General principles of treatment in AYA

Dan Stark, MD

Medical oncology

Leeds

UK

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

AYA in oncology• WHO definition of adolescence 10-19 years, post adolescence 20-

25 years

• In Europe and Australia, Adolescent and Young Adult programs for

patients between 15-25

• In UK, Teenage Cancer Trust for 13-24

• Canada : 15-29

• In USA, NCI program for AYA from 15 to 39

• Advice - Specific groups within 15-39 for specific

challenges

Erikson, E. Identity: Youth and Crisis New York Norton 1968

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)

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, 2013. 108(11): p. 2329-33.2. Tricoli, J.V., et al., Cancer, 2016. 122(7): p. 1017-28.3. Rugbjerg, K., et al. J Natl Cancer Inst, 2014. 106(6): p. dju110.4. Rugbjerg, K. and J.H. Olsen JAMA Oncol, 2015: p. 1-9.5. Woodward, E., et al. Ann Oncol, 2011. 22(12): p. 2561-8.6. Morgan, S., et al., J Clin Oncol, 2010. 28(32): p. 4825-30.7. Viner, R.M., et al., J Epid ComHealth, 2015. 69(8): p. 719-20.8. Bleyer, W.A., et al., Cancer, 1993. 71(7): p. 2413.9. Barr, R.D. et al Cancer, 2006. 106(7): p. 1425-30.10. Michelagnoli, M.P. et al , Eur J Cancer, 2003. 39(18): p. 2571-2.11. Carr, R., et al., Clin Med, 2013. 13(3): p. 258-62.

Stark et al,

2016

Stark et al,

2016

WHAT THAT MEANS IN PRACTICE

(Can be uncomfortable to hear for cancer services)

Different therapeutic approaches may lead to different outcomes

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◼ Protocole FRALLE 93

◼ Pediatric protocol (<20 years)

◼ Start June 1993

◼ 77 adolescents (15-20 years)

◼ Protocole LALA 94

◼ Adult Protocol (15-60 years)

◼ Start October 1994

◼ 100 adolescents

0

,2

,4

,6

,8

1

0 1 2 3 4 5 6

FRALLE 93

LALA 94

P<0.0001

41 % (± 14)

67 % (± 13)

5 year - EFS

Time (years)Boissel N et al. J Clin Oncol 2003;21(5):774-80

$$ and updated 2018 analysis still shows

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

35

age 0-16 years 17-30 yrs > 30 yrs overall

no. patients 46 pts 83 142 271

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 66 108 215% 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 3 14 23 40metastatic disease 2 3 11 16

WHY?

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 1st 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. 2015 Jan 10; 33(2): 195–2012. Lewis et al., J Clin Oncol. 2000 Dec 15;18(24):4028-37.

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, 1979-2005 [1]

Collins et al., J Clin Oncol. 2013 Jun 20;31(18):2303-12.

The 1,147 Children (<12) OS was better than the AYA (12+)

Remains when controlled for site, histology, gender, type of resection

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

0

,2

,4

,6

,8

1

0 50 100 150 200 250 300 350 400 450

C IR1 IR2 M

Delay in protocol phases administration Fralle 2000 regimen (in either place of care)

% p

atie

nts

in t

reat

men

t

Time (days)

▬▬ YAs------ Adolescents

Cluzeau, ASH 2010

Work to improve concordance (perhaps by psychosocial intervention studies)

Thanks to Boissel @ ENTYAC congress Paris 2013

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% distinct-

ongoing research work

Veal et al, JCO 2010, Gaspar

(ACCELERATE) 2018

Biology of TYA tumours

Principal components cluster analysis of gene expression in germ cell tumours in children and adults with malignant GCTsPalmer 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: 288-298.Gramatges MM, Rabin KR. The adolescent and young adult with cancer: state of the art-- acute leukemias. Curr Oncol Rep 2013; 15: 317-324.

Vriens MR, Moses W, Weng J et al. Clinical and molecular features of papillary thyroid cancer in adolescents and young adults. Cancer 2011; 117: 259-267.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: 2718-2725.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: 1759-1768.

Chan JK, Urban R, Cheung MK et al. Ovarian cancer in younger vs older women: a population-based analysis. Br J Cancer 2006; 95: 1314-1320.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: 628-635.

RhabdomyosarcomaKohsaka et al, Nature Genetics, 2014

Melanoma 2018https://doi.org/10.26574/rojced.2018.5.1.12

…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

0%

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0 TO 9 10 TO 18 19 TO 29 30 TO 39 40 TO 49 50 +

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0 TO 9 10 TO 18 19 TO 29 30 TO 39 40 TO 49 50 +

DISTANT

REGIONAL

LOCALIZED0%

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0 TO 9 10 TO 18 19 TO 29 30 TO 39 40 TO 49 50 +

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0 TO 9 10 TO 18 19 TO 29 30 TO 39 40 TO 49 50 +

≥ 5 cm

< 5 cm

Whether SS has unique clinico-biological findings in prepubertal patients, in which this tumor rarely occurs (2.5% of the cases in the SEER series), remains to be proven

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

Jones et al, in press 2018The 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.

Jones et al, in press 2018The social context

• 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].

You as their doctors

unhappiness

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

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1 Collette L et al. J Natl Cancer Inst 1999;91(10):839-462 Wein S et al. J Clin Oncol 2010;28(32):4819-24

3 http://www.nice.org.uk/pdf/ctypevidencereview.pdf 4 AYA progress review group. US Department of Health and Human Services 2006

The IAM

Thoughts & feelings

Education & employment

The IAM

The professional

Political challenges

Organisational (divisional) silos– Ownership of costs & activity

Sensitivity and passionate beliefsEgos and ownershipDifferences 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 groupCharities

Hierarchy of Needs – Maslow (1943)

Hospitals have their own needs

Self-transcendence Champions services to the vulnerable in local communities as a champion of this approach

for wider services

Self-actualization Equality of service for all with unmet needs

Contributes to solving problems caused by silos within healthcare, by crossing traditional

medical boundaries

Esteem Champions excellence, national, international and multi-professional networking and clinical

working

Love/belonging Respected colleagues, asked advice in complex about other patients, or about complex

professional decisions

Safety Embodies values of patient-centred individual care within a governance and clinical practice

framework supporting patient safety

Physiological Provides for all the needs of its local community, whatever their age and whatever the

prevalent societal perspectives

Summary of content

• Who are AYA?• 15-39

• 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