Is histologic necrosis in the primary tumor of patients with renal-cell carcinoma a predictor for survival?
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Journal Article↗
Biomedical subjects
Eric A Klein
Publications and source records attributed to Eric A Klein.
Chemoprevention of prostate cancer.
Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. The Prostate Cancer Prevention Trial has provided the first firm evidence that this cancer can be prevented by a relatively nontoxic oral agent. Additional agents, many of which are antioxidants with antiandrogenic effects, are being tested (or soon will be) in large clinical trials. The current body of evidence is insufficient to make a routine recommendation of any dietary or nutritional supplement for the prevention of prostate cancer.
5-alpha Reductase Inhibitors↗
Phase III prostate cancer prevention trials: are the costs justified?
One randomized, prospective clinical trial for chemoprevention of prostate cancer has been completed, and two additional trials are ongoing. The investment, time, and effort for these trials are substantial. We reviewed the outcomes of these trials to address the value of the investment. The outcomes of the Prostate Cancer Prevention Trial (testing finasteride) and the design of the Selenium and Vitamin E Cancer Prevention Trial (SELECT; testing vitamin E and selenium) trial as well as the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial (testing dutasteride) were reviewed. From a public health standpoint, there is tremendous potential for benefit from large-scale cancer prevention trials. Because of the volume of data that are collected, potential discoveries related to the biology of the disease are substantial. Translational scientific efforts are direct outgrowths of these studies. Prospective, randomized chemoprevention trials for prostate and other cancers are expensive and require long periods of time to conduct, yet the rewards are on a par with the investment.
Clinical Trials, Phase III as Topic↗
PSA kinetics after prostate brachytherapy: PSA bounce phenomenon and its implications for PSA doubling time.
PURPOSE: To analyze prostate-specific antigen (PSA) kinetics in patients treated with prostate brachytherapy (PI) with a minimum of 5 years of PSA follow-up. METHODS AND MATERIALS: The records of 162 patients treated with PI for localized prostate cancer with a minimum of 5 years of PSA follow-up were reviewed. A variety of pretreatment and posttreatment variables were examined. Patients were coded as having a PSA bounce if their PSA achieved a nadir, elevated at least 0.2 ng/mL greater than that nadir, and decreased to, or below, the initial nadir. Two definitions of biochemical failure (bF) or biochemical relapse-free survival (bRFS) were used: the classic American Society for Therapeutic Radiology and Oncology consensus definition of three consecutive rises (bF3) and the nadir plus 2 ng/mL definition (bFn+2). Associations between a PSA bounce and the various pre- and posttreatment factors were assessed with logistic regression analysis, and the association between a PSA bounce and bF was examined with the log-rank test. The Mann-Whitney U test was applied to test for differences in the PSA doubling time (PSADT) and the time to a PSA rise between the PSA bounce patients and the bF patients. PSADT was calculated from the nadir to the time of the first PSA rise, because this point is known first in the clinical setting. RESULTS: The 5-year overall bRFS rate was 87% for the bF3 definition and 96% for the bFn+2 definition. A PSA bounce was experienced by 75 patients (46.3%). Patients who experienced a PSA bounce were less likely to have a bF, regardless of the bRFS definition used (bF3: p=0.0015; bFn+2: p=0.0040). Among the pre- and posttreatment factors, only younger age predicted for a PSA bounce on multivariate analysis (p=0.0018). The use of androgen deprivation had no effect on PSA bounce. No difference was found in the PSADT between patients who had a PSA bounce and those with bF. The median PSADT for those with a PSA bounce was 8.3 months vs. 10.3 months using the bF3 definition and 8.8 months using the bFn+2 definition. However, a significant difference was found in the time to the first rise in PSA after PI for patients with a PSA bounce vs. patients with bF. The median time to the first rise in PSA after nadir for those with a PSA bounce was 15.1 months vs. 30.0 months using the bF3 definition (p=0.001) and 22.3 months using the bFn+2 definition (p=0.013). CONCLUSION: Patients experiencing a PSA bounce are more likely to be younger and will have a better bRFS. The PSADT cannot differentiate a PSA bounce from bF. The time to the initial PSA rise after nadir is an excellent discriminator of bF from PSA bounce. The time of the PSA rise after nadir occurs far sooner for a PSA bounce than for bF. This factor should be considered when assessing a patient with a rising PSA level after PI before a patient is administered salvage therapy.
Age Factors↗
Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy.
PURPOSE: A postoperative nomogram for prostate cancer recurrence after radical prostatectomy (RP) has been independently validated as accurate and discriminating. We have updated the nomogram by extending the predictions to 10 years after RP and have enabled the nomogram predictions to be adjusted for the disease-free interval that a patient has maintained after RP. METHODS: Cox regression analysis was used to model the clinical information for 1,881 patients who underwent RP for clinically-localized prostate cancer by two high-volume surgeons. The model was externally validated separately on two independent cohorts of 1,782 patients and 1,357 patients, respectively. Disease progression was defined as a rising prostate-specific antigen (PSA) level, clinical progression, radiotherapy more than 12 months postoperatively, or initiation of systemic therapy. RESULTS: The 10-year progression-free probability for the modeling set was 79% (95% CI, 75% to 82%). Significant variables in the multivariable model included PSA (P = .002), primary (P < .0001) and secondary Gleason grade (P = .0006), extracapsular extension (P < .0001), positive surgical margins (P = .028), seminal vesicle invasion (P < .0001), lymph node involvement (P = .030), treatment year (P = .008), and adjuvant radiotherapy (P = .046). The concordance index of the nomogram when applied to the independent validation sets was 0.81 and 0.79. CONCLUSION: We have developed and validated as a robust predictive model an enhanced postoperative nomogram for prostate cancer recurrence after RP. Unique to predictive models, the nomogram predictions can be adjusted for the disease-free interval that a patient has achieved after RP.
Adult↗
Hypofractionated intensity-modulated radiotherapy (70 gy at 2.5 Gy per fraction) for localized prostate cancer: long-term outcomes.
PURPOSE: To analyze the long-term relapse-free survival and toxicity rates in patients treated with hypofractionated intensity-modulated radiotherapy. METHODS AND MATERIALS: The study sample includes the first 100 consecutive localized prostate cancer patients treated to 70.0 Gy at 2.5 Gy per fraction. The median follow-up was 66 months (range, 3 to 75 months). Biochemical failure was the study endpoint, using both the ASTRO definition (A-bRFS) and the alternate "nadir + 2 ng/mL" definition (N-bRFS). RTOG scores were used to assess toxicity. RESULTS: The 5-year A-bRFS and N-bRFS rates were 85% (95%CI, 78-93%) and 88% (95%CI, 82-95%) for all cases, respectively. For low, intermediate and high-risk disease, the 5-year A-bRFS rates were 97%, 88%, and 70%. The corresponding 5-year N-bRFS rates were 97%, 93%, and 75%, respectively. The acute rectal toxicity scores were 0 in 20, 1 in 61, and 2 in 19 patients. The acute urinary toxicity scores were 0 in 9, 1 in 76, and 2 in 15 patients. The late rectal toxicity scores were 0 in 71, 1 in 19, 2 in 7, and 3 in 3 patients. The actuarial late Grade 3 rectal toxicity rate at 5 years was 3%. A number of the toxicities observed either resolved spontaneously or were corrected. At last follow-up, the rate of combined Grades 2 and 3 late rectal toxicity at 5 years was only 5%. The late urinary toxicity scores were 0 in 75, 1 in 13, 2 in 11, and 3 in 1 patients. The actuarial late Grade 3 urinary toxicity rate at 5 years was 1%. CONCLUSION: With a median follow-up of 66 months, the long-term results after high-dose hypofractionation are excellent. Late toxicity, urinary and rectal, has been limited. High-dose hypofractionation is an alternative dose escalation method in the treatment of localized prostate cancer.
Aged↗
Assessing benefit and risk in the prevention of prostate cancer: the prostate cancer prevention trial revisited.
PURPOSE: The Prostate Cancer Prevention Trial demonstrated a 25% reduction in period prevalence of prostate cancer in men randomly assigned to 5 mg/d of finasteride. However, widespread use of finasteride for prevention is inhibited by the observed increased risk of high-grade disease. We present a model of risk and benefit that estimates the potential effects of histologic artifact in the assignment of excess risk for high-grade disease and the possible effect of overdetection bias introduced by finasteride-induced volume reduction. METHODS: The absolute benefit/absolute risk ratio of finasteride use was estimated by calculating the ratio of absolute risk reduction in the finasteride arm to the absolute risk of excess high-grade cancers. This ratio was recalculated for assumptions that 10%, 25%, or 50% of the excess high-grade cancers were due to histologic artifact, and that there was a 25% overdetection bias in the finasteride arm. RESULTS: For all cancers the absolute benefit/absolute risk ratio increased from 4.6:1 to 5.1:1, 6.2:1, and 9.2:1 for assumptions of 10%, 25%, or 50% histologic artifact, respectively. The ratio increased from 4.6:1 to 8.2:1 for the assumption of 25% overdetection bias, and to 9.1:1, 10.9:1, and 16.3:1 for combined assumptions of 25% overdetection bias and 10%, 25%, or 50% histologic artifact, respectively. CONCLUSION: The adoption of a prevention strategy hinges on potential benefits weighed against potential risks. This model demonstrates the magnitude of effect for a hypothesized range of histologic artifact and overdetection bias on the assessment of risk versus benefit for finasteride.
Adenocarcinoma↗
Evidence-based review of three-dimensional conformal radiotherapy for localized prostate cancer: an ASTRO outcomes initiative.
PURPOSE: To perform a systematic review of the evidence to determine the efficacy and effectiveness of three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer; provide a clear presentation of the key clinical outcome questions related to the use of 3D-CRT in the treatment of localized prostate cancer that may be answered by a formal literature review; and provide concise information on whether 3D-CRT improves the clinical outcomes in the treatment of localized prostate cancer compared with conventional RT. METHODS AND MATERIALS: We performed a systematic review of the literature through a structured process developed by the American Society for Therapeutic Radiology and Oncology's Outcomes Committee that involved the creation of a multidisciplinary task force, development of clinical outcome questions, a formal literature review and data abstraction, data review, and outside peer review. RESULTS: Seven key clinical questions were identified. The results and task force conclusions of the literature review for each question are reported. CONCLUSION: The technological goals of reducing morbidity with 3D-CRT have been achieved. Randomized trials and follow-up of completed trials remain necessary to address these clinical outcomes specifically with regard to patient subsets and the use of hormonal therapy.
Disease-Free Survival↗
Prophylactic tamsulosin (Flomax) in patients undergoing prostate 125I brachytherapy for prostate carcinoma: final report of a double-blind placebo-controlled randomized study.
PURPOSE: To evaluate the effectiveness of prophylactic tamsulosin (Flomax) in reducing the urinary symptoms in patients undergoing 125I prostate implantation (PI) for prostate adenocarcinoma. METHODS AND MATERIALS: This is a single-institution, double-blind, placebo-controlled, randomized trial for patients undergoing PI for prostate adenocarcinoma comparing prophylactic tamsulosin versus placebo. Eligibility criteria included patients not taking tamsulosin or other alpha-blockers treated with PI. The patients were randomly assigned to either tamsulosin (0.8 mg, orally once a day) or matched placebo. All patients started the medication 4 days before PI and continued for 60 days. The American Urologic Association (AUA) symptom index questionnaire was used to assess urinary symptoms. The AUA questionnaire was administered before PI for a baseline score and weekly for 8 weeks after PI. Patients were taken off the study if they developed urinary retention, had intolerable urinary symptoms, or wished to discontinue with the trial. RESULTS: One hundred twenty-six patients were enrolled in this study from November 2001 to January 2003 (118 were evaluable: 58 in the tamsulosin arm and 60 in the placebo group). Pretreatment and treatment characteristics were comparably matched between the two groups. The urinary retention rate was 17% (10 patients) in the placebo group compared with 10% (6 patients) in the tamsulosin group (p = 0.3161). Eighty-eight percent (14 patients) of those who developed urinary retention experienced it within 2 weeks after the PI. Intolerable urinary symptoms were reported equally (10 patients in each group) with 70% occurring in the first 2 weeks after PI. There was a significant difference in mean AUA score in favor of tamsulosin at Week 5 after PI (p = 0.03). CONCLUSIONS: Prophylactic tamsulosin (0.8 mg/day) before prostate brachytherapy did not significantly affect urinary retention rates, but had a positive effect on urinary morbidity at Week 5 after PI.
Adenocarcinoma↗
Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
Prostate cancer continues to be a major health threat, especially among African American men. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), which opened on July 25, 2001, was planned to study possible agents for the prevention of prostate cancer in a population of 32,400 men in the United States, including Puerto Rico, and Canada. SELECT is a phase III randomized, placebo-controlled trial of selenium (200 microg/day from L-selenomethionine) and/or vitamin E (400 IU/day of all rac alpha-tocopheryl acetate) supplementation for a minimum of 7 years (maximum of 12 years) in non-African American men at least 55 years of age and African American men at least 50 years of age. SELECT is a large, simple trial that conforms as closely as possible with community standards of care. This commentary discusses the design problems the SELECT investigators had to resolve in developing the trial, including the role of prostate cancer screening, the best forms and doses of the study agents, and estimation of the event (prostate cancer) rate of men on the placebo arm.
Black or African American↗
Chemoprevention of prostate cancer.
Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. Prevention of this disease would have a major impact on disease-associated cost, morbidity, and mortality for a large segment of the population. A major advance in prevention of prostate cancer came in 2003 with the publication of the Prostate Cancer Prevention Trial (PCPT). This overview summarizes the results of that trial, the design of other large-scale trials, and advances in understanding of the molecular mechanisms underlying the effect of other promising agents, including dutasteride, selenium, Vitamin E, Vitamin D, COX-2 inhibitors, lycopene, and green tea.
Anticarcinogenic Agents↗
Surgical management of prostate cancer: advances based on a rational approach to the data.
The management of localised prostate cancer has undergone important changes in the past two decades, with major improvements in surgical technique, a greater emphasis on structured assessment of quality of life, and a greater attempt to tailor treatment to biological risk. Disease diagnosis is predicated on identification of demographic risk factors, serum levels of prostate-specific antigen and its derivatives, and extended biopsy techniques. Surgical removal of the prostate may be accomplished by open or minimally invasive techniques and in experienced hands results in good functional outcomes a high rate of cure for those with organ confined disease. Radical prostatectomy is also appropriate in selected patients with locally advanced disease and after failed radiation therapy.
Biopsy↗
Local recurrence of prostate cancer in rectal submucosa after transrectal needle biopsy and radical prostatectomy.
A 69-year-old man with clinical Stage T1cN0M0 prostate cancer underwent radical prostatectomy, revealing negative surgical margins, focal capsular penetration, and negative lymph nodes and seminal vesicles. Five years later, his prostate-specific antigen level had increased to 0.2 ng/mL, and digital rectal examination revealed a palpable submucosal mass in the rectum that was confirmed by colonoscopy and transrectal ultrasonography. Excisional biopsy revealed prostatic adenocarcinoma similar in appearance and grade to the initial needle biopsy. This case report illustrates an extremely rare needle tract adenocarcinoma implantation after needle biopsy of the prostate.
Adenocarcinoma↗
Can prostate cancer be prevented?
The goal of primary chemoprevention is to decrease the incidence of a given cancer, simultaneously reducing both treatment-related adverse events and mortality. Prostate cancer is an attractive and appropriate target for primary prevention because of its incidence, prevalence, and disease-related mortality; its long latency and molecular pathogenesis; and epidemiologic data indicating that modifiable environmental factors may decrease risk. The Prostate Cancer Prevention Trial (PCPT) demonstrated that finasteride can prevent prostate cancer, albeit with an apparently increased risk of high-grade disease. A substantial amount of epidemiologic, molecular, and clinical evidence suggests that both selenium and vitamin E might also prevent prostate cancer, and this combination is being tested in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Ultimately, the adoption of a preventive strategy hinges on its potential benefits weighed against the potential risks of the specific agents used.
Clinical Trials as Topic↗
Bilateral metachronous testicular seminoma.
BACKGROUND: A 33-year-old male presented to hospital with a painless right testicular mass measuring 2 x 3 cm and no systemic symptoms. The patient had no relevant medical history. CT and blood tests did not reveal metastasis and the patient was treated with a right inguinal orchiectomy and radiotherapy. After 4 years a routine follow-up examination revealed a 1 cm palpable mass in the left testis. INVESTIGATIONS: CT, tumor marker assessment, scrotal ultrasonography, Doppler ultrasound examination, and biopsy. DIAGNOSIS: Bilateral metachronous testicular seminoma, stage pT1N0M0S0. MANAGEMENT: Radiotherapy, radical orchiectomy, bilateral placement of testicular prostheses, androgen substitution therapy, regular follow-up assessment.
Adult↗
A retrospective comparison of androgen deprivation (AD) vs. no AD among low-risk and intermediate-risk prostate cancer patients treated with brachytherapy, external beam radiotherapy, or radical prostatectomy.
PURPOSE: To examine the value of androgen deprivation (AD) in the curative treatment of low- and intermediate-risk prostate cancer treated with the three major modalities: radical retropubic prostatectomy (RRP), external beam radiotherapy (EBRT), and permanent prostate implantation (PI). METHODS AND MATERIALS: During 1996-2001, 1668 patients with low- and intermediate-risk prostate cancer were treated at The Cleveland Clinic Foundation. Only patients with a minimum of 2 years of prostate-specific antigen follow-up were included in the analysis, and biochemical relapse-free survival (bRFS) was used as the endpoint. Patients were grouped according to treatment modality and stratified according to the use of AD. RESULTS: The overall 5-year bRFS rate was 87.8%. The 5-year bRFS rate for low-risk patients was 89% and for intermediate-risk patients was 79%. For low-risk patients, the 5-year bRFS rates by treatment modality (without AD vs. with AD, respectively) were PI: 90% vs. 93%; EBRT: 90% vs. 93%; and RRP: 89% vs. 84%. For intermediate-risk patients, the 5-year bRFS rates by treatment modality (without AD vs. with AD, respectively) were PI: 88% vs. 82%; EBRT: 81% vs. 84%; and RRP: 75% vs. 72%. None of the comparisons within risk groups or among modalities supports an increased efficacy with the use of AD. CONCLUSION: Five-year bRFS rates in low-risk and intermediate-risk patients are not improved by the use of AD.
Adult↗
What is 'insignificant' prostate carcinoma?
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Biopsy↗
Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy.
CONTEXT: Salvage radiotherapy may potentially cure patients with disease recurrence after radical prostatectomy, but previous evidence has suggested that it is ineffective in patients at the highest risk of metastatic disease progression. OBJECTIVE: To delineate patients who may benefit from salvage radiotherapy for prostate cancer recurrence by identifying variables associated with a durable response. DESIGN, SETTING, AND PATIENTS: Retrospective review of a cohort of 501 patients at 5 US academic tertiary referral centers who received salvage radiotherapy between June 1987 and November 2002 for detectable and increasing prostate-specific antigen (PSA) levels after radical prostatectomy. MAIN OUTCOME MEASURE: Disease progression after salvage radiotherapy, defined as a serum PSA value > or =0.1 ng/mL above the postradiotherapy PSA nadir confirmed by a second PSA measurement that was higher than the first by any amount, by a continued increase in PSA level after treatment, or by the initiation of androgen deprivation therapy after treatment. RESULTS: Over a median follow-up of 45 months, 250 patients (50%) experienced disease progression after treatment, 49 (10%) developed distant metastases, 20 (4%) died from prostate cancer, and 21 (4%) died from other or unknown causes. The 4-year progression-free probability (PFP) was 45% (95% confidence interval [CI], 40%-50%). By multivariable analysis, predictors of progression were Gleason score of 8 to 10 (hazard ratio [HR], 2.6; 95% CI, 1.7-4.1; P<.001), preradiotherapy PSA level greater than 2.0 ng/mL (HR, 2.3; 95% CI, 1.7-3.2; P<.001), negative surgical margins (HR, 1.9; 95% CI, 1.4-2.5; P<.001), PSA doubling time (PSADT) of 10 months or less (HR, 1.7; 95% CI, 1.2-2.2; P =.001), and seminal vesicle invasion (HR, 1.4; 95% CI, 1.1-1.9; P =.02). Patients with no adverse features had a 4-year PFP of 77% (95% CI, 64%-91%). When treatment was given for early recurrence (PSA level < or =2.0 ng/mL), patients with Gleason scores of 4 to 7 and a rapid PSADT had a 4-year PFP of 64% (95% CI, 51%-76%) and of 22% (95% CI, 6%-38%) when the surgical margins were positive and negative, respectively. Patients with Gleason scores of 8 to 10, positive margins, and receiving early salvage radiotherapy had a 4-year PFP of 81% (95% CI, 57%-100%) when the PSADT was longer than 10 months and of 37% (95% CI, 16%-58%) when the PSADT was 10 months or less. CONCLUSIONS: Gleason score, preradiotherapy PSA level, surgical margins, PSADT, and seminal vesicle invasion are prognostic variables for a durable response to salvage radiotherapy. Selected patients with high-grade disease and/or a rapid PSADT who were previously thought to be destined to develop progressive metastatic disease may achieve a durable response to salvage radiotherapy.
Adult↗