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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 1  |  Page : 26-33

Dosimetric feasibility and clinical outcome of image-guided interstitial brachytherapy using two different fractionation schedule in carcinoma cervix

Department of Radiotherapy, Medical College & Hospital Kolkata, Kolkata, West Bengal, India

Date of Submission24-Jun-2021
Date of Acceptance08-Dec-2021
Date of Web Publication06-Jan-2022

Correspondence Address:
Dr. Janmenjoy Mondal
Department of Radiotherapy, Medical College & Hospital Kolkata, Room no. 13, 88 College Street, Kolkata 700073, West Bengal.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjoc.bjoc_16_21

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Methods and Material: Overall, 60 patients were accrued between 2014 and 2017 and treated with ISBT by using Syed–Neblett Template by iridium 192 with Gamma Med plus HDR after the loader unit. They were allotted in two arms (n = 30) and received nine Gy ×2# and 7 Gy ×3 # respectively. All patients received 50Gy/25# whole pelvis EBRT by Theratron 780C. Coverage Index (CI), dose homogeneity index (DHI), overdose index (OI), dose non-uniformity ratio (DNR), D90Target, and 2cc EQD2 of OARs were calculated and correlated with toxicity, locoregional control, and survival. Statistical Analysis Used: Unpaired t-test and chi-square test were used to compare numerical and categorical variables, using IBM SPSS, V23. PFS and OS were calculated by using Kaplan–Meier analysis, and a log-rank test was used for comparison. A p-value ≤ 0.05 was considered significant. Results: Mean EQD2 for bladder (77.33 vs. 80.24 Gy) and rectum (69.12 vs. 69.87) along with D90 (9.12Gy vs. 7.20Gy) were comparable. With a median follow-up period of 38 months, three-year local control rate was 56.6% vs. 46.60% (P = 0.72) and three-year OS was also similar, 83% vs. 80% (p=.8). Dosimetric parameters and toxicity profile between two groups were comparable. Conclusions: 9Gy ×2 # is a reasonably good alternative for treating the locally advanced carcinoma cervix.

Keywords: Carcinoma cervix, dosimetry, fractionation, interstitial brachytherapy

How to cite this article:
Basu A, Mandal B, Mondal J, Ghosh D, Chakraborty I. Dosimetric feasibility and clinical outcome of image-guided interstitial brachytherapy using two different fractionation schedule in carcinoma cervix. Bengal J Cancer 2021;1:26-33

How to cite this URL:
Basu A, Mandal B, Mondal J, Ghosh D, Chakraborty I. Dosimetric feasibility and clinical outcome of image-guided interstitial brachytherapy using two different fractionation schedule in carcinoma cervix. Bengal J Cancer [serial online] 2021 [cited 2023 Feb 8];1:26-33. Available from: http://www.bengaljcancer.org/text.asp?2021/1/1/26/335056

  Key Messages: Top

In a developing country such as India, keeping the patient compliance and convenience in mind, two fractions of 9 Gy can be safely administered in ISBT for locally advanced and/or recurrent carcinoma cervix.

  Introduction Top

Cervical cancer is the second most common cancer in women in India, with an annual mortality of around 60,000.[1] According to GLOBOCAN 2018, carcinoma cervix occupies fourth in the list of incidence of new cases (6.6% Worldwide) with an annual mortality higher than three lakhs. In developing countries such as India, most of the cases are detected in an advanced stage, that is, in the International Federation of Gynaecology and Obstetrics (FIGO) Stage IIB‑IVA.[2] In the advanced stage disease, external beam radiotherapy (EBRT) along with concurrent chemotherapy followed by brachytherapy becomes the treatment of choice. A dose of EBRT ranges from 4000 to 5000 cGy in 20–30 fractions, 180–200 cGy per fraction over five weeks, and five fractions per week delivered by using the conventional or conformal radiotherapy technique.

Brachytherapy is an integral part of the treatment of cancer cervix. Interstitial brachytherapy (ISBT) is used wherein standard intracavitary brachytherapy (ICBT) or intravaginal brachytherapy is expected to result in inferior local control due to suboptimal dose distribution within the lateral parametrial tissues or for bulky cervical cancers. Apart from these, extensive paravaginal (>0.5 cm) or distal vaginal involvement, gross residual disease after EBRT, disease failure after intracavitary brachytherapy, carcinoma of the vault, and cut through hysterectomy or prior supracervical hysterectomy are other indications for doing ISBT.[3]

There are various dose fractionation regimes for template-based HDR ISBT after EBRT for cancer cervix with consideration of the normal-tissue EQD23Gy dose limits and recommended D90 goal between 85 and 95 Gy EQD210Gy for the HR-CTV.[4]

Data are scarce regarding the impact of different fractionations of HDR ISBT in the Indian context. This single institutional, retrospective study was done to compare and evaluate dosimetry and clinical outcomes by using two different dose fractionations in image-guided ISBT for carcinoma cervix.

  Materials and Methods Top

This retrospective study included 71 patients treated with Syed-Neblett template during the period December 2014 to December 2017, and they were traced till March 2019. Out of these, 56 patients were diagnosed with carcinoma cervix, and 15 were diagnosed with carcinoma of the vault. All these patients were treated with a combination of EBRT followed by interstitial brachytherapy with either 9Gy ×2# or 7Gy×3# using Syed-Neblett applicator. As nine patients were lost to follow-up and two patients did not complete the treatment, 60 patients were finally analyzed and divided equally into two groups (n = 30). All patients had routine workup and were examined under anesthesia, and biopsy was done. All patients were given EBRT up to a dose of 50Gy in 25 fractions with 2Gy /#, five days a week schedule to the whole pelvis using anterior and posterior parallel opposed portals on 780C Theratron Telecobalt. Patients with gross residual disease after EBRT, distorted geometry, FIGO Stage IIB and IIIB (for intact cervix), post-supracervical hysterectomy, and vault carcinoma were included in this study.

Preimplant care

All the patients suitable for ISBT were evaluated on or within one week of EBRT completion and sent for preanesthetic checkup, including routine hematological and biochemical tests and 2D echocardiography. In all patients, a preinsertion imaging in the form of T2W MRI of the pelvis was performed. Eligible patients were admitted a day before the implant and received bowel enema at the night before and on the morning of the day of brachytherapy. The patients were kept fasting overnight for the procedure and were explained about the procedure in detail. Informed consent was taken in all cases and documented in the patient file.

Brachytherapy procedure

Under aseptic precautions and lithotomy position, using spinal anesthesia, per vaginal examination was performed (followed by per rectal and recto-vaginal examination) to assess the tumor dimension, parametrial and paravaginal tissue involvement, lateral spread, and the tumor’s relationship with uterine axis. Foley’s catheterization was completed with 7 ml of Urografin pushed into its bulb. The uterine sounding was done to assess the uterine length in cases with the intact cervix. Vaginal length was assessed, and vaginal obturator (15 cm length and 2 cm diameter) was placed along with the Syed Neblett template. At first, a guide needle/trocar was inserted carefully to avoid perforation of the bladder and rectum. The tip of this needle was taken 1–2 cm beyond the clinically palpable disease. The number of needles and their extent of advancement were determined beforehand from clinical drawings[5] and after consultation with the anesthetist. All the implants were done by or under the direct supervision of radiation oncologists with ≥5 years of experience in the field. The distal or superior extent of the tumor determines the depth to which needles are placed, and the proximal or inferior extension determines the active length required for adequate coverage of the implanted volume.[6] Thorough per rectal examination and checking of urobag was done routinely postinsertion. Packing was done with gauze pieces soaked in povidone-iodine solution to prevent any possible infections.

Contouring and treatment planning

Axial computed tomography (CT) scans of 3-mm slice thickness were taken for planning and were transferred to the brachytherapy treatment planning system, Varian Eclipse TPS (Palo Alto, CA). The dose computation algorithm used was based on TG‑43 (Task group‑43), as recommended by the American Association of Physicists. The clinical target volume (HRCTV) and the OAR, that is, bladder and rectum were delineated as per the GEC‑ESTRO contouring guidelines.[5],[7],[8] Multiplanar reconstruction was used to reconstruct the implant geometry, which allows us to view the reconstructed implant in all three planes, for example, axial, sagittal, and coronal [Figure 1]. Initially, geometrical optimization was performed by using auto-generated basal dose points placed between the implanted needles in the CTV by following the stepping source dosimetric system. Volumetric optimization was performed in select cases to reduce nonhomogeneity and improve target coverage. A step size of 2.5 mm and adequate dwell time in each dwell position was loaded for desired HRCTV coverage (90% of CTV volume to receive 100% of prescribed dose, as per our institution protocol). Treatment was delivered by using iridium 192 with Gamma Med plus HDR after loader unit (Varian Medical Systems). Now, regarding the allocation of treatment groups, the patients who had a brachytherapy plan achieving the dose constraints (bladder and bowel) without compromising the HRCTV coverage were given 9 Gy/# in a nonrandomized way, after consulting two radiation oncologists and one senior medical physicist. Patients whose treatment plans were marginally not meeting the dosimetric criteria (D2cc bladder < 85Gy EQD2, D2cc rectum <75 Gy EQD2) were given 7Gy instead.
Figure 1: ISBT insertion and dose color wash (planning) HRCTV contoured in pink.

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Dosimetric Analysis

The DVH parameters were collected, including V100, V150, V200 (volume receiving 100%, 150%, and 200% of the prescribed dose), the maximum dose to 2 cc of bladder and rectum. The following indices were calculated: CI, DHI, OI, and DNR. The earlier mentioned indices are as follows:[9],[10],[11]

  • 1. Coverage Index (CI): CI is the fraction of the TV (treatment volume) that receives the prescribed dose. This index gives an estimate of how much of the target received 100% of the dose.

CI= TVDreference/ TV = V100 / VHRCTV

(Ideal value of CI = 1).

  • 2. Dose homogeneity index (DHI): DHI is the ratio of the TV receiving a dose of approximately 1.0–1.5 times of the reference dose to the volume of the target that receives a dose equal to or greater than the reference dose.

DHI = TVDreference- TV1.5Dreference/ TVDRef =V100 – V150 / V100

(Ideal value of DHI = 1)

  • 3. Overdose volume index (OI): This is the ratio of the TV that receives dose ≥2.0 times of the reference dose to the volume of the target that receives a dose equal to the reference dose.

OI = TV2Dref/ TVDref= V200 / V100

(Ideal OI = 0).

  • 4. Dose non‑uniformity ratio (DNR): This is the ratio of the TV that receives a dose equal to or greater than 1.5 times the reference dose to the volume of the target that receives a dose equal to the reference dose.

DNR = TV1.5Dref/ TVDref= V150 / V100

(Ideal DNR = 0).

The earlier mentioned substitutions of the equations are possible since here TVD reference = V100 and TV is the volume of the HRCTV.

The 2cc EQD2 of OARs for each patient’s EBRT and ISBT plan were calculated according to the linear-quadratic cell survival model by using an excel spreadsheet (Microsoft Corporation, Redmond, WA, USA) available as a template on the American Brachytherapy Society website (www.americanbrachytherapy.org).[12] Bladder or rectal doses had been summed up arithmetically from each session for every patient and then compared respectively with the other arm.

Postimplant follow-up

For the first three months, all patients were kept on monthly follow-up, quarterly up to two years, six-monthly in the third to fifth year, and thereafter annually. During follow-up, patients were evaluated for parameters such as local response, complications post-treatment, and distant metastasis as documented in file archives.

Statistical analysis

Unpaired t-test and chi-square tests were used to compare numerical and categorical variables. PFS (progression-free survival) and OS (overall survival) were calculated by using Kaplan–Meier analysis, and a log-rank test was used for comparison between two groups. A p-value ≤ 0.05 was considered significant. All the statistical analysis was done by using IBM SPSS software version 23. (Chicago, IL 2015).

  Results Top

The median age of patients in the two arms was similar, and other baseline parameters were also comparable [Table 1]. Cases with intact cervix were slightly higher in arm B (66.6% vs. 56.7%) and arm A had more post-op and vault recurrence cases (43% vs. 33%), though these results were not significant (P = 0.74). The median number of needles used in two arms along with other baseline parameters was similar in both the groups. All patients had received EBRT dose of 50Gy/25#. Patients in 9 Gy arm had received more concomitant chemoradiation (CTRT) during EBRT in the form of weekly cisplatin 40 mg/m2 than 7 Gy arm (80% vs. 66.6%).
Table 1: Baseline patients’ characteristics

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Dosimetric indices (CI, DHI, OI, DNR) were comparable in two groups [Table 2] and [Figure 2]. The mean 2cc bladder EQD23Gy received by patients in arm A from EBRT and both brachytherapy sessions was 77.33 Gy (range 84.2–70.53Gy), and in arm B, it was 80.24 Gy (range 86.7–74.56Gy). The mean 2cc rectum EQD23Gy was 69.12 vs. 69.87 Gy respectively. The mean D90target dose in ISBT was also comparable (P = 0.92). On subgroup analysis, no correlation was found between the dosimetric data and toxicity profile or local control in any arm.
Table 2: Dosimetric indices and DVH parameters

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Figure 2: Bar diagram showing means of dosimetric indices CI = coverage index, DHI = dose homogeneity index, OI = overdose volume index, DNR = dose nonuniformity ratio

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At a median follow-up of 38 months (range 7–54 months vs. 6–56 months), the three-year local control rate was similar (56.6% vs. 46.6%) [Table 3]. Overall, 43.4% of patients had a pelvic relapse in 9 Gy arm compared with 53.4% in 7Gy arm, though this did not translate to any gain in PFS as median PFS was similar (33 months vs. 32 months) (p=.21). The three-year OS was comparable in two groups (83.3% vs. 80%), and median OS has not been achieved [Figure 2] and [Figure 3]. We did not notice any significant difference in late bladder and bowel toxicity in two arms.
Table 3: Patterns of failure and late toxicity profile

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Figure 3: Progression-free survival comparison between the two groups Log rank test P = 0.21

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  Discussion Top

In this study, we investigated the association of two dose fractionation with local control, survival, and late toxicity among patients undergoing HDR ISBT for locally advanced, residual/recurrent cervical cancer. There have been many shreds of evidence in the literature about CT-based interstitial catheter placement for HDR brachytherapy for primary and recurrent carcinoma cervix with quite satisfactory results in terms of local control, toxicity, and survival.[13],[14] Hughes-Davies et al.[15] reported a study with 139 patients treated with ISBT from Harvard Medical School and Stanford University Medical Centre and concluded a modest chance of patient cure with the template parametrial implant. Martinez et al.[16] published a clinical experience with a total of 104 patients with 35.5% cases of bulky stage IIB and IIIB cervical malignancies. The majority of the local failures occurred during the first 10 months of follow-up. In the experience reported by Gupta et al.,[17] disease volume was the sole significant prognostic factor of local recurrence in the multivariate analysis (P = 0.011) with a three-year local control rate of 89% if the disease volume was less than or equal to 100 cc versus 0% when the disease volume exceeded 100.

In this study, we observed around 10% benefit in local control with 9Gy per fraction schedule (P > 0.05) though it did not contribute to PFS or OS benefit [Figure 3] and [Figure 4]. On subgroup analysis, we tried to explore the reason and found that more patients in the 9Gy arm had received concomitant chemoradiation and mean treatment gap between EBRT and ISBT was lesser, 14.5 days versus 20.27 days (P = 0.09). Fowler et al.[18] showed that there is a loss of local control and survival by approximately 1% per day when treatment exceeds 52 days. Though overall treatment time was not possible to account for each case as there were 21.6% cases of vault recurrences (cases that received prior brachytherapy were excluded), more treatment gaps weighed in favor of poor local control. There were three cases (1 in 9Gy arm, 2 in 7Gy arm) of postoperative carcinoma cervix who received 50 Gy /25# EBRT only and then ISBT in view of vault recurrence within eight months of EBRT completion. Stagewise subgroup analysis showed that the recurrence rate was higher in case of the intact cervix (P = 0. 08). In arm A, two patients of stage IIB and six patients in stage IIIB developed locoregional failure; however, in arm B, it was two and eight from stage IIB and IIIB respectively. A combined intracavitary and interstitial application would have avoided this abysmal result in intact cervix cases. Murakami et al.[19] and Mahanshetty et al.[20] recently published their experience regarding the same.
Figure 4: Overall survival comparison between the two groups Log-rank test, P = 0.51

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The optimum schedule of dose fractionation in brachytherapy has been a matter of debate for decades. The ABS recommends an individual fraction size of less than 7.5 Gy per fraction using four to eight fractions. However, ABS includes a caution that these guidelines are no substitute for clinical experience and need to be tested in a clinical setting.[21],[22] In further analyzing various HDR schedules reported in the literature, Orton[23] concluded that acceptable HDR dose per fraction ranges from 4 to 9 Gy, but to decrease late complications, it is important to keep the dose to central normal tissues as low as possible by proper use of midline blocking or packing/retraction techniques. Patel et al.,[22] Sood et al.,[24] and a south Indian institutional experience[25] explored the role of different fractionations in intracavitary brachytherapy, but there is a dearth of data in the field of interstitial brachytherapy. All the earlier mentioned studies had shown equivocal response and toxicity profile while using 9 Gy per fraction. This study probably is the first one from eastern India evaluating the feasibility and efficacy of 9Gy ×2 # versus 7Gy ×3# in CT-based HDR interstitial brachytherapy for carcinoma cervix.

Though we believe that our data are robust, certain drawbacks could impact our results. First, the inherent heterogeneity between the two groups is subjected to recall or reporting bias owing to the retrospective design of this study. Second, the metallic needles used for ISBT lead to streaking artifact, thereby leading to difficulties in identifying the anterior rectal wall and delineation of HRCTV. Although the contours were checked by experienced faculties, still interobserver bias could lead to residual error. Third, there is an inherent displacement of the brachytherapy needles during ISBT that impacts target dose-volume indices and OAR doses. However, for this study, the interfraction changes in EQD2 have not been accounted. Fourth, the choice of the applicator was based on availability; since 9 Gy / # cases were more with Syed Neblett, it became our automatic choice to avoid the confounding bias; and lastly, a median follow-up of 38 months with around 60 patients is one of the noted weaknesses of this study. Having said this, we are also looking forward to analyze the long-term follow-up data of this study cohort.

  Conclusion Top

In a developing country such as India, keeping the patient compliance and convenience in mind, two fractions of 9 Gy can be safely administered in ISBT for locally advanced and/or recurrent carcinoma cervix. This is a practical approach when desired dosimetry has been met, as this reduces multiple hospital admissions, thus coping with the fairly large patient load in a busy government hospital. Further, large prospective, multi-institutional, randomized studies are needed for validation and future direction.


The authors acknowledge the utmost cooperation from their patients and hard work of the Physicist Team and fellow colleagues.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3]


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