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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 50  |  Issue : 2  |  Page : 52-56

Hyperbaric oxygen therapy for hemorrhagic radiation cystitis


1 Department of Surgery, Division of Urology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
2 Department of Hyperbaric Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan

Date of Submission08-Jan-2016
Date of Decision17-Feb-2016
Date of Acceptance18-Jul-2016
Date of Web Publication18-Apr-2017

Correspondence Address:
Hui-Chieh Lee
Department of Hyperbaric Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, #81345, No. 553, Junxiao Road, Zuoying District, Kaohsiung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_19_17

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  Abstract 

Background: Radiation cystitis with macroscopic hematuria is a frustrating clinical problem for urologists. Since 1985, hyperbaric oxygen therapy (HBOT) has been applied as a treatment for radiation cystitis with macroscopic hematuria; numerous studies have shown that this treatment has favorable results.
Purpose: The purpose of this study was to elucidate the HBOT affected the clinical outcomes and treatment of hemorrhagic radiation cystitis (HRC).
Methods: Between November 1989 and June 2014, 42 patients (39 women and three men) with HRC were treated with hyperbaric oxygen at a pressure of 2.5 atmospheres absolute, breathing 100% O2for 120 min in a multiplace hyperbaric chamber.
Results: After an average of 38 hyperbaric oxygen sessions, macroscopic hematuria was completely halted in 35 patients (83.3%) and markedly decreased in three patients (7.1%). A comparison of cystoscopic findings before and after HBOT showed significant decreases in both hemorrhagic sites and telangiectasis of the bladder mucosa. The mean follow-up was 20.7 months (range: 3–49 months). No cases exhibited evidence of barotrauma or oxygen toxicity. One patient underwent a urodynamic study both before and after HBOT, with several changes in bladder function observed after HBOT: urine peak flow increased from 12.8 mL/s before HBOT to 15.0 mL/s after HBOT and urine mean flow increased from 6.5 mL/s to 8.9 mL/s. Urine voiding time decreased from 40.0 s to 28.0 s, urine flow time from 39.0 s to 28.0 s, time to peak flow from 15.0 s to 8.0 s, and voided volume from 251 mL to 248 mL.
Conclusion: The results of this study suggest that early application of HBOT is a safe and effective treatment method for HRC. Whether HBOT is beneficial to urinary bladder function requires further study with a larger patient cohort enrolled.

Keywords: Hemorrhagic radiation cystitis, hyperbaric oxygen therapy, urodynamic


How to cite this article:
Lin KH, Lee HC, Huang WS, Huang PW, Ke SC, Lee MG. Hyperbaric oxygen therapy for hemorrhagic radiation cystitis. Formos J Surg 2017;50:52-6

How to cite this URL:
Lin KH, Lee HC, Huang WS, Huang PW, Ke SC, Lee MG. Hyperbaric oxygen therapy for hemorrhagic radiation cystitis. Formos J Surg [serial online] 2017 [cited 2019 May 26];50:52-6. Available from: http://www.e-fjs.org/text.asp?2017/50/2/52/204658


  Introduction Top


Radiation therapy is often employed for the treatment of pelvic malignancies such as prostate, rectal, endometrial, and cervical cancers. Possible complications include typical radiation-associated injuries to the neighboring organs, most commonly the urinary bladder and rectum. The pathological changes of progressive obliterative endarteritis of the small blood vessels cause acute and chronic fibrosis resulting from cellular hypoxia. This in turn causes fragile vasculature and spontaneous bleeding that may be persistent and difficult to control.

Hemorrhagic radiation cystitis (HRC) is a serious, often refractory clinical problem that occurs after pelvic radiation therapy. HRC can occur months or even years after therapy and manifests as hematuria and associated voiding symptoms.[1]

Radiation therapy has been applied successfully to treat pelvic malignancy, but morbidity from HRC remains a major long-term sequela in 1%–2% of treated patients. Comparatively, conservative techniques are sometimes considered as first-line treatment for HRC; however, because of the low long-term effectiveness of such techniques, most patients ultimately depend on more aggressive surgical procedures to control hematuria.[2],[3] Hyperbaric oxygen therapy (HBOT) has been demonstrated to improve the body's capacity for angiogenesis and fibroplasia and to facilitate healing in radiation-injured tissue, including the bladder.[2]

Before 1990, 5%–20% of patients treated with radiation later developed urologic complications such as HRC, ureteral stricture, urinary incontinence, bladder ulcers, and fistula.[3],[4],[5] HRC remains the most prevalent of these complications. Several previous studies have reported methods of palliating radiation cystitis, including bilateral hypogastric artery occlusion; hydrostatic bladder dilatation;[6] intravesical instillation of formalin, silver nitrate, or alum; fulguration of intravesical bleeding sites; and urinary diversion with cystectomy.[7]

Nevertheless, the following disadvantages have been observed in the aforementioned methods: Lack of efficacy in controlling hematuria, decrease in bladder capacity, pain and temporary cauterization, failure to heal ischemic mucosa, and unacceptable hazards for older patients. In some cases, hematuria may necessitate hospital admission and further clinical measures to control bleeding; however, to date, no definitive curative treatment for HRC has been developed. In the mid-1980s, several cases of the successful reversal of radiation-induced hematuria through HBOT were reported.[8],[9] Subsequently, numerous researchers have reported similar favorable responses to HBOT.[10],[11],[12]

This paper describes the clinical experience of treating 42 patients with HRC, and the results of long-term follow-up for each patient treated with HBOT.


  Methods Top


Between November 1989 and June 2014, 42 patients (39 women and three men with a mean age of 63; range: 42–82 years) with HRC were referred to our hyperbaric facility for HBOT. The reasons for their initial radiotherapy were carcinoma of the uterine cervix (n = 39) and carcinoma of the urinary bladder (n = 3). All patients received an average radiation dose of 6,262 cGy (range: 5000–9000 cGy) to the pelvic region. Most patients were suffering from macroscopic hematuria and were evaluated through cystoscopy to exclude other possible causes of hemorrhagic cystitis.

Gross hematuria appeared on average 9.9 years (range: 2–26 years) after radiotherapy. In all patients, intravesical irrigation, antibiotics, and tranexamic acid had previously been adopted as methods of treatment, but these methods failed to control hematuria. The clinical symptoms consisted of acute hematuria, dysuria, and urgency and frequency of urination.

Before HBOT, each patient underwent routine blood and biochemistry measurements, including bleeding time and coagulation time to exclude clotting disorders bacterial cultures for secondary infections and routine urine analysis. Pelvic examinations, pap smears, and ultrasonography of the abdomen were performed to rule out possible metastasis or the recurrence of carcinoma. Cystoscopic examinations were performed to confirm diagnoses and evaluate the severity of the radiation cystitis. Initially, a Foley catheter with cold normal saline was inserted for intravesical irrigation to manage secondary obstruction resulting from blood clots. Blood transfusions were also administered if necessary. Parenteral antibiotics were used to prevent secondary infection of the urinary tract. HBOT was carried out in a multiplace hyperbaric chamber with 100% oxygen at a pressure of 2.5 atmospheres absolute, administered with a double-seal oronasal mask for 120 min, once a day, 5 days/week. The number of fractions delivered depended on the clinical diagnosis. During HBOT, patients continued to receive standard supportive treatment including wound care management. After completion of HBOT, cystoscopic examination was repeated for comparison with the previous findings.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.


  Results Top


After an average of 38 hyperbaric oxygen sessions (range: 10–87 sessions) for each patient, macroscopic hematuria was completely halted in 35 patients (83.3%) and decreased in three patients (7.1%). Three patients who had complained of urinary frequency and urgency without significant hematuria were relieved of those symptoms after HBOT. One patient with diabetes mellitus and cirrhosis of the liver failed to respond to HBOT and finally underwent ileal conduit diversion. [Table 1] summarizes the results of HBOT treatment on the 42 patients with HRC.
Table 1: Clinical results of 42 cases of hemorrhagic radiation cystitis treated with hyperbaric oxygen

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One patient agreed to undergo an endoscopic biopsy of the bladder mucosa before HBOT to confirm the pathological diagnosis of radiation cystitis. The pathological examination revealed chronic inflammatory cell infiltration in the subepithelial stroma. Hyalinization of arterioles with obliterated lumens – the typical pathological finding of radiation cystitis – was identified in the fibrotic and inflamed stroma [Figure 1].
Figure 1: Bladder stroma. Hyalinization of arterioles with obliterated lumens was identified in the fibrotic and inflamed stroma

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One patient underwent urodynamic study before and after HBOT. She had radiation cystitis without macroscopic hematuria and presented the clinical symptoms of urinary frequency and urgency. Therefore, we conducted the urodynamic study to detect whether there was any change in bladder function before and after HBOT. The results showed that urine peak flow increased from 12.8 mL/s before HBOT to 15.0 mL/s after HBOT and urine mean flow from 6.5 mL/s to 8.9 mL/s. Urine voiding time decreased from 40.0 s to 28.0 s, time to peak flow decreased from 15.0 s to 8.0 s, and voided volume increased from 251 mL to 248 mL.

The mean follow-up period was 20.7 months (range: 3–49 months). No patients experienced oxygen toxicity or barotrauma at any time.


  Discussion Top


Radiation is one of the most common methods for the treatment of abdominal and pelvic malignancies. Once the bladder is exposed to radiation, HRC has the potential to develop. Although HRC is most often caused by radiation therapy, it can also be associated with other factors. The most common symptoms of HRC are hematuria, anemia, urinary frequency, dysuria, and urine incontinence or retention because of secondary obstruction resulting from blood clots.

The results of the present study demonstrate that HRC responds well to HBOT, with control of hematuria in 90.4% of cases. In patients who experience complications after radiotherapy of the pelvis, a progressive obliterative endarteritis develops in small blood vessels of the urinary bladder, which finally develops into tissue that is hypovascular, hypocellular, and hypoxic. Subsequent tissue breakdown may take place spontaneously or may be induced by trauma, leading to bleeding. Secondary infection may further compromise tissue with resultant bleeding. HBOT has three beneficial effects which tend to resolve these problems: (a) increase of blood perfusion and tissue oxygen tensions to improve the hypoxic tissue;[13] (b) enhancement of wound healing by promoting fibroplasia and angiogenesis, the apparent dominant mechanisms in the repair of radiation-damaged tissue;[14] and (c) enhancement of the capacity of leukocytes, allowing for disinfection, and ultimate repair of compromised tissue through the production of a group of highly reactive microbicidal agents secondary to the reduction of molecular oxygen.[15]

On the basis of the results, the most probable reason that HBOT contributed to the control of hematuria in 38 patients with HRC was the gradual healing of mucosal wounds after HBOT. The urodynamic changes shown in the clinical results indicate that HBOT may enhance vesicourethral compliance and improve urinary function. Only one patient experienced a poor outcome, which was probably a result of underlying diabetes mellitus and liver cirrhosis, which compromised wound healing.

Complications of HBOT have been described as barotraumatic lesions caused by the compression or expansion of enclosed gas volumes that can be localized to the nasal sinuses, teeth, lungs, inner ears, and most commonly, middle ears. The current study results show the most common side effect of HBOT to be otalgia, which could be resolved by the Valsalva maneuver or myringotomy. In this study, no patient exhibited evidence of barotrauma or oxygen toxicity.

A possible concern related to HBOT is the fear that improved tissue oxygenation may facilitate the development of residual malignant cells and therefore increase the possibility of cancer recurrence. Feldmeier et al. reviewed the relationship between HBOT and malignant tumors, and their results suggest that HBOT has no substantial effect on the promotion of tumor growth or metastatic cell enhancement.[16],[17],[18],[19],[20] Notably, malignant tumors that thrive under hypoxic conditions seem to be more aggressive and tend to metastasize.[20]

Since 1985, HBOT has emerged as a promising treatment method for HRC as reported in several studies.[13],[14] Bevers et al. assessed HBOT for the treatment of HRC (n = 40) and observed a positive response in 75% of patients. Only three patients experienced recurrent hematuria after a mean follow-up of 29 months.[21] Corman et al. assessed HBOT for the treatment of HRC in a study of 57 patients between May 1988 and March 2001 and observed a positive response in 86% of patients. All patients received an average of 33 sessions of HBOT (range: 9–68 sessions). The authors concluded the study by suggesting that HBOT is a highly effective treatment option for HRC.[22] Ribeiro de Oliveira et al. analyzed 176 patients with refractory radiation-induced hemorrhagic cystitis (to date, this study has the largest patient cohort concerning the use of HBOT for this condition) and reported that the condition can be successfully and safely treated with HBOT.[23] On the basis of the clinical results of the present study, we suggest that HBOT is an effective and safe method for the treatment of HRC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Lawton CA, Won M, Pilepich MV, Asbell SO, Shipley WU, Hanks GE, et al. Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: Analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 1991;21:935-9.  Back to cited text no. 1
    
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Perez CA, Breaux S, Bedwinek JM, Madoc-Jones H, Camel HM, Purdy JA, et al. Radiation therapy alone in the treatment of carcinoma of the uterine cervix. II. Analysis of complications. Cancer 1984;54:235-46.  Back to cited text no. 3
    
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Duncan W, Quilty PM. The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily treated by radical megavoltage X-ray therapy. Radiother Oncol 1986;7:299-310.  Back to cited text no. 5
    
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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.  Back to cited text no. 7
    
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Weiss JP, Boland FP, Mori H, Gallagher M, Brereton H, Preate DL, et al. Treatment of radiation-induced cystitis with hyperbaric oxygen. J Urol 1985;134:352-4.  Back to cited text no. 8
    
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Hart GB, Strauss MB. Hyperbaric oxygen in the management of radiation injury. In: Schmutz J, editor. Proceedings of theFirst Swiss Symposium on Hyperbaric Medicine. Basel, Switzerland: Foundation for Hyperbaric Medicine; 1986. p. 31-51.  Back to cited text no. 11
    
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Rijkmans BG, Bakker DJ, Dabhoiwala NF, Kurth KH. Successful treatment of radiation cystitis with hyperbaric oxygen. Eur Urol 1989;16:354-6.  Back to cited text no. 12
    
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Lee HC, Liu CS, Chiao C, Lin SN. Hyperbaric oxygen therapy in hemorrhagic radiation cystitis: A report of 20 cases. Undersea Hyperb Med 1994;21:321-7.  Back to cited text no. 13
    
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Lee HC, Liu CS, Li SN. Hyperbaric oxygen therapy in radiation-induced hemorrhagic cystitis: A report of 25 cases. Jpn J Hyperb Med 1994;29:23.  Back to cited text no. 14
    
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Sheffield PJ. Tissue oxygen measurements with respect to soft tissue wound healing with normobaric and hyperbaric oxygen. Hyperb Oxyg Rev 1985;6:18-46.  Back to cited text no. 15
    
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Marx RE, Johnson RP. Problem wounds in oral and maxillofacial surgery: The role of hyperbaric oxygen. In: Davis JC, Hunt TK, editors. Problem Wounds: The Role of Oxygen. New York: Elsevier; 1988. p. 65-123.  Back to cited text no. 16
    
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Babior BM. Oxygen-dependent microbial killing by phagocytes ( first of two parts). N Engl J Med 1978;298:659-68.  Back to cited text no. 17
    
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Perrins DJ, Wiernick G. Therapeutic applications of hyperbaric oxygen. Controlled trials in carcinoma of the bladder. In: Proceedings of the 6th International Congress of Hyperbaric Medicine. Scotland: Aberdeen University Press; 1977. p. 253-8.  Back to cited text no. 18
    
19.
Granstrom G, Edstrom S, Westin T, Lyden E, Magnusson B, Gustafsson B. Hyperbaric oxygen does not stimulate experimental tumor growth. Undersea Biomed Res 1990;17 (Suppl):66.  Back to cited text no. 19
    
20.
Feldmeier J, Carl U, Hartmann K, Sminia P. Hyperbaric oxygen: Does it promote growth or recurrence of malignancy? Undersea Hyperb Med 2003;30:1-18.  Back to cited text no. 20
    
21.
Bevers RF, Bakker DJ, Kurth KH. Hyperbaric oxygen treatment for haemorrhagic radiation cystitis. Lancet 1995;346:803-5.  Back to cited text no. 21
    
22.
Corman JM, McClure D, Pritchett R, Kozlowski P, Hampson NB. Treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen. J Urol 2003;169:2200-2.  Back to cited text no. 22
    
23.
Ribeiro de Oliveira TM, Carmelo Romão AJ, Gamito Guerreiro FM, Matos Lopes TM. Hyperbaric oxygen therapy for refractory radiation-induced hemorrhagic cystitis. Int J Urol 2015;22:962-6.  Back to cited text no. 23
    


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