Purpose: To quantitatively evaluate rigid and nonrigid motion of liver tumors based on fiducial tracking in 3D by stereo imaging during CyberKnife SBRT. Methods: Twenty-five liver patients previously treated with three-fractions of SBRT were retrospectively recruited in this study. During treatment, the 3D locations of fiducials were reported by the CyberKnife system after two orthogonal kV X-ray images were taken and further validated by geometry derivations. A total of 5004 pairs of X-ray images acquired during the course of treatment for all the patients, were analyzed. For rigid motion, the rotational angles and translational shifts by aligning 3D fiducial groups in different image pairs after least-square fitting were reported. For nonrigid motion, the relative interfractional tumor shape variations were reported and correlated to the sum of inter-fiducial distances. The individual fiducial displacements were also reported after rigid corrections and without angle corrections. Results: The relative tumor volume variation indicated by the inter-fiducial distances demonstrated an increasing trend in the second (101.6±3.4%) and third fraction (101.2±5.6%) among most patients. The cause could be possibly due to radiation-induced edema. For all the patients, the translational shift was 8.1±5.7 mm, with shifts in LR, AP and SI were 2.1±2.4 mm, 2.8±2.9 mm and 6.7±5.1 mm, respectively. The greatest translation shift occurred in SI, mainly due the breathing motion of diaphragm The rotational angles were 1.1±1.7°, 1.9±2.6° and 1.6±2.2°, in roll, pitch, and yaw, respectively. The 3D fiducial displacement with rigid corrections were 0.2±0.2 mm and increased to 0.6±0.3 mm without rotational corrections. Conclusion: The fiducial locations in 3D can be precisely reconstructed from CyberKnife stereo imaging system during treatment. The fiducials provide close estimation of both rigid and nonrigid motion of .liver tumors. The reported data could be further utilized for tumor margin design and motion management in in conventional linac-based treatments.

This is a prospective clinical study to compare the scattered fetal dose during Accelerated Partial Breast Irradiation (APBI) versus External Beam Radiation Therapy (EBRT). The scattered dose to the lower anterior abdominal wall of 14 consecutive patients treated with Accelerated Partial Breast Brachytherapy (APBI) were recorded using film badges. The film badges were placed on the anterior abdominal wall midway between the umbilicus and symphysis pubis. This is comparative to a 16 week pregnancy. None of the treated women were pregnant. APBI used SAVI devices of different sizes. The dose per treatment was 340 cGy prescribed to one cm around the lumpectomy cavity. One cm bolus was added on top of the film badges. No shielding was attempted for the first 4 cases. For the following 10 cases a lead apron was applied on top of the abdomen and pelvis. The scattered dose was also measured using the same way for another 10 patients treated with external beam radiation using 3D/IMRT to the whole breast. The dose prescribed was 180 cGy per fraction. No abdominal shielding was attempted. The doses were recorded for only five treatments and multiplied by 5 to account for a total dose of 45 Gy. The measured doses for 14 patients treated with APBI (4 without shielding and 10 with lead apron) were analyzed and compared to the doses collected for 10 patients treated with EBRT). Our data showed that APBI patients received much lower doses as compared to patients treated with EBRT. Adding a lead apron had decreased the exposure dose by more than 50% (p = 0.01). The average dose for APBI patients was 9.2 cGy (without shielding) and 4.4 cGy (with shielding) as compared to 15.5 cGy for patients treated with EBRT. The recorded doses were closely related to the distance between the SAVI device and the film badges, (p = 0.05). Also, there was close correlation between the patient weight and the recorded doses (p = 0.05) with heavier patients having lower doses. APBI contributes less scattered dose to the fetus as compared to whole breast radiation. The scattered dose is much easier to block due to the lower energy used. The longer the distance between the SAVI and the pelvis, and the heavier the weight of the patient, the less the dose recorded.

Purpose: To evaluate the internal brain motion between two imaging studies of CT and MRI. A study with 30 healthy volunteers with MRI scans in 4 different positions showed significant brain to skull motion up to 1 cm. Such motion among patients for radiotherapy to the brain is evaluated in this study. Methods: Twenty‐five patients underwent MRI and CT scans in the same day for radiotherapy planning were recruited. A whole brain fusion was first performed. Three to five pairs of control points were selected on both CT and MRI for starting an automated intensity based registration. The fusion was reviewed and fine‐tuned for the best skull‐to‐skull matching. To study potential internal brain motion, a subsequent fine‐tuning of the fusion was performed by matching the visible features, such as gyri, sulci and fissures, near the tumor site. The second fusion was reviewed and fine‐tuned by two physicists until the best visible feature matching could be agreed upon. The resulting rotation and translation between the whole brain and feature‐based fusions indicated potential internal brain motion between the two scans. Results: Between two fusions the mean internal shifts in x (LR), y (AP) and z (SI) were 0.34±0.95 mm, 0.21±1.18 mm and −0.34±0.8 mm, respectively. The mean overall shift was 1.4±1.1 mm, and the largest shift was 3.5 mm. The mean rotation angles were 0.22±1.32° (pitch), 0.14±0.4° (yaw) and 0.08±0.53° (roll), respectively. The pitch motion was predominant (head up and down) due to difference of couch tops of CT and MRI scanners. Conclusion: Our study showed small but measurable internal brain motion among radiotherapy patients with typical clinical setting for CT and MRI imaging. Therefore the CT‐MRI fusion should be carefully checked for internal structure matching. An additional treatment margin may be needed if an internal motion is observed.

Purpose: For CyberKnife based SBRT, CT scan of a single breathing phase is utilized for real‐time tumor tracking. However, x‐ray images for tracking are more often not in phase with the reference CT. Non‐rigid fiducial movement due to tumor deformation can induce significant uncertainties when matching images from different phases and this poses great difficulties for patient setup. A phase resolved fiducial setup scheme is developed that finds the best rigid transformation with tumor deformation corrected. Methods: Five cases (2 liver and 3 lung patients) were retrospectively analyzed in this study. For each patient, two sets of fiducials (at the ends of exhale (EOE) and inhale (EOI)) were first aligned by their centroids and linearly interpolated to generate fiducial sets for the phases in between. The fiducial set in 3D at each phase is iteratively registered to the fiducial set in x‐ray image until minimal residual error (RE) or mean distance between the projected fiducials and fiducials in the x‐ray image is reached. The phase with the smallest RE after registration of fiducial sets in 5 phases is determined as the phase of the x‐ray image. Results: For a liver case, 30 pairs of x‐ray images were registered to all 5 phases. The RE for registration with different phases was a smooth function with a distinct minimum. Fiducial matching for all the x‐ray images was also performed to the EOE phase. The REs resulted by our method were 4.2±0.58 mm, versus 5.3±1.48 mm with only EOE phase used for registration. The latter represented the RE currently achievable in current system. Similar results were also observed for the other 4 patients. Conclusions: In this study, a phase resolved fiducial setup scheme was developed and tested for 5 patients. It facilitates patient setup and tracking accuracy with reduced REs.

Purpose: Treatment planning systems have provided Monte Carlo dose calculations for several years but many physicians are still hesitant to use them clinically due to lack of data. Therefore we recalculated 200 Ray Tracing treatment plans using Monte Carlo with heterogeneity corrections and compared to SBRT dose tolerance limits. Methods: From among these 200 CyberKnife cases, 25 mediastinal lung cases are presented in this study. An extensive literature review obtained 105 published SBRT dose tolerance limits for the mediastinal critical structures aorta, bronchi, esophagus, heart, and trachea. These limits were partitioned into high‐risk and low‐risk categories. The DVH Evaluator software tool was used to generate DVH Risk Maps for these critical structures, which superimpose a) published dose tolerance limits b) unified high‐risk and low‐risk trends and c) published adverse event doses, onto Monte Carlo patient data to assess risk of adverse events. Results: Recalculated treatment plan data is within the expected range of published SBRT dose tolerance limits, providing optimism for clinical use. None of the patients experienced any Grade 3 or higher adverse events. The low‐risk dose tolerance limits were exceeded 22 times in these cases with no severe adverse event, thus helping to validate their safety. Conclusions: The range of doses calculated by Monte Carlo for our historical patient data is compatible with published SBRT dose tolerance limits. SBRT dose tolerance limits should be fine‐tuned by Monte Carlo dose calculations in long‐term statistical followup studies.Disclosure: The first author has developed the DVH Evaluator software.

distance of the tumor increased from the optic disc, lens, and macula, so did the decrease in radiation dose to the critical structures of the eye decrease significantly between EP917 and COMS plans.Thus, the EP917 plaques provide for an overall less radiation exposure to critical ocular structures than COMS treatment plaques, while still achieving an optimal total therapeutic dose to the tumor.

Purpose: It is important to understand the effect of dose calculation on the dosimetric parameters of a critical structure, which are often used to evaluate the risk of toxicity. We present the variation of some dosimetric parameters for brainstem as computed by two different dose algorithms. Methods: Both Ray Tracing and Monte Carlodose algorithms are commissioned for the CyberKnife planning system at Cooper. Study was performed for twenty seven intracranial patients treated with CyberKnife. Dose calculation was carried out in Multiplan workstation by Monte Carlo algorithm with heterogeneity corrections as well as Ray Tracing algorithm without heterogeneity corrections. Brainstem was delineated by the attending radiation oncologist during planning process. The same prescription and optimization as the actual treatment were employed in dose calculation for each patient. Results: Principle dosimetric parameters (D50, D10, D1cc, D0.1cc and maximum dose) of brainstem are derived for each patient. The difference in percentage between Ray Tracing and Monte Carlo calculation is plotted. Significant variation has been observed for each dosimetric parameter between two different dose algorithms. Also plotted is the variation of those dosimetric parameters against the volume of brainstem. Conclusions: The value of dosimetric parameters can be considerately different depending on dose algorithm used in calculation. The evaluation of dose tolerance for a critical structure using those dosimetric parameters needs to be cautious about dose computing methods.

Purpose: Small field dosimetry is challenging in homogeneous medium and extremely difficult in an inhomogeneous medium. Monte Carlo dose calculation algorithms are considered as the most accurate for treatment planning. We present our validation of the Monte Carlo algorithm in the Accuray Multiplan system using measurements in a cork phantom. We also recalculated Ray Tracing treatment plans with the Monte Carlo algorithm and compared to SBRT dose tolerance limits. Methods: In our validation measurements with a cork phantom, an Exradin A16 ion chamber was used for collimators from 60mm to 20mm on a CyberKnife, and a PTW 60012 stereotactic diode for collimators from 60mm to 5mm. A literature review of more than 500 published SBRT dose tolerance limits was partitioned into high-risk and low-risk categories. Two hundred CyberKnife treatment plans were recalculated using Monte Carlo and compared to the dose limits. The DVH Evaluator software tool was used to generate DVH Risk Maps for 25 critical structures throughout the body, which superimpose a) published dose tolerance limits b) unified high-risk and low-risk trends and c) published adverse event doses, onto Monte Carlo patient doses to assess risk of adverse events. Results: The Monte Carlo calculations matched the Exradin A16 measurements to within 2.5% for field sizes down to 20mm, and matched the PTW 60012 measurements to within 2.5% for all field sizes down to 5mm. Recalculated treatment plan data is within the expected range of published SBRT dose tolerance limits, providing optimism for clinical use. Conclusions: The Accuray MultiPlan Monte Carlo algorithm is accurate even for small fields in heterogeneous media. The range of doses calculated by Monte Carlo for our patient data is compatible with published SBRT dose tolerance limits. SBRT dose tolerance limits should be fine-tuned by Monte Carlo dose calculations in long-term statistical followup studies. Disclosure: The first author has developed the DVH Evaluator software.

Purpose: Recently several stereotactic body radiation therapy (SBRT) lung protocols have been developed. To gain insight into the dose tolerance limits and the fractionation schemes, this study is a comparison of the RTOG 0618, 0813, 0915, and Accuray STARS SBRT lung protocols. Method and Materials: To make a fair, unbiased comparison, all selected patients were evaluated according to all six protocol regimens. The DVH Evaluator software tool, which can evaluate a treatment plan according to all selected protocols, was used. Results: When comparing the various dose schemas and normal tissue tolerance limits utilized in currently available protocols, the Accuray STARS protocol incorporates radiobiologically higher dose tolerance limits. There is some discordance in the use of radiobiological equivalent doses as demonstrated with spinal cord limits heavily dependent upon fractionation schema and lung dose limits very similar to standard fractionated target doses. When we compare and contrast the various protocols RTOG 0618 incorporates the highest effective dose, yet some normal tissue tolerance targets are more strict than in other similar trials. Comparative analysis of included patients illustrates that three patients would have received treatment in full compliance with three of six protocols. Another patient was noted to exceed the spinal cord tolerance only for the single fraction arm of RTOG 0915 and skin limit for RTOG 0618, while meeting the esophageal dose limits in three of six protocols. Conclusion: This opens a dialogue regarding SBRT dose limits for the potential delivery of higher effective target doses utilizing the available ranges of acceptable normal tissue tolerance levels for the development of individualized treatment maximizing the risk‐benefit ratio of normal tissue to target dose delivery in an attempt to provide improved outcome for patients.

Purpose/Objective(s)To compile an online database of up-to-date published information on dose tolerance limits for SBRT clinical use and research.Materials/MethodsBased on an extensive literature review and our clinical experience with Gamma Knife and CyberKnife, a database of the dose tolerance limits in hypofractionated SBRT has been developed in our institution. It includes many anatomical structures from the head to the body, and is applicable to SBRT treatments in one to five fractionated sessions. The goal is to make the database available online, to enable other SBRT clinics to contribute to the work and to gain quick access to the information. Dose tolerance limits in hypofractionated SBRT are still evolving and far from consensus. The proposed online database can provide a useful resource for easy access to and better understanding of SBRT dose tolerance limits. The information is organized by each critical structure, followed with the dose limits of specified format (volumes, percentage and maximum, etc.) as well as complication probability and reference source. The newly published QUANTEC report refines the dose tolerance limits for most conventionally fractionated conformal irradiation. It has taken more than 20 years to achieve some limited consensus. Nevertheless, the report also recognizes that much work remains to be done for better understanding of biological and clinical effects of any dose limits. One reason for the slow progress in this effort is related to the traditional way of data collection. The accessible online database that we are proposing would be a more effective and accurate solution to this challenge.ResultsWe have compiled over 500 dose tolerance limits from various publications on hypofractionated SBRT into a database. The numbers vary significantly from study to study. SBRT is a rapidly emerging treatment modality for cancer, so clinicians and researchers are always looking for the latest data in order to understand the biological results of SBRT dose schemes. A software tool called DVH Evaluator has been developed at our institution to facilitate clinicians in summarizing the dose statistics of a given plan and to compare them with the dose tolerance limits from the known data. This tool allows clinicians to organize dose limits of interest to determine how the given data applies to a clinical case. More analysis tools of the full data spectra are to be developed.ConclusionsA database of online information for dose tolerance limits in hypofractionated SBRT can serve as a timely important and useful resource for clinical application and research. This information is needed for continuous development and validation of SBRT dose schemes. Purpose/Objective(s)To compile an online database of up-to-date published information on dose tolerance limits for SBRT clinical use and research. To compile an online database of up-to-date published information on dose tolerance limits for SBRT clinical use and research. Materials/MethodsBased on an extensive literature review and our clinical experience with Gamma Knife and CyberKnife, a database of the dose tolerance limits in hypofractionated SBRT has been developed in our institution. It includes many anatomical structures from the head to the body, and is applicable to SBRT treatments in one to five fractionated sessions. The goal is to make the database available online, to enable other SBRT clinics to contribute to the work and to gain quick access to the information. Dose tolerance limits in hypofractionated SBRT are still evolving and far from consensus. The proposed online database can provide a useful resource for easy access to and better understanding of SBRT dose tolerance limits. The information is organized by each critical structure, followed with the dose limits of specified format (volumes, percentage and maximum, etc.) as well as complication probability and reference source. The newly published QUANTEC report refines the dose tolerance limits for most conventionally fractionated conformal irradiation. It has taken more than 20 years to achieve some limited consensus. Nevertheless, the report also recognizes that much work remains to be done for better understanding of biological and clinical effects of any dose limits. One reason for the slow progress in this effort is related to the traditional way of data collection. The accessible online database that we are proposing would be a more effective and accurate solution to this challenge. Based on an extensive literature review and our clinical experience with Gamma Knife and CyberKnife, a database of the dose tolerance limits in hypofractionated SBRT has been developed in our institution. It includes many anatomical structures from the head to the body, and is applicable to SBRT treatments in one to five fractionated sessions. The goal is to make the database available online, to enable other SBRT clinics to contribute to the work and to gain quick access to the information. Dose tolerance limits in hypofractionated SBRT are still evolving and far from consensus. The proposed online database can provide a useful resource for easy access to and better understanding of SBRT dose tolerance limits. The information is organized by each critical structure, followed with the dose limits of specified format (volumes, percentage and maximum, etc.) as well as complication probability and reference source. The newly published QUANTEC report refines the dose tolerance limits for most conventionally fractionated conformal irradiation. It has taken more than 20 years to achieve some limited consensus. Nevertheless, the report also recognizes that much work remains to be done for better understanding of biological and clinical effects of any dose limits. One reason for the slow progress in this effort is related to the traditional way of data collection. The accessible online database that we are proposing would be a more effective and accurate solution to this challenge. ResultsWe have compiled over 500 dose tolerance limits from various publications on hypofractionated SBRT into a database. The numbers vary significantly from study to study. SBRT is a rapidly emerging treatment modality for cancer, so clinicians and researchers are always looking for the latest data in order to understand the biological results of SBRT dose schemes. A software tool called DVH Evaluator has been developed at our institution to facilitate clinicians in summarizing the dose statistics of a given plan and to compare them with the dose tolerance limits from the known data. This tool allows clinicians to organize dose limits of interest to determine how the given data applies to a clinical case. More analysis tools of the full data spectra are to be developed. We have compiled over 500 dose tolerance limits from various publications on hypofractionated SBRT into a database. The numbers vary significantly from study to study. SBRT is a rapidly emerging treatment modality for cancer, so clinicians and researchers are always looking for the latest data in order to understand the biological results of SBRT dose schemes. A software tool called DVH Evaluator has been developed at our institution to facilitate clinicians in summarizing the dose statistics of a given plan and to compare them with the dose tolerance limits from the known data. This tool allows clinicians to organize dose limits of interest to determine how the given data applies to a clinical case. More analysis tools of the full data spectra are to be developed. ConclusionsA database of online information for dose tolerance limits in hypofractionated SBRT can serve as a timely important and useful resource for clinical application and research. This information is needed for continuous development and validation of SBRT dose schemes. A database of online information for dose tolerance limits in hypofractionated SBRT can serve as a timely important and useful resource for clinical application and research. This information is needed for continuous development and validation of SBRT dose schemes.

Purpose: To make a preliminary estimate of the probability of adverse events for various critical anatomical structures for stereotactic body radiation therapy (SBRT). Method and Materials: An extensive literature search has uncovered a collection of more than 500 published dose tolerance limits for various anatomical critical structures for one to five fractions of SBRT. We have not found any TD5/5 or TD50/5 adverse event probabilities for SBRT yet, and an appreciable number of the authors do not even present minimum dosimetric information for the adverse events they report. We compiled a database from the available published data and performed statistical analysis to obtain a preliminary estimate of probability of adverse events. Results: Sixty five of the 500 dose tolerance limits correspond to a reported adverse event. For nineteen of these cases, the authors reported the number of patients exceeding the stated dose tolerance limit. For brain tumors, details of adverse events were reported in optic chiasm and optic nerve, and for lung tumors details of adverse events were reported in bronchi, lungs, and ribs. For these critical structures we can estimate the adverse event probability, although in some cases the number of data points is quite limited. Conclusion: It would be quite helpful for the future if more authors would present dosimetric data corresponding to the adverse events they report. At a minimum, it would be helpful to report the maximum dose received by the involved critical structure, the doses received by a few selected volumes, and the number of patients that received these dose levels. In the meantime, this work provides preliminary estimates of adverse event probability for selected anatomical critical structures from the sparse data available.

The protein kinase A (PKA) proteins are cAMP-dependent holoenzymes with types 1 and 2 distinguished by their regulatory subunits, RI and RII, respectively. Enhanced expression of these proteins is associated with active cell proliferation and malignant transformation. Knockdown by antisense oligonucleotides, specifically to the PKA RI-α subtype, results in enhanced response of prostate cancer cells to androgen deprivation (AD) with or without radiotherapy (RT) in vitro and in vivo. We previously reported PKA RI-α overexpression was predictive of outcome in prostate cancer patients treated with short term (ST) AD ± RT on RTOG protocol 86-10. Here, we determine if the biomarker is related to poor patient outcome in men treated with RT and either STAD or long term (LT) AD on high-risk prostate cancer protocol, RTOG 92-02. There were 313 cases in the study cohort with available tissue and suitable staining by immunohistochemistry. Median follow-up was 11.2 years. The intensity of PKA RI-α staining was quantified manually and by image analysis. Manual PKA scores were dichotomized (negative/low vs. moderate/high) and image analysis PKA mean intensity scores (MIS) were modeled both as continuous and dichotomized (median: 111.8 arbitrary units) covariates. Univariate and multivariate analyses (MVAs) were performed for the endpoint overall mortality (OM) using Cox proportional hazards models; for local failure (LF), biochemical failure (BF), distant metastasis (DM), and cause specific mortality (CSM) using Fine and Gray's regression model. The MVAs included covariates based on protocol stratification. There was a strong correlation between the dichotomized manual and image analysis data sets (p < 0.0001). In the MVAs, manual PKA intensity was an independent predictor of DM (p = 0.003), LF (p = 0.02), and BF (p = 0.01) but not of CSM or OM. As a dichotomous covariate, PKA MIS was significantly related to DM (p = 0.03) and BF (p = 0.001). PKA MIS as a continuous covariate was an independent predictor of BF only (p = 0.003). The 8 year DM rate was 12% for low versus 21% for high PKA intensity (p = 0.01), and 12% for an MIS ≤111.8 versus 19% for MIS >111.8 (p = 0.09). Patients in the LTAD+RT arm who overexpressed PKA had a lower risk of DM, LF, and BF (p < 0.05). This is the largest study, to our knowledge, describing the association of PKA overexpression to prostate cancer outcome. PKA overexpression was significantly associated with LF, BF, and DM. This biomarker could usefully identify high risk prostate cancer patients who would benefit from the PKA knockdown strategy.

Purpose: The Radiation Therapy Oncolology Group (RTOG) 0116 trial was designed to test the ability of Amifostine to reduce the toxicity of combined chemotherapy with extended-field radiotherapy and brachytherapy (Part 2), after first determining the toxicity rate for the regimen without Amifostine (Part 1). This manuscript reports the results of Part 1.Methods and Materials: Eligibility included patients with cervical carcinoma and high common iliac or para-aortic metastasis. Patients received extended-field radiotherapy to 45 Gy (1.8 Gy/fraction) with intracavitary irradiation. The final point A dose was 85 Gy LDR equivalent. Use of HDR was allowed. The positive para-aortic and high common iliac nodes were boosted to 54 to 59.4 Gy. Cisplatin (40 mg/m(2)) was delivered weekly during external beam and once with brachytherapy. The primary endpoint of Part I was acute Grade 3/4 toxicity, excluding Grade 3 leukopenia.Results: A total of 26 eligible patients were entered between August 1, 2000, and Decemeber 3, 2003. Of these, 21 had para-aortic metastasis (15 also had high common iliac involvement), and 5 had high common iliac involvement only. The median follow-up was 17.1 months (range, 1.8-38.6 months) for all patients and 21.7 months (range, 11.4-38.6 months) for alive patients. The acute Grade 3/4 toxicity rate, excluding Grade 3 leukopenia was 81%. Late Grade 314 toxicity was 40%. Eight patients underwent surgery for complications. Sixteen (62%) patients had a complete response for both local and nodal disease. The complete local response was 92%, the complete overall nodal response rate was 62% and the regional and para-aortic nodal response rates were 60% and 71% respectively. Estimated disease-free and overall survival at 18 months are 46% and 60%.Conclusions: Extended field and intracavitary irradiation with cisplatin for para-aortic or high common iliac metastasis from cervical cancer is associated with significant acute and late toxicity. (C) 2007 Elsevier Inc.

Purpose/Objective: This trial was designed to test the hypothesis that TAS and WP radiotherapy (RT) followed by a prostate boost improves the progression-free survival (PFS) by at least 10% compared to TAS and PO RT. This trial was also designed to test the hypothesis that neoadjuvant hormonal therapy(NHT) followed by concurrent TAS and RT improves the PFS compared to RT followed by adjuvant TAS (AHT) by at least 10%. Materials/Methods: Patients eligible for the study included those with clinically localized adenocarcinoma of the prostate and an elevated prostate specific androgen (PSA) < 100ng/ml. Patients were stratified by T stage, PSA, and Gleason score (GS) and required to have an estimated risk of lymph node (LN) involvement > 15% based on the equation +LN = (2/3) PSA + (GS-6) × 10. TAS consisted of an LHRH agonist (Leuprolide or Goserelin) and Flutamide 250 mg p.o. tid administered two months before and during RT (NHT) or for four months following the completion of RT (AHT). Accrual of 1,323 cases occurred between April 1, 1995 and June 1, 1999. Three hundred and thirty two, 331, 329, and 331men were randomized to WP RT + NHT, PO RT + NHT, WP RT + AHT, and PO RT + AHT respectively. 73% of patients had a Gleason score > 7, median PSA was 23ng/ml and 67% of patients had > T2c disease. The study design resulted in a balance between all four arms for clinical stage, GS, PSA, and estimated risk of lymph node involvement. PSA failure was defined as two consecutive rises or a PSA > 4ng/ml at the last follow up after the PSA nadir value was reached. Results: With a median follow up since study entry for all patients of 5.9 years, patients treated with WP RT + NHT in pair wise comparison analysis show a statistically significant difference in PFS over PO RT +NHT (p=0.0041) and a statistically significant improvement over WP RT + AHT (p=0.0045). WP RT + NHT shows a trend in progression free survival over PO RT + AHT (p= 0.0656). Five year PFS for WP RT + NHT, PO RT + NHT, WP RT + AHT and PO RT + AHT is 48.3%, 36.8%, 38.1%, and 40.4% respectively. Biochemical failure was also statistically significantly improved in pair wise comparison analysis for WP RT + NHT versus PO RT + NHT (p=0.0070), WP RT + NHT versus WP RT + AHT shows a trend towards significance with a (p=0.0699). WP RT + NHT versus PO RT + AHT was not statistically different regarding protocol definition of biochemical failure (p=0.2181). The five year biochemical failure rate for WP RT + NHT, PO RT + NHT, WP RT + AHT, and PO RT + AHT were 35.9%, 45.5%, 42.8%, and 40.0% respectively. To date no overall survival advantage has been seen. At five years overall survival for WP RT + NHT, PO RT + NHT, WP RT + AHT, and PO RT + AHT are 81.6%, 77.8%, 75.5%, and 81.2% respectively. Conclusions: This updated analysis reveals that WP RT + NHT is associated with improved PFS over PO RT + NHT and WP RT + AHT and trends toward improved PFS over PO RT + AHT. WP RT + NHT is associated with improved biochemical failure over PO RT + NHT, marginal improvement over WP RT + AHT, but may not be different from PO RT + AHT. Longer follow up is needed to confirm the benefit of these findings in regards to overall and cause specific survival.

Purpose/Objective: The retinoblastoma (RB) pathway is known to be deregulated in virtually all known human tumors. p16, the upstream regulator of RB, is among the most commonly affected members of this pathway. Previously we reported that loss of p16 expression was associated with adverse clinical outcome (J.Clin. Oncol., 21:3328–34, 2003). In the present study, we examined the prognostic value of p16 expression in men with locally advanced prostate cancer who were enrolled on RTOG 9202. Materials/Methods: Of the 1514 eligible cases, 612 patients had adequate tumor material for p16 analysis. Of these, 327 were randomized to LTAD (long-term androgen deprivation)+RT and 285 were randomized to STAD (short-term androgen deprivation) +RT. Expression levels of p16 were determined by immunohistochemical staining using anti-p16 antibody (Santa Cruz Biotechnology). An image-analysis system (ACIS, Chromavision) was used to measure the percentage of cells with nuclear staining. p16 mean index % was dichotomized as (1) ≤81.3% (percent positive staining, PPV) vs. >81.3% PPV, (2) ≤20% (PPV)vs. >20%. Cox proportional hazards models were utilized to identify the impact of p16 expression as both a continuous and categorical variable to overall survival, prostate cancer survival, distant metastasis, local progression, and biochemical progression. Actuarial estimates for overall and prostate cancer survival were calculated using the Kaplan-Meier method and the cumulative incidence method was used to estimate the local progression, distant metastasis, and biochemical progression failure rates. Results: On multivariate analysis, after adjusting for pretreatment clinical characteristics and assigned treatment, p16 mean index > 81.3% (higher levels of p16) was statistically significantly associated with decreased rate of distant metastases (hazard ratio= 0.60, 95% confidence intervals= 0.38 to 0.96, p= 0.0332). The multivariate analysis of assigned treatment by p16 index revealed that for patients with a mean p16 index > 81.3%, LTAD+RT significantly improved prostate cancer survival (PCS) over STAD+RT (unadjusted 5-year PCS: 97.8% vs. 89.2%, respectively, p=0.0008) and reduced the frequency of distant metastasis DM (unadjusted 5-year rate of DM: 7% vs. 16%, respectively, p=0.0069) over STAD+RT. In contrast, for patients with tumors demonstrating a mean p16 index ≤81.3%, LTAD+RT failed to improve these outcome parameters compared to STAD+RT, but did appear to decrease the frequency of local progression (p=0.02). Further, within the LTAD+RT arm, patients with tumors demonstrating a mean p16 index > 81.3% compared to ≤81.3% were found to have improved prostate cancer survival (unadjusted 5-year PCS: 97.8% vs. 94.1%, respectively, p=0.05) and reduced frequency of distant metastasis (unadjusted 5-year rates: 7.0% vs. 13.0%, respectively, p=0.02). p16 mean index did not appear to be of prognostic value within the STAD+RT arm. Conclusions: p16 mean index % ≤81.3% (indicating a greater degree of p16 loss) on ACIS appears to be significantly associated with higher risk of distant metastases on multivariate analysis in patients with locally advanced prostate cancer who were treated on RTOG 92–02. The patients who appeared to derive the greatest benefit from LTAD+RT were those with tumors demonstrating higher levels of p16 expression (e.g. a mean p16 value of >81.3%).

The purpose of this investigation was to examine changes in pretreatment prostate‐specific antigen (PSA), stage, and grade over the past decade as a function of race and geographic region. A multiinstitutional database representing 6,790 patients (1,417 African‐American, 5,373 white) diagnosed with nonmetastatic prostate cancer between 1988 and 1997 was constructed. PSA, stage, and grade data were tabulated by calendar year and region, and time trend analyses based on race and region were performed. There was an overall decline of PSA of 0.8%/year, which was significant ( P = 0.0001), with a faster rate of decline in African‐Americans (1.9%/year) than for whites (0.6%/year). The odds ratio (OR) for a stage shift was 1.09, which was significant ( P < 0.0001), and this shift was greater in whites. The OR for an overall grade shift was 1.15, which was significant ( P < 0.0001). Although grade and PSA trends were similar for the different regions, there were significant regional differences in stage trends. The implications are that the face of prostate cancer has changed over the past decade; i.e., the distributions of stage, grade, and PSA (the most important prognosticators) have changed. In addition, the countenances of that face are different for whites and African‐Americans. For African‐Americans, this is good news: the stage, grade, and PSA distributions are more favorable now than before. For whites, the trends are more complex and more dependent on region. These findings should be used for future clinical and health‐policy decisions in the screening and treatment of prostate cancer. © 2001 Wiley‐Liss, Inc.