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A reflection on the work of Gianni Bonadonna from the viewpoint of the global challenge of adolescents and young adults with cancer

Abstract

Adolescents and young adults (AYAs – ages 15 to 39) constitute approximately 40% of the world’s population and contribute an estimated one million new cases of cancer annually, the great majority in low- and middle-income countries (LMICs). In high-income countries (HICs) cancer is the commonest cause of disease-related death in AYAs, though overall 5-year survival rates now exceed 80%. A very different circumstance likely holds in LMICs, but accurate assessments are not readily available.

Breast cancer accounts for 40% of tumours in female AYAs and this age group includes the peak incidence of Hodgkin lymphoma. The late Professor Gianni Bonadonna contributed importantly to improved survival in patients with these two diseases. Accordingly, he would be justifiably proud of the advances in AYA oncology that are being made in Italy, especially the impact of his colleagues at the Istituto Nazionale dei Tumori (INT). The initiatives of the Associazione Italiana Ematologia Pediatrica and the Società Italiana Adolescenti con Malattie Onco-ematologiche are particularly noteworthy, with the accomplishment of productive collaboration between paediatric and adult cancer care providers serving as a model for other countries to emulate.

Exporting these advances can be successful through the vehicle of “twinning”: establishing sustainable cooperation between institutions in HICs and partners in LMICs. Colleagues in Monza and at INT have been leaders in such programmes for decades. Cancer in AYAs remains a global challenge to which Gianni Bonadonna surely would have risen with enthusiasm and leadership while securing measurable achievements.

Tumori 2017; 103(6): 489 - 494

Article Type: REVIEW

DOI:10.5301/tj.5000682

Authors

Ronald D. Barr, W. Archie Bleyer

Article History

Disclosures

Financial support: None.
Conflict of interest: The authors have no conflicts of interest to declare.

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Introduction

The authors had the pleasure of meeting Prof. Gianni Bonadonna, both at the National Institutes of Health in Bethesda and at the Istituto Nazionale dei Tumori (INT) in Milan (on the latter occasion after his stroke and remarkable recovery). Consequently it is a particular privilege to be invited to contribute to this series of publications that address the breadth and depth of Prof. Bonadonna’s contributions to our understanding of the biology of cancer and the care of patients with malignant diseases. In doing so we have chosen the perspective of oncology in adolescents and young adults (AYAs) for 3 reasons; it is an area of long-standing personal interest and engagement for the authors; improvements in the care of these young people in Italy owe much to the leadership of the INT, in particular Dr. Andrea Ferrari; and Prof. Bonadonna’s contributions to Hodgkin lymphoma and breast cancer therapy apply directly to AYAs.

In its issue of September 7, 2015, reporting on the death of Gianni Bonadonna, Corriere della Sera noted that he was celebrated around the world for his studies in patients with Hodgkin lymphoma and women with carcinoma of the breast. How true and what a legacy! While Prof. Bonadonna’s original contributions appeared in such high-profile/impact factor publications as the New England Journal of Medicine, his personal reflections on the ABVD regimen (25 years on) for Hodgkin lymphoma (1) and on CMF for breast cancer, with 30 years of follow-up (2), reflect the rigour of his science. These tumours are of special importance in the AYA age group, now commonly defined as 15-39 years (3). The peak incidence for Hodgkin lymphoma is in the age range of 20-34 years, accounting for more than 30% of all cases (4). While the overall survival rate among AYAs may exceed 90%, late effects of treatment are all too common. It is worth noting, however, that the introduction of ABVD was associated with much less infertility (5, 6) and secondary leukemia (6) than occurred with the use of the MOPP regimen that had made such a positive impact on the prognosis of this disease. Late cardiac effects are well recognised with ABVD, related to the component of doxorubicin, as are second solid tumours in the context of combined-modality therapy (1).

Breast cancer accounts for 40% of all tumours in female AYAs and carries a poorer prognosis than in older women, in part due to a higher proportion of triple-negative disease (7) (Fig. 1). Worldwide, breast cancer ranks number 1 in incidence of and mortality from cancer among females aged 15-39 (8). Prof. Bonadonna was the first to test adjuvant chemotherapy after breast cancer surgery. The initial results, presented in 1975, showed that one-half of the women who underwent surgery with no chemotherapy relapsed at 2 years but only about one-third of women given the adjuvant chemotherapy had relapsed. Since female AYAs with breast cancer generally have a worse prognosis, stage for stage, they are more likely to require adjuvant chemotherapy. Also, the as yet unexplained increasing incidence of advanced-stage breast cancer in AYAs has increased the use of chemotherapy in this age group, with anthracycline-based treatment having been first used effectively in metastatic breast cancer by Prof. Bonadonna. Other issues of particular relevance to AYAs are familial disease, future fertility, breast cancer during therapy, and bone health (7). Such is the importance of fertility preservation to AYAs with cancer that the term “oncofertility” has been coined and an international consortium formed (9).

Proportion of breast carcinomas by surface receptor type and age. Her2 = human epidermal growth factor receptor 2; HR = hormone (oestrogen or progesterone) receptor.

A global perspective on cancer in AYAs

Who are AYAs? As proposed originally by the Progress Review Group, which was convened jointly in 2005 by the National Cancer Institute in the US and the Livestrong Foundation (10), the age range is 15-39 years. On this basis it has been estimated that there are approximately 3 billion AYAs on earth, representing some 40% of the world’s population (11), and that they contribute about 1 million new cases of cancer annually (12). In high-income countries (HICs), cancer is the commonest cause of disease-related death among AYAs, though 5-year overall survival rates in HICs continue to rise and now exceed 80% in Western Europe (13), the US (14) and Canada (15). In the absence of population-based cancer registries, corresponding data from low- and middle-income countries (LMICs) are imprecise (16). The overall incidence rates for cancer in AYAs in HICs appear to be rising slowly, though this varies considerably by disease. However, there is concern about overdiagnosis, especially with respect to small papillary carcinomas of the thyroid (17). Overdiagnosis has been defined as the identification of tumours that would not, if left alone, result in symptoms or death. It has been attributed to improved diagnostic technology and increased surveillance (17). In South Korea the incidence of thyroid cancer in the population beyond childhood increased 5-fold from 1993-1997 to 2003-2007, while in Japan the rate was 30 times higher in children and adolescents who were screened in the Fukushima prefecture after the 2011 nuclear accident than in the national population (17). It has been suggested by Dr. Maura Massimino at the INT and colleagues that 2 of every 3 AYAs with thyroid cancer in the USA are overdiagnosed (18).

Clinical initiatives in AYA oncology

Recognition of the special challenges faced by AYAs with cancer Table I (19) occurred in the early 1990s in the UK, Australia and the US. In the UK this was driven by the Teenage Cancer Trust (20), in Australia by CanTeen (21) and in the US by Dr. Gerald Murphy and colleagues, initially at the Roswell Park Memorial Institute (22). This led to the establishment of programmes aimed at patients in the age range from mid-teens to mid-20s, being matched by cancer registration in EUROCARE for those aged 15-24 years (13). The new focus of attention prompted the construction of a classification of cancers in AYAs, then defined as 15-29 years of age (23). That schema has become outmoded as the age range has expanded with greater heterogeneity of diseases, and knowledge of the biology of malignant disease in this age group has increased substantially (24). A new classification system is in development, led by the authors in collaboration with Drs. Annalisa Trama and Gemma Gatta at the INT and others.

Challenges for adolescents and young adults with cancer

“Delay” in diagnosis
Location of care and clinical trial enrolment
Adherence to therapy
Need for psychosocial support
Sexuality and body image
Oncofertility
Rehabilitation and exercise
Financial issues before, during and after treatment
Transitions in medical management
Palliative and end-of-life care

As experience with the provision of health services to AYAs with cancer continues to accumulate, common challenges have been recognised. Among these the following are worthy of special mention. The location of care is manifestly important; so much so that in the UK it has been mandated that adolescents (less than 19 years of age) with cancer must be referred to specialised cancer centres and young adults must be offered this choice (25). The recommendations from the National Institute for Health and Care Excellence are listed in Table II. Treatment of children with cancer on clinical trials has become the standard of care in HICs, but “accrual of AYAs to clinical trials is woefully inadequate worldwide (26, 27), resulting in a loss of critical information on tumour biology, experience in protocol development, and the building of clinical collaborations in addition to the primary purpose of improving clinical outcomes” (19).

NICE Recommendations for children and young people with cancer

NICE = National Institute for Health and Care Excellence.
Care should be coordinated across the whole NHS and be as close to home as possible
Multidisciplinary teams should provide cancer care
All children and young people should have a clearly defined key worker
Care should be appropriate for the child’s or young person’s age and type of cancer
Time in the operating theatre and a children’s anaesthetist should be available when needed
Children and young people should be offered the chance to take part in research trials
Cancer networks should make sure there are enough specialist staff

AYAs with cancer have a considerable need for psychological and psychosocial support. A useful framework for identifying such needs and guiding interventions is provided by the stress-coping model of Chesler and Barbarin (28), which consists of intellectual, practical, interpersonal, emotional and existential domains. The establishment of support groups can provide an opportunity for the added dimension of physical rehabilitation and exercise (29), which can be of measurable benefit (30).

It has long been recognised that AYAs with cancer face particular challenges relating to altered sexuality, self-esteem and body image (31) that should be addressed early in the course of care (32). Because AYAs occupy a large part of the reproductive age group, these concerns add to the risk of impaired fertility consequent on the disease and its treatment. The importance of this matter is evident in the guidelines on fertility preservation published by the American Society of Clinical Oncology (33).

The journey of AYAs with cancer is typically one of a series of transitions (34). These include completion of therapy, transiting to monitoring for relapse, entering long-term follow-up with surveillance for late effects of treatment, moving from paediatric to adult health care systems at any point in the journey, dealing with recurrent disease or a second malignant neoplasm, and shifting from treatment with curative intent to palliative or end-of-life care. The last can be especially difficult (35). Life–long surveillance is demanding of resources but well justified, based on the likely prevalence and severity of late effects, if the experience with children is a guide. Major investments in this undertaking have been made, exemplified by the Childhood Cancer Survivor Study in North America (36), the British Childhood Cancer Survivor Study (37), and the international commitment to harmonisation of the respective guidelines (38).

The Italian experience

An early stimulus to addressing the needs of AYAs with cancer can be traced to the recognition that only 5% of adolescents aged 15-19 years were treated in 1989-1994 within institutions associated with Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP), though this proportion had increased to 18% during 2001-2006, and subsequently, by 2012, to almost 30% (39). In large measure this reflected the upper age limit for admission to children’s hospitals of 16, 15 and even 14 years (40). An additional factor at play may have been “leakage” of teenagers with cancer into facilities for the care of adults, as has been described in Ontario, Canada, within another publicly funded health care system (41). Only 25% of 17-year-olds were treated in pediatric cancer programmes when the upper age limit for admission to children’s hospitals in Ontario was the 18th birthday.

A prompt response to this reality took place in Aviano in 2007 with the Youth Area Project of the Centro di Riferimento Oncologico. This was dedicated to 14- to 24-year-olds in an adult medical oncology setting (42). The Youth Project of the INT was launched within the paediatric oncology unit in 2011 (43), having access to adult cancer services but delivering a paediatric model of care to a similar age group (15-25 years) with emphasis on AYA issues such as fertility preservation (42). Meanwhile, in 2010, AIEOP formed a Committee on Adolescents focusing on 15- to 24-year-olds with cancers common in children. The priorities of the Committee were 3-fold: to improve awareness, promote cooperation with adult medical oncologists, and address issues of particular importance to AYAs with cancer (43).

The first of these was pursued in a survey of 500 healthy adolescents (ages 15-19) that revealed a high level of health awareness in a considerable majority of them but a reluctance among a substantial minority to report early symptoms (44). A separate study of 351 children and adolescents with cancer raised the likelihood that symptom interval may correlate with clinical outcome (45). It is recognised, however, that tumour biology is the major determinant of such outcomes (46). The first and second priorities were advanced with the formation, in 2014, of SIAMO (Società Italiana Adolescenti con Malattie Onco-ematologiche), which is a cooperative venture involving numerous stakeholders including paediatric and adult medical oncologists, nurses, psychologists and social workers, advocacy organisations, cancer survivor associations, cancer agencies and family physicians (47). Increasing awareness of cancer among adolescents is a major goal (48). The opportunities for SIAMO to build bridges between the traditionally separate paediatric and adult cancer care systems are exemplified by the case of soft tissue sarcomas in AYAs who may be subject to treatments for these diseases that can be quite different in paediatric and adolescent cancer centres (49).

The Youth Project in Milan provides a valuable model for the care of AYAs with cancer (50). In attending to the third priority of the AIEOP Committee on Adolescents, the multidisciplinary team at the INT has emphasised the importance of spiritual support (51), a matter of such consequence to AYAs with cancer that similar services are provided in many centres in Italy (and also in predominantly Catholic Spain) (52). In light of this experience it is not surprising that, in a sample of 320 patients with cancer at the INT, almost 93% professed a religious belief that contributed to their sense of hope (53). This critical phenomenon was shown to be sensitive to the quality of relationships with caregivers (53).

In a parallel vein the team at the INT has encouraged AYAs with cancer to express their feelings in ways that are developmentally and culturally intuitive. This initiative has taken several forms, including the medium of music (54, 55) and the presentation of a fashion collection (56) – how very Milanese!

As the activities of the Youth Project at the INT have blossomed, the staff have come to recognise the importance of formally evaluating the programme (57). The metrics selected are listed in Table III. This kind of exercise is ever more attractive to and even demanded by sources of funding support, whether these are governments or philanthropic organisations. The selection of appropriate metrics (indicators) is a rigorous process (58, 59) and can inform economic evaluation, as exemplified by the cooperative study of the treatment of acute lymphoblastic leukemia in children involving colleagues at the Azienda Ospedaliera San Gerardo in Monza (60).

Metrics for the evaluation of the Youth Project

Annual accrual of patients
Proportion enrolled in clinical trials
Proportion considered for fertility preservation
Proportion receiving psychological/spiritual support
Proportion participating in support projects/activities
Level of patient satisfaction
Related research, publications and presentations
Community and media recognition

Closing commentary

Cancer in AYAs is a global challenge. In 2011 the United Nations General Assembly committed to the prevention and control of noncommunicable diseases (NCDs) with a series of Sustainable Development Goals (61). Then the World Health Assembly provided a monitoring framework to effect a reduction in deaths from NCDs, including cancer, by 25% by 2025 (62). How will this be accomplished? In addition to the obvious need for increased investment in population-based cancer registries (63), there must be a coordinated, concerted and collaborative effort to enhance the quality of care delivered to patients with cancer, including AYAs, worldwide. Some 20 years ago it was suggested, by a group led by investigators in Milan and Lausanne (64), that trends in the mortality rate among children with cancer could be used as a quality indicator of medical care in “the developed world”.

The community of paediatric oncology has been at the forefront in twinning programmes linking centres in HICs with those in LMICs; the Monza-Managua (Nicaragua) programme being one of the first (65), joined later by the INT, and still going strong after 30 years. In turn this spawned the Monza International School of Paediatric Haematology and Oncology (65) and the remarkable Central American consortium of paediatric cancer centres (66). Such successes offer a model for tackling AYA oncology around the globe, albeit a bigger and more complex challenge.

Gianni Bonadonna was a quintessential internationalist. He would have been justly proud of the achievements of his colleagues at the INT and in SIAMO, many of whom are committed to enhancing the care of AYAs with cancer at home while engaging with colleagues in less privileged settings to improving clinical outcomes for young people with malignant diseases in these societies.

Disclosures

Financial support: None.
Conflict of interest: The authors have no conflicts of interest to declare.
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Authors

Affiliations

  • Departments of Pediatrics, Pathology and Medicine, McMaster University, Hamilton, Ontario - Canada
  • Oregon Health and Science University, Portland, Oregon, and University of Texas Medical School at Houston, Houston, TX - USA

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