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Three-dimensional-guided perineal-based interstitial brachytherapy in cervical cancer: A systematic review of technique, local control and toxicities

      Abstract

      Objective

      To evaluate local control and toxicities of perineal-based interstitial brachytherapy (P-ISBT) in cervical cancers treated with three-dimensional (3D) image-based planning through a systematic review. The secondary objective of this review is to summarize the implant and dosimetric techniques in 3D P-ISBT.

      Methods

      Systematic review of the literature using the PRISMA guideline was conducted through a search of Medline, EMBASE and Cochrane databases. This search resulted in 19 relevant manuscripts. Selected studies evaluated the role of perineal ISBT in cervical tumours treated using 3D planning. Eleven of nineteen manuscripts contained sufficient information for LC and toxicity calculations. Data were extracted by at least two investigators.

      Results

      A total of 672 cervical cancer patients were treated with P-ISBT and planned with 3D image-based planning. Clinical outcomes could be identified for 392 patients and 60% were staged IIIB or higher. Most patients received 45–50.4 Gy EBRT to the pelvis followed by a P-ISBT boost with a range of dose between 28 and 48 Gy EQD2Gy. Overall LC was 79% (310/392) with a median follow-up ranging from 14 to 55 months. Almost half of the patients (48%) had a median follow-up ≥35 months. Patients treated to a lower tumour EQD2Gy total dose had inferior LC. Procedure-related complications were rare (7 infections and 7 episodes of bleeding) and limited. Combined late gastro-intestinal, genitourinary and vaginal grade 3 and 4 toxicity was 12.1%.

      Conclusion

      Promising LC rates were found in patients with cervical cancers treated with perineal ISBT with 3D image-based planning. In this systematic review, 60% had stage IIIB disease or higher and yet a LC rate of 79% was found. LC seemed to correlate with the dose delivered to the tumour, while toxicity rates were similar to other cervical cancer series using 3D image-based brachytherapy. Perineal ISBT with 3D planning seems to be an effective and safe treatment for large advanced cervical tumours and may be a reasonable alternative to the increasingly more standard and modern intracavitary/interstitial (IC/IS) approaches such as the ‘Vienna’ applicator.

      Keywords

      Brachytherapy is an essential component in the treatment of locally advanced cervical cancers and is independently associated with improved overall survival for patients with this disease [
      • Han K.
      • Milosevic M.
      • Fyles A.
      • et al.
      Trends in the utilization of brachytherapy in cervical cancer in the United States.
      ]. In the last decade, the adoption of three-dimensional (3D) imaging for treatment planning has resulted in a paradigm shift from 2D-planning to a 3D image-guided brachytherapy (IGBT) technique [

      ICRU Report 89: Prescribing, recording, and reporting brachytherapy for Cancer of the Cervix. Volume 13, Issue 1–2; April 2013

      ]. Several recent observational studies have supported this trend while improvements in local control and toxicity associated with IGBT have been reported [
      • Potter R.
      • Georg P.
      • Dimopoulos J.
      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.
      ,
      • Sturdza A.
      • Potter R.
      • Fokdal L.
      • et al.
      Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in retroEMBRACE, a multicenter cohort study.
      ,
      • Potter R.
      • Dimopoulos J.
      • Georg P.
      • et al.
      Clinical impact of MRI assisted dose volume adaptation and escalation in brachytherapy of locally advanced cervix cancer.
      ].
      Current GEC-ESTRO recommendations suggest that 90% of the high-risk CTV (D90-HRCTV) should receive a minimum dose of 85 Gy (EQD2Gy) [
      • Tanderup K.
      • Fokdal L.
      • Sturdza A.
      Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.
      ]. Even with IGBT, this can be challenging for some tumours treated with standard brachytherapy applicators such as ‘ring-and-tandem’ or ‘tandem-and-ovoid’. The dose profile from intracavitary techniques may not adequately cover tumour volumes greater than 30 cc, and these bulkier cancers may require interstitial catheters to improve target coverage and dose. This can lead to an improvement in local control of 2–3% increase per each Gray delivered, as seen when using effective and more modern intracavitary/interstitial (IC/IS) applicators (eg. ‘Vienna’ or ‘Utrecht’) [
      • Fokdal L.
      • Sturdza A.
      • Mazeron R.
      Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ration in locally advanced cervical cancer: analysis from the retroEMBRACE study.
      ].
      Besides IC/IS applicators, another approach to interstitial brachytherapy is the perineal template technique. This has been available for over thirty years and has been shown to be superior to standard non-interstitial intracavitary applicators in delivering dose laterally to large advanced tumours [
      • Hsu I.
      • Speight J.
      • Hai J.
      • et al.
      A comparison between tandem and ovoids and interstitial gynecologic template brachytherapy dosimetry using a hypothetical computer model.
      ]. Historically, perineal ISBT was planned with conventional techniques where dose is prescribed to a defined point based on two-dimensional imaging [
      • Aristizabal S.
      • Surwit E.
      • Hevezi J.
      Treatment of advanced cancer of the cervix with transperineal interstitial irradiation.
      ]. As expected, the lack of volumetric dosimetry and the uncertainty of catheter location with respect to organs-at-risk yielded high toxicity rates and as a result, the adoption of this approach has been limited due to concerns and uncertainty of potential complications.
      However, with the advent of 3D image-based planning, perineal ISBT has become a more systematic technique and needle positioning with respect to organs in the pelvis can now be evaluated with CT or MRI. Furthermore, the use of ultrasound or MRI imaging for real-time guidance can also help improve the accuracy of needle placement.
      The primary goal of this systematic review is to evaluate local control and toxicities following perineal ISBT for the treatment of locally-advanced cervical cancer in the era of 3D image-based planning. This review will also summarize and discuss the characteristics of implant technique and dosimetry of the P-ISBT procedures as a secondary objective.

      Methods

      This systematic review adheres to the Preferred Reported Items for Systematic Reviews and Meta-Analyses protocol (PRISMA) [
      • Mother D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.
      The PRISMA group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
      ].

      Search strategy

      We first identified published manuscripts reporting the use of 3D-planned trans-perineal interstitial brachytherapy in cervical cancers from 1947 to April 2015. The search was performed in April 2015 using the National Library of Medicine (PubMed/MEDLINE), Excerpta Medica Database (EMBASE) and Cochrane database. An updated search was conducted in January 2017, identifying manuscripts from 1947 to January 2017. One recent article was found through PubMed ‘Epub ahead of print’ and was included in this review [
      • Fallon J.
      • Park S.
      • Yang L.
      • et al.
      Long term results from a prospective database on high dose rate (HDR) interstitial brachytherapy for primary cervical carcinoma.
      ]. The full search strategy can be found in Supplementary Data.

      Selection criteria

      The title and abstract of the identified papers were reviewed by two reviewers (EL and YW) and irrelevant papers were excluded if agreed upon by both reviewers. Any disagreements were discussed and resolved by a third reviewer (LM) opinion.
      Eligible studies met the following criteria: published manuscripts addressing adult population with cervical cancers treated with definitive perineal-based interstitial brachytherapy as a boost after external beam radiation and planned with three-dimensional imaging. For this review, three-dimensional treatment planning signifies volumetric delineation of targets and organs-at-risk (OARs) on CT or MRI with dose–volume histograms [
      • Baltas D.
      • Zamboglou N.
      2D and 3D planning in brachytherapy.
      ]. Studies that use 3D imaging exclusively for assessment of catheters position without volumetric delineation of the target and OARs were not categorized as 3D treatment planning.
      Institutional series that evaluated the role of P-ISBT for other primary cancers or recurrent tumours in addition to cervix cancer were excluded from LC and toxicity calculations if the results for cervical patients could not be separated with the provided information from the manuscript. Previous series that were subsequently updated with more recent publications, with exclusive dosimetric data or using 2D techniques were also excluded from this analysis.

      Data extraction

      The following data were collected separately by two reviewers (EL and YW): Study design, number of patients, year of publication, age, external beam radiation therapy (EBRT) dose, use of chemotherapy, P-ISBT dose and technique, treatment volume, follow-up time, local control and toxicity. Discrepancies were resolved by the third reviewer (LM). LC was defined as the absence of disease progression in the site of P-ISBT and was calculated by dividing the number of patients with controlled localized disease by the number of patients treated with P-ISBT. Because of the heterogeneity of follow-up times among the series it was not possible to define one common time point. As such, LC and toxicity endpoints are reported with a time range. Prescribed P-ISBT dose was converted to equivalent 2 Gy dose (EQD2Gy) using the linear quadratic equation and α/β = 10. Treatment clinical outcomes were calculated using the number of local failures or toxicity episodes per number of patients treated. Descriptive and sensitivity analysis was used for data report. Spearman’s rank correlation coefficient quantified correlation strength between LC and dose.

      Results

      A total of 377 citations were identified from database search. Based on the title and abstract, 27 articles were selected for full review (Fig. 1). Nineteen studies met the inclusion criteria and were fully reviewed for data extraction [
      • Fallon J.
      • Park S.
      • Yang L.
      • et al.
      Long term results from a prospective database on high dose rate (HDR) interstitial brachytherapy for primary cervical carcinoma.
      ,
      • Eisbruch A.
      • Johston C.
      • et al.
      Customized gynecologic interstitial implants: CT-based planning, dose evaluation, and optimization aided by laparotomy.
      ,
      • Isohashi F.
      • Yoshioka Y.
      • et al.
      High-dose-rate interstitial brachytherapy for previously untreated cervical carcinoma.
      ,
      • Shah A.
      • Strauss J.
      • Gielda B.
      • et al.
      Toxicity associated with bowel or bladder puncture during gynecologic interstitial brachytherapy.
      ,
      • Sharma D.
      • Rath G.
      • Thulkar S.
      • et al.
      High-dose rate interstitial brachytherapy using two weekly sessions of 10Gy each for patients with locally advanced cervical carcinoma.
      ,
      • Kannan N.
      • Beriwal S.
      • Kim H.
      • et al.
      High-dose-rate interstitial computed tomography- based brachytherapy for the treatment of cervical cancer: early results.
      ,
      • Wang Y.
      • Ye W.
      • Du L.
      Dose-volumes parameters and clinical outcome of CT-guided free-hand high-dose-rate interstitial brachytherapy for cervical cancer.
      ,
      • Thibault I.
      • Lavallé M.
      • Aubin S.
      Inverse-planned gynecologic high-dose-rate interstitial brachytherapy: clinical outcomes and dose-volume histogram analysis.
      ,
      • Lee L.
      • Damato A.
      • Viswanathan A.
      Clinical outcomes of high-dose-rate interstitial gynecological brachytherapy using real-time CT guidance.
      ,
      • Pinn-Bingham M.
      • Puthawala A.
      • Syed A.
      Outcomes of high-dose-rate interstitial brachytherapy in the treatment of locally advanced cervical cancer: long-term results.
      ,
      • Viswanathan A.
      • Szymonifka J.
      • Tempany-Afdhal C.
      • et al.
      A prospective trial of real-time magnetic resonance-guided catheter placement in interstitial gynecologic brachytherapy.
      ,
      • D’Souza D.
      • Wiebe E.
      • Patil N.
      • et al.
      CT-based interstitial brachytherapy in advanced gynecologic malignancies: outcomes from a single institution experience.
      ,
      • Yoshida K.
      • Yamazaki H.
      • Takenaka T.
      Preliminary results of MRI-assisted high-dose-rate interstitial brachytherapy for uterine cervical cancer.
      ,
      • Dyk P.
      • Richardson S.
      • Badiyan S.
      • et al.
      Outpatient-based high-dose-rate interstitial brachytherapy for gynecological malignancies.
      ,
      • Amsbaugh M.
      • Bhatt N.
      • Hunter T.
      • et al.
      Computed tomography-planned interstitial brachytherapy for locally advanced gynecological cancer: Outcomes and dosimetric predictors of urinary toxicity.
      ,
      • Vilalba S.
      • Sancha J.
      • Palacin A.
      • et al.
      Development and clinical implementation of a new template for MRI-based intracavitary/interstitial gynecologic brachytherapy for locally advanced cervical cancers: from CT-based MUPIT to the MRI compatible Template Benidorm. Ten years od experience.
      ,
      • Murakami N.
      • Kobayashi K.
      • Kato T.
      The role of interstitial brachytherapy in the management of primary radiation therapy for uterine cervical cancer.
      ,
      • Aridgides P.
      • Onderdank B.
      • Cunningham M.
      • et al.
      Institutional experience using brachytherapy for the treatment of primary and recurrent pelvic malignancies.
      ,
      • Bailleux C.
      • Falk A.
      • Chand-Fouche M.
      • et al.
      Concomitant cervical and transperineal parametrial high-dose-rate brachytherapy boost for locally advanced cervical cancer.
      ]. Eight studies were excluded after full review: three had no 3D-planning; one used P-ISBT as neoadjuvant treatment, one reported dosimetric outcomes only (no clinical data), one had no primary cervix cancers treated as definitive therapy, one did not use perineal ISBT (intravaginal) and another had a more updated series which was included in our review. Sixteen studies were retrospective and three studies were prospective in design. The combined selected studies reported on a total of 672 cervical cancer patients treated with P-ISBT, of which 392 patients had toxicity and oncological endpoints individually reported. Staging information was available for 375 patients and of these, approximately 48% had stage IIIB cervical tumours, 29% IIB, 12% IVA, 4% IIIA and 3% IB. Fourteen (4%) patients were staged as IVB.

      P-ISBT technique, treatment volume and dose prescription

      P-ISBT was performed using Syed-Neblett (n = 10 studies) [
      • Fallon J.
      • Park S.
      • Yang L.
      • et al.
      Long term results from a prospective database on high dose rate (HDR) interstitial brachytherapy for primary cervical carcinoma.
      ,
      • Shah A.
      • Strauss J.
      • Gielda B.
      • et al.
      Toxicity associated with bowel or bladder puncture during gynecologic interstitial brachytherapy.
      ,
      • Kannan N.
      • Beriwal S.
      • Kim H.
      • et al.
      High-dose-rate interstitial computed tomography- based brachytherapy for the treatment of cervical cancer: early results.
      ,
      • Thibault I.
      • Lavallé M.
      • Aubin S.
      Inverse-planned gynecologic high-dose-rate interstitial brachytherapy: clinical outcomes and dose-volume histogram analysis.
      ,
      • Lee L.
      • Damato A.
      • Viswanathan A.
      Clinical outcomes of high-dose-rate interstitial gynecological brachytherapy using real-time CT guidance.
      ,
      • Pinn-Bingham M.
      • Puthawala A.
      • Syed A.
      Outcomes of high-dose-rate interstitial brachytherapy in the treatment of locally advanced cervical cancer: long-term results.
      ,
      • Viswanathan A.
      • Szymonifka J.
      • Tempany-Afdhal C.
      • et al.
      A prospective trial of real-time magnetic resonance-guided catheter placement in interstitial gynecologic brachytherapy.
      ,
      • Amsbaugh M.
      • Bhatt N.
      • Hunter T.
      • et al.
      Computed tomography-planned interstitial brachytherapy for locally advanced gynecological cancer: Outcomes and dosimetric predictors of urinary toxicity.
      ,
      • Murakami N.
      • Kobayashi K.
      • Kato T.
      The role of interstitial brachytherapy in the management of primary radiation therapy for uterine cervical cancer.
      ,
      • Aridgides P.
      • Onderdank B.
      • Cunningham M.
      • et al.
      Institutional experience using brachytherapy for the treatment of primary and recurrent pelvic malignancies.
      ], custom-made (n = 4 studies) [
      • D’Souza D.
      • Wiebe E.
      • Patil N.
      • et al.
      CT-based interstitial brachytherapy in advanced gynecologic malignancies: outcomes from a single institution experience.
      ,
      • Yoshida K.
      • Yamazaki H.
      • Takenaka T.
      Preliminary results of MRI-assisted high-dose-rate interstitial brachytherapy for uterine cervical cancer.
      ,
      • Dyk P.
      • Richardson S.
      • Badiyan S.
      • et al.
      Outpatient-based high-dose-rate interstitial brachytherapy for gynecological malignancies.
      ,
      • Bailleux C.
      • Falk A.
      • Chand-Fouche M.
      • et al.
      Concomitant cervical and transperineal parametrial high-dose-rate brachytherapy boost for locally advanced cervical cancer.
      ] or MUPIT (n = 2 studies) [
      • Isohashi F.
      • Yoshioka Y.
      • et al.
      High-dose-rate interstitial brachytherapy for previously untreated cervical carcinoma.
      ,
      • Sharma D.
      • Rath G.
      • Thulkar S.
      • et al.
      High-dose rate interstitial brachytherapy using two weekly sessions of 10Gy each for patients with locally advanced cervical carcinoma.
      ] templates. One study performed the procedure by free hand [
      • Wang Y.
      • Ye W.
      • Du L.
      Dose-volumes parameters and clinical outcome of CT-guided free-hand high-dose-rate interstitial brachytherapy for cervical cancer.
      ], one used a Benidorm template 27 and one study did not specify template type [
      • Eisbruch A.
      • Johston C.
      • et al.
      Customized gynecologic interstitial implants: CT-based planning, dose evaluation, and optimization aided by laparotomy.
      ]. All studies used trans-perineal needles. Plastic catheters were used in nine studies [
      • Fallon J.
      • Park S.
      • Yang L.
      • et al.
      Long term results from a prospective database on high dose rate (HDR) interstitial brachytherapy for primary cervical carcinoma.
      ,
      • Eisbruch A.
      • Johston C.
      • et al.
      Customized gynecologic interstitial implants: CT-based planning, dose evaluation, and optimization aided by laparotomy.
      ,
      • Shah A.
      • Strauss J.
      • Gielda B.
      • et al.
      Toxicity associated with bowel or bladder puncture during gynecologic interstitial brachytherapy.
      ,
      • Wang Y.
      • Ye W.
      • Du L.
      Dose-volumes parameters and clinical outcome of CT-guided free-hand high-dose-rate interstitial brachytherapy for cervical cancer.
      ,
      • Lee L.
      • Damato A.
      • Viswanathan A.
      Clinical outcomes of high-dose-rate interstitial gynecological brachytherapy using real-time CT guidance.
      ,
      • Viswanathan A.
      • Szymonifka J.
      • Tempany-Afdhal C.
      • et al.
      A prospective trial of real-time magnetic resonance-guided catheter placement in interstitial gynecologic brachytherapy.
      ,
      • Yoshida K.
      • Yamazaki H.
      • Takenaka T.
      Preliminary results of MRI-assisted high-dose-rate interstitial brachytherapy for uterine cervical cancer.
      ,
      • Dyk P.
      • Richardson S.
      • Badiyan S.
      • et al.
      Outpatient-based high-dose-rate interstitial brachytherapy for gynecological malignancies.
      ,
      • Bailleux C.
      • Falk A.
      • Chand-Fouche M.
      • et al.
      Concomitant cervical and transperineal parametrial high-dose-rate brachytherapy boost for locally advanced cervical cancer.
      ], metallic in five [
      • Isohashi F.
      • Yoshioka Y.
      • et al.
      High-dose-rate interstitial brachytherapy for previously untreated cervical carcinoma.
      ,
      • Sharma D.
      • Rath G.
      • Thulkar S.
      • et al.
      High-dose rate interstitial brachytherapy using two weekly sessions of 10Gy each for patients with locally advanced cervical carcinoma.
      ,
      • Kannan N.
      • Beriwal S.
      • Kim H.
      • et al.
      High-dose-rate interstitial computed tomography- based brachytherapy for the treatment of cervical cancer: early results.
      ,
      • D’Souza D.
      • Wiebe E.
      • Patil N.
      • et al.
      CT-based interstitial brachytherapy in advanced gynecologic malignancies: outcomes from a single institution experience.
      ,
      • Vilalba S.
      • Sancha J.
      • Palacin A.
      • et al.
      Development and clinical implementation of a new template for MRI-based intracavitary/interstitial gynecologic brachytherapy for locally advanced cervical cancers: from CT-based MUPIT to the MRI compatible Template Benidorm. Ten years od experience.
      ]. Four studies did not mention needle characteristics [
      • Thibault I.
      • Lavallé M.
      • Aubin S.
      Inverse-planned gynecologic high-dose-rate interstitial brachytherapy: clinical outcomes and dose-volume histogram analysis.
      ,
      • Pinn-Bingham M.
      • Puthawala A.
      • Syed A.
      Outcomes of high-dose-rate interstitial brachytherapy in the treatment of locally advanced cervical cancer: long-term results.
      ,
      • Murakami N.
      • Kobayashi K.
      • Kato T.
      The role of interstitial brachytherapy in the management of primary radiation therapy for uterine cervical cancer.
      ,
      • Aridgides P.
      • Onderdank B.
      • Cunningham M.
      • et al.
      Institutional experience using brachytherapy for the treatment of primary and recurrent pelvic malignancies.
      ] and one used either plastic or metallic needles [
      • Amsbaugh M.
      • Bhatt N.
      • Hunter T.
      • et al.
      Computed tomography-planned interstitial brachytherapy for locally advanced gynecological cancer: Outcomes and dosimetric predictors of urinary toxicity.
      ]. The median number of catheters varied from 5 to 24 and insertion was guided by ultrasound in 5 studies, CT or MRI (3 studies), surgery (2 studies) and fluoroscopy (2 studies). Two studies used fluoroscopy and/or ultrasound guidance, two relied exclusively on clinical guidance for needle placement. All studies were planned on CT. Four also included MR imaging for tumour delineation (Table 1). Intra-uterine (IU) applicators were used in fourteen studies described either as a tandem or IU catheter. Three studies did not report on the use of an intrauterine source [
      • D’Souza D.
      • Wiebe E.
      • Patil N.
      • et al.
      CT-based interstitial brachytherapy in advanced gynecologic malignancies: outcomes from a single institution experience.
      ,
      • Dyk P.
      • Richardson S.
      • Badiyan S.
      • et al.
      Outpatient-based high-dose-rate interstitial brachytherapy for gynecological malignancies.
      ,
      • Aridgides P.
      • Onderdank B.
      • Cunningham M.
      • et al.
      Institutional experience using brachytherapy for the treatment of primary and recurrent pelvic malignancies.
      ] and two studies did not use an IU applicator [
      • Isohashi F.
      • Yoshioka Y.
      • et al.
      High-dose-rate interstitial brachytherapy for previously untreated cervical carcinoma.
      ,
      • Shah A.
      • Strauss J.
      • Gielda B.
      • et al.
      Toxicity associated with bowel or bladder puncture during gynecologic interstitial brachytherapy.
      ].
      Table 1Studies’ characteristics and P-ISBT technique.
      Studies (First author and published year)Study designRange of ageNumber of patientsEBRT doseTemplate typeDose rateCatheters materialNumber of catheters (median)Implant guidanceTargetPlanning image (s)
      Eisbruch et al. (1998)Retrospective33–711140-45 GyNRL-IDRPlastic19SurgicalGTVCT
      Isohashi et al. (2009)Retrospective35–772530 Gy + 20 Gy centre shieldMUPITHDRPlasticNRUltrasoundCTVCT
      Shah et al. (2010)RetrospectiveNR2032.4–55.8 GySyed-NeblettL-HDRPlastic21FluoroscopyPTVCT
      Sharma et al. (2011)Prospective26–674240 Gy + 10 Gy centre shieldMUPITHDRMetallic10UltrasoundNRCT
      Kannan et al. (2012)Retrospective37–804745 GySyed-NeblettHDRMetallic24UltrasoundCTVCT
      Wang et al. (2012)Prospective27–612050 GyFree-handHDRPlastic5CTHRCTVCT
      Thibault et al. (2012)Retrospective30–821245 GySyed-NeblettHDRNR17US or fluoroscopyHRCTVCT and MRI
      Lee et al. (2013)Retrospective27–891745 GySyed-NeblettHDRPlastic12CTHRCTVCT
      Pinn-Bingham et al. (2013)Retrospective20–8911650.4 GySyed-NeblettHDRNR22No guidanceNRCT
      Viswanathan et al. (2013)Prospective31–88650.4 GySyed-NeblettL-HDRPlasticNRMRIHRCTVCT and MRI
      D'Souza et al. (2014)RetrospectiveNR745 GyCustomHDRMetallic12Surgical or noneCTVCT
      Yoshida et al. (2015)Retrospective37–832930 Gy + 20 Gy centre shieldCustomHDRPlastic14UltrasoundHRCTVCT and MRI
      Dyk et al. (2015)Retrospective40–94250.4 GyCustomHDRPlasticNRNo guidanceNRCT
      Amsbaugh et al. (2016)RetrospectiveNR3645 GySyed-NeblettL-HDRPlastic or Metallic10FluorocopyHRCTVCT
      Villalba et al. (2016)Retrospective33–795950 GyMUPIT or BenidormHDRMetallic17Not reportedHRCTVCT and MRI
      Murakami et al. (2016)Retrospective42–822040 Gy + 10 Gy centre shieldSyed-NeblettHDRNR18UltrasoundCTVCT
      Aridgides et al. (2016)RetrospectiveNR1145 GySyed-NeblettL-HDRNR15Fluorocopy or surgicalCTVCT and MRI
      Bailleux et al. (2016)Retrospective27–793346 GyCustomHDRPlasticNRNot reportedHRCTVCT and MRI
      Fallon et al. (2017)Retrospective22–9215936 Gy + 14 Gy centre shieldSyed-NeblettHDRPlastic24US and fluoroscopy“Brachytherapy” CTVCT
      US – Ultrasound.
      Targeted volumes varied between studies. Fourteen studies contoured and prescribed dose to a CTV, one to a GTV and another to PTV. Eight studies defined volumes as per GEC-ESTRO guidelines. Three studies did not state a clear target definition. All but one study used HDR sources in treatment and two studies had patients also receiving LDR brachytherapy. Eisbruch et al. used low or intermediate dose rate brachytherapy only. Treatment was delivered in 2–8 fractions with EQD2Gy ranging between 28 and 48 Gy.

      Local control and toxicity outcomes

      For calculation of the oncological outcomes, eight publications were excluded (Shah et al., 2010, Thibault et al., 2012, D’Souza et al., 2014, Dyk et al., 2015, Amsbaugh et al., 2016, Aridgides et al., 2016, Bailleux et al., 2016 and Fallon, 2017) due to lack of separately reported 3D planned cervical cancer endpoints. The range of median follow-up time for the remaining eight publications (392 patients in total) varied from 14 to 55 months, but almost half of this population (47.7%) had a median follow-up ≥35 months. All patients received EBRT (typically 45 to 50.4 Gy) as a first phase of treatment and 264 of 339 patients (77.8%) that had chemotherapy information available received concomitant chemotherapy with EBRT. Overall long-term LC was reported in 310 out of 392 patients (79%) treated with P-ISBT. The range of LC was 62–93% among series. Although 29.5% of the included patients are from the Pinn-Bingham et al. study, this publication had a LC of 85%, which lies between the ranges found in the studies (Table 2). A subset analysis of local control in patients with median follow-up ≥35 months was calculated and found to be 82.8% (155 out 187 patients).
      Table 2Local control and toxicity.
      Studies (First author and published year)Number of patientsMedian follow up time (m)StageTotal EQD2GyLocal Control (%)Late toxicity G3-4
      GIGUVagina
      Eisbruch et al. (1998)11421 IIB; 9 IIIB; 1 IVA68 to 73 Gy7 (64%)000
      Isohashi et al. (2009)25551 IB2; 1 IIA; 3 IIB; 1 IIIA; 16 IIIB; 3 IVANot possible to calculate17 (68%)101
      Sharma et al. (2011)422310 IIB; 27 IIIB; 5 IVANot possible to calculate26 (62%)220
      Kannan et al. (2012)47146 IIB; 2 IIIA; 31 IIIB; 8 IVA75 Gy32 (68%)200
      Wang et al. (2012)201711 IIB; 9 IIIB87 Gy18 (90%)100
      Lee et al. (2013)1717Not reported77 Gy15 (88%)200
      Pinn-Bingham et al. (2013)116356 IB1, 4 IB2, 48 IIB, 7 IIIA, 44 IIIB, 7 IVA98 Gy99 (85%)1171
      Viswanathan et al. (2013)6451 IIB; 3 IIIB; 1 IVA; 1 IVB85 Gy5 (83%)NRNRNR
      Yoshida et al. (2015)29482 IIB; 1 IIIA; 18 IIIB; 5 IVA; 3 IVBNot possible to calculate27 (93%)200
      Villalba et al. (2016)59251 IIA; 27 IIB; 3 IIIA; 14 IIIB; 11 IVA; 3 IVB78 Gy46 (78%)
      Local control reported in a 12months follow up.
      1310
      Murakami et al. (2016)20322 IIIA; 10 IIIB; 1 IVA; 7 IVBNot possible to calculate18 (90%)100
      * Local control reported in a 12 months follow up.
      A strong correlation (Spearman’s rho: 0.714) was found between delivered EQD2Gy and LC (Fig. 2), with patients receiving EQD2Gy ≥76 Gy having LC of 84% and <76 Gy of 67%. Four studies (Isohashi et al., Sharma et al., Yoshida et al. and Murakami et al.) were excluded from this correlation analysis since part of the EBRT dose was delivered with centre field blocks in place, complicating the calculation for the total tumour dose.
      Figure thumbnail gr2
      Fig. 2Scatterplot. Total calculated EQD2Gy (EBRT + P-ISBT) plotted against local control in different published series. Note: Four publications with mid-line shielding were not included due to uncertainty of dose delivered to the tumour.
      Late toxicity was obtained from 386 out of 392 patients, since the publication from Viswanathan et al. did not provide enough information to calculate this endpoint. Only Grade 3 and 4 gastro-intestinal (GI), genitourinary (GU) and vaginal late toxicity was calculated. Forty-seven events (12.1%) were found: three-quarters of these related to GI toxicity (G3 30; G4 5), ten with GU toxicity (G3 6; G4 4) and 2 with vaginal toxicity (one necrosis and other complete obliteration) (Table 2).

      Discussion

      With the advent of three-dimensional image-based treatment planning, there is a renewed interest in using interstitial techniques combined with intracavitary applicators (IC) for the treatment of locally-advanced cervical cancer. Interstitial needles can increase the conformality of the delivered brachytherapy dose thereby allowing safe dose escalation and improvement in the therapeutic ratio [
      • Tanderup K.
      • Fokdal L.
      • Sturdza A.
      Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.
      ]. Combined intracavitary/Interstitial (IC/IS) applicators (eg ‘Vienna’ or ‘Utrecht’) [
      • Kirisits C.
      • Lang S.
      • Dimopoulos J.
      • Berger D.
      • et al.
      The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: design, application, treatment planning and dosimetric results.
      ,
      • Nomden C.
      • de Leeuw A.
      • Moerland M.
      • et al.
      Clinical use of the Utrecht applicator for combined intracavitary/interstitial brachytherapy treatment in locally advanced cervical cancer.
      ] are becoming a standard approach due to their similarity to traditional IC applicators, making the transition to interstitial brachytherapy more natural. However, it has not been directly addressed whether perineal-based interstitial brachytherapy can confer the same advantages as IC/IS while achieving reasonable toxicity rates.
      Three-dimensional image-based planning in cervical cancer brachytherapy has transformed perineal ISBT into a more systematic and safe approach. Perineal ISBT has already been widely well-established and may be effective at controlling bulky advanced tumours given the multiple needle positions. Furthermore, cancers with significant vaginal involvement may benefit from the perineal template approach by placing needles into the vaginal portion of the tumour. In fact, newer models of commercially available IC/IS applicators have incorporated a perineal template into the system for reasons such as these.
      Historical series evaluating locally-advanced cervical cancers treated with chemoradiotherapy and 2D brachytherapy have reported a local control of approximately 64% [
      • Potter R.
      • Dimopoulos J.
      • Georg P.
      • et al.
      Clinical impact of MRI assisted dose volume adaptation and escalation in brachytherapy of locally advanced cervix cancer.
      ]. We found through this systematic review that perineal ISBT resulted in a LC of 79% with a median follow-up range from 14 to 55 months. LC seemed to correlate with the prescribed dose (Fig. 2), similar to finding in other studies on intracavitary/interstitial radiation [
      • Fokdal L.
      • Sturdza A.
      • Mazeron R.
      Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ration in locally advanced cervical cancer: analysis from the retroEMBRACE study.
      ].
      Also, in this review, 60% had stage IIIB disease or higher and only one-third had IB (4%) or IIB (28%) cancers. A selection bias may exist since more advanced and radio-resistant cases are often chosen for P-ISBT. In the recent retroEMBRACE study, only 19% of patients had stage IIIB tumours while 96% of all patients were treated with IC/IS applicators [
      • Sturdza A.
      • Potter R.
      • Fokdal L.
      • et al.
      Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in retroEMBRACE, a multicenter cohort study.
      ,
      • Tanderup K.
      • Fokdal L.
      • Sturdza A.
      Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.
      ].
      This favourable effect of P-ISBT on cervical cancer local control seems to be consistent with the recently published large series by Fallon et al. [
      • Fallon J.
      • Park S.
      • Yang L.
      • et al.
      Long term results from a prospective database on high dose rate (HDR) interstitial brachytherapy for primary cervical carcinoma.
      ]. This study reported on 315 locally advanced cervical cancer patients treated with P-ISBT. Over half of the patients (51%) had 3D-CT planning and the overall local control (2D and 3D) was found to be 87% at 10 years. The 2D and 3D outcomes were not separated in the presented manuscript and therefore could not be included in our 3D local control calculation. However, this comprehensive series with long-term follow-up supports the findings that P-ISBT is a safe and effective treatment.
      In the era of 2D image-based planning, concerns regarding perineal interstitial brachytherapy were related to the potential toxicities of the sharp needles and high-doses of radiation delivered to adjacent organs. Previous 2D perineal ISBT studies have indeed shown variable toxicity rates. For instance, the seminal publication by Demanes and colleagues [
      • Demanes D.
      • Rodriguez R.
      • Bendre D.
      • Ewing T.
      High dose rate transperineal interstitial brachytherapy for cervical cancer: high pelvic control and low complication rates.
      ] have reported 6.5% of grade 3/4 late morbidities using the 2D technique, while other series [
      • Aristizabal S.
      • Woolfitt B.
      • Valencia A.
      Interstitial parametrial implants in carcinoma of the cervix Stage II-B.
      ,
      • Monk B.
      • Tewari K.
      • Burger R.
      • et al.
      A comparison of intracavitary versus interstitial irradiation in the treatment of cervical cancer.
      ] have found higher rates (≅21%) of toxicities. Based on the results from this review, and from those of previous IC/IS brachytherapy publications, P-ISBT toxicity rates seem to be more consistent and acceptable using a 3D technique for planning. This is likely related in part to the ability of restricting loading patterns of needle dwell positions that are in close proximity (or within) organs-at-risk [
      • Isohashi F.
      • Yoshioka Y.
      • et al.
      High-dose-rate interstitial brachytherapy for previously untreated cervical carcinoma.
      ]. Overall toxicities and complications found in this systematic review are low and no grade 5 toxicity was seen. Perineal infection (7 patients) and haematuria requiring bladder irrigation (7 patients) were the most common complications. Late toxicity rates experienced by these patients are consistent with current IC/IS literature [
      • Sturdza A.
      • Potter R.
      • Fokdal L.
      • et al.
      Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in retroEMBRACE, a multicenter cohort study.
      ,
      • Tanderup K.
      • Fokdal L.
      • Sturdza A.
      Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.
      ] with around 12% of the patients presenting a G3 and 4 late toxicity- 9% GI and 2.5% GU adverse reactions.
      The studies analysed by this review were published over a period of 19 years (1998 to 2017) with an observed heterogeneity of 3D-image-based perineal ISBT planning protocols. Eight publications followed GEC-ESTRO recommendations [
      • Potter R.
      • Van Haie-Meider C.
      • 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.
      ] and prescribed treatment to an HRCTV and three others studies did not specify their target volume. While more recent publications evaluated by this review used MRI to aid in volume target contouring, the majority of the studies based their treatment on CT imaging. In these cases, tumour volumes can often be over-contoured [
      • Viswanathan A.
      • Dimopoulos J.
      • Kisiritis C.
      Computed tomography versus magnetic resonance imaging-based contouring in cervical cancer brachytherapy: results of a perspective trial and preliminary guidelines for standardized contours.
      ]. It is likely for this reason that most of the studies included in this review prescribed total EQD2Gy doses lower than the current recommendation of 85 Gy as seen with MRI-based planning techniques [
      • Potter R.
      • Van Haie-Meider C.
      • 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.
      ]. When using CT-based planning exclusively in P-ISBT, the target volume may be poorly-defined and lower doses should be considered to minimize complication risks.
      Limitations of this systematic review are related to the heterogeneity and small sample size of the studies identified. Since most of the studies are retrospective single institution reviews, toxicities were captured retrospectively and may have been underestimated. Furthermore, there was no common time-point identified among the evaluated publications for data analysis. Therefore, the LC data could not be calculated with a defined time period. As most studies reported local control as their primary endpoint, it was not possible to calculate overall and cancer-specific survivals among all the manuscripts given the lack homogeneity in the data. One study that did report on survival was Fallon et al. that showed that cause specific survival for all patients (2D and 3D planned) was 56% at 10 years.

      Conclusion

      There is growing interest in the use of interstitial brachytherapy for cervical cancer and the perineal template approach seems to be effective for large locally-advanced tumours. A promising local control of roughly 80% was found with the use of perineal ISBT among patients with advanced stage disease. Local control seems to correlate with higher prescribed doses in the reviewed studies. With 3D image-based planning, procedural complications from this technique are low and toxicity rates with perineal ISBT are similar to other IGBT series. Perineal ISBT may be a reasonable and safe alternative to the more standard IC/IS approach for bulky cervical tumours that would benefit from interstitial needles.

      Conflict of interest statement

      All authors have no conflicts of interest to declare.

      Appendix A. Supplementary data

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