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Purpose This guideline provides evidence-based recommendations for the indications and technique-dose of external beam radiation therapy (EBRT) in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC). Methods The American Society for Radiation Oncology convened a task force to address 5 key questions focused on the indications, techniques, and outcomes of EBRT in HCC and IHC. It is intended to cover the definitive, consolidative, salvage, preoperative (including bridge to transplant), and adjuvant settings as well as palliative EBRT for symptomatic primary lesions. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. Results Strong recommendations are made for using EBRT as a potential first-line treatment in patients with liver-confined HCC who are not candidates for curative therapy, consolidative therapy after incomplete response to liver-directed therapies, and as a salvage option for local recurrences. The guideline conditionally recommends EBRT for patients with liver-confined multifocal or unresectable HCC, or those with macrovascular invasion, sequenced with systemic or catheter-based therapies. Palliative EBRT is conditionally recommended for symptomatic primary HCC and/or macrovascular tumor thrombi. EBRT is conditionally recommended as a bridge to transplant or prior to surgery in carefully selected patients. For patients with unresectable IHC, consolidative EBRT with or without chemotherapy should be considered, typically after systemic therapy. Adjuvant EBRT is conditionally recommended for resected IHC with high-risk features. Selection of dose-fractionation regimen and technique should be based on disease extent, disease location, underlying liver function, and available technologies. Conclusions The task force has proposed recommendations to inform best clinical practices on the use of EBRT for HCC and IHC with strong emphasis on multidisciplinary care. Future studies should focus on further defining the role of EBRT in the context of liver-directed and systemic therapies and refining optimal regimens and techniques.

We report long-term outcomes from our phase 1 dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR pooled with our subsequent single institutional experience with patients treated postprotocol at the highest dose level (40 Gy) established from the phase 1 study.Patients with liver metastases from solid tumors located outside of the central liver zone were treated with single-fraction SABR on a phase 1 dose escalation trial. At least 700 cc of normal liver had to receive9.1 Gy. Seven patients with 10 liver metastases received the initial prescription dose of 35 Gy, and dose was then escalated to 40 Gy for 7 more patients with 7 liver metastases. An additional 19 postprotocol patients with 22 liver metastases were treated to 40 Gy in a single fraction. Patients were followed for toxicity and underwent serial imaging to assess local control.Median imaging follow-up for the combined cohort (n = 33, 39 lesions) was 25.9 months; 38.9 months for protocol patients and 20.2 months for postprotocol patients. Median lesion size was 2.0 cm (range, 0.5-5.0 cm). There were no dose-limiting toxicities observed for protocol patients, and only 3 grade 2 toxicities were observed in the entire cohort, with no grade ≥3 toxicities attributable to treatment. Four-year actuarial local control of irradiated lesions in the entire cohort was 96.6%, 100% in the protocol group and 92.9% in the subsequent patients. Two-year overall survival for all treated patients was 82.0%.For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy was safe and well-tolerated, and shows excellent local control with long-term follow-up; results in subsequent patients treated with single-fraction SABR doses of 40 Gy confirmed our earlier results.

PURPOSE: We assessed the feasibility and safety of placing a radiopaque hydrogel in the pancreaticoduodenal groove via endoscopic ultrasound guidance in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC). METHODS AND MATERIALS: Hydrogel injections were done at time of fiducial placement to form blebs in the pancreaticoduodenal groove. Patients subsequently underwent simulation computed tomography (sim-CT) followed by hypofractionated stereotactic body radiotherapy (SBRT; 33 Gy in 5 fractions). Four to 8 weeks after SBRT, patients underwent CT re-evaluation for surgical candidacy and assessment of hydrogel location and size. Hydrogel placement was considered successful if identified in the pancreaticoduodenal groove on sim-CT scan. Stability was evaluated using equivalence testing analyses, with a null hypothesis of the presence of a ≥20% mean percentage change in volume and ≥change in the median and mean interbleb surface distance with a P value

In patients with borderline resectable or locally advanced pancreatic adenocarcinoma (BRPC/LAPC), local failure rates after resection remain significant, even in the setting of neoadjuvant chemotherapy and radiation. Suboptimal local control may relate to variable radiation target delineation, as no consensus exists around clinical tumor volume (CTV) design in this context. In the surgical literature, recent attention has been given to the "triangle" volume (TV) as a source of subclinical, residual disease. To understand whether the TV can inform optimal CTV design, we mapped locoregional failures after resection in a large cohort of patients with BRPC/LAPC and compared locations of failure to the TV.Patients with BRPC/LAPC of the head or neck diagnosed between 2016 AND 2019 who developed locoregional failure after surgery, neoadjuvant chemotherapy, and radiation were identified. Descriptive statistics were generated to report the frequency of locoregional failures located within the TV and the frequency of new vascular involvement at time of failure, compared with vascular involvement at diagnosis. Additionally, dosimetric coverage of the TV with the preoperative radiation plan that had been used was assessed.In 31 patients who experienced locoregional failure, the centroid of failure was located within the TV in 28 cases (90%). Extent of vascular involvement at time of locoregional failure included vasculature that had not been involved at diagnosis in 13 cases (42%). The preoperative radiation plan that had been used provided a median V33 Gy and V25 Gy of the TV of only 53% (interquartile range, 34%-72%) and 70% (IQR, 48%-85%), respectively.The TV encompassed the vast majority of locoregional failures, but dosimetric coverage of the TV was poor when only targeting gross disease and the full circumference of involved vasculature. As such, the TV may better serve as a basis for CTV design in patients with BRPC/LAPC undergoing neoadjuvant radiation.

Purpose Despite the proliferation of radiation oncology fellowship training programs over the last decade, limited data exist on their actual details. We present findings from a focused survey aiming to evaluate the experiences of fellowship-trained physicians. Methods and Materials A customized 23-item questionnaire was systematically distributed to 127 board-certified or eligible physicians who had completed a radiation oncology fellowship in the United States between 2005 and 2017 and whose contact information was available. The survey queried motivations for pursuing fellowship and aspects of training pertaining to expertise, mentorship, salary, employment outcome, satisfaction, and regret. Results A total of 92 subjects responded. Five were still in fellowship and 3 failed to complete the survey in its entirety, leaving 84 (56 male; 28 female) eligible for analysis. Graduates of US residencies comprised 62% of respondents. The desire to build a career in a particular treatment modality was most commonly cited as the primary motivation for pursuing fellowship (58%), followed by the desire to secure an academic faculty position (16%) and the desire to secure a job in a specific geographic location (14%). Subspecialty fellowships were most often done in proton therapy (27%) and brachytherapy (24%). Among the 26 people who completed proton fellowships, only 10 were currently practicing using protons (38%). The majority of fellows (52%) were compensated between $50,000 and $75,000 annually. Seventy-eight (93%) and 72 (86%) physicians were satisfied with fellowship training and their job after fellowship, respectively. Six of the 52 US graduates (12%) and 0 of the 32 international graduates (0%) reported that they would not recommend fellowship to others. Conclusions The motivations for pursuing radiation oncology fellowships appear to be complex, and variability exists with respect to multiple aspects of training, including those related to satisfaction and employment outcomes.

BACKGROUND: Pre-treatment liver tumor localization remains a challenging task for radiation therapy, mostly due to the limited tumor contrast against normal liver tissues, and the respiration-induced liver tumor motion. Recently, we developed a biomechanical modeling-based, deformation-driven cone-beam CT estimation technique (Bio-CBCT), which achieved substantially improved accuracy on low-contrast liver tumor localization. However, the accuracy of Bio-CBCT is still affected by the limited tissue contrast around the caudal liver boundary, which reduces the accuracy of the boundary condition that is fed into the biomechanical modeling process. In this study, we developed a motion modeling and biomechanical modeling-guided CBCT estimation technique (MM-Bio-CBCT), to further improve the liver tumor localization accuracy by incorporating a motion model into the CBCT estimation process. METHODS: MM-Bio-CBCT estimates new CBCT images through deforming a prior high-quality CT or CBCT volume. The deformation vector field (DVF) is solved by iteratively matching the digitally-reconstructed-radiographs (DRRs) of the deformed prior image to the acquired 2D cone-beam projections. Using the same solved DVF, the liver tumor volume contoured on the prior image can be transferred onto the new CBCT image for automatic tumor localization. To maximize the accuracy of the solved DVF, MM-Bio-CBCT employs two strategies for additional DVF optimization: (I) prior-knowledge-guided liver boundary motion modeling with motion patterns extracted from a prior 4D imaging set like 4D-CTs/4D-CBCTs, to improve the liver boundary DVF accuracy; and (II) finite-element-analysis-based biomechanical modeling of the liver volume to improve the intra-liver DVF accuracy. We evaluated the accuracy of MM-Bio-CBCT on both the digital extended-cardiac-torso (XCAT) phantom images and real liver patient images. The liver tumor localization accuracy of MM-Bio-CBCT was evaluated and compared with that of the purely intensity-driven 2D-3D deformation technique, the 2D-3D deformation technique with motion modeling, and the Bio-CBCT technique. Metrics including the DICE coefficient and the center-of-mass-error (COME) were assessed for quantitative evaluation. RESULTS: Using limited-view 20 projections for CBCT estimation, the average (± SD) DICE coefficients between the estimated and the ‘gold-standard’ liver tumors of the XCAT study were 0.57±0.31, 0.78±0.26, 0.83±0.21, and 0.89±0.11 for 2D-3D deformation, 2D-3D deformation with motion modeling, Bio-CBCT and MM-Bio-CBCT techniques, respectively. Using 20 projections for estimation, the patient study yielded average DICE results of 0.63±0.21, 0.73±0.13 and 0.78±0.12, and 0.83±0.09, correspondingly. The MM-Bio-CBCT localized the liver tumor to an average COME of ~2 mm for both the XCAT and the liver patient studies. CONCLUSIONS: Compared to Bio-CBCT, MM-Bio-CBCT further improves the accuracy of liver tumor localization. MM-Bio-CBCT can potentially be used towards pre-treatment liver tumor localization and intra-treatment liver tumor location verification to achieve substantial radiotherapy margin reduction.

Purpose To improve the accuracy of liver tumor localization, this study tests a biomechanical modeling-guided liver cone-beam CT (CBCT) estimation (Bio-CBCT-est) technique, which generates new CBCTs by deforming a prior high-quality CT or CBCT image using deformation vector fields (DVFs). The DVFs can be used to propagate tumor contours from the prior image to new CBCTs for automatic 4D tumor localization. Methods/Materials To solve the DVFs, the Bio-CBCT-est technique employs an iterative scheme that alternates between intensity-driven 2D-3D deformation and biomechanical modeling-guided DVF regularization and optimization. The 2D-3D deformation step solves DVFs by matching digitally reconstructed radiographs of the 3D deformed prior image to 2D phase-sorted on-board projections according to imaging intensities. This step’s accuracy is limited at low-contrast intra-liver regions without sufficient intensity variations. To boost the DVF accuracy in these regions, we use the intensity-driven DVFs solved at higher-contrast liver boundaries to fine-tune the intra-liver DVFs by finite element analysis-based biomechanical modeling. We evaluated Bio-CBCT-est’s accuracy with seven liver cancer patient cases. For each patient, we simulated 4D cone-beam projections from 4D-CT images, and used these projections for Bio-CBCT-est based image estimations. After Bio-CBCT-est, the DVF-propagated liver tumor/cyst contours were quantitatively compared with the manual contours on the original 4D-CT ‘reference’ images, using the DICE similarity index, the center-of-mass-error (COME), the Hausdorff distance (HD) and the voxel-wise cross-correlation (CC) metrics. In addition to simulation, we also performed a preliminary study to qualitatively evaluate the Bio-CBCT-est technique via clinically acquired cone beam projections. A quantitative study using an in-house deformable liver phantom was also performed. Results Using 20 projections for image estimation, the average (±s.d.) DICE index increased from 0.48 ± 0.13 (by 2D-3D deformation) to 0.77 ± 0.08 (by Bio-CBCT-est), the average COME decreased from 7.7 ± 1.5 mm to 2.2 ± 1.2 mm, the average HD decreased from 10.6 ± 2.2 mm to 5.9 ± 2.0 mm, and the average CC increased from −0.004 ± 0.216 to 0.422 ± 0.206. The tumor/cyst trajectory solved by Bio-CBCT-est matched well with that manually obtained from 4D-CT reference images. Conclusions Bio-CBCT-est substantially improves the accuracy of 4D liver tumor localization via cone-beam projections and a biomechanical model.

Purpose Variation in target positioning represents a challenge to set-up reproducibility and reliability of dose delivery with stereotactic body radiation therapy (SBRT) for pancreatic adenocarcinoma (PDAC). While on-board imaging for fiducial matching allows for daily shifts to optimize target positioning, the magnitude of the shift as a result of inter- and intra-fraction variation may directly impact target coverage and dose to organs-at-risk. Herein, we characterize the variation patterns for PDAC patients treated at a high-volume institution with SBRT. Methods We reviewed 30 consecutive patients who received SBRT using active breathing coordination (ABC). Patients were aligned to bone and then subsequently shifted to fiducials. Inter-fraction and intra-fraction scans were reviewed to quantify the mean and maximum shift along each axis, and the shift magnitude. A linear regression model was conducted to investigate the relationship between the inter- and intra-fraction shifts. Results The mean inter-fraction shift in the LR, AP, and SI axes was 3.1 ± 1.8 mm, 2.9 ± 1.7 mm, and 3.5 ± 2.2 mm, respectively, and the mean vector shift was 6.4 ± 2.3 mm. The mean intra-fraction shift in the LR, AP, and SI directions were 2.0 ± 0.9 mm, 2.0 ± 1.3 mm, and 2.3 ± 1.4 mm, respectively, and the mean vector shift was 4.3 ± 1.8 mm. A linear regression model showed a significant relationship between the inter- and intra-fraction shift in the AP and SI axis and the shift magnitude. Conclusions Clinically significant inter- and intra-fraction variation occurs during treatment of PDAC with SBRT even with a comprehensive motion management strategy that utilizes ABC. Future studies to investigate how these variations could lead to variation in the dose to the target and OAR should be investigated. Strategies to mitigate the dosimetric impact, including real time imaging and adaptive therapy, in select cases should be considered.

Purpose In patients undergoing stereotactic body radiation therapy (SBRT) for pancreatic adenocarcinoma, the reproducibility of tumor positioning between deep-inspiration breath holds is unclear. We characterized this variation with fiducials at simulation and treatment and investigated whether a patient-specific breath-hold (PSBH) margin would help account for intrafraction variation at treatment. Methods and Materials We analyzed 20 consecutive patients with pancreatic cancer who underwent SBRT with deep-inspiration breath holds. At simulation, 3 additional breath-hold scans were acquired immediately after the contrast-enhanced planning computed tomography (CT) scan and used to quantify the mean and maximum variations in the simulation fiducial position (Sim_Varavg and Sim_Varmax), as well as to design the internal target volume (ITV) incorporating a PSBH margin. Results At treatment, a mean of 5 breath-hold cone beam CT (CBCT) scans were acquired per fraction for each patient to quantify the mean and maximum variations in the treatment fiducial position (Tx_Varavg and Tx_Varmax). Various planning target volume (PTV) margins on the gross tumor volume (GTV) versus ITV were evaluated using CBCT scans, with the goal of >95% of fiducials being covered at treatment. The Sim_Varavg and Sim_Varmax were 0.9 ± 0.5 mm and 1.5 ± 0.8 mm in the left-right (LR) direction, 0.9 ± 0.4 mm and 1.4 ± 0.4 mm in the anteroposterior (AP) direction, and 1.5 ± 0.9 mm and 2.1 ± 1.0 mm in the superoinferior (SI) direction, respectively. The Tx_Varavg and Tx_Varmax were 1.2 ± 0.4 mm and 2.0 ± 0.7 mm in the LR direction, 1.1 ± 0.4 mm and 1.8 ± 0.6 mm in the AP direction, and 1.9 ± 1.0 mm and 3.1 ± 1.4 mm in the SI direction, respectively. The ITV was increased by 21.0% ± 8.6% compared with the GTV alone. The PTV margin necessary to encompass >95% of the fiducial locations was 2 mm versus 4 mm in both LR and AP and 4 mm versus 6 mm in SI for the ITV and the GTV, respectively. Conclusions The interbreath-hold variation is not insignificant, especially in the SI direction. Acquiring multiple breath-hold CT scans at simulation can help quantify the reproducibility of the interbreath hold and design a PSBH margin for treatment.

Purpose/objective(s) Multi-agent chemotherapy and radiation therapy (RT) has increased the proportion of locally advanced pancreatic cancer (LAPC) patients (pts) able to undergo resection and improve overall survival compared to those who are not resected. However, prior data from our institution (2016-2019) indicate that despite an R0 rate of 88%, LF developed in > 30% of LAPC pts resected after neoadjuvant therapy (NAT). This high LF rate is a rationale to explore dose escalation (DE) in the NAT setting, as data highlighting the value of DE have been limited to unresectable disease. Importantly, the optimal method for DE remains unclear. While conformal external beam RT can ablate part of the target, under-coverage in close proximity to the stomach and bowel remains problematic. For pancreatic head tumors, Whipple resection presents an opportunity for subsequent DE with IORT, as the duodenum is resected and direct access to microscopic peri-vascular residual disease is allowed. It also allows for precise DE based on the surgeons' recommendations. Herein, we model DE approaches, comparing pre-operative DE-IMRT with an approach in which a high-dose rate (HDR)-IORT boost is given after SBRT, with a goal biological effective dose (BED10) of 100 Gy. Materials/methods Ten consecutive LAPC pts were modeled with both DE-IMRT to 75 Gy in 25 fractions and SBRT to 40 Gy in 5 fractions followed by HDR-IORT to 15 Gy, using an 192Ir source. Notably, to minimize LF after surgery, our clinical tumor volume (CTV) has been the "Heidelberg Triangle" of tissue between the celiac, superior mesenteric, and common hepatic arteries and portal vein, which contains perineural and lymphatic tissue at risk of harboring subclinical disease. A 5mm planning tumor volume (PTV) expansion was used. A 3mm expansion on stomach and bowel was constrained to 60 Gy and 40 Gy for DE-IMRT and SBRT, respectively. For IORT modeling, the Freiburg Flap was superimposed on the planning CT, and dose was prescribed to the target volume surface. Given rapid dose fall-off with HDR-IORT, SBRT was optimized to compensate for IORT under-coverage, with higher dose allowed posteriorly but with an overall hotspot less than 50 Gy. Descriptive statistics were generated for coverage to target structures. Results With DE-IMRT, mean V75Gy for the CTV and PTV was only 79% +/- 14.4% and 52% +/- 13%, respectively. In comparison, posteriorly optimizing the SBRT plan in anticipation of anterior IORT supplementation improved coverage with ablative BED. For the anterior half of the target volume, HDR-IORT created a dose gradient of 10-15 Gy, whereas for the posterior half of the target volume, HDR-IORT created a dose gradient of 5-10 Gy. Optimizing the SBRT plan to complement this with 40 Gy to the anterior half of the volume and 45 Gy to the posterior half of the volume was feasible with > 90% coverage with BED10 of 100Gy in composite. Conclusion Dose escalation with SBRT/IORT may allow for better target coverage with ablative RT dose as compared to DE-IMRT and should be explored clinically.

OBJECTIVES Clinical concerns about hematologic toxicities in human immunodeficiency virus (HIV)+ patients with squamous cell anal cancer (SCAC) may lead to de-escalation of treatment intensity. The objective of this study is to evaluate clinical outcomes including toxicity following standard concurrent curative-intent chemoradiation for HIV+ and HIV- patients with SCAC. MATERIALS AND METHODS Among 97 evaluable patients treated between 2009 and 2016 (median age 52.2 y), 43 (44.3%) were HIV+ and 54 (55.7%) HIV-. The majority of the radiation was delivered using intensity-modulated radiation therapy and chemotherapy consisting primarily (93%) of 5-fluorouracil and mitomycin C. Clinical outcomes assessed included toxicity, locoregional control (LRC), distant metastasis (DM), progression-free survival (PFS), colostomy-free survival (CFS), overall survival (OS), and cause-specific survival (CSS). RESULTS With a median follow-up of 45 months, HIV+ patients exhibited a trend toward reduced OS compared with HIV- patients (4 y OS 61.2% vs. 78.3%; HR 2.09; 95% CI, 0.97-4.52; P=0.055) on univariable analysis, but HIV status was not significant after adjusting for additional parameters on multivariable analysis. Toxicity rates, LRC, CFS, PFS, freedom from DM, and CSS were similar between the 2 cohorts. On multivariable analysis, tumor size >5 cm impacted all clinical outcomes (trend for LRC) except CFS. Radiation treatment extension beyond 7 days was found to negatively impact LRC and CSS. Male sex was associated with worse CFS. CONCLUSIONS Radiation therapy with concurrent 5-fluorouracil and mitomycin C chemotherapy is reasonably well-tolerated as curative treatment for HIV+ patients with SCAC, and no significant difference in outcomes was noted relative to HIV- patients.

Purpose of Review Liver-directed SABR (stereotactic ablative body radiotherapy) is emerging as an effective local therapy option for HCC (hepatocellular carcinoma). This review summarizes recent clinical progresses and proposes future directions. Recent Findings SABR is an effective and safe, non-invasive local therapy option for HCC in the primary and salvage treatment settings, as well as a bridge to liver transplantation in selected patients. Randomized trials comparing SABR with other locoregional modalities are currently ongoing. Summary Research efforts are being made toward better predicting normal tissue toxicity and tumor radiosensitivity for a tailored maximal safe treatment in HCC SABR. More recently, potential synergy with immunotherapies is of increasing interest in HCC.

Purpose: Cancer-associated weight loss is associated with poor prognosis in advanced malignancy; however, its pretreatment prevalence and survival impact are inadequately described in large cohorts. Such data, stratified by tumor type and stage, may facilitate the optimal and timely allocation of complementary care, leading to improvements in patient survival and quality of life. Methods: We performed a retrospective cohort study of 3,180 consecutively treated adult patients with lung or GI (including colorectal, liver, and pancreatic) cancer. Pretreatment cancer-associated weight loss was based on the international consensus definition of cachexia. Prevalence and survival impact of pretreatment cancer-associated weight loss were evaluated using the Kaplan-Meier method and compared using log-rank test. Results: Cancer-associated weight loss was observed at the time of cancer diagnosis in 34.1% of patients. Pretreatment weight loss was documented in 17.6%, 25.8%, 36.6%, and 43.3% of stage I, II, III, and IV cancers, respectively. Wasting was common regardless of tumor type, with prevalence at diagnosis ranging from 27.3% in patients with colorectal cancer to 53.4% in patients with gastroesophageal cancer. Pretreatment weight loss was associated with reduced overall survival after adjusting for stage, size, grade, comorbidity, age, sex, and tobacco history (hazard ratio, 1.26; 95% CI, 1.13 to 1.39). Conclusion: Pretreatment cancer-associated weight loss is common, even in early-stage disease, and is independently associated with reduced survival. Minimal weight loss represents a clinically distinct entity with an associated overall survival intermediate to that of no weight loss and overt wasting. Early diagnosis and treatment of cancer-associated wasting offers a novel therapeutic avenue for reducing cancer mortality.

Purpose: Socioeconomic status (SES) influences health care outcomes, but the influence of primary payer on cancer-associated wasting is unknown. We hypothesized that primary payer as an indicator of SES would influence pretreatment cancer-associated weight loss and treatment outcomes. Materials and Methods: Retrospective review of medical records identified 1,366 patients with non–small-cell lung cancer (NSCLC) consecutively treated at a tertiary care health system between January 1, 2006 and December 31, 2013. Insurance status was obtained from an institutional tumor registry. Cancer-associated weight loss was based on the validated international consensus definition of cachexia. Multivariable regression analyses were used to identify prognostic factors of pretreatment cancer-associated weight loss and survival. Results: The cohort included a representative group of patients with a median age at diagnosis of 64 years, 47% females, and 33% patients of nonwhite race. Pretreatment cancer-associated weight loss was present at the time of NSCLC diagnosis in 17%, 14%, 32%, and 38% of patients with stage I, II, III, and IV disease, respectively. Pretreatment cancer-associated weight loss was associated with increasing age at diagnosis, black race, single marital status, tobacco use, and disease stage. Compared with private insurance, Medicaid insurance (odds ratio, 2.17; 95% CI, 1.42 to 3.30) and lack of insurance (odds ratio, 2.32; 95% CI, 1.50 to 3.58) were associated with pretreatment cancer-associated weight loss. Among cachectic patients, comorbidity, histology, tumor grade, and disease stage were prognostic of survival on multivariable analysis; however, primary payer was not. Conclusion: Pretreatment cancer-associated weight loss is common in patients with NSCLC, and its presence is significantly associated with lower SES. However, among patients with pretreatment cancer-associated weight loss, SES was not predictive of survival. Early use of cancer cachexia–directed therapies may improve outcomes, and further study on the biologic mechanisms of cancer cachexia will provide novel therapeutic avenues.

A variety of surgical and other local-regional approaches to the management of hepatocellular carcinoma (HCC) are in clinical use. External beam radiation therapy is a relative newcomer to the portfolio of treatment options. Advances in planning and delivery of radiation therapy, developing in parallel with and inspiring changing paradigms of tumor management in the field of radiation oncology, have led to growing interest in radiation therapy as a viable treatment option for HCC as well as other liver tumors. In this review, we discuss these advances, current trends in liver radiotherapy, as well as avenues of future clinical and basic research. Liver Transplantation 24 420-427 2018 AASLD.

PURPOSE/OBJECTIVE(S) To evaluate a novel technique for spatially fractionated (GRID) therapy of bulky tumors using proton pencil beam scanning (PBS) and to compare dosimetry to a photon arc (VMAT) technique. MATERIALS/METHODS PBS and VMAT GRID plans were generated for five patients with bulky tumors. GRID targets were arranged along the long axis of gross tumor, spaced at 2 cm and 3 cm apart, and treated with a prescription of 15 Gy in a single fraction. PBS plans utilized two-beam multiple-field optimization with robustness evaluation. Dosimetric parameters including peak-to-edge ratio (PEDR), ratio of dose to 90% of the valley to dose to 10% of the peak (VPDR (D90/D10)), and volume of normal tissue receiving at least 5 Gy (V5) and 10 Gy (V10) were calculated. RESULTS Gross tumor volume values ranged from 826-1468 cc. PEDR for PBS was higher than for VMAT at 7.2 ± 2.51 versus 2.4 ± 0.61 (2-cm spacing, P = 0.02), and 8.4 ± 2.00 versus 2.8 ± 0.37 (3-cm spacing, P = 0.01), respectively. VPDR (D90/D10) for PBS was lower than for VMAT at 0.034 ± 0.031 versus 0.41 ± 0.12 (2-cm spacing, P = 0.004), and 0.008 ± 0.007 versus 0.33 ± 0.08 (3-cm spacing, P = 0.002), respectively. Normal tissue V5 was lower for PBS than for VMAT at 343.2 cc ± 176.4 cc versus 917.6 cc ± 459.0 cc (2-cm spacing, P = 0.03), and 250.3 cc ± 114.7 cc versus 520.7 cc ± 181.1 cc (3-cm spacing, P = 0.02), respectively. Normal tissue mean dose was lower with PBS than with VMAT at 0.20 Gy ± 0.15 Gy versus 0.92 Gy ± 0.41 Gy (2-cm spacing, P = 0.03), and 0.17 Gy ± 0.11 Gy versus 0.82 Gy ± 0.33 Gy (3-cm spacing, P = 0.02), respectively. CONCLUSION PBS GRID for bulky tumors may result in improved dosimetry when compared to a VMAT approach. This PBS technique may be useful in bulky tumors that have a deep-seated location, complex shape, or adjacent critical organs.

Purpose/Objective(s) The role of radiation for pancreatic cancer remains controversial with heterogeneous clinical response. Characterization of molecular biomarkers that predict radiosensitivity may help select patients for radiation therapy. The purpose of this study was to determine if somatic mutations and mutational frequency are associated with pathologic and survival outcomes in a cohort of patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who were treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT) followed by surgical exploration. Materials/Methods Patients treated with neoadjuvant chemotherapy and SBRT followed by surgical exploration from 2017-2019 and who consented to next generation sequencing (NGS) of their primary tumor were included in the study. Tissue samples were obtained with FNA at initial biopsy (n = 5) or from surgical specimen (n = 38). Univariate (UVA) and multivariable analyses (MVA) were performed to determine associations between somatic mutations and variant allele frequency (VAF) with pathologic and survival outcomes. Local response was defined as achieving complete response, marked response, or moderate response on pathology. Results A total of 43 patients underwent NGS of their primary tumor with either solid tumor panel (n = 35) or Foundation One (n = 8). Neoadjuvant therapy consisted of FOLFIRNOX (n = 36) and/or gemcitabine/abraxane (n = 11) followed by SBRT in 33 Gy in 5 fractions (range, 30-36 Gy/5 fractions). Surgical resection was performed in 35/43 patients and aborted in 8/43. Median follow-up time was 20.4 months. Median OS, PFS, DMFS, and LPFS after SBRT were 21.3 months, 9.7 months, 10.0 months, and 22.0 months, respectively. KRAS mutations were observed in 96% (43/45) of patients. On UVA and MVA, tumors with KRAS G12V mutation demonstrated a higher local response rate to neoadjuvant therapy when compared to tumors with other KRAS mutations (100% vs 68.4%, P = 0.003). On UVA and MVA, alterations in NOTCH1/2 and KRAS VAF > 4.3 were associated with worse OS. The median OS for NOTCH1/2 mutated patients was 14.4 months vs 27.5 months in NOTCH1/2 wild type patients (P = 0.045). The median OS for patients with KRAS VAF > 4.3 was 13.8 months vs 31.3 months for patients with KRAS VAF ≤ 4.3 (P = 0.025). KRAS VAF > 4.3 was also associated with worse DMFS (median, not met vs 8.1 months; P = 0.043) and a trend towards significance with worse PFS (median, 8.1 months vs 13.9 months; P = 0.058). Conclusion Tumors with KRAS G12V mutation demonstrated a greater local response in BRPC and LAPC patients treated with neoadjuvant chemotherapy, SBRT, and surgery. Alterations in NOTCH1/2 and KRAS VAF > 4.3 were associated with worse OS. KRAS VAF > 4.3 was also associated with worse DMFS and PFS. As genetic characterization of pancreatic tumors becomes more universal, further investigation into the association between these mutations and radiation-specific response endpoints should be pursued.

PURPOSE/OBJECTIVE(S) Although overshadowed by metastatic failure, patients (pts) with locally advanced pancreatic adenocarcinoma (LAPC) who undergo resection after neoadjuvant therapy (NAT) also experience high rates of locoregional failure (LF). Prior data from our institution indicate LF developed in > 30% of LAPC pts resected after NAT with multi-agent chemotherapy (MA-CT) and RT from 2016-2019 despite an R0 rate of 88%. In this cohort, gross disease and involved vessels were the target, raising the question whether field design modification could reduce LF. Indeed, elective treatment of tissue at risk of harboring microscopic residual disease after resection may be critical, but consensus regarding what constitutes the CTV for NAT does not exist. In the surgical literature, support is growing for extended dissection of the "Heidelberg Triangle" (HT), tissue between the celiac artery (CA), superior mesenteric artery (SMA), common hepatic artery (CHA), and portal vein (PV) that contains key perineural and lymphatic tracts at risk of harboring subclinical disease. Whether this concept can be applied to CTV field design is unclear. In investigation, we mapped LF locations in LAPC pts to assess if the LF distribution matches the anatomy of the Triangle volume (TV). MATERIALS/METHODS A total of 21 consecutive LAPC pts with involvement of the head or neck at diagnosis treated at our institution with MA-CT and stereotactic body radiation who developed LF after resection were reviewed. The TV starts superiorly at the CA take-off point, extends along the CA to the trifurcation, then extends laterally along the CHA and stops at the proximal proper HA. At this lateral boundary, the PV is also included and the TV extends posteriorly to the aorta along the inferior vena cava, including the SMA take-off until the crossing of the left renal vein. From the lateral boundary of the PV, the volume descends to the superior mesenteric vein (SMV) and covers the groove between the SMA-SMV. The inferior boundary is the branching of the first jejunal artery (JA) from the SMA. Descriptive statistics were generated to report the frequency of LF in relation to the TV and the frequency of critical vasculature involvement. RESULTS In 21 consecutive pts, the median TV was 80.2 ± 30.1 cubic centimeters (cc) (27.7-110.3 cc). The LF centroid was located within the TV in 20 pts (95.2%). The SMA from take-off to the JA branch-point was the most common vessel involved at diagnosis (85.7%) and at failure (80.1%) with the next four being the CA (66.7%, 57.1%), SMV (61.9%, 66.7%), CHA (61.9%, 38.1%), and PV (38.1%, 47.6%). CONCLUSION The TV nearly universally encapsulates LF location and could serve as the basis for CTV design in the neoadjuvant setting. Future studies should investigate the feasibility of therapeutic dosimetry to this volume and ultimately whether treatment of the TV reduces LF.

Radiologists play a central role in the assessment of patient response to locoregional therapies for hepatocellular carcinoma (HCC). The identification of viable tumor following treatment guides further management and potentially affects transplantation eligibility. Liver Imaging Reporting and Data Systems (LI-RADS) first introduced the concept of LR-Treated in 2014, and a new Treatment Response Algorithm is included in the 2017 update to assist radiologists in image interpretation of HCC after locoregional therapy. In addition to offering imaging criteria for viable and nonviable HCC, new concepts of nonevaluable tumors as well as tumors with equivocal viability are introduced. Existing guidelines provided by Response Evaluation Criteria In Solid Tumors (RECIST) and modified RECIST address patient-level assessments and are routinely used in clinical trials but do not address the variable appearances following different locoregional therapies. The new LI-RADS Treatment Response Algorithm addresses this gap and offers a comprehensive approach to assess treatment response for individual lesions after a variety of locoregional therapies, using either contrast-enhanced CT or MRI.

Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with an increasing incidence in the United States. We aimed to characterize race- and sex-based disparities in receipt of therapy and overall survival (OS) of SCCA using the SEER database. Methods: Cases of locoregional SCCA (T2-T4 any N M0) diagnosed between 2000 and 2012 in the SEER database were included. Demographics, tumor characteristics, type of therapy, and outcomes were extracted. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HRs) and 95% CIs. Results: A total of 7,882 cases of locoregional SCCA were identified, with a median age of 58 years, 61.2% of whom were women, and 86.3% were white. Most patients (82.3%) received radiation therapy (RT), with the lowest rate in black men (76.7%) and the highest in white women (86.1%). The median OS was 135 months; OS was lower in elderly patients (age ≥65 years; 68 months), men (108 months), blacks (109 months), and those who did not receive RT (121 months). In multivariable analysis, age (HR, 1.19; 95% CI, 1.17-1.21 per 5 years increase), sex (HR, 1.59; 95% CI, 1.47-1.73, men vs women), race (HR, 1.51; 95% CI, 1.34-1.71, black vs white), and RT (HR, 0.90; 95% CI, 0.82-0.99) were independently associated with OS (P

Purpose Renal cell carcinoma is refractory to conventional radiation therapy but responds to higher doses per fraction. However, the dosimetric data and clinical factors affecting local control (LC) are largely unknown. We aimed to evaluate the safety and efficacy of stereotactic ablative radiation therapy (SAbR) for extracranial renal cell carcinoma metastases. Methods and Materials We reviewed 175 metastatic lesions from 84 patients treated with SAbR between 2005 and 2015. LC and toxicity after SAbR were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Predictors of local failure were analyzed with χ 2 , Kaplan-Meier, and log-rank tests. Results In most cases (74%), SAbR was delivered with total doses of 40 to 60 Gy, 30 to 54 Gy, and 20 to 40 Gy in 5 fractions, 3 fractions, and a single fraction, respectively. The median biologically effective dose (BED) using the universal survival model was 134.5 Gy. The 1-year LC rate after SAbR was 91.2% (95% confidence interval, 84.9%-95.0%; median follow-up, 16.7 months). Local failures were associated with prior radiation therapy (hazard ratio [HR], 10.49; P P =.0189), spinal location (HR, 5.36; P =.0041), previous systemic therapy status (0-1 vs >1; HR, 3.52; P =.0217), and BED P =.0254). Dose received by 99% of the target volume was the strongest dosimetric predictor for LC. Upon multivariate analysis, dose received by 99% of the target volume greater than BED of 98.7 Gy and systemic therapy status remained significant (HR, 0.12 and 3.64, with P =.0014 and P =.0472, respectively). Acute and late grade 3 toxicities attributed to SAbR were observed in 3 patients (1.7%) and 5 patients (2.9%), respectively. Conclusions SAbR demonstrated excellent LC of metastatic renal cell carcinoma with a favorable safety profile when an adequate dose and coverage were applied. Multimodality treatment with surgery should be considered for reirradiation or vertebral metastasis. A higher radiation dose may be required in patients who received previous systemic therapies.

Background There is continued debate regarding the optimal combinations of radiation therapy and chemotherapy in the preoperative treatment of locally advanced rectal adenocarcinomas. We report our single-institution experience of feasibility and early oncologic outcomes of short-course preoperative radiation therapy (5 Gy X 5 fractions) followed by consolidation neoadjuvant chemotherapy. Methods We reviewed the records of 26 patients with locally advanced rectal adenocarcinoma. All patients underwent short course radiotherapy (5 Gy X 5 fractions) followed by chemotherapy [either modified infusional and bolus 5-fluorouracail and oxalipatin (mFOLFOX6) or capecitabine and oxaliplatin] prior to consideration for surgery. A full course of chemotherapy was defined as at least 8 weeks of chemotherapy. Results There were five clinical (c) T2, 16 cT3, and five cT4 rectal tumors, with 88% cN+. Twenty-five patients received a median of 4 cycles (range 3 to 8) of mFOLFOX6 (with one cycle defined as a two-week period); one patient received 3 cycles of capecitabine and oxaliplatin. All patients completed SCRT; 81% completed the full course of neoadjuvant chemotherapy with 19% requiring dose reductions in chemotherapy, most commonly due to neuropathy. Nineteen patients underwent post-treatment endoscopic evaluation, and nine patients were noted to achieve a complete clinical response (CCR). Six of the nine patients who achieved CCR opted for a non-operative approach of watch-and-wait. Twenty patients underwent surgical resection; pathologic complete response was observed in seven (35%) of these twenty. The main radiation-associated toxicity was proctitis with CTCAE Grade 2 proctitis observed in seven patients (27%). Post-operative Clavien-Dindo Grade 3 complications within 30 days of surgery were identified in six patients (30%), with no Grade 4 or 5 adverse events. Median length of hospital stay was 4.5 days (range 2–16 days); three patients were readmitted within a 30 day period. Conclusions Short course preoperative radiotherapy followed by neoadjuvant chemotherapy was well-tolerated and achieved oncologic outcomes that compare favorably with short-course radiation therapy alone or long-course chemoradiotherapy. This regimen is associated with high rates of clinical and pathologic complete response.

4134 Background: Management of locally advanced pancreas cancer (LAPC) standardly involves chemotherapy with consolidative radiation and surgery in selected pts. Checkpoint inhibitors have shown limited benefit alone in pancreas cancer but may be primed by radiation and GM-CSF secreting allogeneic pancreatic cancer vaccine (GVAX). We present data from a phase 2 study for LAPC pts who have not developed metastases after standard of care chemotherapy treated with combination cyclophosphamide (CY), GVAX, pembrolizumab (pembro), and stereotactic body radiation therapy (SBRT). Methods: This is a single-arm, single institution, open-label study for pts with LAPC at diagnosis (as per NCCN guidelines, arterial involvement > 180°, or unreconstructible SMV/PV) who remained without metastatic disease after 4-8 28-day cycles FOLFIRINOX or gemcitabine/abraxane based therapy. Pts received CY (200mg/m2 IV) and pembro (200mg IV) on day 1, followed by GVAX (6 intradermal inj) on day 2 q3 wk x 2 cycles, with cycle 2 initiating concurrently with 5 days SBRT. Pts were restaged 4-6 weeks after SBRT, and if non-metastatic, pts underwent surgical resection, irreversible electroporation (IRE), or biopsy (if not undergoing surgical resection). Pts received two cycles of chemotherapy, and if metastasis free, received q3 wk CY/pembro/GVAX x 6 cycles with restaging scans q3 mos. In 5/2017, the protocol was addended to include an extended phase with q3 wk pembro x 9 cycles and q6 mo CY/GVAX x 4. Primary endpoint was distant metastasis free survival (DMFS) defined as C1D1 to distant metastases or death. Results: From Jul 2016-Jan 2021, 58 pts with LAPC were enrolled at the Johns Hopkins Hospital, 54 completed 2 cycles CY/pembro/GVAX and SBRT and were evaluable for response (2 dropouts due to thrombocytopenia, 2 due to irAE (DKA and hepatitis)), median followup was 15.8 mos. Demographics: median age 66 (range 42-84), 53% male, 84% White, 12% African American. At first restaging (N = 54), 8 (15%) had metastatic disease, 9 (17%) were unresectable, 37 (69%) were eligible for surgical resection. 35 pts proceeded to the OR (1 died of cholangitis prior to surgery and 1 declined surgery), 24 had tumors resected (44% of evaluable pts, 10 (42%) had grade 1 (marked) pathologic response), 1 IRE, 2 were unresectable, 8 were metastatic. Common related AEs were vaccine site reactions; grade 3 irAE included 1 case each of dermatitis, colitis, DKA, nephritis, and pneumonitis. DMFS was 9.7 mos [95% CI 6.3-19.3 mos]. Conclusions: We present data from a ph II study of 54 pts w LAPC treated w CY/GVAX/pembro and SBRT. Primary endpoint of DMFS > 13.6 mos not reached, however 44% of pts underwent surgical resection of whom 42% had grade 1 path response rate. Additional correlative studies are underway. Clinical trial information: NCT02648282.

Post-radiation therapy evaluation of distal esophageal cancers with positron emission tomography/computed tomography can be problematic. Differentiation of recurrent neoplasm from postradiation changes is difficult in areas of fluorodeoxyglucose avidity in adjacent, incidentally irradiated organs. Few studies have described the magnetic resonance imaging appearance of radiation-induced hepatic injury. We report a case of focal radiation-induced liver injury with a new focus of fluorodeoxyglucose uptake on posttreatment positron emission tomography as well as masslike enhancement and signal abnormality on magnetic resonance imaging, thus mimicking new liver metastasis. Correlation with radiation planning images suggested the correct diagnosis, which was confirmed on follow-up imaging.

Targeted immunotherapy has emerged as a potentially effective systemic treatment for metastatic cancer in the past decade. However, a significant fraction of patients will either not respond or develop resistance to immunotherapy due to the immune-evasive properties of cancer. Radiation therapy can augment immunotherapy to modulate the immune suppressive tumor microenvironment and promote specific tumor targeting by the adaptive immune system. In this review, we will discuss the rationale for combining radiation therapy with immunotherapy and describe clinical studies using this combination strategy to improve the treatment response by inducing synergistic and abscopal effects. We will discuss ongoing prospective clinical trials that employ the combination of radiation therapy and immunotherapy in the treatment of genitourinary malignancies. Further advances in these combination therapy strategies are expected to improve the clinical response and disease course while further providing insight to the complex interactions and regulations between the immune system and cancer cells. Multiple additional clinical trials will be required to find routine application of this concept to the clinic.

Cutaneous involvement as the presenting sign of internal carcinoma is rare and is associated with poor prognosis. Here we present the case of a 66-year-old woman with anorectal adenocarcinoma who presented with tumor involvement of the skin.

Purpose The purpose of this work was to compare the dosimetry and delivery times of 3D-conformal (3DCRT)-, volumetric modulated arc therapy (VMAT)-, and tomotherapy-based approaches for spatially fractionated radiation therapy for deep tumor targets. Methods Two virtual GRID phantoms were created consisting of 7 "target" cylinders (1-cm diameter) aligned longitudinally along the tumor in a honey-comb pattern, mimicking a conventional GRID block, with 2-cm center-to-center spacing (GRID2 cm ) and 3-cm center-to-center spacing (GRID3 cm ), all contained within a larger cylinder (8 and 10 cm in diameter for the GRID2 cm and GRID3 cm , respectively). In a single patient, a GRID3 cm structure was created within the gross tumor volume (GTV). Tomotherapy, VMAT (6 MV + 6 MV-flattening-filter-free) and multi-leaf collimator segment 3DCRT (6 MV) plans were created using commercially available software. Two tomotherapy plans were created with field widths (TOMO2.5 cm ) 2.5 cm and (TOMO5 cm ) 5 cm. Prescriptions for all plans were set to deliver a mean dose of 15 Gy to the GRID targets in one fraction. The mean dose to the GRID target and the heterogeneity of the dose distribution (peak-to-valley and peak-to-edge dose ratios) inside the GRID target were obtained. The volume of normal tissue receiving 7.5 Gy was determined. Results The peak-to-valley ratios for GRID2 cm /GRID3 cm /Patient were 2.1/2.3/2.8, 1.7/1.5/2.8, 1.7/1.9/2.4, and 1.8/2.0/2.8 for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The peak-to-edge ratios for GRID2 cm /GRID3 cm /Patient were 2.8/3.2/5.4, 2.1/1.8/5.4, 2.0/2.2/3.9, 2.1/2.7/5.2 and for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The volume of normal tissue receiving 7.5 Gy was lowest in the TOMO2.5 cm plan (GRID2 cm /GRID3 cm /Patient = 54 cm3 /19 cm3 /10 cm3 ). The VMAT plans had the lowest delivery times (GRID2 cm /GRID3 cm /Patient = 17 min/8 min/9 min). Conclusion Our results present, for the first time, preliminary evidence comparing IMRT-GRID approaches which result in high-dose "islands" within a target, mimicking what is achieved with a conventional GRID block but without high-dose "tail" regions outside of the target. These approaches differ modestly in their ability to achieve high peak-to-edge ratios and also differ in delivery times.

For patients with locally advanced rectal cancer, neoadjuvant hypofractionated short-course radiation remains an underutilized regimen in the USA. We review the current clinical literature highlighting the relative merits of short-course radiation, along with modern neoadjuvant strategies that incorporate its use. As compared to long-course chemoradiation with delayed surgery, short-course radiation with early surgery offers similar oncologic efficacy for locally advanced rectal cancer patients. Delaying surgery after short-course radiation decreases post-operative complications as compared to early surgery and improves tumor downstaging. Delaying surgery also offers the opportunity to administer neoadjuvant systemic therapy, which may help increase local-regional tumor response and potentially decrease distant relapse rates, the latter a persisting problem in rectal cancer treatment. Short-course radiation, either with immediate or with delayed surgery, represents an appealing treatment alternative to long-course chemoradiation for patients with locally advanced rectal cancer.

There are differing definitions regarding what portion of the large intestine should be considered “rectum” as opposed to “colon.” The transition from intra- to extraperitoneal rectum results in potentially disparate patterns of spread for rectal cancer dependent on tumor location relative to the peritoneal reflection. Here we report the case of a 50-year-old woman with a mid to upper rectal adenocarcinoma who presented with a synchronous biopsy-proven tumor implant in the peritoneal cavity. Her case highlights issues of varying definitions of organ anatomy within the literature, the role of primary tumor localization within different compartments of the abdominopelvic cavity for predicting potential routes of tumor spread, and the implications for adjuvant therapies.

Evidence supporting the synergistic antitumor activity of radiation therapy combined with immune checkpoint inhibitors is rapidly growing. Investigators should consider the characteristics and challenges of gastrointestinal (GI) cancers to evaluate the safety and clinical effectiveness of this combination. In this paper, we present the rationale for exploring this strategy and the opportunities it possesses to challenge our standard of care. We also discuss unique considerations to systematically develop this combination in GI cancers.

Background Nitric oxide donors decreased cell survival in vitro and tumor load in vivo in models of rectal cancer subjected to ionizing radiation. Nitroglycerin (NTG) transdermal patches, added to chemotherapy, have been shown to improve outcomes in lung cancer patients. Methods This open-label, nonrandomized, multicohort, dose escalation, phase I trial had a primary endpoint to evaluate the safety, tolerability, feasibility, dose-limiting toxicity and maximum tolerated dose of topical NTG in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of locoregionally advanced operable rectal cancer. The secondary endpoint was rate of pathologic complete response (pCR). Patients were assigned to 3 sequential cohorts of escalating dose levels of commercially available NTG patches (0.2, 0.4, and 0.6 mg/h), each cohort was intended to consist of 3 patients. Results Thirteen patients were enrolled in the trial as specified in the dose escalation protocol. They were all male with a median age of 59.4 ± 2.5 (SEM) years. The observed toxicities were mild to moderate and manageable. Four patients developed asymptomatic grade 3 lymphopenia during the chemoradiation that resolved promptly upon completion. One patient had a non-ST segment elevation MI and 1 patient developed diarrhea. None of these toxicities were attributed to NTG except for 1 patient who developed a grade 3 headache. This required an additional group of patients at the same dose and no other patient experienced headaches. pCR was 17%. Conclusion NTG patches are well-tolerated and it is feasible to proceed with a phase II trial at the maximum dose examined (0.6 mg/h).

Our understanding of metastatic disease is constantly evolving. Survival outcomes for patients with colorectal cancer metastatic to the liver are poor, although a subset of patients with limited or “oligometastatic” disease may exist in a therapeutic window amenable to aggressive local intervention. The purpose of this review is to describe and compare the range of non-surgical local treatment options available for the treatment of oligometastatic colorectal disease involving the liver.

Background There is significant interest in the use of stereotactic ablative radiotherapy (SABR) as a treatment modality for liver metastases. A variety of SABR fractionation schemes are in clinical use. We conducted a phase I dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR. Methods Patients with liver metastases from solid tumors, for whom a critical volume dose constraint could be met, were treated with single-fraction SABR. Seven patients were enrolled to the first group, with a prescription dose of 35 Gy. Dose was then escalated to 40 Gy in a single fraction, and seven more patients were treated at this dose level. Patients were followed for toxicity and underwent serial imaging to assess lesion response and local control. Results Fourteen patients with 17 liver metastases were treated. There were no dose-limiting toxicities observed at either dose level. Nine of the 13 lesions assessable for treatment response showed a complete radiographic response to treatment; the remainder showed partial response. Local control of irradiated lesions was 100 % at a median imaging follow-up of 2.5 years. Two-year overall survival for all patients was 78 %. Conclusions For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy is tolerable and shows promising signs of efficacy at intermediate follow-up.

In this edition of the Gastrointestinal Oncology Scan, our group has selected several interesting updates of large wellknown randomized trials, and a recent phase 2 trial, that shed further light on earlier results and highlight ongoing areas of debate. These offer a nice complement to some of our earlier Oncology Scans, bringing you the best literature around the journal landscape in gastrointestinal cancers (1-4). The first is the CROSS trial, a landmark study from the Netherlands, which established preoperative radiation given concurrently with carboplatin and paclitaxel, as opposed to surgery alone, as the standard of care for esophageal cancer (5). The follow-up publication provides patterns of failure data, which confirms the expected local control benefit of radiation therapy (6). The second trial is an update on the well-known German Rectal Trial, which cemented preoperative chemoradiation as standard therapy for locally advanced rectal cancer (7). The updated analysis provides important data on the correlation of pathologic response and disease outcome(8).Thequestionofadjuvantchemotherapy for patients with rectal cancer is highlighted in the third update of the EORTC 22921 trial (9). Many clinicians extrapolate from colon cancer data to support the use of adjuvant chemotherapy for high-risk patients. The long-term results of this trial question the soundness of that approach. Finally, the last report we discuss is a phase 2 trial from investigators at Memorial-Sloan Kettering using preoperative chemotherapy alone for locally advanced rectal cancer (10). The results suggest that for carefully selected patients, radiation may be omitted without a compromise in outcome. This approachisnowbeingtestedinarandomizedprospectivetrial.

Radiation therapy as a viable and major treatment option for liver metastases is a relatively recent development in clinical oncology. The limited role of radiation has largely been due to the availability of surgery and percutaneous thermal ablation therapies, as well as the relative radiosensitivity of the liver. Technological advances in treatment planning and radiation delivery have enabled the safe and effective application of hypofractionated radiation treatments to liver tumors, including patients with colorectal cancer liver metastases. In this chapter, I discuss current clinical practice regarding the management of colorectal cancer liver metastases as well as practical details of treatment planning.

There is interest in improving the tumoricidal effects of preoperative radiotherapy for rectal carcinoma by studying new radiosensitizers. The safety and toxicity profile of these combination regimens needs rigorous clinical evaluation. The primary objective of this study was to evaluate the toxicity of combining bavituximab, an antibody that targets exposed phosphatidylserine, with capecitabine and radiation therapy.Patients with stage II or III rectal adenocarcinoma were enrolled on a phase I study combining radiation therapy, capecitabine, and bavituximab. A standard 3+3 trial designed was used.In general, bavituximab was safe and well tolerated in combination with radiation therapy and capecitabine in the treatment of rectal adenocarcinoma. One patient at the highest dose level experienced a grade III infusion reaction related to the bavituximab. One tumor demonstrated a complete pathologic response to the combination treatment.Bavituximab is safe in combination with capecitabine and radiation therapy at the doses selected for the study. Further clinical investigation would be necessary to better define the efficacy of this combination.

Controversies in the selection of radiation treatment dose and fractionation pattern are an important, and ongoing, chapter in the history of radiation oncology. The recent expansion of the clinical practice of extracranial hypofractionated radiation therapy, made possible by advances in radiation treatment planning and image guidance, has raised an important host of biological questions with immediate clinical implications. In this chapter, we provide an overview of some of these questions, concluding with a discussion of the systemic effects of local therapies.