Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study.

PURPOSE: MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial. PATIENTS AND METHODS: From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery. RESULTS: Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens. CONCLUSION: Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.

Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee.

The purpose of this study was to determine patient characteristics and outcomes for bladder/prostate (BP) rhabdomyosarcoma (RMS) using an international cohort of prospectively treated patients comparing different treatment algorithms. Data were collected from 379 patients (1979-1998) treated on protocol; Intergroup Rhabdomyosarcoma Study, IRS-IV (n = 239 patients), International Society of Pediatric Oncology Malignant Mesenchymal Tumors (MMT) Committee MMT-84 and -89 (n = 74), Italian Cooperative Group, RMS-79 and RMS-88 Studies (n = 37) or German Cooperative Soft Tissue Sarcoma Study CWS-91 protocols (n = 29). A total of 322 (85%) patients had localized embryonal RMS (ERMS) and 27 had metastatic disease. Thirty patients (21 local disease; 9 metastatic) had nonembryonal BP RMS. Patients with localized ERMS had large tumors (64% >5 cm) that were invasive (54%) with uninvolved regional lymph nodes (N0, 93%). The 5-year failure-free survival (FFS) was 75% and the overall survival (OS) was 84%, with 89% of deaths attributed to disease. Treatment failures were usually local disease recurrence (60%). Predictors of FFS included T-stage (invasiveness), size, and histology. FFS was decreased for patients not receiving initial radiotherapy but this did not translate into a decreased OS. The 21 patients with localized nonembryonal BP RMS had a FFS and OS of 47%. The 36 patients with metastatic disease were more likely to be older and had large tumors that were invasive with alveolar histology and regional lymph node involvement. The 5-year FFS and OS were 41 and 44%, respectively. In conclusion, the majority of BP RMS patients had localized ERMS with a resultant good prognosis using current treatment algorithms. There were differences in FFS between treatment protocols but this did not result in an altered OS.

Long-term cause-specific mortality among survivors of childhood cancer.

CONTEXT: Survivors of childhood cancer are at increased risk of premature mortality compared with the general population, but little is known about the long-term risks of specific causes of death, particularly beyond 25 years from diagnosis at ages when background mortality in the general population starts to increase substantially. OBJECTIVE: To investigate long-term cause-specific mortality among 5-year survivors of childhood cancer in a large-scale population-based cohort. DESIGN, SETTING, AND PATIENTS: British Childhood Cancer Survivor Study, a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer before age 15 years between 1940 and 1991 in Britain and followed up until the end of 2006. MAIN OUTCOME MEASURES: Cause-specific standardized mortality ratios (SMRs) and absolute excess risks (AERs). RESULTS: Overall, 3049 deaths were observed, which was 11 times the number expected (SMR, 10.7; 95% confidence interval [CI], 10.3-11.1). The SMR declined with follow-up but was still 3-fold higher than expected (95% CI, 2.5-3.9) 45 years from diagnosis. The AER for deaths from recurrence declined from 97 extra deaths (95% CI, 92-101) per 10,000 person-years at 5 to 14 years from diagnosis, to 8 extra deaths (95% CI, 3-22) beyond 45 years from diagnosis. In contrast, during the same periods of follow-up, the AER for deaths from second primary cancers and circulatory causes increased from 8 extra deaths (95% CI, 7-10) and 2 extra deaths (95% CI, 2-3) to 58 extra deaths (95% CI, 38-90) and 29 extra deaths (95% CI, 16-56), respectively. Beyond 45 years from diagnosis, recurrence accounted for 7% of the excess number of deaths observed while second primary cancers and circulatory deaths together accounted for 77%. CONCLUSION: Among a cohort of British survivors of childhood cancer, excess mortality from second primary cancers and circulatory diseases continued to occur beyond 25 years from diagnosis.

Health-status of adult survivors of childhood cancer: a large-scale population-based study from the British Childhood Cancer Survivor Study.

The purpose of this study was to investigate the effect of childhood cancer and its treatment on self-reported health-status in 10,189 adult survivors of childhood cancer in Britain. Age- and sex-adjusted scores on the SF-36 Mental and Physical Component Summary scales (MCS, PCS, respectively) were compared between survivors and UK norms, and between subgroups of survivors, by multiple regression. Survivors had comparable scores to UK-norms on the MCS scale (difference (D) = -0.1, 99% CI: -0.5, 0.3). The difference in scores between survivors and UK-norms on the PCS scale varied by age (p(heterogeneity) < 0.001). Young survivors (16-19 years) scored similarly to UK-norms (D = 0.5, (-1.1, 2.2), whereas the age groups of 25 and older scored statistically and clinically significantly below UK-norms (all p-values < 0.0001), with Ds ranging between -2.3 (-3.5, -1.2) and -3.7 (-5.0, -2.4). Survivors of central nervous system (CNS) and bone tumors scored significantly (p-value at all ages <0.003) below UK-norms on the PCS scale. Specifically, these survivors were substantially more limited in specific daily activities such as, for example, walking a mile (40, 63%, respectively) when compared to UK-norms (16%). In conclusion, childhood cancer survivors rate their mental health broadly similarly to those in the general population. Survivors of CNS and bone tumors report their physical health-status to be importantly below population norms. Although self-reported physical health is at least as good as in the general population among young survivors, this study suggests that perceived physical health declines more rapidly over time than in the general population.

Assessment of health-related quality of life of adolescent cancer patients using the Minneapolis-Manchester Quality of Life Adolescent Questionnaire.

BACKGROUND: Improved survival after childhood cancer has shifted the focus to health-related quality of life (HRQL)-an understudied problem, especially among adolescents. PROCEDURE: We assessed HRQL among adolescents utilizing a validated self-report tool, the Minneapolis-Manchester Quality of Life (MMQL) Adolescent Form, consisting of 46 items comprising seven domains: physical, cognitive, psychological and social functioning, body image, intimate relations, and outlook on life, and computed an overall QoL score. The MMQL Adolescent Form was administered to 226 adolescent survivors of childhood cancer a median of 7.8 years from diagnosis (off therapy-median age: 16.2 years), 136 adolescent cancer patients undergoing therapy (on therapy-median age: 16.4 years), and 134 healthy adolescents (controls-median age: 15.5 years). Primary diagnoses included leukemia (46%), lymphoma (26%), brain tumors (5%), and other solid tumors (23%). RESULTS: Compared to healthy controls, on-therapy patients were at increased risk for reporting poor overall QoL [Odds Ratio (OR) = 3.3, P = 0.002)] and poor physical functioning (OR = 11.8, P < 0.001). Off-therapy survivors did not differ significantly from healthy controls for overall QoL (OR = 1.6, P = 0.5) or any HRQL domains. Female patients, both on- and off-therapy, were more likely to report poorer overall QoL, physical, psychological and cognitive functioning as well as poorer body image when compared with male patients. CONCLUSIONS: While adolescent cancer patients undergoing active therapy report poor physical functioning, there is no evidence of long-term QoL sequelae.

The use of the SF-36 questionnaire in adult survivors of childhood cancer: evaluation of data quality, score reliability, and scaling assumptions.

BACKGROUND: The SF-36 has been used in a number of previous studies that have investigated the health status of childhood cancer survivors, but it never has been evaluated regarding data quality, scaling assumptions, and reliability in this population. As health status among childhood cancer survivors is being increasingly investigated, it is important that the measurement instruments are reliable, validated and appropriate for use in this population. The aim of this paper was to determine whether the SF-36 questionnaire is a valid and reliable instrument in assessing self-perceived health status of adult survivors of childhood cancer. METHODS: We examined the SF-36 to see how it performed with respect to (1) data completeness, (2) distribution of the scale scores, (3) item-internal consistency, (4) item-discriminant validity, (5) internal consistency, and (6) scaling assumptions. For this investigation we used SF-36 data from a population-based study of 10,189 adult survivors of childhood cancer. RESULTS: Overall, missing values ranged per item from 0.5 to 2.9 percent. Ceiling effects were found to be highest in the role limitation-physical (76.7%) and role limitation-emotional (76.5%) scales. All correlations between items and their hypothesised scales exceeded the suggested standard of 0.40 for satisfactory item-consistency. Across all scales, the Cronbach's alpha coefficient of reliability was found to be higher than the suggested value of 0.70. Consistent across all cancer groups, the physical health related scale scores correlated strongly with the Physical Component Summary (PCS) scale scores and weakly with the Mental Component Summary (MCS) scale scores. Also, the mental health and role limitation-emotional scales correlated strongly with the MCS scale score and weakly with the PCS scale score. Moderate to strong correlations with both summary scores were found for the general health perception, energy/vitality, and social functioning scales. CONCLUSION: The findings presented in this paper provide support for the validity and reliability of the SF-36 when used in long-term survivors of childhood cancer. These findings should encourage other researchers and health care practitioners to use the SF-36 when assessing health status in this population, although it should be recognised that ceiling effects can occur.

Health-related quality of life in young survivors of childhood cancer using the Minneapolis-Manchester Quality of Life-Youth Form.

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.

The Minneapolis-Manchester Quality of Life instrument: Reliability and validity of the Youth Form.

OBJECTIVE: Improvements in survival after childhood cancer have increased emphasis on health-related quality of life (HRQoL) of survivors. We developed the Minneapolis-Manchester Quality of Life-Youth Form (MMQL-YF) as a standardized patient self-report instrument designed to assess HRQoL in childhood cancer survivors between the ages of 8 and 12 years. STUDY DESIGN: To validate the instrument, the MMQL-YF was administered to 643 children (481 healthy, 162 with cancer). Factor analysis was conducted to refine the instrument, and Cronbach's alpha coefficient was used to measure its internal reliability. Known-groups validity was determined by comparing healthy children with those with cancer. Construct validity was studied by a comparison of similar domains in the MMQL-YF and the Child Health Questionnaire (CHQ). Stability was tested by re-administration of the MMQL-YF 2 weeks later. RESULTS: Internal consistency reliability was in the acceptable range for this instrument. The MMQL-YF was able to distinguish between known groups, and its scales correlated highly with similar CHQ domains. Test-retest reliability showed that the instrument was extremely stable in all scales tested. CONCLUSION: Data provide evidence for the validity and reliability of the MMQL-YF as a comprehensive, multidimensional, self-report instrument for measuring HRQoL among childhood cancer survivors.

The Minneapolis-Manchester Quality of Life instrument: reliability and validity of the Adolescent Form.

PURPOSE: With improvement in survival after childhood cancer, increasing emphasis is being placed on the impact of treatment and its sequelae on the health-related quality of life (HRQL) of survivors. The Minneapolis-Manchester Quality of Life Instrument (MMQL) is a standardized patient self-report instrument designed to assess HRQL in survivors of childhood cancer. The MMQL is being developed for three age groups to address the changing developmental need of different ages: MMQL-Youth (8 to 12 years), MMQL-Adolescent (13 to 20 years), and MMQL-Young Adult (21 to 45 years). This report focuses on the development and testing of the MMQL-Adolescent Form. PATIENTS AND METHODS: To validate the instrument, the MMQL-Adolescent Form was administered to 397 adolescents (129 healthy individuals, 110 patients with cancer undergoing therapy, and 158 subjects off therapy for cancer). Factor analysis was conducted to refine the instrument. Construct validity was conducted by comparing similar constructs in the MMQL-Adolescent Form and the Child Health Questionnaire (CHQ). Discriminate validity was determined by comparing healthy children with children with cancer either on or off therapy. Stability of the MMQL was tested by readministering the MMQL-Adolescent Form 2 weeks later. RESULTS: Internal consistency reliability was in the acceptable range for this instrument. The MMQL was able to discriminate between the three study populations. There were high correlations between the MMQL scales and similar CHQ domains. Test-retest reliability of the MMQL-Adolescent Form demonstrated that the instrument was extremely stable in all scales tested. CONCLUSION: Overall, the data provide evidence for the validity and reliability of the MMQL-Adolescent Form as a comprehensive, multidimensional self-report instrument for measuring HRQL among adolescent survivors of childhood cancer.