Fluorouracil and recombinant human interferon alfa-2a in the treatment of metastatic chemotherapy-refractory urothelial tumors.

Thirty patients with advanced metastatic and chemotherapy-refractory urothelial tumors received a combination of fluorouracil (5-FU) and recombinant human interferon alfa-2a. Thirty-six sites of metastases were present in the 30 study patients, and the median Eastern Cooperative Oncology Group performance status was 3 (range, 1 to 4). All patients had failed to respond to primary combined methotrexate/cisplatin-based chemotherapy. Nine (30%; confidence interval, 15% to 47%) of the patients achieved a partial response. The mean duration of response was more than 5.2 months (median, 6 months; range, 3 to 8 months). Two patients who achieved a partial response of 5 and 7 months' duration, respectively, had control of residual disease (one with radiation and one with surgical excision) and have remained disease-free for an additional period of more than 7 and 13 months, respectively. These data suggest that the combination of 5-FU and recombinant human interferon alfa-2a is synergistic, with clinical significance for the treatment of urothelial tumors. The response rate for this combination of drugs is higher than that anticipated for either of these agents used alone. Additional confirmatory trials are needed to evaluate the significance of these findings.

Escalated therapy for refractory urothelial tumors: methotrexate-vinblastine-doxorubicin-cisplatin plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor.

Thirty-two assessable patients with metastatic urothelial tumors refractory to standard chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were treated with escalated doses of MVAC plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Results of this phase I trial revealed that escalated MVAC (30 mg of methotrexate/m2, 4 mg of vinblastine/m2, 60 mg of doxorubicin/m2, and 100 mg of cisplatin/m2) can be tolerated by heavily pretreated patients. The side effects of rhGM-CSF are dose- and schedule-dependent. The maximum tolerated dose is 250 micrograms/m2 per day as a single dose administered subcutaneously (SC) for 10 consecutive days. This dose is well tolerated in outpatients, resulting in only modest fever and few side effects. The same dose delivered as a continuous infusion or a higher dose delivered either as a continuous infusion or SC caused significant side effects. For phase II trials, the starting dose of rhGM-CSF when combined with escalated MVAC is 120 micrograms/m2 per day SC for 10 consecutive days. forty percent of the treated patients responded, seven (23%) with complete remission and five (17%) with partial remission. This response rate is higher than anticipated from such a modest dosage escalation in chemotherapy-refractory patients.

Phase II study of coumarin and cimetidine in patients with metastatic renal cell carcinoma.

Fifty patients with locally advanced or metastatic renal cell carcinoma were treated with coumarin (1,2-benzopyrone) at 100 mg orally daily starting on day 1 and cimetidine 300 mg orally four times a day starting on day 15. When disease progressed, coumarin was escalated to 100 mg orally four times a day. Three patients (6%; 95% confidence interval [Cl], 2% to 17%) achieved a partial response, one of those after dose escalation. In addition, one patient had a minor response, then progressing disease, and again had a minor response after dose escalation. All four responders had nonassessable primary tumors (three had had prior nephrectomy and one a renal angioinfarction). The only major toxicity was renal (37 patients had minor to moderate elevations in serum creatinine level). Immunologic studies (hypersensitivity skin testing, lymphocyte blastogenesis response, number of lymphocytes, T lymphocytes, T helper and T suppressor subsets, and T helper: suppressor ratio), performed before and after therapy, showed a relative lymphopenia and decreased hypersensitivity skin-testing results at baseline, and a general decline over time in the number of T cells and T helper and T suppressor subsets. There was no enhancement in any of the immunologic parameters tested. The response rate was 6%, lower than previously reported; a general immunodeficiency was noted at baseline, and the lymphopenia worsened with progressing disease, unaffected by therapy.

A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors.

To evaluate the relative efficacy of cisplatin, cyclophosphamide, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (CISCA) versus methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC), a prospective randomized trial was performed in patients with advanced metastatic urothelial tumors. Patients were stratified by histologic disease type and degree of tumor dissemination. Equal distribution of the clinical characteristics was achieved. One hundred ten patients with metastatic disease of the urinary tract (86 bladder, 16 renal pelvis, seven ureter, one prostatic urethra) met eligibility criteria and were enrolled on study. These represented 82% of the total patients seen during the study period in the Section of Genitourinary Oncology who met the eligibility criteria. The combined complete and partial response rate was significantly higher for patients treated with MVAC than for those treated with CISCA (65% v 46%; P less than .05). The survival duration of MVAC-treated patients was significantly longer than that of CISCA-treated patients (mean, 62.6 weeks; median, 48.3; range, 5.0+ to 162.3+ v mean, 40.4 weeks; median, 36.1; range, 7+ to 147.1+). We conclude that MVAC chemotherapy is superior to CISCA chemotherapy, achieving a higher response rate and a longer survival for equivalent patients with metastatic urothelial tumors.

Adjuvant cyclophosphamide, doxorubicin, and cisplatin chemotherapy for bladder cancer: an update.

Seventy-one patients received adjuvant Cytoxan (cyclophosphamide; Bristol-Myers Co, Evansville, IN), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (CISCA) chemotherapy between March 1981 and March 1986. Patients received adjuvant CISCA chemotherapy if they had pathological findings that were thought to predict for high likelihood of relapse. These included the presence of resected nodal metastases, extravesicular involvement of tumor, lymphatic/vascular permeation of the primary tumor, or pelvic visceral invasion. Sixty-two patients at a similar high risk for recurrence did not receive adjuvant CISCA chemotherapy because they refused, had medical contraindications to therapy, or were not referred for chemotherapy. Two-hundred six patients had a cystectomy performed during the same study period but had none of the poor prognostic features suggesting a high risk for relapse. Sixty-two percent of the patients receiving adjuvant chemotherapy are alive and disease-free for a mean follow-up of 118 weeks (range, 28 to 310 weeks). A survival advantage exists for the adjuvant-treated patients when compared with those with unfavorable pathological findings who did not receive adjuvant chemotherapy (70% v 37%) (P = .00012): no difference exists in long-term disease-free survival for those with favorable pathological findings (long-term disease-free survival 76%) v those who received adjuvant chemotherapy (70%) (P = .33). Adjuvant CISCA chemotherapy prolongs the disease-free survival of some patients following a cystectomy. Patients who benefitted from adjuvant CISCA chemotherapy included those with resected nodal metastases, extra-vesicular involvement of tumor, and direct invasion of the pelvic viscera. Patients not benefitting from adjuvant CISCA chemotherapy in this analysis included those with lymphatic/vascular invasion in their primary tumor as the sole manifestation of high risk for relapse.

Chemotherapy of extragonadal germ cell tumors.

Forty-nine patients with histologically proven germ cell tumors arising in extragonadal sites were retrospectively reviewed. Included in the review were an additional seven patients with undifferentiated tumors with a pathologic appearance compatible with that of a germ cell tumor and elevated levels of serum biomarkers (beta subunit of human chorionic gonadotropin [beta-HCG] +/- alpha-fetoprotein [AFP]. Nineteen patients had a pure seminoma arising in an extragonadal site, whereas 30 patients had nonseminomatous germ cell tumors. Seven patients had primary undifferentiated tumors with elevated levels of serum biomarkers. Sixteen (84%) of the 19 patients with pure extragonadal seminomas with normal levels of serum AFP are alive and free of disease. Eighteen of these 19 patients received platinum-containing regimens and four had received prior chemotherapy that failed. Of the patients with nonseminomatous germ cell tumors, 12 (40%) of the 30 are alive and free of disease with vinblastine/bleomycin +/- cisplatin (13 patients) or CISCAII (cisplatin, cyclophosphamide, and doxorubicin) (nine patients) alternating CISCAII/VBIV (eight patients) chemotherapy. None of the seven patients with undifferentiated germ cell tumors are alive and free of disease. Three of the five patients with pure anterior mediastinal endodermal sinus tumors treated with chemotherapy remain alive and free of disease. Of the seven patients with choriocarcinomas arising in extragonadal sites, three are alive and free of disease. A classification for patients with extragonadal germ cell tumors incorporating site of origin, histology, and likelihood of being truly extragonadal is proposed. The implications of this classification are discussed.

Vinblastine fails to improve response of renal cancer to interferon alfa-n1: high response rate in patients with pulmonary metastases.

One hundred sixty-five patients were randomized to receive either interferon alfa-n1 (Wellferon; Burroughs Wellcome Co, Research Triangle Park, NC) alone or with vinblastine. An initial six-cycle induction treatment consisted of interferon given at daily doses of 3, 5, 20, 20, and 20 x 10(6) U/m2 every 2 weeks. Vinblastine at a dose of 10 mg/m2 (later decreased to 5 mg/m2) was given on day 1 of alternate cycles. Toxicities were generally well tolerated. The overall response rate was 10% with no significant difference between treatment arms. Survival was also not significantly different for the arms. A small subset of patients (16) with metastases only to the lungs had a high complete response (CR) and partial response (PR) rate of 44%. Responses were durable, and overall survival of this group was much better than that of the other patients.

Chemotherapy immediately after surgery for patients with germ cell tumors.

Six patients underwent surgery while receiving active chemotherapy for metastatic germ cell tumors. Surgical procedures included cholecystectomy, thoracotomy with tumor resection, and orchiectomy. Aggressive chemotherapy was reinitiated immediately after the surgery (average, 4.3 days; range, 3-6 days). Myelosuppression with nadir of granulocytes 80/dL (median) developed at day 13 (average). There were no immediate adverse effects of chemotherapy on wound healing, and all treatment courses were uneventful. We conclude that aggressive chemotherapy can safely be delivered to patients with germ cell tumors immediately after surgery.

Radiation therapy-associated invasive bladder tumors.

Radiotherapy-associated bladder carcinoma was found in 3.7 percent of 244 cases of advanced urothelial carcinoma. Average age at diagnosis of the bladder tumor was 63.1 years, with a mean of 20.5 years between radiation treatment and diagnosis. All 9 patients presented with gross hematuria. Eight patients had transitional cell carcinoma, 7/8 (87.5%) also had vascular or lymphatic invasion, and 1 was adenocarcinoma. Mean survival was 15.4 months (range 1-40 mos.), with a 55.5 percent one-year disease-free survival after diagnosis. Four patients died of bladder tumor, 4 were alive with no evidence of disease, and 1 was alive with metastasis.

Association of germ cell tumors and Hodgkin's disease.

Two patients presented with synchronous Hodgkin's disease and testicular germ cell neoplasms. Both patients are in complete remission following treatment with multidrug chemotherapy and radiation therapy. Despite epidemiologic similarities between Hodgkin's disease and testicular cancer, only 13 cases of their association in the same patient have been reported in the literature, and in all those instances the tumors occurred metachronously. However, the very rare occurrence of synchronous presentation suggests a possible common pathogenetic factor in our 2 patients.

Serum biomarkers in metastatic renal cell carcinoma.

To identify possible clinically valuable markers of metastatic renal cell carcinoma, we measured the serum concentrations of several commercially available biomarkers in 117 patients with this disease. The alpha-fetoprotein level was measured in 75 patients and was elevated in 8 (11%); elevation did not correlate with the presence of liver metastasis. Beta subunit of human chorionic gonadotropin levels increased in 8 of 83 patients tested (10%). C-terminal parathyroid hormone levels were measured in 79 patients and were elevated in 15 (19%); their serum creatinine level was normal. Thirteen of this group had normal serum calcium levels, whereas 7 patients with hypercalcemia and no clinically evident bone metastasis had normal parathyroid hormone levels. In only 2 of 72 patients, serum lactate dehydrogenase and its isoenzyme 1 were elevated. Only 1 of 85 patients had mildly elevated serum carcinoembryonic antigen, in contrast to 3 of 7 patients with metastatic transitional cell carcinoma of the renal pelvis who had moderately elevated carcinoembryonic antigen. Elevations in alpha-fetoprotein, human chorionic gonadotropin, and parathyroid hormone correlated with the course of the disease in 13 patients for whom follow-up measurements were available; measurement of these markers, however, is only useful in a small proportion of patients with metastatic renal cell carcinoma.

Interferon alternating with chemotherapy for patients with metastatic renal cell carcinoma.

A prospective randomized trial tested the hypothesis that interferon and cytotoxic chemotherapy delivered sequentially would be synergistic and would increase the response rate in metastatic renal cell carcinoma. Thirty-six patients were entered and randomized to chemotherapy only (5-fluorouracil, doxorubicin, mitomycin, and cis-platin) vs. interferon alternating with the same chemotherapy. Only 4 of 32 evaluable patients (13%), 2 in each arm, had a major response. Three patients in the alternating arm had minor responses. Complete, partial, and minor responses totaled 7 (22%). All four patients whose only disease was lung metastasis had some evidence of response (p = 0.001). Interferon alternating with chemotherapy did not appear to improve the major response rate over chemotherapy alone. Responses in metastatic renal cell carcinoma appear confined to a favorable subset of patients.

Clinical and radiologic staging of locally advanced and inoperable bladder carcinoma.

Twenty-seven patients with locally advanced and inoperable bladder carcinoma (LABCa) were referred for chemotherapy. All were staged by cytoscopy, examination under anesthesia, and computed tomography (CT), and 18 also had bipedal lymphangiography (LAG). In 16 patients (56%), there was agreement between the clinical and the CT staging of the primary bladder tumor. In four of these 16 patients, CT detected lymphadenopathy in three and demonstrated pelvic bone invasion in one. Of the remaining 11 patients, CT underestimated the local extent of the bladder tumor in nine and overestimated in two. Lymphangiography was abnormal in nine patients (50%), in four of whom the abnormality was not seen on CT scan. Among the ten patients with normal LAG, six had abnormal pelvic nodes detected by CT. The LAG affected the overall staging of the tumor in five patients (16.6%). The total incidence of nodal metastasis as seen on CT, LAG, or both was 72%. Although CT and LAG may not add significantly to the clinical staging of the primary tumor in LABCa, they will affect the overall staging of the tumor by detecting lymphadenopathy. Accurate staging of these patients is important because, with aggressive chemotherapy, some of these patients might become candidates for more radical treatment such as surgery or radiotherapy.

CT and MR imaging of malignant germ cell tumor of the undescended testis.

Preoperative localization of the impalpable undescended testis is necessary to facilitate proper surgical planning. There is an increased incidence of malignant change in the undescended testis; demonstration of malignancy before surgery will significantly alter the treatment. We describe the computed tomographic (CT) and magnetic resonance (MR) findings in 2 patients with malignant change in an intraabdominal testis. The CT scan revealed lesions with areas of low density, 1 of which had focal calcifications; MR revealed lesions of predominantly low or intermediate signal intensity on both long and short TR/TE images, with some areas of very high signal on both sequences. After initial management with chemotherapy, the residual tumor was surgically resected. In neither instance was residual normal testis demonstrated. Both CT and MR are ideal methods of examining malignant transformation of the undescended testis, because of their ability to characterize the internal structure of the organ and, in the case of MR, its capacity for multiplanar imaging. They are almost of equal value except for the ability of CT to identify calcification and of MR to diagnose hemorrhage.

Cisplatin combination chemotherapy for elderly patients with urothelial tumours.

The proportion of cancer patients who receive potentially curative therapy declines with increasing chronological age. Between January 1979 and January 1988, 36 patients aged from 76 to 84 years (median 78) consented to cisplatin combination chemotherapy. Eighteen patients received 1 to 7 cycles of adjuvant chemotherapy (median 5). This resulted in a drop in creatinine clearance rate from 70 +/- 28.5 ml/min to 49 +/- 20 ml/min. Eight patients (44%) are alive without evidence of disease, with a whole group median survival of 23 months. The dose intensity of cisplatin was found to predict recurrence. Eighteen other patients were treated for metastatic disease; 39% had an objective response after receiving 2 to 9 cycles (median 7). Only 2 patients (11%) are alive and free of disease. In this group no significant kidney damage occurred and the dose intensity of cisplatin did not predict response. Treatment resulted in a significant sepsis rate (39%) and 6 patients (17%) withdrew from treatment because of toxicity. It was concluded that cisplatin combination chemotherapy can be administered without treatment-related death and its efficacy is similar to that in younger patients. Age should not exclude patients from the potential benefit of such therapy. An important cause of reduced benefit from chemotherapy among elderly patients may be the reduced dosage of cisplatin.

Perianal ulcer in disseminated histoplasmosis.

A 65-year-old man with stage I testicular seminoma, treated with surgery and radiation, had fever of unknown origin, adrenal insufficiency, and an isolated perianal ulcer. Tissue diagnosis of disseminated histoplasmosis was established by biopsy of the perianal ulcer, an unusual cutaneous manifestation of the disease. Treatment with amphotericin B resulted in rapid clinical improvement and complete healing of the perianal ulcer.

Complete responses in metastatic transitional cell carcinoma of the prostate with cisplatin regimens.

We describe 3 patients with metastatic transitional cell carcinoma of the prostate who achieved a complete response with regimens containing cisplatin. Two patients received cyclophosphamide and weekly cisplatin, and 1 was given cyclophosphamide, doxorubicin and cisplatin. All 3 patients had extensive pulmonary metastasis at initiation of chemotherapy. One patient, who also had massive local disease, suffered an isolated brain metastasis 9 months after completion of chemotherapy but he remains in systemic remission 5 months later. Another patient had bilateral brain metastases 3 months after achieving complete remission with chemotherapy, followed 4 months later by systemic relapse. The third patient, who also had bone and bone marrow metastasis, is free of disease 20 months after completion of chemotherapy. In contrast, none of 14 patients with transitional cell carcinoma of the bladder and other sites treated with the same regimens obtained a complete response. Advanced transitional cell carcinoma of the prostate must be recognized promptly, since it is nonresponsive to hormonal manipulation and complete responses have been achieved with cisplatin chemotherapy programs as used in our patients.

Genetic abnormalities in men with germ cell tumors.

We retrospectively reviewed the genetic abnormalities detected clinically in 455 men with advanced germ cell tumors referred for chemotherapy. Of the patients 49 had extragonadal and 406 had testicular germ cell tumors. Of 19 patients with mediastinal germ cell tumors 4 (21 per cent, 3 with teratocarcinoma and 1 with endodermal sinus tumor) had Klinefelter's syndrome. Three of these patients had a 47XXY and 1 had a 48XXYY karyotype. No Klinefelter's syndrome was observed among 30 consecutive patients with retroperitoneal germ cell tumors or among the 406 with testicular tumors. Karyotypes of 35 consecutive patients with testis cancer without evident congenital abnormalities showed normal chromosomal patterns. We found 2 patients with Down's syndrome and testicular tumor, for an incidence of 0.5 per cent (probably significant). We also describe 2 cases of nonseminomatous testicular cancer and Marfan's syndrome (0.5 per cent incidence versus a 5 of 100,000 incidence of Marfan's syndrome in the general population). Apparently, genetic abnormalities are increased in men with germ cell tumors and we discuss the significance of this association.

Acute thyroid dysfunction (thyroiditis) after therapy with interleukin-2.

Interleukin-2 (IL-2) is frequently incorporated in antineoplastic therapy: While the effect of interferon on the thyroid has been extensively studied the impact of other cytokines on thyroid function is less well understood. We monitored the thyroid function in six patients who received IL-2 in combination with tumor necrosis factor-alpha (TNF) or alpha-Interferon (alpha IFN). Hyperthyroxinemia with suppressed TSH developed within the first four weeks of IL-2 administration; during this phase, there was no technetium or iodine uptake by the thyroid gland. During the following few weeks, serum thyroxine decreased and serum TSH rose, consistent with the development of primary hypothyroidism; during this phase, thyroidal isotope incorporation was normal. All hypothyroid patients received thyroxine replacement therapy upon documentation of hypothyroidism; in several cases thyroxine was successfully discontinued after 2-3 months. None of the patients had detectable antithyroidal antibodies and none experienced thyroid-related pain, although two patients developed thyroid enlargement. We conclude that IL-2 administration is associated with the development of transient, subacute, painless thyroiditis. The frequency and severity of this complication requires further elucidation through systematic, prospective study.

Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract.

A total of 14 men with inoperable or metastatic squamous cell carcinoma of the genital tract received methotrexate, bleomycin and cisplatin. In 12 patients the penis was the primary site. Metastases were usually advanced, and 4 patients had ulceration and infection in the inguinal region or perineum secondary to tumor. Two patients had tumor-related hypercalcemia. Of the patients 11 received the 3 drugs intravenously, whereas 3 received methotrexate intravenously, and bleomycin and cisplatin intra-arterially for large unilateral nodal metastasis. Of the 14 patients 10 responded, for a response rate of 72% (95% confidence interval 57 to 92%) and the median response duration was 6 months (range 4 to 24 months). Two patients (14%) who were treated intravenously achieved complete responses lasting 6 and 24+ months. Responses occurred in 3 patients with infection and in both patients with hypercalcemia. The combination of methotrexate, bleomycin and cisplatin has significant activity in patients with advanced squamous cell carcinoma of the male genital tract. This chemotherapy regimen should be evaluated in earlier disease in the adjuvant or neoadjuvant setting.