Antigen-specific active immunotherapy for ovarian cancer.
BACKGROUND
Despite advances in chemotherapy, prognosis of ovarian cancer remains poor. Antigen-specific active immunotherapy aims to induce a tumour-antigen-specific anti-tumour immune responses as an alternative treatment for ovarian cancer.


OBJECTIVE
To assess feasibility of antigen-specific active immunotherapy for ovarian cancer. Primary outcomes are clinical efficacy and antigen-specific immunogenicity with carrier-specific immunogenicity and side-effects as secondary outcomes.


METHODS
A systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2009, Cochrane Gynaecological Cancer Group Specialized Register, MEDLINE and EMBASE databases and clinicaltrials.gov was performed (1966 to July 2009). Hand searches were conducted of the proceedings of relevant annual meetings (1996 to July 2009).


METHODS
Randomised controlled trials (RCTs), as well as non-randomised non-controlled studies that included patients with epithelial ovarian cancer, irrespective of stage of disease, and treated with antigen-specific active immunotherapy, irrespective of type of vaccine, antigen used, adjuvant used, route of vaccination, schedule, and reported clinical or immunological outcomes.


METHODS
Data extraction was performed independently by two review authors. Risk of bias was evaluated with the Delphi-list for RCTs or a selection of quality domains pivotal to the assessment of non-RCTs and deemed best applicable to the non-randomised non-controlled studies.


RESULTS
Thirty-six studies were included. Response definitions showed substantial variation between trials, which makes comparison of trial results unreliable. Information on adverse events was frequently limited. Furthermore, reports of both RCTs and non-RCTs frequently lacked information necessary to assess risk of bias. Serious biases in these trials can thus not be ruled out.The largest body of evidence is currently available for CA-125 targeted antibody therapy (15 studies: 1505 patients). Non-RCTs of this CA-125 targeted antibody therapy suggest increased survival in humoral and/or cellular responders. However, three large randomised placebo-controlled trials did not show any clinical benefit despite induction of immune responses in approximately 60% of patients.Other small studies targeting many different tumour antigens showed promising immunological results. As these strategies have not yet been tested in RCTs, no reliable inferences about clinical efficacy can be made. Given the promising immunological results, limited side effects and toxicity exploration of clinical efficacy in large well-designed RCTs may be worthwhile.


CONCLUSIONS
We conclude that despite promising immunological responses no clinically effective antigen-specific active immunotherapy is yet available for ovarian cancer. Furthermore, the adoption of guidelines to ensure uniformity in trial conduct, response definitions and trial reporting is recommended to improve quality and comparability of immunotherapy trials.
Leffers
Ninke
N
University Medical Center Groningen, Hanzeplein 1, P.O. Box 30.001, Groningen, Netherlands, 9700 RB.
Daemen
Toos
T
Helfrich
Wijnand
W
Boezen
H Marike
HM
Cohlen
Ben J
BJ
Melief
Kees
K
Nijman
Hans W
HW
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018394:CA-125 Antigen / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic
D000911:Antibodies, Monoclonal; D018394:CA-125 Antigen