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Problems of hyperbaric oxygen (HBO) therapy in patients with radiation cystitis
Previous and current studies have demonstrated that HBO therapy for patients with radiation cystitis improves late-radiation damage for a relatively long time period (Figure 1).[1] However, there are some issues that need to be addressed. First, is increased collagen synthesis in irradiated tissue beneficial or harmful in the long process of HBO treatment? The previous supposition of late radiation injury is that it was the result of a loss of parenchymal cells and an overproduction of collagen under the influence of apoptosis. However, late radiation damage has more recently been considered to be caused by the microvascular endothelial injury of the irradiated tissue.[2] The HBO treatment on radiation-induced ischemic tissue appeared to stimulate angiogenesis[3] together with fibroblast proliferation and increased collagen synthesis. Thus the created connective tissue framework and the induced enhanced vascular density served to lessen radiation injury.[4] Indeed, combined treatment with HBO and fibroblast growth factor improved human intractable skin ulcers concomitant with elevation of collagen and non-collagenous protein contents.[5] Feldmeir et al. have demonstrated the decreased fibrosis in the pelvic organs of mice receiving irradiation and then receiving post HBO compared to those receiving the radiation alone. Low levels of collagen and non-collagenous protein in the bowel and kidney in these animals were also confirmed by them.[6] It has been shown previously that treatment with clonidine, phenoxybenzamine, hexamethonium, or denervation reduces non- noncollagenous protein synthesis in rat vasculatures concomitant with improvement of hypertensive vascular lesions.[7, 8] The actual reason for diversified results in studies of non-collagenous protein is uncertain. Fibronectin, collagen, elastin, and proteoglycans are the predominant components of the extracellular matrix of most structures. It is well known that a great amount of collagen is involved in the extracellular matix of fibrous plaques in elderly subjects. Elastin is the first matrix protein to be degraded during the aging of several tissues, such as the dermis, the arterial wall, and the lung. Our previous study demonstrated that levels of collagen and elastin in human vas deferens increased with advancing age.[9] Age-related analysis of these fibrous proteins of the human bladder, with or without HBO treatment, must be carried out further. Based on previous studies and therapeutic results, HBO treatment appears to enhance collagen and non-collagenous protein synthesis in initial period and subsequently reduces fibrosis of irradiated tissues. Second, should we apply HBO therapy for patients with radiation cystitis and colitis? Earlier studies of radiation enteritis, proctitis, and colitis treated with HBO showed beneficial therapeutic results, but most of them are case reports. Mayer et al. demonstrated satisfactory report in many patients with proctitis.[10] Unfortunately, there are also no large and prospective analyses of this disease, but 67% of patients had a partial to good response following HBO therapy.[11] In our previous study, serious ulceration in patients with colitis was completely resolved following HBO therapy (Figure 2).[12] Combined therapy with HBO and prostaglandin E1 also showed efficacy in a patient with cystitis and colitis.[13]
In conclusion, HBO therapy, with or without combined additional non-invasive treatment, might be considered in the late damage of radiation cystitis and colitis. How does one estimate therapeutic results of patients with radiation cystitis? A major symptom of this disease is severe hematuria. But in a long follow-up period, irritative symptoms frequently lowered quality of life of patients. There are no precise methods to manifest subjective symptoms. We have recently used IPSS scores to obtain subjective information of respective patients. Such a trial alone is not sufficient to decide a definite therapeutic outcome, but it can be helpful for gathering revealing information on patients followed up long-term. Feldmeier and Hampson suggested a significant role in the application of the 3 models of HBO intervention for radiation injury - such as the American Heart Association (AHA) grade, National Cancer Institute (NCI) grade, and Clinical Evidence.[14] Application of such grading systems is necessary for determining real efficacy of HBO treatments.
Figure 1: Cystoscopy shows sever radiation cystitis (left) and its reversal (right) following HBO therapy
Figure 2: Endoscopy of the large bowel shows marked hemorrhage (left) and its improvement (right) following HBO therapy.
References:
- Nakada T, Yamaguchi T, Sasagawa I, Kubota Y, Suzuki H, Izumiya K:Successful hyperbaric oxygenation for radiation cystitis due to excessive irradiation to uterus cancer. Eur Urol 1992;22:294-297.
- Paris F, Fuks Z, Kang A, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001; 293: 293-297.
- Marx RE, Ehler, WJ, Tayapongsak P, Pierce LW, Relationship of oxygen does to angiogenesis induction in irradiated tussue. Am J Surg 1990;160:519-524.
- Crew JP, Jephcott CR, Reynard J, Radiation-induced haemorrhagic cystitis. Eur Urol 2001;40:111-123.
- Nakada T, Saito Y, Chikenji M, Koda S, Hiuchi M, Kawata K, Ishida S, Takahashi S, Kondo S, Kubota Y, Kubota I, Simizu Y, Therapeutic outcome of hyperbaric oxygen and basic fibroblast growth factor on intractable skin ulcer in legs:preliminary report. Plast Reconstr Surg 2006; 117:646-651.
- Feldmeier JJ, Davolt DA, Court WS, Onoda JM, Alecu R, Histologic morphometry confirms a prophylactic effect for hyperbaric oxygen in the prevention of delayed radiation enteropathy. UHM 1998; 25: 93-97.
- Nakada T, Lovenberg W, Lysine incorporation in vessels of spontaneously hypertensive rats, Effects of adrenergic drugs. Eur J Pharmacol 1978; 48: 87-96.
- Nakada,T, Iijima Y, Kubota Y, Watanabe M, Ishigooka M, Increased collagen and noncollagenous protein synthesis contributes to sustain chronic phase of two-kidney, one-clip renovascular hypertension. J Urol 1996; 156: 1180-1185.
- Nakada T, Sasagawa I, Furuta H, Kataama T, Shimazaki J, Age-related differences in norepinephrine and non-collagenous protein in human vas deferens. J Urol 1989; 141: 998-1002.
- Mayer R, Klemen H, Quehenberger F et al. Hyperbaric oxygen - an effective tool to treat radiation morbidity in prostate cancer. Radiother Oncol 2001; 61: 151-156.
- Girmius S, Cersonsky N, Gesell L, Cico S, Barnett W, Treatment of refractory radiation-induced hemorrhagic proctitis with hyperbaric oxygen therapy. Am J Clin Oncol 2006; 29:588-592.
- Nakada T, Kubota Y, Sasagawa I, Suzuki H, Yamaguchi T, Ishigooka M, Kakizaki H, Therapeutic experience of hyperbaric oxygenation in radiation colitis. Report of a case. Dis Colon Rectum 1993; 36: 692-695.
- Miura M, Sasagawa I, Kubota Y, Iijima Y, Sawamura T, Nakada T, Effective hyperbaric oxygenation with prostaglndin E1 for radiation cystitis and colitis after pelvic radiotherapy. Int Urol Nephrol 1996; 28: 643-647.
- Feldmeier JJ, Hampson NB, A systematic review of the literature reporting the application of hyperbaric oxygen prevention and treatment of delayed radiation injuries: An evidence based approach. UHM 2002; 29: 4-30.
Written by:
Teruhiro Nakada, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Urology
Kuriyama Central Hospital
Yotsukaido, Japan
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