PubMed Health⌕ Search

Biomedical subjects

Robert G Uzzo

Publications and source records attributed to Robert G Uzzo.

At least 19 recordsLinked to original sources
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

Treatment of patients with metastatic renal cell cancer: a RAND Appropriateness Panel.

BACKGROUND: New developments in the treatment of patients with metastatic renal cell cancer (MRCC) have suggested a need to reevaluate the role of systemic therapies. The authors convened a panel of medical and urologic oncologists to rate the appropriateness of the main options. METHODS: The authors used the RAND/University of California-Los Angeles Appropriateness Method to evaluate systemic therapy options and cytoreductive nephrectomy. After a comprehensive literature review, an expert panel rated the appropriateness of systemic options (108 permutations) and cytoreductive nephrectomy (24 permutations) for patients with MRCC. RESULTS: The appropriateness evaluation indicated that 27.3% of permutations were rated "appropriate," 46.9% were rated "inappropriate," and 25.8% were rated "uncertain." There was a high rate of agreement (95%). Sunitinib and sorafenib were rated appropriate for patients with low-to-moderate risk regardless of prior treatment. Temsirolimus was rated appropriate for first-line therapy for higher risk patients. Interferon-alpha and low-dose interleukin-2 were rated inappropriate or uncertain. In patients who received prior immunotherapy, cytokines were rated inappropriate. In all permutations for evaluating systemic therapy, enrollment into an investigational trial was considered appropriate, treatment with bevacizumab was uncertain, and thalidomide was inappropriate regardless of risk status or prior therapy. For good surgical risk patients with planned immunotherapy, nephrectomy was rated appropriate in patients who had limited metastatic burden regardless of tumor-related symptoms and in symptomatic patients regardless of metastatic burden. Only the most favorable combination of surgical risk, metastatic burden, and symptoms generated an "appropriate" rating for patients with planned targeted therapy. CONCLUSIONS: The current results begin the process of defining an appropriate role for cytokines, newer targeted therapies, and surgery in the treatment of MRCC.

Carcinoma, Renal Cell↗
PubMed2006

Identification of novel target genes by an epigenetic reactivation screen of renal cancer.

Aberrant promoter hypermethylation is a common mechanism for inactivation of tumor suppressor genes in cancer cells. To generate a global profile of genes silenced by hypermethylation in renal cell cancer (RCC), we did an expression microarray-based analysis of genes reactivated in the 786-0, ACHN, HRC51, and HRC59 RCC lines after treatment with the demethylating drug 5-aza-2 deoxycytidine and histone deacetylation inhibiting drug trichostatin A. Between 111 to 170 genes were found to have at least 3-fold up-regulation of expression after treatment in each cell line. To establish the specificity of the screen for identification of genes, epigenetically silenced in cancer cells, we validated a subset of 12 up-regulated genes. Three genes (IGFBP1, IGFBP3, and COL1A1) showed promoter methylation in tumor DNA but were unmethylated in normal cell DNA. One gene (GDF15) was methylated in normal cells but more densely methylated in tumor cells. One gene (PLAU) showed cancer cell-specific methylation that did not correlate well with expression status. The remaining seven genes had unmethylated promoters, although at least one of these genes (TGM2) may be regulated by RASSF1A, which was methylated in the RCC lines. Thus, we were able to show that up-regulation of at least 6 of the 12 genes examined was due to epigenetic reactivation. The IGFBP1, IGFBP3, and COL1A1 gene promoter regions were found to be frequently methylated in primary renal cell tumors, and further study will provide insight into the biology of the disease and facilitate translational studies in renal cancer.

Adult↗
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

Residual and recurrent disease following renal energy ablative therapy: a multi-institutional study.

PURPOSE: In this study we detail the incidence and pattern of residual and recurrent disease after radio frequency ablation or cryoablation of a renal mass and, using this information, determine reasonable minimum recommendations for when to perform surveillance imaging during year 1 after treatment. To our knowledge no evidence based guidelines exist for determining how or when followup abdominal imaging should be performed after renal energy ablative therapy. MATERIALS AND METHODS: We reviewed treatment and followup information of patients who underwent radio frequency ablation or cryoablation for a renal mass at 7 institutions. Postoperative monitoring was performed using a variety of surveillance schedules. RESULTS: Of 616 patients 63 were found to have residual or recurrent disease after primary radio frequency ablation (13.4%) or cryoablation (3.9%) for a median of 8.7% in 7 institutions. Most incomplete treatments (70%) were detected within the first 3 months. After salvage ablative therapy was rendered, therapy failed in only 4.2%. At a mean followup of 2 years patients with residual or recurrent disease had an overall survival rate of 82.5% and a 2-year metastasis-free survival rate of 97.4% for those with localized, unilateral renal tumors. CONCLUSIONS: In most cases initial treatment failure was detected within the first 3 months after treatment. Our findings support a minimum of 3 to 4 imaging studies in year 1 after ablative therapy, and at months 1, 3, 6 (optional) and 12.

Catheter Ablation↗
PubMed2006

The natural history of observed enhancing renal masses: meta-analysis and review of the world literature.

PURPOSE: Standard therapy for an enhancing renal mass is surgical. However, operative treatment may not be plausible in all clinical circumstances. Data on the natural history of untreated enhancing renal lesions is limited but could serve as a decision making resource for patients and physicians. We examined available data on the natural history of observed solid renal masses. MATERIALS AND METHODS: A Medline review of the literature was performed from 1966 to the present regarding untreated, observed, localized solid renal masses. To these data we added our institutional experience with a total of 61 lesions observed in 49 patients for a minimum of 1 year. Variables examined were initial lesion size at presentation, growth rate, duration of followup, pathological findings and progression to metastatic disease. Overall weighted mean estimates were calculated for lesion size at presentation, growth rate and followup based upon combining single institutional series with complete information. RESULTS: We identified 10 reports from 9 single institutional series in the world literature regarding the natural history of untreated solid localized renal lesions. The series included 6 to 40 patients (mean 25) with a mean followup of 30 months (range 25 to 39). When combined with our institutional data, a total of 286 lesions were analyzed, of which 234 could be included in the meta-analysis. Mean lesion size at presentation was 2.60 cm (median 2.48, range 1.73 to 4.08). Meta-analysis revealed a mean growth rate of 0.28 cm yearly (median 0.28, range 0.09 to 0.86) at a mean followup of 34 months (median 32, range 26 to 39) in all series combined. Pathological confirmation was available in 46% of the cases (131 of 286) and it confirmed 92% (120 of 131) as RCC variants. Evaluable data in this subset of confirmed RCC demonstrated a mean growth rate of 0.40 cm yearly (median 0.35, range 0.42 to 1.6). Lesion size at presentation did not predict the overall growth rate (p = 0.46). Progression to metastatic disease was identified in only 1% of lesions (3 of 286) during followup. CONCLUSIONS: The majority of small enhancing renal masses grow at a slow rate when observed. Although metastatic and cancer specific death are low, serial radiographic data alone are insufficient to predict the true natural history of these lesions. Therefore, physicians and patients assume a calculated risk when following these tumors. Basic biological data are needed to assess the natural history of untreated renal masses.

Disease Progression↗
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

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

Methylseleninic acid sensitizes prostate cancer cells to TRAIL-mediated apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytotoxic agent that preferentially induces apoptosis in a variety of human cancer cells. Unfortunately, some tumor cells remain resistant to TRAIL. Therefore, agents that sensitize malignant cells to TRAIL-mediated cell death might be of particular importance for the development of novel antitumor therapeutic regimens. Recent studies establish a critical role of selenium in prostate cancer prevention in vitro and in vivo. Here, we demonstrate that concomitant administration of TRAIL and methylseleninic acid (MSA) produces synergistic effects on the induction of apoptosis in androgen-dependent LNCaP and androgen-independent DU-145 prostate cancer cells. MSA rapidly and specifically downregulates expression of the cellular FLICE inhibitory protein, a negative regulator of death receptor signaling. In addition, we demonstrate that the synergistic effects of MSA and TRAIL result from the activation of the mitochondrial pathway-mediated amplification loop. Addition of MSA effectively blocked TRAIL-mediated BAD phosphorylation at Ser112 and Ser136 in DU-145 cells and was accompanied by induction of the mitochondrial permeability transition and release of apoptogenic cytochrome c and Smac/DIABLO proteins from the mitochondria and into the cytosol. These results suggest that selenium-based dietary compounds may help to overcome resistance to TRAIL-mediated apoptosis in prostate cancer cells.

Antineoplastic Agents↗
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.

Aged↗
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.

Aged↗
PubMed2005

Role of prostate dose escalation in patients with greater than 15% risk of pelvic lymph node involvement.

PURPOSE: To determine whether the radiation dose is a determinant of clinical outcome in patients with a lymph node risk of >15% treated using whole pelvic (WP), partial pelvic (PP), or prostate only (PO) fields. METHODS AND MATERIALS: A total of 420 patients with prostate cancer treated with three-dimensional conformal radiotherapy with or without short-term androgen deprivation (STAD) between June 1989 and July 2000 were included in this study. Patients had an initial pretreatment prostate-specific antigen level of <100 ng/mL and a lymph node index of > or =15% or T2c tumors with a Gleason score of 6-10. No patient had radiologic evidence of lymph node involvement. Of the 460 patients, 48 were treated with PO, 74 with PP, and 298 with WP fields. The median prostate dose was 74 Gy for PO, 82 Gy for PP, and 76 Gy for WP. The median radiation dose to the pelvis was 46 Gy for both PP and WP. Of the 460 patients, 72 underwent STAD for a median of 3 months (range, 3-6 months). Cox regression multivariate analysis was used to identify independent predictors of freedom from biochemical failure (FFBF) defined according to the American Society for Therapeutic Radiology Oncology consensus guidelines. Univariate comparisons were done using the Kaplan-Meier method and the log-rank test. RESULTS: At a median follow-up of 43 months, 121 patients had treatment failure: 22, 7, and 92 in the PO, PP, and WP arms, respectively. Independent predictors of FFBF in multivariate analysis included radiation dose, T stage, Gleason score, and initial prostate-specific antigen level. The 5-year FFBF rate by dose group was 48% for <73 Gy, 64% for 73-76.9 Gy, and 74% for > or =77 Gy (p = 0.002). The use of STAD and radiation field size were not significantly associated with FFBF. CONCLUSION: The radiation dose was the most significant determinant of FFBF in patients with a lymph node risk >15% in the patient population studied. These data suggest that the primary tumor takes precedence over lymph node coverage or the use of STAD. Doses >70 Gy are of paramount importance in such intermediate- and high-risk patients.

Aged↗
PubMed2005

Prior abdominal surgery and radiation do not complicate the retroperitoneoscopic approach to the kidney or adrenal gland.

PURPOSE: Laparoscopic renal and adrenal surgery is an accepted standard of care. This can be accomplished by a transperitoneal or retroperitoneal approach. In patients with extensive prior intra-abdominal surgery with or without radiation the retroperitoneal laparoscopic approach may avoid bowel adhesions and potential operative complications. We compared clinical outcomes of the laparoscopic retroperitoneal approach in patients with prior open abdominal surgery with or without radiation to outcomes in those with no surgical history. MATERIALS AND METHODS: We evaluated clinical and functional parameters in 78 consecutive patients undergoing retroperitoneoscopic renal or adrenal surgery performed by a single surgeon in a 36-month period, including radical nephrectomy with or without ureterectomy in 50, nerve sparing surgery in 8, ablation in 16 and adrenalectomy in 4. All transperitoneal procedures during the same period were excluded from analysis. Patients were divided into 48 who underwent prior abdominal surgery with or without radiation (group 1) and 30 who did not (group 2). Prior abdominal surgeries in group 1 patients were open and they were major in 42 and/or minor in 39. An additional 6 patients in group 1 received prior abdominal radiation overlapping the planned surgical field. RESULTS: No statistically significant differences were noted between the groups in any parameter assessed, including operative time, blood loss, time to first oral intake, hospital stay or the complication rate (p >0.05). There were no enterotomies in either group. There were no open conversions in group 1, while there were 2 in group 2 (renal vein injury and splenorrhaphy secondary to lymphoma, respectively). Pathological findings showed malignancy in 57 cases (renal cell carcinoma, transitional cell carcinoma, carcinoid disease and metastases) and benign disease in 21 (oncocytoma, adenoma, pyelonephritis and complex cysts). All margins were negative except in 1 group patient with carcinoma in situ at the bladder cuff margin. CONCLUSIONS: The retroperitoneoscopic approach to the kidney and adrenal glands can be used in patients with extensive prior open abdominal surgery and/or radiation without significant increases in morbidity or convalescence.

Adrenal Gland Neoplasms↗