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Supplementary figure S1: IL-10, IL-1RA and Eotaxin plasma concentration in patients pre- vs. post-treatment with Cetuximab plus motolimod. Supplementary table S1: 95% confidence interval for figure 5 comparing pre vs post treatment expression changes of TIGIT, PD-1, CTLA-4 and CD27.

Purpose: The response rate of patients with head and neck squamous cell carcinoma (HNSCC) to cetuximab therapy is only 15% to 20%, despite frequent EGFR overexpression. Because immunosuppression is common in HNSCC, we hypothesized that adding a proinflammatory TLR8 agonist to cetuximab therapy might result in enhanced T-lymphocyte stimulation and anti–EGFR-specific priming.Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3 to 4 weekly doses of motolimod (2.5 mg/m2) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells.Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed myeloid-derived suppressor cell (MDSC) suppression of T-cell proliferation in vitro. These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in tumor-infiltrating lymphocytes. Motolimod plus cetuximab also decreased induction of Treg and reduced markers of suppression, including CTLA-4, CD73, and membrane-bound TGFβ. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8+ T-cell infiltration into tumors. These T cells manifested increased T-cell receptor (TCR) clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT.Conclusions: Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC. Clin Cancer Res; 24(1); 62–72. ©2017 AACR.

Supplementary figure S1 & supplementary table S1 legends

PURPOSE: Stereotactic body radiation therapy (SBRT) has emerged as a viable reirradiation strategy for locally recurrent previously-irradiated head and neck cancer. Doses in the literature have varied, which challenges clinical application of SBRT as well as clinical trial design. MATERIAL & METHODS: A working group was formed through the American Association of Physicists in Medicine to study tumor control probabilities for SBRT in head and neck cancer. We herein present a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally recurrent previously-irradiated head and neck cancer. Dose-response models are generated that present tumor control probability as a function of dose. RESULTS: Data from more than 300 cases in 8 publications suggest that there is a dose-response relationship, with superior local control and possibly improved overall survival for doses of 35 to 45 Gy (in 5 fractions) compared with

Purpose: Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4–positive (CTLA-4+) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti–CTLA-4 mAb, to cetuximab-radiotherapy. Patients and Methods: A (3 + 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus–negative (HPV−)] or intermediate-risk HPV-positive (HPV+)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. Results: From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N = 12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57–92] and 72% (90% CI, 56–92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83–37.8; P = 0.08). Conclusions: The RP2D for ipilimumab plus standard cetuximab–radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.

Purpose There is no consensus on treatment volumes for adjuvant stereotactic body radiation therapy (SBRT) for pancreatic cancer. Herein, we report patterns of failure after pancreatic SBRT for close/positive margins, which may inform target volume design. Methods and Materials An institutional review board-approved retrospective review of patients with pancreatic adenocarcinoma treated with adjuvant SBRT for close/positive margins from 2009 to 2018 was conducted. Patterns of failure were defined as local (LF) within the tumor bed, regional (RF) within lymph nodes or anastomoses, or distant (DF). The cumulative incidence of locoregional failure was calculated using the cumulative incidence function accounting for the competing risk of death. LFs were mapped to the planning target volume (PTV) and classified as in-field (completely within the PTV), marginal (partially within the PTV), or out-of-field (completely outside the PTV). The location of LFs was compared with the Radiation Therapy Oncology Group 0848 contouring atlas to determine whether standard postoperative radiation therapy volumes would have included the LF. Results Seventy-six patients were treated with adjuvant SBRT for close (51.3%) or positive (48.7%) margins. Most (81.6%) received 36 Gy in 3 fractions, with a median PTV volume of 17.8 cc (interquartile range, 12.1-25.6). With a median follow-up of 17.0 months (interquartile range, 7.3-28.4), crude rates of first isolated LF, isolated RF, and DF +/– LF or RF were 9.2%, 6.6%, and 56.6%, respectively. Two-year cumulative incidences of LF, RF, locoregional failure, and DF were 34.9%, 30.8%, 49.2%, and 60.4%, respectively. Of 28 reviewable LFs, 21.4% were in-field while the remainder were completely outside (60.7%) or partially outside (17.9%) the PTV. Most LFs (92.9%) would have been encompassed by the Radiation Therapy Oncology Group consensus target volumes. Conclusions After adjuvant pancreatic SBRT for close/positive margins, the majority of LFs were outside the PTV but within contemporary target volumes for conventional radiation therapy.

BACKGROUND AND PURPOSE: The Neck Imaging Reporting and Data System is a standardized reporting system intended to risk stratify patients treated for head and neck squamous cell carcinoma. The purpose of this study is to investigate the positive predictive value of the Neck Imaging Reporting and Data System categories 3 and 4 on posttreatment PET/CT in patients treated definitively for head and neck squamous cell carcinoma. MATERIALS AND METHODS: We retrospectively identified patients treated definitively for head and neck squamous cell carcinoma between 2006 and 2018. Patients whose posttreatment PET/CT scans were interpreted as Neck Imaging Reporting and Data System 3 (suspicious) or 4 (definitive recurrence) at the primary site, regional nodes, or at distant sites were included. The reference standard was histopathology or unequivocal imaging or clinical evidence of treatment failure. The positive predictive values of Neck Imaging Reporting and Data System 3 and 4 posttreatment PET/CT were calculated. RESULTS: Seventy-two of 128 patients with posttreatment PET/CT interpreted as Neck Imaging Reporting and Data System 3 at the primary site, regional nodes, or distant sites were proved to have treatment failure at the suspicious sites, yielding an overall positive predictive value of 56% (95% CI, 48%–65%). The positive predictive values of Neck Imaging Reporting and Data System 3 by subsite were as follows: primary site, 56% (44/79); regional nodes, 65% (34/52); and distant sites, 79% (42/53). All 69 patients with posttreatment PET/CT interpreted as Neck Imaging Reporting and Data System 4 had true treatment failure, yielding a positive predictive value of 100% (95% CI, 96%–100%): primary site, 100% (28/28); regional nodes, 100% (32/32); and distant sites, 100% (29/29). CONCLUSIONS: The positive predictive value of Neck Imaging Reporting and Data System 3 on posttreatment PET/CT is relatively low. Thus, Neck Imaging Reporting and Data System 3 findings should be confirmed with tissue sampling before instituting new salvage treatment regimens to avoid unnecessary overtreatment and its associated toxicities. Neck Imaging Reporting and Data System 4 reliably indicates recurrent disease.

We evaluated daily setup reproducibility of deep inspiration breath hold (DIBH) using mega voltage (MV) imaging for left breast cancer radiation therapy. Analysis of 109 left breast cancer patients across UPMC Hillman Cancer Center network treated using DIBH technique with daily MV imaging was done. Patient characteristics, MV imaging procedure used and inter-fraction directional shifts were collected. For the statistical analyses, we separated all patients into 2 groups in each of the following 3 categories; (1) obese (BMI ≥ 30) vs nonobese, (2) mastectomy vs lumpectomy, (3) internal mammary node (IMN) treatment vs no IMN treatment. The group mean inter-fraction directional shifts were as following: (1) 0.7 mm (superior), 0.8 mm (inferior); (2) 0.65 mm (left), 0.64 mm (right); (3) 0.89 mm (anterior), 0.83 mm (posterior). Also, any directional shift ≥ 2 mm, ≥ 3 mm, ≥ 4 mm, ≥ 5 mm, ≥ 10 mm was found to be 52.9%, 37.6%, 30.9%, 21.9%, 3.7% of total fractions, respectively. In the stratified analysis, obese patients had larger directional shifts (p0.05) and highly associated with number of fractions for ≥ 5 mm in any directional shift compared to nonobese patients (29% vs 17%; p = 0.04). DIBH setup for left breast cancer treatment at our large cancer center network was reproducible with any mean directional shifts less than 1.0 mm using MV imaging. Daily imaging would be more beneficial for obese patients compared to nonobese patients.

Purpose To determine the feasibility of stereotactic body radiation therapy (SBRT) for isolated nodal recurrences of gynecologic malignancies within a previously irradiated area. Methods and Materials A retrospective review was performed on 20 patients who underwent 21 curative-intent reirradiation SBRT treatments for locoregional recurrences of gynecologic malignancies. Disease control and survival outcomes were analyzed with the Kaplan-Meier method and log-rank test. Treatment toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.03. Results All patients had an isolated pelvic, paraortic, or intra-abdominal nodal recurrence, with the exception of 1 patient who had a concurrent paraortic and right acetabulum metastasis, both of which were irradiated with SBRT. Primary sites included cervix (30.0%), uterus (55.0%), vulva (5.0%), vagina (5.0%), and ovary (5.0%). Median prior external beam radiation therapy dose was 45 Gy. Recurrences were in field in 14 (66.7%) and marginal in 7 (33.3%). SBRT was directed to the pelvis in 13 cases (61.9%) and to paraortic or celiac nodes in 8 (38.1%). The most common SBRT regimen was 40 to 45 Gy in 5 fractions (n = 12). At a median follow-up of 31.2 months, 3-year actuarial in-field local control, distant progression-free survival, and overall survival were 61.4%, 44.0%, and 51.9%, respectively. At the time of last follow-up, 9 (45.0%) patients remained alive without evidence of disease. Actuarial 3-year risk of grade ≥2 and grade ≥3 late toxicities was 38.1% and 14.3%, respectively. Conclusions SBRT for isolated pelvic or intra-abdominal recurrences of gynecologic malignancies within a previously irradiated field is feasible with an acceptable toxicity rate. With this approach, about half of patients achieved durable disease-free survival.

Purpose Varian Halcyon linear accelerator version 2 (The Halcyon 2.0) was recently released with new upgraded features. The aim of this study was to report our clinical experience with Halcyon 2.0 for a dual‐isocenter intensity‐modulated radiation therapy (IMRT) planning and delivery for gynecological cancer patients and examine the feasibility of in vivo portal dosimetry. Methods Twelve gynecological cancer patients were treated with extended‐field IMRT technique using two isocenters on Halcyon 2.0 to treat pelvis and pelvic/or para‐aortic nodes region. The prescription dose was 45 Gy in 25 fractions (fxs) with simultaneous integrated boost (SIB) dose of 55 or 57.5 Gy in 25 fxs to involved nodes. All treatment plans, pretreatment patient‐specific QA and treatment delivery records including daily in vivo portal dosimetry were retrospectively reviewed. For in vivo daily portal dosimetry analysis, each fraction was compared to the reference baseline (1st fraction) using gamma analysis criteria of 4 %/4 mm with 90% of total pixels in the portal image planar dose. Results All 12 extended‐field IMRT plans met the planning criteria and delivered as planned (a total of 300 fractions). Conformity Index (CI) for the primary target was achieved with the range of 0.99–1.14. For organs at risks, most were well within the dose volume criteria. Treatment delivery time was from 5.0 to 6.5 min. Interfractional in vivo dose variation exceeded gamma analysis threshold for 8 fractions out of total 300 (2.7%). These eight fractions were found to have a relatively large difference in small bowel filling and SSD change at the isocenter compared to the baseline. Conclusion Halcyon 2.0 is effective to create complex extended‐field IMRT plans using two isocenters with efficient delivery. Also Halcyon in vivo dosimetry is feasible for daily treatment monitoring for organ motion, internal or external anatomy, and body weight which could further lead to adaptive radiation therapy.

Purpose The purpose of this study was to study the correlation between intraoperative and postimplant dosimetry. We investigated the correlation between prostate ( V 150 ) and urethra ( D 30 , D 5 ) dose limits, and whether it is possible to increase prostate D 90 and V 100 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 125 I as monotherapy and the remainder was 103 Pd 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: D 90 , V 150 , V 100 of prostate, D 30 , D 5 of urethra, and V 100 of rectum between intraoperative and postimplant plans were evaluated. Results D 90 and V 100 declined for all implants between intraoperative and postimplant dosimetry. On average, D 90 declined by 17.5% and 21.7% for 125 I and 103 Pb implants, respectively. V 100 declined for all implants between intraoperative and postimplant dosimetry but less pronounced. Prostate V 150 and urethra D 30 and D 5 also showed different tendency of decline. Of the 79 implants, 60 did not meet the postimplant dosimetry target for prostate ( V 150 ≤ 50%), and 46 of the 60 implants met the optimal dosimetry targets for both D 30 ( D 5 ( D 30 or the D 5 limits. All the implants met the postimplant target dose for rectum: V 100 ≤ 1.3 cc . Conclusion Intraoperative implant dosimetry could not accurately predict postimplant dosimetry; however, to avoid underdosage of prostate, intraoperative D 90 should be close to 120% of prescribed dose and V 100 needs to be close to 100% of prescribed dose. Prostate V 150 > 50% does not necessarily indicate the violation of urethra D 30 and D 5 dose limits. For most of the implants, target intraoperative D 90 and V 100 could be raised without violating urethra D 30 and D 5 limits recommended by American Brachytherapy Society in postimplant evaluation.

Purpose: Patients with close or positive margins after surgery for pancreatic carcinoma are at a high risk for recurrence. Stereotactic body radiation therapy (SBRT) allows for safe dose escalation with great conformity and short duration of treatment. Herein, we report the initial results of a prospective observational study that evaluated the efficacy and safety of this treatment option. Methods and Materials: Patients eligible for the study had pathologically proven T1-4N0-1M0 pancreatic adenocarcinoma with a positive margin (≤1 mm) or a close margin defined as

Purpose: Reddit is a social media platform that allows health care professionals (HPs) to anonymously interact with patients. We analyzed content about radiation therapy (RT) on Reddit. Methods and Materials: Reddit.com/r/cancer was queried with 20 search terms related to RT: IMRT, 3D-CRT, SBRT, EBRT, XRT, radiation, radiotherapy, RT, radio, rad, rads, gamma, gamma knife, gammaknife, cyber knife, cyberknife, cyber, brachytherapy, brachy, and cobalt. The search aimed to identify all posts discussing RT. A random sample of posts and their top 3 comments was selected to generate qualitative thematic codes per author consensus, which were used to characterize all posts and their top 3 voted comments. Posts were analyzed for time to first reply, mention of any specific RT modality, whether a self-identified HP responded, and time to first highly voted comment by an HP. Results: Exactly 190 posts about RT by 178 users were shared from February 2011 to May 2018, and 468 replies by 295 users were also analyzed. Twenty-nine of these users (9.8%) were HPs; however, 48 of 181 top comments were contributed by HPs compared with 45 of 288 non–top comments by HPs (odds ratio, 1.95; 95% confidence interval [CI], 1.23-3.08; P

PURPOSE: The 2018 American Society for Radiation Oncology guidelines state that hypofractionated whole-breast irradiation (HF-WBI) may be used for early-stage breast cancer regardless of age, although evidence to support this became available years ago. Before guideline publication, we sought to change the practice pattern within an integrated, comprehensive radiation oncology network using clinical pathways. METHODS: The breast clinical pathway was amended in January 2016 to allow HF-WBI as a pathway-concordant option for women younger than 50 years of age. In December 2016, the pathway was amended to mandate HF-WBI as the only pathway-concordant option. Women younger than 50 years of age treated for stage 0 to IIA breast cancer, without irradiation of regional nodes, were included. Potential predictors of hypofractionation use were analyzed using binary logistic regression. RESULTS: We identified 305 patients treated between 2013 and 2017. From 2013 to December 2015, HF-WBI use was 4.2%. After the first and second amendments, use increased to 53.1% ( P < .001) and 96.5% ( P < .001), respectively. Before amendment 1, there was no difference in use of hypofractionation at academic (2.6%) versus community (4.7%) sites ( P = .568). After amendment 1, academic practices were more likely to use hypofractionation (72.0% v 44.6%; P = .026). After amendment 2, there was, again, no difference between academic (100.0%) and community (95.3%) practices ( P = .999). CONCLUSION: With implementation of a clinical pathway that mandated use of HF-WBI regardless of age, HF-WBI use for women younger than 50 years of age rapidly increased from 4.2% to greater than 95%. Clinical pathways effectively standardize patterns of care to reflect the most up-to-date clinical evidence, independently of guideline publication.

Purpose Severe late toxicity is common after re-irradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck. However, many patients experience complications from tumor progression before manifesting late effects. We constructed a nomogram to examine this relationship between late toxicity and competing risks. Methods and materials Patients with RSP squamous carcinoma originating in a field previously irradiated to ≥40 Gy and treated with IMRT-based re-irradiation to ≥40 Gy were collected. Grade ≥3 late toxicity developing ≥90 days after re-irradiation was collected. A multivariable competing-risk model was fit to the actuarial risk of late toxicity with progression or death as the competing risk. The final bootstrap optimized model was converted into a nomogram. Results From 9 institutions, 505 patients were included. The 2-year incidence of grade ≥3 late toxicity was 16.7% (95% CI 13.2–20.2%) whereas progression or death was 64.2% (95% CI 59.7–68.8%). The median freedom from late toxicity, progression or death was 10.7, 5.5 and 3.2 months for RPA class I-III patients respectively, whereas the median OS was 44.9, 15.9 and 7.9 months, respectively. The final model included six clinical factors. Notably, dose, volume and fractionation did not significantly impact toxicity. Conclusions After re-irradiation, the risk of progression or death is approximately four times the risk of radiation-related severe late toxicity. The risk of late toxicity may be more dependent on patient and disease factors than modifiable treatment factors. This model is useful for patient selection, pre-treatment consent and post-treatment survivorship following re-irradiation.

Background Advances in early diagnosis and curative treatment have reduced high mortality rates associated with non‐small cell lung cancer. However, racial disparity in survival persists partly because Black patients receive less curative treatment than White patients. Methods We performed a 5‐year pragmatic, trial at five cancer centers using a system‐based intervention. Patients diagnosed with early stage lung cancer, aged 18‐85 were eligible. Intervention components included: (1) a real‐time warning system derived from electronic health records, (2) race‐specific feedback to clinical teams on treatment completion rates, and (3) a nurse navigator. Consented patients were compared to retrospective and concurrent controls. The primary outcome was receipt of curative treatment. Results There were 2841 early stage lung cancer patients (16% Black) in the retrospective group and 360 (32% Black) in the intervention group. For the retrospective baseline, crude treatment rates were 78% for White patients vs 69% for Black patients (P

Purpose Underutilization of hypofractionated whole-breast irradiation (HF-WBI) in large-breasted women may be partially explained by concerns about dose heterogeneity. Although modern planning may mitigate this issue, validated dosimetric guidelines are lacking. Our clinical pathway mandates hypofractionation, guided by institutional dosimetric criteria for plan evaluation. We examined acute radiation dermatitis rates with HF-WBI in large-breasted patients when our guidelines are followed and evaluated factors predictive for dermatitis. Methods and Materials Patients with whole-breast clinical target volumes (WB-CTV) of ≥1000 cm3 treated with HF-WBI were reviewed. WB-CTV V105, V107, and V110 were assessed. Our guidelines recommend limiting V105 to Results From 2012 to 2017, 505 breasts in 502 patients were treated with HF-WBI. The median WB-CTV was 1261.3 cm3 (interquartile range [IQR], 1115.3-1510.0). Most plans (99%) delivered 42.56 Gy in 16 fractions. A cavity boost of 10 Gy in 4 fractions was delivered in 99% of plans. Electrons were used in 69% of boost plans. Three-dimensional field-in-field technique was used in 68% of plans and inverse-planned intensity modulated radiation therapy in 32%. The median WB-CTV V105 was 9.7% (IQR, 5.6%-13.3%); the median WB-CTV V107 was 0.8% (IQR, 0.0%-2.5%). The WB-CTV V110 was 0% in 97.4% of plans (median, 0.0%; IQR, 0.0%-0.0%). Grade 1, 2, and 3 dermatitis rates were 55.0%, 40.8%, and 3.4%, respectively. On multivariate analysis, age >64 years (P = .016; odds ratio [OR] 4.0; 95% confidence interval [CI], 1.3-12.3), WB-CTV >1500 cm3 (P = .006; OR, 4.3; 95% CI, 1.5-12.3), body mass index ≥34 (P = .044; OR, 3.9; 95% CI, 1.0-14.5), and WB-CTV V105 >10% (P = .011; OR, 5.3; 95% CI, 1.5-19.3) predicted for grade 3 dermatitis. Conclusions With our institutional dosimetric guidelines, grade 3 dermatitis rates with HF-WBI in large-breasted women was

We investigated the feasibility of measuring daily fiducial length on cone-beam computed tomography (CBCT) images to assess the variation in daily tumor motion for pancreatic SBRT. Motion data for fifty pancreatic SBRT patients with fiducials were analyzed retrospectively to determine the tumor motion statistics. We also performed a phantom study which involved motion analysis of three gold fiducials placed around a solid target inside the Quasar Phantom as a function of variable tumor motion and breathing period. The end-exhalation CT-50 images were compared with the CBCT images acquired prior to treatment delivery on a TrueBeam STx linear accelerator. Sinusoidal tumor motion and patients’ breathing files acquired from a Varian-RPM system were used to simulate patients’ breathing patterns. The fiducial length was measured to determine its correlation with tumor motion. Patient tumor motions along the superior-inferior (SI), anterior-posterior (AP), and left-right (LR) directions were found to be 0.7 ± 0.4 cm, 0.2 ± 0.3 cm, and 0.1 ± 0.2 cm, respectively. Average breathing period was 4.3 ± 0.8 seconds. For sinusoidal and patients’ breathing patterns, a significant correlation was observed between the fiducial length and tumor motions with R2 of 0.99. However, fiducial length was found to be independent of the variation in breathing periods. This work suggests that measuring the fiducial length on daily CBCT images could provide quantitative daily tumor motion for fiducial-based pancreatic SBRT. A timely decision to modify the motion management strategy could be made prior to daily treatment delivery.

Purpose Patients with oligometastatic colorectal cancer have demonstrated excellent clinical outcomes with surgical resection of hepatic and pulmonary metastases. Stereotactic ablative radiation therapy (SABR) has emerged as an alternative local therapy for nonsurgical candidates. Herein, we report the oncologic and patient-reported quality-of-life (PR-QoL) outcomes for a subset of patients with oligometastatic colorectal cancer who were treated in a prospective phase 2 multicenter clinical trial. Methods and materials Patients with a pathologically proven diagnosis of oligometastatic colorectal cancer were enrolled as part of a prospective study. SABR dose and fractionation schedules were dependent on the lesion location and size. Patient follow-up occurred 6 weeks after completion of SABR and at 3-month intervals for the following 3 years. Patients received the Functional Assessment of Cancer Therapy-General questionnaire at baseline and at each follow-up visit to assess PR-QoL. The total Functional Assessment of Cancer Therapy-General questionnaire scores were compared with those from baseline using the Wilcoxon signed rank test. Overall survival, local progression-free survival (PFS), and distant PFS were calculated using the Kaplan-Meier estimation to the date of the last follow-up visit/death or local/distant failure. Results A total of 31 patients with oligometastatic colorectal cancer with 1 (71.0%), 2 (16.1%), 3 (3.2%), 4 (3.2%), or 5 (6.5%) metastatic lesions were identified. After a median follow-up time of 50.1 months, the median OS from the time of completion of the SABR was 53.9 months (95% confidence interval, 23.2-84.6), and the 5-year OS, local PFS, and distant PFS were 45%, 83%, and 27%, respectively. Acute grade 2+ toxicity was 9.7% (pain, nausea, fatigue) and late grade 3+ toxicity (small bowel obstruction) was 3.2% with no significant change in PR-QoL in the year after SABR. Conclusions This subset analysis of a prospective phase 2 study demonstrates that SABR is a safe and effective treatment option for patients with unresectable oligometastic colorectal cancer. In addition, SABR of oligometastatic disease preserves PR-QoL.

Purpose/Objective(s) To measure the biochemical disease-free survival (bDFS) & the rates of acute & late gastrointestinal (GI) or genitourinary toxicity (GU) following stereotactic body radiation therapy (SBRT) for clinically localized prostate adenocarcinoma. Materials/Methods Eligible men aged 18 years & older with NCCN low- & intermediate-risk prostate cancer & ECOG performance status 0-1 were enrolled at two institutions. Participants were simulated with a Foley catheter to visualize the prostatic urethra. All patients received MRI. Participants received 36.25 Gy in 5 fractions on non-consecutive days to the planning target volume (PTV) with a simultaneous boost of 40 Gy to the entire prostate. Treatment was performed on a linear accelerator or frameless robotic radiosurgery system. Androgen deprivation therapy & hydrogel spacer placement were not permitted. The coprimary endpoints were grade 3 or higher GI or GU toxicity as measured by CTCAE v3.0 & bDFS using the Phoenix criteria. This study was designed to test the null hypothesis that the cumulative incidence of Grade 3 or higher GI/GU toxicity rate at 2 years was less than 10%. With n = 200 eligible patients, there was 99% power of identifying an unacceptable toxicity rate if the true toxicity rate was 20% with a one-sided significance level of 0.05. Assuming a 2-year bDFS rate of 97% for SBRT, a sample size of 200 patients also provided 92% power to determine if SBRT was superior to a historical bDFS control rate of 92%. Secondary endpoints were quality of life (QoL), prostate cancer-specific mortality, & overall survival. Results From January 2011 to July 2020, we enrolled 163 men. The trial was stopped early due to slow accrual. Two men were deemed ineligible & one man withdrew consent leaving 160 evaluable men. Median age was 67.9 years (IQR 62.6-73.2), 60 men (37.5%) were low risk, and 100 (62.5%) were intermediate risk. Median prostate volume was 41.5 cm3 (IQR 35.0-59.2), median baseline IPSS was 7 (IQR 3-12), and median baseline SHIM was 15 (IQR 3-23). Median PTV coverage was 96.9%. With a median follow-up of 2.2 years, the worst acute GU toxicity proportions were grade 2 in 51 (31.9%) & grade 1 in 66 (41.2%) patients, and the worst acute GI toxicity proportions were grade 2 in 7 (4.3%) and grade 1 in 30 (18.8%) patients. The cumulative incidence of late GI and GU grade 2 adverse events were 3.1% and 20.6%, respectively. No acute or late grade 3 or higher GI or GU toxicities were reported, meeting the co-primary safety endpoint (P Conclusion In one of the largest prospective series to date, prostate SBRT for low- and intermediate-risk prostate cancer is efficacious and well tolerated, with high rates of early biochemical control and low rates of clinically significant toxicity. Long-term outcomes will be reported with longer follow-up.

PURPOSE/OBJECTIVE(S) Stereotactic body radiation therapy (SBRT) is an emerging treatment option for localized prostate cancer. However, optimal patient selection & normal tissue tolerances for prostate SBRT are not well defined. We therefore analyzed patient factors & dosimetric correlates for genitourinary (GU) and gastrointestinal (GI) toxicity on a multi-institutional prospective trial. MATERIALS/METHODS Patients (pts) with low- and intermediate-risk prostate cancer were enrolled on a phase II trial from 2011-2020. A dose of 36.25 Gy in 5 fractions to the PTV and 40 Gy to the prostate gland was administered on non-consecutive days. No androgen deprivation therapy or rectal spacer were used. Pts received a CT simulation with Foley catheter for urethral delineation. The clinical target volume was prostate (low-risk) or prostate plus 2cm of proximal seminal vesicles (intermediate-risk). Multiple dosimetric measures for bladder, urethra, & rectum were prospectively recorded. The maximum acute & late GU and GI toxicities using CTCAE v.3.0 were assessed at protocol-specific time points. Linear logistic regression was used to assess factors associated with Grade 1+ GI & GU toxicities. A multivariate (MV) model was constructed using all covariates with P-values 0.2). Treatment isodose line (P = 0.065) & age (P = 0.098) reached borderline significance for acute Grade 1+ GI toxicity on UV analysis, though neither were significant on MV analysis (P = 0.057 and P = 0.103, respectively). For late Grade 1+ GU toxicity, prior TURP, bladder V37(cc), bladder D10%, baseline AUA, & treatment isodose line reached borderline significance on UV analysis. On MV analysis, treatment isodose line trended towards significance at P = 0.055. For late Grade 1+ GI toxicity, rectum D20%, rectum D10%, rectum D5%, & history of coronary artery disease reached borderline significance on UV analysis, & a history of coronary artery disease predicted Grade 1+ GI toxicity on MV analysis (odds ratio 4.7, 95% CI 1.37-15.9, P = 0.009). CONCLUSION No patient factor or dosimetric correlate predicted acute GI or GU toxicity after prostate SBRT. Late GU toxicity is possibly attributable to dose inhomogeneity. A history of coronary artery disease predicts for late GI toxicity, possibly due to anticoagulation.

Background Cetuximab combined with radiation therapy (RT) is an evidence-based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer-related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)-antisense plasmid DNA (EGFR-AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR-AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR-AS to cetuximab RT. Methods Antitumor mechanisms were investigated in cell line and xenograft models. Phase 1 trial eligibility required stage IVA through IVC HNSCC and a measurable lesion accessible for repeat injections. Patients received standard cetuximab was for 9 weeks. EGFR-AS was injected weekly until they achieved a lesional complete response. RT was delivered by conventional fractionation for 7 weeks, starting at week 3. Research biopsies were obtained at baseline and week 2. Results When added to cetuximab, EGFR-AS decreased cell viability and xenograft growth compared with EGFR-sense control, partially mediated by reduced EGFR expression. Six patients were enrolled in the phase 1 cohort. No grade 2 or greater EGFR-AS-related adverse events occurred. The best lesional response was a complete response (4 patients), and 1 patient each had a partial response and disease progression. EGFR expression decreased in 4 patients who had available paired specimens. Conclusions In preclinical models, dual EGFR inhibition with cetuximab and EGFR-AS enhanced antitumor effects. In a phase 1 cohort, intratumoral EGFR-AS injections, cetuximab, and RT were well tolerated. A phase 2 trial is needed to conduct an extended evaluation of safety and to establish efficacy.

We sought to evaluate the association between larynx dose and risk of severe late laryngeal toxicity in patients undergoing re-irradiation SBRT for recurrent HNC. Fifty-five patients with an intact larynx underwent re-irradiation SBRT to a median dose of 44 Gy in 5 fractions. Five (41.7%) patients treated for a laryngeal/hypopharyngeal recurrence experienced late grade ≥3 laryngeal toxicity, compared to 0.0-7.1% for other sites. Logistic dose-response models were created to predict risk of severe late laryngeal toxicity, including dysphagia and airway compromise. According to the model, the risk of severe laryngeal toxicity with a larynx D5cc of 5 Gy is 5.8% (95% CI 2.9-9.9%) and rises to 11.4% with a D5cc of 20 Gy and 25.3% with a D5cc of 40 Gy. In patients with a laryngeal/hypopharyngeal recurrence, SBRT planning should carefully assess the dose to laryngeal structures given these dose findings, and SBRT should be approached with significant caution in such patients.

Objectives Adjuvant radiation therapy (RT) is indicated for patients with salivary gland malignancies with risk factors for recurrence following resection. We analyzed patients treated with adjuvant RT with or without concurrent chemotherapy to determine the impact of prognostic and treatment factors. Materials and methods Retrospective analysis was performed of 128 patients treated with surgical resection followed by intensity-modulated radiotherapy. In total, 31 (24.2%) patients were treated with concurrent chemoradiotherapy. The Kaplan-Meier method was used to estimate rates of progression-free survival (PFS), local-regional control, distant control, overall survival. Multivariable Cox regression was performed to evaluate factors significant on univariate analysis. Results The 5-year rates of PFS, local-regional control, freedom-from distant metastasis, and overall survival were 61.2%, 85.8%, 76.5%, and 73.7%, respectively. Predictors of decreased PFS on univariate analyses were age, tumor stage, nodal stage, positive surgical margins, histology, high grade, perineural invasion, lymphovascular space invasion, extranodal extension, and use of chemoradiotherapy. On multivariable analysis, elevated T-stage, positive surgical margins, and presence of extranodal extension were predictive of decreased PFS. The acute toxicity rates were 30.3% grade 1, 51.5% grade 2, 11.4% grade 3, and 0.8% grade 4. There was no difference in rates of grade 3 or higher acute toxicity with use of RT alone versus chemoradiotherapy (P=0.183). Conclusions Use of chemoradiotherapy for adjuvant treatment of salivary gland malignancies was well-tolerated, but no improvement in survival was seen with the use of chemoradiotherapy in both the overall study population and a subset with high-risk features. Caution should be used when using this modality until randomized evidence becomes available.

Purpose The International Atomic Energy Agency (IAEA) and the American Association of Physicists in Medicine (AAPM) have jointly published a new code of practice (CoP), TRS483, for the dosimetry of small static photon fields used in external beam radiotherapy. It gave recommendations on how to perform reference dosimetry in nonstandard machine-specific reference (msr) fields and measure field output factors in small fields. The purpose of this work was to perform a dosimetric evaluation of the recommendations given in this CoP. Methods All measurements were done in a Varian TrueBeam™ STx linear accelerator. Five ionization chambers were used for beam quality measurements, four Farmer type ionization chambers for performing reference dosimetry and two diodes for performing field output factor measurements. Field output factor measurements were done for fourteen field sizes (ranging from 0.5 cm × 0.5 cm to 10 cm × 10 cm). Beam energies used were: 6 MV WFF, 6 MV FFF, 10 MV WFF, and 10 MV FFF. Where appropriate, results from this study were compared with those obtained from the recommendations given in the IAEA TRS398 CoP, AAPM TG51 and TG51 Addendum protocols. Results Beam quality measurements show that for all beam energies and for equivalent square msr field sizes ranging from 4 cm × 4 cm to 10 cm × 10 cm, agreement between calculated and measured values of TPR20,10 (10) was within 0.6%. When %dd(10,10)X was used as beam quality specifier, the agreement was found to be within 0.8%. Absorbed dose to water per unit monitor unit at the depth of maximum dose zmax in a beam of quality Q, Dw,Qzmax/MU, was determined using both %dd(10,10)X and TPR20,10 (10) as beam quality specifiers. Measured ratios of Dw,Q (zmax )/MU, determined using the two approaches, ranged between 0.999 and 1.000 for all the beam energies investigated. Comparison with TRS398, TG51 and TG51 addendum protocols show that depending on beam energy, the mean values of the ratios TRS398/TRS483, TG51/TRS483, and TG51 Addendum/TRS483 of Dw,Q (zmax )/MU determined using both approaches show excellent agreement with TRS398 CoP (to within 0.05%); agreement with TG51 and TG51 addendum was to within 0.3% for all four beam energies investigated. Field output factors, determined using the two methods recommended in the TRS483 CoP, showed excellent agreement between the two methods. For the 1 cm collimator field size, the mean value of the field output factor obtained from an average of the two detectors investigated was found to be 2% lower than the mean value of the uncorrected ratio of readings. Conclusion For beams with and without flattening filters, the values of Dw,Q (zmax )/MU obtained following the new CoP are found to be consistent with those obtained using TRS398, TG51 and TG51 addendum protocols to within 0.3%. Field output factors for small beams can be improved when the correction factors for different detectors included in TRS483 are appropriately incorporated into their dosimetry.

OBJECTIVEAkin to the nonoperative management of benign intracranial tumors, stereotactic body radiation therapy (SBRT) has emerged as a nonoperative treatment option for noninfiltrative primary spine tumors such as meningioma and schwannoma. The majority of initial series used higher doses of 16–24 Gy in 1–3 fractions. The authors hypothesized that lower doses (such as 12–13 Gy in 1 fraction) might provide an efficacy similar to that found with the dose de-escalation commonly used for intracranial radiosurgery to treat acoustic neuroma or meningioma and with a lower risk of toxicity.METHODSThe authors identified 38 patients in a prospectively maintained institutional radiosurgery database who were treated with definitive SBRT for a total of 47 benign primary spine tumors between 2004 and 2016. SBRT consisted of 9–21 Gy in 1–3 fractions using the CyberKnife (n = 11 [23%]), Synergy S (n = 21 [45%]), or TrueBeam (n = 15 [32%]) radiosurgery platform. For a comparison of SBRT doses, patients were dichotomized into 1 of 2 groups (low-dose or high-dose SBRT) using a cutoff biologically effective dose (BED10Gy) of 30 Gy. Tumor control was calculated from the date of SBRT to the last follow-up using Kaplan-Meier survival analysis, with comparisons between groups completed using a log-rank method. To account for potential indication bias, a propensity score analysis was completed based on the conditional probabilities of SBRT dose selection. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4.0 with a focus on grade 3+ toxicity and the incidence of pain flare.RESULTSFor the 38 patients, the most common histological findings were meningioma (15 patients), schwannoma (13 patients), and hemangioblastoma (7 patients). The median age at SBRT was 58 years (range 25–91 years). The 47 treated lesions were located in the cervical (n = 18), thoracic (n = 19), or lumbosacral (n = 10) spine. Five (11%) lesions were lost to follow-up after SBRT. The median follow-up duration for the remaining 42 lesions was 54 months (range 1.2–133 months). Six (16%) patients (with a total of 8 lesions) experienced pain flare after SBRT; no significant predictor of pain flare was identified. No grade 3+ acute- or late-onset complication was noted. The 5-year local control rate was 76% (95% CI 61%–91%). No significant difference in local control according to dose, fractionation, previous radiation, surgery, tumor histology, age, treatment platform, planning target volume, or spine level treated was found. The 5-year local control rates for low- and high-dose treatments were 73% (95% CI 53%–93%) and 83% (95% CI 61%–100%) (p = 0.52). In propensity score–adjusted multivariable analysis, no difference in local control was identified (HR 0.30, 95% CI 0.02–5.40; p = 0.41).CONCLUSIONSLong-term follow-up of patients treated with SBRT for benign spinal lesions revealed no significant difference between low-dose (BED10Gy ≤ 30) and high-dose SBRT in local control, pain-flare rate, or long-term toxicity.

Given the lack of clear dose constraints for the carotid artery, we created dose-response models to better quantify the risk of carotid bleeding events following re-irradiation stereotactic body radiation therapy (SBRT) for head and neck cancer (HNC). We performed a retrospective analysis on 75 patients treated with SBRT for recurrent, previously irradiated HNC. Logistic dose-response models were created to predict the risk of a carotid bleeding event, defined as any mucosal bleeding event or bleeding resulting from rupture of the carotid artery or its major branches in the setting of controlled disease. According to the models, the risk of a carotid bleeding event with a cumulative D(0.1cc) of 20 Gy from SBRT is 0.8% (95% CI 0.1%-3.9%), and rises to 5.0% with a D(0.1cc) of 50 Gy. No patient experienced a carotid bleeding event with D(0.1cc) < 39.4 Gy, and none experienced carotid blowout syndrome with a cumulative D(0.1cc) < 47.6 Gy.

Given the relative novelty of stereotactic body radiation therapy as a treatment modality low-risk and intermediate-risk prostate cancer, little data exist evaluating dosimetry and its impact on patient-reported quality of life (PR-QOL) metrics. Herein, we present an interim analysis of a phase II clinical trial of PR-QOL and dosimetric correlates.Patients with biopsy-proven low-risk or intermediate-risk prostate cancer, prostate volume ≤100 cm, and life expectancy ≥10 years were enrolled. Expanded Prostate Cancer Index Composite (EPIC) scores were tabulated by domain and evaluated in relation to dosimetry. Paired t test was performed to compare differences in scores from baseline. Minimally important differences were established using the anchor-based approach and correlations made using the χ test.A total of 95 patients were analyzed with a median follow-up of 18.1 months (range, 3.0 to 76.9 mo). There were no cases of acute or late grade 3+ GI or GU toxicities. Expanded Prostate Cancer Index Composite scores in urinary obstructive/irritative domain at 1 month (-4.8, P=0.03) and bowel domain at 1, 6, and 12 months (-10.8, -6.1, and -5.2) were significantly different from pretreatment, with both returning to nonsignificant differences around 24 months. Higher bladder V37Gy (≥3.35%) was associated with both late urinary incontinence and obstructive/irritative declines. Both higher rectal D5% and rectal V36Gy0.6 cm were correlated with an enhanced proportion of patients with late minimally important difference declines.Higher dose volumes for the bladder and rectum predicted for poorer PR-QOL. In contrast to prostate brachytherapy data, neither prostate volume nor urethral dosimetry at this dose schedule correlated with urinary symptoms.

Purpose Local failure following concurrent chemoradiation and in-lobe failures following stereotactic body radiation therapy (SBRT) are common. We evaluated our institutional experience using SBRT as salvage in this setting. Methods and materials Seventy-two patients were reirradiated with SBRT for residual, locally recurrent, or new primary non-small cell lung cancer within or adjacent to a high-dose external beam radiation therapy or SBRT field. Kaplan-Meier analysis with log-rank test were used to estimate endpoints and differentiate cohorts. Results Median follow-up was 17.9 months. Patients had residual or recurrent disease (54.2%); 45.8% had new lung primaries. Median reirradiated T size was 2.5 cm (range, 0.8-7.8 cm). Median pre-retreatment maximum standardized uptake value (SUV max ) was 7.15 (range, 1.2-37.6). The most common SBRT reirradiation regimen was 48 Gy in 4 fractions (range, 17-60 Gy in 1-5 fractions). Median progression-free survival was 15.2 months, and median overall survival was 20.8 months. Two-year local failure was 21.6%. Patients with SUV max at reirradiation P P P = .037). Median survival of patients treated for new primary was 25.2 months versus 16.2 months with residual or recurrent disease ( P = .049), and median survival for patients with reirradiation SUV max below the median was 42.0 months versus 9.8 months above the median ( P Conclusions SBRT appears to be a safe and effective means of salvaging recurrent, residual, or new primary NSCLC in or adjacent to a previous high-dose radiation field.

PURPOSE: The therapeutic ratio of reirradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck may be improved in the intensity modulated radiation therapy (IMRT) era. However, patient selection for reirradiation remains challenging. We performed a multi-institution cohort study to investigate modern outcomes after IMRT-based reirradiation and to identify prognostic subgroups. PATIENTS AND METHODS: Patients with RSP squamous carcinoma originating in a previously irradiated field (≥40 Gy) who underwent reirradiation with IMRT (≥40 Gy re-IMRT) were included. Locoregional failure and late toxicity were calculated using the Gray competing risk method. Cox proportional hazards regression was used to identify factors associated with overall survival (OS). Factors associated with OS were entered into a recursive partitioning analysis (RPA) for OS. RESULTS: From 7 institutions, 412 patients were included. The median dose of re-IMRT was 60 Gy, and the median time between RT courses was 2.4 years. Chemotherapy was used in 76% of patients. The rates of grade ≥3, grade ≥4, and grade 5 acute toxicities were 19%, 4.4%, and 1.2%, respectively. The 2-year cumulative incidence of grade ≥3 late toxicity adjusted for the competing risks of recurrence or death was 14.2%. RPA identified 3 prognostic subgroups with distinct and homogenous OS (P2 years from their initial course of RT with resected tumors (2-year OS, 61.9%); class II included patients >2 years with unresected tumors or those ≤2 years and without feeding tube or tracheostomy dependence (2-year OS, 40.0%), and the remaining patients formed class III (2-year OS, 16.8%). Fifty-nine percent of class III patients underwent postoperative re-irradiation. CONCLUSIONS: This study informs outcomes and expectations with IMRT-based reirradiation. The RPA classification identifies 3 distinct subgroups, which can guide patient selection for therapy and clinical trial design. RPA class III patients are not ideal candidates for protracted chemoradiation regardless of resection status.

Purpose Stereotactic ablative radiation therapy's (SABR's) great conformity and short duration has become an attractive treatment modality. We report a phase 2 clinical trial to evaluate efficacy and safety of induction chemotherapy (ICT) followed by SABR in patient with borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Methods and materials Patients with biopsy-proven BR or LA PDAC were treated with four 21-day cycles of intravenous gemcitabine and oral capecitabine. Patients were restaged within 4 weeks after ICT by computed tomography and treated by 3-fraction SABR if no metastasis or progressive disease was identified. Patients were restaged 4 weeks following SABR to determine resectability. Tumor response was assessed with carbohydrate antigen 19-9. Results Thirty-five patients (19 BR/16 LA) were enrolled. The median age was 71.8 years (range, 50.6-81.1). ICT was completed in 91.4% (n = 32) of patients. All patients who completed ICT completed SABR. Of those 32 patients, 34.3% (n = 12: 10 BR, 2 LA) underwent pancreaticoduodenectomy and 11 of 12 (91.7%) received R0 resection. Median overall survival was 18.8, 28.3, and 14.3 months for the entire cohort, BR, and LA, respectively. The 2-year local progression-free survival (LPFS) was 44.9%, 40%, and 52% for the entire cohort, BR, and LA, respectively. For BR patients, multivariate analysis showed surgery was associated with better overall survival and LPFS. One-year LPFS for patients with surgery was 80% and 44% without surgery. Within the 15.4-month follow-up, no grade 3+ toxicity from SABR was observed. No significant quality of life change was observed before and after ICT, SABR, or surgery for BR or LA patients. Conclusions This is the first prospective phase 2 study to investigate the feasibility and efficacy of a 12-week gemcitabine/capecitabine ICT followed by SABR for BR or LA PDAC. The results suggest excellent tolerability, high R0 resection rates, and acceptable posttreatment complications.

Purpose Limited data exist to guide the treatment technique for reirradiation of recurrent or second primary squamous carcinoma of the head and neck. We performed a multi-institution retrospective cohort study to investigate the effect of the elective treatment volume, dose, and fractionation on outcomes and toxicity. Methods and Materials Patients with recurrent or second primary squamous carcinoma originating in a previously irradiated field (≥40 Gy) who had undergone reirradiation with intensity modulated radiation therapy (IMRT); (≥40 Gy re-IMRT) were included. The effect of elective nodal treatment, dose, and fractionation on overall survival (OS), locoregional control, and acute and late toxicity were assessed. The Kaplan-Meier and Gray's competing risks methods were used for actuarial endpoints. Results From 8 institutions, 505 patients were included in the present updated analysis. The elective neck was not treated in 56.4% of patients. The median dose of re-IMRT was 60 Gy (range 39.6-79.2). Hyperfractionation was used in 20.2%. Systemic therapy was integrated for 77.4% of patients. Elective nodal radiation therapy did not appear to decrease the risk of locoregional failure (LRF) or improve the OS rate. Doses of ≥66 Gy were associated with improvements in both LRF and OS in the definitive re-IMRT setting. However, dose did not obviously affect LRF or OS in the postoperative re-IMRT setting. Hyperfractionation was not associated with improved LRF or OS. The rate of acute grade ≥3 toxicity was 22.1% overall. On multivariable logistic regression, elective neck irradiation was associated with increased acute toxicity in the postoperative setting. The rate of overall late grade ≥3 toxicity was 16.7%, with patients treated postoperatively with hyperfractionation experiencing the highest rates. Conclusions Doses of ≥66 Gy might be associated with improved outcomes in high-performance patients undergoing definitive re-IMRT. Postoperatively, doses of 50 to 66 Gy appear adequate after removal of gross disease. Hyperfractionation and elective neck irradiation were not associated with an obvious benefit and might increase toxicity.

Background Clinical pathways outline criteria for dose homogeneity and critical organ dosimetry. Based upon an internal audit showing suboptimal compliance with dosimetric parameters in whole breast irradiation (WBI), we conducted a mandatory web-based teaching conference for the network. This study reports the impact of this initiative on subsequent treatment plans. Methods Radiation treatment plans were collected for the 10 most recent patients receiving WBI at 16 institutions within the UPMC Hillman Cancer Center network. Subsequently, a web-based conference was conducted to educate staff physicians, physicists, and dosimetrists with goals for dose homogeneity and critical organ dosimetry. Six months post-conference, another 10 plans were collected from each site and compared to pre-conference plans for deviations from dosimetric criteria. Results Dose homogeneity significantly improved after the conference with breast V105% decreasing from 15.6% to 11.2% (p = 0.004) and breast V110% decreasing from 1.3% to 0.04% (p = 0.008). A higher percentage of cases were compliant with dosimetric criteria, with breast V105% > 20% decreasing from 22.5% to 7.5% of cases (p = 0.0002) and breast V110% > 0% decreasing from 13.8% to 4.4% of cases (p = 0.003). Conclusions Implementation of a web-based teaching conference helped improve adherence to clinical pathway dosimetric guidelines for WBI. In radiation oncology networks, this may be an effective model to ensure quality in routine practice and can be extrapolated to other disease sites.

Objectives The seminal phase II trial for pulmonary stereotactic body radiation therapy (SBRT) suggested that SBRT to central lesions resulted in unacceptable toxicity. Alternative dose-fractionation schemes have been proposed which may improve safety without compromise of efficacy. We report our institutional outcomes of SBRT for hilar/mediastinal non-small cell lung cancer (NSCLC). Materials and methods A retrospective review was conducted of patients with NSCLC in a hilar or mediastinal nodal station which was treated with SBRT. Patients presented with a lesion involving the hilum or mediastinum from primary or oligorecurrent NSCLC. Kaplan-Meier with log-rank testing and Cox analysis were utilized for outcomes analysis. Results From 2008–2015, 40 patients with median age of 70 were treated with SBRT for primary/oligorecurrent hilar/mediastinal NSCLC with median follow-up of 16.4 months. 85% presented with oligorecurrent disease at a median of 22.4 months following definitive therapy. The aortico-pulmonary window was the target in 40%, the hilum in 25%, lower paratracheal in 20%, subcarinal in 10%, and prevascular in 5%. The median dose was 48 Gy in 4 fractions (range: 35–48 Gy in 4–5 fractions). Median overall (OS) and progression-free (PFS) survivals were 22.7 and 13.1 months, respectively. Two-year local control was 87.7% and not significantly different between hilar and mediastinal targets. Median PFS was significantly improved in patients with hilar vs mediastinal nodal targets: 33.3 vs 8.4 months, respectively (p = 0.031). OS was not statistically different between hilar and mediastinal targets (p = 0.359). On multivariable analysis, hilar vs mediastinal target predicted for PFS (HR 3.045 95%CI [1.044–8.833], p = 0.042), as did shorter time to presentation in patients with oligorecurrence (HR 0.983 [95%CI 0.967–1.000], p = 0.049). Acute grade 3+ morbidity was seen in 3 patients (hemoptysis, pericardial/pleural effusion, heart failure) and late grade 3+ morbidity (hemoptysis) in 1 patient. Conclusion Hilar/mediastinal SBRT appears to be a safe technique for the local control of isolated nodal disease with limited toxicity from the fractionation schemes utilized.

Background Studies demonstrate safety of omitting axillary nodal dissection for early-stage breast cancer with positive sentinel lymph node (+SLN) biopsy, although trial designs differed in radiation therapy (RT) fields. Regional nodal irradiation was separately shown to improve outcomes in high-risk patients. This led to lack of consensus in RT volumes. Clinical pathways (CPs) standardize care where practice varies unnecessarily. We evaluated the impact of changes to a CP guiding postoperative RT in women with +SLNs on practice patterns throughout a network. Methods and materials We implemented a CP for management of breast cancer with postoperative RT designed to promote uniform nodal treatment. The CP recommended modified tangents (MTs) including level I/II nodes for women with micrometastases (pN1mi). For women with macrometastases (pN1a), CPs recommended including level I/II LN in MT and a third supraclavicular node (SCN) LN ± internal mammary nodes for women with adverse factors present. Results RT fields of 233 women undergoing breast-conserving surgery with +SLN but not axillary nodal dissection were retrospectively reviewed: 25% had pN1mi disease and 75% pN1a. Of 127 women treated before CP changes, 35% with pN1mi and 22% with pN1a were treated with whole-breast irradiation alone. Following CP changes, 106 women were treated: 5% with whole-breast irradiation alone, 58% with MT, and 38% with MT + SCN field. Utilization of MT was associated with CP changes. Utilization of a third SCN field was associated with CP changes, pN stage, extracapsular extension, and total number of adverse factors. Conclusions CPs translate published data and institutional experience into management plans that promote evidence-based care and eliminate unnecessary practice variations. Recognizing that postoperative RT treatment volumes were heterogeneous, we modified the CP based upon the latest evidence for regional nodal irradiation, after which we found increased compliance and consistency with quality guidelines, which will also aid in tracking outcomes in future investigations.

Purpose/objective(s) Despite advances in our understanding/treatment of patients with high grade glioma, the current model for prognostication is based on 40-year-old data. We previously generated a new model incorporating clinical and genetic factors utilizing data from patients treated from 2004-2017. Here we sought to validate our prognostic model within data from prospective trials and compare its accuracy against the original RTOG-RPA. Materials/methods Data from RTOG 0525, RTOG 0513 and RTOG BR-0131 was requested through an NRG Ancillary Project application. Subjects were categorized by both RTOG RPA survival class and our new-RPA survival class. We generated Kaplan-Meier survival curves for classes from each model. To compare the accuracy and heterogeneity of each model, we calculated the mean prediction errors and interquartile ranges (IQR) of overall survival (OS). We then compared the two models for their predictive ability and homogeneity within each survival class. Results 960 patients were included in our validation dataset. Using the validation dataset, Kaplan-Meier survival curves for each terminal class were plotted. Log rank tests demonstrated no significant differences between the predicted and observed survival curves of the new RPA for Class 1 (P = 0.39), Class 2 (P = 0.59), Class 4 (P = 0.75), Class 5 (P = 0.18), Class 6 (P = 0.50), and Class 3/5 (P = 0.12). Mean prediction error of median survival was 4.5 months vs 1.9 months for the RTOG- and new-RPA, respectively. Mean Kaplan-Meier OS IQR was 38.1 months and 17.8 months for the RTOG- and new-RPA, respectively. Conclusion We demonstrated that both the RTOG-RPA and our new-RPA classes maintain their relative prognostic significance. Although both models generate 6 distinct survival classes, in this partial validation our updated model more accurately predicts median survival for each class with significantly greater class homogeneity. Additionally, our proposed model utilizes exclusively objective measures decreasing the risk of inter-observer classification variability. Author disclosure P. Sutera: None. J.C. Flickinger: None. H. Wang: None. D.E. Heron: None.

Introduction Google is the most popular search engine in the United States, and patients are increasingly relying on online webpages to seek information about individual physicians. This study aims to characterize what patients find when they search for radiation oncologists online. Methods and Materials The Centers for Medicare and Medicaid Services (CMS) Physician Comparable Downloadable File was used to identify all Medicare-participating radiation oncologists in the United States and Puerto Rico. Each radiation oncologist was characterized by medical school education, year of graduation, city of practice, gender, and affiliation with an academic institution. Using a custom Google-based search engine, up to the top 10 search results for each physician were extracted and categorized as relating to: ( 1 ) physician, hospital, or health care system; ( 2 ) third-party; ( 3 ) social media; ( 4 ) academic journal articles; or ( 5 ) other. Results Among all health care providers in the United States within CMS, 4443 self-identified as being radiation oncologists and yielded 40,764 search results. Of those, 1161 (26.1%) and 3282 (73.9%) were classified as academic and nonacademic radiation oncologists, respectively. At least 1 search result was obtained for 4398 physicians (99.0%). Physician, hospital, and health care–controlled websites (16,006; 39.3%) and third-party websites (10,494; 25.7%) were the 2 most often observed domain types. Social media platforms accounted for 2729 (6.7%) hits, and peer-reviewed academic journal websites accounted for 1397 (3.4%) results. About 6.8% and 6.7% of the top 10 links were social media websites for academic and nonacademic radiation oncologists, respectively. Conclusions Most radiation oncologists lack self-controlled online content when patients search within the first page of Google search results. With the strong presence of third-party websites and lack of social media, opportunities exist for radiation oncologists to increase their online presence to improve patient–provider communication and better the image of the overall field. We discuss strategies to improve online visibility.

The results of Radiation Therapy Oncology Group (RTOG) 0617, which randomized patients with stages IIIA/IIIB non-small cell lung cancer (NSCLC) to definitive chemoradiation therapy to 60 Gy versus 74 Gy, demonstrated a detrimental survival impact with high-dose radiation therapy. We evaluated the impact of changes to a provider-driven clinical pathway (CP) guiding management of NSCLC on practice throughout our cancer center network.In 2001, we implemented a CP for management of stage IIIA/IIIB NSCLC with definitive chemoradiation therapy. In 2013, the CP for NSCLC was amended (amendment 1) to allow a dose range of 60 to 74 Gy. The CP was amended (amendment 2) in January 2016 to specify a dose range of 60 to 70 Gy. Higher doses were considered off-pathway and subject to peer review. Data from decisions entered from 2012 to 2016 were obtained.From 2012 until publication of RTOG 0617 in February 2015, the median prescription dose was 66 Gy delivered in 1.8 to 2.1 Gy fractions. Doses ≤66 Gy were prescribed for 52% of patients. From February 2015 to September 2016, the median prescription dose was 60 Gy, and 91% of prescription doses were ≤66 Gy. After amendment 2, 99% of decisions were ≤66 Gy. Dose ≤66 Gy was associated with treatment following publication of 0617 (P.001) and treatment after amendment 2 (P.001). On multivariable analysis, treatment after amendment 2 was associated with dose ≤66 Gy (odds ratio, 9.9; 95% confidence interval, 5.2-19.0; P.001). The percentage of lung receiving 20 Gy was lower following publication of 0617 (P.001). There was no difference in the percentage of heart receiving 40 Gy.CPs eliminate variations in practice that lead to inferior outcomes. Recognizing that our CP for definitive treatment of patients with locally advanced NSCLC allowed heterogeneous dose prescriptions, we modified the CP based on the publication of RTOG 0617. We found that the CP was a tool to ensure patients receive evidence-based care across a large cancer center network.

Clinical pathways are patient management plans that standardize evidence-based practices to ensure high-quality and cost-effective medical care. Implementation of a pathway is a collaborative process in our network, requiring the active involvement of physicians. This approach promotes acceptance of pathway recommendations, although a peer review process is necessary to ensure compliance and to capture and approve off-pathway selections. We investigated the peer review process and factors associated with time to completion of peer review.Our cancer center implemented radiation oncology pathways for every disease site throughout a large, integrated network. Recommendations are written based upon national guidelines, published literature, and institutional experience with evidence evaluated hierarchically in order of efficacy, toxicity, and then cost. Physicians enter decisions into an online, menu-driven decision support tool that integrates with medical records. Data were collected from the support tool and included the rate of on- and off-pathway selections, peer review decisions performed by disease site directors, and time to complete peer review.A total of 6965 treatment decisions were entered in 2015, and 605 (8.7%) were made off-pathway and were subject to peer review. The median time to peer review decision was 2 days (interquartile range, 0.2-6.8). Factors associated with time to peer review decision48 hours on univariate analysis include disease site (P.0001) with a trend toward significance (P = .066) for radiation therapy modality. There was no difference between recurrent and non-recurrent disease (P = .267). Multivariable analysis revealed disease site was associated with time to peer review (P.001), with lymphoma and skin/sarcoma most strongly influencing decision time48 hours.Clinical pathways are an integral tool for standardizing evidence-based care throughout our large, integrated network, with 91.3% of all treatment decisions being made as per pathway. The peer review process was feasible, with1% selections ultimately rejected, suggesting that awareness of peer review of treatment decisions encourages compliance with clinical pathway recommendations.

Purpose The Google search engine is a resource commonly used by patients to access health-related patient education information. The American Medical Association and National Institutes of Health recommend that patient education resources be written at a level between the third and seventh grade reading levels. We assessed the readability levels of online palliative care patient education resources using 10 readability algorithms widely accepted in the medical literature. Methods and materials In October 2016, searches were conducted for 10 individual terms pertaining to palliative care and oncology using the Google search engine; the first 10 articles written for the public for each term were downloaded for a total of 100 articles. The terms included palliative care, hospice, advance directive, cancer pain management, treatment of metastatic disease, treatment of brain metastasis, treatment of bone metastasis, palliative radiation therapy, palliative chemotherapy, and end-of-life care. We determined the average reading level of the articles by readability scale and Web site domain. Results Nine readability assessments with scores equivalent to academic grade level found that the 100 palliative care education articles were collectively written at a 12.1 reading level (standard deviation, 2.1; range, 7.6-17.3). Zero articles were written below a seventh grade level. Forty-nine (49%) articles were written above a high school graduate reading level. The Flesch Reading Ease scale classified the articles as "difficult" to read with a score of 45.6 of 100. The articles were collected from 62 Web site domains. Seven domains were accessed 3 or more times; among these, www.mskcc.org had the highest average reading level at a 14.5 grade level (standard deviation, 1.4; range, 13.4-16.1). Conclusions Most palliative care education articles readily available on Google are written above national health literacy recommendations. There is need to revise these resources to allow patients and their families to derive the most benefit from these materials.