Christopher Koprowski

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.

Multicenter Phase Ib/II Trial of the Radiation Enhancer Motexafin Gadolinium in Patients With Brain Metastases

PURPOSE Motexafin gadolinium is a magnetic resonance imaging (MRI)--detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival. PATIENTS AND METHODS Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range. RESULTS In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadoliniums tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%. CONCLUSION Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.

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.

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.

Partial vs. whole breast irradiation in a community hospital: A retrospective cohort analysis of 200 patients

PURPOSE We compared patients undergoing partial breast irradiation (PBI) with the MammoSite applicator (Cytyc Corp., Marlborough, MA) to a similar group of patients who underwent whole breast irradiation with external beam radiotherapy. METHODS AND MATERIALS Stage 0-IIA breast cancer patients satisfying American Brachytherapy Society selection criteria and receiving accelerated PBI with the MammoSite system (n=100) were compared for toxicities with similarly staged patients receiving whole breast irradiation using tangential portals (n=100). The MammoSite applicator treatment was prescribed to a total dose of 34 Gy. External beam doses generally ranged from 60 to 66 Gy. RESULTS Based on common toxicity criteria scores for acute toxicities, MammoSite patients experienced less cutaneous toxicity, fatigue, and breast pain and had higher Karnofsky performance status scores during the acute period than external beam patients but experienced more seroma pain during followup. These results were both statistically significant and clinically meaningful. CONCLUSIONS In our institutional experience, PBI using the MammoSite applicator produces less acute toxicity than external beam radiotherapy of the whole breast but is associated with an increased incidence of seroma pain. The rate of disease recurrence in both cohorts was low.

SU‐F‐J‐35: Moving Towards Isocentric Prone Breast Setup with Contralateral Leveling Tattoo and Couch Move Assistant (CMA)

PURPOSE Large setup variability has been observed for prone breast patients due to rotation error. To reduce this uncertainty, we propose a novel implementation of isocentric prone breast method on Elekta linac with couch move assistant (CMA) and on-line KV CBCT. METHODS Daily CBCT is used to evaluate the prone breast patient positioning uncertainty of proposed isocentric technique against our routine manual clinical setup. Clinical setup involves a manual AP shift from the ipsilateral torso tattoos (2PT) to the treatment iso directly underneath and SSD and flash check. While the proposed isocentric prone breast method features an additional contralateral leveling tattoo positioned at mid-level of torso during CT simulation to determine correct patient obliqueness, and an automatic couch shift using Elekta CMA to correct both known distance from 2PT to the iso and daily setup uncertainty. Summary statistics were calculated for a cohort of prone breast patients from our clinic (n=5), and will be updated as more patients get administrated. RESULTS Small field of view partial CBCT acquisition is optimized to achieve clearance and minimize nominal imaging dose to 0.6cGy per scan to a 16cm phantom. Routine clinical setup uncertainty is 0.3±0.2cm, 0.7±0.4cm and 0.4±0.3cm in S/I, L/R and A/P respectively. Using the isocentric prone breast method, the setup uncertainty could be reduced to 0±0.3cm, 0.3±0.4cm and 0.1±0.3cm if the average couch shift in the 1st week of treatment is applied by CMA to the rest of treatment days. The uncertainty could be further reduced to 0.3±0.1cm, 0±0.1cm and 0±0.2cm with additional contralateral leveling tattoo. The improvement in precision is found to be statistically significant (p<0.05) using unpaired student t-tests. CONCLUSION Contralateral leveling tattoo is essential to determine correct patient obliqueness. More consistent and accurate isocentric prone breast patient positioning is achievable on Elekta linac with CMA and CBCT.

SU‐D‐19A‐07: Dosimetric Comparison of HDR Plesiotherapy and Electron Beam Therapy for Superficial Lesions

PURPOSE Large superficial (skin, soft tissue sarcoma) lesions located on curved areas are hard to treat with electrons. The Freiburg Flap (Nucletron, Netherlands) is a flexible mesh style surface which can be easily shaped to fit curved surfaces for reproducible HDR fraction delivery. To understand the fundamental dosimetric differences, a dosimetric comparison was made between HDR plesiotherapy (Freiburg applicator for lesions over 4cm) and external electron beam radiotherapy over cases with varying target curvature (both stylized and clinical cases). METHODS Four stylized cases with variable complexity were created using artificial DICOM axial CT slices and RT structures (a square and three curved structures on a 4.5cm radius cylinder). They were planned using Oncentra v4.3 and exported to Pinnacle v9.6 for electrons planning. The HDR source dwell positions were optimized for the best coverage of the targets using graphical optimization. Electron treatment plans were created in Pinnacle using the same CT and RT structures of three HDR cases with surface lesions previously treated with the Freiburg flap. The En face electron plans used 6-12 MeV electrons and 0.5-1 cm bolus was added to increase surface dose. The electron plans were prescribed to an isodose line to conform to the target. RESULTS For all lesions, the average target dose coverage was similar (D90ave of 100% for HDR vs 101% for electrons). For lesions with high curvature, the HDR coverage was better (D90 102% vs D90 97% for electron). For all cases, adjacent structures high dose region was lower for HDR than electrons (D1cc 100% for HDR vs D1cc 111% for electrons). CONCLUSION HDR plesiotherapy offers excellent target conformity for superficial targets similar to electrons. However, for lesions with complex curved surfaces, HDR has the advantage to achieve better dose distributions using graphical optimization to spare adjacent normal tissue while maximizing target coverage.