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.

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.

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.

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.