Phase II trial of tesmilifene plus mitoxantrone and prednisone for hormone refractory prostate cancer: high subjective and objective response in patients with symptomatic metastases.

PURPOSE: Symptomatic, hormone refractory prostate cancer (HRCAP) is a major cause of morbidity with a median survival of less than 12 months and a 2-year survival of only up to 10% in most series. Mitoxantrone has been approved by the Food and Drug Administration for HRCAP. Preliminary data suggest that DPPE (N,N-diethyl-2-[4-(phenylmethyl) phenoxy]-ethanamine) or tesmilifene modulates cytotoxics to enhance the anticancer effect. In this phase II trial we assessed whether there is sufficient evidence of enhanced efficacy of DPPE and mitoxantrone to lead to a phase III clinical trial. MATERIALS AND METHODS: A total of 29 patients with a median age of 73 years, of whom 10% were older than 80 years, with progressive HRCAP received 5.3 mg/kg DPPE intravenously every 3 weeks, 12 mg/m mitoxantrone intravenously every weeks and 5 mg prednisone orally twice daily. All patients had pain at presentation, while 97% had bone metastases, 10% had liver metastases and 17% had lung metastases. Median prostate specific antigen (PSA) was 210 ng/ml (IQR 77 to 430). RESULTS: Of the patients 75% had some pain improvement, 66% had decreased analgesia, 59% had a PSA decrease of 50% or greater and 45% had a PSA decrease of 75% or greater. Actual (not actuarial) 2-year survival was 21%. CONCLUSIONS: Despite major limitations of historical comparison the PSA decrease and decreased symptoms with DPPE-mitoxantrone-prednisone compare favorably to those of mitoxantrone-prednisone and docetaxel-estramustine in the literature. The 2-year survival rate of 21% mandates further assessment. This will be tested in a phase III Southwest Oncology Group trial.

Mycobacterial cell wall extract for treatment of carcinoma in situ of the bladder.

PURPOSE: Bacillus Calmette-Guerin (BCG) established immunotherapy as an effective modality for carcinoma in situ of the bladder and remains the most effective agent for treatment. However, as a live organism it has the potential for undesirable side effects and toxicity. This result has led to the search for other active and safer biological response modifiers. We investigated the efficacy of a mycobacterial cell wall extract (MCWE) from Mycobacterium phlei, which does not contain live bacteria, for management of carcinoma in situ of the bladder in humans. MATERIALS AND METHODS: The requirement for an emulsified preparation was investigated with photon correlation spectroscopy to determine the stability of the bacterial fragments. A total of 61 patients with histologically documented carcinoma in situ completed the study. Cell wall extract from M. phlei suspended in oil droplets to form an emulsion were instilled into the bladder at a dose of 4 mg. once weekly for 6 weeks and then monthly for 1 year. Response assessment was performed at 3-month intervals. Complete response to treatment indicated the absence of endoscopic and histological evidence of carcinoma in situ. Partial responders were those cases in which cystoscopy and biopsies were negative but cytology was suspicious for malignant cells. All other cases were considered failures. RESULTS: The need for an emulsified suspension of the cell wall extract was confirmed by the demonstration that the cell wall extract alone in urine aggregated, whereas the MCWE emulsion had remained stable. Kaplan-Meier estimates showed negative cystoscopy and biopsies in 62.5% at 12, 49.3% at 24 and 41.1% of patients at 60 weeks after therapy. After this point the number of responders had remained stable. Excellent tolerance with minimal toxicity was observed. CONCLUSIONS: Our study demonstrates clinical activity of low doses of MCWE against human bladder cancer. The results observed at the dosage used in our trial are less than those observed with live BCG. However, MCWE has a better toxicity profile and can be instilled in the presence of a disrupted urothelium. It also appears to exhibit activity in patients in whom BCG has failed.

Durability of results obtained with transurethral microwave thermotherapy in the treatment of men with symptomatic benign prostatic hyperplasia.

To assess the durability of the results of transurethral microwave thermotherapy (TUMT) for symptomatic benign prostatic hyperplasia (BPH), we have reviewed publications describing trials with at least 3 years of follow-up. For men treated only by TUMT, improvement in symptoms and quality of life appears to be maintained for at least 4 to 5 years. Improvement in peak flow rates is modest but is generally maintained, particularly after higher-energy therapies. These results represent responders, and a crucial question is the need for additional treatments. With lower-energy treatment, this is common: between 50% and 60% within 3 to 5 years. With higher-energy TUMT, the retreatment rate appears to be less, approximating 20% within 3 to 4 years. When comparing these results with those of transurethral resection, it should be noted that there is a significant failure rate with surgery, and even if failure is more common with TUMT, men may be prepared to accept this risk rather than the greater morbidity of prostatectomy.

Practice patterns of Canadian urologists in benign prostatic hyperplasia and prostate cancer. Canadian Prostate Health Council.

PURPOSE: We reviewed the practice patterns of Canadian urologists in benign prostatic hyperplasia (BPH) and prostate cancer, and assessed the changes that occurred between 1995 and 1998. MATERIALS AND METHODS: In 1995 and 1998 questionnaires were mailed to all active members of the Canadian Urological Association who practiced adult urology in Canada. Many questions were similar, allowing for the assessment of changes in practice patterns. RESULTS: A number of changes were observed between 1995 and 1998. Cystoscopy and imaging of the upper urinary tract were used less often to evaluate uncomplicated cases of BPH. However, 39% of respondents continued to perform cystoscopy routinely. Finasteride was no longer administered in men with a smaller prostate. In 1998 before radical prostatectomy 28% of respondents routinely performed a bone scan, 29% cystoscopy and 57% chest x-ray. The number believing that maximal androgen blockade is the most effective hormonal therapy decreased from 90% to 62%, while 24% reported in the 1998 survey that they frequently administered intermittent hormonal therapy. Comparison with an American study from 1995 indicated that American urologists used the American Urological Association symptom score and performed a prostate specific antigen test more frequently than Canadian urologists. However, Canadian urologists performed cystoscopy more frequently. CONCLUSIONS: These surveys provide a useful insight into the variations in clinical practice of Canadian urologists and help to determine whether changes are occurring in regard to the development of practice guidelines. They also indicate the need to develop further guidelines, and ensure that these guidelines are widely promoted and accepted by the urological community.

Benign prostatic hyperplasia: a review.

PURPOSE: To provide a review of the natural history, evaluation and management of men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). METHODS: Current literature and guidelines related to BPH were reviewed. RESULTS: The natural history of symptomatic BPH is variable and unpredictable. Initial symptom severity relates to the need for treatment while severity of symptoms, increased age, prostate size and decreased peak flow rate predict an increased incidence of urinary retention. Guidelines for the evaluation of men with LUTS have been developed but there is considerable variation in the extent of investigation among urologists. Complications secondary to BPH are uncommon and treatment decisions relate to improvement in quality of life. Drug therapy usually with an alpha blocker is generally the first treatment choice but for many men with minimal symptoms watchful waiting is an appropriate option. While a number of "less invasive" therapies have been extensively investigated and reported, they have not been widely adopted. Contemporary TURP has become a safer procedure with minimal hospital stay and remains, for many urologists, the interventional treatment of choice. CONCLUSION: BPH is a disease which impacts mainly on quality of life. Patients need to consider the benefits and harms of the treatment options. Treatment will depend on the availability of these treatments and on patient and physician preference.

Impact of a shared decision-making program on patients with benign prostatic hyperplasia.

OBJECTIVES: To determine patient views about the Shared Decision-Making Program (SDP), an interactive videodisk program designed to inform patients with benign prostatic hyperplasia (BPH) about their condition and treatment options and to determine its impact on perceived knowledge and treatment preference. METHODS: Six hundred seventy-eight patients with symptomatic BPH from eight Canadian centers viewed the SDP. Before and after viewing the video, patients answered questionnaires designed to assess treatment preference, knowledge gained, and satisfaction with this educational format. A 1-year follow-up survey was also conducted. RESULTS: Most patients showed a high desire for information and high satisfaction with the SDP; this satisfaction persisted at 1 year. Patients' self-reported knowledge increased significantly (P <0.0001). However, the SDP did not alter initial treatment preferences among those with already formed preferences, although it aided almost half of those initially undecided in forming a preference. Viewing the SDP also appeared to enhance the physician-patient relationship. CONCLUSIONS: Patients saw the SDP as an effective method for teaching patients about BPH and the risks and benefits of various treatments, clarifying particular areas about which many patients appear to have a desire for more information than is often provided. Patients were enthusiastic about the educational value of the program, and their active participation in the decision-making process may actually enhance the physician-patient relationship. Contrary to other studies, we found no significant alterations in treatment preferences. Problems relating to the cost and timely updating of the software need to be addressed for these kinds of programs to realize their full potential.

Prostate cancer: 6. Surgical treatment of localized disease.

A 65-year-old man undergoes a routine checkup before retiring. His wife has urged him to have his prostate examined, because she has read about testing for prostate cancer and a friend has just died of this disease. During the rectal examination, the man's physician discovers some firmness in the right lobe of the prostate gland. The patient has had no urinary symptoms and is in excellent general health. Sexual function is normal. There is no history of prostate cancer; his father died of a stroke at age 86 years. Testing shows that the patient's prostate-specific antigen level is 9.3 ng/mL, and he is referred to a urologist. Transrectal ultrasound-guided needle biopsy reveals adenocarcinoma with a Gleason score of 7 (intermediate grade). At a follow-up meeting with his physician, the patient says, "I have been doing some research, and it appears that I should have treatment. However, what is less clear to me is what form of therapy is best--surgery or radiation treatment. Please tell me what you can about the state of the art with respect to surgery."

Transurethral microwave thermotherapy in the treatment of benign prostatic hyperplasia: results obtained with the Urologix T3 device.

The objective of this study was to assess the efficacy and safety of a new transurethral microwave thermotherapy device, T3, in the treatment of symptomatic benign prostatic hyperplasia. A total of 155 patients were recruited at 3 sites and treated using an identical protocol. The mean AUA symptom score decreased by 58% at 12 months, by 61% at 24 months and by 56% at 36 months. The increase in mean peak flow rates at these time points was 3.9 (47%), 3.4 (44%) and 5.1 ml/s (67%), respectively. Adverse events were minor and the patients' satisfaction with treatment was high. Transurethral microwave thermotherapy with the T3 device provides a safe, effective treatment for symptomatic benign prostatic hyperplasia.

Office treatment of benign prostatic hyperplasia.

The less invasive procedures described herein are suitable for use in the office setting. Improvement in symptoms and quality of life are similar to that achieved with TURP. With the exception of TUIP, flow rate improvement is less than with TURP. TURP, however, tends to produce a "super normal" flow rate, which may be unnecessary. Patients are concerned regarding symptoms and quality of life and the avoidance of complications. In regard to decreased complications, less invasive procedures have an advantage. The main concern with these new treatments, with the exception of TUIP, is durability. Treatment failure may lead to other treatments, thereby increasing overall management costs. In this regard, it must be remembered that there is a significant treatment failure rate with TURP. Although patients failing less invasive treatments are likely to be offered other treatments, this is less likely after an adequate TURP. Therefore, when results are compared, it may be more appropriate to evaluate failure rates based on symptoms and quality of life rather than on the use of additional treatments. More patient follow-up for a longer period of time will be required before a definite answer is available on durability. All of the procedures described herein can be performed to a variable extent using topical anesthesia. TUNA has been performed using topical lidocaine alone but frequently requires intravenous sedation/analgesia and, in some instances, a regional block. If the patient can tolerate rigid cystoscopy fairly well, topical anesthesia alone may suffice. Similar requirements for anesthesia apply to ILC with the Nd:YAG or indigo systems. Using the Targis (T3) microwave device, Peterson and co-workers reported that 60% of patients were treated with topical urethral lidocaine alone, whereas 40% also received oral Toradol. Djavan (personal communication) using the Targis (T3) device randomized patients to topical urethral anesthesia alone or combined with intravenous sedoanalgesia. Pain was evaluated using a 0 to 10 visual analog scale score. At the commencement of treatment, the mean score was 1.4 in the topical anesthesia alone group and 1.3 in the sedoanalgesia group. During therapy, the score increased to a peak at 30 minutes of 2.2 and 2.0 in the topical and sedoanalgesia groups, respectively. After this, the visual analog score declined, falling to 0.2 and 0.1, respectively, by 1 hour following treatment. This study shows that microwave treatment with the Targis (T3) system is well-tolerated using topical urethral anesthesia alone. No difference was observed between outcomes in the two groups. Capital and operating costs as well as reimbursement issues are important in the introduction of these treatments into the office; however, until more information is available on the durability of results, the cost-effectiveness of these newer treatments remains unclear.

A novel transurethral microwave thermal ablation system to treat benign prostatic hyperplasia: results of a prospective multicenter clinical trial.

PURPOSE: We evaluated the efficacy, safety and impact on quality of life of a newly designed microwave thermal ablation system in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Microwave thermal ablation was administered to 154 BPH patients at 3 centers in Canada and the United Kingdom during a single 1 to 2-hour office or clinic procedure without general or regional anesthesia and without need for potent medications necessitating intensive patient monitoring. Various measures of symptoms, voiding function and patient quality of life were assessed at baseline, 6 weeks, and-3, 6, 9 and 12 months after treatment. RESULTS: Mean American Urological Association symptom score 12 months after treatment (8.8, 95% confidence interval 7.7 to 10.0) was significantly lower (p < 0.05) by 56% than that at baseline (20.1, 95% confidence interval 19.1 to 21.0). The incidence of mild symptoms increased from 0 to 57%, while that of severe symptoms decreased from 49 to 8%. There was a significant increase (p < 0.05) in peak flow rate of 45% from 9.3 ml. per second (95% confidence interval 8.8 to 9.7) at baseline to 13.4 ml. per second (95% confidence interval 12.5 to 14.4) at 12 months. Similar symptomatic and urodynamic improvements occurred in all prostate volume categories. Convalescence was rapid after treatment with little or no need for home bed rest or restriction of usual activities. Patients expressed a high level of satisfaction with treatment and found the prostate symptoms to be significantly more tolerable. Adverse events were infrequent, transient and readily managed. CONCLUSIONS: Microwave thermal ablation proved to be safe and effective for treatment of BPH with a significant positive impact on patient quality of life.

Renal autotransplantation in patients with loin pain-hematuria syndrome.

OBJECTIVE: To determine if renal autotransplantation is an effective treatment for the loin pain-hematuria syndrome. DESIGN: Retrospective chart review. SETTING: Tertiary care referral centre in Manitoba. PATIENTS: Four patients referred for diagnosis and management of loin pain-hematuria syndrome. Follow-up for each of the four was 2, 24, 29 and 48 months. INTERVENTION: Renal autotransplantation. MAIN OUTCOME MEASURES: Relief of pain with preservation of renal function and blood pressure. RESULTS: All four patients experienced relief of the pain of loin pain-hematuria syndrome. Renal function was preserved and blood pressure maintained. Narcotic analgesia was discontinued in all cases. CONCLUSION: Renal autotransplantation appears to be an effective treatment for patients with loin pain-hematuria syndrome.

A multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of terazosin in the treatment of benign prostatic hyperplasia.

OBJECTIVES: This study was designed to evaluate the safety and efficacy of the selective alpha 1-adrenoceptor blocker terazosin in the treatment of benign prostatic hyperplasia (BPH). METHODS: Two hundred twenty-four patients aged 50 to 80 years, who had a diagnosis of BPH based on medical history, physical examination, and digital palpation, were recruited from 11 different sites between January 1992 and January 1994. The study consisted of a screening phase, a placebo phase, a double-blind dose-titration phase, and a double-blind maintenance phase. RESULTS: Of the patients recruited, 164 entered the double-blind phase and of these 134 were evaluable. Only 11 patients withdrew because of an adverse event, 7 in the terazosin and 4 in the placebo group. Compared to placebo, terazosin significantly increased peak and mean urine flow rates without significantly affecting voided volume or postvoid residual volume. It significantly improved both the obstructive and irritative symptoms associated with BPH. Fifty-one patients from the terazosin group reported a total of 120 adverse events compared with 83 reported by 42 patients in the placebo group. The majority of these events were mild to moderate. Seventeen terazosin-treated patients reported hypotension-related adverse events and 4 withdrew from the study. However, concurrent treatment with antihypertensive agents did not affect the blood pressure response of the terazosin group. CONCLUSIONS: Overall, this study showed terazosin to be safe and effective in relieving the signs and symptoms of BPH and should be considered as a treatment alternative.

N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine in combination with cyclophosphamide: an active, low-toxicity regimen for metastatic hormonally unresponsive prostate cancer.

PURPOSE: The intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine. HCl (DPPE), potentiates chemotherapy cytotoxicity to malignant cells but protects normal tissue, including bone marrow, gut, and hair. We assessed the response to and clinical toxicity of DPPE/cyclophosphamide therapy in 20 patients with advanced hormonally unresponsive prostate cancer, 19 of whom were symptomatic. PATIENTS AND METHODS: Subjects received a maximally tolerated dose of DPPE (6 mg/kg) intravenously (IV) over 80 minutes. Cyclophosphamide (600 to 800 mg/m2; maximum dose, 1,500 mg) was administered over the last 20 minutes of DPPE infusion. Treatments (usually outpatient) were given once weekly for 4 weeks, followed by a 1-week delay, and then 2 of every 3 weeks as long as the patient was deemed to benefit. RESULTS: Five of seven patients (71%) with measurable soft tissue disease had a partial remission (PR). Three of 16 (19%) with assessable bone disease responded (one complete remission [CR] and two PRs). Nine of 18 (50%) with an elevated serum level of prostate-specific antigen (PSA) had more than a 50% (mean +/- SD, 78% +/- 14%) decrease. Eleven of 13 (85%) with bone pain had partial or complete resolution of this symptom; the PSA level and bone scan improved in six and two of these subjects, respectively. Acute treatment toxicity consisted of nausea/vomiting (six of 20) and ataxia (20 of 20), which correlated with peak serum levels of DPPE. Delayed effects (24 to 48 hours) consisted mainly of tiredness and mild nausea; one patient developed hemorrhagic cystitis. Bone marrow and hair follicle toxicity was negligible in 14 and 15 patients, respectively. CONCLUSION: DPPE/cyclophosphamide appears to be an active regimen for metastatic prostate cancer, with the added benefit of relatively low toxicity.

Transurethral microwave thermotherapy in the treatment of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate uncommon before the age of 40 but occurring in most men as they age. The symptoms of BPH are generally attributed to bladder outlet obstruction from the enlarging prostate gland. However, not all men with enlarged prostates are symptomatic, and similar voiding symptoms can occur from other causes in the absence of BPH. Symptomatic BPH is a major health problem and a major expense to the healthcare system. Transurethral resection of the prostate (TURP) has been the treatment of choice for over 50 years, and until recently, approximately 400,000 TURPs have been performed annually in the United States at an estimated cost of $4 billion to $5 billion per year. TURP is an effective treatment for relief of prostatic obstruction and has generally been referred to as the gold standard.

Total androgen ablation: Canadian experience.

A multicenter randomized, double-blind trial comparing total androgen blockade obtained by the use of castration with a pure anti-androgen (nilutamide) with simple castration was begun. One hundred and five patients received the combined treatment and 103 the orchiectomy plus placebo. Several features were used to evaluate the efficacy. Bone pain responded better to combined treatment at 6 months (P = 0.042). The number of favorable responses, as evaluated by the NPCP criteria, was 61% with simple castration and 78% with the combined treatment (P = 0.013). There was no statistically significant difference between the two groups in time to progression (logrank test P = 0.462) or survival (logrank test P = 0.137) despite an increase in median survival of 5.4 months. All other measures showed no difference between the two treatments. With total androgen blockade, 50% of the patients had disease progression at 1 year, and 45% were dead at 2 years. A review of the results of similar reported studies suggests no improvement or very modest improvement with total androgen blockade over testicular androgen ablation alone.

A controlled trial of castration with and without nilutamide in metastatic prostatic carcinoma.

A randomized double-blind trial in patients with disseminated, previously untreated prostate cancer (Stage D2) was conducted in eight Canadian centers. All 203 patients enrolled in this study underwent bilateral orchiectomy and were randomized to receive either the nonsteroidal anti-androgen nilutamide or a placebo. Patient responses were graded according to the criteria of the National Prostatic Cancer Project (NPCP). Patients treated with nilutamide had a significantly greater number of positive objective responses (partial and complete regression) than did the patients treated with castration alone (46% versus 20%, P = 0.001). Progression-free survival was improved initially in the nilutamide group, but the median time to progression was 12 months for both groups. Despite an increase in the median length of survival from 18.9 to 24.3 months with the nilutamide, the survival time was not significantly longer in the nilutamide group (log = rank test, P = 0.048). Although minor side effects were frequent, adverse effects related to the medication and leading to discontinuation of treatment were observed in 9% of cases. These results suggest some benefit of the combined treatment (orchiectomy + nilutamide) over orchiectomy alone in the treatment of metastatic prostatic carcinoma.