General principles of treatment in AYA. Dan Stark, MD Medical oncology Leeds UK

Transcription

1 General principles of treatment in AYA Dan Stark, MD Medical oncology Leeds UK

2 Summary of content Who are AYA? Why does this matter? What are the key issues and discuss several in more detail How you can continue making AYA outcomes better

3 AYA in oncology WHO definition of adolescence years, post adolescence years In Europe and Australia, Adolescent and Young Adult programs for patients between In UK, Teenage Cancer Trust for Canada : In USA, NCI program for AYA from 15 to 39 Advice - Specific groups within for specific challenges Erikson, E. Identity: Youth and Crisis New York Norton 1968

4 TYA were neglected in NHS Services Access to cancer care varies with adolescents receiving cancer care either surrounded by facilities..suitable for infants and young children, or dispersed across adult site- specific cancer service provision where the average age of patients is often in the 60 to 70 year old range (Michelagnoli 2003)

5 AYA have specific distinct features AYA with cancer are have specific medical needs; their presentations and symptoms are specific [1] biologically their cancer types and treatments are specific[2] they have distinct patterns of adverse effects [3-5] AYA with cancer have specific supportive challenges; social - Balancing family, peers & individual[6]. Personal - where is this young person in their developing biology from early childhood to mature adulthood? [7,8] AYA cancer care cuts across distinct agencies; across site-specific clinical teams (e.g. breast cancer, sarcoma, lymphoma)[8, 9] across administrative boundaries in health care systems (e.g. haematology & oncology, adult & paediatric) [15, 16]. 1. Dommett, R.M., et al. Br J Cancer, (11): p Tricoli, J.V., et al., Cancer, (7): p Rugbjerg, K., et al. J Natl Cancer Inst, (6): p. dju Rugbjerg, K. and J.H. Olsen JAMA Oncol, 2015: p Woodward, E., et al. Ann Oncol, (12): p Morgan, S., et al., J Clin Oncol, (32): p Viner, R.M., et al., J Epid ComHealth, (8): p Bleyer, W.A., et al., Cancer, (7): p Barr, R.D. et al Cancer, (7): p Michelagnoli, M.P. et al, Eur J Cancer, (18): p Carr, R., et al., Clin Med, (3): p

6 Stark et al, 2016

7 Stark et al, 2016

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10 WHAT THAT MEANS IN PRACTICE (Can be uncomfortable to hear for cancer services)

11 Different therapeutic approaches may lead to different outcomes Protocole FRALLE 93 Protocole LALA 94 Pediatric protocol (<20 years) Start June adolescents (15-20 years) Adult Protocol (15-60 years) Start October adolescents $$ and updated 2018 analysis still shows 1,8,6,4 FRALLE 93 LALA 94 5 year - EFS 67 % (± 13) 41 % (± 14),2 P< Time (years) 25/05/ Boissel N et al. J Clin Oncol 2003;21(5):774-80

12 Place of care? Central Nervous System Tumours Worse outcome if not treated in NCI-Comprehensive cancer Centers or Children s Oncology Group centers Wolfson et al, JNCI, 2014

13 age 0-16 years yrs > 30 yrs overall no. patients 46 pts Size > 5 cm 49% 60% 73% 60% Local invasiveness T2 49% 52% 66% 57% Site distal extr 54% 54% 63% 59% prox extr 32% 29% 22% 26% others 13% 16% 14% 15% Histology biphasic 52% 55% 49% 52% grossly-resected disease 41 patients % radiotherapy 58% 45% 49% 50% % chemotherapy 78% 20% 14% 28% 5-year EFS 66.3% 40.5% 30.9% 40.7% 5-year MFS 68.6% 52.6% 42.9% 51.1% 5-year OS 78.5% 72.4% 66.0% 70.6% locally-advanced disease metastatic disease

14 WHY?

15 Dose Intensity Highly relevant in several TYA cancers Hodgkin s Lymphoma (De Vita) Germ cell tumours Etoposide JEB vs PEB [1] Osteosarcoma [2] Ashley-Smith et al Next Steps AYA Cancer April 1 st 2016 Appears AYA receive less intensive Rx than children, more intensive than older adults (e.g. Ewings, by Gupta et al) 1. Frazier et al., J Clin Oncol Jan 10; 33(2): Lewis et al., J Clin Oncol Dec 15;18(24):

16 Large meta-analysis Osteosarcoma LIVESTRONG YA Alliance Meta-analysis of individual patient from prospective neoadjuvant chemotherapy osteosarcoma studies and registries to examine the relationships of sex, age, and toxicity on survival 4403 patients, [1] Collins et al., J Clin Oncol Jun 20;31(18):

17 The 1,147 Children (<12) OS was better than the AYA (12+) Remains when controlled for site, histology, gender, type of resection

18 More toxicity was associated with better OS More G3/4 mucositis (and possibly more thrombocytopenia) was associated with better OS (controlled for other variables) TYA, within the same protocols, have less toxicity and poorer outcomes than children Adults and adolescents experienced less thrombocytopenia Adults and adolescents experienced less good tumour necrosis at surgery Less necrosis was followed by less good survival Age Toxicity Necrosis Survival AYA with high toxicity and necrosis did not have poorer survival AYA girls in particular

19 % patients in treatment Delay in protocol phases administration Fralle 2000 regimen (in either place of care) 1 Cluzeau, ASH 2010,8,6,4,2 0 C IR1 IR2 M YAs Adolescents Thanks to ENTYAC congress Paris Time (days) Work to improve concordance (perhaps by psychosocial intervention studies)

20 Biology of the HOST - specific pharmacology Age and drug clearance relation - for dexamethasone, etoposide, methotrexate - not for temozolomide, topotecan - uncertain for vincristine and etoposide - For developmental agents - 70% of adolescents have PKs like adults, 30% distinctongoing research work Veal et al, JCO 2010, Gaspar (ACCELERATE) 2018

21 Biology of TYA tumours Rhabdomyos arcoma Kohsaka et al, Nature Genetics, 2014 Melanoma /rojced Principal components cluster analysis of gene expression in germ cell tumours in children and adults with malignant GCTs Palmer et al CCR 2008 Bleyer A, Barr R, Hayes-Lattin B et al. The distinctive biology of cancer in adolescents and young adults. Nat Rev Cancer 2008; 8: Gramatges MM, Rabin KR. The adolescent and young adult with cancer: state of the art-- acute leukemias. Curr Oncol Rep 2013; 15: Vriens MR, Moses W, Weng J et al. Clinical and molecular features of papillary thyroid cancer in adolescents and young adults. Cancer 2011; 117: Casanova M, Bisogno G, Gandola L et al. A prospective protocol for nasopharyngeal carcinoma in children and adolescents: the Italian Rare Tumors in Pediatric Age (TREP) project. Cancer 2012; 118: Daniotti M, Ferrari A, Frigerio S et al. Cutaneous melanoma in childhood and adolescence shows frequent loss of INK4A and gain of KIT. J Invest Dermatol 2009; 129: Chan JK, Urban R, Cheung MK et al. Ovarian cancer in younger vs older women: a populationbased analysis. Br J Cancer 2006; 95: Tricoli JV, Seibel NL, Blair DG et al. Unique characteristics of adolescent and young adult acute lymphoblastic leukemia, breast cancer, and colon cancer. J Natl Cancer Inst 2011; 103:

22 if we look to the different decades of patient s age the widest survival gap was observed between prepubertal and postpubertal patients, rather than across the 18 years age cutoff Also concerning initial clinical characteristics, a somewhat different distribution ( better clinical features including more extremity primaries, smaller tumors, mostly localized) was observed in the small group of patients younger than 10 years of age % % % % % % % % 100% 90% 80% 70% 60% 50% 100% 90% 80% 70% 60% 40% 40% DISTANT Whether SS has 30% unique clinico-biological 50% findings in prepubertal 30% patients, in which this tumor 5 cm REGIONAL 20% 20% rarely occurs (2.5% of 40% the cases in the SEER series), remains to be proven < 5 cm 10% 10% LOCALIZED 0% 30% 0 TO 9 10 TO TO TO TO % 100% 90% 80% 70% 60% 50% 0% 0 TO 9 10 TO TO TO TO

23 TYA services for patient and carers Unmet needs of TYA within hospital settings recognised since the 1950s (Stuart-Clark, 1953) Value patients place on specialist TYA care Listening to Patients - Marris, Morgan, Stark 2010 Appropriate information Nursing with a better & ingrained understanding of specialist needs of adolescents TYA unit significantly higher levels of patient satisfaction through: opportunity for contact with patients of the same age the provision of recreational and relaxation facilities, studying space & quiet dissatisfaction - paediatric and adult units Care felt inappropriate to their age for >1/3 of patients experiencing a regional centre, that is not a TYA cancer unit 2/3 treated in a general hospital non TYA unit

24 Jones et al, in press 2018 The social context AYAs are in the process of developing their own thoughts and perceptions of the world, forming new relationships and pushing boundaries. This stage of life is often formative in terms of education, career planning, and for some, family planning. There is often a desire to challenge the rules set by their seniors, and experiment with risk-taking behaviours such as smoking, alcohol consumption, or recreational drug use. With cancer, there are commonly periods of returning to reliance on parents, and moving away from independent thinking and decision making.

25 Jones et al, in press 2018 The social context You as their doctors AYAs are in the process of developing their own thoughts and perceptions of the world, forming new relationships and pushing boundaries [28, 29]. This stage of life is often formative in terms of education [30, 31], career planning [32], and for some, family planning [33]. There is often a desire to challenge the rules set by their seniors, and experiment with risk-taking behaviours such as smoking, alcohol consumption, or recreational drug use [34]. With cancer, there are commonly periods of returning to reliance on parents, and moving away from independent thinking and decision making [29, 35]. unhappiness

26 Management and care: Expertise Adolescents have to be treated by skilled personnel under an appropriate infrastructure. 1 Evidence from retrospective and cohort studies indicate that the outcome is superior when treatment is given in a reference cancer centre. 2 Survival seems to correlate with the number of adolescents with malignancy seen annually in each center. 2 Expertise is largely acquired through regular experience of walking with patients throughout their cancer journey Specialisation Also through national and international forums where experiences and ideas can be shared, and current practices reviewed and developed. Education and Training The National Institute for Health and Clinical Excellence (UK) and the National Cancer Institute (US) have commissioned recommendations for the organization of optimal care of young people with cancer. 3,4 1 Collette L et al. J Natl Cancer Inst 1999;91(10): Wein S et al. J Clin Oncol 2010;28(32): /05/2018 AYA progress 26 review group. US Department of Health and Human Services 2006

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28 The IAM Thoughts & feelings Education & employment

29 The IAM

30 The professional

31 Political challenges Organisational (divisional) silos Ownership of costs & activity Sensitivity and passionate beliefs Egos and ownership Differences of vision A place of care (excellent but needs leadership) Clinical ward and/or place for young people to be? Biomedical excellence above all and/or Bio-psychosocial issues Medical priorities and/or True MDT engagement Steering group Charities

32 Hierarchy of Needs Maslow (1943)

33 Hospitals have their own needs Self-transcendence Self-actualization Esteem Love/belonging Safety Physiological Champions services to the vulnerable in local communities as a champion of this approach for wider services Equality of service for all with unmet needs Contributes to solving problems caused by silos within healthcare, by crossing traditional medical boundaries Champions excellence, national, international and multi-professional networking and clinical working Respected colleagues, asked advice in complex about other patients, or about complex professional decisions Embodies values of patient-centred individual care within a governance and clinical practice framework supporting patient safety Provides for all the needs of its local community, whatever their age and whatever the prevalent societal perspectives

34 Summary of content Who are AYA? Why does this matter? Outcomes remain widely poor, due to lack of specific focus Where services focus, and gain expertise, outcomes improve What are the key issues Cancer outcomes Cancer biology How you can continue making AYA outcomes better be our next CHAMPIONS Treatment choices Treatment delivery (clinical trials) Host biology Psychosocial care Work together in teams Be politically astute