oocytes Effective sterilizing dose (ESD) to the ovary after fractionated RT decreased with increasing age at radiotherapy ESD birth 20.3 Gy 10 years 18.4 Gy 20 years 16.5 Gy 30 years 14.3 Gy Wallace WHB et al. Int J Radiat Oncol Biol Phys 2005, 62: Gender and Late Effects Cranial Irradiation and ALL Tumor Gender Late Effect Acute lymphoblastic leukemia (ALL) Acute lymphoblastic leukemia (ALL) Female > Male Female > Male Cognitive Deficit Height Impairment Hodgkin Lymphoma Female > Male Secondary Tumors Hodgkin lymphoma Female > Male Hypothyroidism 51 patients treated on Dana-Farber protocol. Children either received 18 Gy (standard risk) or 28 Gy (high risk) 50% of girls vs. 14% of boys had IQ < 90 on follow-up (p = 0.01) Increased dose intensity of iv methotrexate was associated with lower IQ, but only in girls Waber DP et al. J Clin Oncol 1992; 10:

5 Cranial Irradiation and ALL Genetic Predisposition Cross sectional study from Childhood Cancer Survivor Study comparing adult height of ALL children (n = 2434) compared to siblings (n = 3009) Risk factors for short stature were higher dose cranial RT (> 20 Gy), any RT to spine and female sex Neurofibromatosis, type 1 and 2 Bilateral Retinoblastoma Gorlin syndrome Li Fraumeni syndrome Chow EJ et al. J Pediatr 2007; 150:370-5 NF-1 and Optic Pathway Glioma NF-1 and Moyamoya Syndrome N = 40 No Radiotherapy 721 person-years of follow-up 8 (20%) developed 9 tumors N = 18 Radiotherapy 308 person-years of follow-up 9 (50%) developed 12 tumors Sharif S et al. J Clin Oncol 2006; 24: Desai S et al. Int J Radiat Oncol Biol Phys 2006; 65: Basal cell carcinomas following craniospinal irradiation for medulloblastoma in Gorlin Syndrome Li Fraumeni Syndrome Of 200 Li Fraumeni syndrome family members diagnosed with cancer, 30 (15%) developed second, 8 (4%) developed third and 4 (2%) developed fourth cancers. Cumulative probability of Second cancer at 30 years: 57% Third cancer at 10 years: 38% RR of second cancer varied according to age at first cancer 83: ages 0-19 years 9.7: ages years 1.5: age 45 years or more Mitchell G et al. Clin Oncol 2005; 17:650-4 Happle R. J Am Acad Dermatol 1999; 41: Hisada M et al. JNCI 1998; 90:

6 Retinoblastoma Treatment Parameters 40-year incidence of secondary malignancy 40-year incidence of secondary malignancy in irradiated patients Standardized incidence ratio (SIR) (median follow-up of 21.9 years) Hereditary RB Non-hereditary RB 28.0% 1.4% 33.2% 13.3% SURGERY RADIOTHERAPY CHEMOTHERAPY Marees T et al. J Natl Cancer Inst 2008; 100: Impact of Surgery Scoliosis in Neuroblastoma Paulino AC and Fowler BZ. Int J Radiat Oncol Biol Phys 61, 2005 Renal Failure in Wilms Tumor Impact of Chemotherapy No of pts No of pts with renal failure Incidence of Renal Failure (%) at 2 years 4 years 16 years Unilateral Bilateral NWTS NWTS NWTS NWTS _ Ritchey ML et al. Med Pediatr Oncol 1996; 26:

7 Congestive Heart Failure Leukoencepalopathy 4.4% at 20 years for those initially treated with doxorubicin (NWTS) 17.4% at 20 years for those treated with doxorubicin for first or subsequent relapse Relative risk of CHF was increased in those receiving whole lung irradiation (RR 1.6/10 Gy) and left abdominal irradiation (RR 1.8/10 Gy) < 2% INTRAVENOUS METHOTREXATE >40-80 mg/m2/week CRANIAL RADIOTHERAPY > 20 Gy < 1% 15% 5% 45% 2% < 1% INTRATHECAL METHOTREXATE > 50 mg Green DM et al. J Clin Oncol 2001; 19: Griffin TW. Radiation damage to nervous system, 1980 Hypothyroidism Strategies in Pediatric Oncology Delaying radiotherapy until child is at least 3 years old (brain tumors) Using hyperfractionated radiotherapy Using radioprotecting agents Decreasing radiotherapy doses and volumes by including chemotherapy in treatment regimen Decreasing radiotherapy volumes from high and low dose radiation using newer technologies Eliminating radiotherapy in favorable subsets of patients Paulino AC. Int J Radiat Oncol Biol Phys 53:543-7, 2002 RADIOTHERAPY IN INFANTS WITH BRAIN TUMORS Delaying or omitting radiotherapy CURE COGNITIVE DEFICIT ENDOCRINOPATHY GROWTH RETARDATION SECONDARY MALIGNANCY Popular approach in the 80s and 90s particularly in children < 3 years with brain tumors Craniospinal radiotherapy is delayed until patient is 3 years or older in medulloblastoma Involved field radiotherapy delayed until patient in 3 years or older in ependymoma, malignant glioma 7

8 Baby POG Study (Medulloblastoma) Infant Studies in Ependymoma 62 children received 2 rounds of 2 cycles of VCR, CPM followed by 1 cycle of VP-16 and CDDP after resection Chemotherapy given from months until child turned 3 years 1- and 2-year PFS rates were 42% and 34% Baby POG study: 1 and 2 year progression free survival rates were 58% and 42% French Society Pediatric Oncology: 4 year progression free survival after resection and chemotherapy: 22% Duffner PK et al. N Engl J Med, 1993; 328: Ependymoma Ependymoma St. Jude study of 88 children treated with 3D conformal RT Dose 50.4 Gy (n = 15, all < 18 months) to 59.4 Gy Median age at RT: 2.85 years Clinical target volume was tumor bed + residual tumor with a 10 mm margin. Planning target volume was CTV with a 3 to 5 mm margin Merchant TE et al. J Clin Oncol 2004; 22: Merchant TE et al. J Clin Oncol 2004; 22: Ewing Sarcoma of Extremity Use of Hyperfractionated Radiation Therapy Conventional Hyperfractionated P-value Local Control 77% 81% n.s. Fractures 5/14 0/17.01 Range of motion (degree loss) Muscle atrophy (circumference loss) 21% 8%.004 Bolek TW et al. Int J Radiat Oncol Biol Phys 1996; 35:

9 Hypothyroidism in Medulloblastoma Hyperfractionated Radiotherapy in Pediatric Oncology Tumor Type Conventional Hyperfractionated Outcome Rhabdomyosarcoma (Group III) IRS-IV 50.4 Gy in 28 fractions at 1.8 Gy 59.4 Gy in 54 fractions at 1.1 Gy BID No difference Brainstem glioma POG 54 Gy in 30 fractions at 1.8 Gy 70.2 Gy in 60 fractions at 1.17 Gy BID No difference P = 0.02 Ewing Sarcoma CESS (postoperative) to 60 Gy (definitive) at 1.8 to 2.0 Gy 44.8 (postoperative) to 60.8 Gy (definitive) at 1.6 Gy BID (up to 44.8 Gy then conventional fractionation) given at 3 week intervals No difference Acute Lymphoblastic Leukemia DFCI Consortium 18 Gy in 10 fractions at 1.8 Gy 18 Gy in 20 fractions at 0.9 Gy BID No difference Medulloblastoma (Standard-Risk) HIT-SIOP PNET Gy in 13 fractions to craniospinal axis followed by 32.4 Gy boost to posterior fossa (total dose: 55.8 Gy in 31 fractions at 1.8 Gy) 36 Gy in 30 fractions to craniospinal axis followed by 24 Gy boost to posterior fossa and 8 Gy tumor bed boost (total 68 Gy in 68 fractions at 1 Gy BID) No difference Chin D et al. Cancer 1997; 80: Amifostine Use of Radioprotectors Phosphorothioate radioprotector prodrug that is unreactive and penetrates poorly into cells until dephosphorylated by enzyme alkaline phosphatase to active metabolite WR-1065 Protector for radiotherapy and chemotherapy COG ARAR0331: Nasopharyngeal Cancer Ototoxicity in Medulloblastoma Multi-institution study (SJMB96 and SJMB03) All patients received cisplatin and radiotherapy (CSI followed by posterior fossa boost or tumor bed boost) Amifostine given before and 3 hours into cisplatin administration Proportion with >Grade 3 Ototoxicity at 1 year posttherapy Amifostine 9/62 (14.5%) No Amifostine 13/35 (37.1%) p = Fouladi M et al. J Clin Oncol 2008; 26:

10 Ototoxicity in Medulloblastoma Children s Hospital of Philadelphia 78% of patients developed significant hearing loss despite amifostine Radiotherapy boost was conventional Texas Children s Hospital All patients received IMRT boost to either posterior fossa or tumor bed + margin Four of 19 (21%) treated with amifostine and 7/25 (28%) who did not have amifostine developed > grade 3 hearing loss (p = n.s.) Reducing Radiotherapy Dose and Volume with Addition of Chemotherapy Fisher MJ et al. Pediatr Blood Cancer 2004; 43:780-4 Paulino AC et al. Int J Radiat Oncol Biol Phys 2010; 78: Wilms Tumor (NWTS-3) Scoliosis and Radiotherapy Dose Treatment Percent alive at 2 years Dose N % Scoliosis N 10 yrs 15 yrs AMD + VCR cgy 88.3% AMD + VCR cgy 91.0% AMD + VCR + ADR cgy 92.7% < 1200 cgy 12 1 (8.3) cgy 11 5 (45.5) AMD + VCR + ADR cgy 93.1% > 2400 cgy (63.2) Thomas PRM et al. Cancer 1991; 68: Paulino AC et al. Int J Radiat Oncol Biol Phys 2000; 46: Medulloblastoma Neurocognitive Effects For decades, standard treatment after resection was CSRT to 36 Gy followed by PF boost Now, standard treatment after resection for standard-risk pts is CSRT to 23.4 Gy followed by boost and chemotherapy N Older Average Risk Intercept Slope Points/ yr Older High Risk Intercept Slope Points/ yr Younger Average Risk Intercept Slope Points/ Yr Younger High Risk Intercept Slope Points/ Yr IQ Reading Spelling Math Mulhern RK et al. J Clin Oncol 2005; 23:

11 ACNS0031 (Standard-risk Medulloblastoma) Medulloblastoma Age 3 to 7 years Average Risk: 23.4 Gy to craniospinal axis, Gy to tumor bed CSRT 18 Gy CSRT 23.4 Gy PFRT 23.4 Gy IFRT 55.8 Gy PFRT 55.8 Gy IFRT 55.8 Gy PFRT 55.8 Gy Age > 8 years CSRT 23.4 Gy IFRT 55.8 Gy PFRT 55.8 Gy Mulhern RK et al. Lancet Oncol 2004, 5: Intracranial Germinoma ACNS0232 Standard treatment for M0 Germinoma was craniospinal or whole brain RT followed by boost Now, current treatments include whole ventricular RT followed by boost or neoadjuvant chemotherapy followed by involved field RT Germinoma M0 Disease Radiotherapy Alone Neoadjuvant chemotherapy Whole Ventricular (24 Gy) (carboplatin/etoposide x 2) Followed by involved field (cisplatin/cyclophosphamide (21Gy) x 2) CR Involved field 30 Gy PR, SD, PD Whole Ventricular (24 Gy) Followed by involved field (21Gy) Germinoma Germinoma: Patterns of Failure WB/WV 24 Gy followed by 16 Gy boost vs. focal RT 45 Gy Four courses of chemotherapy followed by XRT to initial tumor volume + 2cm safety margins to 40 Gy Rogers SJ et al. Lancet Oncol 2005; 6: Alapetite C et al. Neuro-Oncology 2010; 12:

12 Hodgkin lymphoma Hodgkin lymphoma Standard treatment before was subtotal nodal RT (doses 36 to 44 Gy) Late effects were significant including extensive musculoskeletal toxicity and second malignancies Current approach is combination chemotherapy followed by involved field radiotherapy (dose 15 to 25.5 Gy) DeBruin ML et al. J Clin Oncol 27: , 2009 Hodgkin lymphoma Reducing High Dose Radiotherapy Volume with Newer Technology O'Brien MM et al. J Clin Oncol 2010; 28: Ototoxicity Ototoxicity and Medulloblastoma Known complication of cisplatin chemotherapy Can occur after radiotherapy When combined together (RT + cisplatin chemotherapy) will have higher incidence of high grade toxicity Huang E et al. Int J Radiat Oncol Biol Phys 2002; 52:

13 Ototoxicity and IMRT in Medulloblastoma Conventional RT N=11 IMRT N=15 IMRT N=88* Median follow-up (months) Mean dose to cochlea Gy ( ) Gy ( ) (standard risk), 43 Gy (high risk) Mean cisplatin Dose 220mg/ m 2 ( ) 290mg/ m 2 ( ) Grade 0 Pediatric Oncology Group Ototoxicity Grade (number of patients) Grade 1 Grade 2 Grade 3 Grade % % 300 mg/ m 2 * Number of ears 18% Reducing Low Dose Radiotherapy Volume with Newer Technology Huang E et al. IJROBP 2002; 52: , Paulino AC et al. IJROBP 2010; 78: Secondary Malignancy Proton Therapy Tumor Source Incidence Wilms tumor National Wilms Tumor Study 1.6% at 15 years Group Acute lymphoblastic leukemia Childrens Cancer Group 1.3% at 10 years Hodgkin lymphoma Stanford University 9.7% for men, 16.8% for women, 9.2% breast cancer at 20 years Hodgkin lymphoma Late Effects Study Group 10.6% at 20 years, 26.3% at 30 years Retinoblastoma Memorial Sloan Kettering 51% for hereditary and 5% for non-hereditary at 50 years Rhabdomyosarcoma Intergroup Rhabdomyosarcoma Studies I and II 1.7% at 10 years Primary Brain tumor St. Jude Children s Research Hospital 4% at 15 years (malignant tumors) Retinoblastoma and Secondary Malignancy Retrospective study of 86 children treated at MGH from with protons (n = 55) or photons (n = 31) Median follow-up is 6.9 years for protons and 13.1 years for photons 10-year incidence of SMN in RT field was 0% vs. 14% (p = 0.015) and 5% vs. 14% (p = 0.12) for all SMN Int J Radiat Oncol Biol Phys 87(2), 2013 Sethi RV et al. Cancer 2013 Epub 13

14 Ependymoma and Protons 70 pediatric patients treated at MGH Median age at RT was 38 months Two-thirds had gross total resection Median follow-up: 46 months 3-year PFS was 54% vs. 88% for STR and GTR Eliminating Radiotherapy in Favorable Subsets of Patients MacDonald SM et al. Neur-Oncologyy 2013; 15: Wilms Tumor (NWTS-3) Whole Lung Irradiation for Wilms Tumor Treatment Percent alive at 2 years AMD + VCR 98.6% AMD + VCR cgy 98.4% AMD + VCR + ADR 95.5% AMD + VCR + ADR cgy 93.5% POTENTIAL TOXICITIES Pneumonitis Cardiac Toxicity Height Impairment Breast, Bone and Soft Tissue Hypoplasia Secondary Cancer (Breast, Thyroid, Lung) Thomas PRM et al. Cancer 1991; 68: Wilms Tumor and Lung Metastasis CT Only Lung Mets (NWTS-4 and -5) Chest X-ray negative, CT scan positive lung nodules Chemotherapy No. of pts 2 year RFS (%) 5 year RFS (%) P-value 4-year Event-Free Survival 4-year Overall Survival Actinomycin-D and Vincristine Actinomycin-D Vincristine and Doxorubicin Whole lung XRT 89% 91% No whole lung XRT 80% 85% P = 0.23 P = 0.41 Radiotherapy Whole Lung Radiotherapy No Whole Lung Radiotherapy No. of pts 2 year RFS (%) 5 year RFS (%) P-value 0.38 Meisel JA et al. Int J Radiat Oncol Biol Phys 1999; 44:

15 Wilms Tumor and Lung Metastasis Hodgkin Lymphoma Study Eligible Patients Chemotherapy Further Treatment Childrens Oncology Group AHOD431 HOD08 First International Intergroup Study Stage IA, IB Non-bulky Stage IA, IB Non-bulky, < 3 nodal regions, no E Stage IA, IB, IIA, no E AV-PC x 3 cycles (adriamycin, vincristine, prednisone, cyclophosphamide) Stanford V x 8 weeks OEPA X 2 cycles (vincristine, etoposide, prednisone, adriamycin) PR: 21 Gy IFRT CR: Observation PR: 25.5Gy IFRT CR: Observation PR: IFRT CR: Observation Molecular Variants of Medulloblastoma Medulloblastoma Molecular Subtypes Northcott PA et al. J Clin Oncol 2011; 29: Pfister SM et al. Acta Neuropathol 2010; 120: Long-Term Follow-Up Guidelines 15

16 P.E.N.T.E.C. Pediatric Normal Tissue Effects in the Clinic (PENTEC) Pediatric version of QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) which was published in the Int J Radiat Oncol Biol Phys volume 76, #3 Sep 2010 Headed by Dr. Louis Constine Summary Late effects of treatment are an important cause of chronic problems and death in survivors of childhood cancer Late effects of radiotherapy can be dose and volume related and can be influenced by the use of other treatments such as chemotherapy and surgery Summary The age of the child is an important factor in the development of late effects of treatment Newer methods of radiotherapy delivery are currently being used which can impact on late toxicity 16