Summary

METHODS
24 patients treated with IS-ICBT were included in this study. IS-BT was performed 76 of 93 BT fractions. For each patient, two additional IC-BT planning were created: (1) ICBT_{Target-focused} plan: The priority was adequate coverage of CTV_HR. Then, the OARs were spared as much as possible. (2) ICBT_OARs-focused plan: The priority was given to the OAR sparing. Then, highest CTV_HR coverage was tried to achieve within the allowed OAR dose limits. The IS-ICBT plans were compared with these two plans in terms of target coverage and OAR doses.

RESULTS
13 patients had large and 11 patients had small CTV_HR. In IS-ICBT plans, EQD2₁₀ CTV_HR D90 doses were significantly higher compared with ICBT_OARs-focused plans (?dose: 10.5±6.2 Gy, p<0.001), whereas EQD23 OAR D2cc doses were significantly lower compared with ICBT_{Target-focused} plans (Average ?dose, bladder: 24.5±25.9 Gy [p<0.001], rectum: 7.6±9.7 Gy [p=0.001], sigmoid: 18.3±15.3 Gy [p<0.001]). There was no significant difference between patients with small and large CTV_HR in terms of Δdoses of both target and OARs.

CONCLUSION
IS-BT provides significant therapeutic advantage over IC-BT for patients both with small and large CTV_HR.

Introduction

Due to more flexible and adjustable dose optimization characteristics of interstitial brachytherapy (IS-BT), dose distributions that are similar to patients with smaller CTV_HR (<30 cm³) can also obtained in patients a larger CTV_HR. Moreover, an increase by 10% in 3-year local control has been reported in patients with a larger high-risk clinical target volume (CTV_HR; ≥30 cm³) using IS-ICBT, with no increased toxicity.[1]

IS-BT not only facilitates coverage of the parametrial extension of the tumor with an adequate dose, but also accomplishes unacceptable OAR doses due to topography.[4] In our previous study, we have demonstrated the feasibility of the CT-guided needle insertion during combined IS-ICBT in patients with locally advanced cervical cancer using tandem-ovoid Utrecht applicator (Elekta, Veenendaal, The Netherlands). In addition to information provided by magnetic resonance imaging (MRI) in the last week of external-beam radiotherapy (MRI_postEBRT), OAR location and positioning of the tandem on the day of BT evaluated in the CT imaging taken after tandem insertion (CT_preneedle) was used to determine IS-BT indication, needle channels, and insertion lengths. This method is especially beneficial for patients with smaller CTV_HR, as unexpected indication may emerge based on CT_preneedle in these patients, whereas IS-BT indication is already determined based on MRI_postEBRT in patients with larger CTV_HR. However, it remains unknown if advantage provided by the IS-BT in patients with smaller CTV_HR is as great as for those with larger CTV_HR.

Therefore, we aimed to investigate the added value of IS-BT over classical IC-BT in terms of target coverage and OAR sparing among patients for whom an optimal dose distribution could not be provided without IS-ICBT and also determine if the magnitude advantage provided by IS-BT is similar in patients smaller and larger CTV_HR.

Methods

MRI_postEBRT imaging was performed in the last week of EBRT to evaluate the patient"s response and suitability for BT, which was planned within the 1^st week after EBRT completion. The patient preparation, clinical workflow, and CT-guided needle insertion were described in detail in our previous study.[5] Briefly, BT was performed under sedoanalgesia. A CT scan was performed after applicator insertion, that is, CT_preneedle. Together with the MRI_postEBRT, this scan was evaluated by the radiation oncologist to decide needle indication, channels en insertion lengths. If the IS-BT was indicated based on the tumor extension, applicator position and OAR location on the CT, the needles were inserted on the CT table and a second CT scan was performed after needle insertion (CT_postneedle). CT_preneedle and CT_postneedle were used to create BT plans for patients treated with IC-BT and IC-ISBT, respectively.

CT scanning was performed with a 1.25-cm slice thickness using the GEHC Discovery CT750 HD (Waukesha Wisconsin, USA). Three-dimensional BT planning was performed using the Oncentra Brachytherapy Planning System v4.5.3 (Elekta, Veenendaal, The Netherlands) after contouring of the residual gross tumor volume (GTV_res), CTV_HR, and OARs, including the bladder, rectum, and sigmoid on the CT_postneedle.[6-9] The plan was initiated by activating all source positions and was continued by manual optimization of the dwell times in the channels of the intrauterine tandem, ovoids, and needles.

All the treatment procedures reported in this study were a part of the routine clinical practice in the institution and were conducted after obtaining consent as relevant. The ethics committee deemed that additional informed consent for this study was not required, based on the Liv Hospital-Ulus Department of Radiation Oncology Medical Research Involving Human Subjects Act. However, all patients were informed that their data could be used for research purposes and that they could refuse consent for such use.

Dosimetry Goals
The summed biologically equivalent doses in 2-Gy fractions (EQD2) of EBRT and BT were calculated with ?/? of 10 (EQD210) and 3 (EQD23) for CTVHR and OARs, respectively. The aims and limits of planning in the EMBRACE II protocol were used during plan optimization.[10]

Planning Without Needles
To determine the advantage provided by ISBT, plans without needles were created in total for the 76 IC-ISBT fractions, in which dose optimized was in two different ways (in total 76 fractions * 2 plans=156 plans):

1. ICBT_{Target-focused} plan: The priority was that CTV_HR was covered by the minimal dose criteria (CTV_HR D90 >85 Gy) was achieved. Then, the OARs were spared as much as possible. The aim was to determine the IS-BT advantage in terms of OAR sparing when optimal target coverage was maintained

2. ICBT_OARs-focused plan: The priority was given to the OAR sparing. The highest CTV_HR D90 was tried to achieve within the allowed OAR dose limits. The aim was to determine the IS-BT advantage in terms of target coverage when OARs sparing was maintained. The EQD2₁₀ dose for CTV_HR D90 and EQD23 doses

for the 2 cc of the OARs (D2cc) including bladder, rectum, and sigmoid were calculated, and summed with the EBRT EQD2 dose. Eventually, for each of the 24 patients, three different plans were obtained: (1) Plan with needle (IS-ICBT), (2) ICBT_{Target-focused}, and (3) ICBT_OARs-focused.

To determine the benefit of needle use, IS-ICBT plans were compared with these two plans (for target coverage: IS-ICBT vs. ICBT_OARs-focused, for OAR sparing: IS-ICBT vs. ICBT_OARs-focused). The dose difference (Δdose) between the plans was compared further between patients with small and large CTV_HR to establish if the advantage of IS-BT was similar between these two patients group.

Statistical Analysis
The normality of the continuous variables was determined using the Kolmogorov-Smirnov test, and Q-Q plots were checked. Between-group comparisons of continuous variables were performed using the independent t-test and Mann-Whitney U-test for normally and nonnormally distributed variables, respectively. For comparisons between more than two groups, one-way ANOVA and the Kruskal-Wallis test were used for normally and non-normally distributed continuous variables, respectively. Categorical variables were compared using the chi-square test. A two-sided p≤0.05 was considered statistically significant. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) for Windows, version 21.0 (SPSS Inc., Chicago, IL, USA).

Results

The FIGO staging of the patients was as follows: Stages IIA (n=1), IIB (n=4), IIIB (n=4), IIIC1 (n=9; [T2bN1 (n=7), T3bN1 (n=2)]), IIIC2 (n=2; [T1b2N1 (n=1), T2bN1 (n=1)]), IVA (n=3; [T4N0 (n=1), T4N1 (n=2)]), and IVB (n=1; T3aN1M1). Eleven patients had a small CTV_HR and 13 had a large CTV_HR.

Needle Dwell Intensities
The average dwell intensity of an individual needle was 11±8% (range, 0-42), and the dwell intensity was >15% in 63 out of 266 needles. The total contribution of the needles inserted in a fraction was 37.2±19.2% (range, 1.3-84.1). The average contribution of the needles to the complete BT treatment was 30.3±18%.

The Comparison of the IS-ICBT and IC-BT Plans
The IS-ICBT plan resulted in a significant increase in EQD2₁₀ CTV_HR D90 compared with ICBT_OARs-focused plans, with an average of ?dose 10.5±6.2 Gy, which translated into a relative dose increase by 11.9%±7.9 (Table 1, Figs. 1, 2).

Table 1: The comparison of the CTVHR D90 and OAR D2cc doses of IS-ICBT plans with ICBT_{Target-focused} and ICBT_OAR-focused plans

Fig 1: The dose difference between IS-ICBT and ICBT plans in patients with small and large CTV_HR. ISICBT plans were used as reference plan and compared with ICBT_OARs-focused for CTV_HR D90 and ICBT_OARs-focused for D2cc of bladder, rectum and sigmoid.
IS-ICBT: Interstitial intracavitary brachytherapy; CTV_HR: High-risk clinical target volume; Gy: Gray.

Fig 2: CTV_HR D90 EQD2₁₀ doses of the 24 patients included in the study, based on their CTV_HR volume. Red area indicates the doses which is lower than the minimum criteria for CTV_HR D90, that is, 85 Gy.
IS-ICBT: Interstitial intracavitary brachytherapy; CTV_HR: High-risk clinical target volume; OAR: Organ at risk; Gy: Gray.

The OAR 2cc EQD23 doses were significantly decreased with the IS-ICBT plans compared to ICBT_{Target- focused} plans, with an average Δdose of 24.5±25.9 Gy, 7.6±9.7 Gy and 18.3±15.3 Gy for bladder, rectum and sigmoid, respectively (Table 1, Figs. 1, 3).

Fig. 3. OAR D2cc EQD23 doses of the 24 patients included in the study, based on their CTVHR volume. Red area indicates the doses which is higher than the maximal allowable dose criteria for that OAR, that is, 90 Gy for bladder D2cc and 75 Gy for rectum and sigmoid D2cc.
IS-ICBT: Interstitial intracavitary brachytherapy; CTV_HR: High-risk clinical target volume; OAR: Organ at risk; Gy: Gray.

The Comparison of Patients with Small and Large CTV_HR
There was no significant difference between patients with small and large CTV_HR in terms of CTV_HR D90 and OAR D2cc values of the IS-ICBT plans. Moreover, these two patient groups were also similar regarding the ?dose for both target volume and OARs, that is, the dose difference between IS-ICBT and ICBT plans (Table 2, Figs. 1-3).

Table 2: Comparison of the average IS-ICBT doses, Δdose (the difference between IS-ICBT and ICBT) in CTV_HR D90 and OAR D2cc values between patients with small and large CTV_HR

Discussion

True benefit of the IS-ICBT can be best demonstrated by the comparison of the plans with and without IS-CT in the same patient, rather than comparison of different patient groups or historical controls. Using such an in-patient pairwise comparison, the addition of IS-BT has been shown to increase CTV_HR D90 EQD2 doses by 4-8 Gy on average without a significant increase in the OARs doses.[2,3,11,14] Similar therapeutic advantage was also demonstrated in studies comparing different patient groups.[4,13,15,16] The average Δdose between IS-ICBT and ICBT_OAR-focused plan was 10.5±6.2 Gy, which was consistent between patients with small and large CTV_HR.

A notable characteristic of the current study was that IS-BT effect on both target dose and OARs sparing was evaluated separately, to the best of our knowledge, which was not investigated in the previous studies. The dose reduction with the IS-BT was remarkable for bladder and sigmoid, with an average Δdose of 24 and 18 Gy, respectively. Although non-significant, the sigmoid sparing was even higher in patients with small CTV_HR compared with those with large CTV_HR (21.8±19.6 Gy vs. 15.2±10.1 Gy). These extreme dose differences between with and without IS-BT plans can be explained by more effective use of IS-BT using CT-guidance on the day of treatment after applicator insertion, rather than MRI_postEBRT.[5] Considering that 5-10 Gy difference had a clinical effect on tumor control and side effects, based on the evidence from image-guided studies, not only patients with a large CTV_HR but also with small CTVHR can take a great advantage of IS-BT, when indicated.[17-21]

Limitations of the Study
Our study has some limitations. First, it is a single center study, which may not precisely reflect the practice in other institution. Second, IS-ICBT plans were the clinical plans used for patient treatment, whereas IC-BT plans were retrospectively created without time pressure. Therefore, even better dose distribution could have been achieved with IS-ICBT plans if they were also created only for research purposes without haste. Third, CT planning was used in this study, whereas results with MRI planning can deviate from our results.

Conclusion

Acknowledgement: I would like to thank Prof.Dr. Merdan Fayda for providing the clinical data and Busra Tavli for creating the brachytherapy plans.

Peer-review: Externally peer-reviewed.

Conflict of Interest: All authors declared no conflict of interest.

Ethics Committee Approval: All the treatment procedures reported in this study were a part of the routine clinical practice in the institution and were conducted after obtaining consent as relevant. The ethics committee deemed that additional informed consent for this study was not required, based on the Liv Hospital-Ulus Department of Radiation Oncology Medical Research Involving Human Subjects Act. However, all patients were informed that their data could be used for research purposes and that they could refuse consent for such use.

Financial Support: None declared.

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