Adolescents and young adults with cancer and the risk of subsequent primary neoplasms: not just big children
Authors: Sumit Gupta
Journal: The Lancet Oncology (2019)

Improved outcomes in childhood cancer have led to an increased focus on the cost of long-term survival: long-term physical, psychological, and financial morbidities that arise as a consequence of cancer therapy or the cancer itself. Several landmark childhood cancer survivor cohorts have informed our ability to describe, predict, and minimise these late effects.1Reulen RC Winter DL Frobisher C et al.Long-term cause-specific mortality among survivors of childhood cancer.JAMA. 2010; 304: 172-179Crossref PubMed Scopus (328) Google Scholar, 2Gibson TM Mostoufi-Moab S Stratton K et al.Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970–99: a report from the Childhood Cancer Survivor Study cohort.Lancet Oncol. 2018; 19: 1590-1601Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar About 80% of adolescents and young adults (AYAs) with cancer will also achieve long-term cure.3Trama A Botta L Foschi R et al.Survival of European adolescents and young adults diagnosed with cancer in 2000–07: population-based data from EUROCARE-5.Lancet Oncol. 2016; 17: 896-906Summary Full Text Full Text PDF PubMed Scopus (166) Google Scholar Consequently, late effects are also highly relevant to this population, but very few AYA-specific data exist, forcing clinicians to extrapolate from the literature on childhood cancer survivors. Subsequent primary neoplasms (also known as second malignant neoplasms) are one of the most feared late effects, and are associated with substantial morbidity and mortality. Previous work has shown that survivors of AYA cancer have a higher absolute risk of subsequent primary neoplasms than do younger or older populations, which in turn has a substantial impact on overall survival.4Lee JS DuBois SG Coccia PF Bleyer A Olin RL Goldsby RE Increased risk of second malignant neoplasms in adolescents and young adults with cancer.Cancer. 2016; 122: 116-123Crossref PubMed Scopus (92) Google Scholar, 5Keegan T Bleyer A Rosenberg AS Li Q Goldfarb M Second primary malignant neoplasms and survival in adolescent and young adult cancer survivors.JAMA Oncol. 2017; 3: 1554-1557Crossref PubMed Scopus (72) Google Scholar In The Lancet Oncology, Chloe Bright and colleagues6Bright CJ Reulen RC Winter DL et al.Risk of subsequent primary neoplasms in survivors of adolescent and young adult cancer (Teenage and Young Adult Cancer Survivor Study): a population-based, cohort study.Lancet Oncol. 2019; (published online Feb 20.)http://dx.doi.org/10.1016/S1470-2045(18)30903-3Summary Full Text Full Text PDF PubMed Scopus (63) Google Scholar describe the risk of subsequent primary neoplasms in a population-based cohort of more than 200 000 survivors of AYA cancer. The large sample size and more than 2·6 million person-years of follow-up allow the investigators to describe, comprehensively for the first time and in great detail, the risk of specific subsequent primary neoplasms after specific primary cancers. The cumulative incidence of any subsequent primary neoplasm at 35 years from diagnosis ranged from 11·9% in survivors of breast cancer to 26·6% in female survivors of Hodgkin lymphoma. The level of granularity provided in the risk estimates (eg, by primary cancer, type of subsequent primary neoplasm, and years from diagnosis) should assist clinicians and policy makers in determining what type of interventions would be of greatest benefit for specific populations of AYA cancer survivors. Beyond improving risk prediction, several implications of the data are worth highlighting. The results illustrate the dangers of applying findings from childhood cancer survivors to the AYA population. For example, the surprising burden of subsequent lung cancers stands in contrast to the childhood cancer literature.7Reulen RC Frobisher C Winter DL et al.Long-term risks of subsequent primary neoplasms among survivors of childhood cancer.JAMA. 2011; 305: 2311-2319Crossref PubMed Scopus (247) Google Scholar In male survivors of Hodgkin lymphoma, lung cancer accounted for approximately 40% of the total number of excess subsequent primary neoplasms, with a cumulative incidence of lung neoplasms of 5·1% at 35 years from diagnosis. Substantial incidences were also seen in other survivor groups. It is unclear whether this difference compared with childhood cancer survivors is caused by several primary AYA cancers being themselves related to smoking history (eg, cervical cancer), a higher probability of smoking after diagnosis,8Kaul S Veeranki SP Rodriguez AM Kuo Y-F Cigarette smoking, comorbidity, and general health among survivors of adolscents and young adult cancer.Cancer. 2016; 122: 2895-2905Crossref PubMed Scopus (37) Google Scholar increased use of treatments such as lung radiotherapy, greater attained age, or a combination of these factors. Irrespective of the mechanism, Bright and colleagues' results support smoking cessation interventions for survivors and raise the intriguing question of whether lung cancer screening guidelines developed for other high-risk populations may be appropriate.9Oudkerk M Devaraj A Vliegenthart R et al.European position statement on lung cancer screening.Lancet Oncol. 2017; 18: e754-e766Summary Full Text Full Text PDF PubMed Scopus (350) Google Scholar A second difference concerns temporal trends. The risk of subsequent primary neoplasms in childhood cancer survivors has decreased over consecutive cohorts, largely associated with reductions in radiotherapy doses.2Gibson TM Mostoufi-Moab S Stratton K et al.Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970–99: a report from the Childhood Cancer Survivor Study cohort.Lancet Oncol. 2018; 19: 1590-1601Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 10Turcotte LM Liu Q Yasui Y et al.Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970-2015.JAMA. 2017; 317: 814-824Crossref PubMed Scopus (147) Google Scholar In this study, treatment decade was not significantly associated with subsequent primary neoplasm risk, suggesting that no such decline has occurred in the AYA survivor population. The reasons for this finding are unclear. AYA treatment intensity might not have decreased as it has in childhood cancer. Alternatively, reducing the incidence of subsequent primary neoplasms in survivors of AYA cancer might require a stronger focus on lifestyle factors. Although this study represents a substantial contribution, several limitations merit note. Late effects are most closely associated with the types and doses of therapy received. Unfortunately, the investigators did not have access to treatment data, relying instead on diagnosis as proxy. However, a patient with Hodgkin lymphoma might receive only two cycles of chemotherapy or might undergo six cycles and radiotherapy, with consequently vastly different risks for subsequent primary neoplasm. Without treatment data, the clinician is still left uncertain on how to counsel an individual patient on his or her personalised risk, or what screening to recommend. AYA-specific risk prediction models that include treatment exposure are urgently needed. Finally, description of risk is only a first step towards the ultimate goal of improving the quantity and quality of life for survivors of AYA cancer. Studies that identify effective interventions for this population, whether in the prevention, screening, or treatment of late effects, are crucial. Determining what health-care delivery models maximise uptake of such interventions in a population known to face substantial barriers to access will also be necessary. For decades, paediatricians have insisted that children are "not just little adults". We must now be equally emphatic in declaring that when it comes to the late effects of cancer and cancer therapy, AYAs are "not just big children", but instead deserve recognition as their own unique group. I declare no competing interests. Risk of subsequent primary neoplasms in survivors of adolescent and young adult cancer (Teenage and Young Adult Cancer Survivor Study): a population-based, cohort studyOur finding that a small number of specific subsequent primary neoplasms account for a large percentage of the total excess number of neoplasms in long-term survivors of cervical, breast, and testicular cancer, and Hodgkin lymphoma provides an evidence base to inform priorities for clinical long-term follow-up. The prominence of lung cancer after each of these AYA cancers indicates the need for further work aimed at preventing and reducing the burden of this cancer in future survivors of AYA cancer. Full-Text PDF Open Access