Long-term experience of hyperbaric oxygen therapy for refractory radio- or chemotherapy-induced haemorrhagic cystitis

Radiation and cyclophosphamide-induced HC is a severe and potentially life threatening complication. Management can be highly challenging with well-known urological treatment options. It is to be expected that the number of radiation therapies will increase during the next decades [ 17]. In parallel a rise in complications and side effects, such as RHC, can be expected. The results of this study suggest that HBOT is a promising option in therapy-resistant HC with a success rate of more than 90%.

In both CHC and RHC the acute reaction on urothelial damage is an inflammatory response causing oedema, ulceration, neovascularisation and haemorrhagic necrosis. This is usually limited to the treatment period.

In CHC urotoxicity is caused directly by the renal excretion of acrolein, metabolites of oxazaphosphorine alkylated drugs. There is no clear dose-related relationship. Since the 1970s the prophylactic application of Mesna has been used as a standard protocol for prevention of haemorrhagic complications. It neutralises acrolein and its toxic effects to the urothelium. The incidence of CHC is reduced from about 68% to about 5% [ 5].

In RHC urothelial damage is caused by radiolysis of water. The concentration of activated free oxygen radicals increases; as these are highly reactive, they cause cell membrane injury by lipid peroxidation, which induces immediate cell death. Additionally, direct (by radiation energy) and indirect (by oxygen radicals) DNA damage causes replication failures resulting in delayed cell death [ 8]. This damage is dose-related.

This acute reaction can escalate into a chronic endarteritis which seems to be the determining pathology of late-onset RHC and has been described as the “three-H model”: the progressive endarteritis and vascular rarefaction ( hypovascular) results in critical ischaemia ( hypoxia) with a reduction in oxygen concentration of up to 70-80%. Ischaemia of the mucosal tissue can lead to necrosis and sloughed off cells because of impaired healing capacity. A compensatory teleangiectasia develops and causes (persistent) haematuria. Finally, fibrotic repair processes can lead to impaired bladder capacity ( hypocellular) [ 3, 11]. This process can still become relevant up to 20 years after radiation therapy [ 2]. In our study haematuria occurred in a median of 41 months after completion of radiation therapy. This is within the range of previously described periods of 35–48 months [ 1, 2, 8, 10].

Tissue oxygen supply occurs primarily via diffusion from the capillaries by significantly increasing the physically dissolved oxygen in the plasma (100% O ₂ pressure of 1.4 atmosphere). HBOT improves the local and regional tissue oxygen supply. Our results demonstrate a drastically increased pO ₂ in the tissue from 1250 to 1480 mmHg from percutaneous measurements. By increasing pO ₂, macrophages, fibroblasts and granulocytes may resume their normal function and mediate repair processes. In addition, HBOT directly induces neo-angiogenesis, whereby 80% of the normal capillary density can be achieved. Furthermore HBOT causes anti-oedematous vasoconstriction without secondary ischaemic hypoxia [ 18- 20].

Hyperbaric oxygen in patients with severe RHC or CHC not responding to conventional urological treatment is an extremely rare and not yet standardised treatment option.

In RHC different research groups and we have reported success rates between 75 and 96% in both prospective and retrospective study designs [ 10, 13, 19, 21- 23]. In contrast to our study, other cohorts have varied between 13–60 patients with only short follow-up periods of 12–30 months.

We could demonstrate a success rate of 90% even after a median long-term follow-up period of 68 months, confirming the excellent long-term results reported by Nakada et al. whose success rate was 75-88% [ 12].

Only a few cases patients with CHC have been reported. One of the larger series with six CHC patients reported a 100% success rate after 11 to 36 months of follow-up (although they noted that in one patient haematuria recurred after three months) [ 24]. In other reported case reports a complete loss of haematuria occurred after a follow-up period of 11–36 months [ 7, 24- 26].

The main advantage of this therapy is that there are no severe side-effects. The most common adverse effects of HBOT are middle ear or sinus barotraumas requiring myringotomy in up to 5% [ 27]. Reversible myopia has also been described as a dose-dependent HBOT side effect [ 27]. Our study, as many other reports, did not show any adverse effects of HBTO.

So far variable success of HBOT has been discussed without any clear results, mainly because of the small sample size in most series.

In RHC the total radiation dose seems to have an influence on HBOT success: generally, complications such as RHC begin at a total dosage of 45–55 Gy and increase significantly at a cumulative dose of ≥60 Gy (≥5% with late effects) [ 28]. Nakada et al. showed a significantly better HBOT success in patients exposed to lower radiation doses (62Gy vs. 76Gy, p < 0.001). In addition del Pizzo et al. reported relatively poor HBOT long-term success rates (27% after 5 years) in patients with high dosage radiotherapy (75Gy) [ 29]. In the present study most of the patients received a cumulative dose between 60 – 66Gy. One patient with high dose therapy (78 Gy) suffered one unique relapse of haematuria.

Some authors discuss that there might be an influence of the number of HBOT sessions on the therapeutic success in RHC. Most of the studies applied between 30 and 40 treatment sessions [ 13, 19, 21, 29] which is comparable to our data with a median of 34 treatments. The significantly higher number of HBOTs (62) may be the reason for the excellent long-term success in Nakada’s study compared with a study with a success rate of 64% after only 14 HBOTs [ 30]. The few existing data suggest that fewer HBOTs are sufficient in CHC patients. The reported series of six CHC cases required a median of 27 HBOTs, other published cases between 14 and 40 treatments [ 7, 24- 26].

The period of time between the onset of haematuria and the beginning of HBOT is discussed as another success factor for RHC. In some studies, patients with a shorter pre-treatment interval (6–8 months) showed significantly better results on HBOT (p <0.001) [ 12, 13]. We could not demonstrate any relationship between the time to beginning of HBOT and its success. This is most probably because, as CHC is the more acute event, HBOT was started at a mean of 47 days after the onset of symptoms. However, intervals of up to four months between first admission and the beginning of HBOT have been described [ 24].

Finally the influence of patient age is controversially discussed. Some studies suggest that younger patients (≤70 years) have higher success rates. Other studies, as well as ours, have not found any correlation between age and HBOT success. Furthermore, in CHC patients a complete remission of haematuria is reported in cases aged from 15 to 82 years [ 1, 12, 13, 24- 26].

The costs amount to approximately €200 per HBOT session. Accordingly, the median costs per patient in this study were €6,800 (34 HBOT sessions). The costs are comparable to a cost-analysis case study from Australia which showed HBOT to provide major health cost savings [ 31].

Our study, as many others, is certainly limited by the small study population and the retrospective design. Furthermore different treatment protocols reduce the comparability of treatment outcomes. Prospective trials would be desirable for further evaluation but the first planned prospective and randomized study (initiated by the Baromedical Research Foundation) was cancelled because of poor recruitment (NCT00134628). Nevertheless, we believe that our results show the long-term efficiency and safety of this therapy option in patients suffering from radiation- and cyclophosphamide-induced haemorrhagic cystitis.