Conservative treatment of invasive bladder carcinoma by transurethral resection, protracted intravenous infusion chemotherapy, and hyperfractionated radiotherapy

Long-term results

Abstract

BACKGROUND

Organ preservation has been investigated in patients with muscle-invasive bladder carcinoma over the past decades as an alternative to radical cystectomy. The majority of studies reported that trimodal schedules, including transurethral resection of bladder tumor (TURB), radiotherapy (RT), and chemotherapy, are a feasible and safe organ-sparing approach without deferring the survival probability. However, to the authors' knowledge the best combination of RT and chemotherapy has yet to be well defined. The current study evaluated the long-term results of a schedule of concurrent cisplatin and 5-fluorouracil (5-FU) administered as protracted intravenous infusions (PVI) during hyperfractionated radiotherapy (HFRT) with organ-sparing intent in patients with infiltrating transitional cell carcinoma of the bladder (TCCB).

METHODS

Seventy-seven patients with a classification of T2–T4aN0M0 TCCB were enrolled in the current study. After a complete TURB and bladder mapping, 42 of 77 patients underwent 2 cycles of induction chemotherapy. All 77 patients underwent HFRT and a schedule of cisplatin (4–6 mg/m² per day) and 5-FU (180–220 mg/m² per day) as concomitant PVI (radiochemotherapy [RCT]). Six to 8 weeks after RCT, patient response was evaluated by computed tomography scan, urine cytology, and TURB. Patients who achieved a complete response (CR) were followed at regular intervals. For patients with residual or recurrent invasive tumor, salvage cystectomy was recommended.

RESULTS

Seventy-two patients were evaluable for response: 65 achieved a CR (90.3%) and 7 (9.7%) achieved a partial response. No significant difference was observed for the different prognostic factors with the exception of stage of disease (T2 [95.7%] vs. T3–T4a [80.0%]; P = 0.04). The observed toxicity, mainly hematologic, was higher among the patients who received induction chemotherapy compared with the patients who did not receive induction chemotherapy, even though the difference was not statistically significant. After a median follow-up of 82.2 months (range, 30–138 months), 44 of 65 (57.1%) patients who achieved a CR were alive. Of these 44 patients, 33 had tumor-free bladders. The 5-year overall, bladder-intact, tumor-specific, disease-free, and cystectomy-free survival rates for all 77 patients were 58.5%, 46.6%, 75.0%, 53.5%, and 76.1%, respectively. No associations were observed in overall and tumor-specific survival with different prognostic factors.

CONCLUSIONS

Combined treatment appeared to provide high response rates and can be offered as an alternative option to radical cystectomy in selected patients who refuse or are unsuitable for surgery. Cancer 2004. © 2004 American Cancer Society.

In the last decade, several articles have reported encouraging data regarding the response rate and survival of patients with muscle-invading bladder carcinoma using combined modality treatment with bladder preservation.1–9

These series report a median complete response (CR) rate of 70% (range, 56–87%) after transurethral resection of the bladder tumor (TURB) and radiochemotherapy (RCT). The 5-year overall survival rates are comparable to the rates reported in surgical series using immediate radical cystectomy in patients with the same features. In RCT series, the majority of long-term survivors retain their disease-free bladder. Although radical cystectomy remains the standard therapy for muscle-invasive transitional cell carcinoma of the bladder (TCCB), the overall 5-year survival rate is not so different when these 2 treatments are compared, due to the high probability (40–65%) of distant metastases in these patients. Thus, conservative treatment can be offered as an alternative treatment in patients who refuse radical intervention or are considered unsuitable for surgery. Different treatment schedules have been employed in combining chemotherapeutic drugs, cisplatin alone in a large majority of cases, and standard fractionated radiotherapy (RT). Furthermore, several studies, including our own study, were initiated in a period when so-called neoadjuvant chemotherapy with the methotrexate, vinblastine, doxorubicin, and cisplatin or the methotrexate, cisplatin, and vinblastine (MCV) scheme was used in the attempt to increase the survival rates after radical cystectomy.10, 11 However, because of poor patient tolerance after neoadjuvant chemotherapy and concomitant RCT, many studies reported a low protocol completion rate. More recently, the Radiation Therapy Oncology Group (RTOG) reported the results of a randomized trial (RTOG 89-03) comparing two treatment arms of RCT with or without neoadjuvant chemotherapy using the MCV scheme. No differences were observed between the 2 arms in terms of local control, bladder-intact, and overall survival at 5 years, whereas toxicity was found more frequently in the MCV arm.12 Also, in our experience, lower toxicity was observed in patients not submitted to neoadjuvant MCV.

Furthermore, on the basis of experimental data, the question has been raised whether combined approaches with RCT can obtain the same local control when one or two drugs are used. The first evidence that concurrent cisplatin and 5-fluorouracil (5-FU) could be administered safely to outpatients was provided by Housset et al.13 and by our group.14, 15 This study reported excellent results in terms of CR rates using 5-FU and cisplatin protracted intravenous infusion (PVI) during the course of accelerated hyperfractionated radiotherapy (HFRT). The drug doses employed by PVI were tolerated very well even by older patients included in the study.

Experimental and clinical data suggest that the cisplatin–RT interaction is enhanced when RT is administered in multiple fractions and that cisplatin is less toxic and more effective when administered by PVI, preferentially acting on G₁-phase cells.16, 17 Radiobiologic studies and clinical data also have demonstrated that the interaction between RT and 5-FU increases by prolonging the cell exposure time to the drug,18 during the entire period of RT, even for low blood concentrations.19, 20

The concomitant administration of two drugs with different mechanisms of RT enhancement and with cooperative interaction demonstrated in experimental and clinical studies21, 22 appears to increase CR rates compared with other combinations used in the past.

In the current article, the results of our 11-year experience of PVI with 5-FU and cisplatin RCT with bladder-sparing intent are presented and updated with a longer follow-up period.

MATERIALS AND METHODS

Between November 1992 and September 2001, 77 patients with biopsy-confirmed invasive TCCB (i.e, T2–T4aN0M0 disease) were accrued to our bladder-sparing program. The study group included 67 men and 10 women (age range, 43–82 years) with an Eastern Cooperative Oncology Group performance status of 0–1. The distribution of the patients according to the International Union Against Cancer23 T-classification and histopathologic grade is shown in Table 1. In 6 patients (7.8%), the presence of obstructive uropathy required nephrostomy and in 21 patients (27.3%), different grades of urinary tract dilation were present. The majority of patients refused radical cystectomy, whereas others were unsuitable for surgery due to medical reasons. The experimental nature of the treatment procedures was explained fully to the patients and their relatives and informed written consent was obtained from all patients.

Table 1. Tumor and Patient Characteristics

Characteristics	Induction chemotherapy (%)		Total
	MCV+	MCV−
MCV+: induction chemotherapy with methotrexate, cisplatin, and vinblastine given; MCV−: induction chemotherapy with methotrexate, cisplatin, and vinblastine not given, M: male; F: female.
No. of patients	42	35	77
Gender (M/F ratio)	36/6	31/4	67/10
Mean age (yrs) (range)	64.3 (46–75)	65.5 (43–82)	65.3 (43–82)
Median follow-up (mos) (range)	88.5 (49–138)	68.7 (30–118)	82.2 (30–138)
Hydronephrosis
No	30 (71.4)	20 (57.1)	50 (64.9)
Yes	12 (28.6)	15 (42.9)	27 (35.1)
Clinical stage
T2	22 (52.4)	27 (77.1)	49 (63.6)
T3-T4a	20 (47.6)	8 (22.9)	28 (36.4)
Histologic grade
2	23 (54.8)	16 (45.7)	39 (50.6)
3	19 (45.2)	18 (51.4)	37 (48.1)
4	-	1 (2.9)	1 (1.3)

After a computed tomography (CT) scan of the abdomen and pelvis, patients underwent an aggressive macroscopically complete TURB and bladder mapping. In 42 patients, 2 cycles of induction MCV chemotherapy24 were administered before RCT, whereas 35 patients underwent a chemoradiation program after TURB, without induction MCV. Three of six patients, affected by obstructive uropathy with nephrostomy, received the MCV regimen and were hydrated to prevent further renal compromise.

At the completion of the MCV induction, to assess the response to chemotherapy, patients who received MCV (MCV+) underwent CT scans and TURB.

External beam RT, using 9 or 12-megavolt (MV) photon linear accelerators, was initiated 15–45 days after the completion of MCV chemotherapy. Patients not receiving induction chemotherapy (MCV−) underwent RCT 30–40 days after TURB.

Treatment fields included the entire bladder, tumor surface, prostate and prostatic urethra (or proximal vagina), and pelvic lymph nodes. A four-field “box technique” was used as previously described.14, 15 All fields were treated with three 100-centigray (cGy) fractions per day, at an interval of ≥ 5 hours, 5 days per week, to a total dose of 51 gray (Gy) to the pelvis in 23 days. A further dose of 18 Gy with the same scheme was administered to a bladder-reduced volume, to a cumulative dose of 69 Gy. Because of the heavy workload of the Division of Radiation Oncology (Regina Elena Cancer Institute (Rome, Italy), the fractionation schedule was modified in the last 39 patients to 2 150-cGy fractions per day, at 6-hour intervals, to the same total dose.

The concomitant prolonged infusion of two drugs has been possible as an outpatient regimen because of the use of an implantable system in which a double lumen venous catheter connected to a double subcutaneous approach was placed with its tip in the superior vena cava or right atrium. Drug infusion was performed using two external electronic pumps (CADD1® or CADD-PLUS®; Pharmacia Deltec, St. Paul, MN).

From the initiation of RT, the drugs were administered 7 days a week at escalating doses of cisplatin (4–6 mg/m² per day) and 5-FU (180–220 mg/m² per day) in the first 25 patients and then at doses of cisplatin at 5 mg/m² per day and 5-FU at 220 mg/m² per day, defined as the maximum tolerated dose in our dose-finding study.14 When WHO Grade 2 toxicity occurred, infusion was discontinued over the weekend to prevent the occurrence of a higher grade of toxicity. Reductions in drug doses or treatment suspension also were permitted depending on the grade of toxicity.

Two months after the completion of treatment, patients were restaged with CT scans, urine cytology, and TURB to assess tumor response. Patients with infiltrating residual disease underwent an immediate radical cystectomy. Patients with a CR (i.e., negative urine cytology, no visible tumor, and absence of microscopic tumor in the biopsy specimen) were followed with physical and instrumental examination every 3 months for the first 2 years, and every 6 months thereafter. Each year, thoracic and abdominopelvic CT scans, bone scans, and every other instrumental examination or laboratory test, if indicated, were performed. When there were residual or recurrent superficial tumors, TURB followed by intravesical therapy was performed.

Statistical Analysis

Actuarial survival curves were computed using the Kaplan–Meier method.25 Survival intervals were calculated from the day of the first TURB to the time of death or the last follow-up examination. All statistical comparisons were performed using two-tailed tests. SPSS for Windows (SPSS, Inc., Chicago, IL) was used for statistical analyses.

RESULTS

Local Response

Local response evaluation by TURB was possible in 72 of 77 patients; 65 (90.3%) achieved a CR, including 7 patients in whom a CR was obtained after intravesical therapy for superficial residual disease, and 7 (9.7%) achieved a partial response (PR). Five patients died before restaging TURB evaluation, three for intercurrent disease, apparently unrelated to treatment, one for toxicity, and one for metastatic tumor progression soon after the completion of therapy.

In Table 2, local responses to MCV+ or MCV− are reported. Among MCV− patients, a higher percentage of CRs (97% vs. 84.6%) was observed, even though the difference was not found to be statistically significant. CRs according to tumor stage, hydronephrosis, systemic MCV, histologic grade, and treatment delay are shown in Table 3. A statistically significant difference for CR rate was observed only between patients with a T2 and T3–4a classification (P = 0.04). No patient demonstrated tumor progression during therapy.

Table 2. Local Response to Radiochemotherapy

	CR (%)	PR (%)	Total restaged (%)a	Not restaged	Total
CR: complete response; PR: partial response; MCV+: induction chemotherapy with methotrexate, cisplatin, and vinblastine given; MCV−: induction chemotherapy with methotrexate, cisplatin, and vinblastine not given. a By computed tomography and transurethral resection of the bladder.
MCV+	33 (84.6)	6 (15.4)	39 (100.0)	3	42
MCV−	32 (97.0)	1 (3.0)	33 (100.0)	2	35
Total	65 (90.3)	7 (9.7)	72 (100.0)	5	77

Table 3. Complete Responders According to Prognostic Factors

Characteristics	No. of patients	CR (%)a	P valueb
CR: complete response; MCV: induction chemotherapy with methotrexate, cisplatin, and vinblastine; NS: not significant. a Percentage of patients who were complete responders. b P value was determined using the two-tailed Fisher exact test.
MCV
+	39	84.6	NS
−	33	97.0
Histologic grade
2	37	89.2	NS
3	35	91.4
Stage
T2	47	95.7	0.045
T3–T4a	25	80.0
Hydronephrosis
Absent	46	93.5	NS
Present	26	84.6
Treatment suspension
No	50	92.0	NS
1–7 days	12	83.3
> 7 days	10	90.0

Of the seven patients with a PR, four underwent an immediate salvage cystectomy and three received systemic chemotherapy because of the sudden development of regional (one patient) or distant metastases.

Toxicity

All patients were evaluable for toxicity. Treatment was completed in 38 of 42 MCV+ patients (90.5%) and in 34 of 35 MCV− patients (97.1%). Treatment was interrupted in two MCV+ patients because of the development of Grade 3–4 bone marrow toxicity, and in three patients because of intercurrent disease. Treatment was delayed for local or systemic toxicity in 22 of 72 patients (in 12 patients for < 7 days and in 10 patients for > 7 days. A delay of > 7 days was observed in 18% and 9% of MCV+ and MCV− patients, respectively. However, this difference was not statistically significant.

As shown in Table 4, a trend toward higher grade local and systemic toxicities (i.e., Grade 3–4) was observed in MCV+ patients. Thrombocytopenia and leukopenia (18.2%) were the most frequent toxicities, followed by urocystitis (16.9%) and enteritis (10.4%), managed by symptomatic treatment. One patient in the MCV+ group died, most likely of RT enteritis 2 months after the end of the treatment. In one patient, Grade 3 renal toxicity was observed. The patient developed hypercreatininemia, but rapidly recovered after forced hydration.

Table 4. Treatment-Related Toxicity (3–4 WHO Scoring System) by MCV and Total

Characteristics	MCV+ (n = 42) (%)	MCV− (n = 35) (%)	Total (N = 77) (%)	P value
WHO: World Health Organization; MCV: induction chemotherapy with methotrexate, cisplatin, and vinblastine; MCV+: induction chemotherapy with methotrexate, cisplatin, and vinblastine given; MCV−: induction chemotherapy with methotrexate, cisplatin, and vinblastine not given; NS: not significant. a Three cases of fatigue, one case of fatigue plus pain, one case of pain, one case of fatigue plus hypercreatininemia, and one case of peripheral neuropathy.
Bone marrow	9 (21.4)	5 (14.3)	14 (18.2)	NS
Bladder	8 (19.0)	5 (14.3)	13 (16.9)	NS
Intestinal	6 (14.3)	2 (5.7)	8 (10.4)	NS
Othera	6 (14.3)	1 (2.9)	7 (9.1)	NS

In terms of late toxicity, all patients with tumor-free bladders with a 5-year minimum follow-up period were reported to have normal micturition with normal bladder compliance and functional capacity at the time of last follow-up, as reported by the patients and evaluated by CT scans.

Local and Distant Disease Recurrence

After a median follow-up of 82.2 months (range, 30–138 months), no local or distant disesase recurrence was observed in 36 of 65 (55.4%) patients with a CR. Twenty-eight of these 36 patients (77.8%) patients were alive, whereas 8 had died of causes unrelated to bladder carcinoma. Seven of 65 patients with a CR (10.8%) experienced superficial local disease recurrence (3 patients with Ta disesase and 4 patients with T1 disease); 5 were treated conservatively with TURB and intravesical therapy and 2 patients (classified as having T1 tumors) with multiple superficial recurrent tumors underwent cystectomy. At the time of last follow-up, six patients were alive without evidence of disease and one patient had died of disease unrelated to bladder carcinoma. Twelve patients (18.5%) presented with infiltrating local disease recurrence and were scheduled to undergo salvage cystectomy, but 1 patient died before undergoing a cystectomy. At a median follow-up of 86.6 months, 9 of these 12 patients were alive and free of disease, 2 had died of bladder carcinoma, and 1 patient had died of disease unrelated to bladder carcinoma. Ten of 65 (15.4%) patients with a CR presented with distant (n = 9 patients) or regional (n = 1 patient) metastases without tumor recurrence in the bladder. All but one patient died of tumor-related complications.

The median time to local disease recurrence and distant metastases after the end of therapy was 16.9 months (range, 10–79 months) and 15.9 months (range, 1–53 months), respectively, for patients with a CR.

Survival

At a median follow-up of 82.2 months, 44 of 65 (67.7%) patients with a CR are alive, 33 of them with a tumor-free bladder. Among 21 of 65 patients with a CR who died, 2 died of bladder carcinoma, 9 died of tumor metastases without bladder carcinoma recurrence, and 10 died of causes unrelated to bladder carcinoma. All patients with a PR died, 6 with tumor progression (median time to tumor progression of 5.3 months) and 1 of other causes.

For all 77 patients, 5- and 10-year tumor-specific survival, overall survival, and bladder-intact survival curves are depicted in Figure 1. When considering only the 65 patients who achieved a CR, the 5-year tumor-specific, overall, and bladder-intact survival rates were 83.0%, 69.5%, and 55.2%, respectively. Table 5 shows the 5-year survival rates for MCV+ or MCV− patients. No statistically significant differences were observed between the 2 treatment arms and it is interesting to note that cystectomy-free survival was as high as 79.5% in MCV− patients. The 5-year overall and tumor-specific survival rates for potential prognostic factors are reported in Table 6. No significant survival differences were observed among the groups. The 5-year local muscle-invasive disease recurrence incidence (19.7%) reported for the 65 patients with a CR and the distant metastases incidence (25.4%) reported for the 72 restaged patients were calculated from the end of RCT (Fig. 2).

Figure 1. Kaplan–Meier overall survival, tumor-specific survival, and bladder-intact survival curves for the entire study cohort of 77 patients.

Table 5. Five-Year Survival by MCV and Total for all 77 Patients

Characteristics	MCV+		MCV−		Total
	No. of events	Survival (%)	No. of events	Survival (%)	No. of events	Survival (%)
MCV: induction chemotherapy with methotrexate, cisplatin, and vinblastine; MCV+: induction chemotherapy with methotrexate, cisplatin, and vinblastine given; MCV−: induction chemotherapy with methotrexate, cisplatin, and vinblastine not given; CR: complete response.
Overall survival	18	56.9	13	59.7	31	58.5
Bladder-intact survival	22	47.3	18	44.7	40	46.6
Tumor-specific survival	11	70.1	6	80.0	17	75.0
Disease-free survival (65 CR patients)	15	53.8	14	53.5	29	53.5
Cystectomy-free survival	9	73.8	6	79.5	15	76.1

Table 6. Five-Year Overall and Tumor-Specific Survival by Prognostic Factors

Prognostic factors	No. of patients	Overall survival			Tumor-specific survival
		No. of events	Survival (%)	P value	No. of events	Survival (%)	P value
MCV: induction chemotherapy with methotrexate, cisplatin, and vinblastine; NS: not significant.
MCV
Yes	42	18	56.9	NS	11	70.1	NS
No	35	13	59.3		6	80.0
Stage
T2	49	17	63.4	NS	8	82.4	NS
T3–T4a	28	14	50.0		9	62.1
Histologic grade
2	39	16	58.9	NS	9	74.4	NS
3–4	38	15	58.5		8	75.8
Hydronephrosis
No	50	20	58.0	NS	10	76.1	NS
Yes	27	11	59.3		7	72.5
Cystectomy within 5 yrs
No	62	25	58.1	NS	12	77.2	NS
Yes	15	6	60.0		5	66.7
Age (yrs)
≤ 65	34	14	57.8	NS	11	66.1	NS
> 65	43	17	59.1		6	82.9

Figure 2. The Kaplan–Meier 5-year cumulative proportion of local muscle-invasive disease recurrence (65 patients achieved a complete response) and distant metastases (all 72 restaged patients) was calculated after the end of treatment.

DISCUSSION

Over the last decades, concomitant chemotherapy and RT with organ-sparing intent have been applied to different tumor sites (e.g., the breast, head and neck, anus, and rectum) to obtain the same local control and survival as radical surgical procedures. Many urologists26 still consider radical cystectomy to be the gold standard treatment for infiltrating bladder carcinoma, especially after the wide application of orthotopic ileal reservoir. However, because of the high incidence of distant metastases, the 5-year survival rates for cystectomy and RCT are similar. RT and chemotherapy alone produce a high proportion of local disease recurrences, whereas the best results in terms of CR and local disesase recurrence are reportedly obtained with concomitant combination of the two modalities.27

For patients treated with RCT for muscle-invasive bladder carcinoma, published data support the use of bladder-sparing combined treatment after an optimal TURB. To our knowledge to date, neither the role of systemic polychemotherapy nor the best RCT combination, nor their sequence, nor drug infusion modality has been established. However, experimental and clinical studies demonstrate that the best radiosensitization is obtained by concomitant protracted infusion chemotherapy, which results in a high percentage of CRs.

In the current study, the concomitant administration of two drugs with different mechanisms of RT enhancement action and with cooperative interaction combined with HFRT was found to increase CR rates compared with other combinations used in the past. An accelerated HFRT regimen appeared to be superior to standard fractionation, most likely because of the kinetic characteristics of urothelial carcinoma and to the reduction in overall treatment time.28–31 With our treatment schedule, we observed what to our knowledge is one of the highest percentages of CRs published in the literature in spite of acceptable acute toxicity.

Neoadjuvant systemic chemotherapy with the MCV scheme, as also reported by the RTOG,12 did not appear to increase the rate of local control, tumor-specific survival, and overall survival. Conversely, among MCV– patients, a higher percentage of CRs (97% vs. 84.6%) was observed, even if the difference was not statistically significant. This trend toward a better response in MCV− patients could be due to the closer interval between the initial TURB and RCT, even though we cannot exclude the influence of a higher percentage of T2 patients in this group. Furthermore, Grade 3–4 acute toxicity during the combined protocol was higher in MCV+ patients.

Some authors reported an association between a CR to RT and survival probability.32, 33 However, to our knowledge, the prognostic significance of a PR or a CR as assessed cystoscopically after 40 Gy is questionable. The results of the current study appear to confirm the observation of Moonen et al.34 They reported that local control in patients who underwent a cystoscopic evaluation during RT was identical regardless of whether a CR, PR, or no response had been observed. Furthermore, a higher percentage of freedom from cystectomy (approximately 80%) was reported to be observed in studies in which combined treatment was administered without interruption for response assessment in respect to studies where response assessment was performed after 2 weeks of RCT (52–66%). In the current study, cystectomies were performed in 17 of 77 accrued patients, and the 5-year cystectomy-free survival rate was 76.1%. It noteworthy that some cystectomies were avoided or delayed because patients were evaluated at the end of the RCT, without decreasing survival rates. In the current series, a 5-year overall survival rate of 58.5% (T2 [63.4%] vs. T3–4a [50.0%]) was observed.

The data from the current study suggest that the completion of a full combined treatment course with no interruption for response evaluation could allow high CR (90.3%) and 5-year cystectomy-free survival (76.1%) rates, without compromising overall survival rates falling in the range reported by the studies performing an early-response evaluation after 40 Gy.

The very low rate of pelvic disease recurrence (i.e., only 1 of 65 patients with a CR) could further demonstrate the treatment efficacy against potential radiographically occult lymph node metastases in the pelvis.

Furthermore, controversies exist regarding the predictive value of some pretreatment characteristics,35 such as stage of disease, induction chemotherapy, hydronephrosis, or treatment interruption. In the current study, in spite of a better local response achieved in patients with a T2 classification, no differences were observed in terms of survival rates according to these pretreatment features. However, the sample size in the current study was calculated to evaluate local response rates and could not warrant the statistical power for these comparisons.

At the 82.2-month median follow-up (range, 30–138 months), the majority of patients have retained good bladder function and high global health-related quality of life, as also reported by Zietman et al.36 In only two patients was increased bladder frequency reported 26 months and 28 months, respectively, after the initiation of treatment. However, in both patients, multiple superficial disease recurrences also were present together with decreased bladder compliance. Although very long-term follow-up may be necessary to assess late toxicity accurately, we suggest that a sparing effect with HFRT could be obtained. More recently, RTOG initiated a study incorporating twice-daily accelerated irradiation with the aim to reduce toxicity.37

In spite of the higher CR rate obtained with our scheme of combined treatment, the 5-year bladder-intact survival rates (46.6% for all patients and 55.2% for CRs) were within the range reported by other studies in which the CR rate was lower. This most likely is due to the effect of the high proportion of patients who died of causes unrelated to bladder carcinoma, without local disease recurrence or cystectomy, on the total bladder-intact survival curve events. In fact, only 13 of 65 (20%) patients with a CR underwent cystectomy due to infiltrating or multiple superficial disease recurrences in the 5 years considered.

The current study data suggest that this combined treatment provides high response rates and can be offered as an alternative option to radical cystectomy in selected patients who refuse or are unsuitable for surgery, without deferring survival probability. However, when considering the poor prognosis of patients with a PR, major effort should be spent to identify risk factors that enable the better selection of patients to undergo immediate radical cystectomy or conservative therapy.