Neoadjuvant Stereotactic Body Radiotherapy After Upfront Chemotherapy Improves Pathologic Outcomes Compared With Chemotherapy Alone for Patients With Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma Without Increasing Perioperative Toxicity.

BACKGROUND: Patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) are at high risk of margin-positive resection. Neoadjuvant stereotactic body radiation therapy (SBRT) may help sterilize margins, but its additive benefit beyond neoadjuvant chemotherapy (nCT) is unclear. The authors report long-term outcomes for BRPC/LAPC patients explored after treatment with either nCT alone or nCT followed by five-fraction SBRT (nCT-SBRT). METHODS: Patients with BRPC or LAPC from 2011 to 2016 who underwent resection after nCT alone or nCT-SBRT were retrospectively reviewed. Baseline characteristics were compared, and the propensity score with inverse probability weighting (IPW) was used to compare pathologic/survival outcomes. RESULTS: Of 198 patients, 76 received nCT, and 122 received nCT-SBRT. The nCT-SBRT cohort had a higher proportion of LAPC (53% vs 22%; p < 0.001). The duration of nCT was longer for nCT-SBRT (4.6 vs 2.9 months; p = 0.03), but adjuvant chemotherapy was less frequently administered (53% vs 67.1%; p < 0.001). Adjuvant radiation was administered to 30% of the nCT patients. The nCT-SBRT regimen more frequently achieved negative margins (92% vs 70%; p < 0.001), negative nodes (59% vs 42%; p < 0.001), and pathologic complete response (7% vs 0%; p = 0.02). In the multivariate analysis, nCT-SBRT remained associated with R0 resection (p < 0.001). The nCT-SBRT cohort experienced no significant difference in median overall survival (OS) (22.1 vs 24.5 months), local progression-free survival (LPFS) (13.5 vs. 15.4 months), or distant metastasis-free survival (DMFS) (11.7 vs 16.3 months) after surgery. After SBRT, 1-year OS was 77.0% and 2-year OS was 50.4%. Perioperative Claven-Dindo grade 3 or greater morbidity did not differ significantly between the nCT and nCT-SBRT cohorts (p = 0.81). CONCLUSIONS: Despite having more advanced disease, the nCT-SBRT cohort was still more likely to undergo an R0 resection and experienced similar survival outcomes compared with the nCT alone cohort.

Stenting as a treatment for cranio-cervical artery dissection: Improved major adverse cardiovascular event-free survival.

INTRODUCTION: Cranio-cervical artery dissection (CeAD) is a common cause of cerebrovascular events in young subjects with no clear treatment strategy established. We evaluated the incidence of major adverse cardiovascular events (MACE) in CeAD patients treated with and without stent placement. METHODS: COMParative effectiveness of treatment options in cervical Artery diSSection (COMPASS) is a single high-volume center observational, retrospective longitudinal registry that enrolled consecutive CeAD patients over a 2-year period. Patients were ≥ 18 years of age with confirmed extra- or intracranial CeAD on imaging. Enrolled participants were followed for 1 year evaluating MACE as the primary endpoint. RESULTS: One-hundred ten patients were enrolled (age 53 ± 15.9, 56% Caucasian, and 50% male, BMI 28.9 ± 9.2). Grade I, II, III, and IV blunt vascular injury was noted in 16%, 33%, 19%, and 32%, respectively. Predisposing factors were noted in the majority (78%), including sneezing, carrying heavy load, chiropractic manipulation. Stent was placed in 10 (10%) subjects (extracranial carotid n = 9; intracranial carotid n = 1; extracranial vertebral n = 1) at the physician's discretion along with medical management. Reasons for stent placement were early development of high-grade stenosis or expanding pseudoaneurysm. Stented patients experienced no procedural or in-hospital complications and no MACE between discharge and 1 year follow up. CeAD patients treated with medical management only had 14% MACE at 1 year. CONCLUSION: In this single high-volume center cohort of CeAD patients, stenting was found to be beneficial, particularly with development of high-grade stenosis or expanding pseudoaneurysm. These results warrant confirmation by a randomized clinical trial.

Early Anticoagulation or Antiplatelet Therapy Is Critical in Craniocervical Artery Dissection: Results from the COMPASS Registry.

INTRODUCTION: Craniocervical artery dissection (CeAD) is a leading cause of stroke in the young patient population. Recent studies reported a low rate of major adverse cardiac events (MACEs) in patients with CeAD, with no significant difference between patients randomized to anticoagulation or antiplatelet therapy. OBJECTIVE: To compare the effectiveness of anticoagulation and antiplatelet therapy in patients with CeAD. METHODS: All CeAD patients from 2015 to 2017 were consecutively identified by an electronic medical record-based application and enrolled in this prospective longitudinal registry. CeAD was confirmed by imaging and graded using the Denver scale for blunt cerebrovascular injury. Patients were followed for 12 months for MACE defined as stroke, transient ischemic attack (TIA), or death. RESULTS: The cohort included 111 CeAD patients (age 53 ± 15.9 years, 56% Caucasian, 50% female). CeAD was detected by magnetic resonance (5%), computed tomography (88%), or catheter angiography (7%). CeAD was noted in the carotid (59%), vertebral (39%), and basilar (2%) arteries, 82% of which were extracranial dissections. CeAD was classified as grade I, II, III, and IV in 16, 33, 19, and 32%, respectively. A total of 40% of dissections were due to known trauma. A predisposing factor was noted in the majority (78%) of patients, including violent sneezing (21%), carrying a heavy load (19%), sports/recreational activity (11%), chiropractic manipulation (9%), abrupt/prolonged rotation of head (9%), and prolonged phone use (9%). At presentation, 41% had a stroke, 5% had TIA, 39% had headache, and 36% were asymptomatic. Favorable outcome defined as a modified Rankin Scale score of 0-2 was noted in 68% at 3 months and 71% at 12 months. The rate of MACEs at 3 and 12 months was 11 and 14%, respectively, with more events observed in patients who were not receiving anticoagulation/antiplatelet therapy due to contraindications (p = 0.008). CONCLUSIONS: We report diagnostic characteristics, as well as short- and long-term outcomes of CeAD. A high MACE rate was observed within the first 2 weeks of CeAD diagnosis, notably in patients not initiated on anticoagulation or antiplatelet therapy.

Improving prediction of surgical resectability over current staging guidelines in patients with pancreatic cancer who receive stereotactic body radiation therapy.

PURPOSE: For patients with localized pancreatic cancer (PC) with vascular involvement, prediction of resectability is critical to define optimal treatment. However, the current definitions of borderline resectable (BR) and locally advanced (LA) disease leave considerable heterogeneity in outcomes within these classifications. Moreover, factors beyond vascular involvement likely affect the ability to undergo resection. Herein, we share our experience developing a model that incorporates detailed radiologic, patient, and treatment factors to predict surgical resectability in patients with BR and LA PC who undergo stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Patients with BR or LA PC who were treated with SBRT between 2010 and 2016 were included. The primary endpoint was margin negative resection, and predictors included age, sex, race, treatment year, performance status, initial staging, tumor volume and location, baseline and pre-SBRT carbohydrate antigen 19-9 levels, chemotherapy regimen and duration, and radiation dose. In addition, we characterized the relationship between tumors and key arteries (superior mesenteric, celiac, and common hepatic arteries), using overlap volume histograms derived from computed tomography data. A classification and regression tree was built, and leave-one-out cross-validation was performed. Prediction of surgical resection was compared between our model and staging in accordance with the National Comprehensive Care Network guidelines using McNemar's test. RESULTS: A total of 191 patients were identified (128 patients with LA and 63 with BR), of which 87 patients (46%) underwent margin negative resection. The median total dose was 33 Gy. Predictors included the chemotherapy regimen, amount of arterial involvement, and age. Importantly, radiation dose that covers 95% of gross tumor volume (GTV D95), was a key predictor of resectability in certain subpopulations, and the model showed improved accuracy in the prediction of margin negative resection compared with National Comprehensive Care Network guideline staging (75% vs 63%; P < .05). CONCLUSIONS: We demonstrate the ability to improve prediction of surgical resectabiliy beyond the current staging guidelines, which highlights the value of assessing vascular involvement in a continuous manner. In addition, we show an association between radiation dose and resectability, which suggests the potential importance of radiation to allow for resection in certain populations. External data are needed for validation and to increase the robustness of the model.

Cholangiocarcinoma: Treatment, Outcomes, and Nutrition Overview for Oncology Nurses.

BACKGROUND: Cholangiocarcinoma is a cancer that arises from the bile ducts inside or outside of the liver. Although it is a rare cancer, cholangiocarcinoma appears to be rising in incidence in the United States and worldwide. OBJECTIVES: The diagnosis of cholangiocarcinoma frequently presents with biliary emergencies from diagnosis through treatment. The lethality of this cancer stems, in part, from challenges with supportive care during treatment. This article provides an overview of intrahepatic and extrahepatic cholangiocarcinoma, including identification of risk factors, differences in treatment approaches, palliation of symptoms, and insight into commonly asked questions. METHODS: A comprehensive review of the current literature regarding incidence, prevalence, and treatment of cholangiocarcinoma was conducted. FINDINGS: Nursing literature regarding cholangiocarcinoma is scarce. Studies that focus on nursing care, symptom management, and nursing management of patients with biliary obstruction are needed. Nutrition and palliative care management of patients with cholangiocarcinoma are key areas of nursing management.

Stereotactic body radiation therapy for palliative management of pancreatic adenocarcinoma in elderly and medically inoperable patients.

Stereotactic body radiation therapy (SBRT) represents a promising treatment option for patients with localized pancreatic ductal adenocarcinoma (PDAC) who cannot tolerate surgical therapy. We retrospectively reviewed the records of patients with localized PDAC treated with SBRT at our institution between 2010 and 2016 to identify patients deemed medically inoperable due to poor performance status, advanced age, and/or comorbid conditions. Overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were estimated using Kaplan-Meier curves. Twenty-nine patients were included. Median age was 74 (IQR 68-79). Thirteen patients (45%) had an Eastern Cooperative Oncology Group performance status of 2. Six patients (19%) had chronic obstructive pulmonary disease, 9 (31%) had cardiovascular disease, and 17 (58%) had diabetes mellitus. SBRT was delivered over 5 fractions to a median dose of 28 Gy (IQR, 25-33). Twenty-two patients (76%) received induction chemotherapy prior to SBRT, and 9 (31%) received maintenance chemotherapy after SBRT. Median OS was 13 months from diagnosis. Median OS and PFS were 8 and 6 months from SBRT, respectively. Six and 12-month LPFS rates were 91% and 78%, respectively. Patients receiving induction chemotherapy had superior survival from diagnosis than those who did not (14 vs. 7 months, p = 0.01). Three patients (10%) experienced acute grade ≥3 toxicity, and 1 patient (4%) experienced grade ≥3 late toxicity. Symptom relief was achieved at three-month follow-up in 8 of 11 patients (73%) experiencing abdominal pain. These results suggest SBRT may be safe and effective for patients who cannot tolerate surgery.

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

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

Postoperative complications after resection of borderline resectable and locally advanced pancreatic cancer: The impact of neoadjuvant chemotherapy with conventional radiation or stereotactic body radiation therapy.

BACKGROUND: The impact of neoadjuvant stereotactic body radiation therapy on postoperative complications for patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma remains unclear. Limited studies have compared neoadjuvant stereotactic body radiation therapy versus conventional chemoradiation therapy. A retrospective study was performed to determine if perioperative complications were different among patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma receiving neoadjuvant stereotactic body radiation therapy or chemoradiation therapy. METHODS: Patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma who underwent neoadjuvant chemotherapy with stereotactic body radiation therapy or chemoradiation therapy followed by pancreatectomy at the Johns Hopkins Hospital between 2008 and 2015 were included. Predictive factors for severe complications (Clavien grade ≥ III) were assessed by univariate and multivariate analyses. RESULTS: A total of 168 patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma underwent neoadjuvant chemotherapy and RT followed by pancreatectomy. Sixty-one (36%) patients underwent stereotactic body radiation therapy and 107 (64%) patients received chemoradiation therapy. Compared with the chemoradiation therapy cohort, the neoadjuvant stereotactic body radiation therapy cohort was more likely to have locally advanced pancreatic ductal adenocarcinoma (62% vs 43% P = .017) and require a vascular resection (54% vs 37%, P = .027). Multiagent chemotherapy was used more commonly in the stereotactic body radiation therapy cohort (97% vs 75%, P < .001). Postoperative complications (Clavien grade ≥ III 23% vs 28%, P = .471) were similar between stereotactic body radiation therapy and chemoradiation therapy cohort. No significant difference in postoperative bleeding or infection was noted in either group. CONCLUSION: Compared with chemoradiation therapy, neoadjuvant stereotactic body radiation therapy appears to offer equivalent rates of perioperative complications in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma despite a greater percentage of locally advanced disease and more complex operative treatment.

Stereotactic Body Radiation Therapy for Isolated Local Recurrence After Surgical Resection of Pancreatic Ductal Adenocarcinoma Appears to be Safe and Effective.

BACKGROUND: A standardized treatment regimen for unresectable isolated local recurrence (ILR) of pancreatic ductal adenocarcinoma has not been established. This study evaluated the outcomes for patients with ILR who underwent stereotactic body radiation therapy (SBRT). METHODS: The records of patients with ILR who underwent SBRT between 2010 and 2016 were retrospectively reviewed. Symptom palliation and treatment-related toxicity were recorded. Associations between patient or treatment characteristics and overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were assessed. RESULTS: The study identified 51 patients who received SBRT for ILR. Of the 51 patients, 26 (51%) had not received radiation therapy before SBRT. The median OS was 36 months after diagnosis. From the first day of SBRT, the median OS, PFS, and LPFS were respectively 16, 7, and 10 months. Patients with a recurrence-free interval of 9 months or longer after surgery had superior OS (P = 0.019). Maintenance chemotherapy after SBRT was associated with superior OS (P < 0.001) and LPFS (P = 0.027). In the multivariable analysis, poorly differentiated tumor grade [hazard ratio (HR) 11.274], positive surgical margins (HR 0.126), and reception of maintenance chemotherapy (HR 0.141) were independently associated with OS. Positive surgical margins (HR 0.255) and maintenance chemotherapy (HR 0.299) were associated with improved LPFS. Of 16 patients, 10 (63%) experienced abdominal pain relief after SBRT. Four patients (8%) experienced grade 3 gastrointestinal toxicity, and one patient experienced grade 4 gastrointestinal toxicity. CONCLUSIONS: Use of SBRT for ILR improved pain for a majority of the patients with acceptable acute and late toxicity. The findings show that SBRT is a feasible treatment for select patients with ILR. For those who receive SBRT, maintenance chemotherapy should be considered.

Multiplex Proximity Ligation Assay to Identify Potential Prognostic Biomarkers for Improved Survival in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy.

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-ß, 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.

Effects of biodegradable hydrogel spacer injection on contralateral submandibular gland sparing in radiotherapy for head and neck cancers.

Xerostomia is the most common late toxicity after head and neck radiation. We demonstrate injection of a hydrogel spacer anteriorly displacing the submandibular gland. This procedure enables reduced dose to the displaced submandibular gland in cadaveric models of oropharynx cancer treated with IMRT, with potential implications in reducing xerostomia risk.

A rare case of esophageal metastasis from pancreatic ductal adenocarcinoma: a case report and literature review.

PURPOSE: We report a very unique case of an esophageal metastasis from a pancreatic ductal adenocarcinoma (PDAC) primary. METHODS: After obtaining consent from the patient, all relevant records of the case were obtained and retrospectively reviewed. RESULTS: At presentation, the patient was diagnosed with synchronous pancreatic and esophageal cancer. He received six months of neoadjuvant therapy including FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and stereotactic body radiation therapy (SBRT) to the pancreatic tumor followed by a combined pancreaticoduodenectomy and Ivor Lewis esophagectomy. Review of the final esophageal specimen revealed normal overlying squamous mucosa with an underlying focus of metastatic PDAC. The patient remains alive with no evidence of disease 17 months from surgery and 25 months from diagnosis. CONCLUSIONS: Differentiating an esophageal metastasis from a PDAC primary versus a synchronous esophageal carcinoma is very difficult despite state-of-the-art diagnostic techniques performed at a high-volume tertiary cancer center. Extensive evaluation and continued follow-up of PDAC patients presenting with a synchronous esophageal lesion in a multidisciplinary setting may help ensure efficient and accurate management. In our case, neoadjuvant FOLFIRINOX and SBRT to the primary PDAC tumor followed by surgery has been an effective approach for this patient.

A Novel Absorbable Radiopaque Hydrogel Spacer to Separate the Head of the Pancreas and Duodenum in Radiation Therapy for Pancreatic Cancer.

PURPOSE: We assessed the feasibility and theoretical dosimetric advantages of an injectable hydrogel to increase the space between the head of the pancreas (HOP) and duodenum in a human cadaveric model. METHODS AND MATERIALS: Using 3 human cadaveric specimens, an absorbable radiopaque hydrogel was injected between the HOP and duodenum by way of open laparotomy in 1 case and endoscopic ultrasound (EUS) guidance in 2 cases. The cadavers were subsequently imaged using computed tomography and dissected for histologic confirmation of hydrogel placement. The duodenal dose reduction and planning target volume (PTV) coverage were characterized using pre- and postspacer injection stereotactic body radiation therapy (SBRT) plans for the 2 cadavers with EUS-guided placement, the delivery method that appeared the most clinically desirable. Modeling studies were performed using 60 SBRT plans consisting of 10 previously treated patients with unresectable pancreatic cancer, each with 6 different HOP-duodenum separation distances. The duodenal volume receiving 15 Gy (V15), 20 Gy (V20), and 33 Gy (V33) was assessed for each iteration. RESULTS: In the 3 cadaveric studies, an average of 0.9 cm, 1.1 cm, and 0.9 cm HOP-duodenum separation was achieved. In the 2 EUS cases, the V20 decreased from 3.86 cm3 to 0.36 cm3 and 3.75 cm3 to 1.08 cm3 (treatment constraint <3 cm3), and the V15 decreased from 7.07 cm3 to 2.02 cm3 and 9.12 cm3 to 3.91 cm3 (treatment constraint <9 cm3). The PTV coverage improved or was comparable between the pre- and postinjection studies. Modeling studies demonstrated that a separation of 8 mm was sufficient to consistently reduce the V15, V20, and V33 to acceptable clinical constraints. CONCLUSIONS: Currently, dose escalation has been limited owing to radiosensitive structures adjacent to the pancreas. We demonstrated the feasibility of hydrogel separation of the HOP and duodenum. Future studies will evaluate the safety and efficacy of this technique with the potential for more effective dose escalation using SBRT or intensity-modulated radiation therapy to improve the outcomes in patients with unresectable pancreatic cancer.

An unusual genomic variant of pancreatic ductal adenocarcinoma with an indolent clinical course.

We describe an 85-yr-old male of Ashkenazi Jewish descent with biopsy-proven locally advanced pancreatic ductal adenocarcinoma (PDA). The patient underwent a modified course of gemcitabine and stereotactic body radiation therapy and survived for 42 mo with a stable pancreatic head mass and no evidence of metastatic disease before death due to complications from a stroke. Whole-exome sequencing of his tumor revealed a simple genome landscape with no evidence of mutations, copy-number changes, or structural alterations in genes most commonly associated with PDA (i.e., KRAS, CDKN2A, TP53, or SMAD4). An analysis of his germline DNA revealed no pathogenic variants of significance. Whole-exome and whole-genome sequencing identified a somatic mutation of RNF213 and an inversion/deletion of CTNNA2 as the genetic basis of his PDA. Although PDA is classically characterized by a predictable set of mutations, these data suggest that alternate genetic paths to PDA may exist, which can be associated with a more indolent clinical course.

Integration of Stereotactic Body Radiation Therapy into the Multidisciplinary Management of Pancreatic Cancer.

Although most patients with pancreatic cancer die of metastatic disease, an autopsy study showed that up to one-third of patients die of predominantly local disease. This patient population stands to benefit the most from radiation, surgery, or both. Unfortunately, however, single-agent chemotherapy has had minimal benefit in pancreatic cancer, and most patients progress distantly before receiving radiation therapy (RT). With the addition of multiagent chemotherapy, patients are living longer, and RT has emerged as an important modality in preventing local progression. Standard chemoradiation delivered over 5-6 weeks has been shown to improve local control, but this approach delays full-dose systemic therapy and increases toxicity when compared to chemotherapy alone. Stereotactic body RT (SBRT) delivered in 3-5 fractions can be used to accurately target the pancreatic tumor with small margins and limited acute treatment-related toxicity. Given the favorable toxicity profile, SBRT can easily be integrated with other therapies in all stages of pancreatic cancer. However, future studies are necessary to determine optimal dose or fractionation regimens and sequencing with targeted therapies and immunotherapy. The purpose of this review is to discuss our current understanding of SBRT in the multidisciplinary management of patients with pancreatic cancer and future implications.

Personalized Management of Pancreatic Ductal Adenocarcinoma Patients through Computational Modeling.

Phenotypic diversity in pancreatic ductal adenocarcinoma (PDAC) results in a variety of treatment responses. Rapid autopsy studies have revealed a subgroup of PDAC patients with a lower propensity to develop metastatic disease, challenging the common perception that all patients die of widely metastatic disease, but questions remain about root causes of this difference and the potential impact on treatment strategies. In this study, we addressed these questions through the development of a mathematical model of PDAC progression that incorporates the major alteration status of specific genes with predictive utility. The model successfully reproduced clinical outcomes regarding metastatic patterns and the genetic alteration status of patients from two independent cohorts from the United States and Japan. Using this model, we defined a candidate predictive signature in patients with low metastatic propensity. If a primary tumor contained a small fraction of cells with KRAS and additional alterations to CDKN2A, TP53, or SMAD4 genes, the patient was likely to exhibit low metastatic propensity. By using this predictive signature, we computationally simulated a set of clinical trials to model whether this subgroup would benefit from locally intensive therapies such as surgery or radiation therapy. The largest overall survival benefit resulted from complete resection, followed by adjuvant chemoradiation therapy and salvage therapies for isolated recurrence. While requiring prospective validation in a clinical trial, our results suggest a new tool to help personalize care in PDAC patients in seeking the most effective therapeutic modality for each individual. Cancer Res; 77(12); 3325-35. ©2017 AACR.

Role of Stereotactic Body Radiotherapy in the Treatment of Elderly and Poor Performance Status Patients With Pancreatic Cancer.

Literature on the management of nonmetastatic pancreatic ductal adenocarcinoma in patients who are elderly or have poor performance status is sparse. The median survival of this unique cohort of patients is < 6 months, and most patients are only offered single-agent gemcitabine or supportive care. Recently, adding nanoparticle albumin-bound paclitaxel to gemcitabine was shown to improve survival of patients with metastatic disease with Eastern Cooperative Group performance status of 2. Although standard chemoradiotherapy provides long-term locoregional control in locally advanced pancreatic cancer, it is difficult for this group of patients to tolerate 6 weeks of therapy. Stereotactic body radiotherapy (SBRT) can be delivered in only 3 to 5 days, does not require concurrent chemotherapy, and has limited toxicity, and tumor control rates appear to be equivalent to or better than those achieved with standard chemoradiotherapy. Additionally, SBRT has been shown to improve cancer-related pain and patient-reported quality of life. Given the favorable toxicity profile, SBRT seems like an obvious choice for patients who are elderly, have multiple comorbidities, or have poor performance status. Herein, we review the literature on SBRT in this unique patient population and discuss future directions.

Patient-reported outcomes of a multicenter phase 2 study investigating gemcitabine and stereotactic body radiation therapy in locally advanced pancreatic cancer.

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/m2) 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.

Neuroendocrine tumor liver metastases treated with yttrium-90 radioembolization.

OBJECTIVE: Yttrium-90 (Y-90) radioembolization is an emerging treatment option for unresectable neuroendocrine liver metastases (NELM). However, the data regarding this treatment are currently limited. This study evaluates the efficacy and tolerability of Y-90 radioembolization and identifies prognostic factors for radiographic response and survival. METHODS AND MATERIALS: Thirty-eight patients underwent Y-90 radioembolization for NELM at our institution between April 2004 and February 2012. Patients were assessed radiographically (RECIST criteria, enhancement), serologically, and clinically at 1month, and then at every 3months after treatment for tumor response, toxicity, and survival outcomes. RESULTS: Median length of follow-up was 17.0months (IQR, 9.0-37.0). Median survival was 29.2months. Three patients (9%) had a radiographic complete response to treatment, 6 (17%) had a partial response, 21 (60%) had stable disease, and 5 (14%) developed progressive disease. Two factors were significantly associated with a good radiographic response (complete/partial response): islet cell histological subtype (p=0.043) and hepatic tumor burden ≥33% (p=0.031). Multivariate analysis revealed that patients requiring multiple Y-90 treatments (HR 2.9, p=0.035) and patients who had previously failed systemic therapy with octreotide/chemotherapy (HR 4.4, p=0.012) had worse survival. Grade 3 serologic toxicity was observed in 2 patients (5%; hyperbilirubinemia, elevated alkaline phosphatase) after treatment. Grade 3 non-serologic toxicities included abdominal pain (11%), fatigue (11%), nausea/vomiting (5%), ascites (5%), dyspnea (3%), diarrhea (3%), and peripheral edema (3%). No grade 4 or 5 toxicity was reported. CONCLUSIONS: Y-90 radioembolization is a promising treatment option for inoperable NELM and is associated with low rates of grade≥3 toxicity.

Stereotactic body radiotherapy for pancreatic cancer: recent progress and future directions.

Despite advances in surgical, medical, and radiation therapy for pancreatic cancer, the prognosis remains poor. At this time, the only chance for long-term survival is surgical resection. More challenging is the optimal management of unresectable locally advanced pancreatic cancer, which has historically been treated with concurrent chemoradiation or chemotherapy alone. However, the survival and local control benefit of conventional radiotherapy in addition to chemotherapy was unclear. More recently, stereotactic body radiotherapy (SBRT) is emerging as a viable approach to maximizing local tumor control with a tolerable side effect profile. SBRT achieves sharp dose fall-off facilitating safe delivery of highly focused radiation to the tumor over 1-5 days. Although the optimal regimen of pancreas SBRT has not yet been established, its short treatment course limits the delay of additional. Future directions involve prospective study of pancreas SBRT and exploration of biomarkers and imaging technology in order to adopt a personalized management paradigm.