Abstract
Background: With the FDA approval of two hypomethylating agents (HA) for the treatment of myelodysplastic syndromes (MDS), both azacitidine (AZA-C) and decitabine have shown widespread usage. These agents improved response rates (RR) in phase III registration trials, however, overall survival (OS) was not significantly improved. Furthermore, head to head comparison of AZA-C versus decitabine is lacking. We performed a systematic review of randomized controlled trials (RCTs) to assess the efficacy of AZA-C and decitabine versus supportive care (SC), and AZA-C versus decitabine for the treatment of MDS.
Methods: A comprehensive literature search of MEDLINE, EMBASE and Cochrane library database was undertaken to identify all phase III randomized controlled trials (RCT) published through July 2008. Meetings abstracts from ASCO, ASH and European Society for Hematology were searched for the years 2006–2007. Data extraction and meta-analysis on benefits and harms of HA for MDS was performed as per the methods recommended by the Cochrane Collaboration. Indirect comparison of AZA-C versus decitabine was conducted according to the methods developed by Bucher et al and Glenny et al and were extended to calculate hazard ratios (HR). We created the following chain of inference: we first pooled RCTs that compared AZA-C with SC, and decitabine versus SC. We then compared the pooled estimates to obtain the unbiased estimate in treatment differences between decitabine and AZA-C.
Results: We found 4 RCTs assessing the efficacy of HA for the treatment of MDS. Two RCTs compared AZA-C versus SC, and 2 compared decitabine versus SC. The results from 1 trial describing the effects of decitabine versus SC were reported as a press release stating that OS was not significant between two arms, however, data were not available for this analysis. The results for all comparisons are summarized in the table below. Meta-analysis of RCTs comparing HA versus SC showed significantly better OS, EFS, and RR in favor of HA without a significant increase in treatment-related mortality (TRM). Comparison of AZA-C versus SC also showed significantly better OS, EFS and RR favoring AZA-C without significant risk of TRM. In one RCT comparing decitabine versus SC, RR was significantly superior in the decitabine arm. However, there was no difference in OS, EFS and TRM between decitabine and SC. Evaluation of decitabine versus AZA-C showed significantly better OS and RR favoring AZA-C, whereas EFS and TRM were similar.
Conclusion: This first systematic review on the efficacy of HA versus SC shows that OS, EFS and RR are superior with HA without significant TRM. Additionally, use of AZA-C is associated with significantly improved OS and RR compared to decitabine. In order to definitively confirm these findings, a prospective RCT comparing AZA-C and decitabine is warranted. Results from this systematic review on the efficacy of AZA-C and decitabine should be considered the threshold against which efficacy of future agents in MDS should be tested.
Outcome Comparisons Hypo-methylating agents versus supportive care (3 RCTs; N=719) Conclusion Azacitidine versus supportive care (2 RCTs; N= 549) Conclusion Decitabine versus supportive care (1 RCT; N=170) Conclusion Azacitadine versus Decitabine (Indirect comparison) Conclusion Overall Survival Hazard ratio (HR)(95% Confidence Intervals) P-value HR=0.79 (0.67, 0.95) p=0.01 Hypo- methylating agents better HR=0.62 (0.48, 0.78) p=0.00 Azacitidine better HR=1.064 (0.82, 1.38) p=0.636 No difference HR=0.579 (0.41, 0.82) p=0.002 Azacitidine better Event-free survival Hazard ratio (HR) (95% Confidence Intervals) P-value HR=0.59 (0.46, 0.75) p=0.00 Hypo- methylating agents better HR=0.58 (0.44, 0.76) p=0.00 Azacitidine better HR=0.64 (0.35, 1.19) p=0.16 No difference HR=0.89 (0.46, 1.80) p=0.753 No difference Response rate Risk ratio (RR) (95% Confidence Intervals) P-value RR=1.28 (1.19, 1.37) p=0.00 Hypo- methylating agents better RR=1.37 (1.25, 1.52) p=0.00 Azacitidine better RR=1.2 (1.08, 1.31) p=0.00 Decitabine better RR=1.15 (1.0, 1.314) p=0.05 Azacitidine better Treatment-related mortality Risk ratio (RR) (95% Confidence Intervals) P-value RR=0.69 (0.36, 1.32) p=0.264 No difference RR=2.79 (0.12, 67.64) p=0.528 No difference RR=0.65 (0.34, 1.26) p=0.203 No difference RR=4.29 (0.16, 111.1) p=0.381 No difference
Treatment of Advanced Gastro-Entero-Pancreatic Neuro-Endocrine Tumors. A Systematic Review and Network Meta-Analysis of Phase III Randomized Controlled Trials