Because IMRT can deliver treatment to target organs while reducing the volumes of proximal normal structures that are irradiated, it appears to offer several advantages over conventional techniques for the treatment of malignancies  . However, studies on the effects of IMRT in reducing the irradiated volumes of the rectum, small bowel, bladder, and bone marrow have reported inconsistent findings [18, 26, 27, 30, 31, 36–41, 44, 45]. Therefore, we carried out a systematic review to identify all the relevant studies presenting data on DVHs of IMRT and 3D-CRT. Consequently, data from 13 studies were analyzed by calculating the pooled average percent irradiated volumes, and they were used in a comparative analysis of the effects of IMRT and 3D-CRT in the rectum, small bowel, bladder, and bone marrow at various radiation doses.
The studies by Heron et al., Igdem et al., and Roeske et al. reported that IMRT at doses of 30 Gy, 40 Gy, and 45 Gy significantly reduced the irradiated volume of the rectum, as compared to 3D-CRT. Chen et al. reported that, when patients received 70% of the prescribed dose with IMRT, the average percent volume of irradiated rectum was significantly less (p < 0.05). However, the study by Mell et al. found no significant reduction in average percent volumes irradiated by IMRT at those same doses. Our meta-analysis indicated that the pooled average percent volumes of irradiated rectum (at doses of 30 Gy, 35 Gy, 40 Gy, and 4 5Gy) were significantly lower in IMRT than in 3D-CRT. Moreover, this reduction manifested a dose response relationship with increasing radiation doses (P = 0.003). Since some publication bias existed in our meta-analysis, we adjusted the reduction of volumes irradiated by using the trim and fill method, and we found that the differences retained statistical significance. This result illustrated that, the higher the radiation dose prescribed, the better IMRT was at reducing the average percent irradiated volumes for the rectum, as compared to 3D-CRT.
Some studies have reported that IMRT treatment of gynecologic malignancies more effectively protects the small bowel compared to the 3D-CRT technique, especially when radiation doses <20 Gy are used . In the studies by Heron et al. and Roeske et al., it was found that IMRT-delivered doses of >30 Gy and >45 Gy, respectively, produced remarkably less average irradiated volumes of OARs (by more than 10-fold) than 3D-CRT. Other studies also reported that >25 Gy doses delivered by IMRT were more beneficial than those delivered by 3D-CRT [39, 44] . Our meta-analysis results showed that after weighing the sample sizes, IMRT at 40 Gy and 45 Gy significantly reduced the pooled average percent irradiated volumes of the small bowel by 17.80% (p = 0.043) and 17.30% (p = 0.012), respectively. However, at 35 Gy and below, no statistically significant reduction was found between IMRT and 3D-CRT in the pooled average percent of irradiated volumes. In this meta-analysis, there was no publication bias detected for data related to IMRT-delivered 20 Gy, 30 Gy, or 35 Gy or for 3D-CRT-delivered 5 Gy, 20 Gy, or 25 Gy. Although publication bias was observed for data related to both IMRT- and 3D-CRT-delivered 40 Gy and 45 Gy radiation doses, the reduction of pooled average percent irradiated volumes remained significant after adjusting with the trim and fill method.
This meta-analysis found no statistically significant evidence to support the theory that IMRT was an effective approach to reduce the irradiated volumes of the bladder.
Considering the effects of IMRT and 3D-CRT on bone marrow, Brixey et al. showed that IMRT produced no obvious reduction in the volumes of OARs irradiated at the 10 Gy and 30 Gy doses, but reported a statistically significant reduction for doses of 20 Gy, 40 Gy, and 45 Gy (p < 0.001). In the studies by Lujun et al. and Ahmed et al., the average percent volumes of irradiated OARs were found to be reduced at several high radiation levels delivered by IMRT. In contrast, Chen et al.demonstrated a significant reduction in the volume of irradiated bone marrow when IMRT delivered doses of 20 Gy and below. When these seemingly inconsistent results were combined in our meta-analysis, IMRT was found to reduce the average percent volumes of irradiated bone marrow at all radiation doses, but the findings did not reach statistical significance (p > 0.05). Publication bias was observed only for the IMRT-delivered dose of 15 Gy and 3D-CRT-delivered doses of 15 Gy, 20 Gy, and 30 Gy. After adjusting the reduction of irradiated volumes by using the trim and fill method, there was still no statistically significant reduction found between IMRT and 3D-CRT.
High heterogeneity was found for the data of bladder and rectum irradiation from high radiation doses delivered by IMRT and for the data of small bowel and bladder irradiation from 40 Gy and 45 Gy doses delivered by 3D-CRT. Potential explanations exist to explain these instances of heterogeneity. First, the OARs in the abdominal cavity are not static and are in continual motion, and the volumes of irradiated organs are known to be impacted by different postures. Second, the RT physicians defined the extent of OARs that were reported in each study, and they may not have abided by a unified standard. Third, the data from each study was generated independently and may have been influenced by the particular study design.
In our meta-analysis, we determined that toxicity occurred with significantly lower frequency in the IMRT treated patients than in the 3D-CRT patients [25, 39, 46]. In the studies by Mundt et al. and Chen et al., adjuvant IMRT was reported to be well-tolerated with low incidences of acute and chronic toxicity, as compared with 3D-CRT. Although several patients in the studies by Beriwal et al. and Hasselle et al. suffered severe acute and chronic toxicities from IMRT, the incidence of these side effects was not compared with that of 3D-CRT. These two research studies prompted us to theorize that the most significant factor correlated to IMRT-induced toxicity in gynecologic patients is the organ volume receiving 100% (45 Gy) of the prescription dose . Likewise, Rose et al. provided evidence that hematologic toxicity increased with increasing volumes of irradiated pelvic bone marrow.
Finally, the collected IMRT dosimetric data from gynecologic patients used in our meta-analysis suggested that IMRT is safe for use as a treatment of gynecologic cancers. However, all of the research studies with which our meta-analysis was carried out were observational. It is generally believed that findings from observational studies are not as accurate as those from randomized controlled trials, since they can easily overestimate the magnitude of effects. Another limitation in our study was the small sample size and uneven quality of the samples. Thus, our conclusions need to be validated by larger samples and more studies to confirm the benefits of IMRT in patients with gynecologic malignancy and to further study the different acute and chronic toxicities produced by IMRT and 3D-CRT.