COMPLICATIONS OF RADIATION THERAPY FOR CHILDHOOD CANCERS Siddhartha Laskar Associate Professor Department of Radiation Oncology Tata Memorial Hospital, Mumbai INDIA (laskars2000@yahoo.com, www.tatamemorialcenter.com) S Laskar ICARO 2009
CANCER BURDEN CANCER BURDEN CANCER BURDEN NEW CASES OF CANCER YEAR GLOBAL DEVELOPING WORLD PERCENT. (Millions) (Millions) OF GLOBAL 1985 7.6 3.9 52% 1990 8.1 4.1 51% 2000 10.1 5.4 53% 2020* 20.0 14.0 70% “Paediatric Malignancies account for 3-5% of the burden” * WHO Projection - 2005 S Laskar ICARO 2009
AVERAGE ANNUAL INCIDENCE OF CHILDHOOD CANCERS IARC 2005 S Laskar ICARO 2009
RELATIVE FREQUENCIES OF MAJOR TUMOUR TYPES IARC 2005 S Laskar ICARO 2009
ROLE OF RADIOTHERAPY IN CHILDHOOD CANCERS Hodgkin’s Lymphoma Early Stage > 90% Advanced Stage Poor Prognostic Group Nasopharyngeal Carcinoma 100% CNS Tumors > 90% Ewings Sarcoma/ PNET Definitive 40% Post Operative 30-40% Rhabdomyosarcoma IRS Gr III, Unfav. Histology NR- Soft Tissue Sarcoma > 80% Wilms Tumor Stage III FH, All UH Retinoblastoma Non Amenable to Focal Th. Vitreous Seeding Leukemia (CNS Prophylaxis) Depends upon type of CTh Neuroblastoma Residual, Unfavourable S Laskar ICARO 2009
5 YEAR SURVIVAL AT St JUDE CHILDRENS HOSPITAL S Laskar ICARO 2009 Courtesy: Dr Raul Riberio
UNITED STATES DATA 1 in 640 persons between the ages of 20 and 39 years is a childhood cancer survivor (~300,000) S Laskar ICARO 2009 Courtesy: Dr Raul Riberio
ACUTE TOXICITIES S Laskar ICARO 2009
Dermatitis Radiation Dose: 50-60Gy @ 1.8-2.0Gy/ fr Mucositis Potentiating Factors: Enteritis Skin Condition/ Connective Tissue Disorders Prior Interventions: Surgery/ Chemotherapy Cystitis Concurrent Chemotherapy Poor Nutrition & Hyegiene Dysphagia Poor Orodental Hyegiene Poor Skin Care Xerostomia Management: Impaired Taste Optimal Sequencing with Chemo Optimal Dose/ Fractionation & RT Volume Hoarseness of Voice Optimal Radiotherapy Plan (skin dose) Skin Care Headache Maintain Nutrition & Hyegiene Maintain Orodental Hyegiene Nausea & Vomiting Hematological S Laskar ICARO 2009
CARCINOMA OF NASOPHARYNX CHEMOTHERAPY RADIOTHERAPY Neoadjuvant Primary: 66 – 70 Gy Concomittant Neck: 50 Gy/ 25 fr Adjuvant S Laskar ICARO 2009
DOSIMETRIC COMPARISION OF TREATMENT PLANS IMRT CONVENTIONAL RT S Laskar ICARO 2009
IMRT FOR CA NASOPHARYNX PTV70 (70.2Gy/ 33# @ 2.12Gy/#) PTV59.4 (59.4Gy/ 33# 1.8Gy/#) PTV52.8 (52.8Gy/ 33# 1.6Gy/#) PTV70 PTV59.4 PTV52.8 S Laskar NPX IMRT 03
IJROBP DEC 2008 S Laskar ICARO 2009
COMPARATIVE DVH FOR CRITICAL ORGANS 57.4 60 55.4 53.4 52 47.2 50 42.8 41.9 40 Dose in Gy 32.1 30 IMRT Conventional RT 20 10 0 Spinal Cord Brain stem Contralateral Ipsilateral Parotid Parotid Laskar, IJROBP Dec 2008 S Laskar ICARO 2009
Laskar, IJROBP Sept 2008 S Laskar ICARO 2009
TIME TO DEVELOPMENT OF GRADE II TOXICITY Laskar, IJROBP Dec 2008 S Laskar ICARO 2009
HELICAL TOMOTHERAPY Significant Improvement in Normal Tissue Sparing S Laskar ICARO 2009
S Laskar ICARO 2009
PROTON IMRT PHOTON IMRT S Laskar ICARO 2009
LATE TOXICITIES S Laskar ICARO 2009
Neuro cognitive Cardio Auditory vascular Visual Endocrine Psycho Late Second Tumor social Effects Genito Dental urinary Musculo Gastro intestinal skeletal Pulmo nary S Laskar ICARO 2009
CHRONIC CONDITIONS IN ADULT SURVIVORS OF CHILDHOOD CANCER Condition Relative Risk of Grade 3 or 4 Complication as Compared to Siblings Major Joint Replacement 54. 0 Congestive Heart Failure 15.1 Second malignant neoplasm 14.8 Cognitive dysfunction, severe 10.5 Coronary artery disease 10.4 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 et al, NEJM 2006 S Laskar ICARO 2009
CAUSE OF MORTALITY IN SURVIVORS CANCER Recurrent Second Cardiac Pulmonary Other Non ‐ Cancer Toxicity Disease Treatment Malignancy/ Sequelae Neoplasm Related Childhood 57% 15% 7% 2% 4% 15% Cancer Survivor Study N = 2823 Piedmont 62.2% 12.6% 1.4% NA 8.4% 15.4% Region, Italy N = 143 British 69.1% 7.7% 4.4% 2.2% 5.5% 11.1% Columbia, Canada N = 181 S Laskar ICARO 2009
Paulino AC, IJROBP 2004 TIMELINE OF LATE EFFECTS S Laskar ICARO 2009
EFFECT OF RT ON MUSCULOSKELETAL DEVELOPMENT Factors Influencing Growth • Chronological age at treatment • RT volume • Total RT dose • RT dose per fraction • Site of treatment • Homogeneity of growth plate irradiated • Surgery • Chemotherapy S Laskar ICARO 2009
RELATIVE LOSS OF ADULT HEIGHT • 7.7% (13cm) with RT dose > 33Gy, Entire spine (pre-pubertal age) • No clinically significant loss of height with low dose RT • IFRT associated with clinically insignificant height loss • No disproportion between sitting & standing height William KY, IJROBP 1993;28:85 Stanford S Laskar ICARO 2009
HEIGHT DEFICIT FROM RADIOTHERAPY Age at Height deficit (cm) Height deficit (cm) Height deficit (cm) treatment after 10Gy after 20Gy after 30Gy (yrs) 2 2.4 4.8 7.2 4 1.8 3.5 5.3 6 1.2 2.4 3.6 8 0.8 1.5 2.3 Hogeboom et al, Med Pediar Oncol 2001 S Laskar ICARO 2009
• Hypoplasia of right flank secondary to hemiabdomen RT at age 3 years for FH Wilms’ tumor • Dose: 36Gy in 20 fractions S Laskar ICARO 2009
BOWEL OBSTRUCTION • 131 of 1,910 children (6.9%) enrolled in NWTS-3 at median follow-up of 5.1 years • Etiology was bowel adhesions in 104, intussusception in 17, internal hernia in 2 • Risk factors: higher local tumor stage, extrarenal intravascular involvement, en bloc resection of other organs • Postoperative RT not a risk factor Ritchey ML et al, Ann Surg 1993 S Laskar ICARO 2009
BOWEL OBSTRUCTION • At University of Iowa, SBO was seen in 6 of 42 children who received RT with median follow-up of 15.1 years for Wilms’ tumor • 5 yrs:9.5% • 10 yrs:13% • 15 yrs:17% • Time from surgery to RT borderline significant (< 10 days vs. > 10 days) Paulino et al, IJROBP 2000 S Laskar ICARO 2009
PNEUMONITIS: NWTS-3 EXPERIENCE • 153 pts with Stage IV, FH received whole lung RT • 19 (13%) developed diffuse interstitial pneumonitis • 15 unknown etiology, 3 pneumocystis, 1 varicella • Only 4 of 15 (27%) with pneumonia of unknown etiology survived Green DM et al, Cancer 1989
CARDIOVASCULAR LATE EFFECTS STANFORD 2498 Pts. 754 Deaths 16% (1960-1995) CV disease JCRT 794 Pts. 124 Deaths 14% (1969-1996) CV disease EORTC 1449 Pts. 240 Deaths 7% (1963-1986) CV disease BNLI 1043 Pts. 43 Deaths 14% CV disease Decreasing CV deaths with improving therapy (CT & RT) Stage I & II at Stanford (CV deaths after 15yrs of treatment) 1962 - 1980: 812 pts. ------ 5.4% 1980 – 1996: 628 pts. ------ 0.8% S Laskar ICARO 2009
RENAL FAILURE No of pts No of pts Incidence of Renal Failure (%) with renal failure 2 years 4 years 16 years Unilateral 5312 15 0.1 0.2 0.6 Bilateral - - - - - NWTS-1 41 7 9.8 9.8 16.6 NWTS-2 43 7 14.6 14.6 22.3 NWTS-3 181 18 6.6 8.3 12.7 NWTS-4 177 7 2.6 5.8 _ Ritchey ML et al, Med Pediatr Oncol, 1996 S Laskar ICARO 2009
PREGNANCY OUTCOME • Increased frequency of following were seen in female patients who have received prior flank or tumor bed RT on NWTS 1-4 Fetal malposition Premature labor Offspring with low birthweight, premature birth (< 36 weeks of gestation) and congenital anomalies Green DM et al, JCO 2002 S Laskar ICARO 2009
3D-CRT vs. IMRT FOR EXTREMITY SARCOMAS Hong et al., IJROBP 2004 S Laskar ICARO 2009
3D-CRT IMRT CAX 10cm SUP Hong et al., IJROBP 2004 S Laskar ICARO 2009
Reduction of Volumes receiving 100% dose using IMRT Femur: 57% Normal Soft Tissue: 78% Normal Skin: 45% Mean Skin Dose: Decreased by 14% Hong et al., IJROBP 2004 S Laskar ICARO 2009
3D CRT vs. IMRT vs. PROTONS FOR PELVIC SARCOMA b) IMRT c) PROTONS a) 3D CRT Lee et al, IJROBP 2005 S Laskar ICARO 2009
IJROBP 2002 S Laskar ICARO 2009
Significant Reduction in Volume of Bony Wall of Orbit in High Dose Region S Laskar ICARO 2009
2002 2008 S Laskar ICARO 2009 S Laskar STS CRT
2008 2004 S Laskar STS Brachy 04 S Laskar ICARO 2009
RISK OF SECOND CANCERS TYPE/ SITE RELATIVE RISK ABSOLUTE RISK RELATIVE RISK ABSOLUTE RISK /10,000 pts, In 10yr survivor In 10yr survivor Per Yr. Per 10,000 pts, Per Yr. All cancers 3.5 (3.1 – 3.8) 56.2 4.7 (3.8 – 5.7) 111.7 Leukemia 32.4 (25.5 – 40.6) 16.8 16.2 (6.5 – 33.3) 9.9 NHL 18.6 (13.8 – 24.6) 10.7 32.7 (19.7 – 51.1) 27.8 Solid tumors 2.4 (2.1 – 2.7) 29.3 3.6 (2.8 – 4.6) 74.4 Female breast 2.5 (1.8 – 3.4) 11.3 4.6 (3.0 – 6.6) 39.5 Lung 4.2 (3.3 – 5.2) 13.5 7.3 (4.7 – 10.6) 33.8 Van Leeuwen FE, J Clin Oncol 1994;12:312 Swerdlow AJ, Br Med J 1992;304:1137 Tucker MA, NEJM 1988;318:76 S Laskar ICARO 2009
SECOND CANCERS ?????????????????? IJROBP 2003 S Laskar ICARO 2009
Its 15 Years after the first clinical use of IMRT “NO REPORT OF 2 ND MALIGNANCIES TILL DATE” S Laskar ICARO 2009
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