This study aimed to compare treatment outcomes and toxicity profile between imaged-guided brachytherapy (IGBT) versus conventional brachytherapy (CBT) performed by the same practitioner during the same time period.
Medical records of 104 eligible patients who underwent brachytherapy for locally advanced cervical cancer were retrospectively reviewed. Fifty patients (48.1%) underwent IGBT, and 54 (51.9%) patients underwent CBT. All patients underwent concurrent chemoradiation with cisplatin. High-dose-rate intracavitary brachytherapy with dose prescription of 25–30 Gy in 4–6 fractions was performed for all patients. Late lower gastrointestinal (GI) and urinary toxicities occurred more than 3 months after the end of brachytherapy were included for comparative and dosimetric analyses.
The median follow-up period was 18.33 months (range, 3.25 to 38.43 months). There were no differences in oncologic outcomes between the two groups. The IGBT group had lower rate of actuarial grade ≥ 3 toxicity than the CBT group (2-year, 4.5% vs. 25.7%; p=0.030). Cumulative equieffective D2cc of sigmoid colon was significantly correlated with grade ≥ 2 lower GI toxicity (p=0.033), while equieffective D2cc of rectum (p=0.055) and bladder (p=0.069) showed marginal significance with corresponding grade ≥ 2 toxicities in the IGBT group. Half of grade ≥ 3 lower GI toxicities impacted GI tract above the rectum. Optimal thresholds of cumulative D2cc of sigmoid colon and rectum were 69.7 Gy and 70.8 Gy, respectively, for grade ≥ 2 lower GI toxicity.
IGBT showed superior toxicity profile to CBT. Evaluating the dose to the GI tract above rectum by IGBT might prevent some toxicities.
Brachytherapy is essential for better treatment outcomes of locally advanced cervical cancer [
IGBT has been implemented in our institution since 2018. Integration of MRI in brachytherapy planning was started in 2019. Due to limitation of staffing and equipment, only some patients with locally advanced cervical cancer were able to undergo IGBT, leading to a unique situation of our group: IGBT and CBT were practiced simultaneously by the same treating radiation oncologist. Usual comparison studies between IGBT versus CBT have two temporally distinguished cohorts, showing improvement of treatment outcomes and toxicity profile of the IGBT group [
Medical records of 148 patients who underwent intracavitary brachytherapy for locally advanced cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage IB3, IIA2, IIB and above) from October 2018 to December 2021 were retrospectively reviewed. Interstitial brachytherapy was not performed during this time period. Twenty-four patients without follow-up record were excluded. Seven patients with induction chemotherapy and 10 patients without concurrent chemotherapy were also excluded. Two patients with incomplete brachytherapy and one patient treated with both image-guided and conventional planning were ineligible for this study. The remaining 104 patients were included in the analysis. Among them, 50 patients (48.1%) underwent IGBT, and 54 patients (51.9%) underwent CBT.
All patients were treated with pelvic EBRT and concurrent cisplatin-based chemotherapy. Dose-fractionation schedule of pelvic EBRT was 45 to 50.4 Gy with 1.8 Gy of dose per fractions. Most EBRTs were planned by intensity-modulated radiation therapy (IMRT) technique. Twenty patients (19.2%) were treated by 3D conformal radiotherapy. Target volume delineation was based on previously published consensus guidelines [
High-dose-rate (192Ir) intracavitary brachytherapy with dose prescription of 25 to 30 Gy in 4 to 6 fractions was performed for all patients. Response to EBRT and disease extent were re-evaluated by diagnostic MRI scan before brachytherapy planning. Applicator (tandem and ovoids) insertion and planning were performed by an experienced radiation oncologist (H.-C.K.). Allocation of patients to IGBT or CBT was in discretion of the treating radiation oncologist, and mainly based on the availability of staff and 3D image-compatible devices. For CBT, simulation and the first treatment were performed on the same day with fluoroscopy. Point A, Point B, bladder point, and rectal point were set based on the definition from International Commission on Radiation Units and Measurements (ICRU) Report 38 [
To calculate the cumulative dose, dose from EBRT was assumed to be a prescribed dose to the pelvis. The equivalent dose in 2 Gy per fraction was calculated using α/β of 10 for tumor (EQD210) and 3 for OARs (EQD23). For CBT, Cumulative EQD23 of bladder and rectal point was intended to be limited to 75 Gy. For IGBT, cumulative EQD23 D2cc was limited to 75 Gy for rectum and sigmoid colon and 90 Gy for bladder. A treating radiation oncologist reviewed the plan and decided whether to adjust dose-fractionation scheme or affirm the existing plan when these doses exceeded the limitation. Dose calculation and treatment planning were performed by Oncentra Brachy (Elekta AB, Stockholm, Sweden). For every treatment session, fluoroscopy was used to check the location of the applicator.
Clinical endpoints of this study were LC, locoregional control (LRC), progression-free survival (PFS), and overall survival (OS). An LC event was defined as a recurrence in the treated cervix or parametrium, while LRC event was defined as a recurrence in the pelvic or paraaortic regional lymph node area. For PFS, the event was defined as any recurrence or death of the patient. For OS, the event was defined as death of the patient. These clinical outcomes were measured from the date of the completion of brachytherapy for each defined event. Rates were calculated using the Kaplan-Meier method. Clinical endpoints of two groups were compared by log-rank test. Univariate and multivariate analyses were performed for LC, LRC, PFS, and OS to identify covariates potentially affecting clinical outcomes. Statistically significant (p < 0.05) or marginally significant (p < 0.1) variables in univariate analysis and brachytherapy technology (IGBT vs. CBT) were incorporated into multivariate analysis using the Cox proportional hazards model.
New occurrence or worsening of urinary or lower gastrointestinal (GI) toxicities were recorded and graded using the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5 [
Patient characteristics and treatment specifics are summarized in
Several differences between treatment specifics were observed. More patients in the CBT group underwent EBRT with pelvic dose fractionation of 50.4 Gy in 28 fractions (18.5% vs 4.0%, p=0.013). Other dose fractionation schemes were 44 Gy in 22 fractions and 46 Gy in 23 fractions. Parametrial boost was more frequent in IGBT group (52.0% vs. 13.0%, p < 0.001) partly due to the EBRT protocol of the CALLA trial which requires parametrial boost of 54 Gy in 27 fractions and boost to gross lymph node of 58 Gy in 29 fractions. In the IGBT group, tri-weekly cisplatin was more often administered as a concurrent chemoradiation (20.0% vs. 1.9%, p=0.007) with more patients undergoing lymph node surgery (22.0% vs. 3.7%, p=0.013) due to institutional preference. Dosimetric parameters of brachytherapy are summarized in
We also compared patient characteristics between MRI- and CT-based IGBT. There were trends for more FIGO stage III disease (86.7% vs. 60.0%, p=0.088) and larger tumors (median 5.8 cm vs. 5.1 cm, p=0.054) in patients underwent MRI-based IGBT. Most (n=28, 93.3%) of the patients underwent MRI-based IGBT had dose-fractionation regimen of 30 Gy in five fractions, while 12 patients (60.0%) underwent CT-based IGBT had such regimen. Patient characteristics of MRI- and CT-based IGBT were summarized in
Patterns of recurrence are summarized in
Results of univariate and multivariate analyses are summarized in
Overall, six urinary toxicities (12.0%) and 12 lower GI toxicities (24.0%) were reported in the IGBT group, and 12 urinary toxicities (22.2%) and 13 lower GI toxicities (24.1%) were reported in the CBT group. For severe toxicities with grade ≥ 3, there were three lower GI toxicities (6.0%) and 0 urinary toxicity (0.0%) in the IGBT group vs. nine lower GI toxicities (16.7%) and four urinary toxicities (7.4%) in the CBT group. All three patients with severe toxicities in the IGBT group underwent CT-based brachytherapy planning. There was no statistically significant difference in crude rate of overall or severe urinary/lower GI toxicities. Detailed toxicity profile is summarized in
Actuarial rates of severe toxicities are illustrated in
Logistic regression was performed between occurrence of toxicity and cumulative EQD23 D2cc of corresponding OAR in the IGBT group. Occurrence of grade ≥ 2 lower GI toxicities and cumulative EQD23 D2cc of sigmoid colon was significantly correlated (odds ratio [OR], 1.158; 95% CI, 1.012 to 1.326; p=0.033), while the relationship between grade ≥ 2 lower GI toxicities and cumulative EQD23 D2cc of rectum (OR, 1.160; 95% CI, 0.997 to 1.350; p=0.055) and that between grade ≥ 2 urinary toxicities and cumulative EQD23 D2cc of the bladder (OR, 1.049; 95% CI, 0.996 to 1.104; p=0.069) showed marginal significance. ROC analysis showed that cumulative EQD23 D2cc of rectum (area under the curve [AUC], 0.7542; 95% CI, 0.5975 to 0.9108) and sigmoid colon (AUC, 0.8173; 95% CI, 0.6777 to 0.9569) were predictive for grade ≥ 2 lower GI toxicities. Cumulative EQD23 D2cc of bladder did not show significance in ROC analysis (AUC, 0.6711; 95% CI, 0.3558 to 0.9864). The optimal threshold of cumulative EQD23 D2cc of rectum by Youden method was 69.7 Gy with a sensitivity of 85.7% and a specificity of 74.4%. The optimal threshold of cumulative EQD23 D2cc of sigmoid colon was 70.8 Gy with a sensitivity of 85.7% and a specificity of 76.7%.
For the CBT group, logistic regression between cumulative EQD23 of bladder point and occurrence of urinary toxicities did not show a significant or marginally significant correlation. The relationship between cumulative EQD23 of rectal point and lower GI toxicities with grade ≥ 2/3 showed a marginal significance (OR, 1.037; 95% CI, 0.999 to 1.077; p=0.054). Setting the endpoint as grade ≥ 2 or ≥ 3 had the same effect because late lower GI toxicity with grade 2 was not reported in the CBT group. In ROC analysis, cumulative EQD23 of rectal point was predictive for lower GI toxicities with grade ≥ 2/3 (AUC, 0.7111; 95% CI, 0.5206 to 0.9016). The optimal threshold of cumulative EQD23 of rectal point was 101.0 Gy with a sensitivity of 55.6% and a specificity of 84.4%. ROC curves are illustrated in
This study compared IGBT versus CBT performed by the same practitioner in the same time period. Oncologic outcomes were not significantly different between the two groups. However, the actuarial incidence of severe toxicities was higher in the CBT group. Cumulative EQD23 D2cc of sigmoid colon was significantly correlated with lower GI toxicity in the IGBT group, while cumulative EQD23 D2cc of rectum and bladder in the IGBT group and cumulative EQD23 of rectal point in the CBT group showed marginal significance with corresponding toxicities.
Although results from a randomized controlled trial have not been reported, several prospective and retrospective studies have compared efficacy of IGBT versus CBT, with many studies showing better treatment outcomes and toxicity profile of IGBT [
Severe toxicity rate of IGBT (overall crude rate 6.0%) found in this study was comparable to rates from EMBRACE-I (overall grade 3 10.2%, grade 4 4.4%) and RetroEMBRACE (actuarial 3-year 4% for bladder, 6% for GI tract), considering the retrospective nature and a shorter follow-up period of this study [
The optimal threshold of cumulative EQD23 of rectal point in the CBT group was 101.0 Gy in this study, which is relatively high. Although rectal point dose of this study showed statistical significance for association with lower GI toxicities, this high optimal threshold may indicate that rectal point dose often overestimates actual rectal dose depending on clinical situations and practitioners. Although ICRU rectal point dose has some correlation with volumetric dose of the rectum, it also has limitations to evaluate rectal dose compared with volumetric dose calculation [
Half of severe GI toxicity cases in this study showed evidence of bleeding, perforation, or fistula involving colon and ileum. In contrast to IGBT, CBT cannot evaluate dose of GI tract above the rectum. This drawback might have caused severe consequence for some patients. Tandem can be unexpectedly placed proximity to the sigmoid colon, and dose to sigmoid colon is associated with the distance between the tandem and the sigmoid colon [
One distinct feature of IGBT in this study was the utilization of 0.35 T MRI incorporated in MRI-guided radiation therapy system. A previous study has compared image quality of 0.35 T MRI, 1.5 T diagnostic MRI, and CT for brachytherapy planning and concluded that 0.35 T MRI-based planning is anticipated to give similar clinical benefit to diagnostic MRI-based planning [
In the multivariate analysis of this study, lymph node dissection was correlated with worse LC. Considering definition of the event and covariates incorporated in the multivariate analysis for LC, this result was presumably due to patient selection for lymph node dissection. Other than lymph node dissection to LC, treatment specifics including brachytherapy technology did not significantly impact oncologic outcomes in this study.
Several limitations exist in this study mainly due to its retrospective nature. Patient characteristics and treatment specifics were not balanced between the two groups, such as age, concurrent chemotherapy, and lymph node surgery, as more patients were referred from other institutions after concurrent chemoradiation in the CBT group, although effects of different chemotherapeutic regimens [
In conclusion, lower actuarial severe toxicity rate in the IGBT group than in the CBT group was observed for locally advanced cervical cancer, although there were no significant differences in oncologic outcomes between the two groups. Dose to sigmoid colon, rectum, and bladder were significantly or marginally significantly correlated with occurrence of grade ≥ 2 corresponding toxicities in the IGBT group. Half of severe lower GI toxicities reported in this study impacted GI tract above the rectum. Evaluation of dose to GI tract above rectum including sigmoid colon by IGBT might prevent some lower GI toxicities. There is accumulated evidence including this study supporting the benefit of applying IGBT over CBT for locally advanced cervical cancer. Thus, policies to encourage implementation of IGBT in institutions need to be applied.
Supplementary materials are available at Cancer Research and Treatment website (
This study was approved by the Institutional Review Board (IRB) of Seoul National University Hospital (IRB No. H-2204-055-1314) before collecting patient information. Informed consent was waived due to its retrospective nature.
Conceived and designed the analysis: Lee TH, Kang HC.
Collected the data: Lee TH, Kim KS, Kim HJ, Choi CH, Kang S, Kang HC.
Contributed data or analysis tools: Kim HJ, Eom KY, Wee CW, Song YS, Park NH, Kim JW, Chung HH, Kim HS, Lee M, Kang HC.
Performed the analysis: Lee TH, Kim KS, Choi CH, Kang S, Kang HC.
Wrote the paper: Lee TH, Kim KS, Kang HC.
Conflict of interest relevant to this article was not reported.
Kaplan-Meier curves of local control (A), locoregional control (B), progression-free survival (C), and overall survival (D) rates.
Actuarial rates of severe (grade ≥ 3) urinary (A), lower gastrointestinal (GI) (B), and any toxicities (C).
Patient characteristics and treatment specifics
Characteristic | Image-guided brachytherapy (n=50) | Conventional brachytherapy (n=54) | p-value |
---|---|---|---|
|
49.5 (31–80) | 59 (27–88) | < 0.001 |
|
|||
I | 0 | 3 (5.6) | 0.263 |
II | 8 (16.0) | 12 (22.2) | |
III | 38 (76.0) | 34 (63.0) | |
IV | 4 (8.0) | 5 (9.3) | |
|
|||
Squamous cell carcinoma | 40 (80.0) | 42 (77.8) | 0.869 |
Adenocarcinoma | 9 (18.0) | 10 (18.5) | |
Others | 1 (2.0) | 2 (3.7) | |
|
|||
Yes | 41 (82.0) | 42 (77.8) | 0.771 |
No | 9 (18.0) | 12 (22.2) | |
|
|||
Yes | 38 (76.0) | 33 (61.1) | 0.156 |
No | 12 (24.0) | 21 (38.9) | |
|
|||
Yes | 7 (14.0) | 12 (22.2) | 0.406 |
No | 43 (86.0) | 42 (77.6) | |
|
|||
Yes | 3 (6.0) | 3 (5.6) | > 0.99 |
No | 47 (94.0) | 51 (94.4) | |
|
|||
Yes | 1 (2.0) | 2 (3.7) | > 0.99 |
No | 49 (98.0) | 52 (96.3) | |
|
5.4 (2.4–9.6) | 5.2 (2.5–11.5) | 0.757 |
|
30 (25–30) | 27.5 (20–30) | < 0.001 |
|
|||
4 | 6 (12.0) | 2 (3.7) | 0.258 |
5 | 43 (86.0) | 50 (92.6) | |
6 | 1 (2.0) | 1 (2.0) | |
|
|||
IMRT | 44 (88.0) | 40 (74.1) | 0.121 |
3D-CRT | 6 (12.0) | 14 (25.9) | |
|
|||
45.0 Gy/25 fractions | 48 (96.0) | 41 (75.9) | 0.013 |
50.4 Gy/28 fractions | 2 (4.0) | 10 (18.5) | |
Others | 0 | 3 (5.6) | |
|
|||
Yes | 37 (74.0) | 36 (66.7) | 0.547 |
No | 13 (26.0) | 18 (33.3) | |
|
|||
Yes | 26 (52.0) | 7 (13.0) | < 0.001 |
No | 24 (48.0) | 47 (87.0) | |
|
|||
Yes | 3 (6.0) | 4 (7.4) | > 0.99 |
No | 47 (94.0) | 50 (92.6) | |
|
54 (47–63) | 53.5 (45–67) | 0.345 |
|
|||
Weekly cisplatin | 40 (80.0) | 53 (98.1) | 0.007 |
Tri-weekly cisplatin | 10 (20.0) | 1 (1.9) | |
|
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Dissection | 6 (12.0) | 1 (1.9) | 0.010 |
Sampling | 4 (8.0) | 0 | |
None | 40 (80.0) | 53 (98.1) | |
|
|||
Dissection | 1 (2.0) | 1 (1.9) | 0.188 |
Sampling | 3 (6.0) | 0 | |
None | 46 (82.0) | 53 (98.1) | |
|
|||
Yes | 6 (12.0) | 1 (1.9) | 0.019 |
No | 5 (10.0) | 1 (1.9) | |
Not observed | 39 (78.0) | 52 (96.3) | |
|
|||
Yes | 2 (4.0) | 1 (1.9) | 0.946 |
No | 48 (96.0) | 53 (98.1) |
Values are presented as median (range) or number (%). 3D-CRT, 3-dimensional conformal radiation therapy; EBRT, external beam radiotherapy; FIGO, International Federation of Gynecology and Obstetrics; IMRT, intensity-modulated radiation therapy.
Consolidative immunotherapy administered by other prospective trial was excluded.
Dosimetric parameters of brachytherapy
Parameter | Dose (Gy) |
---|---|
|
|
HR-CTV D90% | 31.6 (25.1–35.0) |
Cumulative EQD210 | 87.1 (75.7–93.9) |
HR-CTV D98% | 26.4 (19.7–29.4) |
Cumulative EQD210 | 78.2 (69.8–84.0) |
IR-CTV D90% | 25.4 (17.5–29.9) |
Cumulative EQD210 | 76.2 (67.6–84.0) |
IR-CTV D98% | 20.5 (9.7–25.3) |
Cumulative EQD210 | 68.3 (53.9–75.9) |
Bladder D2cc | 23.3 (9.5–40.9) |
Cumulative EQD23 | 78.8 (52.5–134.8) |
Rectum D2cc | 25.6 (17.8–42.7) |
Cumulative EQD23 | 66.8 (49.4–80.2) |
Sigmoid D2cc | 17.3 (7.8–24.5) |
Cumulative EQD23 | 66.0 (50.3–81.9) |
|
|
A point (left) | 27.9 (19.2–33.1) |
Cumulative EQD210 | 82.5 (67.9–90.1) |
A point (right) | 28.3 (20.8–31.5) |
Cumulative EQD210 | 83.0 (70.6–89.5) |
B point (left) | 7.4 (4.8–9.4) |
Cumulative EQD210 | 51.8 (48.7–57.6) |
B point (right) | 7.7 (5.6–9.4) |
Cumulative EQD210 | 51.9 (49.6–57.6) |
Bladder point | 17.2 (6.7–35.3) |
Cumulative EQD23 | 67.9 (49.6–114.1) |
Rectal point | 25.6 (17.8–42.7) |
Cumulative EQD23 | 85.6 (66.6–143.7) |
Values are presented as median (range). EQD2n, equivalent dose in 2 Gy per fraction with α/β of n; HR-CTV, high risk clinical target volume; IR-CTV, intermediate risk clinical target volume.
Patterns of recurrence
Type of recurrence | Image-guided brachytherapy (n=50) | Conventional brachytherapy (n=54) | p-value |
---|---|---|---|
|
3 (6.0) | 5 (9.3) | 0.799 |
|
8 (16.0) | 11 (20.4) | 0.747 |
Pelvic lymph node only | 7 (14.0) | 2 (3.7) | 0.129 |
Paraaortic lymph node only | 1 (2.0) | 3 (5.6) | 0.666 |
Pelvic and Paraaortic lymph node | 0 | 6 (11.1) | 0.045 |
|
6 (12.0) | 14 (25.9) | 0.121 |
Values are presented as number (%).
Toxicity profile
Late toxicity | Image-guided brachytherapy (n=50) | Conventional brachytherapy (n=54) | p-value |
---|---|---|---|
|
|||
Grade 1 | 1 (2.0) | 1 (1.9) | 0.375 |
Grade 2 | 5 (10.0) | 7 (13.0) | |
Grade 3 | 0 | 3 (5.6) | |
Grade 4 | 0 | 1 (1.9) | |
|
|||
Grade 1 | 2 (4.0) | 0 | 0.042 |
Grade 2 | 1 (2.0) | 7 (13.0) | |
|
|||
Grade 2 | 1 (2.0) | 0 | 0.969 |
|
|||
Grade 1 | 3 (6.0) | 2 (3.7) | 0.930 |
|
|||
Grade 2 | 3 (6.0) | 6 (11.1) | 0.564 |
|
|||
Grade 2 | 1 (2.0) | 0 | 0.969 |
|
|||
Grade 2 | 0 | 1 (1.9) | > 0.99 |
|
|||
Grade 1 | 0 | 1 (1.9) | 0.389 |
Grade 3 | 0 | 1 (1.9) | |
|
|||
Grade 3 | 0 | 2 (3.7) | 0.239 |
Grade 4 | 0 | 1 (1.9) | |
|
|||
Grade 1 | 5 (10.0) | 4 (7.4) | 0.104 |
Grade 2 | 4 (8.0) | 0 | |
Grade 3 | 3 (6.0) | 7 (13.0) | |
Grade 4 | 0 | 2 (3.7) | |
|
|||
Grade 1 | 4 (8.0) | 5 (9.3) | 0.209 |
Grade 2 | 4 (8.0) | 0 | |
Grade 3 | 3 (6.0) | 3 (5.6) | |
|
|||
Grade 1 | 1 (2.0) | 0 | 0.969 |
|
|||
Grade 3 | 0 | 1 (1.9) | 0.239 |
Grade 4 | 0 | 2 (3.7) | |
|
|||
Grade 4 | 0 | 1 (1.9) | > 0.99 |
|
|||
Grade 3 | 0 | 3 (5.6) | 0.269 |
Values are presented as number (%).