Lauren Hein In partial fulfillment of RT 412 University of Wisconsin-La Crosse Radiation Therapy Program Three-dimensional Imaging for High Dose Rate Cervical Brachytherapy Treatment Planning

Background1,2,3 Cervical cancer is the third most common cancer in women worldwide Current standard of care for early stage node positive or locally advanced cervical cancer is external beam radiation therapy with concurrent chemotherapy, followed by high dose rate cervical brachytherapy Intracavitary cervical brachytherapy uses tandem and ovoid applicators

Organs at risk: bladder, rectum and sigmoid colon2 Move around the implanted applicators daily so localization and dose verification is a crucial part of treatment planning4 Success of brachytherapy depends on accurate identification and localization of the uterus, cervix, and residual disease, as well as accurate placement of tandem and ovoid within the uterine canal3 Knowing the OAR movement can help to limit the uncertainties and potentially detrimental consequences of overdosing sensitive organs4

Orthogonal Images2,5 Historically, two-dimensional orthogonal x-ray images were used for treatment planning Do not provide soft tissue visualization Inadequate target coverage, insufficient dose delivery, and a larger percentage of treatment failure Unknown PTV coverage and visibility, limited opportunity for flexibility of dose distribution, unknown spatial relationship between applicator and surrounding OAR Benefit: radiation therapists do not need special training or further education to use the machines and create adequate images

Three-dimensional Imaging2,4,5 Delineate the soft tissue around the applicators Localize the disease site Visualize the PTV Identify the OAR Alter the target volume dose coverage to be more conformal for each individual patient

Visualization of the tumor and adjacent organs2 Improved target coverage Local control Reduced late toxicity

Computed Tomography1,8 Three-dimensional CT vs. two-dimensional imaging Improved local and regional relapse free survival after treatment Decrease in grade 3+ urinary and gynecologic toxicities Urinary frequency, urgency, dysuria, hematuria, and pelvic pain Increases diagnosis of uterine perforation and avoids overtreatment of the fundus and lower uterine segment

CT Benefits1,10 Confirmation of applicator placement Decreased OAR dose for patients with a small cervix Accountability for sigmoid colon dose and reducing tissue toxicity Improved coverage for large volume disease while maintaining organ dosimetry

CT Limitations5 Over-estimating of tumor volumes, resulting in an increased dose delivered to the adjacent normal tissue Less useful for PTV definition than MRI because it overestimates the treatment volume width, leading to irradiation of more normal tissue Lack the ability to accurately assess nodal metastases, which may lead to an underdose to the gross disease and result in a worse prognosis Image is taken first, and then the patient is transported to HDR room, making it challenging to ensure applicator position stability due to patient movement

Magnetic Resonance Imaging5,7,9 Offers enhanced anatomy and tumor recognition when used for treatment planning CT images only provide limited soft tissue definition in the are of interest, while MRI offers a greater soft tissue definition Capable of assessing the tumor size within an accuracy of 0.5cm and are capable of assessing parametrial extension

MRI limitations7,9 Extremely expensive and difficult to access for many clinical centers Not suitable for patients with implanted metal devices Individuals with severe claustrophobia or obesity may have difficulty Lack the ability to accurately assess nodal metastases, which may lead to an underdose to the gross disease and result in a worse prognosis Image is taken first, and then the patient is transported to HDR room, making it challenging to ensure applicator position stability due to patient movement

Ultrasound1,7 Trans-abdominal ultrasound is cost effective, widely available, and has been found to have no significant differences in dosimetry compared to MRI planning, with 90% local control rate for cervical brachytherapy May be substituted for MRI in defining target volume, outlining the cervix and uterus, and planning and verifying for conformal treatment

Ultrasound Benefits6,7,9 Can be used to select appropriate applicator size and to guide tandem and ovoid placement during procedure Decreases rate of uterine perforation because of real time imaging Accessible, portable, and able to be used within the brachytherapy suite, eliminating the need to move the patient during the procedure Non-ionizing, quick and offers real time intra-operative anatomy assessment, reducing dose to OAR while not compromising target volume dose

Ultrasound Limitations6,7,9 Machine needs physical contact with the patient, which creates the potential for tissue deformation Needs an experienced operator No three-dimensional coordinate system or fixed frame of reference to help define the spatial location of the anatomy being viewed Does not offer volumetric analysis of the target coverage or dose to the surrounding organs, which is crucial in the treatment planning process

Future Advances1 Multi-institutional international trial (EMBRACE) is underway to establish a standard for cervical cancer management in terms of tumor control, complications, dose specification, and prospective assessment of quality of life Trial anticipates to advance image based brachytherapy and optimize its outcomes, hopefully by mandating the use of soft tissue three-dimensional imaging for treatment planning

“BodyTom”12 Portable CT scanner which can be transported from room to room, allowing it to be used for verification of the applicator and implanted catheter positions before treatment delivery everyday, without having to physically move the patient Will help to eliminate any error or uncertainty caused by patient transportation during the procedure

Conclusion6,7 Traditional orthogonal x-ray imaging remains the most commonly used imaging modality for planning cervical brachytherapy treatments in areas where incidence of cervical cancer is high Incorporating soft tissue three-dimensional imaging into brachytherapy programs is a slow process due to the decreased availability of planning software, increased cost, and lack of optimal training

Three-dimensional image treatment planning improves the technical accuracy of implants, leading to improved local control and decreased toxicity6 Ideally, an imaging modality should be available for each brachytherapy fraction, and provide good organ and applicator definition with the ability to delineate residual tumor6 This modality should have good soft tissue imaging capabilities, be widely available, portable, and economically attainable6

References 1. Vargo JA, Beriwal S. Image-based brachytherapy for cervical cancer. World Journal of Clinical Oncology. 2014;5(5):921-930. doi: 10.5306/wjco.v5.i5.921. 2. Madan R, Pathy S, Subramani V, et al. Comparative evaluation of two-dimensional radiography and three-dimensional computed tomography based dose-volume parameters for high-dose-rate intracavitary brachytherapy of cervical cancer: A prospective study. Asian Pacific Journal of Cancer Prevention. 2014;15(11):4717-4721. doi: 10.7314/APJCP.2014.15.11.4717 3. Banerjee R, Kamrava M. Brachytherapy in the treatment of cervical cancer: A review. International Journal of Women’s Health. 2014;6:555-564. doi:10.2147/IJWH.S46247 4. Mazeron R, Champoudry J, Gilmore J, et al. Intrafractional organs movement in three-dimensional image-guided adaptive pulsed-dose-rate cervical cancer brachytherapy: Assessment and dosimetric impact. Brachytherapy. 2015;14(2):260-266. doi: 10.1016/j.brachy.2014.11.014. 5. Pouliot J, Sloboda R, Reniers B. Two-, three-, and four- dimensional brachytherapy. In: Venselaar JLM, Baltas D, Meigooni AS, Hoskin PJ, eds. Comprehensive Brachytherapy: Physical and Clinical Aspects. 1st ed. Boca Raton, FL: CRC Press; 2013 http://books.google.com/books?id=jm_RBQAAQBAJ&pg=PA117&source=gbs_toc_r&cad=4#v=onepage&q&f=false Accessed February 26, 2015:117-137. 6. Dyk SV, Schneider M, Chennakesavan S, et al. Ultrasound use in gynecologic brachytherapy: Time to focus the beam. [published online ahead of print January 22, 2015]. Brachytherapy. doi: 10.1016/j.brachy.2014.12.001. 7. Dyk SV, Chennakesavan SK, Schneider M, et al. Comparison of measurements of the uterus and cervix obtained by magnetic resonance and transabdominal ultrasound imaging to identify the brachytherapy target in patients with cervix cancer. International Journal of Radiation Oncology, Biology, Physics. 2014;88(4):860-865. doi: 10.1016/j.ijrobp.2013.12.004 8.Katz A, Eifel PJ. Quantification of intracavitary brachytherapy parameters and correlation with outcome in patients with carcinoma of the cervix. International Journal Radiation Oncology, Biology, Physics. 2000;48(5):1417–1425. PMID:11121642. Accessed February 26, 2015. 9. Dyk SV, Narayan K, Fisher R, Bernshaw D. Conformal brachytherapy planning for cervical cancer using transabdominal ultrasound. International Journal of Radiation Oncology, Biology, Physics. 2009;75(1):64-70. doi: 10.1016.j/ijrobp.2008.10.057. 10. Holloway CL, Racine ML, Cormack RA, et al. Sigmoid dose using 3D imaging in cervical-cancer brachytherapy. Radiotherapy and Oncology. 2009;93(2):307-310. doi: 10.1016/j.radonc.2009.06.032. 11. Haie-Meder C, Pötter R, Van Limbergen E, Briot E, De Brabandere M, Dimopoulos J, Dumas I, Hellebust TP, Kirisits C, Lang S, 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 assessment of GTV and CTV. Radiotherapy and Oncology. 2005;74(3):235–245. PMID:15763303. Accessed February 26 2015. 12. BodyTom. NeuroLogica Web Site. http://www.neurologica.com/products/bodytom 2012. Accessed February 10, 2015. 13. Aubry JF, Cheung J, Morin O, et al. Investigation of geometric distortions on magnetic resonance and cone beam computed tomography images used for planning and verification of high-dose rate brachytherapy cervical cancer treatment. Brachytherapy. 2010;9(1):266-273. doi:10.1016/j.brachy.2009.09.004.