The Delicate Balancing Act of Childhood Cancer Treatment—Not Too Much but Not Too Little

The treatment of childhood cancer is a success story. As a result of marked advances in treatments, death rates from the major types of childhood cancer in the United States have decreased by more than 60% over the past several decades, from 6.3 per 100 000 population in 1970 to 2.0 per 100 000 population in 2017 (1). Today, the overall 5-year relative survival rate for individuals diagnosed with a childhood cancer exceeds 80% compared with 68% in the mid-1970s (1). Although childhood cancer incidence rates are generally higher among Whites compared with Blacks, mortality rates are similar, with a noted disparity in the overall 5-year relative survival rate between Blacks (80.9%) and Whites (86.5%) for those aged 0-14 years at diagnosis (2).

The treatment success for childhood cancers has come with associated costs of increased risks of adverse health and quality-of-life outcomes. These adverse health conditions can include cardiovascular disease, cognitive dysfunction, frailty and, ultimately, premature mortality (3). The Childhood Cancer Survivor Study (CCSS), established in 1994 across selected centers in the United States and Canada, recruited childhood cancer survivors retrospectively in 2 waves covering survivors treated in 1970 through 1999 (4). Noteworthy findings from the CCSS indicate that nearly one-third of childhood cancer survivors report at least 1 severe or life-threatening adverse health condition 20 years after diagnosis (5), resulting in the shortening of life expectancy compared with that of the general population (6).

The challenge of treating childhood cancer is to maintain and improve on treatment success while minimizing late adverse effects. One option to tackle this challenge is tailored treatment approaches, with possible de-escalation of treatment (7). Finding the right amount of treatment is a delicate balancing act: not too much and not too little. The need to find that perfect location on the treatment fulcrum is demonstrated in the study by Fidler-Benaoudia et al. (8) in this issue of the Journal. The authors compared all-cause and cause-specific late mortality among childhood cancer survivors in the United States with those in the United Kingdom using data from the CCSS and the population-based British Childhood Cancer Survivor Study (BCCSS). Findings showed that all-cause cumulative mortality probability at 10 years from diagnosis was statistically significantly lower in the CCSS (4.7%) compared with the BCCSS (6.9%), which is attributed to a lower probability of death from recurrence and progression of the primary cancer. Strikingly, however, at 40 years from diagnosis, the CCSS had a greater cumulative mortality probability than the BCCSS (22.3% vs 19.3%). This greater cumulative mortality probability was found to be due to a 2-fold higher risk of mortality from subsequent malignant neoplasms, cardiac and respiratory diseases, and other health-related causes. As time since diagnosis increased, the differences in cumulative mortality probability from these other late effects increased.

The authors state that these findings suggest that United States survivors have received more intensive regimens, resulting in better remission and cure rates than those in the United Kingdom (8). Unfortunately, detailed treatment information is not available in the BCCSS; however, the authors provide evidence for this supposition by comparing trial protocols and outcomes for acute lymphoblastic leukemia, the most common childhood malignancy, that were used in the 2 countries during the time period in which CCSS and BCCSS cancer survivors were diagnosed. Although the differences in treatment intensity could explain the lower cumulative mortality due to recurrence/progression and higher cumulative mortality due to other late effects, there is a fundamental difference in the design of the CCSS and BCCSS that must be considered when interpreting the results of this study. The BCCSS is a population-based study; the cohort was ascertained using the United Kingdom National Registry of Childhood Tumors, which includes all cancers diagnosed in British residents younger than 15 years of age. Conversely, the CCSS is clinic based, with eligible participants recruited and consented at participating clinical sites. There is, thus, the possibility of selection bias in that individuals in the CCSS are not representative of the entire United States childhood cancer survivor population. In the CCSS, minority participants are underrepresented, and large gaps in regional coverage are noted, particularly in more rural areas in the South and West (9). The participants of the CCSS may, in general, be healthier than childhood cancer survivors in the general population and may have been more adherent to their intensive treatment regimens—both of which may be reflected in the findings of this study (ie, lower cumulative mortality and higher cumulative mortality from other late effects in the United States vs the United Kingdom). This is, in fact, acknowledged by the authors in the discussion—citing Mertens et al. (10), which found superior survival in the CCSS compared with population-based United States data of childhood cancer survivors. Comparing the BCCSS data to a population-based United States childhood cancer survivor cohort, perhaps generated through United States Surveillance, Epidemiology, and End Results program registries or, preferably, all state cancer registries, would provide clarity as to whether there are true differences in long-term cumulative mortality due to recurrence and progression or other late effects. This would also help guide decisions regarding risk-based tailoring of treatment or other approaches to treatment de-escalation (7).

Whether or not the differences between the United States and the United Kingdom reported in the present study reflect true differences, the results from both the United States and the United Kingdom studies emphasize the need to monitor the health of childhood cancer survivors. Continued efforts to quantify cumulative disease burden, determine optimal treatment dose to minimize exposure to toxic treatment and generate cost-effectiveness models to define optimal type and frequency surveillance (11) will help elucidate pathways of survivorship follow-up for childhood cancer survivors who are most in need. Most importantly, ensuring access to both treatment and continued follow-up to enable prevention, recognition of late effects, and prompt intervention is crucial, especially in the absence of universal health care in the United States. These types of activities will greatly help in going beyond what are already considered tremendous advances in the treatment and care of individuals diagnosed with a childhood cancer, with the ultimate goal of improving the health and quality of life of this population.

Notes

Disclosures: The authors have no conflicts of interest to disclose.

Author contributions: LG and KJH contributed to the writing of this editorial.

Disclaimer: The views expressed are those of the authors and do not necessarily reflect the views of the National Cancer Institute.

Data Availability

Not applicable.