Updated results of bladder-sparing trimodality approach for invasive bladder cancer

Urologic Oncology: Seminars and Original Investigations 28 (2010) 368 –374

Original article

Updated results of bladder-sparing trimodality approach for invasive bladder cancer Almudena Zapatero, M.D., Ph.D.a,*, Carmen Martin de Vidales, M.D., Ph.D.a, Ramón Arellano, M.D.b, Gloria Bocardo, M.D.b, Mar Pérez, M.D.c, Patricia Ríos, M.D.a a

Department of Radiation Oncology, Hospital Universitario de la Princesa, Madrid, Spain b Department of Urology, Hospital Universitario de la Princesa, Madrid, Spain c Department of Medical Oncology, Hospital Universitario de la Princesa, Madrid, Spain

Received 15 December 2008; received in revised form 21 January 2009; accepted 22 January 2009

Abstract Purpose: To update long-term results with selective organ preservation in invasive bladder cancer using aggressive transurethral resection of bladder tumor (TURBT) and radiochemotherapy (RCT) and to identify treatment factors that may predict overall survival (OS). Materials and methods: Between 1990 and 2007, a total of 74 patients with T2-T4 bladder cancer were enrolled in 2 sequential bladder-sparing protocols including aggressive TURB and RCT. From 1990 to 1999, 41 patients were included in protocol no. 1 (P1) that consisted of three cycles of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy prior to re-evaluation and followed by radiotherapy (RT) 60 Gy in complete responders. Between 2000 and 2007, 33 patients were entered in protocol no. 2 (P2) that consisted of concurrent RCT 64, 8 Gy with weekly cisplatin. In case of invasive residual tumor or recurrence, salvage cystectomy was recommended. Primary endpoints were OS, overall survival with bladder preservation (OSB), and late toxicity. Results: The mean follow-up for the whole series was 54 months (range 9 –156), 69 months for patients in P1 and 36 months for patients in P2. The actuarial 5-year OS and OSB for all series were 72% and 60%, respectively. Distant metastases were diagnosed in 11 (15%) patients. Grade 3 late genitourinary (GU) and intestinal (GI) complications were 5% and 1.3%, respectively. There were no significant differences in the incidence of superficial recurrences (P ⫽ 0.080), muscle-invasive relapses (P ⫽ 0.722), distant metastasis (P ⫽ 0.744), grade ⱖ2 late complications (P ⫽ 0.217 for GU and P ⫽ 0.400 for GI), and death among the 2 protocols (P value for OS ⫽ 0.643; P value for OSB ⫽ 0.532). Conclusion: These data confirm that trimodality therapy with bladder preservation represents a real alternative to radical cystectomy in selected patients, resulting in an acceptable rate of the long-term survivors retaining functional bladders. © 2010 Elsevier Inc. All rights reserved. Keywords: Bladder cancer; Radiochemotherapy; Cisplatin; Hyperfractionated radiotherapy; Bladder preservation

1. Introduction The optimal management of muscle-invasive bladder cancer remains a continuous subject of controversy. Although trimodality treatment, including transurethral resection of bladder tumor (TURBT) and radio-chemotherapy (RCT), has proven to be an alternative to primary cystectomy, the optimal regimen and combination of RT and chemotherapy remains to be established [1–5]. Over the past years we have investigated 2 prospective approaches in the conservative treatment of invasive bladder cancer. In the first protocol, we used induction chemo* Corresponding author. Tel.: ⫹349-15202315; fax: ⫹349-15202315. E-mail address: [email protected] (A. Zapatero). 1078-1439/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2009.01.031

therapy followed by radiation therapy (RT). Initial results of this trial on 40 patients were reported in the year 2000 [6]. The second protocol consisted of concomitant RCT after initial TURBT using cisplatin as radiosensitizing agent in an effort to improve both local and distant tumor control. In this report, we present updated analysis on 74 patients treated with these 2 protocols in terms of 5-year survival rates, pattern of failure, and late toxicity.

2. Materials and methods Between 1990 and 2007, 74 patients with muscle invasive bladder cancer were treated with bladder-sparing trimodality therapy by a dedicated multidisciplinary team.

A. Zapatero et al. / Urologic Oncology: Seminars and Original Investigations 28 (2010) 368 –374 Table 1 Summary of patients and treatment characteristics according to protocol Characteristics

Total

Protocol no. 1

Protocol no. 2

P value

Number of patients Median age (range), years Sex (M/F) T stage T2 T3/T4 N stage N0 N1 Grade 1/2 3/4 TURB R0 R1 Multiple lesions Associated Tis Hydronephrosis Re-evaluation R0 R1

74 63 (41–77)

41 63 (45–75)

33 60 (41–77)

NS

68/6 40 34

37/4 19 22

31/2 21 12

69 3

37 3

32 0

6 68

4 37

2 31

NS

50 24 31 7 6

27 14 19 3 3

23 10 12 4 3

NS

54 20

29 12

25 8

NS

NS NS

NS

NS NS NS

TURB ⫽ Transurethral resection of bladder tumor; R0 ⫽ microscopically complete TURBT; R1 ⫽ residual tumor.

Pretreatment evaluation included history and physical examination, complete blood cell count and blood chemistry, chest radiography, excretory urogram, and CT of the abdomen and pelvis. Table 1 depicts the characteristics of the patients.

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2.1.2. Protocol no. 2: Concomitant radiochemotherapy (RCT) Concomitant RCT was introduced in 2000. This protocol (P2) included 33 patients between 2000 and 2007. Patients initially underwent a maximum TURBT, followed by induction treatment with RT to 40.8 Gy and concurrent cisplatin chemotherapy. Chemotherapy consisted of weekly cisplatin before RT exposure (20 mg/im2/d, 30-min i.v. infusion, 2 d/wk). Taxol (50 mg/m 2/d), 1 day per week was used in 6 patients with mild renal insufficiency. Induction RT was developed with accelerated hyperfractionated radiotherapy (AHFRT) in 19 patients, whereas the remaining 14 patients were treated with normofractionated radiotherapy (NFRT) (1.8-2 Gy/fraction, 5 fractions/week). AHFRT involved twice-daily RT consisting of 1.8 Gy to bladder and regional lymph nodes, followed 6 hours later by 1.6 Gy of RT to the bladder tumor plus wide margin. In this manner, 40.8 Gy was delivered to the bladder tumor and the regional lymph nodes received 21.6 Gy. Response to treatment was evaluated by restaging TURBT under anesthesia after a 3-week break. Patients with microscopic complete regression of disease proceeded to consolidative CRT. Consolidation included 1.5 Gy pelvic RT delivered twice daily to 24 Gy with same chemotherapy scheme (Fig. 1B, total dose to the bladder 64.8 Gy, total doe to the lymph nodes 45.6 Gy). NFRT consisted of daily fractions of 1-8-2.0 Gy on 5 consecutive days per week. The total dose to the bladder ranged from 64 to 66 Gy and to pelvic lymph nodes from 44 to 46 Gy. We made no effort to include the entire bladder

2.1. Treatment protocols 2.1.1. Protocol no. 1: Neoadjuvant chemotherapy From 1990 to 1999, 41 patients were enrolled in protocol no. 1 (P1). Treatment consisted of aggressive TURBT and 3 cycles of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy followed by re-evaluation under anesthesia and RT 60 Gy (2 Gy/fraction, 5 fractions/week) in complete responders (Fig. 1A). Radiation therapy was initiated within 4 to 6 weeks after completed chemotherapy, using 25-MV photons from a linear accelerator and a 4-field box technique with individually shaped portals. Since1995, with the routine use of three-dimensional radiotherapy planning and treatment delivery in our department, this technique was performed in the last 10 patients included in this protocol. TURB was performed as thoroughly as was judged safely possible. Residual tumor was assessed histologically by biopsies from all resection margins and from the base of the resection. R0 indicated a microscopically complete TURBT, whereas R1 showed tumor residual. The eligibility criteria included: age under 76 years; clinical stage T2– 4NXM0 according to UICC 1989; performance status ⱕ 2 (ECOG); normal bone marrow function and normal renal function. The details of the treatment of this protocol have been previously reported [6].

Fig. 1. Treatment design (TURTBT ⫽ transurethral resection of bladder tumor; MCV ⫽ metotrexate, cisplatin, vinblastine; CR ⫽ complete response; RT ⫽ radiotherapy; CDDP ⫽ cisplatin). (Color version of figure is available online.)

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analysis (MVA) was performed using a Cox regression analysis to determine potential factors for risk of OS and DFS [8]. P ⬍ 0.05 significance level (two-sided) was considered for all statistical tests. Statistical analysis was performed using SPSS for Windows version 10.0 (SPSS, Inc., Chicago, IL).

3. Results 3.1. Outcome

Fig. 2. Kaplan-Meier over all survival (OS) by treatment protocol. (Color version of figure is available online.)

when possible. Cystectomy was undertaken in nonresponder patients. The eligibility criteria included: age under 75 years; clinical stageT2-4N0M0 according to UICC 1997; performance status ⱕ 2 (ECOG); normal bone marrow function and normal renal function; absence of hydronephrosis, and macroscopic complete TURBT. 2.2. Follow-up Patients underwent cystoscopic re-evaluation, biopsy of the tumor site and of all suspected areas, and urine cytology every 3 months for 2 years and every 6 months thereafter. Chest X-ray and abdominal and pelvis CT scans were performed 3 months after the completion of therapy, and then every 6 to 12 months. Exploration under anesthesia and TURB was performed in patients with suspicion of relapse. Evaluation of late treatment-related toxicity was performed according to RTOG/EORTC criteria [7].

The mean follow-up for the whole series is 54 months (range 9 –156), 69 months (range 9 –156) for patients in P1, and 36 months (12–79) for patients in P2. The actuarial 5-year OS were 72% [standard error (SE 6)], 75% (SE 7), and 65% (SE 10) for the whole series, P1, and P2 protocols respectively, P ⫽ 0.591). The corresponding figures for cancer specific survival (CSS) were 80% (SE 8), 80% (SE 8), and 88% (SE 6), (P ⫽ 0.833) (Fig. 2). The 5-year actuarial OSB for all series was 60% (SE 6), for patients treated with P1 was 65% (SE 7) and for those treated with P2 was 47% (SE 12), P ⫽ 0.515) (Fig. 3). Along this series, 66 (89%) of the 74 patients completed radiochemotherapy with bladder preservation and the remaining 8 (11%) patients underwent radical cystectomy due to persistent disease after induction therapy (4 in P1 and 4 in P2, P ⫽ 1.0) (Table 2). Of these 8 cystectomy patients, 4 (50%) are currently alive. Salvage cystectomy was performed in 6/66 patients who failed after conservative radiochemotherapy (4 in P1 and 2 in P2, P ⫽ 0.686), and 4 out of these 6 patients remained alive (67%). No significant difference in OS between both protocols was found for

2.3. Statistics All patients were followed up until June 2008. KaplanMeier product-limit estimates were used to estimate the probabilities of overall survival (OS), OS with bladder preservation (OSB), and disease-free survival. OSB was defined as the probability of remaining alive and with a preserved bladder. DFS was defined as the probability of remaining free of invasive bladder relapse, distant relapse, or death. Actuarial survival rates were calculated from the time of initial TUR to the time of the last follow-up visit or death. For estimation of cause specific survival (CSS), patients who died of unrelated causes were censored at death. Patients whose cause of death was unknown were assumed to have died of bladder cancer. Differences were tested by the log-rank test. The ␹ 2 test (two tailed) was used to determine statistical significance between proportions. Multivariate

Fig. 3. Kaplan-Meier bladder-preserved survival (OSB) by treatment protocol. (Color version of figure is available online.)

A. Zapatero et al. / Urologic Oncology: Seminars and Original Investigations 28 (2010) 368 –374 Table 2 Pattern of failure

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3.2. Pattern of failure and prognostic factors

Bladder-sparing treatment completed with bladder preserved Bladder-sparing treatment completed with cystectomy Superficial recurrences Muscle-invasive recurrences Salvage cystectomy Preserved bladder Distant metastasis Alive Alive with preserved bladder Death from bladder cancer Death from other causes

Total (n ⫽ 74)

Protocol 1 (n ⫽ 41)

Protocol 2 P (n ⫽ 33) value

66 (89%)

37 (90%)

29 (88%)

0.745

8 (11%)

4 (10%)

4 (12%)

0.745

8 (19.5%) 5 (12%)

2 (6%) 3 (9%)

0.080 0.722

10 (13.5%) 8 (11%) 6 (8%) 60 (81%) 11 (15%) 52(70%) 44 (59%)

4 (10%) 33 (81%) 7 (17%) 27 (66%) 22 (54%)

2 (6%) 27 (82%) 4 (12%) 25 (76%) 22 (66%)

0.686 1.0 0.744 0.446 0.197

11 (15%)

7 (17%)

4 (12%)

0.861

10 (13.5%)

7 (17%)

3 (9%)

0.867

patients with salvage cystectomy (P ⫽ 0.545). The 5-year actuarial OS for all 14 patients that underwent any cystectomy (failure following induction or following radical radiochemotherapy) was 59% (SE 14) compared to 74% (SE) for those 60 patients treated with radiochemotherapy with preserved bladder (P ⫽ 0.060).

Main outcomes are illustrated in Fig. 4. Fifty-two of 74 (70%) patients remain alive, 11 patients (15%) died due to bladder tumor, and 10 (13.5%) from other nonrelated causes. The pattern of failure for all patients and according to the treatment protocol is depicted in Table 2. Ten (13.5%) patients experienced superficial bladder relapse, 8 (11%) muscle-invasive relapse, and 11 (15%) patients developed distant metastasis. Patients with superficial disease were treated with TURBT with (3 cases of Ta high grade) or without intravesical therapy. Only 5 out of 10 patients with superficial relapse developed invasive recurrence, 4 of them remaining alive after salvage cystectomy. The median time to bladder relapse was 20 months for both protocols and the median time to distant metastasis was 10 and 16 months for P1 and P2, respectively. There were no significant differences regarding the incidence of superficial recurrences, muscle-invasive relapses, distant metastasis, and deaths among the protocols. Of note, 5 out of 6 patients treated with taxol are currently alive (median follow-up 42 months, range 12– 60). Table 3 summarizes the results of univariate and multivariate analysis (MVA) performed for the whole series to assess potential patient, tumor, and treatment prognostic factors for OS. In univariate analysis patient age ⬍ 65 years (P ⫽ 0.036), extent of TURB (P ⫽ 0.005), absence of

Fig. 4. Main outcomes after combined modality treatment in 74 patients with invasive bladder cancer.

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Table 3 Summary of univariate and multivariate analysis of potential prognostic factors affecting overall survival (OS) Variable Sex M/F Age ⬍65/⬎65 TURB R0/R1 Tumour grade G2/G3-G4 Multifocality Yes/No Tis Yes/No Hydronephrosis Yes/No T stage T2 T3 T4 Re-evaluation R0/R1 RT dose continuous Fractionation NFRT AHFRT Protocol P1/P2

5-y OS

Univariate P

HR for death

95% CI

Multivariate

71%/75%

0.982

80%/53%

0.036

NS

82%/51%

0.005

NS

100%/69%

0.133

66%/76%

0.910

50%/72%

0.888

33%/74%

⬍0.001

74% 68% 50%

13.675

3.143–59.507

⬍0.001

0.825

79%/53%

0.018

NS

0.069 71% 70%

0.903

75%/65%

0.591

NS

HR ⫽ hazard ratio; OS ⫽ overall survival; CI ⫽ confidence interval; TURB ⫽ transurethral resection of the bladder; Tis ⫽ carcinoma in situ; RT ⫽ radiotherapy; NFRT ⫽ normofractionated RT; AHFRT ⫽ accelerated hyperfractionated RT.

hydronephrosis (P ⬍ 0.001), and a R0 response after induction treatment (P ⫽ 0.018) were factors significantly correlated with a superior OS. The results of MVA showed that, after adjusting for other variables, hydronephrosis (P ⬍ 0.001) was the only factor significantly associated with OS. In the present analysis, we failed to show a significant difference in terms of OS between the 2 protocols.

incidence of grade ⱖ2 GU and GI for the whole series was 17% and 8%, respectively. Four (5%) patients suffered from a reduced bladder capacity with less than 2-hour intervals of micturition. In the cross-tab comparison, there were no significant differences in grade ⱖ2 GU and GI complications between both treatment protocols (P ⫽ 0.217 for GU and P ⫽ 0.400 for GI).

3.3. Toxicity 4. Discussion There were no treatment-related deaths. The percentages of patients sustaining chronic sequelae reported during the follow-up period of this study are listed in Table 4. The Table 4 Summary of late complications

Urinary grade ⱖ 2 Grade 2 Grade 3 Grade 4 Intestinal grade ⱖ 2 Grade 2 Grade 3 Grade 4

Total (n ⫽ 74)

Protocol 1 (n ⫽ 41)

Protocol 2 (n ⫽ 33)

13 (17%) 9 (12%) 4 (5%) 0 6 (8%) 5 (7%) 1 (1.3%) 0

5 (12%) 2(5%) 3 (7%) 0 3 (7%) 2 (5%) 1 (2.4%) 0

8 (24%) 7 (21%) 1 (3%) 0 3 (9%) 3 (9%) 0 0

P value

0.217

0.400

The combination of transurethral resection of the bladder, chemotherapy, and radiation therapy is a validated approach to bladder preservation. As more experience is acquired with organ-sparing treatment, it is clear that the future directions of clinical and basic research will focus on the optimization of the treatment modalities and the proper selection of patients who will most probably benefit from the respective treatment alternatives. In the present study, we have updated our single institution experience in order to find out an answer to these questions. Although this is a small cohort restricted to 74 patients treated in 15 years, our results confirm that trimodality treatment with bladder-sparing approach can be performed safely. OS, CSS, and OSB rates at 5 years for all patients reached 72%, 80%. and 60%, respectively. It needs

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to be emphasized that our series included 33 (46%) patients with T3-4 tumors. For nonresponder patients, salvage cystectomy still had a curative potential with a 59% overall survival rates after 5 years. The incidences of grade ⱖ2 GU and GI late complications were also acceptably low (17% and 8%, respectively. These results, similar to those reported by the best reported series, support the use of bladder-sparing treatment in highly selected patients as an alternative to radical cystectomy [2–5,9 –13]. This is a relevant matter because no randomized trials have directly compared survival of patients undergoing trimodality bladder preservation therapy with radical cystectomy. As demonstrated in several studies, the adequate selection of patients is a cornerstone for the success of a bladdersparing protocol. The analysis of prognostic factors performed in this series are in agreement with the extensive evidence from most of the studies [3,13]. In contrast, the optimal combined modality of bladder-sparing regimen is not well defined yet. Concurrent cisplatin radiation with or without neoadjuvant MCV chemotherapy have been two landmark modality treatments with satisfactory results. However, the considerable toxicity and the lack of significant benefit in the largest randomized trial with neoadjuvant MCV chemotherapy [14] led to the abandonment of neoadjuvant chemotherapy in this context, and has not been revisited in the bladder-sparing approach in spite of the positive results of a recent meta-analysis [15]. Several questions remain about how radiotherapy and chemotherapy should be combined to achieve optimal results. It is unclear which subgroups of patients should be treated with neoadjuvant instead of concomitant radio-chemotherapy, the schedule and number of cycles, the role of adjuvant chemotherapy in this setting, whether pelvic/bladder radiotherapy is beneficial only in patients who have a complete response to induction therapy, or if it also provides a benefit to those with residual bladder tumor. Nowadays, ongoing trials are focused on the exploration of concurrent chemotherapy as radiosensitizers (cisplatin-based chemotherapy and new drugs) and adjuvant chemotherapy [1,16 –18]. In the present study, notwithstanding the limitations of this small, nonrandomized analysis, we have also tried to determine whether one of the 2 modality treatments (P1 and P2) prospectively developed along 15 yeas was superior to the other in terms of outcome and quality of life. Our very preliminary data failed to show any significant difference between the two protocols (neoadjuvant MCV induction chemotherapy followed by RT on the one side, and concomitant chemotherapy on the other side), in terms of OS, CSS, OSB, distant metastasis, and late complications. These apparently surprising data might probably indicate that an adequate selection of patients is the main relevant factor for success in bladder cancer patients treated in a dedicated multidisciplinary team with trimodality therapy including cisplatin chemotherapy. Newer chemotherapeutic agents, particularly gemcitabine and the taxane, are now being tested in combination with

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RT, and may further improve organ preservation in bladder cancer [1]. Both agents have shown significant single-agent activity against urothelial tumors, and are potent radiation sensitizers. Of note, our data show that 5 out of 6 patients treated with taxol (as part of an intramural trial for patients not suitable for cisplatin) are currently alive (median follow-up 42 months, range 12– 60). Another controversy is the concern regarding the overall treatment time (OTT) and the impact of accelerated fractionation radiation schedules with or without split in the success of the bladder-sparing approach. Although recent analysis has concluded that OTT does not significantly influence the treatment outcome [19], clinical data in transitional cell carcinoma of the bladder are scarce and not conclusive and, consequently, the role of split-treatments remains controversial. In this setting, the development of hyperfractionated or accelerated radiation treatments with a split for re-evaluation after induction radio-chemotherapy in bladder-sparing protocols has been surrounded with some polemics. One important and collateral result derived from our preliminary analysis is the lack of significant impact on OS and OSB with split-hyperfractionated radiotherapy in this series. Again, we have to weigh this finding against the limitations of the present study. Recent data from a several randomized phase III trials have shown the lack of benefit and the inconveniences of hyperfractionated schedules over NFRT [20,21]. Treatment was generally well tolerated. The incidences of grade 3 GU and GI late complications were 5% and 1.3%, respectively, with no grade 4 toxicities. The small number of events prevented any comparative analysis between the 2 protocols. When irradiating bladder tumors, the organs at risk are normal bladder tissue, bowel, and the rectum. The combination of RT with chemotherapy (mostly cisplatin based) will increase acute toxicity. Partial bladder boosts allow the delivery of a higher dose to the portion of the bladder at highest risk, while limiting the whole bladder dose. We incorporated partial bladder boost in the P2 protocol in order to improve the quality function of the radiatedpreserved bladder. There is evidence from a randomized trial that partial bladder boost is as efficacious as whole bladder irradiation using modern techniques [22]. Cooperation between the treating urologist and radiation oncologist is crucial in this effort. The use of intensity modulated radiation therapy for partial bladder boost will also be explored with the use of daily imaging Owing to the availability of tissue samples before and after radio-chemotherapy, it may be possible to determine molecular and biologic characteristics that predict radio and chemosensitivity. Further evaluation of molecular prognostic factors is essential to advancing the role of combined modality treatment in the management of this disease. Recent research has shown significantly different response rates of muscle-invasive bladder cancers treated with radiation and concurrent chemotherapy, based on the expression of epidermal growth factor receptor (EGFR) and Her-2 [23].

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Pollack et al. [24] have also described a relation between altered expression of the pRB-retinoblastoma and bcl-2 genes and the local response of patients to preoperative radiotherapy. This might have important implications for the design of new RT schedules. We cannot skip that targeted therapy as maintenance or consolidation therapy after definitive local therapy is another new paradigm. 5. Conclusion For patients unwilling to undergo cystectomy, trimodality therapy to preserve the bladder is a therapeutic option that results in a high rate of long-term survivors retaining functional bladders. A multidisciplinary approach and collaboration among basic scientists, oncologists, urologists, and radiation oncologists are necessary to make advances. Further optimization of the respective treatment components, including radiation techniques and fractionation schedules, as well as incorporation of novel cytotoxic and biologic agents, is upcoming and may further improve outcomes of the bladder-preservation approach. References [1] Sweeney C, Bajorin DF, Sternberg C. Muscle-invasive bladder cancer: What have we learned and what’s new on the horizon? J Clin Oncol 2008;8:200 – 8. [2] Rödel C, Weiss C, Sauer R. Organ preservation by combined modality treatment in bladder cancer: The European perspective. Semin Radiat Oncol 2004;15:28 –35. [3] Coen JJ, Zietman AL, Kaufman DS, et al. Benchmarks achieved in the delivery of radiation therapy for muscle-invasive bladder cancer. Urol Oncol 2007;25:76 – 84. [4] Fernando SA, Sandler HM. Multimodality bladder preservation therapy for muscle-invasive bladder tumors. Semin Oncol 2007;34:129 –34. [5] Chung PWM, Bristow RG, Milosevic MF, et al. Long-term outcome of radiation-based conservation therapy for invasive bladder cancer. Urol Oncol 2007;25:303–9. [6] Zapatero A, Martin de Vidales C, Marin A. Invasive bladder cancer: A single-institution experience with bladder-sparing approach. Int J Cancer Radiat Oncol Invest 2000;90:287–94. [7] Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radat Oncol Biol Phys 1995;31:1341– 6. [8] Cox DR. Regression models and life tables. J R Stat Soc B 1972;34: 187–220. [9] Weiss C, Engehausen DG, Krause FS, et al. Radiochemotherapy with cisplatin and 5-fluorouracil after transurethral surgery in patients with bladder cancer. Int J Radiat Oncol Biol Phys 2007;68:1072– 80.

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