1. SPONTANEOUS REGRESSION OF NEUROBLASTOMA IMPLICATIONS FOR THE ROLE OF SURGICAL INTERVENTION IN LOW-RISK DISEASE Elizabeth Killien Pediatric Surgery Seattle Children’s Hospital October 11, 2011

2. Outline 1. Background 2. Historical approach 3. Current approach and staging 4. Evidence of spontaneous regression 5. Molecular hypotheses 6. Future directions

3. Background 7.8% of all childhood cancers in the US 15% of deaths from childhood cancer Peak incidence at 1 year of age Two prominent patterns of disease:  Neuroblastoma arising in infancy with excellent outcomes after minimal treatment  Very unfavorable outcome in children >18 months with n-myc amplification and metastatic spread

4. Background Absence of significant progress in cure rates for high-risk neuroblastoma Potential overtreatment of lower- risk patients Two major challenges in clinical neuroblastoma research:

5. Historical approach Earliest attempts to treat shortly after WWI, management limited to surgical resection Gross, Farber, Martin (1959): Improved survival of patients following resection Also observed 2 patients with unresectable tumors with complete resolution 20 & 25 years later “Possibly there are some poorly understood antibody reactions between host and tumor…there are a few well-documented cases wherein neuroblastoma has disappeared completely and permanently”

6. Historical approach Prior to advent of chemotherapy, early observation that survival was better in infants than in older children Early recognition that infants with metastatic spread to skin and liver could undergo spontaneous remission

7. Treatment Stratification Major prognostic indicators: INSS stage, patient age, n-myc amplification

8. Current approach Complete curative resection whenever possible Survival >90% Complete curative resection whenever possible Survival >90% Low risk Definitive surgical treatment after 12-24 weeks adjuvant chemotherapy Survival 70-90% Definitive surgical treatment after 12-24 weeks adjuvant chemotherapy Survival 70-90% Intermediate risk Multimodal: chemotherapy with autologous stem cell rescue, radiation, surgery Survival 30% Multimodal: chemotherapy with autologous stem cell rescue, radiation, surgery Survival 30% High risk

9. Current approach 19.2% operative complications 20.9% localized, 18.2% Stage 4, 13.3% Stage 4S 20 surgery-related deaths (0.9%) 15 in localized NB 28% operative complications 4 surgery-related deaths (0.02%) 2251 German patients with Stage 1- 4 NB (1979-1999) Multicenter US study 1997-2005 (NEJM 2011) Surgical Resection

10. Spontaneous regression Neuroblastoma demonstrates the highest rate of spontaneous regression among malignant tumors 10-100x greater than for any other human cancer  High incidence of neuroblastomic remnants on autopsies of newborns  Well-known spontaneous regression in 4S disease  Infants with small primary tumor with widespread involvement of liver, bone marrow, and/or skin  Areas with screening programs report a 2 to 3-fold higher incidence of neuroblastoma

11. Screening studies Japan 1984-2004: mass screening at age 6 months Measurement of urine VMA & HVA 2000 infants diagnosed via screening  Overall incidence increased 2.6x (29.8 vs 11.5 per 100,000)  Increased incidence in younger patients (2.6x)  Increase in early stage diagnoses (5.8x)  97% survival (overall mortality rate decreased 45%) Number of older patients with advanced stage NB unchanged Estimated 59-92% regression

12. Role of Observation vs Surgery German neuroblastoma study (2002)  For localized NB, radical resection should only be attempted in patients >1 year of age as long as severe complications can be avoided  In patients <1 year of age, tumors should be observed for possible spontaneous regression

13. NB95-S and NB97 Trials 340 infants (<1yr) with Stage 1-3 Neuroblastoma without n-myc amplification Infants with threatening symptoms Chemotherapy n=57 Risk of operation considered to be low Complete resection n=190 Patients asymptomatic, higher-risk operations Observation n=93

14. NB95-S and NB97 Trials Staging Stage 1 = 157, Stage 2 = 113, Stage 3 = 70 Observation period Ultrasound/CXR Q 6 weeks, MRI Q 3 months Regression: Unambiguous decrease of tumor volume observed in at least two subsequent imaging studies Median follow-up at publication: 58 months

15. NB95-S and NB97 Trials Results 47% of patients with signs of regression 38% complete regression 61% incomplete regression 63% continued observation 33% surgery Time to first sign of regression: 3.3 months (1-18 months) Time to complete regression: 10 months (4-20 months) 34% with first signs of regression >1year old

16. NB95-S and NB97 Trials Progression after observation No difference from those that regressed in age, tumor localization, tumor size, catecholamine levels, NSE, LDH, ferritin, histology, or stage Molecular findings:  Chromosomal aberrations (1p, 3p, 11q) in 9 patients in observation group  Aberrations in 11q in 5 patients with progression (p=0.05)  Aberrations in 3 of 4 patients with progression to Stage 4 Surgical morbidity not different between patients with initial surgical intervention or secondary resection after observation

17. NB95-S and NB97 Trials Outcomes Overall (340 patients): 3 year EFS: 77%3 year overall survival: 98% Overall survival by group: Observation 99% Resected 98% Chemotherapy 95%

18. NB95-S and NB97 Trials Outcomes No difference in metastasis-free survival among groups (11 total patients with progression to Stage 4) 10 patient deaths  1 as a result of progression to Stage 4 in obs pt  5 as a result of surgical complications  1 as a result of chemotherapy  (3 neither tumor- nor therapy-related)

19. Hypotheses  Localized infant neuroblastoma similar biology to stage 4S neuroblastoma?  Lysosomal-associated protein multispanning transmembrane 5 gene (LAPTM5) associated with spontaneous regression Normally down-regulated due to DNA methylation in neuroblastoma cells Has been found to be upregulated in regressing NB cells in tumors detected by mass screening In vitro restoration of expression of LAPTM5 induces cell death Theory: Accumulation of autophagic vacuoles due to LAPTM5-mediated lysosomal destabilization results in programmed cell death

20. Hypotheses Proposed LAPTM5 Mechanism

21. Hypotheses Proposed Model for Regression

22. Future directions NB95-S and NB97 trials: Spontaneous tumor regression in 47% of patients without surgical intervention or chemotherapy with Stage 1-3 disease - May have been even higher if some degree of tumor growth prior to regression accepted (10 patients with progression followed by regression)  Expand trial to older ages (Current trial NB 2004)  Further investigation into molecular markers as indicators of progression – improved risk stratification

23. Future directions New Staging System 4 main prognostic groups Pre-treatment criteria Age cut off for risk-stratification 18 months (from 12)

24. References Baker, D. et al. “Outcome after reduced chemotherapy for intermediate-risk neuroblastoma.” N Engl J Med (2010), 363:14, 1313-1323. Gross, R et al. “Neuroblastoma Sympatheticum: A study and report of 217 cases.” Pediatrics (1050), 23:6. 1179-1191. Hero et al. “Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97.” J Clin Onc (2008) 26:9, 1504-1510. Inoue, J et al. “Lysosomal-associated protein multispanning transmembrane 5 gene (LAPTM5) is associated with spontaneous regression of neuroblastomas.” Plos One (2009), 4:9, 7099. Mullassery, D et al. “Neuroblastoma: contemporary management.” Arch Dis Child Educ (2009) 94, 177-185. Ora, I. and A Eggert. “Progress in treatment and risk stratification of neuroblastoma: Impact on clinical and basic research.” Sem Can Biol (2011), article in press. Salim, et al. “Neuroblastoma: a 20-year experience in a UK regional center.” Pediatr Blood Cancer, (2010). Tajiri et al. “Risks and benefits of ending of mass screening for neuroblastoma at 6 months of age in Japan.” J Ped Surg (2009) 44, 2253-2257 Von Schweinitz, et al. “The impact of surgical radicality on outcomein childhood neuroblastoma.” Eur J Pediatr Surg (2002), 12, 402-409..