Pamela P. Griffin

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.

Selective Bladder Preservation by Combination Treatment of Invasive Bladder Cancer

BACKGROUND For patients with invasive bladder cancer the usual recommended treatment is radical cystectomy, although transurethral resection of the tumor, systemic chemotherapy, and radiotherapy are each effective in some patients. We sought to determine whether these treatments in combination might be as effective as radical cystectomy and thus might allow the bladder to be preserved and the cancer cured. METHODS We enrolled 53 consecutive patients with muscle-invading bladder cancer (stages T2 through T4, NXM0) in a trial of transurethral surgery, combination chemotherapy, and irradiation (4000 cGy) with concurrent cisplatin administration. Urologic evaluation of the tumor response directed further therapy: radical cystectomy in the 8 patients who had incomplete responses, additional chemotherapy and radiotherapy (6480 cGy) in the 34 patients who had complete responses or who were unsuited for cystectomy, and alternative care in the 11 patients who could not tolerate either irradiation or chemotherapy. RESULTS After a median follow-up of 48 months, 24 of the 53 patients (45 percent) were alive and free of detectable tumor. In 31 patients (58 percent) the bladder was free of invasive tumor and functioning well, even though in 9 (17 percent) a superficial tumor recurred and required further transurethral surgery and intravesical drug therapy. Of the 28 patients who had complete responses after initial treatment, 89 percent had functioning tumor-free bladders. CONCLUSIONS Conservative combination treatment may be an acceptable alternative to immediate cystectomy in selected patients with bladder cancer, although a randomized clinical trial that included a group for simultaneous comparison would be required to produce definitive results.

Bladder carcinoma as a systemic disease

One hundred and fifty‐one patients with transitional cell carcinoma of the bladder who were evaluated by conventional means preoperatively underwent a radical cystectomy. They were then classified according to the highest known pathological stage, first site of postoperative metastasis and the temporal relationship of the cystectomy to the appearance of the metastasis. Fifty patients developed metastases, 80% of which were proven histologically. Thirty‐nine of fifty patients (78%) who developed metastases did so within a year of cystectomy. Extent of local tumor was directly related to the incidence of positive pelvic nodes. Metastases occurred most commonly in lung and bone. Soft tissues of the pelvis were involved in thirteen (16%) of the patients who developed metastatic carcinoma and those patients with positive pelvic nodes were more likely to have these kinds of recurrent disease. These evaluations suggest that the metastases must be present at cystectomy or as a result of it. The data imply the existence of appreciable heterogeneity among patients and/or their invasive bladder carcinoma. Disseminated but silent metastases suggest that a relationship between the primary tumor and the occurrence of metastatic disease may exist. Knowledge of this relationship is very important in planning subsequent therapeutic strategies.

Treated History of Noninvasive Grade 1 Transitional Cell Carcinoma

A total of 178 patients with grade 1 noninvasive (stage Ta) bladder tumors followed from 1 to 10 years (median 58 months) was prospectively evaluated by cystoscopy, transurethral resection, mucosal biopsies, cytology, size and number of tumors at diagnosis, recurrences, progression in grade and stage, number of negative or positive cystoscopies and death from all causes. Histopathological and cytological studies were confirmed by a Central Pathology Laboratory using the criteria for grade 1 as described previously. Of the patients 122 (68.5%) had a single tumor. Three-quarters of the patients had tumors of less than 2 cm., 95% had mild or no urothelial dysplasia and 1 had positive cytology results. There were 419 recurrent tumors in 109 patients (61%). Patients with multiple tumors were at a significantly greater risk for recurrences (p < 0.001). Size of tumor significantly affected the rate of recurrence in the first 2 years after initial diagnosis in single tumor patients only. Of the multiple tumor patients 90% experienced a recurrence compared to 46% of the single tumor patients. Of the 1,112 cystoscopies performed in 122 single tumor patients 18% were positive, compared to 33% of the 686 cystoscopies performed in 56 multiple tumor patients. A total of 29 patients had a change in grade, 5 having grade 3 and 24 having grade 2 tumors. Progression to stage T1 occurred in 5 patients and to stage T2 or greater in 3. Of the 36 patients who died, 1 died of obstruction due to bladder cancer. Experimental evidence supports the opinion that the cells of stage Ta, grade 1 tumors are different in several ways from normal urothelium. There are little data to support the use of the term papilloma to describe stage Ta, grade 1 tumors without reservation. The data demonstrate that the tumor diathesis being expressed ceases with time and for unknown reasons. Multiple tumor patients with stage Ta, grade 1 disease might be included in chemotherapy trials only with stratification and a control arm of transurethral resection/fulguration alone.

Photodynamic therapy with hematoporphyrin derivative in the treatment of superficial transitional-cell carcinoma of the bladder

Photodynamic therapy involves light-induced destruction of tumors containing a photosensitizer such as hematoporphyrin derivative. We conducted a collaborative study to evaluate the efficacy of this form of therapy in treating superficial transitional-cell carcinoma of the bladder. Thirty-seven patients were evaluated and 20 were selected for treatment. A total of 50 papillary tumors and 3 areas of carcinoma in situ were treated. All except two tumors were smaller than 2.5 cm. Assessments for treatment response and toxicity were carried out three months after treatment. The initial diagnosis of one patient was revised after the biopsy material was reviewed, and this patient was not included in the analysis. Complete eradication of all tumors was observed in 9 of 19 patients (47 percent), including those with carcinoma in situ. In the remaining 10 of these 19 patients, 13 tumors could not be eradicated (the overall eradication rate was 37 of 50 tumors [74 percent]), but 9 of the 10 patients had a reduction in tumor size, number, or both of 50 percent or more. We conclude that photodynamic therapy is useful in the treatment of superficial transitional-cell carcinoma of the bladder, but controlled trials will be required to define its place in the treatment of cancer.

Nodal Involvement as A Prognostic Indicator in Patients with Prostatic Carcinoma

Between 1969 and 1976, 92 patients with proved prostatic carcinoma in stages T0 and T4 underwent pelvic lymphadenectomy. Median followup has been 43 months. All patients had normal serum acid phosphatase levels and no clinical evidence of metastases as determined by physical examination, bone scans and metastatic bone surveys. Pelvic lymph node metastases were noted in 32 cases. Radical prostatectomy was done in 34 cases and 45 patients received radiotherapy, 11 of whom had 125iodine seeds implanted. Progression of the neoplastic process, almost exclusively in the form of bony metastases, occurred in 18 of the 32 patients who had positive pelvic nodes and in 6 of the 60 patients with negative nodes (p less than 0.001). Patients with poorly differentiated carcinoma were more likely to have progression of the disease than those with moderately differentiated carcinoma (p less than 0.01) and no patient with a well differentiated carcinoma had disease progression.

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.

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.

Invasive Bladder Cancer: Tumor Configuration, Lymphatic Invasion and Survival

The pathologic slides of 86 patients who underwent radical cystectomy for invasive (stage T2 plus) bladder carcinoma were reviewed. The tumors were classified according to the demonstration or absence of small vessel invasion and the papillary or solid configuration. Of the 86 patients regional nodal metastases were noted in 24. Eighteen of 48 patients (38 per cent) with small vessel invasion also had nodal metastases compared to 6 of 38 (16 per cent) without small vessel invasion. Of the 62 patients without nodal metastases the crude 5-year survival was 52 per cent for 32 without small vessel involvement compared to 30 per cent for 30 with small vessel involvement.

Preliminary Results in Invasive Bladder Cancer with Transurethral Resection, Neoadjuvant Chemotherapy and Combined Pelvic Irradiation Plus Cisplatin Chemotherapy

Preliminary data are presented of a clinically feasible pilot study to select a significant subgroup of patients among those with muscle-invading bladder tumors for local cure and bladder preservation, while also to offer all patients the possibility of preventing the development of distant metastases. Transurethral debulking surgical resection was combined with neoadjuvant methotrexate, cisplatin and vinblastine chemotherapy plus 2 additional courses of cisplatin and 4,000 cGy. If tumor was found on cystoscopic re-evaluation by biopsy and for cytology after cisplatin and partial irradiation (4,000 cGy.) immediate cystectomy was advised. If tumor was not found consolidation by a radiotherapy boost to a total of 6,480 cGy. plus 1 additional course of cisplatin was given. Of 53 consecutive patients the planned treatment was completed in 42 (79%). With a median followup of 26 months (range 15 to 42 months), 72% of all entered patients were alive, 70% have not required cystectomy and 74% have not had distant metastases. Among the 42 patients who completed the planned protocol chemotherapy dose reductions were required in 39% for stomatitis, bone marrow depression and/or renal dysfunction. There were 2 serious complications but no treatment-related sepsis, deaths or significant renal dysfunction. Eight patients underwent immediate radical cystectomy because of positive biopsy and/or cytology results after 4,000 cGy., while 34 completed full chemotherapy and radiotherapy without any significant bladder or bowel injury. Of 42 patients 22 (52%) have maintained the bladder without any recurrence, and of those selected for full chemotherapy and radiotherapy this number increased to 65%. To date 12 patients have persistent or recurrent bladder tumors: 5 (15%) had invasive tumors treated by cystectomy and 7 (21%) had carcinoma in situ treated by intravesical therapy. The true success of this or other selective bladder-preserving treatments will require 3 to 5 years of followup to be confident that such treatment has sterilized the bladder of cancer. This feasibility study has been clinically practical, modestly well tolerated and encouraging for the significant proportion of patients with a sustained complete response and for the 70% over-all survival rate at 2 years. To evaluate critically the efficacy of methotrexate, cisplatin and vinblastine chemotherapy in the prevention of occult distant micrometastases and in increasing the rate of successful bladder preservation, in May 1988 we began a randomized phase 3 trial with and without neoadjuvant methotrexate, cisplatin and vinblastine chemotherapy.