Ovarian cancer is the leading cause of death from gynaecological cancers. Standard therapy consists of surgery and chemotherapy. Responses to chemotherapy are generally good, however, the majority of women will relapse, for which no curative treatment is available. The presence of certain immune cells in tumours is associated with longer survival. This suggests that stimulation of anti-tumour immune responses, i.e. immunotherapy, might be a useful approach to improve outcome for women with ovarian cancer.
In this review, the feasibility of antigen-specific active immunotherapy is evaluated. Antigen-specific active immunotherapy aims at the induction of anti-tumour immune responses through the administration of a tumour-antigen, a molecule that is expressed by tumour cells and hardly expressed by healthy cells. Information on clinical outcome, immunological responses, and side effects was collected.
Fifty-five studies, which included 3051 women with ovarian cancer were identified, published between 1966 and 2013. The most frequently described strategy was administration of antibodies targeting the tumour antigen CA-125 (2339 participants in 16 studies). Most of these primarily evaluated safety and immunological responses. Severe flu-like and gastrointestinal symptoms occurred in 7% to 30% of participants. Antibodies and immune cells recognising the tumour antigen CA-125 were frequently detected, albeit response rates varied between studies. Despite these promising immunological responses, no survival advantage for participants treated with CA-125 directed antibody compared to placebo was found in four large studies.
For strategies not relying on antibody administration, similar conclusions cannot be drawn as immune system to the vaccine. Overall, treatment was well-tolerated, with inflammatory side effects at injection site most frequently reported. Responses of the immune system were observed for most strategies studied, but their clinical benefit still has to be evaluated in large trials.
Quality of the evidence and conclusions
Because there is currently no high-quality evidence of clinical benefit, antibody therapy targeting CA-125 should in its current form not be incorporated in standard treatment.
Based on a lack of uniformity in included studies, we strongly advocate universal adoption of response definitions, guidelines for adverse events reporting, and directives for trial conduct and reporting. Furthermore, results from ongoing RCTs are awaited and further RCTs should be conducted.
We conclude that despite promising immunological responses, no clinically effective antigen-specific active immunotherapy is yet available for ovarian cancer. Results should be interpreted cautiously as there was a significant lack of relevant information for the assessment of risk of bias in both RCTs and non-RCTs.
Despite advances in chemotherapy, prognosis of ovarian cancer remains poor. Antigen-specific active immunotherapy aims to induce tumour-antigen-specific anti-tumour immune responses as an alternative treatment for ovarian cancer.
To assess the 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.
For the previous version of this review, a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL) 2009, Issue 3, Cochrane Gynaecological Cancer Group Specialized Register, MEDLINE and EMBASE databases and clinicaltrials.gov was performed (1966 to July 2009). We conducted handsearches of the proceedings of relevant annual meetings (1996 to July 2009).
For this update of the review the searches were extended to October 2013.
Randomised controlled trials (RCTs), as well as non-randomised non-controlled studies that included participants 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.
Two reviews authors independently performed the data extraction. Risk of bias was evaluated for RCTs according to standard methodological procedures expected by The Cochrane Collabororation or for non-RCTs using a selection of quality domains deemed best applicable to the non-randomised non-controlled studies.
Fifty-five studies were included (representing 3051 women with epithelial ovarian cancer). 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 the relevant information necessary to assess risk of bias. Serious biases in most of the included trials can therefore not be ruled out.
The largest body of evidence is currently available for CA-125 targeted antibody therapy (16 studies: 2339 participants). Non-RCTs of CA-125 targeted antibody therapy suggests increased survival in humoral and/or cellular responders. However, four large randomised placebo-controlled trials did not show any clinical benefit despite induction of immune responses in approximately 60% of participants.
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.