Japanese Journal of Clinical Oncology

INTRODUCTION

The standard treatment for muscle-invasive bladder cancer without regional lymph node and/or distant metastasis is radical cystectomy with an incontinent or continent urinary diversion (1). However, for selected patients, it has been demonstrated that intra-arterial chemotherapy with or without radiotherapy produces the same survival outcomes as radical cystectomy (2,3). Since 1990, in our institution we have been conducting a prospective study of a bladder-sparing regimen which consisted of intra-arterial chemotherapy plus concurrent pelvic radiotherapy for the patients with invasive bladder cancer categorized as T2 or T3 N0M0 after informed consent. We have ever treated 42 consecutive patients and over 90% of them preserved their bladders for at least 3 years, while the 3-year actual local control and disease-free survival rates were 84 and 72%, respectively (3). This protocol had been designed mainly to study the anti-tumor effects of the therapy and the survival outcomes of the patients. Therefore, the functional assessment of the preserved lower urinary tract using a urodynamic study had not been scheduled in our regimen, so the function of the preserved lower urinary tract in these patients has not been discussed. However, one of the aims of the bladder-sparing regimens is the maintenance of the quality of life of the patient. Therefore, the treatment must not have any harmful effect upon the lower urinary tract and it is essential to see whether the preserved lower urinary tract has a normal function or not. For this reason, an assessment of the preserved lower urinary tract function is clearly indicated for patients who have undergone the bladder-sparing regimens.

It has been well demonstrated that a poor correlation exists between the lower urinary tract symptoms and the urodynamic findings in patients with bladder outlet obstruction or neurogenic bladder dysfunction (4,5). This is the reason why a precise evaluation of the function cannot be achieved without a very thorough urodynamic study. Accordingly, we conducted urodynamic studies in order to evaluate the efficacy of the bladder-sparing regimen regarding the function of the preserved lower urinary tract.

PATIENTS AND METHODS

We retrospectively evaluated 18 of the 42 consecutive patients who underwent a bladder-sparing regimen at Tsukuba University Hospital. These 18 patients gave informed consent and agreed to undergo a urodynamic study (UDS) before and/or after the treatment. The remainder of the 42 patients could not be examined by UDS, because they had overt neurological diseases (such as post-brain infarction) or rejected the examination. Four patients were eliminated from the study because one had a large benign prostatic enlargement and three underwent the UDS only once. Clinical features between the patients with or without the urodynamic study showed no significant differences (data not shown).

Bladder-sparing Regimen

The bladder-sparing regimen performed at our institute has been explained elsewhere in detail (3). Briefly, the patients with histologically confirmed transitional cell carcinoma after transurethral resection of bladder tumor (TUR-BT) and a clinical stage T2 to T3N0M0 revealed by intravenous urography (IVU), ultrasonography, abdominopelvic computed tomography (CT), chest radiography and radionuclide bone scan received this therapy after informed consent. The bladder-sparing regimen consisted of bilateral internal iliac intra-arterial chemotherapy using Seldinger's technique, which was repeated three times at intervals of 3 weeks and concurrent irradiation to the small pelvis (41.4 Gy). The chemotheraputic agents infused were cisplatin (CDDP: 50 mg/m² per cycle) and methotrexate (MTX: 30 mg/m² per cycle). Three weeks after the last intra-arterial chemotherapy session, transurethral biopsies were performed to confirm the pathological response. If the biopsy did not show a pathological complete response, the patient received boost irradiation to the primary tumor site using Proton (33 Gy) or Linac (19.8 Gy).

Assessment of the Lower Urinary Tract Function

Although our bladder-sparing regimen was performed prospectively, the urodynamic study was not included in the routine follow-up schedule. The UDS consisted of a filling cystometry (FCMG) for assessing the storage function and a pressure flow study (PFS) for assessing the emptying function. Lower urinary tract symptoms (LUTS), including the storage symptoms (daytime frequency, nocturia, urgency, sense of residual urine, urinary incontinence) and emptying symptoms (hesitancy, intermittency, poor stream, straining on void, terminal dribbling) and perineal neurological findings were also examined at each UDS. The UDS, using a UD5000 (Dantec Co., Denmark), was conducted according to ICS recommendations (6). Briefly, the intravesical pressure (P_ves) and intrarectal pressure (P_abd) were measured with the use of an 8Fr double-lumen urodynamic catheter and a `finger of an examination glove'-mounted 12Fr Nelaton catheter, respectively. P<sub>abd</sub> was electrically subtracted from P<sub>ves</sub> to obtain the detrusor pressure (P<sub>det</sub>). Sphincter activity was evaluated via perianal surface electrodes. For the FCMG, room temperature distilled water was instilled into the bladder at a rate of 30-50 ml/min with the patient in a mild lithotomy position. Maximum cystometric capacity (MCC), bladder compliance (V<sub>comp</sub>) that was calculated by the equation compliance = (maximum static P<sub>det</sub> - initial P<sub>det</sub>)/volume at maximum static P<sub>det</sub> and uninhibited detrusor contraction (UIC) were measured and calculated as representatives of storage function. MCC was thought to be within the normal limit when it ranged from 300-600 ml and decreased bladder compliance was defined as V<sub>comp</sub> [le] 20 cmH<sub>2</sub>O. The PFS using the same catheter was conducted with the male subjects in the standing position and the female subjects in the sitting position. Detrusor pressure at maximum flow (P<sub>detQmax</sub>) and maximum flow rate (Q<sub>max</sub>) were measured as representatives of emptying function. The existence of abdominal straining on a pressure-flow tracing was also noted. When the values of P<sub>abd</sub> exceeded the values of P<sub>det</sub> throughout micturition, the condition was defined as `detrusor hypocontractility'. Also, when only the abdominal straining without apparent P_det rise contributed to micturition, the condition was defined as `detrusor acontractility'. The results of the UDS were retrospectively reviewed from the patients’ clinical charts. The pretreatment UDS was not scheduled for all patients, because the interval between the TUR-BT and the first intra-arterial chemotherapy is short. Therefore, only seven patients were able to compare the post-treatment UDS with the pretreatment UDS. At the pretreatment UDS, the patients did not have significant hematopyuria, nor did they have any cystoscopically and/or radiologically visible residual tumor. In these seven patients, the post-treatment UDS was divided into four periods: less than 1 year (seven patients: range 1-9 months, median 5 months), from 1 to 2 years (five patients: range 13-20 months, median 18 months) and more than 2 years (five patients: range 25-36 months, median 30 months) after completion of the treatment. The urodynamic findings of each period were compared with the pretreatment findings. In the remaining seven patients for whom the treatment schedule did not allow pretretment studies, the post-treatment UDS was divided into two periods: less than 2 years (range 16-23 months, median 20 months) and more than 2 years (range 26-57 months, median 46 months). The urodynamic findings were compared within the corresponding patients in order to make sure of the results from the former seven patients. In addition, the existence of upper urinary tract deterioration and bladder deformity on IVU and telangiectasia and/or any urethral abnormality on cystourethroscopy were also noted from retrospectively reviewed clinical charts in the 14 patients.

Statistical Analysis

Differences of the urodynamic parameters in the sequential UDSs were evaluated by the Wilcoxon test and P < 0.05 was considered significant.

RESULTS

Patient Characteristics

We evaluated 14 patients, none of whom had overt neurological diseases or bladder outlet obstruction. The mean age of the patients was 63.6 years (range 45-75 years) at the treatment and the male to female ratio was 9:5. All patients had cT2 (5) to T3 (9) N0M0 transitional cell carcinoma of the urinary bladder and underwent the bladder-sparing regimen with successful results. No significant treatment-related complications occurred, but mild sciatic neuropathy was noted in five patients, all of whom had abnormal urodynamic findings (decreased MCC in one, UIC and/or decreased compliance in three, impaired detrusor contractility in one). At the follow-up UDS, none of the 14 patients showed any recurrence and/or metastasis and had not received medication that affected the lower urinary tract function. The median follow-up period up to the latest UDS of the 14 patients was 34 months (range 3-57 months).

Overall Urodynamic Findings

The results of the UDS are shown in Fig. 1 and Tables 1-3. There were no significant differences in all the urodynamic parameters evaluated (Fig. 1 and Table 3). The pretreatment UDS demonstrated significant lower urinary tract dysfunctions in all of the seven patients and most of the abnormal findings remained during the follow-up period (Table 1). The overall trends of the serial urodynamic findings in the patients without the pretreatment UDS were similar to the findings in the patients with the pretreatment UDS (Tables 1 and 2). It should be noted that the latest UDS revealed some storage dysfunctions in 11 (79%) and some emptying dysfunctions in three (23%) of the 14 patients.

A	B
C	D

Figure 1. Urodynamic parameters before and after the treatment. (A) Maximum cystometric capacity; (B) bladder compliance; (C) detrusor pressure at maximum flow rate; (D) maximum flow rate. Horizontal axis indicates the time at each urodynamic study. Pre, pretreatment; [le]1yr, less than 1 year after the treatment, 1<yr[le]2, 1-2 years after the treatment; >2yr, more than 2 years after the treatment. Cases 6 and 7 underwent the latest urodynamic study 7 and 3 months after the treatment, respectively.

Table 1. Summary of the urodynamic findings before and after the treatment

Case No.	Pretreatment	<1 year	1-2 years	>2years
1	Vcomp[darr]	Vcomp[darr]	UIC, Vcomp[darr]	UIC, Vcomp[darr]
2	Vcomp[darr]	UIC	UIC	Exacerbation of UIC
				Vcomp[darr]
3	Vcomp[darr]	Vcomp[darr]	Improvement of	MCC[darr]
	Hypocontractility	Acontractility	contractility
4	Hypocontractility	UIC	Hypocontractility	Vcomp[darr]
		Hypocontractility		Hypocontractility
5	UIC, MCC[darr]	UIC, Improvement of MCC	UIC	UIC
6	MCC[darr]	UIC, Vcomp[darr], MCC[darr]
7	UIC	MCC[darr]

V_comp[darr], bladder compliance <20 cmH₂O; UIC, uninhibited detrusor contraction; MCC[darr], maximum cystometric capacity <300ml.

Table 2. Summary of the urodynamic findings less than and more than 2 years after the treatment in the patients without the pretreatment urodynamic study

Case No.	<2 years	>2 years
8	Normal	Normal
9	Normal	Normal
10	Vcomp[darr], MCC[darr]	Improvement of Vcomp
		MCC[darr]
11	Vcomp[darr], MCC[darr]	UIC, Vcomp[darr], MCC[darr]
	Hypocontractility	Hypocontractility
12	Vcomp[darr], MCC[darr]	Improvement of Vcomp
	Hypocontractility	MCC[darr]
		Hypocontractility
13	UIC, Vcomp[darr], MCC[darr]	Vcomp[darr], MCC[darr]
	Hypocontractility	Acontractility
14	Hypocontractility	Normal

V_comp[darr], bladder compliance <20 cmH₂O; UIC, uninhibited detrusor contraction; MCC[darr], maximum cystometric capacity <300 ml.

Table 3. Urodynamic findings in the patients without the pretreatment urodynamic study

Parameter	<2 years	>2 years*
MCC (ml)	347.1 ± 131.1	311.6 ± 143.0
Vcomp (ml/cmH2O)	59.5 ± 61.3	43.4 ± 32.4
PdetQmax (cmH2O)	29.5 ± 9.5	29.8 ± 17.8
Qmax (ml/s)	13.7 ± 3.7	13.1 ± 3.3

MCC, maximum cystometric capacity; V_comp, bladder compliance; P_detQmax, detrusor pressure at maximum flow rate; Q_max, maximum flow rate.
*There are no significant differences in any of the urodynamic variables compared with less than 2 years.

Storage Function

UIC and decreased bladder compliance, which might be associated with the storage symptoms, were the most frequent findings and were recorded in 29 and 43% before the treatment, 57 and 43% less than 1 year, 60 and 20% 1-2 years and 60 and 60% more than 2 years after the treatment, respectively (Table 1). UIC was exaggerated in one patient during the follow-up period. MCC tended to decrease less than 1 year after the treatment and to increase gradually with time (Fig. 1A). V_comp decreased in three patients, improved in two and remained below 20 ml/cmH₂O in one (Fig. 1B). It should be noted that all of the patients examined had some storage dysfunctions at the latest FCMG (Table 1). In the patients who had not undergone the pretreatment UDS, decreased MCC and decreased compliance were the most frequent findings and were recorded in 57 and 57% less than 2 years and 53 and 23% more than 2 years after the treatment, respectively (Table 2). It should be noted that four of the seven patients (57%) had some storage dysfunctions at the latest FCMG (Table 2).

Emptying Function

Detrusor contractility was impaired in two of the seven patients at the pretreatment PFS. One patient (case 3) showed some improvement with time, whereas one (case 4) needed to strain on void (Table 1, Fig. 1C and 1D) and this was the only patient who had emptying dysfunctions at the latest UDS. In the patients without the pretreatment UDS, the findings of PFS were able to be evaluated in six patients because tension and embarrassment did not allow one patient to void in the unfamiliar laboratory environment. Detrusor contractility was normal in three patients, was improved in one, was aggravated in one and was completely lost in one during the follow-up period (Table 2). Eventually, two of the six patients (33%) had emptying dysfunctions. No abnormal sphincter activity was noted in the 13 patients.

Symptoms, Perineal Neurological Findings and Morphological Findings

The lower urinary tract symptoms and the perineal neurological findings at each UDS are shown in Tables 4 and 5. Although significant numbers of the patients reported LUTS, especially the storage symptoms, LUTS did not actually keep the patients away from their usual activities. All of the abnormal neurological findings was also mild in degree. On the follow-up IVU, no upper tract deterioration developed in the 14 patients but mild bladder deformity was noted in three patients, all of whom had decreased bladder compliance on the post-treatment UDS. On the follow-up cystourethroscopy, significant telangiectasia, which was considered to represent radiation cystitis, was noted in seven patients. Five of them had abnormal urodynamic findings in the post-treatment UDS [UIC (one), decreased bladder compliance (one) or both (three)].

Table 4. Lower urinary tract symptoms and perineal neurological findings before and after the treatment

Symptom	Pretreatment	<1 year	1-2 years	>2 years
	n = 7	n = 7	n = 5	n = 5
Pollakisuria	5	3		2
Nocturia	1	2
Urgency	2	4	2	1
Urge incontinence	1	2	1	1
Stress incontinence			1
Poor stream	1	1	2
Abnormal sensation	1	1	2	2
Abnormal reflex	3	1	1	1

Table 5. Lower urinary tract symptoms and perineal neurological findings less than and more than 2 years after the treatment

Symptom	<2 years	>2 years
Pollakisuria	3	2
Nocturia	1	1
Urgency		2
Urge incontinence		2
Stress incontinence	1
Poor stream	1
Abnormal sensation	2	2
Abnormal reflex	0	0

DISCUSSION

To our knowledge, the present study is the first urodynamic study to evaluate the preserved lower urinary tract function of the patients who underwent the bladder-sparing regimen of intra-arterial chemotherapy with concurrent pelvic radiotherapy for treating invasive bladder cancer. The present study indicated that significant lower urinary tract dysfunctions existed in most of the patients, although the small numbers of the patients and the short follow-up period made their clinical implications uncertain.

The pretreatment UDS indicated that the lower urinary tract dysfunctions might have already appeared before the treatment. This suggested that the lower urinary tract functions might be adversely affected by the muscle-invasive bladder tumor itself, and/or might develop after TUR-BT. Therefore, the pure effect of the bladder-sparing regimen on the lower urinary tract functions seemed difficult to evaluate precisely. Lundbeck et al. suggested that a large bladder tumor could itself give rise to an unstable bladder and this would probably be exacerbated during radiation (7). In the light of the urodynamic findings before and after the treatment, the bladder-sparing regimen might perpetuate the functional impairment caused by a bladder tumor itself and/or TUR-BT, so that the lower urinary tract function often could not be restored to normal.

In the present study, the treatment could exert some unfavorable influences upon the lower urinary tract function. One of the frequent findings on the UDS was decreased bladder compliance. The lesions which were located at conus medullaris or infrasacral peripheral autonomic nerves, in addition to collagenosis in the detrusor itself, might be responsible for developing the deterioration of bladder compliance (8). As far as the nervous injury is concerned, it has been reported that the peripheral nerves innervating the lower urinary tract may be affected by the chemotherapeutic agents and/or irradiation (7). Intra-arterial infusion of CDDP via the internal or external iliac arteries was reported to induce lumbosacral plexopathies through small vascular damage and direct neurotoxicity such as disturbances of the axonal transport, partial demyelination, damage to the motor end plate and autonomic neuropathy (9-11). Since a higher concentration than that produced by a systemic administration could be achieved in the lower urinary tract together with the surrounding area on intra-arterial infusion, this high concentration of CDDP might have a pronounced effect, and also enhance the radiation effect, on the peripheral nervous system in the pelvic cavity (12). In addition, radiotherapy per se induced lumbosacral radiculoneuropathy due to radiation-induced extensive fibrosis around the plexus, although the incidence was reported to be low (1.3% of patients with abdominal irradiation and 0.32% of patients with pelvic irradiation) (11). We considered that the treatment might injure the peripheral autonomic nervous system, resulting in the development of a neurogenic bladder of infrasacral type. The fact that some of the patients had impaired detrusor contractility might support this assumption. As to the bladder itself, it is well known that radiation altered all of the components of the bladder, such as urothelial sloughing, vascular obliteration, smooth muscle ischemia and progressive collagen deposits among the smooth muscle bundles and nerve fibers, leading to abnormal synchronization of smooth muscle cells and detrusor spasm (13,14). Moreover, CDDP augmented the radiation-induced bladder damage (7,15). The abnormal collagenosis in the bladder might cause decreased bladder compliance (8). It should be noted that UIC was frequently found on the UDS in the present study. Since none of the patients had any overt neurological diseases, UIC was considered to represent detrusor instability rather than detrusor hyper-reflexia (6). From a myogenic point of view, partial denervation of the detrusor might be responsible for altering the properties of smooth muscle cells, leading to increased excitability and increased ability of activity to spread between cells, resulting in the detrusor instability (16). In contrast, from a neurogenic standpoint, sensitization of peripheral afferent terminals in the bladder might unmask primitive voiding reflexes that trigger the detrusor instability (17). These myogenic and neurogenic changes would probably occur after radiotherapy (13,14). Therefore, we thought that the bladder injury induced by the treatment might participate in detrusor instability.

The present study has several limitations. First, since bladder cancer usually occurs in older individuals, the effect of aging on the lower urinary tract might not be negligible. Second, histological evidence of radiation cystitis and neurophysiological evidence of lumbosacral plexopathy were lacking. Third, it was often difficult to perform the UDS at regular intervals. For the early detection of local recurrence and/or distant metastasis, the patients were regularly assessed by many routine examinations including urine cytological study, chest radiograph, IVU, abdominal ultrasonography, abdominopelvic CT, bone scintigram and cystourethroscopy. Therefore, most patients frequently rejected the additional invasive examinations such as the UDS.

In conclusion, the bladder-sparing regimen might not only prevent the pre-existing dysfunctions due to cancer itself and/or TUR-BT from recovering, but also be involved in the `de novo' lower urinary tract dysfunctions. However, since the dysfunctions did not actually bother the patients and no upper tract deterioration was noted in the present study, the clinical implications of the urodynamic findings remain to be solved. For now, we think that the preserved lower urinary tract function might be acceptable, although a definitive conclusion could not be drawn from the present study because of the limited numbers of patients and the short follow-up period. Further studies will be needed to clarify the clinical impact of the treatment on the lower urinary tract function.