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Howard Sandler

Publications and source records attributed to Howard Sandler.

At least 19 recordsLinked to original sources
PubMed2007

Staging for prostate cancer: time to incorporate pretreatment prostate-specific antigen and Gleason score?

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.

Antineoplastic Agents, Hormonal↗
PubMed2006

Results of a phase II trial of transrectal ultrasound-guided permanent radioactive implantation of the prostate for definitive management of localized adenocarcinoma of the prostate (radiation therapy oncology group 98-05).

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.

Adenocarcinoma↗
PubMed2006

Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference.

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.

Androgen Antagonists↗
PubMed2005

A phase II study of external beam radiotherapy combined with permanent source brachytherapy for intermediate-risk, clinically localized adenocarcinoma of the prostate: preliminary results of RTOG P-0019.

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.

Adenocarcinoma↗
PubMed2005

MDM2 as a predictor of prostate carcinoma outcome: an analysis of Radiation Therapy Oncology Group Protocol 8610.

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.

Adult↗
PubMed2005

Health-related quality of life in men receiving prostate brachytherapy on RTOG 98-05.

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.

Aged↗
PubMed2005

Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the Radiation Therapy Oncology Group.

PURPOSE: Erb-1 (epidermal growth factor receptor, EGFR) and Erb-2 (Her-2) are two of the best characterized members in the EGFR pathway. In many tumor types, overexpression of these proteins is associated with enhanced malignant potential. Our objective in this study was to investigate the clinical relevance of EGFR and Her-2 expression in bladder cancer cases from four prospective Radiation Therapy Oncology Group (RTOG) bladder preservation trials using cisplatin-containing chemoradiation (RTOG 8802, 8903, 9506, and 9706). METHODS AND MATERIALS: Tumors from 73 cases from patients with muscle-invading T2-T4a bladder cancers had slides interpretable for EGFR staining; 55 cases had slides interpretable for Her-2 staining. Additionally, the respective prognostic values of p53, pRB, and p16 immunostaining were concomitantly examined. Staining and interpretation of staining were done in a blinded manner, without knowledge of clinical outcome. Staining was judged as positive or negative. Subsequently, staining was correlated with clinical outcome. RESULTS: On univariate analysis, EGFR positivity was significantly associated with improved overall survival (p = 0.044); disease-specific survival (DSS) (p = 0.042); and DSS with intact bladder (p = 0.021). There was also a trend for association between EGFR expression and reduced frequency of distant metastasis (p = 0.06). On multivariate analysis adding tumor stage, tumor grade, whether a visibly complete transurethral resection of bladder tumor (TURBT) was done or not, and patient age to the model, EGFR positivity was significantly associated with improved DSS. On univariate analysis, Her-2 positivity was significantly associated with reduced complete response (CR) rates (50% vs. 81%, p = 0.026) after chemoradiation which remained significant on multivariate analysis. The other markers examined in this study were not found to have any prognostic value in this setting. CONCLUSION: Epidermal growth factor receptor expression appears to correlate significantly with improved outcome in bladder cancer, whereas Her-2 expression is significantly associated only with reduced CR rates after chemoradiation. Further investigations are warranted into how EGFR family members regulate response to chemoradiation in bladder cancer and their potential therapeutic implications.

Analysis of Variance↗
PubMed2005

Year of treatment as independent predictor of relapse-free survival in patients with localized prostate cancer treated with definitive radiotherapy in the PSA era.

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.

Disease-Free Survival↗
PubMed2005

Improved biochemical relapse-free survival with increased external radiation doses in patients with localized prostate cancer: the combined experience of nine institutions in patients treated in 1994 and 1995.

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.

Adenocarcinoma↗
PubMed2005

Failure definition-dependent differences in outcome following radiation for localized prostate cancer: can one size fit all?

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.

Adenocarcinoma↗
PubMed2005

Vessel-sparing prostate radiotherapy: dose limitation to critical erectile vascular structures (internal pudendal artery and corpus cavernosum) defined by MRI.

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.

Angiography↗
PubMed2004

Combined-modality therapy with gemcitabine and radiotherapy as a bladder preservation strategy: results of a phase I trial.

PURPOSE: We conducted a phase I trial of gemcitabine given twice weekly with concurrent radiotherapy in patients with muscle-invasive bladder cancer. PATIENTS AND METHODS: Eligible patients underwent maximal transurethral resection of their bladder tumors followed by twice-weekly infusion of gemcitabine with 2 Gy/d concurrent radiotherapy to the bladder, for a total of 60 Gy over 6 weeks. The starting dose of gemcitabine was 10 mg/m(2) with subsequent dose levels of 20, 27, 30, and 33 mg/m(2). The primary end point was the determination of the maximum-tolerated dose (MTD) of twice weekly gemcitabine with concurrent radiotherapy. Secondary end points included assessment of toxicity associated with combined-modality therapy and initial assessment of the rate of bladder preservation. RESULTS: Twenty-four patients were enrolled and 23 were assessable for toxicity and response. No significant toxicity was demonstrated at the 10 or 20 mg/m(2) twice-weekly doses. Dose-limiting toxicity (DLT) occurred in two of three patients treated at 33 mg/m(2). Intermediate dose levels of 27 and 30 mg/m(2) were then evaluated. The MTD of gemcitabine was 27 mg/m(2). The DLT was systemic, manifested as an elevation in liver function tests, malaise, and edema. Fifteen of 23 patients (65%) are alive with bladders intact and no evidence of recurrent disease at a median follow-up of 43 months. CONCLUSION: Twice-weekly gemcitabine with concurrent radiotherapy at 2 Gy/d to a total dose of 60 Gy is well-tolerated. The MTD of gemcitabine is 27 mg/m(2). There is a high rate of bladder preservation in this selected group of patients.

Aged↗
PubMed2003

Salvage radiotherapy in the treatment of prostate cancer.

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.

Actuarial Analysis↗
PubMed2003

Comparison of alternative biochemical failure definitions based on clinical outcome in 4839 prostate cancer patients treated by external beam radiotherapy between 1986 and 1995.

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.

Adenocarcinoma↗
PubMed2003

A zero PSA slope in posttreatment prostate-specific antigen supports cure of patients with long-term follow-up after external beam radiotherapy for localized prostate cancer.

PURPOSE: To determine whether the rate of change in prostate-specific antigen (PSA) in patients treated with external beam radiotherapy for localized prostate cancer improves our ability to define which patients are likely to be cured of their disease. METHODS AND MATERIALS: Patients treated between 1987 and 1995 at the University of California, San Francisco and the University of Michigan for localized prostate cancer with external beam radiotherapy and without hormonal ablation were evaluated for this study. The PSA slope was calculated for 199 patients who were disease free by the American Society for Therapeutic Radiology and Oncology consensus definition for at least 4 years and at last follow-up. Patients were categorized into groups defined by no increase, minimal increase, modest increase, and a definite increase in change in PSA level, corresponding to slopes of 0.0-0.1, >0.1-0.5, and >0.5 ng/mL/y, respectively. RESULTS: Fifty-four percent of the patients displayed a non-increasing PSA (Group 1), 23% had a minimal increase (Group 2), 17% had a modest increase (Group 3), and 6% had a definite increase (Group 4). Patients with a non-increasing PSA slope had a significantly longer time to nadir (median 47.8, 31.6, 29.9, and 23.3 months for Groups 1-4, respectively, p = 0.0001) and a lower median PSA nadir (median 0.30, 0.40, 0.55, and 1.00 ng/mL for Groups 1-4, respectively, p = 0.0006). CONCLUSION: On the basis of PSA kinetics, we believe that a group of patients can be defined who appear to be cured of localized prostate cancer (i.e., have a zero slope). These patients have a lower and later PSA nadir, as well as a more substantial proportional effect of external beam radiotherapy on their PSA level. Patients with a definite increase in PSA slope are erroneously labeled disease free by the American Society for Therapeutic Radiology and Oncology consensus definition.

Aged↗
PubMed2003

Use of quality indicators to evaluate the care of patients with localized prostate carcinoma.

BACKGROUND: The goal of quality assurance in health care is to preserve and improve patient care. Recently, RAND developed a set of evidence-based candidate indicators for evaluating the quality of care for patients with localized prostate carcinoma; however, the feasibility and sensitivity of these indicators have not been tested in a clinical setting. The objectives of this study were to evaluate the feasibility of measuring these quality indicators and to determine their sensitivity to change in practice patterns over time. METHODS: One hundred sixty-eight men who presented in either 1995 or in 2000 and were treated for localized prostate carcinoma were selected randomly from the University of Michigan tumor registry. A combination of electronic data base review and explicit chart review was used to assess the feasibility of measuring compliance for each indicator. For each indicator in which assessment was feasible, compliance with the RAND indicators was determined for patients in both years. Multivariate regression analysis was used to adjust for potential confounding effects of disease stage, tumor grade, prostate specific antigen (PSA) level, patient age, and therapy. RESULTS: Based on review of available clinical data, measurement of compliance was feasible for 19 of 22 RAND candidate quality indicators (86%). For five indicators, significant differences in documentation (compliance) were detected between 1995 and 2000 (P < 0.05). Treatment received and higher PSA levels were associated independently with documentation of compliance for several indicators (P < 0.05). CONCLUSIONS: Measurement of the majority of the RAND quality indicators for the treatment of patients with localized prostate carcinoma was feasible, and improvements in several indicators were observed between 1995 and 2000. Demonstration of such variation, even within a single institution, suggests that the indicators are sufficiently sensitive to detect differences in practice patterns.

Aged↗
PubMed2002

Daily prostate targeting using implanted radiopaque markers.

PURPOSE: A system has been implemented for daily localization of the prostate through radiographic localization of implanted markers. This report summarizes an initial trial to establish the accuracy of patient setup via this system. METHODS AND MATERIALS: Before radiotherapy, three radiopaque markers are implanted in the prostate periphery. Reference positions are established from CT data. Before treatment, orthogonal radiographs are acquired. Projected marker positions are extracted semiautomatically from the radiographs and aligned to the reference positions. Computer-controlled couch adjustment is performed, followed by acquisition of a second pair of radiographs to verify prostate position. Ten patients (6 prone, 4 supine) participated in a trial of daily positioning. RESULTS: Three hundred seventy-four fractions were treated using this system. Treatment times were on the order of 30 minutes. Initial prostate position errors (sigma) ranged from 3.1 to 5.8 mm left-right, 4.0 to 10.1 mm anterior-posterior, and 2.6 to 9.0 mm inferior-superior in prone patients. Initial position was more reproducible in supine patients, with errors of 2.8 to 5.0 mm left-right, 1.9 to 3.0 mm anterior-posterior, and 2.6 to 5.3 mm inferior-superior. After prostate localization and adjustment, the position errors were reduced to 1.3 to 3.5 mm left-right, 1.7 to 4.2 mm anterior-posterior, and 1.6 to 4.0 mm inferior-superior in prone patients, and 1.2 to 1.8 mm left-right, 0.9 to 1.8 mm anterior-posterior, and 0.8 to 1.5 mm inferior-superior in supine patients. CONCLUSIONS: Daily targeting of the prostate has been shown to be technically feasible. The implemented system provides the ability to significantly reduce treatment margins for most patients with cancer confined to the prostate. The differences in final position accuracy between prone and supine patients suggest variations in intratreatment prostate movement related to mechanisms of patient positioning.

Dose Fractionation, Radiation↗