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Organ preservation in invasive bladder cancer: Brachytherapy, an alternative to cystectomy and combined modality treatment?
Int. J. Radiation Oncology Biol. Phys., Vol. 61, No. 3, pp. 678 – 686, 2005 Copyright © 2005 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/05/$–see front matter
doi:10.1016/j.ijrobp.2004.06.249
CLINICAL INVESTIGATION
Bladder
ORGAN PRESERVATION IN INVASIVE BLADDER CANCER: BRACHYTHERAPY, AN ALTERNATIVE TO CYSTECTOMY AND COMBINED MODALITY TREATMENT? FLORIS POS, M.D.,* SIMON HORENBLAS, M.D., PH.D.,† PAUL DOM, M.D.,† LUC MOONEN, M.D., PH.D.,* AND HARRY BARTELINK, M.D., PH.D.* Departments of *Radiotherapy and †Urology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands Purpose: To evaluate our long-term results of bladder preservation with brachytherapy in the treatment of bladder cancer. Methods and Materials: Between 1987 and 2000, 108 patients with T1-G3 and T2-T3a stages of bladder cancer were treated with a transurethral resection (TUR) and a course of external beam radiotherapy (30 Gy in 15 fractions) followed by brachytherapy (40 Gy). All tumors were solitary lesions with a diameter <5 cm. Median follow-up was 54 months (range, 1–178 months). Results: The 5-year and 10-year overall survival rates were 62% and 50%, respectively. The 5-year and 10-year disease-specific survival rates were 73% and 67%, respectively. The actuarial local control rate was 73% at 5 and 73% at 10 years, respectively. The 5-year and 10-year disease-specific survival rates for patients with a preserved bladder were 68% and 59%, respectively. Of all long-term surviving patients, 90% preserved their native bladders. The treatment was well tolerated. Acute toxicity was mild. Two patients experienced serious late toxicity: 1 patient developed a persisting vesicocutaneous fistula and the other a stricture of the urethra and ureters. Conclusion: For patients with solitary, organ confined invasive bladder cancer <5 cm, bladder preservation with brachytherapy is an excellent alternative to radical cystectomy and combined modality treatment. © 2005 Elsevier Inc. Bladder cancer, Organ conservation, Brachytherapy.
tumors (5) of ⱕ5 cm diameter, this treatment strategy provides high local control rates and excellent maintenance of bladder function without systemic chemotherapy (6 –11). For many years, it has been the policy at the Department of Radiotherapy at The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital in Amsterdam to use brachytherapy in the treatment of solitary invasive bladder cancer up to 5 cm (9). We now present our long-term experience with brachytherapy in the treatment of bladder cancer.
INTRODUCTION Organ preservation has been in the forefront of modern cancer treatment for the last several decades. Conservative treatment is now standard of care for numerous malignancies including breast cancer, laryngeal cancer, anal cancer, and soft-tissue sarcomas of the limb. However, for patients with muscle-invasive bladder cancer, radical surgery is still considered standard treatment. Recently, bladder organ-preserving strategies have gained renewed interest. The discussion on bladder preservation has mainly focused on combinations of cisplatin-containing chemotherapy and external beam radiotherapy (EBRT) after transurethral resection (TUR) of the bladder tumor (1– 4). A disadvantage of these treatment schedules is that all patients receive several courses of systemic chemotherapy with consequent toxicity. In the discussion on bladder-sparing strategies, the treatment of invasive bladder cancer with brachytherapy seems to be largely overlooked. For patients with solitary T1-T3a
METHODS AND MATERIALS Patient and tumor characteristics Between 1987 and 2000, 108 patients were treated with TUR, EBRT, and brachytherapy. The patient selection criteria were histologic confirmed transitional cell carcinoma; solitary lesion with a diameter ⱕ5 cm; T1-G3 and T2-T3a stages (5); being fit for surgery; and adequate bladder capacity as estimated subjectively by the patients themselves. Before referral, all patients underwent
Reprint requests to: Floris J. Pos, M.D., The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Department of Radiation Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Tel: (⫹31) 20-5122124; Fax: (⫹31)
20-6691101; E-mail: [email protected] Received Mar 16, 2004, and received in revised form Jun 18, 2004. Accepted for publication Jun 28, 2004. 678
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Table 1. Patient and tumor characteristics No. patients (n ⫽ 108) Median age (⫾ SD) Sex Male Female T-stage* T1 T2 T3 Grade G2 G3 Adenocarcinoma Tumor A† ⬍1 cm 1–3 cm 3–5 cm Unknown Previous intravesical chemotherapy
63.4 ⫾ 11 years 89 19 17 84 7 26 80 2 9 68 26 5 5
* TNM, 3rd edition, 2nd revision, 1992 (5). † Tumor diameter as estimated by cystoscopy after transurethral resection.
TUR. All the histologic specimens were centrally reviewed. Evaluation before treatment included medical history, physical examination, a cystoscopy in our institution, computed tomography (CT) scan of the pelvis and abdomen and chest X-ray. Patient and tumor characteristics are shown in Table 1.
Treatment All patients received a course of EBRT to the pelvis with a dose of 30 Gy in 2-Gy fractions via a two- or three-field technique. The reason for this short course of EBRT was to prevent scar metastases (12). The irradiated volume extended cranially to the promontorium and caudally to the mid-symphysis pubis; the lateral margins were 1 cm outside the bony pelvic walls. If a three-field technique was used, the anterior and posterior margins on the lateral fields were 2 cm beyond the bladder wall as seen on CT scan. Within 2 weeks after completion of external irradiation, a suprapubic cystotomy was performed. Hollow nylon tubes were then inserted into the tumor area parallel and halfway through the bladder wall. To aid recognition of the target area on treatment planning, four to five small, silver seeds were inserted in the bladder wall at the boundaries of the post-EBRT lesion with a 0.5–1 cm margin. Three tubes in a single plane were usually found to be adequate to encompass the target area. Subsequently, the tubes were brought to the abdominal wall; a suprapubic or a transurethral catheter allowed bladder drainage. In 24 patients, a partial resection was performed limited to the macroscopic lesion. Reasons for tumor resection were: location in the bladder dome or evidence of residual tumor at surgery not amenable to brachytherapy only on the basis of the volume of tissue palpated at surgery. In case of a partial resection, the target area for the brachytherapy planning consisted of the scar. Two tubes were placed parallel to the scar, and silver seeds were placed at the end of the scar to recognize the length on treatment planning.
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Of the 24 partial resections of the bladder, 5 were without evidence of tumor, 3 of the resected tumors were Stage pT1, 12 were Stage pT2, and 4 were Stage pT3, of which 2 were adeno (urachus) carcinomas. The ureter was reimplanted in two cases because the tumor caused persisting ureteric obstruction. Lymph node dissection as a staging procedure was not performed routinely; only in the case of suspicious nodes on the CT scan or suspicion during the surgical procedure was a modified pelvic lymph node dissection done. Of the 11 lymph node dissections, 3 were tumor-positive. Treatment planning was performed a week after surgery. Isodose curves were generated, and the isodose encompassing the tumor area as marked with the silver seeds was selected as a reference. Until 1994, treatment planning was done with stereoshifted radiographs and MPS V7.2 (Nucletron) software; after 1994, treatment planning was CT-based using MPS V11 (Nucletron, Veenendaal, The Netherlands) software. A dose of 40 Gy was delivered by the implant with 192iridium. For the patients treated from 1994 onward, (60 patients) the mean volume encompassed by the 100% isodose was 29.0 cm3 (SD ⫽ 12 cm3) (range, 8 –57 cm3. Data were not available for patients treated before 1994. Until 1990, the treatment was hand loaded; thereafter, a low-dose-rate Microselectron (Nucletron) after-loading device was used. The mean application time was 71 h (range, 36 –102 h) and the mean dose rate was 59 cGy/h (range, 40 –110 cGy/h). Immediately after completion of the treatment, the tubes were removed percutaneously without need of anesthesia or analgesics. The urinary catheter was removed 3 weeks postoperatively after cystographic confirmation of absence of urinary leakage.
Follow-up Patients were followed by regular flexible cystoscopy and urinary cytology. The interval of follow up was every 3 months for the first 2 years and every 6 months thereafter. Median follow-up was 54 months (range, 1–178 months); 48 patients (44%) have been followed 5 years or more and 18 patients (17%) 10 years or more. Biopsies were taken in case of suspicion of recurrence; all recurrences were histologically confirmed. For local control, a distinction is made among all bladder recurrences, recurrences at the site of the original tumor, and recurrences elsewhere in the bladder.
Statistics Survival curves and local control were calculated actuarially according to Kaplan-Meier from the first day of external irradiation to the time of last follow-up visit or death (13). A stepwise procedure using Cox proportional hazard regression analysis was used to identify prognostic factors for local control, overall survival, and disease-specific survival (14). The following parameters were tested: age, sex, T-stage, lymph node status (cN0, pN0, pN⫹), grade, tumor diameter as assessed by cystoscopy, and whether or not partial resection was performed.
Comparison with cystectomy and combined modality series The outcome of three large cystectomy series and several combined modality series and brachytherapy series are summarized in Table 2. For contemporary cystectomy survival rates, recent reports of the University of Southern California, the Memorial Sloan-Kettering Cancer Center, and the University of Bern, Switzerland, are summarized (15–17). For combined modality treatment, the reports of two Radiation Therapy Oncology Group
Table 2. Outcome of cystectomy, brachytherapy, and combined radiotherapy and chemotherapy
Overall survival Series Stein et al. (15)
n
Treatment
680
5 years
10 years 43% Organ confined 54%* —
31% T1 51% T2 32% T3 26% 36% T2 ⫽ 41% T3-4a 31% 50% T1 64% T2 46% — —
1054
Cystectomy
Dalbagni et al. (16)
300
Cystectomy
Madersbacher et al. (17)
507
Cystectomy
RTOG study 88-02 (18) RTOG study 89-03 (19) University of Erlangen (2)
91 123 289
RCT† RCT† RCT†
Massachusetts General (3)
190
RCT†
Current series
108
Brachytherapy
66 63
Brachytherapy Brachytherapy
60% Organ confined 74%* 45% T2a 63% T2b 58% 59% ⱕpT2 pN0 63% 62% 49% 51% T1 75% T2 56% T3 44% 54% T2 62% T3-4a 47% 62% T1 75% T2 60% 48% —
Gonzalez et al. (8)
120
Brachytherapy
67%
63%
Rozan et al.‡ (6)
205
Brachytherapy
—
Pernot et al.‡ (7)
85
Brachytherapy
67% T1 77% T2 63% T3 47% 71% T1 78% T2 66% T3 66%
Wijnmaalen et al. (11) Van der Steen et al. (10)
Disease-specific survival
37%
45%
5 years
10 years
Overall survival with preserved bladder 10 years
% salvage cystectomies
44% 38% 42%
27%
37% (152/415)
45%
—
35% (66/190)
60%
45%
8% (9/108)
47% —
— —
3% (2/66) 21% (13/63)
—
—
5% (6/120)
—
—
7% (14/205)
—
—
5 years —
67% 62% ⱕpT2 pN0 63%
— 50% ⱕpT2 pN0 58%
56%
42%
63% T2 74% T3-4a 53% 73% T1 75% T2 71% 69% T1 80% T2 60% 73% T1 100% T2 80% T3 67% 83% T1 3% T2 81% T3 62% 77% T1 5% T2 76% T3 72%
59% T2 66% T3-4a 53% 67% T1 75% T2 64%
Abbreviation: RCT ⫽ radiotherapy and chemotherapy. * Organ confined disease on pathologic staging including 32% (213/669) noninvasive tumors (stages P0, Pa, and Pis). ‡ Partial cystectomies and brachytherapy. † Combined radiotherapy and chemotherapy.
58%
—
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Fig. 1. Recurrences and salvage treatments. EBRT ⫽ external beam radiotherapy; TUR ⫽ transurethral resection.
studies (18, 19) and two centers with considerable experience (Massachusetts General Hospital, University of Erlangen, Germany) are summarized (2, 3). For brachytherapy, those series reported after 1990 including more than 50 patients are summarized (6 –11).
RESULTS Local control In 23 of 108 patients, a bladder recurrence developed; the mean time to recurrence was 20 months. Seven patients had a superficial (Ta/Tis/T1) and 16 patients a muscle-invasive recurrence (Fig. 1). In 14 cases, the tumor recurred at the original tumor site (mean time to recurrence 18 months); in 9 cases, the relapse was located elsewhere in the bladder (mean time to recurrence 23 months). Local control (all bladder recurrences), local control at the original tumor site, and freedom from a recurrence elsewhere in the bladder at 5 and 10 years is shown in Fig. 2. A partial bladder resection may have reduced the recurrence rate at the original tumor site (0% vs. 20%, p ⫽ 0.08, Table 3). Low-grade tumors may be at higher risk for recurrences elsewhere in the bladder than high-grade tumors; the recurrence rate was 6% for G3 and 33% for G2 tumors (p ⫽ 0.06, Table 3). Salvage after local recurrence Among the 23 patients with a bladder recurrence, lasting local control after salvage treatment was obtained in 13 patients (Fig. 1). For 5 patients, this was achieved after a TUR only (2 patients) or combined with intravesical chemotherapy (3 patients). These 5 patients all had adequate functioning bladders after salvage treatment. Eventually, 90 patients (83%) preserved their bladders without evidence of disease in the bladder. For 10 patients with a bladder recurrence, lasting local
control was never achieved. In 7 cases, distant metastases were diagnosed soon after the local recurrence and salvage was never attempted. In 1 case, a salvage cystectomy was attempted, but soon after the cystectomy a pelvic recurrence occurred. Two patients suffered from recurrent superficial bladder tumors that were treated with TUR and intravesical chemotherapy; however, lasting local control was not achieved. The disease-specific survival rate after the diagnosis of a local recurrence was 43% both at 5 and 10 years. Distant metastases Distant metastases were diagnosed in 32 patients with an actuarial rate of 32% and 38% at 5 and 10 years, respec-
Fig. 2. Probability of remaining local recurrence free (solid line), remaining free from a recurrence at the original tumor site (broken line), and remaining free from recurrences elsewhere in the bladder (dotted line).
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Table 3. Prognostic factors for local control All bladder recurrences
Age ⬍ median vs. age ⬎ median Sex Clinical stage Diameter Grade Lymph node status* pN0 vs. cN0 Partial resection
Recurences at original tumor site
Recurrences elsewhere in bladder
Univariate p
Multivariate p
Univariate p
Multivariate p
Univariate p
Multivariate p
0.34
0.39
0.45
0.49
0.67
0.72
0.81 0.38 0.40 0.37 0.67 0.65 0.18
0.64 0.90 0.57 0.29 0.45 0.88 0.24
0.66 0.60 0.27 0.61 0.82 0.96 0.06
0.69 0.71 0.20 0.60 0.69 0.52 0.08
0.79 0.65 0.60 0.05 0.67 0.42 0.81
0.94 0.83 0.54 0.06 0.99 0.62 0.84
* pN0, cN0, pN⫹.
Survival and bladder preservation Overall survival and disease-specific survival rates for all patients are shown in Figs. 3 and 4. Overall survival at 5 and 10 years was 75% and 64% for T1 tumors, respectively, and 60% and 46% for T2 tumors, respectively. Disease-specific survival at 5 and 10 years was 75% and 75% for T1 tumors and 71% and 64% for T2 tumors. For T3 tumors, the actuarial survival and overall survival could not be calculated because of a low number of events. Of all long-term surviving patients, 90% preserved their native bladder (Fig. 3). Lymph node metastases significantly reduced diseasespecific survival; all pN⫹ patients died within 3 years because of the disease vs. 15% for cN0 patients and 30% pN0 patients (p ⫽ 0.03, Table 4).
patients). The urinary leakage resolved spontaneously after a prolonged period of bladder drainage by a suprapubic or transurethral catheter. One severe complication occurred because of accidental perforation of the sigmoid colon from improper placement of the brachytherapy tubes; another severe complication was osteomyelitis in 1 patient. There were no perioperative or treatment-related deaths. Mean hospitalization time was 18 days (range, 7– 68). Late toxicity. At follow-up, ulceration or necrosis at the site of implant was seen cystoscopically in 54 patients (50%); this was asymptomatic in 45 patients and caused symptoms (increased frequency or dysuria) in 9 (8%) patients. The mean period between brachytherapy and the development of necrosis was 6 months (range, 0 –19 months). Usually, spontaneous healing occurred within 9 months on average (range, 1–33 months). Severe late complications were seen in 2 patients (2%), 1 patient developed a persisting vesicocutaneous fistula, which was treated conservatively. The other patient required a nephrostomy because of a stricture of the ureters and eventually needed self-catheterization because of a stricture of the urethra.
Toxicity Acute toxicity. The incidence and type of acute complications were wound infection (14 patients) and urinary leakage (7
DISCUSSION The presented long-term results demonstrate that the bladder-sparing approach with brachytherapy is a highly
tively. All patients with lymph node metastases on lymph node dissection developed distant metastases (p ⫽ 0.002, Table 4). Lymph node status cN0 vs. pN0 did not influence the development of distant metastases. The rate of distant metastases at 5 years was 25% for pN0 patients and 30% for cN0 patients (p ⫽ 0.64, Table 4).
Table 4. Prognostic factors for overall survival, metastases-free survival, and disease-specific survival Overall survival
Age ⬍ median vs. Age ⬎ median Sex Clinical stage Diameter grade Lymph node status* pN0 vs. cN0 Partial resection * pN0, cN0, pN.
Metastases-free survival
Disease-specific survival
Univariate p
Multivariate p
Univariate p
Multivariate p
Univariate p
Multivariate p
0.02
0.02
0.53
0.30
0.71
0.57
0.58 0.44 0.69 0.21 0.01 0.71 0.54
0.78 0.43 0.47 0.12 0.10 0.54 0.40
0.34 0.56 0.10 0.19 0.005 0.97 0.64
0.17 0.41 0.99 0.13 0.002 0.64 0.70
0.83 0.95 0.39 0.12 0.05 0.64 0.76
0.53 0.87 0.80 0.10 0.03 0.57 0.55
Bladder preservation with brachytherapy
Fig. 3. Overall survival (OS) and overall survival with preserved bladder for all patients. For the lower plot, salvage cystectomy was taken as an additional event.
effective organ-sparing method for solitary bladder cancer with a diameter up to 5 cm. Long-term local control was obtained for the majority of patients (73% both at 5 and 10 years). The disease-specific survival rates after 10 years were 73% and 67%, respectively. Of all long-term surviving patients, 90% preserved their native bladders, which brings up the question of why brachytherapy treatment for invasive bladder cancer remains such an uncommonly performed procedure. Survival of brachytherapy vs. radical cystectomy A reason for reluctance could be the commonly held belief that radiotherapy-based strategies lead to inferior survival. Does the bladder-sparing approach with brachy-
Fig. 4. Disease-specific survival (DS) and disease-specific survival with preserved bladder for all patients. For the lower plot, salvage cystectomy was taken as an additional event.
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therapy compromise survival? The survival rates of brachytherapy have to be compared with those following the surgical standard for the same selection of patients. A direct comparison of survival rates of brachytherapy and surgery has several limitations. Brachytherapy series include only those patients with solitary tumors smaller than 5 cm, whereas cystectomy series also include multifocal tumors and bulky tumors larger than 5 cm. This comparison method might lead to a favorable bias for the brachytherapy series. Conversely, the comparison is confounded by discordance between clinical staging (for brachytherapy) and pathologic staging (for cystectomy series). Clinical staging is more likely to understage the extent of disease (20). Therefore, a favorable bias for the cystectomy series may exist. In the absence of prospective randomized studies, we have to base our decisions on the best available evidence: a comparison of published results. Stein et al. reported a 5- and 10-year overall survival of 74% and 54%, respectively, for 667 radical cystectomy patients with organ confined disease (Table 2) (15). However, this selection of patients included 213 (32%) noninvasive (pT0, pTa, cis) tumors. The Memorial SloanKettering contemporary cystectomy series reports a 5-year overall survival of 63% for T2a and 58% for T2b disease (Table 2) (16). Madersbacher et al. reported an overall 5-year survival of 63% for tumor stages ⱕpT2 pN0 (Table 2) (17). Therefore, one can conclude that the overall survival rates of our and other brachytherapy series compare well with the best cystectomy series for patients with organ-confined disease (Table 2). Notwithstanding the limitations of a nonrandomized comparison of two different treatment forms, this analysis indicates bladder preservation with brachytherapy does not compromise survival and therefore can be offered to patients seeking an alternative to radical cystectomy. Treatment by TUR, partial cystectomy, or EBRT alone A second reason for reluctance about using brachytherapy could be the suggestion that comparable results could be obtained by TUR, partial cystectomy, or EBRT alone. Recently, Herr reported on the 10-year outcome with muscle-invasive bladder cancer treated by TUR alone (21). Only if a restaging TUR showed no, or only nonmuscle invasive residual tumor, were patients suitable for the protocol. Even in this very favorable selection of patients, 34% percent required salvage cystectomy because of progression. Partial cystectomy remains an uncommonly performed procedure; most studies are retrospective reviews with patients treated over a span of many years and a variety of tumor stages. The literature on partial cystectomy was recently reviewed by Kuczyk et al. (22). Local recurrence rates were 38 –78%, half of which appeared during the first half year. Based on these historical results, brachytherapy seems a better method for obtaining local control. Is the combination of EBRT and brachytherapy better than EBRT alone? Reported local control rates of muscle
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invasive bladder cancer treated with EBRT are not higher than 40 –50% (23). The poor outcome of treatment with EBRT occurs because of several reasons. Usually, only those patients who are either poor or not candidates for cystectomy are referred for EBRT. In two recently published population-based studies, the strongest prognostic factors for survival were tumor related and there was no benefit for cystectomy over radiotherapy (24, 25). Another explanation for the poor local control of EBRT can be found in the treatment techniques used. Implementation of modern treatment techniques could allow improvement of the results obtained with EBRT in the future (26, 27). Potential candidates for organ preservation with brachytherapy A third reason for reluctance for using brachytherapy could be the belief that only a small minority of patients is candidate for such treatment. An estimate can be made from the European Organization for Research and Treatment of Cancer/Medical Research Council (MRC) trial assessing the value of neoadjuvant chemotherapy in 976 patients (28). Of all tumors, 82% were smaller than 5 cm and 92% were stage T2-T3. A publication by the M. D. Anderson Cancer Center describing a cystectomy series of 570 patients showed that 78% of the tumors were smaller than 5 cm and 63% were solitary (29). Based on these figures, a considerable proportion of patients with invasive bladder cancer could have saved their bladders if they would have been offered a bladder-sparing approach with brachytherapy. Development of sequential bladder tumors One of the reasons given for removing the bladder is the concern for the development of sequential tumors out of existing premalignant lesions, such as dysplasia and carcinoma in situ. In our series, the recurrence rate outside of the primary tumor site was 11% at 10 years. Apparently, the risk for patients with solitary invasive bladder tumors ⬍5 cm to develop new tumors is low. The selection of bladders at risk for the development of sequential tumors could be further optimized in the future. In our series, the low-grade tumors seemed to be at higher risk for the development of sequential tumors than did high-grade tumors (33% for G2 vs. 6% for G3 tumors, p ⫽ 0.06). This indicates the existence of an entity of invasive bladder cancer at higher risk for the development of sequential tumors. If the pathogenic pathway of this entity could be further identified, it might be of great value in the selection of bladder tumors suitable for organ preservation. Modern techniques in brachytherapy Another reason for reluctance to use brachytherapy could be that brachytherapy for bladder cancer is considered old-fashioned and is associated with potential radiation exposure to medical and nursing staff and a high incidence of postoperative complications. However, in the last few decades, substantial progress has been made
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regarding exposure and better implant techniques have been introduced. After-loading techniques with flexible catheters have eliminated radiation exposure to the medical staff and reduced postoperative complications (9). The introduction of modern CT-based treatment planning (Nucletron) has allowed accurate and reproducible treatment planning and integration of brachytherapy with EBRT treatment planning. The inclusion of a magnetic resonance imaging and a routinely performed pelvic lymph node dissection in the staging procedures allows a better selection of patients who are suitable for treatment with brachytherapy and hence might further improve the outcome in the future.
Brachytherapy vs. combined modality treatment As stated in the introduction, several groups have reported on the value of bladder preservation with combined modality treatment including TUR, EBRT, and systemic chemotherapy. Reports on this approach invariably mention survival rates comparable to the best cystectomy series and excellent bladder-sparing capacities (2, 3, 18, 19) (see Table 2). As a result, there are two successful bladder-preserving strategies: brachytherapy and combined modality treatment. This brings up the question of which form of treatment to choose when considering organ preservation. An important issue is patient selection. Where brachytherapy is only feasible in solitary organ– confined disease with a diameter ⱕ5 cm, combined modality series include all tumor stages up to T4a of any size. Another important issue is that for a successful treatment with brachytherapy, one needs to have the availability of a brachytherapy unit, an experienced brachytherapy team, and cooperation between radiation oncology and urology. If, however, a patient is a candidate for treatment with brachytherapy and the option of brachytherapy is available, this type of treatment must be considered. An important advantage of brachytherapy over combined modality treatment is that patients can be spared the toxicity of chemotherapy. With combined modality treatments, many patients experience serious acute toxicity from systemic treatment. For example, in the Radiation Therapy Oncology Group 89-03 trial in the neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) arm, 62% of the patients experienced ⱖG3 toxicity with three lethal complications (19). In our series, only 2 patients encountered serious acute toxicity and there was no treatment-related mortality. Another advantage of brachytherapy might be the high success rate of this strategy. After brachytherapy, usually ⬍10% of patients eventually require a cystectomy vs. roughly one-third of the patients after chemotherapy-based regimens (Table 2). However, this difference might be explained by differences in patient selection as described previously. Based on these considerations, in our institution, we prefer brachytherapy over combined modality treatment for all potential brachytherapy candidates.
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Organ preservation vs. urinary diversion Both brachytherapy and combined modality series report a good quality of life after treatment; however, this has never been studied in detail. One might argue that, with modern sophisticated techniques for urinary diversion, there is no need for sparing approaches (30). However, a recent population-based study from Sweden concluded that the patient’s situation after cystectomy with urinary diversion is considerably impaired because of changed bowel and sexual function, urinary tract infections, and a sense of decreased attractiveness (31). A definitive randomized trial comparing bladder preservation with cystectomy has never been performed. In the absence of prospective randomized studies, we have to
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base our decisions on the best available evidence: a comparison of published results. Brachytherapy and combined modality series all prove that organ preservation can be safely offered to a patient. For patients with solitary, organ-confined T1-T2 invasive bladder cancer with a diameter ⱕ5 cm, therefore, the situation seems to be similar to early prostate cancer. Where nowadays early prostate cancer patients can choose between radical prostatectomy, brachytherapy, or EBRT (32), these bladder cancer patients can choose between radical cystectomy, brachytherapy, or EBRT in combination with chemotherapy. The choice of treatment can be made the on local availability of the different technologies and personal preferences.
REFERENCES 1. Gospodarowicz M. Radiotherapy and organ preservation in bladder cancer: Are we ignoring the evidence? J Clin Oncol 2002;20:3048 –3050. 2. Rödel C, Grabenbauer GG, Kuhn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: Long-term results. J Clin Oncol 2002;20:3061–3071. 3. Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment: Longterm outcomes of 190 patients with invasive bladder cancer. Urology 2002;60:62– 68. 4. Sternberg CN. Current perspectives in muscle invasive bladder cancer. Eur J Cancer 2002;38:460 – 467. 5. Union Internationale Contre le Cancer. TNM atlas. 3rd edition, 2nd revision. Heidelberg, Germany: Springer-Verlag; 1992. 6. Rozan R, Albuisson E, Donnarieix D, et al. Interstitial iridium-192 for bladder cancer (a multicentric survey: 205 patients). Int J Radiat Oncol Biol Phys 1992;24:469 – 477. 7. Pernot M, Hubert J, Guillemin F, et al. Combined surgery and brachytherapy in the treatment of some cancers of the bladder (partial cystectomy and interstitial iridium-192). Radiother Oncol 1996;38:115–120. 8. Gonzalez D, van der Veen HJ, Ypma AF, et al. Brachytherapy for urinary bladder cancer. Arch Esp Urol 1999;52:655– 661. 9. Moonen LM, Horenblas S, van der Voet JC, et al. Bladder conservation in selected T1G3 and muscle-invasive T2-T3a bladder carcinoma using combination therapy of surgery and iridium-192 implantation. Br J Urol 1994;74:322–327. 10. Van der Steen-Banasik EM, Visser AG, Reinders JG, et al. Saving bladders with brachytherapy: Implantation technique and results. Int J Radiat Oncol Biol Phys 2002;53:622– 629. 11. Wijnmaalen A, Helle PA, Koper PC, et al. Muscle invasive bladder cancer treated by transurethral resection, followed by external beam radiation and interstitial iridium-192. Int J Radiat Oncol Biol Phys 1997;39:1043–1052. 12. van der Werf-Messing B. Carcinoma of the bladder treated by suprapubic radium implants. The value of additional external irradiation. Eur J Cancer 1969;5:277–285. 13. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. 14. Cox DR. Regression models and life tables. J R Stat Soc B 1972;34:187–220. 15. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 2001;19:666 – 675. 16. Dalbagni G, Genega E, Hashibe M, et al. Cystectomy for bladder cancer: A contemporary series. J Urol 2001;165: 1111–1116.
17. Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer today—a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21: 690 – 696. 18. Tester W, Caplan R, Heaney J, et al. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: Results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol 1996;14:119 –126. 19. Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: Initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16:3576 – 3583. 20. Wijkstrom H, Norming U, Lagerkvist M, et al. Evaluation of clinical staging before cystectomy in transitional cell bladder carcinoma: A long-term follow-up of 276 consecutive patients. Br J Urol 1998;81:686 – 691. 21. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19:89 –93. 22. Kuczyk M, Machtens S, Bokemeyer C, et al. Surgical bladder preserving strategies in the treatment of muscle-invasive bladder cancer. World J Urol 2002;20:183–189. 23. Sengelov L, von der Maase H. Radiotherapy in bladder cancer. Radiother Oncol 1999;52:1–14. 24. Hayter CR, Paszat LF, Groome PA, et al. The management and outcome of bladder carcinoma in Ontario, 1982–1994. Cancer 2000;89:142–151. 25. Scrimger RA, Murtha AD, Parliament MB, et al. Muscleinvasive transitional cell carcinoma of the urinary bladder: A population-based study of patterns of care and prognostic factors. Int J Radiat Oncol Biol Phys 2001;51:23–30. 26. Pos FJ, van Tienhoven G, Hulshof MC, et al. Concomitant boost radiotherapy for muscle invasive bladder cancer. Radiother Oncol 2003;68:75– 80. 27. Pos FJ, Koedooder K, Hulshof MC, et al. Influence of bladder and rectal volume on spatial variability of a bladder tumor during radical radiotherapy. Int J Radiat Oncol Biol Phys 2003;55:835– 841. 28. International Collaboration of Trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. Lancet 1999;354: 533–540. 29. Cole CJ, Pollack A, Zagars GK, et al. Local control of muscle-invasive bladder cancer: Preoperative radiotherapy and cystectomy versus cystectomy alone. Int J Radiat Oncol Biol Phys 1995;32:331–340.
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30. Kuczyk M, Turkeri L, Hammerer P, et al. Is there a role for bladder preserving strategies in the treatment of muscle-invasive bladder cancer? Eur Urol 2003;44:57– 64. 31. Henningsohn L, Wijkstrom H, Dickman PW, et al. Distressful symptoms after radical cystectomy with urinary diversion for
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urinary bladder cancer: A Swedish population-based study. Eur Urol 2001;40:151–162. 32. Peschel RE, Colberg JW. Surgery, brachytherapy, and external-beam radiotherapy for early prostate cancer. Lancet Oncol 2003;4:233–241.
doi:10.1016/j.ijrobp.2004.06.249
CLINICAL INVESTIGATION
Bladder
ORGAN PRESERVATION IN INVASIVE BLADDER CANCER: BRACHYTHERAPY, AN ALTERNATIVE TO CYSTECTOMY AND COMBINED MODALITY TREATMENT? FLORIS POS, M.D.,* SIMON HORENBLAS, M.D., PH.D.,† PAUL DOM, M.D.,† LUC MOONEN, M.D., PH.D.,* AND HARRY BARTELINK, M.D., PH.D.* Departments of *Radiotherapy and †Urology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands Purpose: To evaluate our long-term results of bladder preservation with brachytherapy in the treatment of bladder cancer. Methods and Materials: Between 1987 and 2000, 108 patients with T1-G3 and T2-T3a stages of bladder cancer were treated with a transurethral resection (TUR) and a course of external beam radiotherapy (30 Gy in 15 fractions) followed by brachytherapy (40 Gy). All tumors were solitary lesions with a diameter <5 cm. Median follow-up was 54 months (range, 1–178 months). Results: The 5-year and 10-year overall survival rates were 62% and 50%, respectively. The 5-year and 10-year disease-specific survival rates were 73% and 67%, respectively. The actuarial local control rate was 73% at 5 and 73% at 10 years, respectively. The 5-year and 10-year disease-specific survival rates for patients with a preserved bladder were 68% and 59%, respectively. Of all long-term surviving patients, 90% preserved their native bladders. The treatment was well tolerated. Acute toxicity was mild. Two patients experienced serious late toxicity: 1 patient developed a persisting vesicocutaneous fistula and the other a stricture of the urethra and ureters. Conclusion: For patients with solitary, organ confined invasive bladder cancer <5 cm, bladder preservation with brachytherapy is an excellent alternative to radical cystectomy and combined modality treatment. © 2005 Elsevier Inc. Bladder cancer, Organ conservation, Brachytherapy.
tumors (5) of ⱕ5 cm diameter, this treatment strategy provides high local control rates and excellent maintenance of bladder function without systemic chemotherapy (6 –11). For many years, it has been the policy at the Department of Radiotherapy at The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital in Amsterdam to use brachytherapy in the treatment of solitary invasive bladder cancer up to 5 cm (9). We now present our long-term experience with brachytherapy in the treatment of bladder cancer.
INTRODUCTION Organ preservation has been in the forefront of modern cancer treatment for the last several decades. Conservative treatment is now standard of care for numerous malignancies including breast cancer, laryngeal cancer, anal cancer, and soft-tissue sarcomas of the limb. However, for patients with muscle-invasive bladder cancer, radical surgery is still considered standard treatment. Recently, bladder organ-preserving strategies have gained renewed interest. The discussion on bladder preservation has mainly focused on combinations of cisplatin-containing chemotherapy and external beam radiotherapy (EBRT) after transurethral resection (TUR) of the bladder tumor (1– 4). A disadvantage of these treatment schedules is that all patients receive several courses of systemic chemotherapy with consequent toxicity. In the discussion on bladder-sparing strategies, the treatment of invasive bladder cancer with brachytherapy seems to be largely overlooked. For patients with solitary T1-T3a
METHODS AND MATERIALS Patient and tumor characteristics Between 1987 and 2000, 108 patients were treated with TUR, EBRT, and brachytherapy. The patient selection criteria were histologic confirmed transitional cell carcinoma; solitary lesion with a diameter ⱕ5 cm; T1-G3 and T2-T3a stages (5); being fit for surgery; and adequate bladder capacity as estimated subjectively by the patients themselves. Before referral, all patients underwent
Reprint requests to: Floris J. Pos, M.D., The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Department of Radiation Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Tel: (⫹31) 20-5122124; Fax: (⫹31)
20-6691101; E-mail: [email protected] Received Mar 16, 2004, and received in revised form Jun 18, 2004. Accepted for publication Jun 28, 2004. 678
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Table 1. Patient and tumor characteristics No. patients (n ⫽ 108) Median age (⫾ SD) Sex Male Female T-stage* T1 T2 T3 Grade G2 G3 Adenocarcinoma Tumor A† ⬍1 cm 1–3 cm 3–5 cm Unknown Previous intravesical chemotherapy
63.4 ⫾ 11 years 89 19 17 84 7 26 80 2 9 68 26 5 5
* TNM, 3rd edition, 2nd revision, 1992 (5). † Tumor diameter as estimated by cystoscopy after transurethral resection.
TUR. All the histologic specimens were centrally reviewed. Evaluation before treatment included medical history, physical examination, a cystoscopy in our institution, computed tomography (CT) scan of the pelvis and abdomen and chest X-ray. Patient and tumor characteristics are shown in Table 1.
Treatment All patients received a course of EBRT to the pelvis with a dose of 30 Gy in 2-Gy fractions via a two- or three-field technique. The reason for this short course of EBRT was to prevent scar metastases (12). The irradiated volume extended cranially to the promontorium and caudally to the mid-symphysis pubis; the lateral margins were 1 cm outside the bony pelvic walls. If a three-field technique was used, the anterior and posterior margins on the lateral fields were 2 cm beyond the bladder wall as seen on CT scan. Within 2 weeks after completion of external irradiation, a suprapubic cystotomy was performed. Hollow nylon tubes were then inserted into the tumor area parallel and halfway through the bladder wall. To aid recognition of the target area on treatment planning, four to five small, silver seeds were inserted in the bladder wall at the boundaries of the post-EBRT lesion with a 0.5–1 cm margin. Three tubes in a single plane were usually found to be adequate to encompass the target area. Subsequently, the tubes were brought to the abdominal wall; a suprapubic or a transurethral catheter allowed bladder drainage. In 24 patients, a partial resection was performed limited to the macroscopic lesion. Reasons for tumor resection were: location in the bladder dome or evidence of residual tumor at surgery not amenable to brachytherapy only on the basis of the volume of tissue palpated at surgery. In case of a partial resection, the target area for the brachytherapy planning consisted of the scar. Two tubes were placed parallel to the scar, and silver seeds were placed at the end of the scar to recognize the length on treatment planning.
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Of the 24 partial resections of the bladder, 5 were without evidence of tumor, 3 of the resected tumors were Stage pT1, 12 were Stage pT2, and 4 were Stage pT3, of which 2 were adeno (urachus) carcinomas. The ureter was reimplanted in two cases because the tumor caused persisting ureteric obstruction. Lymph node dissection as a staging procedure was not performed routinely; only in the case of suspicious nodes on the CT scan or suspicion during the surgical procedure was a modified pelvic lymph node dissection done. Of the 11 lymph node dissections, 3 were tumor-positive. Treatment planning was performed a week after surgery. Isodose curves were generated, and the isodose encompassing the tumor area as marked with the silver seeds was selected as a reference. Until 1994, treatment planning was done with stereoshifted radiographs and MPS V7.2 (Nucletron) software; after 1994, treatment planning was CT-based using MPS V11 (Nucletron, Veenendaal, The Netherlands) software. A dose of 40 Gy was delivered by the implant with 192iridium. For the patients treated from 1994 onward, (60 patients) the mean volume encompassed by the 100% isodose was 29.0 cm3 (SD ⫽ 12 cm3) (range, 8 –57 cm3. Data were not available for patients treated before 1994. Until 1990, the treatment was hand loaded; thereafter, a low-dose-rate Microselectron (Nucletron) after-loading device was used. The mean application time was 71 h (range, 36 –102 h) and the mean dose rate was 59 cGy/h (range, 40 –110 cGy/h). Immediately after completion of the treatment, the tubes were removed percutaneously without need of anesthesia or analgesics. The urinary catheter was removed 3 weeks postoperatively after cystographic confirmation of absence of urinary leakage.
Follow-up Patients were followed by regular flexible cystoscopy and urinary cytology. The interval of follow up was every 3 months for the first 2 years and every 6 months thereafter. Median follow-up was 54 months (range, 1–178 months); 48 patients (44%) have been followed 5 years or more and 18 patients (17%) 10 years or more. Biopsies were taken in case of suspicion of recurrence; all recurrences were histologically confirmed. For local control, a distinction is made among all bladder recurrences, recurrences at the site of the original tumor, and recurrences elsewhere in the bladder.
Statistics Survival curves and local control were calculated actuarially according to Kaplan-Meier from the first day of external irradiation to the time of last follow-up visit or death (13). A stepwise procedure using Cox proportional hazard regression analysis was used to identify prognostic factors for local control, overall survival, and disease-specific survival (14). The following parameters were tested: age, sex, T-stage, lymph node status (cN0, pN0, pN⫹), grade, tumor diameter as assessed by cystoscopy, and whether or not partial resection was performed.
Comparison with cystectomy and combined modality series The outcome of three large cystectomy series and several combined modality series and brachytherapy series are summarized in Table 2. For contemporary cystectomy survival rates, recent reports of the University of Southern California, the Memorial Sloan-Kettering Cancer Center, and the University of Bern, Switzerland, are summarized (15–17). For combined modality treatment, the reports of two Radiation Therapy Oncology Group
Table 2. Outcome of cystectomy, brachytherapy, and combined radiotherapy and chemotherapy
Overall survival Series Stein et al. (15)
n
Treatment
680
5 years
10 years 43% Organ confined 54%* —
31% T1 51% T2 32% T3 26% 36% T2 ⫽ 41% T3-4a 31% 50% T1 64% T2 46% — —
1054
Cystectomy
Dalbagni et al. (16)
300
Cystectomy
Madersbacher et al. (17)
507
Cystectomy
RTOG study 88-02 (18) RTOG study 89-03 (19) University of Erlangen (2)
91 123 289
RCT† RCT† RCT†
Massachusetts General (3)
190
RCT†
Current series
108
Brachytherapy
66 63
Brachytherapy Brachytherapy
60% Organ confined 74%* 45% T2a 63% T2b 58% 59% ⱕpT2 pN0 63% 62% 49% 51% T1 75% T2 56% T3 44% 54% T2 62% T3-4a 47% 62% T1 75% T2 60% 48% —
Gonzalez et al. (8)
120
Brachytherapy
67%
63%
Rozan et al.‡ (6)
205
Brachytherapy
—
Pernot et al.‡ (7)
85
Brachytherapy
67% T1 77% T2 63% T3 47% 71% T1 78% T2 66% T3 66%
Wijnmaalen et al. (11) Van der Steen et al. (10)
Disease-specific survival
37%
45%
5 years
10 years
Overall survival with preserved bladder 10 years
% salvage cystectomies
44% 38% 42%
27%
37% (152/415)
45%
—
35% (66/190)
60%
45%
8% (9/108)
47% —
— —
3% (2/66) 21% (13/63)
—
—
5% (6/120)
—
—
7% (14/205)
—
—
5 years —
67% 62% ⱕpT2 pN0 63%
— 50% ⱕpT2 pN0 58%
56%
42%
63% T2 74% T3-4a 53% 73% T1 75% T2 71% 69% T1 80% T2 60% 73% T1 100% T2 80% T3 67% 83% T1 3% T2 81% T3 62% 77% T1 5% T2 76% T3 72%
59% T2 66% T3-4a 53% 67% T1 75% T2 64%
Abbreviation: RCT ⫽ radiotherapy and chemotherapy. * Organ confined disease on pathologic staging including 32% (213/669) noninvasive tumors (stages P0, Pa, and Pis). ‡ Partial cystectomies and brachytherapy. † Combined radiotherapy and chemotherapy.
58%
—
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Fig. 1. Recurrences and salvage treatments. EBRT ⫽ external beam radiotherapy; TUR ⫽ transurethral resection.
studies (18, 19) and two centers with considerable experience (Massachusetts General Hospital, University of Erlangen, Germany) are summarized (2, 3). For brachytherapy, those series reported after 1990 including more than 50 patients are summarized (6 –11).
RESULTS Local control In 23 of 108 patients, a bladder recurrence developed; the mean time to recurrence was 20 months. Seven patients had a superficial (Ta/Tis/T1) and 16 patients a muscle-invasive recurrence (Fig. 1). In 14 cases, the tumor recurred at the original tumor site (mean time to recurrence 18 months); in 9 cases, the relapse was located elsewhere in the bladder (mean time to recurrence 23 months). Local control (all bladder recurrences), local control at the original tumor site, and freedom from a recurrence elsewhere in the bladder at 5 and 10 years is shown in Fig. 2. A partial bladder resection may have reduced the recurrence rate at the original tumor site (0% vs. 20%, p ⫽ 0.08, Table 3). Low-grade tumors may be at higher risk for recurrences elsewhere in the bladder than high-grade tumors; the recurrence rate was 6% for G3 and 33% for G2 tumors (p ⫽ 0.06, Table 3). Salvage after local recurrence Among the 23 patients with a bladder recurrence, lasting local control after salvage treatment was obtained in 13 patients (Fig. 1). For 5 patients, this was achieved after a TUR only (2 patients) or combined with intravesical chemotherapy (3 patients). These 5 patients all had adequate functioning bladders after salvage treatment. Eventually, 90 patients (83%) preserved their bladders without evidence of disease in the bladder. For 10 patients with a bladder recurrence, lasting local
control was never achieved. In 7 cases, distant metastases were diagnosed soon after the local recurrence and salvage was never attempted. In 1 case, a salvage cystectomy was attempted, but soon after the cystectomy a pelvic recurrence occurred. Two patients suffered from recurrent superficial bladder tumors that were treated with TUR and intravesical chemotherapy; however, lasting local control was not achieved. The disease-specific survival rate after the diagnosis of a local recurrence was 43% both at 5 and 10 years. Distant metastases Distant metastases were diagnosed in 32 patients with an actuarial rate of 32% and 38% at 5 and 10 years, respec-
Fig. 2. Probability of remaining local recurrence free (solid line), remaining free from a recurrence at the original tumor site (broken line), and remaining free from recurrences elsewhere in the bladder (dotted line).
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Table 3. Prognostic factors for local control All bladder recurrences
Age ⬍ median vs. age ⬎ median Sex Clinical stage Diameter Grade Lymph node status* pN0 vs. cN0 Partial resection
Recurences at original tumor site
Recurrences elsewhere in bladder
Univariate p
Multivariate p
Univariate p
Multivariate p
Univariate p
Multivariate p
0.34
0.39
0.45
0.49
0.67
0.72
0.81 0.38 0.40 0.37 0.67 0.65 0.18
0.64 0.90 0.57 0.29 0.45 0.88 0.24
0.66 0.60 0.27 0.61 0.82 0.96 0.06
0.69 0.71 0.20 0.60 0.69 0.52 0.08
0.79 0.65 0.60 0.05 0.67 0.42 0.81
0.94 0.83 0.54 0.06 0.99 0.62 0.84
* pN0, cN0, pN⫹.
Survival and bladder preservation Overall survival and disease-specific survival rates for all patients are shown in Figs. 3 and 4. Overall survival at 5 and 10 years was 75% and 64% for T1 tumors, respectively, and 60% and 46% for T2 tumors, respectively. Disease-specific survival at 5 and 10 years was 75% and 75% for T1 tumors and 71% and 64% for T2 tumors. For T3 tumors, the actuarial survival and overall survival could not be calculated because of a low number of events. Of all long-term surviving patients, 90% preserved their native bladder (Fig. 3). Lymph node metastases significantly reduced diseasespecific survival; all pN⫹ patients died within 3 years because of the disease vs. 15% for cN0 patients and 30% pN0 patients (p ⫽ 0.03, Table 4).
patients). The urinary leakage resolved spontaneously after a prolonged period of bladder drainage by a suprapubic or transurethral catheter. One severe complication occurred because of accidental perforation of the sigmoid colon from improper placement of the brachytherapy tubes; another severe complication was osteomyelitis in 1 patient. There were no perioperative or treatment-related deaths. Mean hospitalization time was 18 days (range, 7– 68). Late toxicity. At follow-up, ulceration or necrosis at the site of implant was seen cystoscopically in 54 patients (50%); this was asymptomatic in 45 patients and caused symptoms (increased frequency or dysuria) in 9 (8%) patients. The mean period between brachytherapy and the development of necrosis was 6 months (range, 0 –19 months). Usually, spontaneous healing occurred within 9 months on average (range, 1–33 months). Severe late complications were seen in 2 patients (2%), 1 patient developed a persisting vesicocutaneous fistula, which was treated conservatively. The other patient required a nephrostomy because of a stricture of the ureters and eventually needed self-catheterization because of a stricture of the urethra.
Toxicity Acute toxicity. The incidence and type of acute complications were wound infection (14 patients) and urinary leakage (7
DISCUSSION The presented long-term results demonstrate that the bladder-sparing approach with brachytherapy is a highly
tively. All patients with lymph node metastases on lymph node dissection developed distant metastases (p ⫽ 0.002, Table 4). Lymph node status cN0 vs. pN0 did not influence the development of distant metastases. The rate of distant metastases at 5 years was 25% for pN0 patients and 30% for cN0 patients (p ⫽ 0.64, Table 4).
Table 4. Prognostic factors for overall survival, metastases-free survival, and disease-specific survival Overall survival
Age ⬍ median vs. Age ⬎ median Sex Clinical stage Diameter grade Lymph node status* pN0 vs. cN0 Partial resection * pN0, cN0, pN.
Metastases-free survival
Disease-specific survival
Univariate p
Multivariate p
Univariate p
Multivariate p
Univariate p
Multivariate p
0.02
0.02
0.53
0.30
0.71
0.57
0.58 0.44 0.69 0.21 0.01 0.71 0.54
0.78 0.43 0.47 0.12 0.10 0.54 0.40
0.34 0.56 0.10 0.19 0.005 0.97 0.64
0.17 0.41 0.99 0.13 0.002 0.64 0.70
0.83 0.95 0.39 0.12 0.05 0.64 0.76
0.53 0.87 0.80 0.10 0.03 0.57 0.55
Bladder preservation with brachytherapy
Fig. 3. Overall survival (OS) and overall survival with preserved bladder for all patients. For the lower plot, salvage cystectomy was taken as an additional event.
effective organ-sparing method for solitary bladder cancer with a diameter up to 5 cm. Long-term local control was obtained for the majority of patients (73% both at 5 and 10 years). The disease-specific survival rates after 10 years were 73% and 67%, respectively. Of all long-term surviving patients, 90% preserved their native bladders, which brings up the question of why brachytherapy treatment for invasive bladder cancer remains such an uncommonly performed procedure. Survival of brachytherapy vs. radical cystectomy A reason for reluctance could be the commonly held belief that radiotherapy-based strategies lead to inferior survival. Does the bladder-sparing approach with brachy-
Fig. 4. Disease-specific survival (DS) and disease-specific survival with preserved bladder for all patients. For the lower plot, salvage cystectomy was taken as an additional event.
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therapy compromise survival? The survival rates of brachytherapy have to be compared with those following the surgical standard for the same selection of patients. A direct comparison of survival rates of brachytherapy and surgery has several limitations. Brachytherapy series include only those patients with solitary tumors smaller than 5 cm, whereas cystectomy series also include multifocal tumors and bulky tumors larger than 5 cm. This comparison method might lead to a favorable bias for the brachytherapy series. Conversely, the comparison is confounded by discordance between clinical staging (for brachytherapy) and pathologic staging (for cystectomy series). Clinical staging is more likely to understage the extent of disease (20). Therefore, a favorable bias for the cystectomy series may exist. In the absence of prospective randomized studies, we have to base our decisions on the best available evidence: a comparison of published results. Stein et al. reported a 5- and 10-year overall survival of 74% and 54%, respectively, for 667 radical cystectomy patients with organ confined disease (Table 2) (15). However, this selection of patients included 213 (32%) noninvasive (pT0, pTa, cis) tumors. The Memorial SloanKettering contemporary cystectomy series reports a 5-year overall survival of 63% for T2a and 58% for T2b disease (Table 2) (16). Madersbacher et al. reported an overall 5-year survival of 63% for tumor stages ⱕpT2 pN0 (Table 2) (17). Therefore, one can conclude that the overall survival rates of our and other brachytherapy series compare well with the best cystectomy series for patients with organ-confined disease (Table 2). Notwithstanding the limitations of a nonrandomized comparison of two different treatment forms, this analysis indicates bladder preservation with brachytherapy does not compromise survival and therefore can be offered to patients seeking an alternative to radical cystectomy. Treatment by TUR, partial cystectomy, or EBRT alone A second reason for reluctance about using brachytherapy could be the suggestion that comparable results could be obtained by TUR, partial cystectomy, or EBRT alone. Recently, Herr reported on the 10-year outcome with muscle-invasive bladder cancer treated by TUR alone (21). Only if a restaging TUR showed no, or only nonmuscle invasive residual tumor, were patients suitable for the protocol. Even in this very favorable selection of patients, 34% percent required salvage cystectomy because of progression. Partial cystectomy remains an uncommonly performed procedure; most studies are retrospective reviews with patients treated over a span of many years and a variety of tumor stages. The literature on partial cystectomy was recently reviewed by Kuczyk et al. (22). Local recurrence rates were 38 –78%, half of which appeared during the first half year. Based on these historical results, brachytherapy seems a better method for obtaining local control. Is the combination of EBRT and brachytherapy better than EBRT alone? Reported local control rates of muscle
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invasive bladder cancer treated with EBRT are not higher than 40 –50% (23). The poor outcome of treatment with EBRT occurs because of several reasons. Usually, only those patients who are either poor or not candidates for cystectomy are referred for EBRT. In two recently published population-based studies, the strongest prognostic factors for survival were tumor related and there was no benefit for cystectomy over radiotherapy (24, 25). Another explanation for the poor local control of EBRT can be found in the treatment techniques used. Implementation of modern treatment techniques could allow improvement of the results obtained with EBRT in the future (26, 27). Potential candidates for organ preservation with brachytherapy A third reason for reluctance for using brachytherapy could be the belief that only a small minority of patients is candidate for such treatment. An estimate can be made from the European Organization for Research and Treatment of Cancer/Medical Research Council (MRC) trial assessing the value of neoadjuvant chemotherapy in 976 patients (28). Of all tumors, 82% were smaller than 5 cm and 92% were stage T2-T3. A publication by the M. D. Anderson Cancer Center describing a cystectomy series of 570 patients showed that 78% of the tumors were smaller than 5 cm and 63% were solitary (29). Based on these figures, a considerable proportion of patients with invasive bladder cancer could have saved their bladders if they would have been offered a bladder-sparing approach with brachytherapy. Development of sequential bladder tumors One of the reasons given for removing the bladder is the concern for the development of sequential tumors out of existing premalignant lesions, such as dysplasia and carcinoma in situ. In our series, the recurrence rate outside of the primary tumor site was 11% at 10 years. Apparently, the risk for patients with solitary invasive bladder tumors ⬍5 cm to develop new tumors is low. The selection of bladders at risk for the development of sequential tumors could be further optimized in the future. In our series, the low-grade tumors seemed to be at higher risk for the development of sequential tumors than did high-grade tumors (33% for G2 vs. 6% for G3 tumors, p ⫽ 0.06). This indicates the existence of an entity of invasive bladder cancer at higher risk for the development of sequential tumors. If the pathogenic pathway of this entity could be further identified, it might be of great value in the selection of bladder tumors suitable for organ preservation. Modern techniques in brachytherapy Another reason for reluctance to use brachytherapy could be that brachytherapy for bladder cancer is considered old-fashioned and is associated with potential radiation exposure to medical and nursing staff and a high incidence of postoperative complications. However, in the last few decades, substantial progress has been made
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regarding exposure and better implant techniques have been introduced. After-loading techniques with flexible catheters have eliminated radiation exposure to the medical staff and reduced postoperative complications (9). The introduction of modern CT-based treatment planning (Nucletron) has allowed accurate and reproducible treatment planning and integration of brachytherapy with EBRT treatment planning. The inclusion of a magnetic resonance imaging and a routinely performed pelvic lymph node dissection in the staging procedures allows a better selection of patients who are suitable for treatment with brachytherapy and hence might further improve the outcome in the future.
Brachytherapy vs. combined modality treatment As stated in the introduction, several groups have reported on the value of bladder preservation with combined modality treatment including TUR, EBRT, and systemic chemotherapy. Reports on this approach invariably mention survival rates comparable to the best cystectomy series and excellent bladder-sparing capacities (2, 3, 18, 19) (see Table 2). As a result, there are two successful bladder-preserving strategies: brachytherapy and combined modality treatment. This brings up the question of which form of treatment to choose when considering organ preservation. An important issue is patient selection. Where brachytherapy is only feasible in solitary organ– confined disease with a diameter ⱕ5 cm, combined modality series include all tumor stages up to T4a of any size. Another important issue is that for a successful treatment with brachytherapy, one needs to have the availability of a brachytherapy unit, an experienced brachytherapy team, and cooperation between radiation oncology and urology. If, however, a patient is a candidate for treatment with brachytherapy and the option of brachytherapy is available, this type of treatment must be considered. An important advantage of brachytherapy over combined modality treatment is that patients can be spared the toxicity of chemotherapy. With combined modality treatments, many patients experience serious acute toxicity from systemic treatment. For example, in the Radiation Therapy Oncology Group 89-03 trial in the neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) arm, 62% of the patients experienced ⱖG3 toxicity with three lethal complications (19). In our series, only 2 patients encountered serious acute toxicity and there was no treatment-related mortality. Another advantage of brachytherapy might be the high success rate of this strategy. After brachytherapy, usually ⬍10% of patients eventually require a cystectomy vs. roughly one-third of the patients after chemotherapy-based regimens (Table 2). However, this difference might be explained by differences in patient selection as described previously. Based on these considerations, in our institution, we prefer brachytherapy over combined modality treatment for all potential brachytherapy candidates.
Bladder preservation with brachytherapy
Organ preservation vs. urinary diversion Both brachytherapy and combined modality series report a good quality of life after treatment; however, this has never been studied in detail. One might argue that, with modern sophisticated techniques for urinary diversion, there is no need for sparing approaches (30). However, a recent population-based study from Sweden concluded that the patient’s situation after cystectomy with urinary diversion is considerably impaired because of changed bowel and sexual function, urinary tract infections, and a sense of decreased attractiveness (31). A definitive randomized trial comparing bladder preservation with cystectomy has never been performed. In the absence of prospective randomized studies, we have to
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base our decisions on the best available evidence: a comparison of published results. Brachytherapy and combined modality series all prove that organ preservation can be safely offered to a patient. For patients with solitary, organ-confined T1-T2 invasive bladder cancer with a diameter ⱕ5 cm, therefore, the situation seems to be similar to early prostate cancer. Where nowadays early prostate cancer patients can choose between radical prostatectomy, brachytherapy, or EBRT (32), these bladder cancer patients can choose between radical cystectomy, brachytherapy, or EBRT in combination with chemotherapy. The choice of treatment can be made the on local availability of the different technologies and personal preferences.
REFERENCES 1. Gospodarowicz M. Radiotherapy and organ preservation in bladder cancer: Are we ignoring the evidence? J Clin Oncol 2002;20:3048 –3050. 2. Rödel C, Grabenbauer GG, Kuhn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: Long-term results. J Clin Oncol 2002;20:3061–3071. 3. Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment: Longterm outcomes of 190 patients with invasive bladder cancer. Urology 2002;60:62– 68. 4. Sternberg CN. Current perspectives in muscle invasive bladder cancer. Eur J Cancer 2002;38:460 – 467. 5. Union Internationale Contre le Cancer. TNM atlas. 3rd edition, 2nd revision. Heidelberg, Germany: Springer-Verlag; 1992. 6. Rozan R, Albuisson E, Donnarieix D, et al. Interstitial iridium-192 for bladder cancer (a multicentric survey: 205 patients). Int J Radiat Oncol Biol Phys 1992;24:469 – 477. 7. Pernot M, Hubert J, Guillemin F, et al. Combined surgery and brachytherapy in the treatment of some cancers of the bladder (partial cystectomy and interstitial iridium-192). Radiother Oncol 1996;38:115–120. 8. Gonzalez D, van der Veen HJ, Ypma AF, et al. Brachytherapy for urinary bladder cancer. Arch Esp Urol 1999;52:655– 661. 9. Moonen LM, Horenblas S, van der Voet JC, et al. Bladder conservation in selected T1G3 and muscle-invasive T2-T3a bladder carcinoma using combination therapy of surgery and iridium-192 implantation. Br J Urol 1994;74:322–327. 10. Van der Steen-Banasik EM, Visser AG, Reinders JG, et al. Saving bladders with brachytherapy: Implantation technique and results. Int J Radiat Oncol Biol Phys 2002;53:622– 629. 11. Wijnmaalen A, Helle PA, Koper PC, et al. Muscle invasive bladder cancer treated by transurethral resection, followed by external beam radiation and interstitial iridium-192. Int J Radiat Oncol Biol Phys 1997;39:1043–1052. 12. van der Werf-Messing B. Carcinoma of the bladder treated by suprapubic radium implants. The value of additional external irradiation. Eur J Cancer 1969;5:277–285. 13. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. 14. Cox DR. Regression models and life tables. J R Stat Soc B 1972;34:187–220. 15. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 2001;19:666 – 675. 16. Dalbagni G, Genega E, Hashibe M, et al. Cystectomy for bladder cancer: A contemporary series. J Urol 2001;165: 1111–1116.
17. Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer today—a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21: 690 – 696. 18. Tester W, Caplan R, Heaney J, et al. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: Results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol 1996;14:119 –126. 19. Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: Initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16:3576 – 3583. 20. Wijkstrom H, Norming U, Lagerkvist M, et al. Evaluation of clinical staging before cystectomy in transitional cell bladder carcinoma: A long-term follow-up of 276 consecutive patients. Br J Urol 1998;81:686 – 691. 21. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19:89 –93. 22. Kuczyk M, Machtens S, Bokemeyer C, et al. Surgical bladder preserving strategies in the treatment of muscle-invasive bladder cancer. World J Urol 2002;20:183–189. 23. Sengelov L, von der Maase H. Radiotherapy in bladder cancer. Radiother Oncol 1999;52:1–14. 24. Hayter CR, Paszat LF, Groome PA, et al. The management and outcome of bladder carcinoma in Ontario, 1982–1994. Cancer 2000;89:142–151. 25. Scrimger RA, Murtha AD, Parliament MB, et al. Muscleinvasive transitional cell carcinoma of the urinary bladder: A population-based study of patterns of care and prognostic factors. Int J Radiat Oncol Biol Phys 2001;51:23–30. 26. Pos FJ, van Tienhoven G, Hulshof MC, et al. Concomitant boost radiotherapy for muscle invasive bladder cancer. Radiother Oncol 2003;68:75– 80. 27. Pos FJ, Koedooder K, Hulshof MC, et al. Influence of bladder and rectal volume on spatial variability of a bladder tumor during radical radiotherapy. Int J Radiat Oncol Biol Phys 2003;55:835– 841. 28. International Collaboration of Trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. Lancet 1999;354: 533–540. 29. Cole CJ, Pollack A, Zagars GK, et al. Local control of muscle-invasive bladder cancer: Preoperative radiotherapy and cystectomy versus cystectomy alone. Int J Radiat Oncol Biol Phys 1995;32:331–340.
686
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30. Kuczyk M, Turkeri L, Hammerer P, et al. Is there a role for bladder preserving strategies in the treatment of muscle-invasive bladder cancer? Eur Urol 2003;44:57– 64. 31. Henningsohn L, Wijkstrom H, Dickman PW, et al. Distressful symptoms after radical cystectomy with urinary diversion for
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urinary bladder cancer: A Swedish population-based study. Eur Urol 2001;40:151–162. 32. Peschel RE, Colberg JW. Surgery, brachytherapy, and external-beam radiotherapy for early prostate cancer. Lancet Oncol 2003;4:233–241.