SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma.

BACKGROUND: In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. METHODS: Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. RESULTS: In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p = .19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p = .009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). CONCLUSIONS: In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.

Radiation dose is associated with improved local control for large, but not small, hepatocellular carcinomas.

BACKGROUND: With advances in understanding liver tolerance, conformal techniques, image guidance, and motion management, dose-escalated radiotherapy has become a potential treatment for inoperable hepatocellular carcinoma (HCC). We aimed to evaluate the possible impact of biologically effective dose (BED) on local control and toxicity among patients with HCC. METHODS AND MATERIALS: Patients treated at our institution from 2009 to 2018 were included in this retrospective analysis if they received definitive-intent radiotherapy with a nominal BED of at least 60 Gy. Patients were stratified into small and large tumors using a cutoff of 5 cm, based on our clinical practice. Toxicity was assessed using ALBI scores and rates of clinical liver function deterioration. RESULTS: One hundred and twenty-eight patients were included, with a mean follow-up of 16 months. The majority of patients (90.5%) had a good performance status (ECOG 0-1), with Child-Pugh A (66.4%) and ALBI Grade 2 liver function at baseline (55.4%). Twenty (15.6%) patients had a local recurrence in the irradiated field during the follow-up period. Univariate and multivariate Cox proportional hazard analyses showed that only BED significantly predicted local tumor recurrence. Higher BED was associated with improved local control in tumors with equivalent diameters over 5 cm but not in smaller tumors. There was no difference in liver toxicity between the low and high-dose groups. CONCLUSIONS: Higher radiotherapy dose is associated with improved local control in large tumors but not in tumors smaller than 5 cm in diameter. High-dose radiotherapy was not associated with increased liver toxicity.

Radiation Therapy and the Microbiome; More Than a Gut Feeling.

ABSTRACT: It is increasingly recognized that heterogeneities in tumor response and severity of adverse effects in irradiated patients can be attributed to the tumor microenvironment and host-related factors. Among the latter, a growing body of literature in recent years has demonstrated the role of the patient's microbiome in modulating both tumor and normal tissue response to radiotherapy (RT). Upon contact with the environment after birth, the infant's gastrointestinal tract is rapidly colonized by microbiota, which is low in diversity and predominantly characterized by 2 dominant species, Actinobacteria and Proteobacteria. With time, intestinal microbiota diversity increases, and colonization of Firmicutes and Bacteroidetes becomes dominant. By the time a child reaches 3 years, the gut microbiota composition has been reshaped and is relatively similar to that of an adult. The microbiome colonizing the different body organs comprises various species and abundances, which may impact human health. Although the adult microbiome composition is thought to remain stable in health, microbiome diversity and composition respond to different environmental and pathological conditions, including pharmaceutical interventions and RT. Our review focuses on how the gut microbiota modulates normal tissue toxicity and tumor control. Readers who want to learn more about how RT shapes gut microbiome diversity and composition are referred to several excellent recently published reviews.

Adjuvant Chemoradiation in Patients with Lymph Node-Positive Biliary Tract Cancers: Secondary Analysis of a Single-Arm Clinical Trial (SWOG 0809).

BACKGROUND: SWOG 0809 is the only prospective study of adjuvant chemotherapy followed by chemoradiation focusing on margin status in patients with extrahepatic cholangiocarcinoma (EHCC) and gallbladder cancer (GBCA); however, the effects of adjuvant therapy by nodal status have never been reported in this population. METHODS: Patients with resected EHCC and GBCA, stage pT2-4, node-positive (N+) or margin-positive (R1) who completed four cycles of chemotherapy followed by radiotherapy were included. Cox regression was used to compare overall survival (OS), disease-free survival (DFS), local recurrence, and distant metastasis by nodal status. DFS rates were compared with historical data via a one-sample t-test. RESULTS: Sixty-nine patients [EHCC, n = 46 (66%); GBCA, n = 23 (33%)] were evaluated, with a median age of 61.7 years and an R0 rate of 66.7% and R1 rate of 33.3%. EHCC versus GBCA was more likely to be N+ (73.9% vs. 47.8%, p = 0.03). Nodal status did not significantly impact OS (hazard ratio [HR] 1.98, 95% confidence interval [CI] 0.86-4.54, p = 0.11) or DFS (HR 1.63, 95% CI 0.77-3.44, p = 0.20). Two-year OS was 70.6% for node-negative (N0) disease and 60.9% for N+ disease, while 2-year DFS was 62.5% for N0 tumors and 49.8% for N+ tumors. N+ versus N0 tumors showed higher rates of distant failure (42.2% vs. 25.0%, p = 0.04). The 2-year DFS rate in N+ tumors was significantly higher than in historical controls (49.8% vs. 29.7%, p = 0.004). CONCLUSIONS: Adjuvant therapy is associated with favorable outcome independent of nodal status and may impact local control in N+ patients. These data could serve as a benchmark for future adjuvant trials, including molecular-targeted agents.

Activity Monitoring for Toxicity Detection and Management in Patients Undergoing Chemoradiation for Gastrointestinal Malignancies.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

Quantifying the impact of the COVID-19 pandemic on gastrointestinal cancer care delivery.

BACKGROUND AND AIM: This study quantifies how changes in healthcare utilization and delivery during the first months of the COVID-19 pandemic have altered the presentation, treatment, and management of patients with gastrointestinal (GI) malignancies within an academic health system. METHODS AND RESULTS: Patients diagnosed with a GI malignancy (ICD10: C15-C26) who received medical care within the health system during the observation period (first 44 weeks of 2019 and 2020) were identified for a retrospective cohort study. Deidentified patient encounter parameters were collected for this observation period and separated into pre-pandemic (weeks 1-10) and early pandemic (weeks 11-20) study periods. Difference-in-difference analyses adjusted for week-specific and year-specific effects quantified the impact of the COVID-19 pandemic on care delivery between pre-pandemic and early pandemic study periods in 2020. Across all GI malignancies, the COVID-19 pandemic has been associated with a significant decline in the number of patients with new patient visits (NPVs) (p = 1.2 × 10-4 ), Radiology encounters (p = 1.9 × 10-7 ), Surgery encounters (p = 1.6 × 10-3 ), Radiation Oncology encounters (p = 4.1 × 10-3 ), and infusion visits (6.1 × 10-5 ). Subgroup analyses revealed cancer-specific variations in changes to delivery. Patients with colorectal cancer (CRC) had the most significant decrease in NPVs (p = 7.1 × 10-5 ), which was significantly associated with a concomitant decrease in colonoscopies performed during the early pandemic period (r2  = 0.722, p = 2.1 × 10-10 ). CONCLUSIONS: The COVID-19 pandemic has been associated with significant disruptions to care delivery. While these effects were appreciated broadly across GI malignancies, CRC, diagnosed and managed by periodic screening, has been affected most acutely.

Carbon ion radiotherapy as definitive treatment in locally recurrent pancreatic cancer.

PURPOSE: Data on management of locally recurrent pancreatic cancer (LRPC) after primary resection are limited. Recently, surprisingly high overall survival rates were reported after irradiation with carbon ions. Here, we report on our clinical experience using carbon ion radiotherapy as definitive treatment in LRPC at the Heidelberg Ion-Beam Therapy Center (HIT). METHODS: Between 2015 and 2019, we treated 13 patients with LRPC with carbon ions with a median total dose of 48 Gy (RBE) in 12 fractions using an active raster-scanning technique at a rotating gantry. No concomitant chemotherapy was administered. Overall survival, local control, and toxicity rates were evaluated 18 months after the last patient finished radiotherapy. RESULTS: With a median follow-up time of 9.5 months, one patient is still alive (8%). Median OS was 12.7 months. Ten patients (77%) developed distant metastases. Additionally, one local recurrence (8%) and two regional tumor recurrences (15%) were observed. The estimated 1­year local control and locoregional control rates were 87.5% and 75%, respectively. During radiotherapy, we registered one gastrointestinal bleeding CTCAE grade III (8%) due to gastritis. The bleeding was sufficiently managed with conservative therapy. No further higher-grade acute or late toxicities were observed. CONCLUSION: We demonstrate high local control rates in a rare cohort of LRPC patients treated with carbon ion radiotherapy. The observed median overall survival rate was not improved compared to historical in-house data using photon radiotherapy. This is likely due to a high rate of distant tumor progression, highlighting the necessity of additional chemotherapy.

Simultaneous Multiple Liver Metastasis Treated with Pencil Beam Proton Stereotactic Body Radiotherapy (SBRT).

Compared with photon stereotactic body radiotherapy (SBRT) plans that may have to use many more penetrating x-ray beams for each isocenter, proton SBRT with ultrahypofractionated doses use fewer beam angles and offer significantly reduced low-dose radiation bath to normal liver tissue. We demonstrate techniques to deliver safe and effective proton SBRT, where planning and organ motion complexity further increased with multiple liver lesions. For treatment planning, we recommend robust and logical beam angles, avoiding devices and encouraging entry perpendicular to the dominant motion, as well as volumetric repainting to mitigate the interplay effect to clinically acceptable levels. This report highlights the significant technical challenges with ultrahypofractionated proton pencil beam scanning liver therapy, how they are managed, and the effectiveness of this treatment.

Multi-institutional Comparison of Intensity Modulated Photon Versus Proton Radiation Therapy in the Management of Squamous Cell Carcinoma of the Anus.

PURPOSE: Concurrent chemoradiation therapy is a curative treatment for squamous cell carcinoma of the anus, but patients can suffer from significant treatment-related toxicities. This study was undertaken to determine whether intensity modulated proton therapy (IMPT) is associated with less acute toxicity than intensity modulated radiation therapy (IMRT) using photons. MATERIALS AND METHODS: We performed a multi-institutional retrospective study comparing toxicity and oncologic outcomes of IMRT versus IMPT. Patients with stage I-IV (for positive infrarenal para-aortic or common iliac nodes only) squamous cell carcinoma of the anus, as defined by the American Joint Committee on Cancer's AJCC Staging Manual, eighth edition, were included. Patients with nonsquamous histology or mixed IMPT and IMRT treatment courses were excluded. Acute nonhematologic toxicities, per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4, were recorded prospectively at all sites. Acute and late toxicities, dose metrics, and oncologic outcomes were compared between IMRT and IMPT using univariable and multivariable statistical methods. To improve the robustness of our analysis, we also analyzed the data using propensity score weighting methods. RESULTS: A total of 208 patients were treated with either IMPT (58 patients) or IMRT (150 patients). Of the 208 total patients, 13% had stage I disease, 36% stage II, 50% stage III, and 1% stage IV. IMPT reduced the volume of normal tissue receiving low-dose radiation but not high-dose radiation to bladder and bowel. There was no significant difference between treatment groups in overall grade 3 or greater acute toxicity (IMRT, 68%; IMPT, 67%; P = .96) or 2-year overall grade 3 or greater late toxicity (IMRT, 3.5%; IMPT, 1.8%; P = .88). There was no significant difference in 2-year progression-free survival (hazard ratio, 0.8; 95% CI, 0.3-2.0). CONCLUSIONS: Despite reducing the volume of normal tissue receiving low-dose radiation, IMPT was not associated with decreased grade 3 or greater acute toxicity as measured by CTCAE. Additional follow-up is needed to assess whether important differences arise in late toxicities and if further prospective evaluation is warranted.

Concurrent Nab-paclitaxel and Radiotherapy: Novel Radiosensitization for Borderline Resectable or Unresectable Pancreatic Cancer.

PURPOSE: This study evaluates the toxicity and tumor response with concurrent nab-paclitaxel chemoradiotherapy (CRT) compared with standard (5-fluorouracil or gemcitabine) CRT. MATERIALS AND METHODS: Fifty patients with borderline resectable or unresectable pancreatic adenocarcinoma from 2014 to 2017 were divided into 2 groups: concurrent nab-paclitaxel (100 to 125 mg/m2 weekly) CRT (median: 2.1 Gy fraction size and 52.5 Gy total) or standard CRT (median: 1.8 Gy fraction size, 54.5 Gy total). The primary endpoint was toxicity, and secondary endpoints were local failure and conversion to resectability. Comparisons were made using rank-sum or Fisher exact test and multivariable competing risk regression for the cumulative incidence of local failure. RESULTS: There were 28 patients in the nab-paclitaxel CRT group and 22 in the standard CRT group; 88% had the unresectable disease. The median follow-up was 18 months. The median duration of chemotherapy before concurrent CRT was 1.9 and 2.3 months in the nab-paclitaxel and standard CRT groups (P=0.337), and radiotherapy dose was 52.5 Gy (range, 52.5 to 59.4 Gy) and 54.5 Gy (range, 45.0 to 59.4 Gy), respectively. There were no statistically significant grade ≥2 toxicities. The nab-paclitaxel CRT group experienced a nonstatistically significant lower incidence of local failure (hazard ratio=0.91, 95% confidence interval: 0.27-3.03, P=0.536). More patients in the nab-paclitaxel CRT group proceeded to surgery (9/28 compared with 3/22 in the standard CRT, P=0.186); of which 6 (25%) in the nab-paclitaxel CRT and 2 (10%) in the standard CRT groups were initially unresectable. CONCLUSIONS: Nab-paclitaxel CRT had similar toxicity compared with standard CRT in the treatment of borderline resectable or unresectable pancreatic cancer. Its use was associated with an arithmetically lower cumulative incidence of local failure and an arithmetically higher conversion to resectability, both of which were not statistically significant.

Impact of FAPI-PET/CT on Target Volume Definition in Radiation Therapy of Locally Recurrent Pancreatic Cancer.

(1) Background: A new radioactive positron emission tomography (PET) tracer uses inhibitors of fibroblast activation protein (FAPI) to visualize FAP-expressing cancer associated fibroblasts. Significant FAPI-uptake has recently been demonstrated in pancreatic cancer patients. Target volume delineation for radiation therapy still relies on often less precise conventional computed tomography (CT) imaging, especially in locally recurrent pancreatic cancer patients. The need for improvement in precise tumor detection and delineation led us to innovatively use the novel FAPI-PET/CT for radiation treatment planning. (2) Methods: Gross tumor volumes (GTVs) of seven locally recurrent pancreatic cancer cases were contoured by six radiation oncologists. In addition, FAPI-PET/CT was used to automatically delineate tumors. The interobserver variability in target definition was analyzed and FAPI-based automatic GTVs were compared to the manually defined GTVs. (3) Results: Target definition differed significantly between different radiation oncologists with mean dice similarity coefficients (DSCs) between 0.55 and 0.65. There was no significant difference between the volumes of automatic FAPI-GTVs based on the threshold of 2.0 and most of the manually contoured GTVs by radiation oncologists. (4) Conclusion: Due to its high tumor to background contrast, FAPI-PET/CT seems to be a superior imaging modality compared to the current gold standard contrast-enhanced CT in pancreatic cancer. For the first time, we demonstrate how FAPI-PET/CT could facilitate target definition and increases consistency in radiation oncology in pancreatic cancer.

The efficacy and safety of definitive concurrent chemoradiotherapy for non-operable esophageal cancer.

OBJECTIVE: To report outcomes and toxicity in patients who received definitive concurrent chemoradiation (DCCRT) for non-operable esophageal cancer (EC) in the modern era, and to identify markers of overall and disease-free survival (OS/DFS). METHODS: We conducted a retrospective cohort study of patients with unresectable EC who received DCCRT at our institution between 1/2008 and 1/2019. Descriptive statistics were used to report disease-control outcomes and CTCAE v4.0-5.0 toxicities. Univariable and multivariable Cox regression, and stepwise regression were used to identify associations with survival. RESULTS: At a median follow-up of 19.5 months, 130 patients with adenocarcinoma (AC) (62%) or squamous cell carcinoma (SCC) (38%) were evaluable (Stage II-III: 92%). Patients received carboplatin/paclitaxel (75%) or fluorouracil-based (25%) concurrent chemotherapy. Median total RT dose was 50.4 Gy (range, 44.7-71.4 Gy) delivered in 28 fractions (24-35). Locoregional and distant recurrence occurred in 30% and 35% of AC, and 24% and 33% of SCC, respectively. Median OS and DFS were 22.9 and 10.7 months in AC, and 25.7 and 20.2 months in SCC, respectively. On stepwise regression, tumor stage, feeding tube during DCCRT, and change in primary tumor PET/CT SUVmax were significantly associated with OS and DFS. Most severe toxicities were acute grade 4 hematologic cytopenia (6%) and radiation dermatitis (1%). Most common acute grade 3 toxicities were hematologic cytopenia (35%), dysphagia (23%), and anorexia (19%). CONCLUSIONS: Treatment of non-operable EC with DCCRT has acceptable toxicity and can provide multi-year disease control for some patients, even in AC. Continued follow-up and investigation in large studies would be useful.

A Pilot Study of Galunisertib plus Stereotactic Body Radiotherapy in Patients with Advanced Hepatocellular Carcinoma.

TGFß is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFß enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFß inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients (n = 15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150 mg orally twice a day) on days 1 to 14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15 to 28 of cycle 1. Site of index lesions treated with SBRT included liver (9 patients), lymph node (4 patients), and lung (2 patients). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia, possibly related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from nonprogressors. Nonprogressors also had increased CD8+PD-1+TIGIT+ T cells in the blood after treatment. We found galunisertib combined with SBRT to be well tolerated and associated with antitumor activity in patients with HCC. Pre- and posttreatment immune profiling of the blood was able to distinguish patients with progression versus nonprogression.

Radiographic Response of Vessel Involvement and Resectability After Neoadjuvant Chemoradiation in Patients With Locally Advanced Pancreatic Cancer.

OBJECTIVES: Survival of patients with locally advanced pancreatic cancer (LAPC) is improved when neoadjuvant chemoradiation enables subsequent surgical resection. Here, the authors assess changes in vessel involvement as a possible indicator of resectability. METHODS: Pancreatic gross tumor and all major abdominal vessels were contoured for 49 patients with unresectable LAPC before and after neoadjuvant chemoradiation. Changes were compared by paired t tests. Tumor-vessel relationships were automatically quantified using Medical Imaging Interaction Toolkit and examined for correlation with resectability and outcome. RESULTS: Tumor volumes were significantly reduced by chemoradiation (41 to 33 mL, P<0.0001). Maximum circumferential vessel involvement decreased for most patients and was statistically significant for the superior mesenteric (P<0.003) and splenic veins (P<0.038). Resection was possible in some patients and correlated positively with survival (28 vs. 15 mo, r=0.40), a decrease in CA 19.9 levels (r=0.48), and reduced involvement of most vessels. Nevertheless, surgical resection with a successful detachment of tumor tissue from major vessels was also achieved in some patients who did not show improvement in radiographic vessel involvement, but rather a reduction in tumor volume and CA 19.9 levels. CONCLUSIONS: The present analysis demonstrates that neoadjuvant chemoradiation can enable subsequent surgical resection in patients with LAPC. Complete resection substantially prolongs survival. Therefore, surgical exploration should be offered if vessel involvement is improved by chemoradiation and considered in radiographic unchanged vessel involvement if size and CA 19.9 levels decrease, as these factors may indicate resectable disease, too.

Proton beam re-irradiation for gastrointestinal malignancies: a systematic review.

BACKGROUND: Radiotherapy (RT) is part of the standard of care management of most gastrointestinal (GI) cancers. Even with advanced RT, systemic therapy, and surgical techniques, locoregional recurrences or second primary cancers can still occur within previously irradiated fields, which can present challenges in delivering effective and safe treatment. Options for reirradiation are often limited, but given the favorable dosimetric aspects of proton-beam RT, it may provide an effective and safe re-irradiation option for patients with recurrent or second primary GI cancers. METHODS: We conducted a systematic review as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol, assessing for reports of proton-beam reirradiation for recurrent or second primary GI cancers, primarily via PubMed. From the initial 373 articles identified, 7 articles were ultimately included in the analysis. RESULTS: The 7 included studies reported on proton-beam re-irradiation for the following disease sites: esophageal (n=2), pancreas (n=1), liver (n=2), rectal (n=1), and anal (n=1). Study sizes varied from as few as 1 to as many as 83 patients. Across studies, in patients who presented with tumor-related symptoms, palliation (stability/improvement) was achieved in 80-100% of the cases. Local control rates, with variable follow-up, ranged from 36-100%. All median overall survival values, when reported, were greater than 1 year. Across both liver studies, there were no cases of radiation-induced liver disease (RILD) from proton-beam re-irradiation. Across all studies, there were 2 acute (esophagopleural fistula in esophageal cancer, small bowel perforation in pancreatic cancer) and 1 late (esophageal ulcer in esophageal cancer) grade 5 toxicities, all favored to be due to progressive disease, rather than proton-beam re-irradiation. Two studies (1 esophageal, 1 rectal) generated comparison photon plans. One found that proton therapy reduced mean heart and lung doses, spinal cord dose, and lung V5Gy as compared to photon treatment, while resulting in higher lung V20Gy and V30Gy. The other found that protons decreased bowel V10Gy, V20Gy, and the dose to 200 and 150 cc of bowel, as compared to photons. CONCLUSIONS: Based upon the published experiences, proton-beam re-irradiation for recurrent or second primary GI cancers appears effective for palliation, with good disease-control, limited toxicity, favorable dosimetry, and overall compares well with published non-proton-beam experiences. Given short follow-up, additional studies are warranted to determine if dosimetric advantages from proton therapy will translate into comparative toxicity benefits.

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

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

Robust Collaborative Clustering of Subjects and Radiomic Features for Cancer Prognosis.

Feature dimensionality reduction plays an important role in radiomic studies with a large number of features. However, conventional radiomic approaches may suffer from noise, and feature dimensionality reduction techniques are not equipped to utilize latent supervision information of patient data under study, such as differences in patients, to learn discriminative low dimensional representations. To achieve robustness to noise and feature dimensionality reduction with improved discriminative power, we develop a robust collaborative clustering method to simultaneously cluster patients and radiomic features into distinct groups respectively under adaptive sparse regularization. Our method is built upon matrix tri-factorization enhanced by adaptive sparsity regularization for simultaneous feature dimensionality reduction and denoising. Particularly, latent grouping information of patients with distinct radiomic features is learned and utilized as supervision information to guide the feature dimensionality reduction, and noise in radiomic features is adaptively isolated in a Bayesian framework under a general assumption of Laplacian distributions of transform-domain coefficients. Experiments on synthetic data have demonstrated the effectiveness of the proposed approach in data clustering, and evaluation results on an FDG-PET/CT dataset of rectal cancer patients have demonstrated that the proposed method outperforms alternative methods in terms of both patient stratification and prediction of patient clinical outcomes.

COLLABORATIVE CLUSTERING OF SUBJECTS AND RADIOMIC FEATURES FOR PREDICTING CLINICAL OUTCOMES OF RECTAL CANCER PATIENTS.

Most machine learning approaches in radiomics studies ignore the underlying difference of radiomic features computed from heterogeneous groups of patients, and intrinsic correlations of the features are not fully exploited yet. In order to better predict clinical outcomes of cancer patients, we adopt an unsupervised machine learning method to simultaneously stratify cancer patients into distinct risk groups based on their radiomic features and learn low-dimensional representations of the radiomic features for robust prediction of their clinical outcomes. Based on nonnegative matrix tri-factorization techniques, the proposed method applies collaborative clustering to radiomic features of cancer patients to obtain clusters of both the patients and their radiomic features so that patients with distinct imaging patterns are stratified into different risk groups and highly correlated radiomic features are grouped in the same radiomic feature clusters. Experiments on a FDG-PET/CT dataset of rectal cancer patients have demonstrated that the proposed method facilitates better stratification of patients with distinct survival patterns and learning of more effective low-dimensional feature representations that ultimately leads to accurate prediction of patient survival, outperforming conventional methods under comparison.