Search

IMPORTANCE: Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer. OBJECTIVE: To determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine. DESIGN, SETTING, AND PARTICIPANTS: In a phase 2 randomized clinical trial, 87 patients across 23 centers in the National Cancer Institute Experimental Therapeutics Clinical Trials Network were randomized to receive either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). Key eligibility criteria included confirmed metastatic urothelial cancer, no prior cytotoxic therapy for metastatic disease, 12 months or more since perioperative therapy, and eligibility for cisplatin receipt based on standard criteria. The study was conducted from January 27, 2017, to December 15, 2020. INTERVENTIONS: In the control arm, cisplatin, 70 mg/m2, was given on day 1 and gemcitabine, 1000 mg/m2, was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m2, was given on day 1; gemcitabine, 875 mg/m2, on days 1 and 8; and berzosertib, 90 mg/m2, on days 2 and 9 of a 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point of the study was progression-free survival. The analysis was on all patients who started therapy. RESULTS: Of the total of 87 patients randomized, 41 patients received cisplatin with gemcitabine alone and 46 received cisplatin with gemcitabine plus berzosertib. Median age was 67 (range, 32-84) years, and 68 patients (78%) were men. Median progression-free survival was 8.0 months for both arms (Bajorin risk-adjusted hazard ratio, 1.22; 95% CI, 0.72-2.08). Median overall survival was shorter with cisplatin with gemcitabine plus berzosertib compared with cisplatin with gemcitabine alone (14.4 vs 19.8 months; Bajorin risk-adjusted hazard ratio, 1.42; 95% CI, 0.76-2.68). Higher rates of grade 3 vs grade 4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with cisplatin with gemcitabine and berzosertib compared with cisplatin with gemcitabine alone; consequently, more dose reductions were needed in the experimental arm. Patients in the experimental arm received a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in the control arm (P < .001). CONCLUSIONS AND RELEVANCE: The addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02567409

In this retrospective analysis, complete remission (CR) of disease occurred in 1.8% of patients receiving salvage systemic therapy for advanced urothelial carcinoma. CR was strongly associated with longer survival, prior cisplatin therapy, and time from prior chemotherapy of ≥ 3 months. Agents inducing CR as salvage therapy should undergo further development, and tumors of patients showing CR should be selected for molecular profiling.

Dipeptidyl peptidase IV (DPP4) is a cell surface receptor that possesses numerous substrates implicated in tumor growth and metastasis. Prior studies have suggested an association between DPP4 inhibition and increased progression-free survival (PFS) and overall survival (OS) in colorectal and lung cancers but no benefit in breast or pancreatic cancers. However, no studies to date have explored the impact of DPP4 inhibitors (DPP4i) in patients with metastatic renal cell carcinoma (mRCC). In this study we present a first-time analysis examining the impact of DPP4i use on PFS and OS in patients with mRCC and type 2 diabetes mellitus.

Neoadjuvant treatment with nivolumab as monotherapy or in combination with lirilumab for cisplatin-ineligible patients with muscle-invasive bladder cancer was safe and well tolerated. Landmark 2-yr recurrence-free and overall survival rates were consistent with the previously reported data in this treatment setting.

Sunitinib is an inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors, and it has antitumor activity in metastatic renal cell carcinoma and gastrointestinal stromal tumors. To further investigate the fatigue associated with sunitinib therapy, thyroid function tests were performed on patients with metastatic renal cell carcinoma who were receiving sunitinib. Seventy-three patients with metastatic renal cell carcinoma were treated with sunitinib at the Cleveland Clinic Taussig Cancer Center, and 66 of them had thyroid function test results available. Fifty-six (85%) of the 66 patients had one or more abnormality in their thyroid function test results, consistent with hypothyroidism, and 47 (84%) of the 56 patients with abnormal thyroid function tests had signs and/or symptoms possibly related to hypothyroidism. Thyroid hormone replacement was undertaken in 17 patients, and symptoms improved in nine of them. Thyroid function test abnormalities appear to be common in patients with metastatic renal cell carcinoma treated with sunitinib, and routine monitoring is warranted.

ECOG3805 is a randomized trial of testosterone suppression with or without docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC). Deeper prostate-specific antigen (PSA) suppression is prognostic for outcome. However, the concordance of PSA rise and radiographic progression has not been examined previously in mHSPC, whereas this has been reported in metastatic castration-resistant prostate cancer.

The mammalian target of rapamycin (mTOR) pathway is up-regulated in prostate cancer (PCa). We evaluated the tumor tissue expression of downstream mTOR targets in patients with intermediate- and high-risk (IR/HR) PCa and their ability to predict outcome after radical prostatectomy (RP).

Dr. Verdoorn and colleagues have provided a concise summary of the efforts thus far to investigate several classes of targeted agents in patients with advanced urothelial cancers. The urothelial cancer [...]

After several decades with only modest changes in the therapeutic paradigm, rapid progress in understanding the biology of advanced prostate cancer has been translated into more accurate terminology, such as [...]

The availability of several novel antibodies, coupled with viral, DNA, and dendritic-cell vaccines, has renewed interest in immunotherapeutic approaches to the treatment of advanced prostate cancer. Although promising, none of these approaches have led to major clinical activity, and in the case of cell-based immunotherapy with GVAX, new concerns about safety arose when this therapy was used in the castration-resistant setting. A more attractive yet toxic approach has also utilized a check-point blockade with CTLA-4 antibodies. Although initial clinical efficacy has been observed, toxicity appears to be the major limitation of its use in prostate cancer. Sipuleucel-T (Provenge) is an autologous active cellular immunotherapy product that includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphataase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite the lack of objective anti-tumor activity seen with sipuleucel-T, a recently reported phase III trial demonstrated a significant improvement in the overall survival of men with asymptomatic, minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). This agent is the first FDA-approved novel immunotherapeutic compound for the treatment of a solid malignancy. A better understanding of how clinicians should incorporate this novel agent into the current management of CRPC is needed., Introduction Prostate cancer is the second-leading cause of death in men in the United States; more than 217,730 new cases were expected to be diagnosed in 2010. [1] Although the [...]

IMPORTANCE: Preferential delivery of docetaxel to tumors by prostate-specific membrane antigen (PSMA)–targeted nanoparticles is clinically effective, and the selective reduction of PSMA-positive circulating tumor cells (CTCs) after treatment has implications for patient selection and disease monitoring. OBJECTIVE: To determine the safety and efficacy of BIND-014, a PSMA-directed docetaxel-containing nanoparticle, in patients with metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS: A multicenter open-label, phase 2 clinical trial of 42 chemotherapy-naive patients with progressing mCRPC after treatment with abiraterone acetate and/or enzalutamide was conducted from June 24, 2013, to June 10, 2016. INTERVENTION: Treatment with BIND-014 at a dosage of 60 mg/m2 was given intravenously on day 1 of 21-day cycles in combination with prednisone until disease progression or unacceptable toxic effects occurred. MAIN OUTCOMES AND MEASURES: The primary end point was radiographic progression-free survival according to Prostate Cancer Working Group 2 recommendations and Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included prostate-specific antigen (PSA) response (≥50% reduction from baseline) and changes in CTC number (from ≥5 to <5 cells per 7.5 mL of blood) (CellSearch). Changes in CTC number based on PSMA expression levels on CTCs were also evaluated (Epic Sciences). RESULTS: Among the 42 patients (81% white), the median age was 66 (range, 50-85) years, and median number of doses received was 6 (range, 1-21). A PSA response was observed in 12 of 40 patients (30%; 95% CI, 18%-45%), measurable disease response in 6 of 19 (32% [95% CI, 15%-54%]), and CTC conversions in 13 of 26 (50%; 95% CI, 32%-68%). Median radiographic progression-free survival was 9.9 (95% CI, 7.1-12.6) months. With use of the Epic Sciences non-EPCAM-based CTC detection platform, CTCs were detected in 16 of 18 patients (89%); 11 of 18 (61%) had CTCs with PSMA expression above the analytical threshold level (PSMA positive) at baseline (range, 0.4-72.4 CTCs/mL). After treatment, PSMA-positive CTCs were preferentially reduced. Treatment-related adverse events included grade 1 or 2 fatigue (29 of 42 patients [69%]), nausea (23 [55%]), neuropathy (14 [33%]), and neutropenic fever (1 [2%]). CONCLUSIONS AND RELEVANCE: These findings suggest that treatment with BIND-014 is active and well tolerated in patients with chemotherapy-naive mCRPC. Antitumor activity may be related to PSMA expression levels on CTCs, which suggests that patients who are likely to benefit from this treatment can be identified before treatment is initiated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01812746

Renal cell carcinoma (RCC), a malignancy whose incidence is increasing, is frequently encountered in general nephrology practice when acute and chronic kidney disease occurs in the course of disease. Importantly, when kidney disease develops in the setting of RCC, mortality is significantly increased with patients often dying of a non-cancer-related complication of kidney disease. As such, practicing nephrologists need to have a working knowledge of this cancer’s biology, treatment, and complications. Nephrologists should be involved in all aspects of the care of patients with RCC including in the acute setting prior to nephrectomy and in the chronic setting for patients with post-nephrectomy chronic kidney disease and those receiving potentially nephrotoxic anti-cancer agents. This collaborative approach to RCC care will hopefully improve patient outcomes.

Treatment of metastatic renal-cell carcinoma (mRCC) may be associated with significant toxicities necessitating drug holidays. Outcomes of 112 patients who underwent drug holidays were analyzed. Complete response before the initial drug holiday was associated with a longer surveillance period (P = .0004), with median survival of 71.7 months. Select mRCC patients may be eligible for extended drug holidays.

First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.

Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population.

Only one treatment, the chemotherapy drug docetaxel (Taxotere), has been shown to increase survival in men with metastatic, castrate-resistant prostate cancer, meaning it has spread throughout the body and no [...]

Neoadjuvant sunitinib might downsize unresectable renal cell carcinoma (RCC) and enable nephrectomy in a subset of patients. After neoadjuvant sunitinib in 27 RCC patients, tumors were resected in 13 patients. Higher attenuation using computed tomography (CT) scans and favorable response according to Morphology, Attenuation, Size, and Structure (MASS) criteria after 2 cycles of sunitinib were independent predictors of subsequent tumor resection.

Human epidermal growth factor receptor-2 (HER2) is a well-recognized growth-promoting factor in cancer, although its application to urothelial carcinoma has been limited because of a low frequency of gene amplification. We evaluated HER2protein expression and gene amplification in micropapillary carcinoma, a rare but highly aggressive variant of urothelial carcinoma by dual-color in situhybridization. Gene amplification was defined by a HER2:CHR17 ratio of ≥2.2; low and high levels of amplification were further defined as <2.5 and ≥2.5, respectively. Immunohistochemistry was used to determine HER2 protein expression using the American Society of Clinical Oncology/College of American Pathologists Guidelines of HER2 staining. Protein expression, gene amplification, and chromosome 17 aneusomy were compared by Jonchkeere–Terpstra and Cochran–Armitage trend tests. In all, 19 of the 20 micropapillary carcinoma samples yielded usable dual-color in situhybridization and immunohistochemistry results for evaluation. Overall, 68% (n=13) demonstrated HER2 protein expression of 2+ to 3+ staining. Gene amplification was present in 42% of samples (n=8), with 100% correlation with 2+ and 3+ protein expression. Gene amplification and protein expression were significantly associated (P=0.01). Overall, 53% of samples (n=10) had aneusomy of chromosome 17. Chromosome 17 aneusomy was present in approximately half of the samples evaluated, suggesting inherent genomic instability in this variant of urothelial carcinoma. However, increased HER2:CHR17 ratios demonstrate increased HER2 expression due to amplification in the majority of micropapillary carcinomas. These results suggest that HER2-targeted therapy may be successful on the genomic level in patients with this disease.

Human epidermal growth factor receptor-2 (HER2) is a well-recognized growth-promoting factor in cancer, although its application to urothelial carcinoma has been limited because of a low frequency of gene amplification. We evaluated HER2 protein expression and gene amplification in micropapillary carcinoma, a rare but highly aggressive variant of urothelial carcinoma by dual-color in situ hybridization. Gene amplification was defined by a HER2:CHR17 ratio of ≥2.2; low and high levels of amplification were further defined as <2.5 and ≥2.5, respectively. Immunohistochemistry was used to determine HER2 protein expression using the American Society of Clinical Oncology/College of American Pathologists Guidelines of HER2 staining. Protein expression, gene amplification, and chromosome 17 aneusomy were compared by Jonchkeere–Terpstra and Cochran–Armitage trend tests. In all, 19 of the 20 micropapillary carcinoma samples yielded usable dual-color in situ hybridization and immunohistochemistry results for evaluation. Overall, 68% (n=13) demonstrated HER2 protein expression of 2+ to 3+ staining. Gene amplification was present in 42% of samples (n=8), with 100% correlation with 2+ and 3+ protein expression. Gene amplification and protein expression were significantly associated (P=0.01). Overall, 53% of samples (n=10) had aneusomy of chromosome 17. Chromosome 17 aneusomy was present in approximately half of the samples evaluated, suggesting inherent genomic instability in this variant of urothelial carcinoma. However, increased HER2:CHR17 ratios demonstrate increased HER2 expression due to amplification in the majority of micropapillary carcinomas. These results suggest that HER2-targeted therapy may be successful on the genomic level in patients with this disease.

Importance of the field:Patients with prostate cancer who have progression of their disease while on androgen deprivation therapy have limited therapeutic options. Docetaxel is currently the only agent that increases overall survival in patients with metastatic, castration-resistant prostate cancer; additional agents are needed.Areas covered in this review:This review will describe the importance of endothelin-1 (ET-1) for growth of prostate cancer cells, development of bone metastases, and pain responses; the preclinical data for zibotentan, a specific inhibitor of the ETAreceptor; and the clinical development of atrasentan, a first-generation ET receptor inhibitor, and zibotentan, a more selective inhibitor of the ETAreceptor.What the reader will gain:Readers will understand the importance of ET-1 as a novel pathway to target for patients with castration-resistant prostate cancer due to its association with prostate cancer growth, metastases to bone, and pain. Readers will learn about the preclinical and clinical development of zibotentan, including the promising Phase II results that have resulted in an extensive Phase III clinical trials program.Take home message:Modulating the activity of ET-1 through the ETAreceptor is a novel target for treating patients with metastatic, castration-resistant prostate cancer. There are currently three ongoing Phase III trials with zibotentan, a selective ETAinhibitor, to determine the effect of this agent on overall survival in these patients.

Renal cell carcinoma (RCC) is recognized as a neoplasm resistant to chemotherapy. In vitro experiments demonstrated that suramin, at noncytotoxic doses, enhanced the activity of chemotherapy including 5-fluorouracil (5-FU) in xenograft models.

Systemic chemotherapy is the primary treatment modality for patients with advanced urothelial cancer. However, despite a high Initials response rate, durable responses are rare. Angiogenesis has been shown to be important in the development and progression of urothelial cancer. Sunitinib, an oral, multi-targeted, small-molecule inhibitor of multiple tyrosine kinases, is known to inhibit angiogenesis and therefore might decrease progression of urothelial cancer. This phase II trial was designed to investigate the role of sunitinib as maintenance therapy in patients with advanced urothelial cancer. The specific hypothesis of this trial is that sunitinib will decrease progression rates in patients with advanced urothelial cancer who have obtained stable disease or better after standard chemotherapy.

Metastatic renal cell carcinoma has long been recognized as an aggressive, therapy-refractory epithelial cancer. Two decades of clinical experience with the biologic response modifiers, such as interferon and interleukin-2, have produced little in the way of clinically meaningful benefit for patients, with the notable exception of a very small number of patients treated with high-dose interleukin-2. The paradigm shifting development in the understanding of the molecular biology of clear-cell renal cancer and the rapid introduction of kinase inhibitors into our therapeutic armamentarium has provided clinicians and their patients real hope. Two important phase III trials are reviewed and placed into historical context with previous trials of biologic response modifiers.

Non–transitional cell neoplasms of the bladder and upper tract transitional cell carcinomas (ureter and renal pelvis) represent only a small fraction of urothelial carcinomas. Clinicians faced with the rare case are always confronted with management dilemmas complicated by the scarcity of published experience to guide decisions. The current review brings together the best of the limited published data in an attempt to provide some reasonable context to help in the management of these difficult neoplasms.

Summary: Background: The treatment of advanced renal cell cancer remains unsatisfactory, therefore new combination regimens such as thalidomide and IL-2 are of interest. A phase I trial of SC IL-2 and oral thalidomide was performed to identify the toxicity, maximum tolerated dose (MTD) and preliminary clinical activity of this regimen. Methods: 33 patients with advanced/metastatic RCC were enrolled. An established 8-week outpatient schedule of subcutaneously administered IL-2 in escalating doses, days 1–5, for 6 weeks with a 2 week rest was utilized with daily oral thalidomide. Cohorts of 4–6 patients were treated at 4 dose levels. Results: Toxicity was moderate to severe and related to dose level. All patients developed fever, chills and fatigue. 29/33 patients developed ≤Grade 2 desquamation of hands and feet and/or rash. Dose limiting toxicity (DLT) included Grade 3 neutropenia and pulmonary embolus. The maximum tolerated dose (MTD) of IL-2 and thalidomide was 9.0 MIU/m2 SC days 1–5, weeks 1 to 6 and 100 mg po daily, respectively. A median of 2 cycles of therapy was administered (range 1–9). 2/33 patients responded (1 CR—prior IL-2 therapy, 1 PR—no prior therapy) with an overall response of 6% (95% CI, 1–20%). One minimal response was converted to a surgical CR (remains disease free at 24 + months). Conclusion: Outpatient administration of IL-2 and thalidomide is possible with acceptable toxicity. Further evaluation of this regimen is underway.

Radical cystectomy remains the gold standard treatment for muscle-invasive bladder cancer. Although surgery achieves excellent local control, within 5 years almost 50% of patients relapse and subsequently progress to develop systemic disease. Transitional cell carcinoma of the bladder is sensitive to chemotherapy. Although platinum-based chemotherapy can produce relatively high overall response rates, the impact on the survival of patients with advanced disease has, at best, been limited. Randomized trials of cisplatin-based chemotherapy regimens in the neoadjuvant setting have demonstrated the potential to improve survival. By comparison, adjuvant studies have been plagued by suboptimal trial design, limited patient numbers, and lack of standardization of the chemotherapy regimens used. With the introduction of new cytotoxic drugs and novel small molecules, there is a need for well-designed studies to address the optimal utility of perioperative therapy in high-risk patients with bladder cancer.

The regimens of carboplatin plus paclitaxel (CP) and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) were compared in patients with advanced urothelial carcinoma. Patients with metastatic urothelial carcinoma were randomized to receive either CP (paclitaxel at a dose of 225 mg/m² and carboplatin [targeted area under the concentration-time curve (AUC) of 6] given every 21 days) or the standard M-VAC dosage. Eighty-five patients were randomized to the respective treatment regimens (41 to CP and 44 to M-VAC). Response rates and overall survival were similar for both treatment arms. Patients treated with CP had an overall response rate of 28.2% (95% binomial confidence interval, 15.0–44.9%) compared with an overall response rate of 35.9% for the M-VAC arm (95% binomial confidence interval, 21.2–52.8%) (P = 0.63, Fisher exact test). The median progression-free survival among patients who were treated with M-VAC was 8.7 months and was 5.2 months for patients receiving CP (P = 0.24, log-rank test). At a median follow-up of 32.5 months, the median survival for patients treated with M-VAC was 15.4 months versus 13.8 months for patients treated with CP (P = 0.65, log-rank test). Patients treated with M-VAC were found to have more severe worst-degree toxicities compared with patients treated with CP (P = 0.0001). There were no significant differences with regard to quality of life as assessed by the Functional Assessment of Cancer Therapy–Bladder (FACT-BL) instrument (P = 0.33). Interpretation of the results of this study must be made with caution because the study failed to reach its accrual goal. Patients treated with CP had a median survival of 13.8 months compared with 15.4 months for patients treated with M-VAC. Patients treated with CP appeared in general to better tolerate their treatment; however, there were no significant differences noted with regard to measured quality of life parameters. Cancer 2004. © 2004 American Cancer Society.

Muscle-invasive bladder cancer is typically an aggressive solid tumour with the propensity for early systemic dissemination. Although curative-intent local therapy with either radical cystectomy or radiotherapy remains the gold standard intervention, the high rate of systemic failure has prompted investigators to evaluate various strategies in an attempt to improve survival, including the early administration of systemic chemotherapy. Recently completed, Phase III studies of neoadjuvant chemotherapy trials demonstrated a modest, but real survival advantage for a small subset of patients. Other strategies include, attempts to both preserve the bladder using combinations of limited surgical resection, systemic chemotherapy and radiotherapy. This review focuses on the potential of neoadjuvantly-administered therapies to impact the management of muscle invasive bladder cancer.

Gemcitabine and docetaxel are active agents in advanced urothelial carcinoma. A Phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multiinstitutional setting in patients previously treated with one prior chemotherapy regimen. Twenty-nine eligible patients with advanced urothelial carcinoma were treated with docetaxel at a dose of 40 mg/m² over 1 hour followed by gemcitabine, 800 mg/m², over 30 minutes, both intravenously (i.v.) on Days 1 and 8. Cycles were repeated every 21 days until disease progression or a maximum of 6 cycles. Five patients obtained an objective response for an overall response rate of 17% (90% confidence interval, 7–33%). One patient achieved a complete clinical response. The median overall survival of the group was 7.7 months. Toxicity was moderate with granulocytopenia, anorexia, and fatigue being the most commonly noted side effects. Gemcitabine and docetaxel is an active second-line combination in patients with advanced urothelial carcinoma. Responses in visceral, lymph node, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and anorexia was common. Thromboembolic symptoms were reported and are of concern. The combination of gemcitabine and docetaxel has the potential to palliate a subset of previously treated patients with an adequate performance status. Cancer 2003;97:2743–7. © 2003 American Cancer Society. DOI 10.1002/cncr.11413

This was a single-agent phase II clinicaltrial of the antifol piritrexim in patientswith advanced transitional cell carcinomaof the bladder. Methods: Patientswith previously-treated, advancedurothelial carcinoma were treated with oralpiritrexim at a dose of 25 mg three timesdaily for 5 consecutive days each week for3 consecutive weeks followed by a 1-weekrest period. Courses were repeated every28 days. Results: Thirty-fivepatients were enrolled in the study, with28 patients evaluable for survival andtoxicity and 27 evaluable for response. Toxicity: Myelosuppression was themajor dose-limiting toxicity, with WHOgrade 3/4 thrombocytopenia in 4 patients,granulocytopenia in 1 patient, and anemiain 3 patients. Grade 3 nonhematologictoxicity consisted of neuropathy in 5patients, hepatotoxicity in 2, nausea in 2,and 1 each with pulmonary toxicity andrash. Efficacy: Of the 27 patientsevaluable for response, 2 (7%) achieved anobjective response, lasting 112 and 142days, respectively. Conclusion: Piritrexim has minimal activity in patientswith previously treated transitional cellcarcinoma of the bladder, regardless ofprior exposure to methotrexate, and furtherevaluation of this compound in thisclinical setting is not warranted.

We report the presentation of brain metastases from bladder carcinoma. We investigated the role of whole brain radiation therapy for treating this disease.

Objectives. Prostate-specific antigen onlydisease progression following definitivetherapy is significant therapeutic dilemma. The benefit of hormonal therapy remainsunproven and is associated with significanttoxicity, more pronounced with chronic use. Biochemical progression following hormonaltherapy has no standard treatment. Newapproaches to the management of this subsetof patients are needed. A previous studyin advanced prostate cancer demonstratedbiologic activity of granulocytemacrophage-colony stimulating factor. Thepurpose of this study was to evaluate theactivity of granulocyte macrophage-colonystimulating factor in a less heavilypretreated population. Materials and methods. Sixteenpatients with advanced prostate cancer, 7hormonally naïve, and 9 androgenindependent, were treated with granulocytemacrophage-colony stimulating factoradministered subcutaneously at 250 μgthree times a week for up to 6 months. Prostate-specific antigen measurements wereobtained every 2 weeks. Results. No patient achieved anobjective response. Six patientsdemonstrated a 10–15% decline in theirbaseline prostate-specific antigen whichwas maintained during the entire treatmentperiod. Five of these 6 patientsdemonstrated a rise in theirprostate-specific antigen following studycompletion. Therapy was well tolerated,with only 1 grade 3 event which was nottreatment-related. Conclusions. Granulocytemacrophage-colony stimulating factordemonstrates modest biologic evidence ofactivity in prostate cancer as manifestedby prostate-specific antigen response. Further investigation of the mechanism ofactivity and additional clinical evaluationof this agent seems warranted.