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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy: meta-analysis of nine epidemiological studies

K Doi, MN Mieno, Y Shimada, and S Yoshinaga.

Review published: 2009.

Link to full article: [Journal publisher]

CRD summary

The review found the excess relative risk per Gy of second malignant neoplasms in childhood cancer survivors treated with radiotherapy was 0.53, 95% CI 0.22 to 1.31 with significant heterogeneity. The authors suggested that this was an underestimation. Limitations to the review process, uncertainty about the meta-analysis and study heterogeneity implied that the authors’ conclusions should be interpreted with caution.

Authors' objectives

To evaluate the risk of second malignant neoplasms in childhood cancer survivors treated with radiotherapy.

Searching

PubMed was searched from 1950 to April 2008 for publications in any language; search terms were reported. Bibliographies of retrieved articles, review articles, books and reports were handsearched.

Study selection

Cohort or case-control studies that evaluated the risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy and which expressed risk estimates as excess relative risk (ERR) per Gy (absorbed dose of ionising radiation) were eligible for inclusion. Eligible studies had to provide sufficient data to calculate the standard error (SE) of ERR estimates. Primary cancers in most of the included studies included all cancers or all cancers other than leukaemia; other studies were of solid cancer and skin haemangioma. Mean age of primary cancer diagnosis ranged from six months to 6.1 years. Radiotherapy dose ranged from zero to 288Gy. Treatment was mostly at the site of the second malignant neoplasm. Only one cohort study provided details of the mean follow-up period (16 years); for the nested case-control studies mean range of follow-up was 15 to 16 years. The second malignant neoplasms in most of the included studies were restricted to different individual sites and in the remaining studies were in all sites or all sites other than non-melanoma skin cancer (details were provided).

Two researchers independently performed the search. Authors were contacted where information was missing to enable studies to be selected.

Assessment of study quality

A formal validity assessment was not performed.

Data extraction

ERRs were extracted with 95% confidence intervals (CI) or standard errors. Data was then used to calculate the standard error for all studies included in the meta-analysis. Authors were contacted to obtain missing data.

The authors did not report how many reviewers performed the extraction.

Methods of synthesis

Studies were expected to be heterogeneous, so pooled ERR with 95% CI were calculated using both a fixed-effect and a random-effects model. Between-study heterogeneity was determined using the Cochrane Q statistic. Publication bias was assessed using the method of Egger et al. and visually using funnel plots.

Sensitivity analyses were performed in order to assess the effect of study design, individual studies and primary cancer (all, all other than leukaemia, or solid cancer). Results were compared to those for atomic bomb survivors and reasons for differences explored. The authors performed a pooled analysis that excluded two studies which may have included the same participants.

Results of the review

The authors reported that nine relevant studies were identified: three cohort studies and six nested case-control studies. Two of the nested-control studies were from one cohort study. Five studies (two cohort studies and three nested case-control studies) were from a second cohort study. Therefore, overall the studies were derived from four cohort studies (n=70,739, range 4,581 to 26,677).

The pooled analysis found an increased risk of secondary malignant neoplasms after radiotherapy using a fixed-effect model (ERR per Gy 0.50, 95% CI 0.20 to 1.21) and a random-effects model (ERR per Gy 0.53, 95% CI 0.22 to 1.31). There was significant heterogeneity (Q=40.4, p<0.001).

The estimates were similar when ERRs were determined using a random-effects model for cohort and nested case-control studies separately, for the individual analyses of the two cohort studies that contributed more than one study to the analysis (analysis for two and five studies) and for the primary cancer sites of all cancers (three studies), all cancers other than leukaemia (two studies) and solid cancers (two studies). Confidence intervals were very wide for some of the analyses. The final pooled analysis that excluded two studies that may have included the same participants gave larger ERR estimates for both the fixed-effect (ERR per Gy 0.73, 95% CI 0.27 to 1.93) and random-effects models (ERR per Gy 0.69, 95% CI 0.25 to 1.92).

The overall ERR estimate was only slightly higher than solid cancer ERR estimates averaged over age and sex in atomic bomb survivors (Preston et al. 2007, see Other Publications of Related interest) and much lower than the ERR of solid cancer incidence in atomic bomb survivors exposed as young children (Preston et al. 2008, see Other Publications of Related Interest).

Egger’s test gave no evidence for publication bias, but the funnel plot results were less clear.

Authors' conclusions

The overall ERR per Gy estimate of second malignant neoplasms in childhood cancer survivors resulting from radiotherapy were 0.50 (95% CI 0.20 to 1.21) when a fixed-effect model was used and 0.53 (95% CI 0.22 to 1.31) when a random-effects model was used. There was significant heterogeneity. This effect was far smaller than that of atomic bomb survivors exposed as young children, which suggested an underestimation.

CRD commentary

The review addressed a well-defined question in terms of participants, interventions and relevant outcomes, but the delineation between the included studies was less clear. Only one relevant database was searched and unpublished studies were not considered, so some relevant studies may have been missed even though the search was in any language and reference lists were reviewed. Publication bias was assessed. No formal validity assessment was performed. Study selection was performed in duplicate, but whether efforts were made to reduce error and bias in data extraction was not stated. Relevant study details were reported, but there were no details of loss to follow-up and limited details of participants' age. Statistical heterogeneity was assessed and there was evidence for heterogeneity. Unfortunately seven of the included studies were substudies of two cohort studies, so there was a possibility that the same participants contributed to the meta-analysis more than once and, therefore, the statistical analysis method used for the meta-analysis was suspect (although the authors did try to allow for this in sensitivity analyses). Limitations to the review process, uncertainty about the meta-analysis and the heterogeneity of the studies implied that the authors’ conclusions should be interpreted with caution.

Implications of the review for practice and research

The authors did not state any implications for practice.

Research: The authors identified a need for more studies of the risk of secondary malignant neoplasms among childhood cancer survivors in order to understand further the carcinogenic effects of radiotherapy on children, particularly in view of the perceived heterogeneity and underestimation of the ERR in the present review.

Funding

The authors stated that there was no external support for the study.

Bibliographic details

Doi K, Mieno MN, Shimada Y, Yoshinaga S. Risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy: meta-analysis of nine epidemiological studies. Paediatric and Perinatal Epidemiology 2009; 23(4): 370-379. [PubMed: 19523084]

Other publications of related interest

Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M, Mabuchi K, Kodama K. Solid cancer incidence in atomic bomb survivors; 1958-1998. Radiation research 2007; 168(1): 1-64.6

Preston DL, Cullings H, Suyama A, Funamoto S, Nishi N, Soda M, Mabuchi K, Kodama K, Kasagi F, Shore RE. Solid cancer incidence in atomic bomb survivors exposed in utero or as young children. Journal of the National Cancer Institute 2008; 100: 428-436.

Indexing Status

Subject indexing assigned by NLM

MeSH

Child; Child, Preschool; Dose-Response Relationship, Radiation; Epidemiologic Studies; Female; Humans; Male; Neoplasms /radiotherapy; Neoplasms, Radiation-Induced /epidemiology; Neoplasms, Second Primary /epidemiology; Risk Factors; Survivors /statistics & numerical data

AccessionNumber

12009106712

Database entry date

15/09/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 19523084

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