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Alan Pollack

Publications and source records attributed to Alan Pollack.

At least 37 records · Page 2Linked to original sources
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

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

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↗
PubMed2004

MRI-based treatment planning for radiotherapy: dosimetric verification for prostate IMRT.

PURPOSE: Magnetic resonance (MR) and computed tomography (CT) image fusion with CT-based dose calculation is the gold standard for prostate treatment planning. MR and CT fusion with CT-based dose calculation has become a routine procedure for intensity-modulated radiation therapy (IMRT) treatment planning at Fox Chase Cancer Center. The use of MRI alone for treatment planning (or MRI simulation) will remove any errors associated with image fusion. Furthermore, it will reduce treatment cost by avoiding redundant CT scans and save patient, staff, and machine time. The purpose of this study is to investigate the dosimetric accuracy of MRI-based treatment planning for prostate IMRT. METHODS AND MATERIALS: A total of 30 IMRT plans for 15 patients were generated using both MRI and CT data. The MRI distortion was corrected using gradient distortion correction (GDC) software provided by the vendor (Philips Medical System, Cleveland, OH). The same internal contours were used for the paired plans. The external contours were drawn separately between CT-based and MR imaging-based plans to evaluate the effect of any residual distortions on dosimetric accuracy. The same energy, beam angles, dose constrains, and optimization parameters were used for dose calculations for each paired plans using a treatment optimization system. The resulting plans were compared in terms of isodose distributions and dose-volume histograms (DVHs). Hybrid phantom plans were generated for both the CT-based plans and the MR-based plans using the same leaf sequences and associated monitor units (MU). The physical phantom was then irradiated using the same leaf sequences to verify the dosimetry accuracy of the treatment plans. RESULTS: Our results show that dose distributions between CT-based and MRI-based plans were equally acceptable based on our clinical criteria. The absolute dose agreement for the planning target volume was within 2% between CT-based and MR-based plans and 3% between measured dose and dose predicted by the planning system in the physical phantom. CONCLUSIONS: Magnetic resonance imaging is a useful tool for radiotherapy simulation. Compared with CT-based treatment planning, MR imaging-based treatment planning meets the accuracy for dose calculation and provides consistent treatment plans for prostate IMRT. Because MR imaging-based digitally reconstructed radiographs do not provide adequate bony structure information, a technique is suggested for producing a wire-frame image that is intended to replace the traditional digitally reconstructed radiographs that are made from CT information.

Humans↗
PubMed2004

Antisense MDM2 oligonucleotides restore the apoptotic response of prostate cancer cells to androgen deprivation.

BACKGROUND: Early in the malignant transformation of prostate epithelial cells, the apoptotic response to androgen deprivation (AD) is lost and the principle response is a slowing of cell growth. In this study, we tested whether interruption of MDM2 function using antisense MDM2 oligonucleotide (AS) affects the apoptotic response of prostate cancer cells to AD. METHODS: Wild type LNCaP cells and MDM2-overexpressing (LNCaP-MST) cells were treated with AS alone or in combination with AD. Protein levels of MDM2, p53, and p21 were determined by Western blotting. Cell viability was measure by trypan blue staining. Apoptotic cell death was confirmed by cell morphological changes, annexin V/propidium iodide staining and caspase-3 + 7 activity. Overall cell survival was quantified by clonogenic assay. RESULTS: AS inhibited MDM2 expression to a greater extent in LNCaP cells, as compared to LNCaP-MST cells. AS enhanced the expression of p53 and p21 in both cell lines. The growth inhibitory and cell death effects of AS + AD were generally greater than AS alone in LNCaP cells. Treatment of LNCaP cells with AS + AD for 72 hr caused a significant increase in cell death (66%) over AD alone (13%), AS alone (33%), or AD + AS + R1881 (34% with synthetic androgen replacement) that was attributable mainly to apoptosis. Clonogenic survival reflected the same pattern. CONCLUSIONS: Our results suggest that the apoptotic response of prostate cancer to AD is strongly influenced by MDM2 expression. Antisense MDM2 has broad potential as a therapeutic agent to sensitize prostate cancer cells to AD therapy by enhancing apoptotic cell death.

Androgen Antagonists↗
PubMed2004

The radiation doses to erectile tissues defined with magnetic resonance imaging after intensity-modulated radiation therapy or iodine-125 brachytherapy.

PURPOSE: To report penile bulb (PB) and corporal bodies (CB) doses during intensity-modulated radiation therapy (IMRT) and permanent (125)I prostate implant alone (BT) for favorable, early stage, clinically localized prostate cancer using computed tomography (CT) and magnetic resonance imaging (MRI) to provide a basis for comparison as the initial report of a comprehensive project to develop erectile tissues sparing techniques. METHODS AND MATERIAL: Prostate, PB and CB volumes were defined by a fused CT/MRI simulation study performed before treatment in 29 IMRT patients and verification study performed 30 days postimplant in 15 BT patients. The median prescribed prostate dose for the IMRT and BT groups was 74 Gy and 145 Gy, respectively. Dose volume histograms (DVHs) were generated to determine the dose characteristics for the PB, CB, and prostate for each patient. D(90), V(100), and V(50) were used, where D(i) was defined as the dose that covers i% of the prostate volume and V(i) is the fractional volume of the prostate that receives i% of the prescribed dose. The Wilcoxon rank sum test was used to evaluate significance between the groups. RESULTS: The median PB D(90), V(100), and V(50) values were 17.5 Gy, 0%, and 31.9% for the IMRT group; and 52.5 Gy, 21.5%, and 89.7% for the BT group. The median CB D(90), V(100), and V(50) values were 7.3 Gy, 0%, and 0.9% for the IMRT group; and 26.9 Gy, 2.4%, and 20.1% for the BT group. The differences between the IMRT vs. BT V(100) values, but not V(50), were statistically significant for the PB (p = 0.001) and CB (p = 0.001). CONCLUSIONS: Radiation dose to the PB and CB is low with IMRT or BT. Magnetic resonance imaging is superior to CT for the imaging of erectile tissues. Intensity-modulated radiation therapy may offer further reductions in the doses received by the PB and CB; however, at what cost to prostate coverage and normal tissue sparing will be the subject of a follow-up study.

Aged↗
PubMed2004

Ki-67 staining index predicts distant metastasis and survival in locally advanced prostate cancer treated with radiotherapy: an analysis of patients in radiation therapy oncology group protocol 86-10.

PURPOSE: Proliferative activity defined by Ki-67 staining index (SI) has been correlated with progression and prognosis in a number of malignant tumors including prostate cancer. However, few studies have examined Ki-67 SI in pretreatment diagnostic material from patients treated with definitive radiotherapy. In a prior study, we found that a Ki-67 SI of >3.5% was associated with poorer patient outcome. The goals of this analysis were to validate the prognostic value of Ki-67 SI and this cut point. EXPERIMENTAL DESIGN: Of 456 assessable patients in Radiation Therapy Oncology Group Protocol 86-10, diagnostic material from 108 patients was available for Ki-67 analysis using MIB-1 antibody. Sixty patients were treated with external beam radiotherapy (EBRT) alone, and 48 patients were treated with short-term androgen deprivation + EBRT. Median follow-up was 9 years for those living. The relationship of Ki-67 with distant metastasis (DM), disease-specific survival (DSS), and overall survival (OS) was examined. RESULTS: The median Ki-67 SI was 7.1% (range, 0.2-45.5%). The 7.1% cut point was associated with DM and DSS; however, the 3.5% cut point was as strong a determinant and was the focus of this analysis. In Cox proportional hazards regression, Ki-67 SI was independently associated with DM and DSS. When the Ki-67 SI was </=3.5% and >3.5%, the 5-year risk of DM was 13.5% and 50.8% (P = 0.0005), respectively, and the 5-year risk of DSS was 97.3% and 67.7% (P = 0.0039), respectively. No association of Ki-67 SI with OS was observed. CONCLUSIONS: Higher Ki-67 SI was significantly associated with a greater risk of DM and DSS in locally advanced prostate cancer after definitive EBRT or AD + EBRT.

Aged↗
PubMed2004

Soft tissue sarcomas treated with postoperative external beam radiotherapy with and without low-dose-rate brachytherapy.

PURPOSE: Patients treated for soft tissue sarcoma with adjuvant low-dose-rate brachytherapy (BT) plus external beam radiotherapy (EBRT) were compared with those treated with adjuvant EBRT alone. The hypothesis was that higher doses from postoperative BT plus EBRT would improve local tumor control. METHODS AND MATERIALS: The medical records of 130 sarcoma patients definitively treated between February 1983 and February 2001 were reviewed. Of these, 25 patients received BT followed by EBRT, and 61 were treated with EBRT alone. Overall survival, freedom from distant metastasis, and local control were calculated using Kaplan-Meier estimates. Univariate and multivariate analyses were performed. The mean postoperative radiation dose with EBRT alone was 59 Gy (range, 50-74) and 50 Gy (range, 40-70 Gy) when low-dose-rate BT was included. The mean implant dose was 16 Gy (range, 10-20 Gy). RESULTS: The 5-year Kaplan-Meier estimate for overall survival for BT plus EBRT and EBRT alone was 82% and 72% (p = 0.93), respectively. The 5-year freedom from distant metastasis and freedom from local failure rate for BT plus EBRT vs. EBRT alone was 90% vs. 78% (p = 0.15) and 90% vs. 83% (p = 0.25), respectively. In the univariate subset analysis, Stage III patients had better local control at 5 years (100% vs. 62%, p = 0.03) and a trend was noted for better local control for high-grade tumors (100% vs. 74%, p = 0.09) if treated with BT plus EBRT. No statistically significant predictors were found on multivariate analysis for local control. The median follow-up was 62 months. CONCLUSION: Local control at 5 years was high in both groups at 83% and 90%. On univariate analysis, Stage III patients had improved 5-year local control and a trend was found toward better local control for high-grade tumors. On multivariate analysis, no predictors were found for better local control; however, the numbers of Stage III and high-grade patients were small, which may have masked a possible benefit of BT plus EBRT in this population.

Adolescent↗
PubMed2004

A comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with 3D conformal radiotherapy.

PURPOSE: Two models for stratification of prostate cancer aggressiveness predominate for the purposes of daily treatment decision making. This study investigates the relationships between these two clinically popular models. METHODS: Both risk stratification models use the same definition for low risk: Gleason score (GS) 10-20 ng/mL, without the presence of any high-risk feature; high risk (HR) was defined as the presence of GS 8-10, iPSA >20, or palpation stage T3. For the double factor high risk (DF) model, IR and HR were defined as one and more than one of the following: GS >or=7, iPSA >10, or stage T3. Between April 1989 and October 2001, 1,597 patients were treated definitively with 3D conformal radiation therapy (3D-CRT) alone for prostate cancer at our institution. The main clinical endpoint was freedom from biochemical failure (FFBF). RESULTS: The 5-year actuarial FFBF rate for the low-risk group was 83%. The SF model resulted in FFBF rates of 76% and 47% for IR and HR patients respectively. The DF model resulted in FFBF rates of 70% and 52% for IR and HR patients, respectively. The FFBF rate for patients defined as IR and HR by both models was 76% and 40%, respectively. Those classified as IR by the DF model and then further subdivided into IR and HR by the SF model had a 76% and 52% 5-year FFBF rate (p = 0.0004). Those classified as HR by the DF model and then further subdivided into IR and HR by the SF model had a 71% and 40% 5-year FFBF (p = 0.0014). CONCLUSIONS: The SF model created prognostic groups with a greater internal consistency than the DF model. The SF was also better at identifying patients with high-risk prostate cancer who may benefit from a more aggressive approach.

Aged↗
PubMed2004

Intensity-modulated radiotherapy with MRI simulation to reduce doses received by erectile tissue during prostate cancer treatment.

PURPOSE: The radiation doses received by erectile tissue may contribute to erectile dysfunction after treatment of prostate cancer. This is the first description of the ability to limit the dose received by the penile bulb (PB) and corporal bodies (CB) using intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Twenty-three patients with palpation Stage T1c-T2bN0M0 prostate cancer received IMRT alone. The dose prescribed to the planning target volume was 74-78 Gy. All patients underwent CT and MRI simulation to define the target and normal structures. Three plans with identical beam arrangements and energy were generated for each patient, with varying dose constraints for the PB and CB: no dose constraint, intermediate-dose constraint (20 Gy and 15 Gy, respectively) and low-dose constraint (15 Gy and 7 Gy, respectively). All plans were normalized, such that 95% of the planning target volume received at least 100% of the prescribed dose. For each plan, the ability to meet prostate dose homogeneity criteria (PHC; prostate maximal dose </=120% prescribed dose) and rectal tolerance dose-volume histogram criteria (RTC; </=35% and </=17% of rectal volume received 40 Gy and 65 Gy, respectively) was determined. The D(90), V(50), and V(75) were determined for both PB and the CB, where D(i) was the dose received by i% of the target volume and V(i) was the target volume receiving i% of the prescribed dose. RESULTS: The median PB D(90), V(50), and V(75) for the plans with no dose, intermediate-dose, and low-dose constraints was 20.8 Gy, 33.8%, and 9.9%; 8.0 Gy, 1.7%, and 0%; and 7.1 Gy, 0.1%, and 0%, respectively. The median CB D(90), V(50), and V(75) for plans with no dose, intermediate-dose, and low-dose constraints was 10.2 Gy, 3.8%, and 0%; 6.0 Gy, 0%, and 0%; and 4.9 Gy, 0%, and 0%, respectively. Overall differences in the D(90), V(50), and V(75) among the groups were significant for both the PB and the CB (p <0.0001). All plans with no dose constraint met the PHC and RTC. Twenty plans with an intermediate-dose constraint met the PHC and 21 met the RTC. Eighteen plans with a low-dose constraint met the PHC and 19 met the RTC. No statistically significant difference was found in the number of beam segments for the three groups (median of 51, 55, and 53; p = 0.8). CONCLUSION: In the vast majority of cases, it is possible to limit the dose to erectile tissue with IMRT, usually by >/=50% without significantly compromising the PHC, RTC, or treatment duration. A Phase III randomized trial has been designed to test the clinical significance of the erectile tissue-sparing technique described here.

Aged↗
PubMed2004

The relationship of increasing radiotherapy dose to reduced distant metastases and mortality in men with prostate cancer.

BACKGROUND: The association of increasing radiotherapy (RT) dose with reduced biochemical failure (BF) is accepted widely. However, there is little direct evidence that dose escalation has an impact on distant metastasis (DM) or overall mortality (OM). These associations were examined in the current study. METHODS: The outcome of 835 patients who were treated at the Fox Chase Cancer Center (Philadelphia, PA) between 1989 and 1997 using 3-dimensional, conformal RT alone (median dose, 74 Gray [Gy]) was analyzed. Stepwise multivariate Cox proportional hazards regression analyses (MVAs) were performed with RT dose included as a covariate along with log-transformed initial pretreatment PSA level, Gleason score, palpation T status, age, and year of treatment (YOT), where indicated. To minimize the effect of YOT, an analysis was performed on a subgroup of 363 patients who were treated prior to 1994. RESULTS: With a median follow-up of 64 months, there were 220 PSA failures, 44 distant metastases, and 162 deaths. In MVA, RT dose (as a continuous variable) was a significant predictor for BF, DM, and OM. When YOT was included as a covariate, it was related strongly to all endpoints, and the correlations of RT dose with DM and OM were lost. When the effect of YOT was minimized by limiting the MVA to patients who were treated prior to 1994, RT dose again emerged as a significant predictor of DM. CONCLUSIONS: Escalation of RT dose reduced the rates of BF, DM, and OM significantly in patients with prostate cancer. The inclusion of YOT had a pronounced effect on these correlations that may confound interpretation.

Adenocarcinoma↗
PubMed2004

Antisense MDM2 sensitizes prostate cancer cells to androgen deprivation, radiation, and the combination.

PURPOSE: Antisense MDM2 (AS) sensitizes a variety of tumor cell types, including prostate cancer, to radiation and chemotherapy. We have previously described that AS enhances the apoptotic response to androgen deprivation (AD) and that this translates into a reduction in overall cell survival, as measured by clonogenic assay. Because AD + radiation (RT) is a key strategy for the treatment of men with high-risk prostate cancer, AS was tested for the ability to sensitize cells to the combination of AD+RT. METHODS AND MATERIALS: LNCaP cells were cultured in vitro in either complete, androgen deprived (AD), or AD+R1881 (synthetic androgen) medium for 2-3 days before AS was administered. Radiation at 5 Gy was given 18-24 h later. Processing of the cells after RT was done at 3 h for Western blots, 24 and 48 h for trypan blue dye exclusion, 18 h for Annexin V staining by flow cytometric analysis, 18 h for Caspase 3+7 quantification by fluorometric assay, and immediately for clonogenic survival measured 12-14 days later. There were 18 treatment groups that were studied: lipofectin control, AS, antisense mismatch (ASM), AD, AD+R1881, and RT in all possible combinations. Statistical comparisons between groups were accomplished with one-way analysis of variance using the Bonferroni test, considering all 18 groups. RESULTS: AS caused a reduction in MDM2 expression and an increase in p53 and p21 expression. Early cell death by trypan blue was found to be reflective of the apoptotic results by Annexin V and Caspase 3+7. AS caused a significant increase in apoptosis over the lipofectin control, AD, and RT controls. Apoptosis was further increased significantly by the addition of AD or RT to AS. When AS, AD, and RT were combined, there was a consistent increase in early cell death over AS+AD and AS+RT by all of the assay methods, although this increase was not significant. Overall cell death measured by clonogenic assay revealed synergistic cell killing of AS+RT beyond that of ASM+RT and RT alone, and AS+RT+AD beyond that of AS+RT, AS+RT+AD+R1881, ASM+RT+AD, and ASM+RT+AD+R1881. CONCLUSION: AS sensitizes cells to AD, RT, and AD+RT and shows promise in the treatment of the full range of patients with prostate cancer. AS has the potential to sensitize the primary tumor to AD+RT and metastasis to AD.

Androgen Antagonists↗