Radiation Cystitis

Radiation cystitis is a late complication of radiotherapy which, by definition, occurs at least 90 days after the initiation of radiation treatment but maybe delayed up to 10 years or more (Cox et al. 1995). Most patients develop severe irritative voiding symptoms; however, gross hematuria dominates the clinical picture (Pas-quier et al. 2004). While any patient receiving pelvic radiotherapy is at risk, radiation cystitis is most common among those treated for prostate or cervical cancer. Three to five percent of such patients will develop late grade 3 hematuria, the incidence of which is directly related to both the biologic dose and the volume of tissue irradiated (Perez 1998; Lawton et al. 1991; Shipley et al. 1988; Dearnaley et al. 1999). In contrast to acute changes, late radiation injuries are irreversible and often progressive. There appears to be no correlation between the development of early and late radiation injuries. The pathophysiology of late radiation damage includes cellular depletion, fibrosis, and obliterative endarteritis (Pasquier et al. 2004). All of these changes lead to tissue ischemia and, in turn, delayed wound healing. Cystoscopically, such changes give the appearance of pale, frosted mucosa, scattered telangiectasia, and ulcers (Rigaud et al. 2004).

Radiation cystitis is perhaps the most difficult form of bladder hemorrhage to treat. The reason for this lies primarily in the ischemic nature of the injury and the propensity toward poor wound healing. Based on alack of randomized controlled trials comparing available treatment options, firm guidelines for radiation cystitis management cannot be made (Denton et al. 2002). That being said, a tremendous amount of research has been devoted to examining the role of hyperbaric oxygen therapy (HBO) in the treatment of radiation injuries. First introduced into the field of radiation oncology in 1953 as a radiosensitizer, HBO has subsequently been shown to ameliorate radiation damage among a wide range of tissues, including the bladder (Gray et al. 1953; Capelli-Schellpfeffer and Gerber 1999; Feldmeier and Hampson 2002). Hyperbaric oxygen therapy involves the inhalation of 100% oxygen pressurized to 1.4-3.0 atm in sessions of 60-120 min. Under these conditions, alveolar, arterial, and tissue oxygen levels are driven to supraphysiologic levels. By improving the oxygenation of irradiated tissue, HBO stimulates an-giogenesis, fibroblast proliferation, and collagen formation (Marx et al. 1990). Not only does this promote wound healing, but the vasoconstriction induced by an abundance of oxygen may also help to control bleeding (Capelli-Schellpfeffer and Gerber 1999). Retrospective studies examining the role of HBO in severe radiation cystitis report response rates of 77 % -100 % (complete response, 34%-100%; partial response, 12%-45%) (Mathews et al. 1999; Neheman et al. 2005). A single prospective study of HBO demonstrated an overall response rate of 92.5 % among 40 patients with radiation cystitis refractory to standard measures (Bevers et al. 1995). Patients underwent 20 treatment sessions inhal ing 100 % oxygen at 3 atm for 90 min each. With a mean follow-up of 23 months, the recurrence rate of severe hematuria was 12% per year. It is difficult to predict the individual treatment outcome; however, the provision of HBO within 6 months of hematuria onset appears to improve the response rate (96% vs 66%, p = 0.003) (Chong et al. 2005). Cancer patients who do not respond to HBO require evaluation for cancer recurrence since this is a common cause of persistent hematuria (Rijkmans et al. 1989). Hyperbaric oxygen therapy is generally well tolerated, with adverse events limited to case reports of visual disturbance, spontaneous pneumothorax, oxygen toxicity seizures, hypoglycemia, and loss of respiratory drive in hypercapnic patients (Ca-pelli-Schellpfeffer and Gerber 1999). Contraindications to the use of HBO are listed in Table 13.9 (O'Reilly et al. 2002). Concern exists over the theoretic risk of cancer stimulation through HBO-mediated neoangiogenesis, immune suppression, and free radical toxicity. A review of the world literature in 2003, however, found that available in vitro, in vivo, and clinical studies suggested no more than a neutral effect of HBO on tumor growth (Feldmeier et al. 2003). Additional studies have found no evidence that exposure to hyperbaric oxygen promotes tumor growth, including that of prostate cancer (Chong et al. 2004). As such, a history of malignancy should not be considered a contraindication to treatment with HBO. Perhaps the largest obstacle to its use is cost. The average cost per session is $ 300-$ 400, which amounts to an estimated $ 10,000-$ 15,000 per patient (Norkool et al. 1993). While there exist no formal cost-comparisons among available treatments for radiation cystitis, HBO is still regarded as a cost-effective option and should be considered for refractory cases.

WF10, the i.v. formulation of a novel wound-healing agent, tetrachlorodecaoxygen, has demonstrated benefit in patients with wound healing disorders, including that arising from radiation injury (Hinz et al. 1986; Vee-rasarn et al. 2004). As an immune modifier, WF10 promotes the healing process through the inhibition of the chronic inflammatory process. Two human studies, including one randomized trial have evaluated the effica-

Table 13.9. Contraindications to use of hyperbaric oxygen therapy

Absolute contraindications Relative contraindications

Untreated pneumothorax Concurrent treatment with Cis-platinum Doxorubicin Bleomycin Disulfiram Mafenide acetate

Upper respiratory infections Seizure disorders High fevers

History of spontaneous pneumothorax Viral infections Congenital spherocytosis History of optic neuritis History of otosclerosis cy of this novel agent in the treatment of radiation cystitis (Veerasarn et al. 2004, 2006). Among cervical cancer patients with grade 2 or 3 radiation cystitis, WF10 provided a complete response rate of 74 % - 88 %. Although this was not statistically superior to the standard hematuria measures employed in the control arm, patients treated with WF10 demonstrated a lower rate of hematuria recurrence (47% vs 77%, p = 0.01) and a longer estimated time to recurrence (>300 days vs < 100 days, p = 0.004). The administration protocols in both studies involved 0.5 mg/kg WF10 in 250 ml normal saline infused over 2 h on 5 consecutive days every 3 weeks for two cycles. Transient hemoglobinemia may occur in up to one-quarter of treated patients; however, there have been no serious safety concerns with WF10 in these or any other studies to date. At this time, the role of WF10 in the management of radiation cystitis remains investigational.

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