M0 Bladder Cancer Research Articles

A phase I–II study of synchronous chemoradiotherapy for poor prognosis locally advanced bladder cancer

The management of locally advanced bladder cancer remains controversial with poor local control with radiotherapy alone. Synchronous chemotherapy regimens have yielded encouraging results in other primary sites. Patients with T2-T4a N0/NX M0 bladder cancer were entered into this single centre phase I-II study. Patients received radiotherapy to 55 Gy in 20 fractions over four weeks. Concurrent chemotherapy was given with Mitomycin C 12 mg/m2 day 1 and 5-fluorouracil 500 mg/m2/24 hours weeks one and four of radiotherapy for five or seven days on each occasion. Thirty-one patients entered the trial from March 1998 to December 1999 (22: 5-day; 9: 7-day schedule). Median age was 68 (range 58-79) years, 23 males and 8 females. T2: 9 (29%); T3a: 4 (12%); T3b: 9 (29%); T4: 9 (29%); TCC grade 2: 8 (26%) and grade 3: 23 (74%); 14 of 31 had hydronephrosis. Ten of thirty-one had a GFR < 50 ml/min. Toxicity was mild to moderate with the five-day schedule. More severe toxicity was seen with the seven-day schedule: five of nine patients failed to complete planned therapy. Pathological complete response rate at three months was 74% (5-day regimen) and 50% (7-day regimen). Overall 12-month survival was 65%. Chemoradiotherapy with the five-day schedule is feasible with acceptable toxicity in poor prognosis patients. A randomised trial is being launched.

Long–Term Risk of Salvage Cystectomy after Radiotherapy for Muscle–Invasive Bladder Cancer

Objectives: To establish the long–term outcome for muscle–invasive transitional cell carcinoma of the bladder treated by radiotherapy with or without neoadjuvant cisplatin.Methods: 159 patients with T2–T4a NX M0 bladder cancer were entered into a prospective randomized trial between June 1984 and June 1988. Follow–up was by 3–monthly cystoscopy in the first year, 6–monthly the next 2 years and yearly thereafter. Salvage surgery was performed at the discretion of the participating clinician.Results: Minimum follow–up was 9 (median 11) years, at which time 29 patients (18%) remain alive. Median survival was 24 months with no difference between the treatment groups (χ² = 0.08, p = 0.77). Overall cystectomy rate was 24% (radiotherapy alone 20%, combined therapy 28%; p = 0.24). Median time to cystectomy from primary treatment was 12 months; range 56 days to 10 years. The risk of cystectomy was 11, 10 and 7% for the first, second and third years after radiotherapy respectively, and 8% in total after the third year. The proportion of patients alive in each successive year who had required a cystectomy was between 20 and 30% for 5 of the first 8 years after treatment.Conclusions: Salvage cystectomy is necessary in a quarter of patients after radiotherapy and this can be needed up to 10 years after treatment. During this time, multiple invasive procedures are likely to be performed, resulting in significant patient morbidity and cost. Patients should be fully counselled about the need for prolonged surveillance and the persisting risk of salvage surgery when deciding between primary cystectomy and radiotherapy.

Bladder preservation by combined modality therapy for invasive bladder cancer.

To update the efficacy of a selective multimodality bladder-preserving approach by transurethral resection (TURBT), systemic chemotherapy, and radiation therapy. From 1986 through 1993, 106 patients with muscle-invading clinical stage T2 to T4a,Nx,M0 bladder cancer were treated with induction by maximal TURBT and two cycles of chemotherapy (methotrexate, cisplatin, vinblastine [MCV]) followed by 39.6-Gy pelvic irradiation with concomitant cisplatin. Patients with a negative postinduction therapy tumor site biopsy and cytology (a T0 response, 70 patients) plus those with less than a T0 response but medically unfit for cystectomy (six patients), received consolidative chemoradiation to a total of 64.8 Gy. Surgical candidates with less than a T0 response (13 patients) and patients who could not tolerate the chemoradiation (six patients) went to immediate cystectomy. The median follow-up duration is 4.4 years. The 5-year actuarial overall survival and disease-specific survival rates of all patients are 52% and 60%, respectively. For clinical stage T2 patients, the actuarial overall survival rate is 63%, and for T3-4, 45%. Thirty-six patients (34%) underwent cystectomy, all with evidence of tumor activity, including 17 with an invasive recurrence. The 5-year overall survival rate with an intact functioning bladder is 43%. Among 76 patients who completed bladder-preserving therapy, the 5-year rate of freedom from an invasive bladder relapse is 79%. No patient required cystectomy for treatment-related bladder morbidity. Combined modality therapy with TURBT, chemotherapy, radiation, and selection for organ-conservation by response has a 52% overall survival rate. This result is similar to cystectomy-based studies for patients of similar age and clinical stages. The majority of the long-term survivors retain fully functional bladders.

Early results of the value of p53 in predicting survival in a homogeneous cohort of patients with invasive bladder cancer treated with a neoadjuvant carboplatin-based regimen (M-CAVI).

Several reports on prognostic factors for infiltrating-bladder cancer have given controversial results. We assessed the prognostic value of p53 nuclear overexpression together with known prognostic factors for survival in patients with invasive T2-4 N0 M0 bladder cancer treated with neoadjuvant chemotherapy. Thirty-five paraffinized tumor samples from initial transurethral resection of patients with bladder cancer were analyzed immunohistochemically to detect overexpression of p53 protein. Patients were treated with 3 to 4 cycles of neoadjuvant methotrexate, carboplatin, and vinblastine (M-CAVI) and then underwent radical cystectomy. Prechemotherapy, treatment, and postchemotherapy factors were analyzed for correlation with survival by univariate and multivariate analysis. Fifty-seven percent of tumors were positive for p53 protein, 71.5% had grade III-IV tumors, and 72% had organ-confined disease. The median follow-up was 20 months (range 5-71+). By univariate analysis, the significant pretreatment factors were initial tumor (T) stage (P < 0.0001) and the male sex (P = 0.03). Five postchemotherapy variables were found significant: surgery performed according to protocol (P = 0.003), overall clinical (P = 0.004), and overall pathologic (P = 0.02) response to therapy, postchemotherapy pathologic stage (P = 0.0002), and tumor status after surgery (P = 0.0006). By multivariate analysis, the initial prechemotherapy T stage was the only factor that demonstrated independent significance. Although the median follow-up of the study is still too short, in this group of patients treated with a neoadjuvant carboplatin-based regimen, a classical variable (prechemotherapy T stage) rather than p53 nuclear overexpression was an independent prognostic factor for survival. Further follow-up will be required to assess the value of p53 overexpression as a prognostic factor in invasive bladder cancer patients treated with neoadjuvant carboplatin-based chemotherapy.

Genitourinary group phase II study of chemotherapy in stage T3-4 N0-X M0 transitional cell cancer of the bladder: Prognostic factor analysis

The aim of this study was to examine prognostic factors for survival of patients with invasive bladder cancer who had received neoadjuvant chemotherapy followed by further treatment. From 1986 to 1990, 149 eligible patients with T3-4 N0-X M0 bladder cancer were entered into a phase II trial of neoadjuvant chemotherapy, consisting of cisplatin and methotrexate. Patients received two or four courses of chemotherapy, depending on the absence or presence, respectively, of a major clinical response after two courses. 136 patients were evaluable for clinical response after two courses of chemotherapy, and 75 patients were evaluable for pathological response after two or four courses. A multivariate analysis, based on pretreatment variables and the post-treatment variables, clinical response and pathological response, showed that performance status, tumour size and clinical response after two courses of chemotherapy were the only independent prognostic factors for all eligible patients. A second multivariate analysis in the selected subgroup of patients, who underwent a cystectomy, showed that the G-cagetory and pathological response were the only independent prognostic factors. In conclusion, in this group of patients, the response to chemotherapy was a strong and independent prognostic factor in addition to other independent variables. However, it was not accurate or strong enough to allow an impact on the choice of locoregional therapy.

Bladder cancer, 1996.

In superficial Ta or T1 tumors intravesical chemotherapy can eradicate existing carcinoma in one third to one half of patients and reduce tumor recurrence by 12 to 15 percent, on average. Superficial bladder cancer is remarkably sensitive to immunotherapy, particularly BCG. The use of BCG eradicates about two thirds of papillary carcinoma and nearly 90 percent of carcinoma in situ and reduces tumor recurrence by an average of 40 percent. Data now suggest that BCG immunotherapy reduces long-term tumor recurrence, disease progression, and mortality. The proclivity for tumor recurrence makes superficial bladder cancer an ideal malignancy for the evaluation of chemoprevention, and preliminary data suggest that high doses of vitamins may also reduce tumor recurrence. In locally advanced T2b to T4, N0 or N1, M0 bladder cancer, substantial clinical responses can be achieved if chemotherapy is used prior to surgical resection of muscle-invasive tumor (neoadjuvant treatment). Controlled trials are necessary to ascertain whether neoadjuvant chemotherapy improves survival. The use of CMV prior to and concomitant with bladder irradiation is also encouraging, but will require randomized trials to clarify its role in the treatment of invasive, nonmetastatic cancer. Finally, trials suggest benefit for chemotherapy used adjuvantly (after cystectomy) for muscle-invasive bladder cancer. However, further investigation is necessary to clarify and confirm the role of chemotherapy in this setting before it can be recommended routinely for patients. In metastatic disease, chemotherapy with CMV or M-VAC with surgical resection of residual masses can produce a cohort of long-term survivors with advanced bladder cancer. How to increase this small but important population of patients is a question for further research.

1143 Prognostic factors in patients (PTS) with invasive bladder cancer (BC) treated with a bladder sparing approach

In a series of pts with muscle invading BC treated with a conservative approach a multivariate regression analysis was carried on to evaluate the association of clinical and pathological factors with clinical response and survival. Seventy pts with T1G3-T4 N0 M0 BC were treated with transurethral resection (TUR) and an alternating chemo-radiotherapy (CT-RT). Characteristics of pts were: median age, 65 yrs (range 40–75 yrs); median ECOG PS, 0 (range 0–1); M/F, 64/6; T1G3, 7 pts; T2, 40 pts; T3, 19 pts; T4, 4 pts; G2, 24 pts; G3, 42 pts. The first 18 pts received 4 cycles of CDDP 20 mg/sqm and FU 200 mg/sqm dd. 1–5 during wks 1, 4, 7, 10 alternated with RT (40 Gy during wks 2, 3, 8, 9). The second group of 52 pts received 3 cycles of the same CT (wks 1, 4, 7) (except the last 20 pts who received MTX 40 mg/sqm dd. 1, 8 instead of FU) alternated with 50 Gy of RT (wks 2, 3, 5, 6). Correlation of clinical and pathological features with response and survival: Response (P) Survival (P) Tumor stage T1–T2/T3–T4 0.7 0.7 Grade G1–G2/G3 0.5 0.9 TUR complete/incomplete 0.0004 0.009 Preop. hemogl. ≤12/>21 0.5 0.8 Hydronephrosis yes/no 0.6 0.7 In our group of pts the macroscopic radicality of TUR was the only significant prognostic factor. In fact pts with residual macroscopic disease after TUR had a 3.9 higher RR of death than pts with no residual disease.