To assess the effectiveness of more extensive radiotherapy and of adjuvant chemotherapy on the long-term outcome of early-stage Hodgkin's disease.

The authors stated that trials were identified from computerised searches of medical databases and the CLINPROT trial protocol database of the National Cancer Institute. However, they did not state which electronic databases were searched, nor did they provide search terms or dates. Further trials were identified from lists prepared by the Union International Contre le Cancer, the US National Cancer Institute and the UK Coordinating Committee on Cancer Research, as well as from abstracts presented at meetings, from the reference lists of published trials and review articles, and through discussions with investigators. It was not stated whether any language restrictions were applied. However, only studies from Western Europe and North America were included, as the authors were unable to contact the authors of two identified trials from Obminsk and Moscow.

Study designs of evaluations included in the review

The review included individual patient data (IPD) from randomised controlled trials (RCTs) that the review authors assessed as having adequate concealment of allocation.

Specific interventions included in the review

Studies investigating extensive radiotherapy versus less extensive radiotherapy, or radiotherapy with adjuvant chemotherapy versus radiotherapy alone, were eligible for inclusion. The radiotherapy fields were involved field, extended field, mantle field, and subtotal or total nodal irradiation. The chemotherapy combinations were:

MOPP (mechlorethamine, vincristine, procarbazine, prednisone),

LOPP (chlorambucil, vincristine, procarbazine, prednisone),

BOPP (carmustine, vincristine, procarbazine, prednisone),

LVPP (chlorambucil, vinblastine, procarbazine, prednisone),

MOP(P) (MOPP with optional use of prednisone),

COP (cyclophosphamide, vincristine, procarbazine),

ABVD (adriamycin, bleomycin, vinblastine, DTIC), and

VBMtx (vinblastine, bleomycin, methotrexate).

Participants included in the review

Patients with early-stage Hodgkin's disease undergoing treatment with radiotherapy and/or chemotherapy were eligible for inclusion. Most of the included studies only included patients with stage I disease and/or patients with stage II disease.

Outcomes assessed in the review

The authors did not state any inclusion criteria relating to the outcomes. The outcomes assessed in the review were treatment failure at 10 years and death. Treatment failure was defined as death without remission or recurrence after remission.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for review, or how many reviewers performed the selection.

Datasets were compared with published figures and were checked for completeness, for internal consistency, for balance of group sizes overall and of prognostic subgroups, and for other indications of possible errors in the conduct of the trial or the submission of data. Omissions and errors were corrected by correspondence with trial investigators. The review manuscript was sent to trial investigators for comment.The authors did not state how the papers were assessed for validity, or how many reviewers performed the validity assessment.

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. Data were extracted from the IPD provided by the trial authors. The trial authors were asked to provide data on age, stage of disease, date of entry, treatment allocation, date of recurrence, and date and cause of death, or date last seen, for each patient who had been randomised in the trial.

For each trial, the total number of deaths (or failures) observed was compared with the number expected to occur in each year of follow-up. Variance was also calculated. Where separate data for each year of follow-up were not available, the data were derived from the crude total number of deaths in each group.

For the few eligible trials that did not provide IPD, crude mortality data from the investigators or from published data were used wherever possible.

How were the studies combined?

The log rank difference between the observed and expected treatment failures or deaths was summed and, together with study variance, used to calculate an overall odds ratio and its 95% confidence interval.

How were differences between studies investigated?

To assess heterogeneity, chi-squared tests were performed on each group of trials (more versus less radiotherapy, and radiotherapy plus chemotherapy versus radiotherapy alone) and for the individual variables within each group (disease stage, laparotomy, age and gender).

Eight RCTs with 1,974 patients were included in the meta-analysis of more versus less extensive radiotherapy; there were 1,005 and 969 patients in the more and less extensive radiotherapy groups, respectively. There were 4 further trials, with less than 200 patients, that did not provide IPD.

Thirteen RCTs with 1,688 patients were included in the meta-analysis of radiotherapy plus chemotherapy versus radiotherapy alone. There were 236 and 240 patients in the radiotherapy plus chemotherapy and the radiotherapy alone groups, respectively; and there were 603 versus 616 patients in the meta-analysis of radiotherapy plus chemotherapy versus more radiotherapy. There were 5 additional trials, with around 300 patients, that did not provide IPD. In addition, 2 paediatric trials only provided IPD relating to overall mortality (226 patients).

Formal tests for heterogeneity between trials for more versus less radiotherapy, and for radiotherapy plus chemotherapy versus radiotherapy alone, demonstrated marginal significance.

The combined result of the 8 RCTs of more versus less radiotherapy showed an overall reduction in the risk of treatment failure at 10 years with more extensive radiotherapy (31.3% versus 43.4% failures; P<0.00001). However, there was no improvement in the overall 10-year survival between more radiotherapy and less radiotherapy (77.1% versus 77% alive).

The combined result of the 13 RCTs of chemotherapy plus radiotherapy versus radiotherapy alone showed that the addition of chemotherapy to radiotherapy approximately halved the 10-year risk of failure (15.8% versus 32.7%; P<0.00001), with a small non significant improvement in survival (79.4% versus 76.5% alive).

More extensive radiotherapy, or the addition of chemotherapy to radiotherapy, had a large effect on disease control in the initial treatment of early-stage Hodgkin's disease, but only a small effect on overall survival. In addition, more extensive radiotherapy, or the addition of chemotherapy to radiotherapy, could prevent recurrences. If, however, chemotherapy had not been given initially, recurrences were found to be generally salvageable by re-treatment with chemotherapy.

The review addressed a clear question in terms of the participants, intervention and study design. The search strategy appears to have been adequate and it included unpublished and non-English language trials. However, specific details of the computerised searches were not reported, such as which databases were searched, the search terms and dates. The authors stated how many trials were identified for which data could not be retrieved, and the number of participants in such trials. It was not stated how judgements were made about the decision to include studies, or how the data were extracted from trials (e.g. how many reviewers performed the assessment and whether the reviewers were blinded). Therefore, the potential for reviewer bias and error cannot be assessed.

The data were assessed for completeness, internal consistency, and other indications of possible errors in the conduct of the trial or the submission of data. The trial investigators commented on the review manuscript and were involved in correcting omissions and errors, which was appropriate for this type of meta-analysis. The data were analysed using appropriate techniques for the meta-analysis of IPD. Heterogeneity was addressed through subgroup analysis with four different variables, to check for any differences in the results between trials.

Overall, this was a well-conducted IPD meta-analysis, although some methodological details were not reported. The authors' conclusions were supported by the data.

Practice: The authors did not state any implications for practice.

Research: The authors stated that additional RCTs are necessary to determine whether less intensive primary treatment, particularly a reduction in radiotherapy fields, achieves a similar survival rate as more intensive treatment.

United Kingdom Imperial Cancer Research Fund; Danish Medical Research Council, grant number 12-9481; European Community's BIOMED Program, grant number PL 931247; United Kingdom Medical Research Council.

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.