Purpose: We investigated the activity of combination chemotherapy consisting of cisplatin, ifosfamide, methotrexate and vinblastine in patients with metastatic urothelial cancer. Materials and Methods: A total of 32 consecutive patients was treated with 30 mg./m.2 cisplatin on days 1 through 3, 1.5 gm./m.2 ifosfamide with mesna on days 1 through 3, 30 mg./m.2 methotrexate and 3 mg./m.2 vinblastine on day 1 plus 5 μg./kg. granulocyte colony-stimulating factor on days 7 through 11. Courses were repeated every 21 days for a maximum of 6 cycles. Results: Major toxicity was granulocytopenia in 56% of patients, including 11 episodes of granulocytopenic fever. Anemia and thrombocytopenia developed in a third of the cases. No other significant toxicity or treatment related death was noted. An objective response was achieved in 20 patients (62.5%, 95% confidence interval 44 to 79). Median time to progression was 7 months and median survival was 13 months. Conclusions: The cisplatin, ifosfamide, methotrexate and vinblastine regimen appeared active in patients with metastatic urothelial carcinoma. This regimen was associated with significant but manageable hematological toxicity and the incidence of mucositis or renal impairment was low. Prospective randomized studies are needed to assess whether the addition of ifosfamide to other active agents will improve the survival of patients with this disease.

A phase II study of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/gemcitabine was conducted in patients with non-small cell lung cancer (NSCLC) who had failed first-line docetaxel- or cisplatin-based chemotherapy. Eligibility criteria included histologically confirmed measurable stage IIIB or IV NSCLC and previous exposure to docetaxel- or cisplatin-based regimens, World Health Organization performance status between 0 and 2, adequate hematologic parameters, and adequate hepatic, renal, and cardiac function. Gemcitabine (900 mg/m2) was given on days 1 and 8 as a 30-minute infusion; paclitaxel (175 mg/m2) was administered on day 8 as a 3-hour infusion after appropriate premedication. Granulocyte colony-stimulating factor (150 microg/m2 subcutaneously) was given on days 9 to 15. Treatment was repeated every 3 weeks until patients experienced disease progression. From October 1995 to December 1996, 26 patients with advanced NSCLC were enrolled (three stage IIIB, 23 stage IV). All 26 patients were assessable for toxicity, and 24 were evaluable for response. Two complete (8%) and five partial (21%) responses were observed, for an overall response rate of 29% (95% confidence interval, 11% to 47%). The median duration of response was 2.5 months and the median survival was 8 months. A median of three courses per patient was administered, and the median interval between courses was 21 days. The median delivered dose was 579 mg/m2/wk gemcitabine and 54.5 mg/m2/wk paclitaxel, corresponding to a relative dose intensity of 0.97 and 0.96, respectively. Grade 3/4 neutropenia occurred in two patients (8%). Grade 3 conjunctivitis occurred in one (4%) patient and grade 2/3 neurotoxicity in eight (31%) patients. Grade 3/4 and grade 2 fatigue occurred in four (15%) and eight (31%) patients, respectively. Other toxicities were mild to moderate. These preliminary results suggest that the paclitaxel/gemcitabine combination is an active and well-tolerated salvage regimen in patients with NSCLC previously treated with docetaxel- or cisplatin-based chemotherapy. The paclitaxel/gemcitabine combination merits further evaluation as first-line treatment.

Design: Determine the frequency of t(2;5)(p23;q35) in anaplastic large- cell lymphoma (ALCL), non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), and lymphomatoid papulosis (LP). Patients and methods: The t(2;5) was detected with a long-range nested polymerase chain reaction (PCR) using 0,5 μg of DNA (60000-80000 cells), 5'-primers from the NPM gene, 3'primers from the ALK gene, agarose electrophoresis, hybridization, and autoradiography. Patients were evaluable if a 3016 base pair amplicon could be generated from tumor DNA with β-globin primers. Results: Amplicons were detected by PCR of genomic DNA from three ALCL cell lines and four primary ALCLs known to t(2;5) positive. DNA from t(2;5)-positive cell lines diluted 104-fold or 105-fold generated amplicons in 100% or 20% of reactions, respectively. Archival tumor DNA from 144 patients was amplifiable by β-globin amplicons in 126 (88%) who are considered evaluable for this study. Twenty-two had ALCL, 69 other NHLs, 30 HD, and five LP. Genomic DNA PCR detected the t(2;5) in 5 of 22 with ALCL (23%, 95% confidence intervals [95% CI] 8%-45%) but not in those with NHLs, HD, or LP. Among ALCLs the t(2;5) was confined to 5 of 20 with nodal presentations (25%, 95% CI 9%-49%), among whom it was seen in 5 of 15 with T- cell or null-cell phenotype (33%, 95% CI 12%62%), in 4 of 11 with age < 40 years (36%, 95% CI 11%-69%), and in 4 of 9 with nodal presentations, T-cell or null-cell phenotype, and age <40 years (44%, 95% CI 14%-79%). Amplicon sizes were different between cell lines and patients, reflecting unique genomic DNA breakpoints, as confirmed by DNA sequencing, and served as an internal control against specimen cross-contamination in the laboratory. Conclusions: Long-range PCR of genomic DNA detects t(2;5) only in ALCL but not in other NHLs, HD, or LP. Long-range PCR may be useful in establishing diagnosis, determining prognosis, and monitoring minimal residual disease in ALCL.

BACKGROUND. Patients with metastatic carcinoma of the uterine cervix have limited survival. Thus, new chemotherapeutic agents and combinations are needed to improve patient outcome. METHODS. Twenty-seven patients with Stage IV primary or recurrent carcinoma of the uterine cervix were assigned to chemotherapy treatment at 4-week intervals with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The treatment was comprised of methotrexate, 30 mg/m2 administered intravenously (i.v.) on Days 1, 15, and 22; vinblastine, 3 mg/m2 i.v. on Days 2, 15, and 22; doxorubicin, 30 mg/m2 i.v. on Day 2; and cisplatin, 70 mg/m2 i.v. on Day 2. Granulocyte-colony stimulating factor (G-CSF) was given subcutaneously on Days 6-10 at a dose of 5 μg/kg. RESULTS. After a median of 4 cycles (a maximum of 6 in responders), the authors observed objective responses in 14 patients (52%), including 3 complete responses (11%) and 11 partial responses (41%). Median overall survival was 11 months (range, 4-15+ months), and median progression free survival of the responders was 8 months (range, 6-15+ months). Toxicity was acceptable and included neutropenia, alopecia, vomiting, and stomatitis. CONCLUSIONS. MVAC is an active regimen in the treatment of patients with advanced or recurrent carcinoma of the uterine cervix. It produced responses in one-half of the patients in this study, and it can be administered on an outpatient basis. The addition of G-CSF appears to reduce hematologic toxicity.

Late relapses of nonseminomatous germ cell tumors of the testicle are unusual. In such cases, chemotherapy is reported to have only modest success and surgery may be the preferred treatment modality. We report a patient who experienced relapse 11 years after the initial diagnosis of advanced testicular cancer and who achieved a sustained complete remission with salvage chemotherapy alone.

Because the outcome of patients with primary ovarian non-Hodgkin's lymphoma (NHL) is controversial, we retrospectively analyzed experience with adults seen at the University of Texas M. D. Anderson Cancer Center from 1974 to 1993. Patients were included if at least one ovary was pathologically involved, and if combination chemotherapy was used that must have included doxorubicin for intermediate grade histologies. We identified 15 patients who constituted 0.5% of all untreated NHL and 1.5% of untreated ovarian neoplasms that presented to our institution during this time. One patient refused therapy, leaving 14 assessable for response. Nine patients had intermediate- grade, 5 had highgrade, and none had low-grade NHL. One ovary was involved in 4 patients, and both in 10, in 7 of whom additional sites were involved, including supradiaphragmatic nodes in 2. Four patients had AAS I and 10 had AAS IV. Favorable (0 or 1) and unfavorable (> 1) IPI scores were seen in 5 and 9 patients, respectively. The complete remission rate for all patients was 64%, and 5-year survival and FFS for all assessable patients were 57 and 46%, respectively. We conclude that the complete remission rate and FFS of patients with ovarian NHL treated with appropriate chemotherapy appear to be similar to that of patients with other nodal NHLs. Further work is required to determine prognostic factors in ovarian NHL.

Objective: To evaluate the efficacy and toxicity of the combination of ifosfamide (1.5 g/m2 i.v. on days 1, 2, 3) and paclitaxel (135 mg/m2 i.v. over 3 hours on day 3) with G-CSF (5 μg/kg/d subcutaneously, days 7-11) administered every 3 weeks on an outpatient basis in patients with advanced epithelial ovarian cancer previously treated with platinum-based chemotherapy. Patients and methods: Thirty-five consecutive patients were treated, 12 of whom had previously received two regimens. Twelve of the 35 were defined as platinum-resistant and 23 as potentially platinum-sensitive. Results: Fifteen patients (43%; 95% CI: 26%-61%) achieved objective responses, five of them complete and ten partial. Objective responses occurred in 17% of the platinum-resistant patients and in 57% of those with potentially platinum-sensitive disease. The median duration of response was seven months and the median overall survival 11 months. The treatment was well tolerated and only 15% of the patients developed grade 3 or 4 neutropenia. With the exception of alopecia there were no other grade 3 or 4 toxicities. Conclusions: The combination of ifosfamide and paclitaxel was well tolerated and showed activity in patients with ovarian cancer who had previously undergone platinum-based chemotherapy.

Purpose: To determine the feasibility and toxicity of inducing autologous graft-versus-host disease (GVHD) with cyclosporine in patients with multiple myeloma undergoing autologous stem-cell transplantation. Patients and Methods: Fourteen multiple myeloma patients with a median age of 50 years (range, 41 to 63) were enrolled. The median time from diagnosis to transplant was 651 days (range, 229 to 3,353). Ten patients had primary refractory disease, two were in first remission, and two were responsive to salvage therapy. The preparative regimen consisted of thiotepa, busulfan, and cyclophosphamide. Cyclosporine was administered daily for 28 days after the stem-cell infusion, and the dose was adjusted to maintain whole-blood cyclosporine levels between 50 and 150 ng/dL in the first seven patients (low-level group) and between 150 and 300 ng/dL in the other seven patients (high-level group). Results: All patients achieved neutrophil engraftment a median of 11 days after transplant. Four patients developed ≤ grade 2 hepatic toxicity, six developed ≤ grade 2 nephrotoxicity, and four developed reversible cardiac toxicity. Only one treatment-related death occurred. Cyclosporine was withheld in seven patients for a median of 6 days because of renal and/or liver dysfunction. One patient developed clinical skin GVHD, which responded to corticosteroid therapy. Six patients developed histologic evidence of GVHD without clinical signs of GVHD (subclinical GVHD). The incidence of clinical and subclinical GVHD was similar in both cyclosporine groups. Three of 11 patients assessable for response achieved remissions. Three patients experienced disease progression 80, 160, and 354 days after transplant. Ten patients are alive without progression between 56 and 444 days after transplant. Conclusion: Induction of autologous GVHD by post- transplant cyclosporine is feasible and well tolerated in patients with multiple myeloma.

With current treatment modalities, most patients with early stage Hodgkin's disease (HD) can be cured. Patients destined to relapse, usually do so within 3 years after treatment completion. Late relapses do occur but disease recurrence beyond 15 years is extremely rare. We report a patient with clinical stage IIA nodular sclerosis HD, originally treated with radiotherapy alone, who relapsed 24 years after the initial diagnosis. Our patient's case indicates the possible need for lifelong surveillance of patients with Hodgkin's disease.

Objectives. Estramustine and etoposide have been shown to inhibit the growth of prostate cancer cells in experimental models. An in vivo synergism of the two agents, when administered to patients with metastatic prostate cancer refractory to hormone therapy, has been reported. To confirm these results, we administered this combination to a large number of patients with hormone-refractory prostate cancer (HRPC). Methods. Fifty-six patients with metastatic HRPC were treated with oral estramustine 140 mg three times a day and oral etoposide 50 mg/m2/day for 21 days. Therapy was discontinued for 7 days and the cycle was then repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. To control for the possible interference of an antiandrogen withdrawal effect, all patients discontinued antiandrogen therapy and were not enrolled in the study unless there was evidence of disease progression. Results. Forty-five percent of 33 patients with measurable soft tissue disease demonstrated an objective response, which included five complete and ten partial responses. Among 52 patients with osseous disease, 17% showed improvement and 50% showed stability of bone scan. Thirty patients (58%) demonstrated a decrease of more than 50% in pretreatment prostate-specific antigen (PSA) levels. The median survival of all patients was 13 months. Good pretreatment performance status, measurable disease response, improvement or stability of bone scan, and PSA response were important predictors of longer survival. Conclusions. We conclude that the combination of estramustine and etoposide is an active and well-tolerated oral regimen in HRPC.

A phase II study of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/gemcitabine was conducted in patients with non-small cell lung cancer (NSCLC) who had failed first, line docetaxel- or cisplatin- based chemotherapy. Eligibility criteria included histologically confirmed measurable stage IIIB or IV NSCLC and previous exposure to docetaxel, or cisplatin-based regimens. World Health Organization performance status between 0 and 2, adequate hematologic parameters, and adequate hepatic, renal, and cardiac function. Gemcitabine (900 mg/m2) was given on days 1 and 8 as a 30-minute infusion; paclitaxel (175 mg/m2) was administered on day 8 as a 3-hour infusion after appropriate premedication. Granulocyte colony- stimulating factor (150 μg/m2 subcutaneously) was given on days 9 to 15. Treatment was repeated every 3 weeks until patients experienced disease progression. From October 1995 to December 1996, 26 patients with advanced NSCLC were enrolled (three stage IIIB, 23 stage IV). All 26 patients were assessable for toxicity, and 24 were evaluable for response. Two complete (8%) and five partial (21%) responses were observed, for an overall response rate of 29% (95% confidence interval, 11% to 47%). The median duration of response was 2.5 months and the median survival was 8 months. A median of three courses per patient was administered, and the median interval between courses was 21 days. The median delivered dose was 579 mg/m2/wk gemcitabine and 54.5 mg/m2/wk paclitaxel, corresponding to a relative dose intensity of 0.97 and 0.96, respectively. Grade 314 neutropenia occurred in two patients (8%). Grade 3 conjunctivitis occurred in one (4%) patient and grade 213 neurotoxicity in eight (31%) patients. Grade 314 and grade 2 fatigue occurred in four (15%) and eight (31%) patients, respectively. Other toxicities were mild to moderate. These preliminary results suggest that the paclitaxel/gemcitabine combination is an active and well-tolerated salvage regimen in patients with NSCLC previously treated with docetaxel, or cisplatin-based chemotherapy. The paclitaxel/gemcitabine combination merits further evaluation as first-line treatment.

The diagnostic value of antimyosin scanning in 7 patients with biopsy- proven cardiac amyloidosis was examined in this study. Antimyosin imaging was positive in all amyloid patients, with more intense uptake in patients with heart failure.

Approximately 20% of patients with multiple myeloma are recognized by chance without significant symptoms. In order to prevent morbidity with timely therapy, reliable criteria are needed that distinguish those likely to show early or late disease progression. Multiple clinical features were assessed in 101 consecutive, asymptomatic and previously untreated patients. Patients with one or more lytic bone lesions were excluded because this feature had been found previously to be associated with early progression. Multivariate analysis indicated that only serum myeloma globulin > 30 g/l. IgA protein type, and Bence Jones protein excretion > 50 mg/d remained as significant independent variables. The presence of two or more of these features signified high-risk disease with early progression (median 17 months) whereas the absence of any adverse variable was associated with prolonged stability (median 95 months) (P < 0.01). Magnetic resonance (MR) imaging of the spine was useful only in patients with one adverse feature and an intermediate time to progression (median 39 months). An abnormal pattern (40% of patients) helped to distinguish patients with an imminent complication from those with more stable disease. Because a serious complication (fracture, hypercalcaemia) occurred in 35% of patients with early disease progression, chemotherapy seems justified for selected patients with asymptomatic disease at diagnosis. The remaining patients were at such low risk for progression (median 6 years) that they may be followed safely at long intervals without treatment.