A Phase II trial of 8 weeks of degarelix for prostate volume reduction: Efficacy and hormonal recovery.

PURPOSE: The purpose of this study was to determine the efficacy of 8 weeks of degarelix for prostate downsizing before interstitial brachytherapy. We also report associated toxicity and the time course of endocrine recovery over the following 12 months. METHODS AND MATERIALS: Fifty patients were accrued to an open-label Phase II clinical trial (www.clinicaltrials.gov ID NCT01446991). Baseline prostate transrectal ultrasound (TRUS) was performed on all patients followed by degarelix administration and a repeat TRUS at Week 8. Brachytherapy was performed within 4 weeks of the 8-week TRUS for all patients who achieved suitable downsizing. RESULTS: The median prostate volume was reduced from 65.0 cc (interquartile range [IQR]: 55.2-80.0 cc) to 48.2 cc at 8 weeks (IQR: 41.2-59.3 cc), representing a median decrease of 26.2% (IQR: 21-31%). Functional recovery of testosterone within an age-adjusted normal range occurred at a median of 34.1 weeks (IQR: 28.2-44.5 weeks) from the date of the final injection. Despite this recovery, follicle-stimulating hormone and luteinizing hormone levels remained abnormally elevated throughout 12 months. Quality-of-life implications are discussed. CONCLUSIONS: Degarelix is effective for prostate downsizing before prostate brachytherapy with a median volume decrease of 26.2% by 8 weeks. Despite the short course of treatment and eventual testosterone recovery, follicle-stimulating hormone and luteinizing hormone remain elevated beyond 12 months. Further investigation with randomized comparisons to other hormonal agents is warranted.

Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation.

BACKGROUND: Acetylcholine is important to hippocampal function, including the processes of learning and memory. Patients with schizophrenia show impaired learning and memory and hippocampal dysfunction. Thus, acetylcholinergic systems may be primarily or secondarily disrupted in the hippocampal formation of schizophrenic patients. The present study tested the hypothesis that [(3)H]pirenzepine-labeled muscarinic cholinergic receptor levels are altered in the hippocampal formation of patients with schizophrenia. METHODS: We have used quantitative autoradiography to measure [(3)H]pirenzepine binding to M(1) and M(4) receptors in the hippocampal formation from 15 schizophrenic and 18 nonschizophrenic subjects. RESULTS: The mean density of [(3)H]pirenzepine binding was reduced in all regions studied, including the dentate gyrus, subdivisions of Ammon's Horn (CA1-CA4), subiculum, and the parahippocampal gyrus, of the schizophrenic cohort. Moreover, unlike controls, there was no significant variation between the mean levels of [(3)H]pirenzepine binding across the subregions of the hippocampal formation from schizophrenic subjects. CONCLUSIONS: These findings provide support for a possible involvement of the muscarinic cholinergic system in the pathology and/or treatment of schizophrenia.

Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment.

OBJECTIVE: Aberrant cholinergic inputs and synaptic neurotransmission in the prefrontal cortex induce cognitive impairment, which is a central feature of schizophrenia. Postsynaptic excitatory muscarinic cholinergic M(1) and M(4) receptors are the major cholinoceptive targets in the prefrontal cortex and hence may be involved in the pathology and/or pharmacotherapeutics of schizophrenia. METHOD: Using quantitative autoradiography, the authors analyzed the binding of the M(1)/M(4) receptor selective antagonist [(3)H]pirenzepine in prefrontal cortex (Brodmann's areas 8, 9, 10, and 46) from schizophrenia patients who had (N=6) or had not (N=11) been treated with the anticholinergic agent benztropine mesylate and from normal comparison subjects (N=20). Moreover, preliminary studies of [(3)H]pirenzepine binding in rat frontal cortex following administration of antipsychotic drugs or benztropine mesylate were performed. RESULTS: Relative to those of comparison subjects, the mean levels of [(3)H]pirenzepine binding were significantly lower in Brodmann's areas 9 and 46 of the schizophrenia patients not treated with benztropine mesylate (18% lower in Brodmann's area 9 and 21% lower in Brodmann's area 46) and in all four examined regions of the patients who had received benztropine (51%-64% lower). Antipsychotic or anticholinergic drugs tended to increase or have no effect on the density of [(3)H]pirenzepine-labeled receptors in rat frontal cortex. CONCLUSIONS: Because M(1) and M(4) receptors are critical to the functions of prefrontal cortical acetylcholine, the present findings suggest a functional impairment in cholinergic neurotransmission in schizophrenia and the possibility that muscarinic receptors are involved in the pharmacotherapeutics of the disorder.

Dosimetric methods in the optimization of radiotherapy for carcinoma of the uterine cervix.

Pelvic failures and late radiation sequelae were analyzed using the dosimetric parameters of ICRU Report 38 for 338 patients with Stage I-III carcinoma of the uterine cervix treated by radiation alone and followed for a minimum of 2 years. The pelvic recurrence rates were: Stage IB 5.1% (N = 118, 1% pelvis alone), Stage IIA 15.1% (N = 53, 9.4% pelvis alone), Stage IIB 15.8% (N = 76, 9.2% pelvis alone) and Stage IIIB 28.9% (N = 76, 17.1% pelvis alone). For Stages I and II pelvic failure was unrelated to cumulated lateral parametrial dose (CDPW) or reference volumes, but for Stage IIIB was higher for CDPW above 65 Gy. Overall complication rates were: grade 3-10.1% and grade 2-18.1% but were much lower for 176 patients treated with stem and ovoids (S + O: grade 3-5.7%, grade 2-15.7%) than for 43 receiving vaginal cylinders (grade 3-37.2%, grade 2-28%). Grade 3 rectal complications associated with cylinders were related to a maximal vaginal application over 1.50 cGy X m2 of total reference air kerma (or 2080 mgh) and cumulated rectal reference doses (CDRref) above 75 Gy. For the S + O group, grade 2 and 3 rectal complications increased with increasing reference volumes (hwt and HWT) and showed dose thresholds for CDRref and CDRmean (grade 3: 75 Gy). Prospective use of zones of risk defined graphically on a dose-volume plot (CDRref vs HWT) has reduced our severe complication rate without reducing local control. This technique requires individualization of patient therapy, rapid access to computerized dosimetry and the establishment of center- and applicator-specific risks of complications.

Respiratory-induced prostate motion: quantification and characterization.

PURPOSE: The precise localization of the prostate is critical for dose-escalated conformal radiotherapy. This study identifies and characterizes a potential cause of inaccurate prostatic localization-respiratory-induced movement. METHODS AND MATERIALS: Prostate movement during respiration was measured fluoroscopically using implanted gold fiducial markers. Twenty sequential patients with CT(1)-T(3) N(0) M(0) prostate carcinoma were evaluated prone, immobilized in customized thermoplastic shells. A second 20 patients were evaluated both prone (with and without their thermoplastic shells) and supine (without their shells). RESULTS: When the patients were immobilized prone in thermoplastic shells, the prostate moved synchronously with respiration. In the study the prostate was displaced a mean distance of 3.3 +/- 1.8 (SD) mm (range, 1-10.2 mm), with 23% (9/40) of the displacements being 4 mm or greater. The respiratory-associated prostate movement decreased significantly when the thermoplastic shells were removed. CONCLUSION: Significant prostate movement can be induced by respiration when patients are immobilized in thermoplastic shells. This movement presumably is related to transmitted intraabdominal pressure within the confined space of the shells. Careful attention to the details of immobilization and to the possibility of respiratory-induced prostate movements is important when employing small field margins in prostatic radiotherapy.

Prognostic factors of local outcome for T1, T2 carcinomas of oral tongue treated by iridium 192 implantation.

The results of Iridium 192 implantation for 121 node negative T1 or T2 squamous carcinomas of mobile tongue were reviewed to look for predictors of local control and necrosis. Age, sex, total dose, dose rate, linear activity, and intersource spacing were examined. Minimum follow-up was 2 years but no patient with local recurrence or necrosis was excluded. There were 57 T1N0 tumors, 45 T2aN0 (2.1-3.0 cm), and 19 T2bN0 (3.1-4.0 cm). Local failures occurred in 14% of T1, 11% of T2a, and 26% of T2b. Univariate analysis showed that local control increased with increasing dose (55-60 Gy: 73%; 65-75 Gy: 92%, p = 0.005), whereas multivariate analysis revealed both sex and total dose to be significant. Radiation necrosis occurred in 17% of T1, 29% of T2a, and 47% of T2b (p = 0.034). Half were limited to soft tissue and the majority healed with conservative management. Univariate analysis showed that necrosis increased with increasing dose (55-60 Gy: 16%; 65-75 Gy: 33%, p = 0.037), as well as increasing dose rate, linear activity, and intersource spacing. With multivariate analysis only stage, dose rate, and spacing remained predictive of necrosis. Total dose was not adjusted for dose rate or tumor volume. This analysis suggests that within the therapeutic range of low dose rate brachytherapy, correction of total dose according to dose rate is unnecessary. We recommend 65 Gy. Lower dose rate (0.4-0.5 Gy/hr) and closer intersource spacing (12-14 mm) should be aimed for to minimize necrosis.

Interstitial iridium 192 for cutaneous carcinoma of the external nose.

Several implantation techniques useful for nasal skin carcinoma have been developed at the Henri Mondor Hospital in Créteil, France and are described in detail. Iridium 192 wires, 0.3 mm in diameter, are afterloaded into either supple plastic tubes or rigid needles implanted according to the rules of the Paris system. Dosimetry is performed by computer, based on either direct measurements of active lengths and spacing, orthogonal films or a tomogram oriented in the central plane of the implant. According to a recent review by the European Curietherapy Group of 468 implants, the optimal dose is 60 Gy. The overall failure rate was 2.6%. Indications for implantation and choice of technique, based on tumor size, site, and gross morphology are discussed.

Iridium 192 implantation of T1 and T2 carcinomas of the mobile tongue.

Between 1970 and 1986, 166 patients with T1 or T2 epidermoid carcinomas of the mobile tongue were treated by iridium 192 implantation (70 T1N0, 83 T2N0, 13 T1-2 N1-3). Five-year actuarial survival was 52% for T1N0, 44% for T2aN0, and 8% for or T1-2 N1-3. Cause specific survivals were 90%, 71%, and 46%, respectively. Local control was 87% for both T1N0 and T2N0, and 69% for T1-2 N1-3. Seven of 23 failures were salvaged by surgery, increasing local control to 96% for T1 and 90% for T2. Thirty-six patients developed a minor or moderate necrosis (16% T1, 28% T2). Half of these involved bone but only five required surgical intervention. Both local control (LC) and necrosis (nec) increased with increasing dose but improvement beyond 65 Gy is minimal (less than or equal to 60 Gy: LC = 78% nec = 13%; 65 Gy: LC = 90% nec = 29%; greater than or equal to 70 Gy: LC = 94% nec = 23%). For N0 patients, neck management consisted of surveillance (n = 78), elective neck dissection followed with external irradiation for pathologically positive nodes (n = 72), or irradiation (n = 3). Clinically positive nodes (13 patients) were managed by either neck dissection followed by external irradiation if pathologically positive (n = 10) or irradiation alone (n = 3). Regional control was 79% for N0 patients, improving to 88% after surgical salvage, and was 9/13 for N1-3 patients. We recommend that T1 and T2 carcinomas of the mobile tongue be treated by iridium 192 implantation to deliver 65 Gy. Mandibular necrosis should be reduced by using an intra-oral lead-lined dental mold.

Influence of GABA-induced remote inactivation on the orientation tuning of cells in area 18 of feline visual cortex: a comparison with area 17.

We have investigated the effect of iontophoretically applying the inhibitory transmitter gamma-aminobutyric acid (GABA) through four pipettes, each located at a horizontal distance of some 500-600 microns from the recording site, on the orientation tuning of cells in areas 17 and 18 of the cat visual cortex for moving the stationary flash-presented bar stimuli. Forty-five of 74 cells tested in area 18 (61%) showed a significant (greater than 25%) increase in orientation tuning width (at half the maximum response) during GABA application, which reflected an increase in response to non-optimal orientations. The mean orientation tuning width of these cells increased by 79%, and the ratio of responses to the orientation orthogonal to the optimum and to the optimum increased from 0.16 to 0.46. The results were similar to those from area 17, in which 36 of 54 cells (66%) showed significant broadening of orientation tuning during GABA application, with a 90% increase in mean tuning width and an increase in the relative response to the orientation orthogonal to the optimum from 0.17 to 0.42. The distributions of cells in areas 17 and 18 with respect to the magnitude of GABA-induced effects on orientation tuning width were not significantly different (mean increase in tuning width: area 17, 102%; area 18, 87%). Although most cells were tested only with moving bars, comparable effects of remote GABA application on orientation tuning were observed when stationary flash-presented bars were used. Of 11 cells thus tested in area 18, seven showed significantly broader tuning during GABA application, with a 132% increase in mean tuning width. In some 25% of cells in each area which showed a significant effect of GABA application on orientation tuning the response to at least one non-optimal orientation exceeded, during GABA application, the response to the previous optimum. There was essentially no correlation between the changes in orientation tuning and changes in the level of spontaneous activity or in the response to the optimum orientation during GABA application. Thus, an increase in the general excitability of recorded cells or the loss of an unspecific inhibitory input cannot account for the effects of GABA application on orientation tuning. Remote GABA application presumably inactivated cells with different preferred orientations from that of the recorded cell. It is thus argued that the observed broadening of orientation tuning during GABA application reflected the loss of an inhibitory input tuned to non-optimal orientations.(ABSTRACT TRUNCATED AT 400 WORDS)

Prostate motion during standard radiotherapy as assessed by fiducial markers.

From November 1993 to August 1994, 55 patients with localized prostate carcinoma had three gold seeds placed in the prostate under transrectal ultrasound guidance prior to the start of radiotherapy in order to track prostate motion. Patients had a planning CT scan before initial simulation and again at about 40 Gy, just prior to simulation of a field reduction. Seed position relative to fixed bony landmarks (pubic symphysis and both ischial tuberosities) was digitized from each pair of orthogonal films from the initial and boost simulation using the Nucletron brachytherapy planning system. Vector analysis was performed to rule out the possibility of independent seed migration within the prostate between the time of initial and boost simulation. Prostate motion was seen in the posterior (mean: 0.56 cm; SD: 0.41 cm) and inferior directions (mean: 0.59 cm; SD: 0.45 cm). The base of the prostate was displaced more than 1 cm posteriorly in 30% of patients and in 11% in the inferior direction. Prostate position is related to rectal and bladder filling. Distension of these organs displaces the prostate in an anterosuperior direction, with lesser degrees of filling allowing the prostate to move posteriorly and inferiorly. Conformal therapy planning must take this motion into consideration. Changes in prostate position of this magnitude preclude the use of standard margins.

Reference volume, milligram-hours and external irradiation for the Fletcher applicator.

The ICRU Report 38 recommends the use of reference point doses and reference volumes for the reporting of intracavitary gynecologic therapy. The reference volume enclosed by the 60 Gy isodose for intracavitary therapy alone (which can be represented by hwt) and for combined external and intracavitary therapy (HWT) has no conceptual counterpart in the standard intracavitary systems. We report the relationship of the reference volumes (hwt and HWT) to milligram-hours (mgh) radium equivalent and to dose of external irradiation (XRT) for the Fletcher system. HWT and hwt are directly proportional to mgh, the proportionality constant depending on XRT but not appreciably on moderate changes in source geometry. HWT increases slowly with increasing XRT to about 30 Gy, then increases dramatically with even small increases in XRT. The reasons for this behavior and the possible clinical significance are discussed.

Dose-volume analysis and the prevention of radiation sequelae in cervical cancer.

We report a 9 year (1975-1983) experience of treatment of carcinoma of the uterine cervix by radiation alone. Computerized dosimetry conforming to the ICRU 38 recommendations was performed for all 348 patients analyzed. Late sequelae were graded as mild (grade 1), moderate (grade 2) and severe (grade 3). The overall rates were grade 3: 9.8%, grade 2: 18%, and grade 1: 19.5%. Of the moderate to severe sequelae, 48% were rectal, 15% rectosigmoid and 21% urinary. The complication rate was highly dependent on the type of intracavitary applicator: lowest for patients treated by two insertions of a standard Fletcher-Suit applicator (grade 3: 5.4%, grade 2: 14.4%) and highest for those receiving uterine stem plus vaginal line sources (grade 3: 29.5%, grade 2: 26%). For 183 patients treated with stem and standard ovoids, moderate and severe rectal and bladder sequelae were analyzed according to critical organ reference doses and reference treatment volumes as defined by ICRU 38, with the addition of a mean rectal dose. Zones of low, moderate and high risk could be defined on dose-volume plots using these parameters. Modification of treatment plans at the Cancer Institute G. F. Leclerc (CGFL) of Dijon according to these concepts produced a reduction in moderate and severe sequelae (grade 3: 14.4-3.4%) without a concurrent increase in pelvic failures. Although the zones of risk proposed can be used directly only with standard Fletcher-Suit applicators and comparable computer dosimetry, the concept can be applied to other systems.

Effect of intersource spacing on local control and complications in brachytherapy of mobile tongue and floor of mouth.

From 1971 to 1988, 133 T1 and 141 T2 biopsy-proven squamous cell carcinomas of mobile tongue and floor of mouth were definitively managed by Iridium-192. Implantations were performed using either guide gutters or afterloading plastic catheters. The prescribed dose at the reference isodose (85% of the basal dose rate, Paris system) was 60-70 Gy. Total dose was not adjusted to dose rate or tumor volume. Results of the 274 implants have been analysed to look for a possible influence of intersource spacing on local control and necrosis. Follow up for patients free of local recurrence is 1-180 months with median of 35 months. The 274 tumors were divided into two groups according to intersource spacing: 9-14 mm (n = 204), and 15-20 mm (n = 70). At 5 years, the estimated local control (Kaplan Meier) was 86% and 76%; respectively (p = 0.13); the necrosis rate was 33% and 46%, respectively (p = 0.04). Multivariate analysis shows that dose and activity of wires were significantly related to local control, while only tumor site was predictive of necrosis; there was a non-statistically significant relationship between intersource spacing of wires and local control (p = 0.055). When considering only patients with oral tongue cancers, necrosis was significantly related to activity of wires (p = 0.013), and there was a non-significant trend to a relationship between necrosis and intersource spacing (p = 0.066) and tumor diameter (p = 0.065). For patients with floor of mouth cancer, none of these factors was significantly related to necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dose rate on local control and complications in definitive irradiation of T1-2 squamous cell carcinomas of mobile tongue and floor of mouth with interstitial iridium-192.

From 1971 to 1988, 134 T1 and 145 T2 biopsy-proven squamous cell carcinomas of mobile tongue and floor of mouth were definitively managed by iridium-192. Implantations were performed using either guide gutters or afterloading plastic catheters. The prescribed dose at the reference isodose (85% of the basal dose rate, Paris system) was 60-70 Gy. Total dose was not adjusted to dose rate or tumor volume. Results of the 279 implants have been analysed to look for a possible influence of dose rate on local control and necrosis. Follow-up patients free of local recurrence is 1-180 months with average of 51 months. The 279 tumors were divided in four groups according to dose and dose rate: greater than or equal to 62.5 Gy and greater than or equal to 0.5 Gy/h (n = 130), greater than or equal to 62.5 Gy and less than 0.5 Gy/h (n = 36), less than 62.5 Gy and greater than or equal to 0.5 Gy/h (n = 81), less than 62.5 Gy and less than 0.5 Gy/h (n = 32). The four groups were comparable according to age, sex, tumor diameter and macroscopic aspect. At 5 years, the estimated local control (Kaplan Meier) was 93, 87, 79 and 52%, respectively (dose adjusted to dose rate: p less than 0.001, dose rate adjusted to dose: p less than 0.01, Log-rank); the necrosis rate was 44, 24, 37 and 5%, respectively (dose adjusted to dose rate: p = 0.08, dose rate adjusted to dose: p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Cholinergic systems and schizophrenia: primary pathology or epiphenomena?

Post mortem schizophrenia research has been driven first by the dopamine and then the glutamate hypotheses. These hypotheses posit primary pathology in pathways dependent upon dopamine or glutamate neurotransmission. Although the dopamine and glutamate hypotheses retain considerable theoretical strength, neurobiological findings of altered dopamine or glutamate activity in schizophrenia do not explain all features of this disorder. A more synthetic approach would suggest that focal pathological change in either the prefrontal cortex or mesial temporal lobe leads to neurochemical changes in multiple neurotransmitter systems. Despite the limited experimental evidence for abnormal cholinergic neurotransmission in psychiatric disorders, increased understanding of the role of acetylcholine in the human brain and its relationship to other neurotransmitter systems has led to a rapidly growing interest in the cholinergic system in schizophrenia. This review focuses on the basic anatomy of the mammalian cholinergic system, and its possible involvement in the neurobiology of schizophrenia. Summaries of cholinergic cell groups, projection pathways, and receptor systems, in the primate and human brain, are followed by a brief discussion of the functional correlations between aberrant cholinergic neurotransmission and the signs and symptoms of schizophrenia.

Combined physiological-anatomical approaches to study lateral inhibition.

In the visual cortex, large basket cells form the cellular basis of long-range lateral inhibition. The present paper focuses on combinations of methods with which large basket cells can be studied in the context of extensive neuronal representations. In the first approach, the topographic relationship between large basket axons and known functional representations such as orientation, direction, and ocular dominance is analysed. Functional mapping is carried out using extracellular electrode recordings or optical imaging of intrinsic signals followed by 3-dimensional anatomical reconstruction of biocytin stained large basket cells in the same regions. In the second approach, the contribution of lateral inhibition to orientation and direction selectivity is assessed using the GABA inactivation paradigm and direct inhibitory projections from the inactivation to recording sites are demonstrated with biocytin staining and injections of [3H]nipecotic acid, a radioactive marker for GABAergic cells. The limitation of these approaches is that they can only be used in cortical regions which lie on the surface of the brain.

Percent free prostate-specific antigen after radiotherapy for prostate cancer.

OBJECTIVES: The range of "normal" prostate-specific antigen (PSA) values compatible with cure following radiotherapy (RT) for prostate cancer (PCa) has yet to be established. Various thresholds, ranging from 0.5 to 4.0 ng/mL are used to define biochemical disease-free status. Because the proportion of free PSA is lower in men with PCa, the ratio of free PSA to total PSA could theoretically be useful in determining cancer-free status after RT. METHODS: One hundred two men treated with standard external beam RT from October 1988 to October 1994 (median dose, 66 Gy) were chosen for measurement of percent free PSA because they had a routine follow-up visit in November or December of 1996. All patients had undergone systematic transrectal ultrasound-guided biopsies after RT. Biopsies were negative in 66 patients, positive in 21, and indeterminate in 15 (rare, degenerated cancer cells with no evidence of proliferation by immunohistochemical stains). Stage distribution was T1b, 8; T1c, 9; T2a, 25; T2b/c, 40; and T3, 20. Median follow-up is 40 months. RESULTS: Total serum PSA ranged from 0. 1 to 10.0 ng/mL. Because the mean (+/-SD) percent free PSA for patients with negative (n = 66) and indeterminate (n = 15) biopsies were 29% +/- 18% and 25% +/- 7%, respectively (P = 0.13), these were combined. The mean (+/-SD) percent free PSA for those with positive biopsies (n = 21) was 15% +/- 8% and was significantly different from those with negative or indeterminate biopsies (P < 0.001). Patients with negative or indeterminate biopsies were grouped according to their total PSA as 0.1 to 0.5 ng/mL (n = 33), 0.6 to 1.0 ng/mL (n = 23), 1.1 to 2.0 ng/mL (n = 17), and greater than 2.0 ng/mL (n = 7). The mean percent free PSAs were 34%, 28%, 21%, and 12%, respectively. CONCLUSIONS: Percent free PSA may be a useful adjunct in diagnosing recurrent PCa after RT. The ratio is significantly different in patients of known biopsy status, distinguishing a group with positive biopsies from those with negative. However, there is overlap in individual values, and because patients with negative biopsies after RT may have subclinical distant disease, more follow-up is necessary before percent free PSA can be incorporated into a definition of biochemical disease-free status. Percent free PSA may be most useful for PSA from 0.6 to 2.0 ng/mL, where failure is common, but not universal.

Intermittent androgen suppression in the management of prostate cancer.

OBJECTIVES: Intermittent androgen suppression (IAS) has been suggested as a means of attenuating the androgen deprivation syndrome in men with incurable prostate cancer. Laboratory data suggest that intermittent therapy may prolong the duration of androgen dependence. METHODS: Since October 1993, 54 patients have entered a Phase II protocol consisting of 8 months of total androgen blockade (TAB) using leuprolide (Lupron) depot and nilutamide (Anandron) followed by an off-treatment interval of variable length. Eleven patients had biopsy-proven local failure after radiotherapy, 4 had biochemical failure, 24 had distant metastases (fewer than six axial sites on bone scan), 11 had combined local and distant failure, and 4 were treated as primary management for nodal disease. Mean prostate-specific antigen (PSA) at entry was 37 ng/mL (range 3.8 to 196). After 8 months of TAB, hormonal therapy was discontinued for those patients whose PSA was less than 4.0 ng/mL and stable or decreasing and was resumed (cycle 2) when PSA increased to greater than 10 ng/mL. RESULTS: As of April 1 998, mean follow-up was 33 months (range 14 to 53). Patients have completed at least one, and up to five treatment cycles. The mean time to nadir PSA in cycle 1 was 20 weeks, and the mean time off was 35 weeks (31 weeks for those with metastatic disease versus 39 for local or biochemical failure). In cycle 2, the mean time to PSA nadir was 17 weeks, and the mean time off was 30 weeks (28 weeks for metastatic disease and 38 weeks for local or biochemical failure). In cycle 3, the time to PSA nadir was 19 weeks. Full testosterone data are available for 40 patients in cycle 1. Normal levels were achieved during the off-treatment interval in 73% by a mean of 18 weeks (median 9). Testosterone normalization in cycle 2 was achieved in 71% at a mean time of 17 weeks (median 14). CONCLUSIONS: TAB can be used intermittently, and appears to be more appropriate for patients with local or biochemical failure. Testosterone recovery is not universal in the off-treatment intervals. IAS needs to be investigated in a randomized trial to determine the effect on overall survival and quality of life.

Routine prostate biopsies following radiotherapy for prostate cancer: results for 226 patients.

OBJECTIVES: To determine the time course of histologic resolution of prostate cancer following radiotherapy (RT) and to correlate biopsy results with clinical outcome. METHODS: Since July 1990, all patients treated with radical external beam RT for prostate cancer at the General Division of the Ottawa Regional Cancer Centre have had systematic transrectal ultrasound (TRUS) and TRUS-guided biopsies beginning 12 months after RT and then every 6 months until negative or until clinical failure. Thus, 226 patients have had 375 TRUS with four to seven specimens per examination. Stage distribution was T1b: 32, T1c: 11, T2a: 45, T2b: 82, T3: 50, and T4: 6. Median follow-up was 33 months. RESULTS: Biopsy results were negative in 69.5% of patients by 30 months of follow-up. Thirty-two (14%) had local failure (T1b: 12.5%, T1c: 0%, T2a: 11%, T2b: 15%, T3: 18%, T4: 33%). Seven (3%) had chemical failure, and 47 (21%) had biopsy-only failure. Median follow-up for the biopsy-only failure group is only 19.5 months and mean prostate-specific antigen (PSA) is 1.0 ng/mL. Thirty-nine patients, initially with biopsy-only failure, have converted to negative biopsies at a median of 26 months. Nadir PSA for patients with local failure was 3.9 ng/mL at 14 months versus 0.7 ng/mL at 23 months for those without failure. Patients with late conversion to negative biopsy results had a later nadir PSA of 1.3 ng/mL at 27.3 months. CONCLUSIONS: Routine prostate biopsy specimens after RT in an unselected population show tumor clearance that is in agreement with long-term clinical follow-up, although tumor may take more than 30 months to resolve. Nadir PSA can be used to predict outcome.