Potential Clinical Significance of Overall Targeting Accuracy and Motion Management in the Treatment of Tumors That Move With Respiration: Lessons Learnt From a Quarter Century of Stereotactic Body Radiotherapy From Dose Response Models.

OBJECTIVE: To determine the long-term normal tissue complication probability with stereotactic body radiation therapy (SBRT) treatments for targets that move with respiration and its relation with the type of respiratory motion management (tracking vs. compression or gating). METHODS: A PubMed search was performed for identifying literature regarding dose, volume, fractionation, and toxicity (grade 3 or higher) for SBRT treatments for tumors which move with respiration. From the identified papers logistic or probit dose-response models were fitted to the data using the maximum-likelihood technique and confidence intervals were based on the profile-likelihood method in the dose-volume histogram (DVH) Evaluator. RESULTS: Pooled logistic and probit models for grade 3 or higher toxicity for aorta, chest wall, duodenum, and small bowel suggest a significant difference when live motion tracking was used for targeting tumors with move with respiration which was on the average 10 times lower, in the high dose range. CONCLUSION: Live respiratory motion management appears to have a better toxicity outcome when treating targets which move with respiration with very steep peripheral dose gradients. This analysis is however limited by sparsity of rigorous data due to poor reporting in the literature.

Extended-field irradiation and intracavitary brachytherapy combined with cisplatin chemotherapy for cervical cancer with positive para-aortic or high common iliac lymph nodes: results of ARM 1 of RTOG 0116.

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 1 was acute Grade 3/4 toxicity, excluding Grade 3 leukopenia. RESULTS: A total of 26 eligible patients were entered between August 1, 2000, and December 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 3/4 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.

An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions.

PURPOSE: This trial was designed to test the hypothesis that total androgen suppression and whole pelvic radiotherapy (WPRT) followed by a prostate boost improves progression-free survival (PFS) by > or =10% compared with total androgen suppression and prostate only RT (PORT). This trial was also designed to test the hypothesis that neoadjuvant hormonal therapy (NHT) followed by concurrent total androgen suppression and RT improves PFS compared with RT followed by adjuvant hormonal therapy (AHT) by > or =10%. METHODS AND MATERIALS: Patients eligible for the study included those with clinically localized adenocarcinoma of the prostate and an elevated prostate-specific antigen level of <100 ng/mL. Patients were stratified by T stage, prostate-specific antigen level, and Gleason score and were required to have an estimated risk of lymph node involvement of >15%. RESULTS: The difference in overall survival for the four arms was statistically significant (p = 0.027). However, no statistically significant differences were found in PFS or overall survival between NHT vs. AHT and WPRT compared with PORT. A trend towards a difference was found in PFS (p = 0.065) in favor of the WPRT + NHT arm compared with the PORT + NHT and WPRT + AHT arms. CONCLUSIONS: Unexpected interactions appear to exist between the timing of hormonal therapy and radiation field size for this patient population. Four Phase III trials have demonstrated better outcomes when NHT was combined with RT compared with RT alone. The Radiation Therapy Oncology Group 9413 trial results have demonstrated that when NHT is used in conjunction with RT, WPRT yields a better PFS than does PORT. It also showed that when NHT + WPRT results in better overall survival than does WPRT + short-term AHT. Additional studies are warranted to determine whether the failure to demonstrate an advantage for NHT + WPRT compared with PORT + AHT is chance or, more likely, reflects a previously unrecognized biologic phenomenon.

The dosimetric impact of the prescription isodose line (IDL) on the quality of robotic stereotactic radiosurgery (SRS) plans.

PURPOSE: There is no consensus on the optimal prescription isodose line (IDL) in CyberKnife (CK) SRS. We designed a strategy to search for optimal CK plans at different levels of IDLs and investigated the dosimetric impact on the quality of CK plans. METHODS AND MATERIALS: The retrospective study consisted of 13 CK patients with 16 brain tumors. The mean volume and size of the tumors was 9.7 ± 10.4 cc and 30.3 ± 10.9 mm, respectively. Four shells were created at distances of 2-3 mm to 60 mm from the target. The constraint dose of the innermost shell (D1) was the primary optimization parameter. For isolated brain tumors, D1 started from the prescription dose and gradually reduced after optimization started over. The optimal plans were reached when the coverage started to degrade and the desired IDL was achieved. For eight tumors abutting an OAR, both the D1 and constraint dose to the OAR were gradually pushed until an optimal plan was reached for the desired IDL. RESULTS: For the isolated tumors, the V5 Gy, V10 Gy, V15 Gy, V20 Gy, and V25 Gy of low IDL (49.6 ± 2.1%) plans were on average 23.6%, 28.6%, 33.8%, 26.2%, and 10.6% lower, respectively, comparing to the high IDL (88.6 ± 1.3%) plans. The Conformality Index (CI) of the low IDL plans outperformed the high IDL plans (mean: 1.15 vs. 1.24), except for a lesion under 0.5 cc. The quality of the middle IDL plans (69.6 ± 1.5%) was close to the low IDL plans. Similar results were observed for tumors abutting an OAR. CONCLUSIONS: Low IDL plans outperformed high IDL plans for all metrics in tumors > 0.5 cc. The lower dose exposure of normal brain tissue and better CI could potentially reduce radiation necrosis while the higher maximum dose could improve local control.

Stereotactic Body Radiotherapy for Large (> 5 cm) Non-Small-Cell Lung Cancer.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is a well-established treatment option for early stage non-small-cell lung cancer (NSCLC) tumors < 5 cm. There is limited information on tumors > 5 cm. PATIENTS AND METHODS: We performed retrospective data collection of patients enrolled onto a prospective SBRT registry study. Eligible patients for this study had node-negative NSCLC measuring > 5 cm in any dimension. Data from 41 patients were analyzed. Median patient age was 75 years, and median tumor size was 5.6 cm (range, 5.0-12.2 cm). Sixteen patients had squamous disease, 20 patients adenocarcinoma, and 1 mixed tumor; 4 patients had no biopsy. Median radiation dose per fraction was 50 Gy in 5 fractions. Radiation was prescribed to isodose line, median 66% (range, 50%-84%). RESULTS: Before SBRT, 6 patients had previous chemotherapy and 7 patients had previous radiation. Median follow-up for all patients was 15.2 months (range, 0.56-48.1 months). At last follow-up, 16 patients were still alive, with a median follow-up of 16.1 months for surviving patients. The median survival was 17.5 months with 1- and 2-year survivals of 65% and 34%. Two patients (4.8%) had local failure, and 13 patients (31%) had distant failure. Four patients (9.8%) had acute toxicity, and 7 patients (17.1%) had late toxicity, including 2 (4.8%) grade 3 late toxicities. CONCLUSION: SBRT for tumors > 5 cm is effective, with good local control rates and acceptable toxicity. The main pattern of failure is distant, suggesting a possible role for systemic chemotherapy in these patients.

Whole-pelvis, "mini-pelvis," or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) 9413 trial demonstrated a better progression-free survival (PFS) with whole-pelvis (WP) radiotherapy (RT) compared with prostate-only (PO) RT. This secondary analysis was undertaken to determine whether "mini-pelvis" (MP; defined as > or = 10 x 11 cm but < 11 x 11 cm) RT resulted in progression-free survival (PFS) comparable to that of WP RT. To avoid a timing bias, this analysis was limited to patients receiving neoadjuvant and concurrent hormonal therapy (N&CHT) in Arms 1 and 2 of the study. METHODS AND MATERIALS: Eligible patients had a risk of lymph node (LN) involvement > 15%. Neoadjuvant and concurrent hormonal therapy (N&CHT) was administered 2 months before and during RT for 4 months. From April 1, 1995, to June 1, 1999, a group of 325 patients were randomized to WP RT + N&CHT and another group of 324 patients were randomized to receive PO RT + N&CHT. Patients randomized to PO RT were dichotomized by median field size (10 x 11 cm), with the larger field considered an "MP" field and the smaller a PO field. RESULTS: The median PFS was 5.2, 3.7, and 2.9 years for WP, MP, and PO fields, respectively (p = 0.02). The 7-year PFS was 40%, 35%, and 27% for patients treated to WP, MP, and PO fields, respectively. There was no association between field size and late Grade 3+ genitourinary toxicity but late Grade 3+ gastrointestinal RT complications correlated with increasing field size. CONCLUSIONS: This subset analysis demonstrates that RT field size has a major impact on PFS, and the findings support comprehensive nodal treatment in patients with a risk of LN involvement of > 15%.

Introduction and Clinical Overview of the DVH Risk Map.

Radiation oncologists need reliable estimates of risk for various fractionation schemes for all critical anatomical structures throughout the body, in a clinically convenient format. Reliable estimation theory can become fairly complex, however, and estimates of risk continue to evolve as the literature matures. To navigate through this efficiently, a dose-volume histogram (DVH) Risk Map was created, which provides a comparison of radiation tolerance limits as a function of dose, fractionation, volume, and risk level. The graphical portion of the DVH Risk Map helps clinicians to easily visualize the trends, whereas the tabular portion provides quantitative precision for clinical implementation. The DVH Risk Map for rib tolerance from stereotactic ablative body radiotherapy (SABR) and stereotactic body radiation therapy (SBRT) is used as an example in this overview; the 5% and 50% risk levels for 1-5 fractions for 5 different volumes are given. Other articles throughout this issue of Seminars in Radiation Oncology present analysis of new clinical datasets including the DVH Risk Maps for other anatomical structures throughout the body.

Validity of Current Stereotactic Body Radiation Therapy Dose Constraints for Aorta and Major Vessels.

Understanding dose constraints for critical structures in stereotactic body radiation therapy (SBRT) is essential to generate a plan for optimal efficacy and safety. Published dose constraints are derived by a variety of methods, including crude statistics, actuarial analysis, modeling, and simple biologically effective dose (BED) conversion. Many dose constraints reported in the literature are not consistent with each other, secondary to differences in clinical and dosimetric parameters. Application of a dose constraint without discriminating the variation of all the factors involved may result in suboptimal treatment. This issue of Seminars in Radiation Oncology validates dose tolerance limits for 10 critical anatomic structures based on dose response modeling of clinical outcomes data to include detailed dose-volume metrics. This article presents a logistic dose-response model for aorta and major vessels based on 238 cases from the literature in addition to 387 cases from MD Anderson Cancer Center at Cooper University Hospital, for a total of 625 cases. The Radiation Therapy Oncology Group (RTOG) 0813 dose-tolerance limit of Dmax = 52.5Gy in 5 fractions was found to have a 1.2% risk of grade 3-5 toxicity, and the Timmerman 2008 limit of Dmax = 45Gy in 3 fractions had 2.3% risk. From the model, the 1% and 2% risk levels for D4cc, D1cc, and D0.5cc are also provided in 1-5 fractions, in the form of a dose-volume histogram (DVH) Risk Map.

Small Bowel Dose Tolerance for Stereotactic Body Radiation Therapy.

Inconsistencies permeate the literature regarding small bowel dose tolerance limits for stereotactic body radiation therapy (SBRT) treatments. In this review, we organized these diverse published limits with MD Anderson at Cooper data into a unified framework, constructing the dose-volume histogram (DVH) Risk Map, demonstrating low-risk and high-risk SBRT dose tolerance limits for small bowel. Statistical models of clinical data from 2 institutions were used to assess the safety spectrum of doses used in the exposure of the gastrointestinal tract in SBRT; 30% of the analyzed cases had vascular endothelial growth factor inhibitors (VEGFI) or other biological agents within 2 years before or after SBRT. For every dose tolerance limit in the DVH Risk Map, the probit dose-response model was used to estimate the risk level from our clinical data. Using the current literature, 21Gy to 5cc of small bowel in 3 fractions has low toxicity and is reasonably safe, with 6.5% estimated risk of grade 3 or higher complications, per Common Terminology Criteria for Adverse Events version 4.0. In the same fractionation for the same volume, if lower risk is required, 16.2Gy has an estimated risk of only 2.5%. Other volumes and fractionations are also reviewed; for all analyzed high-risk small bowel limits, the risk is 8.2% or less, and the low-risk limits have 4% or lower estimated risk. The results support current clinical practice, with some possibility for dose escalation.

Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31.

PURPOSE: Radiation Therapy Oncology Group protocol 85-31 was designed to evaluate the effectiveness of adjuvant androgen suppression, using goserelin, in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy (RT). METHODS AND MATERIALS: Eligible patients were those with palpable primary tumor extending beyond the prostate (clinical Stage T3) or those with regional lymphatic involvement. Patients who had undergone prostatectomy were eligible if penetration through the prostatic capsule to the margin of resection and/or seminal vesicle involvement was documented histologically. Stratification was based on histologic differentiation, nodal status, acid phosphatase status, and prior prostatectomy. The patients were randomized to either RT and adjuvant goserelin (Arm I) or RT alone followed by observation and application of goserelin at relapse (Arm II). In Arm I, the drug was to be started during the last week of RT and was to be continued indefinitely or until signs of progression. RESULTS: Between 1987 and 1992, when the study was closed, 977 patients were entered: 488 to Arm I and 489 to Arm II. As of July 2003, the median follow-up for all patients was 7.6 years and for living patients was 11 years. At 10 years, the absolute survival rate was significantly greater for the adjuvant arm than for the control arm: 49% vs. 39%, respectively (p = 0.002). The 10-year local failure rate for the adjuvant arm was 23% vs. 38% for the control arm (p <0.0001). The corresponding 10-year rates for the incidence of distant metastases and disease-specific mortality was 24% vs. 39% (p <0.001) and 16% vs. 22% (p = 0.0052), respectively, both in favor of the adjuvant arm. CONCLUSION: In a population of patients with unfavorable prognosis carcinoma of the prostate, androgen suppression applied as an adjuvant after definitive RT was associated not only with a reduction in disease progression but in a statistically significant improvement in absolute survival. The improvement in survival appeared preferentially in patients with a Gleason score of 7-10.

Factors that may determine the targeting accuracy of image-guided radiosurgery.

PURPOSE: The AAPM TG-135 report is a landmark recommendation for the quality assurance (QA) of image-guided robotic radiosurgery. The purpose of this paper is to present results pertaining to intentionally offsetting the phantom as recommended by TG-135 and to present data on targeting algorithm accuracy as a function of imager parameters in less than ideal circumstances, which had not been available at the time of publication of TG-135. METHODS: All tests in this study were performed at the Cooper University Hospital CyberKnife Center in Mt. Laurel, NJ. For intentional offsets, initial tests were performed on the Accuray-supplied anthropomorphic head and neck phantom, whereas for subsequent tests, the Accuray-supplied alignment quality assurance (AQA) phantom was used. To simulate the effects of imager parameters for larger patients, slabs of Blue Water (Standard Imaging, Inc., Middleton, WI) were added to attenuate the x-ray images in some of the tests. In conjunction with attenuated x-ray tests, the number of fiducials was varied by systematically deselecting them one at a time at the CyberKnife console. RESULTS: Tests using the AQA phantom verified that submillimeter alignments were consistently achieved even with intentional shifts and rotations of up to 10.0 mm and 1.0°, respectively. An analysis of 17 months of daily QA alignment tests showed that submillimeter alignments were achieved more than 99% of the time even with such intentional shifts and rotations of the phantom. When additional slabs of Blue Water were added to simulate patient attenuation of the x-ray images, targeting errors could be induced depending on imager parameters and the amount of Blue Water used. A series of consecutive tests showed that two helpful variables to ensure good accuracy of the system were (1) the fiducial extraction confidence level (FECL) system parameter and (2) the number of targeted fiducials. When fewer than four fiducials were used, the FECL reported by the CyberKnife was sometimes high even when a false lock occurred, so using multiple fiducials helped to ensure reliable targeting. CONCLUSIONS: Radiosurgery requires the highest degree of targeting accuracy, and in our experience, the CyberKnife has been able to maintain submillimeter accuracy consistently. It has been verified that our CyberKnife can correct for phantom shifts of up to 10.0 mm and rotations of up to 1.0°. It has also been discovered that false locks are more likely to occur with a single fiducial than with multiple fiducials. Although targeting accuracy can only be measured on a phantom, the insight gained from analyzing the QA tests can help us in devising better strategies for achieving the best treatment for our patients.

The impact of regional nodal radiotherapy (dose/volume) on regional progression and survival in unresectable non-small cell lung cancer: an analysis of RTOG data.

PURPOSE: To evaluate in-field progression and survival of patients with unresectable non-small cell lung cancer (NSCLC) in relation to adequacy of coverage of thoracic regional nodal areas in the radiotherapy volume. MATERIALS AND METHODS: A total of 1705 patients from four large RTOG trials (78-11, 79-17, 83-11 and 84-07) were analyzed for this purpose. For each of these trials, the dose delivered to nodal regions was recorded and an assessment of adequacy of field borders was made. Each nodal site was assessed for progression, defined as in-field or out-of-field. In patients who had adequate borders on nodal regions, the results were analyzed according to the dose delivered. RESULTS: The majority (74%) of patients were between the age of 55-75. Forty-six percent of the patients had KPS of 60-80 and 52% had KPS of 90-100. Sixty percent of patients had a weight loss of less than 5% in the 6 months prior to diagnosis. Deviations from the protocol in field borders (borders not per protocol) were most frequent for the contralateral hilum (25.2%) and least frequent in the ipsilateral hilum (6.3%). The adequacy of ipsilateral hilar coverage was important for preventing the in-field progression (11.6 vs. 22% for adequately vs. inadequately covered ipsilateral hilum, respectively, P=0.01), however, did not influence the 2-year-survival (35 vs. 37%) or median survival (1.3 vs. 1.1 year). Neither the in-field progression nor the 2-year-survival were affected by adequacy of nodal coverage in the mediastinum, ipsilateral supraclavicular area and contralateral hilum, even when different doses were analyzed. CONCLUSION: These data suggest that elective irradiation of mediastinal, contralateral hilar and supraclavicular lymph nodes may not be necessary in the treatment of unresectable NSCLC.

Quantifying rigid and nonrigid motion of liver tumors during stereotactic body radiation therapy.

PURPOSE: To quantify rigid and nonrigid motion of liver tumors using reconstructed 3-dimensional (3D) fiducials from stereo imaging during CyberKnife-based stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Twenty-three liver patients treated with 3 fractions of SBRT were used in this study. After 2 orthogonal kilovoltage images were taken during treatment, the 3D locations of the fiducials were generated by the CyberKnife system and validated using geometric derivations. A total of 4824 pairs of kilovoltage images from start to end of treatment were analyzed. For rigid motion, the rotational angles and translational shifts were reported by aligning 3D fiducial groups from different image pairs, using least-squares fitting. For nonrigid motion, we quantified interfractional tumor volume variations by using the proportional volume derived from the fiducials, which correlates to the sum of interfiducial distances. The individual fiducial displacements were also reported (1) after rigid corrections and (2) without angle corrections. RESULTS: The proportional volume derived by the fiducials demonstrated a volume-increasing trend in the second (101.9% ± 3.6%) and third (101.0 ± 5.9%) fractions among most patients, possibly due to radiation-induced edema. For all patients, the translational shifts in left-right, anteroposterior, and superoinferior directions were 2.1 ± 2.3 mm, 2.9 ± 2.8 mm, and 6.4 ± 5.5 mm, respectively. The greatest translational shifts occurred in the superoinferior direction, likely due to respiratory motion from the diaphragm. The rotational angles in roll, pitch, and yaw were 1.2° ± 1.8°, 1.8° ± 2.4°, and 1.7° ± 2.1°, respectively. The 3D individual fiducial displacements with rigid corrections were 0.2 ± 0.2 mm and increased to 0.5 ± 0.4 mm without rotational corrections. CONCLUSIONS: Accurate 3D locations of internal fiducials can be reconstructed from stereo imaging during treatment. As an effective surrogate to tumor motion, fiducials provide a close estimation of both rigid and nonrigid motion of liver tumors. The reported displacements could be further utilized for tumor margin definition and motion management in conventional linear accelerator-based liver SBRT.

Low toxicity for lung tumors near the mediastinum treated with stereotactic body radiation therapy.

PURPOSE: To report the local control, survival, and low toxicity observed at the Cooper University Hospital CyberKnife Center post stereotactic body radiation therapy (SBRT) in the treatment of lung tumors near the mediastinum. METHODS AND MATERIALS: Twenty-four medically inoperable lung cancer patients with tumors near the mediastinum were treated using the Accuray CyberKnife system (Accuray, Sunnyvale, CA) with Monte Carlo dose calculations and heterogeneity corrections from July 2008 to May 2010. The prescription dose ranged from 28.5 Gy to 60 Gy in 3-5 fractions. For conventional fractionation schemes, Emami et al(1) organized the dose tolerance limits into a unified format for clinical utility and partitioned them into 2 risk levels (5% and 50%) with preset volumes for most critical structures throughout the body. In contrast, statistical SBRT dose tolerance limits for mediastinal structures have not been established yet. We have sufficient experience at least to begin organizing a unified format with low-risk and high-risk partitions and preset volumes for 1-5 fractions exposing mediastinal structures. With the help of the (dose-volume histogram) DVH Evaluator, a software tool developed by our senior author, each treatment plan was assessed for safety and feasibility prior to treatment. The DVH Evaluator was also used to analyze the follow-up data and to create graphs of risk, called DVH Risk Maps, superimposing clinical data onto the unified SBRT dose tolerance limits. RESULTS: It was not feasible to prescribe the doses of peripheral lung lesions for all tumors near the mediastinum because of known toxicity. The crude local tumor control rate achieved in our series was 92%. Median survival was 26.8 months for the primary lung cases and 9.6 months for the metastatic cases. No patients experienced grade 3 or higher toxicities. CONCLUSIONS: We affirm that SBRT is feasible in the treatment of centrally located lung cancers when the dose tolerance limits of critical structures are diligently respected. The low adverse event rates that we have experienced, combined with a good local tumor control rate, are encouraging.

Stereotactic body radiotherapy as an alternative to brachytherapy in gynecologic cancer.

INTRODUCTION: Brachytherapy plays a key role in the treatment of many gynecologic cancers. However, some patients are unable to tolerate brachytherapy for medical or other reasons. For these patients, stereotactic body radiotherapy (SBRT) offers an alternative form of treatment. METHODS: Retrospective review of patients prospectively collected on SBRT database is conducted. A total of 11 gynecologic patients who could not have brachytherapy received SBRT for treatment of their malignancies. Five patients have been candidates for interstitial brachytherapy, and six have required tandem and ovoid brachytherapy. Median SBRT dose was 25 Gy in five fractions. RESULTS: At last followup, eight patients were alive, and three patients had died of progressive disease. One patient had a local recurrence. Median followup for surviving patients was 420 days (median followup for all patients was 120 days). Two patients had acute toxicity (G2 dysuria and G2 GI), and one patient had late toxicity (G3 GI, rectal bleeding requiring cauterization). CONCLUSIONS: Our data show acceptable toxicity and outcome for gynecologic patients treated with SBRT who were unable to receive a brachytherapy boost. This treatment modality should be further evaluated in a phase II study.

Phase III multi-institutional trial of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide combined with long-term androgen suppression therapy and radiotherapy versus long-term androgen suppression plus radiotherapy alone for high-risk prostate cancer: preliminary toxicity analysis of RTOG 99-02.

PURPOSE: Long-term androgen suppression plus radiotherapy (AS+RT) is standard treatment of high-risk prostate cancer. A randomized trial, Radiation Therapy Oncology Group trial 9902, was undertaken to determine whether adjuvant chemotherapy with paclitaxel, estramustine, and etoposide (TEE) plus AS+RT would improve disease outcomes with acceptable toxicity. METHODS AND MATERIALS: High-risk (prostate-specific antigen 20-100 ng/mL and Gleason score >or=7; or Stage T2 or greater, Gleason score 8, prostate-specific antigen level <100 ng/mL) nonmetastatic prostate cancer patients were randomized to AS+RT (Arm 1) vs. AS+RT plus four cycles of TEE (Arm 2). TEE was delivered 4 weeks after RT. AS continued for 2 years for both treatment arms. RT began after 8 weeks of AS began. RESULTS: The Radiation Therapy Oncology Group 9902 trial opened January 11, 2000. Excess thromboembolic toxicity was noted, leading to study closure October 4, 2004. A total of 397 patients were accrued, and the data for 381 were analyzable. An acute and long-term toxicity analysis was performed. The worst overall toxicities during treatment were increased for Arm 2. Of the 192 patients, 136 (71%) on Arm 2 had RTOG Grade 3 or greater toxicity compared with 70 (37%) of 189 patients on Arm 1. Statistically significant increases in hematologic toxicity (p < 0.0001) and gastrointestinal toxicity (p = 0.017) but not genitourinary toxicity (p = 0.07) were noted during treatment. Two Grade 5 complications related to neutropenic infection occurred in Arm 2. Three cases of myelodysplasia/acute myelogenous leukemia were noted in Arm 2. At 2 and 3 years after therapy completion, excess long-term toxicity was not observed in Arm 2. CONCLUSION: TEE was associated with significantly increased toxicity during treatment. The toxicity profiles did not differ at 2 and 3 years after therapy. Toxicity is an important consideration in the design of trials using adjuvant chemotherapy for prostate cancer.

The importance of protein kinase A in prostate cancer: relationship to patient outcome in Radiation Therapy Oncology Group trial 92-02.

PURPOSE: We previously reported that protein kinase A type I (PKA(RIalpha)) overexpression was predictive of outcome in prostate cancer patients treated with radiotherapy (RT) +/- short-term androgen deprivation (STAD) on Radiation Therapy Oncology Group (RTOG) protocol 86-10. Here, we attempt to verify our prior findings and test the hypothesis that the relationship of the length of AD to patient outcome is affected by PKA(RIalpha) overexpression. EXPERIMENTAL DESIGN: There were 313 cases in the RTOG 92-02 study cohort with available tissue and suitable staining by immunohistochemistry. Median follow-up was 10.1 years. The intensity of PKA(RIalpha) staining intensity was quantified manually and by image analysis. Multivariate analyses were done for overall mortality using Cox proportional hazards models and for local failure, biochemical failure, distant metastasis, and cause-specific mortality using Fine and Gray's regression models. RESULTS: The expression levels of PKA(RIalpha), determined by manual and image analysis, were strongly correlated (P < 0.0001). In the multivariate analyses, manual-quantified and image analysis-quantified PKA(RIalpha) staining intensities were independent predictors of distant metastasis (P < 0.01), local failure (P < 0.05), and biochemical failure (P

Prognostic value of p16 in locally advanced prostate cancer: a study based on Radiation Therapy Oncology Group Protocol 9202.

PURPOSE: Deregulation of the retinoblastoma (RB) pathway is commonly found in virtually all known human tumors. p16, the upstream regulator of RB, is among the most commonly affected member of this pathway. In the present study, we examined the prognostic value of p16 expression in men with locally advanced prostate cancer who were enrolled on Radiation Therapy Oncology Group protocol 9202. PATIENTS AND METHODS: RTOG 9202 was a phase III randomized study comparing long-term (LT) versus short-term (ST) androgen-deprivation therapy (AD). Of the 1,514 eligible cases, 612 patients had adequate tumor material for p16 analysis. Expression levels of p16 were determined by immunohistochemistry (IHC). IHC staining was scored quantitatively using an image analysis system. RESULTS: On multivariate analysis, intact p16 expression was significantly associated with decreased rate of distant metastases (P = .0332) when both STAD and LTAD treatment arms were considered together. For patients with intact (high levels of immunostaining) p16 (mean p16 index > 81.3%), LTAD plus radiotherapy (RT) significantly improved prostate cancer survival (PCS) compared with STAD plus RT (P = .0008) and reduced the frequency of distant metastasis (P = .0069) compared with STAD plus RT. In contrast, for patients with tumors demonstrating p16 loss (low levels of immunostaining, mean p16 index < or = 81.3%), LTAD plus RT significantly improved biochemical no evidence of disease survival over STAD (P < .0001) primarily by decreasing the frequency of local progression (P = .02), as opposed to distant metastasis, which was the case in the high-p16 cohort. CONCLUSION: Low levels of p16 on image analysis appear to be associated with a significantly higher risk of distant metastases among all study patients. p16 expression levels also appear to identify patients with locally advanced prostate cancer with distinct patterns of failure after LTAD.

Race and survival of men treated for prostate cancer on radiation therapy oncology group phase III randomized trials.

PURPOSE: We assessed the impact of race on survival in men treated with external beam radiotherapy with or without hormonal therapy for localized prostate cancer in Radiation Therapy Oncology Group randomized trials. MATERIALS AND METHODS: Between 1975 and 1992, 2,048 men were treated for clinically localized prostate cancer in 1 of 4 consecutive prospective phase III randomized trials. After excluding nonblack and nonwhite men 2,012 remained for analysis. Patients were included in this analysis if they were deemed evaluable and eligible for the trial, and followup information and centrally reviewed pathological results were available. Short-term hormonal therapy consisted of goserelin acetate and flutamide administered 2 months before and during radiotherapy. Long-term hormonal therapy consisted of adjuvant goserelin acetate, which was generally given for 2 years or more. Pretreatment prostate specific antigen (PSA) findings were available in 430 cases (21%), including 213 treated with radiotherapy alone, 60 treated with short-term hormonal therapy and 157 on long-term hormonal therapy. Mean pretreatment PSA was 68.8 and 35.2 ng./ml. in black and white patients, respectively. Cox proportional hazards models were used to identify the impact of previously defined risk groups on overall and disease specific survival. Multivariate analysis was done for the significance of race using a stratified Cox model. Median followup in patients treated in early and late studies exceeded 11 and 6 years, respectively. RESULTS: On univariate analysis black race was associated with lower overall and disease specific survival (p = 0.04, RR = 1.24 and p = 0.016, RR = 1.41, respectively). After adjusting for risk group and treatment type (with or without short-term or long-term hormonal therapy) race was no longer associated with outcome (p >0.05). The trend for a persistent difference in survival was likely due to the higher tumor burden in black men, as reflected in higher PSA. CONCLUSIONS: As previously reported, tumor grade (Gleason score), palpation T stage, lymph node status, pretreatment PSA and treatment type are major predictors of overall and disease specific survival. We noted no evidence that race has independent prognostic significance in patients treated for prostate cancer in Radiation Therapy Oncology Group prospective randomized trials.