Prostatic Neoplasms: Sandler H

Mohler J, Babaian RJ, Bahnson RR, Boston B, D'Amico A, Eastham JA, Hauke RJ, Huben RP, Kantoff P, Kawachi M, Kuettel M, Lange PH, Logothetis C, MacVicar G, Pollack A, Pow-Sang JM, Roach M, Sandler H, Shrieve D, Srinivas S, Twardowski P, Urban DA, Walsh PC, Anonymous00332. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #17692170 No free full text.

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Bahnson RR, Hanks GE, Huben RP, Kantoff P, Kozlowski JM, Kuettel M, Lange PH, Logothetis C, Pow-Sang JM, Roach M, Sandler H, Scardino PT, Taylor RJ, Urban DA, Walsh PC, Wilson TG, Anonymous00207. · James Cancer Hospital and Solove Research Institute at Ohio State University, Columbus, Ohio, USA. · Oncology (Williston Park). · Pubmed #11195405 No free full text.

Abstract: Systemic therapies for prostate cancer are likely to improve, and as they do, they will have enormous impact on the treatment of high-risk and locally advanced cancers. Further technical improvements in radiotherapy and alternative local modalities, such as cryoablation, are also likely, and will bring even more options for local control. It is certain these guidelines will continue to evolve.

Lee I, Sandler H. · Department of Radiation Oncology, University of Michigan, 1500 Medical Center Drive, Ann Arbor, MI, USA. · Semin Radiat Oncol. · Pubmed #18082583 No free full text.

Abstract: The optimal therapy for prostate cancer classified as "intermediate risk" on the basis of prostate-specific antigen, Gleason score, and clinical T stage is currently evolving. The role of hormonal therapy in these patients remains controversial, particularly in the setting of dose-escalated radiation. In this review, we examine the currently available data and describe maturing studies that address the optimal timing, duration, and potential risks and benefits of adding hormonal therapy to external-beam radiation for intermediate-risk patients. We conclude that until additional data become available, a short course of androgen deprivation, concurrent with radiation, should be considered in selected intermediate-risk patients who may be at greatest risk for failure if treated with external-beam radiation alone.

Carroll PR, Chan JM, D'Amico AV, Gelmann EP, Iversen P, Klotz L, Nelson JB, Nelson PS, Nelson WG, Oh WK, Rosen N, Rubin MA, Sandler H, Sellers WR, Smith MR, Xu J, McMann MC, Kantoff PW. · Department of Urology, University of California School of Medicine, San Francisco 94115-1711, USA. · J Urol. · Pubmed #15535434 No free full text.

This publication has no abstract.

Tsien C, Sandler H. · Department of Radiation Oncology, University of Michigan Medical Center, University of Michigan, Ann Arbor, Michigan 48109, USA. · Urology. · Pubmed #14747043 No free full text.

Abstract: For patients undergoing radical prostatectomy for prostate adenocarcinoma, the most common cause of failure is an asymptomatic increase in levels of prostate-specific antigen (PSA). Salvage radiotherapy (RT) to the prostate bed has been used when there is no clinical evidence of metastatic disease. However, this is still not widely accepted because there is currently no consensus on the optimal management of an isolated PSA failure. Salvage RT given in a select group of patients is effective, with a 70% to 80% biochemical response rate and a long-term biochemical control rate as high as 35% to 40%. These data indicate that RT offers a substantial risk of curative salvage of patients who fail radical prostatectomy. Although there is interest in studying investigational modalities (eg, vaccine therapy) among patients with asymptomatic, PSA-detected recurrences after surgery, caution must be applied, and treatment modalities with known curative potential (ie, RT) should be used before noncurative techniques are attempted. This article outlines the rationale, results, and toxicity of salvage RT for an asymptomatic increase in PSA levels, with emphasis on identifying patients with favorable prognostic factors with higher rates of long-term biochemical control with local treatment.

Roach M, De Silvio M, Rebbick T, Grignon D, Rotman M, Wolkov H, Fisher B, Hanks G, Shipley WU, Pollack A, Sandler H, Watkins-Bruner D. · Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #17498886 No free full text.

Abstract: PURPOSE: Inherited genotypes may explain the inferior outcomes of African American (AA) men with prostate cancer. To understand how variation in CYP3A4 correlated with outcomes, a retrospective examination of the CYP3A4 *1B genotype was performed on men treated with Radiation Therapy Oncology Group (RTOG) 92-02. METHODS AND MATERIALS: From 1,514 cases, we evaluated 56 (28.4%) of 197 AA and 54 (4.3%) of 1,274 European American (EA) patients. All patients received goserelin and flutamide for 2 months before and during RT (STAD-RT) +/- 24 months of goserelin (long-term androgen deprivation plus radiation [LTAD-RT]). Events studied included overall survival and biochemical progression using American Society for Therapeutic Radiology and Oncology consensus guidelines. RESULTS: There were no differences in outcome in patients in with or without CYP3A4 data. There was an association between race and CYP3A4 polymorphisms with 75% of EAs having the Wild Type compared to only 25% of AA men (p <0.0001). There was no association between CYP3A4 classification or race and survival or progression. CONCLUSIONS: The samples analyzed support previously reported observations about the distribution of CYP3A4 *1B genotype by race, but race was not associated with poorer outcome. However, patient numbers were limited, and selection bias cannot be completely ruled out.

Torres-Roca JF, DeSilvio M, Mora LB, Khor LY, Hammond E, Ahmad N, Jove R, Forman J, Lee RJ, Sandler H, Pollack A. · Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. · Urology. · Pubmed #17382154 No free full text.

Abstract: OBJECTIVE: STAT3 participates in the regulation of cellular growth, survival, and oncogenesis. We evaluated the association between activated STAT3 expression and overall survival, disease-specific survival, distant metastasis, and local progression in a cohort of patients treated with either radiotherapy alone or radiotherapy plus short-term androgen blockade. METHODS: A total of 456 assessable patients were included in the Radiation Therapy Oncology Group 86-10 trial. Of these, 62 patients had sufficient tissue for the analysis of STAT3 expression by immunohistochemistry. Nuclear staining was quantified by an image analysis system. RESULTS: No significant difference was found in the distribution of clinical characteristics and assigned treatment between the patients available for STAT3 analysis (STAT3 cohort) and the others in the Radiation Therapy Oncology Group 86-10 trial (n = 394). Activated STAT3 correlated inversely with the development of distant metastasis (risk ratio [RR] = 0.81, P = 0.04) but not with overall survival, cause-specific survival, or local progression. Similar results were obtained when the data were dichotomized (ACIS index greater than 29%, RR = 0.41, P = 0.07). On multivariate analysis, activated STAT3 (continuous variable) was an independent predictor of distant metastasis (RR = 0.79, P = 0.04). CONCLUSIONS: Activated STAT3 was inversely related to the development of distant metastasis in prostate cancer. This marker should be evaluated further in a larger cohort of patients.

Lee WR, Bae K, Lawton C, Gillin M, Morton G, Firat S, Baikadi M, Kuettel M, Greven K, Sandler H. · Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina 27710, USA. · Cancer. · Pubmed #17340591 links to  free full text

Abstract: BACKGROUND: The combination of external-beam radiotherapy and brachytherapy is used commonly to treat men with prostate cancer. In this analysis, the authors examined the rate of biochemical recurrence (BR) and late grade > or =3 genitourinary (GU) and gastrointestinal (GI) toxicity after treatment with external-beam radiotherapy and brachytherapy in a multiinstitutional, cooperative group setting. METHODS: All eligible patients received external-beam radiotherapy (45 Gray [Gy] in 25 fractions) followed 2 to 6 weeks later by an interstitial implant using iodine-125 to deliver an additional 108 Gy. BR was defined in 2 ways: according to the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Definition (ACD) and according to the Phoenix definition (PD) (prostate-specific antigen nadir +2 ng/mL). The Radiation Therapy Oncology Group(RTOG)/European Organization for Research and Treatment of Cancer late radiation morbidity scoring system was used to grade all toxicity. RESULTS: One hundred thirty-eight patients were enrolled, and 130 were eligible for the current analysis. The median follow-up for surviving patients was 49 months (range, 20-60 months). The 48-month estimate of late grade > or =3 GU/GI toxicity was 15% (95% confidence interval [95% CI], 8-21%), and the 48-month estimate of BR was 19% (95% CI, 12-26%) and 14% (95% CI, 8-20%) according to the ACD and PD, respectively. CONCLUSIONS: The morbidity observed in this multiinstitutional, cooperative group study was slightly higher than that reported in recent RTOG studies using brachytherapy alone or high-dose external-beam radiotherapy. The BR rate observed in this report was similar to that observed with high-dose external-beam radiotherapy alone in similar patients.

Lawton CA, DeSilvio M, Lee WR, Gomella L, Grignon D, Gillin M, Morton G, Pisansky T, Sandler H. · Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #17084551 No free full text.

Abstract: PURPOSE: To evaluate the effectiveness of transrectal ultrasound-guided permanent radioactive (125)I implantation of the prostate for organ-confined adenocarcinoma of the prostate compared with historical data of prostatectomy and external beam radiotherapy within a cooperative group setting. METHODS AND MATERIALS: Patients accrued to this study had histologically confirmed, locally confined, adenocarcinoma of the prostate with clinical Stage T1b, T1c, or T2a, no nodal or metastatic disease, prostate-specific antigen level of < or =10 ng/mL, and Gleason score of < or =6. All patients underwent transrectal ultrasound-guided radioactive (125)I permanent seed implantation into the prostate. The prescribed dose was 145 Gy to the prostate planning target volume. RESULTS: A total of 27 institutions accrued a total of 101 patients to this protocol, with no institution accruing >8 patients. Six patients were ineligible, leaving 95 properly entered as eligible in the study. The median follow-up was 5.3 years (range, 0.4-6.5 years). At 5 years, 5 patients had local failure, 1 had evidence of distant failure, and 6 (6%) had biochemical failure. The overall survival rate at 5 years was 96.7%. At last follow-up, no patient had died of prostate cancer or related toxicities. Eight patients had a maximal acute toxicity level of 3, and no patient had Grade 4 or 5 acute toxicity. During follow-up, 2 patients had maximal Grade 3 toxicity, both related to bladder issues, and no patient experienced Grade 4 or 5 toxicity. CONCLUSION: The results of this clinical protocol (a multi-institutional trial of brachytherapy for localized adenocarcinoma of the prostate) have demonstrated that this type of trial can be successfully completed through the Radiation Therapy Oncology Group. Biochemical disease-free survival was comparable with other brachytherapy published series and with the results after surgery and external beam radiotherapy.

Lee WR, DeSilvio M, Lawton C, Gillin M, Morton G, Firat S, Baikadi M, Kuettel M, Greven K, Sandler H. · Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1030, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #16289906 No free full text.

Abstract: PURPOSE: To estimate the rate of acute and late Grade 3-5 genitourinary and gastrointestinal toxicity after treatment with external beam radiotherapy and permanent source brachytherapy in a multi-institutional, cooperative group setting. METHODS AND MATERIALS: All patients were treated with external beam radiotherapy (45 Gy in 25 fractions), followed 2-6 weeks later by an interstitial implant using 125I to deliver an additional 108 Gy. Late genitourinary toxicity was graded according to the Common Toxicity Criteria Version 2.0, and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring system was used for all other toxicity. RESULTS: A total of 138 patients from 28 institutions were entered on this study. Acute toxicity information was available in 131 patients, and 127 patients were analyzable for late toxicity. Acute Grade 3 toxicity was documented in 10 of 131 patients (7.6%). No Grade 4 or 5 acute toxicity has been observed. The 18-month month estimate of late Grade 3 genitourinary and gastrointestinal toxicity was 3.3% (95% confidence interval, 0.1-6.5). No late Grade 4 or 5 toxicity has been observed. CONCLUSIONS: The acute and late morbidity observed in this multi-institutional, cooperative group study is consistent with previous reports from single institutions with significant prostate brachytherapy experience.

Feigenberg SJ, Lee WR, Desilvio ML, Winter K, Pisansky TM, Bruner DW, Lawton C, Morton G, Baikadi M, Sandler H. · Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #15989995 No free full text.

Abstract: PURPOSE: To prospectively assess health-related quality of life (HRQOL) during the first year after treatment with prostate brachytherapy (PB) alone for T1c-2a prostate cancer. MATERIALS AND METHODS: Ninety-eight patients from 24 institutions were eligible and properly entered on this study. All patients were treated with PB alone using I-125 (Oncura Model 6711). The prescription dose was 145 Gy. Three separate health-related quality of life questionnaires (HRQOL) (Functional Assessment of Cancer Therapy-Prostate [FACT-P], Sexual Adjustment Questionnaire [SAQ], and International Prostate Symptom Score [IPSS]) were self-administered before and after PB (baseline; 3, 6, 9, and 12 months after PB). The standard error of the mean (SEM) was used to analyze changes in HRQOL scores over time. Patients who improved greater than the SEM were categorized as improved; patients that declined greater than the SEM were categorized as declined; patients were otherwise categorized as stable. All changes are measured using the pretreatment HRQOL score as baseline. RESULTS: The percentage of men who reported the ability to have an erection decreased from 73% at baseline (65% unassisted, 8% assisted) to 57% at 1 year (36% unassisted, 21% assisted). The rate of urinary incontinence increased to 14% at 6 months but had decreased to 1% at the 12-month follow-up. At 1 year after PB, 80% of men reported decreased sexual functioning according to SAQ scores. More than 60% of men reported decreased urinary function at 12 months compared with baseline. CONCLUSIONS: This article represents the first prospective, multi-institutional study of HRQOL in men treated with PB and demonstrates that patients undergoing PB have a very high overall HRQOL. The rate of incontinence by 1 year after PB is low, but many patients continue to have obstructive symptoms at 1 year. Although 78% of 1-year respondents state that they can achieve an erection with or without assistance, almost 50% report a decrease in sexual function.

Michalski JM, Winter K, Purdy JA, Wilder R, Perez CA, Roach M, Parliament M, Pollack A, Markoe A, Harms WB, Sandler H, Cox JD. · Washington University Medical School, St Louis, MO 63110, USA. · Semin Radiat Oncol. · Pubmed #11917289 No free full text.

Abstract: The aim of this study was to evaluate and compare the rates of grade 2 or worse late effects in patients treated for prostate cancer on Radiation Therapy Oncology Group (RTOG) 9406. The authors previously have reported the results of patients treated on the first 2 dose levels of this study with respect to grade 3 or greater late toxicity. This analysis examines the incidence of grade 2 toxicity in this study. From August 1994 to September 1999, 424 patients were entered on this dose escalation trial of 3-dimensional conformal radiation therapy (3D CRT) for localized adenocarcinoma of the prostate at doses of 68.4 Gy (level I) and 73.8 Gy (level II). All radiation prescriptions were a minimum dose to a planning target volume. Patients were stratified according to clinical stage and risk of seminal vesicle invasion based on Gleason score and presenting prostate-specific antigen. Average time at risk after completion of therapy ranged from 33.1 to 40.1 months for patients treated at dose level I and 15.6 to 34.2 months for patients at dose level II. The frequency of late effects > or = grade 2 was compared with a similar group of patients treated on RTOG studies 7506 and 7706 with adjustments made for the interval from completion of therapy. The RTOG toxicity scoring scales for late effects were used. The rate of grade 3 or greater late toxicity continues to be low compared with RTOG historical controls. No grade 4 or 5 late complications were reported in any of the 406 evaluable patients during the period of observation. Interestingly, the incidence of grade 2 late toxicity was increased relative to historical controls in all groups and dose levels. In group 1, level I and group 3, level II, the increase in grade 2 complications was statistically significant; 16 complications were observed in group 1, level I when 9.2 were expected (P =.026) and 22 were observed in group 3, level II when 7.6 were expected (P <.0001). When examining all late effects > or = grade 2, there were no significant differences in the rate of late effects in both groups and both dose levels with the exception of group 1, level II. This, in combination with the statistically significant decrease in late effects > or = grade 3, suggests that in most circumstances there has been a shift of grade 3 complications to grade 2. In group 1, dose level II there was a statistically significant reduction in > or = grade 2 late effects, suggesting there was no shift from grade 3 to grade 2 in these patients. In this circumstance there may have been a global reduction in all complications or a shift to late effects less severe than grade 2. In group 2, dose level II there is a trend (P =.085) toward this same result. It is important to continue to examine late effects closely in patients treated on RTOG 9406. The primary objective of dose escalation without an increase rate of > or = grade 3 complications has been achieved. However, the reduction in grade 3 complications may have resulted in a higher incidence of grade 2 late effects. Because grade 2 late effects may have a significant impact on a patient's quality of life, it is important to reduce these complications as much as possible. Improved conformal treatment delivery with intensity-modulated radiation therapy or the use of radioprotective agents could be considered. Clinical trials should use quality-of-life measures to determine that trade-offs between severity and rates of toxicity are acceptable to patients.

Souhami L, Bae K, Pilepich M, Sandler H. · Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec H3G 1A4, Canada. · J Clin Oncol. · Pubmed #19307511 No free full text.

Abstract: PURPOSE: Radiation Therapy Oncology Group 85-31 was a randomized trial of androgen suppression for life for patients with locally advanced prostate cancer. However, not all patients continued on the protocol-mandated long-term hormonal therapy despite no evidence of recurrence. We correlated duration of adjuvant hormonal therapy and outcomes among patients who prematurely discontinued hormonal therapy. PATIENTS AND METHODS: The protocol mandated pelvic radiotherapy followed by goserelin given indefinitely or until disease progression. There were 189 analyzable patients. Patients were divided in groups based on the tertile of hormonal therapy duration (HTD) as follows: < or = 1 year, more than 1 year and < or = 5 years, and more than 5 years. Overall survival (OS), disease-free survival (DFS), cause-specific mortality, local failure (LF), and distant metastasis (DM) were studied. Kaplan-Meier estimation and Cox proportional hazards regression model were used for OS and DFS, and Fine and Gray's regression model was used for the other outcomes. RESULTS: The median follow-up for surviving patients is 9.6 years. The median duration of adjuvant hormonal therapy was 2.2 years. The HTD more than 5 years group is significantly associated with an improved survival and DFS and fewer DMs than other HTD groups. After adjustment for age, radical prostatectomy, nodal status, Gleason score, and stage variables, the HTD more than 5 years group remains significantly associated with better OS and DFS than other HTD groups. CONCLUSION: In this hypothesis-generating analysis, prolonged HTD of more than 5 years seems significantly associated with improvements in most outcomes. Given these data, decreasing HTD to < or = 5 years may have a detrimental effect on patients with locally advanced prostate cancer. Only a randomized trial will conclusively clarify this issue.

Zhang M, Ho A, Hammond EH, Suzuki Y, Bermudez RS, Lee RJ, Pilepich M, Shipley WU, Sandler H, Khor LY, Pollack A, Chakravarti A. · Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #18977097 No free full text.

Abstract: PURPOSE: To examine the prognostic value of nuclear and cytoplasmic survivin expression in men with locally advanced prostate cancer who were enrolled in Radiation Therapy Oncology Group (RTOG) protocol 8610. METHODS AND MATERIALS: RTOG 8610 was a Phase III randomized study comparing the effect of radiotherapy plus short-term androgen deprivation with radiotherapy alone. Of the 456 eligible patients, 68 patients had suitably stained tumor material for nuclear survivin analysis and 65 patients for cytoplasmic survivin. RESULTS: Compared with patients with nuclear survivin intensity scores of <or=191.2, those with intensity scores >191.2 had significantly improved prostate cancer survival (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-1.00, p = 0.0452). On multivariate analysis, nuclear survivin intensity scores >191.2 were significantly associated with improved overall survival (HR, 0.46; 95% CI, 0.25-0.86; p = 0.0156) and prostate cancer survival (HR, 0.36; 95% CI, 0.16-0.84; p = 0.0173). On univariate analysis, compared with patients with cytoplasmic survivin integrated optical density <or=82.7, those with an integrated optical density >82.7 showed a significantly increased risk of local progression (HR, 2.49; 95% CI, 1.03-6.01; p = 0.0421). CONCLUSION: Nuclear overexpression of survivin was associated with improved overall and prostate cancer survival on multivariate analysis, and cytoplasmic overexpression of survivin was associated with increased rate of local progression on univariate analysis in patients with locally advanced prostate cancer treated on RTOG 8610. Our results might reflect the different functions of survivin and its splice variants, which are known to exist in distinct subcellular compartments.

Lawton CA, Michalski J, El-Naqa I, Kuban D, Lee WR, Rosenthal SA, Zietman A, Sandler H, Shipley W, Ritter M, Valicenti R, Catton C, Roach M, Pisansky TM, Seider M. · Medical College of Wisconsin, Milwaukee, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #18947941 No free full text.

Abstract: PURPOSE: We conducted a comparative study of clinical target volume (CTV) definition of pelvic lymph nodes by multiple genitourinary (GU) radiation oncologists looking at the levels of discrepancies amongst this group. METHODS AND MATERIALS: Pelvic computed tomography (CT) scans from 2 men were distributed to 14 Radiation Therapy Oncology Group GU radiation oncologists with instructions to define CTVs for the iliac and presacral lymph nodes. The CT data with contours were then returned for analysis. In addition, a questionnaire was completed that described the physicians' method for target volume definition. RESULTS: Significant variation in the definition of the iliac and presacral CTVs was seen among the physicians. The minimum, maximum, mean (SD) iliac volumes (mL) were 81.8, 876.6, 337.6 +/- 203 for case 1 and 60.3, 627.7, 251.8 +/- 159.3 for case 2. The volume of 100% agreement was 30.6 and 17.4 for case 1 and 2 and the volume of the union of all contours was 1,012.0 and 807.4 for case 1 and 2, respectively. The overall agreement was judged to be moderate in both cases (kappa = 0.53 (p < 0.0001) and kappa = 0.48 (p < 0.0001). There was no volume of 100% agreement for either of the two presacral volumes. These variations were confirmed in the responses to the associated questionnaire. CONCLUSIONS: Significant disagreement exists in the definition of the CTV for pelvic nodal radiation therapy among GU radiation oncology specialists. A consensus needs to be developed so as to accurately assess the merit and safety of such treatment.

Williams SG, Taylor JM, Liu N, Tra Y, Duchesne GM, Kestin LL, Martinez A, Pratt GR, Sandler H. · Division of Radiation Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia. · Int J Radiat Oncol Biol Phys. · Pubmed #17448868 No free full text.

Abstract: PURPOSE: To examine the effect of fraction size and total dose of radiation on recurrence of localized prostate cancer. METHODS AND MATERIALS: A total of 3756 patients treated with radiation monotherapy at three institutions were analyzed, including 185 high-dose-rate brachytherapy (HDRB) boost patients. The 5th to 95th centiles of external beam radiotherapy (EBRT) fraction sizes and doses were 1.8 to 2.86 Gy, and 57.4 to 77.4 Gy, respectively, and HDRB fractional doses were between 5.5 and 12 Gy, totaling 147 unique fractionation schedules. Failure was defined by one biochemical (nadir + 2 ng/ml) and two advanced disease endpoints. The alpha/beta ratios were estimated via a proportional hazards model stratified by risk severity and institution. RESULTS: The alpha/beta ratio using biochemical recurrence was 3.7 Gy (95% confidence interval [95% CI], 1.1, infinity Gy) for EBRT-only cases and 2.6 Gy (95% CI, 0.9, 4.8 Gy) after the addition of HDRB data. This estimate was highly dependent on an HDRB homogeneity correction factor (120% HDRB dose increase; alpha/beta ratio 4.5 Gy, 95% CI 1.6, 8.7 Gy). A 5-Gy increase in total dose reduced the hazard of failure by 16% (95% CI 11, 21%, p < 0.0001), and had more impact as follow-up matured (p < 0.0003). The clinically advanced endpoints concurred with the biochemical failure results, albeit with less precision. CONCLUSIONS: This study supports the concept that the alpha/beta ratio of prostate cancer is low, although considerable uncertainty remains in the estimated value. Outcome data from EBRT studies using substantially higher doses per fraction are needed to show increased precision in these estimates.

Roach M, Weinberg V, Sandler H, Thompson I. · Department of Radiation Oncology, University of California San Francisco Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143-1708, USA. · Cancer. · Pubmed #17167758 links to  free full text

Abstract: BACKGROUND: The American Joint Committee on Cancer (AJCC) staging system for prostate cancer is based primarily based on clinical tumor (T) classification. In this article, the authors summarize arguments for incorporating additional pretreatment parameters and creating a new staging system for prostate cancer. METHODS: Men with localized prostate cancer who received treatment with external beam radiation alone were analyzed using the 1997 AJCC staging system compared with a system that included pretreatment prostate-specific antigen (pPSA) level and Gleason score (GS). Multivariate analyses using a Cox proportional-hazards model were carried out to evaluate T classification, GS, and pPSA as predictors of overall survival (OS), disease-specific survival (DSS), and freedom from PSA failure (FFPF). RESULTS.: Based on pretreatment characteristics in a series of contemporary patients, only 0.6% of patients were classified with AJCC stage I disease, 16.0% were classified with AJCC stage III disease, and 83.4% were classified with AJCC stage II disease. Multivariate analyses indicated the independent statistical significance of T classification, GS, and pPSA in predicting OS, DSS, and FFPF (model chi-square value, P < .0001 for each). Using these 3 predictors, subsets of patients who had similar outcomes were combined to provide examples of the insensitivity of the AJCC system for predicting outcomes. Incorporating pPSA and GS allowed the identification of differences in OS, DSS, and FFPF for subsets of patients with AJCC stage II disease (P < .0001, P = .005, and P < .0001, respectively). CONCLUSIONS: The current AJCC staging system does not divide contemporary patients with prostate cancer into prognostic subgroups and does not identify patients who have comparable biochemical control and survival. The AJCC staging system for prostate cancer should be changed to incorporate pPSA, GS, and risk stratification.

Lee WR, Bae K, Lawton CA, Gillin MT, Morton G, Firat S, Baikadi M, Kuettel M, Greven K, Sandler H. · Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA. · Brachytherapy. · Pubmed #17118317 No free full text.

Abstract: BACKGROUND: To date, there are few descriptive analyses of postimplant dosimetry from multi-institutional clinical trials. The purpose of this report is to describe the postimplant dosimetry achieved in Radiation Therapy Oncology Group (RTOG) 0019. METHODS AND MATERIALS: Patients were treated with external beam radiation therapy (45 Gy/25 fractions) followed by a prostate implant (I-125, prescription dose 108 Gy). Postimplant dosimetric assessment was accomplished by obtaining a CT scan of the prostate 1 month after the date of the implant procedure. Prostate volume was outlined by the first author. Dose-volume histograms were calculated by the Radiologic Physics Center. Four dosimetric quantifiers (DQs) were examined: D90 is the dose (reported as percentage of the prescription dose) received by 90% of the prostate; V100, V150, V200 is the percentage of the prostate volume receiving 100%, 150%, and 200% of the prescription dose, respectively. For the purposes of analysis, institutions were divided into three groups according to accrual (<5, 6-9, 10-12). RESULTS: One hundred thirty-eight patients from 27 institutions were registered in the study. Nineteen patients were excluded from this analysis; 14 who had no data and 5 who were ineligible, leaving 119 for analysis. The mean, median, and range of the four DQs are as follows: D90 105.6%, 106.0%, 57.6-174.8%; V100 89.8%, 92.6%, 11.2-100%; V150 58.4%, 59.6%, 0.9-93.7%; and V200 27.9%, 25.1%, 0.3-85.2%. Statistically significant differences according to institutional accrual were observed for D90 (p = 0.0283) and V200 (p = 0.0075), but not for V100 (p = 0.1534) and V150 (p = 0.0509). CONCLUSIONS: The DQ observed in this multi-institutional prospective study are roughly comparable to series from single institutions with considerable brachytherapy experience. Differences in DQs were observed according to institutional accrual. These data could be used to determine a community standard with respect to postimplant dosimetry.

Roach M, Hanks G, Thames H, Schellhammer P, Shipley WU, Sokol GH, Sandler H. · Department of Radiation Oncology, University of California San Francisco, San Francisco, CA 94143-1708, and Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #16798415 No free full text.

Abstract: In 1996 the American Society for Therapeutic Radiology and Oncology (ASTRO) sponsored a Consensus Conference to establish a definition of biochemical failure after external beam radiotherapy (EBRT). The ASTRO definition defined prostate specific antigen (PSA) failure as occurring after three consecutive PSA rises after a nadir with the date of failure as the point halfway between the nadir date and the first rise or any rise great enough to provoke initiation of therapy. This definition was not linked to clinical progression or survival; it performed poorly in patients undergoing hormonal therapy (HT), and backdating biased the Kaplan-Meier estimates of event-free survival. A second Consensus Conference was sponsored by ASTRO and the Radiation Therapy Oncology Group in Phoenix, Arizona, on January 21, 2005, to revise the ASTRO definition. The panel recommended: (1) a rise by 2 ng/mL or more above the nadir PSA be considered the standard definition for biochemical failure after EBRT with or without HT; (2) the date of failure be determined "at call" (not backdated). They recommended that investigators be allowed to use the ASTRO Consensus Definition after EBRT alone (no hormonal therapy) with strict adherence to guidelines as to "adequate follow-up." To avoid the artifacts resulting from short follow-up, the reported date of control should be listed as 2 years short of the median follow-up. For example, if the median follow-up is 5 years, control rates at 3 years should be cited. Retaining a strict version of the ASTRO definition would allow comparisons with a large existing body of literature.

Khor LY, Desilvio M, Al-Saleem T, Hammond ME, Grignon DJ, Sause W, Pilepich M, Okunieff P, Sandler H, Pollack A, Anonymous00151. · Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. · Cancer. · Pubmed #16007688 links to  free full text

Abstract: BACKGROUND: The MDM2 oncoprotein promotes p53 degradation via ubiquitin, establishing negative feedback control of p53 and consequently affecting cell cycle arrest and apoptosis. The authors evaluated the association between MDM2 expression and local failure, distant metastasis (DM), cause-specific mortality, and overall mortality in men treated in Radiation Therapy Oncology Group 8610 with radiotherapy, with or without androgen deprivation. METHODS: Of the 456 eligible and analyzable patients (parent cohort), adequate archival diagnostic tissue specimens from 108 patients were available for MDM2 analysis (MDM2 cohort). Cox proportional hazards multivariate analysis (MVA) was used to determine the relation of MDM2 to the endpoints. MDM2 overexpression was manually classified as > 5% nuclear staining. An image analysis system was also used to quantify the proportion of tumor nuclei with MDM2 staining (ACIS index) and staining intensity. RESULTS: Overexpression of MDM2 by manual counts was seen in 44% (n = 47) of the patients. In the manual count analysis, there was no significant relation between MDM2 overexpression and outcome. The ACIS index, using a cutoff point defined by the median value, < or = 3% versus > 3%, was related to 5-year DM rates in univariate analyses (32.6% vs. 45.8%; P = 0.057) and MVA (P = 0.06). The intensity of MDM2 staining was not significant. CONCLUSIONS: MDM2 expression quantified by image analysis was weakly associated with DM. The cohort examined was relatively small and with larger patient numbers, MDM2 overexpression may emerge as a more significant covariate.

Kupelian P, Thames H, Levy L, Horwitz E, Martinez A, Michalski J, Pisansky T, Sandler H, Shipley W, Zelefsky M, Zietman A, Kuban D. · Department of Radiation Oncology, M. D. Anderson Cancer Center Orlando, Orlando, FL 32806, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #15925452 No free full text.

Abstract: PURPOSE: To study the use of the year of therapy as an independent predictor of outcomes, serving as a proxy for time-related changes in therapy and tumor factors in the treatment of prostate cancer. Accounting for these changes would facilitate the retrospective comparison of outcomes for patients treated in different periods. METHODS AND MATERIALS: Nine institutions combined data on 4,537 patients with Stages T1 and T2 adenocarcinoma of the prostate who had a pretherapy prostate-specific antigen (PSA) level and biopsy Gleason score, and who had received > or = 60 Gy external beam radiotherapy without neoadjuvant androgen deprivation or planned adjuvant androgen deprivation. All patients were treated between 1986 and 1995. Two groups were defined: those treated before 1993 (Yr < or = 92) vs. 1993 and after (Yr > or = 93). Patients treated before 1993 had their follow-up truncated to make the follow-up time similar to that for patients treated in 1993 and after. Therefore, the median follow-up time was 6.0 years for both groups (Yr < or = 92 and Yr > or = 93). Two separate biochemical failure endpoints were used. Definition A consisted of the American Society for Therapeutic Radiology Oncology endpoint (three PSA rises backdated, local failure, distant failure, or hormonal therapy). Definition B consisted of PSA level greater than the current nadir plus two, local failure, distant failure, or hormonal therapy administered. Multivariate analyses for factors affecting PSA disease-free survival (PSA-DFS) rates using both endpoints were performed for all cases using the following variables: T stage (T1b, T1c, T2a vs. T2b, T2c), pretreatment PSA (continuous variable), biopsy Gleason score (continuous variable), radiation dose (continuous variable), and year of treatment (continuous variable). The year variable (defined as the current year minus 1960) ranged from 26 to 35. To evaluate the effect of radiation dose, the multivariate analyses were repeated with the 3,897 cases who had received < 72 Gy using the same variables except for radiation dose. RESULTS: For all 4,537 patients, the 5- and 8-year PSA-DFS estimate using definition A (ASTRO consensus definition) was 60% and 55%, respectively. The 8-year PSA-DFS estimate for Yr < 93 vs. Yr > or = 93 was 52% vs. 57%, respectively (p < 0.001). In the subgroup of patients receiving < 72 Gy, the 8-year PSA-DFS estimate for Yr < 93 vs. Yr > or = 93 was 52% and 55%, respectively (p = 0.004). The differences in PSA-DFS rates in the different subgroups were similar when definition B was used. The multivariate analyses for all 4,537 cases with either PSA-DFS definition revealed T stage (p < 0.001), pretherapy PSA level (p < 0.001), Gleason score (p < 0.001), radiation dose (p < 0.001), and year of treatment (p < 0.001) to be independent predictors of outcomes. The multivariate analyses restricted to the 3,897 cases receiving < 72 Gy still revealed year of treatment to be an independent predictor of outcomes (p < 0.001), in addition to T stage (p < 0.001), pretherapy PSA level (p < 0.001), and Gleason score (p < 0.001). CONCLUSIONS: Independent of tumor stage, radiation dose, failure definition, and follow-up parameters, the year in which RT was performed was an independent predictor of outcomes. These findings indicate a more favorable presentation of localized prostate cancer in current years that is not necessarily reflected in the patients' PSA levels or Gleason scores. This phenomenon is probably related to a combination of factors, such as screening, increased patient awareness leading to earlier biopsies and earlier diagnosis, more aggressive pretherapy staging, and unrecognized improvements in therapy, but perhaps also to changing tumor biology. Outcomes predictions should be based on contemporaneous series. Alternatively, the year of therapy could be incorporated as a variable in outcomes analyses of localized prostate cancer patients treated in different periods within the PSA era.

Kupelian P, Kuban D, Thames H, Levy L, Horwitz E, Martinez A, Michalski J, Pisansky T, Sandler H, Shipley W, Zelefsky M, Zietman A. · Department of Radiation Oncology, M. D. Anderson Cancer Center Orlando, Orlando, FL 32806, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #15667961 No free full text.

Abstract: PURPOSE: To study the radiation dose-response as determined by Kaplan-Meier prostate-specific antigen (PSA) disease-free survival (PSA-DFS) estimates in patients with stage T1-T2 prostate cancer treated within a 2-year period (1994-1995). METHODS: Nine institutions combined data on 4839 patients with stage T1 and T2 adenocarcinoma of the prostate who received > or =60 Gy external beam radiation therapy (RT) as sole treatment. No patient received neoadjuvant androgen deprivation or planned adjuvant androgen deprivation. Of the 4839 patients, 1325 were treated in 1994 and 1995; 1061 were treated with <72 Gy and 264 with > or =72 Gy. The median RT doses for the <72 Gy and the > or =72 Gy groups were 68.4 Gy and 75.6 Gy, respectively. The median follow-up for the <72 Gy and the > or =72 Gy groups were 5.8 and 5.7 years, respectively. Risk groups, defined on the basis of T stage, pretherapy PSA level, and biopsy Gleason score (GS), were as follows: low risk--T1b, T1c, T2a, GS < or =6 and PSA < or =10 ng/mL; intermediate risk--T1b, T1c, T2a, GS < or =6 and PSA >10 ng/mL but < or =20 ng/mL or T2b, GS < or =6 and PSA < or =20 ng/mL or GS 7 and PSA < or =20 ng/mL; high risk--GS 8-10 or PSA >20 ng/mL. The endpoint for outcome analysis was PSA-DFS at 5 years after therapy using the American Society for Therapeutic Radiology and Oncology failure definition. RESULTS: Patients receiving > or =72 Gy had significantly more advanced cancers. The proportion of stage T2b/T2c cancers in the > or =72 Gy group was 42% compared with 32% in the <72 Gy group (p = 0.027). The mean pretherapy PSA was 11.4 ng/mL in the > or =72 Gy group compared with 10.7 ng/mL in the <72 Gy group (p = 0.001). The proportion of GS > or =8 cancers in the > or =72 Gy group was 9% compared with 7% in the <72 Gy group (p = 0.309). Overall, 15% of patients receiving <72 Gy had high-risk disease, compared with 22% of patients receiving > or =72 Gy (p = 0.034). The > or =72 Gy group had a greater number of follow-up PSA levels (mean 10.6/patient) compared with the <72 Gy group (mean 9.6/patient) (p = 0.007). For all 1325 patients, the 5- and 8-year PSA-DFS estimates were 64% and 62%, respectively. The 5-year PSA-DFS estimates for <72 Gy vs. > or =72 Gy were 63% vs. 69%, respectively (p = 0.046). Multivariate analysis for factors affecting PSA-DFS was performed for all cases using the following variables: pretherapy PSA (continuous), biopsy GS (continuous), stage (T1 vs. T2), radiation dose (continuous), and radiation technique (three-dimensional conformal vs. conventional). Pretreatment PSA (p < 0.001, chi-square 112.2), GS (p < 0.001, chi-square 12.8), radiation dose (p < 0.001, chi-square 13.5), and stage (p = 0.007, chi-square 7.2) were independent predictors of outcome. Radiotherapy technique was not (p = 0.50). CONCLUSION: Differences in PSA-DFS estimates observed in multiple retrospective series have been attributed to differences in follow-up duration between patients treated to conventional doses (longer follow-up intervals) and those treated to higher doses (shorter follow-up intervals). In this report, the median follow-up duration in the > or =72 Gy group was essentially identical to the <72 Gy group, because the study included a large number of patients treated consecutively during a narrow time range (1994-1995). With similar follow-up duration, higher than conventional radiotherapy doses were associated with improved PSA-DFS when controlled for the influence of pretreatment PSA levels, biopsy GS, and clinical T stage.

Kuban D, Thames H, Levy L, Horwitz E, Kupelian P, Martinez A, Michalski J, Pisansky T, Sandler H, Shipley W, Zelefsky M, Zietman A. · Department of Radiation Oncology, MD Anderson Cancer Center Orlando, Houston, TX 77030, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #15667960 No free full text.

Abstract: PURPOSE: To compare long-term outcome using alternative failure definitions after external beam radiation for localized prostate cancer. METHODS AND MATERIALS: Data from 4839 patients with stage T1b, T1c, and T2 adenocarcinoma of the prostate who were treated solely with external beam radiation between 1986 and 1995 at nine U.S. institutions were analyzed. Outcome using the following prostate-specific antigen (PSA) failure definitions was compared: (1) three consecutive PSA rises backdated (American Society for Therapeutic Radiology and Oncology [ASTRO]), (2) two PSA rises of at least 0.5 ng/mL each, backdated (0.5 x 2), (3) three consecutive PSA rises with failure recorded at the call date (ASTRO call date), (4) PSA > or =current PSA nadir + 2 ng/mL (Houston + 2), (5) PSA > or =current PSA nadir + 3 ng/mL (Houston + 3), (6) PSA >0.2 ng/mL, or (7) PSA >0.5 ng/mL. For definitions 3-7, the failure date was recorded as the date the criterion was met, without backdating. RESULTS: PSA disease-free survival (PSA-DFS) varied according to the failure definition used with differences of up to 13% with PSA rise definitions and up to 44% with absolute nadir value surgical-type definitions within the first 5 years post-therapy as compared with the ASTRO definition. PSA-DFS was 66%, 66%, 68%, 72%, 15%, and 25% at 5 years postradiation for definitions 2-7, respectively, vs. 59% for the ASTRO definition. Sensitivity and specificity of definitions 2, 4, and 5 were better than for the ASTRO definition, whereas, for definitions 6 and 7, the sensitivity was at least 90% but the specificity was only 9% and 26%, respectively. This analysis shows that the ASTRO definition does not overestimate outcome, particularly in the first 5 years after therapy, as compared with other definitions appropriate to irradiated patients. CONCLUSION: There are notable differences in both short- and long-term outcomes after definitive radiation for prostate cancer depending on the failure definition applied. Failure definitions must be tested objectively for sensitivity and specificity in predicting clinical outcome, and it is only in this manner that reasonable choices can be made. Although traditional surgical-type failure definitions do not seem applicable to patients treated with external beam radiation, further analysis of definitions across multiple therapeutic modalities is necessary to determine whether a universal failure definition might be feasible, at least for research and comparative purposes.

McLaughlin PW, Narayana V, Meirovitz A, Meriowitz A, Troyer S, Roberson PL, Gonda R, Sandler H, Marsh L, Lawrence T, Kessler M. · Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #15629590 No free full text.

Abstract: PURPOSE: Most evidence suggests that impotence after prostate radiation therapy has a vascular etiology. The corpus cavernosum (CC) and the internal pudendal artery (IPA) are the critical vascular structures related to erectile function. This study suggests that it is feasible to markedly decrease radiation dose to the CC and the IPA and directly determine the impact of dose limitation on potency. METHODS AND MATERIALS: Twenty-five patients (10 external beam, 15 brachytherapy) underwent MRI/CT-based treatment planning for prostate cancer. In addition, 10 patients entered on the vessel-sparing protocol underwent a time-of-flight MRI angiography sequence to define the IPA. The distance from the MRI-defined prostate apex to the penile bulb (PB), CC, and IPA was measured and compared to the distance from the CT-defined apex. Doses (D5 and D50) to the PB, CC, and IPA were determined for an 80 Gy external beam course. In 5 patients, CT plans were generated and compared to MRI-based plans. RESULTS: The combination of coronal, sagittal, and axial MRI data sets allowed superior definition of the prostate apex and its relationship to critical vascular structures. The apex to PB distance averaged 1.45 cm (0.36 standard deviation) with a range of 0.7 cm to 2.1 cm. Peak dose (D5) to the proximal CC in the MRI-planned 80 Gy course was 26 (9) Gy (0.36 of CT-planned dose), and peak dose to the IPA was 39 (13) Gy (0.61 of CT-planned dose). CONCLUSION: The distance between the prostate apex and critical vascular structures is highly variable. Current empiric rules for CT contouring (apex 1.5 cm above PB) overestimate or underestimate the distance between the prostate apex and critical vascular structures. When defined by MRI T2 and MRI angiogram with CT registration, limitation of dose to critical erectile structures is possible, with a more significant gain than has been previously reported using dose limitation by commonly applied intensity modulated radiation therapy studies based on CT imaging. These techniques make "vessel-sparing" prostate radiotherapy feasible.

Thames H, Kuban D, Levy L, Horwitz EM, Kupelian P, Martinez A, Michalski J, Pisansky T, Sandler H, Shipley W, Zelefsky M, Zietman A. · Department of Biomathematics, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #14575823 No free full text.

Abstract: PURPOSE: To assess the merit of the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure after external beam radiotherapy for prostate cancer by testing alternative prostate-specific antigen (PSA) failure definitions against the "gold standard" of clinical failure and to study the effect of backdating the time of failure. METHODS AND MATERIALS: Nine participating institutions agreed to submit follow-up results for all patients with clinically localized prostatic cancer (Stage T1b, T1c, T2, N0M0) treated between 1986 and 1995 by external beam radiotherapy only, to doses of >or=60 Gy, with no androgen deprivation before treatment. A total of 4839 men met the study criteria, with a median follow-up time of 6.3 years. The prediction of clinical failure by 102 definitions of biochemical failure was assessed using various quantitative measures. RESULTS: Four definitions were superior as measured by the sensitivity, specificity, positive and negative predictive values, and hazard of clinical failure after biochemical failure: two rises of at least 0.5 ng/mL backdated, PSA level at or greater than the absolute nadir plus 2 ng/mL at the call date, and PSA level at or greater than the current nadir plus 2 or 3 ng/mL at the call date. The absolute nadir was the lowest measured PSA level during all of follow-up, and the current nadir was the lowest PSA measured previous to a particular PSA measurement during follow-up. With the possible exception of patients in the low-risk group, the likelihood of ultimate clinical failure decreased as the time of biochemical failure increased. Failure definitions based on PSA levels >0.2 or 0.5 ng/mL were inferior to other definitions. Backdating the failure time introduced bias into the estimate of freedom from biochemical failure, which was increasingly overestimated at shorter median follow-up times. This bias can be circumvented either by using a failure definition based on the call date or by backdating the censoring times of patients with one or two rises who could potentially have failure at a future (unobserved) time. A short follow-up time as such does not result in bias unless the failures are backdated; in the absence of backdating, it is the precision of failure-free survival that is increasingly compromised as the follow-up time is reduced. CONCLUSION: The ASTRO failure definition ended the confusion resulting from different failure definitions that had been in use, and it did so accurately enough that it is probably not necessary to recalculate previously published results. Nevertheless, for the current pooled analysis of outcome in 4839 men with a 6.3-year median follow-up, other definitions of biochemical failure were superior as assessed by various quantitative measures of concordance of biochemical and ultimate clinical failure. An additional disadvantage of the ASTRO definition is the bias introduced by backdating failures, as well as the necessarily retrospective nature of its application. Some "current" definitions, but not those based on the PSA level rising above a fixed threshold, have significantly higher sensitivity and specificity, do not lead to biased estimations of biochemical disease-free survival, and are directly applicable during patient counseling. These are all issues that would play a role in replacing the ASTRO consensus definition.