Advertisement

Results of computer tomography-based adaptive brachytherapy in combination with whole-pelvic- and central-shielding-external beam radiotherapy for cervical cancer

Open AccessPublished:August 01, 2022DOI:https://doi.org/10.1016/j.brachy.2022.06.009

      ABSTRACT

      PURPOSE

      To evaluate treatment results and investigate predictors of local control.

      METHODS AND MATERIALS

      In this retrospective study of 236 patients with cervical cancer, we administered CT-based adaptive brachytherapy (BT) in combination with whole- pelvic (WP)- and central shielding (CS)- external beam radiotherapy (EBRT) with or without chemotherapy. The study cohort comprised patients with cervical cancer treated with definitive radiotherapy (RT) or concurrent chemoradiotherapy between June 2013 and March 2019. Local control (LC), overall survival (OS), and late toxicity were evaluated. Predictive factors for LC were analyzed by univariate and multivariate analyses.

      RESULTS

      Median doses of WP- and CS-EBRT and BT were 30.6 GyEQD2, 19.8 GyEQD2, and 40.3 GyEQD2, respectively. The 3-year LC rates for T1b2, T2a, T2b, T3b, and T4 were 100%, 100%, 97.3%, 86.9%, and 91.7%, respectively (p = 0.346). The 3-year OS for Stages IB, IIB, IIIB, IIIC, and IVA were 100%, 94.8%, 82.5%, 81.7%, and 74.6%, respectively (p = 0.037). Rates of Grade 3–4 gastrointestinal and genitourinary toxicities were 3.8% and 1.7%, respectively. Multivariate analysis showed that T3–4, nonsquamous cell histology, and high-risk clinical target volume (CTVHR) D90 of BT < 36GyEQD2 were independently associated with significantly poorer LC.

      CONCLUSIONS

      The combination of WP- and CS-EBRT and CT-based IGBT with or without concurrent chemotherapy produced favorable LC outcomes with low rates of late toxicities for patients with small or medium-sized tumors. However, LC was less favorable for patients who had large T3 disease, and the use of CS requires caution in these patients.

      Keywords

      Introduction

      A combination of external beam radiotherapy (EBRT) to the pelvis and brachytherapy (BT) is the standard radiotherapy (RT) approach for cervical cancer. BT plays an important role in controlling primary disease. Because the development of three-dimensional image-guided BT (3D-IGBT) using MRI or CT for treatment planning in the early 2000s (
      • Haie-Meder C.
      • Pötter R.
      • Van Limbergen E.
      • et al.
      Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV.
      ,
      • Pötter R.
      • Haie-Meder C.
      • Van Limbergen E.
      • et al.
      Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology.
      ,
      International Commission on Radiation Units and Measurements
      ICRU report 89. Prescribing, recording, and reporting brachytherapy for cancer of the cervix.
      ), it has been increasingly used worldwide (
      • Tan L.T
      Implementation of image-guided brachytherapy for cervix cancer in the UK: progress update.
      ,
      • Ohno T.
      • Toita T.
      • Tsujino K.
      • et al.
      A questionnaire-based survey on 3D image-guided brachytherapy for cervical cancer in Japan: advances and obstacles.
      ,
      • Grover S.
      • Harkenrider M.M.
      • Cho L.P.
      • et al.
      Image Guided Cervical Brachytherapy: 2014 Survey of the American Brachytherapy Society.
      ). In 3D-IGBT, doses to cervical tumors and organs at risk (OARs), such as the rectum, sigmoid colon, and bladder, can be assessed using 3D dose distributions and dose-volume histograms (DVHs). 3D-IGBT enables the delivery of a very high-dose to the tumor while minimizing doses to the OARs. Several studies have suggested that 3D-IGBT achieves favorable treatment outcomes (
      • Pötter R.
      • Georg P.
      • Dimopoulos J.C.A.
      • et al.
      Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer.
      ,
      • Gill B.S.
      • Kim H.
      • Houser C.J.
      • et al.
      MRI-guided high dose-rate intracavitary brachytherapy for treatment of cervical cancer: the University of Pittsburgh experience.
      ,
      • Sturdza A.
      • Pötter R.
      • Fokdal L.U.
      • et al.
      Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study.
      ,
      • Zolciak-Siwinska A.
      • Gruszczynska E.
      • Bijok M.
      • et al.
      Computed tomography-planned high-dose-rate brachytherapy for treating uterine cervical cancer.
      ,
      • Pötter R.
      • Tanderup K.
      • Schmid P.M.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicenter prospective cohort study.
      ).
      Regarding BT techniques, intracavitary brachytherapy (IC-BT) using a combination of intrauterine and intravaginal applicators has long been widely used. Recently, combined intracavitary and interstitial brachytherapy (IC/IS-BT), which involves implanting additional interstitial needles, has been increasingly administered. IC/IS-BT has the advantage over conventional IC-BT of delivering sufficiently high-doses, especially to extensive and large tumors or those with unfavorable topography (
      • Wakatsuki M.
      • Ohno T.
      • Yoshida D.
      • et al.
      Intracavitary combined with CT-guided interstitial brachytherapy for locally advanced uterine cervical cancer: introduction of the technique and a case presentation.
      ,
      • Oike T.
      • Ohno T.
      • Noda S.E.
      • et al.
      Can combined intracavitary/interstitial approach be an alternative to interstitial brachytherapy with the Martinez Universal Perineal Interstitial Template (MUPIT) in computed tomography-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumors?.
      ). Several studies have reported achieving favorable local control (LC) by IC/IS-BT in patients with advanced cervical cancer (
      • Pötter R.
      • Tanderup K.
      • Schmid P.M.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicenter prospective cohort study.
      ,
      • Fokdal L.
      • Sturda A.
      • Mazeron R.
      • et al.
      Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: analysis from the retroEMBRACE study.
      ,
      • Murakami N.
      • Kobayashi K.
      • Shima S.
      • et al.
      A hybrid technique of intracavitary and interstitial brachytherapy for locally advanced cervical cancer: initial outcomes of a single-institute experience.
      ).
      Late radiation toxicities in the rectum and bladder are major problems after RT for cervical cancer because EBRT and BT may deliver high-doses to these organs. In particular, in patients with small pelvises, BT applicators are often in very close proximity to the rectum and bladder, inevitably resulting in exposure of these organs to very high-doses of BT. Central-shielding (CS)-EBRT enables the reduction of doses to the rectum and bladder. Several studies have demonstrated that a combination of WP- and CS-EBRT and BT yields favorable LC and has a low incidence of late rectal and bladder toxicities (
      • Nakano T.
      • Kato S.
      • Ohno T.
      • et al.
      Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix.
      ,
      • Toita T.
      • Kato S.
      • Niibe Y.
      • et al.
      Prospective multi-institutional study of definitive radiotherapy with high-dose-rate intracavitary brachytherapy in patients with nonbulky (<4-cm) stage I and II uterine cervical cancer (JAROG0401/JROSG04-2).
      ,
      • Toita T.
      • Kitagawa R.
      • Hamano T.
      • et al.
      Phase II study of concurrent chemoradiotherapy with high-dose-rate intracavitary brachytherapy in patients with locally advanced uterine cervical cancer: efficacy and toxicity of a low cumulative radiation dose schedule.
      ,
      • Kato S.
      • Ohno T.
      • Thephamongkhol K.
      • et al.
      Long-term follow up results of a multi-institutional phase 2 study of concurrent chemoradiation therapy for locally advanced cervical cancer in east and southeast Asia.
      ). However, CS-EBRT potentially risks reducing the dose to the target volume, which may impair LC. Therefore, the contribution of BT is very important: it is imperative that sufficiently high-doses be delivered to the target volume at BT when CS-EBRT is administered (
      • Viswanathan A.N.
      • Creutzberg C.L.
      • Craigheas P.
      • et al.
      International brachytherapy practice patterns: a survey of the Gynecologic Cancer Intergroup (GCIG).
      ).
      In a previous study, we showed that BT contributes significantly to local tumor control when patients are treated with WP- and CS-EBRT and BT (
      • Okazaki S.
      • Murata K.
      • Noda S.E.
      • et al.
      Dose-volume parameters and local tumor control in cervical cancer treated with central-shielding external-beam radiotherapy and CT-based image-guided brachytherapy.
      ). In the present study, we retrospectively evaluated the treatment results and investigated predictors of LC in patients with cervical cancer treated with WP- and CS-EBRT and CT-based adaptive BT.

      Methods and materials

      Patients

      Patients with cervical cancer who were treated with RT or concurrent chemoradiotherapy (CCRT) at our hospital between June 2013 and March 2019 were enrolled in the study in accordance with the following criteria: (1) histologically confirmed, previously untreated carcinoma of the uterine cervix; (2) ≥ 20 years of age; (3) thorough pre-treatment evaluation by CT, MRI, and gynecological examination; (4) International Federation of Gynecology and Obstetrics (FIGO) 2018 Stage IB1–IVA; (5) treated with definitive RT or CCRT using CT-based IGBT; and (6) DVH data available. The study was approved by the institutional review board of our hospital (registration number: 2021–075). All patients underwent pretreatment diagnostic studies including physical and pelvic examinations by gynecologists and radiation oncologists, cervical biopsy, routine blood cell counts, chemistry profile, CT scans of the chest, abdomen, and pelvis, and MRI of the pelvis. Most patients also underwent 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan. Cervical tumor size was measured on MRI T2 weighted images. Lymph node status was diagnosed according to the findings of CT, MRI, and/or FDG-PET. A lymph node ≥ 1 cm in its short axis on CT or MRI and/or positive findings on FDG-PET was diagnosed as lymph node metastasis. N factor was classified as N0, N1, and N2 by UICC TNM 8th edition.

      Radiotherapy

      EBRT was delivered to the pelvis with 10 MV X-rays. The CTV for the WP-EBRT consisted of the primary tumor, whole uterus, bilateral parametria, at least the upper half of the vagina, and pelvic lymph nodes. Three-dimensional conformal RT with a four-field box technique was used, whereas intensity-modulated radiotherapy was not used. A dose of 1.8–2.0 Gy/fraction and five fractions/week were delivered by EBRT. The radiotherapy was based on the Japanese treatment protocols for cervical cancer (
      • Nakano T.
      • Kato S.
      • Ohno T.
      • et al.
      Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix.
      ,
      • Toita T.
      • Kato S.
      • Niibe Y.
      • et al.
      Prospective multi-institutional study of definitive radiotherapy with high-dose-rate intracavitary brachytherapy in patients with nonbulky (<4-cm) stage I and II uterine cervical cancer (JAROG0401/JROSG04-2).
      ,
      • Toita T.
      • Kitagawa R.
      • Hamano T.
      • et al.
      Phase II study of concurrent chemoradiotherapy with high-dose-rate intracavitary brachytherapy in patients with locally advanced uterine cervical cancer: efficacy and toxicity of a low cumulative radiation dose schedule.
      ). Briefly, for patients with Stage IB1–2 or IIA1 disease, 20 Gy EBRT was delivered to the WP, followed by 30 Gy CS-EBRT and BT. For patients with advanced-stage of disease, 30 Gy (for medium-sized tumors) or 40 Gy (for large tumors) WP-EBRT was delivered, followed by 20 or 10 Gy CS-EBRT and BT. When a patient had bulky pelvic lymph node(s), an additional 5–10 Gy was delivered to the lesion(s). Regarding Stage IIIC2r disease, 40 Gy EBRT was delivered to the whole abdominal para-aortic lymph node region, and an additional 10–20 Gy was delivered to the enlarged lymph node(s) to boost the dose to a total of 50–60 Gy in 25–30 fractions over 5–6 weeks.
      Four weekly sessions of CT-based IGBT were initiated after completion of WP-EBRT. A high-dose-rate 192Ir source was used. IC- or IC/IS-BT was performed to adapt to the tumor volume. IC/IS-BT was adopted for patients with extremely extensive or large tumors. IS needles were inserted with free-hand technique. The high-risk clinical target volume (CTVHR) and OARs, including the rectum, sigmoid colon, bladder, and small bowel, were delineated on CT images in accordance with published recommendations (
      • Haie-Meder C.
      • Pötter R.
      • Van Limbergen E.
      • et al.
      Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV.
      ,
      • Pötter R.
      • Haie-Meder C.
      • Van Limbergen E.
      • et al.
      Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology.
      ,
      International Commission on Radiation Units and Measurements
      ICRU report 89. Prescribing, recording, and reporting brachytherapy for cancer of the cervix.
      ,
      • Ohno T.
      • Wakatsuki M.
      • Toita T.
      • et al.
      Recommendations for high-risk clinical target volume definition with computed tomography for three-dimensional image-guided brachytherapy in cervical cancer patients.
      ) and the dose distributions and DVHs were calculated. All radiation doses were biologically converted to equivalent doses in 2 Gy (EQD2) by a linear quadratic model using an alpha/beta ratio of 10 Gy for CTVHR and 3 Gy for OARs. Regarding the DVH parameters, the dose delivered to 90% and 98% of the CTVHR (CTVHR D90 and D98) and the minimum dose delivered to 2 cm3 (D2cm3) of the rectum, sigmoid colon, and bladder were calculated, recorded, and reported. The planned dose and dose constraints were as follows: (1) minimum CTVHR D90 ≥ 6.5 Gy in each BT session; and (2) D2cm3 of the rectum and sigmoid colon ≤ 70 GyEQD2 and D2cm3 of the bladder ≤ 90 GyEQD2 by a combination of WP-EBRT and BT. When the dose constraints for the CTVHR and OARs were not both achievable, the constraints for the OARs were prioritized. Radiotherapy was withheld if patients developed Grade 4 hematological toxicities or Grade 3–4 non-hematological toxicities as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0 (
      Common Terminology Criteria For Adverse Events (CTCAE) Version 4.0.
      ). Radiotherapy was resumed when the toxicities had recovered to Grade 2.

      Chemotherapy

      Patients with Stage IB1–2 or IIA1 disease were treated with RT alone, whereas those with more advanced-stage disease were treated with concurrent chemoradiotherapy (CCRT) unless they were aged ≥ 75 years, had a performance status (PS) score of 3 or 4, and/or insufficient organ function. Most patients received weekly cisplatin (40 mg/m2); however, those for whom this was considered contraindicated received monthly nedaplatin. Chemotherapy was discontinued when patients developed Grade 3–4 hematological or non-hematological toxicities and resumed when the toxicities had recovered to Grade 1.

      Follow-up and evaluation

      After completion of treatment, patients were followed up every 1–3 months for the first 2 years and every 3–6 months from the third year. Post-treatment evaluation and assessment of adverse events were achieved by medical interviews, physical and gynecological examinations, and blood tests at scheduled checkup visits. Patients also underwent CT and/or MRI 1 month after treatment and every 6–12 months thereafter. If a recurrence was suspected, CT, MRI, and/or FDG-PET were performed to assess disease status. Biopsies were also performed whenever possible.
      The primary endpoint of the study was LC, and the secondary endpoints were overall survival (OS) and late toxicities. LC was defined as the absence of any recurrent or progressive disease in the cervix, parametrium, uterine corpus, and/or vagina. Pelvic and/or para-aortic nodal recurrence or progression within the irradiated volume was not classified as local failure. Late toxicities were defined as adverse events in the pelvis occurring more than 3 months after completing treatment. Late toxicities were classified as gastrointestinal, genitourinary, or other and were graded according to the CTCAE version 4.0. Duration of LC was measured from initiation of treatment to the date of diagnosis of local failure or the most recent follow-up. Duration of OS was measured from initiation of treatment to the date of death from any cause or the most recent follow-up. The duration of late toxicities was measured from initiation of treatment to diagnosis of toxicities or the most recent follow-up.

      Statistical analysis

      Statistical analysis was performed using SPSS version 26 (IBM; Armonk, NY). The rates of LC, OS, and late toxicities were calculated using the Kaplan–Meier method. Predictive factors for LC were investigated by univariate analysis using the log-rank test and multivariate analysis using the Cox proportional hazard model, with respect to the following clinicopathological and treatment factors: age (≤ 50 years or > 50 years); maximum tumor diameter (< 60 mm or ≥ 60 mm); T factor (T1–2 or T3–4), N factor (N0 or N1/2); para-aortic lymph node status (negative or positive); histology (squamous cell or non-squamous cell carcinoma); treatment (RT or CCRT); BT technique (IC-BT or IC/IS-BT); overall treatment time (< 56 days or ≥ 56 days); CTVHR volume for the first BT; and DVH parameters (CTVHR D90 of BT only or of WP-EBRT plus BT). The cut-off values for CTVHR volume in the first BT and DVH parameters for LC were determined using receiver operating characteristic (ROC) analysis. p < 0.05 was considered to denote statistical significance in univariate and multivariate analyses.

      Results

      Patient and treatment characteristics

      The cohort of the present study comprised 236 patients. The characteristics of these patients and their treatment are summarized in Table 1. CCRT (cisplatin, 159; nedaplatin, 21) was administered to 80 patients, and the remaining 56 patients underwent RT alone. Regarding EBRT, a total dose of 39.6–60 Gy (median, 50 Gy) was delivered. A CS was inserted after delivering 19.8–45 Gy (median, 30.6 Gy) to the WP. Regarding BT, 187 patients were treated with IC-BT and 49 with IC/IS-BT. The volume of CTVHR in the first BT session was 7.6–195.4 cm3 (median, 30.0 cm3). The median CTVHR D90 and D98 of BT was calculated to be 40.3 GyEQD2 (range, 19.1–76.1 GyEQD2) and, 31.9 GyEQD2 (range, 15.2–61.3 GyEQD2), respectively. Regarding the cumulative dose delivered to CTVHR, CTVHR D90 of WP-EBRT and BT was calculated because the value was conventionally used. However, this calculation may underestimate the cumulative dose to CTVHR when CS-EBRT is used. CTVHR D98 of WP + CS-EBRT and BT was also calculated in this study, because, for CTVHR with larger than 3 cm in width, CTVHR D98 is derived by the dose outside the CS (Table 2).
      Table 1
      Age (years) (median, range)62.5(29–94)
      FIGO StageIB18
      IIB78
      IIIA2
      IIIB43
      IIIC171
      IIIC211
      IVA13
      T factorT1b115
      T1b26
      T2a1
      T2b112
      T3a4
      T3b85
      T413
      N factoN0146
      N179
      N211
      HistologySCC200
      Non-SCC36
      Tumor size at diagnosis (cm) (median, range)5.0(1.0–11.0)
      TreatmentCCRT180
      RT56
      EBRT dose (GyEQD2) (median, range)
      Total50(39.6–60)
      Whole Pelvis30.6(19.8–45)
      Central Shielding19.8(0–30)
      BT techniqueIC-BT187
      IC/IS-BT49
      Overall treatment time (days) (median, range)50 (
      • Okonogi N.
      • Wakatsuki M.
      • Kato S.
      • et al.
      Significance of concurrent use of weekly cisplatin in carbon-ion radiotherapy for locally advanced adenocarcinoma of the uterine cervix: a propensity score-matched analysis.
      -92)
      SCC = squamous cell carcinoma; CCRT = concurrent chemoradiotherapy; RT = radiotherapy; IC-BT = intracavitary brachytherapy; IC/IS-BT = combined intracavitary and interstitial brachytherapy.
      Table 2
      All (n = 236)
      CTVHR D90 of BT (GyEQD2) (median, range)40.3(19.1–76.1)
      CTVHR D98 of BT (GyEQD2) (median, range)31.9(15.2–61.3)
      CTVHR D90 of WP-EBRT + BT (GyEQD2) (median, range)73.8(56.0–116.1)
      CTVHR D98 of WP+CS-EBRT + BT (GyEQD2) (median, range)81.6(59.4–111.3)
      Rectum D2cm3 (GyEQD2) (median, range)59.4(29.0–89.1)
      Bladder D2cm3 (GyEQD2) (median, range)73.4(37.3–112.7)
      CTVHR = high-risk clinical target volume; WP-EBRT = whole pelvic external beam radiotherapy; BT = brachytherapy; D90m = the dose delivered to 90%; D98 = the dose delivered to 98%; D2cm3 = the minimum dose delivered to 2 cm3; EQD2 = equivalent doses in 2 Gy.

      Outcomes

      The median duration of follow-up was 45 months (range, 2.2–90.1 months). Eighteen patients developed local recurrence during follow-up, 12 developed pelvic and/or paraaortic lymph node metastases, and 69 developed distant metastases. Regarding the sites of local recurrence, nine patients had recurrences in their uterine cervixes, two in their uterine corpuses, six in their vaginas, and three in their parametria. The 3-year LC for all patients was 92.6%. The 3-year LC according to T status was 90.9% for T1b1, 100% for T1b2, 100% for T2a, 97.3% for T2b, 75% for T3a, 86.9% for T3b, and 91.7% for T4 (p = 0.346) (Fig. 1). During follow-up, 37 patients died of cervical cancer and 4 died of other diseases. The 3-year OS according to FIGO stage was 100% for Stage IB, 94.8% for Stage IIB, 100% for Stage IIIA, 82.5% for Stage IIIB, 81.7% for Stage IIIC, and 74.6% for Stage IVA (p = 0.037) (Fig. 2).
      The incidences of Grade 3–4 gastrointestinal and genitourinary adverse events were 3.8% and 1.7%, respectively. Two of the seven patients who developed rectovaginal fistulae and one of the four who developed vesicovaginal fistulae had Stage IVA disease with rectal or bladder invasion (Table 3).
      Table 3
      Adverse eventsAll (n = 236)
      Gastrointestinal
       All grades58 (24.6%)
       Grade 3–49 (3.8%)
      Genitourinary
       All grades26 (11.0%)
       Grade 3–44 (1.7%)

      Predictors of local control

      The cutoff value calculated from the ROC curve for CTVHR volume for the first BT was 35 cm3 (AUC = 0.663), whereas the cutoff values for cumulative CTVHR D90 of BT only and WP-EBRT plus BT were 36 GyEQD2 (AUC = 0.424) and 72 GyEQD2 (AUC = 0.522), respectively. Univariate analyses showed that T status, histology, CTVHR volume for the first BT, and CTVHR D90 and D98 of BT only were significant predictors of LC, T3–4, nonsquamous cell histology, CTVHR volume ≥ 35 cm3, and CTVHR D90 of BT < 36 GyEQD2, with CTVHR D98 of BT < 28 GyEQD2 being associated with significantly poorer LC. However, CTVHR D90 of WP-EBRT plus BT was not significantly correlated with LC (Table 4). Because D90 and D98 have a strong positive correlation coefficient of 0.94 and are considered conceptually closely related variables, we selected only D90 for multivariate analysis. After multivariate analyses, T factor, histology, and CTVHR D90 of BT remained significant predictors of LC (Table 5).
      Table 4
      Factors3y-LC (%)p-value
      Age≦5093.30.726
      >5092.3
      Tumor size<60 mm93.90.346
      ≧60 mm89.7
      T factorT1–296.70.001
      T3–487.0
      N factorN094.40.245
      N1/289.6
      Paraaortic lymph nodePositive100.00.366
      Negative92.2
      HistologySCC95.20.001
      Non SCC76.4
      Treatment strategyCCRT91.80.974
      RT95.2
      Brachytherapy techniqueIC-BT93.60.291
      IC/IS-BT88.7
      Overall treatment time<56 days94.50.133
      ≧56 days84.7
      CTVHR volume at first BT<35 cc96.10.001
      ≧35 cc86.3
      CTVHR D90 WP+BT<72 GyEQD293.00.852
      ≧72 GyEQD292.9
      CTVHR D98 WP+BT<63 GyEQD291.50.336
      ≧63 GyEQD293.4
      CTVHR D90 BT<36 GyEQD277.80.000
      ≧36 GyEQD293.7
      CTVHR D98 BT<28 GyEQD278.30.000
      ≧28 GyEQD294.7
      CTVHR = high-risk clinical target volume; BT = brachytherapy; WP = whole pelvic external beam radiotherapy; D90 = the dose delivered to 90%; D98 = the dose delivered to 98%; EQD2 = equivalent doses in 2 Gy; SCC = squamous cell carcinoma; IC-BT = intracavitary brachytherapy; IC/IS-BT = combined intracavitary and interstitial brachytherapy.
      Table 5
      Factorsp-value
      T factorT1–20.014
      T3–4
      HistologySCC0.000
      Non SCC
      CTVHR volume at first BT<35 cc0.056
      ≧35 cc
      CTVHR D90 BT<36 GyEQD20.019
      ≧36 GyEQD2
      CTVHR = high-risk clinical target volume; BT = brachytherapy; D90 = the dose delivered to 90%; EQD2 = equivalent doses in 2 Gy; SCC = squamous cell carcinoma.
      The relationships between CTVHR volume, CTVHR D90 of BT, and LC were determined using scatter plots (Fig. 3). Three-year LC for patients with CTVHR volume < 35 cm3 and CTVHR D90 ≥ 36 GyEQD2, CTVHR volume ≥ 35 cm3 and CTVHR D90 ≥ 36 GyEQD2, CTVHR volume < 35 cm3 and CTVHR D90 < 36 GyEQD2, and CTVHR volume ≥ 35 cm3 and CTVHR D90 < 36 GyEQD2, were 98%, 89%, 80%, and 78%, respectively.
      Fig 3
      Fig. 3Relationship between local control and CTVHR volume and CTVHR D90. Open and filled circles represent local control and failure, respectively. Abbreviations: CTVHR = high-risk clinical target volume, LC = local control rate.

      Discussion

      In the present study, patients with cervical cancer were treated with RT or CCRT using a combination of approximately 30 Gy WP- and 20 Gy CS-EBRT and CT-based 3D-IGBT. The median CTVHR D90 of BT only was 40.3 GyEQD2. We achieved a 3-year LC of 92.6% for all patients and 96.7% and 87% for those with stage IB-IIB and III-IVA, respectively. Several studies on MRI- or CT-based 3D-IGBT have demonstrated favorable treatment outcomes. In a series from the Medical University of Vienna, the 3-year LC after CCRT and MRI-based IGBT was 100% for Stage IB, 96% for Stage IIB, and 86% for Stage IIIB, respectively (
      • Pötter R.
      • Georg P.
      • Dimopoulos J.C.A.
      • et al.
      Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer.
      ). The RetroEMBRACE study, which was a multicenter retrospective cohort study on CT- or MRI-based IGBT, reported a 3-year LC of 91% for all patients, comprising 98% for Stage IB, 93% for Stage IIB, and 79% for Stage IIIB, respectively (
      • Sturdza A.
      • Pötter R.
      • Fokdal L.U.
      • et al.
      Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study.
      ). More recently, the EMBRACE-I studies, a multicenter prospective cohort study on CCRT and MRI-based IGBT, reported a 5-year LC of 91%–98% for patients with Stages IB1–IVA (
      • Pötter R.
      • Tanderup K.
      • Schmid P.M.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicenter prospective cohort study.
      ). We consider that the results of the present study were almost similar to those of these other 3D-IGBT studies, however, the LC for patients with T3 disease was less favorable when compared with that of the EMBRACE-I study.
      In the present study, univariate and multivariate analyses showed that T status, histology, and the cumulative CTVHR D90 of BT were statistically significant predictors of LC (Tables 4 and 5). Regarding the dose to the cervical tumor, several 3D-IGBT studies reported the dose-response relationship of the cumulative CTVHR D90 of WP-EBRT plus BT (
      • Pötter R.
      • Dimopoulos J.
      • Georg P.
      • et al.
      Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer.
      ,
      • Mazeron R.
      • Castelnau-Marchand P.
      • Dumas I.
      • et al.
      Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy.
      ,
      • Tanderup K.
      • Fokdal L.U.
      • Sturdza A.
      • et al.
      Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.
      ). The series in Vienna found that, in large tumors, dose escalation of CTVHR D90 from 81 GyEQD2 to 90 GyEQD2 between two time periods resulted in improvement of LC from 71% to 90% (
      • Pötter R.
      • Dimopoulos J.
      • Georg P.
      • et al.
      Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer.
      ). DVH analyses of the retroEMBRACE study findings demonstrated that dose escalation from 75 GyEQD2 to 85 GyEQD2 resulted in a 3% increase in LC for tumors of limited to intermediate size (20–30 cm3) and a 7% increase for large tumors (≥70 cm3) CTVHR. These researchers estimated that CTVHR D90 of ≥ 85 GyEQD2 delivered in 7 weeks achieved a 3-year LC of > 93–94% for tumors of limited or intermediate size and > 86% in larger tumor CTVHR (
      • Tanderup K.
      • Fokdal L.U.
      • Sturdza A.
      • et al.
      Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.
      ). In the EMBRACE-I study, approximately 90 GyEQD2 (85–94 Gy) delivered to CTVHR D90 achieved a 5-year LC of 91–92%, even in patients with Stage IIIB–IVA disease (
      • Pötter R.
      • Tanderup K.
      • Schmid P.M.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicenter prospective cohort study.
      ). Because most patients in these studies received 45–50 Gy WP-EBRT, dose escalation of BT was the main contributor to the improved LC, CTVHR D90 of BT ≥ 40 GyEQD2, resulting in the high LC.
      In contrast, patients in the present study were treated with a combination of WP- and CS-EBRT and BT. Previous clinical studies using WP- and CS-EBRT and BT reported the Point A dose or HR-CTVHR D90 by simply adding the doses of WP-EBRT and BT while omitting the dose of CS-EBRT (
      • Murakami N.
      • Kobayashi K.
      • Shima S.
      • et al.
      A hybrid technique of intracavitary and interstitial brachytherapy for locally advanced cervical cancer: initial outcomes of a single-institute experience.
      ,
      • Toita T.
      • Kato S.
      • Niibe Y.
      • et al.
      Prospective multi-institutional study of definitive radiotherapy with high-dose-rate intracavitary brachytherapy in patients with nonbulky (<4-cm) stage I and II uterine cervical cancer (JAROG0401/JROSG04-2).
      ,
      • Toita T.
      • Kitagawa R.
      • Hamano T.
      • et al.
      Phase II study of concurrent chemoradiotherapy with high-dose-rate intracavitary brachytherapy in patients with locally advanced uterine cervical cancer: efficacy and toxicity of a low cumulative radiation dose schedule.
      ). According to this method, the median CTVHR D90 of WP-EBRT plus BT in the present study was 73.8 GyEQD2, which is very low compared with the cited European and North American studies (
      • Pötter R.
      • Georg P.
      • Dimopoulos J.C.A.
      • et al.
      Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer.
      ,
      • Gill B.S.
      • Kim H.
      • Houser C.J.
      • et al.
      MRI-guided high dose-rate intracavitary brachytherapy for treatment of cervical cancer: the University of Pittsburgh experience.
      ,
      • Sturdza A.
      • Pötter R.
      • Fokdal L.U.
      • et al.
      Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study.
      ,
      • Zolciak-Siwinska A.
      • Gruszczynska E.
      • Bijok M.
      • et al.
      Computed tomography-planned high-dose-rate brachytherapy for treating uterine cervical cancer.
      ,
      • Pötter R.
      • Tanderup K.
      • Schmid P.M.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicenter prospective cohort study.
      ). Furthermore, no correlation was found between CTVHR D90 of WP-EBRT plus BT and LC (Table 4). These results suggest that simply adding the WP-EBRT and BT doses while omitting the CS-EBRT dose may underestimate the actual dose to the CTVHR (
      • Viswanathan A.N.
      • Creutzberg C.L.
      • Craigheas P.
      • et al.
      International brachytherapy practice patterns: a survey of the Gynecologic Cancer Intergroup (GCIG).
      ).
      Several dosimetric studies showed that the CS-EBRT dose contributes to some extent to the total dose delivered to CTVHR, and the dose should not be omitted for evaluation (
      • Tharavichitkul E.
      • Wanwilairat S.
      • Watcharawipha A.
      • et al.
      The effect of central shielding in the dose reporting for cervical cancer in EQD2 era.
      ,
      • Tamaki T.
      • Ohno T.
      • Noda S.E.
      • et al.
      Filling the gap in central shielding: three-dimensional analysis of the EQD2 dose in radiotherapy for cervical cancer with the central shielding technique.
      ,
      • Tamaki T.
      • Noda S.E.
      • Ohno T.
      • et al.
      Dose–volume histogram analysis of composite EQD2 dose distributions using the central shielding technique in cervical cancer radiotherapy.
      ). The lateral regions of CTVHR, which are outside CS, can be covered with adequately high-doses by EBRT and BT when BT is optimally performed. In the central regions of CTVHR, which are inside CS, EBRT doses are lowered by CS, but substantial doses may be delivered by BT because of the close proximity of the sources. Consequently, high enough doses for tumor control may be delivered to the central regions of CTVHR (
      • Tharavichitkul E.
      • Wanwilairat S.
      • Watcharawipha A.
      • et al.
      The effect of central shielding in the dose reporting for cervical cancer in EQD2 era.
      ,
      • Tamaki T.
      • Ohno T.
      • Noda S.E.
      • et al.
      Filling the gap in central shielding: three-dimensional analysis of the EQD2 dose in radiotherapy for cervical cancer with the central shielding technique.
      ,
      • Tamaki T.
      • Noda S.E.
      • Ohno T.
      • et al.
      Dose–volume histogram analysis of composite EQD2 dose distributions using the central shielding technique in cervical cancer radiotherapy.
      ). However, there are several limitations in evaluating the cumulative CTVHR D90 or D98 when CS-EBRT is used. First, the presence of large dose gradients from both CS-EBRT and BT in the same regions makes it difficult to evaluate the cumulative doses (
      International Commission on Radiation Units and Measurements
      ICRU report 89. Prescribing, recording, and reporting brachytherapy for cancer of the cervix.
      ,
      • Tharavichitkul E.
      • Wanwilairat S.
      • Watcharawipha A.
      • et al.
      The effect of central shielding in the dose reporting for cervical cancer in EQD2 era.
      ,
      • Tamaki T.
      • Ohno T.
      • Noda S.E.
      • et al.
      Filling the gap in central shielding: three-dimensional analysis of the EQD2 dose in radiotherapy for cervical cancer with the central shielding technique.
      ). Second, the abovementioned hypothesis requires a good geometrical relationship between CS and the high-dose regions at BT. However, uncertainties exist regarding the interfractional variations during CS-EBRT and BT phases, which cause difficulties in the evaluation (
      • Tharavichitkul E.
      • Wanwilairat S.
      • Watcharawipha A.
      • et al.
      The effect of central shielding in the dose reporting for cervical cancer in EQD2 era.
      ,
      • Tamaki T.
      • Ohno T.
      • Noda S.E.
      • et al.
      Filling the gap in central shielding: three-dimensional analysis of the EQD2 dose in radiotherapy for cervical cancer with the central shielding technique.
      ,
      • Tamaki T.
      • Noda S.E.
      • Ohno T.
      • et al.
      Dose–volume histogram analysis of composite EQD2 dose distributions using the central shielding technique in cervical cancer radiotherapy.
      ). Further studies are needed to establish a more precise formula for estimating the cumulative doses of WP- and CS-EBRT and BT to the CTVHR.
      The dose contribution of CS-EBRT to the dose of CTVHR varies significantly by CS width (3 cm or 4 cm) and dose of CS-EBRT (10–30 Gy). When the CS width is smaller, the impact of dose reduction to CTVHR is less significant (
      • Tharavichitkul E.
      • Wanwilairat S.
      • Watcharawipha A.
      • et al.
      The effect of central shielding in the dose reporting for cervical cancer in EQD2 era.
      ,
      • Tamaki T.
      • Ohno T.
      • Noda S.E.
      • et al.
      Filling the gap in central shielding: three-dimensional analysis of the EQD2 dose in radiotherapy for cervical cancer with the central shielding technique.
      ,
      • Tamaki T.
      • Noda S.E.
      • Ohno T.
      • et al.
      Dose–volume histogram analysis of composite EQD2 dose distributions using the central shielding technique in cervical cancer radiotherapy.
      ). In the present study, 3-cm width CS was used, and the CS-EBRT dose was changed according to the stage and tumor size (CS-EBRT dose 30 Gy for Stage IB1–2 or Stage IIA1, 20–10 Gy for more advanced-stage disease with medium-sized or large tumor). These treatment methods and adequately high-dose delivery at BT may have resulted in the favorable LC outcomes in the present study.
      However, when a tumor is large and has significant AP extension, the use of CS-EBRT has the potential risk of under dosage of CTVHR (
      • Tamaki T.
      • Ohno T.
      • Noda S.E.
      • et al.
      Filling the gap in central shielding: three-dimensional analysis of the EQD2 dose in radiotherapy for cervical cancer with the central shielding technique.
      ,
      • Tamaki T.
      • Noda S.E.
      • Ohno T.
      • et al.
      Dose–volume histogram analysis of composite EQD2 dose distributions using the central shielding technique in cervical cancer radiotherapy.
      ). In the present study, LC for patients with T3 disease or for those with bulky disease (> 35 cc of CTVHR volume at first BT) were less favorable when compared with those of the EMBRACE-I study (
      • Pötter R.
      • Tanderup K.
      • Schmid P.M.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicenter prospective cohort study.
      ). To achieve favorable LC for large Stage III-IVA tumors, the planned dose of CTVHR D90 ≥ 85–90 GyEQD2 is recommended (
      • Pötter R.
      • Tanderup K.
      • Schmid P.M.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicenter prospective cohort study.
      ,
      • Pötter R.
      • Tanderup K.
      • Kirisits C.
      • et al.
      The EMBRACE II study: the outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies.
      ,
      • Tanderup K.
      • Nesvacil N.
      • Kirchheiner K.
      • et al.
      Evidence-based dose planning aims and dose prescription in image-guided brachytherapy combined with radiochemotherapy in locally advanced cervical cancer.
      ). Therefore, CS-EBRT requires caution in patients who have large tumors with significant AP extension.
      In the present study, CTVHR D90 in the BT sessions were significant predictors of LC, and CTVHR D90 ≥ 36 GyEQD2 at BT had significantly better LC (Tables 4 and 5). In addition, CTVHR D98 was strongly correlated with D90, suggesting that D98 was a significant predictor for LC as well as D90, and CTVHR D98 ≥ 28 GyEQD2 at BT may have had significantly better LC. These results suggested that BT makes a very important contribution to achieving LC and indicated that 90% or 98% of the CTVHR should be covered with at least 6.5 Gy (approximately ∼9 GyEQD2) or 5.5 Gy (approximately ∼7 GyEQD2), respectively, at each BT session. Our previous study reported that local recurrence occurred outside the 6 Gy isodose line at BT (
      • Okazaki S.
      • Murata K.
      • Noda S.E.
      • et al.
      Dose-volume parameters and local tumor control in cervical cancer treated with central-shielding external-beam radiotherapy and CT-based image-guided brachytherapy.
      ). Interestingly, these results are almost comparable to those of the retroEMBRACE study, which demonstrated that CTVHR D90 ≥ 85 GyEQD2 or CTVHR D98 ≥ 75 GyEQD2 had better LC (
      • Tanderup K.
      • Fokdal L.U.
      • Sturdza A.
      • et al.
      Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.
      ,
      • Tanderup K.
      • Nesvacil N.
      • Kirchheiner K.
      • et al.
      Evidence-based dose planning aims and dose prescription in image-guided brachytherapy combined with radiochemotherapy in locally advanced cervical cancer.
      ). Because most patients received 45–50 Gy WP-EBRT in this study, CTVHR D90 ≥ 40 GyEQD2 or CTVHR D98 ≥ 30 GyEQD2 was associated with favorable LC.
      In the present study, IC/IS-BT was used for only 20% of the patients because of a personnel shortage in the early period of the study. This may have resulted in the poor LC outcomes for patients with extensive and large tumors. As described above, it is important to cover the whole tumor volume with high-dose BT using IC/IS-BT (
      • Fokdal L.
      • Sturda A.
      • Mazeron R.
      • et al.
      Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: analysis from the retroEMBRACE study.
      ).
      Non-squamous cell histology was a significant predictor of LC in the current study (Tables 4 and 5). Notably, 7of the 36 patients with non-squamous cell carcinomas (6 adenocarcinomas and 1small cell carcinoma) developed local recurrence. The local recurrences were located in the uterine cervices of five of these seven patients, this region having received high-doses of radiation. Several studies have also achieved poor LC and OS of locally advanced cervical adenocarcinomas treated with RT or CCRT (
      • Eifel P.J.
      • Burke T.W.
      • Morris M.
      • Smith T.L.
      Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma.
      ,
      • Baalbergen A.
      • Ewing-Graham P.C.
      • Hop W.C.J.
      • et al.
      Prognostic factors in adenocarcinoma of the uterine cervix.
      ). Further studies are needed regarding the optimum dose to CTVHR and/or the appropriate combination of RT and chemotherapy or immune therapy to achieve LC of advanced cervical adenocarcinomas. The results of several studies suggested that carbon ion radiotherapy may be an effective alternative for these radioresistant tumors (
      • Okonogi N.
      • Wakatsuki M.
      • Kato S.
      • et al.
      Clinical outcomes of carbon ion radiotherapy with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma in a phase 1/2 clinical trial (Protocol 1001).
      ,
      • Okonogi N.
      • Wakatsuki M.
      • Kato S.
      • et al.
      Significance of concurrent use of weekly cisplatin in carbon-ion radiotherapy for locally advanced adenocarcinoma of the uterine cervix: a propensity score-matched analysis.
      ).
      In the current study, the rates of late Grade 3–4 gastrointestinal and genitourinary adverse events were 3.8% and 1.7%, respectively. The RetroEMBRACE study reported 5-year rates of Grade 3–5 gastrointestinal and genitourinary toxicities of 7% and 5%, respectively (
      • Sturdza A.
      • Pötter R.
      • Fokdal L.U.
      • et al.
      Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study.
      ), whereas the corresponding rates in the EMBRACE-I study were 8.5% and 6.8%, respectively (
      • Pötter R.
      • Tanderup K.
      • Schmid P.M.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicenter prospective cohort study.
      ). The low incidence of severe late toxicities in the current study may have been attributable to lower doses of radiation to the rectum and bladder as a result of inserting CS during EBRT. However, because late radiation toxicities may continue to manifest long after the completion of RT, evaluation of treatment safety requires long-term follow-up (
      • Nakano T.
      • Kato S.
      • Ohno T.
      • et al.
      Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix.
      ).
      This study had several limitations. First, as a retrospective single-institutional study, there was a potential selection bias. Second, there were few local recurrences, which may have limited the statistical reliability. However, in the present study, 3D-IGBT treatment planning, including delineation of CTVHR and OARs and recording and reporting for DVH parameters, strictly complied with the published recommendations. Furthermore, almost all patients were strictly followed up. The present study therefore provides useful information on treatment.

      Conclusions

      We evaluated the treatment outcomes of a combination of WP- and CS-EBRT with 3-cm CS width and CT-based IGBT with or without concurrent chemotherapy for patients with cervical cancer. This treatment produced favorable LC outcomes with low rates of late toxicities for patients with small- or medium-sized tumors. However, LC was less favorable for patients who had large T3 disease, and the use of CS requires caution in these patients.

      Declaration of Competing Interest

      The authors declare no conflicts of interest.

      Acknowledgments

      We thank Dr. Trish Reynolds, MBBS, FRACP, and H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

      References

        • Haie-Meder C.
        • Pötter R.
        • Van Limbergen E.
        • et al.
        Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV.
        Radiother Oncol. 2005; 74: 235-245
        • Pötter R.
        • Haie-Meder C.
        • Van Limbergen E.
        • et al.
        Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology.
        Radiother Oncol. 2006; 78: 67-77
        • International Commission on Radiation Units and Measurements
        ICRU report 89. Prescribing, recording, and reporting brachytherapy for cancer of the cervix.
        J ICRU. 2013; 13 (Bethesda)
        • Tan L.T
        Implementation of image-guided brachytherapy for cervix cancer in the UK: progress update.
        Clin Oncol. 2011; 23: 681-684
        • Ohno T.
        • Toita T.
        • Tsujino K.
        • et al.
        A questionnaire-based survey on 3D image-guided brachytherapy for cervical cancer in Japan: advances and obstacles.
        J Radiat Res. 2015; 56: 897-903
        • Grover S.
        • Harkenrider M.M.
        • Cho L.P.
        • et al.
        Image Guided Cervical Brachytherapy: 2014 Survey of the American Brachytherapy Society.
        Int J Radiat Oncol Biol Phys. 2016; 94: 598-604
        • Pötter R.
        • Georg P.
        • Dimopoulos J.C.A.
        • et al.
        Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer.
        Radiother Oncol. 2011; 110: 116-123
        • Gill B.S.
        • Kim H.
        • Houser C.J.
        • et al.
        MRI-guided high dose-rate intracavitary brachytherapy for treatment of cervical cancer: the University of Pittsburgh experience.
        Int J Radiat Oncol Biol Phys. 2015; 91: 540-547
        • Sturdza A.
        • Pötter R.
        • Fokdal L.U.
        • et al.
        Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study.
        Radiother Oncol. 2016; 120: 428-433
        • Zolciak-Siwinska A.
        • Gruszczynska E.
        • Bijok M.
        • et al.
        Computed tomography-planned high-dose-rate brachytherapy for treating uterine cervical cancer.
        Int J Radiat Oncol Biol Phys. 2016; 96: 87-92
        • Pötter R.
        • Tanderup K.
        • Schmid P.M.
        • et al.
        MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicenter prospective cohort study.
        Lancet Oncol. 2021; 22: 538-547
        • Wakatsuki M.
        • Ohno T.
        • Yoshida D.
        • et al.
        Intracavitary combined with CT-guided interstitial brachytherapy for locally advanced uterine cervical cancer: introduction of the technique and a case presentation.
        J Radiat Res. 2011; 52: 54-58
        • Oike T.
        • Ohno T.
        • Noda S.E.
        • et al.
        Can combined intracavitary/interstitial approach be an alternative to interstitial brachytherapy with the Martinez Universal Perineal Interstitial Template (MUPIT) in computed tomography-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumors?.
        Radiat Oncol. 2014; 9: 222
        • Fokdal L.
        • Sturda A.
        • Mazeron R.
        • et al.
        Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: analysis from the retroEMBRACE study.
        Radiother Oncol. 2016; 120: 434-440
        • Murakami N.
        • Kobayashi K.
        • Shima S.
        • et al.
        A hybrid technique of intracavitary and interstitial brachytherapy for locally advanced cervical cancer: initial outcomes of a single-institute experience.
        BMC Cancer. 2019; 19: 221
        • Nakano T.
        • Kato S.
        • Ohno T.
        • et al.
        Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix.
        Cancer. 2005; 103: 92-101
        • Toita T.
        • Kato S.
        • Niibe Y.
        • et al.
        Prospective multi-institutional study of definitive radiotherapy with high-dose-rate intracavitary brachytherapy in patients with nonbulky (<4-cm) stage I and II uterine cervical cancer (JAROG0401/JROSG04-2).
        Int J Radiat Oncol Biol Phys. 2012; 82: e49-e56
        • Toita T.
        • Kitagawa R.
        • Hamano T.
        • et al.
        Phase II study of concurrent chemoradiotherapy with high-dose-rate intracavitary brachytherapy in patients with locally advanced uterine cervical cancer: efficacy and toxicity of a low cumulative radiation dose schedule.
        Gynecol Oncol. 2012; 126: 211-216
        • Kato S.
        • Ohno T.
        • Thephamongkhol K.
        • et al.
        Long-term follow up results of a multi-institutional phase 2 study of concurrent chemoradiation therapy for locally advanced cervical cancer in east and southeast Asia.
        Int J Radiat Oncol Biol Phys. 2013; 87: 100-105
        • Viswanathan A.N.
        • Creutzberg C.L.
        • Craigheas P.
        • et al.
        International brachytherapy practice patterns: a survey of the Gynecologic Cancer Intergroup (GCIG).
        Int J Radiat Oncol Biol Phys. 2012; 82: 250-255
        • Okazaki S.
        • Murata K.
        • Noda S.E.
        • et al.
        Dose-volume parameters and local tumor control in cervical cancer treated with central-shielding external-beam radiotherapy and CT-based image-guided brachytherapy.
        J Radiat Res. 2019; 4: 490-500
        • Ohno T.
        • Wakatsuki M.
        • Toita T.
        • et al.
        Recommendations for high-risk clinical target volume definition with computed tomography for three-dimensional image-guided brachytherapy in cervical cancer patients.
        J. Radiat Res. 2017; 58: 341-350
      1. Common Terminology Criteria For Adverse Events (CTCAE) Version 4.0.
        National Cancer Institute, 2010 (21 March 2019, date last accessed)
        • Pötter R.
        • Dimopoulos J.
        • Georg P.
        • et al.
        Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer.
        Radiother Oncol. 2007; 83: 148-155
        • Mazeron R.
        • Castelnau-Marchand P.
        • Dumas I.
        • et al.
        Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy.
        Radiother Oncol. 2015; 114: 257-263
        • Tanderup K.
        • Fokdal L.U.
        • Sturdza A.
        • et al.
        Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.
        Radiother Oncol. 2016; 120: 441-446
        • Tharavichitkul E.
        • Wanwilairat S.
        • Watcharawipha A.
        • et al.
        The effect of central shielding in the dose reporting for cervical cancer in EQD2 era.
        J Contemp Brachyther. 2013; 5: 236-239
        • Tamaki T.
        • Ohno T.
        • Noda S.E.
        • et al.
        Filling the gap in central shielding: three-dimensional analysis of the EQD2 dose in radiotherapy for cervical cancer with the central shielding technique.
        J Radiat Res. 2015; 56: 804-810
        • Tamaki T.
        • Noda S.E.
        • Ohno T.
        • et al.
        Dose–volume histogram analysis of composite EQD2 dose distributions using the central shielding technique in cervical cancer radiotherapy.
        Brachytherapy. 2016; 15: 598-606
        • Pötter R.
        • Tanderup K.
        • Kirisits C.
        • et al.
        The EMBRACE II study: the outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies.
        Clin Trans Radiat Oncol. 2018; 9: 48-60
        • Tanderup K.
        • Nesvacil N.
        • Kirchheiner K.
        • et al.
        Evidence-based dose planning aims and dose prescription in image-guided brachytherapy combined with radiochemotherapy in locally advanced cervical cancer.
        Semin Radiat Oncol. 2020; 30: 311-327
        • Eifel P.J.
        • Burke T.W.
        • Morris M.
        • Smith T.L.
        Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma.
        Gynecol Oncol. 1995; 59: 38-44
        • Baalbergen A.
        • Ewing-Graham P.C.
        • Hop W.C.J.
        • et al.
        Prognostic factors in adenocarcinoma of the uterine cervix.
        Gynecol Oncol. 2004; 92: 262-267
        • Okonogi N.
        • Wakatsuki M.
        • Kato S.
        • et al.
        Clinical outcomes of carbon ion radiotherapy with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma in a phase 1/2 clinical trial (Protocol 1001).
        Cancer Med. 2018; 7: 351-359
        • Okonogi N.
        • Wakatsuki M.
        • Kato S.
        • et al.
        Significance of concurrent use of weekly cisplatin in carbon-ion radiotherapy for locally advanced adenocarcinoma of the uterine cervix: a propensity score-matched analysis.
        Cancer Med. 2020; 9: 1400-1408