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Previous Volume 349:640-649 August 14, 2003 Number 7 Next

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ABSTRACT

Background Children who survive acute lymphoblastic leukemia are at risk for leukemia-related or treatment-related complications, which can adversely affect survival and socioeconomic status. We determined the long-term survival and the rates of health insurance coverage, marriage, and employment among patients who had attained at least 10 years of event-free survival.

Methods A total of 856 eligible patients were treated between 1962 and 1992 in 13 consecutive clinical trials. Survival rates, the cumulative risk of a second neoplasm, and selected indicators of socioeconomic status were analyzed for the entire group and for patients who did or did not receive cranial or craniospinal radiation therapy during initial treatment.

Results Fifty-six patients had major adverse events, including 8 deaths during remission, 4 relapses, and 44 second neoplasms (41 of them radiation-related); most of the second neoplasms were benign or of a low grade of malignant potential. The risk of a second neoplasm was significantly higher in the 597 patients who received radiation therapy (irradiated group) than in the 259 patients who did not receive radiation therapy (nonirradiated group) (P=0.04; estimated cumulative risk [±SE] at 20 years, 20.9±3.9 percent vs. 0.95±0.9 percent). The death rate for the irradiated group slightly exceeded the expected rate in the general U.S. population (standardized mortality ratio, 1.90; 95 percent confidence interval, 1.12 to 3.00), whereas that for the nonirradiated group did not differ from the population norm (standardized mortality ratio, 1.75; 95 percent confidence interval, 0.34 to 5.00). The rates of health insurance coverage, marriage, and employment in the nonirradiated group were similar to the age- and sex-adjusted national averages. Despite having health insurance rates similar to those in the general population, men and women in the irradiated group had higher-than-average unemployment rates (15.1 percent vs. 5.4 percent and 35.4 percent vs. 5.2 percent, respectively), and women in the irradiated group were less likely to be married (35.2 percent vs. 48.8 percent).

Conclusions Children with acute lymphoblastic leukemia who did not receive radiation therapy and who have attained 10 or more years of event-free survival can expect a normal long-term survival. Irradiation is associated with the development of second neoplasms, a slight excess in mortality, and an increased unemployment rate.

Adverse events after treatment of acute lymphoblastic leukemia tend to occur within the first decade after diagnosis.^7,8 We therefore sought to determine the prospects for normal survival among patients attaining at least 10 years of complete remission.

Methods

Study Population and Treatment Protocols

From 1962 through 1992, 2069 patients with acute lymphoblastic leukemia under 21 years of age were enrolled in 13 consecutive clinical trials (Table 1)^{9,10,11,12,13} at St. Jude Children's Research Hospital in Memphis, Tennessee; 1112 patients survived for 10 years or more after the induction of remission. In this cohort of survivors, 856 who had no leukemic recurrence were considered eligible for the follow-up analysis.

View this table: [in this window] [in a new window]   Table 1. General Characteristics of Treatment Protocols.

 
Follow-up Procedures

After the completion of therapy, all patients were examined at least annually at our center. Patients who had remained in remission for at least 10 years and were 18 years of age or older were subsequently monitored by their local physicians. The status of these patients was ascertained by questionnaires sent annually by the hospital's tumor registrar. The records of patients who died or had a second cancer were reviewed. Histopathological samples of second cancers were reviewed by St. Jude pathologists. For deaths outside the institution, death certificates were routinely requested, and the reported cause was verified by telephone conversations with the local physician, the family, or both. When available, reports of postmortem examinations were also reviewed. At the time of our analysis, only 44 patients (5.1 percent) lacked a documented contact within the previous three years; 599 (70.0 percent) had been contacted within the previous year. The median follow-up for patients attaining at least 10 years of event-free survival was 18.9 years (range, 10.0 to 38.6).

With the approval of the institutional review board, a questionnaire was mailed to all eligible patients who were at least 18 years of age to ascertain health insurance coverage and other socioeconomic characteristics. The results were compared with findings in the general population of the United States in 2000 and 2001.^14,15,16

Statistical Analysis

Survival and event-free survival from the 10th anniversary date of event-free survival (base line) were estimated by the method of Kaplan and Meier, and the associated standard errors were calculated by the method of Peto and Pike.¹⁷ Survival estimates for different groups of patients were compared by a Cox proportional-hazards regression model adjusted for age at the diagnosis of leukemia, sex, race, and treatment era (studies 1 to 10 vs. studies 11 to 13). The duration of event-free survival was measured from base line to the date of the first treatment failure of any kind (relapse, second cancer, or death) or to the date of the last follow-up. Cumulative incidence functions for second cancers, relapses, and deaths during remission were analyzed by Gray's method¹⁸ and with use of a proportional-hazards model adjusted for age and leukocyte count at diagnosis.¹⁹

Standardized mortality ratios (the observed number of deaths divided by the expected number) and their 95 percent confidence intervals were calculated by the method of Breslow and Day.²⁰ The expected number of deaths was calculated with the Epilog Plus Program²¹ by multiplying the number of person-years of follow-up by the corresponding mortality rate in the general population matched for age, sex, race, and calendar year (1973 to 2000) in which our patients achieved their first 10 years of event-free survival. Confidence intervals were calculated by Byar's approximation.²⁰ The survival curve of the U.S. population was constructed as a linear interpolation of the expected survival for each year from 1973 to 2000. The expected survival in a calendar year was calculated as 1 minus the expected risk of death in that year, which was defined as the expected number of deaths in that year divided by the total number of patients at risk. The expected number of deaths in a calendar year was calculated by multiplying the number of patients at risk in that year by the average death rate in the U.S. population from 1973 to 2000, after adjustment for age, sex, and race.

The standardized incidence ratio, or the number of observed cases divided by the number of expected cases, for second cancers was calculated on the basis of data from the Surveillance, Epidemiology, and End Results (SEER) program, adjusted for age and sex. Confidence intervals were calculated by Byar's approximation or, in cases with two or fewer observed events, by the exact Poisson distribution.

The summary statistics and national average rates of marriage, employment, and health insurance coverage were stratified according to sex and age categories identical to those of the Medical Expenditure Panel Survey¹⁴ or the Current Population Surveys of the U.S. Census Bureau.^15,16 Confidence intervals were calculated by exact multinomial statistics. The age-adjusted national average was calculated as the sum of the fraction of participants in each age category multiplied by the sex-specific rate of employment or marital status (Current Population Surveys) or by the insurance rate for that age category (Medical Expenditure Panel Survey). Multiple logistic-regression analysis was used to compare the rates of marriage, employment, and health insurance coverage between the patients who received cranial or craniospinal radiation therapy as part of their initial treatment (irradiated group) and those who did not receive such therapy (nonirradiated group), with adjustment for age and leukocyte count at the diagnosis of acute lymphoblastic leukemia, age at the time of survey, sex, and race. All reported P values are two-sided.

Results

Patient Characteristics

Of the 856 patients studied, 419 (48.9 percent) were male and 788 (92.1 percent) were white. Their ages ranged from 0.2 to 20 years (median, 4.5) at the time of diagnosis and from 10.3 to 30.2 years (median, 14.6) when they attained 10 years of event-free survival. The median leukocyte count at diagnosis was 8600 per cubic millimeter (range, 800 to 999,000). Of the 549 cases with successful immunophenotyping, 475 (86.5 percent) were classified as B-lineage acute lymphoblastic leukemia. Hyperdiploid karyotypes (more than 50 chromosomes) were identified in 195 of the 499 cases analyzed (39.1 percent).

Adverse Events

Fifty-six patients had adverse events after the 10th anniversary date of event-free survival (Table 2). The cumulative incidence (±SE) of any adverse event was 5.1±0.9 percent at 10 years after base line (20 years after the induction of remission) and 22.0±3.8 percent at 20 years after base line (30 years after the induction of remission). When basal-cell carcinoma was excluded, these rates were 4.7±0.9 percent and 14.7±2.9 percent, respectively (Figure 1). With three exceptions, the second neoplasms occurred within or adjacent to the field of cranial or craniospinal irradiation. Only one second neoplasm (Hodgkin's disease) was found among the 259 patients in the nonirradiated group.

View this table: [in this window] [in a new window]   Table 2. Timing and Cumulative Risk of Adverse Events after the 10th Anniversary of Event-free Survival.

 

View larger version (7K): [in this window] [in a new window]   Figure 1. Mean (±SE) Cumulative Incidence of Any Adverse Event in Patients Attaining 10 or More Years of Event-free Survival.

 
In a proportional-hazards regression model adjusted for age and leukocyte count at diagnosis, the 597 patients in the irradiated group had a significantly higher cumulative risk of second neoplasms than did the 259 patients in the nonirradiated group (P=0.04; estimated cumulative incidence rate at 20 years after base line, 20.9±3.9 percent vs. 0.95±0.9 percent) (Figure 2). By comparison with data from the SEER program, we determined that the risk of a second neoplasm was increased only in the irradiated group (Table 3). The irradiated group also appeared to be at greater risk for any adverse event (P=0.08; estimated cumulative risk rate at 20 years from base line, 23.0±3.8 percent vs. 2.7±1.4 percent) (Figure 2).

View larger version (18K): [in this window] [in a new window]   Figure 2. Mean (±SE) Cumulative Incidence of Second Neoplasms or Any Adverse Event among Patients Attaining 10 or More Years of Event-free Survival, According to Whether or Not They Received Cranial or Craniospinal Radiation.

 

View this table: [in this window] [in a new window]   Table 3. Comparison of the Incidence of Cancer in the Study Group with That in the General Population.

 
Survival

At 20 years from base line (30 years from achievement of the first complete remission), the estimated survival rates for the entire group and the irradiated and nonirradiated groups were 95.3±2.2, 95.1±2.3, and 98.3±7.4 percent, respectively, as compared with 99.7 percent for the general U.S. population (Figure 3). Twenty-one patients, of whom 18 were in the irradiated group, died at 1.0 to 17.6 years (median, 5.5) from base line. Of the 18 deaths in the irradiated group, 12 were due to a second cancer and 1 was due to a relapse of leukemia. Of the three deaths in the nonirradiated group, two were due to suicide and one to a car accident. According to multivariate analysis adjusted for age at the diagnosis of acute lymphoblastic leukemia, sex, race, and treatment era, the probability of survival did not differ significantly between the irradiated and nonirradiated groups (hazard ratio for death in the irradiated group, 1.27; 95 percent confidence interval, 0.36 to 4.47; P=0.71). Comparison of survival data between patients and the general population revealed a higher standardized mortality ratio in the irradiated group (1.90; 95 percent confidence interval, 1.12 to 3.00) but not in the nonirradiated group (1.75; 95 percent confidence interval, 0.34 to 5.00).

View larger version (7K): [in this window] [in a new window]   Figure 3. Overall Survival of the Entire Group of Patients Attaining 10 or More Years of Event-free Survival (N=856), the Irradiated Group (N=597), the Nonirradiated Group (N=259), and the General U.S. Population Matched for Age, Sex, and Race. Bars indicate 95 percent confidence intervals for the mean survival of nonirradiated and irradiated cohorts 20 years after the 10th anniversary of continuous complete remission (30 years after diagnosis).

 
Marital, Employment, and Health Insurance Status and Access to Health Care

Of the 694 eligible patients, 584 (84.1 percent) responded to the study questionnaire. Only 44 patients (6.3 percent) declined to participate; current addresses and telephone numbers were not available for the remaining 66 patients. The median age of the respondents was 27 years (range, 18 to 50), and the median time from the diagnosis of leukemia to the date of response to the survey was 20 years (range, 10 to 37). Forty-seven percent of the respondents were men.

The marital rate (the proportion of patients currently married) was similar to that in the age- and sex-matched general population, with the exception of women in the irradiated group, whose marital rate (35.2 percent; 95 percent confidence interval, 27.6 to 43.3 percent) was lower than in the corresponding general population (48.8 percent) (Table 4). Most respondents were employed full time (51.7 percent) or part time (7.8 percent); 22.0 percent were students. The rate of full-time employment for nonirradiated patients was similar to that of the age- and sex-matched general population (Table 4). However, in the irradiated group the unemployment rates for both women (35.4 percent; 95 percent confidence interval, 27.0 to 44.1 percent) and men (15.1 percent; 95 percent confidence interval, 9.2 to 22.7 percent) were higher than those in the corresponding general population (5.2 and 5.4 percent, respectively); women in the irradiated group were also less likely to be employed full time.

View this table: [in this window] [in a new window]   Table 4. Marital, Employment, and Health Insurance Status According to Sex and History of Irradiation.

 
Health insurance was provided through the employer, spouse, or parent in 59.2 percent of cases; federal or state-supported health plans in 15.1 percent; and self-purchase in 6.9 percent. Only 19.7 percent of the respondents lacked health insurance. A history of leukemia had resulted in the denial of health insurance to 28.4 percent of the respondents, prohibitive premiums for 18.6 percent, and restrictions on health care plans for 7.0 percent. As compared with those with private insurance, respondents with public insurance were more likely to report some difficulty in obtaining health care (13.9 percent vs. 6.6 percent) or not receiving needed care (20.9 percent vs. 4 percent). Not surprisingly, an even greater proportion of uninsured survivors reported difficulties in obtaining health care (19.6 percent) or not receiving needed care (27.7 percent). Although 89.3 percent of the long-term survivors reported using a community physician for their health care needs, only 53.2 percent had seen a physician in the preceding 12 months.

Multiple logistic-regression analysis, adjusted for potentially confounding factors, indicated similar rates of health insurance coverage and marriage for irradiated and nonirradiated patients of the same sex. However, the unemployment rate was higher among female survivors in the irradiated group than in the nonirradiated group (odds ratio, 2.15; 95 percent confidence interval, 1.10 to 4.20).

Discussion

Among survivors of childhood acute lymphoblastic leukemia who were event-free for 10 years after the induction of remission, the cumulative risk of relapse was only 0.63±0.32 percent at 20 years (30 years after the induction of an initial complete remission). Another research group reported an actuarial risk of relapse of 1 percent at 20 years of follow-up among 1134 survivors who were event-free for 10 years and who had been treated between 1970 and 1984, but the investigators did not determine the incidence of other adverse events in their cohort.²² The risk of late relapse is likely to be even less in survivors who are event-free for 10 years and who have been treated according to contemporary protocols.²³ Our results suggest a new working definition of cure: 10 or more years of continuous complete remission, a standard that could be used to gauge the effectiveness of current and future treatment plans.

The cumulative risk of second neoplasms in children treated for acute lymphoblastic leukemia is less than 4 percent 15 to 20 years after the diagnosis.^{3,6,24,25,26,27} Our study showed that the cumulative incidence of second neoplasms in patients who received cranial or craniospinal irradiation rose sharply 20 years after the diagnosis of acute lymphoblastic leukemia, a finding not previously appreciated because of shorter follow-up in other studies. Most of these late-onset second neoplasms were benign tumors or low-grade cancers, and only 12 of 44 patients with second neoplasms died, in contrast to the high mortality rate among patients whose second neoplasms developed within 10 years after the diagnosis of acute lymphoblastic leukemia.^{3,6,7,8,24,25,26,27,28,29} Consequently, the long-term survival in the irradiated group in our study was only slightly less than that in sex- and age-matched persons in the general population (Figure 3). Survival in the nonirradiated group was virtually identical to that in the general population.

Any assessment of the long-term survival of persons cured of cancer must consider the quality of life.³⁰ Young adult survivors of childhood cancer have lower marital rates than the general population,^{31,32,33,34,35,36} and survivors of brain tumors are especially vulnerable.^32,36 This finding has been attributed to the sequelae of the treatment, including neuroendocrine dysfunction that affects height and body build and neurocognitive deficits that influence social and emotional development.³² Cranial irradiation is a risk factor for learning deficits in survivors of brain tumors or acute lymphoblastic leukemia, especially in young patients treated with high doses of radiation.^35,37

Although the doses of cranial radiation delivered to our patients were relatively low (18 to 24 Gy), we found higher unemployment rates and lower marital rates among the women in the irradiated group than in the age- and sex-matched general population, a result consistent with the greater vulnerability of female patients to the adverse effects of cranial irradiation on the central nervous system.^38,39,40 These results support current efforts to limit the use of cranial irradiation in initial therapy for acute lymphoblastic leukemia.^3,41,42 In two recently published clinical trials, cranial irradiation was omitted altogether, without an undue increase in the rate of central nervous system relapse.^43,44

Previous investigations of the insurance coverage of survivors of childhood cancer found clear evidence of discrimination, particularly in employment-related health insurance.^{34,35,45,46,47,48,49} Survivors were also more likely than sibling controls to have policies with clauses excluding coverage of preexisting health conditions.^34,35,48 More recent studies of older survivors treated according to contemporary protocols indicate improved access to insurance and less economic discrimination,^34,35 probably because of the public's awareness of the favorable prognosis for most survivors of childhood cancer and because of legislation prohibiting discrimination in employment and promoting insurance portability.^50,51,52 Our data indicate that the rate of insurance coverage for long-term survivors of acute lymphoblastic leukemia is at least similar to or, in the case of female survivors, higher than that in the general population.

Adult survivors of childhood cancer are at risk for health problems that may adversely affect their quality of life and long-term survival.^7,8,53,54 Because these risks may be exacerbated by the physiologic changes associated with normal aging, lifelong medical monitoring is recommended for all survivors of childhood cancer. Although 89 percent of the survivors of acute lymphoblastic leukemia who were discharged from follow-up at our institution reported having a usual place to obtain health care, only 53 percent had had a medical evaluation within the previous year. This rate appears to be lower than that in the general population (approximately 80 percent),⁵⁵ underscoring the need for further investigation of the patterns of health care use among long-term survivors of acute lymphoblastic leukemia.

Supported in part by a grant (21765) from the National Institutes of Health, a Center of Excellence grant from the state of Tennessee, and the American Lebanese Syrian Associated Charities. Dr. Pui is the American Cancer Society F.M. Kirby Clinical Research Professor.

We are indebted to Deqing Pei and Shelly Lensing for statistical analysis, Dr. James Boyett for statistical consultation, John Gilbert for assistance with scientific editing, Dr. Sarah Scholle for assistance with the insurance survey, Annette Stone and Margie Zacher for data management, Julie Groff for assistance with the figures, Kimberly Gayden for assistance in the preparation of the manuscript, many physicians (especially Drs. Rhomes J. Aur, H. Omar Hustu, Donald Pinkel, and Joseph V. Simone) for their contributions to the design and conduct of early Total Therapy studies, and the many patients and parents who participated in the research program.

Source Information

From the Departments of Hematology–Oncology (C.-H.P., W.L., G.K.R., J.T.S., R.C.R., M.M.H.), Pathology (C.-H.P.), Biostatistics (C.C., S.N.R.), Pharmaceutical Sciences (M.V.R., W.E.E.), and Radiation Oncology (L.E.K.), St. Jude Children's Research Hospital; and the Colleges of Medicine (C.-H.P., W.L., G.K.R., J.T.S., R.C.R., M.V.R., L.E.K., W.E.E., M.M.H.) and Pharmacy (M.V.R., W.E.E.), University of Tennessee Health Science Center — all in Memphis.

Address reprint requests to Dr. Pui at St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, or at ching-hon.pui{at}stjude.org.

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Long-Term Survivors of Acute Lymphoblastic Leukemia
Nuver J., van den Belt-Dusebout A. W., Gietema J. A., Pui C.-H., Evans W. E., Hudson M. M.
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N Engl J Med 2003; 349:1973, Nov 13, 2003. Correspondence

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