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. Author manuscript; available in PMC: 2021 Feb 10.
Published in final edited form as: Semin Radiat Oncol. 2020 Oct;30(4):300–310. doi: 10.1016/j.semradonc.2020.05.002

Aiming for 100% Local Control in Locally Advanced Cervical Cancer: The Role of Complex Brachytherapy Applicators and Intraprocedural Imaging

Christen R Elledge 1, Anna W LaVigne 1, Rohini K Bhatia 1, Akila N Viswanathan 1
PMCID: PMC7875154  NIHMSID: NIHMS1663640  PMID: 32828386

Abstract

The use of brachytherapy for the treatment of gynecologic malignancies, particularly cervical cancer, has a long and rich history that is nearly as long as the history of radiation oncology itself. From the first gynecologic brachytherapy treatments in the early 20th century to the modern era, significant transformation has occurred driven largely by advancements in technology. The development of high-dose rate sources, remote afterloaders, novel applicators, and 3-dimensional image guidance has led to improved local control, and thus improved survival, solidifying the role of brachytherapy as an integral component in the treatment of locally advanced cervical cancer. Current research efforts examining novel magnetic resonance imaging sequences, active magnetic resonance tracking, and the application of hydrogel aim to further improve local control and reduce treatment toxicity.

Introduction

Throughout the history of radiation oncology, cervical cancer has represented the perfect paradigm demonstrating the relationship between local control and survival. Cancers of the cervix often spread locally, from the cervix, to the uterus, parametria and vaginal tissues, then to lymph nodes, bladder and rectum before spreading to distant metastatic sites such as lung or bone. Therefore, improving local control has directly impacted disease control and survival rates. For this reason, aiming for 100% local control has directed several advances in this disease over the past century.

The Origins of Gynecologic Brachytherapy

The use of brachytherapy to treat cervical cancer is nearly as old as the known history of radioactivity. In 1896, 1 year after the discovery of x-rays in 1895 by Wilhelm Konrad von Röentgen, A. Henri Becquerel discovered natural radioactivity by exposing photographic plates to uranium salts.1 Marie and Pierre Curie subsequently discovered 2 other sources of natural radioactivity, polonium and radium. Together, the Curies and Henri Becquerel were awarded the 1903 Nobel Prize in Physics for their work on spontaneous radioactivity.2 In October 1903, Dr. Margaret Cleaves described the first published case of a patient with advanced cervical cancer with rectal and bladder involvement that was treated with intracavitary brachytherapy using a sealed glass tube containing radium bromide. The patient was treated with 2 separate applications to the anterior and posterior fornices (ten minutes on the first day and 5 minutes on the second day). Several days later, an examination revealed “no bleeding, no odor, no discharge, no ulceration, and vaginal and cervical mucous membrane normal in appearance.”3

Simultaneously, in October 1903, Dr. William Morton published a report of the first known illustration of an intracavitary device to treat carcinoma of the cervix or throat (Fig. 1).4 A publication by Abbe in January 1904, states “Dr. Morton of New York, reports 3 cases of cancer of the cervix, or post-operative recurrences, under radium treatment, with better results than he was able to get with X-rays.”5 Abbe goes on to describe using a “specimen of German radium;” the patient received 100 hours of exposure, which resulted in a significant reduction in pain and vaginal discharge. Though palliative in nature, the responses seen were promising.

Figure 1.

Figure 1

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The first known illustration of an intracavitary brachytherapy device.4

The role of brachytherapy for the curative treatment of cervical cancer was solidified by the work of Dr Howard Kelly, the Gynecologist-in-Chief at the Johns Hopkins Hospital. In November of 1915, Dr Kelly published a series of 213 cases of cancer of the uterine cervix and vagina treated with radium.6 In this cohort, 199 cases were described as inoperable of which 53 were clinically cured with radium and 109 were markedly improved. In this same publication, Dr Kelly established the role of radiation as adjuvant therapy, defined the role of brachytherapy in the treatment of inoperable recurrences, described the use of interstitial brachytherapy using hypodermic needles loaded with radium “emanation” (emanation led to the production of radon, the daughter product of radium) and stated the importance of the use of different applicators tailored to individual cases. In addition, he provided an early description of normal tissue tolerances and described complications of radiation therapy such as nausea, weakness, rectal ulcers and rectovaginal fistulas. Dr Kelly also treated some patients neoadjuvantly (cases that were initially inoperable but became operable after radium treatment), but he stated, “…when clinical cures have occurred in operable cases, operations are probably best not carried out.” However, these cases provided some of the earliest cellular and histopathologic studies of the effect of radiation on normal and cancerous tissue.6 It was not until the 1970s that Gilbert Fletcher published the relationship of dose to tumor control, showing the inherent survival benefit with providing higher doses of radiation.7–10

With a continued goal to prevent local recurrences, tremendous technological advancements were achieved in brachytherapy with the introduction of computer-aided, image-based 3-D treatment planning,11 commercialization of afterloaders,12 and the development of novel applicators, including template-based applicators designed for use with remote afterloaders for interstitial treatments.13

Gynecologic Brachytherapy in the Modern Era

Applicators

Radiation dose escalation provides improved local control, but requires a conformal dose distribution. There are 2 challenges associated with designing a conformal computer-optimized dose distribution to the tumor: first, the applicators should maximally conform to the shape of the tumor; and, second, the applicators should be standardized for efficiency and consistency. Several types of applicators arose in the history of gynecologic brachytherapy. Radium needles transitioned to hollow rubber tube applicators and customized molds in Paris, while a fixed-geometry box arose in Stockholm, and separate ovoids were developed in Manchester and later in the United States (US) (Fletcher-Suit-Delclos tandem and ovoids). Similarly, interstitial applicators including the Syed and Martinez templates were created for vaginal or locally advanced large volume cervical cancer with vaginal, sidewall or adjacent organ invasion.

Local control is directly linked to tumor coverage, which depends on appropriate applicator selection. Applicators used in gynecologic brachytherapy for the treatment of cervical cancers broadly consist of intracavitary, interstitial, or hybrid (combination intracavitary/interstitial) applicators. The initial clinical examination, serial examinations during the course of external beam radiation therapy (EBRT) to monitor tumor response, and the pre-brachytherapy examination will guide the selection of the most appropriate applicator.14 Ultimately, appropriate applicator selection based on patient anatomy and disease extent is of critical importance. Inappropriate applicator selection or improper implantation may lead to inadequate tumor coverage resulting in decreased local control, decreased disease-free survival and increased toxicity.15 Plan optimization cannot make up for poor quality applicator placement, and thus, inaccurate placements or implants should be corrected prior to treatment planning if possible.16

Currently, intracavitary applicators have an intrauterine component (the tandem) and a vaginal component, which generally consists of a ring or ovoids. The most commonly used applicator in the U.S. is the tandem and ovoids, though the tandem and ring has increased in popularity.17 There are a variety of tandem angles, lengths, and diameters; and, selection of a tandem depends on patient anatomy determined at the time of the procedure.18 Gauze packing around the vaginal component of the applicator increases the stability of the applicator and the distance between the applicator and organs at risk (OARs) such as the bladder and rectum.

Throughout the 20th century, intracavitary applicators were preferred due to their availability and ease of use. However, intracavitary applicators alone are inadequate in cases where there is (1) significant bulky tumor remaining after external beam treatment (2) advanced disease with extension to the parametria or pelvic sidewall (3) a very narrow vaginal apex due to disease, treatment effects from external beam radiation therapy, or patient anatomy, and/or (4) stenosis of the cervical os or obliteration of the endocervical canal to the extent that even the smallest available tandem cannot be used. In addition, if there is significant vaginal extension to the distal aspect of the vagina, an intracavitary applicator will not provide adequate tumor coverage and an interstitial or hybrid applicator should be considered.14

To provide adequate treatment in these cases, an interstitial template is required. Most commonly, this is in the form of a Syed-Neblett template13 or Martinez Universal Perineal Interstitial Template applicator.19 The Syed-Neblett template was first described in 1978.13 It consists of an intrauterine tandem, vaginal obturator, and perineal template that can be placed vertically or horizontally depending on the location of greatest disease extension. Of note, the intrauterine tandem should always be used in patients with an intact uterus as there is retrospective evidence that use of a tandem provides a survival advantage compared to when interstitial needles are used alone with no tandem.20 In patients who have had a supracervical hysterectomy, a short tandem should be used.14 The main advantage of the interstitial template is its versatility and improved tumor coverage in patients with bulky or extensive disease. Given the number and location of holes for needle placement, combined with how the perineal template can be placed either horizontally or vertically, it allows for adequate coverage of very large, extensive tumors. In addition, the template is disposable, thus reducing the need for applicator sterilization. The disadvantages of the Syed-Neblett template are (1) general anesthesia is required for insertion, (2) the template must be secured to the perineum with sutures, (3) the patient requires inpatient hospitalization for the duration of treatment, and (4) increased technical skill is required for accurate, safe insertion of needles.

Most recently, hybrid applicators such as the Venezia applicator (Elekta) and interstitial ring have been developed with the intent to maximize dose delivery to regions of the tumor in close proximity to normal tissues and/or at a significant distance from the central tandem or ovoids. The Venezia allows for the delivery of outpatient high-dose rate (HDR) treatment to patients that would otherwise require treatment with a template and inpatient hospital admission. The Venezia contains an intrauterine tandem, 2 lunar-shaped ovoids, multichannel vaginal caps, and a perineal template. The lunar-shaped ovoids attach to form a ring allowing for the advantages of the dose distribution associated with a tandem and ring.21 There are holes for needle placement in the ovoids, which allow for the placement of parallel or oblique (angled at a 20-degree angle) needles to improve parametrial coverage. The multi-channel vaginal caps can be used to treat vaginal extension and a perineal template is provided for far lateral or anterior/posterior disease extension. Each of the parts snap into place and no complex assembly is required allowing for ease of use. In addition, the radiation oncologist can choose which components of the applicators to use (e.g., vaginal caps, needles, perineal template) depending on the patient’s anatomy and disease extent making it extremely versatile. The disadvantages of these new applicators are the expense as well as the cleaning and sterilization of the applicators as these are not disposable. In addition, given the number of parts and complexity, there is a learning curve associated with the initial use of these combination applicators. Furthermore, treatment planning with such applicators must be performed with extreme care to avoid excessive dose (“hot spots”) in areas adjacent to single catheters.

Contouring

Cervical cancer control has increased with CT-based planning to over 95% for patients with stage I-II disease.22–25 3D-based planning has allowed for increased precision with applicator placement26 and most importantly, has enabled the use of volume-based dosimetry. Volume-based planning enhances the accuracy of dose calculations not only for OARs, but also for tumor volumes, with the ability to reassess over time—an element essential to the adaptive planning required with HDR therapy. These advantages have proven toincrease local disease control, decrease toxicity, and improve overall survival.22,27–29

In recent years, comparison between computed tomography (CT) and magnetic resonance imaging (MRI) has become a dominant component of efforts to optimize 3D-based planning.26 Key considerations include the degree of tissue delineation, interoperator variability, and logistics such as availability, equipment specifications and procedure duration. Table 1 demonstrates the clinical outcomes of CT and MR-image-guided brachytherapy for the treatment of cervical cancer.

Table 1.

Clinical Outcomes of Image-guided Brachytherapy for Cervical Cancer

Site (Year) Number of Patients Mode of Treatment Stages Included Imaging During BT BT Applicator Median Follow-up (Years) Local Control (%) Disease-specific Survival (%) Overall Survival (%) Late Grade 3–4 Toxicity % (Number)
Vienna (1993–1997)30 189 EB/HDR (167) EB/PDR (22) IA-IVB CT T & R 2.8 78* 69* 58* 13
Vienna (1998–2003)31 145 EB ± Ch†-HDR IB-IVA MR T & R (116) hybrid‡ (29) 4.3 85*,## 68* 58* 5 (3 GU) (4 GI) (5 V)
Vienna (2001–2008)32 156 EB ± Ch§-HDR IB-IVA MR IC (87) or hybrid‡ (69) 3.5 95* 74* 68* 7 (3 GU) (5 GI) (3 V)
IGR (2000–2004)33 39 Preop LDR IB1-IIB MR Vaginal mould 4.4 97∥ 94∥ 0
IGR (2000–2004)34 84 ChRT/LDR IB2-IVB MR Vaginal mould 4.4 89 57∥ (3 GU) (1 GI)
IGR (2004–2006)35 45 ChRT/PDR IB-IVA MR Vaginal mould 2.2 100 78 (1 Fi)
GRCC (2005–2011)36 225 ChRT/PDR IB1-IVA MR (201); CT (24) Vaginal mould 3.2 86* 76* 7∥ GI and GU (6 GU) (7 GI) (5 Fi)
National Cancer Center, Korea (2001–2005)25 230
133 ChRT/HDR IB1-IVB X-ray T & O 4.7 91* 10% LRB
97 ChRT/HDR IB1-IVB CT T & O 3.4 97* 2% LRB
French STIC** (2005–2007)22 705 IB-IIIB 2.0
76 Preop LDR or PDR IB1-IIB X-ray 2.0 92 95 14.6
89 Preop PDR IB1-IIB CT 2.0 100 96 8.9
142 Preop ChRT/LDR or PDR IB1-IIIB X-ray 2.0 85 85 12.5
163 Preop ChRT/PDR IB1-IIIB CT 2.0 93 86 8.8
118 ChRT/LDR or PDR IB1-IIIB X-ray 2.0 74 65 22.7
117 ChRT/PDR IB1-IIIB CT 2.0 79 74 2.6
Leuven Cancer Institute, Belgium (2002–2012)37 170 ChRT/PDR (161); ChRT/LDR (9) IB1-IVB MR (161); CT (9) T & O (143) (or combination IC/IS (27) 3.1 95# 65# 12
Addenbrooke’s (2005–2007)24 28 ChRT/HDR IB1-IIIB CT T & R 1.9 96*,## 81* 14* (3 GI)
Tata Memorial Hospital, Mumbai (2006–2007)38 24 ChRT/HDR IB2-IIIB MR + CT (MR used for 32 of 77 total fx and CT for 45/77) T & O 2.0 88 96 4 (1 GI)
UMCU (2006–2008)39 46 EB ±- Ch††- -PDR (39); -HDR (5); combined HDR/PDR (2) IB-IVB MR T & O (18) or hybrid‡ (28) 3.4 93* 74* 65* 9.5
UPMC (2007–2010)40 44 ChRT/HDR IB-IIIB MR + CT (MR 1st fx only) T & R 0.7 88 85 86 0
UPMC (2007–2013)41 128 ChRT/HDR IB1-IVA MR + CT (MR 1st fx only) (66) MR (62) T & R (121) or hybrid‡ (7) 2.0 92* 85* 77* 1
BW/DFCC (2004–2014)23 128 ChRT/HDR IA2-IIB T & R (60), T & O (20), T & C (6), combination (42) 2.5 96 88 0
SJUH (2008–2012)42 76 ChRT/HDR IB-IVA
49 ChRT/HDR IB1-IVA MR + CT (MR 1st fx only) T&R 3.4 93* 78* 16 (5 GI) (3 GU)
27 ChRT/HDR IB2-IIB MR T & R or hybrid‡ 3.4 92* 70* 4 (1 GI)
BW/DFCC (2005–2015)27 56 ChRT/HDR IB2-IVA Int. 1.6
27 ChRT/HDR IB2-IVA CT Int. 1.5 87 56 19 (4 GI) (1 GU)
29‡‡ ChRT/HDR IB2-IVA MR†† Int. 1.6 96 84 21 (3 GI) (3 GU)
UCSD (2007–2014)43 76 ChRT/HDR IB1-IVA MR + CT (MR 2nd fx only)§§ T & O (67), T & C (5), Int. (4) 1.4 94 75 (1 GI)
UHL, Belgium (2007–2014)44 85 ChRT/PDR IB-IVA MR T & O or T & R (75); hybrid‡ (10) 3.0 94* 85* 81* (5 GU), (5 GI), (5 V)
RetroEMBRACE (1998–2012)45 731 EB ± Ch∥∥-IGBT IA-IVB MR¶¶ (592) + CT (139) IC (563) or hybrid‡ (168) 3.6 89# 73# 65# (27 GU) (31 GI) (22 V)
Leiden University (2000–2012)28 126 IB-IVA T & O
43 ChRT/LDR (34) or ChRT/HDR (9) IB-IVA X-ray T & O 10.2 68* 51* 15*
83 ChRT/HDR IB-IVA MR¶¶ (72) or CT (11) T & O 3.5 93* 86* 8*
UCSF (2003–2009)46 111 ChRT/HDR IB1-IVB CT (67) or MR (44) Hybrid 3.5 94∥ 64∥ 8∥ (2 GU) (4 GI)
Aarhus University29 229
(1994–2000) 99 EB/MDR (43), EB/PDR (46) IIB-IVA X-Ray T & R 2.9 76*,## 68* 63* 15*
(2005–2011) 140 EB ± Ch***-PDR IB-IVA MR T & R (80) or hybrid‡ (60) 3.0 91*; 85*,## 87* 79* 7*
CMUH, Thailand (2011–2012)47 17 ChRT/HDR IIB-IIIB CT 1.2 93 93 0
MCW (2008–2012)48 18 ChRT/HDR IB2-IVA MR T & R; T & O 1.7 100 93 11 (2 GI)
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BT, brachytherapy; BW/DFCC, Brigham and Women’s/Dana Farber Cancer Center; Ch, chemotherapy; ChRT, concurrent chemotherapy and radiation; CMUH, Chiang Mai University Hospital; CT, computed tomography; GU, genitourinary; EB, external beam radiation therapy; Fi, fistula; Fx, fraction; GI, gastrointestinal; GRCC, Gustave-Roussy Cancer Center; IC, intracavitary; Int, interstitial; HDR, high-dose rate; IGR, Institut Gustave-Roussy; LDR, low-dose rate; LRB, late rectal bleed; MCW, Medical College of Wisconsin; MDR, medium-dose rate (1 Gy/hr at point A using a caesium tube and box system); MR, magnetic resonance imaging; PDR, pulsed-dose rate; Preop, preoperative therapy; SJUH, St. James’s University Hospital (United Kingdom) STIC, Soutien aux Thérapeutiques Innovantes et Couteuses; T & C, tandem and cylinder; T&O, tandem and ovoids; T & R, tandem and ring; UCSD, University of California San Diego; UCSF, University of California San Francisco; UHL, University Hospital of Liège; UPMC, University of Pittsburgh Medical Center; UMCU, University Medical Center Utrecht; V, vaginal.

*

3-year

†

Ch administed to 55%

‡

combined intracavitary/interstitial

§

Ch administered to 73%

∥

4-year

2-year

#

5-year

**

prospective trial

††

Ch administered to 74%

‡‡

Patients had been prospectively enrolled on a phase II trial

§§

MR guidance in 60/76 patients

∥∥

Ch administered to 77%

¶¶

MR guidance for at least 1 fx

##

pelvic control

***

Ch administered to 79%.

CT vs. MRI: Tissue Delineation

The superior ability of MRI to delineate between disease and normal tissues, and its impact on treatment doses has become the driving argument for MRI-based planning. Several studies have shown that contouring and dose optimization for OARs does not differ appreciably between CT and MRI-based planning.49,50 However, MRI-planning offers key advantages with regards to tumor volumes.

When treating locally advanced cervical cancer, adaptive treatment planning is essential due to the dynamic relationship between tumor and normal structures in the context of tumor response, variations in positioning of the uterus, and bladder and rectal filling. Moreover, due to the sharp dose fall off and inhomogeneous dose distribution with brachytherapy, accuracy in tissue delineation is essential in optimizing treatment planning. Several studies have shown a high rate of pelvic recurrence51 and persistent disease52 with inadequate dose coverage to tumor volumes.

Due to decreased soft-tissue resolution, CT imaging, while time-efficient, is inferior to MRI in distinguishing between disease and normal tissue, most often leading to an overestimation of tumor volume.50,53,54 The uterus and cervix can appear similar on CT, while bowel loops can also prove to be difficult to accurately delineate. Moreover, the use of intravenous (IV) contrast with CT is not a reliable solution due to the challenges in timing of administration and the variable enhancement of disease, with central areas of cervical tumors often enhancing more than the periphery.50 Furthermore, visualization of superior disease extension is often less determinate on CT, resulting in reliance on pretreatment MRI imaging.46

When contouring the high-risk clinical target volume (HR-CTV), CT imaging cannot match the ability of MRI to delineate parametrial extension and the lateral cervical borders. Wider cervix contours on CT lead to decreased D100 and D90.50 In addition, MRI-delineated tumor volumes may be more accurate due to improved discrimination between residual disease and post-EBRT scarring on MRI compared to CT.26,50 However, there is no known difference in the rate of parametrial failure with MRI-based planning.26 Moreover, the greatest concordance between CT and MRI-based planning was found for cases with smaller volume disease that lacked parametrial extension.26 The current body of literature therefore suggests that while CT-planning is typically comparable in the contouring of OARs, MRI is the superior modality for maximizing gross tumor volume (GTV) conformality. To date, trials have not assessed dose escalation to the GTV alone; rather they have focused on the HR-CTV. GTV dose escalation will be assessed in the EMBRACE II prospective registry (www.embracestudy.dk).

CT vs. MRI: Interoperator Variability

The extent to which variability in contouring impacts local control is not well defined. In 2007, Hricak et al found that in the pretreatment evaluation of 156 cervical cancer cases, greater interobserver agreement amongst participating radiologists was found with MRI vs CT-imaging, with a statistically significant AUC increase by 0.2 for tumor visualization.55 In another study, a greater level of interobserver agreement was found with CT-imaging for clinical target volume (CTV) contouring in comparison to MRI, with a higher conformality index; however, the use of a more distinct contrast medium was felt to be contributory.26 Structured teaching has been shown to increase interobserver agreement,56 and in an effort to decrease interobserver variability, the first contouring consensus atlas in the US was developed in 2014.26

CT vs. MRI: Logistical Considerations

CT scanners are more readily available, as most radiation oncology centers are now equipped with CT-based simulation suites. Although MR imaging is widely considered the gold standard for visualization of gynecologic malignancies and the surrounding bowel, MRI scanners, in contrast, are less likely to be found on-site and more often, patients must travel outside a department to undergo MRI-specific imaging. Specific equipment considerations for CT include the potential for increased artifact from applicators and catheters, while for MRI, there is an added expense required for MRI-compatible applicators.50 Moreover, MRI-based procedures are inherently longer, necessitating more time under anesthesia and thus, there must be consideration of the increased costs and risks associated with such extension.

MRI Sequence Specificity

T2-weighted fast spin-echo imaging has long been considered the best series for evaluation of the primary tumor, disease extension into the lower uterine segment, and parametrial invasion.57 Paratransverse imaging is superior to transverse (T) imaging alone due to the ability to view the cervical volume circumferentially, in the context of the relationship of tissue structures to the applicator.56 Further investigation has led to the identification of 3-T MR 3D-balanced steady state free precession as a feasible sequence for catheter identification.58 In addition, functional imaging with diffusion-weighted MRI and dynamic contrast-enhanced MRI sequences has been studied and new sequence development is the subject of ongoing research.59

Planning

After each applicator insertion, treatment planning and dosimetry should be performed to assess target coverage and dose as well as dose to OARs. Historically, treatment planning was performed using 2-D imaging, generally with orthogonal plain films obtained with the applicator in place. Most commonly, dose was prescribed to point A, as defined in the “modified Manchester method” described by Margaret Tod and W.J. Meredith in 195360 and the desired dose distribution took on a pear shape.61 With the use of low-dose rate brachytherapy, there was minimal dose optimization beyond the standard pear shape due to the limited number of sources and source strengths.16 However, the use of HDR brachytherapy has allowed for further plan optimization due to an increased number of available dwell positions and the ability to control dwell times in each position. Furthermore, the use of postimplant 3-D imaging for treatment planning has provided the opportunity to prescribe dose to volumes instead of points and has led to improved plan optimization.62 While 3-D planning is now preferred and has demonstrated improved local control and decreased toxicity compared to 2-D planning,22 the 2-D approach is still used globally out of necessity in centers without 3-D imaging capability.

For 3-D planning, a CT or MRI should be performed with less than 3 mm slice thickness and the field of view should cover the entirety of the applicator (including the template) and all relevant anatomy.61 If a digital model of the applicator is not available, dummy catheters containing a CuSO4 solution63 can be inserted in the catheters to increase visibility on T1-weighted images or dummy catheters containing saline solution can be used to increase visibility on T2-weighted images.48 Finally, an alternative approach is to perform a post-implant CT scan which can then be fused to the MRI to digitize the applicator. To reduce changes in applicator or needle displacement, the patient should be immobilized during the MRI and prior to treatment if possible. In addition, at our institution, a confirmatory CT-scan is performed prior to each treatment to confirm the position of the applicator and needles for patients with interstitial implants who stay inpatient for the duration of their brachytherapy. Bladder-filling protocols can be used to ensure reproducible bladder filling and position. Finally, a rectal tube may be considered in patients with significant interfraction variability in rectal distension or position due to gas or stool.61 A physicist then imports the images into a treatment planning system and identifies the applicator and interstitial catheters, if present. The physician then contours the OARs (bladder, rectum, sigmoid, vagina, bowel) as well the targets (GTV and HR-CTV).

Once the radiation oncologist has drawn the contours, a qualified physicist works with the radiation oncologist to begin the process of plan optimization. Plan optimization can be performed manually or with partially automated optimization algorithms. In manual optimization, dwell positions are activated or de-activated by the user and dwell times are adjusted by trial and error, all while continuously monitoring the dose distribution, HR-CTV coverage, and dose to OARs.64 With manual planning, the recommendation is to start with the standard pear-shaped distribution and then “sculpt the pear” by activating/de-activing dwell positions and varying dwell times.

Finally, the radiation oncologist reviews the spatial dose distribution, simultaneously assessing the HR-CTV coverage, conformality, hot spots, cold spots, and dose to OARs. A dose volume histogram is used for assessing plan safety and quality. However, the exclusive use of a dose volume histogram to determine dwell positions and times is not recommended because this may result in considerable and sometimes undesirable, changes to the spatial dose distribution.16 Dose-volume parameters used for 3-D plan evaluation have been previously defined by the Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology65 and the American Brachytherapy Society.16 The radiation oncologist may make final manual adjustments to the dwell positions and dwell times to further optimize the treatment plan.

Brachytherapy to Achieve 100% Local Control

Brachytherapy has solidified its role as a requisite component in the definitive management of patients diagnosed with Federation of Gynecology and Obstetrics stage IB3 to IVA cervical cancer along with external beam and concurrent chemotherapy.45,66 However, the future success of brachytherapy programs in the United States depends on adequate exposure to brachytherapy cases during residency. In addition, brachytherapy schools such as those supported by the American Brachytherapy Society, may be used to fill gaps in knowledge and increase providers’ technical skills and comfort level.

Another potential strategy to increase provider comfort with MRI-guided brachytherapy may come from the use of an MR tracking (MRTR) device that would allow for real-time image guidance during brachytherapy catheter positioning.67 Without real-time image guidance, the radiation oncologist does not know if the interstitial needle has been advanced into a nearby critical structure such as the rectum or the bladder or if there is adequate coverage of disease extension. To assess the adequacy and safety of the interstitial implant, a post-implant MRI must be performed. In many radiation oncology departments, the MRI is not located within the department. Therefore, if needles need to be added, removed, advanced or retracted; the patient has to be brought back to the procedure suite or operating room for implant adjustment and then be taken back to the MRI for a subsequent post-implant scan. This increases clinic and hospital resource use (increased MRI time, increased patient transport), increases the patient’s exposure to general anesthesia, and increases cost.

Active MRTR was developed in the 1990s for endovascular navigation of non-metallic catheters.67 MRTR is achieved by mounting a small radiofrequency microcoil to the end of the stylet. Specific radiofrequency coil geometries and MRTR pulse sequences have been developed to facilitate the use of MRTR in gynecologic brachytherapy.68,69 A patient can then be moved into the bore of the MRI and the physician can insert catheters loaded with MRTR stylets (Fig. 2). In 1 study, an MRI was then performed every 5 minutes during implantation, and the catheter tip locations were overlaid on the revised images. The physician could then use the real time imaging changes to determine placement of subsequent catheters in order to provide optimal HR-CTV coverage.67 In addition, after positioning is complete, the MRTR stylets can be removed within the MRI to determine the catheter trajectory. This information can subsequently be used for applicator reconstruction at the time of planning. This provides several advantages over the currently used method of passive tracking, which relies on image susceptibility artifact (loss of signal) produced by the metallic composition of stylets. Susceptibility artifact is generally larger than the actual object, leading to decreased spatial resolution and it can be difficult to discern the track of individual catheters if they approach or cross the path of another catheter.67 Ultimately, in the future, the use of MRTR may allow physicians to produce safe, high-quality implants with improved coverage of disease without the need to transport the patient to the MRI multiple times. MRTR may also allow for greater accuracy of applicator reconstruction, further increasing the provider’s comfort level with MRI-guided brachytherapy.

Figure 2.

Figure 2

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Screenshot of active tracking feed that shows the actively tracked needle (red) being inserted into the high-risk CTV (yellow). The tracking feed is displayed on a monitor inside the MRI room allowing for observation and assessment of catheter placement during insertion or manipulation.

Another area of active research within gynecologic brachytherapy is the exploration of the potential use of biodegradable hydrogel as vaginal packing70 and as a fiducial marker.71 Hydrogel is a biocompatible, biodegradable polyethylene glycol-based gel that is injected into the desired location as a liquid, which quickly solidifies into a flexible gel that has enough inelasticity to displace nearby normal tissue. The gelification reaction occurs within 90 seconds of injection and results in a volume-occupying gel that is larger than the initial liquid volume secondary to hydrophilic residues that increase water absorption.71 The volume of gel can lead to increased distance between radiation targets and nearby OARs; thereby, reducing the dose to OARs and treatment toxicity (Fig. 3). The gel is generally visible for approximately 3 months before biodegradation begins. The gel is then slowly degraded and absorbed over a period of 6 months.

Figure 3.

Figure 3

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Axial MR images pre- (left) and post-hydrogel insertion (right). The hydrogel displaces the rectum away from the obturator reducing the dose delivered to the anterior rectal wall.

Traditionally, gauze has been used for vaginal packing and has been placed by using fingers or forceps to advance the gauze between the applicator and the nearby OARs in order to increase the space between them. Care must be taken to not allow the packing to go superior to the applicator where it creates distance between the applicator and the cervix. However, this technique has been described as cumbersome and time consuming and requires technical skill and experience. A prior study found on multivariate analysis that patients with unacceptable vaginal packing had twice the risk of failure (disease-free survival, DFS) compared to patients with acceptable packing after adjusting for nodal status.15 Several early cadaveric studies have shown that hydrogel may hold promise as an alternative to vaginal packing with gauze.70 Further research is needed to determine the safety and efficacy of this approach compared to conventional packings.

Although hydrogel is generally visible by CT and MRI, another type of hydrogel has been developed which contains polyethylene-glycol hydrogel microparticles covalently bound to iodine contrast material to improve its visibility on CT, MRI, cone-beam CT, and ultrasound (TraceIT Tissue Marker; Augmenix, Waltham, MA). Given the radiopaque nature, this hydrogel can be injected directly into the target or into key anatomical landmarks where it will serve as a fiducial.71 Injection of the tumor with the hydrogel fiducial allows for more precise radiation targeting than treating without a fiducial. In addition, the hydrogel creates less artifact than traditional metal fiducials, has greater conformality to anatomical space due to its undefined shape, and can be introduced with a smaller needle than those used to implant metallic fiducials, resulting in less tissue trauma and pain.71 Although further research is required, the use of hydrogel as a fiducial for improved tumor targeting is a promising option for future patients.

Conclusions

Achieving 100% local control in cervical cancer is now a reality for many patients. From the first gynecologic brachytherapy treatment in 1903 to today, gynecologic brachytherapy has undergone significant transformation largely driven by the growth of new technologies. Several examples include the development of novel applicators and implants, the invention and commercialization of remote afterloaders, the development of new sources capable of delivering HDR brachytherapy, and, most recently, the use of CT and MRI in applicator placement and treatment planning. Future research should focus on methods to reduce toxicity, or dose escalate only to visible areas of residual disease. In addition, distant metastases remain an issue, and the optimal use of chemotherapy will need to be studied in the future.

Footnotes

Conflict of Interest: CE, AL, RB have nothing to disclose. AV is the principal investigator for NIH R01CA237005.

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