Comparison of intravesical hyaluronic acid instillation and hyperbaric oxygen in the treatment of radiation-induced hemorrhagic cystitis

Authors


Professor Zhou-jun Shen, MD, PhD, Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China. e-mail: shenzhoujun@hotmail.com

Abstract

Study Type – Therapy (RCT)

Level of Evidence 1b

What's known on the subject? and What does the study add?

Hemorrhagic cystitis (HC) is a relatively rare bladder disease with a complex etiology. With the growing number of patients with pelvic radiation therapy, incidence of this disease has risen considerably. Although treatments like hyperbaric oxygen (HBO) had some benefit to improve the symptoms, the optimal treatment of this disease still remains a tough problem.

We reported our experience of intravesical hyaluronic acid (HA) and HBO in treating HC and the results seemed interesting. Intravesical HA is easier to do and well tolerated, and it showed a sustained decrease of bladder bleeding, pelvic pain and frequency of voiding for at least 12 months. We suggest it as an alternative and potential way in treating HC.

OBJECTIVE

  • • To compare the efficacy of intravesical hyaluronic acid (HA) instillation and hyperbaric oxygen (HBO) in the treatment of radiation-induced haemorrhagic cystitis (HC).

PATIENTS AND METHODS

  • • In total 36 patients who underwent radiotherapy for their pelvic malignancies and subsequently suffered from HC were randomly divided into an HA group and an HBO group.
  • • Symptoms of haematuria, frequency of voiding and the visual analogue scale of pelvic pain (range 0–10) were evaluated before and after the treatment with follow-up of 18 months.

RESULTS

  • • All patients completed this study and no obvious side effects of intravesical HA were recorded.
  • • The improvement rate showed no statistical difference between the two groups at 6, 12 and 18 months after treatment.
  • • Decrease of frequency was significant in both groups 6 months after treatment, but was only significant in the HA group 12 months after therapy.
  • • The improvement in the visual analogue scale remained significant in both groups for 18 months.

CONCLUSIONS

  • • Intravesical instillation of HA was as effective in treating radiation-induced HC as HBO.
  • • It is well tolerated and resulted in a sustained decrease of bladder bleeding, pelvic pain and frequency of voiding for at least 12 months.
Abbreviations
HC

haemorrhagic cystitis

HSCT

haematopoietic stem cell transplantation

IC

interstitial cystitis

HBO

hyperbaric oxygen

HA

hyaluronic acid

VAS

visual analogue scale

CR

complete response

PR

partial response.

INTRODUCTION

Haemorrhagic cystitis (HC) is defined as a diffuse inflammatory condition of the bladder due to an infectious or non-infectious aetiology resulting in bleeding from the bladder mucosa. It is a relatively common and potentially severe complication of high-dose chemoradiotherapy for the treatment of pelvic malignancies, especially in conjunction with haematopoietic stem cell transplantation (HSCT) [1]. The clinical manifestations of this disorder vary from microscopic haematuria to severe haemorrhage with clot formation and urinary tract obstruction, even leading to hydronephrosis and acute renal failure when it becomes chronic and recurrent. In the late stage of the disease, acute and chronic ischaemia of the bladder wall occurs as described for interstitial cystitis (IC) [2]. Symptoms commonly associated with both bladder diseases include urinary frequency, urgency and pelvic pain [3]. Many patients develop a significant reduction in bladder capacity secondary to fibrosis of the bladder wall [4].

Hyperbaric oxygen (HBO) treatment of urology patients has already been used extensively and successfully for the treatment of HC and has gained considerable clinical recognition during the last 15 years [5,6]. But the cost is high and the treatment is still not available in most hospitals in China who lack the hardware. Intravesical instillation of hyaluronic acid (HA) has shown some benefit in the treatment of IC and also in HC according to other reports [1,7]. Because of its ease of use and safety, we think it is valuable to evaluate the efficacy of intravesical HA in the treatment of radiation-induced HC.

PATIENTS AND METHODS

In all, 36 patients who underwent radiotherapy for their pelvic malignancies (including cervical cancer, rectal cancer and prostatic cancer) from November 2004 to December 2008 and who subsequently suffered from HC were included in this study. Patients receiving radiotherapy for bladder cancer were excluded. Every patient signed a written consent form before receiving intravesical HA instillation or HBO treatment. This study was approved by the institutional ethics review board.

HC was defined as the presence of macroscopic haematuria in the absence of other conditions such as gynaecological-related bleeding, nephrolithiasis and/or bacterial or fungal infection of the lower urinary tract. Urine cultures for bacterial and fungal pathogens were obtained from all patients during the episode of haematuria. The severity of HC was graded according to the following criteria [8]: I, microscopic haematuria; II, macroscopic haematuria; III, macroscopic haematuria with the presence of clots and/or decrease in haemoglobin levels necessitating blood transfusions; IV, life-threatening bleeding, not responding to treatment and necessitating surgical intervention.

Patients were randomly divided into two groups, the HA group (n= 16) with a median (range) age of 59 (46–74) years and the HBO group (n= 20) with a median (range) age of 60 (39–77) years. We used computer-generated random numbers to perform the randomization. Patients' characteristics are shown in Table 1.

Table 1.  Patients' characteristics before the treatment
 HA groupHBO group
  1. F, female; M, male.

Original disease  
 Cervical cancer (radiation dose)5 (50–60 Gy)7 (50–60 Gy)
 Prostatic cancer (radiation dose)4 (55–70 Gy)4 (55–70 Gy)
 Rectal cancer (radiation dose)7 (F1; M6) (45–60 Gy)9 (F1; M8) (45–60 Gy)
Age (range)59.3 (46–74)60.3 (44–78)
 Degree of haematuria  
 I00
 II6/1610/20
 III10/1610/20
 IV00
Bladder irrigation3/163/20

In the HA group, 40 mg of HA was slowly instilled into the bladder of the patients through a Foley catheter. When all the solution had been instilled the catheter was clamped for a minimum of 20 min. Bladder irrigation (if performed) was usually resumed following drug administration only when urine excretion was decreased due to clot formation. All patients received intravesical instillation weekly in the first month and then monthly in the following 2 months. In the HBO group, patients received 100% oxygen in a hyperbaric chamber at a pressure of 2.5 atm absolute, 60 min bottom time, once a day, 7 days a week, for at least 1 month and were followed up over 18 months. In principle, 30 HBO treatments per course were performed.

Symptoms of haematuria, frequency of voiding and the visual analogue scale (VAS) of pelvic pain (range 0–10) were evaluated before and after the course of treatment; therapeutic efficacy was evaluated every 6 months up to 18 months. Response to treatment was defined as follows. Initial response was defined as the day when amelioration of symptoms appeared; complete response (CR) was defined as the day on which all symptoms including macroscopic haematuria, dysuria etc. disappeared. Disappearance of clots but with persistence of macroscopic haematuria was defined as partial response (PR). Any other result was considered as no response.

RESULTS

All 36 patients completed this study and only one case in the HA group took a second course of HA instillation 15 months after the first HA treatment due to HC recurrence. No obvious side effect of intravesical HA was recorded.

Our analysis included all those cases that completed their treatment and follow-up. The age, gender and primary disease showed no statistical difference between the two groups. The improvement rate (CR and PR) of both groups is shown in Table 2. At 6, 12 and 18 months after treatment, the improvement rate showed no statistical difference between the two groups.

Table 2.  Improvement rate after treatment in the HA and HBO groups
Time aftertreatment (months)Improvement rate
HAHBO
  1. *P > 0.05. The P value was determined using Fisher's exact test for proportions. It refers to the comparison before and after treatment in the HA and HBO groups.

6  
 CR14/16*15/20*
 PR16/16*19/20*
12  
 CR12/16*10/20*
 PR15/16*17/20*
18  
 CR8/16*9/20*
 PR12/16*15/20*

The change in voiding frequency and VAS are listed in Tables 3 and 4. A decrease in frequency was significant in both groups 6 months after treatment, but only significant in the HA group 12 months after therapy. The Wilcoxon signed-rank test showed a statistical difference in the reduction in frequency 12 months after treatment (P= 0.002). The improvement in VAS remained significant in both groups until the last follow-up at 18 months.

Table 3.  Changes in voids per day and VAS in the HA group
 Time after treatment (months)
0 (baseline)61218
  1. *P < 0.01; **P < 0.05. The P value was determined using the Wilcoxon signed-rank test. It refers to the comparison before and after treatment in the HA group.

Voids per day10.4 ± 1.87.5 ± 0.9*8.9 ± 1.4*10.3 ± 1.5
 Change from baseline −2.9 ± 1.7−1.5 ± 1.4−0.18 ± 0.54
VAS2.75 ± 2.241.88 ± 1.41**1.44 ± 1.36*1.25 ± 1.53*
 Change from baseline −0.88 ± 1.41−1.31 ± 1.3−1.50 ± 1.21
Table 4.  Changes in voids per day and VAS in the HBO group
 Time after the treatment (months)
0 (baseline)61218
  1. *P < 0.01. The P value was determined using the Wilcoxon signed-rank test. It refers to the comparison before and after treatment in the HBO group.

Voids per day9.8 ± 1.748.6 ± 1.35*9.7 ± 1.9810.0 ± 1.97
 Change from baseline −1.2 ± 1.06−0.15 ± 0.990.2 ± 0.83
VAS2.5 ± 2.241.6 ± 1.79*1.6 ± 1.88*1.35 ± 1.69*
 Change from baseline −0.9 ± 0.79−0.9 ± 1.02−1.15 ± 1.22

The main side effect of HA instillation was urinary tract infection due to repeated urethral catheterization. Its incidence seemed higher than HBO (42.8% vs 10%, P= 0.034) in the first 6 months but with no significant difference at 12 (50% vs 25%, P= 0.132) and 18 months (50% vs 30%, P= 0.135) after treatment.

DISCUSSION

Radiation-induced HC is difficult to treat because of its unknown aetiology. Since there are no well controlled trials available comparing the existing treatment options, firm guidelines cannot be made [9]. Attempts to reduce radiation-induced HC using various oral agents such as steroids, vitamin E and orgotein have not met with success. Currently, accurately tailoring the irradiation field and limiting the radiation dose to the bladder are employed to reduce the incidence of haematuria.

Several studies have shown the use of HBO in patients with HC and have reported remarkable response rates regarding the reduction of pelvic pain, irritative voiding symptoms, particularly urgency, and gross haematuria [10,11]. HBO therapy was initially introduced in 1953 as a radiosensitizer in radiation oncology. It was later found to decrease the radiation effects on various organs including the bladder [12]. Under the condition of HBO, alveolar, arterial and tissue oxygen levels are driven to supraphysiological levels, thereby stimulating angiogenesis, fibroblast proliferation and collagen formation [13]. Bevers et al. [14] reported the only prospective study so far on the role of HBO. The patients underwent 20 sessions of 100% oxygen inhalation at 3 bar for 90 min. At 3 months follow-up, an overall response rate of 92.5% was demonstrated among 40 patients who were refractory to standard measures. With a mean follow-up of 23 months, the recurrence rate of severe haematuria was 12% per year. In another study employing an HBO protocol of 2.36 atm of absolute pressure with 90 min of 100% oxygen per treatment for a minimum of 40 sessions, Chong et al. [15] reported that early intervention, within 6 months of haematuria, resulted in a superior therapeutic response in complete (96%) or partial (66%) resolution of symptoms. HBO is generally well tolerated. Initially concerns were raised regarding the risk of tumour growth because of HBO-mediated angiogenesis, immunosuppression and free radical toxicity. Following a review of all the available literature in 2003, Fieldmeier and Hampson [16]. concluded that HBO had no more than a neutral effect on tumour growth.

HA is a major mucopolysaccharide found widely in the connective, epithelial and neural tissues. It is one of the main components of the extracellular matrix that contributes significantly to cell proliferation and migration. It also constitutes a protective barrier against irritating agents that can potentially cause damage to epithelium [1,17]. HA exhibits a variety of properties that may contribute to its prophylactic mechanism [18,19], which include inhibition of immune complexes, adherence to poly-morphonuclear cells, inhibition of leucocyte migration, regulation of fibroblast and endothelial cell proliferation, enhancement of connective tissue healing etc. A damaged glycosaminoglycan layer may lead to direct exposure of epithelial cells to components of urine; for this reason the possibility of bacterial adherence and infection increases [17]. This damage is proposed to be a causative factor in the development of HC especially due to HSCT.

HA has been used in patients with IC in previous studies with beneficial results [20]. In view of the different mechanisms of action of HA and its known effectiveness in the setting of IC, it has been used as an alternative treatment in patients with HC. In the study of Miodosky et al. [1], seven patients suffering from HA as a complication of HSCT received HA instillation once a day for an average of 3 days, range 2–7. Four out of seven HC patients achieved an initial response and three who did not respond received a second course of treatment during the first 7 days after treatment with HA. Overall, six out of seven patients achieved an initial response at an average of 3.5 days, range 2–23. Five out of seven patients achieved a complete response at an average of 12 days, range 7–23. One of seven patients had a partial response and one had no response (death from septic shock). But no local or systemic side effects occurred. HA instillation can show immediate benefit in releasing the macroscopic haematuria, pain and frequency of voiding in these patients. And its effective duration after therapy is quite satisfactory.

In our study, intravesical HA can provide sustained amelioration of haematuria of HC just as well as HBO. Reduction of voiding frequency was significant at 6 and 12 months after HA instillation, while this effect of HBO could only last for 6 months. The significant improvement of VAS was maintained for 18 months in both groups.

Despite its slightly higher incidence of urinary tract infection, intravesical instillation of HA is cheaper and much more convenient than HBO treatment. Intravesical HA can be an alternative therapy in the management of radiation-induced HC, although part of its efficacy may decrease after 12 months.

The main limitation of this study was the small number of patients and the relatively short follow-up time. A prospective randomized control study with a large number of patients and long-term follow-up is recommended.

Intravesical instillation of HA appears to be effective to treat HC patients. It is well tolerated and resulted in a sustained decrease of bladder bleeding, pelvic pain and frequency of voiding for at least 12 months. Our results showed that HA was as effective as HBO as a potential treatment for patients with HC.

CONFLICT OF INTEREST

None declared.

Ancillary