Bisogno_A4_2011 25/05/2012 12:12 Page 130

Paediatric Oncology

Very Rare Tumours in Paediatric Age – From ‘Tumori Rari in Età Pediatrica’ to the European Cooperative Study Group for Paediatric Rare Tumours

Gianni Bisogno,1 Giovanni Cecchetto2 and Andrea Ferrari3

1. Paediatric Consultant and Head, Solid Tumour Unit, Haematology/Oncology Division, Department of Paediatrics, University Hospital of Padua; 2. Associate Professor, Division of Paediatric Surgery, Department of Paediatrics, University Hospital of Padua; 3. Oncologist Consultant and Head, Outpatient Service, Paediatric Oncology Unit, National Tumour Institute, IRCCS, Milan, Italy

Abstract Very rare tumours (VRTs) in paediatric age are a heterogeneous group of cancers very rarely encountered in daily practice, even in large paediatric oncology centres. Some of them are typical of paediatric age, such as pleuropulmonary blastoma or pancreatoblastoma; others are typically found in adulthood, such as carcinomas and melanoma. With the objective of improving the research on, and management of, paediatric VRTs, a national study group was founded and the Tumori Rari in Età Pediatrica (Rare Tumours in Paediatric Age [TREP]) project was launched in Italy in 2000. For the purposes of this project, VRTs have been defined as “any solid malignancy characterized by an annual incidence of <2 cases/million children and not considered in other clinical trials”. From January 2000 to December 2011, 652 patients <18 years of age were registered in the TREP database. This article presents the experience gathered so far and underlines the need to develop international collaborations dedicated to paediatric VRTs. With this aim, national groups from Italy, Germany, France, Poland and the UK have created, in June 2008, a new collaborative group named European Cooperative Study Group for Paediatric Rare Tumours (EXPeRT).

Keywords Very rare tumours, paediatric patients, pleuropulmonary blastoma, nasopharyngeal carcinoma, pancreatic tumours, thyroid carcinoma, melanoma, Tumori Rari in Età Pediatrica (TREP) project, European Cooperative Study Group for Paediatric Rare Tumours (EXPeRT)

Disclosure: The authors have no conflicts of interest to declare Acknowledgement: The Tumori Rari in Età Pediatrica (TREP) project has been supported by a grant from the Fondazione Città della Speranza, Padova, and the Fondazione Cassa di Risparmio di Padova e Rovigo. Received: 16 January 2012 Accepted: 6 February 2012 Citation: European Oncology & Haematology, 2012; 8(2):130–4 DOI: 10.17925/EOH.2012.08.02.130 Correspondence: Gianni Bisogno, Haematology/Oncology Division, Department of Paediatrics, University Hospital of Padua, Via Giustiniani 3, 35128 Padova, Italy. E: [email protected].

Malignant tumours are relatively uncommon in children, especially blastoma or pancreatoblastoma, and are very rarely encountered in considering the incidence of cancer in adults. The difficulty of daily practice, even in large paediatric oncology centres. Others are performing meaningful studies due to the limited numbers of patients typically found in adulthood, such as thyroid carcinoma, colorectal treated at each paediatric oncology centre has encouraged carcinoma, melanoma, thymic tumours and renal carcinoma. oncologists to embark on national and international collaboration schemes in order to perform significant research. The positive results So far, the paediatric oncology community has shown little interest in achieved by these schemes seem evident from the gradual this group of tumours, which partially explains our lack of improvement in the survival rates in nearly all paediatric tumours, to understanding of the biology of these disorders and the difficulties a point where nearly three in four children diagnosed in developed encountered in conducting clinical trials. In fact, survival rates have countries can currently be expected to be ‘cured’. not changed substantially over the years and have remained unsatisfactory for some histotypes. In several European countries, Unfortunately, not all children benefit from these efforts; for those national groups focusing specifically on rare cancers in children have affected by exceptionally rare tumours, the very low incidence of their recently been founded to deal with these issues. disease has often limited the interest in research programmes capable of collecting meaningful clinical and biological data. As a The ‘Tumori Rari in Età Pediatrica’ Project consequence, it is extremely difficult to produce evidence-based The Tumori Rari in Età Pediatrica (Rare Tumours in Paediatric Age treatment guidelines for these patients and physicians are forced [TREP]) project was launched in Italy in 2000 and represents a model to treat them on an individual basis. of network dedicated to rare paediatric tumours. It has not only created a registry for collecting cases, but has also established Paediatric very rare tumours (VRTs) comprise a variety of entities. treatment guidelines for various rare tumours and a network of Some of them are typical of paediatric age, such as pleuropulmonary medical experts who can help clinicians manage their patients.1

130 © TOUCH BRIEFINGS 2012 Bisogno_A4_2011 28/05/2012 15:38 Page 131

Very Rare Tumours in Paediatric Age

One of the initial issues faced by the project’s team was to define Table 1: Paediatric Very Rare Tumours Included its target. For the purposes of the project, VRTs were defined as in the ‘Tumori Rari in Età Pediatrica’ Project “any solid malignancy characterized by an annual incidence of <2 cases/million children and not considered in other clinical trials”. • Nasopharyngeal carcinoma The epidemiological cut-off was chosen arbitrarily after an analysis • Adrenocortical carcinoma of the tumours identified for inclusion in the project. The second • Pleuropulmonary blastoma (and other lung tumours) part of the definition underlined the fact that a number of VRTs had • Carcinoid tumours not received enough attention from paediatric oncologists, • Cutaneous tumours cooperative groups and scientists. • Renal cell carcinoma • Pancreatoblastoma (and other pancreatic tumours) It must be acknowledged that some tumours that we have included in • Non-germ cell gonadal tumours (ovary/testis) our list of VRTs have an incidence higher than two cases/million • Pheochromocytoma and paraganglioma children; this is the case of thyroid carcinoma and melanoma, where • Thyroid carcinoma the incidence increases during adolescence. These tumours have • Salivary gland tumours been included in the project because, at the time, they shared the • Breast tumours status of ‘orphan disease’ and the problems of other, less frequent • Gastrointestinal tumours entities. We used the same criteria for rare haematological conditions • Carcinoma of the thymus and central nervous system neoplasms, which were consequently • Other rare malignant and borderline tumours excluded because they came under the remit of other co-operative groups. The list of paediatric VRTs included in the TREP project is given in Table 1. Figure 1: Number of Patients Registered in the ‘Tumori Rari in Età Pediatrica’ Project by Tumour Type

Fifteen different working groups (one for each type of tumour) were 140 gradually formed with a view to developing diagnostic and treatment 130 guidelines. Each working group was co-ordinated by one or two 120 experts, who were also in charge of analysing the data collected, 110 regularly updating the guidelines and advising clinicians on the 100 treatment of children with VRTs. Clinical and treatment data were 90 prospectively collected in a central registry after consent from the 80 patients’ families had been received. The possibility of collecting 70 60 biological samples was also contemplated for some tumours (e.g., 50 Number of patients adrenocortical carcinoma, pheochromocytoma). 40 30 To improve the dissemination of knowledge in Italy, a website 20 (http://trepproject.org) was created to describe the TREP project 10 activities and publish information on different paediatric VRTs. 0

Number of Patients Included From January 2000 to December 2011, 652 patients <18 years Breast tumours Thyroid carcinoma CarcinoidCutaneous tumours tumours Pancreatic tumours Other rare tumours of age were registered in the TREP database by 38 different Italian Renal cell carcinomaPheochromocytoma SalivatoryCarcinoma glandGastrointestinal tumours of the thymus tumours centres. The median number of patients recruited annually was 54. NasopharyngealAdrenocortical carcinoma carcinomaPleuropulmonary blastoma Non-germ cell gonodal tumours The most ‘common’ VRTs were thyroid carcinoma, carcinoid of the appendix, cutaneous tumours and non-germ cell gonadal Adolescents (15–18 years) are shown in blue and children (0–14 years) in red. tumours (see Figure 1). Data on an interesting number of exceptionally rare tumours, e.g., carcinoma of the thymus and Lessons Learned gastrointestinal tumours, were also prospectively collected. In general, the TREP project has demonstrated that cooperative prospective research on paediatric VRTs is feasible. Merely registering An analysis performed in collaboration with the Italian Paediatric cases would not have been enough, and the success of the project was Haematology/Oncology Association (Associazione Italiana Ematologia due to the clinical guidelines and advice provided to all centres taking Oncologia Pediatrica [AIEOP]) epidemiology group showed that the part and to the involvement of specialists from different disciplines. TREP project was able to register 85 % of the cases of VRTs expected to occur in children aged 0–14 years in Italy, judging from incidence For specific types of tumour, various series of cases included in the data in population-based cancer registries.2 This figure was similar to project were analysed and, despite the limited numbers involved, those obtained for more common paediatric tumours by other some key messages were identified. national cooperative groups that started operating much earlier. Unfortunately, the percentage was only 19 % in adolescents (15- to For some tumours, it was possible to assess the results of 18-year-olds). Again, the figure was very similar to those seen in multidisciplinary treatments and identify prognostic factors. This was the other, more common tumours;3 in a way, it can be seen as more case, for instance, of pleuropulmonary blastoma: an analysis of acceptable if one considers that most adolescent patients have 22 patients treated using the multimodal strategy recommended by the adult-type epithelial cancers. TREP guidelines showed estimated 15-year event-free and overall

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Paediatric Oncology

Table 2: Adult Cancers in Children and Adolescents in studies on a national scale – and the need for international the US – Numbers of Cases Registered in the Surveillance cooperative efforts to tackle their treatment. Epidemiology and End Results Database (1973–2006)

For other entities, the prospective registration and follow-up of Type of Cancer Adults 0–14 years 15–19 years children enabled us to shed light on some recurrent controversies. n Rate n Rate n Rate This was the case of carcinoid tumour of the appendix, for which the Renal cell carcinoma 98,587 10.49 72 0.03 84 0.10 best surgical approach is still a debated matter. Traditionally, right Hepatocarcinoma 41,605 4.06 101 0.04 86 0.08 hemicolectomy has been recommended for lesions larger than 2 cm Adrenocortical carcinoma 1,097 0.12 59 0.02 18 0.03 in diameter to reduce the risk of metastasis. A retrospective analysis Thyroid carcinoma 80,702 8.35 515 0.18 1,485 1.58 Nasopharyngeal of 14 cases treated at two institutions belonging to the TREP network 7 carcinoma 7,470 0.85 72 0.02 123 0.14 prompted us to adopt a more conservative approach. The TREP Malignant melanoma 187,891 20.29 468 0.16 1,368 1.47 guidelines were distributed in 2002 and recommended not to perform Carcinoma of the hemicolectomy whenever the carcinoid tumour was completely salivary glands 12,571 1.44 115 0.04 148 0.17 resected, irrespective of its size. A close follow-up (every three Carcinoma of the months for one year after surgery and at increasingly longer intervals colon/rectum 584,427 69.66 31 0.01 143 0.13 thereafter) was recommended, using investigations including Carcinoma of the lung 618,614 71.87 16 0.01 35 0.03 5-hydroxyindoleacetic acid testing, abdominal ultrasound and Carcinoma of the thymus 2,414 0.26 11 0.01 13 0.01 octreotide scan. An ongoing analysis of more than 100 prospectively Breast carcinoma 752,728 86.04 10 <0.01 55 0.05 registered cases has confirmed that this conservative approach Cervical carcinoma 59,125 6.80 8 <0.01 87 0.12 is appropriate and has shown that an intensive follow-up is Carcinoma of the bladder 135,399 16.82 9 <0.01 49 0.07 Carcinoma of other sites 1,309,251 149.40 96 0.04 216 0.25 unnecessary. As a consequence, the TREP guidelines have been Gastrointestinal stromal amended to reduce the burden of investigations performed after the tumour 3,484 0.25 9 <0.01 11 0.01 tumour’s resection. Mesothelioma 10,667 1.18 3 <0.01 8 0.01 Total 4,121,450 3,032 6,457 A particular aspect of VRTs in children is that some of them may be The incidence rates shown are per 100,000 population. relatively common in adults (see Table 2). This is the case of all 8 Source: modified from Ferrari et al., 2010. carcinoma types, but also of melanomas and gastrointestinal tumours. Diagnosis and treatment guidelines adopted for children are survival rates of 44 % and 49 %, respectively. Performing total resection generally extrapolated from those used to treat adults; however, the of the tumour at any time during its treatment resulted in a significantly clinical and biological characteristics of the diseases may differ in better prognosis, whereas extrapulmonary involvement at diagnosis paediatric age. And the more severe long-term consequences of coincided with a significantly worse prognosis. On these bases, different radiotherapy and chemotherapy in children must be taken into risk group were identified and a treatment protocol has been proposed.4 account. Taken together, these factors emphasise the need for a tailored therapeutic approach. Another example is that of nasopharyngeal carcinoma. In a series of 46 paediatric patients prospectively treated over a 10-year period with Paediatric papillary thyroid carcinoma has a more aggressive onset in three courses of cisplatin/5-fluorouracil induction chemotherapy children than in adults; approximately 50 % of cases are pluricentric followed by radiotherapy (doses of up to 65 Gy) with concomitant at onset and 70 % extend beyond the thyroid capsule with nodal cisplatin, the five-year overall and progression-free survival rates (70 %) or distant (20 %) metastases. The clinical course of the disease were 80.9 % and 79.3 %, respectively. The only statistically significant differs from that in adult cases and the outcomes are unaffected by prognostic variable was the presence or absence of distant variables known to influence the prognosis in older patients (e.g., metastases. These findings are consistent with recent reports in the low- versus high-risk histological subtype, extrathyroid local invasion, literature, despite the use of lower radiotherapy doses than in adults. nodal or distant metastases, recurrence and type of surgery). This is They are important considering the need to reduce the overall burden due mainly to the fact that thyroid-stimulating hormone (TSH) of therapy and severity of long-term sequelae for paediatric patients.5 suppression therapy (L-thyroxine) is extremely effective in controlling tumour growth and survival approaches 100 %. The difference Over an eight-year period, 21 patients <18 years of age with between paediatric and adult disease is also supported by biological pancreatic tumours were prospectively registered as part of the TREP and genetic findings: paediatric papillary subtypes are often project, including four with pancreatoblastomas, two with pancreatic characterised by the RET/PCR3 translocation (not seen in adult cases), carcinomas, three with neoplasms of the endocrine pancreas and while they lack the BRAF involvement typical of adult disease.8 12 with solid pseudopapillary tumours. This series included rather different entities, since pancreatoblastoma is an aggressive Approximately 2 % of all cases of melanoma occur in patients under embryonic tumour typical of paediatric age while pseudopapillary 20 years of age, but only an exceedingly small minority of these tumour is a lesion of intermediate malignancy. Overall, the analysis develop in prepubertal children. The clinical features of childhood showed that, as in adults, surgery remains the keystone of treatment melanoma may feature a nodular, pedunculated or amelanotic for pancreatic tumours in paediatric patients. Interesting results were lesion, sometimes simulating a pyogenic granuloma. The ABCDE achieved in the four patients with pancreatoblastomas, since three (asymmetry–border irregularity–colour variability–dimension over were alive in first remission after a multimodal treatment that 6 mm–evolution) clinical rule commonly adopted in adults may included chemotherapy.6 The analysis confirmed the extreme rarity of consequently be useless and even misleading in cases of childhood these tumours – which makes it impossible to develop prospective melanoma. The biological characteristics of paediatric melanoma

132 EUROPEAN ONCOLOGY & HAEMATOLOGY Bisogno_A4_2011 25/05/2012 12:12 Page 133

Very Rare Tumours in Paediatric Age

partially coincide with those of adult melanoma – for instance, Table 3: Examples of Hereditary Cancer Syndromes BRAF oncogene activation and frequent loss of the CDKN2A gene Known to Be Associated with Rare Paediatric Tumours have been reported – but other traits have been found that seem to be peculiar to the younger age group (frequent c-Kit gene Affected Gene Syndrome alterations), hinting at the involvement of novel genetic networks. Adrenocortical carcinoma p53 mutation Li–Fraumeni syndrome Most of the clinical information on paediatric melanoma comes Pheochromocytoma VHL gene, RET VHL syndrome, from retrospective reports, and treatment strategies have generally proto-oncogene MEN2 syndrome Colorectal carcinoma APC gene Familial adenomatous been extrapolated from experience with adults. In various series, polyposis authors reported thicker lesions and more advanced stages at Pleuropulmonary blastoma DICER1 DICER1 syndrome diagnosis, but also the impression that melanoma may behave Ovarian Sertoli cell tumour DICER1 DICER1 syndrome 8 better in younger patients. Testicular Sertoli cell tumour PRKAR1A Carney complex

APC = adenomatous polyposis coli; MEN2 = multiple endocrine neoplasia type 2; Although experience with thyroid papillary carcinoma and melanoma VHL = von Hippel–Lindau. seems to indicate that these tumours tend to behave less aggressively in children than in adults, this is not true of all adult Other VRTs have been found to be associated with hereditary genetic tumours occurring in paediatric age. For instance, carcinoma of the syndromes, such as adrenocortical carcinoma with Li–Fraumeni thymus shares the same dismal prognosis in adults and in children, syndrome or pleuropulmonary blastoma with the recently described and effective chemotherapy regimens are yet to be identified.9 DICER1 syndrome (see Table 3). It therefore seems appropriate to recommend systematically searching for genetic alterations in all In the case of colorectal carcinoma, the prognosis is even worse children diagnosed with a VRT. when the tumour occurs in paediatric age. This has been explained by a higher incidence of unfavourable aggressive histotypes and an New Entities advanced clinical stage at onset. Reported survival estimates at five Pathologists and biologists are continually identifying new malignant years were 40 % for children and adolescents and 60 % for adults.8 neoplasms or variants of more classical lesions. This process may be accelerated in the near future thanks to the availability of more All these findings show that the TREP project was able to collect modern tools which, by using new immunohistochemical markers and prospective data and, in many cases, provide homogeneous searching for new genetic abnormalities, will enhance our diagnostic treatment for a significant number of children with VRTs in Italy. On capacity. Paediatric oncologists are expected to increasingly the other hand, it has become clear that the number of patients who encounter new entities, such as nuclear protein in testis (NUT) could be enrolled within a reasonable time period in a national-scale carcinoma, myoepithelial carcinoma or rare subtypes of soft tissue protocol would never be sufficient to conduct randomised clinical sarcomas. The recognition and treatment of such patients poses a trials designed to answer specific therapeutic questions. real challenge for paediatric oncologists and it may take many years in order to gain at least a general idea of how to establish a diagnosis Hereditary Cancer Syndromes and how to treat the children concerned. The development in a child of a tumour typically seen in adults may lie on the left edge of a Gaussian distribution curve of a relatively An international network dedicated to VRTs should be able to take in frequent adult cancer, or it may be the sign of a more complex charge these ‘new tumours’ as promptly as possible, reducing situation. It is now clear that there may be a relatively higher the time gap between the first description of a tumour and the proportion of hereditary cancer syndromes among young patients formulation of guidelines or treatment protocols. with VRTs, and a VRT in a child may be the hallmark of one of these syndromes. Pheochromocytoma is a typical example, as it may be From ‘Tumori Rari in Età Pediatrica’ to the associated with alterations of the von Hippel–Lindau (VHL) gene, of European Cooperative Study Group for the genes encoding the subunits B and D of succinate Paediatric Rare Tumours dehydrogenase, of the RET proto-oncogene predisposing to multiple The need to develop projects dedicated to paediatric VRTs has been endocrine neoplasia type 2, or of the neurofibromatosis type 1 gene. recognised in other countries too. In the UK, the Children’s Cancer A germ line mutation typical of one of these hereditary conditions and Leukaemia Group founded a Rare Tumour Working Group in 1997. has been identified in up to 59 % of apparently sporadic Since then, guidelines on endocrine tumours have been prepared, but pheochromocytomas found in patients aged up to 18 years, and in no attempts have been made to register patients prospectively, so the 70 % of those detected in patients aged up to 10 years.10 Based on the group relies mainly on information collected in a national registry. TREP guidelines, 17 patients with pheochromocytoma were screened and genetic anomalies were found in 10 of them, confirming that Between 2002 and 2006, national groups were founded in other sporadic pheochromocytoma may be the first sign of a hereditary European countries, with goals similar to those of the TREP group: the syndrome and that genetic screening is appropriate in order to Seltene Tumoren in der Pädiatrie (Rare tumours in paediatrics) provide counselling for the families affected. working group in Germany, the Polish Paediatric Rare Tumours Study Group in Poland and the Groupe Français des Tumeurs Rares de The TREP project also investigated a possible association between l’Enfant (French group for rare tumours in children) in France. Albeit renal cell carcinoma and VHL mutations, because the latter occur in featuring rather different organisation modes and activity levels, these adults with clear cell renal carcinoma. None of the 13 patients groups all share the idea that multinational cooperation is needed to analysed was found positive for VHL mutations, suggesting that any improve our knowledge of paediatric VRTs as well as outcomes for such association would be a very rare event. children. This led, in June 2008, to the foundation of a new

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Paediatric Oncology

collaborative group called the European Cooperative Study Group for that, even at European level, this disease is too rare to enable the Paediatric Rare Tumours (EXPeRT). The EXPeRT’s main aim is to recruitment of a sufficient number of cases to conduct clinical trials empower research on paediatric VRTs by promoting cooperative leading to evidence-based treatment guidelines. The EXPeRT group has schemes between its founding national groups – i.e., from Italy, nonetheless been able to propose a standardised approach to France, the UK, Poland and Germany. pancreatoblastoma including a surgical staging system, an initial conservative surgical approach, chemotherapy according to the PLADO As a first step, the EXPeRT decided to combine data collected by each (cisplatin and doxorubicin) regimen and aggressive surgery after national group on certain tumours included in the list of paediatric chemotherapy on both primary tumour and any metastases.11 VRTs. A harmonised core data sheet for the standardised documentation of clinical data of children with rare cancers was We expect that this positive experience will strengthen the developed, and this data sheet was subsequently adapted for three collaboration between the countries involved in the EXPeRT and retrospective studies focusing on ovarian Sertoli–Leydig cell tumours, stimulate the formation of similar groups in other European countries. pancreatoblastoma and pleuropulmonary blastoma. In addition, collaboration with already existing disease-oriented registries and collaborative groups will be actively sought, as Pancreatoblastoma was selected as the first tumour type to be analysed worldwide initiatives are necessary. This will hopefully improve the and was the subject of a publication in 2011.11 Over a 10-year period, quality of research and the outcomes of treatment for children who only 20 cases had been collected in the EXPeRT countries, suggesting have, until recently, been rather neglected. n

1. Ferrari A, Bisogno G, De Salvo GL, et al., The challenge of 48:318–23. features and tailored management of adult cancers very rare tumours in childhood: the Italian TREP project, 5. Casanova M, Bisogno G, Gandola L, et al., A prospective occurring in pediatric age, Expert Rev Anticancer Ther, Eur J Cancer, 2007;43:654–9. protocol for nasopharyngeal carcinoma in children and 2010;10:1837–51. 2. Pastore G, De Salvo GL, Bisogno G, et al., Evaluating the adolescents: the Italian Rare Tumors in Pediatric Age (TREP) 9. Carretto E, Inserra A, Ferrari A, et al., Epithelial thymic access to pediatric cancer care centers of children and project, Cancer, 2012;118:2718–25 tumours in paediatric age: a report from the TREP project, adolescents with rare tumors in Italy: the TREP project, 6. Dall’Igna P, Cecchetto G, Bisogno G, et al., Orphanet J Rare Dis, 2011;6:28. Pediatr Blood Cancer, 2009;53:152–5. Pancreatic tumors in children and adolescents: 10. Armstrong R, Sridhar M, Greenhalgh KL, et al., 3. Ferrari A, Dama E, Pession A, et al., Adolescents with the Italian TREP project experience, Pediatr Blood Cancer, Phaeochromocytoma in children, Arch Dis Child, 2008;93: cancer in Italy: entry into the national cooperative 2010;54:675–80. 899–904. paediatric oncology group AIEOP trials, Eur J Cancer, 7. Dall’Igna P, Ferrari A, Luzzatto C, et al., Carcinoid tumor of 11. Bien E, Godzinski J, Dall’Igna P, et al., Pancreatoblastoma: a 2009;45:328–34. the appendix in childhood: the experience of two Italian report from the European cooperative study group for 4. Indolfi P, Bisogno G, Casale F, et al., Prognostic factors in institutions, J Pediatr Gastroenterol Nutr, 2005;40:216–9. paediatric rare tumours (EXPeRT), Eur J Cancer, 2011; pleuro-pulmonary blastoma, Pediatr Blood Cancer, 2007; 8. Ferrari A, Casanova M, Massimino M, Sultan I, Peculiar 47:2347–52.

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