Conceived and designed the experiments: SE NXvdW MPFS CER GM CSR FKN CEK. Performed the experiments: SE MPFS CER GM CSR CEK. Analyzed the data: SE MPFS CER GM CSR CEK. Contributed reagents/materials/analysis tools: MPFS CER CSR CEK. Wrote the paper: SE NXvdW MPFS CER GM CSR FKN CEK.
The authors have declared that no competing interests exist.
Relapses occur in about 20% of children with acute lymphoblastic leukemia (ALL). Approximately one-third of these children can be cured. Their risk for late effects is high because of intensified treatment, but their health-related quality of life (HRQOL) was largely unmeasured. Our aim was to compare HRQOL of ALL survivors with the general population, and of relapsed with non-relapsed ALL survivors.
As part of the Swiss Childhood Cancer Survivor Study (SCCSS) we sent a questionnaire to all ALL survivors in Switzerland who had been diagnosed between 1976–2003 at age <16 years, survived ≥5 years, and were currently aged ≥16 years. HRQOL was assessed with the Short Form-36 (SF-36), which measures four aspects of physical health and four aspects of mental health. A score of 50 corresponded to the mean of a healthy reference population. We analyzed data from 457 ALL survivors (response: 79%). Sixty-one survivors had suffered a relapse. Compared to the general population, ALL survivors reported similar or higher HRQOL scores on all scales. Survivors with a relapse scored lower in general health perceptions (51.6) compared to those without (55.8;p=0.005), but after adjusting for self-reported late effects, this difference disappeared.
Compared to population norms, ALL survivors reported good HRQOL, even after a relapse. However, relapsed ALL survivors reported poorer general health than non-relapsed. Therefore, we encourage specialists to screen for poor general health in survivors after a relapse and, when appropriate, specifically seek and treat underlying late effects. This will help to improve patients’ HRQOL.
Acute lymphoblastic leukemia (ALL) is the most common cancer in children younger than 15 years of age, accounting for about 28% of malignancies in the pediatric population
We know a good deal about late effects, but less is known about health-related quality of life (HRQOL) of relapsed and non-relapsed ALL survivors
Our goal was to better understand the role that relapse plays in the HRQOL of patients who have survived the complex course of ALL and its treatment. Therefore, we compared HRQOL of ALL survivors with the general population (1) and of relapsed and non-relapsed ALL survivors, accounting for late effects (2).
Since 2004, all patients and their families give informed consent at the time of cancer diagnosis for their data to be included in the Swiss Childhood Cancer Registry (SCCR) and used for research. Patients who had been diagnosed in the early years of the registry received the information retrospectively and could object to their inclusion in the registry (right of veto). This procedure was decided by the Swiss Federal Commission of Experts for Professional Secrecy in Medical Research when granting the general cancer registry permission to the SCCR, and was endorsed by the ethics committee of the canton of Bern. Similarly, the questionnaire survey of the Swiss Childhood Cancer Survivor Study was approved by the ethics committee of the canton of Bern. When returning the questionnaire, cancer survivors consented that their data are used for research. All information regarding individuals was made anonymous to investigators prior to analysis.
The Swiss Childhood Cancer Survivor Study (SCCSS) is a population-based long-term follow-up study of all childhood cancer patients registered in the Swiss Childhood Cancer Registry (SCCR), diagnosed 1976–2003, who survived for at least 5 years
Eligible participants were traced with an extensive address search procedure. Between 2007 and 2010, survivors with identified addresses received an information letter from their former pediatric oncology clinic, followed in two weeks by a questionnaire that included a pre-paid return envelope. Four weeks later, non-responders received a reminder letter, and a phone call six weeks later. Letters and questionnaires were written in the three national languages: German, French and Italian. For the current analyses we included only ALL survivors at least 16 years old at the time of the study, who had had no relapse and no second malignancies in the five years before survey. For the current analyses we included only ALL survivors at least 16 years old at the time of the study, who had had no relapse and no second malignancies in the five years before survey. This was done because we wanted to assess quality of life in state of relative health not during treatment of a relapse or second tumor.
The SCCSS used an extensive questionnaire similar to that used in US and British childhood cancer survivors studies
Information on baseline demographics and prospectively collected medical information on survivor diagnosis and treatment was extracted from the Swiss Childhood Cancer Registry: current age; gender; age at diagnosis; time since diagnosis; chemo- and radiotherapy (chemotherapy: without radiotherapy, may have surgery/radiotherapy: with or without chemotherapy or surgery); bone marrow transplantation; duration of therapy; and relapse status. Therapy variables included treatment both for initial and relapsed ALL. This information was extracted from the SCCSS questionnaire: having a partner (yes/no); education; and self-reported late effects. Education was divided into four categories according to the Swiss Census: compulsory schooling; vocational training; upper secondary education; and, university education
We determined the quality of HRQOL data by calculating missing values per item, item-scale internal consistency, and Cronbach’s alpha.
We calculated the ALL survivors’ (all, relapsed only, non-relapsed only) mean t-scores for each scale to find out if they were within one standard deviation of the population norms (Aim 1). HRQOL within one standard deviation of the general population was considered “normal”
We also compared HRQOL of relapsed with non-relapsed ALL survivors (Aim 2), performing univariable and multivariable linear regressions for each SF-36 scale (dependent variables). Relapse status was the independent variable in univariable analysis. We added more variables in two steps in multivariable analysis:
Step 1, baseline model, adjusting for possible confounders (variables: gender, current age, time since diagnosis);
Step 2, extended models, adjusting for additional variables to investigate associations between relapse and HRQOL:
Social model (having a partner, education)
Therapy model (chemo−/radiotherapy, bone marrow transplantation, duration of therapy)
Late effects model (self-reported late effects)
Full model (adjusting for all variables)
We performed in-depth analysis of SF-36 scales associated with relapse status checking the answers that aggregated into the respective scales.
In sensitivity analyses, we used the French and Italian population norms instead of the German.
Analyses were carried out using the software package STATA version 12 (Stata Corporation, Austin, TX, USA).
We successfully traced addresses for 621 of 658 eligible ALL survivors (
As of May 19, 2011. *of those traced and sent questionnaire. ALL: acute lymphoblastic leukemia; SF-36: Short Form-36.
Participants (n=457) were more often female (50% vs. 35%, p=0.001), and more often treated with a bone marrow transplantation (11% vs. 4%, p=0.016) than those who did not reply or completed only an abridged questionnaire (n=164) (
Non-participants | Participants | ||||||||||
All (n=164) | All (n=457) | Relapse (n=61) | Non-Relapse (n=396) | ||||||||
n | % | n | % | p |
n | % | n | % | p |
||
Gender | Male | 107 | 65.2 | 229 | 50.1 | 36 | 59.0 | 193 | 48.7 | ||
Female | 57 | 34.8 | 228 | 49.9 | 0.001 | 25 | 41.0 | 203 | 51.3 | 0.135 | |
Current age | 16–24.9 y | 75 | 45.7 | 236 | 51.6 | 26 | 42.6 | 210 | 53.0 | ||
25–29.9 y | 31 | 18.9 | 110 | 24.1 | 12 | 19.7 | 98 | 24.7 | |||
30–34.9 y | 28 | 17.1 | 62 | 13.6 | 12 | 19.7 | 50 | 12.6 | |||
≥35 y | 25 | 15.2 | 49 | 10.7 | 0.057 | 11 | 18.0 | 38 | 9.6 | 0.015 | |
Having a partner | No | n/a | 234 | 51.2 | 32 | 52.5 | 202 | 51.0 | |||
Yes | n/a | 209 | 45.7 | n/a | 27 | 44.3 | 182 | 46.0 | 0.815 | ||
Education | Compulsory schooling | n/a | 114 | 24.9 | 13 | 21.3 | 101 | 25.5 | |||
Vocational training | n/a | 179 | 39.2 | 29 | 47.5 | 150 | 37.9 | ||||
Upper secondary education |
n/a | 88 | 19.3 | 11 | 18.0 | 77 | 19.4 | ||||
University education | n/a | 58 | 12.7 | n/a | 7 | 11.5 | 51 | 12.9 | 0.966 | ||
Age at diagnosis | 0–4.9 y | 72 | 43.9 | 227 | 49.7 | 29 | 47.5 | 198 | 50.0 | ||
5–9.9 y | 56 | 34.1 | 136 | 29.8 | 20 | 32.8 | 116 | 29.3 | |||
≥10 y | 36 | 22.0 | 94 | 20.6 | 0.317 | 12 | 19.7 | 82 | 20.7 | 0.895 | |
Time since diagnosis | 5–14.9 y | 44 | 26.8 | 125 | 27.4 | 8 | 13.1 | 117 | 29.5 | ||
15–24.9 y | 52 | 31.7 | 239 | 52.3 | 32 | 52.5 | 207 | 52.3 | |||
≥25 | 38 | 23.2 | 93 | 20.4 | 0.717 | 21 | 34.4 | 72 | 18.2 | 0.001 | |
Chemo−/Radiotherapy | Chemotherapy |
104 | 63.4 | 312 | 68.3 | 8 | 13.1 | 304 | 76.8 | ||
Radiotherapy |
60 | 36.6 | 145 | 31.7 | 0.257 | 53 | 86.9 | 92 | 23.2 | <0.001 | |
No | 157 | 95.7 | 409 | 89.5 | 41 | 67.2 | 368 | 92.9 | |||
Yes | 7 | 4.3 | 48 | 10.5 | 0.016 | 20 | 32.8 | 28 | 7.1 | <0.001 | |
Duration of therapy | ≤2 y | 101 | 61.6 | 305 | 66.7 | 18 | 29.5 | 287 | 72.5 | ||
>3 y | 42 | 25.6 | 119 | 26.0 | 0.765 | 42 | 68.9 | 77 | 19.4 | <0.001 | |
Self-reported late effects | No | n/a | 334 | 73.1 | 26 | 42.6 | 308 | 77.8 | |||
Yes | n/a | 119 | 26.0 | n/a | 35 | 57.4 | 84 | 21.2 | <0.001 | ||
Relapse status | No | 133 | 81.1 | 396 | 86.7 | 0 | 0 | 396 | 100 | ||
Yes | 31 | 18.9 | 61 | 13.3 | 0.086 | 61 | 100 | 0 | 0 | n/a |
Abbreviation: n/a, not applicable.
all non-participants vs. all participants; p-values calculated from chi-square statistics.
relapsed vs. non-relapsed participants; p-values calculated from chi-square statistics.
includes high school, teachers training colleges, technical colleges and upper vocational education.
without radiotherapy, may have surgery.
with or without chemotherapy or surgery.
Compared to survivors of non-relapsed ALL (n=396), survivors of relapsed ALL (n=61) were older, diagnosed earlier, more likely to report late effects, and more likely to have received radiotherapy, bone marrow transplant or treatment lasting 3 years or longer. There was no difference in gender, relationship status, education, or age at diagnosis.
Data on HRQOL was nearly complete, missing values per item ranging from 1–2%. The correlation between each item with its hypothesized scale exceeded the suggested standard of 0.40 for satisfactory item-consistency (0.44–0.82). Cronbach’s alpha was high for all scales (0.78–0.90) suggesting good reliability.
Compared with the German population norm, survivors’ scores on all HRQOL scales were similar or higher (
Unadjusted | Adjusted, full model |
||||||||
All(n=457) | Non-relapse (n=396) | Relapse (n=61) | p | All(n=457) | Non-relapse (n=396) | Relapse (n=61) | p |
||
Physical functioning | Mean | 52.0 | 52.1 | 50.8 | 0.126 | 52.0 | 51.8 | 53.4 | 0.219 |
95CI | [51.2–52.7] | [51.4–52.9] | [48.8–52.8] | [51.3–52.8] | [51.0–52.6] | [51.1–55.7] | |||
Role physical | Mean | 51.0 | 51.1 | 49.8 | 0.132 | 51.0 | 51.0 | 51.2 | 0.817 |
95CI | [50.3–51.6] | [50.5–51.8] | [47.9–51.7] | [50.4–51.6] | [50.3–51.7] | [49.2–53.3] | |||
Bodily pain | Mean | 57.1 | 57.1 | 57.1 | 0.781 | 57.1 | 56.9 | 58.3 | 0.245 |
95CI | [56.5–57.8] | [56.4–57.9] | [55.2–58.9] | [56.4–57.8] | [56.1–57.7] | [56.1–60.5] | |||
General health | Mean | 55.3 | 55.8 | 51.6 | 0.005 | 55.4 | 55.8 | 53.0 | 0.135 |
95CI | [54.2–56.3] | [54.7–57.0] | [48.6–54.7] | [54.3–56.5] | [54.6–57.0] | [49.6–56.4] | |||
Vitality | Mean | 57.0 | 57.4 | 54.3 | 0.087 | 57.0 | 57.1 | 56.1 | 0.606 |
95CI | [55.8–58.1] | [56.1–58.6] | [50.7–57.8] | [55.8–58.1] | [55.8–58.4] | [52.3–59.8] | |||
Social functioning | Mean | 50.9 | 51.1 | 49.3 | 0.113 | 50.9 | 51.0 | 50.6 | 0.799 |
95CI | [50.0–51.8] | [50.2–52.1] | [46.2–52.4] | [50.0–51.9] | [50.0–52.0] | [47.6–53.5] | |||
Role emotional | Mean | 48.8 | 49.1 | 47.4 | 0.230 | 48.8 | 48.8 | 48.7 | 0.931 |
95CI | [48.0–49.6] | [48.2–49.9] | [44.7–50.1] | [47.9–49.6] | [47.9–49.7] | [46.0–51.3] | |||
Mental health | Mean | 54.0 | 54.2 | 52.8 | 0.488 | 54.0 | 54.0 | 53.9 | 0.989 |
95CI | [53.0–55.0] | [53.1–55.2] | [49.9–55.7] | [52.9–55.0] | [52.8–55.1] | [50.7–57.2] |
Abbreviation: 95CI, 95% confidence interval.
adjusted for gender, current age, time since diagnosis, having a partner, education, chemo−/radiotherapy, bone marrow transplantation, duration of therapy, and self-reported late effects.
p-values calculated from likelihood-ratio tests.
In a comparison of relapsed and non-relapsed ALL survivor HRQOL, those who relapsed tended to be low in some SF-36 scales, but on only one scale was relapse significantly associated in univariable analysis. Survivors of relapsed ALL had a lower “general health” score than survivors of non-relapsed ALL (51.6 vs. 55.8, p=0.005).
In multivariable analysis, the difference in general health between survivors with and without relapse remained statistically significant in baseline, social and therapy models (51.1 vs. 55.9, p=0.003; 51.2 vs. 55.8, p=0.004; 56.0 vs. 50.8, p=0.008) (
Full model, adjusted for gender, current age, time since diagnosis, having a partner, education, chemo−/radiotherapy, bone marrow transplantation, duration of therapy, and self-reported late effects; German population norm used. SF-36: Short Form-36.
We looked at the distribution of the answers aggregated into “general health” in order to better understand the difference. Fewer survivors of relapsed ALL chose the statements, “I am as healthy as anybody I know,” and, “My health is excellent,” than survivors of non-relapsed ALL (38% vs. 58%, p=0.006; and 39% vs. 55%, p=0.004 respectively) (
All (n=457) | Relapse (n=61) | Non-relapse (n=396) | p | |||||||
N | % | n | % | 95CI | n | % | 95CI | |||
|
definitively true | 23 | 5.1 | 4 | 6.7 | 0.2 – 13.2 | 19 | 4.8 | 2.7 – 7.0 | 0.051 |
mostly true | 47 | 10.4 | 7 | 11.7 | 3.3 – 20.0 | 40 | 10.2 | 7.2 – 13.2 | ||
don’t know | 49 | 10.8 | 10 | 16.7 | 7.0 – 26.4 | 39 | 9.9 | 7.0 – 12.9 | ||
mostly false | 99 | 21.9 | 15 | 25.0 | 13.7 – 36.3 | 84 | 21.4 | 17.3 – 25.4 | ||
definitively false | 235 | 51.9 | 24 | 40.0 | 27.2 – 52.8 | 211 | 53.7 | 48.7 – 58.6 | ||
|
definitively true | 249 | 55.1 | 22 | 36.7 | 24.1 – 49.2 | 227 | 57.9 | 53.0 – 62.8 | 0.006 |
mostly true | 119 | 26.3 | 23 | 38.3 | 25.7 – 51.0 | 96 | 24.5 | 20.2 – 28.8 | ||
don’t know | 34 | 7.5 | 7 | 11.7 | 3.3 – 20.0 | 27 | 6.9 | 4.4 – 9.4 | ||
mostly false | 34 | 7.5 | 7 | 11.7 | 3.3 – 20.0 | 27 | 6.9 | 4.4 – 9.4 | ||
definitively false | 16 | 3.5 | 1 | 1.7 | −1.7 – 5.0 | 15 | 3.8 | 1.9 – 5.7 | ||
|
definitively true | 3 | 0.7 | 1 | 1.7 | −1.7 – 5.1 | 2 | 0.5 | −0.2 – 1.2 | 0.045 |
mostly true | 16 | 3.6 | 4 | 6.8 | 0.2 – 13.4 | 12 | 3.1 | 1.4 – 4.8 | ||
don’t know | 63 | 14.0 | 12 | 20.3 | 9.8 – 30.9 | 51 | 13.1 | 9.7 – 16.4 | ||
mostly false | 65 | 14.5 | 8 | 13.6 | 4.6 – 22.6 | 57 | 14.6 | 11.1 – 18.1 | ||
definitively false | 302 | 67.3 | 34 | 57.6 | 44.6 – 70.6 | 268 | 68.7 | 64.1 – 73.3 | ||
|
definitively true | 239 | 53.0 | 23 | 39.0 | 26.2 – 51.8 | 216 | 55.1 | 50.2 – 60.0 | 0.004 |
mostly true | 151 | 33.5 | 20 | 33.9 | 21.5 – 46.3 | 131 | 33.4 | 28.7 – 38.1 | ||
don’t know | 26 | 5.8 | 7 | 11.9 | 3.4 – 20.4 | 19 | 4.8 | 2.7 – 7.0 | ||
mostly false | 21 | 4.7 | 7 | 11.9 | 3.4 – 20.4 | 14 | 3.6 | 1.7 – 5.4 | ||
definitively false | 14 | 3.1 | 2 | 3.4 | −1.4 – 8.1 | 12 | 3.1 | 1.3 – 4.8 |
Abbreviation: 95CI, 95% confidence interval.
Repeated analyses with French and Italian norm population HRQOL produced similar results, both in univariable and in multivariable regressions (
We found that ALL survivors, on average, reported HRQOL similar to the norm population, even after a relapse. Survivors of relapsed ALL perceived their general health to be lower than did non-relapsed ALL survivors. This difference became insignificant when we adjusted for late effects, indicating that late effects are a major underlying reason for the lower HRQOL in relapsed survivors.
A major strength of our study is the focus on relapse in ALL survivors. Most previous studies mixed all relapses across diagnostic groups. This was a problem because relapse is defined differently and leads to different treatment modifications. Large sample size, high response rate and the population-based nature of our study make it stronger than most other studies that investigated the role of relapse on HRQOL in childhood cancer survivors (
Cohort | Sample Size | Type of Cancer | Measurement Tool | Multivariable result | Independent variables in multivariable regressions | |
Present paper | Population basedSwiss ChildhoodCancer SurvivorStudy | 396 N-R, 61 R | ALL | SF-36 | Survivors of relapsed andnon-relapsed ALL had similarHRQOL, except in generalhealth. In regression analysis,this difference wasexplained by late effects. | Gender, age, time since diagnosis, having a partner, education, chemo−/radiotherapy, bone marrow transplantation, duration of therapy, self- reported late effects and relapse |
Stam and colleagues (2006) |
Attendants of Dutch long-term follow-up clinic | 310 N-R, 43 R | mixed | SF-36 | Relapse did not contributeto HRQOL. | Gender, age, diagnosis, treatment, age at first diagnosis, duration of treatment, and “relapse or second malignancy” |
Zebrack and Chesler (2002) |
Former patients of a “mid-western children’s hospital” | 160 N-R, 15 R | mixed | Quality ofLife-CancerSurvivors | Relapse did not contributeto HRQOL. | Gender, age, parent income, living arrangement, diagnosis, medical condition, age at diagnosis, after-effects reported and relapse |
Maunsell andcolleagues (2006) |
Canadian Childhood Cancer Surveillance and ControlProgram | 1178 N-R, 156 R | mixed | SF-36, self-esteem and optimismscales, satisfactionwith life scale | More than one treatmentseries (as a proxy for relapse)was independently associatedwith poorer HRQOL inthe physical dimensions. | “CNS or bone cancer”, two organs with dysfunction, “all three treatment modalities” (surgery, chemo-, and radiotherapy), cranial radiation, more than one treatment series |
Harila and colleagues (2010) |
Hospital-based studyin Oulu/Finland | 63 N-R, 11 R | ALL | SF-36 | − | − |
Abbreviations: N-R, Survivors of non-relapsed childhood cancer; R, Survivors of relapsed childhood cancer; ALL, acute lymphoblastic leukemia; SF-36, Short Form-36; HRQOL, health-related quality of life; CNS, central nervous system.
Our study also has limitations. Due to limited statistical power we could not look at different subgroups of relapses (late or early, isolated bone marrow or extramedullary relapses, combined relapses), nor could we distinguish between different subgroups of late effects. We did not consider the exact drugs and cumulative doses used in treatment, nor the sites of radiation. Finally, no SF-36 norm data is available for Switzerland.
Previous studies comparing HRQOL of ALL survivors with population norms found similar results. Zeltzer and colleagues (2009) compared ALL survivors with US norms and siblings
In Zebrack and Chesler’s study (2002), relapse did not contribute to HRQOL, even when late effects were adjusted for
Several earlier studies attempted to explain the rather surprising result that childhood cancer survivors often report similar or better HRQOL than general populations. Survivors’ subjective perception of HRQOL may be affected by a desire to be “as normal as possible,” causing a response shift (a change in the meaning of one’s self-evaluation of quality of life)
Relapsed and non-relapsed ALL survivors reported on similar HRQOL, except on one SF-36 scale. In relapsed patients, general health was significantly poorer, very likely as a consequence of late effects associated with relapse. As it was described in earlier studies, those late effects can become severe; therefore, our results have implications for follow-up care: We encourage specialists who conduct follow-up to screen for poor general health in survivors after a relapse and, when appropriate, specifically seek and treat underlying late effects.
The small effect we found in the present study requires in-depth investigation in larger groups of patients. Treatment intensity, adjuvant radiotherapy and stem cell transplantation with myeloablative regimens may induce a series of somatic and mental late chronic conditions after a relapse almost unknown after first-line treatments for pediatric ALL. We should attempt to better describe and quantify late effects by promoting regular long-term follow-up visits, where survivors can be examined and interviewed. Further preventing and minimizing late effects will help to improve quality of life in survivors of ALL, particularly those who had experienced a relapse.
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We thank all survivors for participating in our survey. We also thank Kali Tal for providing editorial help with the manuscript.