Of 133 patients with advanced urothelial tract cancer given methotrexate (MTX), vinblastine (VBL), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (DDP) (M‐VAC ...regimen), significant tumor regression occurred in 72% ± 8% of 121 with transitional cell carcinoma (TCC) evaluable for response. Complete remission (CR) was achieved in 36% ± 9% of patients, of whom 11% required the addition of surgical resection of residual disease. Although 68% of CR patients have relapsed, CR median survival will exceed 38 months compared with 11 months for partial (36%) and minor (6%) responders, and 8 months for nonresponders: 2‐year and 3‐year survivals were 68% and 55%, respectively, versus 0% to 7% for the remaining patients. Sixteen percent of responders developed brain lesions, half of whom had no systemic relapse at the time of progression. Three patients with non‐TCC histologies did not respond. In 32 patients who had pathologic restaging, the clinical (T) understaging (T < pathologic P restaging) error was 35%. Although all metastatic sites showed evidence of tumor regression, CR was noted more frequently in lung, in intraabdominal lymph nodes and masses, and in bone (24% to 35%); the rate for hepatic lesions was 15%. There were 52% of 21 N3–4Mo patients who achieved CR versus 33% of 100 with No‐+M+ lesions. Toxicity was significant with 4 (3%) drug‐related deaths, 25% incidence of nadir sepsis, 58% ⩾ 3+ myelosuppression, and 49% with mucositis. Responsiveness of metastasis in various sites, patterns of relapse, and the usefulness of the new CR response criteria are reported, as is the current status of cisplatin and methotrexate combination regimens. Cancer 64:2448–2458, 1989.
Of 92 patients who received methotrexate, vinblastine, doxorubicin and cisplatin complete and partial remissions were observed in 69 +/- 10 per cent of 83 adequately treated measurable and evaluable ...patients with advanced stages (N+M0 and N0M+) transitional cell urothelial cancer. Complete remission was achieved in 37 +/- 10 per cent of the patients clinically, pathologically and after surgical resection of residual disease. With 17 of 31 complete responders (55 per cent) surviving for 26+ to 49+ months, the estimated probability of survival at 2 and 3 years was 71 and 55 per cent, respectively. Partial remission occurred in 31 +/- 10 per cent of the patients, while 8 per cent had a minor response and 23 per cent had progression with median survivals of 11, 11 and 7 months, respectively. Whereas all metastatic sites responded, including the bone and liver, complete tumor regression was observed more frequently with nodal, pulmonary and local-regional lesions. Brain metastases occurred within 6 to 42 months in 18 per cent of the responders, half of whom never had systemic relapse. Of the remaining 9 patients 2 with nontransitional cell histological tumors did not respond, 5 (5 per cent) were inadequately treated and 2 were excluded from response data because of inevaluable disease parameters but they were free of disease at 16+ and 31+ months. Toxicity was significant, with 20 per cent of the patients experiencing nadir sepsis, 4 per cent a drug-related death, 31 per cent +1 renal toxicity and 41 per cent +1 mucositis. The applications and advantages of the newly proposed international response criteria for bladder cancer are discussed in reference to 25 patients who underwent surgical re-staging, indicating that the disease was understaged clinically in 24 per cent (T less than P), as well as in reference to attainment of true (pathological) complete remission and to other urothelial tract trials. While this therapy seems to have limited antitumor activity against nontransitional cell histological cancer, stage Tis disease and later development of de novo lesions, the regimen is efficacious in selected patients with advanced urothelial tract transitional cell carcinoma.
Superficial bladder tumors (stage Ta, T1, and Tis) may progress to invade the bladder muscle and cause death from metastatic cancer. Transurethral tumor resection (TURB) is the standard therapy for ...such tumors, but surgery alone may not prevent tumor progression. Intravesical therapy is widely used as an adjunct to TURB. Bacillus Calmette-Guérin (BCG) is the most active intravesical agent, but whether BCG prevents tumor progression and death from bladder cancer is unknown.
Between 1978 and 1981, 86 high-risk patients with superficial bladder cancer were randomly assigned to receive either TURB (n = 43) or TURB plus BCG (n = 43). Adverse tumor features for progression were equally distributed between the two groups. BCG was administered weekly for 6 weeks. Patients were evaluated every 3 to 6 months thereafter for progression to muscle invasion or metastasis. Control (TURB) patients with recurrent superficial tumors were eligible for crossover to the BCG arm. All patients have been monitored until event or for a minimum of 10 years (range, 10 to 14).
The 10-year progression-free rate was 61.9% (95% confidence interval CI, 47.2% to 76.7%) for patients treated with BCG and 37% (95% CI, 22.9% to 53.1%) for control patients. The median progression-free interval was not reached for the BCG group and was 46 months for the control group (P = .0063). Of 18 control patients crossed over to BCG (median, 29 months), 15 did not show tumor progression. TURB plus BCG resulted in a 10-year disease-specific survival rate of 75%, compared with 55% with TURB alone (P = .03).
This study shows that intravesical therapy with BCG delays tumor progression and death from tumor in patients who present with superficial bladder cancer.
The sensitivity of voided urinary cytology (VUC), bladder wash cytology (BWC), and bladder wash flow cytometry (BWFCM) in detecting cancer was studied in 70 patients with biopsy‐proven bladder ...tumors. There were 11 Grade I papillomas, 14 Grade II TA, 18 Grade II‐III TIS, 19 Grade II‐III T1, and eight Grade II‐III T2 carcinomas. One to five VUCs per patient (mean, 2.63) were obtained within the 24 hours preceding biopsy. At endoscopy a bladder wash specimen was obtained and divided for cytologic and flow cytometric examinations. For all tumor categories combined, the sensitivity for one, two, and three voided cytology examinations per patient was 41%, 41%, and 60%, respectively. The sensitivity of a single BWC was 61%, of a single BWFCM, 83%. Thus, one BWFCM is more sensitive than three VUC (binomial test; P = 0.006); one BWC is more sensitive than two VUC (P = 0.01); and one BWFCM is more sensitive than one BWC (P = 0.003). These findings remain significant when papillomas are excluded from the analysis (P ≤ 0.03) and when papillomas and T2 tumors are jointly excluded (P ≤ 0.02). Only four of 70 patients (6%) had their cancers detected by VUC and/or BWC rather than BWFCM. In summary, irrigation cytology specimens are more sensitive than voided urinary cytology, and bladder wash flow cytometry is more sensitive than either in diagnosing bladder cancer. Flow cytometry is more sensitive because of the better sampling of bladder irrigation compared with voided urine and because of the measurement technique itself.
The M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) regimen was used to treat 25 patients with transitional cell carcinoma of the urothelial tract. Treatment consisted of monthly cycles ...of 30 mg. per m.2 methotrexate, followed 24 hours later by 3 mg. per m.2 vinblastine, 30 mg. per m.2 doxorubicin and 70 mg. per m.2 cisplatin, and concluded with repeat vinblastine and methotrexate on days 15 and 22. Significant tumor regression was noted in 71 per cent of the patients. Complete clinical remission was observed in 12 of 24 patients (50 per cent, 95 per cent confidence limits 30 to 70 per cent) with bidimensionally measurable indicator lesions, 6 of whom had pathological confirmation. After surgical exploration 4 patients required downstaging to a partial remission. The median duration of response has not yet been reached at 9.5 plus months, range 4.5 plus to 16 plus. Five patients (21 per cent) had a partial clinical remission for 4 to 8 plus months, 1 had a minor response for 4 months and 1 had stable disease for 11 months. All metastatic sites responded, including bone (6 of 8 cases), liver (3 of 5), locoregional (12 of 17) and intravesical (6 of 7) disease. Toxicity included moderately severe myelosuppression that resulted in nadir sepsis in 4 patients and a drug-related death in 1, mild to moderate anorexia, vomiting, alopecia and renal dysfunction. These preliminary results suggest that treatment with methotrexate, vinblastine, doxorubicin and cisplatin is extremely effective against locoregional and disseminated urothelial tract tumors, with the expectation (95 per cent confidence limits) of inducing objective tumor regression in 53 to 89 per cent of the cases.
Between March 1970 and December 1978 there were 366 patients with prostatic cancer treated by 125I seed implants and pelvic lymph node dissection. All had a minimum of 5 years follow-up. One hundred ...thirty-three patients had metastatic prostatic cancer in lymph nodes (Stage D1) at the time of lymph node dissection and seed implantation. Ninety-one of the 133 patients were judged to have sufficient metastatic prostatic cancer in their nodal tissue (greater than 50% replacement with tumor) to justify flow cytometric cellular DNA measurements on the involved paraffin-embedded nodal tissue. Nine patients were excluded due to uninterpretable DNA histograms leaving 82 patients for analysis. Forty-nine patients had aneuploid and 33 had diploid tumors. There was no statistical bias between the aneuploid and diploid groups due to age (P = 0.970, chi 2 test), time between diagnosis and implantation (P = 0.217, chi 2 test), number of positive nodes (P = 0.669, two-sample t test of means), or tumor grade (P = 0.332, chi 2 test). Median survival time of the aneuploid and diploid groups was 5.0 and 8.8 years, respectively (P = 0.0109, log rank test). Cox regression analysis confirmed the effect of aneuploidy versus diploidy on survival by controlling for other potentially confounding variables (age, time from diagnosis to implantation, number of positive nodes, and grade). Grade as a predictor of survival did not approach statistical significance in this series of relatively small size (P = 0.116). Thirty-eight of the 82 patients had moderately differentiated neoplasms. Nineteen of these were aneuploid and 19 diploid. The median survival was 5.8 and 9.1 years, respectively, for these grade-matched aneuploid and diploid groups (P = 0.039, log rank test). We conclude that flow cytometric DNA measurements on archived paraffin-embedded tumor in nodal metastases appear to be a strong predictor of survival for Stage DI prostatic cancer.
The natural history and staging of prostatic cancer, directly or indirectly, involve natural expectancy of the host, malignant potential of the tumor, extent of the tumor, and response of the tumor ...to treatment. Discussion of these topics is followed by a description of the systems of clinical staging of the disease.
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