Radiation Therapy Oncology Group Trial Research Articles

Single‐fraction radiotherapy versus multifraction radiotherapy for palliation of painful vertebral bone metastases—Equivalent efficacy, less toxicity, more convenient

AbstractBACKGROUND:The Radiation Therapy Oncology Group (RTOG) trial 97‐14 revealed no difference between radiation delivered for painful bone metastases at a dose of 8 gray (Gy) in 1 fraction (single‐fraction radiotherapy [SFRT]) and 30 Gy in 10 fractions (multifraction radiotherapy [MFRT]) in pain relief or narcotic use 3 months after randomization. SFRT for painful vertebral bone metastases (PVBM) has not been well accepted, possibly because of concerns about efficacy and toxicity. In the current study, the authors evaluated the subset of patients that was treated specifically for patients with PVBM.METHODS:PVBM included the cervical, thoracic, and/or lumbar spine regions. Among patients with PVBM, differences in retreatment rates and in pain relief, narcotic use, and toxicity 3 months after randomization were evaluated.RESULTS:Of 909 eligible patients, 235 (26%) had PVBM. Patients with and without PVBM differed in terms of the percentage of men (55% vs 47%, respectively; P = .03) and the proportion of patients with multiple painful sites (57% vs 38%, respectively; P < .01). Among those with PVBM, more patients who received MFRT had multiple sites treated (65% vs 49% for MFRT vs SFRT, respectively; P = .02). There were no statistically significant treatment differences in terms of pain relief (62% vs 70% for MFRT vs SFRT, respectively; P = .59) or freedom from narcotic use (24% vs 27%, respectively; P = .76) at 3 months. Significant differences in acute grade 2 through 4 toxicity (20% vs 10% for MFRT vs SFRT, respectively; P = .01) and acute grade 2 through 4 gastrointestinal toxicity (14% vs 6%, respectively; P = .01) were observed at 3 months, with lower toxicities seen in the patients treated with SFRT. Late toxicity was rare. No myelopathy was recorded. SFRT produced higher 3‐year retreatment rates (5% vs 15%; P = .01).CONCLUSIONS:Results for the subset of patients with PVBM in the RTOG 94‐17 randomized controlled trial were comparable to those for the entire population. SFRT produced less acute toxicity and a higher rate of retreatment than MFRT. SFRT and MFRT resulted in comparable pain relief and narcotic use at 3 months. Cancer 2013. © 2012 American Cancer Society.

Evolving Concepts Regarding the Use of Radiotherapy in the Adjuvant Management of Periampullary Pancreatic Adenocarcinoma

Presently, many oncologists feel that radiotherapy should not be part of curative intent, adjuvant management for pancreatic adenocarcinoma ("pancreatic cancer"). Historically, among oncologists who provided adjuvant therapy in this context, radiotherapy was included. This review examines the historical development of this controversy as well as (a) the history and principles of systemic and regional adjuvant therapy, (b) relevant nonsurgical studies using combined radiotherapy and chemotherapy for curative intent management of locally unresectable pancreatic cancer, (c) relevant results from surgical adjuvant studies using combined radiotherapy and chemotherapy for curative intent management of resected pancreatic cancer, and (d) results from phase III cooperative group studies of the adjuvant management of pancreatic cancer. Whether we conclude that adjuvant management should be used in a given clinical context depends on the disease and stage-specific results with surgery alone, risk of local and/or systemic failure, efficacy of chemotherapy and radiotherapy for addressing subclinical disease in this context, and the quality of data and studies available for making these assessments. In some settings where locoregional and systemic failure are codominant, both radiotherapy and chemotherapy are required for optimal results. For the adjuvant management of pancreatic cancer, many relevant studies with chemoradiotherapy have had serious limitations because they were nonrandomized, otherwise flawed in design and/or execution, inadequately stratified for currently known prognostic factors, or did not adequately consider radiotherapy technical details and quality assurance. As demonstrated in a secondary analysis of Radiation Therapy Oncology Group trial 9704, these factors are sufficiently powerful, when inadequately recognized and considered, to have obscured the potential therapeutic benefit of radiotherapy. Progress in pancreatic cancer has been hard to achieve. There are many indications that radiotherapy should be of benefit in the curative intent management of pancreatic cancer and we can ill afford to dismiss its use inappropriately. Therefore, well-designed, scientifically based, and appropriately executed phase III cooperative group studies aimed at providing improved clinical outcomes and addressing radiotherapy questions are both appropriate and necessary. Radiation Therapy Oncology Group trial 0848, currently accruing and ongoing, has been designed to clarify the role of radiotherapy in the adjuvant management of pancreatic cancer.

Hypopharyngeal Dose Is Associated With Severe Late Toxicity in Locally Advanced Head-and-Neck Cancer: An RTOG Analysis

Concurrent chemoradiation therapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases local tumor control but at the expense of increased toxicity. We recently showed that several clinical/pretreatment factors were associated with the occurrence of severe late toxicity. This study evaluated the potential relationship between radiation dose delivered to the pharyngeal wall and toxicity. This was an analysis of long-term survivors from 3 previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG trials 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for a feeding tube≥2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Radiation dosimetry (2-dimensional) analysis was performed centrally at RTOG headquarters to estimate doses to 4 regions of interest along the pharyngeal wall (superior oropharynx, inferior oropharynx, superior hypopharynx, and inferior hypopharynx). Case-control analysis was performed with a multivariate logistic regression model that included pretreatment and treatment potential factors. A total of 154 patients were evaluable for this analysis, 71 cases (patients with severe late toxicities) and 83 controls; thus, 46% of evaluable patients had a severe late toxicity. On multivariate analysis, significant variables correlated with the development of severe late toxicity, including older age (odds ratio, 1.062 per year; P=.0021) and radiation dose received by the inferior hypopharynx (odds ratio, 1.023 per Gy; P=.016). The subgroup of patients receiving ≤60 Gy to the inferior hypopharynx had a 40% rate of severe late toxicity compared with 56% for patients receiving >60 Gy. Oropharyngeal dose was not associated with this outcome. Severe late toxicity following CCRT is common in long-term survivors. Age is the most significant factor, but hypopharyngeal dose also was associated.

Minding the Ps and Qs: Perseverance and Quality Studies Lead to Major Advances in Patients With Anaplastic Oligodendroglioma

Almost 6 years ago, the results of two similar studies that described the outcomes for patients with anaplastic oligodendroglial (AO) tumors were published in Journal of Clinical Oncology. These studies were launched in 1994 and 1995 and built on the observations from the late 1980s and early 1990s that some patients with AO had dramatic and durable responses to chemotherapy. The Radiation Therapy Oncology Group (RTOG), in collaboration with four other North American–based cooperative groups, launched the RTOG 9402 trial. This phase III clinical trial compared the standard of care, external beam radiation, to preradiation chemotherapy using up to four cycles of intensive procarbazine, lomustine (CCNU), and vincristine (the iPCV regimen). Within 1 year of the initiation of the RTOG trial, the European Organisation for Research and Treatment of Cancer (EORTC) launched a study of patients with the same tumor type, but the experimental arm differed in that radiation was followed by up to six cycles of standard-dose PCV chemotherapy. When the results of these two trials were published in 2006, they both demonstrated a significant improvement in progression-free survival for patients who received the combination regimens, but there was no difference in overall survival. However, in both studies, approximately 80% of the patients who were randomly assigned to the radiation-only arms were treated with chemotherapy at tumor relapse (in contrast, only 50% of patients who were given up-front chemotherapy received chemotherapy salvage treatment). The conclusions in 2006 were that either treatment approach was acceptable, given that the patients who received only radiation as first-line treatment would then benefit from chemotherapy as second-line treatment. The editorial that accompanied these publications highlighted the need for patient outcomes measures such as neurocognitive and symptom burden consequences that might help determine whether early or late chemotherapy should be the standard of care. In other words, are the early toxicities from the chemotherapy offset by the preservation of function that results from the delay in tumor progression? These trials did not directly address these issues. However, both studies attempted to prospectively collect tumor tissues, although at the time that the studies were launched, no specific molecular markers were known. In 1998, the association of allelic loss of the short arm (p) of chromosome 1 and the long arm (q) of chromosome 19 with some AOs was published. Retrospective series strongly suggested that these changes were highly prognostic; subsequently, the status of 1p/19q was determined in the available tumor samples from both the RTOG and EORTC studies. The 2006 publications analyzed the survival outcomes, stratifying by the 1p/19q loss, and confirmed the prognostic importance of these chromosome changes, but survival was not improved by early chemotherapy in either the patients with 1p/19q loss or those without. However, in 2006, for the group with 1p/19q loss, the median survival had not been reached. As evidenced by the two articles that accompany this editorial, 6 years later the story has dramatically changed. Additional tumor samples were obtained from the original study participants and long-term follow-up data were obtained for both studies, now more than 17 years after their initiation. Remarkably, once again the two trials were complementary. Now with this long-term follow-up, there is clear evidence that for patients with AOs that contain the 1p/19q loss, early chemotherapy with radiation offers a significant improvement in overall survival compared with early radiation even with salvage chemotherapy at tumor relapse. This survival benefit was not found for patients with tumors that did not have the chromosomal deletions, highlighting the clinical importance of this molecular marker. These results have several important implications. These studies establish a new standard of care for patients with AO tumors that harbor the 1p/19q loss. No longer is radiation considered an adequate treatment for this patient population. As a result, the international cooperative group study of newly diagnosed AO with 1p/19q loss, CODEL, which compared radiation therapy with the combination of radiation and chemotherapy (temozolomide) and included an exploratory arm with chemotherapy (temozolomide alone), was halted because the control arm (radiation alone) is no longer viable. There are now ongoing discussions about a new trial design, with considerations ranging from comparing the PCV combination (used in these clinical trials) with temozolomide, an oral agent with a better toxicity profile and proven efficacy in glioblastoma. Further complicating the study design are the reports of tumor response with chemotherapy (PCV or temozolomide) alone, generating the question of whether to evaluate chemotherapy alone as first-line therapy, reserving a radiation-containing regimen for relapse. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 3 JANUARY 2

Prognostic factors for recurrence and survival in anal cancer

Only 2 prospective studies have previously reported prognostic factors for anal cancer, European Organization for Research and Treatment of Cancer trial 22861 (EORTC 22861) and Radiation Therapy Oncology Group trial 98-11 (RTOG 98-11). Both of those trials reported that clinically positive lymph nodes and male sex predicted poorer overall survival (OS). The EORTC 22861 trial indicated that the same factors were prognostic for locoregional control. In the current report, the authors investigated potential prognostic factors from the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I), in which patients were randomized to receive either radiotherapy alone or chemoradiation (CRT) with concurrent 5-fluorouracil/mitomycin C. In the ACT I trial, associations between several baseline characteristics and 3 endpoints were investigated: locoregional failure (LRF), anal cancer death (ACD), and OS. The analyses were restricted to 292 patients who received CRT, which subsequently became standard treatment. A score was derived using multivariable Cox regression to identify the set of factors that, together, had the best prognostic performance. This score was then validated with a large, independent prospective trial (the ACT II trial). Palpable, clinically positive lymph nodes were associated with LRF (P = .012), a greater risk of ACD (P = .031), and decreased OS (P = .006) in multivariable analyses. Men had worse outcomes than women for LRF (P = .036), ACD (P = .039), and OS (P = .008). On average, a lower hemoglobin level had an adverse effect on ACD (P = .008), and a higher white blood cell count had an adverse effect on OS (P = .001). However, external validation of the score was poor for LRF (area under the curve [AUC] = 54%) but was better for ACD (AUC = 67%) and OS (AUC = 63%). The results from this analysis of the ACT I trial supported evidence for palpable lymph nodes and male sex as prognostic factors for LRF and OS, and lower hemoglobin levels and a higher white blood cell count were identified as prognostic factors for ACD and OS, respectively.

Five Year Results of US Intergroup/RTOG 9704 With Postoperative CA 19-9 ≤90 U/mL and Comparison to the CONKO-001 Trial

Radiation Therapy Oncology Group (RTOG) trial 9704 was the largest randomized trial to use adjuvant chemoradiation therapy for patients with pancreatic cancer. This report analyzes 5-year survival by serum level of tumor marker CA 19-9 of ≤90 vs >90 U/mL and compares results to the those of the CONKO-001 trial. CA 19-9 expression was analyzed as a dichotomized variable (≤90 vs >90 U/mL). Cox proportional hazard models were used to identify the impact of the CA 19-9 value on overall survival (OS). Actuarial estimates of OS were calculated using the Kaplan-Meier method. Both univariate (hazard ratio [HR] = 3.2; 95% confidence interval [CI], 2.3-4.3, P<.0001) and multivariate (HR = 3.1; 95% CI, 2.2-4.2, P<.0001) analyses demonstrated a statistically significant decrease in OS for CA 19-9 serum level of ≥90 U/mL. For patients in the gemcitabine (Gem) treatment arm with CA 19-9 <90 U/mL, median survival was 21 months. For patients with CA 19-9 ≥90 U/mL, this number dropped to 10 months. In patients with pancreatic head tumors in the Gem treatment arm with RT quality assurance per protocol and CA 19-9 of <90 U/mL, median survival and 5-year rate were 24 months and 34%. In comparison, the median survival and 5-year OS rate for patients in the Gem arm of the CONKO trial were 22 months and 21%. This analysis demonstrates that patients with postresection CA 19-9 values ≥90 U/mL had a significantly worse survival. Patients with pancreatic head tumors treated with Gem with CA 19-9 serum level of <90 U/mL and per protocol RT had favorable survival compared to that seen in the CONKO trial. CA 19-9 is a stratification factor for the current RTOG adjuvant pancreas trial (0848).

Implementation of Remote 3-Dimensional Image Guided Radiation Therapy Quality Assurance for Radiation Therapy Oncology Group Clinical Trials

To report the process and initial experience of remote credentialing of three-dimensional (3D) image guided radiation therapy (IGRT) as part of the quality assurance (QA) of submitted data for Radiation Therapy Oncology Group (RTOG) clinical trials; and to identify major issues resulting from this process and analyze the review results on patient positioning shifts. Image guided radiation therapy datasets including in-room positioning CT scans and daily shifts applied were submitted through the Image Guided Therapy QA Center from institutions for the IGRT credentialing process, as required by various RTOG trials. A centralized virtual environment is established at the RTOG Core Laboratory, containing analysis tools and database infrastructure for remote review by the Physics Principal Investigators of each protocol. The appropriateness of IGRT technique and volumetric image registration accuracy were evaluated. Registration accuracy was verified by repeat registration with a third-party registration software system. With the accumulated review results, registration differences between those obtained by the Physics Principal Investigators and from the institutions were analyzed for different imaging sites, shift directions, and imaging modalities. The remote review process was successfully carried out for 87 3D cases (out of 137 total cases, including 2-dimensional and 3D) during 2010. Frequent errors in submitted IGRT data and challenges in the review of image registration for some special cases were identified. Workarounds for these issues were developed. The average differences of registration results between reviewers and institutions ranged between 2 mm and 3 mm. Large discrepancies in thesuperior-inferior direction were found for megavoltage CT cases, owing to low spatial resolution in this direction for most megavoltage CT cases. This first experience indicated that remote review for 3D IGRT as part of QA for RTOG clinical trials is feasible and effective. The magnitude of registration discrepancy between institution and reviewer was presented, and the major issues were investigated to further improve this remote evaluation process.

Long-Term Follow-Up of a Paradigm-Changing Study: The Paradigm Still Holds

Long-Term Follow-Up of a Paradigm-Changing Study: The Paradigm Still Holds

Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas

To define a male and female pelvic normal tissue contouring atlas for Radiation Therapy Oncology Group (RTOG) trials. One male pelvis computed tomography (CT) data set and one female pelvis CT data set were shared via the Image-Guided Therapy QA Center. A total of 16 radiation oncologists participated. The following organs at risk were contoured in both CT sets: anus, anorectum, rectum (gastrointestinal and genitourinary definitions), bowel NOS (not otherwise specified), small bowel, large bowel, and proximal femurs. The following were contoured in the male set only: bladder, prostate, seminal vesicles, and penile bulb. The following were contoured in the female set only: uterus, cervix, and ovaries. A computer program used the binomial distribution to generate 95% group consensus contours. These contours and definitions were then reviewed by the group and modified. The panel achieved consensus definitions for pelvic normal tissue contouring in RTOG trials with these standardized names: Rectum, AnoRectum, SmallBowel, Colon, BowelBag, Bladder, UteroCervix, Adnexa_R, Adnexa_L, Prostate, SeminalVesc, PenileBulb, Femur_R, and Femur_L. Two additional normal structures whose purpose is to serve as targets in anal and rectal cancer were defined: AnoRectumSig and Mesorectum. Detailed target volume contouring guidelines and images are discussed. Consensus guidelines for pelvic normal tissue contouring were reached and are available as a CT image atlas on the RTOG Web site. This will allow uniformity in defining normal tissues for clinical trials delivering pelvic radiation and will facilitate future normal tissue complication research.

External-beam radiation therapy should be given with androgen deprivation treatment for intermediate-risk prostate cancer: new confirmatory evidence

External-beam radiation therapy should be given with androgen deprivation treatment for intermediate-risk prostate cancer: new confirmatory evidence

Vaccine-Derived Poliomyelitis 12 Years after Infection

1. Valicenti R, Lu J, Pilepich M, Asbell S, Grignon D. Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the Radiation Therapy Oncology Group trials. J Clin Oncol 2000;18:2740-6. 2. Valicenti RK, Bae K, Michalski J, et al. Does hormone therapy reduce disease recurrence in prostate cancer patients receiving dose-escalated radiation therapy? An analysis of Radiation Therapy Oncology Group 94-06. Int J Radiat Oncol Biol Phys 2011;79:1323-9.

Process and Initial Experience of Remote Credentialing of 3D IGRT Data for Institutions Participating in RTOG Clinical Trials

To report the process and initial experience of a remote credentialing of 3D image-guided radiation therapy (IGRT) as part of quality assurance (QA) of submitted data by institutions participating in Radiation Therapy Oncology Group (RTOG) clinical trials. The following data sets were submitted through Image-Guided Therapy QA Center (ITC) from institutions for IGRT credentialing process as required by various RTOG trials: planning CT, plan, structures, positioning CT for one or a number of days, all in DICOM format. Daily shifts were also collected, along with descriptions of the imaging techniques. A centralized virtual environment is established at RTOG core laboratory containing analysis tools and database infrastructure for remote review by Physics Principal Investigators (Physics-PI). Appropriateness of IGRT technique (visibility of anatomical structures of interest) and volumetric image registration accuracy were evaluated. Registration accuracy was verified by repeat registration with a third party registration software and comparison with the institution's submitted data. With the accumulated review results, registration differences between those obtained by Physics-PI and from institutions were analyzed for different trial protocols (imaging sites), shift directions, and imaging modalities. This remote review process was successfully carried out for 87 3D cases (out of 137 total cases including 2D and 3D) during 2010. Differences of registration results between reviewers and institutions were 1.80 ± 1.06mm, 2.05 ± 1.05mm, 2.01 ± 0.93mm (mean ± SD; in left-right, superior-inferior, and anterior-posterior directions respectively) for lung cases; 0.69 ± 0.61mm, 2.89 ± 3.84mm, 0.40 ± 0.07mm for spine cases; and 1.52 ± 1.03mm, 2.51 ± 2.24mm, 1.45 ± 1.12mm for head and neck cases. The registration differences for kV CBCT cases were 1.73 ± 1.09mm, 1.59 ± 0.95mm, 1.74 ± 1.10mm, and for MVCT cases were 1.51 ± 0.98mm, 3.71 ± 1.67mm, 1.87 ± 0.86mm. Relatively large discrepancy in superior-inferior direction was found for MVCT cases due to the low spatial resolution (6mm slice spacing) in this direction for most MVCT cases. Major issues in repeating the registration included difficulty in reproducing initial patient setup position in some CBCT cases with pre-imaging couch shift and in some MVCT cases where the setup laser center was unknown. Additional information was requested from the institution if necessary and workarounds for these issues were developed. Preliminary review experience and clinical data indicated that remote review for 3D IGRT as part of QA for RTOG clinical trials is feasible and effective. Further improvements are expected to mature this remote evaluation process.

Reply to M.C. Chamberlain

regard to the safety of HA-WBRT, previous work by Gondi et al 4 evaluating 1,133 metastases in 371 patients revealed perihippocampal lesions in 8.6% of patients. Moreover, only 4.5% of patients who developed intracranial progression in Radiation Therapy Oncology Group trial RTOG 0933 progressed in the hippocampal-avoidance area. 2 Therefore, for the vast majority of patients undergoing WBRT, HA would be associated with a low risk of compromising intracranial disease control. Next, patients with a good performance status (Karnofsky performance status 70) and favorable long-term prognosis would likely benefit most from this technique and were specifically enrolled onto this trial. As a result of advancements in imaging techniques, better availability of and access to health care resources, and improvement in systemic therapies, we suspect that the proportions of these patients with favorable risk will continue to increase. Another concern raised addresses the role of HA-WBRT in the current era of stereotactic radiosurgery (SRS) given that focal therapies are quickly becoming the primary and adjuvant treatment of choice for patients with brain metastases. The updated National Cancer Center Network 2015 guidelines recommend either WBRT or SRS alone as primary treatment options for patients with multiple lesions ( 3 lesions). Despite the increasing adoption of primary SRS, randomized phase III trials have clearly demonstrated that the addition of WBRT improves local control and distant brain failure, minimizes the need for salvage therapies, and most importantly, decreases neurologic death. 5 Therefore, HA-WBRT may offer an attractive alternative treatment, especially in patients with a high probability of distant intracranial failure, with a reduced risk for neurocognitive deterioration. Over time, cooperative group trials in patients with brain metastases have transitioned from evaluating survival as the primary end point to focus on neurocognitive metrics. This was clearly fueled by additional analyses of the trials by Chang et al 6 and Kocher et al, 7 which demonstrated a decline in the Hopkin’s Verbal Learning TestRevised results and cognitive functioning, respectively, in patients who underwent WBRT. To compare their work with the previous research in this domain, Gondi et al 2 specifically evaluated a change in results measured by the Hopkin’s Verbal Learning Test-Revised as the primary end point for RTOG 0933. This decision was also supported by previous research by Li et al 8 who determined that memory function, unlike other neurocognitive domains, continued to decline after WBRT despite tumor shrinkage. Although a more complete battery of tests would be interesting to analyze, choosing the specific test that has been uniquely linked to neurocognitive deterioration after WBRT and used in previous studies has the advantage of being feasible and practical for study. Ultimately, the discovery of a reliable biomarker that correlates with neurocognitive functioning would allow survival to also be a recognized end point in future trials. In the current era of value-based care, cost-effectiveness studies are clearly needed when multiple treatment options exist. 9 In one of the few studies on this topic, Lal et al 10 used the economic data from the trial by Chang et al 6 to demonstrate the cost effectiveness and cost utility of primary SRS with observation when compared with SRS with WBRT. Although SRS with observation was associated with a higher cost, it was also associated with a higher effectiveness and cost effectiveness, even when considering additional salvage therapies, with a gain of cost per life-year well within the standards for other medical therapies. As more experience and economic data are generated in association with HA-WBRT, similar types of analyses will generate useful comparative data. In all, given the scrutiny on costs, future trials

Acute Esophagitis and Late Lung Toxicity in Concurrent Chemoradiotherapy Trials in Patients with Locally Advanced Non–Small-Cell Lung Cancer: Analysis of the Radiation Therapy Oncology Group (RTOG) Database

Background We analyzed time course and factors associated with acute esophagitis (ES) and late lung toxicity (PN), as well as any association between ES and PN in patients (pts) with non–small-cell lung cancer (NSCLC) treated with concurrent chemoradiation (chemo-RT) on the Radiation Therapy Oncology Group (RTOG) trials. Materials and Methods Multivariable analysis was used to investigate factors associated with ES or PN. Results Patients (n = 528) received standard fractionated (SFX; 63 Gy) or hyperfractionated (HFX; 69.6 Gy) radiation therapy (RT) with cisplatin-based chemotherapy. Grade > 2 ES developed in 75% of pts; Grade > 3 ES, in 34%. Nineteen percent of pts developed ES by the first, 32% by the second, and 33% by the third month (and for Grade > 3 PN, 9% by 6 months, 15% by year 1, and 18% by year 2). Any PN developed in 59% of pts; Grade > 2, in 39%; Grade > 3, in 18%; and lethal PN, in 2%. Grade > 2 PN was associated with increasing RT dose and Grade > 3 PN, with HFX RT. No association was seen with ES. Grade > 3 ES was less likely to occur in non-whites and more likely, in pts treated with HFX RT. Conclusion Most (95%) pts developed ES, and 33% had severe ES, peaking within the first or second month of RT. PN developed in 57% of pts, with 18% experiencing Grade > 3 PN, with most diagnosed by 1 year from RT. No relationship was observed between 1 toxicity (ES or PN) as predictor of the other. HFX RT was associated with more severe PN or ES.

Impact of Gender, Partner Status, and Race on Locoregional Failure and Overall Survival in Head and Neck Cancer Patients in Three Radiation Therapy Oncology Group Trials

We investigated the impact of race, in conjunction with gender and partner status, on locoregional control (LRC) and overall survival (OS) in three head and neck trials conducted by the Radiation Therapy Oncology Group (RTOG). Patients from RTOG studies 9003, 9111, and 9703 were included. Patients were stratified by treatment arms. Covariates of interest were partner status (partnered vs. non-partnered), race (white vs. non-white), and sex (female vs. male). Chi-square testing demonstrated homogeneity across treatment arms. Hazards ratio (HR) was used to estimate time to event outcome. Unadjusted and adjusted HRs were calculated for all covariates with associated 95% confidence intervals (CIs) and p values. A total of 1,736 patients were analyzed. Unpartnered males had inferior OS rates compared to partnered females (adjusted HR = 1.22, 95% CI, 1.09-1.36), partnered males (adjusted HR = 1.20, 95% CI, 1.09-1.28), and unpartnered females (adjusted HR = 1.20, 95% CI, 1.09-1.32). White females had superior OS compared with white males, non-white females, and non-white males. Non-white males had inferior OS compared to white males. Partnered whites had improved OS relative to partnered non-white, unpartnered white, and unpartnered non-white patients. Unpartnered males had inferior LRC compared to partnered males (adjusted HR = 1.26, 95% CI, 1.09-1.46) and unpartnered females (adjusted HR = 1.30, 95% CI, 1.05-1.62). White females had LRC superior to non-white males and females. White males had improved LRC compared to non-white males. Partnered whites had improved LRC compared to partnered and unpartnered non-white patients. Unpartnered whites had improved LRC compared to unpartnered non-whites. Race, gender, and partner status had impacts on both OS and locoregional failure, both singly and in combination.

Older Age Predicts Decreased Metastasis and Prostate Cancer-Specific Death for Men Treated With Radiation Therapy: Meta-Analysis of Radiation Therapy Oncology Group Trials

The impact of age on prostate cancer (PCa) outcome has been controversial; therefore, we analyzed the effect of age on overall survival (OS), distant metastasis, prostate cancer-specific death (PCSD), and nonprostate cancer death (NPCD) on patients with locally advanced PCa. Patients who participated in four Radiation Therapy Oncology Group (RTOG) phase III trials, 8531, 8610, 9202, and 9413, were studied. Cox proportional hazards regression was used for OS analysis, and cumulative events analysis with Fine and Gray's regression was used for analyses of metastasis, PCSD, and NPCD. Median follow-up of 4,128 patients with median age of 70 (range, 43-88 years) was 7.3 years. Most patients had high-risk disease: cT3 to cT4 (54%) and Gleason scores (GS) of 7 (45%) and 8 to 10 (27%). Older age (≤70 vs. >70 years) predicted for decreased OS (10-year rate, 55% vs. 41%, respectively; p<0.0001) and increased NPCD (10-year rate, 28% vs. 46%, respectively; p<0.0001) but decreased metastasis (10-year rate, 27% vs. 20%, respectively; p<0.0001) and PCSD (10-year rate, 18% vs. 14%, respectively; p<0.0001). To account for competing risks, outcomes were analyzed in 2-year intervals, and age-dependent differences in metastasis and PCSD persisted, even in the earliest time periods. When adjusted for other covariates, an age of >70 years remained associated with decreased OS (hazard ratio [HR], 1.56 [95% confidence interval [CI], 1.43-1.70] p<0.0001) but with decreased metastasis (HR, 0.72 [95% CI, 0.63-0.83] p<0.0001) and PCSD (HR, 0.78 [95% CI, 0.66-0.92] p<0.0001). Finally, the impact of the duration of androgen deprivation therapy as a function of age was evaluated. These data support less aggressive PCa in older men, independent of other clinical features. While the biological underpinning of this finding remains unknown, stratification by age in future trials appears to be warranted.

Phase III Trial of Prophylactic Cranial Irradiation Compared With Observation in Patients With Locally Advanced Non–Small-Cell Lung Cancer: Neurocognitive and Quality-of-Life Analysis

There are scant data regarding the effects of prophylactic cranial irradiation (PCI) on neurocognitive function (NCF) and quality of life (QOL). Radiation Therapy Oncology Group trial 0214 showed no overall survival (OS) benefit for PCI in stage III non-small-cell lung cancer (NSCLC) at 1 year. However, there was a significant decrease in brain metastases (BM). This analysis focuses on the impact of PCI on NCF and QOL. Patients with stage III NSCLC who completed definitive therapy without progression were randomly assigned to PCI or observation. NCF was assessed with Mini-Mental Status Examination (MMSE), Activities of Daily Living Scale (ADLS), and Hopkins Verbal Learning Test (HVLT). QOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) core tool (QOL Questionnaire-QLQC30) and brain module (QLQBN20). There were no statistically significant differences at 1 year between the two arms in any component of the EORTC-QLQC30 or QLQBN20 (P > .05), although a trend for greater decline in patient-reported cognitive functioning with PCI was noted. There were no significant differences in MMSE (P = .60) or ADLS (P = .88). However, for HVLT, there was greater decline in immediate recall (P = .03) and delayed recall (P = .008) in the PCI arm at 1 year. PCI in stage III NSCLC significantly decreases the risk of BM without improving 1-year OS. There were no significant differences in global cognitive function (MMSE) or QOL after PCI, but there was a significant decline in memory (HVLT) at 1 year. This study provides prospective data regarding the relative risks and benefits of PCI in this setting and the need to use sensitive cognitive assessments.

Multi-System Verification of Registrations for Image-Guided Radiotherapy in Clinical Trials

To provide quantitative information on the image registration differences from multiple systems for image-guided radiotherapy (IGRT) credentialing and margin reduction in clinical trials. Images and IGRT shift results from three different treatment systems (Tomotherapy Hi-Art, Elekta Synergy, Varian Trilogy) have been sent from various institutions to the Image-Guided Therapy QA Center (ITC) for evaluation for the Radiation Therapy Oncology Group (RTOG) trials. Nine patient datasets (five head-and-neck and four prostate) were included in the comparison, with each patient having 1-4 daily individual IGRT studies. In all cases, daily shifts were re-calculated by re-registration of the planning CT with the daily IGRT data using three independent software systems (MIMvista, FocalSim, VelocityAI). Automatic fusion was used in all calculations. The results were compared with those submitted from institutions. Similar regions of interest (ROIs) and same initial positions were used in registrations for inter-system comparison. Different slice spacings for CBCT sampling and different ROIs for registration were used in some cases to observe the variation of registration due to these factors. For the 54 comparisons with head-and-neck datasets, the absolute values of differences of the registration results between different systems were 2.6±2.1 mm (mean±SD; range 0.1-8.6 mm, left-right [LR]), 1.7±1.3 mm (0.0-4.9 mm, superior-inferior [SI]), and 1.8±1.1 mm (0.1-4.0 mm, anterior-posterior [AP]). For the 66 comparisons in prostate cases, the differences were 1.1±1.0 mm (0.0-4.6 mm, LR), 2.1±1.7 mm (0.0-6.6 mm, SI), and 2.0±1.8 mm (0.1-6.9 mm, AP). The differences caused by the slice spacing variation were relatively small, and the different ROI selections in FocalSim and MIMvista also had limited impact. The extent of differences was reported when different systems were used for image registration. Careful examination and quality assurance of the image registration process are crucial before considering margin reduction using IGRT in clinical trials.

Higher Biologically Effective Dose of Radiotherapy Is Associated With Improved Outcomes for Locally Advanced Non–Small Cell Lung Carcinoma Treated With Chemoradiation: An Analysis of the Radiation Therapy Oncology Group

Patients treated with chemoradiotherapy for locally advanced non-small-cell lung carcinoma (LA-NSCLC) were analyzed for local-regional failure (LRF) and overall survival (OS) with respect to radiotherapy dose intensity. This study combined data from seven Radiation Therapy Oncology Group (RTOG) trials in which chemoradiotherapy was used for LA-NSCLC: RTOG 88-08 (chemoradiation arm only), 90-15, 91-06, 92-04, 93-09 (nonoperative arm only), 94-10, and 98-01. The radiotherapeutic biologically effective dose (BED) received by each individual patient was calculated, as was the overall treatment time-adjusted BED (tBED) using standard formulae. Heterogeneity testing was done with chi-squared statistics, and weighted pooled hazard ratio estimates were used. Cox and Fine and Gray's proportional hazard models were used for OS and LRF, respectively, to test the associations between BED and tBED adjusted for other covariates. A total of 1,356 patients were analyzed for BED (1,348 for tBED). The 2-year and 5-year OS rates were 38% and 15%, respectively. The 2-year and 5-year LRF rates were 46% and 52%, respectively. The BED (and tBED) were highly significantly associated with both OS and LRF, with or without adjustment for other covariates on multivariate analysis (p < 0.0001). A 1-Gy BED increase in radiotherapy dose intensity was statistically significantly associated with approximately 4% relative improvement in survival; this is another way of expressing the finding that the pool-adjusted hazard ratio for survival as a function of BED was 0.96. Similarly, a 1-Gy tBED increase in radiotherapy dose intensity was statistically significantly associated with approximately 3% relative improvement in local-regional control; this is another way of expressing the finding that the pool-adjusted hazard ratio as a function of tBED was 0.97. Higher radiotherapy dose intensity is associated with improved local-regional control and survival in the setting of chemoradiotherapy.

Impact of Overall Treatment Time on Survival and Local Control in Patients With Anal Cancer: A Pooled Data Analysis of Radiation Therapy Oncology Group Trials 87-04 and 98-11

To determine whether increased duration of radiation therapy (RT) and overall treatment (RX) time has a detrimental effect in anal cancer. Data from Radiation Therapy Oncology Group (RTOG) 87-04 and RTOG 98-11 trials were combined to form three treatment groups: RT/fluorouracil (FU)/mitomycin (n = 472), RT/FU/cisplatin (n = 320), and RT/FU (n = 145). Cox proportional hazards models were used with the following variables: RT duration, RT intensity, RX duration, treatment group, age, sex, Karnofsky performance score (KPS), T stage, N stage, and RT dose. In the univariate analysis, there was a significant association between RX duration and colostomy failure (CF; hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.14; P = .02), local failure (HR = 1.52; 95% CI, 1.14 to 2.03; P = .005), locoregional failure (HR = 1.51; 95% CI, 1.15 to 1.98; P = .003), and time to failure (HR = 1.40; 95% CI, 1.10 to 1.79; P = .007). The significance of RX duration was maintained after adjusting for treatment group. In multivariate modeling there was a trend toward an association between RX duration and CF (HR = 1.57; 95% CI, 0.98 to 2.50; P = .06) and a statistically significant association with local failure (HR = 1.96; 95% CI, 1.34 to 2.87; P = .0006). Age, sex, KPS, T stage, N stage, and RT dose, but not RT duration, RT intensity, or RX duration, were found to be statistically significant predictors of OS and colostomy-free survival. Total treatment time, but not duration of radiation therapy, seems to have a detrimental effect on local failure and colostomy rate in anal cancer. Induction chemotherapy may contribute to local failure by increasing total treatment time.