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Combined intracavitary and interstitial brachytherapy of cervical cancer using the novel hybrid applicator Venezia: Clinical feasibility and initial results

Open AccessPublished:June 22, 2018DOI:https://doi.org/10.1016/j.brachy.2018.05.009

      Abstract

      Purpose

      To report on first-in-human experience and the initial clinical results using the hybrid applicator Venezia (Elekta, Sweden) in the treatment of patients with locally advanced cervical cancer.

      Material and Methods

      Between March, 2017, and February, 2018, a total of 40 fractions were performed on patients undergoing definitive chemoradiation and brachytherapy (BT) for cervical cancer. A plan comparison was conducted evaluating the hybrid applicator with the clinically used intracavitary and interstitial (IC/IS) BT against a standard plan prescribed to Point A and a manually optimized plan using only intracavitary (IC) BT. Overall 80 treatment plans were retrospectively generated.

      Results

      The clinical use of the hybrid applicator system proved to be feasible in all 40 treatment fractions. The applicator consists of the IC tandem and two lunar-shaped ovoids forming a ring that serves as a template for defined parallel and oblique (12°) needle insertion. MRI preplanning was performed the day before the implant. One to six needles were placed per fraction, and overall a total of 66 needles were used. No complications such as bleeding or organ penetration occurred due to needle placement. Significant differences in IC/IS, Point A, and IC plans were derived for dose application to the target volume; D90 high-risk clinical target volume was 90.7 vs. 88.1 vs. 80.8 Gy (p = 0.008). Likewise, sparing of organs at risk differed significantly for bladder D2cc 79.4 vs. 91.8 vs. 79.2 Gy (p = 0.03) and rectum D2cc 58.7 vs. 67.3 vs. 62.5 Gy (p = 0.03).

      Conclusion

      The clinical application of the Venezia applicator is feasible and allows significantly improved dose coverage while at the same time sufficiently sparing organs at risk.

      Keywords

      Introduction

      External beam radiation therapy (EBRT) with concurrent platinum-based chemotherapy followed by brachytherapy (BT) is the standard treatment in locally advanced cervical cancer. In recent years, advances have been made regarding the application of both EBRT and BT. Highly conformal techniques such as intensity-modulated radiation therapy and volumetric modulated arc therapy have become widely available and allow for a homogenous dose application in pelvic EBRT [
      • Marnitz S.
      • Wlodarczyk W.
      • Neumann O.
      • et al.
      Which technique for radiation is most beneficial for patients with locally advanced cervical cancer? Intensity modulated proton therapy versus intensity modulated photon treatment, helical tomotherapy and volumetric arc therapy for primary radiation - an intraindividual comparison.
      ]. MRI-based planning was implemented for BT of cervical cancer because it has been proven to be highly appropriate to assess the tumor size and configuration [
      • Subak L.L.
      • Hricak H.
      • Powell C.B.
      • et al.
      Cervical carcinoma: computed tomography and magnetic resonance imaging for preoperative staging.
      ], thus ensuring ideal tumor delineation and identification of high- or intermediate-risk areas for local recurrence. Based on the recommendations of the GEC-ESTRO BT committee, a standardized terminology has been implemented [
      • 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.
      ].
      The concept of image-guided adaptive brachytherapy requires MRI of the tumor on the day of BT with an MRI-compatible BT applicator in place for assessment of tumor extension and localization of organs at risk (OARs). However, the treatment of larger and/or irregular-shaped tumors proves challenging. The dose distribution is limited by the doses applied to the OARs, such as the bladder, the sigmoid colon, the small intestines, and the rectum. For OARs, the hot spot dose is reported in 2 cm3 (D2cc) according to the GEC-ESTRO recommendation [
      • 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.
      ]. In the prospective multicenter EMBRACE study, a rectum D2cc ≥ 75 Gy was associated with a significantly higher risk of late toxicity than doses ≤ 75 Gy [
      • Mazeron R.
      • Fokdal L.U.
      • Kirchheiner K.
      • et al.
      Dose-volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive brachytherapy for locally advanced cervical cancer: Results from the prospective multicenter EMBRACE study.
      ]. A technical solution to the problem of irregular vertical extension of the tumor (e.g., in cases of parametrial infiltration) is the implementation of interstitial (IS) BT complementing the intracavitary (IC) BT using a hybrid applicator system (IC/IS). Several devices have successfully been adopted to conquer these shortcomings such as the Vienna applicator [
      • Dimopoulos J.C.
      • Kirisits C.
      • Petric P.
      • et al.
      The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: Clinical feasibility and preliminary results.
      ], which combines a tandem/ring applicator in which the ring is used as a template for needle placement into the parametria. In a further development, the Venezia applicator (Elekta, Sweden) was introduced, allowing for even more degrees of freedom as it combines a tandem with two lunar-shaped ovoids forming a ring and a template to inserting parallel and/or oblique interstitial needles for even more advanced tailoring of dose distribution. We therefore report on our initial results implementing the Venezia applicator in our clinical routine. Moreover, a plan comparison simulating BT without the insertion of interstitial needles and even dose prescription to Point A (pA) was conducted.

      Material and methods

      Patients

      Between March 2017 and February 2018, a total of 10 consecutive patients with biopsy-proven advanced cervical cancer not eligible for surgical therapy underwent curative intended chemoradiotherapy followed by BT using the new Venezia advanced gynecological applicator (Elekta AB, Sweden) at the LMU hospital. In 8 patients, the IC BT using the intrauterine tube and two lunar-shaped ovoids was complimented by parallel and/or oblique interstitial needles. The present study was conducted in accordance with the ethical principles of the Declaration of Helsinki and did not require further ethical committee approval.
      Following initial clinical assessment according to the Fèdèration Internationale de Gynècologie et d'Obstètrique (FIGO) staging requirements, patients routinely underwent laparoscopic lymph node assessment, as recommended by the national interdisciplinary treatment guidelines for cervical cancer in Germany []. In cases of locally advanced tumor stage (>cT2b) or positive lymph nodes, patients were considered unsuitable for a unimodal surgical approach and therefore received definitive chemoradiation. Staging was performed using CT or PET-CT and pelvic MRI, as well as cystoscopy or rectoscopy, in cases of suspect organ infiltration.

      Chemoradiotherapy

      A planning CT scan was obtained with a slice thickness of 3 mm, without the application of intravenous contrast. Target volume delineation, treatment planning, and dose concepts were made according to the GEC-ESTRO recommendations and the EMBRACE study protocols [
      • Mazeron R.
      • Fokdal L.U.
      • Kirchheiner K.
      • et al.
      Dose-volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive brachytherapy for locally advanced cervical cancer: Results from the prospective multicenter EMBRACE study.
      ]. The clinical target volume (CTV) included the primary tumor and internal iliac, external iliac, common iliac, obturator, and presacral lymph node regions. In cases of positive paraaortal lymph nodes, the paraaortic lymph node region was included in the CTV. The prescribed dose was 45 Gy in 25 fractions to the primary tumor and the lymphatic pathways; in case of lymphonodal involvement, a simultaneous integrated boost of 55 Gy was applied [
      • Cihoric N.
      • Tapia C.
      • Krüger K.
      • et al.
      IMRT with 18FDG-PET∖CT based simultaneous integrated boost for treatment of nodal positive cervical cancer.
      ]. For treatment planning, the Monaco system (Elekta AB, Sweden) based on a Monte Carlo algorithm was used. External beam radiotherapy (EBRT) was delivered by volume-modulated radiotherapy on an Elekta Synergy Linac with daily image guidance (IGRT). Cisplatin was given intravenously once a week at a dose of 40 mg/m2 of body surface area. A maximum of six doses of cisplatin was administered.

      Brachytherapy

      Combined IC and IS BT (combined IC/IS BT) was conducted after completion of EBRT with a planning aim to the high-risk clinical target volume (HR-CTV) with a biologically equivalent dose of 90–95 Gy (D90) in four BT sessions. MRI was obtained before initial treatment and during the last week of EBRT to assess treatment response. Preplanning for BT was based on tumor anatomy assessed by clinical examination and MRI. The extension of the cervical tumor and the flexion of the cervix were measured to determine the choice of the IC applicator and the ovoids. An estimate of the vertical extension, including infiltration of the parametria, was conducted to determine the number and position of interstitial needles.
      BT was applied as high-dose-rate (HDR) BT in four fractions within two implants, once a week. The overall duration of EBRT plus BT was aimed to be less than 50 days. The Venezia applicator was positioned in general or epidural anesthesia using ultrasound guidance. To verify correct positioning of interstitial needles, a planning CT was obtained and adjustments of needle position were made if required. With the hybrid applicator in place, an MRI was obtained for BT treatment planning on a 1.5 T MRI (Magnetom Aera; Siemens Healthineers, Erlangen, Germany). All patients followed a bowel preparation and bladder filling protocol to minimize internal organ motion. A planning CT with OAR delineation for dose optimization was performed for every single treatment fraction.
      The treatment target volumes—gross tumor volume (GTV), HR-CTV, and intermediate-risk CTV (IR-CTV)—were delineated based on MRT according to GEC-ESTRO recommendations using an Oncentra Brachy treatment planning software (Elekta, Sweden). OARs such as rectum, bladder, sigmoid colon, and small intestines were defined likewise. The EQD2–sum of all BT fractions and EBRT fractions were calculated—an α/β of 10 Gy was assumed for target volume and α/β of 3 Gy was used for OARs.

      Plan comparison

      To assess the difference in dose distribution achieved by using the hybrid applicator system with interstitial needles (IC/IS), we conducted a plan comparison including a traditional plan with dose prescription of 7 Gy to pA with no further optimization. Moreover, a manually optimized plan using only the tandem/ring without the use of interstitial needles (IC) was generated by one radiation oncologist and one medical physicist, with the planning goal of meeting the constraints for OARs and simultaneously achieving the best possible HR-CTV coverage. For plan comparison, both plans (pA and IC) were simulated on the clinical CTs used for the actual BT for every single treatment fraction. Therefore, overall 80 treatment plans were retrospectively generated. The Oncentra Brachy planning software was used for plan simulation. Dose to target volumes and OAR structures were summed up, and EQD2-sums were calculated equivalent to the treatment sessions.

      Plan evaluation

      For plan evaluation, a set of OAR constraints and dose parameters was used to determine if a plan achieved sufficient dose coverage with good sparing of OARs. Planning aims were a dose applied to 98% of the GTV (D98 GTV) of >90 Gy, a dose applied to 90% of the HR-CTV (D90 HR-CTV) of >85 Gy, a dose applied to 98% of the HR-CTV (D98 HR-CTV) of >75 Gy, and a dose applied to 98% of the IR-CTV (D98 IR-CTV) of > 60 Gy. For OARs, the dose in 2 cm3 (D2cc) was evaluated. A planning aim of bladder D2cc of <90 Gy, rectum D2cc < 75 Gy, sigmoid colon D2cc < 75 Gy, and small intestines D2cc < 75 Gy was scored as acceptable.

      Statistical analyses and endpoints

      Statistical analyses were conducted using IBM SPSS Statistics 24.0. Patient and treatment characteristics were analyzed using descriptive statistics. Samples were tested using the Friedman test. Two patients were excluded from the test of significance (Patients No. 3 and 7) because they did not receive treatment with interstitial needles, therefore IC/IS equals IC. Significance level was set at 5%. Primary endpoint was clinical feasibility.

      Results

      Clinical results and feasibility

      A total of 10 patients have been treated using the hybrid applicator with a median age of 40 years (range 28–83 years). Two patients presented with FIGO Stage IIB, 5 had FIGO IIIB, 1 had FIGO IVA, and 2 had FIGO IVB. Patient characteristics are listed in detail in Table 1. All patients received EBRT with concomitant chemotherapy with at least 45 Gy, 4 patients were treated with a simultaneous integrated boost to involved lymph nodes. With a median followup of 4 months, 9 of 10 patients are in full remission. One patient developed distant metastases, but no locoregional relapse. All patients underwent MRI before BT planning. Tumor response to EBRT was scored by largest diameter on MRT before the start and at the end of EBRT. All but 1 patient had radiological tumor response, and in 8 patients, the tumor diameter decreased by more than 30%. In 8 of 10 patients, interstitial needles were used for tailoring dose distribution. One to six needles were placed per fraction, and a total of 66 needles were used. In 1 patient, no needles were placed for the first two BT treatment sessions, but two needles were applied for the third and fourth BT treatment. The overall amount of time needed for needle placement was estimated to be 10–15 min per needle. No complications such as bleeding or organ penetration occurred due to needle placement.
      Table 1Patient and treatment characteristics (n)
      Age (years)PET staging
       Median40Yes9
       Range28–83No1
      HistologyMRI response after EBRT
       SCC8Yes9
       Adenocarcinoma2No1
      GradingStaging LAE
       G25Yes6
       G35No4
      cT stage
       T1b22EBRT dose
       T2b745 Gy10
       T3b1
      Boost dose
      N stage10 Gy3
       N027 Gy1
       N18
      cM stageInterstitial needles
       M08Yes8
       M12No2
      The HR-CTV as defined on MRI had a median size of 42 cm3 ranging from 76 to 19 cm3. The median D90 HR-CTV was 90.7 Gy with a D98 HR-CTV of 80.4 Gy and a D98 IR-CTV of 65.5 Gy. Median D2cc of bladder, rectum, and sigmoid colon was 79.4 Gy, 58.7 Gy, and 64.8 Gy, respectively. Detailed information is listed in Table 2.
      Table 2Plan evaluation
      IC/ISpAICp-value
      MedianRangeMedianRangeMedianRange
      D98 GTV113.978.1–253.1126.361.4–322.697.064.2–208.40.008
      D90 HR-CTV90.772.2–100.888.163.4–142.680.864.4–95.80.008
      D98 HR-CTV80.462.9–88.578.257.1–118.172.459.0–85.50.01
      D98 IR-CTV65.557.2–67.066.054.0–88.463.154.7–102.00.3
      Bladder D2cc79.466.9–89.791.874.4–113.279.266.9–82.70.03
      Rectum D2cc58.751.1–68.767.361.3–83.862.549.0–69.00.03
      Sigmoid D2cc64.850.0–71.271.948.5–93.965.648.9–70.90.9
      Small intestine D2cc50.245.7–71.248.046.0–69.047.845.8–63.40.1

      Plan comparison

      For all patients, additional pA and IC plans were generated and plan parameters were evaluated accordingly. Fig 1 illustrates the measurements of all three plans per patient in relation to the planning aim. A significant difference was reached for D98 GTV (113.9 vs. 126.3 vs. 97.0 Gy; p = 0.008), D90 HR-CTV (90.7 vs. 88.1 vs. 80.8 Gy; p = 0.008), D98 HR-CTV (80.4 vs. 78.2 vs. 72.4 Gy; p = 0.01), bladder D2cc (79.4 vs. 91.8 vs. 79.2 Gy; p = 0.03), and rectum D2cc (58.7 vs. 67.3 vs. 62.5 Gy; p = 0.03). No statistical significant difference was found in D98 IR-CTV, sigmoid colon D2cc, and small intestines D2cc (Table 2.).
      Figure thumbnail gr1
      Fig. 1Parameters for dose distribution of the target volume and organs at risk for each patient compared for IC/IS, pA, and IC. The gray line indicates the planning aim.

      Plan evaluation

      All plans were evaluated according to four parameters describing dose coverage and adherence to four OAR constraints so that a maximum score of 8 points could be achieved. In each clinically applied IC/IS plan, all OAR constraints were met, while one plan only scored three of four dose parameters and one plan did not score any dose parameter. In the pA plans, all but two plans failed to meet all OAR constraints, six plans scored all dose parameters, and four plans scored none of the dose parameters. In the manually optimized IC plans, all OAR constraints were met in every plan, but four plans did not score any dose parameters, two plans scored two plan parameters, and one scored three, and three scored four dose parameters. Results are described in Fig 2.
      Figure thumbnail gr2
      Fig. 2Individual plans were scored regarding four parameters describing dose coverage and adherence to four OAR constraints (a maximum score of 8 points could be achieved). Parameters for dose coverage: D98 GTV (>90 Gy); D90 HR-CTV (>85 Gy); D98 HR-CTV (>75 Gy); D98 IR-CTV (>60 Gy); and for organs at risk: bladder D2cc (<90 Gy), rectum D2cc (<75 Gy), sigmoid colon D2cc (<75 Gy), and small intestines D2cc (<75 Gy). * censored for statistical evaluation.

      Discussion

      MRI-based BT is well established in the treatment of cervical cancer and should be considered clinical standard. Improved imaging allows for a better delineation of target volumes and OARs. More sophisticated delineation frequently results in complex-shaped target volumes that require elaborate means of dose tailoring. The use of a hybrid applicator combining IC and IS BT is the best “all-in-one” technical solution available to date and facilitates the implementation of the combined BT in centers without special expertise in free-hand or perineal template-based IS BT. A recent analysis from the retroEMBRACE cohort enhanced the importance of meticulous dose tailoring. The study included 610 patients from eight institutions and was able to show that with the systematic use of a combined IC/IS BT, the D90 of HR-CTV significantly increased (83 Gy–92 Gy; p < 0.01) with no difference in doses to OARs. Fokdal et al. could demonstrate that this was even correlated with an increase of 3-year local control rate in patients with a large HR-CTV volume (≥30 cm3) [
      • Fokdal L.
      • Sturdza 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.
      ].
      In our clinical routine, the Venezia applicator was introduced in March 2017: a 51-year-old patient with advanced cervical cancer became the world's first to receive BT assisted by the new hybrid applicator at our department. To our knowledge, no data on the clinical application of this device have been previously published. The clinical use of this specific hybrid applicator system proved to be feasible in all 40 treatment fractions. The applicator consists of the IC tandem and two lunar-shaped ovoids forming a ring that holds a template for defined parallel and oblique (12°) needle insertion (Fig 3c). The implant was performed by an experienced radiation oncologist and gynecologist under ultrasound guidance. Preplanning to determine the number and position of the interstitial needles was performed the day before the implant to accelerate the workflow. Patients had peridural anesthesia during the entire treatment time of two fractions during two consecutive days; no significant prolongation of time needed for applicator positioning was noted. All patients well tolerated the applicator positioning, as the applicator stayed in place overnight. No dislocations occurred overnight, and no prolongation in hospital stay as compared to the previously applied IC tandem/ring BT was noted. No severe acute complications such as bleeding or infections occurred.
      Figure thumbnail gr3
      Fig. 3Example of MRI-based BT planning with interstitial needles a) MRI sagittal: cervical cancer with right-sided parametric infiltration b) and dose distribution achieved with tandem/lunar ovoids and interstitial needles c) reconstructed image of the Venezia applicator. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      Our current comprehensive plan comparison demonstrates well the advantages and disadvantages of different planning and treatment approaches. With the IC/IS approach, a median D90 HR-CTV of 90.7 Gy was achieved, which differed significantly from values achieved with the pA or IC plans and met the requirement of ≥85 Gy by the GEC-ESTRO recommendations. These findings are in line with other published data comparing hybrid applicator techniques to standard plans. A similar analysis on the Utrecht applicator reported a mean D90 HR-CTV of 83.9 Gy with the hybrid applicator, 79.5 Gy and 77.1 Gy for an optimized IC plan and a standard plan, respectively [
      • Nomden C.N.
      • de Leeuw A.A.
      • Moerland M.A.
      • et al.
      Clinical use of the Utrecht applicator for combined intracavitary/interstitial brachytherapy treatment in locally advanced cervical cancer.
      ]. In this study, however, 50% of patients were treated with less than the prescribed dose of 84 Gy. In our clinical cohort, only 1 patient received less than 85 Gy, which was due to a very large tumor volume.
      Because not one single parameter determines the quality of a plan but rather a combination of a set of parameters, we decided to analyze the available data as a synopsis for each treatment plan. Both the IC/IS and the IC plans were optimized by a radiation oncologist to fulfill all given OAR constraints. This resulted in compromising dose distribution to the target volume; however, the effect was much more pronounced in the IC plans. Clinically only 2 patients had to be treated with less than the prescribed doses of 90 Gy to D90 HR-CTV, while the IC plans did not achieve the prescribed doses for all but 2 patients. This clearly shows that the combined IC/IS BT by using a hybrid applicator can not only improve dose conformity and dose coverage of the target volume but at the same time increase dose sparing of OARs. The pA plans were not manually optimized. For patients with favorable anatomy, a sufficient dose to the target volume could be achieved by a standard plan but no dedicated sparing of OARs. This might explain some of the toxicity reported in older publications. It can therefore be expected that in more recently treated patients, a better sparing of OARs and therefore less toxicity can be achieved. Accordingly, Harkenrider et al. conducted an analysis including patients who were treated with MRI-based BT planning in an early and a late IC-only era, as well as patients treated with combined IC/IS BT. An increase in D90 HR-CTV was reported from 88.0 Gy to 92.9 Gy with the IC/IS technique, whereas no difference was found between early and late IC-only plans. The authors concluded that the introduction on an IC/IS applicator had the biggest impact on dosimetric improvements [
      • Harkenrider M.M.
      • Surucu M.
      • Harmon G.
      • et al.
      Early outcomes and impact of a hybrid IC/IS applicator for a new MRI-based cervical brachytherapy program.
      ].

      Conclusion

      The first results achieved by the implementation of the Venezia applicator into clinical routine concerning dose tailoring and sparing of OARs are encouraging. The comparison with previously adapted techniques is promising in favor of the hybrid applicator technique. However, these are initial results in a small patient cohort, and followup data will mature because more patients will be treated and analyzed.

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