Declining Childhood and Adolescent Cancer Mortality

Declining Childhood and Adolescent Cancer Mortality Malcolm A. Smith, MD, PhD 1 ; Sean F. Altekruse, DVM, PhD 2 ; Peter C. Adamson, MD 3 ; Gregory H. Reaman, MD 4 ; and Nita L. Seibel, MD 1 BACKGROUND: To evaluate whether progress continues in identifying more effective treatments for children and adolescents with cancer, the authors examined both overall and disease-specific childhood cancer mortality rates for the United States, focusing on data from 2000 to 2010. METHODS: Age-adjusted US mortality trends from 1975 to 2010 were estimated using joinpoint regression analysis. Analyses of annual percentage change (APC) were performed on the same diagnostic groupings for the period restricted to 2000 through 2010 for groupings ages <20 years, <15 years, and 15 to 19 years. RESULTS: After a plateau in mortality rates during 1998 to 2002 (APC, 0.3%), the annual decline in childhood cancer mortality from 2002 to 2010 (APC, 22.4%) was similar to that observed from 1975 to 1998 (APC, 22.7%). Statistically significant declines in mortality rates from 2000 to 2010 were noted for acute lymphoblastic leukemia, acute myeloid leukemia, non-hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, central nervous system cancers, and gonadal cancers. From 2000 to 2010, the rates of decline in mortality for the group ages 15 to 19 years generally were equal to or greater than the rates of decline for the group ages birth to 14 years. Improvements in treatment since 1975 resulted >45,000 cancer deaths averted through 2010. CONCLUSIONS: Cancer mortality for both children and adolescents declined from 2000 to 2010, with significant declines observed for multiple cancer types. However, greater than 1900 cancer deaths still occur each year among children and adolescents in the United States, and many survivors experience long-term effects that limit their quality of life. Continued research directed toward identifying more effective treatments that produce fewer long-term sequelae is critical to address these remaining challenges. Cancer 2014;120:2497-506. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. KEYWORDS: childhood cancer, adolescents, childhood leukemia, mortality rates, childhood solid tumors. INTRODUCTION Treatment of childhood cancer is 1 of the important success stories of 20th century medicine. This success is exemplified by acute lymphoblastic leukemia (ALL), an incurable disease in the 1950s that, by the end of the century, had 5-year survival rates approaching 90%. Other childhood cancers also exhibited marked improvements in outcome in the 20th century, including Wilms tumor, non-hodgkin lymphoma (NHL), Hodgkin lymphoma, and germ cell tumors. Despite the successes in identifying effective treatments for some cancer diagnoses, at the end of the 20th century, >20% of children diagnosed with cancer still died from their disease, and many survivors experienced long-term effects that negatively affected their quality of life. In addition, for some childhood cancers, progress was very limited (eg diffuse intrinsic brainstem gliomas, high-grade gliomas, and metastatic sarcomas). Of concern, a slowing in the rate of decline in childhood cancer mortality has been described for both European and North American populations, suggesting that a plateau is being reached in the ability of childhood cancer researchers to identify more effective treatments for children with cancer. 1,2 To ascertain whether progress in identifying more effective treatments for children and adolescents with cancer is continuing, we examined overall and disease-specific childhood cancer mortality rates for the United States, focusing on more recent data from 2000 to 2010. MATERIALS AND METHODS Incidence Data Incident cases that formed the basis for the survival estimates included in this report were identified in the Surveillance, Epidemiology, and End Results (SEER) 9 registries among patients who were aged <20 years at the time of diagnosis, Corresponding author: Malcolm A. Smith, MD, PhD; Cancer Therapy Evaluation Program, National Cancer Institute, 9609 Medical Center Drive, RM 5-W414, MSC 9737; Bethesda, MD 20892 Fax: (240) 276-7892, Malcolm.Smith@nih.gov 1 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; 2 Surveillance Research Program, National Cancer Institute, Bethesda, Maryland; 3 Department of Clinical Pharmacology and Therapeutics, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania; 4 Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland Additional supporting information may be found in the online version of this article. See related editorial on pages 2388-91, this issue. DOI: 10.1002/cncr.28748, Received: September 4, 2013; Revised: October 3, 2013; Accepted: October 17, 2013, Published online May 22, 2014 in Wiley Online Library (wileyonlinelibrary.com) Cancer August 15, 2014 2497

between 1975 and 2010. The SEER 9 registries, which cover approximately 10% of the US population, are Metropolitan Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, and Utah. 3 Rates were age-adjusted to the US 2000 standard population. Mortality Data Mortality data were based on deaths in the United States that were reported to the Centers for Disease Control and Prevention. Rates were age-adjusted to the US 2000 standard population. For all children aged <20 years, ages 15 to 19 years, and aged <15 years, mortality rates per 100,000 and the proportion of all US childhood cancer deaths during the periods from 2000 to 2002, from 2003 to 2006, and from 2007 to 2010 that were attributable to specific cancer sites were determined for selected sites: leukemia, including ALL and acute myeloid leukemia (AML); lymphomas (with Hodgkin lymphoma and NHL analyzed separately); brain and other nervous system; neuroblastoma; bone and joint; soft tissue (including heart); kidney and renal pelvis; gonads (ovary and testis); liver and intrahepatic bile duct; all other malignant cancers combined; and in situ tumors, benign tumors, and tumors with unknown behavior. Mortality Trends Age-adjusted US mortality trends were estimated for hematopoietic cancers (leukemia and lymphoma combined) and for all other cancers combined from 1975 to 2010 using joinpoint regression analysis (Joinpoint 3.3; Information Management Services, Silver Spring, Md) to fit a series of joined straight lines on a logarithmic scale to annual age-standardized rates. 4 A maximum of 5 joinpoints were allowed. Trends for various periods were described as the annual percentage change (APC), ie, the slope of the line segment. We also determined the APC restricted to the period from 2000 to 2010. Statistical significance was defined by rejection of the null hypothesis that the APC is equal to zero with significance level of.05. We also examined absolute declines in mortality rates for the period from 2000 to 2010, specifically comparing mortality in the first 3 years of the decade (2000-2002) with that in the last 4 years of the decade (2007-2010) for those aged <20 years. Deaths Averted The numbers of childhood malignant cancer deaths averted in the United States from 1975 through 2010 were estimated on the basis of observed deaths per year versus expected deaths if there had been no decrease in the rate since 1975. Observed annual age-specific counts of deaths caused by malignant cancer were determined by age group: birth (0 years) and ages 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 19 years. Age-specific expected deaths were estimated by multiplying the 1975 age-specific rates by annual age-specific populations from 1975 through 2010. Estimated deaths averted were calculated as the differences between expected and observed deaths. Total childhood cancer deaths averted were calculated as the sum across age strata. Survival Data We used the International Childhood Cancer Classification to examine the 5-year survival rates for selected childhood age groups during successive 4-year periods (1975-1978 and 2003-2007). The year 2007 was the last year included in survival analyses, allowing follow-up from the time of diagnosis through 2010. Additional information regarding the analysis of survival data are provided online (see online supporting materials). RESULTS Childhood Cancer Mortality From 2000 to 2010 First, we examined mortality for the period from 2000 to 2010 for children and adolescents ages <20 years, <15 years, and 15 to 19 years. These age groupings were used because of differences between the histologies that present in younger children and older adolescents and because of concerns that improvements in adolescent outcomes may lag behind those for younger children. The APC was determined for aggregated diagnoses and for specific diagnoses. Statistically significant declines in mortality rates were noted for all age groups when considering all malignant cancers and all leukemias and also were noted across all age groups for ALL, AML, and NHL considered separately (Table 1). In addition, significant declines were observed for Hodgkin lymphoma and germ cell tumors for the groups ages <20 years and 15 to 19 years and for neuroblastoma and brain cancers for the groups ages <20 years and <15 years. Next, we compared mortality rates from 2000 to 2002 with those from the last 4 years for which data were available (2007-2010) to document the absolute decline in mortality rates between the early and latter parts of that period (Table 1). The decline in cancer mortality for patients aged <20 years was 214%, and the decline was slightly greater for the group ages 15 to 19 years (218.1%) compared with the decline for children aged <15 years (212.3%). The decline in mortality among 2498 Cancer August 15, 2014

Childhood & Adolescent Cancer Mortality/Smith et al TABLE 1. US Childhood Cancer Mortality Rates, 2000-2010 Rate per 100,000 (95% CI) Site 2000-2002 2003-2006 2007-2010 Percentage Change 2000-2002 to 2007-2010 APC 2000-2010 Aged <20 y All malignant cancer 2.79 (2.72-2.86) 2.64 (2.59-2.7) 2.4 (2.34-2.45) 214.1 22.1 a Leukemia 0.88 (0.84-0.92) 0.79 (0.76-0.83) 0.71 (0.68-0.73) 219.9 23.1 a ALL 0.4 (0.37-0.42) 0.35 (0.33-0.37) 0.31 (0.29-0.33) 223.1 23.8 a AML 0.27 (0.25-0.29) 0.25 (0.23-0.27) 0.23 (0.21-0.24) 216.7 22.3 a Brain and ONS 0.68 (0.64-0.71) 0.68 (0.65-0.71) 0.63 (0.6-0.66) 26.8 21.1 a Ganglioneuroblastoma 0.23 (0.21-0.25) 0.23 (0.21-0.25) 0.2 (0.18-0.21) 213.3 21.9 a Bone and joint 0.22 (0.21-0.24) 0.23 (0.21-0.24) 0.21 (0.19-0.22) 28.5 21.3 Soft tissue including heart 0.18 (0.17-0.2) 0.19 (0.17-0.2) 0.18 (0.17-0.2) 20.5 20.1 NHL 0.14 (0.12-0.15) 0.12 (0.11-0.13) 0.1 (0.09-0.11) 228.8 24.4 a Hodgkin lymphoma 0.04 (0.03-0.05) 0.03 (0.02-0.03) 0.02 (0.02-0.02) 249.1 27.6 a Kidney & renal pelvis 0.07 (0.06-0.08) 0.07 (0.07-0.08) 0.06 (0.05-0.07) 213.2 22.1 Gonads 0.02 (0.02-0.03) 0.02 (0.02-0.03) 0.02 (0.01-0.02) 230.8 24.6 a Liver 0.07 (0.06-0.08) 0.06 (0.05-0.07) 0.06 (0.06-0.07) 26.3 21.1 Ages 15-19 y All malignant cancer 3.59 (3.44-3.74) 3.32 (3.2-3.44) 2.94 (2.83-3.06) 217.9 22.6 a Leukemia 1.15 (1.06-1.24) 0.97 (0.9-1.03) 0.83 (0.77-0.89) 227.8 24.0 a ALL 0.5 (0.45-0.56) 0.41 (0.36-0.45) 0.33 (0.29-0.37) 234.7 25.2 a AML 0.37 (0.32-0.42) 0.32 (0.29-0.36) 0.28 (0.25-0.32) 222.3 22.7 a Brain and ONS 0.52 (0.46-0.58) 0.53 (0.48-0.58) 0.46 (0.42-0.51) 210.9 21.7 Ganglioneuroblastoma 0.06 (0.04-0.09) 0.06 (0.05-0.08) 0.06 (0.04-0.08) 25.1 0 Bone and joint 0.48 (0.42-0.54) 0.54 (0.49-0.59) 0.48 (0.43-0.53) 0.4 20.4 Soft tissue including heart 0.31 (0.27-0.36) 0.32 (0.28-0.36) 0.3 (0.26-0.33) 25.3 21 NHL 0.27 (0.23-0.31) 0.24 (0.2-0.27) 0.2 (0.17-0.23) 225.2 24.4 a Hodgkin lymphoma 0.12 (0.09-0.15) 0.07 (0.06-0.09) 0.06 (0.04-0.08) 249.6 28.2 a Kidney & renal pelvis 0.04 (0.02-0.06) 0.04 (0.03-0.06) 0.04 (0.03-0.05) 2.6 20.1 Gonads 0.08 (0.06-0.11) 0.08 (0.06-0.1) 0.05 (0.04-0.07) 234.8 26.1 a Liver 0.06 (0.04-0.08) 0.05 (0.04-0.07) 0.06 (0.04-0.08) 5.1 0.4 Aged <15 y All malignant cancer 2.52 (2.45-2.59) 2.42 (2.35-2.48) 2.21 (2.15-2.27) 212.2 21.8 a Leukemia 0.79 (0.75-0.83) 0.74 (0.7-0.77) 0.66 (0.63-0.7) 216 22.7 a ALL 0.36 (0.34-0.39) 0.33 (0.31-0.36) 0.3 (0.28-0.32) 217.8 23.3 a AML 0.24 (0.22-0.26) 0.23 (0.21-0.25) 0.21 (0.19-0.23) 213.7 22.1 a Brain and ONS 0.73 (0.69-0.77) 0.73 (0.69-0.76) 0.69 (0.65-0.72) 25.8 20.9 a Ganglioneuroblastoma 0.29 (0.26-0.31) 0.29 (0.27-0.31) 0.25 (0.23-0.27) 213.9 22.0 a Bone and joint 0.14 (0.12-0.16) 0.12 (0.11-0.14) 0.11 (0.1-0.13) 218.8 22.3 Soft tissue including heart 0.14 (0.12-0.16) 0.14 (0.13-0.16) 0.14 (0.13-0.16) 3.1 0.6 NHL 0.09 (0.08-0.11) 0.08 (0.07-0.09) 0.06 (0.05-0.07) 232.4 24.8 a Hodgkin lymphoma 0.01 (0.01-0.02) 0.01 (0.01-0.02) 0.01 (0-0.01) 247 24.2 Kidney & renal pelvis 0.08 (0.07-0.095) 0.08 (0.07-0.11) 0.07 (0.06-0.08) 215.7 22.4 Gonads 0.01 (0.002-0.01) 0.01 (0.004-0.01) 0.01 (0.002-0.01) 28.4 3.1 Liver 0.07 (0.06-0.09) 0.07 (0.06-0.08) 0.07 (0.06-0.08) 29.3 21.5 Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; APC, annual percentage change; CI, confidence interval; NHL, non-hodgkin lymphoma; ONS, other nervous system. a These values indicate a statistically significant decrease. those aged <20 years for leukemias was 219.3%, with declines of 222.5% for ALL and 214.8% for AML. It is noteworthy that the declines in total leukemia and ALL mortality were greater for those ages 15 to 19 years (227.8% and 234%, respectively) compared with those aged <15 years (216.5% and 216.7%, respectively). The declines in AML mortality also were numerically greater for adolescents compared with younger children (224.3% and 212.5%, respectively). Large percentage declines in Hodgkin lymphoma and NHL mortality were noted for the group aged <20 years (228.6% and 250%, respectively). For solid tumors, the largest percentage decline among cancers with significant decreases based on the APC was for neuroblastoma (213%). The pattern of mortality from 2007 to 2010 differed markedly between patients aged <15 years and ages 15 to 19 years (Fig. 1). For the younger age group, leukemias, brain tumors, and neuroblastoma accounted for nearly 3 quarters (71%) of all cancer-related mortality; whereas those diagnoses accounted for less than half (46%) of cancer mortality in the group ages 15 to 19 years. By contrast, bone and soft tissue cancers and NHL accounted for Cancer August 15, 2014 2499

Figure 1. Patterns of mortality are illustrated for children and adolescents ages (Top) <15 years and (Bottom) 15 to 19 years for the period from 2007 to 2010. NHL indicates non- Hodgkin lymphoma; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; Oth Leuk, other leukemia; CNS, central nervous system. approximately one-third of mortality in older patients but for less than one-sixth of mortality in younger patients. Kidney and liver tumors together accounted for 5% to 6% of mortality in the group aged <15 years, whereas gonadal tumors and Hodgkin lymphoma were associated with <1% of mortality in that age group. Among those ages 15 to 19 years, each of these cancers accounted for approximately 2% of overall cancer-related mortality. Trends in Cancer Mortality From 1975 to 2010 We next sought to understand patterns of cancer mortality for the period from 2000 to 2010 in the context of trends in mortality since 1975. Overall childhood cancer mortality declined by 52% from 1975 to 1977 to 2007 to 2010 (Supporting Table 1; see the online supporting materials). The greatest percentage declines in mortality were for Hodgkin lymphoma and gonadal tumors (282% and 283%, respectively). Declines exceeding 50% were also were noted for leukemias (264%), renal tumors (257%), and NHL (274%). Smaller declines were noted for neuroblastoma (243%), brain tumors (229%), and bone tumors (236%). The smallest declines were observed for liver tumors (222%) and for tumors of the soft tissue including heart (a category that primarily included soft tissue sarcomas; 25%). Joinpoint analysis was applied to mortality rates for the group aged <20 years. With the addition of 4 years of mortality data (2007-2010) compared with the data from 1975 to 2006 reported previously, 1 the best-fitting joinpoint model contained a new joinpoint segment. The new segment corresponded with a period of stable mortality rates from 1998 to 2002 (APC, 0.3) that was followed by a period of more pronounced decreasing rates from 2002 to 2010 (APC, 22.4; P.05) (Fig. 2). When we separately analyzed leukemias and lymphomas compared with other cancers (solid tumors and brain cancers), distinctive patterns of declining mortality rates were observed (Fig. 3). For leukemias and lymphomas, the APC from 1975 to 1999 was 23.7%, a new segment for the period from 1999 to 2002 had near stable mortality (APC, 20.4%), and a third segment from 2002 to 2010 had an APC of 23.7% (identical to that observed for the 1975-1999 period). For all other cancer sites combined, declining rates of various magnitude were observed from 1975 to 1997, followed by a period of near stable mortality from 1997 to 2003 (APC, 0.2%), and then significantly declining rates from 2003 to 2010 (APC, 22%). In analyses of more discrete disease groupings, multiple joinpoints were present for leukemias (in the group ages <20 years), and relatively rapid declines in mortality (from 23.2% to 25%) were identified for the periods from 1975 to 1989, from 1992 to 1998, and from 2001 to 2010 that were interspersed with periods of relatively stable mortality rates from 1989 to 1992 (APC, 20.8%) and from 1998 to 2001 (APC, 11.1%), as indicated in Supporting Table 2 (see online supporting materials). In both Hodgkin lymphoma and NHL (for the group ages <20 years), there were no joinpoints, and the APCs for each exceeded 24% from 1975 to 2010. Among the solid tumors, joinpoints were present for gonadal tumors and bone tumors; and the first joinpoint period extended from 1975 to approximately 1990 for each with APCs of 28.3% and 23.1%, respectively. This period coincided with the time during which cisplatin-based regimens became a component of frontline standard therapy for pediatric germ cell tumors and osteosarcoma; subsequently, declines in mortality were slower for both tumor types (APC, 23.2% and 20.3%, respectively). For kidney tumors (in the group aged <15 years), there were also 2 joinpoint segments, with the first from 1975 to 1992 2500 Cancer August 15, 2014

Childhood & Adolescent Cancer Mortality/Smith et al Figure 2. Age-adjusted mortality trends are illustrated for all malignant cancers among children aged <20 years in the United States from 1975 through 2010 along with the annual percentage change (APC) for joinpoint segments and the estimated number of deaths averted per year. An asterisk indicates that the slope of the joinpoint segment is statistically different from zero (P <.05). CI indicates confidence interval. exhibiting a more rapid decline (APC, 23.9%) than the latter from 1992 to 2010 (APC, 21.3%). For some other solid tumors, there were significant declines in mortality rates from 1975 to 2010, but without joinpoints, including: neuroblastoma (in the group aged <15 years: APC, 21.8%), brain tumors (APC, 21.1%), and liver tumors (APC, 21.1%). Soft tissue cancers declined significantly during the period from 1979 to 2010 (APC, 21%). We also determined the number of deaths averted as a result of advances in treatment for children with cancer since 1975. Assuming that the 1975 baseline persisted, an estimated 47,871 childhood malignant cancer deaths were averted from 1975 through 2010, with more than 2300 cancer deaths averted in 2010 (Fig. 2). Twenty-six percent of the averted deaths were for the population ages 15 to 19 years. Survival Correlates of Declines In Mortality The 5-year survival rate increased to 83% or 84% for all groups (aged <20 years) from 2003 to 2007 (Fig. 4). For ALL, the 5-year survival rate among children aged <15 years increased to 91%, whereas the rate increased to 78% among those ages 15 to 19 years (Fig. 5). Even when patients with ALL were excluded from the survival analyses, the 5-year survival rate remained above 80% (82% for all groups aged <20 years). For AML, the survival rates increased to 68% for children aged <15 years and to 57% for those ages 15 to 19 years; whereas, for Hodgkin lymphoma, the 5-year survival rates were 98% and 97%, respectively, in those age cohorts. For NHL, the 5-year survival rate exceeded 80% for all age groups (Fig. 5). For solid tumors, the 5-year survival rates were approximately 90% or greater for Wilms tumor, neuroblastoma (in children aged <1 year), and germ cell tumors, as indicated in Supporting Figure 1 (see online supporting information). For neuroblastoma in children aged >1year, the 5-year survival rate increased to 68%. Supporting Figures 2 and 3 provide 5-year survival rates for the periods from 1975 to 1978 through 2003 to 2007 for central nervous system tumors and sarcomas (bone and soft tissue), respectively, with 5-year survival rates for 2003 to 2007 ranging between 51% and 79% depending upon age and tumor type. (see online supporting information). DISCUSSION The significant decline in childhood and adolescent cancer mortality in the early years of the 21st century is reassuring in light of concerns that childhood cancer mortality rates had plateaued after decades of consistent decline. 1,2 Our report documents a plateau in mortality rates from 1998 to 2002, which we interpret as reflecting a period of several years in which more effective treatments were not identified or broadly adopted for Cancer August 15, 2014 2501

Figure 3. Age-adjusted mortality trends are illustrated for all malignant cancers among children aged <20 years in the United States from 1975 through 2010 along with annual percentage changes (APCs) for joinpoint segments. An asterisk indicates that the slope of the joinpoint segment is statistically different from zero (P <.05). The green line indicates leukemias and lymphomas, and the blue line indicates all other cancer sites. CI indicates confidence interval. childhood cancers. The more recent results highlight both the importance of advances in pediatric oncology research during the past 10 to 15 years and areas of limited progress in which paradigm-shifting therapies are critically needed for future progress to occur. The declines in mortality cannot be explained by reduced incidence of childhood cancer during this period, because the incidence of childhood cancers trended upward from 2000 to 2010, as indicated in Supporting Figure 4 (see online supporting information). Stiller et al noted that, although the diffusion of breakthrough developments in the treatment of adult cancers can take an extended period, the diffusion of improved treatment regimens occurs quickly for childhood cancers. 5 This results in part from the widespread participation of children in clinical trials developed by experts in which the control arm represents the best available therapy. In addition, children who are not enrolled in clinical trials are likely to be treated the same as the control arm of the current (or most recent) clinical trial. The improved outcome for children with ALL likely illustrates this effect, because discoveries from Children s Oncology Group (COG) clinical trials in the late 1990s identified more effective treatment regimens, which, in turn, became control arms for clinical trials during the period from 2000 through 2010. These advances included the use of postinduction treatment with intensified courses of methotrexate and asparaginase as well as the use of dexamethasone throughout therapy for children aged <10 years. 6-8 Further advances through COG clinical trials in the past decade included a determination that high-dose methotrexate is more effective than an alternative method of methotrexate administration for children with highrisk, B-precursor ALL. 9 In addition, the AALL0031 COG clinical trial conducted from 2002 to 2006 and first reported in 2007 demonstrated that the Bcr-Abl inhibitor, 2502 Cancer August 15, 2014

Childhood & Adolescent Cancer Mortality/Smith et al Figure 4. Five-year relative survival is illustrated for all malignant cancers combined among children and adolescents who were ages birth to 4 years, 5 to 14 years, and 15 to 19 years at diagnosis in the Surveillance, Epidemiology, and End Results (SEER) 9 registries during the 4-year periods from 1975 to 1978 and from 2003 to 2007 who had follow-up through 2010. imatinib, markedly improves outcome when added to standard chemotherapy for children with Philadelphia chromosome-positive ALL. 10,11 For solid tumors, a COG phase 3 trial determined that dose-intensification through interval compression improves outcome for patients with Ewing sarcoma, which may have contributed to the nominal decline in mortality for bone tumors from 2000 to 2010. 12 There have been concerns that the improvements in outcome observed for many childhood cancers have not been observed for adolescents or young adults with cancer. 13 The results we report here indicate that, from 2000 to 2010, mortality rates among adolescents with cancer decreased in a manner similar to that observed among children aged <15 years. It is particularly noteworthy that adolescents with ALL had a greater decline in mortality compared with children aged <15 years. It is likely that broader acceptance of the improved efficacy of pediatric-based treatment approaches compared with adult-based treatment regimens for ALL played a role in this improvement. 14,15 There are clear opportunities for further declines in mortality for ALL, AML, NHL, and Hodgkin lymphoma based on highly active agents in development for these diagnoses. For ALL, antibody-based therapies such as blinatumomab, inotuzumab ozogamicin, and SAR3419 are under development for adult leukemias and lymphomas and have the potential for producing high-level activity in pediatric ALL. 16 For AML, COG initiated a clinical trial in 2009 combining arsenic trioxide with tretinoin for newly diagnosed acute promyelocytic leukemia; and, based on adult studies with this combination, it is likely that treatment failure will be reduced to a very small percentage of patients who achieve remission. 17,18 For anaplastic large cell lymphoma, both crizotinib and brentuximab vedotin have produced objective response rates in relapsed=refractory patients well above 50%. 19,20 Incorporating 1 or both of these agents into standard frontline chemotherapy for anaplastic large cell lymphoma (which is effective for approximately 70% of newly diagnosed patients) has the potential to further improve outcome. Reliably identifying the effectiveness of these novel agents will require well designed clinical trials that are implemented expeditiously and supported enthusiastically by the pediatric oncology research community. Whereas opportunities for improving outcome are readily apparent for the hematologic malignancies, they are less apparent for solid tumors, although there are exceptions. For neuroblastoma, the observation that disialoganglioside 2 (GD2)-targeted chimeric monoclonal antibody 14.18 (ch14.18) improved the outcome of children with these tumors suggests that declines in neuroblastoma mortality can be anticipated as the impact of widespread use of ch14.18 for high-risk neuroblastoma is realized. 21 Developing novel immunotherapy approaches is an important line of future research for childhood solid tumors and brain tumors. 22-24 Cancer August 15, 2014 2503

Figure 5. Five-year relative survival is illustrated for hematopoietic cancers, including (A) acute lymphoblastic leukemia, (B) acute myeloid leukemia, (C) non-hodgkin lymphoma, and (D) Hodgkin lymphoma, among children who were ages <15 years and 15 to 19 years at diagnosis in the Surveillance, Epidemiology, and End Results (SEER) 9 registries from 1975 to 1978 and from 2003 to 2007 who had follow-up through 2010. For childhood and adolescent solid tumors and brain cancers, large-scale genomic studies are being conducted in part with the goal of identifying actionable, recurring mutations for specific cancers that can be used to guide future clinical research for these cancers. However, to date, few such mutations have been identified. There are exceptions to this generalization, such as the presence of activating v-raf murine sarcoma viral oncogene homolog B (BRAF) fusion genes and point mutations in children with low-grade gliomas. 25-27 However, the paucity of recurring mutations in kinase genes and other actionable genes means that many of the kinase inhibitors and other targeted agents that are being developed for adult cancers may have a limited role for most pediatric cancers. Furthermore, the emerging results from genomic studies highlight the distinctive molecular characteristics of childhood cancers compared with adult cancers, as illustrated by the differing mutations that are identified in adult and pediatric highgrade gliomas as well as the chromosomal translocations specific for pediatric sarcomas. 28-32 Given the distinctive genomic alterations associated with many childhood cancers compared with adult cancers, it will be increasingly important to identify and develop agents that are able to selectively block the oncogenic activity of these unique childhood cancer therapeutic targets. The development of ch14.18 for neuroblastoma, which is now moving toward regulatory approval, may provide a blueprint for how such agents can be developed. 21 In addition, recent legislative initiatives such as the Creating Hope Act may stimulate the development of childhood cancer-specific agents by providing an incentive to industry by issuing transferrable, high-priority review vouchers when drugs are developed for specific, rare pediatric diseases, including cancers. 33 More generally regarding the role of the US Food and Drug Administration, provisions of the 2012 US Food and Drug Administration Safety and Innovation Act, including permanent reauthorization of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, have the potential to accelerate the evaluation of new 2504 Cancer August 15, 2014

Childhood & Adolescent Cancer Mortality/Smith et al therapies for childhood cancers, because there is now a requirement to consider and discuss pediatric development plans at end of phase 2 meetings for new agents under development for adult malignancies. This should lead to the generation and submission of written requests for pediatric evaluations at an earlier point in the drugdevelopment timeline. Reducing childhood cancer mortality is not the sole goal of childhood cancer research, because this goal must be accomplished within the context of high-quality-of-life opportunities for survivors. Some progress has been made in improving the quality of survivorship, including the omission of cranial radiation for most children with ALL, reductions in the cumulative anthracycline dose for some cancers, the use of cardioprotectants to reduce long-term cardiac toxicity, and reductions in radiation dose and field volume for some lymphomas and solid tumors. That said, some children continue to receive treatments that are known to induce cognitive impairment, ototoxicity, and bone damage; impair fertility; and cause other long-term, deleterious effects. Thus, as curative treatments are identified for more and more children and adolescents, continued research is essential to refine treatments, reduce the long-term burden of therapy, and monitor survivors for long-term sequelae of their cancer therapy. In conclusion, significant declines in childhood cancer mortality occurred in the first decade of the 21st century across the pediatric age spectrum. However, the acute and long-term burdens of cancer therapy remain high for some children who are cured of their cancer, and many challenges remain to more effectively treat those cancers for which current frontline therapy is not adequate. These remaining challenges highlight the importance of continued cooperative research activities to identify more effective treatments that provide cure and high-quality survival for all children with cancer. FUNDING SUPPORT This work was supported by a grant from the National Cancer Institute (U10CA98543) to Dr. Adamson. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. REFERENCES 1. Smith MA, Seibel NL, Altekruse SF, et al. Outcomes for children and adolescents with cancer: challenges for the 21st century. J Clin Oncol. 2010;28:2625-2634. 2. Pritchard-Jones K, Pieters R, Reaman GH, et al. Sustaining innovation and improvement in the treatment of childhood cancer: lessons from high-income countries [serial online]. Lancet Oncol. 2013;14: e95-e103. 3. National Cancer Institute;Surveillance, Epidemiology, and End Results (SEER) Population Estimates Used in NCI s SEER*Stat Software. Available at: http:==seer.cancer.gov=popdata=methods. html. 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