Is There a Role for Bladder Preserving Strategies in the Treatment of Muscle-Invasive Bladder Cancer?

European Urology

European Urology 44 (2003) 57–64

IsThere a Role for Bladder Preserving Strategies in the Treatment of Muscle-Invasive Bladder Cancer? M. Kuczyka,*, Levent Turkerib, Peter Hammererc, Vincent Raveryd on behalf of the European Society for Oncological Urology a

Department of Urology, Hannover University Medical School, D-30625 Hannover, Germany Department of Urology, Marmara University Medical School, Istanbul, Turkey c Department of Urology, University Medical School Eppendorf, Hamburg, Germany d Department of Urology, Hopital Bichat, Paris, France b

Accepted 19 March 2003

Abstract Single modality bladder sparing therapy for muscle-invasive bladder cancer, including transurethral resection, systemic chemotherapy or radiotherapy have been demonstrated to result in insufficient local control of the primary tumor as well as decreased long-term survival of the patients when compared to radical cystectomy. Therefore, multimodality treatment protocols that aim at bladder preservation and involve all of the aforementioned approaches have been established. Arguments for combining systemic chemotherapy with radiation are to sensitize tumor tissue to radiotherapy and to eradicate occult metastases that have already developed in as many as 50% of patients at the time of first diagnosis. It has been shown that the clinical outcome observed with this approach approximates that after radical cystectomy. Additionally, a substantial number of patients survive with an intact bladder. However, bladder preserving approaches are costly, and require close co-operation between different clinical specialists as well as very close follow-up. The good long-term results obtained after cystectomy and creation of an orthotopic neobladder make the possible advantage of a bladder preservation strategy questionable in consideration of quality of life issues. Additionally, side effects related to bladder sparing therapy may result in an increased morbidity and mortality in those patients who in fact need to undergo surgery due to recurrent or progressive disease. Multimodality bladder sparing treatment is a therapeutic option that can be offered to the patient at centres that have a dedicated multidisciplinary team at their disposal. However, radical cystectomy remains the standard of care for muscle-invasive bladder tumors. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Bladder cancer; Radical cystectomy; Bladder sparing treatment

1. Introduction Transitional cell carcinoma of the bladder is the fifth most common cancer in Western countries. With a continuously increasing incidence over the last few years, the actual annual incidence of bladder cancer has reached about 16 to 20 per 100,000 population in the USA. Approximately 80% of the tumors are diagnosed as superficial cancers and only 10–20% are advanced *

Corresponding author. Tel. þ49-511-532-6673; Fax: þ49-511-532-3481. E-mail address: [email protected] (M. Kuczyk).

stage disease or metastatic at primary diagnosis. Recurrences of superficial bladder cancer will remain confined to the bladder wall in 70–80% of patients, but 20– 30% of recurrent tumors will subsequently become muscle invasive and lead to metastatic disease. Approximately half of the patients with muscle-invasive bladder cancer at initial diagnosis have already developed occult regional or distant metastases, with an extremely poor prognosis [49,66]. Radical cystectomy has been considered the gold standard for the treatment of muscle-invasive bladder cancer. However, several attempts at bladder preservation utilising single and multimodality treatment

0302-2838/03/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0302-2838(03)00150-7

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strategies have been made. Single modality, organ preserving treatment options include complete TUR of the primary tumor, systemic chemotherapy or external beam radiation. In contrast, multimodality treatment strategies aim to achieve local tumor control as well as the eradication of micrometastases that have already occurred at the time of first diagnosis.

2. Single modality therapy for muscle-invasive bladder cancer Recurrence-free and long-term survival of patients with T2–3 bladder cancer achieved by single modality therapy were disappointing compared to a radical surgical approach. Treating patients classified as T3, Whitmore et al. [72] did not observe any complete remissions following TUR only. Barnes et al. [2] reported a 5-year survival of 27% for 85 patients exclusively undergoing TUR for the treatment of well to moderately differentiated stage T2 bladder cancer specimens. In contrast, Herr et al. [26,27] achieved a 5year survival rate of 70% in patients treated for T2 bladder cancers. However, during the further course of this investigation, only 45/217 patients with no evidence of bladder cancer at repeat resections were considered candidates for bladder preservation. Finally, not more than 16% of patients survived with the bladder intact, a highly selective subgroup that was initially characterized by a favourable clinical prognosis. Currently, the 5-year survival following TUR for T2 bladder tumors can be expected to range between 45–70% [19,25]. One explanation for these diverging results might be a substantial staging error regarding the histopathological classification of the resected tumor specimens that make the clinical outcome reported within former investigations difficult to compare [37,72]. Assessing the induction of complete or partial tumor remissions after a neo-adjuvant systemic chemotherapy according to clinical criteria, Scher et al. [54] observed complete remissions in 56% of cases. However, the histopathological examination of the cystectomy specimens revealed residual tumors in 61%, indicating a substantial clinical staging error. Similarly, in a phase II study of cisplatin and methotrexate as primary therapy for locally advanced (T3/T4) bladder tumors, Roberts et al. [52] observed complete local responses in only 11%, with partial responses seen in 34%. Thus, the local response rate observed following the application of systemic chemotherapy as single modality treatment appears rather poor [36,40,41,43].

Initially, primary radiotherapy as a single modality therapy was applied to patients judged unfit for cystectomy due to poor performance status [28,42,51,64]. The results of retrospective investigations regarding the clinical outcome following EBT alone were inferior to those observed with a radical surgical approach [8,9,28]. For a group of 699 patients subjected to EBT for muscle-invasive bladder cancer, Duncan [9] reported an average 5-year survival rate of only 30%. Treatment of 121 patients with EBT by Gospodarowicz et al. [17,18] resulted in an average 5-year-survival of 32%. In an investigation reported by Pollack et al. [48] the long-term survival following EBT was 26%. Long-term survival by stage was 40–59% for T2 and 0–50% for T3 tumors during former studies. It has been argued that these results could not be directly compared to that observed after radical cystectomy because 15% of patients were found to have previously undetected extravesical tumor growth at the time of surgery. It was indicated that these patients had been excluded from analysis in cystectomy but not in radiation series, thus creating a selection bias. Currently, several randomized trials comparing the efficacy of primary radiation followed by salvage cystectomy in case of persistent or recurrent tumor growth with an immediate cystectomy after radiotherapy are available. Miller [44] reported the clinical course of 35 patients with large T3 tumors either treated by radiation or surgery (Table 1). Significantly increased long-term survival observed after cystectomy (22% vs. 45%). In contrast, with 5- (and 10)-year survival rates of 39% (19%) and 28% (15%) after cystectomy vs. radiotherapy, there was no difference between treatments in a study initiated by the Urologic Cooperative Group from the United Kingdom [30]. Similarly, Sell et al. [57] were not able to detect any difference between the long-term survival of patients randomized to external beam radiation with cystectomy versus radiotherapy. However, while the frequency of distant metastases at 5 years was almost equal within both groups (32% vs. 34%), a significantly higher number of patients undergoing EBT as single modality therapy had local or pelvic recurrences (35% vs. 7%) (Table 1). Jenkins et al. [33] reported that a combination of radiotherapy and early cystectomy suggested a tendency towards an improved long-term survival of patients with T2–3 cancer. Also, the study reported by Miller [44] indicated EBT as primary and exclusive therapy to be inferior to EBT plus cystectomy. This is likely because EBT as monotherapy does not prevent the subsequent development of local or pelvic recurrences.

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Table 1 Randomized studies that have investigated the impact of external beam radiation with and without immediate cystectomy on the long-term survival of bladder cancer patients Author

Total number of patients (n)

Treatment modality

5-year survival (%)

Statistical calculation

Miller et al. [44]

67

50 Gy þ cystectomy vs. 60 Gy þ salvage cystectomy

46 22

s.

Bloom et al. [3]

189

40 Gy þ radical cystectomy 60 Gy þ salvage cystectomy

39 28

n.s.

Sell et al. [57]

183

40 Gy þ radical cystectomy 60 Gy þ salvage cystectomy

29 23

n.s.

Horwich et al. [30]

189

40 Gy þ radical cystectomy 60 Gy þ salvage cystectomy

39 28

n.s.

s.: difference significant; n.s.: difference not significant.

3. Multimodality bladder sparing treatment Since none of the single modality approaches (TUR, EBT or chemotherapy) show acceptable clinical efficacy against muscle-invasive bladder cancer, recent strategies have combined the aforementioned interventions in an attempt to improve the long-term survival and bladder preservation rates [10,12,13,16,20,21,32, 35,50,53,59,65,68,69,73], Table 2. The main arguments for combining systemic chemotherapy with EBT are to increase radiosensitivity and to eradicate occult metastases that have already developed in as many as 50% of T2–3 patients at the time of first diagnosis [29,34,46,58,62]. In the majority of clinical investigations aimed at bladder preservation by a multimodality approach, methotrexate, vinblastine and cisplatin (MCV) have been administered before or after EBT. Usually, induction chemotherapy and EBT that is combined with a concurrently applied radiosensitizer are utilized after TUR of the primary tumor. Following the determination of the response to induction chemotherapy by repeat TUR, clinically ‘‘complete responders’’ are considered candidates for bladder preservation and therefore subjected to a consolidation therapy with

additional radiation and concurrent radiosensitizer. Presence of any residual tumor indicates radical cystectomy. The rationale for this approach is based on the hypothesis that the application of concurrent chemotherapy and EBT is associated with a significantly higher clinical response than that seen with sequential treatment schedules. Utilizing a multimodality therapy, Housset et al. [31,32] performed TUR of the primary bladder tumor, followed by an induction therapy that included 24 Gy bifractionated EBT plus concurrent cisplatin and 5fluorouracil [29,46]. Radical cystectomy was performed in 18 patients after induction therapy for T2–4 disease. The histopathological examination of the cystectomy specimens revealed a complete pathological response in all patients. After the inclusion of 120 patients, the complete responses dropped to 77% as determined by repeat TUR. Complete responders were considered candidates for bladder preservation, and underwent consolidation therapy. Immediate cystectomy was performed for incomplete response after induction therapy and repeat TUR. This treatment strategy resulted in a 5-year survival of 63% (Table 3). Fellin et al. [13] treated 56 patients with T2–4 bladder tumors with TUR and 2 courses of MCV,

Table 2 Impact of different treatment modalities on the recurrence and response rate observed in bladder cancer patients Treatment modality

Studies available (n)

Total number of patients (n)

No evidence of recurrent muscle-invasive bladder cancer (%)

Transurethral resection External beam radiation Chemotherapy (cisplatin þ methotrexate)

2 5 1

331 949 27

20 41 19

Complete responses External beam radiation Chemotherapy TUR-B plus chemotherapy TUR-B plus radiation and application of radiosensitizer

4 6 4 4

721 301 225 218

45 27 51 71

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Table 3 Results of multimodality bladder preservation strategies as available from the current literature Author

Pat. (n)

Induction treatment

Complete response, CR (%)

Long-term survival (years)

Survival with bladder preservation (years)

Dunst et al. [10] Housset et al. [32] Sauer et al. [53] Shipley et al. [59] Fellin et al. [13] Tester et al. [69] Kachnic et al. [35] Zietman et al. [73] Given et al. [16] Srougi et al. [65] Sternberg et al. [68]

79 120 184 61 56 91 106 18 93 30 64

Cisplatin þ external beam radiation Bifractionated EBR þ cisplatin þ 5-FU 45–54 Gy EBR þ cisplatin/carboplatin MCV x 2, 39.6 Gy EBR þ cisplatin MCV x 2, 40 Gy EBR þ cisplatin MCV x 2, 39.6 Gy EBR þ cisplatin MCV x 2, 40 Gy EBR þ cisplatin Bifractionated EBR þ cisplatin þ 5-FU MCV þ cisplatin þ EBR (49 Pat.) M-VAC þ partial cystectomy M-VAC (without cystectomy in 31 Pat.)

– 77 80 61 50 75 66 78 – – –

52% 63% 56% 48% 55% 62% 52% 83% 51% 53% –

41% – 41% 36% 41% 44% 43% 78% 18% 20% 33%

followed by radiotherapy (40 Gy) and concurrent cisplatin. Complete responses after induction therapy were observed in 50% of cases. The latter patients were consolidated with 24 Gy radiation therapy and concurrent cisplatin. The overall 5-year survival was 55% and the survival with intact bladder was 41%. An investigation by Sauer et al. [53] included 184 patients with muscle invasive or undifferentiated T1 (G3) bladder cancer who were subjected to TUR followed by 45–54 Gy EBT and concurrent chemotherapy (cisplatin or carboplatin). Repeat TUR revealed complete responses in 85% receiving cisplatin and 70% for those receiving carboplatin. With a 5-year survival of 56% for the entire cohort, 41% of patients survived with the bladder intact. Depending on tumor stage, long-term survival ranged from 22% for T4 to 77% for T1 disease. Recently, the results of phase I to III trials initiated by the Radiation Therapy Oncology Group (RTOG) for the evaluation of bladder preserving strategies in the treatment of T2–4 tumors were presented. The treatment of 49 patients with TUR plus 40 Gy EBT and concurrent cisplatin resulted in complete responses in 66% of cases, a long-term survival (4 years) of 60% and a bladder preservation rate of 44% [69,70]. Complete responses were seen in 75% after the application of 2 cycles of neoadjuvant chemotherapy using the MCV regimen. In the RTOG III trial, 123 patients were randomized to a treatment schedule that did or did not include neoadjuvant MCV in addition to EBT and concurrent cisplatin as part of induction therapy. Consolidation was performed by using 24 Gy radiation therapy and concurrent cisplatin. However, with long-term survival in 48% without MCV vs. 49% with MCV and bladder preservation in 36% vs. 40% in these groups respectively, neoadjuvant chemotherapy demonstrated no increase in efficacy over the aforementioned approach [59–61]. Kachnic et al. [35] treated

(5) (5) (5) (5) (5) (4) (5) (3)

(5) (5) (5) (4) (5) (3)

106 patients with stage T 2–4 bladder tumors with a multimodality approach that included induction therapy with TUR, 2 cycles of MCV, and 40 Gy EBT in combination with concurrent cisplatin. Patients with complete response received consolidation therapy with 24.8 Gy EBT and concurrent cisplatin. Complete response to induction therapy occurred in 66% of the patients, resulting in a long-term survival in 52% and bladder preservation in 43%. A detailed list of the longterm survival in several multimodality bladder preservation strategies is given in Table 3.

4. Long-term survival following bladder preservation and radical cystectomy During former investigations, patients undergoing primary cystectomy after the diagnosis of T2–4 bladder cancer have shown long-term survival of 54–64% [4,14,15,45,47,71]. Thus, it could be assumed that the clinical prognosis appears to be similar to a multimodality bladder sparing treatment. However, both treatment options have never been directly compared by a randomized study. It has been suggested that delay in cystectomy which is usually recommended in most bladder preservation protocols may increase the risk for tumor progression during the initial chemotherapy and EBT phase [6,23]. In this context, Hautmann [23] compared 210 patients subjected to immediate cystectomy to 88 patients undergoing delayed cystectomy at some point during the course of their disease. In the latter group of patients, cystectomy was delayed either due to neoadjuvant chemotherapy, radiation or the treatment of T1 bladder cancer by repeat transurethral resections in combination with intravesical instillation therapy. The number of patients with regional lymph node metastases at the time of surgery was significantly higher in the delayed cystectomy group (26% vs. 12%).

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Also, in advanced stage bladder cancer patients, the 5-year disease specific survival was significantly higher with immediate cystectomy (80% vs. 56%). Similarly, Abratt et al. [1] observed an improved long-term survival for patients treated with early cystectomy (50% vs. 32%). In contrast, Schultz et al. [56] were not able to demonstrate any difference in survival between early cystectomy or surgical therapy after neoadjuvant MVAC chemotherapy. It is important to note that the lag time between the initial diagnosis and cystectomy in ‘‘delayed’’ cases may have an important impact on the outcome. In summary, according to currently available data, the question if an attempt at bladder preservation or an early aggressive surgical treatment might be associated with an improved long-term survival of the patients, is difficult to answer. First, bladder preservation strategies are based on a multitude of treatment protocols that are continuously modified. Secondly, the delay intervals from the diagnosis of muscle-invasive bladder cancer to radical cystectomy differ significantly when previously reported investigations are compared. Finally, different tumor stage distributions within former studies have been suggested to substantially alter the comparability of the results reported so far [23]. Although data given in Table 3 might indicate that bladder preserving strategies may perform equally well compared to initial radical surgical approach in terms of long-term survival, several points have to be addressed in this context. As point of concern when the long-term survival rates reported for both treatment options are compared is has been indicated that according to a supposed selection bias only patients revealing favourable clinical characteristics at first diagnosis (e.g. monofocal T2 tumors, possibility of complete transurethral resection without residual tumor during a second TUR) are usually subjected to a conservative therapeutical approach. In contrast, patients recurring with mutifocal muscle-invasive tumors and high volume disease are considered candidates for radical cystectomy in the vast majority of cases. This selection bias is argued to falsify the outcome of former series that have reported long-term survival rates for a bladder-sparing treatment that seem to be comparable to those observed after a radical surgical treatment but in fact do result from the aforementioned negative selection within cystectomy series. Another argument against a bladder preserving strategy is the therapeutical benefit patients with only microscopic nodal disease derive from the surgical removal of the affected lymph nodes. There is serious concern whether the chance of cure for this selected group of patients can also be maintained by a combined chemo/radiotherapy.

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Taken these points together, the question if the favourable clinical outcome reported for a multimodality bladder-preserving approach within former investigations is due to a selection bias that leads to the inclusion of patients with a less favourable clinical prognosis in cystectomy series can only be answered if both treatment options are directly compared within a randomized trial.

5. Disadvantages of a multimodality bladder sparing treatment After multimodality bladder sparing treatment, approximately 40% of the ptients will survive with their bladder intact. The most important advantage of this modality compared to radical cystectomy is quality of life. However, several points have to be recognized when the advantages and disadvantages of both treatment options are discussed. Multimodality bladder preserving strategies are very complex and require, apart from a high compliance on the part of the patient, the close cooparation between several clinical specialties. In most European countries, this often is not easy to coordinate [73]. Therefore, it has been suggested that this treatment option should be preserved for a dedicated multimodality team within selected clinical centres [60]. Although for Germany cost calculations are not available at the moment, for the United States bladder sparing protocols have been suggested to be significantly more costly than radical surgical approaches at the treatment of muscle-invasive bladder cancer. The most obvious reason for the establishment of bladder preservation strategies is to avoid the surgical removal of the bladder, resulting in an improvement of the quality of life. However, improvements in surgical technique and mainly the introduction of the orthotopic neobladder into the clinical routine have weakened this argument [22]. An excellent daytime continence (over 90%) and nighttime incontinence rate as low as 10–15% following radical cystectomy and orthotopic neobladder creation have been reported [5,6,38,67]. Additionally, intermittent catheterization due to an incomplete emptying of the neobladder is necessary in less than 5% of patients [24]. The development of nerve sparing radical cystectomy seems to increase the number of patients being potent after surgery [4]. Meanwhile, it has to be recognized that external beam radiation that is an integral part of most multimodality treatment protocols can induce erectile dysfunction as well. An improvement of quality of life by preserving the tumor-bearing bladder assumes normal bladder

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function. However, while a maintained normal bladder function can be observed in a substantial number of cases [7,39], at least some patients will have reduced bladder capacity and/or suffer from severe urgency afterwards. In conclusion, an improvement of quality of life by a bladder-preserving approach has not been substantiated so far. Therefore, future studies will have to address the question if current surgical approaches at bladder substitution do result in a more extensive impairment of the patients’ quality of life when compared to results reported for multimodality treatment protocols. Currently, the assumption of an improvement of patients’ quality of life by leaving the native bladder intact during the treatment of muscle-invasive bladder cancer has not been sufficiently verified. A substantial number of bladder cancer patients— usually older—suffer from significant side-effects of systemic chemotherapy [27,28]. Shipley et al. [60] reported a mortality rate of 4% that was associated with induction therapy during a multimodality bladder sparing treatment. Also, the RTOG III trial was prematurely closed due to untolerable side-effects of systemic chemotherapy (MCV regimen). In an investigation by Kachnic et al. [35] who described a similarily high mortality rate, the chemotherapy regimen applied during the induction treatment had to be modified in 20% of patients due to significant toxicity. On the other hand, the mortality rate associated with contemporary radical cystectomy series has been reported to range between 1% and 2.8% [63]. One of the most obvious disadvantages of bladder preserving strategies is the detorioration of the performance status in those patients who need to undergo surgery after an incomplete response to induction therapy or tumor progression at some point during their follow-up. Surgery appears to be associated with higher morbidity and mortality than primary cystectomy in these cases. Furthermore, patients living with their bladders intact are not devoid of future tumor developments. Shipley et al. [60] and Kachnic et al. [35] reported patients who underwent a bladder preserving treatment and were alive at 5 years with their bladder intact. Superficial recurrences of bladder cancer were seen in 28% of the cases. These data and the observation that

local recurrences can occur even in patients who are disease-free more than 5 years after diagnosis of the primary tumor [11,56] thus, emphasize the need for consequent close follow-up [11]. However, even among patients who are followed carefully, the development of clinically unrecognized local recurrences can not be totally excluded. Scher et al. [54] reported muscle invasive bladder tumors in 33% of patients who were considered disease-free after TUR and neoadjuvant chemotherapy. Subsequently, Lynch et al. [39] observed clinically inapparent residual bladder cancer in 5 patients who underwent radical cystectomy after bladder preserving treatment due to intolerable urgency. In contrast, patients who have failed to recur at 5 years after primary cystectomy can be expected to remain continuously disease-free [55].

6. Conclusion In patients with muscle-invasive bladder cancer, currently available multimodality bladder preservation treatment results in long-term survival rates comparable to those observed after radical cystectomy. Additionally, a significant number of patients survive with their urinary bladder intact. However, the treatment regimens have never been directly compared, and bladder preserving approaches are costly and complex. They require the close cooperation between different clinical specialties and a careful follow-up of the patients even beyond 5 years after first diagnosis. These points have to be taken into consideration when discussing bladder preserving strategies that mainly address an improvement of quality of life by retaining the native bladder. Additionally, due to the excellent long-term results that are observed after creation of an orthotopic neobladder, the substantial advantages of a bladder preserving strategy compared to radical cystectomy may be questionable. Therefore, a radical surgical approach currently remains the standard treatmentof muscle-invasive bladder cancer. Bladder-sparing multimodality regimens may be of value in selected centres and highly selected patients in experimental protocols.

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