David M. Reese

Immunotherapy of Hormone-Refractory Prostate Cancer With Antigen-Loaded Dendritic Cells

PURPOSE Provenge (Dendreon Corp, Seattle, WA) is an immunotherapy product consisting of autologous dendritic cells loaded ex vivo with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor. Sequential phase I and phase II trials were performed to determine the safety and efficacy of Provenge and to assess its capacity to break immune tolerance to the normal tissue antigen PAP. PATIENTS AND METHODS All patients had hormone-refractory prostate cancer. Dendritic-cell precursors were harvested by leukapheresis in weeks 0, 4, 8, and 24, loaded ex vivo with antigen for 2 days, and then infused intravenously over 30 minutes. Phase I patients received increasing doses of Provenge, and phase II patients received all the Provenge that could be prepared from a leukapheresis product. RESULTS Patients tolerated treatment well. Fever, the most common adverse event, occurred after 15 infusions (14.7%). All patients developed immune responses to the recombinant fusion protein used to prepare Provenge, and 38% developed immune responses to PAP. Three patients had a more than 50% decline in prostate-specific antigen (PSA) level, and another three patients had 25% to 49% decreases in PSA. The time to disease progression correlated with development of an immune response to PAP and with the dose of dendritic cells received. CONCLUSION Provenge is a novel immunotherapy agent that is safe and breaks tolerance to the tissue antigen PAP. Preliminary evidence for clinical efficacy warrants further exploration.

Prospective Trial of the Herbal Supplement PC-SPES in Patients With Progressive Prostate Cancer

PURPOSE PC-SPES is an herbal supplement for which there are anecdotal reports of anti-prostate cancer activity. This phase II study was undertaken to assess the efficacy and toxicity of PC-SPES in prostate cancer patients. PATIENTS AND METHODS Thirty-three patients with androgen-dependent prostate cancer (ADPCa) and 37 patients with androgen-independent prostate cancer (AIPCa) were treated with PC-SPES at a dose of nine capsules daily. Clinical outcome was assessed with serial serum prostate-specific androgen (PSA) level measurement and imaging studies. RESULTS One hundred percent of ADPCa patients experienced a PSA decline of >/= 80%, with a median duration of 57+ weeks. No patient has developed PSA progression. Thirty-one patients (97%) had declines of testosterone to the anorchid range. Two ADPCa patients had positive bone scans; both improved. One patient with a bladder mass measurable on computed tomography scan experienced disappearance of this mass. Nineteen (54%) of 35 AIPCa patients had a PSA decline of >/= 50%, including eight (50%) of 16 patients who had received prior ketoconazole therapy. Median time to PSA progression was 16 weeks (range, 2 to 69+ weeks). Of 25 patients with positive bone scans, two had improvement, seven had stable disease, 11 had progressive disease, and five did not have a repeat bone scan because of PSA progression. Severe toxicities included thromboembolic events (n = 3) and allergic reactions (n = 3). Other frequent toxicities included gynecomastia/gynecodynia, leg cramps, and grade 1 or 2 diarrhea. CONCLUSION PC-SPES seems to have activity in the treatment of both ADPCa and AIPCa and has acceptable toxicity. Further study is required to determine whether its effects exceed those expected with estrogen therapy.

Phase 1b Study of Dulanermin (recombinant human Apo2L/TRAIL) in Combination With Paclitaxel, Carboplatin, and Bevacizumab in Patients With Advanced Non-Squamous Non–Small-Cell Lung Cancer

PURPOSE To determine the safety, pharmacokinetics (PK), and maximum-tolerated dose (MTD) up to a prespecified target dose of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients with previously untreated, nonsquamous, stage IIIb (with pleural effusion)/IV or recurrent non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS In this phase 1b study, patients (n = 24) received PCB on day 1 of each 21-day cycle then dulanermin at 4 or 8 mg/kg/d for 5 consecutive days or 15 or 20 mg/kg/d for 2 consecutive days per assigned treatment cohort. Incidence of dose-limiting toxicities (DLTs), adverse events, and antidulanermin antibodies were assessed. PK parameters were recorded for each agent. Tumor response was measured by modified Response Evaluation Criteria in Solid Tumors. RESULTS Twenty-four patients received at least one dose of dulanermin plus PCB, six in each treatment cohort. There were no DLTs. An MTD was not reached, and the drug combination was well tolerated. Treatment-emergent adverse events were generally as expected for the PCB regimen. Adverse events attributed to dulanermin were grade 1/2; no significant hepatotoxicity occurred. There was minimal impact of PCB on the PK of dulanermin. There was one confirmed complete response and 13 confirmed partial responses. The overall response rate was 58% (95% CI, 37 to 78). Median progression-free survival was 7.2 months (95% CI, 4.7 to 10.3). CONCLUSION Dulanermin plus PCB was well tolerated with no occurrence of DLTs and demonstrated antitumor activity in this patient population. Dulanermin at 8 mg/kg/d for 5 days and 20 mg/kg/d for 2 days every 3 weeks in combination with PCB is being studied in a phase II trial.

Modulation of omega-3/omega-6 polyunsaturated ratios with dietary fish oils in men with prostate cancer

OBJECTIVES The results of epidemiologic and animal studies support the role of a low-fat diet supplemented with omega-3 fatty acids contained in fish oil in preventing the development and progression of prostate cancer. As a first step in studying the role of a low-fat, fish oil-supplemented (LF/FOS) diet in a clinical setting, we conducted a prospective study in men with untreated prostate cancer to evaluate whether a 3-month dietary intervention affects the ratio of omega-3 to omega-6 fatty acids in plasma and gluteal fat. In addition, we evaluated the feasibility of studying cyclooxygenase-2 (COX-2) expression in serial prostate needle biopsy specimens before and after the diet. METHODS Nine men with untreated prostate cancer consumed an LF/FOS diet for 3 months. Plasma, gluteal adipose tissue, and prostate needle biopsy specimens were obtained from each patient before and after the intervention. The fatty acid compositions of the plasma and gluteal adipose tissue were determined by gas-liquid chromatography, and the COX-2 expression in the prostatic tissue specimens was determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS Short-term intervention with an LF/FOS diet caused a significant increase in the omega-3/omega-6 fatty acid ratio in plasma (P = 0.002) and gluteal adipose tissue (P = 0.002) in men with prostate cancer. The COX-2 expression in prostatic tissue was quantitated by RT-PCR in 7 of 9 patients, and COX-2 expression decreased in 4 of these 7 patients. CONCLUSIONS A short-term dietary intervention in men with prostate cancer leads to a significant increase in the omega-3/omega-6 fatty acid ratios in plasma and adipose tissue. The potential for this diet to prevent the development and progression of prostate cancer by way of altered COX-2 expression and prostaglandin production in prostatic tissue requires further study.

HER2 Protein Expression and Gene Amplification in Androgen-Independent Prostate Cancer

The role of the HER2 receptor remains uncertain in the pathogenesis and progression of human prostate cancer. Previous studies have reported widely divergent rates for HER2 expression in primary prostate tumors, probably owing to significant methodologic differences in the studies. Few data exist about the frequency of HER2 protein overexpression and gene amplification in androgen-independent prostate cancer (AIPC), although recent xenograft models suggest HER2 expression may be up-regulated in the transition from androgen-dependent to androgen-independent disease. We studied the role of HER2 protein in AIPC by immunohistochemical and fluorescence in situ hybridization (FISH) analyses on AIPC specimens using well-characterized and validated reagents. Fourteen (36%) of 39 specimens expressed HER2; however, only 2 (5%) had moderate (2+) expression, and 2 (5%) had high-level (3+) expression. Two (6%) of 36 specimens had gene amplification by FISH. These data suggest that HER2 protein overexpression and gene amplification are relatively uncommon in AIPC.

Intermittent androgen deprivation: Update of cycling characteristics in patients without clinically apparent metastatic prostate cancer

OBJECTIVES To update the cycling characteristics and patterns of treatment in patients receiving intermittent androgen deprivation (IAD) for clinically localized and recurrent prostate cancer. METHODS We report our experience with 61 patients treated with IAD. Thirty-four patients had received no prior treatment, and 27 had developed recurrent disease after previous local therapy. No patient had clinically apparent metastatic disease before the initiation of therapy. The mean and median serum prostate-specific antigen (PSA) level before treatment was 25.3 ng/mL and 16.0 ng/mL, respectively (range 0.5 to 190 ng/mL). For each cycle, androgen deprivation was continued until PSA became undetectable or a nadir level was reached. Patients were then observed without treatment, and therapy was reinstituted after the serum PSA value reached a predetermined level. Patients were no longer eligible to cycle off treatment when their serum PSA increased despite ongoing androgen deprivation or if any objective evidence of disease progression was present on imaging studies. RESULTS Follow-up ranged from 7 to 60 months (mean 30) from the start of treatment. Patients received from one to five treatment cycles (median two), with a median cycle length of 14 months. The median nadir serum PSA level during androgen deprivation was 0.01 ng/mL and was reached within an average of 6 months (range 4 to 9) after beginning treatment. Patients spent an average of 45% of the time not receiving therapy, but the time off therapy decreased as the number of treatment cycles increased. Five patients (8.1%) demonstrated progressive disease, with a median time to progression of 48 months. When examining the cycling characteristics of these patients, no consistent pattern of failure emerged. CONCLUSIONS IAD appears to be a viable treatment option in select patients with localized prostate cancer. With each consecutive cycle, the amount of time the patient was not receiving therapy decreased, despite achieving a low nadir PSA. Longer follow-up with more patients failing IAD will be required before clear patterns of failure emerge in these patients.

Docetaxel, estramustine, plus trastuzumab in patients with metastatic androgen-independent prostate cancer

The incidence of human epidermal growth factor receptor 2 (HER2) protein overexpression and its prognostic value are not well characterized in patients with prostate cancer. A phase I study was designed to evaluate docetaxel/estramustine plus trastuzumab, a humanized monoclonal antibody that binds to the HER2 receptor, in patients with metastatic androgen-independent prostate cancer (AIPC). HER2 positivity was not required because safety was the primary endpoint. Patients received oral estramustine 280 mg three times daily (days 1 to 5); docetaxel, 70 mg/m(2) intravenously (day 2); and trastuzumab, 2 mg/kg intravenously (days 2, 9, and 19), every 21 days until the disease progressed or toxicity became unacceptable. This regimen was well tolerated among the first 13 treated patients. Grade 4 neutropenia was seen in 10% of administered cycles. There were two episodes of febrile neutropenia and two thrombembolic events. Of the 13 patients evaluable for prostate-specific antigen (PSA) response, nine (69%) experienced a decrease in PSA level of >50%. Two (33%) of six patients with measurable disease had objective responses, and one complete response was seen on bone scan. Docetaxel/estramustine/trastuzumab appears to be a safe combination when used in the treatment of metastatic AIPC. The response data are too preliminary for speculation about the relative benefits of this 3-drug regimen compared with the combination of only docetaxel and estramustine in this clinical setting.

Potential role of nephrectomy in the treatment of metastatic renal cell carcinoma: a retrospective analysis

OBJECTIVES To examine the outcomes of patients with newly diagnosed metastatic renal cell carcinoma (RCC) who underwent initial nephrectomy as a component of therapy, because the role of nephrectomy in the treatment of patients with metastatic RCC is uncertain. METHODS A retrospective review of 63 patients who underwent radical nephrectomy with or without additional surgical procedures in the setting of metastatic RCC was performed. Pretreatment characteristics and the type of surgery were examined as predictors of outcome, and the type of systemic therapy received (if any) and overall survival were determined. RESULTS The median patient age was 59 years (range 39 to 79). Thirty-two patients had a single metastatic site, with the most common sites being the lung (n = 33), lymphatics (n = 32), and bone (n = 19). Seventeen patients (27%) also underwent vena cavotomy during surgery. Two patients died perioperatively. Thirty-nine (62%) patients underwent systemic therapy after surgery, and 6 patients (9.5%) were rendered free of disease and elected not to receive systemic treatment. The median survival was 17.8 months. CONCLUSIONS Primary renal surgery may be beneficial for selected patients with metastatic RCC, and most patients will be able to receive postoperative systemic therapy.

SECONDARY HORMONAL MANIPULATIONS IN HORMONE REFRACTORY PROSTATE CANCER

Hormone refractory prostate cancer is clinically heterogeneous, and many patients retain sensitivity to subsequent hormonal manipulations, even after combined androgen blockage. Antiandrogen withdrawal is a mandatory first step. Subsequent treatment with an alternate antiandrogen, adrenal androgen inhibitor (such as ketoconazole), or glucocorticoid may provide both subjective and objective clinical benefit in up to 65% of patients.

Docetaxel in the treatment of breast cancer: An update on recent studies

Recently there has been great interest in developing combination regimens involving taxanes and anthracyclines for the treatment of advanced breast cancer. Docetaxel in particular has substantial activity when combined with doxorubicin. In one randomized trial, the combination of doxorubicin 50 mg/m(2) and docetaxel 75 mg/m(2) showed significantly greater activity than doxorubicin plus cyclophosphamide (AC), producing a higher response rate (60% v 47%) and longer time to progression. In a second study, 484 patients were randomized to receive either docetaxel plus doxorubicin and cyclophosphamide (TAC) or 5-florouracil plus doxorubicin and cyclophosphamide. The response rate was significantly higher in the TAC arm (54% v 42%), including patients with unfavorable prognostic factors. Febrile neutropenia occurred more frequently in patients receiving TAC, but the incidence of infection and septic death was low and no greater than in the 5-florouracil/doxorubicin/cyclophosphamide arm. TAC was not associated with an increased risk of cardiotoxicity. Data on time to progression and survival are not yet available. The TAC and doxorubicin/docetaxel regimens have been compared with non-docetaxel-containing programs in randomized adjuvant trials which have completed accrual but are not yet mature. A second generation of adjuvant trials compares sequential versus synchronous docetaxel-based polychemotherapy. In addition, based on preclinical data suggesting a synergistic interaction between docetaxel, platinum salts, and trastuzumab, as well as preliminary data from pilot studies in patients with HER2-positive metastatic disease showing tolerability and activity, adjuvant studies of this novel three-agent combination are in progress in patients with HER2-positive early breast cancer.