Abstract

Background

Advances in the treatment of childhood hematologic malignancies have led to improvements in survival for several of these conditions during the past few decades, but most population-based survival data available to date refer only to patients diagnosed up to the mid-1990s.

Methods

We used period analysis to assess trends in 5- and 10-year survival in US patients younger than 15 years of age at diagnosis with four hematologic malignancies—acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma—over three recent 5-year intervals, 1990–1994, 1995–1999, and 2000–2004, using data on a total of 6957 patients from the Surveillance, Epidemiology, and End Results database. Expected survival for 2005–2009 was estimated by modeling from trends in the preceding intervals.

Results

Major improvements in 5- and 10-year relative survival between 1990–1994 and 2000–2004 were seen for acute lymphoblastic leukemia (from 80.2% to 87.5% and from 73.4% to 83.8%, respectively), acute non-lymphoblastic leukemia (from 41.9% to 59.9% and from 38.7% to 59.1%, respectively), and non-Hodgkin lymphoma (from 76.6% to 87.7% and from 73.0% to 86.9%, respectively). For those diagnosed with Hodgkin lymphoma, 5- and 10-year survival rates for the 1990–1994 period were 96.1% and 94.4%, respectively, and these rates did not change substantially in the later time periods. Projected 10-year survival rates for children diagnosed in the 2005–2009 period were 88.0% for acute lymphoblastic leukemia, 63.9% for acute non-lymphoblastic leukemia, 90.6% for non-Hodgkin lymphoma, and 94.3% for Hodgkin lymphoma.

Conclusions

Application of period analysis to a population-based study of childhood hematologic malignancies reveals ongoing increases in survival for three of the four common childhood hematologic malignancies.

Context and Caveats
Prior knowledge

The available estimates of long-term survival for survivors of childhood hematologic malignancies are based on data from children who were diagnosed in the early and mid-1990s and thus may not reflect the possible impact of recent advances in treatment on survival.

Study design

A period analysis of 5- and 10-year survival probabilities for US children diagnosed before the age of 15 years with acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma diagnosed during three recent 5-year intervals—1990–1994, 1995–1999, and 2000–2004—based on Surveillance, Epidemiology, and End Results data for 6957 patients.

Contribution

Both 5- and 10-year survival of children diagnosed with acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, and non-Hodgkin lymphoma have improved from the 1990–1994 period to the 2000–2004 period. The 5- and 10-year survival rates for children diagnosed with Hodgkin lymphoma during the 1990–1994 period (96.1% and 94.4%, respectively) did not change substantially in the later time periods.

Implications

Improvements in survival in childhood hematologic malignancies are most likely attributable to changes in how these diseases are treated. The timely disclosure of these improvements may encourage compliance with available and effective therapies.

Limitations

The 95% confidence intervals for some survival estimates were wide. Even with period analysis, the estimates of survival for the 2000–2004 period tend to underestimate the survival of newly diagnosed patients.

From the Editors

Great progress has been made in the treatment of childhood cancers over the past several decades ( 1–3 ). However, childhood hematologic malignancies continue to claim a substantial number of lives, and, in some cases, treatment-related morbidity is considerable ( 2 , 4 , 5 ). The available estimates of long-term survival for survivors of childhood hematologic malignancies are based on data from children who were diagnosed in the early and mid-1990s ( 6–9 ) and thus may not reflect the possible impact of recent advances in the standards of care on survival. In this article, we used period analysis ( 10 , 11 ) to examine recent changes in 5- and 10-year survival probabilities for children diagnosed before the age of 15 years with acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma.

Methods

We used data that were extracted from the 9-registries limited-use database of the Surveillence, End Results, and Epidemiology (SEER) Program that was issued in April 2007 and includes records of patients diagnosed from 1973 to 2004 ( 12 ). Data included in the SEER 9 registries database are from population-based cancer registries in Connecticut, New Mexico, Utah, Iowa, Hawaii, Atlanta, Detroit, Seattle–Puget Sound, and San Francisco–Oakland, which together cover a population of approximately 30 million people. The SEER 9 registries population is comparable to the general United States population except that it is more urban and has a higher proportion of foreign-born persons. The SEER Program registries routinely collect data on patient demographics, primary tumor site, tumor morphology and stage at diagnosis, the first course of treatment, and follow-up for vital status (through linkage with the National Death Index data from the National Center for Health Statistics). The SEER Program is considered the standard for quality among cancer registries around the world. Quality control has been an integral part of SEER since its inception. Every year, studies are conducted in SEER areas to evaluate the quality and completeness of the data being reported.

For this analysis, we included 6957 patients who were younger than 15 years at first diagnosis of an acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma between 1980 and 2004 that was reported to a population-based SEER Program registry; had no prior malignancy; and were followed up for vital status until December 31, 2004. Patients whose cancer was diagnosed by autopsy (n = 6) or reported only on a death certificate (n = 6) were excluded, leaving 6945 patients (99.8%) for the analysis.

We calculated 5- and 10-year survival for three calendar periods―1990–1994, 1995–1999, and 2000–2004―using the period analysis method ( 10 , 13 ); 95% confidence intervals (CIs) were calculated as described by Rothman ( 14 ), using Greenwood's ( 15 ) variance equation. We also tested the statistical significance of trends in 5- and 10-year year survival between the earliest and the latest of these calendar periods (ie, 1990–1994 and 2002–2004, respectively) by using a modeling approach that was described by Brenner and Hakulinen ( 11 ). Survival was analyzed overall and according to sex. Due to case number limitations, age-specific analyses were performed for children with acute lymphoblastic leukemia only.

Briefly, period analysis consists of restricting the analysis to survival during a period of interest, which is achieved by left truncation of observations at the beginning of the period and right censoring of observations at the end of the study period. In this analysis, survival was monitored in 5-year periods of follow-up rather than in 5-year cohorts of patients (ie, patients diagnosed in defined 5-year periods). For example, a period estimate of 10-year survival for 2000–2004 using follow-up data available up to the year 2004 exclusively reflects the survival experience between 2000 and 2004, as shown in Figure 1 (solid frame). With this approach, the survival experience during the early years of follow-up, which is when most cancer-related deaths occur, is derived exclusively from patients who were diagnosed more recently. By contrast, the most up-to-date estimate of 10-year survival obtained by traditional “cohort analysis” would reflect survival experience of patients who were diagnosed and treated 10 years earlier, that is, between 1990 and 1994 ( Figure 1 , dashed frame).

Figure 1

Comparison of the principle of period analysis vs traditional cohort analysis. The solid frame shows the data used to estimate 10-year survival for the 2000–2004 period using period analysis. The dashed frame shows the data used to derive the most up-to-date estimate of 10-year survival from the same database (pertaining to the 1990–1994 cohort) using traditional cohort analysis. The numbers within the cells indicate the number of years of follow-up since diagnosis. For example, for patients diagnosed in 1991, the first year of follow-up is spread over the years 1991 and 1992, the second year of follow-up is spread over the years 1992 and 1993, and so on.

Figure 1

Comparison of the principle of period analysis vs traditional cohort analysis. The solid frame shows the data used to estimate 10-year survival for the 2000–2004 period using period analysis. The dashed frame shows the data used to derive the most up-to-date estimate of 10-year survival from the same database (pertaining to the 1990–1994 cohort) using traditional cohort analysis. The numbers within the cells indicate the number of years of follow-up since diagnosis. For example, for patients diagnosed in 1991, the first year of follow-up is spread over the years 1991 and 1992, the second year of follow-up is spread over the years 1992 and 1993, and so on.

Extensive empiric evaluation has shown that period analysis provides more up-to-date long-term survival estimates than cohort-based survival analysis and predicts long-term survival expectations of cancer patients diagnosed within the period of interest quite well ( 16–18 ). The 10-year period survival estimate for the 2000–2004 period quantifies the expected survival for patients who were diagnosed between 2000 and 2004, assuming that conditional survival in each year of follow-up remains at the level observed in the 2000–2004 period. To the degree that these conditional survival rates improve over time, even period estimates may underestimate the survival expectations of patients diagnosed in 2000–2004, albeit to a much lesser degree than traditional cohort survival analysis.

We also derived survival projections for the 2005–2009 period by using a novel modeling approach ( 19 ). First, we calculated the number of patients at risk and the number of deaths by year of follow-up for each of the three preceding 5-year periods (1990–1994, 1995–1999, and 2000–2004), just as we did in the conventional period analysis. Next, we estimated and tested for survival trends between the 1990–1994 period and the 2000–2004 period and used those estimates to project survival for the 2005–2009 period by using a previously described and validated ( 19 ) Poisson regression model. Briefly, the number of deaths for each combination of 5-year calendar period and year of follow-up was modeled as a function of the calendar period and the year of follow-up. On the basis of this model, we calculated the projected numbers of deaths and the conditional survival probabilities for each year of follow-up in the 2005–2009 period by assuming that the linear trend in estimated survival parameters from the 1990–1994 period to the 2000–2004 period would prevail and that the pattern of follow-up year–specific survival would remain otherwise unchanged. The model-based period estimates of 5- and 10-year survival for the 2005–2009 period were then calculated as the product of these conditional survival probabilities.

We also estimated 25-year survival curves in the 2000–2004 period for children with hematologic malignancies to address concerns about the potential long-term effects of novel effective treatment regimens. All analyses were performed using SAS statistical software, version 9.1 (SAS Institute, Cary, NC) and used adapted versions of previously described macros for conventional ( 16 ) and modeled ( 19 ) period analysis.

Results

The number of children aged 15 years or younger who were diagnosed with leukemia or lymphoma between the 1990–1994 and 2000–2004 time periods is shown in Table 1 . From 1990 to 2004, the number of children diagnosed with leukemia increased by more than 10%, from 1119 in the 1990–1994 period to 1259 in the 2000–2004 period. The number of children diagnosed with non-Hodgkin lymphoma increased by more than 50%, from 126 in the 1990–1994 period to 191 in the 2000–2004 period. No major change was seen in the numbers of children diagnosed with Hodgkin lymphoma.

Table 1

Numbers of children diagnosed with lymphomas and leukemias included in the analysis by 5-year period of diagnosis, SEER 9 registries database, 1990–2004 *

   Year of diagnosis
 
 
Sex  Type of malignancy † 1990–1994 1995–1999 2000–2004 Total (1990–2004) 
Both ALL, all ages at diagnosis 866 1004 985 2855 
     0–2 y at diagnosis 196 182 205 583 
     3–4 y at diagnosis 286 349 321 956 
     5–9 y at diagnosis 268 336 309 913 
     10–14 y at diagnosis 116 137 150 403 
 ANLL 176 193 191 560 
 All forms of leukemia 1119 1244 1259 3622 
 HL 128 117 132 377 
 NHL 126 136 191 453 
 All forms of lymphoma 330 326 389 1045 
Male ALL 471 571 535 1577 
 ANLL 91 103 115 309 
 All forms of leukemia 607 700 697 2004 
 HL 73 63 83 219 
 NHL 84 98 112 294 
 All forms of lymphoma 218 222 247 687 
Female ALL 395 433 450 1278 
 ANLL 85 90 76 251 
 All forms of leukemia 512 544 562 1618 
 HL 55 54 49 158 
 NHL 42 38 79 159 
 All forms of lymphoma 112 104 142 358 
   Year of diagnosis
 
 
Sex  Type of malignancy † 1990–1994 1995–1999 2000–2004 Total (1990–2004) 
Both ALL, all ages at diagnosis 866 1004 985 2855 
     0–2 y at diagnosis 196 182 205 583 
     3–4 y at diagnosis 286 349 321 956 
     5–9 y at diagnosis 268 336 309 913 
     10–14 y at diagnosis 116 137 150 403 
 ANLL 176 193 191 560 
 All forms of leukemia 1119 1244 1259 3622 
 HL 128 117 132 377 
 NHL 126 136 191 453 
 All forms of lymphoma 330 326 389 1045 
Male ALL 471 571 535 1577 
 ANLL 91 103 115 309 
 All forms of leukemia 607 700 697 2004 
 HL 73 63 83 219 
 NHL 84 98 112 294 
 All forms of lymphoma 218 222 247 687 
Female ALL 395 433 450 1278 
 ANLL 85 90 76 251 
 All forms of leukemia 512 544 562 1618 
 HL 55 54 49 158 
 NHL 42 38 79 159 
 All forms of lymphoma 112 104 142 358 
*

SEER = Surveillance, Epidemiology, and End Results Program; ALL = acute lymphoblastic leukemia; ANLL = acute non-lymphoblastic leukemia; HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma.

Coded according to SEER modification of the International Classification of Childhood Cancer ( 35 ). All forms of leukemia and of lymphoma include other and undefined forms of leukemias and lymphomas, respectively.

We detected statistically significant increases in 5- and 10-year survival for children with acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, and non-Hodgkin lymphoma between the 1990–1994 and 2000–2004 time periods ( Tables 2 and 3 ). For those diagnosed with acute lymphoblastic leukemia, 5-year survival increased from 80.2% to 87.5% and 10-year survival increased from 73.4% to 83.8% ( Ptrend < .001 in both cases). Because the absolute increase in 10-year survival was greater than for 5-year survival (+10.4 vs +7.3 percentage points, respectively), the difference between the 5- and 10-year estimates for children diagnosed with acute lymphoblastic leukemia was less in the 2000–2004 period (4.2%) than in the 1990–1994 period (6.8%). The increase in both 5- and 10-year survival from the 1990–1994 period to the 2000–2004 period was greatest for children who were 10–14 years old at diagnosis and who traditionally have a poorer prognosis. Thus, the survival disadvantage of patients in this age group compared with patients in the other age groups diminished. For the other hematologic malignancies, case numbers were too small to derive age-specific survival estimates with reasonable precision; see also Methods. For children diagnosed with acute non-lymphoblastic leukemia, 5-year survival increased by 18 percentage points, from 41.9% in the 1990–1994 period to 59.9% in the 2000–2004 period ( Ptrend < .001), and 10-year survival increased by 20.4 percentage points, from 38.7% to 59.1% ( Ptrend < .001). For children diagnosed with any type of leukemia, 5-year survival increased from 73.0% to 82.5% and 10-year survival increased from 66.8% to 79.4% ( Ptrend < .001 for both). Substantial increases in survival were also seen for those diagnosed with non-Hodgkin lymphoma: 5-year survival increased by 11.1 percentage points, from 76.6% to 87.7%, and 10-year survival increased by 13.9 percentage points, from 73.0% to 86.9% ( Ptrend = .015 and Ptrend = .005, respectively). For those diagnosed with Hodgkin lymphoma, 5- and 10-year survival for the 1990–1994 period were already as high as 96.1% and 94.4%, respectively, and did not change substantially in the later time periods. In the 2000–2004 period, 5- and 10-year survival were both 95.4%, that is, not a single death occurred among children diagnosed with Hodgkin lymphoma between 5 and 10 years after diagnosis. When all lymphomas were considered together, 5-year survival increased from 84.7% to 91.0% ( Ptrend = .01) and 10-year survival increased from 82.6% to 89.9% ( Ptrend = .006) between the 1990–1994 period and the 2000–2004 period.

Table 2

Trends in 5-year survival from the1990–1994 period to the 2000–2004 period and projected 5-year survival for the 2005–2009 period *

   Period estimate of 5-year survival, % (95% CI)
 
   Projected 5-year survival, % (95% CI)
 
Sex  Type of malignancy † 1990–1994 1995–1999 2000–2004  Difference ‡ Ptrend§ 2005–2009 
Both ALL, all ages at   diagnosis (y) 80.2 (77.5 to 82.6) 85.5 (83.0 to 87.7) 87.5 (85.2 to 89.5) +7.3 <.001 90.6 (88.0 to 92.7) 
     0–2 y at diagnosis 77.8 (71.4 to 83.1) 84.9 (79.1 to 89.3) 85.8 (80.0 to 90.2) +8.0 .04 89.5 (82.4 to 93.9) 
     3–4 y at diagnosis 86.7 (82.0 to 90.3) 89.1 (85.1 to 92.1) 92.7 (89.2 to 95.1) +6.0 .02 94.4 (90.4 to 96.8) 
     5–9 y at diagnosis 79.9 (75.0 to 84.0) 85.1 (80.3 to 88.9) 86.2 (82.1 to 89.5) +6.3 .02 89.4 (84.0 to 93.1) 
     10–14 y at diagnosis 68.4 (59.1 to 76.4) 77.5 (69.5 to 83.9) 80.7 (73.2 to 86.5) +12.3 .03 85.6 (76.3 to 91.6) 
 ANLL 41.9 (34.5 to 49.6) 44.8 (37.5 to 52.3) 59.9 (52.5 to 66.9) +18.0 <.001 64.8 (55.2 to 73.3) 
 All forms of leukemia 73.0 (70.4 to 75.5) 78.8 (76.4 to 81.1) 82.5 (80.2 to 84.6) +9.5 <.001 86.3 (83.6 to 88.7) 
 HL 96.1 (91.2 to 98.3) 93.2 (87.2 to 96.5) 95.4 (90.5 to 97.8) −0.7 .80 94.2 (84.1 to 98.0) 
 NHL 76.6 (68.4 to 83.2) 82.6 (75.2 to 88.1) 87.7 (82.0 to 91.8) +11.1 .02 90.8 (83.8 to 95.0) 
 All forms of lymphoma 84.7 (80.4 to 88.2) 86.6 (82.4 to 89.9) 91.0 (87.6 to 93.5) +6.3 .01 92.6 (88.5 to 95.3) 
Male ALL 79.4 (75.7 to 82.7) 84.5 (81.1 to 87.4) 87.0 (83.8 to 89.7) +7.6 .001 90.0 (86.2 to 92.9) 
 ANLL 38.3 (22.7 to 50.2) 47.6 (37.7 to 57.7) 57.1 (47.4 to 66.3) +18.8 .02 64.0 (50.9 to 75.3) 
 All forms of leukemia 71.9 (68.2 to 75.3) 78.5 (75.2 to 81.5) 81.0 (77.9 to 83.8) +9.1 .001 85.1 (81.2 to 88.3) 
 HL 96.2 (89.2 to 98.7) 93.6 (84.7 to 97.5) 93.8 (86.2 to 97.3) −2.4 .50 91.5 (74.3 to 97.6) 
 NHL 79.7 (69.6 to 87.1) 81.9 (72.8 to 88.4) 87.3 (79.7 to 92.3) +7.6 .17 89.2 (78.9 to 94.8) 
 All forms of lymphoma 85.0 (79.7 to 89.1) 87.0 (81.8 to 90.9) 91.1 (86.9 to 94.0) +6.1 .04 92.8 (87.5 to 95.9) 
Female ALL 81.1 (76.9 to 84.7) 86.8 (83.1 to 89.8) 88.2 (84.7 to 91.0) +7.1 .004 91.2 (87.0 to 94.1) 
 ANLL 45.1 (35.1 to 55.5) 41.4 (31.4 to 52.1) 63.7 (52.1 to 73.9) +18.6 .02 65.9 (51.4 to 77.9) 
 All forms of leukemia 74.3 (70.4 to 77.8) 79.1 (75.4 to 82.4) 84.4 (81.0 to 87.3) +10.1 <.001 87.8 (83.8 to 90.9) 
 HL 95.9 (85.9 to 98.9) 92.7 (82.7 to 97.1) 97.9 (89.5 to 99.6) +2.0 .58 97.3 (84.7 to 99.6) 
 NHL 71.0 (56.4 to 82.2) 84.8 (70.6 to 92.8) 88.5 (78.7 to 94.1) +17.5 .03 93.1 (82.5 to 97.5) 
 All forms of lymphoma 84.1 (76.1 to 89.8) 86.1 (78.4 to 91.4) 90.9 (84.8 to 94.7) +6.8 .15 92.3 (83.9 to 96.5) 
   Period estimate of 5-year survival, % (95% CI)
 
   Projected 5-year survival, % (95% CI)
 
Sex  Type of malignancy † 1990–1994 1995–1999 2000–2004  Difference ‡ Ptrend§ 2005–2009 
Both ALL, all ages at   diagnosis (y) 80.2 (77.5 to 82.6) 85.5 (83.0 to 87.7) 87.5 (85.2 to 89.5) +7.3 <.001 90.6 (88.0 to 92.7) 
     0–2 y at diagnosis 77.8 (71.4 to 83.1) 84.9 (79.1 to 89.3) 85.8 (80.0 to 90.2) +8.0 .04 89.5 (82.4 to 93.9) 
     3–4 y at diagnosis 86.7 (82.0 to 90.3) 89.1 (85.1 to 92.1) 92.7 (89.2 to 95.1) +6.0 .02 94.4 (90.4 to 96.8) 
     5–9 y at diagnosis 79.9 (75.0 to 84.0) 85.1 (80.3 to 88.9) 86.2 (82.1 to 89.5) +6.3 .02 89.4 (84.0 to 93.1) 
     10–14 y at diagnosis 68.4 (59.1 to 76.4) 77.5 (69.5 to 83.9) 80.7 (73.2 to 86.5) +12.3 .03 85.6 (76.3 to 91.6) 
 ANLL 41.9 (34.5 to 49.6) 44.8 (37.5 to 52.3) 59.9 (52.5 to 66.9) +18.0 <.001 64.8 (55.2 to 73.3) 
 All forms of leukemia 73.0 (70.4 to 75.5) 78.8 (76.4 to 81.1) 82.5 (80.2 to 84.6) +9.5 <.001 86.3 (83.6 to 88.7) 
 HL 96.1 (91.2 to 98.3) 93.2 (87.2 to 96.5) 95.4 (90.5 to 97.8) −0.7 .80 94.2 (84.1 to 98.0) 
 NHL 76.6 (68.4 to 83.2) 82.6 (75.2 to 88.1) 87.7 (82.0 to 91.8) +11.1 .02 90.8 (83.8 to 95.0) 
 All forms of lymphoma 84.7 (80.4 to 88.2) 86.6 (82.4 to 89.9) 91.0 (87.6 to 93.5) +6.3 .01 92.6 (88.5 to 95.3) 
Male ALL 79.4 (75.7 to 82.7) 84.5 (81.1 to 87.4) 87.0 (83.8 to 89.7) +7.6 .001 90.0 (86.2 to 92.9) 
 ANLL 38.3 (22.7 to 50.2) 47.6 (37.7 to 57.7) 57.1 (47.4 to 66.3) +18.8 .02 64.0 (50.9 to 75.3) 
 All forms of leukemia 71.9 (68.2 to 75.3) 78.5 (75.2 to 81.5) 81.0 (77.9 to 83.8) +9.1 .001 85.1 (81.2 to 88.3) 
 HL 96.2 (89.2 to 98.7) 93.6 (84.7 to 97.5) 93.8 (86.2 to 97.3) −2.4 .50 91.5 (74.3 to 97.6) 
 NHL 79.7 (69.6 to 87.1) 81.9 (72.8 to 88.4) 87.3 (79.7 to 92.3) +7.6 .17 89.2 (78.9 to 94.8) 
 All forms of lymphoma 85.0 (79.7 to 89.1) 87.0 (81.8 to 90.9) 91.1 (86.9 to 94.0) +6.1 .04 92.8 (87.5 to 95.9) 
Female ALL 81.1 (76.9 to 84.7) 86.8 (83.1 to 89.8) 88.2 (84.7 to 91.0) +7.1 .004 91.2 (87.0 to 94.1) 
 ANLL 45.1 (35.1 to 55.5) 41.4 (31.4 to 52.1) 63.7 (52.1 to 73.9) +18.6 .02 65.9 (51.4 to 77.9) 
 All forms of leukemia 74.3 (70.4 to 77.8) 79.1 (75.4 to 82.4) 84.4 (81.0 to 87.3) +10.1 <.001 87.8 (83.8 to 90.9) 
 HL 95.9 (85.9 to 98.9) 92.7 (82.7 to 97.1) 97.9 (89.5 to 99.6) +2.0 .58 97.3 (84.7 to 99.6) 
 NHL 71.0 (56.4 to 82.2) 84.8 (70.6 to 92.8) 88.5 (78.7 to 94.1) +17.5 .03 93.1 (82.5 to 97.5) 
 All forms of lymphoma 84.1 (76.1 to 89.8) 86.1 (78.4 to 91.4) 90.9 (84.8 to 94.7) +6.8 .15 92.3 (83.9 to 96.5) 
*

CI = confidence interval; ALL = acute lymphoblastic leukemia; ANLL = acute non-lymphoblastic leukemia; HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma.

Coded according to Surveillance, Epidemiology, and End Results Program modification of the International Classification of Childhood Cancer (35).

Difference in survival for 1990–1994 vs 2000–2004.

§

Two-sided P values for trend are from Poisson regression models.

Table 3

Trends in 10-year survival from the1990–1994 period to the 2000–2004 period and projected 10-year survival for the 2005–2009 period *

   Period estimate of 10-year survival, % (95% CI)
 
   Projected 10-year survival, % (95% CI)
 
Sex  Type of malignancy † 1990–1994 1995–1999 2000–2004  Difference ‡ Ptrend§ 2005–2009 
Both ALL, all ages at   diagnosis 73.4 (70.4 to 76.2) 81.0 (78.3 to 83.4) 83.8 (81.3 to 86.0) +10.4 <.001 88.0 (85.0 to 90.5) 
     0–2 y at diagnosis 72.3 (65.4 to 78.3) 80.9 (74.6 to 85.9) 83.4 (77.2 to 88.2) +11.1 .01 87.9 (80.8 to 92.6) 
     3–4 y at diagnosis 80.9 (75.8 to 85.2) 84.9 (80.3 to 88.6) 88.9 (84.9 to 92.0) + 8.0 .006 91.6 (86.8 to 94.8) 
     5–9 y at diagnosis 71.4 (65.8 to 76.4) 80.4 (75.3 to 84.7) 81.4 (76.7 to 85.3) +10.0 .004 86.1 (80.2 to 90.4) 
     10–14 y at diagnosis 61.3 (51.8 to 70.0) 72.3 (63.7 to 79.5) 78.2 (70.4 to 84.4) +16.9 .007 83.9 (74.6 to 90.2) 
 ANLL 38.7 (31.2 to 46.7) 42.7 (35.5 to 50.2) 59.1 (51.7 to 66.1) +20.4 <.001 63.9 (54.1 to 72.6) 
 All forms of leukemia 66.8 (63.8 to 69.7) 74.6 (72.0 to 77.1) 79.4 (77.0 to 81.7) +12.6 <.001 84.1 (81.2 to 86.7) 
 HL 94.4 (88.7 to 97.3) 90.8 (84.4 to 94.7) 95.4 (90.5 to 97.8) +1.0 .79 94.3 (85.3 to 97.9) 
 NHL 73.0 (64.6 to 80.1) 81.7 (74.2 to 87.4) 86.9 (81.0 to 91.2) +13.9 .005 90.6 (83.6 to 94.8) 
 All forms of lymphoma 82.6 (78.1 to 86.3) 85.3 (81.0 to 89.9) 89.9 (86.3 to 92.6) +7.3 .006 91.9 (87.6 to 94.8) 
Male ALL 73.1 (68.8 to 77.0) 78.9 (75.2 to 82.2) 82.8 (79.2 to 85.9) +9.7 <.001 86.6 (82.2 to 90.0) 
 ANLL 35.2 (24.3 to 47.9) 45.2 (34.9 to 56.0) 55.8 (46.2 to 65.0) +20.6 .01 62.7 (49.5 to 74.2) 
 All forms of leukemia 66.0 (62.0 to 69.8) 73.4 (69.7 to 76.8) 77.5 (74.2 to 80.5) +11.5 <.001 82.1 (77.9 to 85.7) 
 HL 93.6 (85.8 to 97.3) 91.1 (81.8 to 95.9) 93.8 (86.2 to 97.3) +0.2 .94 92.4 (77.6 to 97.7) 
 NHL 75.7 (65.0 to 83.9) 81.9 (72.8 to 88.4) 86.1 (78.4 to 91.4) +10.4 .09 89.1 (79.1 to 94.6) 
 All forms of lymphoma 82.5 (76.8 to 87.0) 86.0 (80.6 to 90.1) 89.5 (84.9 to 92.8) +7.0 .03 91.9 (86.2 to 95.4) 
Female ALL 74.0 (69.3 to 78.2) 83.8 (79.7 to 87.2) 85.1 (81.2 to 88.3) +11.1 <.001 89.7 (85.4 to 92.9) 
 ANLL 41.8 (31.8 to 52.5) 39.2 (29.3 to 50.0) 63.7 (52.1 to 73.9) +21.9 .01 65.3 (50.9 to 77.4) 
 All forms of leukemia 67.8 (63.6 to 71.8) 76.1 (72.2 to 79.6) 81.9 (78.3 to 85.0) +14.1 <.001 86.5 (82.3 to 89.8) 
 HL 95.9 (85.9 to 98.9) 90.7 (79.9 to 96.0) 97.9 (89.5 to 99.6) +2.0 .58 96.8 (83.6 to 99.4) 
 NHL 65.8 (49.3 to 79.2) 82.7 (68.2 to 91.4) 88.5 (78.7 to 94.1) +22.7 .01 93.0 (82.5 to 97.4) 
 All forms of lymphoma 82.6 (74.0 to 88.8) 84.1 (76.1 to 89.8) 90.9 (84.8 to 94.7) +8.3 .10 92.1 (83.8 to 96.3) 
   Period estimate of 10-year survival, % (95% CI)
 
   Projected 10-year survival, % (95% CI)
 
Sex  Type of malignancy † 1990–1994 1995–1999 2000–2004  Difference ‡ Ptrend§ 2005–2009 
Both ALL, all ages at   diagnosis 73.4 (70.4 to 76.2) 81.0 (78.3 to 83.4) 83.8 (81.3 to 86.0) +10.4 <.001 88.0 (85.0 to 90.5) 
     0–2 y at diagnosis 72.3 (65.4 to 78.3) 80.9 (74.6 to 85.9) 83.4 (77.2 to 88.2) +11.1 .01 87.9 (80.8 to 92.6) 
     3–4 y at diagnosis 80.9 (75.8 to 85.2) 84.9 (80.3 to 88.6) 88.9 (84.9 to 92.0) + 8.0 .006 91.6 (86.8 to 94.8) 
     5–9 y at diagnosis 71.4 (65.8 to 76.4) 80.4 (75.3 to 84.7) 81.4 (76.7 to 85.3) +10.0 .004 86.1 (80.2 to 90.4) 
     10–14 y at diagnosis 61.3 (51.8 to 70.0) 72.3 (63.7 to 79.5) 78.2 (70.4 to 84.4) +16.9 .007 83.9 (74.6 to 90.2) 
 ANLL 38.7 (31.2 to 46.7) 42.7 (35.5 to 50.2) 59.1 (51.7 to 66.1) +20.4 <.001 63.9 (54.1 to 72.6) 
 All forms of leukemia 66.8 (63.8 to 69.7) 74.6 (72.0 to 77.1) 79.4 (77.0 to 81.7) +12.6 <.001 84.1 (81.2 to 86.7) 
 HL 94.4 (88.7 to 97.3) 90.8 (84.4 to 94.7) 95.4 (90.5 to 97.8) +1.0 .79 94.3 (85.3 to 97.9) 
 NHL 73.0 (64.6 to 80.1) 81.7 (74.2 to 87.4) 86.9 (81.0 to 91.2) +13.9 .005 90.6 (83.6 to 94.8) 
 All forms of lymphoma 82.6 (78.1 to 86.3) 85.3 (81.0 to 89.9) 89.9 (86.3 to 92.6) +7.3 .006 91.9 (87.6 to 94.8) 
Male ALL 73.1 (68.8 to 77.0) 78.9 (75.2 to 82.2) 82.8 (79.2 to 85.9) +9.7 <.001 86.6 (82.2 to 90.0) 
 ANLL 35.2 (24.3 to 47.9) 45.2 (34.9 to 56.0) 55.8 (46.2 to 65.0) +20.6 .01 62.7 (49.5 to 74.2) 
 All forms of leukemia 66.0 (62.0 to 69.8) 73.4 (69.7 to 76.8) 77.5 (74.2 to 80.5) +11.5 <.001 82.1 (77.9 to 85.7) 
 HL 93.6 (85.8 to 97.3) 91.1 (81.8 to 95.9) 93.8 (86.2 to 97.3) +0.2 .94 92.4 (77.6 to 97.7) 
 NHL 75.7 (65.0 to 83.9) 81.9 (72.8 to 88.4) 86.1 (78.4 to 91.4) +10.4 .09 89.1 (79.1 to 94.6) 
 All forms of lymphoma 82.5 (76.8 to 87.0) 86.0 (80.6 to 90.1) 89.5 (84.9 to 92.8) +7.0 .03 91.9 (86.2 to 95.4) 
Female ALL 74.0 (69.3 to 78.2) 83.8 (79.7 to 87.2) 85.1 (81.2 to 88.3) +11.1 <.001 89.7 (85.4 to 92.9) 
 ANLL 41.8 (31.8 to 52.5) 39.2 (29.3 to 50.0) 63.7 (52.1 to 73.9) +21.9 .01 65.3 (50.9 to 77.4) 
 All forms of leukemia 67.8 (63.6 to 71.8) 76.1 (72.2 to 79.6) 81.9 (78.3 to 85.0) +14.1 <.001 86.5 (82.3 to 89.8) 
 HL 95.9 (85.9 to 98.9) 90.7 (79.9 to 96.0) 97.9 (89.5 to 99.6) +2.0 .58 96.8 (83.6 to 99.4) 
 NHL 65.8 (49.3 to 79.2) 82.7 (68.2 to 91.4) 88.5 (78.7 to 94.1) +22.7 .01 93.0 (82.5 to 97.4) 
 All forms of lymphoma 82.6 (74.0 to 88.8) 84.1 (76.1 to 89.8) 90.9 (84.8 to 94.7) +8.3 .10 92.1 (83.8 to 96.3) 
*

CI = confidence interval; ALL = acute lymphoblastic leukemia; ANLL = acute non-lymphoblastic leukemia; HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma.

Coded according to Surveillance, Epidemiology, and End Results Program modification of the International Classification of Childhood Cancer (35).

Difference in survival for 1990–1994 vs 2000–2004.

§

Two-sided P values for trend are from Poisson regression models.

Improvements in survival were observed in both sexes. In most cases, period estimates of survival were higher in girls with leukemia than in boys with leukemia. However, the differences between the period estimates were generally small and the confidence intervals overlapped. In the 2000–2004 period, 85.1% of girls diagnosed with acute lymphoblastic leukemia, 63.7% of girls diagnosed with acute non-lymphoblastic leukemia, and 81.9% of girls diagnosed with any leukemia survived for 10 years ( Table 3 ). Among girls diagnosed with acute non-lymphoblastic leukemia, both 5- and 10-year survival were 63.7% in the 2000–2004 period, that is, not a single death occurred between 5 and 10 years after diagnosis. Estimates of 10-year survival for the 2000–2004 period for boys diagnosed with acute lymphoblastic leukemia and acute non-lympholastic leukemia were 82.8% and 55.8%, respectively. In non-Hodgkin lymphoma, particularly strong improvement in survival was seen in girls: 5-year survival increased from 71.0% in the 1990–1994 period to 88.5% in the 2000–2004 period ( Ptrend = .03) and, in the 2000–2004 period, 10-year survival was identical to 5-year survival ( Tables 2 and 3 ). We also observed an increase in 5-year survival among boys diagnosed with non-Hodgkin lymphoma, from 79.7% in the 1990–1994 period to 87.3% in the 2000–2004 period. However, this increase was not statistically significant ( Ptrend = .17), perhaps because of the relatively small number of cases of this disease among boys ( Table 1 ). Among girls diagnosed with Hodgkin lymphoma, both 5- and 10-year survival were 97.9% in the 2000–2004 period. Both 5- and 10-year survival for girls diagnosed with any lymphoma were 90.9% in the 2000–2004 period.

A more comprehensive picture of survival estimates according to time since diagnosis and calendar period for children diagnosed with acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, and non-Hodgkin lymphoma is shown in Figure 2 . For acute lymphoblastic leukemia, the greatest improvement in survival occurred between the 1990–1994 period and the 1995–1999 period, whereas for acute non-lymphoblastic leukemia most of the dramatic improvement in the survival curves occurred between the 1995–1999 period and the 2000–2004 period. The 2000–2004 survival curves for acute non-lymphoblastic leukemia and non-Hodgkin lymphoma became essentially flat after approximately 5 years after diagnosis.

Figure 2

Ten-year survival curves for children with common hematologic malignancies. Period estimates for calendar periods 1990–1994 (lower solid curve) , 1995–1999 (long-dashed curve) , and 2000–2004 (upper solid curve) and projected survival for calendar period 2005–2009 (short-dashed curve) . The 95% confidence intervals are given in Tables 2 and 3 . ALL = acute lymphoblastic leukemia; ANLL = acute non-lymphoblastic leukemia; NHL = non-Hodgkin lymphoma.

Figure 2

Ten-year survival curves for children with common hematologic malignancies. Period estimates for calendar periods 1990–1994 (lower solid curve) , 1995–1999 (long-dashed curve) , and 2000–2004 (upper solid curve) and projected survival for calendar period 2005–2009 (short-dashed curve) . The 95% confidence intervals are given in Tables 2 and 3 . ALL = acute lymphoblastic leukemia; ANLL = acute non-lymphoblastic leukemia; NHL = non-Hodgkin lymphoma.

Model-based projections of trends in survival observed from the 1990–1994 period to the 2000–2004 period yielded 5-year survival estimates of 90.6%, 64.8%, 94.2%, and 90.8% for children with acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma, respectively, for 2005–2009 and, with the exception of acute lymphoblastic leukemia, almost identical estimates for 10-year survival (88.0%, 63.9%, 94.3%, and 90.6%, respectively) ( Tables 2 and 3 ).

The 25-year survival curves for children diagnosed with four common hematologic malignancies based on period estimates for the 2000–2004 calendar period are shown in Figure 3 . Survival curves continued to decline over the entire 25-year period for all hematologic malignancies. This pattern was most pronounced for Hodgkin lymphoma: despite the much higher survival of children with Hodgkin lymphoma up to 10 years after diagnosis, the 25-year survival of children with Hodgkin lymphoma, acute lymphoblastic leukemia, and non-Hodgkin lymphoma was expected to be about the same, that is, close to 80%.

Figure 3

Twenty-five–year survival curves for children with common hematologic malignancies. Period estimates for the 2000–2004 calendar period. Point estimates for 25-year survival (95% confidence intervals): ALL, 80.0% (77.1% to 82.7%); ANLL, 50.6% (40.9% to 60.3%); HD, 80.9% (73.0% to 87.8%); NHL, 80.4% (72.7% to 87.1%). ALL = acute lymphoblastic leukemia; ANLL = acute non-lymphoblastic leukemia; HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma.

Figure 3

Twenty-five–year survival curves for children with common hematologic malignancies. Period estimates for the 2000–2004 calendar period. Point estimates for 25-year survival (95% confidence intervals): ALL, 80.0% (77.1% to 82.7%); ANLL, 50.6% (40.9% to 60.3%); HD, 80.9% (73.0% to 87.8%); NHL, 80.4% (72.7% to 87.1%). ALL = acute lymphoblastic leukemia; ANLL = acute non-lymphoblastic leukemia; HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma.

Discussion

Our findings indicate that survival of children diagnosed with three of the four most common childhood hematologic malignancies—acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, and non-Hodgkin lymphoma—has further improved from the 1990–1994 period to the 2000–2004 period. In particular, 10-year survival increased by more than 20 percentage points for acute non-lymphoblastic leukemia. Moreover, comparisons of 5- and 10-year survival rates suggest that deaths due to a late relapse of these hematologic malignancies may be decreasing. Projections for the 2005–2009 period suggest that the chances of 10-year survival are close to 90% or higher for children diagnosed with acute lymphoblastic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma and close to 65% for children diagnosed with acute non-lymphoblastic leukemia.

Compared with traditional methods for estimating survival, the period analysis used in this study provides more up-to-date estimates of long-term survival ( 16–18 ). Most recent population-based studies on childhood leukemia and lymphoma incidence and survival have used cohort or complete analysis and presented survival data only up to the mid-1990s ( 6–9 ). For example, in the Automated Childhood Cancer Information System project, 5-year survival of children diagnosed with acute lymphoblastic leukemia and acute non-lymphoblastic leukemia during 1993–1997 was 82% and 53%, respectively, for European registries combined and 87% and 56%, respectively, for Northern Europe, the European region with the highest survival rates ( 6 ). For Hodgkin lymphoma and non-Hodgkin lymphoma, 5-year survival estimates were 95% and 77% for Europe combined and 95% and 83% for western Europe, the European region with the highest lymphoma survival rates ( 7 , 8 ). Our survival estimates for the 1995–1999 period are close to the best European estimates for children diagnosed with acute lymphoblastic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma during 1993–1997. For children diagnosed with acute non-lymphoblastic leukemia, our survival estimates for 1995–1999 were considerably lower than the best European estimates but similar to those for children diagnosed with acute non-lymphoblastic leukemia in Northern and Western Europe in the 1980s ( 6 ). By contrast, our estimates of 5-year survival for the 2000–2004 period exceed the best European estimates for the 1993–1997 period by 4 percentage points. A period analysis of 5- and 10-year survival of children with acute non-lymphoblastic leukemia in Germany for the 1996–1998 period ( 20 ) revealed similar levels of survival to those achieved in the United States in the 2000–2004 period as in our analysis. For acute lymphoblastic leukemia and non-Hodgkin lymphoma, our survival estimates for the 2000–2004 period exceed both the US estimates (as reported herein) and the best European estimates for the 1990s and thereby reveal further improvement in survival from the 1990s to the early 21st century.

To our knowledge, this is the first study to apply a modeled period analysis to project survival estimates for children recently diagnosed with hematologic malignancies. Although projected period estimates of survival are expected to be even more up-to-date than conventional period estimates because they overcome the common delay in availability of cancer registry data ( 19 ), period estimates are statistically less precise and their validity depends on the validity of the underlying assumptions, especially the assumption that previously observed trends will continue. A final judgment of the validity of our projections will only be possible in retrospect a few years from now. However, the model-based projection method has been extensively validated in adult cancer patients, for whom it has been found to provide much better estimates of survival of recently diagnosed patients than all other methods, including conventional period analysis in most cases ( 19 ). To validate the model-based projection approach in childhood hematologic malignancies, we did an analogous projection of survival as shown in this paper for the 2000–2004 period. We then examined the agreement between these projections and the actual period estimates obtained for the 2000–2004 period by “conventional” period analysis. For 17 of the 22 estimates of 5-year survival in 2000–2004 shown in Table 2 , and for 19 of the 22 estimates of 10-year survival shown in Table 3 , the difference between the projected estimates and the actual estimates was smaller than the difference between the 1995–1999 period survival estimates (the most up-to-date conventional period estimates available at the beginning of this century) and the 2000–2004 period survival estimates (data not shown). This finding strongly supports the use of the model-based projection approach for deriving up-to-date survival estimates for children with hematologic malignancies.

With regard to possible reasons for the improved survival of children with hematologic malignancies, there is no evidence that early detection plays a substantial role in improving survival of children with leukemia. Although patients with early-stage lymphoma have better survival than those with late-stage disease, there are no systematic screening programs for lymphoma, and the ability of clinicians to detect lymphoma at early stages has not changed substantially in recent years. Therefore, improvements in survival in childhood hematologic malignancies are most likely attributable to changes in how these diseases are treated.

Much recent research into childhood acute lymphoblastic leukemia has focused on identifying factors associated with the risk of recurrence and ways to decrease the toxic effects of treatment. Four major risk groups have been identified, based on patient and disease characteristics ( 2 ). Having reliable information on the risk of recurrence has allowed for more intensive treatment of some patients with high-risk disease [ie, early postinduction intensification ( 22 )] and, conversely, less intensive—and therefore less toxic—treatment for patients with low-risk disease. One area in which the standard of care has evolved over the past decade is in prophylaxis against leukemic spread into the central nervous system. Previously, all children diagnosed with acute lymphoblastic leukemia received cranial irradiation. However, cranial irradiation is highly toxic to the developing brain and has been found to lead to neurocognitive deficits in children who survived acute lymphoblastic leukemia ( 4 ). Intrathecal chemotherapy is effective in many patients with acute lymphoblastic leukemia and seems to produce fewer long-term neurologic problems than cranial irradiation ( 23 , 24 ). Guidelines for the use of intrathecal chemotherapy have been developed and have spared some patients the toxic effects of cranial irradiation.

Unlike childhood acute lymphoblastic leukemia, childhood acute non-lymphoblastic leukemia is still highly lethal and work in this disease has, necessarily, concentrated on improving survival. Fortunately, our period analysis revealed that attempts to improve survival appear to have been successful. Long-term survival is expected to be greater than 60% for children who are diagnosed with acute non-lymphoblastic leukemia from 2005 through 2009. Reasons for the increased survival include improvements in clinicians’ ability to predict relapse, which has allowed for more tailored treatment. Intensification of therapy for acute non-lymphoblastic leukemia, including the administration of intensive high-dose cytarabine, has led to improvements in survival in childhood acute non-lymphoblastic ( 24 ). In addition, improvements in stem cell transplantation techniques and supportive care have probably played a role in the improvement in survival we observed. Finally, an increasing awareness of the responsiveness of Down syndrome–related acute non-lymphoblastic leukemia to therapy ( 24 ) may have led to better treatment and therefore more long-term survival in this patient group. Down syndome patients are more sensitive to some chemotherapeutic agents and do not, in most cases, benefit from intensive therapy ( 25 ). Thus, improvements in the specific treatment of this patient cohort may have contributed to the overall improvement we observed.

Non-Hodgkin lymphoma is uncommon in children younger than 15 years compared with adults. When non-Hodgkin lymphoma does occur in children, it is almost always of high- or intermediate-grade histology, and the most common histologies are Burkitt lymphoma (35%–40% of childhood cases), diffuse large B-cell lymphoma (15%–20%), lymphoblastic lymphoma (25%–30%), and anaplastic large-cell lymphoma (5%–10%) ( 1 , 12 ). Although such lymphomas are highly aggressive and can be rapidly fatal, they are also more curable than low-grade lymphomas. With the exception of diffuse large B-cell lymphoma, these histologies necessitate more aggressive treatments than those commonly used in adult non-Hodgkin lymphoma. Therefore, improvements in supportive care and more accurate assessment of risk in younger patients may play more of a role in improving survival in childhood compared with adult non-Hodgkin lymphoma.

Given the young age at which the patients studied were diagnosed, the follow up of at least 25 years is of considerable interest in order to determine whether survivors of childhood hematologic malignancies are at increased risk of death in young adulthood. The estimated persistent decrease in survival between 10 and 25 years after diagnosis for all hematologic malignancies assessed ( Figure 3 ) in the 2000–2004 period analysis is concerning. Several studies have shown that long-term survivors of childhood hematologic malignancies are vulnerable to a number of health problems later in life. For example, an increased risk of a second malignancy has been observed in survivors of childhood acute lymphoblastic leukemia ( 26–28 ). A recent study with up to 30 years of follow-up observed an increased risk of acute non-lymphoblastic leukemia up to 10 years after successful treatment of childhood acute lymphoblastic leukemia and an increased risk of solid tumors that continued for up to 30 years after diagnosis ( 28 ). Although the risk of brain tumors was lower in children with acute lymphoblastic leukemia who had not received cranial irradiation than in those who had, it was higher in both groups of patients than in the general population ( 27 , 28 ). Children who are treated with anthracyclines, which are used in the treatment of many common childhood malignancies, are at a higher risk of cardiac complications later in life than those who are not treated with anthracyclines ( 29 , 30 ). However, this effect is dose dependent and can be mitigated by using the minimum necessary dose. Nevertheless, cardiac disease is a potentially serious late toxic effect of anthracycline therapy. Increased incidences of cardiac disease ( 31 ), second malignancies ( 32 ), and stroke ( 33 ) have been reported in survivors of childhood Hodgkin lymphoma. In summary, patients who are successfully treated for childhood hematologic malignancies are at increased risk for a number of serious health problems and require close monitoring of their health throughout life.

Our study has some limitations. First, although our survival estimates were based on a large SEER database, some had wide 95% confidence intervals, especially those in the age-specific analyses. Second, although period estimates of survival are more up-to-date than estimates from traditional cohort analyses of survival, they tend to underestimate the survival of newly diagnosed patients to some extent ( 19 , 34 ). In particular, the data we used to generate the 25-year survival curves included patients who were treated with older protocols, and therefore the 25-year survival of recently diagnosed patients who were likely to have been treated with more effective protocols may be underestimated. Thus, the survival rates of children recently diagnosed with hematologic malignancies may be slightly higher than those shown in our analysis.

In summary, our period analysis revealed that survival after diagnosis with childhood hematologic malignancies has improved greatly over the past decade. Survival projections for children diagnosed in the 2005–2009 period suggest that 10-year survival is at least 90% or higher for those diagnosed with acute lymphoblastic leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma and close to 65% for those diagnosed with acute non-lymphoblastic leukemia. We hope that the timely disclosure of these improvements to patients and their families, clinicians, and the public will reduce the level of fear engendered by a diagnosis of a childhood hematologic malignancy and encourage compliance with available and effective therapies. Further improvements in survival may be observed in the future as newer protocols are incorporated into the treatment of these malignancies.

References

1.
Cairo
MS
Raetz
E
Lim
MS
Davenport
V
Perkins
SL
Childhood and adolescent non-Hodgkin lymphoma: new insights in biology and critical challenges for the future
Pediatr Blood Cancer
 , 
2005
, vol. 
45
 
6
(pg. 
753
-
769
)
2.
Pui
CH
Schrappe
M
Ribeiro
RC
Niemeyer
CM
Childhood and adolescent lymphoid and myeloid leukemia
Hematology Am Soc Hematol Educ Program
 , 
2004
(pg. 
118
-
145
)
3.
Woods
WG
Curing childhood acute myeloid leukemia (AML) at the half-way point: promises to keep and miles to go before we sleep
Pediatr Blood Cancer
 , 
2006
, vol. 
46
 
5
(pg. 
565
-
569
)
4.
Moore BD III
Neurocognitive outcomes in survivors of childhood cancer
J Pediatr Psychol.
 , 
2005
, vol. 
30
 
1
(pg. 
51
-
63
)
5.
Robison
LL
Green
DM
Hudson
M
, et al.  . 
Long-term outcomes of adult survivors of childhood cancer
Cancer
 , 
2005
, vol. 
104
 
suppl 1
(pg. 
2557
-
2564
)
6.
Coebergh
JW
Reedijk
AM
de Vries
E
, et al.  . 
Leukaemia incidence and survival in children and adolescents in Europe during 1978–1997. Report from the Automated Childhood Cancer Information System project
Eur J Cancer
 , 
2006
, vol. 
42
 
13
(pg. 
2019
-
2036
)
7.
Clavel
J
Steliarova-Foucher
E
Berger
C
Danon
S
Valerianova
Z
Hodgkin's disease incidence and survival in European children and adolescents (1978–1997): report from the Automated Cancer Information System project
Eur J Cancer
 , 
2006
, vol. 
42
 
13
(pg. 
2037
-
2049
)
8.
Izarzugaza
MI
Steliarova-Foucher
E
Martos
MC
Zivkovic
S
Non-Hodgkin's lymphoma incidence and survival in European children and adolescents (1978–1997): report from the Automated Childhood Cancer Information System project
Eur J Cancer
 , 
2006
, vol. 
42
 
13
(pg. 
2050
-
2063
)
9.
McNeil
DE
Cote
TR
Clegg
L
Mauer
A
SEER update of incidence and trends in pediatric malignancies: acute lymphoblastic leukemia
Med Pediatr Oncol.
 , 
2002
, vol. 
39
 
6
(pg. 
554
-
557
discussion 552–553
10.
Brenner
H
Gefeller
O
An alternative approach to monitoring cancer patient survival
Cancer
 , 
1996
, vol. 
78
 
9
(pg. 
2004
-
2010
)
11.
Brenner
H
Hakulinen
T
Up-to-date and precise estimates of cancer patient survival: model-based period analysis
Am J Epidemiol
 , 
2006
, vol. 
164
 
7
(pg. 
689
-
696
)
12.
Surveillance, Epidemiology, and End Results (SEER) Program
 
( www.seer.cancer.gov ) Limited-Use Data (1973–2004), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2007, based on the November 2006 submission, last accessed April 19, 2008
13.
Brenner
H
Gefeller
O
Hakulinen
T
Period analysis for ‘up-to-date’ cancer survival data: theory, empirical evaluation, computational realisation and applications
Eur J Cancer
 , 
2004
, vol. 
40
 
3
(pg. 
326
-
335
)
14.
Rothman
KJ
Estimation of confidence limits for the cumulative probability of survival in life table analysis
J Chron Dis.
 , 
1978
, vol. 
31
 (pg. 
557
-
560
)
15.
Greenwood
M
A report on the natural duration of cancer. London, Ministry of Health, His Majesty's Stationery Office (Reports on public health and medical subjects, no. 33)
16.
Brenner
H
Hakulinen
T
Up-to-date long-term survival curves of patients with cancer by period analysis
J Clin Oncol
 , 
2002
, vol. 
20
 
3
(pg. 
826
-
832
)
17.
Brenner
H
Soderman
B
Hakulinen
T
Use of period analysis for providing more up-to-date estimates of long-term survival rates: empirical evaluation among 370,000 cancer patients in Finland
Int J Epidemiol
 , 
2002
, vol. 
31
 
2
(pg. 
456
-
462
)
18.
Brenner
H
Up-to-date survival curves of children with cancer by period analysis
Br J Cancer
 , 
2003
, vol. 
88
 
11
(pg. 
1693
-
1697
)
19.
Brenner
H
Hakulinen
T
Up-to-date estimates of cancer patient survival even with common latency in cancer registration
Cancer Epidemiol Biomarkers Prev.
 , 
2006
, vol. 
15
 
9
(pg. 
1727
-
1732
)
20.
Brenner
H
Kaatsch
P
Burkhardt-Hammer
T
Harms
DO
Schrappe
M
Michaelis
J
Long-term survival of children with leukemia achieved by the end of the second millennium
Cancer
 , 
2001
, vol. 
92
 
7
(pg. 
1977
-
1983
)
21.
Langer
T
Martus
P
Ottensmeier
H
Hertzberg
H
Beck
JD
Meier
W
CNS late-effects after ALL therapy in childhood. Part III: neuropsychological performance in long-term survivors of childhood ALL: impairments of concentration, attention, and memory
Med Pediatr Oncol.
 , 
2002
, vol. 
38
 
5
(pg. 
320
-
328
)
22.
Seibel
NL
Steinherz
PG
Sather
HN
, et al.  . 
Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group
Blood
 , 
2008
, vol. 
111
 
5
(pg. 
2548
-
2555
)
23.
von der Weid
N
Late effects in long-term survivors of ALL in childhood: experiences from the SPOG late effects study
Swiss Med Wkly
 , 
2001
, vol. 
131
 
13–14
(pg. 
180
-
187
)
24.
Ravindranath
Y
Chang
M
Steuber
CP
, et al.  . 
Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000
Leukemia
 , 
2005
, vol. 
19
 
12
(pg. 
2101
-
2116
)
25.
Gamis
AS
Acute myeloid leukemia and Down syndrome evolution of modern therapy—state of the art review
Pediatr Blood Cancer
 , 
2005
, vol. 
44
 
1
(pg. 
13
-
20
)
26.
Neglia
JP
Meadows
AT
Robison
LL
, et al.  . 
Second neoplasms after acute lymphoblastic leukemia in childhood
N Engl J Med.
 , 
1991
, vol. 
325
 
19
(pg. 
1330
-
1336
)
27.
Loning
L
Zimmermann
M
Reiter
A
, et al.  . 
Secondary neoplasms subsequent to Berlin-Frankfurt-Munster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy
Blood
 , 
2000
, vol. 
95
 
9
(pg. 
2770
-
2775
)
28.
Hijiya
N
Hudson
MM
Lensing
S
, et al.  . 
Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia
Jama
 , 
2007
, vol. 
297
 
11
(pg. 
1207
-
1215
)
29.
Lipshultz
SE
Lipsitz
SR
Sallan
SE
, et al.  . 
Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia
J Clin Oncol.
 , 
2005
, vol. 
23
 
12
(pg. 
2629
-
2636
)
30.
Sorensen
K
Levitt
GA
Bull
C
Dorup
I
Sullivan
ID
Late anthracycline cardiotoxicity after childhood cancer: a prospective longitudinal study
Cancer
 , 
2003
, vol. 
97
 
8
(pg. 
1991
-
1998
)
31.
Swerdlow
AJ
Higgins
CD
Smith
P
, et al.  . 
Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study
J Natl Cancer Inst.
 , 
2007
, vol. 
99
 
3
(pg. 
206
-
214
)
32.
Swerdlow
AJ
Barber
JA
Hudson
GV
, et al.  . 
Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment
J Clin Oncol.
 , 
2000
, vol. 
18
 
3
(pg. 
498
-
509
)
33.
Bowers
DC
McNeil
DE
Liu
Y
, et al.  . 
Stroke as a late treatment effect of Hodgkin's disease: a report from the Childhood Cancer Survivor Study
J Clin Oncol.
 , 
2005
, vol. 
23
 
27
(pg. 
6508
-
6515
)
34.
Zuccolo
L
Dama
E
Maule
MM
Pastore
G
Merletti
F
Magnani
C
Updating long-term childhood cancer survival trend with period and mixed analysis: good news from population-based estimates in Italy
Eur J Cancer
 , 
2006
, vol. 
42
 
8
(pg. 
1135
-
1142
)
35.
Steliarova-Foucher
E
Stiller
C
Lacour
B
Kaatsch
P
International Classification of Childhood Cancer
Cancer
 , 
2005
 
3rd ed. 103 1457 1467
The work of Dianne Pulte was supported by a Faculty Research Visit Grant from the German Academic Exchange Service and a grant from the CLL Research Center at Cornell Medical Center. The sponsor had no role in the study design, collection or interpretation of the data, the writing of the report, or the decision to submit the report for publication.