Borealis-1: a randomized, first-line, placebo-controlled, phase II study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer.

BACKGROUND: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients. PATIENTS AND METHODS: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N = 62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N = 61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS. RESULTS: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms. CONCLUSIONS: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted.

Quality of life in advanced prostate cancer: results of a randomized therapeutic trial.

BACKGROUND: For patients with metastatic prostate cancer, treatment is primarily palliative, relying mainly on the suppression of systemic androgen hormone levels. To help document the achievement of palliation and to characterize positive and negative effects of treatment, we evaluated quality-of-life (QOL) parameters in patients with metastatic prostate cancer who were randomly assigned to two methods of androgen deprivation. METHODS: Patients (n = 739) with stage M1 (bone or soft tissue metastasis) prostate cancer were enrolled in a QOL protocol that was a companion to Southwest Oncology Group INT-0105, a randomized double-blind trial comparing treatment with bilateral orchiectomy (surgical castration) plus either flutamide or placebo. Patients completed a comprehensive battery of QOL questionnaires at random assignment to treatment and at 1, 3, and 6 months later. Data were collected on three treatment-specific symptoms (diarrhea, gas pain, and body image), on physical functioning, and on emotional functioning. All P values are two-sided. RESULTS: Questionnaire return rates for this study never dropped below 80%; only 2% of the patients did not submit baseline QOL assessments. Cross-sectional analyses (corrected for multiple testing) identified statistically significant differences that favored orchiectomy plus placebo for two of the five primary QOL parameters as follows: patients receiving flutamide reported more diarrhea at 3 months (P = .001) and worse emotional functioning at 3 and 6 months (both P<.003). Longitudinal analyses replicated these findings. Other analyzed QOL parameters favored the group receiving placebo but were not statistically significant after adjustment for multiple testing. CONCLUSIONS: We found a consistent pattern of better QOL outcomes at each follow-up assessment during the first 6 months of treatment for orchiectomized patients with metastatic prostate cancer who received placebo versus flutamide. Improvement over time was evident in both treatment groups but more so for patients receiving placebo.

Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk.

We analyzed the polymorphic (CAG)n and (GGN)n regions within the androgen receptor gene from participants in a population-based case-control study of prostate cancer in middle-aged (40-64 years) Caucasian men. The associations between repeat lengths and risk of prostate cancer and the effects of confounding and modifying factors, such as age, family history of prostate cancer, and body mass index, were evaluated. DNA was available for 301 cases and 277 controls. The overall age-adjusted relative odds of prostate cancer associated with the number of (CAG) repeats as a continuous variable was 0.97 [95% confidence interval (CI), 0.92-1.03], suggesting a 3% decrease in risk of prostate cancer for each additional (CAG) repeat. Further analyses identified several subgroups at increased risk. These were men with less than the median number of CAG repeats (< 22) that were younger [< 60 years; relative odds (RO), 1.47; 95% CI, 0.96-2.25], had an affected first-degree relative (RO, 1.59; 95% CI, 0.62-4.14), or were relatively thin (Quetelet index < 24.4; RO, 2.21; 95% CI, 1.07-4.69). Although only the latter result was statistically significant, these results are provocative and support the hypothesis that (CAG)n array length is a predictor of risk for prostate cancer. Similar analyses of (GGN)n showed that with the exception of men with a family history of prostate cancer and those in the highest quartile of body mass index, men with < or = 16 repeats had higher risk estimates than did men with > 16 repeats. Overall, those men who had < or = 16 repeats had a significant elevation in risk (RO, 1.60; 95% CI, 1.07-2.41). When both repeat lengths were considered jointly, the subgroup with two short repeats (CAG, < 22; GGN, < or = 16) had a 2-fold elevation in odds (RO, 2.05; 95% CI, 1.09-3.84) relative to those with two long repeats (CAG, > or = 22; GGN, > 16). These data suggest that determination of both androgen receptor repeats within germ-line DNA may be useful in assessing an individual's risk of developing prostate cancer.

Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: final results of a randomized Southwest Oncology Group study.

Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer, although it has been used most frequently in patients with far-advanced, refractory disease. To evaluate the effects of chemotherapy given earlier in the course of the disease, the Southwest Oncology Group (SWOG) performed a randomized trial between September 1982 and October 1986 comparing endocrine therapy (diethylstilbestrol [DES] or orchiectomy) alone followed by cyclophosphamide-Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) chemotherapy at progression versus initial combined chemo-endocrine therapy. One hundred forty-three patients were registered, and only six were declared ineligible. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63%) compared with endocrine therapy alone (48%). A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm (P = .059). Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy, while two others had stable disease. Despite the difference in initial response rate, time to treatment failure and survival were identical in the two treatment arms. Seventy-seven percent of patients on the initial endocrine therapy alone arm have died (median survival, 25.6 months) compared with 78% on the chemo-endocrine therapy arm (median survival, 22.0 months). No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model. Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy. Eighty-six percent of patients treated by orchiectomy have died compared with only 65% of those treated with DES. These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer.

A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study.

This is a Southwest Oncology Group (SWOG) prospective randomized trial of cisplatin, vinblastine, and bleomycin (PVB) versus vinblastine, cisplatin, and etoposide (VP-16) (VPV) in the treatment of advanced germ cell tumors of the testis. The study objective was to determine what effect the replacement of bleomycin with VP-16 has on complete response (CR), survival, and drug toxicity. One hundred sixty-nine patients were registered and randomized. Of these patients, 160 were assessable for response. All had histologically confirmed disseminated germ cell neoplasms of testicular origin. Forty-six had minimal metastatic disease, and 114 had maximal disease. Seventy-seven were randomized to PVB and 83 to VPV chemotherapy. There was no significant difference in pretreatment characteristics between the two arms with regard to tumor burden, histologic type, and overall performance status. Patients received four courses of induction chemotherapy, either PVB (cisplatin 120 mg/m2 day 3, vinblastine 12 mg/m2 day 1, bleomycin 15 U/m2 twice per week) or VPV (vinblastine 8 mg/m2 day 1, cisplatin 120 mg/m2 day 3, VP-16 50 mg/m2 days 2 to 5). Chemotherapy was given every 3 weeks. Cytoreductive surgery was done postinduction if a chemotherapy CR was not achieved. There was no difference in the percentage of patients achieving a disease-free status between PVB (77%) and VPV (73%). The mean leukocyte nadir was similar for both treatments, but the mean platelet nadir was significantly lower (P = .003) in the VPV arm. All bleomycin-related toxicities (pulmonary, mucositis, skin) were avoided in the VPV arm. We conclude that bleomycin can be replaced in first-line therapy for advanced germ cell tumors without sacrificing efficacy and with the advantage of avoiding unnecessary drug toxicity.

Malfunction of continuous subcutaneous insulin infusion systems: a one-year prospective study of 127 patients.

Malfunction of portable continuous subcutaneous insulin infusion (CSII) systems may result in either ketoacidosis or serious hypoglycemia. To determine the types and frequencies of infusion system failure and the resulting clinical consequences, we recorded their occurrences in a 1-yr prospective study of 127 patients who were using insulin infusion pumps in a clinical practice setting. Of the 127 patients, 109 (86%) experienced at least one infusion system failure during the study. Most of the infusion system failures (96%) occurred in the syringe, infusion tube and connections, or subcutaneous infusion site. Virtually all malfunctions resulted in interruption of insulin flow, and most were associated with temporary loss of diabetes control. Equipment malfunction was documented in 6 of 7 patients who used insulin pumps and were treated in our hospital for diabetic ketoacidosis during the study. Pump "runaway" was not observed. We conclude that infusion system malfunction resulting in interruption of insulin flow is a common occurrence, is often associated with temporary hyperglycemia, and may account for some of the increased incidence of diabetic ketoacidosis previously described in these patients.

Phase II study of platinum and mitoxantrone in metastatic prostate cancer: a Southwest Oncology Group Study.

44 eligible patients with measurable or evaluable metastatic prostate cancer were treated with monthly cycles of cisplatin and mitoxantrone. Good-risk patients received cisplatin 60 mg/m2 intravenously and mitoxantrone 10 mg/m2 intravenously every 4 weeks. The dose in poor-risk patients (elderly or white blood cell count less than 4000/microliters, 4 x 10(9)/l, or extensive prior radiation) was reduced to 8 mg/m2. Toxicity was manageable and consisted primarily of myelosuppression. There were no complete responses and the partial response rate was only 12%. Median progression-free survival was 2.7 months for measurable and 4.1 months for evaluable disease patients. Median survivals were 4.9 and 8.7 months, respectively. This combination has minimal activity in hormone refractory metastatic prostate cancer.

Southwest Oncology Group studies in hormone-refractory prostate cancer.

Virtually all patients with hormone-refractory prostate cancer will eventually succumb to their diseases with no demonstrable increase in survival with any second-line therapy, thus making the conventional approach to the treatment of this disease palliative. The Southwest Oncology Group (SWOG) Genitourinary Committee strategy in investigating therapy for hormone-refractory prostate cancer is focused on the application of biologically guided treatments targeting primary patients with limited prior hormonal therapy, taking into account evolving concepts regarding the definitions of "hormone-refractory" disease and response criteria. This report reviews data from selected SWOG studies conducted in the past 10 years, and outlines the rationale and design of current and future studies conducted by the Genitourinary Committee of the SWOG in hormone-refractory prostate cancer.

Time course of regression of left ventricular hypertrophy in treated hypertensive patients.

In a prospective study, 32 hypertensive patients with echocardiographic evidence of left ventricular hypertrophy were treated with methyldopa, hydrochlorothiazide, or methyldopa and hydrochlorothiazide combined. Echocardiograms and electrocardiograms were obtained in each of the 32 patients before treatment, at the point of initial blood pressure control, and then one, three, and six months thereafter; in 27 patients these studies were also obtained after 12 and 18 months. Left ventricular end-diastolic posterior wall thickness decreased in seven patients whose blood pressure was controlled with methyldopa alone (p less than 0.01) and in 17 patients whose blood pressure was controlled with methyldopa and hydrochlorothiazide combined (p less than 0.01); in both groups, the reduction in left ventricular posterior wall thickness at end-diastole was apparent one month after blood pressure control was established (p less than 0.05). In contrast, no significant reduction in left ventricular posterior wall thickness at end-diastole was observed in eight patients who had equivalent control of blood pressure with hydrochlorothiazide alone (p = 0.34). During the 18-month follow-up period, ventricular septal thickness at end-diastole decreased in the group treated with methyldopa and hydrochlorothiazide combined (p = 0.03); whereas, ventricular septal thickness at end-diastole appeared to increase in the group treated with hydrochlorothiazide alone (p less than 0.01). These results suggest that evidence of regression of left ventricular hypertrophy may be detected as early as one month after blood pressure is controlled with methyldopa or methyldopa and hydrochlorothiazide combined; whereas, long-term control of hypertension with hydrochlorothiazide alone was not associated with evidence of regression of left ventricular hypertrophy. Although the patient number are small, these data suggest that there are differences in the long-term effects of diuretics and sympatholytic drugs on left ventricular anatomy, which may, in part, relate to divergent effects on the sympathetic nervous system.

Intraventricular hemorrhage: a prospective evaluation of etiopathogenesis.

In a study population of 151 newborn infants less than 35 weeks gestation, who required intensive care for more than 24 hours, clinical and biochemical factors associated with the presence of intraventricular hemorrhage (IVH) were prospectively evaluated. The diagnosis of IVH was confirmed by computed tomography, ventricular tap, or autopsy. Alveolar rupture was highly correlated with the presence of IVH. Other factors associated with IVH were: hypoxemia, hypercarbia, mechanical ventilation, peak inflation presser > 25 cm H2O, inspiratory to expiratory ratio > 1:1, patent ductus arteriosus, bicarbonate administration after the first day of life, volume expansion in the first day of life, hypotension, stages III and IV hyaline membrane disease, and intrauterine growth retardation. Early bicarbonate administration (first day), sodium administration > 8 mEq/kg/day, acidosis and birth weight less than or equal to 1,200 gm were associated with IVH only in the infants who died with IVH. Factors not associated with IVH were Apgar less than or equal to 5 at one and five minutes, birth weight, gestational age, male sex, osmolality greater than or equal to 300, serum sodium greater than or equal to 150, hypothermia, continuous distending pressure > 6 cm H2O, positive end-expiratory pressure > 5 cm H2O, outborn birth, obstetric trauma, or coagulopathy. Certain therapeutic interventions may lead to an increase incidence of intracerebral hemorrhage in the high-risk preterm infant.

Comparison of the Bard BTA test with voided urine and bladder wash cytology in the diagnosis and management of cancer of the bladder.

OBJECTIVES: To compare the Bard BTA test, a simple latex-agglutination test for cancer of the bladder (BC) that can be performed in less than 3 minutes in the urologist's office, with voided urine or bladder wash cytology in the diagnosis of subjects suspected of having BC on the basis of symptoms or recent abnormal cystoscopy or intravenous urography. METHODS: The study was performed at three medical centers in 414 subjects (147 female and 267 male; mean age 60 years), 345 of whom (83%) had no prior history of BC. The cytologic examinations were performed by pathologists unaware of the results of the BTA test. RESULTS: Cystoscopy or cystoscopy and biopsy revealed BC in 71 subjects (17%). The overall sensitivities of the BTA test and cytology were 70% and 25%, respectively. The specificities of the BTA test and cytology in the 337 subjects without BC were 90% and 100%, respectively. The sensitivities of the BTA test by tumor grade were 17%, 64%, and 92% for grades 1, 2, and 3, respectively; those of cytology were 17%, 14%, and 44%. Regression analysis suggests that tumor grade but no other study variable explains the sensitivity of the BTA test. CONCLUSIONS: The BTA test is considerably more sensitive than cytology in the detection of BC. For urologists who use cytology in the diagnosis and follow-up of patients with BC, the BTA test may replace cytology.

Clinical evaluation of the BTA TRAK assay and comparison to voided urine cytology and the Bard BTA test in patients with recurrent bladder tumors. The Multi Center Study Group.

OBJECTIVES: To assess the clinical performance of the BTA TRAK assay and to compare it with that of voided urine cytology (VUC) and the Bard BTA test (BTA) in the detection of recurrent bladder cancer (BC). METHODS: The study was performed on randomly selected archival voided urine samples for many of which VUC and/or BTA information was available. Sensitivity was determined in samples from patients with histologically confirmed recurrent BC. Specificity was determined in samples from healthy volunteers, patients with three categories of current medical conditions, and patients with a history of BC but no current evidence of disease. RESULTS: The TRAK assay was positive in 156 of 216 samples for patients diagnosed with BC, for an overall sensitivity of 72%. Mean values increased with progressing grade and stage of disease. In the comparison between TRAK and VUC, the overall sensitivities were 68% and 25%, respectively (P < 0.001). For Stages Ta and T1 and for all tumor grades, the sensitivity of the TRAK assay was significantly greater than that of VUC (P < 0.001). TRAK sensitivity was also significantly better than that of BTA (73% versus 58%, P = 0.005). The specificity of the TRAK assay ranged from 75% in samples from patients with genitourinary disease to 97% in healthy volunteers. CONCLUSIONS: The TRAK assay is superior to VUC and the original BTA test in the detection of BC. The results of the study indicate that the TRAK assay may be a useful adjunct to cystoscopy in the management of patients with recurrent BC.

Phase II studies on prostate cancer.

OBJECTIVES: To evaluate different study designs and the general utility of phase II trials on prostate cancer. METHODS: Extensive literature studies and correspondance within the working group during 1 year were summarized in a preliminary manuscript. The manuscript was finalized at a 1 day meeting and is presented here as a consensus document. RESULTS: The main objectives of phase II studies are to assess whether a treatment is sufficiently active to justify comparative phase III studies, and to obtain further information on adverse reactions. Bidimensionally measurable lesions are traditionally studied, allowing objective criteria for response and progression to be applied. However, as skeletal metastases do not fulfill the criteria for such lesions, the majority of patients with metastatic prostate cancer are not eligible for traditionally-designed phase II trials. Therefore, ancillary response parameters, especially serum prostate-specific antigen (PSA), have been proposed for use. For the evaluation of adverse reactions, the criteria of the World Health Organization were proposed for use. A review of various statistical designs was presented, with a focus on their advantages and disadvantages in phase II trials. CONCLUSIONS: The role of PSA in phase II trials has not yet been firmly established. Further study of its correlation with other endpoints is needed. In future phase II trials, a shift to softer endpoints than traditionally used may enhance the process of evaluation of new antitumor drugs. Phase II studies may even be replaced by early phase III studies, especially in situations where new drugs do not have very heavy adverse effects.

Serum percent free prostate-specific antigen in metastatic prostate cancer.

OBJECTIVES: To define the serum prostate-specific antigen (PSA) isoform profile in patients who have prostate cancer but do not have a prostate gland, that is, men who have had a previous radical prostatectomy (RP) and subsequently persistent disease as evidenced by elevated PSA. PSA can be reliably measured in the serum in two major isoforms: PSA complexed to alpha1-antichymotrypsin and uncomplexed free PSA (fPSA). Multiple investigations have illustrated the usefulness of the free/total PSA proportion (percent fPSA) in differentiating prostate cancer from benign prostate disease in patients who still have their prostate gland in situ. METHODS: Sera were evaluated from 52 men who underwent RP and postoperatively had increased PSA. fPSA and total PSA (tPSA) concentrations were determined using the Abbott AxSYM PSA assays. Percent fPSA was calculated for all patients. RESULTS: Median tPSA was 5.45 ng/mL (range 0.93 to 214.99). Median fPSA was 0.69 ng/mL (range 0.11 to 54.93); the median percent fPSA was 13.3% (range 3.9% to 62.9%). There were 27 (52%) patients with percent fPSA less than 15%, 25 (48%) patients with greater than 15%, and 7 (13%) with greater than 30%. No significant relationship was found between percent fPSA and grade, stage, and severity of disease. Percent fPSA was significantly increased in patients who received hormonal, radiation, or combination treatment versus those who received no treatment (P = 0.02 to 0.0007). CONCLUSIONS: Serum percent fPSA in men after RP with persistent prostate cancer encompasses a wide range of values with no clear stratifying factor or factors. These observations and further serial studies in patients with progressive metastatic disease may be important in determining the mechanism(s) for lower percent fPSA in men with newly diagnosed prostate cancer.

Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies.

OBJECTIVES: Clinical staging of prostate cancer is inaccurate, often with significant upstaging on final pathologic review. We previously demonstrated the ability to predict extraprostatic extension of cancer by use of the Gleason score and serum prostate-specific antigen (PSA) measurements. Herein we present an interim analysis of data from an ongoing multi-institutional study to determine the predictive power of an enhancement of microvessel density analysis in combination with Gleason score and serum PSA to predict extraprostatic extension. METHODS: We evaluated a total of 186 randomly selected biopsy samples and matched totally embedded radical prostatectomy samples with preoperative PSA concentrations and patient demographics. Gleason score and optimized microvessel density (OMVD) were determined from the needle biopsy samples; pathologic stage was verified by independent review of the radical prostatectomy samples. An automated digital image analysis system measured microvessel morphology and calculated the OMVD in the biopsy samples (Biostage; Bard Diagnostic Sciences, Seattle, Wash). RESULTS: Prediction of extraprostatic extension was increased significantly when OMVD analysis was added to Gleason score and serum PSA concentration (P = 0.003). CONCLUSIONS: Optimized microvessel density analysis significantly increases the ability to predict extraprostatic extension of cancer preoperatively when combined with Gleason score and serum PSA concentration. This method appears to be a useful tool that can assist with treatment decisions in selected patients.

Improved detection of recurrent bladder cancer using the Bard BTA stat Test.

OBJECTIVES: To evaluate the BTA stat Test in the detection of recurrent bladder cancer. METHODS: Sensitivity and specificity were determined using frozen voided urine samples from patients with recurrent bladder cancer, volunteers, patients with nonurologic conditions, and patients with a history of bladder cancer but free of disease. Results of cytology and the original BTA Test were compared with the sensitivity of the BTA stat Test in a large subgroup of the patients with cancer. RESULTS: The BTA stat Test detected 147 (67%) of 220 recurrent cancers. For those urine samples with previous cytologic and BTA Test results available, cytology had a sensitivity of 23%, the BTA Test 44%, and the BTA stat Test 58% for detection of recurrent cancer (P < 0.001, stat versus cytology). The specificity of the BTA stat Test was 72% for benign genitourinary disease and 95% in healthy volunteers. CONCLUSIONS: The BTA stat Test has high sensitivity and is significantly superior to voided urine cytologic analysis in the detection of recurrent bladder cancer.

Presence of the "Beaumont" protein in serum of oral contraceptive users.

The level of the "Beaumont" protein present in serum was measured by a population of 223 black and 76 Caucasian women with different exposures to oral contraceptives (OCs). No differences were found in the values in nonusers, past users, current users, or new users of OCs. The values were higher in black nonusers and users than in comparable Caucasian groups, suggesting a racial difference. A group of 55 thrombotic women were subclassified by type of thrombosis and exposure to OC therapy. No significant difference was seen between the values in thrombotic women exposed or not exposed to OCs. A similar result was obtained when the types of thrombosis (arterial or venous) were compared. These results do not confirm Beaumont's hypothesis that antibodies are induced by contraceptive steroids in a subgroup of women on OC therapy.

Overview analysis issues using combined androgen deprivation overview analysis as an example.

The validity of an overview analysis depends on addressing specific concerns, including identification of the trials, collection of the data, trial design heterogeneity, data incompatibilities, treatment arm comparability, trial maturity heterogeneity, data quality, funding, and administrative problems. This article reviews various issues in metaanalysis and overview analysis methodologies and then discusses these issues in the context of the combined androgen deprivation (CAD) overview analysis effort. Following small clinical series reports of promising efficacy for CAD, over 20 randomized clinical trials designed to confirm this result were initiated. Subsequently, an overview analysis was planned, resulting in an international effort to collect data from these confirmatory trials. The overview analysis was motivated in part by a realization that the size of the CAD benefit was smaller than originally thought and that the confirmatory trials were underpowered relative to revised estimates of benefit.

Phase II evaluation of doxorubicin/vinblastine combined with inhibitors trifluoperazine/verapamil of P-glycoprotein in patients with advanced renal carcinoma.

Doxorubicin/vinblastine combined with the P-glycoprotein inhibitors trifluoperazine and verapamil was evaluated in the treatment of patients with metastatic renal carcinoma. Patients were treated with starting doses of doxorubicin/vinblastine of 30 mg/m(2) (doxorubicin) and 3 mg/m(2) (vinblastine) intravenously every 2 weeks, combined with 4 days of oral trifluoperazine/verapamil at 2 mg tid (trifluoperazine) and 160 mg tid (verapamil) administered I day before the chemotherapy was initiated. Response was assessed every three cycles of treatment. Of 26 evaluable patients, there were no responders. Six patients had stable disease for greater than 6 months on treatment. Therapy was generally well tolerated but 7 of 26 patients developed grade 4 granulocytopenia, including one patient who died due to sepsis. The possible reasons for the failure of P-glycoprotein inhibitors to enhance the effect of chemotherapy are discussed.

Randomized intergroup comparison of bacillus calmette-guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a southwest oncology group study.

To compare the toxicity and efficacy of intravesical bacillus Calmette-Guérin (BCG) immunotherapy and mitomycin C (MMC) chemotherapy in the prophylaxis of recurrent transitional cell carcinoma, 469 patients with completely resected stage Ta or TI transitional cell carcinoma were enrolled in a randomized Southwest Oncology Group Phase III study. All patients were judged to be at increased risk for tumor recurrence due to having had two occurrences of tumor within 56 weeks, stage T I tumor or three or more tumors within 16 weeks, or concurrent carcinoma in situ. Three hundred and seventy-seven evaluable patients received either 50 mg of Tice BCG in 50 cc saline or 20 mg MMC in 20 cc water weekly for 6 weeks and then monthly to one year. Local and systemic grade I and 2 toxicity was seen significantly more frequently following BCG treatment (P = 0.003), but no life threatening toxicity was seen with either treatment. Recurrence-free survival was significantly prolonged (P = 0.017, proportional hazard regression) in patients randomized to the BCG arm compared to the MMC arm, but there were no statistically significant differences at this analysis for worsening-free survival and overall survival, although the number of these events is too low for a definitive analysis of these long-term outcomes. Therefore, when compared to MMC chemotherapy, BCG immunotherapy is associated with a significantly higher frequency of grade 1 and 2 adverse reactions and a significantly lower first recurrence hazard rate.