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Abstract: Colorectal cancer is one of the most common malignancies in the United States as well as a leading cause of cancer-related death. Upward of 30% of patients ultimately develop metastatic disease, most commonly to the liver and lung. Untreated, patients have poor survival. Historically, patients with oligometastatic disease were treated with resection leading to long-term survival; however, there are many patients who are not surgical candidates. Innovations in thermal ablation, hepatic artery infusions, chemoembolization and radioembolization, and stereotactic ablative radiation have led to an expansion of patients eligible for local therapy. This review examines the evidence behind each modality for the most common locations of oligometastatic colorectal cancer., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

There is debate about why stereotactic body radiation therapy (SBRT) produces superior control of hepatocellular cancer (HCC) compared to fractionated treatment. Both preclinical and clinical evidence has been presented to support a "classic" biological explanation: the greater BED of SBRT produces more DNA damage and tumor cell kill. More recently, preclinical evidence has supported the concept of a "new biology", particularly radiation-induced vascular collapse, which increases hypoxia and free radical activation. This is hypothesized to cause much greater tumor cell death than was produced by the initial radiation-induced DNA damage to the tumor. We decided to investigate if vascular collapse occurs after standard SBRT for patients with HCC. Eight patients with 10 lesions underwent dynamic contrast enhanced MRI at the time of simulation and either 48 or 96 hours after the first fraction. Only three of 10 tumors showed a decrease in blood flow. These findings suggest that vascular collapse does not typically occur after SBRT for HCC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy., Objective: To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control., Design, Setting, and Participants: This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3)., Intervention: Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3., Main Outcome: Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up., Results: In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects)., Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials., Trial Registration: ClinicalTrials.gov Identifier: NCT01463423.

Purpose: Although arterial phase enhancement is commonly used to evaluate treatment response for hepatocellular carcinoma, it may not accurately describe response for lesions treated with stereotactic body radiation therapy (SBRT). We aimed to describe the post-SBRT imaging findings to better inform the optimal timing of salvage therapy after SBRT., Methods and Materials: We retrospectively reviewed patients with hepatocellular carcinoma treated with SBRT from 2006 to 2021 at a single institution with available imaging showing lesions with characteristic arterial enhancement and portal venous washout. Patients were then stratified into 3 groups based on treatment: (1) concurrent SBRT and transarterial chemoembolization, (2) SBRT only, and (3) SBRT followed by early salvage therapy due to persistent enhancement. Overall survival was analyzed with the Kaplan-Meier method, and cumulative incidences were calculated with competing risk analysis., Results: We included 82 lesions in 73 patients. The median follow-up time was 22.3 months (range, 2.2-88.1 months). The median time to overall survival was 43.7 months (95% confidence interval, 28.1-57.6 months) and median progression-free survival was 10.5 months (95% confidence interval, 7.2-14.0 months). There were 10 (12.2%) lesions that experienced local progression and there was no difference in rates of local progression between the 3 groups (P = .32). In the SBRT-only group, the median time to resolution of arterial enhancement and washout was 5.3 months (range, 1.6-23.7 months). At 3, 6, 9, and 12 months, 82%, 41%, 13%, and 8% of lesions, respectively, continued to show arterial hyperenhancement., Conclusions: Tumors treated with SBRT may continue to exhibit persistence of arterial hyperenhancement. Without an increase in size of enhancement, continued surveillance may be appropriate for these patients., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Pancreatic stereotactic body radiation therapy (SBRT) is limited to gross tumor without elective coverage for subclinical disease. Given a better understanding of recurrence patterns, we hypothesized that the addition of elective nodal irradiation (ENI) to pancreatic SBRT would be tolerable and would decrease locoregional progression., Methods and Materials: We conducted a retrospective 1:2 propensity-matched cohort study to compare toxicity and locoregional progression among patients treated with pancreatic SBRT with or without ENI. In the SBRT + ENI cohort, an elective target volume was delineated per Radiation Therapy Oncology Group guidelines and treated to 25 Gy in 5 fractions alongside 40 Gy in 5 fractions to gross disease. The primary outcome was the cumulative incidence of locoregional progression, with death as a competing risk., Results: Among 135 candidate controls treated with SBRT alone, 100 were propensity-matched to 50 patients treated with SBRT + ENI. All patients completed SBRT. Median potential radiographic follow-up was 28 months. The incidence of late and serious acute toxicity was similar between matched cohorts. However, SBRT + ENI was associated with a statistically significant increase in acute grade 1 to 2 nausea (60% vs 20%, P < .001). The 24-month cumulative incidences of locoregional progression with and without ENI were 22.6% (95% confidence interval [CI], 10.0%-35.1%) versus 44.6% (95% CI, 34.8%-54.4%; multivariable-adjusted hazard ratio, 0.39; 95% CI, 0.18-0.87; P = .021). This was stable in sensitivity analyses of uniform prescription dose, multiagent chemotherapy, and resectability. There were fewer peripancreatic (0% vs 7%), porta hepatis (2% vs 7%), and peri-aortic/aortocaval (5% vs 12%) recurrences after SBRT + ENI, but no difference in survival., Conclusions: Pancreatic SBRT + ENI was tolerable and did not increase late or serious acute toxicity relative to a matched cohort undergoing SBRT alone, but did increase acute grade 1 to 2 nausea. The addition of ENI to SBRT was associated with decreased locoregional progression but not improved survival. Further studies are warranted to determine whether ENI offers meaningful benefit., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: William A. HallResearch Funding: ElektaTravel, Accommodations, Expenses: Elekta Laura A. DawsonResearch Funding: Merck Theodore S. HongStock and Other Ownership Interests: PanTher TherapeuticsConsulting or Advisory Role: Merck, Synthetic Biologics, Novocure, SyndaxResearch Funding: Taiho Pharmaceutical, AstraZeneca, IntraOp, Tesaro, Bristol Myers Squibb, Ipsen Manisha PaltaHonoraria: OakstoneConsulting or Advisory Role: Syntactx, VoxelMetrixResearch Funding: Merck, Varian Medical SystemsPatents, Royalties, Other Intellectual Property: UpToDate—Annual royalties for being a section author Joseph M. HermanHonoraria: Sirtex MedicalTravel, Accommodations, Expenses: Varian Medical SystemsOther Relationship: 1440 Foundation Jason B. FlemingLeadership: Bio-Path Holdings, IncConsulting or Advisory Role: Johnson and Johnson, GlycosBio, Moleculin Biotech, Perthera, Covidien LP/Medtronic, PanTher TherapeuticsPatents, Royalties, Other Intellectual Property: US Application No. 15/780,799, based on International Application No. PCT/US2016/065763, titled Polymeric Drug Delivery Systems for Treatment of Disease, by Chun Li et al; In the Name of Board of Regents, The University of Texas System Daniel T. ChangStock and Other Ownership Interests: ViewRayResearch Funding: Varian Medical Systems, Reflexion MedicalOther Relationship: ViewRay Christopher CraneStock and Other Ownership Interests: Oncternal TherapeuticsHonoraria: ElektaConsulting or Advisory Role: TriSalus Life SciencesResearch Funding: Elekta Albert C. KoongStock and Other Ownership Interests: Aravive Parag ParikhStock and Other Ownership Interests: NuvairaHonoraria: ViewRaySpeakers' Bureau: ViewrayResearch Funding: ViewRayTravel, Accommodations, Expenses: IBA Beth EricksonResearch Funding: ElektaTravel, Accommodations, Expenses: Elekta Sarah HoffeStock and Other Ownership Interests: VitalAireHonoraria: UpToDateConsulting or Advisory Role: MerckResearch Funding: Varian Medical Systems, Galera TherapeuticsPatents, Royalties, Other Intellectual Property: I cowrote the bone metastases chapter for UpToDate. They pay royalties/honoraria for that yearlyTravel, Accommodations, Expenses: Varian Medical SystemsOther Relationship: Beyond the White Coat, VitalAireUncompensated Relationships: Galera Therapeutics, ViewRay Karyn A. GoodmanConsulting or Advisory Role: RenovoRx, Roche/Genentech, NovartisNo other potential conflicts of interest were reported.

Purpose: The aim of this study was to report local failure (LF) outcomes and associated predictors in patients with oligometastatic colorectal cancer (CRC) treated with stereotactic ablative radiotherapy (SABR)., Materials and Methods: We retrospectively reviewed patients with CRC metastases to the brain, liver, spine, or lung treated with SABR between 2001 and 2016. Time to LF was summarized using cumulative incidence of LF curves with death as a competing risk., Results: The analysis included a total of 130 patients and 256 lesions. Of the metastases treated, 129 (50%) were brain, 50 (20%) liver, 49 (19%) spine, and 28 (11%) lung. Median gross tumor volume was 24 mL for liver metastases, 2 mL for brain metastases, 4 mL for spine metastases, and 1 mL for lung metastases. The overall 1, 2, and 3-year cumulative incidence of LF rates were 21.6% (16.5, 27.1), 28.2% (22.3, 34.4), and 31.5% (25.2, 38.0), respectively. LF was highest among the liver metastases (1 y: 26.0%, 2 y: 38.5%), followed by spine (1 y: 25.1%, 2 y: 31.1%), brain (1 y: 20%, 2 y: 25.2%), and lung (1 y: 13.7%, 2 y: insufficient data). Metastases from right-sided primary CRC were significantly more likely to have LF (P=0.0146, HR=2.23). Biologically effective dose>70 Gy, defined using a standard linear quadratic model using α/β ratio of 10 on the individual lesion level, and pre-SABR chemotherapy were also significant predictors of LF (P= 0.0009 and 0.018, respectively)., Conclusions: CRC metastases treated with SABR had significantly higher rates of LF if they originated from right-sided primary CRC, compared with left-sided. Liver metastases had the highest rates of LF compared with other metastatic sites. Thus, CRC liver metastases and metastases from right-sided CRC may benefit from more aggressive radiotherapy., Competing Interests: S.G.S.: Inovio Pharmaceuticals Inc. (Consultant), Zap Surgical Inc. (Speaker Honoraria), Novocure (Research Funding). B.W.L.Jr: TibaRay (Board member, Cofounder, Stock ownership), Varian Medical Systems (Research funding). E.L.P.: Accuray (Honorarium), Genentech (Research Funding). The remaining authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: We evaluated the outcomes of metastatic pancreatic cancer (MPC) patients who underwent liver metastases (LMs)-directed ablative radiotherapy (RT) and sought to characterize patients with more favorable prognosis., Methods: A retrospective analysis of 76 MPC patients who underwent ablative RT (median dose, 50 Gy) to LM at 3 academic centers between 2008 and 2018 was performed. Endpoints were local control (LC), progression-free survival, and overall survival (OS) since RT., Results: Median follow-up was 10.9 months. Liver metastases were metachronous in 68%. Before RT, LM was responsive/stable on chemotherapy (CTX) in 36% whereas progressive in 43%. Median carbohydrate antigen 19-9 (CA 19-9) at RT was 334 U/mL. After RT, 32% had ≥6 months of CTX break. Twelve-month outcomes were: LC, 66%; progression-free survival, 7%; and OS, 38%. On multivariable analysis, Eastern Cooperative Oncology Group 2-3 (hazard ratio [HR], 13.49; P < 0.01), progressive LM on CTX (HR, 3.26; P < 0.01), and higher CA 19-9 (log10 scale; HR, 1.39; P < 0.01) at RT predicted worse OS., Conclusions: Ablative RT to LM in setting of MPC may offer LC of systemic disease and thus quality time off CTX. Selected patients with good performance status, stable/responsive LM on CTX, and lower CA 19-9 have more favorable prognosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: We aimed to report the long-term impact of modern chemotherapy and SABR dose regimens on oncologic outcomes of unresectable pancreatic adenocarcinoma (PA)., Materials and Methods: We reviewed the treatment characteristics and outcomes of all patients who received multi-fraction SABR for unresectable PA between February 2007 and August 2018 at our institution. Time-to-events were calculated from date of diagnosis treating death as a competing risk., Results: A total of 149 patients were identified. Median follow-up was 15 months (range: 5-47). Median SABR dose was 33 Gy (range: 20-45) delivered in 5 fractions in 143 patients, and 3 or 6 fractions in 6 patients. 107 patients (72%) received gemcitabine-based chemotherapy while 31 (21%) received modified FOLFIRINOX (mFFX). Median OS was 16 months (95% CI, 14-17), with a 1-year cumulative incidence of LF of 14%. The combination of SABR doses ≥40 Gy and mFFX (n = 21) showed a superior PFS and OS to the use of GEM-based chemotherapy with <40 Gy SABR doses (median PFS: 14 vs. 10 months, HR: 0.46, 95% CI: 0.29-0.71, P = 0.003; median OS: 24 vs. 14 months, HR: 0.36, 95% CI: 0.22-0.59, P = 0.002), with 1-year PFS and OS of 67% and 90% compared to 35% and 59% for those who received GEM-based chemotherapy with <40 Gy SABR doses, respectively., Conclusions: The use of mFFX and a SABR dose ≥40 Gy in 5 fractions may be superior compared to regimens that utilize gemcitabine-based chemotherapy or SABR doses <40 Gy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Radiation therapy (RT) is prescribed for curative and palliative treatment for around 50% of patients with solid tumors. Radiation-induced toxicities of healthy organs accompany many RTs and represent one of the main limiting factors during dose delivery. The existing RT planning solutions generally discard spatial dose distribution information and lose the ability to recognize radiosensitive regions of healthy organs potentially linked to toxicity manifestation. This study proposes a universal deep learning-based algorithm for recognitions of consistent dose patterns and generation of toxicity risk maps for the abdominal area., Methods: We investigated whether convolutional neural networks (CNNs) can automatically associate abdominal computed tomography (CT) images and RT dose plans with post-RT toxicities without being provided segmentation of abdominal organs. The CNNs were also applied to study RT plans, where doses at specific anatomical regions were reduced/increased, with the aim to pinpoint critical regions sparing of which significantly reduces toxicity risks. The obtained risk maps were computed for individual anatomical regions inside the liver and statistically compared to the existing clinical studies., Results: A database of 122 liver stereotactic body RT (SBRT) executed at Stanford Hospital from July 2004 and November 2015 was assembled. All patients treated for primary liver cancer, mainly hepatocellular carcinoma and cholangiocarcinoma, with complete follow-ups were extracted from the database. The SBRT treatment doses ranged from 26 to 50 Gy delivered in 1-5 fractions for primary liver cancer. The patients were followed up for 1-68 months depending on the survival time. The CNNs were trained to recognize acute and late grade 3+ biliary stricture/obstruction, hepatic failure or decompensation, hepatobiliary infection, liver function test (LFT) elevation or/and portal vein thrombosis, named for convenience hepatobiliary (HB) toxicities. The toxicity prediction accuracy was of 0.73 measured in terms of the area under the receiving operator characteristic curve. Significantly higher risk scores (P < 0.05) of HB toxicity manifestation were associated with irradiation for the hepatobiliary tract in comparison to the risk scores for liver segments I-VIII and portal vein. This observation is in strong agreement with anatomical and clinical expectations., Conclusion: In this work, we proposed and validated a universal deep learning-based solution for the identification of radiosensitive anatomical regions. Without any prior anatomical knowledge, CNNs automatically recognized the importance of hepatobiliary tract sparing during liver SBRT., (© 2020 American Association of Physicists in Medicine.)

Purpose: Our purpose was to report the outcome of stereotactic ablative radiation therapy (SABR) to the primary tumor for patients with metastatic pancreatic cancer., Methods and Materials: We examined the records of patients with metastatic pancreatic cancer treated with SABR to the primary tumor between 2002 and 2018. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. Pain intensity pre- and post-SABR was scored according to the Stanford Pain Scale as reported by the patient. Time-to-events were calculated from the date of end of SABR delivery., Results: In total, 27 patients were identified that met the inclusion criteria. Seventeen (63%) patients received single fraction SABR with a median dose of 25 Gy (range, 12.5-25), and 10 (37%) patients were treated in 5 fractions with a median dose of 33 Gy (range, 25-40). Before the start of SABR, 17 (63%) patients reported having abdominal pain, with a median intensity of 5 in the 0 to 10 pain scale (range, 1-9), 11 (41%) of them needing continuous opioid use. The median follow-up was 6 months (range, 0-18). Median overall survival was 7 months (95% confidence interval, 3-10), with a cumulative incidence of local failures at 1 year of 25% (95% confidence interval, 10-44). After SABR, there was a significant reduction in the mean intensity of pain (P = .01), and a 46% relative reduction in continuous opioid use. Only 2 patients (7%) presented a grade 3 toxicity that could be attributed to treatment., Conclusions: In this small series, SABR was a safe and effective option for the local palliation of metastatic pancreatic cancer, with measurable improvements in abdominal pain and the need for opioids., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Nonrandomized data exploring pancreas stereotactic body radiation therapy (SBRT) has demonstrated excellent local control rates and low toxicity. Before commencing a randomized trial investigating pancreas SBRT, standardization of prescription dose, dose constraints, simulation technique, and clinical target volume delineation are required., Methods and Materials: Specialists in radiation oncology, medical oncology, hepatobiliary surgery, and gastroenterology attended 2 consecutive Australasian Gastrointestinal Trials Group workshops in 2017 and 2018. Sample cases were discussed during workshop contact with specifically invited international speakers highly experienced in pancreas SBRT. Furthermore, sample cases were contoured and planned between workshop contact to finalize dose constraints and clinical target volume delineation., Results: Over 2 separate workshops, consensus was reached on dose and simulation technique. The working group recommended a dose prescription of 40 Gy in 5 fractions. Treatment delivery during end-expiratory breath hold with triple-phase contrast enhanced computed tomography was recommended. In addition, dose constraints, stepwise contouring guidelines, and an anatomic atlas for pancreatic SBRT were developed., Conclusions: Pancreas SBRT is emerging as a promising treatment modality requiring prospective evaluation in randomized studies. This work attempts to standardize dose, simulation technique, and volume delineation to support the delivery of high quality SBRT in a multicenter study., (Copyright © 2019 American Society for Radiation Oncology. All rights reserved.)

Background and Purpose: The optimal neoadjuvant approach in patients with resectable pancreas cancer is unclear. We investigated outcomes after preoperative chemotherapy alone, chemotherapy with conventionally-fractionated radiation (CFRT), or chemotherapy with stereotactic body radiotherapy (SBRT)., Materials and Methods: The NCDB was queried for patients with resectable pancreatic adenocarcinoma (pretreatment stage T1-3, N0-1, M0) who received preoperative, multiagent chemotherapy and definitive surgery from 2010 to 2015. CFRT was 40-60 Gy in 20-35 fractions. SBRT was 20-25 Gy in 1 fraction or 30-50 Gy using at least 5 Gy per fraction. Multivariable regression and propensity score matching were used to adjust for potential confounders, including age, comorbidity score, and pretreatment extent of disease. The primary outcome was overall survival measured from surgery., Results: In total, 1355 patients received preoperative chemotherapy alone, 552 patients received preoperative chemotherapy with CFRT, and 175 patients received preoperative chemotherapy with SBRT. Receipt of SBRT was associated with significantly improved overall survival compared to chemotherapy alone (median 30 vs 21 months, p = 0.02; adjusted hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.47-0.90, p = 0.01). Similarly, SBRT was associated with significantly improved overall survival compared to CFRT (median 29 vs 16 months, p = 0.002; adjusted HR 0.53, 95% CI 0.37-0.76, p = 0.001). Additionally, SBRT was associated with significantly increased rates of pathological complete response and margin-negative resection. Rates of postoperative readmissions and mortality were comparable., Conclusions: Neoadjuvant chemotherapy with SBRT is associated with favorable survival and pathological outcomes, warranting consideration for prospective validation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Stereotactic body radiation therapy (SBRT) is a relatively novel treatment modality, with little post-treatment prognostic information reported. This study proposes a novel neural network based paradigm for accurate prediction of liver SBRT outcomes. We assembled a database of patients treated with liver SBRT at our institution. Together with a three-dimensional (3-D) dose delivery plans for each SBRT treatment, other variables such as patients' demographics, quantified abdominal anatomy, history of liver comorbidities, other liver-directed therapies, and liver function tests were collected. We developed a multi-path neural network with the convolutional path for 3-D dose plan analysis and fully connected path for other variables analysis, where the network was trained to predict post-SBRT survival and local cancer progression. To enhance the network robustness, it was initially pre-trained on a large database of computed tomography images. Following n-fold cross-validation, the network automatically identified patients that are likely to have longer survival or late cancer recurrence, i.e., patients with the positive predicted outcome (PPO) of SBRT, and vice versa, i.e., negative predicted outcome (NPO). The predicted results agreed with actual SBRT outcomes with 56% of PPO patients and 0% NPO patients with primary liver cancer survived more than two years after SBRT. Similarly, 82% of PPO patients and 0% of NPO patients with metastatic liver cancer survived two-year threshold. The obtained results were superior to the performance of support vector machine and random forest classifiers. Furthermore, the network was able to identify the critical-to-spare liver regions, and the critical clinical features associated with the highest risks of negative SBRT outcomes.

Surgical resection or liver transplantation offers the best chance of cure for patients with hepatocellular carcinoma (HCC). Unfortunately, most patients are not good candidates for liver resection due to locally advanced disease or compromised liver function. Moreover, liver transplantation waiting lists are long. For those cases not amenable for resection, a variety of local treatment modalities are available, such as image-guided ablative procedures, transarterial chemoembolization, and radioembolization, as well as external beam radiation. HCC presentation can vary considerably in size, number, and location of lesions. The management of inoperable HCC is, therefore, quite complex, and there is a lack of consensus on the best local treatment modality for each type tumor presentation. Here, we present 4 clinical case scenarios representative of commonly seen cases in the clinical setting, with different therapeutic perspectives from institutions with high expertise in the management of HCC., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: To explore seromarker levels for associations with outcomes in locally advanced pancreatic cancer (LAPC) patients who received chemotherapy and stereotactic body radiation therapy (SBRT)., Methods and Materials: Serum from LAPC patients in 2 prospective trials of hypofractionated SBRT (5-6.6 Gy × 5) was collected before SBRT. Proximity ligation assay quantified the expression levels of 36 pancreatic cancer-specific candidate seromarkers: Axl, BMP2, CA 125, CA 19-9, CEA, CXCL-1/6/9/10, EGFR, Gas6, Her2, IGF-2, IGFBP-2/3/7, IL-6/6Ra/7/8/12, mesothelin, MMP-1/2/3/7, osteopontin, PDGFRa, PDK1, PF4, RegIV, SPARC, TGF-β, VEGF-A/D, and YKL40. Seromarker values were log transformed owing to log-normal distribution of the values, and Cox regression analysis was performed to assess for any association with overall survival. The Benjamini-Hochberg method was used to control for a false discovery rate (FDR) of only 10%., Results: Sixty-four patients with LAPC were included. No clinical factors (including surgical resection, receipt of pre-SBRT chemotherapy, receipt of post-SBRT chemotherapy, performance status, and age) or potential biomarkers in the panel were associated with improved survival in this cohort after application of the FDR correction. Potential prognostic factors for improved survival for future investigation included surgical resection (P=.007, adjusted P=.153) and the serum expression of IL-8 (P=.006, adjusted P=.153), CA 19-9 (P=.031, adjusted P=.377), and MMP-1 (P=.036, adjusted P=.377)., Conclusions: These data explore the expression of a panel of proteins in pre-SBRT serum of LAPC patients in the context of a conservative FDR correction. None of the clinical factors or expression levels of the serum proteins were found to be associated with survival; however, IL-8, CA 19-9, and MMP-1 were highlighted as possible candidates warranting inclusion in future seromarker studies in the ongoing efforts to identify tools for risk stratification and treatment allocation in LAPC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Although stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy has become an established standard of care for the treatment of a variety of malignancies, our understanding of normal tissue dose tolerance with extreme hypofractionation remains immature. Since Timmerman initially proposed normal tissue dose constraints for SBRT in the 2008 issue of Seminars of Radiation Oncology, experience with SBRT has grown, and more long-term clinical outcome data have been reported. This article reviews the modern toxicity literature and provides updated clinically practical and useful recommendations of SBRT dose constraints for extracranial sites. We focus on the major organs of the thoracic and upper abdomen, specifically the liver and the lung., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose To assess the cost-effectiveness of stereotactic body radiation therapy (SBRT) versus radiofrequency ablation (RFA) for patients with inoperable localized hepatocellular carcinoma (HCC) who are eligible for both SBRT and RFA. Materials and Methods A decision-analytic Markov model was developed for patients with inoperable, localized HCC who were eligible for both RFA and SBRT to evaluate the cost-effectiveness of the following treatment strategies: (a) SBRT as initial treatment followed by SBRT for local progression (SBRT-SBRT), (b) RFA followed by RFA for local progression (RFA-RFA), (c) SBRT followed by RFA for local progression (SBRT-RFA), and (d) RFA followed by SBRT for local progression (RFA-SBRT). Probabilities of disease progression, treatment characteristics, and mortality were derived from published studies. Outcomes included health benefits expressed as discounted quality-adjusted life years (QALYs), costs in U.S. dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analysis was performed to assess the robustness of the findings. Results In the base case, SBRT-SBRT yielded the most QALYs (1.565) and cost $197 557. RFA-SBRT yielded 1.558 QALYs and cost $193 288. SBRT-SBRT was not cost-effective, at $558 679 per QALY gained relative to RFA-SBRT. RFA-SBRT was the preferred strategy, because RFA-RFA and SBRT-RFA were less effective and more costly. In all evaluated scenarios, SBRT was preferred as salvage therapy for local progression after RFA. Probabilistic sensitivity analysis showed that at a willingness-to-pay threshold of $100 000 per QALY gained, RFA-SBRT was preferred in 65.8% of simulations. Conclusion SBRT for initial treatment of localized, inoperable HCC is not cost-effective. However, SBRT is the preferred salvage therapy for local progression after RFA. © RSNA, 2017 Online supplemental material is available for this article.

Purpose: This study aims to determine how the albumin-bilirubin (ALBI) score compares with the Child-Pugh (CP) score for assessing liver function following stereotactic body radiation therapy (SBRT)., Methods and Materials: In total, 60 patients, 40 with hepatocellular carcinoma (HCC) and 20 with cholangiocarcinoma (CCA), were treated with SBRT. Liver function panels were obtained before and at 1, 3, 6, and 12 months after SBRT. Laboratory values were censored after locoregional recurrence, further liver-directed therapies, or liver transplant., Results: A significant decline in hepatic function occurred after SBRT for HCC patients only (P = .001 by ALBI score; P < .0001 by CP score). By converting radiation doses to biologically equivalent doses by using a standard linear quadratic model using α/β of 10, the strongest dosimetric predictor of liver function decline for HCC was the volume of normal liver irradiated by a dose of 40 Gy when assessing liver function by the ALBI score (P = .07), and the volume of normal liver irradiated by a dose of 20 Gy by using the CP score (P= .0009). For CCA patients, the volume of normal liver irradiated by a dose of 40 Gy remained the strongest dosimetric predictor when using the ALBI score (P = .002), but no dosimetric predictor was significant using the CP score. Hepatic function decline correlated with worse overall survival for HCC (by ALBI, P = .0005; by CP, P < .0001) and for CCA (by ALBI, P = NS; by CP, P = .008)., Conclusions: ALBI score was similarly able to predict hepatic function decline compared with CP score, and both systems correlated with survival., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Evaluation of local tumor progression (LP) has typically been defined by contrast-enhanced computed tomography (CT) imaging after stereotactic body radiation therapy (SBRT) for locally advanced pancreatic cancer (PDAC). The purpose of this study is to determine the benefit of adding 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging to CT for LP assessment of PDAC after SBRT., Methods and Materials: We retrospectively reviewed pretreatment, follow-up images, and outcomes of all patients treated with definitive SBRT for unresectable PDAC between December 2002 and December 2015 at our institution. For each patient, we independently analyzed LP both by CT and by FDG-PET criteria, using the Response Evaluation Criteria In Solid Tumors version 1.1 and the FDG-PET Response Evaluation Criteria In Solid Tumors version 1.0, respectively., Results: Among 206 patients treated with definitive SBRT for unresectable PDAC, we identified 30 with LP on follow-up. Four did not undergo follow-up FDG-PET. Median time to LP after SBRT was 7.5 months (range, 2-25 months). Of the 26 patients with LP who had follow-up FDG-PET, 21 were diagnosed by FDG-PET (80.7%), 14 by CT (53.8%), and 9 by both FDG-PET and CT (34.6%). Use of CT alone revealed only 53.8% of cases of LP detected when FDG-PET and CT were combined. The cumulative incidence of LP, based on competing risk of death, at 1 and 2 years after SBRT was 9.6% and 16.7% by CT and 11% and 29.1% by FDG-PET, respectively., Conclusion: FDG-PET increases the chance of detecting LP of unresectable PDAC after SBRT and can have an important impact on reported outcomes. We recommend obtaining FDG-PET to assess treatment response when evaluating efficacy of SBRT and taking its use into account when comparing clinical data., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: To further explore the correlation of central biliary tract (cHBT) radiation doses with hepatobiliary toxicity (HBT) after stereotactic body radiation therapy (SBRT) in a larger patient dataset., Methods: We reviewed the treatment and outcomes of all patients who received SBRT for primary liver cancer (PLC) and metastatic liver tumors between July 2004 and November 2015 at our institution. The cHBT was defined as isotropic expansions (5, 10, 15, 20 and 25mm) from the portal vein (PV). Doses were converted to biologically effective doses by using the standard linear quadratic model with α/β of 10 (BED 10 ). HBT was graded according to the Common Terminology Criteria for Adverse Events v4.03., Results: Median follow-up was 13months. Out of the 130 patients with complete follow-up records analyzed, 60 (46.1%) had liver metastases, 40 (30.8%) had hepatocellular carcinoma (HCC), 26 (20%) had cholangiocarcinoma (CCA) and 4 (3.1%) patients other PLC histologies. Thirty-three (25.4%) grade 2+ and 28 (21.5%) grade 3+ HBT were observed. Grade 3+ HBT was seen in 13 patients (50%) with CCA, 7 patients (17.5%) with HCC and 7 (11.7%) patients with liver metastases. SBRT doses to the cHBT were highly associated with HBT, but only for PLC patients when analyzed by histological subtype. The 15mm expansion from the PV (cHBT 15 ) proved to be an appropriate surrogate for the cHBT. The strongest cHBT 15 dose predictors for G3+ HBT for PLC were the V BED10 40⩾37cc (p<0.0001) and the V BED10 30⩾45cc (p<0.0001)., Conclusion: SBRT doses to the cHBT are associated with occurrence of HBT only in PLC patients. Limiting the dose to the cHBT to V BED10 40<37cc and V BED10 30<45cc when treating PLC patients with SBRT may reduce the risk of HBT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: We previously reported clinical outcomes and physician-reported toxicity of gemcitabine and hypofractionated stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (LAPC). Here we prospectively investigate the impact of gemcitabine and SBRT on patient-reported quality of life (QoL)., Methods and Materials: Forty-nine LAPC patients received 33 Gy SBRT (6.6 Gy daily fractions) upfront or after ≤3 doses of gemcitabine (1000 mg/m 2 ) followed by gemcitabine until progression. European Organization for Research and Treatment of Cancer QoL core cancer (QLQ-C30) and pancreatic cancer-specific (European Organization for Research and Treatment of Cancer QLQ-PAN26) questionnaires were administered to patients pre-SBRT and at 4 to 6 weeks (first follow-up [1FUP]) and 4 months (2FUP) post-SBRT. Changes in QoL scores were deemed clinically relevant if median changes were at least 5 points in magnitude., Results: Forty-three (88%) patients completed pre-SBRT questionnaires. Of these, 88% and 51% completed questionnaires at 1FUP and 2FUP, respectively. There was no change in global QoL from pre-SBRT to 1FUP (P = .17) or 2FUP (P > .99). Statistical and clinical improvements in pancreatic pain (P = .001) and body image (P = .007) were observed from pre-SBRT to 1FUP. Patients with 1FUP and 2FUP questionnaires reported statistically and clinically improved body image (P = .016) by 4 months. Although pancreatic pain initially demonstrated statistical and clinical improvement (P = .020), scores returned to enrollment levels by 2FUP (P = .486). A statistical and clinical decline in role functioning (P = .002) was observed in patients at 2FUP., Conclusions: Global QoL scores are not reduced with gemcitabine and SBRT. In this exploratory analysis, patients experience clinically relevant short-term improvements in pancreatic cancer-specific symptoms. Previously demonstrated acceptable clinical outcomes combined with these favorable QoL data indicate that SBRT can be easily integrated with other systemic therapies and may be a potential standard of care option in patients with LAPC., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: To present a system for robotic 4D ultrasound (US) imaging concurrent with radiotherapy beam delivery and estimate the proportion of liver stereotactic ablative body radiotherapy (SABR) cases in which robotic US image guidance can be deployed without interfering with clinically used VMAT beam configurations., Methods: The image guidance hardware comprises a 4D US machine, an optical tracking system for measuring US probe pose, and a custom-designed robot for acquiring hands-free US volumes. In software, a simulation environment incorporating the LINAC, couch, planning CT, and robotic US guidance hardware was developed. Placement of the robotic US hardware was guided by a target visibility map rendered on the CT surface by using the planning CT to simulate US propagation. The visibility map was validated in a prostate phantom and evaluated in patients by capturing live US from imaging positions suggested by the visibility map. In 20 liver SABR patients treated with VMAT, the simulation environment was used to virtually place the robotic hardware and US probe. Imaging targets were either planning target volumes (PTVs, range 5.9-679.5 ml) or gross tumor volumes (GTVs, range 0.9-343.4 ml). Presence or absence of mechanical interference with LINAC, couch, and patient body as well as interferences with treated beams was recorded., Results: For PTV targets, robotic US guidance without mechanical interference was possible in 80% of the cases and guidance without beam interference was possible in 60% of the cases. For the smaller GTV targets, these proportions were 95% and 85%, respectively. GTV size (1/20), elongated shape (1/20), and depth (1/20) were the main factors limiting the availability of noninterfering imaging positions. The robotic US imaging system was deployed in two liver SABR patients during CT simulation with successful acquisition of 4D US sequences in different imaging positions., Conclusions: This study indicates that for VMAT liver SABR, robotic US imaging of a relevant internal target may be possible in 85% of the cases while using treatment plans currently deployed in the clinic. With beam replanning to account for the presence of robotic US guidance, intrafractional US may be an option for 95% of the liver SABR cases.

Purpose: To identify prognostic biomarkers in pancreatic cancer using high-throughput quantitative image analysis., Methods and Materials: In this institutional review board-approved study, we retrospectively analyzed images and outcomes for 139 locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy (SBRT). The overall population was split into a training cohort (n=90) and a validation cohort (n=49) according to the time of treatment. We extracted quantitative imaging characteristics from pre-SBRT (18)F-fluorodeoxyglucose positron emission tomography, including statistical, morphologic, and texture features. A Cox proportional hazard regression model was built to predict overall survival (OS) in the training cohort using 162 robust image features. To avoid over-fitting, we applied the elastic net to obtain a sparse set of image features, whose linear combination constitutes a prognostic imaging signature. Univariate and multivariate Cox regression analyses were used to evaluate the association with OS, and concordance index (CI) was used to evaluate the survival prediction accuracy., Results: The prognostic imaging signature included 7 features characterizing different tumor phenotypes, including shape, intensity, and texture. On the validation cohort, univariate analysis showed that this prognostic signature was significantly associated with OS (P=.002, hazard ratio 2.74), which improved upon conventional imaging predictors including tumor volume, maximum standardized uptake value, and total legion glycolysis (P=.018-.028, hazard ratio 1.51-1.57). On multivariate analysis, the proposed signature was the only significant prognostic index (P=.037, hazard ratio 3.72) when adjusted for conventional imaging and clinical factors (P=.123-.870, hazard ratio 0.53-1.30). In terms of CI, the proposed signature scored 0.66 and was significantly better than competing prognostic indices (CI 0.48-0.64, Wilcoxon rank sum test P<1e-6)., Conclusion: Quantitative analysis identified novel (18)F-fluorodeoxyglucose positron emission tomography image features that showed improved prognostic value over conventional imaging metrics. If validated in large, prospective cohorts, the new prognostic signature might be used to identify patients for individualized risk-adaptive therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To identify dosimetric predictors of hepatobiliary (HB) toxicity associated with stereotactic body radiation therapy (SBRT) for liver tumors., Methods and Materials: We retrospectively reviewed 96 patients treated with SBRT for primary (53%) or metastatic (47%) liver tumors between March 2006 and November 2013. The central HB tract (cHBT) was defined by a 15-mm expansion of the portal vein from the splenic confluence to the first bifurcation of left and right portal veins. Patients were censored for toxicity upon local progression or additional liver-directed therapy. HB toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0. To compare different SBRT fractionations, doses were converted to biologically effective doses (BED) by using the standard linear quadratic model α/β = 10 (BED10)., Results: Median follow-up was 12.7 months after SBRT. Median BED10 was 85.5 Gy (range: 37.5-151.2). The median number of fractions was 5 (range: 1-5), with 51 patients (53.1%) receiving 5 fractions and 29 patients (30.2%) receiving 3 fractions. In total, there were 23 (24.0%) grade 2+ and 18 (18.8%) grade 3+ HB toxicities. Nondosimetric factors predictive of grade 3+ HB toxicity included cholangiocarcinoma (CCA) histology (P<.0001), primary liver tumor (P=.0087), and biliary stent (P<.0001). Dosimetric parameters most predictive of grade 3+ HB toxicity were volume receiving above BED10 of 72 Gy (VBED1072) ≥ 21 cm(3) (relative risk [RR]: 11.6, P<.0001), VBED1066 ≥ 24 cm(3) (RR: 10.5, P<.0001), and mean BED10 (DmeanBED10) cHBT ≥14 Gy (RR: 9.2, P<.0001), with VBED1072 and VBED1066 corresponding to V40 and V37.7 for 5 fractions and V33.8 and V32.0 for 3 fractions, respectively. VBED1072 ≥ 21 cm(3), VBED1066 ≥ 24 cm(3), and DmeanBED10 cHBT ≥14 Gy were consistently predictive of grade 3+ toxicity on multivariate analysis., Conclusions: VBED1072, VBED1066, and DmeanBED10 to cHBT are associated with HB toxicity. We suggest VBED1072 < 21 cm(3) (5-fraction: V40 < 21 cm(3); 3-fraction: V33.8 < 21 cm(3)), VBED1066 < 24 cm(3) (5-fraction: V37.7 < 24 cm(3); 3-fraction: V32 < 24 cm(3)) as potential dose constraints for the cHBT when clinically indicated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC)., Methods: A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m(2)) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT., Results: The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥ 2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections., Conclusions: Fractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy., (© 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Pancreatic cancer (PCA) remains a disease with a poor prognosis. The majority of PCA patients are unable to undergo surgical resection, which is the only potentially curative option at this time. A combination of chemotherapy and chemoradiation (CRT) are standard options for patients with locally advanced, unresectable disease, however, local control and patient outcomes remains poor. Stereotactic body radiation therapy (SBRT) is an emerging treatment option for PCA. SBRT delivers potentially ablative doses to the pancreatic tumor plus a small margin over a short period of time. Early studies with single-fraction SBRT demonstrated excellent tumor control with high rates of toxicity. The implementation of SBRT (3-5 doses) has demonstrated promising outcomes with favorable tumor control and toxicity rates. Herein we discuss the evolving role of SBRT in PCA treatment.

Purpose: We report updated outcomes of single- versus multifraction stereotactic body radiation therapy (SBRT) for unresectable pancreatic adenocarcinoma., Methods and Materials: We included 167 patients with unresectable pancreatic adenocarcinoma treated at our institution from 2002 to 2013, with 1-fraction (45.5% of patient) or 5-fraction (54.5% of patients) SBRT. The majority of patients (87.5%) received chemotherapy., Results: Median follow-up was 7.9 months (range: 0.1-63.6). The 6- and 12-month cumulative incidence rates (CIR) of local recurrence for patients treated with single-fraction SBRT were 5.3% (95% confidence interval [CI], 0.2%-10.4%) and 9.5% (95% CI, 2.7%-16.2%), respectively. The 6- and 12-month CIR with multifraction SBRT were 3.4% (95% CI, 0.0-7.2%) and 11.7% (95% CI, 4.8%-18.6%), respectively. Median survival from diagnosis for all patients was 13.6 months (95% CI, 12.2-15.0 months). The 6- and 12- month survival rates from SBRT for the single-fraction group were 67.0% (95% CI, 57.2%-78.5%) and 30.8% (95% CI, 21.9%-43.6%), respectively. The 6- and 12- month survival rates for the multifraction group were 75.7% (95% CI, 67.2%-85.3%) and 34.9% (95% CI, 26.1%-46.8%), respectively. There were no differences in CIR or survival rates between the single- and multifraction groups. The 6- and 12-month cumulative incidence rates of gastrointestinal toxicity grade ≥3 were 8.1% (95% CI, 1.8%-14.4%) and 12.3% (95% CI, 4.7%-20.0%), respectively, in the single-fraction group, and both were 5.6% (95% CI, 0.8%-10.5%) in the multifraction group. There were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT (P=.005). Local recurrence and toxicity grade ≥2 were independent predictors of worse survival., Conclusions: Multifraction SBRT for pancreatic cancer significantly reduces gastrointestinal toxicity without compromising local control., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Most patients diagnosed with pancreatic cancer are unable to have a curative surgical resection. Chemoradiation is a standard of care treatment for patients with locally advanced unresectable disease, but local failure rates are high with conventionally fractionated radiotherapy. However, stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy offers an alternative type of radiation therapy, which allows for the delivery of high-dose, conformal radiation. The high doses and shorter overall treatment time with SBRT may provide advantages in local control, disease outcomes, quality of life, and cost-effectiveness, and further investigation is currently underway. Here, we review the technology behind SBRT for pancreatic malignancy and its future direction in the overall management of pancreatic cancer., (© 2013 Published by Elsevier Inc.)

Purpose: To determine how the respiratory phase impacts dose to normal organs during stereotactic body radiation therapy (SBRT) for pancreatic cancer., Methods and Materials: Eighteen consecutive patients with locally advanced, unresectable pancreatic adenocarcinoma treated with SBRT were included in this study. On the treatment planning 4-dimensional computed tomography (CT) scan, the planning target volume (PTV), defined as the gross tumor volume plus 3-mm margin, the duodenum, and the stomach were contoured on the end-expiration (CTexp) and end-inspiration (CTinsp) phases for each patient. A separate treatment plan was constructed for both phases with the dose prescription of 33 Gy in 5 fractions with 95% coverage of the PTV by the 100% isodose line. The dose-volume histogram (DVH) endpoints, volume of duodenum that received 20 Gy (V20), V25, and V30 and maximum dose to 5 cc of contoured organ (D5cc), D1cc, and D0.1cc, were evaluated., Results: Dosimetric parameters for the duodenum, including V25, V30, D1cc, and D0.1cc improved by planning on the CTexp compared to those on the CTinsp. There was a statistically significant overlap of the PTV with the duodenum but not the stomach during the CTinsp compared to the CTexp (0.38 ± 0.17 cc vs 0.01 ± 0.01 cc, P=.048). A larger expansion of the PTV, in accordance with a Danish phase 2 trial, showed even more overlapping volume of duodenum on the CTinsp compared to that on the CTexp (5.5 ± 0.9 cc vs 3.0 ± 0.8 cc, P=.0003) but no statistical difference for any stomach dosimetric DVH parameter., Conclusions: Dose to the duodenum was higher when treating on the inspiratory than on the expiratory phase. These data suggest that expiratory gating may be preferable to inspiratory breath-hold and free breathing strategies for minimizing risk of toxicity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To verify the geometric accuracy of gated RapidArc treatment using kV images acquired during dose delivery., Methods and Materials: Twenty patients were treated using the gated RapidArc technique with a Varian TrueBeam STx linear accelerator. One to 7 metallic fiducial markers were implanted inside or near the tumor target before treatment simulation. For patient setup and treatment verification purposes, the internal target volume (ITV) was created, corresponding to each implanted marker. The gating signal was generated from the Real-time Position Management (RPM) system. At the beginning of each fraction, individualized respiratory gating amplitude thresholds were set based on fluoroscopic image guidance. During the treatment, we acquired kV images immediately before MV beam-on at every breathing cycle, using the on-board imaging system. After the treatment, all implanted markers were detected, and their 3-dimensional (3D) positions in the patient were estimated using software developed in-house. The distance from the marker to the corresponding ITV was calculated for each patient by averaging over all markers and all fractions., Results: The average 3D distance between the markers and their ITVs was 0.8 ± 0.5 mm (range, 0-1.7 mm) and was 2.1 ± 1.2 mm at the 95th percentile (range, 0-3.8 mm). On average, a left-right margin of 0.6 mm, an anterior-posterior margin of 0.8 mm, and a superior-inferior margin of 1.5 mm is required to account for 95% of the intrafraction uncertainty in RPM-based RapidArc gating., Conclusion: To our knowledge, this is the first clinical report of intrafraction verification of respiration-gated RapidArc treatment in stereotactic ablative radiation therapy. For some patients, the markers deviated significantly from the ITV by more than 2 mm at the beginning of the MV beam-on. This emphasizes the need for gating techniques with beam-on/-off controlled directly by the actual position of the tumor target instead of external surrogates such as RPM., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Radiotherapy may improve the outcome of patients with pancreatic cancer but at an increased cost. In this study, the authors evaluated the cost-effectiveness of modern radiotherapy techniques in the treatment of locally advanced pancreatic cancer., Methods: A Markov decision-analytic model was constructed to compare the cost-effectiveness of 4 treatment regimens: gemcitabine alone, gemcitabine plus conventional radiotherapy, gemcitabine plus intensity-modulated radiotherapy (IMRT); and gemcitabine with stereotactic body radiotherapy (SBRT). Patients transitioned between the following 5 health states: stable disease, local progression, distant failure, local and distant failure, and death. Health utility tolls were assessed for radiotherapy and chemotherapy treatments and for radiation toxicity., Results: SBRT increased life expectancy by 0.20 quality-adjusted life years (QALY) at an increased cost of $13,700 compared with gemcitabine alone (incremental cost-effectiveness ratio [ICER] = $69,500 per QALY). SBRT was more effective and less costly than conventional radiotherapy and IMRT. An analysis that excluded SBRT demonstrated that conventional radiotherapy had an ICER of $126,800 per QALY compared with gemcitabine alone, and IMRT had an ICER of $1,584,100 per QALY compared with conventional radiotherapy. A probabilistic sensitivity analysis demonstrated that the probability of cost-effectiveness at a willingness to pay of $50,000 per QALY was 78% for gemcitabine alone, 21% for SBRT, 1.4% for conventional radiotherapy, and 0.01% for IMRT. At a willingness to pay of $200,000 per QALY, the probability of cost-effectiveness was 73% for SBRT, 20% for conventional radiotherapy, 7% for gemcitabine alone, and 0.7% for IMRT., Conclusions: The current results indicated that IMRT in locally advanced pancreatic cancer exceeds what society considers cost-effective. In contrast, combining gemcitabine with SBRT increased clinical effectiveness beyond that of gemcitabine alone at a cost potentially acceptable by today's standards., (Copyright © 2011 American Cancer Society.)

Purpose: This Phase II trial evaluated the toxicity, local control, and overall survival in patients treated with sequential gemcitabine and linear accelerator-based single-fraction stereotactic body radiotherapy (SBRT)., Methods and Materials: Twenty patients with locally advanced, nonmetastatic pancreatic adenocarcinoma were enrolled on this prospective single-institution, institutional review board-approved study. Gemcitabine was administered on Days 1, 8, and 15, and SBRT on Day 29. Gemcitabine was restarted on Day 43 and continued for 3-5 cycles. SBRT of 25 Gy in a single fraction was delivered to the internal target volume with a 2- 3-mm margin using a nine-field intensity-modulated radiotherapy technique. Respiratory gating was used to account for breathing motion. Follow-up evaluations occurred at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT., Results: All patients completed SBRT and a median of five cycles of chemotherapy. Follow-up for the 2 remaining alive patients was 25.1 and 36.4 months. No acute Grade 3 or greater nonhematologic toxicity was observed. Late Grade 3 or greater toxicities occurred in 1 patient (5%) and consisted of a duodenal perforation (G4). Three patients (15%) developed ulcers (G2) that were medically managed. Overall, median survival was 11.8 months, with 1-year survival of 50% and 2-year survival of 20%. Using serial computed tomography, the freedom from local progression was 94% at 1 year., Conclusion: Linear accelerator-delivered SBRT with sequential gemcitabine resulted in excellent local control of locally advanced pancreatic cancer. Future studies will address strategies for reducing long-term duodenal toxicity associated with SBRT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: This study was undertaken to determine outcomes of stereotactic body radiotherapy for colorectal liver metastases in a pooled patient cohort., Methods: Patients with colorectal liver metastases from 3 institutions were included if they had 1 to 4 lesions, received 1 to 6 fractions of stereotactic body radiotherapy, and had radiologic imaging ≥ 3 months post-treatment. Sixty-five patients with 102 lesions treated from August 2003 to May 2009 were retrospectively analyzed. A tumor control probability (TCP) model was used to estimate the 3-fraction dose required for > 90% local control after converting the schedule into biologically equivalent dose (BED), single-fraction equivalent dose, or linear quadratic model-based single-fraction dose., Results: Forty-seven (72%) patients had ≥ 1 chemotherapy regimen before stereotactic body radiotherapy, and 27 (42%) patients had ≥ 2 regimens. The median follow-up was 1.2 years (range, 0.3-5.2 years). The median dose was 42 gray (Gy; range, 22-60 Gy). When evaluated separately by multivariate analysis, total dose (P = .0015), dose/fraction (P = .003), and BED (P = .004) all correlated with local control by lesion. On multivariate analysis, nonactive extrahepatic disease was associated with overall survival (OS; P = .046), and sustained local control was closely correlated (P = .06). By using single-fraction equivalent dose, BED, or linear quadratic model-based single-fraction dose in the TCP model, the estimated dose range needed for 1-year local control > 90% is 46 to 52 Gy in 3 fractions., Conclusions: Liver stereotactic body radiotherapy is well tolerated and effective for colorectal liver metastases. The strong correlation between local control and OS supports controlling hepatic disease even for heavily pretreated patients. For a 3-fraction regimen of stereotactic body radiotherapy, a prescription dose of ≥ 48 Gy should be considered, if normal tissue constraints allow., (Cancer 2011 © 2011 American Cancer Society.)

Stereotactic body radiotherapy (SBRT) is an emerging treatment for pancreas cancer and liver tumors. Early data suggest excellent control rates for locally advanced pancreas cancer. However, due to the close proximity of the duodenum and stomach, steps to effectively minimize toxicities must be taken through image guidance of treatments. SBRT for liver tumors has also shown high rates of local control with low risks for hepatic toxicity. Careful selection of cases for SBRT is essential to achieve disease control and to minimize toxicity for patients. In treatment, attention must be paid to minimizing exposure of nearby normal tissues, including ribs, skin and bowel as well as the functioning organs surrounding the tumors. There is no accepted standard for the SBRT dose/fractionation schedule for these cases and the optimal strategy will likely depend on the size, number and location of lesions for each patient. However, the published data seem to suggest an overall dose-response effect. To realize the clinical potential of SBRT for these tumors, investigations are needed to determine optimum fractionation schedules and to integrate its use with systemic chemotherapy programs., (Copyright © 2011 S. Karger AG, Basel.)

Introduction: Dose escalation for pancreas cancer is limited by the tolerance of adjacent normal tissues, especially with stereotactic body radiotherapy (SBRT). The duodenum is generally considered to be the organ at greatest risk. This study reports on the dosimetric determinants of duodenal toxicity with single-fraction SBRT., Methods and Materials: Seventy-three patients with locally advanced unresectable pancreatic adenocarcinoma received 25 Gy in a single fraction. Dose-volume histogram (DVH) endpoints evaluated include V(5) (volume of duodenum that received 5 Gy), V(10), V(15), V(20), V(25), and D(max) (maximum dose to 1 cm(3)). Normal tissue complication probability (NTCP) was evaluated with a Lyman model. Univariate and multivariate analyses were conducted with Kaplan-Meier and Cox regression models., Results: The median time to Grade 2-4 duodenal toxicity was 6.3 months (range, 1.6-11.8 months). The 6- and 12-month actuarial rates of toxicity were 11% and 29%, respectively. V(10)-V(25) and D(max) all correlated significantly with duodenal toxicity (p<0.05). In particular, V(15)≥9.1 cm(3) and V(15)<9.1 cm(3) yielded duodenal toxicity rates of 52% and 11%, respectively (p=0.002); V(20)≥3.3 cm(3) and V(20)<3.3 cm(3) gave toxicity rates of 52% and 11%, respectively (p=0.002); and D(max)≥23 Gy and D(max)<23 Gy gave toxicity rates of 49% and 12%, respectively (p=0.004). Lyman NTCP model optimization generated the coefficients m=0.23, n=0.12, and TD(50)=24.6 Gy. Only the Lyman NTCP model remained significant in multivariate analysis (p=0.001)., Conclusions: Multiple DVH endpoints and a Lyman NTCP model are strongly predictive of duodenal toxicity after SBRT for pancreatic cancer. These dose constraints will be valuable in future abdominal SBRT studies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: This study analyzed the prognostic value of positron emission tomography (PET) for locally advanced pancreas cancer patients undergoing stereotactic body radiotherapy (SBRT)., Patients and Methods: Fifty-five previously untreated, unresectable pancreas cancer patients received a single fraction of 25-Gy SBRT sequentially with gemcitabine-based chemotherapy. On the preradiation PET-CT, the tumor was contoured and the maximum standardized uptake value (SUVmax) and metabolic tumor burden (MTB) were calculated using an in-house software application. High-SUVmax and low-SUVmax subgroups were created by categorizing patients above or below the median SUVmax. The analysis was repeated to form high-MTB and low-MTB subgroups as well as clinically relevant subgroups with SUVmax values of <5, 5-10, or >10. Multivariate analysis analyzing SUVmax, MTB, age, chemotherapy cycles, and pretreatment carbohydrate antigen (CA)19-9 was performed., Results: For the entire population, median survival was 12.7 months. Median survival was 9.8 vs.15.3 months for the high- and low- SUVmax subgroups (p <0.01). Similarly, median survival was 10.1 vs. 18.0 months for the high MTB and low MTB subgroups (p <0.01). When clinical SUVmax cutoffs were used, median survival was 6.4 months in those with SUVmax >10, 9.5 months with SUVmax 5.0-10.0, and 17.7 months in those with SUVmax <5 (p <0.01). On multivariate analysis, clinical SUVmax was an independent predictor for overall survival (p = 0.03) and progression-free survival (p = 0.03)., Conclusion: PET scan parameters can predict for length of survival in locally advanced pancreas cancer patients., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: The use of imaging-guided radiation therapy (IGRT) to treat thoracic and abdominal tumors is increasing. In this article, we review the process of IGRT and describe techniques to implant fiducial markers in the optimal geometry., Conclusion: Implantation of fiducial markers can be challenging. A better understanding of the physics of IGRT can help optimize fiducial marker placement for precise tumor targeting.

Background: The authors report on the local control and toxicity of stereotactic body radiotherapy (SBRT) for patients with unresectable pancreatic adenocarcinoma., Methods: Seventy-seven patients with unresectable adenocarcinoma of the pancreas received 25 gray (Gy) in 1 fraction. Forty-five patients (58%) had locally advanced disease, 11 patients (14%) had medically inoperable disease, 15 patients (19%) had metastatic disease, and 6 patients (8%) had locally recurrent disease. Nine patients (12%) had received prior chemoradiotherapy. Sixteen patients (21%) received between 45 to 54 Gy of fractionated radiotherapy and SBRT. Various gemcitabine-based chemotherapy regimens were received by 74 patients (96%), but 3 patients (4%) did not receive chemotherapy until they had distant failure., Results: The median follow-up was 6 months (range, 3-31 months) and, among surviving patients, it was 12 months (range, 3-31 months). The overall rates of freedom from local progression (FFLP) at 6 months and 12 months were 91% and 84%, respectively. The 6- and 12-month isolated local recurrence rates were 5% and 5%, respectively. There was no difference in the 12-month FFLP rate based on tumor location (head/uncinate, 91% vs body/tail, 86%; P = .52). The progression-free survival (PFS) rates at 6 months and 12 months were 26% and 9%, respectively. The PFS rate at 6 months was superior for patients who had nonmetastatic disease versus patients who had metastatic disease (28% vs 15%; P = .05). The overall survival (OS) rates at 6 months and 12 months from SBRT were 56% and 21%, respectively. Four patients (5%) experienced grade > or = 2 acute toxicity. Three patients (4%) experienced grade 2 late toxicity, and 7 patients (9%) experienced grade > or = 3 late toxicity. At 6 months and 12 months, the rates of grade > or = 2 late toxicity were 11% and 25%, respectively., Conclusions: SBRT for pancreatic adenocarcinoma was effective for local control with associated risk of toxicity and should be used with rigorous attention to quality assurance. Efforts to reduce complications are warranted. Distant metastases account for the vast majority of disease-related mortality., ((c) 2008 American Cancer Society.)