Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational, Multicenter, Phase III Study.

PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8, and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI, 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively) and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

Polarization phase in aberration compensation.

A phase/amplitude mask on the aperture of an imaging system results in a pupil function that is multiplicative with the lens function, resulting in a morphological transformation of the imaging wavefront. It was shown that such amplitude and phase functions can be implemented using polarization masks, with the advantage that the phase and amplitude can be controlled in real time and in some cases, independently of each other. The phase and amplitude variation over the mask can be controlled either by changing the polarization of the mask or by changing the input beam parameters. Wavefront tailoring using polarization-masked apertures is therefore feasible and may be utilized for focal shift and partial aberration compensation. For complete compensation of aberration, the phase distribution over the mask should be conjugate to that of the phase error of the aberrant wavefront, which necessitates the use of a continuously variable polarization mask. Since such a mask is difficult to implement, we have considered polarizing masks consisting of discrete polarized zones on the lens aperture, leading to polarization phase steps on the exit pupil of the imaging system. The simulation results presented in this paper show that effects of focal shift, partial compensation of primary spherical aberration and astigmatism can indeed be achieved by the proper use of polarization masked apertures.

Optimized sequence of drug administration and schedule leads to improved dose delivery for gemcitabine and paclitaxel in combination: a phase I trial in patients with recurrent ovarian cancer.

We examined appropriate sequence, schedule, and doses of gemcitabine (G) and paclitaxel (T) in patients with persistent or recurrent epithelial ovarian cancer. Patients received a maximum of six cycles of gemcitabine on days 1 and 8 (starting 1000 mg/m(2)), and paclitaxel (starting 135 mg/m(2)) on day 8 (groups A and B) or day 1 (group C). Drug sequences (G-->T and T-->G) were tested in group A. In group A, changing sequences of gemcitabine and paclitaxel infusion were evaluated. Sequence G-->T raised grade 3 alanine transaminase in two of three patients leading to use of T-->G sequence for remainder of study. In group B, maximum tolerable dose was reached at gemcitabine 1000 mg/m(2) and paclitaxel 175 mg/m(2). Reducing paclitaxel to 150 mg/m(2) allowed escalation of gemcitabine to 1250 mg/m(2), but neutropenia-related treatment delays occurred. Giving paclitaxel on day 1 (group C) enabled administration of paclitaxel 175 mg/m(2) and gemcitabine 1250 mg/m(2) with minimal dose adjustments. The overall response rate was 41.0%, with 2 complete responses and 14 partial responses in 39 eligible patients. The schedule of paclitaxel 175 mg/m(2) (day 1) and gemcitabine 1250 mg/m(2) (days 1 and 8), with sequence of T-->G, appears most suitable with tolerable toxicity and promising activity.

First-line gemcitabine versus epirubicin in postmenopausal women aged 60 or older with metastatic breast cancer: a multicenter, randomized, phase III study.

BACKGROUND: This randomized, phase III study compared the efficacy and safety of first-line gemcitabine versus epirubicin in the treatment of postmenopausal women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients aged > or = 60 years (median 68 years) with clinically measurable MBC received either gemcitabine 1200 mg/m(2) or epirubicin 35 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. RESULTS: Of 410 patients entered, 397 (198 gemcitabine and 199 epirubicin) were randomized and qualified for the time to progressive disease (TTP) and survival analyses. Total cycles administered in 185 gemcitabine and 192 epirubicin patients, respectively, were 699 (mean 3.5, range 0-12) and 917 (mean 4.6, range 0-10). Epirubicin demonstrated statistically significant superiority in TTP (6.1 and 3.4 months, P=0.0001), overall survival (19.1 and 11.8 months, P=0.0004), and independently assessed response rate (40.3% and 16.4% in 186 and 183 evaluable patients, P <0.001). For gemcitabine (n=190) and epirubicin (n=192), respectively, common WHO grade 3/4 toxicities were neutropenia (25.3% and 17.9%) and leukopenia (14.3% and 19.3%). Of the 28 on-study deaths (17 gemcitabine, 11 epirubicin), three were considered possibly or probably related to treatment (gemcitabine). CONCLUSIONS: Postmenopausal women > or =60 years of age with MBC tolerate chemotherapy well. In this study, epirubicin was superior to gemcitabine in the treatment of MBC in women age > or =60, confirming that anthracyclines remain important drugs for first-line treatment of MBC.

Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer.

PURPOSE: This retrospective analysis examined prognostic significance of health-related quality-of-life (HRQoL) parameters combined with baseline clinical factors on outcomes (overall survival, time to progressive disease, and time to treatment failure) in bladder cancer. PATIENTS AND METHODS: Outcome and HRQoL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30) data were collected prospectively in a phase III study assessing gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in locally advanced or metastatic bladder cancer. Prespecified baseline clinical factors (performance status, tumor-node-metastasis staging, visceral metastases [VM], alkaline phosphatase [AP] level, number of metastatic sites, prior radiotherapy, disease measurability, sex, time from diagnosis, and sites of disease) and selected HRQoL parameters (global QoL; all functional scales; symptoms: pain, fatigue, insomnia, dyspnea, anorexia) were evaluated using Cox's proportional hazards model. Factors with individual prognostic value (P <.05) on outcomes in univariate models were assessed for joint prognostic value in a multivariate model. A final model was developed using a backward selection strategy. RESULTS: Patients with baseline HRQoL were included (364 of 405, 90%). The final model predicted longer survival with low/normal AP levels, no VM, high physical functioning, low role functioning, and no anorexia. Positive prognostic factors for time to progressive disease were good performance status, low/normal AP levels, no VM, and minimal fatigue; for time to treatment failure, they were low/normal AP levels, minimal fatigue, and no anorexia. Global QoL was a significant predictor of outcome in univariate analyses but was not retained in the multivariate model. CONCLUSION: HRQoL parameters are independent prognostic factors for outcome in advanced bladder cancer; their prognostic importance needs further evaluation.

Cisplatin, etoposide, and paclitaxel with granulocyte colony-stimulating factor in untreated patients with extensive-stage small cell lung cancer: a phase II trial of the Southwest Oncology Group.

PURPOSE: This study was designed to determine the efficacy and toxicity of cisplatin, etoposide, and paclitaxel (PET) in patients with extensive-stage small cell lung cancer (ES-SCLC). EXPERIMENTAL DESIGN: Chemo-naive adult patients with a performance status (PS) of 0-2 and adequate organ function were eligible. Patients received cisplatin 80 mg/m(2) i.v., etoposide 80 mg/m-2 i.v., and paclitaxel 175 mg/m(2) i.v. over a 3-h period on day 1 followed by etoposide 160 mg/m(2) p.o. on days 2 and 3 every 21 days for six cycles. G-CSF 5 microg/kg was injected s.c. on days 4-14. RESULTS: Eighty-eight patients were assessable. The median age was 60 years; 50% were male, 78% had PS of 0-1, 28% had PS of 2, 53% had multiple sites, and 13% had brain involvement. The overall response rate was 57% with 10 (12%) of 84 patients achieving a complete response. Median progression-free survival was 6 months [95% confidence interval (CI), 5-7 months] with a median survival of 11 months (95% CI, 8-13 months) and a 1-year survival rate of 43% (95% CI, 33-54%). Six patients (7%) died from toxicity. Grade 5 toxicity occurred in 3 (14%) of 22 patients (with a PS of 2) versus 3 (5%) of 61 patients (with a PS of 0-1; P, not significant). Grade 4 neutropenia developed in 40% of patients. Grade 3 nonhematological toxicities were primarily nausea (20%), vomiting (16%), and fatigue (14%). CONCLUSION: The survival result achieved was superior to prior SWOG experiences; however, the toxic death rate was unacceptably high in PS-2 patients. These results provide the largest database for the ongoing randomized Intergroup trial comparing PET to cisplatin+etoposide in PS-0-1 patients with ES-SCLC.

Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.

PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8 and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively), and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

Multilobated large B-cell lymphoma diagnosed cytologically. A case report.

BACKGROUND: Fine needle aspiration (FNA) biopsy can be used to reliably classify most conditions involving lymph nodes or, at least, significantly reduce the differential diagnosis. CASE: A 70-year-old male presented with an ulcerated mass arising from the left tonsillar fossa and involving the anterior and posterior pillars. A biopsy of the tonsillar mass performed at an outside hospital was interpreted as a large cell undifferentiated carcinoma. Subsequently the patient developed systemic lymphadenopathy. A bone scan showed intense uptake within the medial tibial plateau of the left knee. FNA biopsy of the right axillary mass was interpreted at University of Cincinnati Medical College as a large cell lymphoma, multilobated type. Histologic and immunohistochemical studies of the lymph node confirmed the presence of multilobated B-cell lymphoma. Lymphoma chemotherapy was initially successful but was discontinued due to toxicity. The patient died two months after the initial cytologic diagnosis of lymphoma. CONCLUSION: Multilobated lymphomas are an unusual variant of non-Hodgkin's lymphomas (mostly B-cell type). Cytology and immunocytochemistry are useful diagnostic procedures that can help to diagnose this relatively uncommon type of lymphoma and significantly reduce the possibility of misdiagnosis.

Paclitaxel (3-hour infusion) followed by carboplatin (24 hours after paclitaxel): a phase II study in advanced non-small cell lung cancer.

This phase II study was performed to investigate the efficacy of a 3-hour 225 mg/m2 paclitaxel infusion (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) followed 24 hours later by a 30-minute infusion of carboplatin (dosed to an area under the concentration-time curve of 6) in patients with stage IIIA, IIIB, or IV non-small cell lung cancer. Patients received chemotherapy and were monitored for toxicity, response, quality of life, and survival. Paclitaxel and carboplatin pharmacokinetics were also determined with the first cycle of chemotherapy. Eleven men have been treated to date. Eight were white and three black, with a median age of 65 years. All patients had a performance status of 0 or 1. The regimen was well tolerated, with no deaths or grade 4 toxicities noted. The most common grade 3 toxicity was neutropenia, thrombocytopenia, and parasthesias (observed in <10% of cycles). The overall response rate was 57% (14% complete and 43% partial responses). Quality of life improved in most patients. Physical and emotional well-being improved in 57%, functional well-being in 43%, and social/family well-being in 14% of patients. Pharmacokinetic data are being analyzed by limited sampling technique to predict the paclitaxel area under the concentration-time curve. This unique schedule of paclitaxel and carboplatin is well tolerated and active, and is associated with improvements in various aspects of quality of life.

New prognostic factors in nasopharyngeal carcinoma. Tumor angiogenesis and C-erbB2 expression.

BACKGROUND: This study was conducted to determine the prognostic significance of tumor angiogenesis, c-erbB2, epidermal growth factor receptor, Ki-67, and p53 for patients with nasopharyngeal carcinoma. METHODS: In this retrospective study, the authors retrieved clinical data and made immunohistochemical preparations on archival tissue specimens from 30 patients with nasopharyngeal carcinoma treated with radiation therapy at the University of California at San Francisco between 1956 and 1990. The pretreatment clinical and immunohistochemical data were correlated with cervical lymph node metastasis at diagnosis, and endpoints including development of locoregional failure, distant metastasis, disease free survival, and overall survival. RESULTS: Intense tumor angiogenesis, defined as microvessel counts for 60 or more microvessels per 200 x field correlated with the development of distant metastasis (P = 0.03), shorter overall survival (P = 0.02), and disease free survival (P = 0.05). Strong c-erbB2 expression correlated with a shorter overall survival (P = 0.02) and disease free survival (P = 0.02). Stage IV disease (P = 0.04) and the presence of cervical lymph node metastasis (P = 0.05) correlated with a shorter overall survival. A duration of symptoms of fewer than 6 months correlated with a shorter disease free survival (P = 0.05). No association was observed between any of the biologic prognostic factors and lymph node involvement or locoregional failure. CONCLUSIONS: The results of this study show that the tumor angiogenesis and c-erbB2 expression are significant prognostic indicators for patients with nasopharyngeal carcinoma. The presence of cervical lymph node metastasis, Stage IV disease, and a duration of symptoms fewer than 6 months also indicate a poor prognosis. The authors did not find any prognostic significance for epidermal growth factor receptor, Ki-67, or p53. These results suggest that tumor microvessel counts and c-erbB2 may be useful in identifying patients who may benefit from systemic chemotherapy or other novel treatment strategies.

Pure red cell aplasia complicating an ABO-compatible allogeneic bone marrow transplantation, treated successfully with antithymocyte globulin.

A patient underwent an HLA-identical ABO-compatible allogeneic bone marrow transplant for aplastic anemia. She then developed pure red cell aplasia which was treated successfully with antithymocyte globulin and methylprednisolone, after failing to respond to intravenous immune globulin infusion.

Effects of acute administration of nifedipine on glomerular filtration rate and urinary excretion of sodium and uric acid in patients with mild-moderate essential hypertension.

A prospective study was conducted in 25 patients with essential hypertension to study the effects of sublingual administration of nifedipine on some renal functions. Glomerular filtration rate was estimated by radioisotope clearance techniques using Tc-99m diethylene triamine pentaacetic acid (DTPA). The change in urinary excretion of sodium and uric acid were also monitored. A basal estimation of these parameters was followed by repeat studies after lowering the blood pressure to normotensive levels by sublingual administration of nifedipine. It was observed that acute administration of nifedipine does not produce a significant change in the glomerular filtration rate, but causes marked and significant natriuresis and uricosuria.

Effect of prostaglandins A-1, E-2 and F-2 alpha on blood plasma levels of testosterone, LH and FSH in male rats.

Effects of the administration of PGs A-1, E-2 and F-2 alpha (150 micrograms/rat b.i.d. for 10 days) were studied. Significant increase in testicular weight was observed only in PGE-2 treated group. Testicular ascorbic acid content reduced significantly by treatment with all the PGs. PGE-2 treatment caused a significant decrease in the content of testicular cholesterol, while no change was observed in the same and prostatic acid phosphatase activity in any of the PG treated groups. Blood plasma levels of testosterone drastically reduced by both PGE-2 and PGF-2 alpha, while there was no change in the levels of plasma LH in any of the groups. Plasma FSH levels increased significantly in PGA-1 treated rats only. The results suggest that 1) There is a direct action of PG particularly PGE-2 on testicular weight. PGE-2 increases testicular weight possibly by preventing degeneration of spermatids, 2) PGE-2 acting directly on the testis, reduces testicular ascorbic acid content, stimulates the conversion of cholesterol to pregnenolone but depresses the conversion of the latter to testosterone.

Effect of aspirin on spermatogenesis in mature and immature rats.

Aspirin administration for 30 days (5 mg/100 g body weight) caused a significant decrease in the weight of testis of immature rats. Decrease in the activities of sorbitol dehydrogenase and hyaluronidase was observed in both immature and mature rats. Decrease in the number of spermatids and increase in size of spermatocytes nuclei were observed. It is concluded that aspirin causes impairment of the later stages of spermatogenesis.