Evaluation of dose–Volume-based image-guided high-dose-rate brachytherapy in carcinoma uterine cervix: A prospective study

Nancy Lal; Suresh Yadav; Veenita Yogi; Om Prakash Singh; Hameed Uzzafar Ghori; Megha Choudhary; Rishika Saxena; Sachet Saxena

doi:10.4103/jrcr.jrcr_39_21

ORIGINAL ARTICLE

Year : 2022 | Volume : 13 | Issue : 1 | Page : 12-18

Evaluation of dose–Volume-based image-guided high-dose-rate brachytherapy in carcinoma uterine cervix: A prospective study

Nancy Lal, Suresh Yadav, Veenita Yogi, Om Prakash Singh, Hameed Uzzafar Ghori, Megha Choudhary, Rishika Saxena, Sachet Saxena
Department of Radiation Oncology, Gandhi Medical College, Bhopal, Madhya Pradesh, India

Date of Submission	01-Oct-2021
Date of Acceptance	03-Nov-2021
Date of Web Publication	09-Feb-2022

Correspondence Address:
Dr. Veenita Yogi
Department of Radiation Oncology, Gandhi Medical College, Bhopal, Madhya Pradesh
India

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/jrcr.jrcr_39_21

Abstract

Background: In recent few decades, the evolution in imaging technology, especially computed tomography (CT) and magnetic resonance imaging, results in widespread availability and its use in high-dose-rate (HDR) intracavitary brachytherapy (ICBT) applications. Aim: The present study was aimed to analyze the cumulative dose–volume histogram of the tumor and organs at risk (OARs) in three-dimensional (3D) CT image-based brachytherapy planning and clinical outcomes of the treated patients. Materials and Methods: This prospective observational study included 40 patients with carcinoma cervix. After external beam radiotherapy (EBRT), a dose of 6 Gy per fraction of HDR ICBT in four fractions with a total dose to point “A” approximately 80–85 Gy was given. For planning, the tumor volumes (high-risk clinical target volume [HR-CTV]) and volume of OARs (bladder, rectum, and sigmoid colon) were contoured on each CT slice. The dose–volume parameters, i.e., minimum dose received to 90% and 100% by HR-CTV volume (D₉₀ and D₁₀₀) for target and the maximum dose received by minimum volume of 2CC (D_2CC) for OARs, were calculated and assessed for clinical response in patients. Results: The mean D_2CC dose was 18.24 ± 0.93 Gy, 16.44 ± 1.11 Gy, and 16.37 ± 0.67 Gy for bladder, rectum, and sigmoid colon, respectively. The combined (EBRT and HDR ICBT) mean equieffective dose in 2 Gy per fraction (EQD₂) dose for bladder was 76.71 ± 2.05 Gy, for rectum was 72.82 ± 2.58 Gy, and for sigmoid colon was 72.71 ± 1.41 Gy, and its comparison with baseline values showing P < 0.01 for bladder, rectum, and sigmoid colon was considered statistically significant. The mean EQD₂ dose of HR-CTV D₉₀ was 151 ± 27.3 Gy. Patients who had received HR-CTV D₉₀ of >90 Gy compared with <90 Gy had exceptionally better local control and complete response. Conclusion: The present study suggested that CT is a favorable modality for treatment planning in cervical cancer with limited resources setup in terms of improved tumor coverage, lesser toxicity, confirmation of applicator placement, and accounting dose to OARs.

Keywords: Carcinoma uterine cervix, computed tomography, high-dose-rate, intracavitary brachytherapy

How to cite this article:
Lal N, Yadav S, Yogi V, Singh OP, Ghori HU, Choudhary M, Saxena R, Saxena S. Evaluation of dose–Volume-based image-guided high-dose-rate brachytherapy in carcinoma uterine cervix: A prospective study. J Radiat Cancer Res 2022;13:12-8

How to cite this URL:
Lal N, Yadav S, Yogi V, Singh OP, Ghori HU, Choudhary M, Saxena R, Saxena S. Evaluation of dose–Volume-based image-guided high-dose-rate brachytherapy in carcinoma uterine cervix: A prospective study. J Radiat Cancer Res [serial online] 2022 [cited 2023 Jun 7];13:12-8. Available from: https://www.journalrcr.org/text.asp?2022/13/1/12/337481

Introduction

Intracavitary brachytherapy (ICBT) is a principal component in the curative management of cervical cancer either alone or in combination with external beam radiotherapy (EBRT). The American Brachytherapy Society (ABS) Task Group Report has been recommended that cervical cancer patients with clinical stage IB2–IVA should be primarily treated with concurrent chemotherapy and EBRT along with ICBT.^[1],[2] The overall treatment time of EBRT and brachytherapy should be less than 8 weeks. The consequences of delayed treatment time result in decreased tumor control and higher recurrence with lesser survival.^{[3],[4],[5],[6]} The major advantage of ICBT is that it delivers a very high dose to tumor volume with rapid dose falls of outside due to inverse square law, hence less dose to adjacent organs at risk (OARs) such as bladder, rectum, and sigmoid colon. The estimation of the dose received by OARs is very important because these count as dose-limiting structures in ICBT.^[7],[8]

There is a paradigm shift from conventional two-dimensional (2D) orthogonal X-ray planning to three-dimensional (3D) computed tomography (CT) and magnetic resonance imaging (MRI)-based treatment planning for ICBT. The 3D image-based brachytherapy planning gives better information on anatomy regarding the target and its relation to the surrounding anatomy and the OARs. It has shown a major therapeutic gain in terms of improvement in local control with high radiation dose and reduced normal tissue toxicities by sparing OARs.^[9],[10]

In recent few decades, the evolution in imaging technology, especially CT and MRI, results in the widespread availability and its use in high-dose-rate (HDR) ICBT applications. Recently published advanced guidelines International Commission on Radiation Units and Measurements report 89 (ICRU-89)^[11] and Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO)^[12],[13] have strongly recommended image-based brachytherapy applications. Besides evolution in computerized treatment planning systems (TPS) and imaging technology, the traditional template-based treatment planning for HDR ICBT is still in practice by many radiotherapy centers, especially in low- and middle-income countries (LMICs). A study reported an increase in the dose for both the tumor and OARs when template-based planning was performed for HDR ICBT of carcinoma uterine cervix (Ca-Cx) rather than volumetric image-based ICBT planning.^[14] Yadav et al.'s study suggested CT may be a moderate imaging modality in HDR ICBT treatment planning of Ca-Cx for radiotherapy clinics, especially in LMICs.^[15] However, due to lack of affordability and/or limited resources, many clinics are unable to follow image-based brachytherapy planning in routine clinical practices. In these sets of conditions, the first fraction treatment plan based on the 3D-CT image dataset can be utilized for successive brachytherapy treatment fractions of Ca-Cx by careful applicator insertions, proper packing, and the use of a Fletcher-style fixed geometry applicator.^[16] Yogi et al.'s study compared two type's applicator geometry in ICBT treatment of Ca-Cx based on 3D-CT image, and the results emphasized that the selection of a suitable geometry applicator would depend on the patient's anatomical structure.^[17]

In this study, we analyzed the cumulative dose–volume histogram (cDVH) of the tumor and OARs in 3D-CT image-based brachytherapy planning and clinical outcome of the treated patients in terms of complications and response.

Materials and Methods

This is a single-institution, prospective observational study conducted at the Government Medical College of Central India. This study was initiated and followed by approval from the institutional ethical committee, and written informed consent was taken from each patient included in the study. The study period was between January 2017 and December 2018. This study included 40 cervical cancer patients.

Eligibility criteria

Histologically proven squamous cell carcinoma
Age between 30 and 70 years
International Federation of Gynaecology and Obstetrics (FIGO) Stage IB2–IVA
The patient did not have any distant metastasis
No history of prior radiation therapy to the pelvis.

Pretreatment evaluation

Complete history and general, systemic, and local examination
Baseline hematological and biochemical investigations
X-ray pelvis, X-ray chest, ultrasonography of the abdomen and pelvis, CT scan, and MRI of the pelvis

Clinical staging was done as per the FIGO staging system.

Treatment protocol

The treatment protocol for cervical cancer patients incorporated a combination of EBRT with concurrent weekly chemotherapy followed by ICBT.

Radiotherapy planning

The whole pelvis irradiation was performed up to a total dose of 50 Gy in 25 fractions with midline shielding after 46 Gy over 5 weeks using teletherapy Cobalt-60 Theratron Th-780 machine. Chemoradiotherapy with concurrent cisplatin 40 mg/m² weekly was given in all patients. A dose of 6 Gy per fraction (total 24 Gy) of HDR ICBT was performed in four fractions with an interval of 1 week with a total dose to point “A” approximately 80–85 Gy. In all patients, the treatment was completed within 58 days of starting EBRT.

Pretreatment procedure

All patients reported in this study underwent our standard brachytherapy treatment preprocedures, which included a routine bowel preparation procedure in the morning of the procedure day by giving enema. Patients were also instructed to be on a clear liquid diet on the day before the procedure followed by overnight fasting. Following induction of anesthesia, a Foley's catheter was aseptically inserted in the bladder; the bladder balloon was filled with 7 ml of contrast to ease the identification of the bladder reference point. A thorough gynecological examination was performed, and tumor factors were assessed. The length of the uterine cavity was intended using a uterine sound. Fletcher style applicator set with fixed geometry was used in this study; the Gamma Med Fletcher applicator set (Part no. GM11000810) was made by Varian Medical Systems, Inc., Palo Alto, CA 9430, USA. The fixed geometry applicator containing one tandem (6.0 cm uterine length and 15° angles) and two-ovoid diameter range (1.5–2.5 cm) was used in all patients. Appropriate anterior and posterior vaginal packing was used to fix the applicators in position and to keep the bladder and rectum away from the vaginal applicators. To reduce the patient's movement during CT scans, every effort was done to keep the applicators in place and to conclude the entire procedure as early as possible. Postimplant pelvic CT with slice thickness 2.5 mm was obtained on CT simulator (WIPRO GE Discovery). The CT images were imported into the TPS Brachy Vision version 8.9 (Varian Medical Systems, Inc., Palo Alto, CA 9430, USA) for planning through DICOM port or CD/DVD. The tumor volumes (high-risk clinical target volume [HR-CTV]) and volume of OARs (bladder, rectum, and sigmoid colon) were contoured on each CT slice by the treating physician following ABS,^[1],[2] GEC-ESTRO,^[12],[13] and Viswanathan et al.'s^[18] contouring guidelines. The cDVH of tumor volumes and OARs were generated for each application. The dose–volume parameters, i.e., minimum dose received to 90% and 100% by HR-CTV volume (D₉₀ and D₁₀₀) for target volume, were calculated and assessed for clinical response in patients. For OARs, the dose–volume parameters, i.e., the maximum dose received by minimum volume of 2CC (D_2CC), were calculated and assessed. Brachytherapy was performed with a remote afterloading HDR, a radioactive iridium-192 source Gamma Med unit (Varian Medical Systems, Inc., Palo Alto, CA 9430, USA).

Subjective response to the treatment was perceived by the patients in terms of increase in well-being, decrease in pain, and decrease in discharge and bleeding per vagina. Objective response was assessed by a complete gynecological examination and radiological examination. Clinical tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors.^[19] Total follow-up period was 3 years; in every follow-up, the patient was assessed for brachytherapy complications and response.

Statistical analysis was done by using Microsoft Excel and Epi Info version 7 (developed by CDC-INFO, Atlanta, GA, USA). The mean and standard deviation were calculated for each of the quantitative values, and then, comparisons were made using an independent t-test. A P < 0.05 was taken as a level of statistical significance.

Results

In this study, the mean age of the patients was 47.2 ± 8.31 years, ranging from 31 to 67 years. The majority of the patients were between 50 and 60 years. Sixty to seventy percent of patients were from a rural background, were illiterate, and belonged to lower socioeconomic status. Eighty percent of patients had high parity (≥4). All the patients included in this study presented with locally advanced cervical cancer, and 47.5% were of stage IIIB, as shown in [Table 1]. [Figure 1] illustrates the applicator, target (HR-CTV), OARs (bladder, rectum, and sigmoid colon) positions, and typical isodose distribution in a 3D-CT image-based ICBT treatment plan for a reference patient. The dosimetric parameters D_2CC for OARs of each patient were summarized as follows: the mean dose to the bladder was 18.24 ± 0.93 Gy for D_2CC, mean rectal dose was 16.44 ± 1.11 for D_2CC, and sigmoid colon was 16.37 ± 0.67 Gy for D_2CC [Table 2].

Figure 1: Three-dimensional computed tomography image-guided intracavitary high-dose-rate brachytherapy applications of a reference patient showing applicator, target (high-risk clinical target volume), organs at risk (bladder, rectum, and sigmoid colon), and isodose distribution in (a) axial view, (b) frontal view, (c) sagittal view, and (d) model view

Click here to view

Table 1: Characteristics of patients and their disease

Click here to view

Table 2: Mean and standard deviations of the various variables

Click here to view

The total and physical EQD₂ doses from HDR and combined (EBRT and HDR ICBT) EQD₂ doses for OARs are summarized in [Table 3]. The α/β for OARs was taken 3 Gy. The mean EQD₂ and t-score for bladder were 76.71 ± 2.05 Gy and 41.01, for rectum were 72.82 ± 2.58 Gy and 5.34, and for sigmoid colon were 72.71 ± 1.41 Gy and 10.27, which was less than that of baseline limits as laid down by the ABS. As per ABS guidelines, the baseline D_2CC dose for the bladder is 90 Gy and 75 Gy for the rectum and sigmoid colon. In comparison of both these values, the P < 0.01 for bladder, rectum, and sigmoid colon was considered statistically significant. The statistically significant difference was determined by the unpaired t-test, and the level of significance was set at P < 0.05 [Table 3].

Table 3: Comparison of doses received by organs at risk with their baseline level

Click here to view

The mean tumor volume was 24.3 ± 6.5 cubic centimeters (CC) [Table 4]. The mean of HR-CTV D₉₀ was 151 ± 27.3 [Table 5]. Patients who had received HR-CTV D₉₀ of >90 Gy compared with <90 Gy had exceptionally better local control and complete response [Table 6]. As noticed by patients, subjective response was very encouraging. Almost every patient experienced relief from presenting symptoms; this may be due to control of infection, bleeding, discharge, and pain.

Table 4: Tumor volume.wise distribution

Click here to view

Table 5: Distribution among patients according to D₉₀

Click here to view

Table 6: Response among patients to treatment

Click here to view

Overall objective responses, after brachytherapy, were as follows: 77.5% of patients had complete response while 22.5% of patients had partial response [Table 6], and this percentage of partial response among patients might be due to the presence of large residual disease after EBRT in locally advanced cervical cancer. On 3 years of periodic follow-up, late complications of brachytherapy were observed in terms of vaginal fibrosis, hydrometra, and pyometra in 38.5% of patients. These complications were more frequent in patients who had not attended out patient clinics on a regular basis. On follow-up, two patients developed rectal proctitis and one patient developed cystitis as late complications. None of the patients reported vesicovaginal fistula or rectovaginal fistula during follow up.

Discussion

In this study, maximum patients belong to rural areas, have low socioeconomic status, and are illiterate and presented with locally advanced disease. Hence, these results explained that cervical cancer is associated with illiteracy and low socioeconomic status in developing countries.^[20]

For treatment of carcinoma cervix, definitive radiotherapy procedure, intensity-modulated radiation therapy/volumetric modulated arc therapy, allows highly conformal dose delivery to the target volume and lower dose to the OARs in comparison to the four-field conformal pelvic radiotherapy. Previous studies have demonstrated that doses to point a greater than 85 Gy were achieved better central tumor control. Some studies suggested that it is not advisable to use only IMRT as definitive radiotherapy due to internal organ motion and less tumor regression in comparison to combined EBRT and ICBT.^[21] High dose with ICBT can compensate for the insufficient dose to the central tumor caused by the potential internal organ motion of the target volume during IMRT.

Advancement in the software and hardware techniques for ICBT planning has more recently paved the way for the 3D-CT–based image-guided brachytherapy. This is entitled to improving volumetric optimization of primary tumor coverage and sparing of OARs which probably increases local control rate, reduces acute and late toxicities, and helps predict after-effect.

Although MRI is presumed to be the gold standard for ICBT planning and treatment, MRI and MRI-compatible applicators are not universally available in radiation oncology departments, which create executive and financial impediments that have limited universal suitability of MRI-based brachytherapy planning.^[22] On the other hand, CT simulators are readily and widely available in radiation oncology departments. Thus, interest grew in using CT-based brachytherapy planning.

The CT-based planning provides better information on target volumes and OARs volumes and dose-volume histogram, better sparing of normal tissues concerning in comparison to 2D orthogonal brachytherapy. To address this matter, a prospective International Co-operative Group Trial compared CT to MRI-based planning showed that tumor height, thickness, and total volume measurements as determined by CT were not significantly different compared with MRI volumes; similarly, the MRI and CT dose–volume histogram values of the D_2CC, D_1CC, and D_0.1CC for the OARs were similar. However, the extent measurements differed in HR-CTV for CT versus MRI.^[15],[23]

Similarly, various ongoing prospective trials suggest limiting the D_2CC rectum dose to 70–75 Gy, D_2CC sigmoid dose to 75 Gy, and D_2CC bladder dose to 90 Gy. There is no clear correlation between dose to volume relationship, and no toxicities have been set on for the urethra, ureters, and vaginal mucosa. Our study is comparable to the study conducted by Hashim et al.;^[24] the mean dose to the bladder was 6.00 ± 1.90 Gy for D_2CC and the mean rectal dose at D_2CC 4.58 ± 1.22 Gy. For bladder, the mean EQD2 dose was 68.52 ±7.24 Gy using α/β=3 and mean D2CC dose was 81.85±13.03 Gy using α/β=3. The inference was that the mean rectal D_2CC dose differed significantly from the mean dose calculated at the ICRU reference points (P < 0.005). Similarly, Onal et al. studied and validated that the CT plan is superior to the conventional plan in target volume coverage and appropriate evaluation of critical organs as the conventional plan overestimates tumor doses and underestimates OARs doses.^[25]

The CT-based HR-CTV D₉₀ was found to be an important prognostic indicator of tumor control in cervical cancer patients treated with definitive radiotherapy or concurrent chemoradiotherapy. The HR-CTV D₉₀ and HR-CTV volume were remarkable image-guided ICBT parameters for antedating pelvic control rate.^[26] Similar importance of the D₉₀ was demonstrated by GEC-ESTRO^[12],[13] study and a European study on MRI-guided brachytherapy in locally advanced cervical cancer^[27] study data (patients with MRI- or CT-guided 3D treatment). It was illustrated in 592 patients (with a median follow-up of 31 months). D₉₀ to the HR-CTV was 92 Gy and that results in an overall local control rate of 95%.^[28] Our study showed that CT-based IGBT could reduce the dose to OARs with adequate dose to HR-CTV.

The main limitation of this study is the small number of cases. Favorable treatment outcomes were obtained in terms of complete tumor response and lower rectal and bladder complications.

Conclusion

The present study validates that it is suitable to perform planning on CT-based volumes in terms of improved tumor coverage, lesser toxicity, confirmation of applicator placement, and accounting dose to OARs. CT is a favorable modality for treatment planning in cervical cancer patients. IGBT provides potential protection of critical organs with adequate primary tumor coverage with higher dose.

Acknowledgment

We would like to thank all the authors whose manuscripts were used in this article. We also thank all our patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Viswanathan AN, Thomadsen B; American Brachytherapy Society Cervical Cancer Recommendations Committee; American Brachytherapy Society. American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part I: General principles. Brachytherapy 2012;11:33-46.
2.	Viswanathan AN, Beriwal S, De Los Santos JF, Demanes DJ, Gaffney D, Hansen J, et al. American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part II: High-dose-rate brachytherapy. Brachytherapy 2012;11:47-52.
3.	Lanciano RM, Won M, Coia LR, Hanks GE. Pretreatment and treatment factors associated with improved outcome in squamous cell carcinoma of the uterine cervix: A final report of the 1973 and 1978 patterns of care studies. Int J Radiat Oncol Biol Phys 1991;20:667-76.
4.	Montana GS, Martz KL, Gerald EH. Patterns and sites of failure in cervix cancer treated in the USA in 1978. Int J Radiat Oncol Biol Phys 1991;20:87-93.
5.	Perez CA, Grigsby PW, Castro-Vita H, Lockett MA. Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1995;32:1275-88.
6.	Petereit DG, Sarkaria JN, Chappell R, Fowler JF, Hartmann TJ, Kinsella TJ, et al. The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys 1995;32:1301-7.
7.	ICRU Report 38. Dose and Volume Specification for Reporting Intracavitary Brachytherapy in Gynaecology. Vol. 38. Bethesda, Md.: International Commission on Radiation Units and Measurements; 1985. p. 1-20.
8.	Demanes DJ, Rodriguez RR, Bendre DD, Ewing TL. High dose rate transperineal interstitial brachytherapy for cervical cancer: High pelvic control and low complication rates. Int J Radiat Oncol Biol Phys 1999;45:105-12.
9.	Georg P, Lang S, Dimopoulos JC, Dorr W, Sturdza AE, Berger D, et al. Dose-volume histogram parameters and late side effects in magnetic resonance image-guided adaptive cervical cancer brachytherapy. Int J Radiat Oncol Biol Phys 2011;79:356-62.
10.	Pötter R, Georg P, Dimopoulos JC, Grimm M, Berger D, Nesvacil N, 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;100:116-23.
11.	ICRU report 89. Prescribing, recording, and reporting brachytherapy for cancer of cervix, ICRU reportn89. J ICRU 2013; 13:NP. DOI: doi.org/10.1093/jicru/ndw042.
12.	Haie-Meder C, Pötter R, Van Limbergen E, Briot E, De Brabandere M, Dimopoulos J, et al. Recommendations from gynecological (GYN) GEC-ESTRO working group (I): Concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessments of GTV and CTV. Radiother Oncol 2005;74:235-45.
13.	Pötter R, Haie-Meder C, Van Limbergen E, Barillot I, De Brabandere M, Dimopoulos J, 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.
14.	Yadav S, Choudhary S, Singh OP, Saroj DK. Dosimetric comparison of two type brachytherapy planning approaches in HDR treatment of carcinoma uterine cervix: Standard library plan approaches vs. 3D CT image based planning. Anusandhan 2019;9:65-70.
15.	Yadav S, Chandel SS, Choudhary S, Yogi V, Singh OP, Saroj DK, et al. Dosimetric Analysis of 3D-CT Image Based High Dose Rate Brachytherapy Treatment Planning of Carcinoma Uterine Cervix: Initial Experiences at Central India Government Institute. J Cancer Sci Ther. 2019;11:244-250.
16.	Yadav S, Singh OP, Choudhary S, Saroj DK, Maurya AK, Yogi V. Interfraction physical dose variations in high-dose-rate brachytherapy for carcinoma cervix based on computed tomography image dataset to find the compatibility of the first fraction plan to treat successive fractions. J Cancer Res Ther 2019;15:1304-8.
17.	Yogi V, Chandel SS, Yadav S, Singh OP, Goswami B, Ghosh G, et al. Dosimetric comparison of two type's applicator geometry in the three-dimensional computed tomography image-based intracavitary brachytherapy treatment planning of carcinoma uterine cervix. J Radiat Cancer Res 2021;12:1-9. [Full text]
18.	Viswanathan AN, Dimopoulos J, Kirisits C, Berger D, Pötter R. Computed tomography versus magnetic resonance imaging-based contouring in cervical cancer brachytherapy: Results of a prospective trial and preliminary guidelines for standardized contours. Int J Radiat Oncol Biol Phys 2007;68:491-8.
19.	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
20.	Mandloi V, Yogi V, Singh OP, Ahirwar MK, Yadav S, Ghori HU. A comparative study of nab-paclitaxel versus cisplatin concurrent chemoradiotherapy in locally advanced cervical cancer. Clin Cancer Investig J 2019;8:198-204. [Full text]
21.	van de Bunt L, Jürgenliemk-Schulz IM, de Kort GA, Roesink JM, Tersteeg RJ, van der Heide UA. Motion and deformation of the target volumes during IMRT for cervical cancer: What margins do we need? Radiother Oncol 2008;88:233-40.
22.	Hricak H, Gatsonis C, Coakley FV, Snyder B, Reinhold C, Schwartz LH, et al. Early invasive cervical cancer: CT and MR imaging in preoperative evaluation – ACRIN/GOG comparative study of diagnostic performance and interobserver variability. Radiology 2007;245:491-8.
23.	Anderson J, Huang Y, Kim Y. Dosimetric impact of point A definition on high-dose-rate brachytherapy for cervical cancer: Evaluations on conventional point A and MRI- guided, conformal plans. J Contemp Brachyther 2012;4:241-6.
24.	Hashim N, Jamalludin Z, Ung NM, Ho GF, Malik RA, Phua VC. CT based 3-dimensional treatment planning of intracavitary brachytherapy for cancer of the cervix: Comparison between dose-volume histograms and ICRU point doses to the rectum and bladder. Asian Pac J Cancer Prev 2014;15:5259-64.
25.	Onal C, Arslan G, Topkan E, Pehlivan B, Yavuz M, Oymak E, et al. Comparison of conventional and CT-based planning for intracavitary brachytherapy for cervical cancer: Target volume coverage and organs at risk doses. J Exp Clin Cancer Res 2009;28:95.
26.	Dimopoulos JC, Pötter R, Lang S, Fidarova E, Georg P, Dörr W, et al. Dose-effect relationship for local control of cervical cancer by magnetic resonance image-guided brachytherapy. Radiother Oncol 2009;93:311-5.
27.	Pötter R, Tanderup K, Kirisits C, de Leeuw A, Kirchheiner K, Nout R, 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 Transl Radiat Oncol 2018;9:48-60.
28.	Dimopoulos JC, Petrow P, Tanderup K, Petric P, Berger D, Kirisits C, et al. Recommendations from gynaecological (GYN) GEC-ESTRO working group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy. Radiother Oncol 2012;103:113-22.