Marital Status and Overall Survival in Patients with Resectable Pancreatic Cancer: Results of an Ancillary Analysis of NRG Oncology/RTOG 9704.

BACKGROUND: Several registry-based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population-based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial. MATERIALS AND METHODS: This is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97-04. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: Of 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease-free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients. CONCLUSION: Ancillary analysis of data from NRG Oncology/RTOG 97-04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216. IMPLICATIONS FOR PRACTICE: Several population-based studies have shown an epidemiological link between marital status and survival in patients with pancreatic cancer. A better understanding of this association could offer an opportunity to improve outcomes through psychosocial interventions designed to mitigate the negative effects of not being married. Based on the results of this analysis, patients who have undergone a resection and are receiving adjuvant therapy on a clinical trial are unlikely to benefit from such interventions. Further efforts to study the association between marital status and survival should be focused on less selected subgroups of patients with pancreatic cancer.

Post-treatment neutrophil-to-lymphocyte ratio predicts for overall survival in brain metastases treated with stereotactic radiosurgery.

INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR) is a surrogate for systemic inflammatory response and its elevation has been shown to be a poor prognostic factor in various malignancies. Stereotactic radiosurgery (SRS) can induce a leukocyte-predominant inflammatory response. This study investigates the prognostic impact of post-SRS NLR in patients with brain metastases (BM). METHODS: BM patients treated with SRS from 2003 to 2015 were retrospectively identified. NLR was calculated from the most recent full blood counts post-SRS. Overall survival (OS) and intracranial outcomes were calculated using the Kaplan-Meier method and cumulative incidence with competing risk for death, respectively. RESULTS: 188 patients with 328 BM treated with SRS had calculable post-treatment NLR values. Of these, 51 (27.1%) had a NLR > 6. The overall median imaging follow-up was 13.2 (14.0 vs. 8.7 for NLR ≤ 6.0 vs. > 6.0) months. Baseline patient and treatment characteristics were well balanced, except for lower rate of ECOG performance status 0 in the NLR > 6 cohort (33.3 vs. 44.2%, p = 0.026). NLR > 6 was associated with worse 1- and 2-year OS: 59.9 vs. 72.9% and 24.6 vs. 43.8%, (p = 0.028). On multivariable analysis, NLR > 6 (HR: 1.53; 95% CI 1.03-2.26, p = 0.036) and presence of extracranial metastases (HR: 1.90; 95% CI 1.30-2.78; p < 0.001) were significant predictors for worse OS. No association was seen with NLR and intracranial outcomes. CONCLUSION: Post-treatment NLR, a potential marker for post-SRS inflammatory response, is inversely associated with OS in patients with BM. If prospectively validated, NLR is a simple, systemic marker that can be easily used to guide subsequent management.

Angiotensin receptor blockade: a novel approach for symptomatic radiation necrosis after stereotactic radiosurgery.

Preclinical evidence suggests angiotensin blockade therapy (ABT) decreases late radiation toxicities. This study aims to investigate the association between ABT and symptomatic radiation necrosis (SRN) following stereotactic radiosurgery (SRS). Resected brain metastases (rBM) and arteriovenous malformation (AVM) patients treated with SRS from 2002 to 2015 were identified. Patients in the ABT cohort were on therapy during SRS and at 1-month follow up. Kaplan Meier method and cumulative incidence model were used to analyze overall survival (OS) and intracranial outcomes. 228 consecutive patients were treated with SRS: 111 with rBM and 117 with AVM. Overall, 51 (22.4%) patients were in the ABT group: 32 (28.8%) in the rBM and 19 (16.2%) in AVM cohorts. Baseline characteristics were similar, except for higher Graded Prognostic Analysis (3-4) in the rBM (ABT: 25.0% vs. non-ABT: 49.0%, p = 0.033) and median age in the AVM (ABT: 51.4 vs. non-ABT: 35.4, p < 0.001) cohorts. In both populations, OS and intracranial efficacy (rBM-local control; AVM-obliteration rates) were statistically similar between the cohorts. ABT was associated with lower 1-year SRN rates in both populations: rBM, 3.1 versus 25.3% (p = 0.003); AVM, 6.7 vs. 14.6% (p = 0.063). On multivariate analysis, ABT was a significant predictive factor for rBM (HR: 0.17; 95% CI 0.03-0.88, p = 0.035), but did not reach statistical significance for AVM (HR: 0.36; 95% CI 0.09-1.52, p = 0.165). ABT use appears to be associated with a reduced risk of SRN following SRS, without detriment to OS or intracranial efficacy. A prospective trial to validate these findings is warranted.

ACR Appropriateness Criteria® Borderline and Unresectable Pancreas Cancer.

The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature and voted on five variants to establish appropriate recommended treatment of borderline and unresectable pancreatic cancer. The guidelines reviewed the use of radiation, chemotherapy, and surgery. Radiation technique, dose, and targets were evaluated, as was the recommended chemotherapy, administered either alone or concurrently with radiation. This report will aid clinicians in determining guidelines for the optimal treatment of borderline and unresectable pancreatic cancer.

Retroperitoneal sarcoma (RPS) high risk gross tumor volume boost (HR GTV boost) contour delineation agreement among NRG sarcoma radiation and surgical oncologists.

PURPOSE: Curative intent management of retroperitoneal sarcoma (RPS) requires gross total resection. Preoperative radiotherapy (RT) often is used as an adjuvant to surgery, but recurrence rates remain high. To enhance RT efficacy with acceptable tolerance, there is interest in delivering "boost doses" of RT to high-risk areas of gross tumor volume (HR GTV) judged to be at risk for positive resection margins. We sought to evaluate variability in HR GTV boost target volume delineation among collaborating sarcoma radiation and surgical oncologist teams. METHODS: Radiation planning CT scans for three cases of RPS were distributed to seven paired radiation and surgical oncologist teams at six institutions. Teams contoured HR GTV boost volumes for each case. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. RESULTS: HRGTV boost volume contour agreement between the seven teams was "substantial" or "moderate" for all cases. Agreement was best on the torso wall posteriorly (abutting posterior chest abdominal wall) and medially (abutting ipsilateral para-vertebral space and great vessels). Contours varied more significantly abutting visceral organs due to differing surgical opinions regarding planned partial organ resection. CONCLUSIONS: Agreement of RPS HRGTV boost volumes between sarcoma radiation and surgical oncologist teams was substantial to moderate. Differences were most striking in regions abutting visceral organs, highlighting the importance of collaboration between the radiation and surgical oncologist for "individualized" target delineation on the basis of areas deemed at risk and planned resection.

Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial.

BACKGROUND: In the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer. METHODS: In this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m(2) on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m(2) twice daily on days 1-21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0-1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m(2) once per week) or capecitabine (830 mg/m(2) twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987. FINDINGS: 114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6-73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4-63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9-19·2) in the capecitabine group and 13·4 months (95% CI 11·0-15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18-0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1-89·5) in the capecitabine group and 64·2 (95% CI 46·4-77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2-14·6) in the capecitabine group and 10·4 months (95% CI 8·9-12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32-1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3-4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy. Of the 34 patients in the capecitabine group who received chemoradiotherapy, 25 (74%) received the full protocol dose of radiotherapy, compared with 26 (68%) of 38 patients in the gemcitabine group. Quality-of-life scores were not significantly different between the treatment groups. INTERPRETATION: Our results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer. However, these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small. FUNDING: Cancer Research UK.

Analysis of Radiation Therapy Quality Assurance in NRG Oncology RTOG 0848.

PURPOSE: NRG/Radiation Therapy Oncology Group 0848 is a 2-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiation therapy (RT) after adjuvant chemotherapy (second step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed on each patient who underwent RT. This analysis aims to evaluate adherence to protocol-specified contouring and treatment planning and to report the types and frequencies of deviations requiring revisions. METHODS AND MATERIALS: In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume through the creation of specific regions of interest. The planning target volume was a uniform 0.5 cm clinical treatment volume expansion. One of 2 radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and resubmitted until approved. Treatment started after final approval of the RT plan. RESULTS: From 2014 to 2018, 354 patients were enrolled in the second randomization. Of these, 160 patients received RT and were included in the QA analysis. Resubmissions were more common for patients planned with 3-dimensional conformal RT (43%) than with intensity modulated RT (31%). In total, at least 1 resubmission of the treatment plan was required for 33% of patients. Among patients requiring resubmission, most only needed 1 resubmission (87%). The most common reasons for resubmission were unacceptable deviations with respect to the preoperative gross target volume (60.7%) and the pancreaticojejunostomy (47.5%). CONCLUSION: One-third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on real-time, pretreatment QA in trials evaluating the use of RT, particularly for pancreas cancer. Rigorous QA is critically important for clinical trials involving RT to ensure that the true effect of RT is assessed. Moreover, RT QA serves as an educational process through providing feedback from specialists to practicing radiation oncologists on best practices.

Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study.

BACKGROUND: Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS: Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS: During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS: Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

A simplified technique for delivering total body irradiation (TBI) with improved dose homogeneity.

PURPOSE: Total body irradiation (TBI) with megavoltage photon beams has been accepted as an important component of management for a number of hematologic malignancies, generally as part of bone marrow conditioning regimens. The purpose of this paper is to present and discuss the authors' TBI technique, which both simplifies the treatment process and improves the treatment quality. METHODS: An AP/PA TBI treatment technique to produce uniform dose distributions using sequential collimator reductions during each fraction was implemented, and a sample calculation worksheet is presented. Using this methodology, the dosimetric characteristics of both 6 and 18 MV photon beams, including lung dose under cerrobend blocks was investigated. A method of estimating midplane lung doses based on measured entrance and exit doses was proposed, and the estimated results were compared with measurements. RESULTS: Whole body midplane dose uniformity of ±10% was achieved with no more than two collimator-based beam modulations. The proposed model predicted midplane lung doses 5% to 10% higher than the measured doses for 6 and 18 MV beams. The estimated total midplane doses were within ±5% of the prescribed midplane dose on average except for the lungs where the doses were 6% to 10% lower than the prescribed dose on average. CONCLUSIONS: The proposed TBI technique can achieve dose uniformity within ±10%. This technique is easy to implement and does not require complicated dosimetry and/or compensators.

A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation.

PURPOSE: Surgical resection provides the only possibility of cure for pancreas cancer. A standard adjuvant approach has not been established. We tested the safety and efficacy of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapy administered in patients with resected pancreatic adenocarcinoma. PATIENTS AND METHODS: A single institution phase II study of 60 patients with resected pancreatic adenocarcinoma was performed. Each immunotherapy treatment consisted of a total of 5 × 108 GM-CSF-secreting cells distributed equally among 3 lymph node regions. The first immunotherapy treatment was administered 8 to 10 weeks after surgical resection. Subsequently, patients received 5-FU based chemoradiation. Patients who remained disease-free after completion of chemoradiotherapy received treatments 2 to 4, each 1 month apart. A fifth and final booster was administered 6 months after the fourth immunotherapy. The primary endpoint was disease free survival and secondary endpoints were overall survival and toxicity, and the induction of mesothelin specific T cell responses. RESULTS: The median disease-free survival is 17.3 months (95% CI, 14.6-22.8) with median survival of 24.8 months (95% CI, 21.2-31.6). The administration of immunotherapy was well tolerated. In addition, the post-immunotherapy induction of mesothelin-specific CD8+ T cells in HLA-A1+ and HLA-A2+patients correlates with disease-free survival. CONCLUSIONS: An immunotherapy approach integrated with chemoradiation is safe and demonstrates an overall survival that compares favorably with published data for resected pancreas cancer. These data suggest additional boost immunotherapies given at regular intervals beyond 1 year postsurgery should be tested in future studies, and provide the rationale for conducting a multicenter phase II study.

Standardization of surgical and pathologic variables is needed in multicenter trials of adjuvant therapy for pancreatic cancer: results from the ACOSOG Z5031 trial.

BACKGROUND: Standardization of surgical and pathologic techniques is crucial to the interpretation of studies evaluating adjuvant therapies for pancreatic cancer (PC). METHODS: To assess the degree to which treatment administered prior to enrollment of patients in trials of adjuvant therapy is quality controlled, the operative and pathology reports of patients in American College of Surgeons Oncology Group (ACOSOG) Z5031-a national trial of chemoradiation following pancreaticoduodenectomy (PD)-were rigorously evaluated. We analyzed variables with the potential to influence staging or outcome. RESULTS: 80 patients reported to have undergone R0 (75%) or R1 (25%) pylorus-preserving (38%) or standard (62%) PD were evaluated. A search for metastases was documented in 96% of cases. The proximity of the tumor to the superior mesenteric vein was reported in 69%; vein resection was required in 9% and lateral venorrhaphy in 14%. The method of dissection along the superior mesenteric artery (SMA) was described in 68%, being ultrasonic dissection (17%), stapler (24%), and clamp and cut (59%). SMA skeletonization was described in 25%, and absence of disease following resection was documented in 24%. The surgeon reported marking the critical SMA margin in 25%; inking was documented in 65% of cases and evaluation of the SMA margin was reported in 47%. A range of 1-49 lymph nodes was evaluated. Only 34% of pathology reports met College of American Pathologists criteria. CONCLUSIONS: Trials of adjuvant therapy following PD suffer from a lack of standardization and quality control prior to patient enrollment. These data suggest areas for improvement in the design of multidisciplinary treatment protocols.

Impact of Diabetes and Insulin Use on Prognosis in Patients With Resected Pancreatic Cancer: An Ancillary Analysis of NRG Oncology RTOG 9704.

PURPOSE: Diabetes mellitus (DM) has been proposed to be tumorigenic; however, prior studies of the association between DM and survival are conflicting. The goal of this ancillary analysis of RTOG 9704, a randomized controlled trial of adjuvant chemotherapy in pancreatic cancer, was to determine the prognostic effects of DM and insulin use on survival. METHODS AND MATERIALS: Eligible patients from RTOG 9704 with available data on DM and insulin use were included. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and variable levels were compared using log-rank test. Cox proportional hazards models were created to assess the associations among DM, insulin use, and body mass index phenotypes on outcomes. RESULTS: Of 538 patients enrolled from 1998 to 2002, 238 patients were eligible with analyzable DM and insulin use data. Overall 34% of patients had DM and 66% did not. Of patients with DM, 64% had insulin-dependent DM, and 36% had non-insulin-dependent DM. On univariable analysis, neither DM nor insulin dependence were associated with OS or DFS (P > .05 for all). On multivariable analysis, neither DM, insulin use, nor body mass index were independently associated with OS or DFS. Nonwhite race (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.35-3.50; P = .0014), nodal involvement (HR, 1.74; 95% CI, 1.24-2.45; P = .0015), and carbohydrate antigen 19-9 (CA19-9) ≥90 U/mL (HR, 3.61; 95% CI, 2.32-5.63; P < .001) were associated with decreased OS. Nonwhite race (HR, 1.67; 95% CI, 1.05-2.63; P = .029) and CA19-9 ≥90 U/mL (HR, 2.86; 95% CI, 1.85-4.40; P < .001) were associated with decreased DFS. CONCLUSIONS: DM and insulin use were not associated with OS or DFS in patients with pancreatic cancer in this study. Race, nodal involvement, and increased CA19-9 were significant predictors of outcomes. These data might apply to the more modern use of neoadjuvant therapies for potentially resectable pancreatic cancer.

Final report from Intergroup NCCTG 86-72-51 (Alliance): a phase III randomized clinical trial of high-dose versus low-dose radiation for adult low-grade glioma.

BACKGROUND: The optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma. METHODS: Between 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. RESULTS: For all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2-10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3-6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter <5 cm and baseline Mini-Mental State Examination (MMSE) >27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter <5 cm, patients who had gross total resection, and patients with baseline MMSE >27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. CONCLUSIONS: Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.

Results of the NRG Oncology/RTOG 0848 Adjuvant Chemotherapy Question-Erlotinib+Gemcitabine for Resected Cancer of the Pancreatic Head: A Phase II Randomized Clinical Trial.

PURPOSE: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. METHODS: Eligibility-within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm-6 cycles of gemcitabine. Gemcitabine+erlotinib arm-gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2. RESULTS: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, (P=0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P=0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). CONCLUSIONS: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.

Application of holographic display in radiotherapy treatment planning II: a multi-institutional study.

We hypothesized that use of a true 3D display providing easy visualization of patient anatomy and dose distribution would lead to the production of better quality radiation therapy treatment plans. We report on a randomized prospective multi-institutional study to evaluate a novel 3D display for treatment planning.The Perspecta Spatial 3D System produces 360 degrees holograms by projecting crosssectional images on a diffuser screen rotating at 900 rpm. Specially-developed software allows bi-directional transfer of image and dose data between Perspecta and the Pinnacle planning system.Thirty-three patients previously treated at three institutions were included in this IRB-approved study. Patient data were de-identified, randomized, and assigned to different planners. A physician at each institution reviewed the cases and established planning objectives. Two treatment plans were then produced for each patient, one based on the Pinnacle system alone and another in conjunction with Perspecta. Plan quality was then evaluated by the same physicians who established the planning objectives. All plans were viewable on both Perspecta and Pinnacle for review. Reviewing physicians were blinded to the planning device used. Data from a 13-patient pilot study were also included in the analysis.Perspecta plans were considered better in 28 patients (61%), Pinnacle in 14 patients (30%), and both were equivalent in 4 patients. The use of non-coplanar beams was more common with Perspecta plans (82% vs. 27%). The mean target dose differed by less than 2% between rival plans. Perspecta plans were somewhat more likely to have the hot spot located inside the target (43% vs. 33%). Conversely, 30% of the Pinnacle plans had the hot spot outside the target compared with 18% for Perspecta plans. About 57% of normal organs received less dose from Perspecta plans. No statistically significant association was found between plan preference and planning institution or planner.The study found that use of the holographic display leads to radiotherapy plans preferred in a majority of cases over those developed with 2D displays. These data indicate that continued development of this technology for clinical implementation is warranted.

Neoadjuvant Interdigitated Chemoradiotherapy Using Mesna, Doxorubicin, and Ifosfamide for Large, High-grade, Soft Tissue Sarcomas of the Extremity: Improved Efficacy and Reduced Toxicity.

OBJECTIVES: Patients with large, high-grade extremity soft tissue sarcoma (STS) are at high risk for both local and distant recurrence. RTOG 95-14, using a regimen of neoadjuvant interdigitated chemoradiotherapy with mesna, doxorubicin, ifosfamide, and dacarbazine followed by surgery and 3 cycles of adjuvant mesna, doxorubicin, ifosfamide, and dacarbazine, demonstrated high rates of disease control at the cost of significant toxicity (83% grade 4, 5% grade 5). As such, this regimen has not been widely adopted. Herein, we report our institutional outcomes utilizing a modified interdigitated chemoradiotherapy regimen, without dacarbazine, and current radiotherapy planning and delivery techniques for high-risk STS. MATERIALS AND METHODS: Adults with large (≥5 cm; median, 12.9 cm), grade 3 extremity STS who were prospectively treated as part of our institutional standard of care from 2008 to 2016 are included. Neoadjuvant chemoradiotherapy consisted of 3 cycles of mesna, doxorubicin, and ifosfamide (MAI) and 44 Gy (22 Gy in 11 fractions between cycles of MAI) after which patients underwent surgical resection and received 3 additional cycles of MAI. RESULTS: Twenty-six patients received the MAI treatment protocol. At a median follow-up of 47.3 months, 23 (88.5%) patients are still alive. Three year locoregional recurrence-free survival, disease-free survival, and overall survival are 95.0%, 64.0%, and 95.0%, respectively. There have been no therapy-related deaths or secondary malignancies. The nonhematologic grade 4 toxicity rate was 7.7%. CONCLUSIONS: Neoadjuvant interdigitated MAI radiotherapy followed by resection and 3 cycles of adjuvant MAI has resulted in acceptable and manageable toxicity and highly favorable survival in patients at greatest risk for treatment failure.

The Impact of Graduates' Job Preferences on the Current Radiation Oncology Job Market.

PURPOSE: To examine the role of radiation oncology (RO) graduates' application patterns and personal preferences in current labor concerns. METHODS AND MATERIALS: An anonymous, voluntary survey was distributed to 665 domestic RO graduates from 2013 to 2017. Questions assessed graduates' regional (Northeast [NE]; Midwest [MW]; South [SO]; West [WT]) job type and population size preferences. Top regional choice was compared across other categorical and numerical variables using the χ2 test and analysis of variance, respectively. RESULTS: Complete responses were obtained from 299 (45.0% response rate) participants: 82 (27.4%), 74 (24.7%), 85 (28.4%), and 58 (19.4%) graduated from NE, MW, SO, and WT programs. The most to least commonly applied regions were SO (69.2%), MW (55.9%), and then NE/WT (55.2% each). The first and last regional choices were the WT (29.4%) and MW (15.7%), respectively. The most and least common application and top choice preferences were consistent in terms of city size: >500,000 (86.0% and 64.5%, respectively) and <100,001 (26.1% and 7.0%, respectively). The majority of applicants applied to both academic and nonacademic positions (60.9%), with top job type choice being equally split. The majority of respondents independently received a job offer in their preferred region (75.3%), city population size (72.6%) or job type (81.9%). Additionally, 52.5% received a job offer that included all three preferences. Those who underwent residency training (44.3% vs 62.0%-83.6%, P < .001) or medical schooling (50.7% vs 56.3%-75.6%, P < .001) or grew up in the MW (60.8% vs 70.0%-74.7%, P < .001) were least likely to choose this region as their top regional choice compared with other regions. CONCLUSIONS: The MW and jobs in smaller cities are less appealing to RO graduates, even if they receive training in the MW, which may contribute to current job market concerns. Nonetheless, the majority of respondents received a job offer in the region, population size, and job type of their top choice. Assessing prospective candidates' city size and geographic preferences and prioritizing applicants who are compatible with positions may help address potential job market discrepancies.

Management of a patient with borderline resectable pancreatic cancer. Case report and review.

The definition and management of borderline resectability for periampullary pancreatic adenocarcinoma are evolving. In this case report, we discuss the presentation, workup, and therapeutic management of a 40-year-old man who presented with borderline resectable, periampullary pancreatic cancer and underwent a margin-negative resection following neoadjuvant chemoradiotherapy.

Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial.

CONTEXT: Among patients with locally advanced metastatic pancreatic adenocarcinoma, gemcitabine has been shown to improve outcomes compared with fluorouracil. OBJECTIVE: To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18, 2006, at 164 US and Canadian institutions. INTERVENTION: Chemotherapy with either fluorouracil (continuous infusion of 250 mg/m2 per day; n = 230) or gemcitabine (30-minute infusion of 1000 mg/m2 once per week; n = 221) for 3 weeks prior to chemoradiation therapy and for 12 weeks after chemoradiation therapy. Chemoradiation with a continuous infusion of fluorouracil (250 mg/m2 per day) was the same for all patients (50.4 Gy). MAIN OUTCOME MEASURES: Survival for all patients and survival for patients with pancreatic head tumors were the primary end points. Secondary end points included toxicity. RESULTS: A total of 451 patients were randomized, eligible, and analyzable. Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65-1.03]; P = .09). The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63-1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P < .001) without a difference in febrile neutropenia or infection. There were no differences in the ability to complete chemotherapy or radiation therapy (>85%). CONCLUSIONS: The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003216.

Long-term analysis of 2 prospective studies that incorporate mitomycin C into an adjuvant chemoradiation regimen for pancreatic and periampullary cancers.

PURPOSE: The purpose of this study was to report toxicity and long-term survival outcomes of 2 prospective trials evaluating mitomycin C (MMC) with 5-fluorouracil-based adjuvant chemoradiation in resected periampullary adenocarcinoma. METHODS AND MATERIALS: From 1996 to 2002, 119 patients received an adjuvant 4-drug chemotherapy regimen of 5-fluorouracil, leucovorin, MMC, and dipyridamole with chemoradiation on 2 consecutive trials (trials A and B). Trial A patients received upfront chemoradiation (50 Gy split-course, 2.5 Gy/fraction) followed by 4 cycles of the 4-drug chemotherapy with bolus 5-fluorouracil. Trial B patients received 1 cycle of the 4-drug chemotherapy with continuous infusion 5-fluorouracil followed by continuous chemoradiation (45-54 Gy, 1.8 Gy/fraction) and 2 additional cycles of chemotherapy. Cox proportional hazards models were performed to identify prognostic factors for overall survival (OS). RESULTS: Of the 62 trial A patients, 61% had pancreatic and 39% nonpancreatic periampullary carcinomas. Trial B (n = 57) consisted of 68% pancreatic and 32% nonpancreatic periampullary carcinomas. Resection margin and lymph node status were similar for both trials. Median follow-up was longer for trial A than trial B (197.5 vs 107.0 months), with median OS of 32.2 and 24.2 months, respectively. Rates of 3-, 5-, and 10-year OS were 48%, 31%, and 26% in trial A and 32%, 23%, and 9% in trial B. On multivariate analysis, lymph node-positive resection was the strongest prognostic factor for OS. A pancreatic primary and positive margin status were also associated with inferior survival (P < .05). Rates of grade ≥3 treatment-related toxicity in trials A and B were 2% and 7%, respectively. CONCLUSIONS: This is the first study to report long-term outcomes of MMC with 5-fluorouracil-based adjuvant chemoradiation in periampullary cancers. Because MMC may be considered in DNA repair-deficient carcinomas, randomized trials are needed to determine the true benefit of adjuvant MMC.