High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study

PURPOSE: We determined the safety and preliminary efficacy of the combination of high dose pulse calcitriol (1,25-dihydroxycholecalciferol) with a standard regimen of docetaxel plus estramustine in patients with metastatic androgen independent prostate cancer. MATERIALS AND METHODS: Patients were treated with 60 microg calcitriol orally on day 1, 280 mg estramustine orally 3 times daily on days 1 to 5 and 60 mg/m docetaxel on day 2 (70 mg/m after cycle 1) every 21 days for up to 12 cycles. Patients also received 325 mg aspirin and 1 or 2 mg warfarin orally daily. Regimen safety was assessed in the first 6 patients and a dose de-escalation scheme for calcitriol was planned if dose limiting toxicities were noted during treatment cycle 1 in greater than a third of patients. RESULTS: A total of 24 patients, including 11 who were chemotherapy na?ve and 13 who had previously been treated with docetaxel, were evaluable for toxicity and 22 for prostate specific antigen decrease data. The regimen was generally well tolerated. Treatment related grades 3 or greater toxicity seen in more than 1 patient included hypophosphatemia in 16.7% and neutropenia in 12.5%. Four patients had thromboembolic complications. Asymptomatic hypercalcemia was seen in 4 patients, including grades 2 and 1 in 1 and 3, respectively. Six of 11 evaluable, chemotherapy na?ve patients (55%) met prostate specific antigen response criteria. One of 11 patients (9%) treated with prior docetaxel met these criteria. CONCLUSIONS: High dose calcitriol may be safely added to docetaxel and estramustine administered on a 21-day schedule.     

Transurethral microwave thermal therapy: Pathologic findings in the canine prostate

Microwave irradiation administered by transurethral transducer to the prostate permits focused hyperthermia with resultant tissue ablation; a cooling system within the catheter allows urethral preservation. We evaluated the effect of microwave hyperthermia in 13 dogs receiving 48–79 min of focused irradiation (16–45 watts, intraprostatic temperature >45°C) delivered by a specially-designed transducer with an operator-controlled directional antenna (T3, Urologix Inc., Minneapolis, MN); one other dog had transducer placement without irradiation (sham control). After treatment, the dogs were in good health, voiding well without complications, and were sacrificed after 5–38 days. The prostate and vasa deferentia were removed, fixed in 10% formalin, grossly inspected, cut at 5 mm intervals, and serially sectioned with whole mount sections; representative sections of the adjacent rectum and distal bladder were also obtained. All cases were histologically evaluated with prostatic mapping without knowledge of treatment or time of sacrifice. In the acute phase (5–13 days), the prostate showed sharply circumscribed periurethral coagulative necrosis with hemorrhage; necrosis was also seen in the mucosa and bladder wall of those with transducers placed at the bladder neck. In the subacute phase (17 days), the hemorrhagic necrosis was resolving, often with cystically dilated urethra due to sloughed necrotic tissue; the urothelium was intact. By 24–38 days, the necrosis was in the late stages of resolution, with residual patchy acute and chronic inflammation at the periphery, and frequent persistence of megalourethra. In all cases, the prostatic capsule was intact, the urethral mucosa was preserved, and the vasa deferentia and rectum were normal except for two cases with mild fat necrosis. Microwave irradiation allows precisely localized thermal ablation of prostatic tissue and enlargement of the urethral bore without clinical complications in dogs, offering promise as a therapeutic alternative to surgery in select patients with symptomatic prostatic nodular hyperplasia.     

Gene therapy for prostate cancer: current status and future prospects

PURPOSE: Locally advanced, relapsed and metastatic prostate cancer has a dismal prognosis with conventional therapies offering no more than palliation. In recent years advances achieved in understanding the molecular biology of cancer have afforded clinicians and scientists the opportunity to develop a range of novel genetic therapies for this disease. MATERIALS AND METHODS: We performed a detailed review of published reports of gene therapy for prostate cancer. Particular emphasis was placed on recent developments in the arena of nonviral (plasmid DNA, DNA coated gold particles, liposomes and polymer DNA complexes) and viral (adenovirus, retrovirus, adeno-associated virus, herpes virus and pox virus) vectors. Therapeutic strategies were categorized as corrective, cytoreductive and immunomodulatory gene therapy for the purpose of data analysis and comparison. RESULTS: Locoregional administration of nonviral and viral vectors can yield impressive local gene expression and therapeutic effects but to our knowledge no efficient systemically delivered vector is available to date. Corrective gene therapy to restore normal patterns of tumor suppressor gene (p53, Rb, p21 and p16) expression or negate the effect of mutated tumor promoting oncogenes (ras, myc, erbB2 and bcl-2) have efficacy in animal models but this approach suffers from the fact that each cancer cell must be targeted. A wide variety of cytoreductive strategies are under development, including suicide, anti-angiogenic, radioisotopic and pro-apoptotic gene therapies. Each approach has strengths and weaknesses, and may best be suited for use in combination. Immunomodulatory gene therapy seeks to generate an effective local immune response that translates to systemic antitumor activity. Currently most studies involve immunostimulatory cytokine genes, such as granulocyte-macrophage colony-stimulating factor, or interleukin-2 or 12. CONCLUSIONS: Various therapeutic genes have proved activity against prostate cancer in vitro and in vivo. However, the chief challenge facing clinical gene therapy strategies is the lack of efficient gene delivery by local and systemic routes. For the foreseeable future vector development may remain a major focus of ongoing research. Despite this caveat it is anticipated that gene therapy approaches may significantly contribute to the management of prostate cancer in the future.     

Transurethral microwave therapy in 200 patients with a minimum followup of 2 years: urodynamic and clinical results

PURPOSE: We investigated the long-term efficacy of the second generation Targis thermotherapy device (Urologix, Inc., Minneapolis, Minnesota) for decreasing outflow obstruction caused by benign prostatic hyperplasia. MATERIALS AND METHODS: At a minimum followup of 24 months 200 patients with bladder outlet obstruction documented on urodynamics and cystoscopy document with preserved detrusor function underwent transurethral microwave therapy while under local anesthesia. In 45% of cases the general American Society of Anesthesiologists health score was 3 or greater. RESULTS: After a median observation time of 42 months (range 2 to 72) 43 patients (22%) who required additional treatment (repeat thermotherapy, transurethral prostate resection or permanent cystostomy) were excluded from further analysis, as were 15 (7.5%) who died of causes unrelated to treatment during followup and 13 (6.5%) who were lost to followup or refused followup investigations. In the 162 patients evaluated 6 months after treatment the median International Prostate Symptom Score decreased from 23 points (range 10 to 34) before treatment to 3 (range 0 to 21) and remained stable at 12 and 24 months. Median maximum flow increased from 6 ml. per second (range 1 to 15) before treatment to 14.5 (range 4 to 50) 6 months after treatment and remained stable at 12 and 24 months. Median post-void residual urine volume decreased from 170 ml. (range 35 to 720) before treatment to 17 (range 0 to 327) after 6 months and then remained unchanged. Urodynamic evaluation in the 162 patients after 6 months showed a decrease from pretreatment median detrusor opening pressure of 87.5 to 53 cm. water. Median detrusor pressure at maximum flow decreased from 86 to 58 cm. water 6 (p <0.0001). At the 24-month followup 59 of the 129 evaluable patients agreed to undergo repeat urodynamic evaluation. Pressure flow analysis in these 59 cases revealed a decrease in median minimal urethral opening pressure from 70 to 40 cm. water at 6 months and to 38 cm. water at 24 months (p <0.0001). Median detrusor pressure at maximum flow decreased significantly from the pretreatment value of 86 to 55 cm. water at 6 months and 58 cm. water at 24 months (p <0.0001). CONCLUSIONS: In patients with a good initial response to treatment, which is achieved in approximately 80%, transurethral microwave therapy provides excellent long-term subjective and objective results. Improved urinary flow, decreased post-void residual urine volume and urodynamic parameters remain stable at 2 years. Transurethral microwave therapy with second generation microwave equipment did not compromise any conventional treatment needed in the 22% of patients who were nonresponders at 6 months.     

Vascular targeted photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response

PURPOSE: Tookad is a novel intravascular photosensitizer. When activated by 763 nm light, it destroys tumors by damaging their blood supply. It then clears rapidly from the circulatory system. To our knowledge we report the first application of Tookad vascular targeted photodynamic therapy in humans. We assessed the safety, pharmacokinetics and preliminary treatment response as a salvage procedure after external beam radiation therapy. MATERIALS AND METHODS: Patients received escalating drug doses of 0.1 to 2 mg/kg at a fixed light dose of 100 J/cm or escalated light doses of 230 and 360 J/cm at the 2 mg/kg dose. Four optical fibers were placed transperineally in the prostate, including 2 for light delivery and 2 for light dosimetry. Treatment response was assessed primarily by hypovascular lesion formation on contrast enhanced magnetic resonance imaging and transrectal ultrasound guided biopsies targeting areas of lesion formation and secondarily by serum prostate specific antigen changes. RESULTS: Tookad vascular targeted photodynamic therapy was technically feasible. The plasma drug concentration was negligible by 2 hours after infusion. In the drug escalation arm 3 of 6 patients responded, as seen on magnetic resonance imaging, including 1 at 1 mg/kg and 2 at 2 mg/kg. The light dose escalation demonstrated an increasing volume of effect with 2 of 3 patients in the first light escalation cohort responding and all 6 responding at the highest light dose with lesions encompassing up to 70% of the peripheral zone. There were no serious adverse events, and continence and potency were maintained. CONCLUSIONS: Tookad vascular targeted photodynamic therapy salvage therapy is safe and well tolerated. Lesion formation is strongly drug and light dose dependent. Early histological and magnetic resonance imaging responses highlight the clinical potential of Tookad vascular targeted photodynamic therapy to manage post-external beam radiation therapy recurrence.     

Long-term effects of finasteride on prostate specific antigen levels: results from the prostate cancer prevention trial

PURPOSE: Studies have shown that finasteride decreases prostate specific antigen (PSA) by approximately 50% during the first 12 months of use. We estimated the long-term effects of finasteride on PSA in men with and without a prostate cancer diagnosis at the end of the study. MATERIALS AND METHODS: We analyzed serial PSA in participants in the Prostate Cancer Prevention Trial who had an end of study biopsy (928 with cancer and 8,620 with negative biopsy) or an interim diagnosis of prostate cancer (671). Linear mixed effects regression models were fit to longitudinal PSA values beginning 1 year after randomization. RESULTS: In subjects with no cancer in the end of study biopsy PSA in the finasteride arm showed a median annual decrease of 2% [corrected] after year 1, while PSA in the control arm showed an annual increase of 3% (p <0.001). In end of study cases PSA increased annually by 6% (placebo) and 7% (finasteride). In those with interim diagnoses PSA increased by 11% (placebo) and 15% (finasteride) each year prior to diagnosis. Cases with high grade disease (Gleason 7 and above) had greater PSA increases than cases with low grade disease (p <0.001). CONCLUSIONS: In men who have been receiving finasteride for more than 1 year time varying adjustment factors may be needed to determine whether PSA is in the normal range. In the Prostate Cancer Prevention Trial cohort the adjustment factor required to preserve median PSA increased from 2 at 24 months to 2.5 at 7 years after the initiation of finasteride.     

Predictors of secondary cancer treatment in patients receiving local therapy for prostate cancer: data from cancer of the prostate strategic urologic research endeavor

PURPOSE: Secondary cancer treatment is common after definitive local therapy for prostate cancer and it may be an indicator of the efficacy and cost of primary local treatment. We determined predictors of secondary cancer treatment in patients initially treated with radical prostatectomy or external beam radiation. MATERIALS AND METHODS: We examined 2,336 patients in Cancer of the Prostate Strategic Urologic Research Endeavor, a longitudinal registry of patients with prostate cancer, who underwent initial treatment with radical prostatectomy (1,744) or external beam radiation (592). Patients had at least 1 month of followup and all pretreatment information was available. The percent of patients receiving secondary cancer treatment, time to secondary treatment and type of secondary treatment delivered was determined. Multivariate analysis was done to determine independent predictors of secondary cancer treatment. In patients initially treated with prostatectomy a similar analysis was performed to identify predictors of receiving androgen deprivation versus radiation. RESULTS: A total of 590 patients (25%) received secondary cancer treatment, including prostatectomy in 391 (22%) and radiation in 199 (34%). Secondary cancer treatment was equally divided between radiation and androgen deprivation in 52% and 47%, respectively, of those initially treated with prostatectomy, while 92% initially treated with radiation received androgen deprivation. Predictors of any secondary treatment included patient age, biopsy Gleason score and prostate specific antigen at diagnosis. There was a trend toward increased secondary treatment more than 6 months after local therapy in patients initially treated with radiation. Increased age and lymph node metastases were independent predictors of receiving androgen deprivation after prostatectomy, while there was increased use of radiation in patients with positive surgical margins or extracapsular disease extension. CONCLUSIONS: Secondary treatment differs in patients initially treated with radical prostatectomy and radiation. Pretreatment factors can be used to counsel patients regarding the likelihood of secondary treatment, while age and prostatectomy results appear to determine the type of secondary treatment in those initially treated with prostatectomy.     

The prostate cancer prevention trial: design, biases and interpretation of study results

PURPOSE: We describe the complexities of the study design of the PCPT and how they influenced the end point chosen, trial implementation, analysis and interpretation of the results. MATERIALS AND METHODS: Data from the PCPT are provided to evaluate and quantify the potential biases of this trial design. RESULTS: Six potential sources of bias, including prostate specific antigen, digital rectal examination, prostate biopsy technique, study medication nonadherence and contamination, and transurethral prostate resection are presented. These biases resulted in the need for the end of study biopsy to evaluate the trial objectives. CONCLUSIONS: There were a large number of known and potential biases that worked for and against finasteride. Because of the trial design and inherent biases, it is imperative that interim biopsy results should be interpreted with caution. While the period prevalence end point that relied on an end of study biopsy was perhaps not the most clinically relevant, it was the only way to remove as much bias as possible and meet the study objective of determining if finasteride could decrease the risk of prostate cancer. The success of the PCPT depended on constant scrutiny by the Data and Safety Monitoring Committee to monitor these biases. The design and biopsy assumptions outlined at the inception of the trial were met, including adherence and contamination rates, the for-cause biopsy rate and the final percent of men with study end points.     

Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study

PURPOSE: Cyclophosphamide is a bifunctional alkylating agent long associated with immune activation. Continuous, uninterrupted, low (so-called metronomic) doses of cyclophosphamide can lead to enhanced immunity against a variety of antigens possibly by targeting regulatory T cells and/or tumor angiogenesis. In this study we tested the observations from animal models and evaluated the safety and efficacy of continuous low dose oral cyclophosphamide in patients with hormone resistant prostate cancer. MATERIALS AND METHODS: A total of 80 patients were recruited during a 2-year period and 58 received at least 2 cycles (8 weeks) of 50 mg/m(2) oral cyclophosphamide to be included in the safety and intent to treat analysis. RESULTS: Metronomic cyclophosphamide was safe and well tolerated, and although lymphopenia (up to grade 3) was observed in a third of all patients, there were no clinical complications. The response rate was 34.5% inclusive of objective and prostate specific antigen (absolute reduction and reduction in prostate specific antigen velocity). The median duration of response was 7.5 months (range 3 to 18). CONCLUSIONS: Oral cyclophosphamide can be used on a metronomic basis safely in men with hormone resistant prostate cancer. The efficacy, low toxicity, low cost and ease of administration of cyclophosphamide justifies further studies in prostate cancer in combination with other agents.     

Secondary hormonal therapy for advanced prostate cancer

PURPOSE: Androgen ablation remains the cornerstone of management for advanced prostate cancer. Therapeutic options in patients with progressive disease following androgen deprivation include antiandrogen withdrawal, secondary hormonal agents and chemotherapy. Multiple secondary hormonal agents have clinical activity and the sequential use of these agents may lead to prolonged periods of clinical response. We provide a state-of-the-art review of the various agents currently used for secondary hormonal manipulation and discusses their role in the systemic treatment of patients with prostate cancer. MATERIALS AND METHODS: A comprehensive review of the peer reviewed literature was performed on the topic of secondary hormonal therapies, including oral antiandrogens, adrenal androgen inhibitors, corticosteroids, estrogenic compounds, gonadotropin-releasing hormone antagonists and alternative hormonal therapies for advanced prostate cancer. RESULTS: Secondary hormonal therapies can provide a safe and effective treatment option in patients with AIPC. The use of steroids and adrenolytics, such as ketoconazole and aminoglutethimide, has resulted in symptomatic improvement and a greater than 50% prostate specific antigen decrease in a substantial percent of patients with AIPC. A similar clinical benefit has been demonstrated with estrogen based therapies. Furthermore, these therapies have demonstrated a decrease in metastatic disease burden. Other novel hormonal therapies are currently under investigation and they may also show promise as secondary hormonal therapies. Finally, guidelines from the United States Food and Drug Administration Prostate Cancer Endpoints Workshop were reviewed in the context of developing new agents. CONCLUSIONS: Secondary hormonal therapy serves as an excellent therapeutic option in patients with AIPC in whom primary hormonal therapy has failed. Practicing urologists should familiarize themselves with these oral medications, their indications and their potential side effects.     

Hormone therapy for locally advanced prostate cancer

PURPOSE: We assessed cause specific and all cause survival in men with locally advanced prostate cancer after hormone therapy. MATERIALS AND METHODS: Between February 1991 and November 2000, 208 men with locally advanced prostate cancer were treated with gonadal androgen ablation or gonadal androgen ablation and an antiandrogen at a single medical center. Median PSA was 46 ng./ml. (range 2 to 748). Median potential followup was 78 months (range 4 to 122) and the median observation period was 46 months (range 3 to 122). RESULTS: Of the patients 14 (7%) died of causes related to cancer and 71 (34%) died of competing co-morbid disease. Actuarial cause specific survival at 5 and 8 years was 92% and 80%, respectively. The only demographic or tumor related variable that influenced cause specific survival was Gleason score less than 8 versus 8 or greater (p = 0.02). Actuarial all cause survival at 5 and 8 years was 59% and 41%, respectively. The only variable that influenced all cause survival was a Charlson weighted co-morbidity score of less than 2 versus 2 or greater (p <0.0001). Major morbidity from the primary tumor, including bothersome obstructive voiding symptoms requiring transurethral prostate resection, ureteral obstruction or persistent hematuria, developed in 13 patients (6%), while major treatment related morbidity, including flutamide hepatotoxicity and hip fracture, developed in 4. CONCLUSIONS: Hormone therapy for locally advanced prostate cancer is associated with minimal morbidity from the primary tumor and from treatment. All cause survival parallels that reported for integrated hormone and radiation therapy.     

Comorbidity and primary treatment for localized prostate cancer: data from CaPSURE

PURPOSE: The optimal approach for treating localized prostate cancer remains controversial, leading to a multifactorial decision making process. We characterized the extent to which the presence and number of comorbidities affects treatment for localized prostate cancer. MATERIALS AND METHODS: Data were abstracted from a longitudinal observational database of men with prostate cancer. A total of 5,149 men diagnosed with localized prostate cancer between 1995 and 2001 were included in this analysis if they had been treated with RP, external beam radiation, brachytherapy, hormonal therapy or surveillance. Comorbidity was assessed through a patient reported checklist of conditions. Multinomial logistic regression was used to determine the OR of the likelihood of receiving each type of therapy. The number of comorbidities and specific comorbidities in patients receiving RP were compared with comorbidities in patients receiving other treatment. RESULTS: The adjusted OR showed a dose response between the number of comorbidities and an increasing probability of any nonRP treatment. In addition, heart disease, stroke or another urinary condition were found to be associated with treatment. CONCLUSIONS: Patient comorbidities affect decision making regarding treatment for localized prostate cancer. Urologists and other physicians treating this disease appear to evaluate patient comorbidities when selecting treatment options.     

Strategies combining total and percent free prostate specific antigen for detecting prostate cancer: a prospective evaluation

PURPOSE: Determining total prostate specific antigen (PSA) in plasma can often identify men who are subsequently diagnosed with prostate cancer. However, excess false-positives create large financial and psychological burdens in prostate cancer screening. The percent free PSA is lower when prostate cancer is present, although to our knowledge no large prospective analyses to date have evaluated whether adding testing for free PSA may decrease false-positives, while maintaining or perhaps improving the detection of potentially curable tumors. MATERIALS AND METHODS: We measured total and percent free PSA in banked plasma samples from the Physicians' Health Study in 430 men who were later diagnosed with prostate cancer and 1,642 age matched controls who were not diagnosed with prostate cancer during a 12-year observation period. We calculated the number of cancers detected and the number of false-positives for various strategies of combined free and total PSA levels, and compared them to the use of total PSA alone. RESULTS: Total PSA with a cutoff of 4 ng./ml. detected 149 cases but also yielded 144 false-positives. A strategy that applied percent free PSA to men with total PSA 4 to 10 ng./ml. detected 133 to 140 cancers and decreased false-positives to 83 of 117 depending on the percent free PSA cutoff used. As the percent free PSA cutoff was lowered from 25% to 20%, additional undetected cancers did not occur until year 9 of followup and the 20% cutoff decreased false-positives and, thus, potential negative biopsies, by 42%. Percent free PSA was superior to total PSA for discriminating cases from controls within the total PSA range of 4 to 10 or 3 to 10 ng./ml. (p <0.0001). A percent free PSA cutoff of 20% in men with total PSA 3 to 10 ng./ml. detected 10% more cancers with 12.5% fewer false-positives than the conventional strategy of total PSA greater than 4 ng./ml. Cancers missed by combined total and free PSA testing had longer intervals between blood sampling and diagnosis, and a greater likelihood of later diagnosis at an organ confined stage. CONCLUSIONS: These results demonstrate that in a prospective setting with long-term followup free PSA strategies can be identified that decrease unnecessary biopsies, while preserving or even improving cancer detection. Thus, total and free PSA can be combined without the need to weigh subjectively the trade-offs and relative costs of false-negative and false-positive results.     

Prostate specific antigen testing and digital rectal examination before and during a randomized trial of screening for prostate cancer: European randomized study of screening for prostate cancer, Rotterdam

PURPOSE: Worldwide 2 large-scale randomized screening trials for prostate cancer have been initiated. Determining prostate specific antigen (PSA) involves a simple test that may influence the outcome of these trials if frequently done in the control arm or before study enrollment. We quantified PSA and digital rectal examination before and during the screening trial in Rotterdam, The Netherlands and in the general population. MATERIALS AND METHODS: Trial participants were administered study intake questionnaires on tests done before study participation. Data on PSA from the regional general practice laboratory were correlated with participant data. Various sources were used to quantify PSA tests and digital rectal examinations in the general population. RESULTS: Of men 55 to 74 years old 45% underwent digital rectal examination at 1 time and 13% reported that PSA was tested before trial participation. Each rate increased with age. No statistically significant effect of former PSA testing or digital rectal examination on the cancer detection rate was identified. The rate of PSA determination after initial screening and/or randomization in the control arm was 2-fold that in the screening arm (76 versus 33/1,000 person-years). PSA determination initially decreased in the screening arm but increased rapidly after some time. The number of PSA determinations in the general population was estimated to be 45/1,000 person-years at ages 55 to 69 years. CONCLUSIONS: PSA testing was moderate in the control arm but if different men undergo this test each year, the contamination rate may become rather high. In the final analysis of mortality PSA testing should be considered.