Bladder preservation by combined modality therapy for invasive bladder cancer.

PURPOSE: To update the efficacy of a selective multimodality bladder-preserving approach by transurethral resection (TURBT), systemic chemotherapy, and radiation therapy. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Prognostic factors in invasive bladder carcinoma in a prospective trial of preoperative adjuvant chemotherapy and radiotherapy.

Clinical and pathologic factors were analyzed in 40 patients with localized muscle-invasive bladder carcinoma treated in a prospective bladder-preserving program consisting of transurethral tumor resection, neoadjuvant chemotherapy (methotrexate, cisplatin, and vinblastine [MCV]), and 4,000 cGy radiotherapy with concurrent cisplatin. Patients with biopsy-proven complete response after chemotherapy and 4,000 cGy radiation received full-dose radiotherapy (6,480 cGy) with cisplatin. Cystectomy was recommended to patients with residual disease. Distant metastasis rate was associated with tumor stage and size: 0% in T2 patients, 39% in T3-4 patients (P = .035), 6% for tumors less than 5 cm, and 59% for tumors greater than or equal to 5 cm (P = .002). Risk of bladder tumor recurrence was higher in patients with tumor-associated carcinoma in situ (CIS; 40%) than those without CIS (6%; P = .075). Papillary tumors and solid tumors both had similar treatment outcomes. By multivariate analysis, tumor stage T2 (P = .04) and absence of CIS (P = .03) were significant predictors of complete response; CIS was predictive of local bladder recurrence (P = .07); and tumor size (P = .03), response after chemoradiotherapy (P = .02), and vascular invasion (P = .08) were associated with distant metastasis. Six of eight local bladder tumor recurrences were superficial tumors. The low actuarial distant metastasis rate of T2 patients (0% at 3 years), the 3-year actuarial overall survival rates for T2 (89%) and T3-4 (50%) patients, and the similar treatment outcomes for papillary versus solid tumors are encouraging when compared with published historical controls. These results provide preliminary evidence (median follow-up, 30 months) that the current chemoradiotherapy regimen may have beneficial effects in the treatment of muscle-invasive bladder carcinoma. The true efficacy of neoadjuvant chemotherapy remains to be proven by ongoing randomized trials.

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.

PURPOSE: To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation. PATIENTS AND METHODS: One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months. RESULTS: Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant. CONCLUSION: Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.

Conservative surgery, patient selection, and chemoradiation as organ-preserving treatment for muscle-invading bladder cancer.

Multimodality organ-sparing treatment has, during the last decade, become the standard of care for many common malignancies. In appropriately selected patients with muscle-invading bladder cancer, bladder-preserving treatment combining surgical transurethral resection (TUR) with chemoradiation therapy offers a chance for long-term cure and survival equal to cystectomy, while also affording a 60% to 70% chance of maintaining a normally functioning bladder. Selection criteria helpful in determining appropriate patients for bladder preservation include such variables as small tumor size, that a visibly complete TUR is possible, the absence of hydronephrosis and that a complete response (CR) to induction chemoradiotherapy was achieved. Selecting patients based on response to induction therapy allows for prompt cystectomy if residual disease is found or for prompt consolidation chemoradiotherapy if a CR with induction therapy is achieved. Bladder-preserving treatment usually results in a normally functioning bladder without incontinence or hematuria for stage T2 and T3a patients. Stage T3b-T4 patients are locally controlled less frequently using these techniques. However, no data exist to suggest that patients with more advanced disease are in any way disadvantaged by preoperative chemoradiotherapy as an attempt at bladder conservation. Patients require close urological surveillance as do any patients with superficial bladder cancer who are being treated conservatively. As studies addressing the possibility of organ preservation continue to show positive results, more patients will become informed about and will be offered selective bladder-sparing approaches as one-treatment option.

Invasive bladder cancer: treatment strategies using transurethral surgery, chemotherapy and radiation therapy with selection for bladder conservation.

PURPOSE: Combined modality therapy has become the standard oncologic approach to achieve organ preservation in many malignancies. METHODS AND MATERIALS: Although radical cystectomy has been considered as standard treatment for invasive bladder carcinoma in the United States, good results have been recently reported from several centers using multimodality treatment, particularly in patients with clinical T2 and T3a disease who do not have a ureter obstructed by tumor. RESULTS: The components of the combined treatment are usually transurethral resection of the bladder tumor (TURBT) followed by concurrent chemotherapy and radiation therapy. Following an induction course of therapy a histologic response is evaluated by cystoscopy and rebiopsy. Clinical "complete responders" (tumor site rebiopsy negative and urine cytology with no tumor cells present) continue with a consolidation course of concurrent chemotherapy and radiation. Those patients not achieving a clinical complete response are recommended to have an immediate cystectomy. Individually the local monotherapies of radiation, TURBT, or multidrug chemotherapy each achieve a local control rate of the primary tumor of from 20 to 40%. When these are combined, clinical complete response rates of from 65 to 80% can be achieved. Seventy-five to 85% of the clinical complete responders will remain with bladders free of recurrence of an invasive tumor. CONCLUSIONS: Bladder conservation trials using combined modality treatment approaches with selection for organ conservation by response of the tumor to initial treatment report overall 5-year survival rates of approximately 50%, and a 40-45% 5-year survival rate with the bladder intact. These modern multimodality bladder conservation approaches offer survival rates similar to radical cystectomy for patients of similar clinical stage and age. Bladder-conserving therapy should be offered to patients with invasive bladder carcinoma as a realistic alternative to radical cystectomy by experienced multimodality teams of urologic oncologists.

Invasive bladder carcinoma: preliminary report of selective bladder conservation by transurethral surgery, upfront MCV (methotrexate, cisplatin, and vinblastine) chemotherapy and pelvic irradiation plus cisplatin.

Methotrexate, Cisplatin, and Vinblastine (MCV) was followed by Cisplatin plus radiation therapy in 19 patients with muscle-invading clinical Stage T2-4NXM0 transitional cell carcinoma of the urinary bladder (including cystectomy candidates), to achieve local control and prevent distant metastases. Radical cystectomy was recommended for all patients who failed to reach a complete response (CR = biopsy negative and cytology not positive) following MCV and Cisplatin X 2 plus 4000 cGy. Completely responding patients, and those partially responding patients unsuited for cystectomy, were selected for bladder conservation treated with additional irradiation to the bladder tumor volume (total 6,480 cGy) plus one additional Cisplatin treatment. Dose reductions were required for stomatitis in 26%, mild bone marrow depression in 58%, and renal toxicity in 5% of the patients. During the Cisplatin/4000 cGy, mild dysuria occurred in 68% of patients and 36% had mild bowel hyperactivity. Serious complications have occurred in two patients to date. One patient had recurrent pulmonary emboli, marked reduction in bladder capacity, and diarrhea. A second had bladder perforation during cystoscopic evaluation after MCV and a small bowel obstruction after Cisplatin and 4000 cGy. There was no treatment-related sepsis. Three patients had initial complete transurethral resection of their tumors and therefore 16 patients are evaluable for tumor responsiveness to this protocol. Four patients (25%) were biopsy negative and cytology negative, whereas three additional patients (19%) were biopsy negative but cytology positive following initial MCV. Six patients (38%) were biopsy negative and cytology negative whereas three additional patients (19%) were biopsy negative and cytology positive following MCV and Cisplatin X 2 plus 4000 cGy pelvic radiation. Of the entire group, 9 patients were treated with full-dose radiotherapy. All of these patients are alive without evidence of tumor on rebiopsy of the original tumor site, but one has a persistent positive cytology. Seven patients had a radical cystectomy and 6 are disease free. The treatment of 3 patients deviated from the protocol. Overall, only one patient has developed distant metastases and currently 84% of the patients are disease-free, although follow-up is short. To date, this feasibility study has been clinically practical and well tolerated. The proportion of CR's suggests that this program may prove to be an organ-sparing and curative approach for a significant number of patients, but more experience and follow-up are required.

Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer.

PURPOSE: We performed a retrospective analysis to assess the durability of benefit derived from irradiation after prostatectomy for pT3N0 disease, and the possibility of cure. METHODS AND MATERIALS: We studied 88 patients who were irradiated after prostatectomy and had available prostate specific antigen (PSA) data, no known nodal or metastatic disease, no hormonal treatment, and follow-up of at least 12 months from surgery. Forty patients received adjuvant therapy for a high risk of local failure with undetectable PSA. Forty-eight patients received salvage therapy for elevated PSA levels. Mean follow up was 44 months from date of surgery and 31 months from irradiation. Biochemical failure was strictly defined as a confirmed rise in PSA of >10%, or as the ability to detect a previously undetectable PSA value. RESULTS: After salvage irradiation, 69% of patients attained an undetectable PSA. Eighty-eight percent of adjuvant patients were biochemically and clinically free of disease (bNED) at 3 years from prostatectomy. Sixty-eight percent of those receiving salvage irradiation were bNED 3 years after surgery. On univariate analysis, treatment group (adjuvant or salvage), pre-operative PSA, and the status of seminal vesicles were significant prognostic factors. The extent of PSA elevation in the salvage group was also significant. We did not demonstrate a significant difference between those salvage patients referred for persistently elevated PSA as compared to those with a late rise in PSA. On multivariate analysis, the only significant predictor of outcome was treatment group, with adjuvant irradiation having better outcome than salvage. CONCLUSION: More than two-thirds of this group of patients remain biochemically disease free at 3 years following irradiation, attesting to a number of potential cures. For patients with stage pT3N0 prostate cancer following radical prostatectomy, our data support the use of either routine postoperative adjuvant irradiation or close PSA follow-up with early salvage treatment.

Intravesical chemotherapy: how effective is it?

Intravesical chemotherapy has been shown to reduce or prevent recurrence of low-grade, low-stage transitional cell tumors of the bladder. Thiotepa, mitomycin C, doxorubicin, and bacillus Calmette-Guérin (BCG) are the drugs most widely used for intravesical chemotherapy in the United States; only thiotepa has FDA approval for use within the bladder. Results of studies with these agents are reviewed. Prospective, randomized studies are needed to determine the ability of the agents to prevent progression of high-grade tumors to muscle invasion.

First-line chemotherapy of superficial bladder cancer: mitomycin vs thiotepa.

A prospective randomized study has been conducted to compare the efficacy and toxicity of thiotepa with mitomycin in patients with transitional cell carcinoma of the bladder. The 156 patients entered to date in the study were distributed by tumor grade and stage as follows: grade 1, 36 patients; grade 2, 49 patients; grade 3, 18 patients; Ta, 67 patients; T1, 33 patients; and TIS, 56 patients. All patients had tumor present in the bladder on entry to the study and after eight instillations at weekly intervals; evaluative cystoscopy and biopsy were performed four weeks later. Preliminary analysis of 156 patients indicated on overall complete response of 39 per cent for mitomycin and 27 per cent for thiotepa, which is a statistically significant difference (P = 0.02). Moderate to severe leukopenia was the most common single toxic effect with thiotepa, and a rash was the most common single toxic effect with mitomycin.

Primary adenocarcinoma of urinary bladder.

We reviewed the clinical course and pathologic findings of 17 patients with adenocarcinoma of the urinary bladder at Massachusetts General Hospital between 1962 and 1978. The 12 men and 5 women were between thirty-eight and eighty-six years old (mean, sixty years). Five patients had urachal adenocarcinoma, 8 had pure adenocarcinoma, and 4 had mixed adenocarcinoma and transitional cell carcinoma. Twelve of 17 patients (71 per cent) had muscle invasion (T2-T3), and none had evidence of regional or distant metastases at initial presentation. The mean follow-up was four years. The treatment modalities included transurethral resection alone in 3 patients, radical cystectomy in 4, simple cystectomy in 2, salvage radical cystectomy in 1, and partial cystectomy in 7, 3 of whom also received radiation therapy. Over-all crude three and five-year survival rates were 60 per cent and 27 per cent, respectively; patients with invasive disease did poorly regardless of treatment modality. Five of 8 patients who died had evidence of metastatic disease, and only 1 patient with invasive disease was alive more than five years. However, 2 of 3 patients with invasive urachal adenocarcinoma who had preoperative radiotherapy plus partial cystectomy are free of disease at thirty-eight and sixty months.

Time to second prostate-specific antigen failure is a surrogate endpoint for prostate cancer death in a prospective trial of therapy for localized disease.

OBJECTIVES: The most relevant endpoint in comparing the efficacy of curative therapies for prostate cancer is cancer-specific death. Prospective trials need to mature for a least a decade to yield meaningful cancer death data due to the long natural history of the disease amd the use of salvage androgen suppression. This delay may be long enough that the tested treatments are outdated by the time of reporting; thus, there is a need for reliable early surrogate endpoints for cancer survival. METHODS: This report evaluates 202 patients entered into a single institution prospective randomized study for T3-4 prostate cancer. Patients were accrued between 1982 and 1992 and received radical irradiation to either a standard dose of 67.2 Gy or a higher dose of 75.6 Gy. Median follow-up was 5.4 years. A total 76 men have received androgen suppression or orchiectomy for salvage following relapse. Of this group, 35 experienced a second relapse heralded by a rise in the serum prostate-specific antigen (PSA). RESULTS: The median survival from the time of second biochemical relapse (defined as a progression with a rise in serum PSA more than 10% above the nadir after androgen suppression) was 27 months. Kaplan-Meier analysis projected a 0% survival for this group at 4 years. All those dying after second biochemical failure died of the prostate cancer. CONCLUSIONS: Second PSA failure (or PSA progression on hormonal therapy) has potential as a surrogate for impending cancer death and its use as an endpoint in prospective studies could allow earlier reporting by 2 to 4 years.

Autosuturing device in intestinal urinary conduits.

The autosuturing device has been used to close the base of 41 urinary intestinal conduits: 12 colonic, 25 ileal, and 4 jejunal. The techniques are described. There were no urine or bowel leaks, although in one postoperative gastrointestinal bleeding occurred in association with a partial small-bowel obstruction probably related to the stapled enteroanastomosis. Use of the instruments reduced peritoneal contamination and facilitated conduit manipulation. Operating time was reduced. Four patients have passed stones composed of struvite and apatite with staples embedded within. The autosuturing device should be considered an alternative rather than a substitute for conventional proximal conduit closure and bowel anastomoses.

Ileal conduit hemorrhage secondary to portal hypertension.

The clinical features and management of 3 patients who presented with the triad of massive hemorrhage from the ileal conduit, portal hypertension due to liver disease, and portosystemic varices related to the conduits are described. One patient, a class C cirrhotic, was treated conservatively and died of blood loss and hepatic coma. Two patients were managed with splenorenal shunts initially, followed by creation of colon conduits, and are currently doing well. Surgical approximation of areas draining in the portal and systemic circulation with subsequent development or adhesion-related varices probably explains the predilection for involvement of the ileal conduit and may explain the presence of varices in mild to moderate portal hypertension before other signs of hepatic decompensation are evident. Superior mesenteric angiography with special attention directed at the venous phase is necessary to document this entity.

Transitional cell carcinoma of renal pelvis.

Sixty-eight patients with transitional cell carcinoma of the renal pelvis were studied with respect to clinical presentation, tumor grade, stage and location, subsequent development of other urothelial tumors, and patient survival. Of the 66 patients with adjacent mucosa available for evaluation, 63 (95 per cent) had abnormal findings with severe dysplasia and CIS common in the high-grade, high-stage tumors. Twenty-eight patients (41 per cent) had transitional cell carcinoma previously, concomitantly, and/or subsequently, and in 14 patients (21 per cent) subsequent bladder tumors developed. Because of the relatively high tumor recurrence rate in the ureter (16 per cent) in patients who underwent subtotal ureterectomies, nephrectomy and complete ureterectomy including a bladder cuff should be the operation of choice in patients with carcinoma of the renal pelvis.

Mitomycin for patients who have failed on thiotepa. The National Bladder Cancer Group.

The National Bladder Cancer Group undertook a study to determine the effectiveness and toxicity of mitomycin in patients who failed on thiotepa. A total of 117 patients with residual superficial transitional cell bladder cancer (Ta, T1, Tis) who had previously failed on intravesical thiotepa were treated with 40 mg of mitomycin instilled intravesically weekly for eight weeks. Four to six weeks after the last treatment, tumor response was evaluated by cystoscopy, biopsy of the site of the index lesion, and cytology. In 57 patients (48.7%), visible tumor had been ablated. Results of cystoscopy, biopsy, and cytology were negative in 32 (27.4%) patients. Eleven patients (9.4%) had no visible tumor and negative cytology unconfirmed by biopsy. In 14 patients (12%) who had complete destruction of the tumor at cystoscopy, and biopsy specimen was negative for tumor, cytology was positive, indicating a partial response. Six patients (5.1%) withdrew from the study before the first evaluation because of local toxicity (cystitis).

Natural history of superficial bladder cancer. Prognostic features and long-term disease course.

Superficial bladder cancer or, more accurately, stages Ta, T1, and Tis encompass a spectrum that ranges from innocuous to life-threatening lesions. There is growing evidence that Ta grade 1 tumors rarely become invasive; although when there is associated carcinoma in situ or severe dysplasia, the risk of invasiveness increases. Carcinoma in situ is treacherous, with unpredictable behavior. Predictors of recurrence and progression are beginning to be identified for the various superficial tumors.

Interval report of a phase I-II study utilizing multiple modalities in the treatment of invasive bladder cancer. A bladder-sparing trial.

Clinicians at the Massachusetts General Hospital have used two cycles of methotrexate, cisplatin, and vinblastine (MCV) before radiotherapy and cisplatin in 53 patients with muscle-invasive bladder cancer. Eleven patients did not complete the protocol, but overall, the toxicity was not formidable. Of the total patients accessioned, 34 are alive. Of the 34 patients in the series who completed the full treatment protocol, the estimated survival rate at 54 months is 77%. This interim analysis suggests that the treatment is achieving at least limited success in saving lives and bladders.

Can chemo-radiotherapy plus transurethral tumor resection make cystectomy unnecessary for invasive bladder cancer?

The standard treatment for muscle-invading bladder tumors is, in the US, radical cystectomy +/- radiation; in Europe, it is radical radiotherapy. Neither of these therapies alone is wholly satisfactory. Suggested improvements in the complete response rates of the primary tumor have been reported with combination chemotherapy and with chemo-radiotherapy. Selecting for full chemo-radiotherapy only patients having a biopsy-proven CR to initial chemotherapy and/or to 4,000-4,500 cGy of radiation may further increase the success of bladder-preserving programs and not compromise survival (relative to immediate cystectomy), but this has not yet been proven. Randomized trials of neoadjuvant chemotherapy must be finished before its efficacy in subclinical systemic disease will be known. Likewise, proof of the efficacy of neoadjuvant chemotherapy in improving bladder preservation by chemo-radiotherapy must await completion of randomized trials. Three to five years of follow-up will be necessary before chemo-radiotherapy can be recommended as curing the bladder of cancer.