Pii: s0140673695916202

Hyperbaric oxygen treatment for haemorrhagic radiation materais ana metnOas Radiation-induced severe haemorrhagic cystitis is difficult January, 1986, until January, 1994, 40 patients with severe haemorrhagic radiation-induced cystitis were treated with HBO.
Inclusion criteria were severe haemorrhagic cystitis due to haematuria but do not affect the radiocystitis itself.
radiotherapy, not responding to other treatments. Exclusion Hyperbaric oxygen treatment has been reported to do both.
criteria were tumour recurrence in the bladder at cystoscopy We report the results of a prospective study of before treatment, concomitant bleeding disorders, and severe hyperbaric oxygen (20 sessions of 100% oxygen inhalation pulmonary disease with pulmonary bullae. End points of the at 3 bar for 90 min in a multiplace hyperbaric chamber) to study were recurrence of severe haematuria, cystectomy, or 40 patients with biopsy-proven radiation cystitis and severe death. 33 patients were referred to our centre from other disappeared completely or hospitals; 27 were male; mean age was 71-4 years (range 56-86).
improved in 37 patients after treatment. Mean follow-up Patients had received radiotherapy for a pelvic cancer (table 1).
Mean interval between radiation-therapy and the development of was 23·1 months (range 1-74); and the recurrence rate haematuria was 53-1 months (range 4-253).
was 0·12/year. There were no adverse effects.
Patients had received one or more unsuccessful treatments for Hyperbaric oxygen treatment should be considered for haematuria: clot evacuation/electrocoagulation (40), tranexamic patients with severe radiation-induced haematuria.
acid (12), alum (11), corticosteroids (3), neomycin (1), Lancet 1995; 346: 803-05 etoglucide (1), propantheline (1), silver nitrate (1), unspecified (17). Most patients required multiple blood transfusions (mean [range 0-36]). A modified Radiation therapy is used classification was used to as treatment for several pelvic categorise the severity of haematuria,'4 according to transfusion needs during the 3 months preceding cancers. Radiation-induced cystitis is a late adverse during hyperbaric oxygen treatment: slight haematuria can develop after a delay of up to 21 years.
required no transfusion, moderate haematuria required 1-6 units Radiation causes a progressive obliterative endarteritis of of blood; and severe haematuria required over 6 units (table 2).
the small blood vessels, resulting in cellular hypoxia.' Severe haematuria was most often seen in patients who had had Patients with severe haemorrhagic radiation-induced radiotherapy for bladder carcinoma. Pretreatment investigations cystitis may need regular blood transfusions. Different were cystoscopy, intravenous urograms/or ultrasound of the local treatments have been advocated, eg, aminocaproic upper urinary tract, chest radiograph, blood examination, acid; tranexamic acid; corticosteroids; exclusion of coagulation disorders, and urine culture.
antibiotics; prostaglandins; sodium pentosanpolysulphate; HBO treatment was 20 sessions of 100% oxygen inhalation at bladder distension; electrocoagulation; laser-coagulation; 3-bar pressure for 90 minutes in a multiplace hyperbaric arterial ligation; embolisation; and intravesical instillation chamber. Treatment was given in daily sessions 5 or 6 times aweek. In 4 with alum, silver nitrate, phenol patients, 40 sessions were given because of persistence or formalinY These of haematuria. Most patients required bladder washouts during treatments do not cure the radiation-induced cystitis the early phase of treatment. Before patients entered the itself, nor prevent recurrence of severe haematuria. The chamber, eustachian-tube function was assessed, and a nasal most successful (formalin and phenol) have serious side- decongestive spray was given if necessary. When this was effects and add to the bladder fibrosis brought on by insufficient, tympanostomy tubes or a myringotomy were radiation treatment. considered. After HBO treatment, patients had a cystoscopy to Hyperbaric oxygen (HBO) is a relatively new treatment evaluate the effects. Further follow up was carried out at our for radiation-induced haemorrhagic cystitis; 56 cases have centre or by the referring urologist.
been reported,4 apart from our experience.'" It is the onlytreatment which is thought to reverse the vascular radiation-induced pathophysiology,2,11 Median follow up was 13 months. 11 patients died, after a neovascularisation of the bladder wall and so increasing mean of 23-8 months (range 1-61). Causes of death were: tissue oxygen tension. HBO has potential side effects12 cancer metastasis (4), unrelated causes (3), unknown (4).
caused by barometric pressure changes or oxygen toxicity.
Four patients had a cystectomy for small bladder However, serious complications such as central nervous capacity (3) or recurrence of bladder cancer (1).
system toxicity and decompression sickness are rare in the Recurrence of severe macroscopic haematuria occurred in low-pressure, short-duration oxygen inhalation treatments nine patients, leading to cystectomy in four. Figure 1 used clinically. shows a Kaplan-Meier curve of cumulative freedom from We report results of treatment in 40 patients with recurrence of severe haematuria; cystectomy or death radiation-induced severe haematuria.
were censored observations.
Overall recurrence of severe haematuria was 0'12/year.
Academic Medical Center (R F M Bevers MD, K H Kurth PhD), Three groups of patients could be distinguished according University of Amsterdam, Departments of Urology and Surgery to their reaction to HBO: group 1 had no haematuria J Bakker PhD), Amsterdam, The Netherlands after treatment for at least 3 months; group 2 had Correspondence to: Dr R F M Bevers, AMC University Hospital, occasionally slight haematuria, and group 3 did not react Meibergdreef 9, 1105 AZ, Amsterdam ZO, The Netherlands to treatment.
*Good=no haematuria, moderate=occaslonal slight haematuna.
Table 4: Cancer type and results of HBO Table 2: Cancer type, severity of haemorrhagic cystitis, andtransfusion requirements (blood units) was seen only in patients with a very severe haemorrhagic Group one (30 patients) radiocystitis. However, the majority of patients with Mean follow up was 29-3 months (range 3-74). In this severe haematuria improved on HBO (table 3).
group, three patients had a recurrence of haematuriarequiring treatment after a mean period of 13-3 months; haematuria was due to cancer recurrence in two. In three These results confirm our initial findings" that HBO is patients cystectomy was done because of small bladder useful in patients with severe radiation-induced cystitis capacity after a mean of 9-0 months. During follow up causing haematuria.
(mean 27-6 months) 9 patients died without cystectomy.
Adverse effects of HBO have been reported'2,13 but were not observed in the present study. The effect of treatment Group two (seven patients) was not influenced by sex, age, or radiation dose.
Mean follow up was 5-1 months (range 1-13). Severe Differences were seen according to the initial type of recurrent haematuria was seen in 4 patients after a mean cancer for which patients were treated (table 4). In group of 2-3. In one patient, cystectomy was done for cancer two (7 patients) occasional slight haematuria after recurrence; one patient died from metastases. All patients treatment was due to cancer recurrence. Cancer was only in group two had recurrence of bladder (6) or prostate (1) recognised after HBO when oedema disappeared and cancer. In three patients, recurrence was seen 3 months normal mucosa was restored in non-cancerous areas of after HBO. In these patients judgment of bladder the bladder-HBO may be even more effective if patients pathology at pre-treatment cystoscopy was not possible with cancer recurrence could be diagnosed with more because of bleeding, oedema, and inflammation. Random accuracy before starting treatment.
biopsy taken before treatment showed radiation-induced HBO does not promote cancer growth. Feldmeier et al cystitis but no cancer. After HBO had cured the radiation conclude in a review article that most published reports cystitis, the previously hidden cancer became apparent show no evidence for tumour growth-enhancement by (see Discussion).
HBO." Until now, HBO has been used only for patientswith severe end-stage haemorrhagic radiation cystitis. We Group three (three patients) treated patients who showed no reaction to conventional These patients did not benefit from HBO. They had a therapy. Because the only alternative treatment in such mean transfusion need of 25-7 units blood. HBO was patients is cystectomy, a prospective randomised trial is stopped, and further treatment carried out in the referring not possible.
urologists' hospitals: 1 patient had a cystectomy and 2 In this study, bladder preservation (in regard to died due to heart disease.
cystectomy for recurrent severe haematuria) was achieved Comparison of the severity of initial haematuria and in 36 patients. HBO deserves a position in the treatment haematuria after HBO revealed that failure of treatment of radiation-induced haemorrhagic cystitis and should notbe reserved only for severely affected and conventionaltherapy-resistant patients only.
Moss WT, Brand WN, Battifora H. Radiation Oncology: Rationale,Technique, Results. St. Louis: C V Mosby, 1979; 246-51.
2 Noordzij JW, Dabhoiwala NF. Hemorrhagic radiation cystitis.
Int Urogynecol J 1993; 4: 160-67.
3 Parsons CL. Successful management of radiation cystitis with sodium pentosanpolysulfate. J Urol 1986; 136: 813-14.
4 Schoenrock GJ, Cianci P. Treatment of radiation cystitis with hyperbaric oxygen. Urology 1986; 27: 271-72.
5 Nakada T, Yamaguchi T, Sasagawa I, Kubota Y, Suzuki H, Izumiya K. Successful hyperbaric oxygenation for radiation cystitis dueto excessive irradiation to uterus cancer. Eur Urol 1992; 22: 294-97.
6 Norkool DM, Hampson NB, Gibbons RP, Weissman RM. Hyperbaric 10 Rijkmans BG, Bakker DJ, Dabhoiwala NF, Kurth KH. Successful oxygen therapy for radiation-induced hemorrhagic cystitis. J Urol 1993; treatment of radiation cystitis with hyperbaric oxygen. Eur Urol 1989; 150: 332-34.
7 Weiss JP, Mattei DM, Neville EC, Hanno PM. Primary treatment of 11 Kindwall EP. Hyperbaric oxygen treatment of radiation cystitis: radiation-induced hemorrhagic cystitis with hyperbaric oxygen: 10 year management of chronic radiation wounds. Clin Plast Surg 1993; 589-92.
experience. J Urol 1994; 151: 1514-17.
12 Gabb G, Robin ED. Hyperbaric oxygen: a therapy in search of 8 Lee HC, Liu CS, Chiao C, Lin SN. Hyperbaric oxygen therapy in diseases. Chest 1987; 92: 1074-82.
haemorrhagic radiation cystitis: a report of 20 cases. Undersea Hyperb 13 Grim PS, Gottlieb LJ, Boddie A, Batson E. Hyperbaric oxygen therapy.
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9 Akiyama A, Ohkubo Y, Takashima R, Furugen N, Tochimoto M, 14 Feldmeier JJ, Heimbach RD, Davolt DA, Brakora MJ, Sheffield PJ, Tsuchiya A. Hyperbaric oxygen therapy in the successful treatment of Porter AT. Does hyperbaric oxygen have a cancer-causing or promoting two cases of radiation-induced hemorrhagic cystitis (Japanese). Nippon review of the pertinent literature. Undersea Hyperb Med 1994; Hinyokika Gakkai Zasshi 1994; 85: 1269-72.
responses to available therapy, and 1-year survival remains at 15% or less.5 CBL-1 is a murine IgM monoclonalantibody directed against a 15 kDa glycolipid antigen of Response of steroid-resistant graft-versus- unknown function on activated T cells, natural killer cells, host disease to lymphoblast antibody and a subpopulation of monocytes.7 CBL-1 infusion canreverse rejection of human kidney allografts.8 Because of the antibody's activity against a spectrum of cellsimplicated in established GVHD, we have assessed its effect in patients with the severe, steroid-resistant form ofthe disease.
The study was approved by our institutional review board and all patients gave informed consent. All ten patients (table) Therapy of steroid-resistant graft-versus-host disease received targeted-dose cyclosporin for GVHD prophylaxis. As (GVHD) with antibodies to T cells or cytokines is of limited additional prophylaxis, all marrow from HLA-mismatched familymembers value because GVHD is mediated or from matched unrelated donors was first a pleomorphic group of T cells.o Acute GVHD was graded' daily in these patients.
effective cells and cytokines. CBL-1, a murine monoclonal Patients on study had grade II or greater GVHD that had antibody, recognises an antigen on activated T cells, B persisted or progressed despite 8-42 days' treatment with cells, and natural killer cells. We administered CBL-1 to ten steroids, including 5 mg/kg methylprednisolone for at least patients with grade III or IV steroid-resistant GVHD.
5 days. CBL-1 was given as a test dose of 0-01 mL/kg Complete remissions occurred in five cases and partial (concentration varies with batch). 4 hours later, 0-1 mL/kg (up to remissions in four. The organ system(s) affected by GVHD mL) was infused in 100 mL 5% dextrose and saline intravenously over 1 hour. This dose was repeated for was not a predictor of response. CBL-1 was well tolerated 3 days. CBL-1 was then given on alternate days in halving doses, and did not exacerbate post-transplant immunodeficiency.
until 0-025 mUkg was reached. This lower dose was continued Our findings support the use of CBL-1 in primary weekly for up to 6 weeks if mild to moderate GVHD prophylaxis for GVHD.
GVHD completely resolved in five patients and in four Lancet 1995; 346 : 805-06 others the disease improved by at least two grades, whichgives an overall response rate of 90% (table). In allresponders, GVHD discernibly improved 2-14 days after Graft-versus-host disease (GVHD) continues to be a the antibody infusion was begun. Remissions were major source of morbidity and mortality in patients generally well maintained in complete responders, even undergoing allogeneic bone-marrow transplantation.' after the CBL-1 infusion had been discontinued. The Whilst improved GVHD prophylaxis lowers the frequency only recurrence of acute GVHD in a complete responder and severity of this complication in recipients of MHC- developed 4 weeks after cessation of therapy and, unlike matched sibling allografts,' the increased use of MHC- the primary condition, was steroid-responsive. One partial mismatched or unrelated-donor grafts has allowed GVHD responder (case 138) had a recurrence in the gut 2 weeks to retain its status as the primary cause of death in after CBL-1 was discontinued, which was eventually fatal.
allogeneic marrow-transplant recipients. Patients with The child (case 167) who failed to respond to CBL-1 severe (grade III or IV) GVHD who fail to respond to subsequently responded to anti-thymocyte globulin and is steroid therapy have an especially poor prognosis.
alive with limited chronic skin GVHD at 1173+ days. Of Immunomodulation six evaluable patients, four went on to develop chronic antagonists intended to inactivate cellular or cytokine disease that was confined to the skin in three cases. The components of the immune system'-5 are the most widely median survival of patients who received CBL-1 was 194 used second-line therapies, but none are satisfactory.
days (range 37-1000+ days), and four patients are still Most antibody therapies are directed at T lymphocytes.
Whereas these cells initiate GVHD, various additional Whether or not a patient responded to CBL-1 did not cellular and cytokine mechanisms contribute to its appear to depend on the organ systems affected (table), so persistence and progression. Although higher response that even patients with severe involvement of skin, gut, rates may be seen with agents that interrupt the action of: and liver responded. CBL-1 administration was well effector molecules, such as interleukin 1 or tumourv tolerated. Two patients had fever, chills, muscle pain, and necrosis factor, GVHD frequently recurs after the agents mild hypotension 1-2 hours after their initial dose, but have been stopped.4,1> Overall, fewer than 30% of patients; these side-effects were controlled with diphenhydramine with steroid-resistant GVHD have complete or partialI and hydrocortisone. No patient developed symptoms or

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