Trimodality bladder-sparing approach without neoadjuvant chemotherapy for node-negative localized muscle-invasive urinary bladder cancer resulted in comparable cystectomy-free survival

Between July 2004 and February 2012, 91 patients diagnosed with muscle-invasive (T2 to T4) bladder cancer who were treated with curative intent in our institution were retrospectively reviewed. Patients with pelvic lymph node metastases and distant metastases, as detected by computed tomography (CT), magnetic resonance imaging (MRI) or other modalities before RT were excluded in this review. Seventy patients with newly diagnosed or recurrent disease after initial TURBT treated with CCRT after TURBT or partial cystectomy were included in this analysis. This review was approved by the institutional review board of our hospital (No.20130506R). T-category was re-assigned according to the American Joint Committee on Cancer (AJCC) tumor-node-metastasis classification of 2010. The majority of patients included in the study had pathological evidence of tumoral invasion of the muscular layer, either after a TURBT (n = 64; 91.4%) or partial cystectomy (n = 4, 5.7%). The remaining patients (n = 2; 2.9%) received only biopsy, but had radiographical evidence of T4 disease. The majority of the population had urothelial cell carcinoma (n = 65, 92.9%). 55 of the patients (78.6%) had high grade disease on pathology.

Patients were referred from urologist. Those patients were not candidates for radical cystectomy because of comorbidities or personal preference. Radiotherapy was performed 4 to 8 weeks after TURBT or partial cystectomy. Planning CT scan with 3-mm slices was acquired for all patients undergoing RT. The patients were simulated in supine position with distended bladder. They were instructed to void and take a fixed amount of fluid (350-500 mL) thirty minutes prior to both simulation and treatment. Large field irradiation to subclinical disease by 3D-CRT followed by tumor-directed boost by IMRT was our treatment guideline. High risk clinical target volumes (CTV-H) were defined as preoperative tumor bed, which were delineated on the planning CT with respect to preoperative MRI or CT images registered by image fusion. In those who underwent partial cystectomy, the positions of surgical clips needed to be taken into consideration for delineating CTV-H. In the presence of gross residual tumor, the gross tumor volume (GTV) was delineated on planning CT. The whole bladder was treated as CTV-H in the presence of multifocal disease. A 1-2 cm margin was added to CTV-H and GTV in all directions to account for organ motion and formed the planning target volume (PTV-H). IMRT was delivered via 4-10 MV photons using 5 to 7 static IMRT fields to PTV-H volume. The clinical target volume at intermediate risk (CTV-M) encompassed whole bladder in T2 disease and included pelvic nodal regions (including hypogastric, obturator, external iliac and perivesical nodes) in T3 and T4 disease. A 2-cm margin was given to CTV-M in the cranial and anterior directions and 1-cm in posterior, lateral and caudal directions, forming PTV-M. PTV-M was treated with 10 MV photons by 4-field 3D-CRT technique. All treatment planning was performed by Pinnacle version 9.0 (Philips Healthcare, Bothell, WA).

RT was initiated 4 to 8 weeks after urological procedure. Patients were treated with the same requirements as in the planning phase. A median total dose of 59.4Gy (range, 44.5 to 66.6Gy) was delivered to the PTV-H, and the PTV-M was irradiated with a median total dose of 40.0Gy (range, 36.0 to 54.0Gy) at 1.8-2.0 Gy per daily fraction. The prescribed doses should cover at least 95% of PTV volumes. The dose constraints were V₅₅ < 50% for rectum, and D_max <45Gy to both bowels and femoral heads.

Concurrent platinum-based chemotherapy was offered and consisted of cisplatin (30 mg/m²/week) for patients without impaired renal function defined as glomerular filtration rate (GFR) >50mL/min, or carboplatin (100 mg/m² on days 1, 15, 31) for patients with renal function impairment. The treatment-related characteristics were summarized in Table 1.

Patients were observed at 3-month intervals for the first 3 years and every 6 months thereafter. Post-treatment follow-up consisted of pertinent medical history, physical examination, urine cytology, cystoscopy, and radiological evaluation as clinically indicated. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) [15] both cystoscopically and radiographically (either CT or MRI) three months after treatment. Complete response (CR) was defined as the absence of detectable tumor as well as negative urine cytology. Among patients with less than CR, cystectomy was offered by the treating physicians. Salvage therapy for non-muscle invasive recurrences consisted of TUR-BT followed by intravesical therapy for non-muscle invasive recurrence and radical cystectomy for muscle-invasive recurrences. However, the final decision was determined at the discretion of urologist and patient’s own will. In case of distant failure, combination cisplatin and gemcitabine was offered as first line chemotherapy. Evaluation of late treatment-related toxicity was performed according to the toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) [16, 17].

Among the 70 patients, 64 patients were evaluable for response (3 patients died of non-cancer comorbidities shortly after treatment, and 3 patients refused cystoscopic evaluation). Of the evaluable 64 patients, 78.1% (50 patients) achieved CR (Table 2). Of the remaining patients with non-CR, two (3.1%) had partial response (PR), three (4.7%) had stable disease, and nine (11.4%) had progressive disease. Although radical cystectomy was offered to all patients with less than CR, none of the patients underwent this procedure due to patients' refusal or medical inoperability.

The median survival was 64.6 months after a median follow-up of 24 months. OS and PFS at 2 year were 65.7% and 51.9%. Local-regional control and distant metastasis free survival at 2 year were 69.8% and 73.5%, respectively. Bladder cancer specific survival and survival with intact bladder at 2 year were 77.3% and 64.2% respectively. The clinical outcomes at 2 year and 5 year were illustrated in Table 3.

Univariate analysis of 12 treatment-related factors influencing OS was shown in Table 4. Age, performance status, T stage, prescribed dose to primary site and CR demonstrated significant hazard ratio on OS. Multivariate analysis showed age, performance status and CR as independent predictors on two-year overall survival (Table 4). Two-year overall survival rate was statistically higher among those with complete response than those without (79.4% [95% CI, 67.2% to 91.6%] vs. 33.3% [95% CI, 7.6% to 59.9%]; p < 0.001), while the median survival was 85.0 and 15.8 months (p < 0.001) (Figure 1).

Of the 70 patients, isolated local-regional recurrence was observed in 10 patients (15.6%); isolated distant metastasis was observed in seven (9.4%); while both local-regional and distant metastasis developed in 12 patients (18.8%) (Figure 2). Of those 50 patients with CR, local recurrence occurred in 10 patients during the course of follow-up. Among whom six were muscle invasive, three were superficial, and the remaining one had missing histology record (Table 5). Among patients who developed muscle invasive recurrences, only one patient ultimately underwent radical cystectomy as salvage treatment, while the others refused salvage cystectomy or were medically inoperable due to old age or comorbidity. None of the patients with superficial recurrences died, whereas three of the invasive recurrences did. Distant metastasis developed in one of the surviving patients with muscle invasive recurrences.

All of the radiation induced acute genitourinary (GU) and gastrointestinal (GI) toxicities and were limited to grade 2 (Table 6), and manageable. Acute grade 2 GU toxicities accounted for 28.6% and grade 2 GI toxicities in 11.4%. Chronic GU and GI toxicities of grade 2 or more were encountered in 11 and 4 patients, respectively, while no patient with ≧ grade 3 GI toxicity. Chronic grade 3 GU toxicity developed in one patient and manifested as gross hematuria and needed repeated blood transfusion. No patient died from toxicities.