Biomedical subjects

Eric M Horwitz

Publications and source records attributed to Eric M Horwitz.

At least 19 recordsLinked to original sources

PubMed2007

Prostate-specific antigen nadir within 12 months of prostate cancer radiotherapy predicts metastasis and death.

BACKGROUND: The nadir prostate-specific antigen (PSA) at 1 year (nPSA12) was investigated as an early estimate of biochemical and clinical outcome after radiotherapy (RT) alone for localized prostate cancer.METHODS.From May 1989 to November 1999, 1000 men received 3D conformal RT alone (median, 76 Gy) with minimum and median follow-up periods of 26 and 58 months, respectively, from the end of treatment. The calculation of PSA doubling time (PSADT) was possible in 657 patients. Multivariate analyses (MVAs) via Cox proportional hazards regression were used to determine the association of nPSA12 to biochemical failure (BF; ASTRO definition), distant metastasis (DM), cause-specific mortality (CSM), and overall mortality (OM). Dichotomization of nPSA12 was optimized by evaluating the sequential model likelihood ratio and P-values.RESULTS.In MVA, nPSA12 as a continuous variable was independent of RT dose, T-stage, Gleason score, pretreatment initial PSA, age, and PSADT in predicting for BF, DM, CSM, and OM. Dichotomized nPSA12 (2 versus >2 ng/mL) was independently related to DM and CSM. Kaplan-Meier 10-year DM rates for nPSA12 2 versus >2 ng/mL were 4% versus 19% (P<.0001).CONCLUSIONS.nPSA12 is a strong independent predictor of outcome after RT alone for prostate cancer and should be useful in identifying patients at high risk for progression to metastasis and death.

Aged↗

PubMed2006

Radiation dose and late failures in prostate cancer.

PURPOSE: To quantify the impact of radiation dose escalation on the timing of biochemical failure (BF) and distant metastasis (DM) for prostate cancer treated with radiotherapy (RT) alone. METHODS: The data from 667 men with clinically localized intermediate- and high-risk prostate cancer treated with three-dimensional conformal RT alone were retrospectively analyzed. The interval hazard rates of DM and BF, using the American Society for Therapeutic Radiology and Oncology (ASTRO) and Phoenix (nadir + 2) definitions, were determined. The median follow-up was 77 months. RESULTS: Multivariate analysis showed that increasing radiation dose was independently associated with decreased ASTRO BF (p < 0.0001), nadir + 2 BF (p = 0.001), and DM (p = 0.006). The preponderance (85%) of ASTRO BF occurred at < or =4 years after RT, and nadir + 2 BF was more evenly spread throughout Years 1-10, with 55% of BF in < or =4 years. Radiation dose escalation caused a shift in the BF from earlier to later years. The interval hazard function for DM appeared to be biphasic (early and late peaks) overall and for the <74-Gy group. In patients receiving > or =74 Gy, a reduction occurred in the risk of DM in the early and late waves, although the late wave appeared reduced to a greater degree. CONCLUSION: The ASTRO definition of BF systematically underestimated late BF because of backdating. Radiation dose escalation diminished and delayed BF; the delay suggested that local persistence may still be present in some patients. For DM, a greater radiation dose reduced the early and late waves, suggesting that persistence of local disease contributed to both.

Aged↗

PubMed2006

Nadir prostate-specific antigen within 12 months after radiotherapy predicts biochemical and distant failure.

OBJECTIVES: To determine whether nadir prostate-specific antigen (PSA) levels within 12 months (nadir PSA12) after completion of radiotherapy (RT) can be used as an early marker of recurrence risk. METHODS: A total of 4839 patients were treated with RT and without hormonal therapy from 1986 to 1995 for Stage T1-T2 prostate cancer at nine institutions. Of these 4839 patients, 4833, with a median follow-up of 6.3 years, met the criteria for analysis. The study endpoints included freedom from PSA failure, initiation of androgen deprivation, or documented local or distant failure (PSA-DFS); freedom from clinically apparent distant metastasis (DMFS); and overall survival (OS). RESULTS: Patients with a nadir PSA12 of 2.0 ng/mL or less had an 8-year PSA-DFS, DMFS, and OS rate of 55%, 95%, and 73%, respectively, compared with 40%, 88%, and 69%, respectively, for patients with a nadir PSA12 of more than 2.0 ng/mL. Multivariate analysis confirmed that a nadir PSA12 of greater than 2 ng/mL was an independent predictor of PSA-DFS, DMFS, and OS. Classification and regression tree analysis identified the nadir PSA12 levels after RT associated with PSA-DFS, DMFS, and OS. Nadir PSA12, combined with the pretreatment PSA level, identified patients at particularly high risk of distant metastasis. CONCLUSIONS: The results of this large, multi-institutional study have demonstrated that nadir PSA12 is predictive of clinical outcomes for patients with localized prostate cancer after RT. A high pretreatment PSA level and high nadir PSA12 will identify patients at particularly high risk who might benefit from early adjuvant therapy.

Adenocarcinoma↗

PubMed2006

Multi-institutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation.

PURPOSE: To assess long-term prostate-specific antigen (PSA) outcome after permanent prostate brachytherapy (BT) and identify predictors of improved disease-free survival. METHODS AND MATERIALS: Eleven institutions combined data on 2,693 patients treated with permanent interstitial BT monotherapy for T1-T2 prostate cancer. Of these patients, 1,831 (68%) were treated with I-125 (median dose, 144 Gy) and 862 (32%) were treated with Pd-103 (median dose, 130 Gy). Criteria for inclusion were: available pre-BT PSA, BT > or =5 years before data submission, BT between 1988-1998, and no androgen deprivation before failure. The median follow-up was 63 months. RESULTS: Among patients where the I-125 dose to 90% of the prostate (D90) was > or =130 Gy, the 8-year PSA relapse-free survival (PRFS) was 93% compared with 76% for those with lower D90 dose levels (p < 0.001). A multivariable analysis identified tumor stage (p = 0.002), Gleason score (p < 0.001), pretreatment PSA level (p < 0.001), treatment year (p = 0.001), and the isotope used (p = 0.004) as pretreatment and treatment variables associated with PRFS. When restricted to patients with available postimplantation dosimetric information, D90 emerged as a significant predictor of biochemical outcome (p = 0.01), and isotope was not significant. The 8-year PRFS was 92%, 86%, 79%, and 67%, respectively, for patients with PSA nadir values of 0-0.49, 0.5-0.99, 1.0-1.99, and >2.0 ng/mL (p < 0.001). Among patients free of biochemical relapse at 8 years, the median nadir level was 0.1 ng/mL, and 90% of these patients achieved a nadir PSA level <0.6 ng/mL. CONCLUSIONS: Outcome after permanent BT for prostatic cancer relates to tumor stage, Gleason score, pretreatment PSA, BT year, and post-BT dosimetric quality. PSA nadir < or =0.5 ng/mL was particularly associated with durable long-term PSA disease-free survival. The only controllable factor to impact on long-term outcome was the D90 which is a reflection of implant quality.

Brachytherapy↗

PubMed2006

Biochemical and clinical significance of the posttreatment prostate-specific antigen bounce for prostate cancer patients treated with external beam radiation therapy alone: a multiinstitutional pooled analysis.

BACKGROUND: The posttreatment prostate-specific antigen (PSA) bounce phenomenon has been recognized in at least 20% of all patients treated with radiation. The purpose of the current report was to determine if there was a difference in biochemical and clinical control between the bounce and nonbounce (NB) patients using pooled data on 4839 patients with T1-2 prostate cancer treated with external beam radiation therapy (RT) alone at 9 institutions between 1986 and 1995. METHODS: The median follow-up was 6.3 years. A posttreatment PSA bounce was defined by a minimal rise of 0.4 ng/mL over a 6-month follow-up period, followed by a drop in PSA level of any magnitude. Endpoints included no biochemical evidence of disease (bNED) failure (BF) (ASTRO definition), distant failure (DF), cause-specific failure (CSF), and overall survival (OS). Patients were stratified by pretreatment PSA, Gleason score, T stage, age, dose, and risk group. RESULTS: In all, 978 (20%) patients experienced at least 1 posttreatment PSA bounce. Within 3 subgroups (risk group, pretreatment PSA, and age), statistically significant differences of remaining bounce-free were observed on univariate analysis. Patients < 70 years had a 72% chance of remaining bounce-free at 5 years compared with 75% for older patients (P = .04). The NB patients had 72% bNED control at 10 years compared with 58% for the bounce patients. The effect of a bounce remained statistically significant on multivariate analysis (P < .0001). No statistically significant difference in DF, CSF, or OS was observed. CONCLUSIONS: Patients treated with external beam radiation therapy alone who experience a posttreatment PSA bounce have increased risk of BF. However, this did not translate into a difference in clinical failure with the available follow-up in the current study.

Adult↗

PubMed2006

Using decision analysis to determine the cost-effectiveness of intensity-modulated radiation therapy in the treatment of intermediate risk prostate cancer.

BACKGROUND: The specific aim of this study is to evaluate the cost-effectiveness of intensity-modulated radiation therapy (IMRT) compared with three-dimensional conformal radiation therapy (3D-CRT) in the treatment of a 70-year-old with intermediate-risk prostate cancer. METHODS: A Markov model was designed with the following states; posttreatment, hormone therapy, chemotherapy, and death. Transition probabilities from one state to another were calculated from rates derived from the literature for IMRT and 3D-CRT. Utility values for each health state were obtained from preliminary studies of preferences conducted at Fox Chase Cancer Center. The analysis took a payer's perspective. Expected mean costs, cost-effectiveness scatterplots, and cost acceptability curves were calculated with commercially available software. RESULTS: The expected mean cost of patients undergoing IMRT was $47,931 with a survival of 6.27 quality-adjusted life years (QALYs). The expected mean cost of patients having 3D-CRT was $21,865 with a survival of 5.62 QALYs. The incremental cost-effectiveness comparing IMRT with CRT was $40,101/QALYs. Cost-effectiveness acceptability curve analysis revealed a 55.1% probability of IMRT being cost-effective at a $50,000/QALY willingness to pay. CONCLUSION: Intensity-modulated radiation therapy was found to be cost-effective, however, at the upper limits of acceptability. The results, however, are dependent on the assumptions of improved biochemical disease-free survival with fewer patients undergoing subsequent salvage therapy and improved quality of life after the treatment. In the absence of prospective randomized trials, decision analysis can help inform physicians and health policy experts on the cost-effectiveness of emerging technologies.

Aged↗

PubMed2006

Increasing external beam dose for T1-T2 prostate cancer: effect on risk groups.

PURPOSE: The aim of this study was to investigate effect of increasing dose on risk groups for clinical failure (CF: local failure or distant failure or hormone ablation or PSA>or=25 ng/ml) in patients with T1-T2 prostate cancer treated with external beam radiotherapy. METHODS AND MATERIALS: Patients (n=4,537) were partitioned into nonoverlapping dose ranges, each narrow enough that dose was not a predictor of CF, and risk groups for CF were determined using recursive partitioning analysis (RPA). The same technique was applied to the highest of these dose ranges (70-76 Gy, 1,136 patients) to compare risk groups for CF in this dose range with the conventional risk-group classification. RESULTS: Cutpoints defining low-risk groups in each dose range shifted to higher initial PSA levels and Gleason scores with increasing dose. Risk groups for CF in the dose range 70-76 Gy were not consistent with conventional risk groups. CONCLUSIONS: The conventional classification of risk groups was derived in the early PSA era, when total doses<70 Gy were common, and it is inconsistent with risk groups for patients treated to doses>70 Gy. Risk-group classifications must be continuously re-examined whenever the trend is toward increasing total dose.

Humans↗

PubMed2006

Comparison of biochemical failure definitions for permanent prostate brachytherapy.

PURPOSE: To assess prostate-specific antigen (PSA) failure definitions for patients with Stage T1-T2 prostate cancer treated by permanent prostate brachytherapy. METHODS AND MATERIALS: A total of 2,693 patients treated with radioisotopic implant as solitary treatment for T1-T2 prostatic adenocarcinoma were studied. All patients had a pretreatment PSA, were treated at least 5 years before analysis, 1988 to 1998, and did not receive hormonal therapy before recurrence. Multiple PSA failure definitions were tested for their ability to predict clinical failure. RESULTS: Definitions which determined failure by a certain increment of PSA rise above the lowest PSA level to date (nadir + x ng/mL) were more sensitive and specific than failure definitions based on PSA doubling time or a certain number of PSA rises. The sensitivity and specificity for the nadir + 2 definition were 72% and 83%, vs. 51% and 81% for 3 PSA rises. The surgical type definitions (PSA exceeding an absolute value) could match this sensitivity and specificity but only when failure was defined as exceeding a PSA level in the 1-3 ng/mL range and only when patients were allowed adequate time to nadir. When failure definitions were compared by time varying covariate regression analysis, nadir + 2 ng/mL retained the best fit. CONCLUSIONS: For patients treated by permanent radioisotopic implant for prostate cancer, the definition nadir + 2 ng/mL provides the best surrogate for failure throughout the entire follow-up period, similar to patients treated by external beam radiotherapy. Therefore, the same PSA failure definition could be used for both modalities. For brachytherapy patients with long-term follow-up, at least 6 years, defining failure as exceeding an absolute PSA level in the 0.5 ng/mL range may be reasonable.

Adenocarcinoma↗

PubMed2006

Diverse effects of zinc on NF-kappaB and AP-1 transcription factors: implications for prostate cancer progression.

Nuclear factor-kappaB (NF-kappaB) and AP-1 nuclear transcriptional factors regulate expression of multiple genes involved in tumor growth, metastasis and angiogenesis; however, the relative contribution of each factor to cancer initiation and progression has not been established. Prostate carcinogenesis involves transformation of normal zinc-accumulating epithelial cells to malignant cells that do not accumulate zinc. Whereas activation of both NF-kappaB and AP-1 has been implicated in prostate cancer development and growth, we tested the relative effects of zinc supplementation on these important transcriptional factors. Herein, we demonstrate that physiological levels of zinc inhibit NF-kappaB but augment activities of AP-1 in DU-145 and PC-3 human prostate cancer cells. Additionally, we show that chelation of zinc with membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) abolishes this effect. We further propose a potential mechanism for this observation by demonstrating that zinc supplementation induces phosphorylation of the members of three major MAPK subfamilies regulating AP-1 and NF-kappaB activation (ERK 1/2, JNK and p38) while blocking TNF-alpha-mediated degradation of the inhibitory subunit I kappa B alpha and nuclear translocation of RelA in prostate cancer cells. VEGF, IL-6, IL-8 and MMP-9 are major pro-angiogenic and pro-metastatic molecules whose promoter regions contain binding sites for both NF-kappaB and AP-1. These cytokines have been associated with negative prognostic features in prostate cancer. We demonstrate that treatment of human prostate cancer cell lines with zinc reduces expression of VEGF, IL-6, IL-8 and MMP-9. We further show that zinc reduces expression of intercellular adhesion molecule-1 and functionally suppresses tumor cell invasiveness and adhesion. Therefore, the ability of zinc supplementation to inhibit NF-kappaB supercedes zinc-mediated activation of AP-1 family members. Upregulation of intracellular zinc levels may have important implications for inhibiting the angiogenic and metastatic potentials of malignant cells, predominantly through suppression of NF-kappaB signaling.

Cell Adhesion↗

PubMed2006

Phase I trial of concurrent hyperfractionated split course radiotherapy (HFx RT), cisplatin (cDDP), and paclitaxel in patients with recurrent, previously irradiated, or treatment-naïve locally advanced upper aerodigestive malignancy.

PURPOSE: Phase I study to determine the maximally tolerated dose (MTD) of cisplatin (cDDP), paclitaxel (P), and concurrent split course hyperfractionated (BID) RT in advanced squamous cell carcinoma of the head and neck (SCCHN) and other upper aerodigestive tumors. MATERIALS AND METHODS: Eligibility stipulated ECOG performance status 0-2 and either Tx-naïve, locally advanced, or locally recurrent, previously radiated, surgically unresectable upper aerodigestive cancer. Metastases were permitted if disease was predominantly locoregional. RT-naïve patients received 150 cGy bid x 5 d Q 2 wks x 4. Previously radiated patients received 150 cGy bid x 5, wk 1; then 120 cGy bid x 5 Q 2 wk x 3 (later increased to 150 cGy BID for the entire treatment). Treatment fields included recurrent tumor only with 2 cm margins. Whenever possible, conventional and 3-D conformal techniques were used. Elective nodal radiation was not administered. Starting doses of cDDP and P were 12 mg/m2/d x 5 and 15 mg/m2/d x 5, respectively, Q 2 wk x 4, each given on RT days only. At dose level 2, cDDP was increased to 15 mg/m2/d x 5. At dose level 3, P was increased to 20 mg/m2/d x 5. Granulocyte colony stimulating factor (G-CSF) days 6-12 (off treatment week) was added if cumulative neutropenia precipitated treatment delays. RESULTS: Thirty-one patients (21 men, 10 women) were treated. Eight had received prior chemotherapy, 27 prior RT. At dose level three, regular treatment delays of >or=1 week due to slow neutrophil recovery occurred. Addition of G-CSF (dose level 3b) reduced treatment delays from 100 percent to 28 percent and decreased the incidence of Grade >or=2 neutropenia and mucositis. Six of 7 patients at this dose level completed all 4 cycles of treatment and all received full dose RT (60 Gy). No other dose-limiting toxicities occurred. Of 22 assessable patients with locally recurrent SCCHN, 12 (55 percent) responded. Median time to progression in this group was 6 months, with median and one-year survival of 9.5 mos and 41 percent, respectively. CONCLUSION: Concurrent daily cisplatin/paclitaxel and split course hyperfractionated RT (60 Gy) is feasible in previously radiated patients. G-CSF, administered between each cycle, reduces the incidence of treatment delays. Activity is promising and toxicity acceptable.

Adult↗

PubMed2006

A prostate specific antigen (PSA) bounce greater than 1.4 ng/mL Is clinically significant after external beam radiotherapy for prostate cancer.

OBJECTIVE: The purpose of this report is to determine whether any specific magnitude in the prostate specific antigen (PSA) bounce predicted for a clinically poorer outcome. METHODS AND MATERIALS: Between May 1989 and August 1999, 568 prostate cancer patients were treated with 3-dimensional conformal radiotherapy (RT). All patients had at least 5 years of follow up, 6 post-RT PSA measurements and received no hormonal therapy as part of their initial management. The median follow up was 85 months. The median RT dose was 74 Gy. A bounce was defined by a minimum rise in PSA of 0.4 ng/mL over a 6-month period, followed by a drop of PSA of any magnitude. The analysis of the optimal PSA bounce cut-point was based upon a recursive partitioning approach (RPA) for censored data using the log-rank test for nodal separation of freedom from biochemical failure (FFBF) as defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. Cox multivariate regression analysis (MVA) was used to confirm independent predictors of outcome among clinical and treatment related factors: PSA bounce as defined by the RPA, pretreatment PSA (continuous), Gleason score (2-6 versus 7-10), T stage (T1c/T2ab versus T2c/T3), and total radiation dose (continuous). RESULTS: There were 154 patients (27%) experienced a bounce with a median magnitude of 0.6. The RPA resulted in an optimal PSA bounce cut-point of 1.4 ng/mL such that 5-year Kaplan-Meier estimates of FFBF were 71%, 59%, and 38% for nonbouncers, a bounce < or =1.4 ng/mL and >1.4 ng/mL, respectively. Twenty-one (14%) of the 154 patients who experienced a bounce had a PSA bounce magnitude >1.4 ng/mL. Stepwise MVA demonstrated that the PSA bounce grouped as above was an independent predictor of FFBF (P = 0.0013), freedom from distant metastases (P = 0.0028) and cause specific survival (P = 0.0266). Lower RT dose (P < 0.0001) was the only independent predictor of a PSA bounce >1.4 ng/mL. CONCLUSIONS: Using recursive partitioning techniques, a clinically significant PSA bounce occurred when the magnitude of the bounce was >1.4 ng/mL. This is important information to aid clinicians in determining management after RT.

Aged↗

PubMed2005

Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial.

PURPOSE: The alpha/beta ratio for prostate cancer is postulated to be between 1 and 3, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. The dosimetry and acute toxicity are described in the first 100 men enrolled in a randomized trial. PATIENTS AND METHODS: The trial compares 76 Gy in 38 fractions (Arm I) to 70.2 Gy in 26 fractions (Arm II) using intensity modulated radiotherapy. The planning target volume (PTV) margins in Arms I and II were 5 mm and 3 mm posteriorly and 8 mm and 7 mm in all other dimensions. The PTV D95% was at least the prescription dose. RESULTS: The mean PTV doses for Arms I and II were 81.1 and 73.8 Gy. There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity acutely. However, there was a slight but significant increase in Arm II GI toxicity during Weeks 2, 3, and 4. In multivariate analyses, only the combined rectal DVH parameter of V65 Gy/V50 Gy was significant for GI toxicity and the bladder volume for GU toxicity. CONCLUSION: Hypofractionation at 2.7 Gy per fraction to 70.2 Gy was well tolerated acutely using the planning conditions described.

Dose Fractionation, Radiation↗

PubMed2005

PSA nadir predicts biochemical and distant failures after external beam radiotherapy for prostate cancer: a multi-institutional analysis.

PURPOSE: To determine the significance of prostate-specific antigen (PSA) nadir (nPSA) and the time to nPSA (T(nPSA)) in predicting biochemical or clinical disease-free survival (PSA-DFS) and distant metastasis-free survival (DMFS) in patients treated with definitive external beam radiotherapy (RT) for clinical Stage T1b-T2 prostate cancer. METHODS AND MATERIALS: Nine participating institutions submitted data on 4839 patients treated between 1986 and 1995 for Stage T1b-T2cN0-NxM0 prostate cancer. All patients were treated definitively with RT alone to doses > or =60 Gy, without neoadjuvant or planned adjuvant androgen suppression. A total of 4833 patients with a median follow-up of 6.3 years met the criteria for analysis. Two endpoints were considered: (1) PSA-DFS, defined as freedom from PSA failure (American Society for Therapeutic Radiology and Oncology definition), initiation of androgen suppression after completion of RT, or documented local or distant failure; and (2) DMFS, defined as freedom from clinically apparent distant failure. In patients with failure, nPSA was defined as the lowest PSA measurement before any failure. In patients without failure, nPSA was the lowest PSA measurement during the entire follow-up period. T(nPSA) was calculated from the completion of RT to the nPSA date. RESULTS: A greater nPSA level and shorter T(nPSA) were associated with decreased PSA-DFS and DMFS in all patients and in all risk categories (low [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level < or =10 ng/mL], intermediate [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level >10 but < or =20 ng/mL, or Stage T2b or T2c, Gleason score < or =6, and PSA level < or =20 ng/mL, or Gleason score 7 and PSA level < or =20 ng/mL], and high [Gleason score 8-10 or PSA level >20 ng/mL]), regardless of RT dose. The 8-year PSA-DFS and DMFS rate for patients with nPSA <0.5 ng/mL was 75% and 97%; nPSA > or =0.5 but <1.0 ng/mL, 52% and 96%; nPSA > or =1.0 but <2.0 ng/mL, 40% and 91%; and nPSA > or =2.0 ng/mL, 17% and 73%, respectively. The 8-year PSA-DFS and DMFS rate for patients with T(nPSA) <6 months was 27% and 66%; T(nPSA) > or =6 but <12 months, 31% and 85%; T(nPSA) > or =12 but <24 months, 42% and 94%; and T(nPSA) > or =24 months, 75% and 99%, respectively. A shorter T(nPSA) was associated with decreased PSA-DFS and DMFS, regardless of the nPSA. Both nPSA and T(nPSA) were significant predictors of PSA-DFS and DMFS in multivariate models incorporating clinical stage, Gleason score, initial PSA level, and RT dose. The significance of nPSA and T(nPSA) was supported by landmark analysis, as well as by analysis of nPSA and T(nPSA) as time-dependent covariates. A dose > or =70 Gy was associated with a lower nPSA level and longer T(nPSA) in all risk categories, and a greater dose was significantly associated with greater PSA-DFS and DMFS in multivariate analysis. Regression analysis confirmed that higher clinical stage, Gleason score, and initial PSA were associated with a greater nPSA level. CONCLUSION: The results of this large, multi-institutional analysis of 4833 patients have provided important evidence that nPSA and T(nPSA) after definitive external beam RT are not only predictive of a predominantly PSA endpoint (PSA-DFS), but are also predictive of distant metastasis in all clinical risk categories. Greater RT doses were associated with lower nPSA, longer T(nPSA), and improved PSA-DFS and DMFS.

Disease-Free Survival↗

PubMed2005

Defining biochemical failure after radiotherapy with and without androgen deprivation for prostate cancer.

PURPOSE: To compare several characteristics of alternative definitions of biochemical failure (BF) in men with extended follow-up after radiotherapy (RT) with or with androgen deprivation therapy (ADT) for prostate cancer. METHODS AND MATERIALS: From December 1, 1991, to April 30, 1998, 688 men with Stage T1c-T3NX-N0M0 prostate cancer received RT alone (n = 586) or RT plus ADT (n = 102) with a minimal follow-up of 4 years and five or more "ADT-free" posttreatment prostate-specific antigen levels. BF was defined by three methods: (1) the ASTRO definition (three consecutive rises in prostate-specific antigen level); (2) a modified American Society for Therapeutic Radiology Oncology (ASTRO) definition requiring two additional consecutive rises when a decline immediately subsequent to three consecutive rises occurred; and (3) the "Houston" or nadir plus 2-ng/mL definition (a rise of at least 2 ng/mL greater than the nadir). The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were determined for each using clinical progression as the endpoint. Furthermore, the misclassification rates for a steadily rising prostate-specific antigen level, ability to satisfy the proportional hazards (RT with or without ADT), effects of short follow-up, and intervals to the diagnosis of BF were compared. RESULTS: The misclassification rate for BF using the nadir plus 2-ng/mL definition was 2% for RT alone and 0% for RT plus ADT compared with 0% and 0% for the modified ASTRO definition, and 5% and 23% for the ASTRO definition, respectively. The hazard rates for RT alone and RT plus ADT were proportional only for the nadir plus 2 ng/mL definition and seemingly unaffected by the length of follow-up. For RT with or without ADT, the nadir plus 2 ng/mL definition was the most specific (RT, 80% vs. RT plus ADT, 75%) with the greatest positive predictive value (RT, 36% vs. RT plus ADT, 25%) and overall accuracy (RT, 81% vs. RT plus ADT, 77%). A greater proportion of BF was diagnosed in the first 2 years of follow-up with the nadir plus 2 ng/mL definition compared with the ASTRO definition (13% vs. 5%, p = 0.0138, chi-square test). CONCLUSION: The nadir plus 2 ng/mL definition was the best predictor of sustained, true, biochemical, and clinical failure, and was not affected by the use of ADT or follow-up length.

Aged↗

PubMed2005

Does a delay in external beam radiation therapy after tissue diagnosis affect outcome for men with prostate carcinoma?

BACKGROUND: Physicians involved in the care of men diagnosed with prostate carcinoma must assess the urgency of treatment. For those men who choose external beam radiation therapy (EBRT), the delay from the time of biopsy to treatment may be stressful. There are limited data on the consequences of radiation treatment delay. The purpose of the current study was to evaluate the effect of time to treatment (TTT) on outcomes. METHODS: The authors of the current study analyzed 1322 patients who were treated with EBRT alone. Overall survival (OS), cause specific survival (CSS), distant metastasis (DM), and freedom from biochemical failure (FFBF) were calculated. TTT was first analyzed at 4 intervals: < 3, 3-6, 6-9 and > 9 months, and at the median TTT. Cox multivariate analysis (MVA) was then performed with 2002 American Joint Commission on Cancer T-stage, Gleason score, prostate specific antigen (PSA), radiation dose, and TTT as covariates. RESULTS: There were no statistical differences in OS, CSS, DM, or FFBF among men whose EBRT began < 3, 3-6, 6-9, or > 9 months after diagnosis. This was also true at the median TTT of 3.1 months. A subgroup analysis was performed in which patients were stratified into low-, intermediate- and high-risk groups based on pretreatment PSA, Gleason score and AJCC T-stage. FFBF, and DM were calculated above and below the median TTT of 3.1 months. In this analysis, there was no statistically significant difference in FFBF or DM within the risk groups. CONCLUSIONS: Within the limits of the current study, data indicate that a treatment delay, even in high-risk patients, has little effect on clinical or biochemical outcome.

Adenocarcinoma↗

PubMed2005

Long-term androgen deprivation increases Grade 2 and higher late morbidity in prostate cancer patients treated with three-dimensional conformal radiation therapy.

PURPOSE: To determine whether the use of androgen deprivation (AD) increases late morbidity when combined with high-dose three-dimensional conformal radiation therapy (3D-CRT). METHODS AND MATERIALS: Between May 1989 and November 1998, 1,204 patients were treated for prostate cancer with 3D-CRT to a median dose of 74 Gy. Patients were evaluated every 3-6 months. No AD was given to 945 patients, whereas 140 and 119 patients, respectively, received short-term AD (STAD; < or =6 months) and long-term AD (LTAD; > 6 months). Radiation morbidity was graded according to the Fox Chase modification of the Late Effects Normal Tissue Task Force late morbidity scale. Covariates in the multivariate analysis (MVA) included age, history of diabetes mellitus, prostate-specific antigen (PSA) level, Gleason score, T category, RT field size, total RT dose, use of rectal shielding, and AD status (no AD vs. STAD vs. LTAD). RESULTS: The only independent predictor for Grade 2 or higher genitourinary (GU) morbidity in the MVA was the use of AD (p = 0.0065). The 5-year risk of Grade 2 or higher GU morbidity was 8% for no AD, 8% for STAD, and 14% for LTAD (p = 0.02). Independent predictors of Grade 2 or higher gastrointestinal (GI) morbidity in the MVA were the use of AD (p = 0.0079), higher total radiation dose (p < 0.0001), the lack of a rectal shield (p = 0.0003), and older age (p = 0.0009). The 5-year actuarial risk of Grade 2 or higher GI morbidity was 17% for no AD vs. 18% for STAD and 26% for LTAD (p = 0.017). CONCLUSIONS: The use of LTAD seems to significantly increase the risk of both GU and GI morbidity for patients treated with 3D-CRT.

Aged↗

PubMed2005

Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation.

PURPOSE: The accuracy of the American Society of Therapeutic Radiation Oncology consensus definition of biochemical failure (BF) after radiation therapy (RT) and androgen deprivation (AD) has been questioned, because posttreatment prostate-specific antigen (PSA) levels typically rise after release from AD, and misclassification of BF may be made. The temporal kinetics of posttreatment PSA levels was examined to define the error in the classification of BF. METHODS AND MATERIALS: Between December 1, 1991 and April 30, 1998, 688 men with T1c-T3 NX/0 M0 prostate cancer received three-dimensional conformal RT alone (n = 586) or in combination with either short-term (STAD: 3 to 12 months, n = 82) or long-term (LTAD: 12 to 36 months, n = 20) AD. Follow-up, calculated from the end of all treatment, was >/=48 months. The mean posttreatment PSA was calculated in 3-month intervals. RESULTS: The median posttreatment clinical follow-up period was 76 months (range, 48-152 months). The posttreatment PSA values from the end of all treatment for the RT+STAD-BF group showed an initial period of rise followed by a period of decline at 30 months and then a continued rise again. The decline in the mean posttreatment PSA is explained in part by stabilization in PSA level after 3 consecutive rises. Nonbiochemical failures (NBF) after RT+STAD had a relatively constant mean PSA over time of approximately 0.5 ng/mL. Unlike the RT+STAD-NBF profile, the RT+LTAD-NBF profile rose continuously and steadily to a level approaching 1 ng/mL. The RT+LTAD-BF profile rose continuously but at a slower rate over time. Nine RT+STAD-NBF patients (22%) and 2 RT+LTAD-BF (29%) patients experienced 3 consecutive rises followed by a subsequent decline and stabilization of PSA compared to 10 RT-BF patients (5%). Redistributing these misclassified patients to their respective NBF groups changed the mean posttreatment PSA profiles as follows: The RT+LTAD-BF profile rose constantly and steadily with a doubling time of approximately 16 months, and the RT+LAD-NF initially rose to a value of approximately 0.5 ng/mL, then at 36 months began to decline. CONCLUSIONS: The temporal kinetics of posttreatment PSA after RT+AD and RT alone are different. The American Society of Therapeutic Radiation Oncology definition for biochemical failure overestimates BF in 20-30% after RT+AD compared to 5% after RT alone.

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PubMed2005

What pretreatment prostate-specific antigen level warrants long-term androgen deprivation?

PURPOSE: Several large randomized prospective studies have demonstrated a survival benefit with the addition of long-term androgen deprivation to definitive radiotherapy for patients with Gleason score 8-10 or T3-T4 prostate cancer. However, these studies were performed before the routine use of prostate-specific antigen (PSA) measurement. The purpose of this study was to determine what pretreatment (initial) PSA (iPSA) level, if any, warrants the addition of long-term androgen deprivation in the PSA era. METHODS AND MATERIALS: The data set evaluated consisted of 1003 prostate cancer patients treated definitively with three-dimensional conformal radiotherapy between May 1, 1989 and November 30, 1999 (median follow-up, 61 months). Specifically excluded were patients with T3-T4 disease or Gleason score greater than 7 or those who had undergone androgen deprivation as a part of their initial therapy. The median radiation dose was 76 Gy. Patients were randomly split into two data sets, with the first (n = 487) used to evaluate the optimal iPSA cutpoint for which a statistically significant difference in outcome was noted. The second data set (n = 516) served as a validation data set for the initial modeling. The analysis of the optimal iPSA cutpoint was based on a recursive partitioning approach for censored data using the log-rank test for nodal separation of freedom from biochemical failure (FFBF) as defined by the American Society for Therapeutic Radiology and Oncology definition. Cox multivariate regression analysis was used to confirm independent predictors of outcome among the clinical and treatment-related factors: iPSA (grouped as defined by the recursive partitioning analysis), Gleason score (2-6 vs. 7), T stage (T1c-T2a vs. T2b-T2c), and total radiation dose (continuous). RESULTS: The recursive partitioning analysis data set resulted in an optimal iPSA cutpoint of 35 ng/mL, such that the 5-year Kaplan-Meier estimate of FFBF was 80%, 69%, and 19% for iPSA groups of 0-9.9, 10-35, and >35 ng/mL, respectively. The validation data set demonstrated the optimal iPSA cutpoint to be 30 ng/mL. Conservatively choosing 30 ng/mL as the optimal cutpoint, the 5-year FFBF estimate for the entire 1003 patients was 82%, 69%, and 20% for iPSA groups 0-9.9 (n = 630), 10-30 (n = 329), and >30 (n = 44) ng/mL, respectively. On multivariate regression analysis, with the iPSA grouped as above, the Gleason score and radiation dose were independent predictors of outcome in this patient group (all p < 0.001). On univariate analysis, a higher radiation dose improved FFBF when the iPSA level was between 10 and 30 ng/mL (p = 0.001) but not when the iPSA level was >30 or <10 ng/mL. CONCLUSION: Recursive partitioning techniques defined an iPSA cutpoint of 30 ng/mL for delineating intermediate vs. high risk. Patients with a PSA level >30 ng/mL in the absence of Gleason score >7 or T3 disease do poorly when treated with radiotherapy alone and should be considered for long-term androgen deprivation or other aggressive systemic therapy.

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