Current evidence suggests that, despite promising immune responses, no clinically effective antigen-specific active immunotherapy is yet available for ovarian cancer. It should be noted that this review used inappropriate criteria to assess risk of bias of non-randomised studies, therefore these results should be interpreted with caution. Further studies with standardised clinical endpoints (to improve comparability) are needed to address the current review question.
Overall summary High risk of bias in the review
The author's used an inappropriate (non-validated) tool to assess the risk of bias in non-randomised controlled trials.
|A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4?||Probably no|
|B. Was the relevance of identified studies to the review's research question appropriately considered?||Probably yes|
|C. Did the reviewers avoid emphasizing results on the basis of their statistical significance?||Probably yes|
|Risk of bias in the review||High|
|Number of studies||67|
|Number of participants||3632|
|Last search date||July 2017|
|Objective||To evaluate the clinical efficacy of antigen-specific active immunotherapy for the treatment of ovarian cancer (based on tumour response measured by RECIST criteria and/or cancer antigen (CA)-125 levels, response to post-immunotherapy treatment, and survival differences); and to establish which combinations of immunotherapeutic strategies with tumour antigens provide the best immunological and clinical results.|
|Population||Women with epithelial ovarian cancer, irrespective of disease stage.|
|Interventions||Any antigen-specific active immunotherapy irrespective of the type of vaccine, antigen or adjuvant; or the route of vaccination; or the vaccination schedule.|
|Comparator||Any other type of antigen-specific active immunotherapy.|
|Outcome||Primary outcomes: clinical efficacy (tumour responses to immunotherapy (complete/partial response, stable/progressive disease), as measured by cancer antigen (CA)-125 levels according to or transposable to Gynaecologic Cancer Intergroup (GCIG) criteria; or tumour response according to World Health Organisation (WHO) criteria - WHO 1979 - or Response Evaluation Criteria in Solid Tumors (RECIST) criteria; responses to post-immunotherapy treatment; survival differences, including time to relapse or progression-free survival); and antigen-specific immunogenicity (numbers of observed antigen-specific humoral and cellular responses).
Secondary outcomes: carrier-specific immunogenicity; and adverse events.
|Study design||Phase I and II non-randomised studies and phase III randomised controlled trials.|
In terms of tumour response assessed using RECIST criteria, 12 out of 355 patients (0.03%) were reported to have no evidence of disease, 2 out of 355 patients (0.01%) were reported to have a complete response, 9 out of 355 (0.03%) patients were reported to have a partial response, 50 out of 355 patients (14%) were reported to have stable disease, 64 out of 355 patients were reported to have progressive disease and 64 out of 355 patients (18%) were not mentioned (based on 17 observational studies, n=355 patients).
In terms of tumour response assessed with CA-125 based on GCIG criteria, 22 out of 64 patients (34%) were reported to have stable or decreasing CA-125, 8 out of 64 patients (13%) were reported to have an increase in CA-125 and 34 out of 64 patients (53%) were considered not evaluable or were not mentioned (based on 6 observational studies, n=64 patients).
In terms of post-immunotherapy treatment response assessed with survival, two out of four studies reported that antigen-specific immunotherapy may lead to improved responses; while two out of four studies reported no evidence of a difference (based on 4 observational studies, n=88 patients).
In terms of overall survival, no significant differences were reported (based on 3 randomised controlled trials (RCTs), n=1062 patients).
In terms of progression-free survival, no significant differences were reported. Time to relapse was reported to range from 10.3 to 18.9 months (for anti-CA-125 immunotherapy) vs. 10.3 to 13 months (for placebo) (based on 6 RCTs, n=1882 patients).
In terms of antigen-specific humoural responses assessed by ELISA/Luminex, anti-idiotropic (Ab2) responses were reported to range from 3% to 100% (based on 9 observational studies), anti-idiotropic (Ab3) responses were reported to range from 0% to 100% (based on 10 observational studies) and IgG responses were reported to range from 8% to 96% (based on 9 observational studies).
In terms of antigen-specific humoural responses assessed by ELISPOT, proliferation assays or IFNg secretion, 39 out of 40 studies reported an induced cellular immune response in at least 1 cohort to at least 1 target antigen. Positive responses were reported to range from 18% to 100% (based on 40 observation studies, n=966 patients).
In terms of adverse events, only moderate adverse events were reported.
The research objective was clearly stated and appropriate inclusion criteria were defined. No restrictions were applied on the eligibility criteria based on study characteristics or sources of information.
|1.1 Did the review adhere to pre-defined objectives and eligibility criteria?||Probably yes|
|1.2 Were the eligibility criteria appropriate for the review question?||Probably yes|
|1.3 Were eligibility criteria unambiguous?||Probably yes|
|1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)?||Probably yes|
|1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)?||Probably yes|
|Concerns regarding specification of study eligibility criteria||Low|
Searching for this review was first conducted in 2009 and included Cochrane Central Register of Controlled Trials (CENTRAL; 2009, Issue 3), in the Cochrane Library, the Cochrane Gynaecological Cancer Group Specialised Register, MEDLINE and EMBASE databases and clinicaltrials.gov (1966 to July 2009). Additional studies were obtained by searching the prospective trial register at www.clinicaltrials.gov, hand searches of the proceedings of relevant annual meetings (1996 to July 2009) like the Society of Gynecologic Oncologists, the American Association for Cancer Research, the International Society for Biological Therapy of Cancer and Society for Immunotherapy of Cancer, and checking the bibliographies of relevant studies. The database searches were updated in 2013, and a more recent partial update was conducted in 2017, and included Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 6), in The Cochrane Library; MEDLINE via OVID (October 2013 to June week 4 2017); and Embase via OVID (October 2013 to 2017 week 27). Conference proceeding handsearching and trials register searches were last conducted in 2009. A full search strategy was reported and appeared to be appropriate. The searches were not restricted based on date, publication format or language. Two reviewers were independently involved in study selection and any discrepancies were resolved by discussion or by a third reviewer.
|2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports?||Probably yes|
|2.2 Were methods additional to database searching used to identify relevant reports?||Probably yes|
|2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible?||Probably yes|
|2.4 Were restrictions based on date, publication format, or language appropriate?||Probably yes|
|2.5 Were efforts made to minimise error in selection of studies?||Yes|
|Concerns regarding methods used to identify and/or select studies||Low|
Two reviewers independently extracted the data; a third reviewer checked the results. Sufficient study characteristics appear to have been extracted for the interpretation of results. Relevant study results appear to have been extracted. While the methodological quality of the included studies was appropriately assessed using the Cochrane ’Risk of bias’ tool for randomised controlled trials (for RCTs), the author's used an inappropriate (non-validated) tool to assess the risk of bias in non-randomised controlled trials. Two reviewers were involved in the risk of bias assessment, and disagreements were resolved by discussion or through consultation with a third reviewer.
|3.1 Were efforts made to minimise error in data collection?||Yes|
|3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results?||Probably yes|
|3.3 Were all relevant study results collected for use in the synthesis?||Probably yes|
|3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria?||Probably no|
|3.5 Were efforts made to minimise error in risk of bias assessment?||Yes|
|Concerns regarding methods used to collect data and appraise studies||High|
The synthesis appeared to include all eligible studies. The method of analysis was explained and appeared appropriate. Due to high heterogeneity among the studies, a narrative synthesis was performed to summarise the findings. Publication bias was not formally assessed, but was narratively discussed. The quality of the individual studies was considered in the synthesis.
|4.1 Did the synthesis include all studies that it should?||Probably yes|
|4.2 Were all pre-defined analyses reported or departures explained?||Probably yes|
|4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies?||Probably yes|
|4.4 Was between-study variation minimal or addressed in the synthesis?||Probably yes|
|4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses?||Probably yes|
|4.6 Were biases in primary studies minimal or addressed in the synthesis?||Probably yes|
|Concerns regarding synthesis and findings||Low|