Michael J. Morse

Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse

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.

M-Vac (Methotrexate, Vinblastine, Doxorubicin and Cisplatin) for Advanced Transitional Cell Carcinoma of the Urothelium

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.

Intermittent endocrine therapy for advanced prostate cancer

Twenty patients with advanced prostate cancer have been treated with an intermittent endocrine therapy schedule. Hormone therapy (diethylstilbestrol in 19 patients and flutamide in 1 patient) was administered until a clinical response was clearly demonstrated and then it was withheld until symptoms recurred. Prior to treatment 17 of 20 patients had bone pain and positive radionuclide scans, two had asymptomatic pulmonary metastases, and one had symptomatic localized disease. Duration of endocrine therapy prior to withdrawal of all treatment ranged 2 to 70 months (median, 10 months). Disease progression occurred 1 to 24 months (median, 8 months) after interruption of therapy. All patients who relapsed had a rapid clinical response following resumption of endocrine therapy. Nine of ten patients rendered impotent by endocrine therapy resumed sexual activity within 3 months of stopping treatment. This data indicates that satisfactory palliation of advanced prostatic cancer can be achieved in selected patients using intermittent endocrine therapy.

Penile Cancer: Relation of Extent of Nodal Metastasis to Survival

A retrospective review of 199 patients with penile cancer revealed that the extent of inguinal nodal metastasis was related to survival after radical ilioinguinal dissection. Patients with unilateral inguinal nodal involvement had a 56 per cent median 5-year survival rate, whereas those with bilateral inguinal nodal metastasis, extranodal tumor extension or iliac nodal involvement had a 9 per cent median 5-year survival rate.

Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin)effect on the primary bladder lesion

Of 50 patients with bladder cancer given 1 to 5 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin in a pilot phase I and II study 63 per cent of 41 with pure transitional cell stage T2-4 lesions responded. While significant downstaging occurred by transurethral resection of the bladder in 70 per cent and by cytology in 60 per cent of the patients, the final T response rate by all noninvasive clinical staging procedures, including sonography and computerized tomography, revealed complete remission in 24 per cent and partial remission in 39 per cent. Of 30 patients who underwent pathological staging 33 per cent achieved stage P0 and 17 per cent stage Tis disease or P less than T. Despite extensive re-evaluation by transurethral resection of the bladder and other noninvasive staging procedures, a clinical staging error (T versus P) of 38 per cent was observed. Of the other 9 patients 4 with mixed nontransitional cell histological findings at presentation never achieved complete remission, although 3 had resolution of all transitional cell elements and 5 (10 per cent) were inevaluable. The toxicity of the regimen was generally acceptable but 6 per cent of the patients required hospitalization for neutropenic fever. While this active regimen can clinically (T) and pathologically (P) induce downstaging in a significant number of patients with primary bladder tumors, this pilot study has raised serious questions concerning the design of future nonrandomized and randomized neoadjuvant studies.

Endoscopic diagnosis and treatment of upper‐tract urothelial tumors. A preliminary report

The technique of transurethral ureteropyeloscopy allows many standard cystoscopic procedures to be extended into the upper urinary tract. This endoscopic method was used to evaluate 31 patients suspected to have urothelial malignancies of the ureter or renal pelvis. Twenty‐eight of the patients had the procedure successfully completed (90%), 11 of whom were found to have urothelial tumors. Diagnostic ureteroscopic biopsy in three of these patients revealed high‐grade, multifocal tumors and was followed by nephroureterectomy (two patients) or partial ureterectomy (one patient). However, in eight patients, ureteroscopy and biopsy revealed apparently localized, low‐grade tumors which were treated by ureteroscopic fulguration or resection. The latter patients have undergone endoscopic surveillance every 3 months (average follow‐up, 21 months). The technique of ureteropyeloscopy permits endoscopic access into the ureter and renal pelvis, enabling tissue diagnosis and better preoperative cancer staging without surgical exploration. Although follow‐up is short, selected patients with low‐grade tumors may be treated primarily by endoscopic means. Cancer 55:1422‐1428, 1985.

Salvage chemotherapy for patients with germ cell tumors. The memorial sloan‐kettering cancer center experience (1979–1989)

Twenty‐eight of 124 (23%) advanced germ cell tumor (GCT) patients who were treated on four successive platin‐based induction regimens and who failed to achieve a durable complete response (CR) remain alive (median follow‐up, 50 months). An analysis of prognostic factors for response and survival was conducted on the 94 patients who received salvage chemotherapy. Survival and/or response to salvage therapy were significantly enhanced for patients with a prior CR to induction chemotherapy, treatment with a cisplatin‐based salvage regimen, a testis primary site, a normal serum human chorionic gonadotropin level, a normal serum lactate dehydrogenase level, one site of metastasis, and an Indiana Class of 6 or less. Patients with a prior incomplete response (IR) had a particularly poor prognosis (P = 0.00007) with only 4 of 52 (9%) patients alive (median follow‐up, 37 months) compared with 15 of 42 (36%) patients with a prior best response of a CR (median follow‐up, 35 months). The poor survival of patients who fail to achieve a durable CR to induction chemotherapy warrants the continued investigation of new salvage therapy. The identification of prognostic features may direct salvage therapy and aid in the interpretation of clinical trials of salvage regimens.

Enhanced Bladder Cancer Detection with the Lewis X Antigen as a Marker of Neoplastic Transformation

Recent evidence indicates that the Lewis X determinant is a tumor-associated antigen in the urothelium. Immunohistochemical analyses on frozen and deparaffinized, formalin-fixed tissue sections have demonstrated that the Lewis X antigen is not detected in normal adult urothelium except for occasional umbrella cells. However, papillomas and transitional cell carcinomas express this blood group-related antigen in more than 90% of the cases regardless of the grade or stage of the tumor, or the blood type or secretor status of the individual. To determine the presence of Lewis X antigen on exfoliated bladder epithelial cells we used an anti-Lewis X monoclonal antibody (P-12) and the avidin-biotin-peroxidase technique on 129 bladder barbotage specimens. Of 40 controls 34 were negative for Lewis X antigen, for a specificity of 85%. The 89 bladder tumor patients consisted of 14 with papilloma, 13 with flat carcinoma in situ, 49 with transitional cell carcinoma, and 13 with a positive cytology and negative biopsy results. Of these 89 patients 76 were considered positive for Lewis X antigen, for an over-all sensitivity 85.4%. The sensitivity for cytology alone was 61.2%. However, the combination of a positive cytology and/or positive Lewis X antigen result yielded a sensitivity of 93.2%. The data suggest that immunocytological detection of the Lewis X antigen on exfoliated bladder cells enhances the detection of urothelial tumor cells, particularly from low grade and low stage neoplasms.

Endocrine and Exocrine Profiles of Men with Testicular Tumors Before Orchiectomy

In 15 patients with germ cell testicular tumors serum hormone profiles and semen analysis before orchiectomy were evaluated to determine the incidence of defective spermatogenesis associated with testicular tumors. Defective spermatogenesis was noted in 10 patients (66 per cent) on the basis of low sperm concentration, motility or semen volume. Of the 10 patients 7 had sperm concentrations less than 10 million per cc. Endocrine abnormalities occurred in 10 patients, the most common of which were elevations in serum human chorionic gonadotropin and estradiol, and a relative decrease in follicle-stimulating hormone. Three patients who presented with subfertile semen analyses were treated with orchiectomy alone. Repeat semen analyses 4 to 12 months after orchiectomy showed improvement in spermatogenesis and 2 patients achieved a normal semen analysis. Endocrine abnormalities and defective spermatogenesis are common in patients with testicular tumors. These abnormalities precede orchiectomy and imply that a primary germ cell defect exists in these patients.

Sequential excision of residual thoracic and retroperitoneal masses after chemotherapy for stage III germ cell tumors

Twenty‐three patients with advanced (Stage III) mixed germ cell tumors underwent laparotomy and thoracotomy or neck dissection for excision of persistent radiographic masses after systemic chemotherapy. In those who received multidrug regimens incorporating high‐dose cisplatin, 4 of 15 (27%) harbored persistent tumor in at least one site, 6 of 15 (40%) demonstrated necrotic tumor or fibrosis only in all sites examined, and the remaining 5 of 15 (33%) harbored mature teratoma in at least one area. In patients treated with high‐dose platinum chemotherapy regimens 11 of 15 (73%) remain disease‐free with a median follow‐up period of 29 months (range, 1–58 months). Histologic comparison of tissues resected during thoracotomy and retroperitoneal node dissection indicated that patterns were dissimilar in 8 of 23 patients (35%). These data indicate the favorable impact of combined sequential chemotherapy and surgery in patients with advanced mixed germ cell tumors. In patients with Stage III tumors, persistent radiographic disease after cyclic cisplatin‐based chemotherapy is appropriately managed by excision of both thoracic and retroperitoneal deposits.