1. 31 March – 1 April 2011, Stresa Lessons from pediatric cancers [email_address]

3. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 The successful treatment of children with cancer has been a remarkable accomplishment of the last forty years Today, approximately 75% of children diagnosed in countries with highly developed health care systems can be expected to be “cured”

5. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 alliance network centralization in dedicated centers (referral centers/satellite centers) framework method and discipline essential to cooperation dual aim a) research b) practical clinical guidelines / advisory service

7. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 53 centers

8. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011

9. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 E O

11. 1970 1980 1990 2000 2010 IRS-I 1972-1978 IRS-II 1978-1984 IRS-III 1984-1990 IRS-IV 1991-1998 IRS-V 1999-2005 EpSSG RMS 2005 ARST 0531 2006 + COG AIEOP-STSC SIOP-MMT CWS RMS 75 MMT 84 MMT 89 MMT 95 RMS79 RMS88 RMS96 RMS4.99 # MMT 98 # MMT 91 # # M+ patients ARST 0431 # CWS-81 86 CWS-96 CWS 2007-HR CWS 2002-P Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 No. Patients ~ 10,000 patients 799 1115 1194 989 + 151 621 1,828 91 1,578 176 67 825

12. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 EpSSG RMS 2005 From June 2005 to November 2010: 1556 patients registered, from 150 different centers and 14 different countries: 680 eligible in the RMS 2005 protocol, 452 in the NRSTS 2005 protocol, 30 in the Bernie study

13. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 … however, there is a hierarchy in the studies of childhood cancers... … pediatric oncologists have been able to develop national multicenter and ultimately international cooperative protocols for most tumors, and in particular for the relatively more common histotypes… … but not for the less common …

14. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 The very rare pediatric tumors remains “ orphan diseases” , indicating that… … no clinical structures have yet been developed aiding in the diagnosis and treatment of these patients … no standardized diagnostic and therapeutic guidelines are available … so that each patient is usually treated on an individual basis, their biological/clinical characteristics and treatment management are generally unappreciated by most of the pediatric oncologists and surgeons, that may rarely or never encounter them in their daily activities

15. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 the exception to the rule

16. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 SIOPEL - Pre-treatment extend of disease evaluation system (PRETEXT)

17. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 SIOPEL 3 Recruitment by Country/Year 1998 1999 2000 2001 2002 Total Argentina 1 6 3 4 4 18 Australia 2 4 5 7 2 20 Belgium 2 1 3 6 5 17 Brazil 1 2 3 4 3 13 Cuba 0 0 0 2 1 3 Czech Republic 3 2 2 1 0 8 Denmark 1 3 2 0 0 6 France 0 1 11 9 12 33 Greece 0 2 0 0 1 3 Hungary 0 0 0 0 2 2 Ireland 0 0 0 1 0 1 Israel 0 0 0 0 1 1 Italy 2 8 6 4 8 28 New Zealand 0 1 2 1 0 4 Norway 0 1 2 1 2 6 Poland 2 10 7 5 6 30 Slovak Republic 0 0 1 4 0 5 Slovenia 0 0 2 0 0 2 Spain 3 0 2 4 3 12 Sweden 1 0 3 2 2 8 Switzerland 2 1 4 2 0 9 The Netherlands 4 1 4 8 6 23 Turkey 0 0 0 3 2 5 UK 4 11 18 22 18 73 Yugoslavia 0 0 0 0 1 1 Total 28 54 80 90 79 331

18. SIOPEL 1 closed (1990 - 1994) and late effects study group SIOPEL 2 FU closed (1994 - 1998) Phase II study on Cyclo (closed) SIOPEL 3 Closed Data complete SR paper on NEJM HR paper on JCO SIOPEL 4 HR- HB Closed Phase II study on Irinotecan Closed Publication in preparation SIOPEL 5 HCC closed (low accrual) New trial on HCC with SORAFENIB in preparation SIOPEL 6 SR- HB Open!!! 31 March – 1 April 2011 Rare solid cancer: lessons from pediatric cancers

21. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 very rare pediatric tumors = orphan diseases … no clinical structures … no standardized diagnostic and therapeutic guidelines … patient usually treated on an individual basis

22. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 It seems that the first decade of the new millennium may be a key time for the so called “ rare (or very rare ) pediatric tumors ” , no longer seen as “orphan” diseases or object of a small group of dedicated experts or collectors of rarities, but as a primary subject of the pediatric oncology community aiming to run dedicated clinical research programs

23. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 To improve basic research on rare pediatric tumors and their clinical management, a nationwide Italian cooperative project called the TREP (Tumori Rari in Età Pediatrica - Rare Tumors in Pediatric Age) was launched in 2000 in Italy (under the auspices of the Associazione Italiana Ematologia Oncologia Pediatrica – AIEOP, and in cooperation with the Società Italiana Chirurgia Pediatrica - SICP) Coordinators: G.Bisogno, G.Cecchetto, A.Ferrari The challenge of very rare pediatric tumors: the Italian TREP project

24. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 … an arbitrary and pragmatic definition… any solid malignancy characterized by an annual incidence < 2/million and not considered in other clinical trials The TREP project: defining Very Rare Pediatric Tumors a definition that does not simply reflect the low incidence but mainly refers to its status as an “orphan disease”

25. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 ...the TREP project did not include tumors with such a low incidence but already “covered” by other national studies, i.e. renal rhabdoid tumors were registered in the national Wilms study; rare histotypes of soft part sarcomas were covered by the cooperative study on soft tissue sarcomas, and so on…

27. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 Andrea Ferrari, Iyad Sultan

28. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 Melanomas Thyroid carcinomas

29. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 Adult cancers (which are mainly epithelial tumors) differ substantially from pediatric neoplasms (which are mainly embryonal tumors)… … so the right diagnostic and therapeutic approach may differ from the one generally adopted in the pediatric oncologist’s world to deal with neuroblastoma, rhabdomyosarcoma or Wilms tumor

30. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 It is crucial to decide where children with adult cancers should be treated and who should treat them Letting these patients be treated by experts on the tumors concerned (i.e. at adult facilities) is one option, in particular for older adolescents. On the other hand, few pediatricians/parents would probably be happy about referring a 10 year-old to an adult cancer department (…a good solution for the tumor , but not for the patient …) Children suffering from adult tumors would be best treated in a pediatric setting, but by specialists who are experts on adult tumors But this seems very difficult (not to say impossible to achieve)…

32. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 … things are more complicated than they seem… Children are not “small adults” They differ significantly from adults in terms of numerous physical, physiological, cognitive and behavioral characteristics, especially in the pre-pubertal period. Differences in anthropometric measures, body composition, organ size and maturity, and hormone status may directly influence the relationship between the tumor cells and the host, the disposition and clearance of drugs, and susceptibility to treatment morbidities . 

33. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 … things are more complicated than they seem… Children are not “small adults” They differ significantly from adults in terms of numerous physical, physiological, cognitive and behavioral characteristics, especially in the pre-pubertal period. Differences in anthropometric measures, body composition, organ size and maturity, and hormone status may directly influence the relationship between the tumor cells and the host, the disposition and clearance of drugs, and susceptibility to treatment morbidities .  This may restrict any straightforward application of therapeutic schemes tailored to adults in children with the same disease (of course, the same applies vice versa, when it comes to using pediatric protocols in adults)

34. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 … things are more complicated than they seem…  There is increasing evidence to suggest that the biology and clinical history of some adult tumor types is not the same when the same neoplasm occurs in a child

35. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 melanoma

36. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 The commonly-used ABCD clinical rule (Asymmetry – Border irregularity – Color variability – Dimension > 6 mm) may be useless and even misleading in childhood melanoma

38. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 colorectal carcinoma

39. Author Patients Comments La Quaglia MP, 1992 Memorial Sloan-Kettering, N Y 29 pts < 21 yrs, in a 40-year period 3-yr survival 28%, very high incidence of high-grade histologies Cozart DT, 1993 Little Rock, Arkansas 55 pts < 30 yrs from 24 different centers 5-yr survival 56% - feasibility of studies on rare tumors using a registry framework Rodriguez-Bigas MA, 1996 Buffalo, NY 68 pts < 30 yrs (median age 27 yrs), in a 25-year period poor prognosis (only 9 pts were alive) Chung YFA, 1998 Singapore General Hospital 23 pts < 29 yrs (out of 110 < 40 yrs), young age is not a clear poor prognostic marker Karnak I, 1999 Ankara, Turkey 20 pts < 16 yrs, delayed diagnosis, advanced disease and mucinous type determine poor outcome Pratt CB, 1999 St. Jude, Memphis 13 patients 11-23 years of age 5-fluorouracil, leucovorin,  -interferon for advanced disease Bhatia S, 1999 St. Jude, Memphis 53 pts < 21 years seen from 1960 to 1998 25 cases: interview on family history on cancer, increased risk of colorectal cancer in relatives Sule AZ, 1999 Nigeria 35 cases < 30 yrs (median age 25 yrs) poor prognosis Vastyan AM, 2000 Pecs, Hungary / Sheffield, UK 7 cases < 15 yrs, poor outcome Chen LK, 2001 Taiwan 28 cases < 20 yrs no crucial role for family history, inflammatory bowel disease, or familial polyposis Radhakrishnan CN, 2003 Manchestern, UK 8 pts < 16 yrs all died of tumor Durno C, 2005 Toronto, Canada 16 cases < 24 years genetic analysis: inherited predisposition for early onset cases Chantada GL, 2005 Buenos Aires, Argentina 14 pts < 20 yrs, compared to 7 from 21 to 30 yrs advanced disease and poor prognosis for pts < 20 yrs Kravarusic D, 2007 Israel 7 children poor outcome, delayed diagnosis Hill DA, 2007 St. Jude, Memphis 77 children and adolescents (ages 7 to 19 years), from 1964 to 2003 high frequency of mucinous histology, poor outcomes Ferrari A, 2008 INT, Milan, Italy 7 children (<18 yrs), compared to 20 young adults and 2,340 older adults rarity and poor prognosis (advanced stage, aggressive biology) Salas-Valverde S, 2009 San Josè, Costarica 11 children a high level of awareness and early diagnosis are critical Sultan I, 2010 Amman, Jordan, SEER database 159 children/adolescents comparison with adults high-risk features and worse outcome than adults

43. FAMILIARITY ( HNPCC and FAP) 14% of children , 55% of young adults and 13% of adults It is still debated whether a family history of bowel cancer increases the risk of CRC before the age of 20 years the tumorigenesis of childhood CRC may differ from the well-described multi-step process of adult CRC (which usually takes around 10 years) 31 March – 1 April 2011 Rare solid cancer: lessons from pediatric cancers

44. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 gastrointestinal stromal tumors (GIST)

45. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 Pediatric GIST SEER 2001-2005: 12 cases Literature review: 21 familial GIST 113 sporadic GIST age < 21 yrs Incidence 0.02/1,000,000/year

48. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 thyroid carcinoma

50. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 This peculiar clinical behaviour may have a corresponding biological finding in the evidence of the RET/PCR3 translocation in the pediatric papillary subtype , while adult tumors (in particular the tall cell variant) are characterised by BRAF mutation, that would be related to unfavourable outcome A crucial feature of childhood papillary carcinoma lies in its marked sensitivity to hormonal manipulation : the tumor cells are stimulated by thyroid-stimulating hormone (TSH) activity, while TSH suppression therapy (with l-thyroxin) is extremely effective in controlling tumor growth

51. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 These findings strongly suggest that children with papillary thyroid carcinoma should be treated differently from adult patients, although there is still some controversy regarding the therapeutic approach, the extent of thyroidectomy and neck node dissection, and the need for radioactive iodine (RAI) therapy RADICAL same as for adults THERAPEUTIC APPROACH CONSERVATIVE tailored for selected pediatric patients (tumors limited to one lobe, ± clinical evidence of monolateral N) initial eradication of all clinical and subclinical neoplastic foci (at T, N and M) strategy remove of only grossly detectable disease, without searching for microscopic disease after surgery improve progression-free survival by detecting and treating all tumor cells, and preventing any dedifferentiation of occult neoplastic micro-foci aims contain treatment morbidity, without jeopardizing the zero mortality rate (the risk of tumor dedifferentiation from microscopic disease seems to be merely theoretical in children) total thyroidectomy (regardless of the tumor extent) thyroid resection removal of the thyroid lobe affected by clinically detectable disease and the isthmus (hemithyroidectomy) prophylactic lymphadenectomy lymphadenectomy selective neck dissection of only the clinically involved node levels RAI scintigraphic scan to seek any subclinical metastases staging No RAI scintigraphic scan (macrostaging instead of microstaging) treatment with 131 I ablation, where necessary post-operative treatment TSH suppression therapy to control subclinical disease serum thyroglobulin level is a very sensitive marker of post-treatment relapse follow-up presence of thyroid tissue would prevent the effective use of thyroglobulin assay as a marker of tumor relapse hypoparathyroidism (36%) recurrent laryngeal nerve paralysis and spinal accessory nerve paralysis (28%) risk of iatrogenic effects of metabolic radiotherapy risk of permanent morbidity very low

52. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 … many children/adolescents currently received aggressive surgery, though they could be treated with a more conservative approach, paying the price of a high risk of permanent morbidity This occurs because children are treated by adult surgeons, or following guidelines tailored for adults, without taking into account the peculiarity of the tumor in pediatric age

53. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 The challenge of very rare pediatric tumors: the Italian TREP project

54. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 The challenge of very rare pediatric tumors: the Italian TREP project

60. http://www.trepproject.org

62. F M 10-14 yrs 15-17 yrs 5-9 yrs <5 yrs The TREP project: the accrual January 2000 – January 2010 636 registered cases 528 eligible from 34 Centers

63. THYROID CARCINOID NPC GONADAL MELANOMA ADRENO RENAL PHEO PPB THYMUS G-I PANCREAS SALIVARY others The TREP project: the accrual

64. The TREP project: the accrual To compare the number of patients actually enrolled (between 2000 and 2006) with the number of rare pediatric tumors expected to be diagnosed in Italy based on incidence data from the well-established Italian network of population-based cancer registries (the AIRTum, which comprises 22 general registries and 3 specialist registries, covering 32.9% of Italian children) The prediction of the expected number according to AIRTum was generally confirmed by using, as control group, the United Kingdom National Childhood Tumour Registry (UK NCTR) data for children, and the Automated Childhood Cancer Information System (ACCIS) data for adolescents

65. The TREP project: the accrual Period 2000-2006 0-14 year-olds 15-17 year-olds Expexted cases 305 400 Observed cases 271 75

66. The TREP project: the accrual 271 / 305 75 / 400 0-14 yrs 15-17 yrs Cancer Types O E O/E (95%CI) O E O/E (95%CI) nasopharyngeal carcinoma 19 14 1.36 (0.65-2.92) 13 13 1.00 (0.43-2.34) adrenocortical tumors 23 17 1.35 (0.69-2.70) 2 4.4 0.45 (0.04-2.99) pleuro-pulmonary blastoma 13 1.9 6.84 (1.51-67.67) 1 0.0 - carcinoids of appendix 49 25 1.96 (1.19-3.31) 7 30 0.23 (0.09-0.54) cutaneous melanoma 19 62 0.31 (0.17-0.52) 8 107 0.07 (0.03-0.15) renal carcinoma 20 24 0.83 (0.44-1.57) 2 8.7 0.23 (0.02-1.12) pancreatoblastoma 11 1.8 6.11 (1.26-67.16) 1 4.4 0.23 (0.00-2.17) gonadal non-germ-cell tumors 27 41 0.66 (0.39-1.10) 3 39 0.08 (0.02-0.24) pheochromocytoma 18 3.6 5.00 (1.58-22.21) 0 0.0 - thyroid carcinoma 50 91 0.55 (0.38-0.78) 32 159 0.20 (0.13-0.30) salivary gland tumors 5 22 0.23 (0.07-0.62) 1 26 0.04 (0.00-0.23) breast carcinoma 1 0.0 - 1 0 - carcinoma of the GI tract 3 1.8 1.67 (0.18-23.40) 3 8.7 0.34 (0.06-1.40) carcinoma of the thymus 3 0.0 - 1 0 -

68. 271 / 305 75 / 400 For the 0-14 year-olds, the O/E ratio was around 1:1 for several tumors (i.e. nasopharyngeal carcinoma, adrenocortical tumors, renal cell carcinoma and gonadal non-germ-cell tumors) 0-14 yrs 15-17 yrs Cancer Types O E O/E (95%CI) O E O/E (95%CI) nasopharyngeal carcinoma 19 14 1.36 (0.65-2.92) 13 13 1.00 (0.43-2.34) adrenocortical tumors 23 17 1.35 (0.69-2.70) 2 4.4 0.45 (0.04-2.99) pleuro-pulmonary blastoma 13 1.9 6.84 (1.51-67.67) 1 0.0 - carcinoids of appendix 49 25 1.96 (1.19-3.31) 7 30 0.23 (0.09-0.54) cutaneous melanoma 19 62 0.31 (0.17-0.52) 8 107 0.07 (0.03-0.15) renal carcinoma 20 24 0.83 (0.44-1.57) 2 8.7 0.23 (0.02-1.12) pancreatoblastoma 11 1.8 6.11 (1.26-67.16) 1 4.4 0.23 (0.00-2.17) gonadal non-germ-cell tumors 27 41 0.66 (0.39-1.10) 3 39 0.08 (0.02-0.24) pheochromocytoma 18 3.6 5.00 (1.58-22.21) 0 0.0 - thyroid carcinoma 50 91 0.55 (0.38-0.78) 32 159 0.20 (0.13-0.30) salivary gland tumors 5 22 0.23 (0.07-0.62) 1 26 0.04 (0.00-0.23) breast carcinoma 1 0.0 - 1 0 - carcinoma of the GI tract 3 1.8 1.67 (0.18-23.40) 3 8.7 0.34 (0.06-1.40) carcinoma of the thymus 3 0.0 - 1 0 -

69. 271 / 305 75 / 400 For the adolescents, under-reporting was statistically significant for all tumor types except nasopharyngeal carcinoma 0-14 yrs 15-17 yrs Cancer Types O E O/E (95%CI) O E O/E (95%CI) nasopharyngeal carcinoma 19 14 1.36 (0.65-2.92) 13 13 1.00 (0.43-2.34) adrenocortical tumors 23 17 1.35 (0.69-2.70) 2 4.4 0.45 (0.04-2.99) pleuro-pulmonary blastoma 13 1.9 6.84 (1.51-67.67) 1 0.0 - carcinoids of appendix 49 25 1.96 (1.19-3.31) 7 30 0.23 (0.09-0.54) cutaneous melanoma 19 62 0.31 (0.17-0.52) 8 107 0.07 (0.03-0.15) renal carcinoma 20 24 0.83 (0.44-1.57) 2 8.7 0.23 (0.02-1.12) pancreatoblastoma 11 1.8 6.11 (1.26-67.16) 1 4.4 0.23 (0.00-2.17) gonadal non-germ-cell tumors 27 41 0.66 (0.39-1.10) 3 39 0.08 (0.02-0.24) pheochromocytoma 18 3.6 5.00 (1.58-22.21) 0 0.0 - thyroid carcinoma 50 91 0.55 (0.38-0.78) 32 159 0.20 (0.13-0.30) salivary gland tumors 5 22 0.23 (0.07-0.62) 1 26 0.04 (0.00-0.23) breast carcinoma 1 0.0 - 1 0 - carcinoma of the GI tract 3 1.8 1.67 (0.18-23.40) 3 8.7 0.34 (0.06-1.40) carcinoma of the thymus 3 0.0 - 1 0 -

71. The incidence of all tumors listed in the TREP project was <2/million a year among 0-14 year-olds … … but >2/million a year among 15-17 year-olds for some histotypes (melanoma, thyroid cancer, gonadal tumors, carcinoid tumors, salivary gland tumors)… … in other words, some of the “TREP tumors” should not be classed as “rare tumors” in adolescents… Incidence rates (per million person-years) rates recorded by the Italian network of cancer registries-AIRTUM during 1988-2002 Cancer Types 0 1-4 5-9 10-14 15-17 nasopharyngeal carcinoma 0.00 0.00 0.00 0.73 1.08 adrenocortical tumors 2.04 0.38 0.10 0.09 0.36 pleuro-pulmonary blastoma (and other lung tumors) 0.00 0.13 0.00 0.00 0.00 carcinoids of appendix 0.00 0.00 0.20 1.10 2.51 cutaneous melanoma 0.00 0.64 0.30 2.38 8.78 renal carcinoma 1.02 0.13 0.50 0.46 0.72 pancreatoblastoma (and other pancreatic exocrine tumors) 0.00 0.00 0.00 0.09 0.36 gonadal non-germ-cell tumors (ovary/testis) 1.02 0.51 0.40 1.10 3.23 pheochromocytoma and paraganglioma 0.00 0.00 0.00 0.18 0.00 thyroid carcinoma 0.00 0.00 0.89 3.75 13.08 salivary gland tumors 0.00 0.00 0.00 1.10 2.15 breast carcinoma 0.00 0.00 0.00 0.00 0.00 carcinoma of the gastrointestinal tract 0.00 0.00 0.00 0.09 0.72 carcinoma of the thymus 0.00 0.00 0.00 0.00 0.00

73. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011

74. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011

75. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011

76. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011

77. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 A PROSPECTIVE PROTOCOL FOR NASOPHARINGEAL CARCINOMA IN CHILDREN AND ADOLESCENTS: THE ITALIAN TREP PROJECT Michela Casanova, Gianni Bisogno, Giovanni Cecchetto, Andrea Di Cataldo, Eleonora Basso, Paolo Indolfi, Francesca Favini, Lorenza Gandola, Andrea Ferrari 46 patients, prospectively registered and treated

80. Rare solid cancer: lessons from pediatric cancers 31 March – 1 April 2011 A PROSPECTIVE PROTOCOL FOR NASOPHARINGEAL CARCINOMA IN CHILDREN AND ADOLESCENTS: THE ITALIAN TREP PROJECT Michela Casanova, Gianni Bisogno, Giovanni Cecchetto, Andrea Di Cataldo, Eleonora Basso, Paolo Indolfi, Francesca Favini, Lorenza Gandola, Andrea Ferrari Table 2. Stage distribution of the 46 patients Table 3 . 5-yearPFS according to clinical variables (univariate analysis) No. 5-year PFS p-value Whole series 46 79.0 % Gender male 29 72.9 % female 17 88.2 % p = 0.2235 Age ≤ 14 yrs 27 87.8 % ≥ 15 yrs 19 66.7 % p = 0.0762 T stage T1-3 28 73.9 % T4 18 87.5 % p = 0.3298 N stage N0-1 12 83.3 % N2-3 34 77.3 % p = 0.6880 M stage M0 41 86.8 % M1 5 20.0 % p < 0.0001 AJCC stage II 6 100 % III 15 85.7 % IV 25 69.6 % p = n.e. Table 4. Incidence of late sequelae in the 26 surviving patients with a follow-up of at least 24 months (data not available in 4 cases) Any morbidity 65% Hypothytoidism 54% Caries 23% Xerostomy 50% Recurrent sinusitis and otitis 19% Neck fibrosis 38% Pulmonary fibrosis 15% Trismus 35% Recurrent pneumothorax 7% Hearing loss 27% LH/FSH deficiency 4% GH deficiency 23% Renal dysfunction 4% Stage No. (%) T1 T2 T3 T4 8 (17.4%) 12 (26.1%) 8 (17.4%) 18 (39.1%) N0 N1 N2 N3 1 (2.2%) 11 (23.9%) 24 (52.2%) 10 (21.7%) M0 M1 41 (89.1%) 5 (10.9%) AJCC stage IIB 6 (13.0%) AJCC stage III 15 (32.6%) AJCC stage IVA 11 (23.9%) AJCC stage IVB 9 (19.6%) AJCC stage IVC 5 (10.9%)

84. E u r o p e a n C o o p e r a t i v e S t ud y Pediatric Ra r e T umo r s B.Brennan (UK) D.Orbach (Fr), Y.Reguerre (Fr) J.Godzinski (P), E.Bien (P) D.Schneider (D), I.Brecht (D) G.Bisogno (It), G.Cecchetto (It), A.Ferrari (It) E X PeRT

85. PANCREATOBLASTOMA: A REPORT FROM THE EUROPEAN COOPERATIVE STUDY GROUP FOR PEDIATRIC RARE TUMORS (EXPeRT) Ewa Bien, Jan Godzinski, Patrizia Dall’Igna, Anne-Sophie Defachelles, Teresa Stachowicz-Stencel, Daniel Orbach, Gianni Bisogno , Giovanni Cecchetto, Steven Warmann, Verena Ellerkamp, Bernadette Brennan, Anna Balcerska, Ines Brecht, Dominik Schneider, Andrea Ferrari Background. Pancreatoblastoma is a very rare malignant tumor typically occurring in the early years of life. Due to its rarity, standardized diagnostic and therapeutic guidelines are not available for pancreatoblastoma. Methods. The newborn cooperative group denominated ExPeRT - European cooperative study group for Paediatric Rare Tumours – combined in a joint analysis all cases registered between 2000 and 2009 by national groups of Italy, France, United Kingdom, Poland and Germany . Results. Twenty patients < 18 years old (median age 4 years) were analysed: 7 had tumor confined to the pancreas (stage I-II), 4 tumor extended beyond the pancreas or with lymph nodes metastases (stage III), 9 had distant metastases. Seventeen patients had tumor resection, at initial or delayed surgery. Eighteen received chemotherapy (response rate 73%), 6 received radiotherapy. For the whole series, 5-year event-free survival and overall survival were 58,8% and 79,4%, respectively. Outcome did not correlate with tumor site and size, but was influenced by the tumor stage and by the feasibility of complete resection. Conclusions. This international study confirms the rarity of the disease, the critical role of surgical resection, headstone of the therapy and main prognostic variable, and the potential efficacy of chemotherapy. The adoption of an intensive multidisciplinary approach is required, as well as the referral to highly experienced centers. Further international cooperation is needed to collect more experiences and stimulate biological studies to improve our understanding of the biology and the natural history of PBL. Eur J Cancer, accepted for publication E X PeRT

86. PANCREATOBLASTOMA: A REPORT FROM THE EUROPEAN COOPERATIVE STUDY GROUP FOR PEDIATRIC RARE TUMORS (EXPeRT) Ewa Bien, Jan Godzinski, Patrizia Dall’Igna, Anne-Sophie Defachelles, Teresa Stachowicz-Stencel, Daniel Orbach, Gianni Bisogno , Giovanni Cecchetto, Steven Warmann, Verena Ellerkamp, Bernadette Brennan, Anna Balcerska, Ines Brecht, Dominik Schneider, Andrea Ferrari Eur J Cancer, accepted for publication … though further studies are clearly needed to validate any formal guideline for this very rare tumor, the EXPeRT group would propose a sort of standard approach for PBL, including a surgical staging system, an initial conservative surgical approach, chemotherapy according to PLADO regimen, and a post-chemotherapy aggressive surgery, on both primary tumor and metastases, when present … this study demonstrates that international cooperation in very rare tumors is feasible, and supports the benefit of the foundation of the EXPeRT group E X PeRT

87. The TREP project: ACKNOWLEDGEMENT Gianni Bisogno and Giovanni Cecchetto TREP project co-coordinators E.Mancini data manager G.L. De Salvo responsible Data Center P.Indolfi, M.Massimino, A.Inserra, C.Spinelli, L.Gandola, M.Casanova, P.Dall’Igna, A.Bono, M.Guzzo, A.Rizzo, G.Bernini, G.Pettinato, G.Magro, R.Alaggio, R.Boldrini, P.Collini, C.Gambini…and many others The TREP project has been supported by grants from the “Fondazione Città della Speranza”, Padova, and the “Fondazione Fondazione Cassa di Risparmio di Padova e Rovigo CARIPARO”. … the TREPpers Thank you for the attention