National Cancer Research Institute Teenage and Young Adult Clinical Studies Group: The United Kingdom Approach to Research. International Perspectives on AYAO,Part 4

Abstract

The unique psychosocial needs of teenagers and young adults (TYAs) with cancer have been recognized for some time in the United Kingdom. The non-profit Teenage Cancer Trust pioneered dedicated units for TYAs in 1990, and by 2005, the United Kingdom National Institute for Health and Clinical Excellence (NICE) issued healthcare policy advocating age-appropriate care. The National Cancer Research Institute Teenage and Young Adult Clinical Studies Group (NCRI TYA CSG) was also established in 2005. This national research group promotes and generates research specifically for TYAs with cancer, broadly those aged 13–24 years at diagnosis. The work of the TYA CSG to date has focused on six themes: (1) benchmarking clinical trial availability and access for TYAs; (2) developing links with other NCRI tumor-specific Clinical Studies Groups; (3) identifying priority areas for health services research; (4) evaluating the requirement for a cancer registry function for TYAs; (5) identifying issues for late effects and survivorship; and (6) identifying host- and tumor-specific biological differences in TYA cancer. Here we describe some of the research developments of the NCRI TYA CSG in the context of cancer research in the United Kingdom and healthcare policy for TYAs.

The United Kingdom is comprised of four devolved nations—England, Wales, Scotland, and Northern Ireland—and has a total population of 63.2 million.¹ In 2009, approximately 320,467 new cases of cancer were recorded in the United Kingdom; almost 80% were epithelial cancers, and half of these were cancers of the breast (48,788), lung (41,428), colon (41,142), or prostate (40,841).² In the United Kingdom, one in four deaths is attributed to cancer, resulting in approximately 150,000 cancer deaths annually.² Despite a highly coordinated approach to cancer research and nationwide access to free healthcare, the United Kingdom has poorer 1- and 5-year survival rates compared to many of its European counterparts. It is thought that this may be related to a prolonged period to cancer diagnosis for some cancers.^3,4

Cancer Incidence in Teenagers and Young Adults in the United Kingdom

In the United Kingdom, teenagers and young adults (TYAs) are defined as those aged 13–24 years old at diagnosis. Approximately 2000 new cases of cancer are diagnosed annually in TYAs in the United Kingdom. Young people in the United Kingdom present with a spectrum of malignant diseases, with lymphomas, leukemias, germ cell tumors, brain and other central nervous system (CNS) cancers, and bone and soft tissue sarcomas accounting for approximately 70% of newly diagnosed TYA patients;⁵ melanoma and early-onset carcinomas account for the great majority of remaining cases.⁵ Although cancers in young people constitute less than 1% of newly diagnosed cancers in the United Kingdom, cancer is the leading cause of disease-related death in this age group, responsible for 11% of deaths each year (preceded in frequency only by accidents),⁶ yet cancer research for young people is relatively limited. As such, risk factors, etiology, and the optimal treatment for many cancer types are not well defined.

Despite this, overall survival rates for TYA cancer patients in the United Kingdom are approximately 80%,⁷ though there are large variations in survival rates dependent on cancer type. For example, 5-year survival for Hodgkin lymphoma patients aged 15–24 years at diagnosis is approximately 94%, while for same-aged patients with bone sarcomas it is 56%, with only modest improvements in survival observed over the past two decades.⁷ Gender-related differences in 5-year survival also exist; for some cancers, males are reported to fare considerably less well than females.⁷ The National Cancer Intelligence Network⁸ recently reported that females aged 20–24 with soft tissue sarcoma have a 5-year survival rate of 68% compared to only 55% for males (p=0.006), with similar trends in melanoma (95% vs. 89%; p<0.003). There was no gender effect for young adults with leukemias or bone sarcomas, and a gender effect was not apparent in 5-year survival for teenagers aged 15–19. Differences in cancer biology and healthcare delivery may be causally implicated in these findings.⁸

Delivery of Care for Teenagers and Young Adults in the United Kingdom

The most recognizable starting point for TYAs in United Kingdom healthcare policy was the 1995 ‘Calman–Hine’ report, which was a blueprint for the ordered disposition of cancer care between hospitals to provide a complete range of cancer services.^9,10 The report mandated uniform access to high quality cancer care for all,^9,10 with section 4.4.1 (“special medical and psycho-social needs of adolescents”) specifically referring to TYAs. At the time, this represented the consensus view of a handful of professionals rather than evidence arising from comprehensive research into young people with cancer.⁹

Ten years later, in August 2005, the National Institute for Health and Clinical Excellence in England issued guidance on cancer services in its document “Improving Outcomes Guidance in Children and Young People with Cancer” (NICE IOG).¹¹ Within this document is a list of key recommendations for children and young people aged up to 24, including access to clinical trials. The document mandates that all young people aged 16–18 should be treated in an age-appropriate environment, and those aged 19–24 should be offered a choice between treatment in a specialized TYA environment or treatment closer to their home. Thirteen age-appropriate specialist centers or “Principal Treatment Centres” were established across England. These are supported by “Shared Care Centres” that offer less specialized services. Although it advocates age-appropriate care, the document provides neither a specification nor a description of the contribution it may make to improving outcomes. As a consequence, there has been regional variation of interpretation and implementation of this guidance and little systematically generated evidence to encourage the two distinct adult and pediatric healthcare systems to adopt a holistic approach to TYA cancer care. Despite this national policy advocating referral of young people to specialized cancer centers, approximately half of all young people are referred to Principal Treatment Centres in England, and this varies by age, cancer type, and location.¹²

Challenges to Cancer Research in Teenagers and Young Adults in the United Kingdom

A diagnosis of cancer during a period of intense physical and psychological growth creates a characteristic set of tensions unique to this age group.¹² Research into this group is further complicated by small numbers of a heterogeneous group of malignancies. Less is known about the molecular and cellular aberrations and host environment for cancers in young people compared to adults, and extrapolation from research of cancers in adults or children can only be recommended with caution.

Challenges to TYA cancer research in the United Kingdom are numerous. The four devolved nations have different healthcare policies and systems, and this complexity is increased by some funding bodies that restrict the use of their research money to their own country, therefore making United Kingdom-wide research difficult. Despite the United Kingdom being the second-most densely populated country in Europe, TYAs are geographically dispersed, so studies must be conducted at multiple centers in order to accrue sufficient numbers of participants. In addition, young people tend to be a more mobile population due to life stage commitments such as going to university, which can make study retention problematic.

The allocation of research funding and/or the decision to open studies within a cancer center is very much driven by cancer incidence. Research into breast, prostate, colorectal, and lung cancer dominates much of the research landscape in the United Kingdom. With approximately 2000 incident cases geographically dispersed, research proposals for young people may be overlooked in favor of studies that will recruit large numbers of patients with more common cancers. Focusing on incident cases does not fairly represent the burden of many cancers on society. A more equitable benchmark may be to evaluate life-years at risk or lost, which would more fully indicate the socioeconomic impact of some cancers and may result in a shift of research priorities, possibly benefiting those with rarer diseases, particularly young people. In addition, the restrictive age eligibility criteria imposed by many studies, based on whether the study arose from an adult or a pediatric research group, further excludes many TYAs from participation. Finally, as research studies are often run through either pediatric or adult cancer centers; young people's access to the studies they are eligible for may be further restricted by the type of institution from which they are receiving care.

The National Cancer Research Institute Teenage and Young Adult Clinical Studies Group

Shortly after the release of the NICE IOG in 2005, the National Cancer Research Institute (NCRI) established a dedicated Teenage and Young Adult Clinical Studies Group. The NCRI is a consortium of organizations established in 2001 to provide a coordinated approach to cancer research in the United Kingdom in order to prevent duplication of research and ensure appropriate distribution of research funding. At the same time, the National Cancer Research Network, now known as the National Institute for Health Research Cancer Research Network (NCRN), was established. This is nationwide cancer research network providing researchers with practical support to facilitate cancer clinical studies in the National Health Service. The NCRN was tasked with an initial remit to double the proportion of cancer patients entering clinical trials from the 2001 baseline of 3.5%. Within 3 years, the NCRN had far surpassed this figure, and in 2008 the United Kingdom was crowned “Cancer Clinical Trials Recruitment Capital of the World,” with approximately 14% of all cancer patients entering trials.¹³ Trials run through the NCRN are largely generated by NCRI Clinical Studies Groups (CSGs), although an increasing number of industry-sponsored trials are supported. There are 21 CSGs, each responsible for generating a balanced portfolio of tumor- or topic-specific studies, which are then run through the NCRN. In addition, six cross-cutting CSGs address a topic rather than a type of cancer: primary care, palliative and supportive care, psychosocial oncology, biomarkers and imaging, children's cancer and leukemia, and TYAs.

When the TYA CSG was established in 2005, membership was sought from a range of backgrounds, and this multidisciplinary group reflects the complex nature of TYA cancer care. The group was given a United Kingdom-wide remit to generate and promote cancer research in TYAs—broadly those aged 13–24 at diagnosis. However, no precise age boundaries are imposed and for some research studies the TYA CSG may include patients up to aged 39 years at diagnosis.

The tumor-specific NCRI CSGs have a remit to establish a balanced portfolio of tumor-specific studies. For example, the sarcoma CSG develops a portfolio of observational and interventional sarcoma studies. The remit of the TYA CSG, however, differs, with a role not to develop a trials portfolio for young people but to ensure that relevant tumor-specific CSGs are considering the needs of young people during study development and then recruiting young people to studies in their portfolios. Studies the TYA CSG is accountable for developing are those which address psychosocial factors, biological factors relating to the etiology and behavior of cancer in TYAs, research into the optimal provision of healthcare for TYAs, and provision of an evidence base for the present and future NICE “Improving Outcomes Guidance in Children and Young People with Cancer.”

The research priorities of the TYA CSG have centered around six themes:

1. Benchmarking trial availability and access for TYAs.

2. Developing links with other NCRI CSGs.

3. Identifying priority areas for health services research:

a. Evaluating if specialized cancer services for TYAs adds value;

b. Improving cancer diagnosis.

4. Evaluating the requirement for a specialized cancer registry for TYAs collecting additional information, similar to the children's cancer registry based in Oxford, United Kingdom.¹⁴

5. Identifying issues for late effects and survivorship.

6. Studying host- and tumor-specific biological differences in TYA cancer.

Below is a summary of work relating to two of these themes—the participation of TYAs in cancer clinical trials and TYA-relevant health services research.

Benchmarking trial availability and access

Much of the attention concerning cancer in young people has been driven by evidence suggesting lesser improvements in survival over the past two decades compared to children.¹⁵ A prolonged period to diagnosis, unique cancer biology, and lower rates of participation in cancer clinical trials are all implicated.^15–19 Underrepresentation of TYAs in cancer clinical trials has been reported by a number of countries, and may be associated with lesser improvements in survival rates.^16–18 When the TYA CSG was established, clinical trial entry rates for young people with cancer in England had been assumed to be less than for children and older adults, but this was not systematically investigated.²¹ By 2008, it was reported that for selected TYA-relevant studies in the Children's Cancer and Leukaemia Group and selected NCRN portfolio trials during 2005 and 2006, the proportion of patients enrolling by age group was 50% for children aged 5–14 years compared to only 19% for those aged 15–24.²¹

Tracking and promoting recruitment of TYAs and cancer clinical trials is a priority area of research for the TYA CSG and is set alongside national healthcare policies aimed at increasing participation of TYAs in cancer clinical trials. In recent years, the TYA CSG has seen increases in the proportion of young people aged 15–19 entering trials, but lesser improvement for those aged 20–24 (unpublished data). There are a number of reasons for improved participation in cancer clinical trials for 15–24 year olds, some of which may be related to the work of the TYA CSG. Evidence of the underrepresentation of TYAs in clinical trials has provided a platform for collaborative meetings between adult and pediatric communities, resulting in increased activity in the recruitment of TYAs.^21–23 The TYA CSG has also shown that expanding trials' restrictive age eligibility criteria has increased the numbers of TYAs entering these trials, such as those for acute lymphoblastic leukemia.²⁴ TYA CSG members' widespread dissemination of TYA accrual rates to pediatric and adult healthcare professionals, other NCRI CSGs, and policy makers has increased awareness of the need to offer trial entry to TYAs; it is believed that this has subsequently influenced accrual rates.

Identifying priority areas for health services research

BRIGHTLIGHT—Do specialized cancer services for TYAs add value?

Young people in the United Kingdom benefit from access to free healthcare and a national healthcare policy that recognizes their unique psychosocial needs.¹¹ In addition, Teenage Cancer Trust—a United Kingdom-based charity committed to improving outcomes for young people with cancer with a strong advocacy role—provides specialized dedicated hospital units in which young people receive treatment.²⁵ The first of these was established in 1990; there are now more than 22 units across the United Kingdom. However, to date there is a lack is systematically derived evidence of outcomes associated with specialized TYA cancer care.²⁶ Specialized services and units have been implemented enthusiastically without any real systematic evidence of their benefit or cost-effectiveness. The international community and national healthcare funders are now looking to the United Kingdom to demonstrate whether specialized services for TYAs add value and improve outcomes.

In June 2009, the TYA CSG embarked on a program of feasibility work to underpin a research program to identify outcomes associated with specialized TYA care. The feasibility work was essential to explore how to answer the question of whether specialist cancer services for TYAs adds value, recognizing that the gold standard approach of a randomized controlled trial of specialist care versus non-specialist care would not be ethically appropriate or feasible. This feasibility work is now completed, much of which has been published.^27–29 Critically, the developmental work informed a 5-year program of research that will evaluate specialized cancer services for TYAs in England—BRIGHTLIGHT (www.brightlightstudy.com; NIHR Ref: RP-PG-1209-10013).

BRIGHTLIGHT consists of four workstreams. Workstream 1 aims to describe specialized TYA cancer care. Workstream 2 is a nationwide longitudinal cohort study that will recruit 2012 TYAs and examine associations between levels of specialized care and outcomes; the primary outcome measures are quality of life and patient satisfaction. Patients will be recruited through the NCRN nationwide network of researchers, who will, for the first time, recruit to an age group rather than a disease- or topic-specific study. Workstream 3 will examine the costs of specialized care to both patients and families and also to the healthcare system, and Workstream 4 will develop and pilot interventional studies based on emerging results. Recruitment of TYAs to BRIGHTLIGHT began in September 2012, with results expected to begin dissemination by September 2014.

Improving cancer diagnosis for young people

Young people often describe a lengthy and complex journey to cancer diagnosis. Consequently, when the TYA CSG was established, improving young people's time to cancer diagnosis was identified as a priority research area. Two subsequent consultations with young people demonstrated that they viewed improving the time to cancer diagnosis as the most important area of research being carried out by the TYA CSG.³¹

Since then, increasing evidence has emerged from the United Kingdom that young people experience a longer time to diagnosis than children and older adults; however, the outcomes associated with this are not clear.¹⁹ There are a number of reasons why young people experience a longer time to diagnosis. Cancer awareness and recognition of potential TYA cancer symptoms has been shown to be low, and thus young people may not fully appraise the seriousness of their symptoms and not seek help immediately.³¹ Once in primary care, young people are twice as likely to have three or more consultations prior to referral compared to adults; the number of pre-referral consultations has been shown to be a good proxy for time.^32,33 There are a number of reasons why this may occur. The incidence of cancer in TYAs is low—a general practitioner may only see one case in their lifetime—and while the incidence of cancer “alert” symptoms in the general TYA population is low,³⁴ the positive predictive value of “alert” symptoms (the number of times a cancer will be diagnosed) is also low, even when combined with multiple consultations.³⁵ This highlights the difficulties of identifying young people with a potential malignancy in primary care and referring them appropriately without overwhelming services and causing unnecessary anxiety.

There is a critical need for interventions to improve the cancer diagnosis experience for young people. Future plans of the TYA CSG in this area are to carry out a nationwide collaborative study with pediatric and primary care practitioners examining cancer awareness in young people and health professionals, cancer diagnosis in primary care and secondary care, and evaluating potential interventions along the diagnostic pathway.

Conclusion

In recent years, the United Kingdom has made considerable progress in research related to cancer in TYAs. We have been fortunate to benefit from healthcare policy that recognizes the needs of TYAs (such as NICE's “Improving Outcomes Guidance in Children and Young People with Cancer”), a United Kingdom-wide charity providing specialized units (the Teenage Cancer Trust), and a dedicated research group charged with generating and promoting research specifically for young people with cancer (the NCRI Teenage and Young Adult Clinical Studies Group). Since 2005, improvements in clinical trial participation for TYAs have been observed, most notably amongst those aged 15–19. However, strategies to improve participation of young adults aged 20–24 years are still required. A national evaluation of the benefits of specialized cancer services for young people (BRIGHTLIGHT) began in late 2012 and should provide much-needed evidence of outcomes associated with specialized care and associated costs to patients, families, and the healthcare system. Despite progress in the United Kingdom for young people with cancer, many research questions are still to be addressed. The next priority area of research for the NCRI TYA CSG is improving cancer diagnosis for young people.

Footnotes

Acknowledgments

Lorna Fern is funded by the Teenage Cancer Trust, and this work was undertaken at University College London Hospitals/University College London, who received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. We would like to thank all of the members of the National Cancer Research Institute's Teenage and Young Adult Clinical Studies Group for their continued contribution and commitment.

Author Disclosure Statement

No competing financial interests exist.

References

Office for National Statistics. Statistical bulletin. 2011 census: population estimates for the United Kingdom, 27 March 2011. Titchfield, UK: Office for National Statistics; December 12, 2012.

Cancer Research UK. Cancer incidence and mortality in the UK for the 20 most common cancers. London: Cancer Research UK; May 2012.

Richards

. EUROCARE-4 studies bring new data on cancer survival. Lancet Oncol., 2007; 8(9):752–3.

Sant

, Allemani

, Santaquilani

, et al. EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary. Eur J Cancer., 2009; 45(6):931–91.

Birch

, Alston

, Kelsey

, et al. Classification and incidence of cancers in adolescents and young adults in England 1979–1997. Br J Cancer., 2002; 87(11):1267–74.

Office for National Statistics. Mortality statistics: deaths registered in England and Wales (series DR), 2011. London: Office for National Statistics; November 6, 2012.

O'Hara

, Moran

, TYA National Cancer Intelligence Advisory Group. Survival in teenagers and young adults with cancer in the UK. London: National Cancer Intelligence Network; August 2012.

National Cancer Intelligence Network. Gender differences in survival among teenagers and young adults (TYA) with cancer in England. London: National Cancer Intelligence Network; 2011.

Whelan

, Fern

. Cancer in adolescence: incidence and policy issues. In: Kelly

, Gibson

(Eds). Cancer care for adolescents and young adults. Oxford: Blackwell; 2008; pp. 7–20.

10.

Calman

, Hine

. A policy framework for commissioning cancer services: a report by the Expert Advisory Group on Cancer to the chief medical officers of England and Wales. London: Department of Health; 1995.

11.

National Institute for Health and Clinical Excellence. Guidance on cancer services: improving outcomes in children and young people with cancer. London: National Institute for Health and Clinical Excellence; August 2005.

12.

O'Hara

, Khan

, McCabe

, et al. Notifications of teenagers and young adults with cancer to a Principal Treatment Centre 2009–2010. London: National Cancer Intelligence Network; April 2013.

13.

Sinha

. United Kingdom becomes the cancer clinical trials recruitment capital of the world. J Natl Cancer Inst., 2007; 99(6):420–2.

14.

Childhood Cancer Research Group. National Registry of Childhood Tumours. Accessed December 3, 2013 from: www.ccrg.ox.ac.uk/

15.

Smith

, Seibel

, Altekruse

, et al. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol., 2010; 28(15):2625–34.

16.

Bleyer

. Older adolescents with cancer in North America deficits in outcome and research. Pediatr Clin North Am., 2002; 49(5):1027–42.

17.

Bleyer

, Budd

, Montello

. Adolescents and young adults with cancer: the scope of the problem and criticality of clinical trials. Cancer., 2006; 107(7 Suppl):1645–55.

18.

Bleyer

, Montello

, Budd

, Saxman

. National survival trends of young adults with sarcoma: lack of progress is associated with lack of clinical trial participation. Cancer., 2005; 103(9):1891–7.

19.

Lethaby

, Picton

, Kinsey

, et al. A systematic review of time to diagnosis in children and young adults with cancer. Arch Dis Child., 2013; 98(5):349–55.

20.

Ferrari

, Montello

, Budd

, Bleyer

. The challenges of clinical trials for adolescents and young adults with cancer. Pediatr Blood Cancer., 2008; 50(5 Suppl):1101–4.

21.

Fern

, Davies

, Eden

, et al. Rates of inclusion of teenagers and young adults in England into National Cancer Research Network clinical trials: report from the National Cancer Research Institute (NCRI) Teenage and Young Adult Clinical Studies Development Group. Br J Cancer., 2008; 99(12):1967–74.

22.

Murray

, Fern

, Stark

, et al. Breaking down barriers: improving outcomes for teenagers and young adults with germ cell tumours. Oncol Rev., 2009; 3(4):201–6.

23.

Taylor

, Pizer

, Short

. Promoting collaboration between adult and paediatric clinical trial groups. Clin Oncol (R Coll Radiol)., 2008; 20(9):714–6.

24.

Fern

, Rowntree

, Hough

, et al. Barriers to clinical trial enrolment for teenagers and young adults with acute lymphoblastic leukaemia: the impact of age eligibility criteria. Presented at American Society of Hematology Annual Meeting, New Orleans, December 7–10, 2013.

25.

Teenage Cancer Trust. What we do: specialist services—units. Accessed September 15, 2013 from: www.teenagecancertrust.org/what-we-do/specialist-services/units

26.

Whelan

. Where should teenagers with cancer be treated?. Eur J Cancer., 2003; 39(18):2573–8.

27.

Gibson

, Fern

, Whelan

, et al. A scoping exercise of favourable characteristics of professionals working in teenage and young adult cancer care: ‘thinking outside of the box.’. Eur J Cancer Care (Engl)., 2012; 21(3):330–9.

28.

Taylor

, Fern

, Whelan

, et al. “Your place or mine?” Priorities for a specialist teenage and young adult (TYA) cancer unit: disparity between TYA and professional perceptions. J Adolesc Young Adult Oncol., 2011; 1(3):145–51.

29.

Fern

, Taylor

, Whelan

, et al. The art of age-appropriate care: reflecting on a conceptual model of the cancer experience for teenagers and young adults. Cancer Nurs., 2013; 36(5):E27–38.

30.

Fern

, Ashton

, Bookman

, et al. Involving young people with cancer in research: the National Cancer Research Institute's Teenage and Young Adult (TYA) Core Consumer Group (CCG)—a new and evolving model. Presented at National Cancer Research Institute Cancer Conference, Birmingham, AL, October 4–7, 2009.

31.

Kyle

, Forbat

, Hubbard

. Cancer awareness among adolescents in Britain: a cross-sectional study. BMC Public Health., 2012; 12:580.

32.

Lyratzopoulos

, Neal

, Barbiere

, et al. Variation in number of general practitioner consultations before hospital referral for cancer: findings from the 2010 National Cancer Patient Experience Survey in England. Lancet Oncol., 2012; 13(4):353–65.

33.

Lyratzopoulos

, Abel

, McPhail

, et al. Measures of promptness of cancer diagnosis in primary care: secondary analysis of national audit data on patients with 18 common and rarer cancers. Br J Cancer., 2013; 108(3):686–90.

34.

Fern

, Campbell

, Eden

, et al. How frequently do young people with potential cancer symptoms present in primary care?. Br J Gen Pract., 2011; 61(586):e223–30.

35.

Dommett

, Redaniel

, Stevens

, et al. Features of cancer in teenagers and young adults in primary care: a population-based nested case-control study. Br J Cancer., 2013; 108(11):2329–33.