Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.

BACKGROUND: We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer. METHODS: In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949. FINDINGS: Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001). INTERPRETATION: 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients. FUNDING: National Cancer Institute and Bristol-Myers Squibb.

ACR-ASTRO Practice Parameter for Image-guided Radiation Therapy (IGRT).

AIM/OBJECTIVES/BACKGROUND: The American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) have jointly developed the following practice parameter for image-guided radiation therapy (IGRT). IGRT is radiation therapy that employs imaging to maximize accuracy and precision throughout the entire process of treatment delivery with the goal of optimizing accuracy and reliability of radiation therapy to the target, while minimizing dose to normal tissues. METHODS: The ACR-ASTRO Practice Parameter for IGRT was revised according to the process described on the ACR website ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parametersand-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the ASTRO. Both societies then reviewed and approved the document. RESULTS: This practice parameter is developed to serve as a tool in the appropriate application of IGRT in the care of patients with conditions where radiation therapy is indicated. It addresses clinical implementation of IGRT including personnel qualifications, quality assurance standards, indications, and suggested documentation. CONCLUSIONS: This practice parameter is a tool to guide clinical use of IGRT and does not make recommendations on site-specific IGRT directives. It focuses on the best practices and principles to consider when using IGRT effectively, especially with the significant increase in imaging data that is now available with IGRT. The clinical benefit and medical necessity of the imaging modality and frequency of IGRT should be assessed for each patient.

Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer.

PURPOSE: RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC). METHODS: The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS). RESULTS: Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively (P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months (P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% (P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms. CONCLUSION: A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.

Correlation between real-time intraoperative and postoperative dosimetry and its implications on intraoperative planning.

PURPOSE: The purpose of this study was to study the correlation between intraoperative and postimplant dosimetry. We investigated the correlation between prostate (V150) and urethra (D30, D5) dose limits, and whether it is possible to increase prostate D90 and V100 in intraoperative planning without violating postimplant urethra and rectum dose limits. METHODS AND MATERIALS: Seventy-nine patients who underwent real-time ultrasound-guided prostate implants using intraoperative planning from 2013 to 2017 were analyzed. Forty-one of the 79 implants were 125I as monotherapy and the remainder was 103Pd as boost to external beam radiation therapy or external beam radiation therapy plus androgen deprivation therapy. Prescriptions followed the guidelines of AAPM TG-137. The urethra was catheterized during intraoperative implantation and postimplant imaging to facilitate the urethra identification. T2-cubed MRI and CT were acquired on the same day and about 1 month after the low-dose-rate procedure, and MRI was later fused with the CT scan for accurate delineation of the prostate and postimplant dosimetry evaluation. An institutionally based peer-review process and document procedure were established based on national recommendations. Correlation of dose parameters: D90, V150, V100 of prostate, D30, D5 of urethra, and V100 of rectum between intraoperative and postimplant plans were evaluated. RESULTS: D90 and V100 declined for all implants between intraoperative and postimplant dosimetry. On average, D90 declined by 17.5% and 21.7% for 125I and 103Pb implants, respectively. V100 declined for all implants between intraoperative and postimplant dosimetry but less pronounced. Prostate V150 and urethra D30 and D5 also showed different tendency of decline. Of the 79 implants, 60 did not meet the postimplant dosimetry target for prostate (V150 ≤ 50%), and 46 of the 60 implants met the optimal dosimetry targets for both D30 (<125%) and D5 (<150%), and the other 14 of the 60 implants failed to meet either the D30 or the D5 limits. All the implants met the postimplant target dose for rectum: V100≤ 1.3 cc. CONCLUSION: Intraoperative implant dosimetry could not accurately predict postimplant dosimetry; however, to avoid underdosage of prostate, intraoperative D90 should be close to 120% of prescribed dose and V100 needs to be close to 100% of prescribed dose. Prostate V150> 50% does not necessarily indicate the violation of urethra D30 and D5 dose limits. For most of the implants, target intraoperative D90 and V100 could be raised without violating urethra D30 and D5 limits recommended by American Brachytherapy Society in postimplant evaluation.

Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial.

Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.

Institutional Enrollment and Survival Among NSCLC Patients Receiving Chemoradiation: NRG Oncology Radiation Therapy Oncology Group (RTOG) 0617.

BACKGROUND: The purpose of this analysis is to evaluate the effect of institutional accrual volume on clinical outcomes among patients receiving chemoradiation for locally advanced non-small cell lung cancer (LA-NSCLC) on a phase III trial. METHODS: Patients with LA-NSCLC were randomly assigned to 60 Gy or 74 Gy radiotherapy (RT) with concurrent carboplatin/paclitaxel +/- cetuximab on NRG Oncology RTOG 0617. Participating institutions were categorized as low-volume centers (LVCs) or high-volume centers (HVCs) according to the number of patients accrued (≤3 vs > 3). All statistical tests were two-sided. RESULTS: Range of accrual for LVCs (n = 195) vs HVCs (n = 300) was 1 to 3 vs 4 to 18 patients. Baseline characteristics were similar between the two cohorts. Treatment at a HVC was associated with statistically significantly longer overall survival (OS) and progression-free survival (PFS) compared with treatment at a LVC (median OS = 26.2 vs 19.8 months; HR = 0.70, 95% CI = 0.56 to 0.88, P = .002; median PFS: 11.4 vs 9.7 months, HR = 0.80, 95% CI = 0.65-0.99, P = .04). Patients treated at HVCs were more often treated with intensity-modulated RT (54.0% vs 39.5%, P = .002), had a lower esophageal dose (mean = 26.1 vs 28.0 Gy, P = .03), and had a lower heart dose (median = V5 Gy 38.2% vs 54.1%, P = .006; V50 Gy 3.6% vs 7.3%, P < .001). Grade 5 adverse events (AEs) (5.3% vs 9.2%, P = .09) and RT termination because of AEs (1.3% vs 4.1%, P = .07) were less common among patients treated at HVCs. HVC remained independently associated with longer OS (P = .03) when accounting for other factors. CONCLUSION: Treatment at institutions with higher clinical trial accrual volume is associated with longer OS among patients with LA-NSCLC participating in a phase III trial.

Quality of Life Analysis of a Radiation Dose-Escalation Study of Patients With Non-Small-Cell Lung Cancer: A Secondary Analysis of the Radiation Therapy Oncology Group 0617 Randomized Clinical Trial.

IMPORTANCE: A recent randomized radiation dose-escalation trial in unresectable stage III non-small-cell lung cancer (NSCLC) (Radiation Therapy Oncology Group [RTOG] 0617) showed a lower survival rate in the high-dose radiation therapy (RT) arm (74 Gy) than in the low-dose arm (60 Gy) with concurrent chemotherapy. OBJECTIVE: The primary QOL hypothesis predicted a clinically meaningful decline in quality of life (QOL) via the Functional Assessment of Cancer Therapy (FACT)-Lung Cancer Subscale (LCS) in the high-dose RT arm at 3 months. DESIGN, SETTING, AND PATIENTS: The RTOG 0617 trial was a randomized phase 3 study (conducted from November 2007 to November 2011) in stage III NSCLC using a 2 × 2 factorial design and stratified by histology, positron emission tomography staging, performance status, and irradiation technique (3-dimensional conformal RT [3D-CRT] vs intensity-modulated RT [IMRT]). A total of 185 institutions in the United States and Canada took part. Of 424 eligible patients with stage III NSCLC randomized, 360 (85%) consented to QOL evaluation, of whom 313 (88%) completed baseline QOL assessments. INTERVENTION: Treatment with 74-Gy vs 60-Gy RT with concurrent and consolidation carboplatin/paclitaxel with or without cetuximab. MAIN OUTCOMES AND MEASURES: The QOL data were collected prospectively via FACT Trial Outcome Index (FACT-TOI), calculated as the sum of the following measures: Physical Well Being (PWB), Functional Well Being (FWB), and the LCS. Data are presented at baseline and 3 and 12 months via minimal clinically meaningful changes of 2 points or more for PWB, FWB, and LCS or 5 points or more for TOI. RESULTS: Of the 313 patients who completed baseline QOL assessments, 219 patients (70%) completed the 3-month QOL assessments, and 137 of the living patients (57%) completed the 12-month assessment. Patient demographics and baseline QOL scores were comparable between the 74-Gy and 60-Gy arms. Significantly more patients in the 74-Gy arm than in the 60-Gy arm had clinically meaningful decline in FACT-LCS at 3 months (45% vs 30%; P = .02). At 12 months, fewer patients who received IMRT (vs 3D-CRT) had clinically meaningful decline in FACT-LCS (21% vs 46%; P = .003). Baseline FACT-TOI was associated with overall survival in multivariate analysis. CONCLUSIONS AND RELEVANCE: Despite few differences in clinician-reported toxic effects between treatment arms, QOL analysis demonstrated a clinically meaningful decline in QOL in the 74-Gy arm at 3 months, confirming the primary QOL hypothesis. Baseline QOL was an independent prognostic factor for survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00533949.

Reduction of treatment breaks and radiation-induced esophagitis and pneumonitis using amifostine in unresectable non-small cell lung cancer patients receiving definitive concurrent chemotherapy and radiation therapy: a prospective community-based clinical trial.

Concurrent chemotherapy with daily thoracic radiation therapy is a common regimen used in patients with non-small cell lung cancer resulting in excellent response rates but with appreciable morbidity. Radiation-induced toxicities may increase the number of treatment breaks and then may limit the use of this aggressive treatment approach for some patients. We are conducting an open-label, multicenter trial determining the incidence of radiation treatment breaks and severity of treatment-related toxicities with the concurrent use of a cytoprotective agent. Approximately 15 to 20 sites in the United States will participate with a total of 200 patients. Patients will receive one of two chemotherapy regimens and daily radiation (1.8 to 2.0 Gy daily; total dose, 60 to 70 Gy) and amifostine 500 mg subcutaneously or intravenous push daily over a 6- to 7-week period. Patients will receive amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) 500 mg daily. The route of amifostine administration chosen at the time of patient registration must be adhered to throughout the study. In addition, all patients may receive consolidation chemotherapy consisting of intravenous docetaxel 75 mg/m 2 once every 3 weeks for three courses, starting more than 30 but less than 60 days after the last dose of amifostine or thoracic radiation therapy, whichever is the last therapy discontinued. The objectives of this study are to determine the incidence of radiation treatment breaks and evaluate acute radiation esophagitis, acute radiation pneumonitis, chronic radiation pneumonitis, and pulmonary function in patients with measurable, medically inoperable non-small cell lung cancer stage II, unresectable stage IIIA, or IIIB disease receiving combined modality therapy and amifostine.

Improving diversity, inclusion, and representation in radiology and radiation oncology part 2: challenges and recommendations.

The ACR Commission for Women and General Diversity is committed to identifying barriers to a diverse physician workforce in radiology and radiation oncology (RRO), and to offering policy recommendations to overcome these barriers. Part 2 of a 2-part position article from the commission addresses issues regarding diversity and inclusion in the context of career choices and professional advancement. Barriers to improving diversity and representation in RRO are reviewed. Discussion focuses on the development and implementation of concrete strategies designed to eliminate the current subspecialty disparity and highlights the need for the ACR to introduce programs and incentives with targeted and achievable goals with measurable outcomes. Recommendations are made aimed at fostering an environment of inclusion and diversity, so as to secure a successful future for all members of the RRO workforce. The future of radiology will be enhanced by increasing diversity and representation in the professional workforce, which will allow us to better address the varied needs of increasingly diverse patient populations, and to mitigate disparities in healthcare access, delivery, and outcomes. By leveraging diverse backgrounds, experiences, and skills of those in RRO, we will create new, effective ways to not only educate our trainees, medical colleagues, and patients but also improve delivery of health care and our service to society.

Improving diversity, inclusion, and representation in radiology and radiation oncology part 1: why these matter.

The ACR Commission for Women and General Diversity is committed to identifying barriers to a diverse physician workforce in radiology and radiation oncology (RRO), and to offering policy recommendations to overcome these barriers. In Part 1 of a 2-part position article from the commission, diversity as a concept and its dimensions of personality, character, ethnicity, biology, biography, and organization are introduced. Terms commonly used to describe diverse individuals and groups are reviewed. The history of diversity and inclusion in US society and health care are addressed. The post-Civil Rights Era evolution of diversity in medicine is delineated: Diversity 1.0, with basic awareness, nondiscrimination, and recruitment; Diversity 2.0, with appreciation of the value of diversity but inclusion as peripheral or in opposition to other goals; and Diversity 3.0, which integrates diversity and inclusion into core missions of organizations and their leadership, and leverages its potential for innovation and contribution. The current states of diversity and inclusion in RRO are reviewed in regard to gender, race, ethnicity, sexual orientation, and gender identity. The lack of representation and unchanged demographics in these fields relative to other medical specialties are explored. The business case for diversity is discussed, with examples of successful models and potential application to the health care industry in general and to RRO. The moral, ethical, and public health imperative for diversity is also highlighted.

Dose escalation of docetaxel concomitant with hypofractionated, once weekly chest radiotherapy for non-small-cell lung cancer: a phase I study.

Hypofractionated chest radiotherapy has been used as an alternative when standard fractionated schedules are neither practical nor feasible. To explore docetaxel as radiosensitizer in a hypofractionated chest irradiation schedule, a docetaxel dose escalation study was conducted in which 26 patients with advanced non-small-cell lung cancer (NSCLC) (stages III and IV) were enrolled. Docetaxel was administered 24 hours prior to irradiation (starting dose 10mg/m2; escalating in 5mg/m2 increments). Radiation was administered at 500 cGy (one fraction) once/wk for 10 consecutive weeks (5000 cGy total). The docetaxel dose was escalated up to 45 mg/m2/wk. The treatment was well tolerated over 10 consecutive weeks without requiring dose reductions or interruptions. Toxicities were mainly docetaxel related. One of 19 evaluable patients had a complete radiographic response within the radiation treatment port, 13 had a partial response, and 5 had stable disease. No patient recurred within the radiation field. Three patients who underwent surgical resection following treatment were pathologically down staged to stage I. This trial of a small group of patients supports, in selected patients, synchronous administration of effective hypofractionated, radiosensitized radiation therapy and optimized systemic chemotherapy.

Recombinant human erythropoietin as an adjunct to radiation therapy and cisplatin for stage IIB-IVA carcinoma of the cervix: a Southwest Oncology Group study.

OBJECTIVE: The survival of cervix cancer patients is associated with their hemoglobin (Hgb) level during radiotherapy. The Southwest Oncology Group (SWOG) conducted a phase II trial to determine whether recombinant human erythropoietin (rHuEPO) safely corrects anemia during chemoradiotherapy for cervix cancer. METHODS: Patients had stage IIB-IVA cervix cancer and a Hgb between 8.0 and 12.5 g/dl. All patients received rHuEPO thrice weekly and oral iron starting 10-15 days before their 5-week course of whole pelvic irradiation and weekly cisplatin followed by intracavitary brachytherapy. RESULTS: Fifty-three patients from 26 institutions received the protocol treatment. The mean Hgb was 10.4 +/- 1.3 g/dl on the first day of rHuEPO administration (baseline), 11.0 +/- 1.6 g/dl on the first day of chemoradiotherapy, 11.6 +/- 1.9 g/dl at the midpoint of chemoradiotherapy, and 11.8 +/- 2.2 g/dl at the end of chemoradiotherapy. The target Hgb level of 12.5 g/dl was achieved in 40% of patients (95% CI 26-56%) by the midpoint of Chemoradiotheraphy. Change in Hgb was associated with baseline serum iron (P = 0.008) and transferrin saturation (P = 0.05) levels, but not with baseline Hgb or serum ferritin, or patient age. Seven patients developed deep vein thrombosis. Two-year progression-free survival (PFS) was 43% and overall survival (OS) was 51%. Survival was significantly associated with Hgb level at the end of chemoradiotherapy, but not with the baseline Hgb level. CONCLUSIONS: rHuEPO and iron gradually increased Hgb levels in anemic women with local advanced cervix cancer during chemoradiotherapy. There was a higher than expected incidence of deep vein thrombosis. The progression-free and overall survival rates were lower than reported for women with normal Hgb levels.