Authors' objectives

To evaluate the timing (immediate versus deferred) and intensity (combination chemotherapy versus single-agent chlorambucil) of initial chemotherapy for chronic lymphocytic leukemia (CLL).

Searching

Most of the RCTs were identified through the International Workshop on CLL. Searches of MEDLINE, a clinical trials database, meeting abstracts, and reference lists were also conducted to identify all of the relevant trials that started before 1990.

Study selection

Assessment of study quality

The authors do not state that they assessed validity.

Data extraction

It was not stated how many reviewers were involved in data extraction. For each individual patient, information was requested on his or her status at randomisation, sex, dates of birth, randomisation, death (or last follow-up) and cause of death. Queries, together with tables of deaths by allocated treatment and by other patient variables, were sent back to the responsible trialists for checking and, where necessary, the data were amended.

Methods of synthesis

Results of the review

Seven RCTs of immediate versus deferred chemotherapy were identified, involving 2210 patients. Three trials involving 242 patients (19 of whom had no follow-up data) investigated chlorambucil versus chlorambucil with the addition of a steroid. There were 2035 patients in ten trials (mostly with Binet stage B or C disease) of combination chemotherapy versus chlorambucil. Of these ten trials, four used COP, five used CHOP and one used chlorambucil plus epirubicin.

There were 2048 patients with early disease in six trials included in the analysis of immediate versus deferred chemotherapy (chlorambucil or chlorambucil plus prednisone/ prednisolone). Overall, there was a slightly larger death rate among patients allocated immediate chemotherapy (42.6%) than those allocated deferred treatment (41.6%), but the excess was not statistically significant (NS) (ratio of all death rates = 1.08; 95% CI 0.95 to 1.24, chi-square with 5 degrees of freedom = 1.7, p>0.1 (NS)). The 10 year survival was slightly worse (but NS) with immediate chemotherapy (44% versus 47% survival; difference: -3%, 95% CI -10% to 4%). A meta-analysis of 3 trials did not suggest that the addition of a steroid to chloroambucil affected patients survival (ratio of deaths with versus without steroid = 0.98, 95% CI 0.77 to 1.25). 2022 patients were included in the analysis of combination chemotherapy versus chlorambucil, with or without prednisone/ prednisolone (13 patients had no follow up data. The 5 year survival was 48% in both cases (difference: 0%, 95% CI -6% to 5%). A subgroup of six of these 10 trials involved anthracycline-containing regimen but again overall survival appeared no better than chlorambucil (anthracyclin-based regimen: 325 deaths among 627 patients; chlorambucil: 306 deaths among 636 patients; death rate ratio: 1.07; 95% CI 0.91 to -1.25, NS).

Authors' conclusions

In terms of survival, these trials support a conservative treatment strategy for CLL, i.e. no chemotherapy for most patients with early-stage disease, and single-agents chlorambucil as the first line treatment for most patients with advanced disease, with no evidence of benefits from early inclusion of an anthrocycline. The strategy will, however, need to be reconsidered as mature results become available from trials of other agents.

CRD commentary

The review included a clear objective. MEDLINE and clinical trials databases were the only electronic databases searched although a good effort was made to locate studies (including those unpublished) by other means. Information about the method of the review process (such as how decisions on the relevance of primary studies was made, and whether more than one reviewer conducted data extraction) was not available. There was no reported structured validity assessment of included studies (such as the use of a validity checklist), however, only RCTs were included in the review.

Implications of the review for practice and research

The authors did not state any implications for further research and practice.

Bibliographic details

CLL Trialists' Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. Journal of the National Cancer Institute 1999; 91(10): 861-868. [PubMed: 10340906]

Original Paper URL

http://jnci.oxfordjournals.org/content/91/10/861.abstract

Other publications of related interest

1. Binet JL, Antiquier A, Dighiero G, Chatang C, Pignet H, Goasguen J, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48:198-206. 2. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46:219-34.

Indexing Status

Subject indexing assigned by NLM

MeSH

Antineoplastic Combined Chemotherapy Protocols /administration & dosage /therapeutic use; Chlorambucil /administration & dosage; Cyclophosphamide /administration & dosage; Doxorubicin /administration & dosage; Drug Administration Schedule; Epirubicin /administration & dosage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell /drug therapy; Prednisone /administration & dosage; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Vincristine /administration & dosage

AccessionNumber

11999001115

Database entry date

30/09/2000

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.