Toxicity Outcome Using Bladder-Rectum Spacer Balloon Versus Vaginal Gauze Packing in Brachytherapy in Cervical Cancer.

BACKGROUND To compare the clinical impact in terms of toxicity outcomes with RayshieldTM bladder rectum spacer balloon (BRSB) versus vaginal gauze packing (VGP) in patients treated with high dose rate intracavitary brachytherapy for carcinoma cervix. Follow-up and dosimetric data of patients in whom BRSB and VGP were used in a previously reported randomized study were retrieved, 8. Out of 80 patients analysed, late toxicities assessment (according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4). was possible in 65 patients as 14 patients were lost to follow-up and one patient died. Grade 2 bladder toxicity was observed in 2 patients in each arm. Only 1 patient in VGP arm experienced grade 3 proctitis while none of the patient in BRSB arm had ³Grade 2 rectal toxicity. Vaginal toxicity was comparable in both the arms. No difference was in and toxicities using the versus


Background
Intracavitary brachytherapy forms an integral part of curative radiotherapy. With brachytherapy, high doses can be delivered to the tumour, but the high dose delivered to adjoining organs at risks (OAR) like rectum, vagina and bladder can result in late toxicity (1). The doses to the organs at risk depend on the patient's anatomy, proper placement of applicator, displacement of OAR's, and stability of the applicator.
In high dose rate (HDR) brachytherapy, because of inverse square law, the radiation effects are observed more noteworthy at short distances from the source and less at longer separation (2,3). Hence, in cervical cancer brachytherapy adequate displacement of organs at risk i.e. bladder and rectum and high radiation tolerance of the cervico-uterine complex allows therapeutic doses to be delivered to the target simultaneously respecting the radiation tolerance to the adjoining OARs. Thus a good intra-cavitary application is necessary to achieve the required geometry, the lack of which has been associated with inferior therapeutic outcomes. Displacement of the bladder and/or rectum can be done using various methods like vaginal gauze packing, rectal retractors, posterior vaginal speculum blades, and shielded ovoids (5, 6).
In our previously published experience of using the RayshieldTM bladder rectum spacer balloon (BRSB), the use of BRSB resulted in a statistically signi cant reduction in rectal 0.1cc and 2 cc doses on dosimetric analysis (7,8). Although various dosimetric studies have been done using Balloon based system, clinical experiences with respect to bladder and rectal toxicity are lacking. In the present study, we evaluated the outcomes in terms of toxicities comparing the BRSB with VGP.

Study design and setting
This study was a review of follow up and dosimetric data of patients included in our previously published randomized dosimetric BRSB-II study conducted between April 2013-March 2014.7-8 The study was approved by the institute ethics committee and registered under Clinical Trial Registry of India (CTRI/2009/091/000840). The patients were treated with three-dimensional conformal or intensity modulated radiotherapy with a dose of 46 Gy over 4.5 weeks with concurrent cisplatin followed by brachytherapy with 2 fractions of 9 Gy each which were delivered 1 week apart (9). Prior to brachytherapy, the patients were randomized to Vaginal gauze packing (VGP) and the BRSB (Fig. 1). The procedure was performed under general anaesthesia. In all patients, a rectal enema was given before the procedure to ensure complete emptying of the rectum. A reproducible bladder lling protocol was followed before the scan and patient treatment. The bladder was rst emptied under gravity and 50 ml saline was inserted in the bladder. It was then allowed to drain freely under gravity. The dose was prescribed to point A (EQD2 74.5 Gy) and the 2cc doses were evaluated for the bladder, rectum and sigmoid (constraints for bladder D2cc < 90Gy EQD2, rectum < 75Gy EQD2 and sigmoid < 75Gy EQD2).

Follow up
Patients were followed every 3 months for the rst 2 years and 6 months thereafter. Toxicity assessment was done according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4). The maximum score in any symptom in any of the follow-up visits was considered as the score for statistical analysis. In addition to the bladder and rectal toxicity assessment, vaginal toxicity was also analysed.
Since the baseline vaginal length was not available, a subjective assessment was done and any obvious shortening in vaginal length was documented.

Statistics
Patient details, late toxicities, and dosimetry were entered in SPSS version 19. Descriptive statistics were described for late toxicities and dosimetry. Dosimetry and the incidence of toxicities were compared using paired T-test. A p-value of < .05 implied a signi cant difference in incidence. Univariate analyses were used to look for co-relations between late toxicities and dosimetric parameters.

Results
There were 80 patients in which VGP was compared to BRSB. Assessment of late toxicities was possible in 65 patients as 14 patients were lost to follow up and one patient died due to chronic renal failure secondary to diabetes. Out of the total patients, 35 patients were evaluable in BRSB arm and 31 patients in VGP arm (Fig. 2). The mean follow up period was 74.1 months

Rectal toxicity
There was only one patient out of 31 patients(3.2%) in VGP arm who experienced grade 3 proctitis. She underwent colonoscopy which showed telangiectasia and to manage the symptoms two applications of Argon plasma coagulation were done. There were no grade 2 toxicities. There were no reported had rectal ulceration, pain, haemorrhage, obstruction, perforation, and stula in both arms.

Vaginal toxicity
In BRSB arm, 31% (n = 11) of patient had vaginal shortening, out of which 11% (n = 4) had grade 1 and 20 % (n = 7) had grade 3 shortening. One patient in both arms had grade 1 vaginal telengectasia. (Table 1).   Table 2. There was no correlation of EQD2 with grade 2 toxicity.  (10,11,12). The clinical outcome of these different methods in terms of late toxicity has not been assessed. In our previous dosimetric analysis using the BRSB, a signi cant reduction in the dose, as well as the inter-fraction dose variation of D2cc of rectum, was observed with the use of BRSB compared to VGP. Although based on the small number of events it does not ascertains the impact of the BRSB, but BRSB and VGB seem to be comparable in terms of OAR toxicity.
As HDR practice over LDR brachytherapy is increasing amongst radiation oncologists, the management of OAR toxicity remains the main goal (13). As the previous studies suggest, the dose delivered to surrounding structures depends upon patient geometry, positional stability of the apparatus, and degree of isodose invasion into critical tissues (14). The skill and expertise of the radiation oncologist and proper applicator placement are critical determinants of dose speci cation and outcome. In a study by A.N. Viswanathan et al, it was seen that the technical precision of brachytherapy implant placement, especially, the symmetry of the ovoids in relation to the tandem, the displacement of the ovoids in relation to the cervical os, and the appropriateness of packing, affects relapse and disease-free survival rates (15). These parameters should be considered for each brachytherapy implant. Hence, to achieve maximum therapeutic ratio, the dose to the OARs should be minimised by proper displacement in accordance with inverse square law. Studies using the different types of rectum spacers (hydrogel, hyaluronic acid, collagen, biodegradable balloon) in prostate carcinoma have shown a relative reduction in the rectal volume receiving at least 70 Gy (V70) in the order of 43% to 84 % and thus reducing rectal toxicities (16). Similarly, reduced rectal doses have been documented with the use of various balloon based systems in cervical cancer brachytherapy.
Despite the evidence that brachytherapy is associated with improved outcomes in cervical cancer, there has been a decline in the use of brachytherapy. Numerous studies have demonstrated that omitting or substituting brachytherapy with other options impairs cancer control and survival (17,18). This decline may be a result of the increase use of conformal external beam radiation therapy techniques, most notably intensity modulated radiation therapy (IMRT). The other reason could be its complex procedure which requires training and expertise for optimal application. In a study by Marcrom et al, young residents were more con dent in starting an SBRT/SRS practice than a brachytherapy practice, despite SBRT/SRS being a newer treatment technique as brachytherapy requires technical expertise and skill set distinct from that of SBRT/SRS(18). It was believed that trainees can be made expert in brachytherapy with proper training. In case of lack of experience in the initial phases, BRSB could offer an advantage to the learning physicians, decrease the inter-observer variation, and can help in achieving reproducibility. In centers where the procedure is done under sedation or conscious anaesthesia, effective vaginal packing may not be possible because of inadequate relaxation of the patient. In such situations, BRSB offers advantage both in terms of adequate displacement and reproducibility. The other advantages include its CT/MRI compatibility and cost-effectiveness. The cost-effectiveness (BRSB costs around $13.94(Rs 990)) allows its use even in resource constrained countries which cater to the large burden of cervical cancer. The balloon is reusable and can be used for multiple brachytherapy fractions in a patient. However, the BRSB is limited for use only in the tandem-ovoid applicators and has not been tested for ring applicators. A modi cation in its design would be hence be required for its wider applicability. In addition, the availability of the balloon in a single size restricts its usage in patients with a narrow vagina, wherein a larger balloon tends to get folded inside the vaginal canal further hindering applicator insertion (7).

Conclusion
Based on our previous dosimetric results and the clinical data in the present study, RayshieldTM bladder rectum spacer balloon (BRSB) seems to be a propitious alternative to VGB in reducing OAR toxicity.

Consent for publication
Consent for publication of patient data was taken from all the patients who were part of the study. We con rm that no identifying images or other personal or clinical details of participants are presented that compromise anonymity.

Availability of data and material
Data is available with the corresponding author

Competing Interests
The RayshieldTM Bladder-Rectum balloon was provided by HLL life care limited .
Funding There was no funding for this study.

Authors Contribution
All authors have read and approved the manuscript.   Consort ow chart