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

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

Oxidative DNA damage in patients with prostate cancer and its response to treatment

PURPOSE: We evaluated the significance of oxidative DNA damage in patients with prostate cancer based on the measurement of urinary 8-OHdG (8-hydroxy-2'-deoxyguanosine) and analyzed changes in urinary 8-OHdG before and after initial treatment. MATERIALS AND METHODS: A total of 82 patients with prostate cancer were included in this study. Of these 82 patients 42 underwent radical prostatectomy and the remaining 40 received hormonal therapy as initial treatment. Urinary 8-OHdG and creatinine (Cr), and serum prostate specific antigen (PSA) in these 82 patients were assessed before and 2 months after the initiation of treatment. RESULTS: The ratio of urinary 8-OHdG-to-Cr (8-OHdG/Cr) in patients with prostate cancer was significantly higher than in age matched healthy controls. Only age was significantly associated with 8-OHdG/Cr in prostate cancer cases among several clinicopathological factors, including serum PSA clinical T stage, metastasis and Gleason score. There was no significant difference in urinary 8-OHdG/Cr in 42 patients before and after radical prostatectomy, while urinary 8-OHdG/Cr in 40 patients after hormonal therapy was significantly lower than before hormonal therapy. In addition, changes in PSA after initial treatment were not related to changes in urinary 8-OHdG/Cr in either treatment group. CONCLUSIONS: These findings suggest that oxidative stress may be involved in an early event in prostate cancer development and androgen suppression is capable of decreasing oxidative stress. Accordingly androgen withdrawal therapy combined with antioxidative agents may inhibit the progression of prostate cancer.     

Penile length changes in men treated with androgen suppression plus radiation therapy for local or locally advanced prostate cancer

PURPOSE: We determined penile length alterations in men treated with androgen suppression plus radiation therapy for local or locally advanced prostate cancer. MATERIALS AND METHODS: From November 2000 to November 2005, 47 patients were enrolled in this prospective study. After clinical staging all patients received hormonal therapy (luteinizing hormone releasing agonist, leuprolide acetate or goserelin every 3 months for a total of 3 injections) and at month 7 of hormonal therapy radiation therapy was begun (total 70 Gy) for 7 weeks. Stretched penile length measurements were performed before starting androgen suppression therapy and every 3 months thereafter with a paper ruler. RESULTS: With the initiation of therapy a gradual decrease in stretched penile length was observed. Penile shortening was statistically significant at a mean followup of 18 months (mean 14.2 to 8.6 cm, p <0.001). CONCLUSIONS: Our findings support observations of decreased penile length after neoadjuvant hormonal therapy plus external beam radiation therapy for local or locally advanced prostate cancer. Patients should be counseled before therapy that penile shortening may occur.     

The natural history of androgen independent prostate cancer

PURPOSE: We describe the natural history of androgen independent prostate cancer (AIPC) in the modern prostate specific antigen (PSA) era. MATERIALS AND METHODS: Data from 160 patients diagnosed with AIPC between 1989 and 2002 were reviewed. No patient had received cytotoxic chemotherapy. Univariate and multivariate proportional hazards models were constructed to identify significant risk factors for cancer specific survival. Recursive partitioning analysis stratified patients into prognostic risk groupings. The types and frequencies of cancer specific complications per risk grouping were compared. RESULTS: The final prognostic risk model included nadir PSA on androgen deprivation therapy (p = 0.023), time to PSA recurrence (p = 0.006) and prostate specific antigen doubling time (p <0.01). Three highly independent risk groupings were identified. The observed median cancer specific survivals were 14.0 months (95% CI, 8.3-19.8), 38.4 months (95% CI, 26.9-49.9) and 89.1 months (95% CI, 69.0-109.2) for low, intermediate and high risk groupings, respectively (p <0.001). Patients in the low risk grouping experienced significantly fewer cancer specific complications (p = 0.003). CONCLUSIONS: This prognostic model stratified patients into 3 highly significant and independent risk groupings. A detailed PSA history alone is sufficient to risk stratify patients with AIPC.     

The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer

PURPOSE: We evaluated the benefits and sequencing of androgen suppression (AS) administered with external beam radiation therapy (EBRT) in T2-T3 prostate cancers. MATERIALS AND METHODS: Between 1990 and 1999, 481 patients were entered in 2 successive, prospective, randomized studies, including 161 in the study 1 and 325 in study 2. Eligible patients had clinical stages T2-T3 prostate cancer. In the first study (L-101) subjects were randomly allocated among EBRT alone (group 1), EBRT preceded by 3 months of AS (group 2), and neoadjuvant, concomitant and adjuvant AS for a total of 10 months (group 3). In the second study (L-200) we analyzed neoadjuvant and concomitant AS (total 5 months) vs neoadjuvant, concomitant and short course adjuvant (total 10 months) AS with EBRT. In each study we used a total AS (a luteinizing hormone-releasing hormone agonist plus an antiandrogen) and a standard dose of radiation therapy at that time. Patient characteristics were well balanced in regard to age, stage, prostate specific antigen and Gleason score. No biochemical evidence of disease (BNED) was defined as an end point according to the Vancouver rule. RESULTS: In the study 1 at a median followup of 5 years 7-year biochemical-free survival rates were 42%, 66% and 69% in groups 1 to 3, respectively. BNED was significantly different between groups 1 and 2 (p = 0.009) and between groups 1 and 3 (p = 0.003) but not between groups 2 and 3 (p = 0.6). Multivariate analysis using a Cox proportional hazards model showed an HR of 6.1 for Gleason score (p = 0.001), 1.4 for PSA (p = 0.002), 0.5 for group 1 vs group 2 (p = 0.01) and 0.35 for group 1 vs group 3 (p = 0.008). In study 2 BNED at 4 years was 65%. There was no significant difference between arms 1 and 2 (p = 0.55). CONCLUSIONS: The analysis of study 1 shows a benefit of using a short course of neoadjuvant AS with EBRT vs EBRT alone for localized T2-T3 prostate cancers. Moreover, in each study adding a short course of adjuvant AS after neoadjuvant 1 provided no more advantage in these patients.     

Efficacy of digital rectal examination after radiotherapy for prostate cancer

PURPOSE: Digital rectal examination is widely performed for following patients with localized prostate cancer after definitive therapy. This examination has marginal efficacy for detecting initial prostate cancer and postoperative recurrence. To determine the efficacy of digital rectal examination in terms of new information provided after radiotherapy we analyzed the results of digital rectal examination in the followup of patients with prostate cancer after radiotherapy. MATERIALS AND METHODS: We performed a nonrandomized study in 235 consecutive patients with prostate cancer followed at a large tertiary care military hospital between January 1, 1995 and December 31, 1999. All patients had been treated with prostate radiotherapy and had no evidence of metastatic disease at the first visit within that interval. Digital rectal examination was done at followup and the main outcome measure was new information provided by that examination. RESULTS: A total of 1,544 digital rectal examinations were performed in 1,627 visits. New information was provided by digital rectal examination in only 30% of 286 abnormal examinations, of which more than three-quarters were related to bleeding and would otherwise have been noted on routine examination by the primary care provider. All 8 persistent recurrent prostate nodules were noted in the context of increasing prostate specific antigen. CONCLUSIONS: Routine digital rectal examination in patients with prostate cancer after radiotherapy may be omitted from followup protocols.     

Urothelial carcinoma after external beam radiation therapy for prostate cancer

PURPOSE: We reviewed the clinical course of patients in whom urothelial carcinoma developed following radiation therapy for prostate cancer. MATERIALS AND METHODS: A retrospective review of all patients between 1990 and 2005 with the diagnosis of bladder and prostate cancer was performed. Of 125 total patients new onset urothelial carcinoma developed in 11 after undergoing external beam radiation therapy for prostate cancer. RESULTS: Whole pelvis external beam radiation therapy with a proton boost to the prostate was the radiation modality in 7 of the 11 patients (64%), while the remaining 4 patients received standard external beam radiation only. Urothelial carcinoma was detected a mean of 3.07 years after completion of radiation therapy in the proton group, compared to a mean latency period of 5.75 years in the standard radiation group (p = 0.09). Average patient age at diagnosis was 72 years (range 64 to 84). All patients presented with gross hematuria and had cystoscopic findings of coexisting radiation cystitis. Of the 11 patients 5 (45%) presented with grade 3 carcinoma and eventually 7 (64%) required radical cystectomy. Urothelial tumors with sarcomatoid features (carcinosarcoma and spindle cell sarcomatoid) developed in 2 patients (18%). Of the 11 patients 10 (91%) were nonsmokers at the time of urothelial carcinoma diagnosis. CONCLUSIONS: Urothelial carcinoma in patients with previous radiation therapy for prostate cancer is often high grade, and the majority of patients have cancer progression requiring cystectomy. A high incidence of urothelial carcinoma with sarcomatoid features was seen in these patients.     

Osteoporosis in men treated with androgen deprivation therapy for prostate cancer

PURPOSE: We surveyed the growing literature on osteoporosis secondary to androgen deprivation therapy and provide suggestions regarding its identification and treatment. MATERIALS AND METHODS: We reviewed pertinent studies of male osteoporosis, osteoporotic fracture incidence or bone mineral density loss as a possible side effect of prostate cancer treatment and potential therapies for this side effect. RESULTS: Hypogonadism is a well-known cause of secondary osteoporosis in men. There is evidence of decreased bone mineral density with all types of androgen deprivation therapy, presumably due to its anti-testosterone effect. Bone mineral density loss is 3% to 5% yearly in the first few years of androgen deprivation therapy with an increase in osteoporotic fracture incidence. There are little data on potential treatments, although bisphosphonates and intermittent androgen deprivation therapy may have salutary effects. CONCLUSIONS: Osteoporosis is an important and debilitating side effect of androgen deprivation therapy, although precise estimates of its incidence, degree and cost are not completely elucidated. Until more data are available, it is prudent for all men beginning androgen deprivation therapy to receive calcium and vitamin D, and maintain a moderate exercise regimen. Baseline and at least 1 followup bone density measurement seem appropriate with bisphosphonate treatment a possibility in those in whom osteoporosis develops. More research is needed to explore the effect of bisphosphonates, calcium and vitamin D supplementation, exercise, calcitonin, selective estrogen re-uptake inhibitors, estrogens and intermittent androgen deprivation therapy on the course of androgen deprivation therapy induced osteoporosis. The osteoporotic fracture incidence and bone mineral density should be regularly incorporated into studies involving the hormonal treatment of prostate cancer.     

Bone mineral density changes in patients with prostate cancer during the first 2 years of androgen suppression

PURPOSE: We characterized bone mineral density changes in patients with prostate cancer on androgen deprivation therapy during the first 2 years of uninterrupted therapy, and identified which location most reflects bone mass loss. MATERIALS AND METHODS: Using dual energy x-ray absorptiometry, bone mineral density was prospectively assessed in patients with nonmetastatic prostate cancer at the lumbar spine and femoral neck, Ward's triangle, trochanter and total hip. Measurements were performed at baseline and yearly thereafter in patients on ADT, and at baseline and 1 year in controls (age matched patients with prostate cancer, free of biochemical progression after radical prostatectomy). RESULTS: A total of 62 patients were included in the study, 31 in each group. Median age (70 and 69 years, respectively), mean Gleason score and mean baseline serum testosterone did not significantly differ. Patients receiving ADT experienced a significant bone mass loss at 12 months in all locations, ranging from 2.29% to 5.55% (p <0.001). In contrast, bone mineral density did not change significantly (0.64% to 1.68%) in patients not receiving ADT. In the 20 patients on ADT after 24 months, the second year decrease was not as severe, nor was it significant compared to first year values. The major bone mass loss occurred in Ward's triangle, with decreases of 5.55% at 12 months and 7.05% at 24 months. CONCLUSIONS: Bone mineral density decreases during the first 24 months of androgen suppression with the most relevant effect occurring in the first year. Ward's triangle is the axial skeletal site that reflects the major bone mass loss. Because the deleterious impact of long-term androgen suppression on bone mineral density is inversely related to fracture risk and indirectly related to survival in patients with prostate cancer, early diagnosis and prevention of bone mass loss are warranted in these patients.     

Prostate specific antigen bounce phenomenon after external beam radiation for clinically localized prostate cancer

PURPOSE: We characterize the prostate-specific antigen (PSA) bounce in patients who underwent external beam radiation therapy for prostate cancer and correlate the PSA bounce with the development of biochemical disease progression. MATERIALS AND METHODS: In this study 964 patients received full dose radiation therapy alone. Followup PSA values were obtained 3 months after completion of radiotherapy and every 3 to 6 months thereafter. Median followup of the entire study group was 48 months. All time intervals were calculated from the completion date of radiation therapy. PSA bounce was defined as an initial increase in serum PSA of at least 0.5 ng./ml., followed by a decrease to pre-bounce baseline serum PSA values no more than 60 months after external beam radiation therapy. RESULTS: Of the 964 patients 119 (12%) had a PSA bounce. PSA bounce was unrelated to age, race, pretreatment PSA, Gleason score, clinical T stage or radiation dose. Mean time to PSA bounce was 9 months from the time of therapy. The respective 1 and 5-year biochemical disease-free survival rates were 100% and 82.1% for patients with PSA bounce and 93.9% and 57.7% for those without PSA bounce (p = 0.0001). CONCLUSIONS: Of men with prostate cancer treated with external beam radiation therapy 12% experienced a transient increase in PSA (PSA bounce) followed by a return to pre-bounce levels after radiation. The PSA bounce phenomenon was not predictive of time to biochemical recurrence.     

Nilutamide as second line hormone therapy for prostate cancer after androgen ablation fails

PURPOSE: We investigate the prostate specific antigen (PSA) response rate with nilutamide as a second line hormonal agent in patients with advanced prostate cancer in whom androgen ablation failed. MATERIALS AND METHODS: From 1998 to 2001, 28 patients with hormone resistant prostate cancer were treated with nilutamide as second line hormonal therapy. Average patient age +/- SD was 72.9 +/- 9.1 years. Median time from diagnosis of cancer to hormone failure was 48 months (range 2 to 120). Median followup from initiation of nilutamide therapy was 26 months (range 15 to 44). All patients had previously received at least 1 antiandrogen (flutamide or bicalutamide) in addition to medical or surgical castration, which failed. RESULTS: Upon initiation of nilutamide therapy 18 of the 28 patients (64%) had an initial reduction in PSA and 8 (29%) sustained a PSA response (greater than 50% decrease) beyond 3 months (range 3 to 21). PSA response to nilutamide in patients with a previous antiandrogen withdrawal response versus nonresponse was 100% and 18%, respectively. In 10 of the 28 patients, (36%) PSA continued to increase. Interstitial pneumonitis developed, in 1 patient and 5 had nonspecific complaints (headaches, nausea, dizziness). During followup 6 of the 28 patients died 1 of whom was a nilutamide responder. No patient died while on nilutamide. CONCLUSIONS: Nilutamide can achieve a significant sustained PSA response with a favorable toxicity profile. Patients with a previous antiandrogen withdrawal response have a significantly greater chance of responding to nilutamide.     

Long-term survival in men with high grade prostate cancer: a comparison between conservative treatment, radiation therapy and radical prostatectomy--a propensity scoring approach

PURPOSE: We performed a retrospective cohort study using propensity score analysis to calculate long-term survival in patients with prostate cancer with Gleason score 8 or greater who were treated with conservative therapy, radiation therapy and radical prostatectomy. MATERIALS AND METHODS: Between January 1, 1980 and December 31, 1997, 3,159 patients in the Henry Ford Health System were diagnosed with clinically localized prostate cancer. Of these patients 453 had a Gleason score of 8 or greater in the biopsy specimen and they were the cohort. The end points were overall and prostate cancer specific survival. Propensity score analysis was used to more precisely compare the 3 treatments of observation, radiation and radical prostatectomy. Median patient followup was longer in the radical prostatectomy arm than in the conservative treatment and radiation therapy arms (68 months vs 52 and 54, respectively). RESULTS: Of the 453 patients 197 (44%) were treated conservatively, 137 (30%) received radiation therapy and 119 (26%) underwent radical prostatectomy. Using propensity scoring analysis median overall survival for conservative therapy, radiation and radical prostatectomy was 5.2, 6.7 and 9.7 years, respectively. Median cancer specific survival was 7.8 years for conservative therapy and more than 14 years for radiation therapy and radical prostatectomy. The risk of cancer specific death following radical prostatectomy was 68% lower than for conservative treatment and 49% lower than for radiation therapy (p<0.001 and 0.053, respectively). CONCLUSIONS: Survival of men with high grade prostate cancer can be improved by radical prostatectomy or radiation therapy.     

Osteoporosis and spinal fractures in men with prostate cancer: risk factors and effects of androgen deprivation therapy

PURPOSE: We determined the risk factors for osteoporosis and spinal fractures in men with prostate cancer receiving androgen deprivation therapy. MATERIALS AND METHODS: We performed a retrospective analysis of 87 consecutive men with prostate cancer receiving androgen deprivation therapy referred for evaluation of osteoporosis. Data were comprised of lateral thoracolumbar radiographs, bone densitometry, serum biochemistry and a detailed assessment of osteoporotic risk factors. Multivariate regression analysis was used to determine the major risk factors for osteoporosis and spinal fractures. RESULTS: There were 38 (44%) men who were 74.5 years old with radiographic evidence of spinal fractures. They had an initial mean prostate specific antigen of 52.8 ng/ml and had received androgen deprivation therapy for a mean of 39.6 months (95% confidence interval 28.7 to 50.4). Mean spinal (quantitative computerized tomography t-score -4.2) and femoral neck bone mineral densities (dual energy x-ray absorptiometry t-score -2.1) were significantly lower than in men without spinal fractures (p < 0.001 for all measurements). In the regression analysis the duration of androgen deprivation therapy (p = 0.002), serum 25-hydroxyvitamin D levels (p = 0.003) and a history of alcohol excess (defined as more than 4 standard drinks daily, p = 0.04) were the main determinants of spinal fractures. CONCLUSIONS: Prolonged androgen deprivation therapy, low serum 25-hydroxyvitamin D levels and a history of alcohol excess are important risk factors for osteoporosis and spinal fractures in men with prostate cancer.