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KSR Number: KSRA80670

Antigen‐specific active immunotherapy for ovarian cancer

  • Cochrane Database Syst Rev 2018, 9, CD007287, 10.1002/14651858.CD007287.pub4
  • Full report

Risk of Bias Assessment

Overall summary: High risk of bias in the review

Bottom Line

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.

Risk of Bias Assessment

Overall summary High risk of bias in the review

High

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

Details of Review

Number of studies 67
Number of participants 3632
Last search date July 2017
Review type Intervention
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.

Results

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.

Full Risk of Bias Assessment

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

Abstract

Abstract - Background This is the second update of the review first published in the Cochrane Library (2010, Issue 2) and later updated (2014, Issue 9). Despite advances in chemotherapy, the 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. Objectives Primary objective 
 • To assess the clinical efficacy of antigen‐specific active immunotherapy for the treatment of ovarian cancer as evaluated by tumour response measured by Response Evaluation Criteria In Solid Tumors (RECIST) and/or cancer antigen (CA)‐125 levels, response to post‐immunotherapy treatment, and survival differences ◦ In addition, we recorded the numbers of observed antigen‐specific humoral and cellular responses
 Secondary objective 
 • To establish which combinations of immunotherapeutic strategies with tumour antigens provide the best immunological and clinical results Search methods For the previous version of this review, we performed a systematic search of the 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). We also conducted handsearches of the proceedings of relevant annual meetings (1996 to July 2009). For the first update of this review, we extended the searches to October 2013, and for this update, we extended the searches to July 2017. Selection criteria We searched for randomised controlled trials (RCTs), as well as non‐randomised studies (NRSs), that included participants with epithelial ovarian cancer, irrespective of disease stage, who were treated with antigen‐specific active immunotherapy, irrespective of type of vaccine, antigen used, adjuvant used, route of vaccination, treatment schedule, and reported clinical or immunological outcomes. Data collection and analysis Two reviews authors independently extracted the data. We evaluated the risk of bias for RCTs according to standard methodological procedures expected by Cochrane, and for NRSs by using a selection of quality domains deemed best applicable to the NRS. Main results We included 67 studies (representing 3632 women with epithelial ovarian cancer). The most striking observations of this review address the lack of uniformity in conduct and reporting of early‐phase immunotherapy studies. Response definitions show substantial variation between trials, which makes comparison of trial results unreliable. Information on adverse events is frequently limited. Furthermore, reports of both RCTs and NRSs frequently lack the relevant information necessary for risk of bias assessment. Therefore, we cannot rule out serious biases in most of the included trials. However, selection, attrition, and selective reporting biases are likely to have affected the studies included in this review. GRADE ratings were high only for survival; for other primary outcomes, GRADE ratings were very low. The largest body of evidence is currently available for CA‐125‐targeted antibody therapy (17 studies, 2347 participants; very low‐certainty evidence). Non‐randomised studies of CA‐125‐targeted antibody therapy suggest improved survival among humoral and/or cellular responders, with only moderate adverse events. However, four large randomised placebo‐controlled trials did not show any clinical benefit, despite induction of immune responses in approximately 60% of participants. Time to relapse with CA‐125 monoclonal antibody versus placebo, respectively, ranged from 10.3 to 18.9 months versus 10.3 to 13 months (six RCTs, 1882 participants; high‐certainty evidence). Only one RCT provided data on overall survival, reporting rates of 80% in both treatment and placebo groups (three RCTs, 1062 participants; high‐certainty evidence). Other small studies targeting many different tumour antigens have presented 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 and the limited side effects and toxicity reported, exploration of clinical efficacy in large well‐designed RCTs may be worthwhile. Authors' conclusions 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 review authors found a significant dearth of relevant information for assessment of risk of bias in both RCTs and NRSs. Plain language summary Antigen‐specific active immunotherapy for ovarian cancer Background 
 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, most women experience 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 for improving outcomes among women with ovarian cancer. Review question 
 This review evaluated the feasibility of antigen‐specific active immunotherapy. Antigen‐specific active immunotherapy aims to induce anti‐tumour immune responses through administration of a tumour antigen ‐ a molecule that is expressed by tumour cells and is hardly expressed by healthy cells. Reviewers collected information on clinical outcomes, immunological responses, and side effects. Main findings 
 We identified 67 studies, which included 3632 women with ovarian cancer and were published between 1966 and 2017. The most frequently described strategy was administration of antibodies targeting the tumour antigen CA‐125 (2347 participants in 17 studies). Most of these studies primarily evaluated safety and immunological responses. Severe flu‐like and gastrointestinal symptoms occurred in 7% to 30% of participants. Researchers frequently detected antibodies and immune cells recognising the tumour antigen CA‐125, albeit response rates varied between studies. Despite these promising immunological responses, four large studies reported no survival advantage for participants treated with CA‐125‐directed antibody over those given placebo. For strategies not relying on antibody administration, similar conclusions cannot yet be drawn. Overall, study authors report that treatment was well tolerated and inflammatory side effects at the injection site were most frequently observed. Researchers observed responses of the immune system for most strategies studied, but the clinical benefit of these strategies remains to be evaluated in large trials. Certainty of the evidence and conclusions 
 Because no high‐certainty evidence of clinical benefit is currently available, antibody therapy targeting CA‐125 should not be incorporated into standard treatment in its current form. Based on 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 randomised controlled trials (RCTs) are awaited, and further RCTs should be conducted.