The effect of 3D-BT was most evident in reducing toxicity. Although half of the six studies were not included for meta-analysis for toxicity, the excluded studies also reported meaningful reductions of ≥ grade 3 toxicity in 3D-BT patients. The toxicity outcomes of previous EMBRACE studies evaluating MRI based 3D-BT have shown favorable results. The 2-year actuarial probability of severe vaginal morbidity was 3.6%, which was less than has been reported from earlier studies of ~30%(4, 23). Likewise, late severe rectal toxicities were rare (1.7%), and they were strongly related to dosimetric parameters (e.g., ) which available through 3D image guidance(24). The incidence of women diagnosed with cervical cancer in their 20s has increased from 1993 through 2002(25), and the younger population tends to be more affected by severe toxicity owing to their long life expectancy, so the rapid introduction of 3D-BT should be needed.
LRRFS was also considerably improved with 3D-BT, and this might contribute to the improvement of PFS. These results seem reasonable, since 3D imaging may be more likely to have sufficient radiation dose coverage for primary cervical tumors. The previous RetroEMBACE study also reported excellent 3-year local control of 91% and pelvic control of 87%(26). This was 10% improvement of pelvic control compared to that of a historical 2D-BT cohort. A recent EBRACE report also found that nodal failure rate after concurrent chemoradiotherapy and 3D-BT was 11%, with a median follow-up time of 34 months, and one quarter of which were diagnosed with simultaneous local recurrence(27).
The present study failed to show the improvement of OS in patients treated with 3D-BT compared to 2D-BT. However, there should be a group of patients who might have improved OS with 3D-BT, such as patients with bulky primary tumors. The majority of the patients included in the present study utilized intracavitary BT consisted of tandem and ovoid/ring sources. Only a few patients received interstitial BT using needles. The guideline from the American Brachytherapy Society recommends high-dose rate interstitial BT for patients with bulky tumors, a narrow vaginal apex, inaccessible cervical os, tumor invasion to the lateral parametria or pelvic sidewall, and extension to the lower vagina(28). As multiple needle insertions for bulky or advanced tumor are needed, it is more invasive than intracavitary BT, making 3D imaging is essential. Interstitial BT could be more widely utilized, and could lead to improvement of OS.
In addition, ~ 40% of patients included in the present meta-analysis received CT based 3D-BT. MRI provides superior soft tissue delineation compared with CT, so that there has been a concern that target volume might different between CT and MRI (29, 30). A previous planning study compared CT and MRI guided brachytherapy, and resulted in that CT planning may compromise target volume coverage and increase OAR dose (29). Increasing the use of MRI based brachytherapy also could lead the improvement of survival and toxicities.
Use of 3D-BT does carry added cost compared to 2D-BT. Not only costs for cross-sectional imaging, but also additional time, the availability of imaging machines, and longer planning time should be taken into consideration. Therefore, cost-effectiveness could be another issue. A cost-effectiveness analysis performed in the United States using a Markov state transition model based on 3-year survival estimates and severe complication rates from the previous studies concluded that 3D-BT is a cost-effective option compared to 2D-BT, and supporting the routine use of 3D-BT in locally advanced cervical cancer(31). Although the exact costs differ between the United States and Korea, the result suggests that adoption of 3D-BT could save medical costs.
With the growing evidence, 3D-BT is becoming a new standard worldwide. In the United States, there was an increased percentage of using CT for BT from 55–95%) or MRI for BT from 2–34% between 2007 and 2014(32). A 2015 survey in Japan found that only 16% of facilities had adopted 3D-BT, but 53% of facilities had plans to adopt 3D-BT in the future(33). However, adoption of 3D-BT in Korea is limited due to low medical reimbursement(10). Apart from EBRT, BT is another independent treatment modality which has advantages of rapid dose fall-off around the radioactive sources. There have been attempts to replace the BT boost to EBRT in cervical cancer, but they resulted in worsening of survival by 12%(34). BT could be applied to other cancers in addition to cervical cancer, such as for malignancies in the prostate, breast, head and neck, respiratory tract, and digestive organs. Re-irradiation also could be performed with escalating doses with BT compared to EBRT.
There were several limitations in this meta-analysis. First of all, a majority of the studies included were retrospective trials, which might lead to an overestimation of pooled HRs. Also, all retrospective studies were limited by shorter follow-up time in 3D-BT patients compared to 2D-BT patients. Furthermore, the number of studies for meta-analysis was small, and due to the lack of provided data, only 3 studies were included for meta-analysis of cumulative incidence of toxicity and PFS. The characteristics were varied among the studies (Tables 1 and 2), and analyses for LRRFS and OS had moderate heterogeneity. Meta-regression analysis could be used to evaluate the impact of these factors; however, it was impossible in the present study due to the limited number of studies and available data. In addition, this was not an individual patient data meta-analysis. Lastly, patients included in the 3D-BT group tended to receive more advanced EBRT techniques such as 3D conformal or IMRT. Although well designed large randomized controlled studies are warranted to confirm the present findings, so far, the present study is the first systematic review and meta-analysis of clinical outcomes of patients with cervical cancer who have received 3D-BT or 2D-BT.