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This article was published in an Elsevier journal. The attached copy is furnished to the author for non-commercial research and education use, including for instruction at the author’s institution, sharing with colleagues and providing to institution administration. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Cancer Treatment Reviews (2007) 33, 603– 608 available at www.sciencedirect.com journal homepage: www.elsevierhealth.com/journals/ctrv TUMOUR REVIEW Participation of adolescents with cancer in clinical trials Andrea Ferrari a,* , Archie Bleyer b a Pediatric Oncology Unit, Istituto Nazionale Tumori, Via G. Venezian, 1 20133 Milano MI, Italy Cancer Treatment Center, St. Charles Medical Center, Bend, Oregon, and CureSearch/National Childhood Cancer Foundation and Children’s Oncology Group, Arcadia, CA, USA b Received 30 October 2006; received in revised form 29 November 2006; accepted 30 November 2006 KEYWORDS Summary Adolescent patients with cancer reside in a ‘‘no-man’s land’’ between the world of pediatric oncology and that of ‘‘adult’’ medical oncology. As compared to younger and older patients, adolescents and young adults are under-represented on clinical trials. This relative lack of participation in clinical protocols has been associated to a lack of progress in survival improvement over the last years. One of the main reasons for the deficit in protocol enrolment and the worse outcome of adolescents (when compared in particular to children) is the lack of awareness by the public, community and healthcare systems that cancer may occur in this age group. However, physicians – inadequately trained or reluctant to care for adolescents – have important responsibilities. Most 15- to 19-year-olds diagnosed with cancer are treated at adult facilities, although two-thirds to three-fourths of their cancers are typical of those that occur in the pediatric age range. The best choice may be to treat them according to their type of tumor, not according to their age: ‘‘pediatric’’ tumors treated by pediatric oncologists, ‘‘adult’’ tumors by adult medical oncologists, regardless of the patient’s age. This solution, however, is probably appropriate for the tumor, but not necessarily for the patient. Adolescents are neither old children nor young adults, and are very complicated individuals, with unique socio-psychological problems and needs, that may be addressed only by dedicated professionals, adequately trained and supported. The ultimate challenge is the development of a new discipline, adolescent/teenage and young adult oncology, devoted to the care of these patients. c 2006 Elsevier Ltd. All rights reserved. Adolescents with cancer; Young adults with cancer; Clinical trials Introduction * Corresponding author. Tel.: +39 02 23902588; fax: +39 02 2665642. E-mail address: [email protected] (A. Ferrari). By comparison with adults, children and adolescents rarely suffer from cancer, but it is nonetheless the primary cause of death due to disease in this age group. 0305-7372/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2006.11.005 Author's personal copy 604 For a half century, pediatric oncologists have been striving to develop national and international multicenter research and treatment protocols, and this cooperation has progressively led to advances in our understanding of pediatric malignancies, with a consequent improvement in the outcome of their treatment. Developing clinical protocols is a fundamental part of cancer research. It is undeniable that clinical trials benefit the scientific community and subsequent generations of patients, and cooperative clinical trials involving large numbers of patients, preferably using a randomized design, are the best way to assess the effectiveness of new treatments by comparison with the standard therapeutic options. Publishing the results of clinical trials makes the new findings available to the whole scientific world and provides the input for more clinical studies and further scientific progress. Being involved in clinical trials may also benefit participating patients, at least in the quality of their care and life during participation in the trial. Having the attention of a broader group of professional and the rigor of the trial provides a quality of care – secondary gain in a positive sense – and generally enhances the cancer experience. There is also the possibility of a longer survival and higher cure rate since the trial provides potentially improved treatment that is not otherwise available to the patient. The Dana Farber group attempted to assess the empirical evidence supporting such a positive effect of participation in clinical trials, using a conceptual framework and a structured literature review: the authors concluded that, although most published studies gave the impression of a favorable fallout for patients, the available data were not sufficient to conclude that such a trial effect really existed.1 A retrospective study of 126 randomized trials conducted in 36,567 patients by the Children’s Oncology Group (COG) between 1955 and 1997 concluded that new experimental treatments for childhood cancer assessed in phase III randomized trials are just as likely not to extend survival as they are to be better than standard treatments (which are usually the best available at the time) in prolonging survival.2 Whereas this observation may limit the potential for direct patient benefit in survival prolongation, it verifies the quality of the trials conducted since the principle of equipoise specifies that the likelihood of survival benefit should be unknown when the trial is designed. Studies performed in the 1970s and early 1980s suggested a directed benefit for patients treated in organized pediatric oncology setting (for acute lymphoblastic leukemia,3 non-Hodgkin’s lymphoma,4 Wilms’ tumor5 and medulloblastoma6). In North America, an analysis concerning adolescent patients with acute leukemia also showed better survival results for patients treated in cooperative group trials.7 While it is difficult to assert that taking part in clinical trials affords a personal benefit in terms of a better chance of cure, there is direct benefit of clinical participation in the breadth and quality of care, and associated quality of survival. Clinical trial participation rates Pediatric oncologists tend to assume that enlisting their patients in clinical trials is the way to offer them the best A. Ferrari, A. Bleyer chance of survival and one of the fundamentals of quality treatment. Despite their conviction, patient enrolment rates are high for younger children, but disappointing for adolescents. It has been estimated that around 80% of 0–14 year-olds with cancer in Italy are included in national cooperative protocols (coordinated by the Associazione Italiana Ematologia Oncologia Pediatrica – AIEOP), as opposed to just 25–30% of patients over 15 years old (Fig. 1) (G. Pastore, personal communication). In the United States, the participation for 15–19 year-olds in treatment protocols sponsored by the National Cancer Institute (NCI) between 1997 and 2003 was between 10% and 15%, that means about one-fourth of the corresponding rate among younger children.8–10 A population-based analysis (cooperative group entries from 1992 to 1997) reported that 71% of children under 15 were formally registered with current national pediatric cancer cooperative groups (which subsequently merged to form the COG), while this was true of only 24% of the 15–19 year-olds.11 The situation is even worse when adults are considered: with the exception of the very elderly (over 85), the 20–29 year-old age group has the lowest rate of participation in clinical trials (less than 2%) (Fig. 2).8–10 Figure 1 Percentage of Italian patients (younger and older than 15 years) enrolled in clinical trials of the Associazione Italiana Ematologia Oncologia Pediatrica – AIEOP (courtesy: Guido Pastore and Andrea Pession, data base modello 1.01 AIEOP). Figure 2 Entries of 51,395 patients age < 45 years onto US National Cooperative Group treatment trials sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute Division of Cancer Treatment and Diagnosis during 1997–2003, inclusive (from: Bleyer A, Budd T, Montello M. Adolescents and young adults with cancer: the scope of the problem and criticality of clinical trials. Cancer. 2006; 107(S7):1645–1655. Walking two worlds – Adolescent and young adult oncology. Proceedings of a symposium held by the pediatric Oncology Group of Ontario. Authorized by the author and by the journal). Author's personal copy Participation of adolescents with cancer in clinical trials The accrual pattern in the United States is much the same for all racial and ethnic groups, gender (though the nadir in the participation rate is even more striking in males), place of residence (metropolitan or rural areas) and type of cancer.8 Survival The age-related rate of involvement in clinical trials strongly reflects the steep V-shaped figures for the mean annual improvement in survival rates in the last 25 years. The Survival, Epidemiology and End Results (SEER) analysis found an average annual improvement in survival of more than 1.5% a year among children under 15 and adults over 50, but it dropped to less than 0.5% in the 15–24 year-olds (and in the 25–34 year-olds there was no perceptible improvement at all) (Fig. 3).8–10,12–14 Thus, the poor rate of accrual in clinical protocols coincides with a worse rate of progress in improving the survival of older adolescents and young adults by comparison with all the other age groups – and this may be probably applied not only to the United States, but to the rest of the world too. The recent report on the European situation from the Automated Childhood Cancer Information System (ACCIS) project described a very similar global survival rate for all cancers in Europe among children and adolescents, but this was influenced by the higher proportion of ‘‘favorable’’ tumors (i.e. Hodgkin’s disease, thyroid and testis cancer) in the adolescent group. When the different types of cancer were considered separately, significant differences in outcome became apparent, with adolescents revealing a worse survival than children for leukemia, sarcomas and cerebral tumors.15 605 Possible explanations for adolescents having a worse outcome This a complex issue and there may be several reasons why adolescents fare less well than children with the same disease, and why in the last 25 years we have failed to reduce the mortality rates among adolescent and young adult cancer patients to the same degree that has occurred for other age groups.9,16,17 First, there may be a greater incidence of adverse prognostic variables in older patients and age may itself be an independent negative prognostic factor in some pediatric tumors (i.e. rhabdomyosarcoma).18,19 Other factors relating to the patients and their families, the society or community in which they live, or the health professionals who take care of them may also be involved, however.8–10 One of the main concerns is that adolescents, their families, the community and the healthcare system seem scarcely aware that cancer can affect this age group.8–10,13,16 Adolescents tend to have a age-specific strong sense of independence and invincibility; they may be reluctant to trust the medical establishment and to have a known primary physician; they may delay speaking about their symptoms to parents and physicians, and even when they see the physician, they may give poor information. The lack of awareness that cancer can arise in adolescents might be understandable in the young patients involved, but it is more difficult to explain in other members of the community and amongst health operators. Since it is assumed that adolescents do not get cancer, clinical attention to telltale signs may be low and symptoms are often attributed to physical exertion, fatigue, trauma, and stress. This means that the diagnosis comes late: the interval between the onset of Figure 3 Average annual percent change (AAPC) in the 5-year survival rate of patients with invasive cancer who were in the U.S. Survival, Epidemiology, and End Results (SEER) registry from 1975 to 1997 (courtesy from: Bleyer A, O’Leary M, Barr R, Ries LAG (eds): Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975–2000. National Cancer Institute, NIH Pub. No. 06-5767. Bethesda, MD 2006). Author's personal copy 606 the early symptoms and the diagnosis of cancer is longer in adolescents than in children, with obvious effects on the stage of the disease and the final outcome.20–22 Another factor limiting their recourse to medical care (particularly in the United States) is that adolescents (and young adults) are no longer covered by their parents’ health insurance policies: nearly half of the adolescents lose the insurance provided by their parents and do not acquire adequate coverage at their next destination in life. The 18- 24year age group has the lowest rate of health insurance among all ages in the United States.23 Nonetheless, an important factor behind the worse outcome of cancer in adolescents than in children could well have to do with their more limited participation in clinical trials: adolescents are less likely to gain access to optimal cancer services at comprehensive cancer centers and consequently are not offered participation in clinical trials. And even when referred to a tertiary center, there are fewer clinical trials open to patients in the age group that for other ages.8–10,12,13 The healthcare system – and physicians – are the responsible for this situation. Physicians (and other professionals) may be poorly trained, or unwilling, to care for adolescents; moreover, they may even be reluctant to recommend enrolling adolescents and young adults in clinical trials, because they could perceive these patients as likely to be non-adherent with the trial requirement, or because of the time, cost and effort involved, not only for themselves but also for the patients and their families. Another main problem is that sometimes there are no clinical trials available: adult cooperative groups and cancer centers may lack treatment protocols designed for younger patients, while pediatric cooperative groups and hospitals may lack treatment protocols for older ones. Children’s hospitals often have upper age limits and consequently reject older patients, and the same applies vice versa to patients too young to join protocols at oncology units intended primarily for adult patients.8–10,12,13 The clinical trial itself may sometimes establish age limits that exclude otherwise eligible patients. It is possible to say that adolescent patients are left in a ‘‘no-man’s (also no woman’s) land’’ somewhere between the worlds of pediatric oncology and of ‘‘adult’’ medical oncology. To make matters worse, pediatric oncologists and medical oncologists may be reluctant to co-operate with one another (though they are dealing with very similar diseases), and a 15-year-old with a given type of cancer is often treated quite differently from a 22-year-old with the same disease, even when they are both seen at the same experienced institution.24,25 Another explanation for the deficit in the enrollment of adolescents suffering from cancer onto clinical trials may be the peculiar spectrum of cancers that affect this agegroup. It is a fact that there is no a discipline, in medicine, dedicated to this group of tumor. However, while it is true that adolescents may have a combination of tumor types unique to their age, it is evident that the majority are types of tumors typical of pediatric age (i.e. brain tumors, leukemia and lymphoma, sarcomas and germ cell tumors), while the remainder are tumors of adulthood (i.e. melanoma, thyroid carcinoma and other carcinomas) (Fig. 4).9 Of course, it is hard to say, on the other hand, whether a given type of A. Ferrari, A. Bleyer Figure 4 Cancers in 15- to 19-year-olds, U.S. Survival, Epidemiology, and End Results (SEER) registry, 1975-2001.Segments in color represent ‘‘pediatric malignancies’’. (courtesy from: Bleyer A, O’Leary M, Barr R, Ries LAG (eds): Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975– 2000. National Cancer Institute, NIH Pub. No. 06-5767. Bethesda, MD 2006). cancer would have a different biological behavior when it occurs in adults as opposed to children. These considerations make the referral of adolescent patients even more difficult. It is often the first physician to see the patient who refers the case to an adult or pediatric oncologist, which may mean a number of things (an internist, family physician, emergency room physician, neurologist, and so on) and the pattern of referral can be very different. At the end, though the majority of tumor of adolescents are ‘‘pediatric’’ cancers, most 15- to 19-year-olds are primarily sent and then treated at adult facilities (that often lack treatment protocols designed for ‘‘pediatric’’ cancers), because the age cut-off for managing them as pediatric or adult cases is often considered by most physicians as setting not at 18, but at 15 years of age. As a result, only about 30% of adolescents are usually treated at pediatric oncology centers.16,26,27 Pediatric oncologists (and pediatric oncology units) may be considered naturally more appropriate for managing adolescents with ‘‘pediatric’’ malignancies, and the same principle applies to young adults with ‘‘pediatric’’ cancers. In North-American28 and European studies,29–33 older adolescents with acute lymphoblastic leukemia fared considerably better when treated as part of pediatric clinical trials than using adult leukemia protocols. An analysis from the United States National Cancer Data Base reported that 15- to 19year-olds with leukemia, lymphoma, liver tumors, and bone sarcomas had a better outcome when treated at an NCI pediatric center.7 A German study showed that 15–20 year-old patients with Ewing sarcoma treated at pediatric cancer centers survived better than those treated at other institutions, although the same clinical protocol was adopted.34 The study also confirmed that the overall outcome was better for children than for adolescents and young adults, possibly due to differences in clinical presentation (larger tumors and a more axial location in older patients) and treatment tolerance. That adolescents treated at pediatric centers should Author's personal copy Participation of adolescents with cancer in clinical trials do better than those treated with the same protocol at adult oncology centers may have to do with the former centers having more experience of this particular disease and a different approach to patient care (a pediatric oncologist may be more expert in delivering intensive chemotherapy). Studies on adult patients with rhabdomyosarcoma,19 medulloblastoma35 and Wilms’ tumor36 have been conducted by the Istituto Nazionale Tumori (INT) of Milan, Italy (where the pediatric oncology unit is part of a cancer institute and not of a pediatric department, as is generally the case, so the INT pediatric oncologists can treat adolescent and young adult patients with ‘‘pediatric’’ tumors disregarding the age cut-off). The INT studies emphasized that adult patients with rhabdomyosarcoma19 and medulloblastoma35 had a better outcome when directly enrolled in pediatric trials, or at least when treated ‘‘according to’’ the protocols for children, and similar findings emerged for patients with synovial sarcoma.24,25 Conversely, adult patients with Wilms’ tumor had a worse prognosis than is usually reported for the children (whose treatment strictly followed the rules of the clinical trial), and this seemed to be a matter of undertreatment or erroneous treatment, or poor compliance with the proposed therapeutic guidelines.36 Possible solutions Finding a solution to the deficit in clinical trial enrolment and outcome for adolescents with cancer is no easy matter. It is true that adolescents with cancer seem, on the whole, to benefit from being managed by the multidisciplinary team typical of the pediatric oncology unit, which includes the pediatric oncologist, surgeon, radiotherapist, nutritionist, infectious disease expert, neurologist and endocrinologist, and also the psychologist and social worker. Choosing the right specialist for adolescents with ‘‘adult’’ cancers may prove more difficult, however. Patients with melanoma or colorectal carcinoma should fare better in the care of an adult medical oncologist, who will have more expertise on the treatment of such neoplasms.37 In short, the best choice may be to treat adolescent (and young adult) patients according to their type of tumor, not according to their age: ‘‘pediatric’’ tumors should be treated by pediatric oncologists, ‘‘adult’’ tumors by adult medical oncologists, regardless of the patient’s age. This solution is not ideal, however. It is probably ideal for the tumor, but not for the patient. Adolescents with cancer are neither old children nor young adults. They are very complicated individuals, with unique emotional, spiritual, social and psychological problems to cope with, and particular needs. A 20-year-old young man with medulloblastoma or rhabdomyosarcoma is going to feel ill at ease with the cartoons on the walls of a pediatric center, a motherly style of care and little recognition of his concerns regarding fertility, absence from work, damage to his social (and sexual) life, while a 15-year-old with colorectal cancer may well feel intimidated in an adult hospital ward and may need the parental involvement that adult medical oncologists are less likely to be able to deal with. Adolescents may be individuals with very diverse levels of maturity, different temperaments and different needs. Specific communication skills are needed to relate with ado- 607 lescents, and neither pediatric nor adult oncologists have the necessary training to talk about such problem topics as sexuality or fertility. The needs of adolescents with cancer can only be addressed by specifically trained and focused people, with the support of specialized clinics and inpatient units and, moreover, dedicated research strategies that are not a part of pediatric or adult care programs. Multiple organizations need to be involved for this challenge, including national and local governments, the health insurance industry (at least in the United States), cooperative groups running the clinical trials, and healthcare providers. Improving awareness of the problem at various levels (patient, community, healthcare system) is a primary goal, requiring a major effort in public information and education programs. A more fruitful cooperation is also needed between pediatric and medical oncologists. The ultimate challenge, however, lies in developing oncologists (and oncology centers) dedicated to the care of adolescent patients. The best answer would be to create a new discipline, adolescent and young adult oncology, with its own training programs, clinical and translational research and national and international organizations.8–10 Few cancer centers have special units for adolescents and young adults, but specific programs have been established in the United Kingdom,38,39 Australia and North America (e.g. at the Dana Farber Cancer Institute in Boston).9 In 2000, the COG, in conjunction with the NCI and NCI-sponsored adult cooperative groups, formed the Adolescent and Young Adult (AYA) Committee, whose main aim is to facilitate the access to clinical trials of adolescents and young adults with cancer.9 The Committee’s first steps focused on sarcoma patients and led to the intergroup sarcoma committees and clinical protocols including both pediatric and adult cases. Similar strategies were recommended for other malignancies spanning the adolescent– young adult age bracket (i.e. leukemia and Hodgkin’s disease), for which the upper age limit for pediatric oncology clinical trials has been raised to 30 or 40.9 The proportion of adolescents and young adults entering clinical trials has thus increased in the United States, especially as concerns sarcomas, and this improvement has occurred despite a general decline in the protocol enrolment figures for younger and older patients. Over the next few years, we would naturally expect to see a further increase in this positive trend.8 The relatively poor participation of adolescents in clinical trials in the past has certainly affected their chances of achieving an outcome as good as in children. The chances of reversing this situation depend largely on the efficacy of action to educate the public, health professionals, insurers and cancer policy administrators. References 1. 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