Section of Nephrology Department of Medical Research, Children's Mercy Hospital, University of Missouri, Kansas City, Missouri
http://www.100md.com
《小儿科》
Division of Pediatric Oncology, Vanderbilt University, Nashville, Tennessee
Division of Epidemiology and Clinical Research
Division of Health Services Research and Policy, University of Minnesota, Minneapolis, Minnesota
Department of Child Health, Llandough Hospital, South Glamorgan, United Kingdom
Division of Pediatric Oncology, City of Hope National Medical Center, Duarte, California
Division of Pediatric Oncology, Children's Hospital of Oakland, Oakland, California
Division of Pediatric Oncology, University of Washington, Seattle, Washington
ABSTRACT
Objective. To assess the health-related quality of life (HRQL) of 8- to 12-year-old children undergoing therapy for cancer or childhood-cancer survivors by using the Minneapolis-Manchester Quality of Life-Youth Form (MMQL-YF), a comprehensive, multidimensional self-report instrument with demonstrable reliability and validity.
Design, Setting, and Patients. The MMQL-YF consists of 32 items comprising 4 scales: physical functioning, psychologic functioning, physical symptoms, and outlook on life. Scoring on the MMQL ranges from 1 to 5; 5 indicates maximal HRQL. An overall quality-of-life (QOL) score is also computed. By using a cross-sectional study design, the MMQL-YF was administered to 90 off-therapy cancer survivors, 72 children with cancer undergoing active therapy, and 481 healthy children without a history of cancer or other chronic disease.
Results. Compared with healthy controls, children actively undergoing cancer treatment report low overall QOL, physical functioning, and outlook-on-life scores. However, off-therapy survivors report a superior overall QOL, compared with age-matched healthy controls.
Conclusions. Young survivors of childhood cancer report a favorable HRQL relative to healthy controls. These results are reassuring, suggesting that this group of survivors may have been too young to encounter some of the negative psychosocial impacts of cancer and its treatment.
Key Words: health-related quality of life childhood-cancer survivors
Abbreviations: HRQL, health-related quality of life QOL, quality of life MMQL, Minneapolis-Manchester Quality of Life YF, Youth Form RR, relative risk CI, confidence interval
Treatment advances over the past decades have greatly increased the prospects of surviving childhood cancer.1 Improved survival has placed increasing emphasis on the health status and health-related quality of life (HRQL) in childhood-cancer survivors. Numerous studies have shown that cancer and its treatment predispose to late morbidity and increase the risk of mortality in long-term childhood-cancer survivors.2–6 Treatment-related complications such as neurocognitive dysfunction, cardiopulmonary toxicity, endocrinopathies, and secondary malignancies may significantly impact the physical functioning of the survivors of childhood cancer.7,8 Studies of psychosocial functioning of adult survivors of childhood cancer have shown that 10% to 20% of individuals show signs of psychologic maladjustment in the form of mood disturbances, behavioral problems, and somatic distress.9–11 Few studies have focused on the impact of childhood cancer and its treatment on the health status and quality of life (QOL) of survivors.12–16 Most of these studies focus on adult survivors of childhood cancer and seem to indicate that the general health as perceived by these adult survivors of childhood cancer is very good, with only a small proportion of patients reporting fair or poor health.11 Female gender, a lower socioeconomic background, and a primary diagnosis of brain tumors, sarcomas, and Hodgkin's lymphoma have been associated with impaired health status among adult survivors of childhood cancer.15 Few studies address these issues among young children who are survivors of childhood cancer.17,18 These studies have relied on parents and/or clinicians to describe the health status in these young survivors, and the methodology involves comparisons between groups of childhood-cancer survivors treated with differing intensities of treatment, without comparisons to a healthy referent population. Small sample size has limited the generalizability of the findings from these studies. Thus, little information is available about the overall HRQL among children between 8 and 12 years old who are either undergoing active therapy for cancer or are long-term survivors, as compared with an age-matched healthy population.
The goal of this study was to describe HRQL in children between 8 and 12 years old diagnosed with cancer, either undergoing active therapy or after completion of therapy, using well-validated, age-appropriate, self-report tools and to compare the results with healthy children of the same age. We hypothesized that, when compared with an age-matched healthy population, children between 8 and 12 years old receiving active therapy for cancer would demonstrate significant deficits within the various domains of HRQL tested, whereas those who had completed treatment successfully would have an HRQL that was comparable to that of the general population.
METHODS
Instrument
The Minneapolis-Manchester Quality of Life-Youth Form (MMQL-YF) is a standardized patient self-report instrument designed to assess HRQL in childhood-cancer survivors between 8 and 12 years old.19 The MMQL was developed in 3 versions to address the developmental needs of different age groups. The YF was developed for children between 8 and 12 years old and is administered to the child by interview. The Adolescent Form was developed for adolescents between 13 and 20 years old and is self-administered.20 The Adult Form currently is under development for cancer survivors between 21 and 55 years old.
The MMQL-YF was created by using the experience of patients and their parents, nurses, and doctors to identify particular long-term problems that these patients may face. The instrument defines HRQL in terms of the effects of disease and treatment on physical and psychologic functioning as well as overall outlook on life. The chief domains defined relate to different aspects of the child's health: activity, mobility, relationship with family members, moods and feelings, hearing, speech and sight, and outlook on life. It consists of 32 items comprising 4 scales: physical functioning, psychologic functioning, physical symptoms, and outlook on life/family dynamics (Table 1). The physical-functioning scale measures activity and mobility, and the physical-symptoms scale focuses on pain and difficulties in speech, hearing, vision, and sleep. The psychologic-functioning domain assesses feelings, moods, and relationships with others, and the outlook-on-life/family-dynamics scale focuses on the interaction of the respondent with his/her parents and other family members and his/her outlook of the current and future life. An overall QOL score is also computed. Scoring ranges from 1 to 5, with 5 indicative of maximal HRQL. Higher MMQL-YF scores indicate minimal negative effect and thus greater HRQL. Data regarding reliability and validity of this instrument have been reported previously.19
Thus, the MMQL-YF is specific for survivors of childhood cancer between 8 and 12 years old and defines HRQL in terms of the impact of disease and treatment on an individual's physical and psychologic functioning, as well as overall outlook on life. Yet, at the same time, the domains and the items within them do not specifically address issues related to the actual disease (cancer in this case), and hence the questionnaire can be used to assess HRQL among off-therapy cancer survivors and healthy controls.
Patients and Procedures
Twenty institutions within the United States participated in this study (see "Acknowledgments"). The institutional review board at each participating institution approved this research protocol. The study population included children between 8 and 12 years old drawn from 2 pools: (1) patients actively undergoing treatment for cancer for at least 2 months (cancer patients on active therapy) and (2) patients who had successfully completed treatment for cancer and were in remission for 1 years (off-therapy survivors). Primary physicians gave permission to contact patients and their parents. Informed consent was obtained in person or by mail. In all cases, initial contact with the children was made through the parents. For patients undergoing active therapy and for cancer survivors, the participating institutions attempted to enroll consecutive patients seen at the treating institution into the study. Nonetheless, study participants represent a convenience sample, because the institutions did not systematically quantify the eligible patient population, nor did they implement procedures to ensure that all eligible patients were invited to participate. All patients were interviewed in person or by telephone by a trained interviewer. All interviews were conducted without the family member being present in the room to ensure that responses were truly self-reported. Most (99%) interviews took place in person in the clinic.
A control group of healthy children between 8 and 12 years old from throughout the United States was identified by random-digit dialing (healthy controls).21 The interviewer explained the study to the parents and obtained informed consent from the parents and study participants. To avoid influence from family members in the child's responses and to ensure that all answers were those of the participant, the interviewer emphasized to the parents that the child should be alone in the room throughout the interview. Once their assurance and compliance had been obtained, the interviewer explained the study to the child and proceeded with questioning. The interviewer checked with the child periodically throughout the interview to ensure that no family member was within hearing distance.
All completed questionnaires were entered into a database, and all personal identifying information was removed. Data from all institutions were merged into a final comprehensive dBase file.
Statistical Analysis
Statistical analysis of the data was performed by using the Epilog plus, Windows alpha version 1.00 statistical software (J.D. Buckley, Epilog Windows Procedure, Pasadena Epicenter Software, Pasadena, CA). Scoring on the MMQL-YF ranges from 1 to 5, with 5 indicative of maximal HRQL. An overall QOL score was computed also.
Three sets of analyses are reported here. The first set compares the responses of the off-therapy survivors and healthy controls. The second set compares the responses of the cancer patients undergoing therapy with those of the healthy controls. Finally, the third set compares only the survivors' responses by diagnoses (acute leukemia, lymphoma, brain tumors, and other solid tumors), gender, ethnicity, age at study participation, and time since diagnosis. This last set of analyses was conducted for all survivors together and also as a stratified analysis of survivors by individual diagnoses.
Comparisons of means between the various groups were conducted by using analysis-of-variance techniques. Multiple-regression analysis was used to investigate predictors of poor QOL. Variables in the model included primary diagnosis, age at completion of survey, time since diagnosis, gender, and ethnicity. The level of statistical significance was set at .05. All P values were 2-sided. To calculate relative-risk (RR) estimates for poor QOL while controlling for the effects of demographic variables, we constructed multivariate models for poor overall QOL as well as poor QOL in each of the 4 domains as an outcome. HRQL was defined arbitrarily as being "poor" if the overall QOL score or the QOL scores for each domain were <25th percentile for the healthy controls. The final model comparing cancer patients with healthy controls included gender, age at questionnaire completion, ethnicity, and the respondent status (cancer patient versus healthy control). The final model analyzing cancer patients only included gender, age at questionnaire completion, ethnicity, primary diagnosis, and time since diagnosis. The median time between diagnosis and study participation was 5.9 years. To test the hypothesis that the HRQL would improve with time since diagnosis, and also get a better understanding of the impact of time since diagnosis on the HRQL among the off-therapy survivors, we chose to use 6 years as an arbitrary cutoff point.
RESULTS
Over a 5-year period (January 1997 to March 2002), 643 subjects between 8 and 12 years old participated in the study: 90 off-therapy cancer survivors, 72 children undergoing therapy for cancer, and 481 healthy controls.
Comparison of Cancer Survivors With Healthy Controls
A comparison of the HRQL scores between the off-therapy cancer survivors and the healthy controls is shown in Table 3.
Overall QOL
The overall QOL of the off-therapy cancer survivors was significantly better than that of healthy controls (mean scores: 4.15 vs 4.05; P = .04). The higher QOL score was statistically significant among male but not female survivors (P = .02 and 0.58, respectively). Off-therapy survivors of nonneurologic solid tumors reported significantly superior QOL than healthy controls (P = .05). No significant differences were observed in children with other diagnoses, although the brain-tumor survivors reported lower scores in overall QOL and in all domains examined. Off-therapy survivors between 10.5 and 12 years old at study participation reported higher scores than the healthy controls (P = .03), as did off-therapy survivors who were >6 years from diagnosis (P = .04).
Physical Functioning
Overall physical-functioning scores of the off-therapy cancer survivors did not differ significantly from those of healthy controls (mean score: 3.99 vs 4.0; P = .83).
Physical Symptoms
Off-therapy cancer survivors reported higher scores in physical symptoms than did healthy controls (4.30 vs 4.15; P < .001). Higher physical-symptoms scores were reported by both males and females, by survivors of nonneurologic solid tumors, and by survivors who were between 10.5 and 12 years old at study participation.
Psychologic Functioning
Overall, off-therapy cancer survivors reported higher scores in the psychologic-functioning domain than did healthy controls (3.98 vs 3.92; P = .01). Again, certain subpopulations of off-therapy cancer survivors were more likely to report higher psychologic-functioning scores than were healthy controls. These subpopulations included male survivors, survivors of nonneurologic solid tumors, and survivors who were >6 years from diagnosis at the time of study participation.
Outlook on Life/Family Dynamics
The overall outlook on life/family dynamics of the off-therapy cancer survivors did not differ significantly from that of healthy controls (mean score: 4.23 vs 4.2; P = .62)
Comparison of Cancer Patients Undergoing Therapy With Healthy Controls
Multivariate Analysis: Comparison With Healthy Controls
Off-Therapy Cancer Survivors Compared With Healthy Controls
The results for off-therapy cancer survivors and cancer patients undergoing therapy are summarized in Table 5. When compared with healthy controls, off-therapy cancer survivors did not report any difference in their overall QOL, physical functioning, psychologic functioning, and outlook on life. However, off-therapy cancer survivors were more likely to report better QOL in the physical-symptoms domain when compared with the healthy controls, as were older study participants (10.5- to 12-year-olds) when compared with the younger ones (8- to 10.5-year-olds). Nonwhite children, when compared with the white children, reported poorer overall QOL and poorer QOL in the individual domains.
Cancer Patients Undergoing Therapy Compared With Healthy Controls
When compared with the healthy controls, cancer patients undergoing therapy were more likely to report poorer overall QOL (RR: 2.0; 95% confidence interval [CI]: 1.0–3.5), poorer physical functioning (RR: 2.5; 95% CI: 1.1–3.6), and poorer outlook on life (RR: 5.0; 95% CI: 1.5–8.5) (Table 5). Nonwhite children reported poorer QOL overall and in all domains when compared with the white children. Older study participants reported better QOL when compared with the younger participants.
Multivariate Analysis: HRQL Among Cancer Survivors
Off-Therapy Cancer Survivors
The results of the multivariate analysis are shown in Table 6. Female cancer survivors were 5 times more likely to report poor QOL in the physical-functioning domains when compared with males (RR: 5.0; 95% CI: 1.9–13.4). Older cancer survivors were less likely to report poorer QOL in the outlook-on-life domains when compared with the younger cancer survivors (RR: 0.2; 95% CI: 0.03–0.9). Primary diagnosis and time since diagnosis did not predict for poor QOL overall or among any of the domains studied.
Cancer Patients Undergoing Therapy
As can be seen in Table 6, among patients undergoing therapy for cancer, nonwhite children were more likely to report poorer psychologic functioning when compared with white children (RR: 9.3; 95% CI: 1.9–44.4). No other risk factor for poor QOL could be identified among patients receiving cancer therapy.
DISCUSSION
This study provides information regarding HRQL in a large and previously understudied cohort of young children between 8 and 12 years old who were either undergoing active treatment for cancer or survivors of cancer using the MMQL-YF.19 The MMQL-YF is designed specifically for survivors of cancer between 8 and 12 years old and measures HRQL as viewed by the affected children, not from the point of view of surrogates such as parents or guardians.
In this study, off-therapy cancer survivors reported statistically significantly higher overall QOL scores when compared with healthy controls. However, the clinical significance of a difference of this magnitude remains to be defined. Subgroups of off-therapy cancer survivors reporting higher overall QOL scores when compared with healthy controls included boys, survivors of nonneurologic solid tumors, and survivors who had been diagnosed with cancer 6 years before the study. Physical functioning and outlook on life did not differ between cancer survivors and healthy controls. The cancer survivors had significantly higher psychologic-functioning and physical-symptoms scores than did healthy controls. Examining predictors of poor QOL revealed nonwhite children to be at a higher risk of reporting poor QOL overall and among the various domains. Examining predictors of poor QOL among survivors revealed no significant associations with gender, primary diagnosis, age at participation, or time since diagnosis except for poorer physical functioning among females. However, only a small number of subjects in our study reported poor QOL, which may have limited our ability to identify predictors of poor QOL. The excellent HRQL observed in this group of survivors may be explained by an adjustment of attitude and overall view of life that may occur after experiencing a life-threatening situation. Thus, the survivors probably find their current life more satisfying and might very well perceive a smaller impact from the deficiencies in their current health status. They also may be comparing their current status with the status during the time of illness and hence perceive a superior HRQL than healthy controls. Improvements in the affected child's psychologic adjustment also may be caused by increased parental attention, as observed in some sibling studies.22,23 Unfortunately, this study was not designed to explore in greater detail the impact of the various reasons responsible for the reported HRQL in this patient population.
Previous studies have also reported a better QOL among the off-therapy survivors than healthy controls, with the finding being more marked among the younger survivors.10,24 Apajasalo et al24 evaluated the HRQL in young adult survivors (16–35 years old) of cancer. The survivors reported significantly better levels of vitality, distress, depression, discomfort, elimination, and sleeping dimensions. The difference was statistically significant but not thought to be clinically significant. There was no association of HRQL with original diagnosis. There were no patients with brain tumors in this group of survivors. Elkin et al10 studied the psychologic functioning of 161 cancer survivors >14.5 years old. Symptom Checklist-90 Revised, a self-report measure of psychologic symptomatology, was used to assess psychologic functioning. The survivors were found to have very low levels of psychologic distress and significantly better psychologic health than expected from normative data. In another study on psychologic functioning of 7- to 15-year-old cancer survivors based on parental reporting, a fourfold increase in social and behavioral problems was found.25 The difference in the outcomes of these studies is thought to be due to methodologic issues, ie, self-report versus parent report and potential influence of repressive adaptation on the self-reports of pediatric cancer survivors.10 In general, parent-child agreement is low, and, when direct comparisons can be made, there is a tendency for children to underreport symptoms relative to reports made by their parents.26–28 Studies describing the overall sense of well-being show no difference between young-adult survivors of nonneurologic tumors and healthy controls in overall sense of well-being.29–31 Certain vulnerable populations do exist, such as patients with acute lymphoblastic leukemia and brain tumors exposed to cranial radiation.30–32
Most studies assessing HRQL in childhood-cancer survivors have focused on young adults,9–15 with a few exceptions in which the focus was primarily younger children.17 A comparison of young off-therapy survivors of advanced neuroblastoma with Wilms' tumor survivors revealed a greater burden of morbidity in the former.17 In particular, survivors of advanced neuroblastoma were more likely to exhibit deficits in hearing and speech. However, this study relied on parent report, and there was no comparison with healthy children.
As anticipated, children on active therapy for cancer reported worse overall QOL than healthy controls in the current study. Their scores were significantly lower in the physical-functioning and outlook-of-life domains as compared with the healthy children. Furthermore, nonwhite children were more likely to report poorer QOL overall and in the individual domains, whereas older children reported better QOL when compared with younger children. Few studies have focused on the HRQL issues among young children undergoing active therapy for cancer. Waters et al18 studied HRQL in 31 children between 5 and 18 years old on maintenance therapy for acute lymphocytic leukemia by using parental reports on the Child Health Questionnaire and Pediatric Cancer Quality of Life Inventory-32 (PCQOL). The parents reported significantly lower functioning and well-being than population norms for all Child Health Questionnaire scales.
Our study has several limitations. First, this study lacks a random sample; participation was voluntary, and although we attempted to enroll all eligible subjects at each participating institution, the clinical characteristics of those who were not recruited are not available. Because there may exist a correlation between HRQL and willingness to participate, the results could potentially be biased. The study cohort had few survivors of brain tumors, a particularly high-risk group, as indicated by the lower scores reported by the brain-tumor group when compared with the healthy controls. The small numbers in the brain-tumor group precluded us from arriving at more meaningful conclusions. Future studies need to focus on this particularly vulnerable population.
Treatment-related information was not available in this study and hence could not be assessed as a risk factor for HRQL. Moreover, details regarding medical and functional late effects were not available and could not be investigated in this study. This study used a cross-sectional study design for evaluation of HRQL. Because HRQL can change over time, longitudinal assessments are preferable. Thus, it would be ideal to assess HRQL periodically with standardized, disease-specific instruments such as the MMQL as part of therapeutic cancer trials.
Healthy individuals between 8 and 12 years old (with no history of cancer or any other chronic illness) from throughout the United States were identified by random-digit dialing to procure normative data for the MMQL-YF, whereas a trained interviewer interviewed cancer patients in person in the clinic. No systematic differences were observed in the patterns of responses obtained from telephone interviews versus face-to-face interviews. Although it would have been ideal to use the same methodology for both these groups, it was not feasible to do face-to-face interviews of a large population of geographically diverse control subjects. It is for this reason that this difference in methodology was accepted despite its limitations.
The major strength of this study includes the use of a validated, comprehensive, multidimensional self-report instrument developed to assess HRQL among childhood-cancer survivors between 8 and 12 years old. HRQL among survivors in this age group is understudied. Despite its limitations, this remains one of the largest studies of self-reported HRQL in children with cancer between 8 and 12 years old. Few investigations have focused exclusively on this age group; instead, many have incorporated them into a larger study with either adults or children of other ages. The large control population for comparison and lack of proxy responses further strengthen this study.
We have demonstrated that although children undergoing treatment for cancer may report low overall QOL, physical functioning, and outlook on life, survivors report QOL scores that are as good, if not better, than age-matched controls. The results of this study are reassuring. However, it is possible that this group of survivors may have been too young to encounter some of the negative psychosocial impacts of cancer and its treatment.
Survival will always remain the ultimate goal in treatment of children with cancer. As treatments and clinical outcomes improve, attention needs to be focused on the long-term well-being of the survivors. The ultimate goal is to identify and minimize the negative consequences of childhood cancer and its treatment. We hope that, in the future, standardized instruments such as the MMQL-YF would be incorporated into therapeutic cancer trials to obtain measurements of HRQL longitudinally.
ACKNOWLEDGMENTS
This work was supported in part by National Cancer Institute grants U10CA 098543 and COG AS972.
Participating institutions in the Children's Oncology Group Study AS972 (and principal investigators) are C.S. Mott Children's Hospital, Ann Arbor, MI (Raymond Hutchinson; National Cancer Institute grant 02971); Children's Health Care-Minneapolis, Minneapolis, MN (Maura C. O'Leary); Children's Hospital and Regional Medical Center, Seattle, WA (Douglas Hawkins); Children's Hospital at the Cleveland Clinic, Cleveland, OH (Joanne M. Hilden); Children's Hospitals and Clinics-St Paul, St Paul, MN (Christopher L. Moertel); Childrens Hospital Oakland, Oakland, CA (James Feusner); Childrens Hospital of Philadelphia, Philadelphia, PA (Beverly Lange; National Cancer Institute grant 11796); City of Hope National Medical Center, Duarte, CA (Judith Sato); DeVos Children's Hospital, Grand Rapids, MI (David R. Freyer); Hackensack University Medical Center, Hackensack, NJ (Michael Harris); Hurley Medical Center, Flint, MI (Susumu Inoue); Kalamazoo Center for Medical Studies, Kalamazoo, MI (Leonard A. Mattano, Jr); Marshfield Clinic, Marshfield, WI (Michael J. McManus); Memorial Sloan Kettering Cancer Center, New York, NY (Peter G. Steinherz; National Cancer Institute grant 42764); Miami Children's Hospital, Miami, FL (Enrique Escalon); Schneider Children's Hospital at North Shore, Manhasset, NY (Arlene Redner); St John's Hospital and Medical Center, Detroit, MI (Hadi Sawaf); University of Mississippi Medical Center Children's Hospital, Jackson, MS (Jeanette Pullen; National Cancer Institute grant CA 15989); University of Missouri-Columbia, Columbia, MO (Katherine P. Kelly); and University of Illinois, Chicago, IL (Mary Lou Schmidt).
FOOTNOTES
Accepted Aug 26, 2004.
No conflict of interest declared.
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Division of Epidemiology and Clinical Research
Division of Health Services Research and Policy, University of Minnesota, Minneapolis, Minnesota
Department of Child Health, Llandough Hospital, South Glamorgan, United Kingdom
Division of Pediatric Oncology, City of Hope National Medical Center, Duarte, California
Division of Pediatric Oncology, Children's Hospital of Oakland, Oakland, California
Division of Pediatric Oncology, University of Washington, Seattle, Washington
ABSTRACT
Objective. To assess the health-related quality of life (HRQL) of 8- to 12-year-old children undergoing therapy for cancer or childhood-cancer survivors by using the Minneapolis-Manchester Quality of Life-Youth Form (MMQL-YF), a comprehensive, multidimensional self-report instrument with demonstrable reliability and validity.
Design, Setting, and Patients. The MMQL-YF consists of 32 items comprising 4 scales: physical functioning, psychologic functioning, physical symptoms, and outlook on life. Scoring on the MMQL ranges from 1 to 5; 5 indicates maximal HRQL. An overall quality-of-life (QOL) score is also computed. By using a cross-sectional study design, the MMQL-YF was administered to 90 off-therapy cancer survivors, 72 children with cancer undergoing active therapy, and 481 healthy children without a history of cancer or other chronic disease.
Results. Compared with healthy controls, children actively undergoing cancer treatment report low overall QOL, physical functioning, and outlook-on-life scores. However, off-therapy survivors report a superior overall QOL, compared with age-matched healthy controls.
Conclusions. Young survivors of childhood cancer report a favorable HRQL relative to healthy controls. These results are reassuring, suggesting that this group of survivors may have been too young to encounter some of the negative psychosocial impacts of cancer and its treatment.
Key Words: health-related quality of life childhood-cancer survivors
Abbreviations: HRQL, health-related quality of life QOL, quality of life MMQL, Minneapolis-Manchester Quality of Life YF, Youth Form RR, relative risk CI, confidence interval
Treatment advances over the past decades have greatly increased the prospects of surviving childhood cancer.1 Improved survival has placed increasing emphasis on the health status and health-related quality of life (HRQL) in childhood-cancer survivors. Numerous studies have shown that cancer and its treatment predispose to late morbidity and increase the risk of mortality in long-term childhood-cancer survivors.2–6 Treatment-related complications such as neurocognitive dysfunction, cardiopulmonary toxicity, endocrinopathies, and secondary malignancies may significantly impact the physical functioning of the survivors of childhood cancer.7,8 Studies of psychosocial functioning of adult survivors of childhood cancer have shown that 10% to 20% of individuals show signs of psychologic maladjustment in the form of mood disturbances, behavioral problems, and somatic distress.9–11 Few studies have focused on the impact of childhood cancer and its treatment on the health status and quality of life (QOL) of survivors.12–16 Most of these studies focus on adult survivors of childhood cancer and seem to indicate that the general health as perceived by these adult survivors of childhood cancer is very good, with only a small proportion of patients reporting fair or poor health.11 Female gender, a lower socioeconomic background, and a primary diagnosis of brain tumors, sarcomas, and Hodgkin's lymphoma have been associated with impaired health status among adult survivors of childhood cancer.15 Few studies address these issues among young children who are survivors of childhood cancer.17,18 These studies have relied on parents and/or clinicians to describe the health status in these young survivors, and the methodology involves comparisons between groups of childhood-cancer survivors treated with differing intensities of treatment, without comparisons to a healthy referent population. Small sample size has limited the generalizability of the findings from these studies. Thus, little information is available about the overall HRQL among children between 8 and 12 years old who are either undergoing active therapy for cancer or are long-term survivors, as compared with an age-matched healthy population.
The goal of this study was to describe HRQL in children between 8 and 12 years old diagnosed with cancer, either undergoing active therapy or after completion of therapy, using well-validated, age-appropriate, self-report tools and to compare the results with healthy children of the same age. We hypothesized that, when compared with an age-matched healthy population, children between 8 and 12 years old receiving active therapy for cancer would demonstrate significant deficits within the various domains of HRQL tested, whereas those who had completed treatment successfully would have an HRQL that was comparable to that of the general population.
METHODS
Instrument
The Minneapolis-Manchester Quality of Life-Youth Form (MMQL-YF) is a standardized patient self-report instrument designed to assess HRQL in childhood-cancer survivors between 8 and 12 years old.19 The MMQL was developed in 3 versions to address the developmental needs of different age groups. The YF was developed for children between 8 and 12 years old and is administered to the child by interview. The Adolescent Form was developed for adolescents between 13 and 20 years old and is self-administered.20 The Adult Form currently is under development for cancer survivors between 21 and 55 years old.
The MMQL-YF was created by using the experience of patients and their parents, nurses, and doctors to identify particular long-term problems that these patients may face. The instrument defines HRQL in terms of the effects of disease and treatment on physical and psychologic functioning as well as overall outlook on life. The chief domains defined relate to different aspects of the child's health: activity, mobility, relationship with family members, moods and feelings, hearing, speech and sight, and outlook on life. It consists of 32 items comprising 4 scales: physical functioning, psychologic functioning, physical symptoms, and outlook on life/family dynamics (Table 1). The physical-functioning scale measures activity and mobility, and the physical-symptoms scale focuses on pain and difficulties in speech, hearing, vision, and sleep. The psychologic-functioning domain assesses feelings, moods, and relationships with others, and the outlook-on-life/family-dynamics scale focuses on the interaction of the respondent with his/her parents and other family members and his/her outlook of the current and future life. An overall QOL score is also computed. Scoring ranges from 1 to 5, with 5 indicative of maximal HRQL. Higher MMQL-YF scores indicate minimal negative effect and thus greater HRQL. Data regarding reliability and validity of this instrument have been reported previously.19
Thus, the MMQL-YF is specific for survivors of childhood cancer between 8 and 12 years old and defines HRQL in terms of the impact of disease and treatment on an individual's physical and psychologic functioning, as well as overall outlook on life. Yet, at the same time, the domains and the items within them do not specifically address issues related to the actual disease (cancer in this case), and hence the questionnaire can be used to assess HRQL among off-therapy cancer survivors and healthy controls.
Patients and Procedures
Twenty institutions within the United States participated in this study (see "Acknowledgments"). The institutional review board at each participating institution approved this research protocol. The study population included children between 8 and 12 years old drawn from 2 pools: (1) patients actively undergoing treatment for cancer for at least 2 months (cancer patients on active therapy) and (2) patients who had successfully completed treatment for cancer and were in remission for 1 years (off-therapy survivors). Primary physicians gave permission to contact patients and their parents. Informed consent was obtained in person or by mail. In all cases, initial contact with the children was made through the parents. For patients undergoing active therapy and for cancer survivors, the participating institutions attempted to enroll consecutive patients seen at the treating institution into the study. Nonetheless, study participants represent a convenience sample, because the institutions did not systematically quantify the eligible patient population, nor did they implement procedures to ensure that all eligible patients were invited to participate. All patients were interviewed in person or by telephone by a trained interviewer. All interviews were conducted without the family member being present in the room to ensure that responses were truly self-reported. Most (99%) interviews took place in person in the clinic.
A control group of healthy children between 8 and 12 years old from throughout the United States was identified by random-digit dialing (healthy controls).21 The interviewer explained the study to the parents and obtained informed consent from the parents and study participants. To avoid influence from family members in the child's responses and to ensure that all answers were those of the participant, the interviewer emphasized to the parents that the child should be alone in the room throughout the interview. Once their assurance and compliance had been obtained, the interviewer explained the study to the child and proceeded with questioning. The interviewer checked with the child periodically throughout the interview to ensure that no family member was within hearing distance.
All completed questionnaires were entered into a database, and all personal identifying information was removed. Data from all institutions were merged into a final comprehensive dBase file.
Statistical Analysis
Statistical analysis of the data was performed by using the Epilog plus, Windows alpha version 1.00 statistical software (J.D. Buckley, Epilog Windows Procedure, Pasadena Epicenter Software, Pasadena, CA). Scoring on the MMQL-YF ranges from 1 to 5, with 5 indicative of maximal HRQL. An overall QOL score was computed also.
Three sets of analyses are reported here. The first set compares the responses of the off-therapy survivors and healthy controls. The second set compares the responses of the cancer patients undergoing therapy with those of the healthy controls. Finally, the third set compares only the survivors' responses by diagnoses (acute leukemia, lymphoma, brain tumors, and other solid tumors), gender, ethnicity, age at study participation, and time since diagnosis. This last set of analyses was conducted for all survivors together and also as a stratified analysis of survivors by individual diagnoses.
Comparisons of means between the various groups were conducted by using analysis-of-variance techniques. Multiple-regression analysis was used to investigate predictors of poor QOL. Variables in the model included primary diagnosis, age at completion of survey, time since diagnosis, gender, and ethnicity. The level of statistical significance was set at .05. All P values were 2-sided. To calculate relative-risk (RR) estimates for poor QOL while controlling for the effects of demographic variables, we constructed multivariate models for poor overall QOL as well as poor QOL in each of the 4 domains as an outcome. HRQL was defined arbitrarily as being "poor" if the overall QOL score or the QOL scores for each domain were <25th percentile for the healthy controls. The final model comparing cancer patients with healthy controls included gender, age at questionnaire completion, ethnicity, and the respondent status (cancer patient versus healthy control). The final model analyzing cancer patients only included gender, age at questionnaire completion, ethnicity, primary diagnosis, and time since diagnosis. The median time between diagnosis and study participation was 5.9 years. To test the hypothesis that the HRQL would improve with time since diagnosis, and also get a better understanding of the impact of time since diagnosis on the HRQL among the off-therapy survivors, we chose to use 6 years as an arbitrary cutoff point.
RESULTS
Over a 5-year period (January 1997 to March 2002), 643 subjects between 8 and 12 years old participated in the study: 90 off-therapy cancer survivors, 72 children undergoing therapy for cancer, and 481 healthy controls.
Comparison of Cancer Survivors With Healthy Controls
A comparison of the HRQL scores between the off-therapy cancer survivors and the healthy controls is shown in Table 3.
Overall QOL
The overall QOL of the off-therapy cancer survivors was significantly better than that of healthy controls (mean scores: 4.15 vs 4.05; P = .04). The higher QOL score was statistically significant among male but not female survivors (P = .02 and 0.58, respectively). Off-therapy survivors of nonneurologic solid tumors reported significantly superior QOL than healthy controls (P = .05). No significant differences were observed in children with other diagnoses, although the brain-tumor survivors reported lower scores in overall QOL and in all domains examined. Off-therapy survivors between 10.5 and 12 years old at study participation reported higher scores than the healthy controls (P = .03), as did off-therapy survivors who were >6 years from diagnosis (P = .04).
Physical Functioning
Overall physical-functioning scores of the off-therapy cancer survivors did not differ significantly from those of healthy controls (mean score: 3.99 vs 4.0; P = .83).
Physical Symptoms
Off-therapy cancer survivors reported higher scores in physical symptoms than did healthy controls (4.30 vs 4.15; P < .001). Higher physical-symptoms scores were reported by both males and females, by survivors of nonneurologic solid tumors, and by survivors who were between 10.5 and 12 years old at study participation.
Psychologic Functioning
Overall, off-therapy cancer survivors reported higher scores in the psychologic-functioning domain than did healthy controls (3.98 vs 3.92; P = .01). Again, certain subpopulations of off-therapy cancer survivors were more likely to report higher psychologic-functioning scores than were healthy controls. These subpopulations included male survivors, survivors of nonneurologic solid tumors, and survivors who were >6 years from diagnosis at the time of study participation.
Outlook on Life/Family Dynamics
The overall outlook on life/family dynamics of the off-therapy cancer survivors did not differ significantly from that of healthy controls (mean score: 4.23 vs 4.2; P = .62)
Comparison of Cancer Patients Undergoing Therapy With Healthy Controls
Multivariate Analysis: Comparison With Healthy Controls
Off-Therapy Cancer Survivors Compared With Healthy Controls
The results for off-therapy cancer survivors and cancer patients undergoing therapy are summarized in Table 5. When compared with healthy controls, off-therapy cancer survivors did not report any difference in their overall QOL, physical functioning, psychologic functioning, and outlook on life. However, off-therapy cancer survivors were more likely to report better QOL in the physical-symptoms domain when compared with the healthy controls, as were older study participants (10.5- to 12-year-olds) when compared with the younger ones (8- to 10.5-year-olds). Nonwhite children, when compared with the white children, reported poorer overall QOL and poorer QOL in the individual domains.
Cancer Patients Undergoing Therapy Compared With Healthy Controls
When compared with the healthy controls, cancer patients undergoing therapy were more likely to report poorer overall QOL (RR: 2.0; 95% confidence interval [CI]: 1.0–3.5), poorer physical functioning (RR: 2.5; 95% CI: 1.1–3.6), and poorer outlook on life (RR: 5.0; 95% CI: 1.5–8.5) (Table 5). Nonwhite children reported poorer QOL overall and in all domains when compared with the white children. Older study participants reported better QOL when compared with the younger participants.
Multivariate Analysis: HRQL Among Cancer Survivors
Off-Therapy Cancer Survivors
The results of the multivariate analysis are shown in Table 6. Female cancer survivors were 5 times more likely to report poor QOL in the physical-functioning domains when compared with males (RR: 5.0; 95% CI: 1.9–13.4). Older cancer survivors were less likely to report poorer QOL in the outlook-on-life domains when compared with the younger cancer survivors (RR: 0.2; 95% CI: 0.03–0.9). Primary diagnosis and time since diagnosis did not predict for poor QOL overall or among any of the domains studied.
Cancer Patients Undergoing Therapy
As can be seen in Table 6, among patients undergoing therapy for cancer, nonwhite children were more likely to report poorer psychologic functioning when compared with white children (RR: 9.3; 95% CI: 1.9–44.4). No other risk factor for poor QOL could be identified among patients receiving cancer therapy.
DISCUSSION
This study provides information regarding HRQL in a large and previously understudied cohort of young children between 8 and 12 years old who were either undergoing active treatment for cancer or survivors of cancer using the MMQL-YF.19 The MMQL-YF is designed specifically for survivors of cancer between 8 and 12 years old and measures HRQL as viewed by the affected children, not from the point of view of surrogates such as parents or guardians.
In this study, off-therapy cancer survivors reported statistically significantly higher overall QOL scores when compared with healthy controls. However, the clinical significance of a difference of this magnitude remains to be defined. Subgroups of off-therapy cancer survivors reporting higher overall QOL scores when compared with healthy controls included boys, survivors of nonneurologic solid tumors, and survivors who had been diagnosed with cancer 6 years before the study. Physical functioning and outlook on life did not differ between cancer survivors and healthy controls. The cancer survivors had significantly higher psychologic-functioning and physical-symptoms scores than did healthy controls. Examining predictors of poor QOL revealed nonwhite children to be at a higher risk of reporting poor QOL overall and among the various domains. Examining predictors of poor QOL among survivors revealed no significant associations with gender, primary diagnosis, age at participation, or time since diagnosis except for poorer physical functioning among females. However, only a small number of subjects in our study reported poor QOL, which may have limited our ability to identify predictors of poor QOL. The excellent HRQL observed in this group of survivors may be explained by an adjustment of attitude and overall view of life that may occur after experiencing a life-threatening situation. Thus, the survivors probably find their current life more satisfying and might very well perceive a smaller impact from the deficiencies in their current health status. They also may be comparing their current status with the status during the time of illness and hence perceive a superior HRQL than healthy controls. Improvements in the affected child's psychologic adjustment also may be caused by increased parental attention, as observed in some sibling studies.22,23 Unfortunately, this study was not designed to explore in greater detail the impact of the various reasons responsible for the reported HRQL in this patient population.
Previous studies have also reported a better QOL among the off-therapy survivors than healthy controls, with the finding being more marked among the younger survivors.10,24 Apajasalo et al24 evaluated the HRQL in young adult survivors (16–35 years old) of cancer. The survivors reported significantly better levels of vitality, distress, depression, discomfort, elimination, and sleeping dimensions. The difference was statistically significant but not thought to be clinically significant. There was no association of HRQL with original diagnosis. There were no patients with brain tumors in this group of survivors. Elkin et al10 studied the psychologic functioning of 161 cancer survivors >14.5 years old. Symptom Checklist-90 Revised, a self-report measure of psychologic symptomatology, was used to assess psychologic functioning. The survivors were found to have very low levels of psychologic distress and significantly better psychologic health than expected from normative data. In another study on psychologic functioning of 7- to 15-year-old cancer survivors based on parental reporting, a fourfold increase in social and behavioral problems was found.25 The difference in the outcomes of these studies is thought to be due to methodologic issues, ie, self-report versus parent report and potential influence of repressive adaptation on the self-reports of pediatric cancer survivors.10 In general, parent-child agreement is low, and, when direct comparisons can be made, there is a tendency for children to underreport symptoms relative to reports made by their parents.26–28 Studies describing the overall sense of well-being show no difference between young-adult survivors of nonneurologic tumors and healthy controls in overall sense of well-being.29–31 Certain vulnerable populations do exist, such as patients with acute lymphoblastic leukemia and brain tumors exposed to cranial radiation.30–32
Most studies assessing HRQL in childhood-cancer survivors have focused on young adults,9–15 with a few exceptions in which the focus was primarily younger children.17 A comparison of young off-therapy survivors of advanced neuroblastoma with Wilms' tumor survivors revealed a greater burden of morbidity in the former.17 In particular, survivors of advanced neuroblastoma were more likely to exhibit deficits in hearing and speech. However, this study relied on parent report, and there was no comparison with healthy children.
As anticipated, children on active therapy for cancer reported worse overall QOL than healthy controls in the current study. Their scores were significantly lower in the physical-functioning and outlook-of-life domains as compared with the healthy children. Furthermore, nonwhite children were more likely to report poorer QOL overall and in the individual domains, whereas older children reported better QOL when compared with younger children. Few studies have focused on the HRQL issues among young children undergoing active therapy for cancer. Waters et al18 studied HRQL in 31 children between 5 and 18 years old on maintenance therapy for acute lymphocytic leukemia by using parental reports on the Child Health Questionnaire and Pediatric Cancer Quality of Life Inventory-32 (PCQOL). The parents reported significantly lower functioning and well-being than population norms for all Child Health Questionnaire scales.
Our study has several limitations. First, this study lacks a random sample; participation was voluntary, and although we attempted to enroll all eligible subjects at each participating institution, the clinical characteristics of those who were not recruited are not available. Because there may exist a correlation between HRQL and willingness to participate, the results could potentially be biased. The study cohort had few survivors of brain tumors, a particularly high-risk group, as indicated by the lower scores reported by the brain-tumor group when compared with the healthy controls. The small numbers in the brain-tumor group precluded us from arriving at more meaningful conclusions. Future studies need to focus on this particularly vulnerable population.
Treatment-related information was not available in this study and hence could not be assessed as a risk factor for HRQL. Moreover, details regarding medical and functional late effects were not available and could not be investigated in this study. This study used a cross-sectional study design for evaluation of HRQL. Because HRQL can change over time, longitudinal assessments are preferable. Thus, it would be ideal to assess HRQL periodically with standardized, disease-specific instruments such as the MMQL as part of therapeutic cancer trials.
Healthy individuals between 8 and 12 years old (with no history of cancer or any other chronic illness) from throughout the United States were identified by random-digit dialing to procure normative data for the MMQL-YF, whereas a trained interviewer interviewed cancer patients in person in the clinic. No systematic differences were observed in the patterns of responses obtained from telephone interviews versus face-to-face interviews. Although it would have been ideal to use the same methodology for both these groups, it was not feasible to do face-to-face interviews of a large population of geographically diverse control subjects. It is for this reason that this difference in methodology was accepted despite its limitations.
The major strength of this study includes the use of a validated, comprehensive, multidimensional self-report instrument developed to assess HRQL among childhood-cancer survivors between 8 and 12 years old. HRQL among survivors in this age group is understudied. Despite its limitations, this remains one of the largest studies of self-reported HRQL in children with cancer between 8 and 12 years old. Few investigations have focused exclusively on this age group; instead, many have incorporated them into a larger study with either adults or children of other ages. The large control population for comparison and lack of proxy responses further strengthen this study.
We have demonstrated that although children undergoing treatment for cancer may report low overall QOL, physical functioning, and outlook on life, survivors report QOL scores that are as good, if not better, than age-matched controls. The results of this study are reassuring. However, it is possible that this group of survivors may have been too young to encounter some of the negative psychosocial impacts of cancer and its treatment.
Survival will always remain the ultimate goal in treatment of children with cancer. As treatments and clinical outcomes improve, attention needs to be focused on the long-term well-being of the survivors. The ultimate goal is to identify and minimize the negative consequences of childhood cancer and its treatment. We hope that, in the future, standardized instruments such as the MMQL-YF would be incorporated into therapeutic cancer trials to obtain measurements of HRQL longitudinally.
ACKNOWLEDGMENTS
This work was supported in part by National Cancer Institute grants U10CA 098543 and COG AS972.
Participating institutions in the Children's Oncology Group Study AS972 (and principal investigators) are C.S. Mott Children's Hospital, Ann Arbor, MI (Raymond Hutchinson; National Cancer Institute grant 02971); Children's Health Care-Minneapolis, Minneapolis, MN (Maura C. O'Leary); Children's Hospital and Regional Medical Center, Seattle, WA (Douglas Hawkins); Children's Hospital at the Cleveland Clinic, Cleveland, OH (Joanne M. Hilden); Children's Hospitals and Clinics-St Paul, St Paul, MN (Christopher L. Moertel); Childrens Hospital Oakland, Oakland, CA (James Feusner); Childrens Hospital of Philadelphia, Philadelphia, PA (Beverly Lange; National Cancer Institute grant 11796); City of Hope National Medical Center, Duarte, CA (Judith Sato); DeVos Children's Hospital, Grand Rapids, MI (David R. Freyer); Hackensack University Medical Center, Hackensack, NJ (Michael Harris); Hurley Medical Center, Flint, MI (Susumu Inoue); Kalamazoo Center for Medical Studies, Kalamazoo, MI (Leonard A. Mattano, Jr); Marshfield Clinic, Marshfield, WI (Michael J. McManus); Memorial Sloan Kettering Cancer Center, New York, NY (Peter G. Steinherz; National Cancer Institute grant 42764); Miami Children's Hospital, Miami, FL (Enrique Escalon); Schneider Children's Hospital at North Shore, Manhasset, NY (Arlene Redner); St John's Hospital and Medical Center, Detroit, MI (Hadi Sawaf); University of Mississippi Medical Center Children's Hospital, Jackson, MS (Jeanette Pullen; National Cancer Institute grant CA 15989); University of Missouri-Columbia, Columbia, MO (Katherine P. Kelly); and University of Illinois, Chicago, IL (Mary Lou Schmidt).
FOOTNOTES
Accepted Aug 26, 2004.
No conflict of interest declared.
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