Highlights from the 98th Annual Meeting of the American Urological Association Chicago, IL April 26 to May 1, 2003

Meeting Highlights Highlights from the

98th Annual Meeting of the American Urological Association Chicago, IL April 26 to May 1, 2003 Carbon-11 Acetate Positron Emission Tomography May Be Useful in Detecting Prostate Cancer Positron emission tomography (PET) is a sensitive imaging method that works by detecting altered function in tissue rather than tumor mass, whereas conventional anatomic imaging methods such as computed tomography (CT) and magnetic resonance imaging (MRI) generally work by detecting a mass lesion. The disadvantages of these anatomic methods include the inability to detect very small tumors and the inability to distinguish tumor from normal variants in tissue anatomy. Positron emission tomography with [18F]fluorodeoxyglucose (FDG) relies on the increased expression of glucose transporters and glycolytic enzymes in tumor cells, which facilitates the uptake of the FDG into the tumor cells at a higher rate than normal surrounding tissue. FDGPET is now routinely used in the clinical diagnosis of many types of cancer, including lung, colorectal, esophageal, and breast cancers, as well as lymphoma and melanoma. However, its use in prostate cancer has proven disappointing, primarily because of the relatively low glycolytic rate of most prostate cancers.1 This results in low tracer uptake, making the delineation of tumor from benign prostatic hyperplasia difficult, as well as the delineation of postprostatectomy recurrence from scar tissue. In addition, accumulation of excreted FDG in the ureters and Prepared by: Heather DeGrendele, PhD, Jennifer Klem, PhD, Mary Hightower, PhD Reviewed by: Michael P. Kosty, MD, Oliver Sartor, MD

8 • Clinical

Prostate Cancer

bladder can obstruct the physician’s view of the prostate and nearby pelvic lymph nodes.2 In order to overcome difficulties encountered with FDG-PET, investigators have shifted their focus to the use of choline labeled with radioactive carbon (11C) as an alternate radiotracer. Malignant prostate epithelial cells oxidize citrate rather than produce citrate, resulting in an increased uptake of acetate. Carbon-11 choline is taken up via an active transport mechanism into these cancer cells and has the further benefit of negligible urinary excretion.3 To evaluate the use of [11C]choline acetate and compare its efficacy to FDGPET in the detection of prostate cancer and its metastases, Machtens and colleagues initiated a study enrolling 25 patients with prostate cancer.4 The results of this trial were presented at the American Urological Association 98th Annual Meeting. All patients were evaluated during follow-up of primary prostate cancer and suspected relapse or metastatic disease with [11C]choline acetate PET. Fifteen patients were additionally evaluated with FDG-PET. Lesions were detected in 10 of 15 patients using FDG-PET and 20 of 25 patients using [11C]choline acetate PET (Table 1). Using histology, CT, or ultrasonography, the diagnosis of primary or recurrent prostate cancer was confirmed in 43% and 70% of patients initially diagnosed by FDG-PET and [11C]choline acetate PET, respectively. Carbon-11 acetate PET also correctly diagnosed more cases of localized lymph node metastases (75%) than did FDG-PET (30%). However, among patients with distant metastases, including mostly osseous

June 2003

TABLE 1

Accuracy of FDG-PET and [11C ]choline Acetate PET in Prostate Cancer FDG-PET [11C]choline Acetate PET Group Group 10/15

20/25

Total

6/14

14/20

Lymph node metastases

3/10

12/16

Distant metastases

6/8

4/8

Total

8/14

6/20

Lymph node metastases

7/10

4/16

Distant metastases

2/8

4/8

Lesions Detected True-Positive Lesions*

False-Positive Lesions*

*Determined by magnetic resonance imaging, computed tomography, and/or transrectal ultrasonography. Abbreviations: FDG = [18F]fluorodeoxyglucose; PET = positron emission tomography

lesions, FDG-PET correctly diagnosed more cases (75% vs. 50%). In addition, prostate-specific antigen (PSA) values were seen to have a stronger correlation with the standard uptake value of [11C]choline acetate PET compared with FDG-PET. In a study presented by Alavi and colleagues, 53 clinically asymptomatic patients with increasing or elevated PSA levels (mean, 3.51 ng/mL ± 2.2) after radical prostatectomy were evaluated by [11C]choline acetate PET.5 Abnormal uptake of [11C]choline acetate was observed in 40 of the 53 patients, 18 of whom had local recurrence proven by biopsy (Table 2). Of interest, in 7 of these 18 patients, CT and MRI were nondiagnostic. Eleven of the 40 [11C]choline acetate PET–positive patients were shown to be tumor-free by

TABLE 2

[11C ]choline Acetate PET in Patients with High PSA After Prostatectomy

[11C]choline Acetate Uptake Increased

Number of Patients 18

Lymph node involvement

10

False-positive results*

11

Normal False-negative results*

FIGURE 1

Treatment Schema of Phase II Trial of a GM-CSF Gene-Transduced Prostate Cancer Cell Line Vaccine

Screening (≤ 4 weeks) ≥ 2 Successive PSA level increases

Prime Vaccination 500 million cells, day 1, week 0

Low-Dose Regimen 100 million cells biweekly for 24 weeks

High-Dose Regimen 300 million cells biweekly for 24 weeks

13 1

*Determined by computed tomography, magnetic resonance imaging, bone scan, and transrectal ultrasonography. Abbreviations: PET = positron emission tomography; PSA = prostate-specific antigen

CT, MRI, bone scan, and biopsy. Among the 13 patients who had normal [11C]choline acetate uptake, only 1 was shown to have a false-negative biopsy result. Based on these results, the overall sensitivity of [11C]choline acetate PET was determined to be 78%, with an overall specificity of 86% in patients with recurrent prostate cancer.5

Clinical Relevance The use of [11C]choline acetate PET imaging in prostate cancer shows promise in the detection of local recurrence, lymph node metastases, and diagnosis of primary tumor. This technique overcomes the difficulties encountered with FDG-PET imaging, such as low tracer uptake in tumor, and provides sensitivity as high as 78%, with 86% specificity.5 However, for patients with distant metastases, specifically to bone, FDG-PET may be a more accurate imaging technique. The precise role of either form of PET imaging in prostate cancer awaits the results of ongoing clinical investigation.

GranulocyteMacrophage ColonyStimulating Factor Gene-Transduced Prostate Cancer Vaccine in HormoneRefractory Prostate Cancer Patients with hormone-refractory prostate cancer (HRPC) have relatively limited treatment options because their disease is unresponsive to hormonal

Abbreviations: GM-CSF = granulocyte-macrophage colony-stimulating factor; PSA = prostate-specific antigen

agents, they may have already received radiation and chemotherapy treatment, or they might be unfit for cytotoxic therapy. Novel therapeutic agents that provide a measure of disease control or regression are therefore needed for patients with advanced prostate cancer. Adenoviral GVAX® cancer vaccines, one such novel modality, are comprised of irradiated tumor cells genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) and thereby stimulate an immune response in patients against their tumor. In a phase II study presented at the 2002 annual meeting of the American Society of Clinical Oncology, Simons and colleagues demonstrated that treatment with allogeneic prostate cancer cell lines genetically engineered to secrete GMCSF can delay time to progression (TTP) and increase median survival in patients with hormone-refractory metastatic prostate cancer.6 Patients with bone metastases treated with a high dose of 300 million cells every 2 weeks had a median survival of 31 months with a median TTP

TABLE 3

of 140 days. Those treated with the low dose of 100 million cells every 2 weeks had a median survival of 22 months and a median TTP of 85 days.7 Based on the superior activity of the high-dose vaccine, a reengineered version designed to secrete higher levels of GM-CSF was introduced (G-9803). Results from a phase II trial of this reengineered prostate cancer cell line vaccine in patients with HRPC were presented by Ando and colleagues at the American Urological Association 98th Annual Meeting.7 Patients with adenocarcinoma of the prostate, ≥ 2 successive PSA increases within 4 weeks before starting therapy, and no previous chemotherapy or gene therapy were eligible for enrollment. Patients enrolled into this cohort were further required to have positive bone scan results without bone pain requiring narcotic analgesics. The vaccine tested was comprised of irradiated allogeneic prostate carcinoma cell lines (PC-3 and lymph node carcinoma of the prostate) that were genetically modified to secrete GM-CSF. Patients were given a 500-mil-

Results of Phase II Trial of a GM-CSF Gene-Transduced Prostate Cancer Cell Line Vaccine High-Dose Vaccination (n = 10)*

Low-Dose Vaccination (n = 24)†

Median TTP (by PSA)

3.7 months

2.3 months

Median TTP (by Bone Scan)

5.1 months

2.9 months

Median Survival

31 months

21 months

Result

*300 Million cells every 2 weeks for 12 cycles.

†100 Million cells every 2 weeks for 12 cycles. Abbreviations: GM-CSF = granulocyte-macrophage colony-stimulating factor; PSA = prostate-specific antigen; TTP = time to progression

Clinical Prostate Cancer

June 2003 •

9

Meeting Highlights lion-cell prime vaccination followed by 12 booster doses of either 100 million cells (low dose) or 300 million cells (high dose) every 2 weeks (Figure 1). A total of 34 patients were enrolled on this cohort. Ten patients were treated with the high-dose vaccine regimen and 24 were given the low-dose regimen. The 2 arms were balanced for age, sex, Gleason score, and mean PSA (201 and 257.4 for the low- and high-dose groups, respectively). At the 2.5-year follow-up, median TTP as determined by PSA levels and bone scan was prolonged for patients treated with the high-dose regimen (3.7 months and 5.1 months, respectively) compared with those treated with the low-dose regimen (2.3 months and 2.9 months, respectively; Table 3). Furthermore, median survival was increased on the high-dose arm, at 31 months compared with 21 months on the low-dose arm. All 34 patients experienced injectionsite reaction, 1 of which was grade 3 in intensity. All other toxicities, the most common of which were fatigue (32%) and flu-like syndrome (21%), were grade 1 or 2. No autoimmune reactions were generated in response to vaccination, and all patients tested negative for antinuclear antibodies after vaccination, with no trend toward an increase in erythrocyte sedimentation rate reported.

Clinical Relevance Vaccination with this GM-CSF transduced prostate cancer cell line resulted in a dose-dependent response in patients with HRPC. The median survival durations of 21 and 31 months seen on the low- and high-dose vaccine arms, respectively, was encouraging, and no dose-limiting toxicity or autoimmunity was reported. Accrual for a phase III trial in HRPC is nearly complete.

Continuous Androgen Suppression Results in Osteoporosis in Prostate Cancer Loss of bone mineral density (BMD) is a serious complication for men with prostate cancer. It arises not only as a result of bone metastases, but also occurs in response to androgen suppression, a standard treatment for many subsets of

10 • Clinical

Prostate Cancer

TABLE 4

Bone Mineral Density as a Function of Treatment Control Group (n = 57)

Androgen Suppression (n = 53)

P Value

Normal

16 (28.1%)

7 (13.2%)

0.034

Slight Osteopenia

8 (14.0%)

6 (11.3%)

0.765

Moderate Osteopenia

8 (14.0%)

8 (15.1%)

0.856

Severe Osteopenia

9 (15.8%)

10 (18.9%)

0.876

Total Osteoporosis

16 (28.1%)

22 (41.5%)

0.162

Rating

men with prostate cancer. Although the pathogenesis of this is not well understood, it is believed that testosterone plays a role in bone homeostasis and that androgen-deprivation therapies lead to increased turnover in bone tissue, with overall detrimental effects on density. Androgen suppression is used as primary therapy in patients with locally advanced, nonmetastatic disease; as adjuvant therapy for patients with locally advanced disease treated with radiation therapy and for men with node-positive disease treated with radical prostatectomy and pelvic lymphadenopathy; and as second-line treatment in men with increasing PSA levels after surgery or radiation therapy for early-stage disease. Patients with prostate cancer treated for 9 months with androgen suppression demonstrated a loss in BMD of 4.7% for the lumbar spine and 2.7% for the hip compared with baseline levels.8 Loss of BMD results in osteoporosis, a leading cause of morbidity and mortality in elderly people. To better define the risks of osteoporosis to patients treated with androgen suppression, Morote and colleagues conducted a cross-sectional study designed to analyze the rate of osteoporosis in patients with prostate cancer, examine the influence of the modality and duration of androgen suppression in the

TABLE 5

development of osteoporosis, and assess the influence of androgen suppression on the relative risk of hip fracture.9 Bone densitometry was assessed in 110 patients, 57 of whom underwent radical prostatectomy alone and 53 of whom submitted to androgen suppression for ≥ 1 year (range, 12-191 months). Diagnosis of osteoporosis was established according to the World Health Organization criteria (T score > –2.5). Relative risk of hip fracture was estimated by 2.7Z score. The subsets of patients had similar mean ages (70.4 years vs. 69.2 years). Although significantly fewer patients undergoing androgen suppression had normal bone mass compared with patients in the control group (13.2% vs. 28.1%; P = 0.034; Table 4), there was no significant difference between the 2 subsets in the overall percentage of patients developing osteoporosis (41.5% vs. 28.1%; P = 0.162). However, there was a positive correlation between the length of treatment and the development of osteoporosis: 36.4% of patients developed osteoporosis when treated for 1236 months, compared with 42.1% of those treated for 37-60 months and 50% of those treated for > 60 months (Table 5). Similarly, the relative risk of hip fracture increased as the length of treatment

Rate of Osteoporosis and Relative Risk of Hip Fracture Relative to Length of Androgen Suppression Duration of Androgen Suppression

Measure Rate of Osteoporosis Relative Risk of Hip Fracture

June 2003

P Values

None

12-36 Months

37-60 Months

> 60 Months

28.1%

36.4%

42.1%

50%

0.0472

2

2.4

2.9

3.9

0.041

Meeting Highlights increased. Patients treated for 12-36 months had a relative risk of 2.4, compared with 2.9 for those treated for 3760 months and 3.9 for those treated for > 60 months (Table 5). The modality of androgen suppression, however, had no effect on the development of osteoporosis (41.4% vs. 41.7%, complete androgen blockade vs. chemical castration).

Clinical Relevance These results demonstrate that androgen suppression increased the rate of osteoporosis development in patients with treatments lasting > 60 months (P = 0.0472; Table 5). Given the morbidity associated with osteoporosis, minimization of this complication would be beneficial to patients with prostate cancer. This might be accomplished by reduction of the length of androgen-suppression treatment, as evidenced by these results; however, it is unclear how this might negatively affect outcome in these patients. Another option is to concurrently provide an agent that could prevent loss of bone mass. A study by Smith and colleagues demonstrated that, in patients with prostate cancer treated with androgen suppression, bone loss was prevented by the addition of pamidronate, a second-generation bisphosphonate that inhibits osteoclast-mediated bone resorption.10 Pamidronate has also been shown to increase bone mineral density in women with postmenopausal osteoporosis.11 Therefore, the concurrent administration of bisphosphonates with androgen-suppression therapy might also be considered as a way to minimize the occurrence of osteoporosis in this patient population.

Zoledronic Acid Is Effective in the Treatment of Prostate Cancer Patients with Bone Metastases Bone metastases commonly occur in patients with primary prostatic tumors, leading to skeletal-related events (SREs) such as pathologic bone fractures and spinal cord compression. The resulting pain and immobility decrease the quality of life (QOL) for these patients. Pamidronate inhibits osteoclastic bone resorption12,13 and was the first bisphosphonate to receive Food and Drug Administration approval for the treatment of lytic bone disease in patients

with breast cancer.14 However, it did not show similar benefit for patients with prostate cancer.15 Zoledronic acid is a third-generation bisphosphonate which, in 2 randomized, parallel trials, was shown superior to pamidronate in reducing hypercalcemia of malignancy (88% vs. 70%; P = 0.002).16 Preclinical studies showed that zoledronic acid disrupted the growth of prostate cancer cell lines17 and might reduce the number of SREs experienced by patients with metastatic tumors to the bone.18 In a randomized phase III trial in patients with prostate cancer, Saad et al found that the treatment arm receiving zoledronic acid experienced fewer SREs than the placebo group (33% vs. 44%; P = 0.021).19 The time to first SRE was increased, mean skeletal morbidity rate was significantly decreased (P = 0.006), and median survival was also significantly longer for the zoledronic acid group (P = 0.091). Those participants who completed the initial 15month study were allowed to continue treatment for an additional 9 months. Saad and colleagues reported the results of the zoledronic acid extension trial at the American Urological Association 98th Annual Meeting.20,21 The study objectives were to evaluate the activity of long-term zoledronic acid administration for prevention of SREs and reduction of bone pain.20 Patients had been stratified by presence or absence of distant metastases and then randomized to treatment with either placebo or zoledronic acid 4 mg or 8 mg intravenously for 15 minutes every 3 weeks for 15 months. All patients received oral vitamin D 400 IU and calcium 500 mg daily. Patients who participated in the extension continued under the same schedule, and only those randomized to placebo and zoledronic acid 4 mg were included in the extension study. Of the 214 patients receiving 4 mg zoledronic acid, 75 continued treatment, along with 58 of 208 placebotreated patients. The baseline characteristics of patients in both treatment arms were well balanced with respect to age, performance status, PSA levels, composite pain and analgesic scores, QOL scores, and presence of distant metastases

at diagnosis. The results at 24 months were similar to what had been observed at 15 months. Zoledronic acid reduced the percentage of patients experiencing an SRE by 22% compared with patients receiving placebo (38% vs. 49%; P = 0.028).21 Moreover, this difference was maintained when asymptomatic fractures were excluded from analysis (30% vs. 41%, P = 0.019). The skeletal morbidity rate (mean SREs/year) was significantly lower in the zoledronic acid group (0.77 vs. 1.47, P = 0.005), and the risk of developing a skeletal complication was reduced by 36% (hazard ratio = 0.64; P = 0.002). Bone pain indicators were also improved for the patients receiving zoledronic acid, with only 26% requiring radiation therapy versus 33% of patients receiving placebo.20 The median time to radiation therapy was not reached in the zoledronic acid arm and was 640 days in the placebo arm. Although the brief

TABLE 6

Treatment of Skeletal Complications with Zoledronic Acid Versus Placebo in Patients with Prostate Cancer Zoledronic Placebo Acid (n = 208) 4 mg (n = 214)

P Value

SRE in All Patients

38%

49%

0.028

Radiation to bone

26%

33%

NS

Pathologic fractures

17%

25%

NS

Spinal cord compression

4%

8%

NS

Change of antineoplastic therapy

6%

7%

NS

Surgery to bone

2%

4%

NS

Median Time to First SRE (Days)

488

321

0.009

Mean Skeletal Morbidity Rate

0.77

1.47

0.005

Relative Risk for Skeletal Complication

0.64

NS

0.002

Abbreviation: NS = not significant; SRE = skeletal-related event

Clinical Prostate Cancer

June 2003 •

11

Meeting Highlights TABLE 7

Adverse Events with Zoledronic Acid Versus Placebo Zoledronic Acid (n = 214)

Placebo (n = 208)

Bone Pain

114 (53%)

134 (64%)

Fatigue

75 (35%)

56 (27%)

Anemia

66 (31%)

42 (20%)

Myalgia

56 (26%)

42 (20%)

Fever

46 (22%)

31 (15%)

Dizziness

44 (21%)

27 (13%)

Lower-Limb Edema

44 (21%)

32 (15%)

Weight Loss

41 (19%)

28 (14%)

Event

higher after 2 years of zoledronic acid treatment (hazard ratio = 1.137; P = 0.752).21

composite pain scores increased in both groups, they were significantly lower in the zoledronic acid group at all assessment points (P = 0.024 at 24 months). No significant differences were observed between groups in analgesic scores, Functional Assessment of Cancer Therapy–General QOL scores, or performance status (Table 6). Incidents associated with bisphosphonates, including fatigue, fever, and myalgia, were more common in the zoledronic acid group than in the placebo arm (Table 7).20 Also, symptoms of anemia, dizziness, lower-limb edema, and weight loss were ≥ 5% more common in the treatment group. The risk for elevated serum creatinine level was only slightly

Extended treatment with zoledronic acid produced long-term prevention of skeletal complications in men with bone metastases from prostate cancer. It extended the time to first SRE and reduced the risk of skeletal complications at all time points in the study up to 24 months. Moreover, it decreased bone pain and reduced need for palliative radiation therapy. The 4-mg dose was tolerated well and did not significantly impair kidney function. Zoledronic acid is the first and only bisphosphonate that has shown long-term palliative activity for bone metastases from prostate cancer.

with intermittent androgen suppression (IAS). Proc Am Soc Clin Oncol 1999; 18:314a (Abstract #1207). Morote J, Martinez E, Trilla E, et al. Influence of the type and length of continuous androgen suppression in the development of osteoporosis in patients with prostate cancer. Presented at the 2003 American Urological Association meeting; April 26 to May 1, 2003; Chicago, IL. Abstract #100376. Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345:948-955. Thiebaud D, Burckhardt P, Melchior J, et al. Two years’ effectiveness of intravenous pamidronate (APD) versus oral fluoride for osteoporosis occurring in the postmenopause. Osteoporos Int 1994; 4:76-83. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000; 88:1082-1090. Conte PF, Latreille J, Mauriac L, et al. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. The Aredia Multinational Cooperative Group. J Clin Oncol 1996; 14:2552-2559. Imaginis.com Breast Health News: Scientists investigate treatments for breast cancer that has spread to the bone (dateline August 21, 2001). Available at: http://www.imaginis.

com/breasthealth/news/news8.21.01.asp. Accessed June 5, 2003. Lipton A, Small E, Saad F, et al. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest 2002; 20(suppl 2):45-54. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001; 19:558-567. Lee MV, Fong EM, Singer FR, et al. Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res 2001; 61:2602-2608. Mundy G, Yoneda T, Hiraga T. Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. Semin Oncol 2001; 28:35-44. Saad F, Gleason DM, Murray R, et al. A Randomized, placebo-controlled trial of zoledronic acid in patients with hormonerefractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94:1458-1468. Saad F, Gleason DM, Murray R, et al. Longterm reduction of bone pain with zoledronic acid in patients with advanced prostate cancer metastatic to bone. J Urol 2003; 169(suppl 4):394 (Abstract #1473). Saad F, Gleason DM, Murray R, et al. Zoledronic acid is well tolerated for up to 24 months and significantly reduces skeletal complications in patients with advanced prostate cancer metastatic to bone. J Urol 2003; 169(suppl 4):394 (Abstract #1472).

Clinical Relevance

References 01. Shvarts O, Han KR, Seltzer M, et al. Positron emission tomography in urologic oncology. Cancer Control 2002; 9:335-342. 02. Liu IJ, Zafar MB, Lai YH, et al. Fluorodeoxyglucose positron emission tomography studies in diagnosis and staging of clinically organ-confined prostate cancer. Urology 2001; 57:108-111. 03. Roivainen A, Forsback S, Gronroos T, et al. Blood metabolism of [methyl-11C]choline; implications for in vivo imaging with positron emission tomography. Eur J Nucl Med 2000; 27:25-32. 04. Machtens S, Fricke E, Knapp W, et al. 11 Cacetate positron emission tomography in prostate cancer patients. J Urol 2003; 169(suppl):291-292 (Abstract #1134). 05. Alavi S, Kurtaran A, Hruby S, et al. European multicenter evaluation of carbon11 acetate positron emission tomorgraphy imaging in men with PSA progression following radical prostatectomy. J Urol 2003; 169(suppl):291 (Abstract #1133). 06. Simons J, Nelson W, Nemunaitis J, et al. Phase II trial of a GM-CSF gene-transduced prostate cancer cell line vaccine (GVAX) in hormone refractory prostate cancer. Proc Am Soc Clin Oncol 2002; 21:183a (Abstract #729). 07. Ando D, Simons J, Nelson W, et al. Phase II trial of a GM-CSF gene-transduced prostate cancer cell line vaccine in hormone refractory prostate cancer. J Urol 2003; 169(suppl):396 (Abstract #1479). 8. Higano C, Stephens C, Nelson P, et al. Prospective serial measurements of bone mineral density (BMD) in prostate cancer patients without bone metastases treated

12 • Clinical

Prostate Cancer

9.

10.

11.

12.

13.

14.

June 2003

15.

16.

17.

18.

19.

20.

21.