|Clinical outcomes of active specific immunotherapy in advanced colorectal cancer and suspected minimal residual colorectal cancer: a meta-analysis and system review
|Rao B, Han M, Wang L, Gao X, Huang J, Huang M, Liu H, Wang J
This review concluded that active specific immunotherapy worked best in patients with suspected minimal residual colorectal cancer, where evidence clearly supported a significant improvement in disease-free survival and/or overall survival. The evidence supported these conclusions, but there are a number of potential issues with the primary studies and the review methods that suggest a cautious interpretation is required.
To assess the objective clinical outcomes of active specific immunotherapy for the treatment of advanced colorectal cancer and suspected minimal residual colorectal cancer.
PubMed was searched for studies published in English from January 1998 to January 2010. Search terms were reported. Reference lists of relevant reviews were examined for further studies.
Studies of histopathologically defined colorectal cancer treated by active specific immunotherapy were eligible for inclusion in the review, with the exception of case studies, review articles and studies with fewer than three patients. Eligible studies had to report a minimum of four weeks between the time of completion of prior chemotherapy and/or radiation therapy and the beginning of active specific immunotherapy. Studies were excluded if patients were receiving concurrent chemotherapy, radiotherapy, or drugs which affected immune function (such as glucocorticoids or cimetidine) during active specific immunotherapy or follow-up. Studies were also excluded if there was no specific documentation to prove the colorectal origin of the tumour, but if studies presented separate data for relevant patients they were still included.
The randomised controlled trials (RCTs) included in the meta-analysis varied in type of active specific immunotherapy (including antilogous tumour cells, autologous tumour vaccine-Newcastle disease virus, antilogous tumour cell-bacillus Calmette-Guerin, and 17-1 antibody). The stage of disease for the included patients also differed between studies and included stages II, III, I-IV and IV. Further details of the type of active specific immunotherapy and disease stage were reported in the review.
Of the other 43 studies included in the review, all were described as having comparable baseline characteristics of active specific immunotherapy including the number of evaluated colorectal cancer patients, the type of vaccine, the route of vaccination, adjuvants, the toxicity, and the objective clinical responses. Clinical outcomes evaluated in suspected minimal residual colorectal cancer were overall survival and disease-free survival. In advanced colorectal cancer the outcomes valuated were complete response, partial response, mixed or minor response, and stable disease (according to the criteria of the World Health Organisation, WHO).
Two reviewers independently selected the trials for inclusion; discrepancies were resolved through discussion.
Assessment of study quality
The overall methodological quality of each study was assessed using the Jadad criteria (randomisation, concealment, blinding and an adequate description of withdrawals and drop-outs). For each criterion, the studies were awarded a grade: A was adequate with correct procedures; B was unclear without a description of methods; and C was inadequate procedures, methods, or information. Studies with all A grades were considered to have a low risk of bias; studies with one or more B grades had a moderate risk of bias; and studies with one or more C grades had a high risk of bias.
The authors did not state how many reviewers performed the quality assessment.
Two reviewers independently extracted the study data; discrepancies were resolved through discussion. Relative risks (HRs [sic]) with 95% confidence intervals (CIs) were reported for dichotomous outcomes; means with standard deviations were reported for continuous outcomes. The clinical benefit rate was reported as the sum of patients with complete response, partial response, mixed or minor response, and stable disease.
Methods of synthesis
Studies were grouped according to study design, outcome and whether they assessed ASI in advanced CRC or in suspected minimal residual CRC. Pooled RRs with 95% CIs were calculated for dichotomous outcomes, and weighted mean differences (WMD) with 95% CIs for continuous outcomes using either a fixed effect or random effects model according to whether there was any evidence of statistical heterogeneity. Statistical heterogeneity was assessed using the Χ2 and I2 tests, with the statistical significance set at P < 0.10. The overall effect was tested using Z scores. Further post-hoc analyses were performed to investigate potential sources of heterogeneity including the effect of various vaccine formulations, the route of vaccination, and the use of adjuvants.
Results of the review
Six RCTs were included in the meta-analysis. Three RCTs reported data for seven years follow-up; the other three RCTs followed up patients for one year, five years and 7.6 years. Two RCTs were rated as category B, and four as category C for methodological quality.
Forty-three observational studies were also considered in the assessment of advanced colorectal cancer. Among these, all had clearly stated inclusion and exclusion criteria.
Active specific immunotherapy for suspected minimal residual colorectal cancer (six RCTs; n=1,375 patients): For all patients, a statistically significant difference in favour of active specific immunotherapy compared with control was reported for overall survival (HR 0.76, 95% CI 0.68 to 0.86; I2=55%; six RCTs) and for disease-free survival (HR 0.76, 95% CI 0.59 to 0.97, I2=0; two RCTs). For stage II suspected minimal residual colorectal cancer, there was no statistically significant difference between active specific immunotherapy and control for overall survival (I2=0; two RCTs), but a statistically significant difference in favour of active specific immunotherapy was reported for disease-free survival (HR 0.66, 95% CI 0.47 to 0.94, I2=0; two RCTs). For stage III suspected minimal residual colorectal cancer patients, there was a statistically significant difference in favour of active specific immunotherapy compared with control for overall survival (HR = 0.76, 95% CI 0.61 to 0.96; I2=26%; three RCTs) and disease-free survival (HR = 0.81, 95% CI 0.67 to 0.97; I2=0; three RCTs).
Active specific immunotherapy for advanced colorectal cancer (43 studies, n=656 patients): The overall response rate was 1.68% (11 studies). In a post-hoc subgroup analyses according to route of vaccination, the clinical benefit rate ranged from 19.7% (intravenous) to 34% (subcutaneous); and according to vaccine type ranged from 22.4% (dendritic cell vaccines) to 31.7% (peptide vaccines).
No serious adverse events were reported in any of the included studies.
Active specific immunotherapy worked best in patients with suspected minimal residual colorectal cancer, where evidence clearly supported a statistically significant improvement in disease-free survival and/or overall survival in all stages of suspected disease.
This review answered a clearly defined review question using a broad range of relevant study designs. However, relevant data may have been missed as only one database was searched and there was a risk of language and publication biases through the inclusion of only studies published in English. The risk of reviewer error and bias was reduced when selecting studies for inclusion and extracting the study data, but it was unclear whether appropriate precautions were taken the assessment of study quality.
The methodological quality of the studies included in the meta-analysis was assessed using relevant criteria. Overall, the quality of the randomised studies included in the meta-analysis was limited and most trials were considered to be at a high risk of bias, with the rest at moderate risk of bias. The clinical characteristics of the studies included in the meta-analysis differed considerably in the type of intervention and the disease stage of patients. Some attempts to take account of the potential sources of heterogeneity were made; subgroup analyses were performed, although they were mainly performed post-hoc. Statistical heterogeneity was assessed and was mostly low or not present. The analysis of advanced colorectal cancer patients was reliant on observational data only, which was less reliable given the inherent biases within this type of study design.
The evidence supported the authors' conclusions, but there are a number of potential issues with both the primary studies and the review methods that suggest a cautious interpretation is required.
Implications of the review for practice and research
Practice: The authors stated that, although their findings indicated that active specific immunotherapy may provide a new promising targeted therapeutic approach in suspected minimal residual colorectal cancer, it was unlikely that this therapy would provide a standard complementary therapeutic approach for advanced colorectal cancer in the near future.
Research: The authors did not state any implications for research.
Doctor Dot Research Program of China.
Rao B, Han M, Wang L, Gao X, Huang J, Huang M, Liu H, Wang J. Clinical outcomes of active specific immunotherapy in advanced colorectal cancer and suspected minimal residual colorectal cancer: a meta-analysis and system review. Journal of Translational Medicine 2011; 9:17
Subject indexing assigned by NLM
Colorectal Neoplasms /immunology /pathology /therapy; Disease-Free Survival; Humans; Immunotherapy, Active /adverse effects; Neoplasm Staging; Neoplasm, Residual; Treatment Outcome
Date bibliographic record published
Date abstract record published
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.