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.

Phase II study of interferon-alpha and chemotherapy (5-fluorouracil and mitomycin C) in metastatic renal cell cancer.

A total of 49 patients with metastatic renal cell cancer underwent recombinant interferon-alpha 2a therapy combined with chemotherapy. Before therapy the patients without nephrectomy underwent angioinfarction of the primary renal tumor. Combined treatment included interferon at 5 x 10(6) units per m.2 intramuscularly daily, 5-fluorouracil at 750 mg./m.2 daily by continuous infusion intravenously (days 1 to 5) and mitomycin C at 5 mg./m.2 per day intravenously (days 1 and 2) repeated every 28 days. Of the patients 17 (35%, 95% confidence interval 22 to 49%) responded, and all 17 had partial remission that lasted a median of 7.1 months (range 4.2 to 20.9+ months). Response rate differed by metastatic sites: lung 46% (18 of 39 patients), lymph nodes 46% (6 of 13), mediastinum 20% (2 of 10) and liver 18% (2 of 11). Grade 3 to 4 toxicity (World Health Organization) included neutropenia (79% of the patients), thrombocytopenia (45%), stomatitis (34%), diarrhea (8%), nausea (18%) and central nervous system disorders (18%). The overall 35% response rate suggests that the combination of interferon-alpha 2a, 5-fluorouracil and mitomycin C is synergistic. Future studies are needed to confirm this finding and to assess the role of mitomycin C.

Chemotherapy for small cell carcinoma of prostatic origin.

A total of 21 patients with metastatic small cell carcinoma of the prostate was treated with combination chemotherapy, either following initial hormonal therapy (15) or as initial therapy (6). Of the patients 13 (62%) had pure small cell carcinoma, whereas 8 (38%) had mixed histology of small cell carcinoma and adenocarcinoma. Patients presented with a characteristic clinical picture of a large primary mass (16 cases) with a high frequency of visceral metastases to the liver (9), lungs (7) and brain (2). The majority of the patients did not have an elevated serum prostate specific antigen (1 of 14, 7%) or prostatic acid phosphatase (2 of 21, 10%). Serum carcinoembryonic antigen was elevated in 13 patients (62%). Of the 21 patients 13 (62%) responded to chemotherapy. Survival after the diagnosis of small cell carcinoma of the prostate resulted in a median of 9.4 months with a range of 1 to 25 months. The regimens used were those considered active in the treatment of small cell carcinoma of the lung (vincristine, doxorubicin and cyclophosphamide, or etoposide and cisplatin with or without doxorubicin). Small cell carcinoma of the prostate has a characteristic clinical picture and a high response rate to cytotoxic therapy. Early introduction of chemotherapy in the treatment of small cell carcinoma of the prostate may increase the survival rate.

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.

Evidence of malignant features in histologically mature teratoma.

A total of 33 specimens from 29 patients with residual stable teratoma and mature growing teratoma after chemotherapy was analyzed for clinicopathological and deoxyribonucleic acid (DNA) flow cytometric variables, as well as the presence of proliferative antigen and tumor marker levels in an attempt to explain their clinical behavior. We compared the flow cytometric and histological data of these stable and growing teratomas, and of nonseminomatous germ cell tumors before chemotherapy. The DNA content of residual teratoma did not differ significantly from that of the primary testicular tumors (1.38 versus 1.48). Histological analysis of stable and growing teratomas revealed no significant difference but proliferative cellular nuclear antigen was expressed mainly in the epithelial component of the growing teratoma. alpha-Fetoprotein, beta-human chorionic gonadotropin and carcinoembryonic antigen were elevated in the fluid of 6 excised teratomas, while concomitant serum levels were normal. The aneuploidy and elevated cystic fluid tumor markers confirm the malignant phenotype of post-chemotherapy residual teratomas. Therefore, complete surgical removal is essential despite the benign histological appearance.

Circadian infusion of floxuridine in patients with metastatic renal cell carcinoma.

A total of 42 patients with metastatic renal cell carcinoma received floxuridine infusion for 14 days at monthly intervals. The drug was delivered via an external programmable pump on a time-modified or circadian schedule; the highest dose of 68% was given between 3 and 9 p.m. Of the 42 patients 25 (60%) had undergone prior nephrectomy. Of the 40 evaluable patients 4 (10%, 95% confidential interval 3 to 24%) achieved a partial response: 3 of the 4 had undergone prior nephrectomy, while 1 had undergone renal angioinfarction. Another 4 patients (10%) had responses at metastatic sites but no response in the primary kidney tumor. The median duration of response for these 2 groups of patients was 65 and 27 weeks, respectively, and the most responsive site was the lungs. The treatment was generally well tolerated and could be administered on an outpatient basis. Our study confirms the limited but definite activity of floxuridine infused on a circadian schedule in patients with metastatic renal cell carcinoma. We observed responses in metastasis equally in patients with or without prior nephrectomy.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.