Differences in characteristics of men with localised prostate cancer who demonstrate low, intermediate or high prostate-specific antigen velocity.

BACKGROUND: Current diagnostic tools are inadequate for reliable prediction of prostate cancer (PCa) aggressiveness in patients with localised disease. This results in many patients being exposed to potentially unnecessary invasive treatment and its associated morbidities. In order to develop appropriate treatment strategies, it is essential to understand the differences between patients who will develop aggressive disease and those who will not. METHODS: A longitudinal study was conducted in men with localised PCa on active surveillance for their disease in which 140 subjects were followed every 3 months for up to 5 years. Change in prostate-specific antigen (PSA) over time (PSA velocity) was used as a marker for PCa progression. Subjects were categorised as slow, intermediate and fast progressors based on tertiles of PSA velocity. Differences in baseline markers were investigated using logistic regressions. Two approaches were used, slow progressors were compared with fast progressors (model 1) and slow progressors were compared with combination of intermediate and fast progressors (model 2). RESULTS: Aspirin was negatively associated with high PSA velocity in model 1 (odds ratio (95% confidence interval): 0.24 (0.06, 0.94), P-value = 0.04) and model 2 (odds ratio = 0.22 (0.08, 0.59), P-value = 0.003), whereas smoking was positively associated with high PSA velocity in model 1 (1.03 (0.92, 1.13), P-value = 0.01). CONCLUSIONS: These findings highlight the role of aspirin and smoking in PCa progression. They have potential towards risk stratification as well as PCa prevention and hence need to be investigated further.

MVA-MUC1-IL2 vaccine immunotherapy (TG4010) improves PSA doubling time in patients with prostate cancer with biochemical failure.

PURPOSE: TG4010 is a recombinant MVA vector expressing the tumor-associated antigen MUC1 and IL2. We explored the effect two schedules of TG4010 on PSA in men with PSA progression. PATIENTS AND METHODS: A randomized phase II trial was conducted in 40 patients with PSA progression. Patients had PSA doubling times less than 10 months, with no overt evidence of disease. Patients received either weekly subcutaneous injection (sc) of TG4010 10(8) pfu for 6 weeks, then one injection every 3 weeks or sc injection of TG4010 10(8) pfu every 3 weeks. RESULTS: The primary endpoint of a 50% decrease in PSA values from baseline was not observed. Nevertheless, 13 of 40 patients had a more than two fold improvement in PSA doubling time. Ten patients had their PSA stabilized for over 8 months. Therapy was well tolerated. CONCLUSIONS: Although the primary endpoint was not achieved, there is evidence of biologic activity of TG4010 in patients with PSA progression, further investigation in prostate cancer is warranted.

ATP assay: ability to distinguish cytostatic from cytocidal anticancer drug effects.

A bioluminescence assay for ATP was adapted to human cancer cell lines and used to study the effect of anticancer drugs on malignant cell growth by following serial ATP measurements. Eleven drugs were tested against a colon cancer cell line (WiDR). Excellent correlation was observed between simultaneously performed soft-agar colony-forming assays and the ATP assay. In addition, cytostatic (growth inhibitory) drug effects could be distinguished from cytocidal (lethal) effects by using the ATP assay. Cytocidal drugs resulted in a reduction of ATP level below baseline levels, whereas cytostatic drugs merely yielded a reduction in the rate of increase in ATP level, i.e., slower growth. Such characterizations are not possible in colony-forming assays. Changes in ATP were correlated with the number of viable cells present. Drug concentration and duration of exposure both were important. Some drugs became cytocidal only when exposures longer than the customary 1 hour were used. The ATP assay has excellent potential as a simple, inexpensive, and rapid technique for new drug screening in cell lines, with classification of drug effects as cytostatic or cytocidal.

Growth in semisolid agar of prostate cancer cells obtained from bone marrow aspirates.

Thirty-one bone marrow aspirations were performed on patients with prostatic carcinoma metastatic to bone. After separation over a Ficoll-Hypaque gradient viable nucleated cells were cultured in semisolid agar. Colony formation occurred in 14 of 27 (52%) nonbacterially contaminated cultures. Characterization of cells from the colonies showed them to be consistent with malignant prostate cells. After staining, these cells were periodic acid-Schiff positive, prostatic acid phosphatase positive, and prostatic specific antigen positive. Other studies demonstrated the cells to be karyotypically abnormal, ultrastructurally similar to epithelial cells, and capable of secondary colony formation. Three bone marrow aspirate specimens did not have metastatic prostatic carcinoma detected by standard methods but did demonstrate colony formation. However, colony formation was most frequently seen when a radionuclide scan was positive at the aspiration site and when tumor cells were microscopically detectable by Wright staining of a smeared aspirate. The potential utility of colony forming cultures in prostate cancer is discussed. In working with bone marrow aspirates, additional cell separation procedures may be required to calculate and maximize plating efficiencies.

Adrenal steroid levels in castrated men with prostatic carcinoma treated with aminoglutethimide plus hydrocortisone.

Monthly serum dehydroepiandrosterone sulfate, androstenedione, testosterone, dihydrotestosterone, and free testosterone levels were measured in 94 of 129 patients with castration resistant prostatic carcinoma treated on a clinical protocol with aminoglutethimide (1000 mg/day) plus hydrocortisone (40 mg/day) Base-line steroid levels were not found to be age related. Therapy reduced the median levels of all monitored steroids but this suppression was not uniform. Although 87% of dehydroepiandrosterone sulfate levels were suppressed compared to base-line measurements, only 52% of androstenedione and 49% of testosterone levels were reduced. Androstenedione levels in 34% of patients actually rose to greater than twice base-line levels with similar but less frequent rises seen in testosterone, free testosterone, and dihydrotestosterone levels. The highest testosterone level measured was 190 ng/ml. Neither the cause, the deviation, nor the clinical significance of the androgen rise seen in these patients was established. Therapy with aminoglutethimide plus hydrocortisone as administered in this study may not uniformly achieve the objective of suppressing adrenal androgen production.

In vitro chemosensitivities of human tumor stem cells to the Phase II drug 4'-(9-acridinylamino)methanesulfon-m-anisidide and prospective in vivo correlations.

A potential application of the human tumor stem cell colony assay is to guide Phase II clinical investigations by identifying classes of tumors (or individual patients) which are sensitive in vitro to a new antitumor compound. We have tested human tumor stem cells from 140 tumor biopsies representing 20 different tumor types for chemosensitivity to the Phase II drug 4'-(9-acridinylamino)methanesulfon-m-anisidide. In vitro sensitivity was defined as a reduction in the number of tumor colony-forming cells to 30% of the control or less after a 1-hr exposure to one-tenth of the pharmacologically achievable plasma concentration of 4'-(9-acridinylamino)methanesulfon-m-anisidide. In vitro sensitivity was found in 29 cases: non-Hodgkin's lymphoma (2 of 2); cervical carcinoma (1 of 1); sarcoma (3 of 6); neuroblastoma (1 of 2); acute myelogenous leukemia (6 of 16); chronic myelogenous leukemia (1 of 3); melanoma (8 of 34); uterine carcinoma (1 of 5); lung carcinoma (1 of 9); ovarian carcinoma (4 of 36); and breast carcinoma (1 of 11). Prospective in vitro-in vivo correlations in eight patients with various tumor types showed that three of three patients sensitive in vitro to 4'-(9-acridinylamino)methanesulfon-m-anisidide responded in vivo, while five of five patients resistant in vitro had no clinical response. The results provide support for further evaluation of the utility of the human tumor stem cell colony assay for targeting Phase II clinical trials.

Cytokeratin characterization of human prostatic carcinoma and its derived cell lines.

Two murine monoclonal anti-cytokeratin antibodies with defined specificity were shown to distinguish between basal cells and luminal cells in human prostate tissue. Forty-one biopsies or transurethral resection specimens were characterized using these two antibodies. In cases of benign prostatic hyperplasia, focal loss of the basal cell layer was noted in areas of glandular proliferation. Ten cases of adenocarcinoma of the prostate, varying in Gleason's histological grade from 2 to 4, were also studied. In each case the carcinoma was shown to represent the luminal cell phenotype with no evidence of involvement of the basal cell phenotype. An analysis of three established metastatic prostatic carcinoma cell lines (DU-145, PC-3, and LNCaP) using two-dimensional electrophoresis showed that the cytokeratin complement of each cell line was slightly different but retained the phenotype of the luminal cell. It was concluded that during both hyperplasia and neoplastic transformation of the prostate, the luminal cell phenotype is primarily involved and that the basal cell phenotype does not appear to contribute to either intraluminal proliferation or invasive cell populations.

A reassessment of the clinical implications of the superior vena caval syndrome.

For the past 30 years patients presenting with the superior vena caval syndrome (SVCS) have, as a recommended practice, been treated with radiotherapy without necessarily establishing a tissue diagnosis. This practice has been pursued as it was accepted that the probability that unresectable lung cancer was the cause of the syndrome was high; that SVCS was a condition for which diagnostic procedures carried a high risk; and that SVCS was a life-threatening situation requiring immediate relief. To assess the validity of this practice, the literature since 1934 was reviewed. One thousand nine hundred eighty-six cases of reported SVCS were identified resulting in the emergence of several important facts: (1) small cell lung cancer is currently the leading etiology of SVCS accounting for approximately 40% of all cases due to lung cancer; (2) the experience with performing thoracotomies, mediastinoscopies, bronchoscopies, lymph node biopsies, and venograms as reported in the literature suggests that all of these diagnostic procedures can be performed safely; (3) while the SVCS can cause worrisome symptomatology, there is little reported clinical or experimental evidence that an unrelieved SVCS is life threatening; and (4) patency of the SVCS may not be reestablished after palliative therapy even though signs and symptoms may resolve. Because of therapeutic advances in the treatment of small cell lung cancer, lymphoproliferative disorders, and other malignant etiologies of the SVCS, the findings of this review suggest that a policy of treatment without histologic diagnosis is ill advised.

Predictive initial parameters for response of stage D prostate cancer to treatment with the luteinizing hormone-releasing hormone agonist goserelin.

One hundred eighteen patients with stage D (D1 or D2) prostate cancer with a mean age of 69 years were treated with monthly goserelin (Zoladex; ICI 118, 630; ICI Americas Inc, Wilmington, DE, property of Imperial Chemical Industries PLC) injections and the data were analyzed for predictive parameters for best response and time to treatment failure (National Prostatic Cancer Project [NPCP] and Eastern Cooperative Oncology Group [ECOG] criteria). For best response in a univariate analysis, the performance status (PS 0-1 v 2-3) (P = .01), hematocrit (P = .04), and pain (P = .04) were significant. For time to treatment failure by univariate analysis, ECOG performance status (0-1 v 2-3) was most predictive (P less than .0001), followed by pain at entry (P = .0002), initial testosterone (T) level (greater than 250 ng/dL) (P = .0005), age less than 69 years (P = .02), alkaline phosphatase (less than 115 IU/L) (P = .03), hemoglobin (less than 14 g/dL) (P = .03), whereas normal acid phosphatase (less than 3 IU/mL) (P = .29) was not predictive. In multivariate analysis for time to treatment failure, only the ECOG performance status was of significance (P = .01). Estimated median time to treatment failure for PS of 0-1 was 88 weeks and for PS of 2-3 was 31 weeks.

Zoladex: a sustained-release, monthly luteinizing hormone-releasing hormone analogue for the treatment of advanced prostate cancer.

Zoladex, a sustained-release luteinizing hormone--releasing hormone (LHRH) analogue administered by subcutaneous injection every 28 days, was evaluated at three dose levels in 46 men with untreated advanced prostate cancer. All three Zoladex doses yielded similar endocrinologic effects. After initial transient increases in serum luteinizing hormone, follicle-stimulating hormone, and testosterone concentrations, serum testosterone was suppressed uniformly to castration levels within 22 days. At a median follow-up of 41 weeks, Zoladex had maintained persistent suppression of serum testosterone. Measurements of serum Zoladex levels indicated that release of the drug from the injected depot was sustained over a period of 1 month and that there was no drug accumulation as evaluated over an initial 3-month period. No antibodies to Zoladex were detected. Tumor regression rates and side effects with Zoladex therapy were similar to those reported with daily injections of subcutaneous LHRH therapy. Signs and symptoms consistent with a brief tumor flare after the first injection of the LHRH analogue were noted in eight (17%) of the study entrants. Spinal cord compression was observed in two patients within 1 week from the onset of therapy. Zoladex is considered to be an effective, sustained-release LHRH analogue for the treatment of patients with prostate cancer.

Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial.

PURPOSE: To evaluate the effectiveness and safety of samarium-153 (153Sm) lexidronam (EDTMP) in a double-blind, placebo-controlled study. PATIENTS AND METHODS: Patients with painful bone metastases secondary to a variety of primary malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia. RESULTS: One hundred eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg of active drug had significant reductions in pain during each of the first 4 weeks in both patient-rated and physician-rated evaluations. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg, of active drug. A significant correlation (P = .01) was observed between reductions in opioid analgesic use and pain scores only for those patients who received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity. CONCLUSION: A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded.

Tin-117m(4+)DTPA: pharmacokinetics and imaging characteristics in patients with metastatic bone pain.

UNLABELLED: Biokinetics and imaging characteristics of 117mSn(4+)DTPA have been studied in patients with metastatic bone pain. METHODS: Seventeen patients with bone pain due to metastasis were given three dose levels: 180 microCi/kg (6.66 MBq/kg), 229 microCi/kg (8.47 MBq/kg) and 285 microCi/kg (10.55 MBq/kg) body weight. Periodic blood and daily urine samples were collected for 14 days to measure percent injected activity retained in blood and that excreted in urine. Simultaneous anterior and posterior view whole-body images were obtained under identical scan settings at 1, 3.5 and 24 hr and on Days 3 and 7 and between 4-6 and 8-10 wk postinjection. The total body retention was calculated using the geometric mean counts. RESULTS: After intravenous injection, the total body clearance of 117mSn(4+)DTPA shows two components: a soft-tissue component and a bone component. The soft-tissue component accounts for 22.4% of the dose and consists of four subcomponents with an average biologic clearance half-time of 1.45 days (range 0.1-3.2 days). The bone component accounting for the remaining 77.6% of the dose shows no biologic clearance. A mean 22.4% of the dose is excreted in urine in 14 days; 11.4% within 24 hr. The uptake pattern appears similar to that of 99mTc-MDP. Peak uptake is observed in normal bone by 24 hr and metastatic lesions by 3-7 days. Pain palliation was observed with all three doses levels. CONCLUSION: Among the four potential bone pain palliation radionuclides, 117mSn(4+)DTPA demonstrates the highest bone uptake and retention. Some biokinetic and radionuclidic features of 117mSn(4+)DTPA are similar to other agents, but many features are different and unique and may make it an ideal bone pain palliation agent. Double-blind comparative studies are needed to determine its exact role in bone pain palliation.

Treatment of castration-induced menopausal symptoms with low dose diethylstilbestrol in men with advanced prostate cancer.

Menopausal symptoms manifesting as hot flashes and sweats occur in up to 75 percent of patients following either orchiectomy or treatment with a luteinizing hormone-releasing hormone agonist for prostate cancer. As many as one third of these patients will experience symptoms severe enough to seek palliation. We treated 12 such patients with low dose diethylstilbestrol (1/3 mg daily). Nine patients demonstrated both objective and subjective improvement in their menopausal symptoms. Five patients experienced toxicity including new onset of gynecomastia or breast soreness although no patient discontinued treatment on this basis. No cardiovascular complications were noted. We conclude that low dose diethylstilbestrol is an inexpensive, effective means of controlling troublesome postorchiectomy menopausal symptoms in carefully selected patients.

Ketoconazole-induced adrenal crisis in a patient with metastatic prostatic adenocarcinoma: case report and review of the literature.

Ketoconazole has been used with success to treat disseminated intravascular coagulation and acute spinal cord compression syndromes associated with metastatic prostatic adenocarcinoma. It effects prompt, reversible medical castration, making it especially useful as empiric therapy when histologic diagnosis is delayed but prostate cancer is suspected. Side effects are usually limited to asthenia, nausea, diarrhea, and gynecomastia, but a theoretical risk of adrenal suppression exists. We report a case of fulminant adrenal crisis precipitated by ketoconazole given on a 6-hour dosing schedule in a patient with nerve root compression secondary to prostatic metastases. Through a review of the literature, we attempt to provide a better understanding of the use and potential dangers associated with ketoconazole therapy.

Cranial metastases from prostate cancer simulating meningioma: report of two cases and review of the literature.

Two cases of prostatic carcinoma metastatic to the cranium that presented with clinical and radiographic features simulating meningioma are described. The literature was reviewed, and 13 similar cases were identified. From the data gathered, we conclude that metastatic prostate cancer should be considered in the differential diagnosis of elderly males who present with characteristic clinical and radiological features of meningioma and that the classical description of meningioma is not specific.

The effect of digital rectal examination on serum levels of prostatic-specific antigen.

Serum prostate-specific antigen (PSA) and acid phosphatase (AP) levels were measured before and after digital rectal examination in 26 patients with varying genitourinary complaints. Prostate examination had no effect on the level of these markers. However, AP levels demonstrated greater within-day, intraindividual variance than PSA levels. Digital rectal examination does not appear to be a source of preanalytical error for serum PSA or AP determinations.

Dilemmas in managing prostate carcinoma (Part II): Metastatic disease.

All newly diagnosed patients should be evaluated for ureteral obstruction and impaired renal function. Partial ureteral obstruction frequently responds to androgen suppression therapy. Most patients eventually have significant pain, usually due to bone destruction from metastases. Pharmaceutical palliation is usually required. Drug intervention should be on a regular schedule--avoid prn dosage of pain medications.

Dilemmas in managing prostate carcinoma. (Part I): Localized disease.

Since we cannot predict which patients have biologically significant prostate carcinoma, except in the face of other known, significantly life-limiting disease, all palpable abnormalities should be considered for a diagnostic procedure. Negative core needle biopsy, fine needle aspiration, open perineal biopsy, transurethral biopsy, or urinary and prostatic fluid cytology results do not exclude cancer. If cancer is suspected, repeat biopsies and careful, frequent follow-up are mandatory.

Failure of allopurinol to provide clinically significant protection against the hematologic toxicity of a bolus 5-FU schedule.

Allopurinol has been shown to ameliorate the myelotoxicity of 5-fluorouracil (5-FU) given as an infusion. To study the potential effectiveness of allopurinol in modifying the toxicity of 5-FU given as a bolus, 8 adult patients with metastatic malignancies were given 11 courses of bolus 5-FU with allopurinol. Allopurinol was administered at a dose of 900 mg/day orally beginning a week prior to the 5-FU therapy and continued a week after the last dose of 5-FU was administered. Three patients received a total of 5 courses of 600 mg/m2 of 5-FU via bolus injection for 4 consecutive days every 28 days. Six patients were given 6 courses of 800 mg/m2 of 5-FU via bolus injection in the same schedule. Gastrointestinal toxicity was mild and no significant neurotoxicity was documented. However, severe myelosuppression occurred at the 800 mg/m2 dosage which led to marked leukopenia in 5 of the 6 patient courses and thrombocytopenia in 1. Gram-negative sepsis developed in 3 of the leukopenic patients with 2 resultant deaths. Allopurinol does not appear to allow clinically significant dose escalation of bolus 5-FU given on this schedule.