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Endoscopic argon plasma coagulation and bipolar electrocautery are currently preferred treatments for chronic radiation proctitis, but ulcerations and strictures frequently occur. Radiofrequency ablation (RFA) has been successful for mucosal ablation in the esophagus. Here we report the efficacy of RFA with the BarRx Halo90 system in three patients with bleeding from chronic radiation proctitis. In all cases, the procedure was well tolerated and hemostasis was achieved after 1 or 2 RFA sessions. Re-epithelialization of squamous mucosa was observed over areas of prior hemorrhage. No stricturing or ulceration was seen on follow-up up to 19 months after RFA treatment. Real-time endoscopic optical coherence tomography (EOCT) visualized epithelialization and subsurface tissue microvasculature pre- and post-treatment, demonstrating its potential for follow-up assessment of endoscopic therapies.
Chronic radiation proctitis is a long-term complication of radiotherapy for malignancies of the pelvis, particularly prostate and cervical cancer, occurring in 5–7.5% of patients receiving pelvic irradiation [Donaldson, 1994]. Radiation causes microvascular injury to the mucosa, resulting in ischemia, fibrosis and ultimately development of neovascular lesions [Haboubi et al. 1988]. Symptoms from chronic radiation proctitis include hematochezia, diarrhea, mucus discharge, tenesmus, urgency, rectal pain and fecal incontinence. While the disease may resolve spontaneously, in severe cases persistent bleeding can cause iron deficiency, anemia, and the need for blood transfusions [Gilinsky et al. 1983].
Effective therapy for chronic radiation proctitis has been limited. Medical therapies including topical sucralfate [Kochhar et al. 1991], 5-amino-salicylic acid enemas [Baum et al. 1989], short-chain fatty acids [Talley et al. 1997], vitamin E [Kennedy et al. 2001], and topical application of formalin [De Parades et al. 2005; Counter et al. 1999] have been largely disappointing. Surgical management carries significant morbidity and mortality risks [Lucarotti et al. 1991]. Endoscopic therapy is currently the preferred modality for treating this disease. Options include heater and bipolar probes [Jensen et al. 1997; Maunoury et al. 1991], neodymium/ yttrium aluminum garnet (Nd:YAG) lasers [Ventrucci et al. 2001; Barbatzas et al. 1996; Viggiano et al. 1993], potassium titanyl phosphate (KTP) lasers [Taylor et al. 1993], epinephrine or sclerosant injections [Bloomfeld et al. 2001; Ramirez et al. 1996], argon lasers [Taylor et al. 1993], and most recently, argon plasma coagulation (APC) [Sebastian et al. 2004; Rotondano et al. 2003; Villavicencio et al. 2002; Taieb et al. 2001; Tjandra and Sengupta, 2001; Kaassis et al. 2000; Fantin et al. 1999]. However, these methods may be complicated by development of rectal pain, diarrhea, tenesmus, ulcers, fistula, rectal stenosis and anal strictures [Rotondano et al. 2003; Villavicencio et al. 2002; Taieb et al. 2001; Taylor et al. 2000]. These complications are likely related to the high variability in depth of burn achieved by these different modalities. Radiofrequency ablation (RFA) with the BarRx Halo90 system has achieved superficial and broad fields of ablation in the esophagus [Sharma et al. 2008, 2007; Mashimo et al. 2007; Hubbard and Velanovich 2007; Dunkin et al. 2006], suggesting that similar benefits could be derived in the colon and rectum. In this report, RFA with the Halo90 system was used to treat three patients with lower gastrointestinal bleeding from chronic radiation proctitis, including two who failed conventional therapy.
Three male patients at the VA Boston Healthcare System (VABHS) with lower gastrointestinal bleeding from endoscopically confirmed chronic radiation proctitis were selected for this case report. After standard polyethylene glycol colonic lavage, RFA was performed in the outpatient endoscopy unit using the Halo90 system (BarRx Medical Inc. Sunnyvale, CA). A single use Halo90 electrode catheter was fit on the distal end of a standard flexible endoscope. Three-hundred watts of energy per application at 10 J/cm2 was delivered to areas of bleeding at the distal rectum. This dosage has been demonstrated to be effective in treating Barrett's esophagus without generating submucosal injury [Dunkin et al. 2006; Ganz et al. 2004]. White light video endoscopy and narrow band imaging (NBI) using the Evis Extra II high definition system (Olympus America, Center Valley, PA), and endoscopic optical coherence tomography (EOCT) [Tearney et al. 1997] was performed pretreatment and at follow-up endoscopies. Two different EOCT systems, one standard speed [Chen et al. 2008] and one high-speed [Adler et al. 2009; Adler et al. 2007], were employed to obtain cross-sectional images of colon architectural morphology. The high-speed system [Adler et al. 2007] was available for some patients, and enabled EOCT imaging over larger fields of view with higher frame rates. Imaging was performed by inserting a thin fiber-optic imaging probe down the working channel of the video endoscope.
The EOCT imaging protocol was approved by the Internal Review Boards at VABHS and the Harvard Medical School, and by the Committee on the Use of Humans as Experimental Subjects at MIT. Informed consent was obtained for each EOCT imaging session.
A 68-year-old man with a history of prostate cancer status post prostatectomy and radiation therapy (total dose 70.2 Gy) 3 years ago presented with rectal bleeding from chronic radiation proctitis. The patient underwent flexible sigmoidoscopy with APC, but returned to ER 3 days later with continuous and worsened bleeding. Repeat flexible sigmoidoscopy revealed persistent bleeding from multiple ulcerations at sites of prior APC (Figures 1a and and1b).1b). On EOCT, ectatic blood vessels measuring approximately 50 mm in diameter were identified as hyperscattering structures that cast a hypointense shadow underneath. Circumferential RFA was performed over areas of bleeding just proximal to the dentate line in the distal rectum with successful hemostasis. Flexible sigmoidoscopy was performed 2 months later and squamous epithelium was found at the site of prior RFA, extending approximately 1cm from the dentate line (Figures 1c and and1d).1d). A second session of RFA was performed to ablate remaining ectatic vessels. The patient did not experience rebleeding afterward. Follow-up endoscopies with EOCT were performed at 8, 12 and 14 months. The neosquamous epithelium was clearly seen 14 months after the initial RFA treatment (Figures 1e and and1f). 1f). The RFA procedures were tolerated well and there have been no complications including strictures or ulcerations in the 17 months since the last treatment.
A 76-year-old man with a history of prostate cancer status post radiation therapy (total dose 77.4 Gy) 2 years ago presented with rectal bleeding and underwent direct bipolar electrocautery therapy for bleeding ectatic vessels. The patient presented again with rectal bleeding 1 year later and was treated with APC. He noted occasional blood per rectum, approximately once a month. Eight months later, the patient returned with continued oozing of blood from the rectum for 1 week. RFA was performed over areas of bleeding ectatic vessels. The patient was examined with white light video endoscopy pre-RFA treatment, 8 months post-RFA treatment, and 13 months post-RFA treatment. EOCT images were taken pre-RFA treatment and 8 months post-RFA treatment. The patient's tolerance of the procedures was good. Similar to the first case, ectatic blood vessels (40–110mm in diameter) were clearly identified in the EOCT and video endoscopy images prior to the RFA-treatment (Figures 2a and and2b).2b). Images from 8 months post-RFA (Figures 2c and and2d)2d) showed squamous epithelialization over prior hemorrhagic sites with orad marching of the border of the dentate line by about 2cm, covering former sites of distal ectatic vessels. Similar observations were noted at 13 months post-RFA treatment. No rebleeding, stricture or ulceration was observed after the RFA treatment.
A 72-year-old man with a history of prostate cancer underwent 45Gy radiation to the pelvis followed by boost branchytherapy seed implant and concomitant hormonal therapy. The patient presented with rectal bleeding 14 months after his last hormonal therapy injection and was diagnosed with chronic radiation proctitis. Ectatic vessels (~50 μm in diameter) were observed under white light video endoscopy and EOCT (Figures 3a and and3b).3b). The patient underwent circumferential RFA treatment over areas of active bleeding in the most caudal 2 cm span above the dentate line. Good stasis of bleeding was achieved immediately. Six months later, the patient returned with a small area containing ectatic vessels (~40 μm in diameter) orad to the treatment site. The remainder of the rectum was well epithelialized (Figures 3c and and3d).3d). The area of bleeding was treated with focal application of RFA (300 W and 10J/cm2), resulting in stasis of bleed. No subsequent bleeding was reported following this treatment. Endoscopic imaging at 12 months post the initial RFA treatment showed excellent re-epithelialization over prior oozing vessels, extending the dentate line by about 1-2 cm orad. The patient's tolerance of the procedures was good.
As demonstrated from the three cases, RFA possesses several benefits compared to other treatments for radiation proctitis. For example, APC can result in post-treatment ulceration from deeper injury in relatively ischemic mucosa [Rotondano et al. 2003; Villavicencio et al. 2002; Taieb et al. 2001; Taylor et al. 2000]. By comparison, the tightly spaced bipolar array of the RFA catheter limited the radiofrequency energy penetration, restricting the RFA treatment to the superficial mucosa, thereby avoiding deep tissue injury. This observation is consistent with previous reports using RFA for the treatment of Barrett's esophagus [Sharma et al. 2008, 2007; Dunkin et al. 2006; Ganz et al. 2004]. Furthermore, squamous re-epithelialization following RFA may play a significant role in the prevention of rebleeding, whereas strictures, ulceration and rebleeding in the formerly inflamed mucosa are commonly noted following conventional endoscopic therapies. The relative lack of stricturing observed following RFA treatments in the upper gastrointestinal tract [Sharma et al. 2008; 2007; Smith et al. 2007; Ganz et al. 2004] was also noted upon follow-up of these patients. Finally, RFA allows broad areas of tissue to be treated simultaneously compared to the point-by-point approach required with heater or bipolar probes [Jensen et al. 1997; Maunoury et al. 1991], or APC [Kaassis et al. 2000; Fantin et al. 1999]. However, systematic assessment of any superiority of the RFA method over traditional treatments would require recruitment of a larger number of patients.
Optical coherence tomography (OCT) is an emerging medical imaging technique that is analogous to ultrasound, except that images are generated by measuring echo time delays of light waves instead of sound [Huang et al. 1991]. Endoscopic OCT (EOCT), performed with a small diameter fiber-optic imaging probe introduced in the working channel of standard endoscopes, enables two-dimensional (2D) depth-resolved imaging of tissue microstructure over several millimeters with micron-scale resolutions [Tearney et al. 1997]. EOCT has been applied for general GI imaging [Bouma et al. 2000; Jäckle et al. 2000; Sivak et al. 2000] and has been intensely studied for the analysis of Barrett's esophagus [Chen et al. 2007; Evans et al. 2006; Qi et al. 2006; Isenberg et al. 2005; Poneros et al. 2001; Li et al. 2000]. In this report, white light video endoscopy combined with NBI and real-time in vivo EOCT enabled assessment of treatment efficacy following RFA treatment of chronic radiation proctitis. EOCT can resolve subsurface tissue microstructure in real time without the need for excisional biopsy. This is particularly important for patients with radiation proctitis since biopsy is contraindicated due to the high risk of bleeding. Recent advances in ultra-high-speed EOCT technology have enabled 3D volumetric imaging over several square centimeters, enabling comprehensive analysis of tissue architectural morphology. Ultrahigh speed technology can also be combined with Doppler OCT [Chen et al. 1997a; Chen et al. 1997b; Izatt et al. 1997], which analyzes the Doppler shift of the backscattered light to detect blood flow. Ectatic vessels could be more clearly distinguished from the surrounding tissue using Doppler OCT. Ectatic sites could be mapped over a large field of view in three dimensions using ultra-high-speed OCT and Doppler detection, which could lead to new analytic methods for evaluating inflammatory pathologies such as radiation proctitis. Accurate quantification of subsurface vessel diameter, vascular density and blood flow rates are therefore possible when Doppler OCT is employed in conjunction with ultra-high-speed OCT.
In addition to the RFA treatment presented in this report, a variety of endoscopic ablative therapies [Fantin et al. 1999; Jensen et al. 1997; Ramirez et al. 1996; Viggiano et al. 1993; Taylor et al. 1993; Maunoury et al. 1991] are currently available to treat lower gastrointestinal bleeding in patients with chronic radiation proctitis. The selection of an optimal treatment may be aided by a detailed microstructural analysis of the lesion in vivo. Following endoscopic therapies, pathologic structures may persist or grow underneath neo-epithelialized tissue. These changes can be difficult or impossible to detect using white light video endoscopy. EOCT, on the other hand, can be used to determine the stage or severity of pathology in diseased tissue in order to select an appropriate therapy by providing depth-resolved morphological images. EOCT can also be used to check the treatment site for recurrence or to assess healing following therapies. Therefore, gastroenterolo-gists could benefit from the wide application of EOCT in the future to aid in preinterventional planning and follow-up assessment of endoscopic therapies.
In summary, we have achieved effective control of lower gastrointestinal bleeding in three patients with chronic radiation proctitis using RFA with the BarRx Halo90 system. Excellent re-epithelialization and absence of ulcerations or strictures was observed following the RFA treatment. EOCT, used in conjunction with white light video endoscopy and NBI, was demonstrated to be a uniquely suited imaging modality for assessing treatment by providing real-time subsurface imaging of tissue microstructure in vivo.
CZ, DCA, YC, JGF and HM have assisted with study design; CZ, DCA, LB, YC, THT, MF and HM have assisted with data collection; CZ, DCA, LB and HM have assisted with data analysis; all the authors have contributed to the manuscript preparation.
JGF receives royalties from intellectual property owned by the Massachusetts Institute of Technology (MIT) and licensed to LightLab Imaging. JS is an employee of LightLab Imaging. HM, CZ, DCA, LB, YC, THT and MF have no competing financial interests in this work.
This work was supported by the NIH grants R01-CA75289-12 (JGF and HM), Air Force Office of Scientific Research contract FA9550-07-1-0014 (JGF) and Medical Free Electron Laser Program contract FA9550-07-1-0101 (JGF). LB acknowledges support from NIH grant T32 DK 07760. DCA acknowledges support from the Natural Sciences and Engineering Research Council of Canada and the Heritage Scholarship Fund of the Province of Alberta. THT acknowledges support from the Taiwan Merit Scholarship from the National Science Council of Taiwan. The authors acknowledge the facility support from VA Boston Healthcare System and useful discussions with Dr. Qin Huang.
Chao Zhou, Department of Electrical Engineering and Computer Science and Research Laboratory of Electronics Massachusetts Institute of Technology, Cambridge, MA, USA.
Desmond C. Adler, Department of Electrical Engineering and Computer Science and Research Laboratory of Electronics Massachusetts Institute of Technology, Cambridge, MA, USA.
Laren Becker, VA Boston Healthcare System and Harvard Medical School, MA, USA.
Yu Chen, Department of Electrical Engineering and Computer Science and Research Laboratory of Electronics Massachusetts Institute of Technology, Cambridge, MA, USA.
Tsung-Han Tsai, Department of Electrical Engineering and Computer Science and Research Laboratory of Electronics Massachusetts Institute of Technology, Cambridge, MA, USA.
Marisa Figueiredo, VA Boston Healthcare System and Harvard Medical School, MA, USA.
Joseph M. Schmitt, LightLab Imaging Inc., Westford, MA, USA.
James G. Fujimoto, Department of Electrical Engineering and Computer Science and Research Laboratory of Electronics Massachusetts Institute of Technology, Cambridge, MA, USA.
Hiroshi Mashimo, A Boston Healthcare System and Harvard Medical School, MA, USA ; Email: ude.dravrah.smh@omihsamh.