REVIEW ARTICLE
Hemorrhagic Radiation Cystitis William M. Mendenhall, MD,* Randal H. Henderson, MD,* Joseph A. Costa, DO,w Bradford S. Hoppe, MD,* Roi Dagan, MD,* Curtis M. Bryant, MD,* Romaine C. Nichols, MD,* Christopher R. Williams, MD,w Stephanie E. Harris, MD,w and Nancy P. Mendenhall, MD*
Abstract: The optimal management of persistent hemorrhagic radiation cystitis is ill-defined. Various options are available and include oral agents (ie, sodium pentosan polysulfate), intravenous drugs (ie, WF10), topical agents (ie, formalin), hyperbaric oxygen, and endoscopic procedures (ie, electrical cautery, argon plasma coagulation, laser coagulation). In general, it is best to manage patients conservatively and intervene only when necessary with the option least likely to exacerbate the cystitis. More aggressive measures should be employed only when more conservative approaches fail. Bladder biopsies should be avoided, unless findings suggest a bladder tumor, because they may precipitate a complication. Key Words: radiotherapy, radiation cystitis, prostate
evaluation of hematuria includes a urine analysis, urine culture and sensitivity, urine cytology, evaluation of the upper urinary tracts by ultrasonography or excretory urography, and cystoscopy. Urine cytology should be interpreted cautiously because changes due to prior RT may be confused with tumor. Cystoscopy may reveal atrophic mucosa with bleeding telangiectatic blood vessels, sometimes associated with ulceration and necrosis. The area of HRC should be within the prior RT treatment volume. If not, another diagnosis should be considered. Biopsy, if obtained, should also be interpreted with the knowledge that changes due to prior RT may be confused with malignancy.
(Am J Clin Oncol 2015;38:331–336)
Grading of Hematuria
H
A variety of grading systems are available including the Late Effects Normal Tissues-Subjective Objective Management Analysis (LENT-SOMA) scale and the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE).5,6 The LENT-SOMA grading system for bladder/ urethra toxicity is presented in Table 1.5 The CTCAE version 4.0 grading system for hematuria is depicted in Table 2.6
emorrhagic radiation cystitis (HRC) may occur after radiotherapy (RT) for a variety of pelvic malignancies, including gynecologic neoplasms and prostate cancer.1 Hemorrhagic cystitis may also be observed after treatment with some chemotherapy agents, particularly cyclophosphamide, in the absence of pelvic RT.2 The interval between the onset of HRC and prior RT varies from months to years after treatment.1,3 Shilo et al4 reported on 32 patients with HRC and observed a median interval between RT and HRC of 4 years (range, 1 to 26 y). The likelihood of developing HRC is related to the total RT dose, dose per fraction, and the volume of the bladder irradiated. Other factors that may impact the likelihood of developing HRC include conditions such as diabetes, connective tissue disorders, and blood thinners such as warfarin. The probability of severe HRC after pelvic RT is approximately r5%.1 HRC is likely due to an obliterative endarteritis that results in atrophy and fibrosis of the mucosa and submucosa and the development of dilated telangiectatic blood vessels that are fragile and may result in bleeding. The irradiated bladder is hypovascular, hypocellular, and hypoxic.1 Severe HRC may be associated with necrosis and fistulae.3
DIAGNOSTIC EVALUATION The diagnosis of HRC is based on excluding other potential causes of hematuria such as a urinary tract infection and malignancy, such as a bladder cancer. The diagnostic From the *Department of Radiation, University of Florida Proton Therapy Institute; and wDivision of Urology, College of Medicine, University of Florida, Jacksonville, FL. The authors declare no conflicts of interest. Reprints: William M. Mendenhall, MD, Department of Radiation, University of Florida Proton Therapy Institute, 2015 North Jefferson Street, Jacksonville, FL 32206. E-mail: [email protected]. Copyright r 2013 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/3803-0331 DOI: 10.1097/COC.0000000000000016
American Journal of Clinical Oncology
Management The initial management includes bladder irrigation and clot evacuation.7 Intravenous fluids and blood transfusions are administered if indicated. Thereafter, a variety of therapeutic options are available if the hematuria is persistent.1,3,8–23 Following is a discussion of some of these alternatives. A small proportion of patients with HRC has severe, refractory, life-threatening hematuria and may require urinary diversion alone or combined with cystectomy.24–27
ORAL OR PARENTERAL AGENTS Hampson and Woodhouse2 reported on 14 patients treated at the Royal Marsden Hospital (London, UK) for HRC in 13 patients or severe hemorrhagic cystitis due to cyclophosphamide (CTX-HC) in 1 patient with sodium pentosan polysulfate (SPPS). SPPS, a sulphated polysaccharide that can be taken sublingually, resulting in 3% to 5% being excreted in the urine, is thought to reduce transitional cell injury by cytotoxins.2 Hematuria was graded as mild in 8 patients (requiring no transfusions or surgery), moderate in 2 patients (requiring 20% decrease in hemoglobin
Ulcerations into muscle
Perforation, fistula
> 100-200
r100
Decreased stream Occasionally weak Objective Hematuria
Microscopic, normal hemoglobin
Endoscopy
Patchy atrophy or telangiectasia without bleeding Maximum volume > 300-400 (mL) Residual volume 25 (mL) Management Dysuria Occasional non-narcotic Frequency
Alkalization
Hematuria/ telangiectasia Incontinence
Iron therapy Occasional use of incontinence pads
Decreased stream
Persistent and intense
Grade 4
1-2 h intervals
Refractory and excruciating Hourly Refractory
> 25-100
> 100
Regular non-narcotic
Regular narcotic
Occasional antispasmodic Occasional transfusion or single cauterization Intermittent use of incontinence pads < Once-a-day selfcatheterization
Regular narcotic Frequent transfusion or coagulation Regular use of pad or self-catheterization Dilation, > once-a-day self-catheterization
Score Scoring instructions score the 14 SOMA parameters with 1-4 score = 0 if there are no toxicities total the scores and divide by 14
LENT score
Surgical intervention Cystectomy Surgical intervention Permanent catheter Permanent catheter, surgical intervention
Analytic Cystography
Assessment of mucosal surface Volumetric Assessment of bladder analysis capacity in milliliters Contrast Assessment for ulcers, radiography capacity and contractility Ultrasound Assessment of wall thickness, sinus, and fistula formation Electromyography Assessment of sphincter activity using intraluminal pressure transducer, contraction pressure, and volume curves
Y/N
Date:
Y/N
Date:
Y/N
Date:
Y/N
Date:
Y/N
Date:
LENT-SOMA indicates Late Effects Normal Tissues-Subjective Objective Management Analysis.
Sandhu et al28 reported on 60 patients treated at the Royal Marsden Hospital for HRC (53 patients) or CTX-HC (7 patients) between 1991 and 2000. Fifteen of 60 patients had required hospitalization for bladder irrigation and 14 patients required a blood transfusion.28 Patients received SPPS 100 mg tid with a reduction of the dose when possible. Patients received SPPS for a median of 180 days (range, 21 to 1745 d) and were followed for a median of 450 days (range, 19 to
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4526 d) from the onset of hematuria. No adverse effects secondary to SPPS were observed. Fifty-one patients had adequate follow-up. Twenty patients (33%) died from other causes while taking SPPS, 21 patients (35%) had the SPPS dose reduced to 100 mg once daily (qd), and 10 patients (17%) had the SPPS discontinued after the hematuria stopped. Veerasarn et al29 reported on 16 patients treated at Mahidol University (Bangkok, Thailand) for grade 2 to 3 HRC
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American Journal of Clinical Oncology
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TABLE 2. CTCAE version 4.0 Grading System for Hematuria
Grade
Definition
Grade 1
Asymptomatic; clinical or diagnostic observation only; intervention not indicated Symptomatic, urinary catheter, or bladder irrigation indicated, limiting instrumental ADL Gross hematuria; transfusion, IV medications or hospitalization indicated; elective endoscopic, radiologic, or operative intervention indicated; limiting self-care ADL Life-threatening consequences; urgent radiologic or operative intervention indicated Death
Grade 2 Grade 3
Grade 4 Grade 5
ADL indicates activities of daily living; IV, intravenous.
with intravenous (IV) WF10 (Immunokine), which was administered 0.5 mL/kg diluted with 250 mL of 5% D/W over 2 hours, 5 days per week every 3 weeks for 2 to 4 weeks combined with standard therapy. WF10 is a chlorite-based drug thought to inhibit the inflammatory process associated with submucosal endarteritis.29 Standard therapy included oral antibiotics, antispasmodics, iron supplements, bladder irrigation, and/or blood transfusion. Median follow-up was 51 months. Fourteen (88%) of 16 patients improved to grade 0 to 1 HRC; 4 (28%) of 14 patients who responded relapsed with grade 2 HRC. No toxicity due to WF10 was observed. Veerasarn et al30 reported on a multicenter trial that included 100 patients with grade 2 to 3 HRC after RT for cervical cancer. Patients were randomized to receive 2 cycles of WF10, as previously described, plus standard therapy (50 patients) or standard therapy alone (50 patients). Patients were followed for 1 year. At week 7, 37 WF10 patients (74%) and 32 control patients (64%) had a CR (P = 0.28). WF10 was associated with a significant reduction in the use of antibiotics (P = 0.002) and antispasmodics (P < 0.001). Among the responders, 17 WF10 patients (47%) and 24 control patients (77%) had recurrent hematuria (P = 0.01). Hematuria recurred faster in control patients compared with those who received WF10 (P = 0.004). Cystoscopy at 1 year showed overall improvement and no significant differences between the two groups of patients. No severe toxicity due to WF10 was observed.
TOPICAL AGENTS Dewan et al31 reported on 35 patients treated between 1984 and 1990 at the Cancer Institute (Adyar, Madras) for HRC after RT for cervical cancer. All had failed conservative therapy with adequate hydration, bladder irrigation, and clot evacuation. HRC was mild in 9 patients (gross hematuria with occasional clots), moderate in 16 patients (clots at least every 2 d), and severe in 10 patients (hemodynamically unstable). Patients were treated with diluted formalin instillation (1%, 22 patients; 2%, 10 patients; 4%, 4 patients) under regional anesthesia after clot evacuation. The bladder was passively irrigated with formalin under r15 cm pressure for 20 to 30 minutes followed by continuous saline irrigation for 12 to 48 hours. Thirty-one patients (89%) had a CR after 1 instillation and 3 patients (8%) had a PR. Hematuria recurred in 7 (23%) of 31 patients who had a CR after a mean of 8 months. One percent formalin was as effective as 2% or 4% formalin. Minor complications were observed in 19 patients (54%) and included mild fever, frequency, dysuria, suprapubic pain, temporary incontinence, unilateral hydronephrosis, grade 2 Copyright
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ureterovesical reflux, and decreased bladder capacity not requiring diversion. Major complications were observed in 11 patients (31%) and included bilateral hydronephrosis due to ureteral stenosis, vesicovaginal fistula, decreased bladder capacity requiring diversion, and death. Overall, 5 patients (14%) required urinary diversion and 1 patient died due to bleeding and formalin toxicity. Lojanapiwat et al32 reported on 19 women treated for intractable HRC after RT for cervix cancer at Chiangmai University (Chiangmai, Thailand). Group 1 included 11 women who underwent instillation of 4% formalin for half of the bladder volume for 15 minutes followed by bladder irrigation with saline for 12 to 24 hours. Group 2 included 8 women who underwent endoscopic placement of 10% formalin soaked pledgets (1 1 cm) on bleeding points for 15 minutes. The average number of pledgets employed was 5.5 (range, 4 to 6). One patient required 2 treatments. Average follow-up was 25 months (range, 6 to 84 mo) for group 1 and 15 months (range, 6 to 40 mo) for group 2. A CR was observed in 9 (82%) of 11 patients in group 1 compared with 6 (75%) of 8 patients in group 2. There were 4 major complications in group 1 and none in group 2. Major complications included anuria and bilateral hydronephrosis (1), vesicovaginal fistula (2), and septic death (1). There were 11 minor complications in group 1 and 3 in group 2. Shao et al33 reported on 36 patients with HRC treated at Shanghai Jiaotong University (Shanghai, PRC) between 2004 and 2008. Patients were randomized to receive hyaluronic acid (HA) instillation (16 patients) or hyperbaric oxygen (HBO) therapy (20 patients). HA treatment entailed 40 mg of HA instilled in the bladder by Foley catheter for a minimum of 20 minutes weekly for 1 month and monthly for the following 2 months. HBO therapy consisted of 100% O2 at 2.5 atm for 60 minutes 7 days a week for 30 days. All patients completed treatment. No adverse complications were observed in either group other than increased urinary tract infections in the HA group, likely due to repeated catheterizations. The CR rates after HA versus HBO were: 6 months, 14 of 16 patients (88%) versus 15 of 20 patients (75%); 12 months, 12 of 16 patients (75%) versus 10 of 20 patients (50%); and 18 months, 8 of 16 patients (50%) versus 9 of 20 patients (45%). The CR/PR rates after HA vs. HBO were: 6 months, 16 of 16 patients (100%) versus 19 of 20 patients (95%); 12 months, 15 of 16 patients (94%) versus 17 of 20 patients (85%); and 18 months, 12 of 16 patients (75%) versus 15 of 20 patients (75%).
HBO Vilar et al34 reported on 38 patients treated with HBO for HRC at Hospital General de Castellon (Castellon de la Plana, Spain) and followed for a median of 56 months (range, 4 to 72 mo). Twenty-six patients had gross hematuria and a bladder capacity 6 months, 21 of 32 patients (66%) (P = 0.003). Thus the overall CR/PR rate was 48 of 60 patients (80%) with a significantly higher rate of a favorable response if the interval was r6 months. Twenty-five of 60 patients had clot retention before HBO; 18 (72%) had a CR or PR after treatment. The rates of CR/PR versus interval between onset of HRC and HBO were: r6 months, 11 of 11 patients (100%) and >6 months, 7 of 14 patients (50%) (P = 0.007). Prior intravesical chemical instillation did not adversely impact the efficacy of HBO. Oscarsson et al36 reported on 39 patients with radiation cystitis and proctitis who were treated with HBO at the Sahlgrenska University Hospital (Gothenburg, Sweden) between 2008 and 2011. Patients requiring blood transformations were excluded. Patients had received external beam RT for prostate cancer (n = 34), cervix cancer (n = 2), or rectal cancer (n = 3). HBO consisted of 100% O2 for 90 minutes at 2.0 to 2.4 atm.
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The mean number of dives was 39 (range, 28 to 40). Patient perceived quality of recovery was prospectively assessed using the Expanded Prostate Index Composite score before, during, and 6 to 12 months after HBO. No severe adverse effects due to HBO were observed. Symptoms were alleviated in 76% for patients with cystitis, 89% for those with proctitis, and 88% for patients with both cystitis and proctitis. The Expanded Prostate Index Composite score in the urinary domain improved from 50 to 66 after HBO (P < 0.001). The improvement was sustained at 6 to 12 months after treatment. Lee et al37 reported on 20 women with HRC after treatment for cervix (19 patients) or bladder (1 patient) cancer who were treated with HBO between 1989 and 1992 at the Naval General Hospital (Kaoshiung, Taiwan) and followed for a mean of 14 months (range, 5 to 41 mo). HBO consisted of 100% O2 at 2.5 atm for 100 minutes for an average of 44 dives. Sixteen patients (80%) had a CR; 2 patients (10%) had a PR. One patient required a diverting ileal conduit.
Intravesical Endoscopic Procedures Ravi38 reported on 42 patients with HRC after RT for pelvic malignancies (cervix, 39 patients; bladder, 2 patients; rectal, 1 patient) treated at the Cancer Institute (Adyar, Madras) with the Nd:YAG laser coagulation under anesthesia with a laser power r30 W and pulse duration r3 seconds. Thirteen patients had mild hematuria (gross hematuria with clots at least twice-weekly), 21 patients had moderate hematuria (clots at least every 2 d, hemodynamically stable), and 8 patients had severe hematuria requiring blood transfusions. Thirty-nine patients (93%) had a CR after 1 treatment and 2 patients (5%) had a CR after 2 treatments. The patient who failed to respond had presented with severe hematuria.
TABLE 3. Treatment of HRC
Administered Route Oral/IV Pentosan polysulfate (SPPS)
Oral
Dose 100 mg oral TID
WF10 IV (Immunokine)
0.5-0.75 mg/kg diluted in a minimum of 250 mL over no less than 1 h5 consecutive days
Pharmacology
Intravesicular 1%-4% solution (irrigation or passively irrigated soaked pledgets) for 20-30 min following by saline irrigation (12-48 h) Hyaluronic acid Intravesicular
Endoscopic procedures Laser coagulation
NA
2-2.5 atm, 90 min, approximately 30 dives
NA
NA
Results (CR/RR) (%)
Forms protective coating Diarrhea, dyspepsia CR: 71 on bladder wall reducing transitional cell injury Immune modulation Tachycardia, CR: 74-88 inhibiting the phlebitis (with RR: 24-47 inflammatory response rapid infusion)
Topical Formalin
Hyperbaric O2 HBO
Common AEs
Mild fever, frequency, dysuria, suprapubic pain
References 2,28
29,30
CR: 75-89 RR: 23
31,32
CR: 88-100 RR: 25
33
NA
CR: 59-96 RR: 16-34
4,34,35,36,37
NA
CR: 93-100 RR: 10
38,39,40,41
AE indicates adverse event; atm, atmosphere; CR, complete response; HBO, hyperbaric oxygen; HRC, hemorrhagic radiation cystitis; IV, intravenous; NA, not applicable; RR, relapse rate; TID, three times per day.
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Wines and Lynch39 reported on 7 patients with HRC requiring blood transfusions who were treated with argon plasma coagulation at St. George Public Hospital (Kogarah, Australia). The gas flow rate was 1.5 L/min, and the power was 40 to 60 W. Patients were followed for an average of 15 months. Six patients had a CR after 1 argon plasma coagulation session; the remaining patient has a CR after 2 sessions. No significant toxicity was observed. Zhu et al40 reported on 10 patients with intractable HRC who failed conservation management who were treated with transurethral greenlight KTP laser between 2004 and 2011 at Soochow University (Suzhou City, PRC). Two of 10 patients had required blood transfusions before treatment. Follow-up ranged from 6 to 36 months (mean, 17 mo). A CR was observed in all patients after 1 session; all 10 patients underwent cystoscopy 3 months after laser therapy, and no bleeding or scar from the procedure were observed. One patient had recurrent hematuria 7 months after a laser therapy and had a CR after a second laser procedure. Kaushik et al41 reported on 4 patients with refractory HRC that had failed to respond to conservative therapy as well as standard cystoscopic electrocautery. Patients underwent laser fulguration with a 980 nm diode laser at the University of Michigan. All 4 patients had a CR for an average of 11 months (range, 3 to 17 mo).
CONCLUSIONS Patients with HRC are initially treated with hydration, bladder irrigation, and clot evacuation. Thereafter, a diagnostic evaluation is performed to exclude other potential etiologies, including a urothelial neoplasm. The majority of patients with HRC will respond to this conservative approach. The management of those with persistent gross hematuria is problematic. In general, it is best to start with the least aggressive intervention that is least likely to exacerbate the HRC and progress to more aggressive measures only when necessary (Table 3). Thus, oral or parenteral agents may be employed, followed by HBO if these interventions fail. Topical agents are probably a next reasonable step, reserving surgical or endovascular interventions for the most refractory cases. REFERENCES 1. Smit SG, Heyns CF. Management of radiation cystitis. Nat Rev Urol. 2010;7:206–214. 2. Hampson SJ, Woodhouse CR. Sodium pentosanpolysulphate in the management of haemorrhagic cystitis: experience with 14 patients. Eur Urol. 1994;25:40–42. 3. Denton AS, Clarke NW, Maher EJ. Non-surgical interventions for late radiation cystitis in patients who have received radical radiotherapy to the pelvis. Cochrane Database Syst Rev. 2002;3: CD001773. 4. Shilo Y, Efrati S, Simon Z, et al. Hyperbaric oxygen therapy for hemorrhagic radiation cystitis. Isr Med Assoc J. 2013;15: 75–78. 5. LENT SOMA scales for all anatomic sites. Int J Radiat Oncol Biol Phys. 1995;31:1049–1091. 6. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. National Cancer Institute. 2009;4:59–60. 7. Kaplan JR, Wolf JS Jr. Efficacy and survival associated with cystoscopy and clot evacuation for radiation or cyclophosphamide induced hemorrhagic cystitis. J Urol. 2009;181:641–646. 8. Soares RS, de Abreu RA Jr, Tavora JE. Laparoscopic ureteral reimplant for ureteral stricture. Int Braz J Urol. 2010;36: 38–43.
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9. Neheman A, Nativ O, Moskovitz B, et al. Hyperbaric oxygen therapy for radiation-induced haemorrhagic cystitis. BJU Int. 2005;96:107–109. 10. Pomer S, Karcher G, Simon W. Cutaneous ureterostomy as last resort treatment of intractable haemorrhagic cystitis following radiation. Br J Urol. 1983;55:392–394. 11. Vicente J, Rios G, Caffaratti J. Intravesical formalin for the treatment of massive hemorrhagic cystitis: retrospective review of 25 cases. Eur Urol. 1990;18:204–206. 12. Hemal AK, Vaidyanathan S, Sankaranarayanan A, et al. Control of massive vesical hemorrhage due to radiation cystitis with intravesical instillation of 15 (s) 15-methyl prostaglandin F2-alpha. Int J Clin Pharmacol Ther Toxicol. 1988;26:477–478. 13. Geisler JP, Linnemeier GC, Manahan KJ. Recombinant factor VIIa to treat late radiation-induced hemorrhagic cystitis: a case report. J Reprod Med. 2008;53:360–362. 14. Connolly SS, D’Arcy FT, Corcoran MO. Recombinant activated factor VII to control life-threatening haemorrhagic radiation cystitis. Ir J Med Sci. 2010;179:431–433. 15. Lowe BA, Stamey TA. Endoscopic topical placement of formalin soaked pledgets to control localized hemorrhage due to radiation cystitis. J Urol. 1997;158:528–529. 16. Arrizabalaga M, Extramiana J, Parra JL, et al. Treatment of massive haematuria with aluminous salts. Br J Urol. 1987;60: 223–226. 17. Smart D, Wallington M. A cost-analysis case study of radiation cystitis treatment including hyperbaric oxygen therapy. Diving Hyperb Med. 2012;42:92–97. 18. Mathews R, Rajan N, Josefson L, et al. Hyperbaric oxygen therapy for radiation induced hemorrhagic cystitis. J Urol. 1999;161:435–437. 19. Yoshida T, Kawashima A, Ujike T, et al. Hyperbaric oxygen therapy for radiation-induced hemorrhagic cystitis. Int J Urol. 2008;15:639–641. 20. Del Pizzo JJ, Chew BH, Jacobs SC, et al. Treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen: long-term followup. J Urol. 1998;160:731–733. 21. Oliai C, Fisher B, Jani A, et al. Hyperbaric oxygen therapy for radiation-induced cystitis and proctitis. Int J Radiat Oncol Biol Phys. 2012;84:733–740. 22. Chuang YC, Kim DK, Chiang PH, et al. Bladder botulinum toxin A injection can benefit patients with radiation and chemical cystitis. BJU Int. 2008;102:704–706. 23. Weiss JP, Mattei DM, Neville EC, et al. Primary treatment of radiation-induced hemorrhagic cystitis with hyperbaric oxygen: 10-year experience. J Urol. 1994;151:1514–1517. 24. Fergany AF, Moussa AS, Gill IS. Laparoscopic cystoprostatectomy for radiation-induced hemorrhagic cystitis. J Endourol. 2009;23:275–278. 25. Adeyoju AB, Thornhill J, Lynch T, et al. The fate of the defunctioned bladder following supravesical urinary diversion. Br J Urol. 1996;78:80–83. 26. Sneiders A, Pryor JL. Percutaneous nephrostomy drainage in the treatment of severe hemorrhagic cystitis. J Urol. 1993;150: 966–967. 27. Zagoria RJ, Hodge RG, Dyer RB, et al. Percutaneous nephrostomy for treatment of intractable hemorrhagic cystitis. J Urol. 1993;149:1449–1451. 28. Sandhu SS, Goldstraw M, Woodhouse CR. The management of haemorrhagic cystitis with sodium pentosan polysulphate. BJU Int. 2004;94:845–847. 29. Veerasarn V, Boonnuch W, Kakanaporn C. A phase II study to evaluate WF10 in patients with late hemorrhagic radiation cystitis and proctitis. Gynecol Oncol. 2006;100:179–184. 30. Veerasarn V, Khorprasert C, Lorvidhaya V, et al. Reduced recurrence of late hemorrhagic radiation cystitis by WF10 therapy in cervical cancer patients: a multicenter, randomized, two-arm, open-label trial. Radiother Oncol. 2004;73:179–185. 31. Dewan AK, Mohan GM, Ravi R. Intravesical formalin for hemorrhagic cystitis following irradiation of cancer of the cervix. Int J Gynaecol Obstet. 1993;42:131–135.
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32. Lojanapiwat B, Sripralakrit S, Soonthornphan S, et al. Intravesicle formalin instillation with a modified technique for controlling haemorrhage secondary to radiation cystitis. Asian J Surg. 2002;25:232–235. 33. Shao Y, Lu GL, Shen ZJ. Comparison of intravesical hyaluronic acid instillation and hyperbaric oxygen in the treatment of radiation-induced hemorrhagic cystitis. BJU Int. 2012;109: 691–694. 34. Vilar DG, Fadrique GG, Martin IJ, et al. Hyperbaric oxygen therapy for the management of hemorrhagic radio-induced cystitis. Arch Esp Urol. 2011;64:869–874. 35. Chong KT, Hampson NB, Corman JM. Early hyperbaric oxygen therapy improves outcome for radiation-induced hemorrhagic cystitis. Urology. 2005;65:649–653. 36. Oscarsson N, Arnell P, Lodding P, et al. Hyperbaric oxygen treatment in radiation-induced cystitis and proctitis: a prospective cohort study on patient-perceived quality of recovery. Int J Radiat Oncol Biol Phys. 2013;87:670–675.
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37. Lee HC, Liu CS, Chiao C, et al. Hyperbaric oxygen therapy in hemorrhagic radiation cystitis: a report of 20 cases. Undersea Hyperb Med. 1994;21:321–327. 38. Ravi R. Endoscopic neodymium: YAG laser treatment of radiation-induced hemorrhagic cystitis. Lasers Surg Med. 1994;14:83–87. 39. Wines MP, Lynch WD. A new minimally invasive technique for treating radiation cystitis: the argon-beam coagulator. BJU Int. 2006;98:610–612. 40. Zhu J, Xue B, Shan Y, et al. Transurethral coagulation for radiation-induced hemorrhagic cystitis using Greenlight potassium-titanyl-phosphate laser. Photomed Laser Surg. 2013;31: 78–81. 41. Kaushik D, Teply BA, Hemstreet GP 3rd. Novel treatment strategy for refractory hemorrhagic cystitis following radiation treatment of genitourinary cancer: use of 980-nm diode laser. Lasers Med Sci. 2012;27:1099–1102.
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Hemorrhagic Radiation Cystitis William M. Mendenhall, MD,* Randal H. Henderson, MD,* Joseph A. Costa, DO,w Bradford S. Hoppe, MD,* Roi Dagan, MD,* Curtis M. Bryant, MD,* Romaine C. Nichols, MD,* Christopher R. Williams, MD,w Stephanie E. Harris, MD,w and Nancy P. Mendenhall, MD*
Abstract: The optimal management of persistent hemorrhagic radiation cystitis is ill-defined. Various options are available and include oral agents (ie, sodium pentosan polysulfate), intravenous drugs (ie, WF10), topical agents (ie, formalin), hyperbaric oxygen, and endoscopic procedures (ie, electrical cautery, argon plasma coagulation, laser coagulation). In general, it is best to manage patients conservatively and intervene only when necessary with the option least likely to exacerbate the cystitis. More aggressive measures should be employed only when more conservative approaches fail. Bladder biopsies should be avoided, unless findings suggest a bladder tumor, because they may precipitate a complication. Key Words: radiotherapy, radiation cystitis, prostate
evaluation of hematuria includes a urine analysis, urine culture and sensitivity, urine cytology, evaluation of the upper urinary tracts by ultrasonography or excretory urography, and cystoscopy. Urine cytology should be interpreted cautiously because changes due to prior RT may be confused with tumor. Cystoscopy may reveal atrophic mucosa with bleeding telangiectatic blood vessels, sometimes associated with ulceration and necrosis. The area of HRC should be within the prior RT treatment volume. If not, another diagnosis should be considered. Biopsy, if obtained, should also be interpreted with the knowledge that changes due to prior RT may be confused with malignancy.
(Am J Clin Oncol 2015;38:331–336)
Grading of Hematuria
H
A variety of grading systems are available including the Late Effects Normal Tissues-Subjective Objective Management Analysis (LENT-SOMA) scale and the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE).5,6 The LENT-SOMA grading system for bladder/ urethra toxicity is presented in Table 1.5 The CTCAE version 4.0 grading system for hematuria is depicted in Table 2.6
emorrhagic radiation cystitis (HRC) may occur after radiotherapy (RT) for a variety of pelvic malignancies, including gynecologic neoplasms and prostate cancer.1 Hemorrhagic cystitis may also be observed after treatment with some chemotherapy agents, particularly cyclophosphamide, in the absence of pelvic RT.2 The interval between the onset of HRC and prior RT varies from months to years after treatment.1,3 Shilo et al4 reported on 32 patients with HRC and observed a median interval between RT and HRC of 4 years (range, 1 to 26 y). The likelihood of developing HRC is related to the total RT dose, dose per fraction, and the volume of the bladder irradiated. Other factors that may impact the likelihood of developing HRC include conditions such as diabetes, connective tissue disorders, and blood thinners such as warfarin. The probability of severe HRC after pelvic RT is approximately r5%.1 HRC is likely due to an obliterative endarteritis that results in atrophy and fibrosis of the mucosa and submucosa and the development of dilated telangiectatic blood vessels that are fragile and may result in bleeding. The irradiated bladder is hypovascular, hypocellular, and hypoxic.1 Severe HRC may be associated with necrosis and fistulae.3
DIAGNOSTIC EVALUATION The diagnosis of HRC is based on excluding other potential causes of hematuria such as a urinary tract infection and malignancy, such as a bladder cancer. The diagnostic From the *Department of Radiation, University of Florida Proton Therapy Institute; and wDivision of Urology, College of Medicine, University of Florida, Jacksonville, FL. The authors declare no conflicts of interest. Reprints: William M. Mendenhall, MD, Department of Radiation, University of Florida Proton Therapy Institute, 2015 North Jefferson Street, Jacksonville, FL 32206. E-mail: [email protected]. Copyright r 2013 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/3803-0331 DOI: 10.1097/COC.0000000000000016
American Journal of Clinical Oncology
Management The initial management includes bladder irrigation and clot evacuation.7 Intravenous fluids and blood transfusions are administered if indicated. Thereafter, a variety of therapeutic options are available if the hematuria is persistent.1,3,8–23 Following is a discussion of some of these alternatives. A small proportion of patients with HRC has severe, refractory, life-threatening hematuria and may require urinary diversion alone or combined with cystectomy.24–27
ORAL OR PARENTERAL AGENTS Hampson and Woodhouse2 reported on 14 patients treated at the Royal Marsden Hospital (London, UK) for HRC in 13 patients or severe hemorrhagic cystitis due to cyclophosphamide (CTX-HC) in 1 patient with sodium pentosan polysulfate (SPPS). SPPS, a sulphated polysaccharide that can be taken sublingually, resulting in 3% to 5% being excreted in the urine, is thought to reduce transitional cell injury by cytotoxins.2 Hematuria was graded as mild in 8 patients (requiring no transfusions or surgery), moderate in 2 patients (requiring 20% decrease in hemoglobin
Ulcerations into muscle
Perforation, fistula
> 100-200
r100
Decreased stream Occasionally weak Objective Hematuria
Microscopic, normal hemoglobin
Endoscopy
Patchy atrophy or telangiectasia without bleeding Maximum volume > 300-400 (mL) Residual volume 25 (mL) Management Dysuria Occasional non-narcotic Frequency
Alkalization
Hematuria/ telangiectasia Incontinence
Iron therapy Occasional use of incontinence pads
Decreased stream
Persistent and intense
Grade 4
1-2 h intervals
Refractory and excruciating Hourly Refractory
> 25-100
> 100
Regular non-narcotic
Regular narcotic
Occasional antispasmodic Occasional transfusion or single cauterization Intermittent use of incontinence pads < Once-a-day selfcatheterization
Regular narcotic Frequent transfusion or coagulation Regular use of pad or self-catheterization Dilation, > once-a-day self-catheterization
Score Scoring instructions score the 14 SOMA parameters with 1-4 score = 0 if there are no toxicities total the scores and divide by 14
LENT score
Surgical intervention Cystectomy Surgical intervention Permanent catheter Permanent catheter, surgical intervention
Analytic Cystography
Assessment of mucosal surface Volumetric Assessment of bladder analysis capacity in milliliters Contrast Assessment for ulcers, radiography capacity and contractility Ultrasound Assessment of wall thickness, sinus, and fistula formation Electromyography Assessment of sphincter activity using intraluminal pressure transducer, contraction pressure, and volume curves
Y/N
Date:
Y/N
Date:
Y/N
Date:
Y/N
Date:
Y/N
Date:
LENT-SOMA indicates Late Effects Normal Tissues-Subjective Objective Management Analysis.
Sandhu et al28 reported on 60 patients treated at the Royal Marsden Hospital for HRC (53 patients) or CTX-HC (7 patients) between 1991 and 2000. Fifteen of 60 patients had required hospitalization for bladder irrigation and 14 patients required a blood transfusion.28 Patients received SPPS 100 mg tid with a reduction of the dose when possible. Patients received SPPS for a median of 180 days (range, 21 to 1745 d) and were followed for a median of 450 days (range, 19 to
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4526 d) from the onset of hematuria. No adverse effects secondary to SPPS were observed. Fifty-one patients had adequate follow-up. Twenty patients (33%) died from other causes while taking SPPS, 21 patients (35%) had the SPPS dose reduced to 100 mg once daily (qd), and 10 patients (17%) had the SPPS discontinued after the hematuria stopped. Veerasarn et al29 reported on 16 patients treated at Mahidol University (Bangkok, Thailand) for grade 2 to 3 HRC
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American Journal of Clinical Oncology
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TABLE 2. CTCAE version 4.0 Grading System for Hematuria
Grade
Definition
Grade 1
Asymptomatic; clinical or diagnostic observation only; intervention not indicated Symptomatic, urinary catheter, or bladder irrigation indicated, limiting instrumental ADL Gross hematuria; transfusion, IV medications or hospitalization indicated; elective endoscopic, radiologic, or operative intervention indicated; limiting self-care ADL Life-threatening consequences; urgent radiologic or operative intervention indicated Death
Grade 2 Grade 3
Grade 4 Grade 5
ADL indicates activities of daily living; IV, intravenous.
with intravenous (IV) WF10 (Immunokine), which was administered 0.5 mL/kg diluted with 250 mL of 5% D/W over 2 hours, 5 days per week every 3 weeks for 2 to 4 weeks combined with standard therapy. WF10 is a chlorite-based drug thought to inhibit the inflammatory process associated with submucosal endarteritis.29 Standard therapy included oral antibiotics, antispasmodics, iron supplements, bladder irrigation, and/or blood transfusion. Median follow-up was 51 months. Fourteen (88%) of 16 patients improved to grade 0 to 1 HRC; 4 (28%) of 14 patients who responded relapsed with grade 2 HRC. No toxicity due to WF10 was observed. Veerasarn et al30 reported on a multicenter trial that included 100 patients with grade 2 to 3 HRC after RT for cervical cancer. Patients were randomized to receive 2 cycles of WF10, as previously described, plus standard therapy (50 patients) or standard therapy alone (50 patients). Patients were followed for 1 year. At week 7, 37 WF10 patients (74%) and 32 control patients (64%) had a CR (P = 0.28). WF10 was associated with a significant reduction in the use of antibiotics (P = 0.002) and antispasmodics (P < 0.001). Among the responders, 17 WF10 patients (47%) and 24 control patients (77%) had recurrent hematuria (P = 0.01). Hematuria recurred faster in control patients compared with those who received WF10 (P = 0.004). Cystoscopy at 1 year showed overall improvement and no significant differences between the two groups of patients. No severe toxicity due to WF10 was observed.
TOPICAL AGENTS Dewan et al31 reported on 35 patients treated between 1984 and 1990 at the Cancer Institute (Adyar, Madras) for HRC after RT for cervical cancer. All had failed conservative therapy with adequate hydration, bladder irrigation, and clot evacuation. HRC was mild in 9 patients (gross hematuria with occasional clots), moderate in 16 patients (clots at least every 2 d), and severe in 10 patients (hemodynamically unstable). Patients were treated with diluted formalin instillation (1%, 22 patients; 2%, 10 patients; 4%, 4 patients) under regional anesthesia after clot evacuation. The bladder was passively irrigated with formalin under r15 cm pressure for 20 to 30 minutes followed by continuous saline irrigation for 12 to 48 hours. Thirty-one patients (89%) had a CR after 1 instillation and 3 patients (8%) had a PR. Hematuria recurred in 7 (23%) of 31 patients who had a CR after a mean of 8 months. One percent formalin was as effective as 2% or 4% formalin. Minor complications were observed in 19 patients (54%) and included mild fever, frequency, dysuria, suprapubic pain, temporary incontinence, unilateral hydronephrosis, grade 2 Copyright
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ureterovesical reflux, and decreased bladder capacity not requiring diversion. Major complications were observed in 11 patients (31%) and included bilateral hydronephrosis due to ureteral stenosis, vesicovaginal fistula, decreased bladder capacity requiring diversion, and death. Overall, 5 patients (14%) required urinary diversion and 1 patient died due to bleeding and formalin toxicity. Lojanapiwat et al32 reported on 19 women treated for intractable HRC after RT for cervix cancer at Chiangmai University (Chiangmai, Thailand). Group 1 included 11 women who underwent instillation of 4% formalin for half of the bladder volume for 15 minutes followed by bladder irrigation with saline for 12 to 24 hours. Group 2 included 8 women who underwent endoscopic placement of 10% formalin soaked pledgets (1 1 cm) on bleeding points for 15 minutes. The average number of pledgets employed was 5.5 (range, 4 to 6). One patient required 2 treatments. Average follow-up was 25 months (range, 6 to 84 mo) for group 1 and 15 months (range, 6 to 40 mo) for group 2. A CR was observed in 9 (82%) of 11 patients in group 1 compared with 6 (75%) of 8 patients in group 2. There were 4 major complications in group 1 and none in group 2. Major complications included anuria and bilateral hydronephrosis (1), vesicovaginal fistula (2), and septic death (1). There were 11 minor complications in group 1 and 3 in group 2. Shao et al33 reported on 36 patients with HRC treated at Shanghai Jiaotong University (Shanghai, PRC) between 2004 and 2008. Patients were randomized to receive hyaluronic acid (HA) instillation (16 patients) or hyperbaric oxygen (HBO) therapy (20 patients). HA treatment entailed 40 mg of HA instilled in the bladder by Foley catheter for a minimum of 20 minutes weekly for 1 month and monthly for the following 2 months. HBO therapy consisted of 100% O2 at 2.5 atm for 60 minutes 7 days a week for 30 days. All patients completed treatment. No adverse complications were observed in either group other than increased urinary tract infections in the HA group, likely due to repeated catheterizations. The CR rates after HA versus HBO were: 6 months, 14 of 16 patients (88%) versus 15 of 20 patients (75%); 12 months, 12 of 16 patients (75%) versus 10 of 20 patients (50%); and 18 months, 8 of 16 patients (50%) versus 9 of 20 patients (45%). The CR/PR rates after HA vs. HBO were: 6 months, 16 of 16 patients (100%) versus 19 of 20 patients (95%); 12 months, 15 of 16 patients (94%) versus 17 of 20 patients (85%); and 18 months, 12 of 16 patients (75%) versus 15 of 20 patients (75%).
HBO Vilar et al34 reported on 38 patients treated with HBO for HRC at Hospital General de Castellon (Castellon de la Plana, Spain) and followed for a median of 56 months (range, 4 to 72 mo). Twenty-six patients had gross hematuria and a bladder capacity 6 months, 21 of 32 patients (66%) (P = 0.003). Thus the overall CR/PR rate was 48 of 60 patients (80%) with a significantly higher rate of a favorable response if the interval was r6 months. Twenty-five of 60 patients had clot retention before HBO; 18 (72%) had a CR or PR after treatment. The rates of CR/PR versus interval between onset of HRC and HBO were: r6 months, 11 of 11 patients (100%) and >6 months, 7 of 14 patients (50%) (P = 0.007). Prior intravesical chemical instillation did not adversely impact the efficacy of HBO. Oscarsson et al36 reported on 39 patients with radiation cystitis and proctitis who were treated with HBO at the Sahlgrenska University Hospital (Gothenburg, Sweden) between 2008 and 2011. Patients requiring blood transformations were excluded. Patients had received external beam RT for prostate cancer (n = 34), cervix cancer (n = 2), or rectal cancer (n = 3). HBO consisted of 100% O2 for 90 minutes at 2.0 to 2.4 atm.
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The mean number of dives was 39 (range, 28 to 40). Patient perceived quality of recovery was prospectively assessed using the Expanded Prostate Index Composite score before, during, and 6 to 12 months after HBO. No severe adverse effects due to HBO were observed. Symptoms were alleviated in 76% for patients with cystitis, 89% for those with proctitis, and 88% for patients with both cystitis and proctitis. The Expanded Prostate Index Composite score in the urinary domain improved from 50 to 66 after HBO (P < 0.001). The improvement was sustained at 6 to 12 months after treatment. Lee et al37 reported on 20 women with HRC after treatment for cervix (19 patients) or bladder (1 patient) cancer who were treated with HBO between 1989 and 1992 at the Naval General Hospital (Kaoshiung, Taiwan) and followed for a mean of 14 months (range, 5 to 41 mo). HBO consisted of 100% O2 at 2.5 atm for 100 minutes for an average of 44 dives. Sixteen patients (80%) had a CR; 2 patients (10%) had a PR. One patient required a diverting ileal conduit.
Intravesical Endoscopic Procedures Ravi38 reported on 42 patients with HRC after RT for pelvic malignancies (cervix, 39 patients; bladder, 2 patients; rectal, 1 patient) treated at the Cancer Institute (Adyar, Madras) with the Nd:YAG laser coagulation under anesthesia with a laser power r30 W and pulse duration r3 seconds. Thirteen patients had mild hematuria (gross hematuria with clots at least twice-weekly), 21 patients had moderate hematuria (clots at least every 2 d, hemodynamically stable), and 8 patients had severe hematuria requiring blood transfusions. Thirty-nine patients (93%) had a CR after 1 treatment and 2 patients (5%) had a CR after 2 treatments. The patient who failed to respond had presented with severe hematuria.
TABLE 3. Treatment of HRC
Administered Route Oral/IV Pentosan polysulfate (SPPS)
Oral
Dose 100 mg oral TID
WF10 IV (Immunokine)
0.5-0.75 mg/kg diluted in a minimum of 250 mL over no less than 1 h5 consecutive days
Pharmacology
Intravesicular 1%-4% solution (irrigation or passively irrigated soaked pledgets) for 20-30 min following by saline irrigation (12-48 h) Hyaluronic acid Intravesicular
Endoscopic procedures Laser coagulation
NA
2-2.5 atm, 90 min, approximately 30 dives
NA
NA
Results (CR/RR) (%)
Forms protective coating Diarrhea, dyspepsia CR: 71 on bladder wall reducing transitional cell injury Immune modulation Tachycardia, CR: 74-88 inhibiting the phlebitis (with RR: 24-47 inflammatory response rapid infusion)
Topical Formalin
Hyperbaric O2 HBO
Common AEs
Mild fever, frequency, dysuria, suprapubic pain
References 2,28
29,30
CR: 75-89 RR: 23
31,32
CR: 88-100 RR: 25
33
NA
CR: 59-96 RR: 16-34
4,34,35,36,37
NA
CR: 93-100 RR: 10
38,39,40,41
AE indicates adverse event; atm, atmosphere; CR, complete response; HBO, hyperbaric oxygen; HRC, hemorrhagic radiation cystitis; IV, intravenous; NA, not applicable; RR, relapse rate; TID, three times per day.
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Wines and Lynch39 reported on 7 patients with HRC requiring blood transfusions who were treated with argon plasma coagulation at St. George Public Hospital (Kogarah, Australia). The gas flow rate was 1.5 L/min, and the power was 40 to 60 W. Patients were followed for an average of 15 months. Six patients had a CR after 1 argon plasma coagulation session; the remaining patient has a CR after 2 sessions. No significant toxicity was observed. Zhu et al40 reported on 10 patients with intractable HRC who failed conservation management who were treated with transurethral greenlight KTP laser between 2004 and 2011 at Soochow University (Suzhou City, PRC). Two of 10 patients had required blood transfusions before treatment. Follow-up ranged from 6 to 36 months (mean, 17 mo). A CR was observed in all patients after 1 session; all 10 patients underwent cystoscopy 3 months after laser therapy, and no bleeding or scar from the procedure were observed. One patient had recurrent hematuria 7 months after a laser therapy and had a CR after a second laser procedure. Kaushik et al41 reported on 4 patients with refractory HRC that had failed to respond to conservative therapy as well as standard cystoscopic electrocautery. Patients underwent laser fulguration with a 980 nm diode laser at the University of Michigan. All 4 patients had a CR for an average of 11 months (range, 3 to 17 mo).
CONCLUSIONS Patients with HRC are initially treated with hydration, bladder irrigation, and clot evacuation. Thereafter, a diagnostic evaluation is performed to exclude other potential etiologies, including a urothelial neoplasm. The majority of patients with HRC will respond to this conservative approach. The management of those with persistent gross hematuria is problematic. In general, it is best to start with the least aggressive intervention that is least likely to exacerbate the HRC and progress to more aggressive measures only when necessary (Table 3). Thus, oral or parenteral agents may be employed, followed by HBO if these interventions fail. Topical agents are probably a next reasonable step, reserving surgical or endovascular interventions for the most refractory cases. REFERENCES 1. Smit SG, Heyns CF. Management of radiation cystitis. Nat Rev Urol. 2010;7:206–214. 2. Hampson SJ, Woodhouse CR. Sodium pentosanpolysulphate in the management of haemorrhagic cystitis: experience with 14 patients. Eur Urol. 1994;25:40–42. 3. Denton AS, Clarke NW, Maher EJ. Non-surgical interventions for late radiation cystitis in patients who have received radical radiotherapy to the pelvis. Cochrane Database Syst Rev. 2002;3: CD001773. 4. Shilo Y, Efrati S, Simon Z, et al. Hyperbaric oxygen therapy for hemorrhagic radiation cystitis. Isr Med Assoc J. 2013;15: 75–78. 5. LENT SOMA scales for all anatomic sites. Int J Radiat Oncol Biol Phys. 1995;31:1049–1091. 6. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. National Cancer Institute. 2009;4:59–60. 7. Kaplan JR, Wolf JS Jr. Efficacy and survival associated with cystoscopy and clot evacuation for radiation or cyclophosphamide induced hemorrhagic cystitis. J Urol. 2009;181:641–646. 8. Soares RS, de Abreu RA Jr, Tavora JE. Laparoscopic ureteral reimplant for ureteral stricture. Int Braz J Urol. 2010;36: 38–43.
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32. Lojanapiwat B, Sripralakrit S, Soonthornphan S, et al. Intravesicle formalin instillation with a modified technique for controlling haemorrhage secondary to radiation cystitis. Asian J Surg. 2002;25:232–235. 33. Shao Y, Lu GL, Shen ZJ. Comparison of intravesical hyaluronic acid instillation and hyperbaric oxygen in the treatment of radiation-induced hemorrhagic cystitis. BJU Int. 2012;109: 691–694. 34. Vilar DG, Fadrique GG, Martin IJ, et al. Hyperbaric oxygen therapy for the management of hemorrhagic radio-induced cystitis. Arch Esp Urol. 2011;64:869–874. 35. Chong KT, Hampson NB, Corman JM. Early hyperbaric oxygen therapy improves outcome for radiation-induced hemorrhagic cystitis. Urology. 2005;65:649–653. 36. Oscarsson N, Arnell P, Lodding P, et al. Hyperbaric oxygen treatment in radiation-induced cystitis and proctitis: a prospective cohort study on patient-perceived quality of recovery. Int J Radiat Oncol Biol Phys. 2013;87:670–675.
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37. Lee HC, Liu CS, Chiao C, et al. Hyperbaric oxygen therapy in hemorrhagic radiation cystitis: a report of 20 cases. Undersea Hyperb Med. 1994;21:321–327. 38. Ravi R. Endoscopic neodymium: YAG laser treatment of radiation-induced hemorrhagic cystitis. Lasers Surg Med. 1994;14:83–87. 39. Wines MP, Lynch WD. A new minimally invasive technique for treating radiation cystitis: the argon-beam coagulator. BJU Int. 2006;98:610–612. 40. Zhu J, Xue B, Shan Y, et al. Transurethral coagulation for radiation-induced hemorrhagic cystitis using Greenlight potassium-titanyl-phosphate laser. Photomed Laser Surg. 2013;31: 78–81. 41. Kaushik D, Teply BA, Hemstreet GP 3rd. Novel treatment strategy for refractory hemorrhagic cystitis following radiation treatment of genitourinary cancer: use of 980-nm diode laser. Lasers Med Sci. 2012;27:1099–1102.
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