Third-generation aromatase inhibitors in the treatment of advanced breast cancer.
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Adult↗
Biomedical subjects
D M Reese
Publications and source records attributed to D M Reese.
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.
Aged↗
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.
Adenocarcinoma↗
New agents for prostate cancer.
Given the poor results with currently available therapies, it is imperative that new treatments be developed for patients with advanced prostate cancer. The next generation of therapies will include many novel biologic agents targeted at molecular defects in the cancer cell. Investigating the efficacy and safety of these compounds and evaluating their utility in combination with traditional therapies such as chemotherapy or radiotherapy are major goals of prostate cancer clinical research for the next decade.
Adenocarcinoma↗
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.
Adenoma↗
Treatment options in hormone-refractory prostate cancer: current and future approaches.
Prostate cancer is the second leading cause of cancer mortality among men in Western countries. The initial treatment of advanced prostate cancer is suppression of testicular androgen production by medical or surgical castration, but nearly all men with metastases will develop disease progression. Patients with hormone refractory prostate cancer (HRPC) have a median survival of approximately 18 months and no therapy has yet demonstrated a definitive survival advantage. However, in the past several years, a number of promising new treatment strategies have emerged. One of the most important new treatment strategies involves secondary hormonal manipulation after the failure of primary androgen deprivation. This approach is predicated on the recognition that HRPC is a heterogeneous disease and some patients may respond to alternative hormonal interventions despite the presence of castrate levels of testosterone. Until recently, cytotoxic chemotherapy was felt to be relatively ineffective in the treatment of HRPC. Combination regimens incorporating new active agents have demonstrated significant activity in this setting, renewing interest in the use of chemotherapy to treat HRPC. Recent advances in the understanding of prostate cancer biology have led to the development of drugs directed against precise molecular alterations in the prostate tumour cell. Biologic agents now in development include those capable of altering signal transduction, blocking angiogenesis, inhibiting cell cycle progression, and stimulating apoptosis. In addition, many types of immune therapies are showing promise. Evaluating these agents, and incorporating them into existing regimens, are major goals of ongoing clinical research in advanced prostate cancer.
Androgen Antagonists↗
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.
Acid Phosphatase↗
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.
Adenocarcinoma↗
Choice of hormonal therapy for prostate cancer.
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Androgen Antagonists↗
Infusional floxuridine-based therapy for patients with metastatic renal cell carcinoma.
BACKGROUND: The treatment of patients with metastatic renal cell carcinoma (RCC) continues to pose a major clinical challenge. Previous studies have suggested that infusional floxuridine (FUDR) has antitumor efficacy and is well tolerated. To the authors knowledge the combination of infusional FUDR with biologic response modifiers (BRMs) has not been evaluated extensively in patients with metastatic RCC. METHODS: Thirty-nine previously untreated patients with metastatic RCC were treated with infusional FUDR at 0.075 mg/kg/day for 14 days of a 28-day cycle. Beginning with the second cycle of FUDR, 24 patients received subcutaneous interferon-alpha-2b (3 million U 3 times a week for Weeks 1 and 2) and 15 received subcutaneous interleukin-2 (IL-2) (5 million U/m(2) 5 days a week for 3 weeks, followed by 1 week off). The dose of FUDR was increased by 0.025 mg/kg each cycle until the maximum tolerated dose for each patient was reached. RESULTS: Five patients receiving FUDR plus interferon achieved a partial response and 1 achieved a complete response whereas 3 patients receiving FUDR plus IL-2 achieved a partial response, for an overall response rate of 23%. The median survival for all patients was 21 months, and 8 patients still were alive 6-57+ months after the initiation of therapy. Toxicity was mild to moderate, and was comprised primarily of fatigue, diarrhea, dacryocystitis, and fluid retention (in the IL-2 cohort). CONCLUSIONS: FUDR in conjunction with IL-2 or interferon appears to produce response rates comparable to those observed with other programs utilizing BRMs and generally is well tolerated. FUDR regimens may be useful in the treatment of metastatic RCC in the outpatient community setting.
Adult↗
New treatment strategies in advanced prostate cancer.
The treatment of advanced prostate cancer has evolved rapidly in the last 5 years. Therapeutic options for patients with advanced disease, once essentially limited to the use of androgen deprivation, have expanded to include a number of interventions, including secondary hormonal manipulations, chemotherapy, and a variety of investigational approaches. Novel therapeutic approaches in prostate cancer patients are likely to be undertaken in patients with disease that is at or below the limits of detection by current imaging technology, so novel methods will be essential to the successful evaluation and use of these agents.
Androgen Antagonists↗
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.
Adult↗
An update on prostate cancer research.
The pathogenesis of prostate cancer reflects complex interactions among environmental and genetic factors. Recent advances suggest molecular mechanisms that may explain geographic and ethnic variations in prostate cancer incidence, and understanding of molecular disease progression is advancing rapidly. Clinically, the case for screening has become stronger, and declining prostate cancer mortality rates may be due in part to early detection and treatment. Improved risk assessment for patients with localized disease is now available, although further refinement in predictive algorithms will need to incorporate validated molecular prognostic markers. Treatment options for patients with localized prostate cancer have expanded and the role of androgen deprivation further delineated. Finally, treatment strategies for patients with androgen-independent disease have also expanded, although novel therapies are required to improve survival in this group of patients.
Clinical Trials as Topic↗
Restoring the literary to medical writing.
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History, 19th Century↗
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.
Androgen Antagonists↗
Therapy of advanced prostate cancer with granulocyte macrophage colony-stimulating factor.
Granulocyte macrophage colony-stimulating factor is a pleiotropic cytokine capable of inducing systemic immune responses against experimental and human tumors. To evaluate the efficacy of GM-CSF treatment in patients with hormone-refractory prostate cancer, we conducted sequential Phase II studies in 36 men with progressive disease after androgen deprivation and antiandrogen withdrawal. In a first cohort of patients (n = 23), GM-CSF was administered s.c. at a dose of 250 microg/m2 daily for 14 days of a 28-day treatment period. After we observed oscillating prostate-specific antigen (PSA) responses in several patients in this first cohort, a second trial was performed in which patients (n = 13) received maintenance GM-CSF (250 microg/m2 three times weekly) after the first 14 days of daily GM-CSF. All patients were treated until disease progression. Response was assessed by evaluation of serial changes in serum PSA and sequential imaging studies. In cohort I, 10 of 22 patients (45%) had a PSA versus time plot with a sawtooth pattern, with PSA declining during GM-CSF therapy and climbing during the off-therapy period; 5 patients had at least two consecutive declines in PSA, with a median response duration of 3.5 months. All but one patient in cohort II experienced a decline in PSA (median decline, 32%), but a PSA decline greater than 50% and sustained for more than 6 weeks was seen in only one patient, who had a >99% decline in PSA and an improvement in bone scan lasting for 14+ months. Changes in PSA levels could not be attributed to direct or indirect effects of GM-CSF on the PSA assay or down-regulation of PSA expression by GM-CSF. Toxicity was very mild, consisting primarily of transient constitutional symptoms and injection site reactions. These data suggest that GM-CSF may have antitumor activity in advanced prostate cancer, and the use of GM-CSF may be a confounding variable when PSA responses are used as an end point in clinical trials evaluating new regimens for the treatment of advanced prostate cancer.
Aged↗
Hormone-refractory prostate cancer: an evolving standard of care.
The treatment of advanced prostate cancer has evolved rapidly in the last several years. Therapeutic options for patients with advanced disease, once limited to the use of androgen deprivation, have expanded to include a number of interventions, including secondary hormonal manipulations, chemotherapy, and a variety of investigational approaches.
Antineoplastic Agents, Hormonal↗
Undetectable serum prostate-specific antigen associated with metastatic prostate cancer: a case report and review of the literature.
A 63-year-old man, who had undergone prostatectomy for prostate cancer that was positive for prostate-specific antigen (PSA) was examined and found to have metastatic disease, proven radiologically and pathologically, but with an undetectable PSA and highly elevated prostatic acid phosphatase (PAP). Prostatic acid phosphatase levels fell in response to chemotherapy but his clinical status continued to deteriorate. A review of the literature is presented and several possible explanations for PSA remaining undetectable in these situations are discussed. The authors conclude that although PSA can be used to monitor the majority of patients postprostatectomy, physicians may still need to rely on clinical suspicion, serum PAP, and bone scan for the detection of recurrent disease.
Acid Phosphatase↗