Publications by authors named "Albert C Koong"

206 Publications

Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16 Cancers.

Cancer Immunol Res 2022 Jan 19. Epub 2022 Jan 19.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Human papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival. Using T cells from 2 HPV16 patients, we conducted functional T-cell assays to identify candidate HPV-specific T cells and common T-cell receptor motifs, which we then analyzed across 86 patients with HPV-related cancers. The HPV-specific clones and E7-related T-cell receptor motifs expanded in the tumor microenvironment over the course of treatment, whereas non-HPV-specific T cells did not. In HPV16 patients, improved recurrence-free survival was associated with HPV-responsive T-cell expansion during chemoradiotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-21-0119DOI Listing
January 2022

Implementation and Assessment of an Informal Virtual Elective for Medical Student Radiation Oncology Exploration During the COVID19 Pandemic: a Brief Report.

J Cancer Educ 2022 Jan 11. Epub 2022 Jan 11.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 0097, 1515 Holcombe Blvd, Houston, TX, USA.

Subspecialty exposure during medical school can be limited. Moreover, the COVID19 pandemic prevented most onsite elective medical student (MS) rotations during 2020. Therefore, we sought to create and assess the efficacy of an informal virtual elective (IVE) for MSs to explore radiation oncology (RO) at our institution. We created IVE activities including invitations to resident didactics, a faculty lecture series, and interactive virtual events with residents and faculty. MSs were offered RO resident and faculty mentors and the opportunity to deliver a lecture. Pre- and post-IVE evaluation surveys were sent to 27 4th year MSs. Surveys utilized importance ordering (1=most important; reported as median (interquartile range), free response, and Likert-type questions (5 = extremely, 1=not at all). Our IVE, held from July to October 2020, had a median of 11 students (range 7-18) attend each activity. Pre- and post-IVE surveys were completed by 22/27 (81%) and 20/27 (74%) MSs, respectively. In pre-IVE, MSs reported participating in the IVE for faculty/resident interaction (1.5 [1, 2]), networking (3 [2, 3]), and learning (4 [3-5]). In post-IVE, MSs reported benefit from faculty mentors (5 [4, 5]), delivering a presentation (5 [3-5]), and faculty lectures (4.5 [4, 5]). In post-IVE, MSs preferred a full onsite away elective (16, 80%) over an official virtual elective (1, 5%) or IVE (3, 15%). Overall, MSs reported that the IVE provided an adequate introduction to RO at our institution (4 [4, 5]). Alternative virtual elective experiences allow MSs to informally evaluate medical subspecialties and could be offered even if formal elective opportunities are available.
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http://dx.doi.org/10.1007/s13187-021-02122-yDOI Listing
January 2022

Benchmarking Outcomes after Ablative Radiotherapy for Molecularly Characterized Intrahepatic Cholangiocarcinoma.

J Pers Med 2021 Dec 1;11(12). Epub 2021 Dec 1.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

We have previously shown that ablative radiotherapy (A-RT) with a biologically effective dose (BED) ≥ 80.5 Gy for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is associated with longer survival. Despite recent large-scale sequencing efforts in ICC, outcomes following RT based on genetic alterations have not been described. We reviewed records of 156 consecutive patients treated with A-RT for unresectable ICC from 2008 to 2020. For 114 patients (73%), next-generation sequencing provided molecular profiles. The overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS) were estimated using the Kaplan-Meier method. Univariate and multivariable Cox analyses were used to determine the associations with the outcomes. The median tumor size was 7.3 (range: 2.2-18.2) cm. The portal vein thrombus (PVT) was present in 10%. The RT median BED was 98 Gy (range: 81-144 Gy). The median (95% confidence interval) follow-up was 58 (42-104) months from diagnosis and 39 (33-74) months from RT. The median OS was 32 (29-35) months after diagnosis and 20 (16-24) months after RT. The one-year OS, LC, and intrahepatic DMFS were 73% (65-80%), 81% (73-87%), and 34% (26-42%). The most common mutations were in (25%), (22%), (19%), and (13%). Upon multivariable analysis, the factors associated with death included worse performance status, larger tumor, metastatic disease, higher CA 19-9, PVT, satellitosis, and and mutations. mutation was associated with local failure. Further investigation into the prognostic value of individual mutations and combinations thereof is warranted.
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http://dx.doi.org/10.3390/jpm11121270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703854PMC
December 2021

Stereotactic Versus Conventional Radiation Therapy for Patients With Pancreatic Cancer in the Modern Era.

Adv Radiat Oncol 2021 Nov-Dec;6(6):100763. Epub 2021 Jul 29.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Patients with pancreatic cancer often receive radiation therapy before undergoing surgical resection. We compared the clinical outcomes differences between stereotactic body radiation therapy (SBRT) and 3-dimensional (3D)/intensity-modulated radiation therapy (IMRT).

Methods And Materials: We retrospectively collected data from the University of Texas MD Anderson Cancer Center. Patients with borderline resectable/potentially resectable or locally advanced pancreatic cancer receiving neoadjuvant SBRT (median, 36.0 Gy/5fx), 3D conformal radiation (median, 50.4 Gy/28 fx) or IMRT (median, 50.4 Gy/28 fx) were included. Overall survival (OS) and progression-free survival were analyzed using Cox regression.

Results: In total, 104 patients were included in our study. Fifty-seven patients (54.8%) were treated with SBRT, and 47 patients (45.2%) were treated with 3D/IMRT. Patients in the SBRT group were slightly older (median age: 70.3 vs 62.7 in the 3D/IMRT group). Both groups had similar proportions of patients with locally advanced pancreatic cancer (SBRT: 30, 52.6%; 3D/IMRT: 24, 51.1%). All patients were treated with chemotherapy. Patients in the SBRT group underwent more surgical resection compared with the 3D/IMRT group (38.6% vs 23.4%, respectively). At a median follow-up of 22 months, a total of 60 patients (57.7%) died: 25 (25/57, 43.9%) in the SBRT group, and 35 (35/47, 74.5%) in the 3D/IMRT group. Median OS was slightly higher in the SBRT group (29.6 months vs 24.1 months in the 3D/IMRT group). On multivariable Cox regression, the choice of radiation therapy technique was not associated with differences in OS (adjusted hazard ratios [aHR] = 0.5; 95% confidence interval [CI], 0.2%-1.3%,  = .18). Moreover, patients that underwent surgical resection had better OS (aHR = 0.3, 95% CI, 0.1%-0.8%,  = .01). Furthermore, progression-free survival was also similar between patients treated with SBRT and those treated with 3D/IMRT (aHR = 0.9, 95% CI, 0.5%-1.8%,  = .81).

Conclusions: SBRT was associated with similar clinical outcomes compared with conventional radiation techniques, despite being delivered over a shorter period of time which would spare patients prolonged treatment burden. Future prospective data are still needed to better assess the role of SBRT in patients with pancreatic cancer.
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http://dx.doi.org/10.1016/j.adro.2021.100763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655391PMC
July 2021

The radiotherapy quality assurance gap among phase III cancer clinical trials.

Radiother Oncol 2021 Nov 25;166:51-57. Epub 2021 Nov 25.

The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address:

Purpose: Quality assurance (QA) practices improve the quality level of oncology trials by ensuring that the protocol is followed and the results are valid and reproducible. This study investigated the utilization of QA among randomized controlled trials that involve radiotherapy (RT).

Methods And Materials: We searched ClinicalTrials.gov in February 2020 for all phase III oncology randomized clinical trials (RCTs). These trials were screened for RT-specific RCTs that had published primary trial results. Information regarding QA in each trial was collected from the study publications and trial protocol if available. Two individuals independently performed trial screening and data collection. Pearson's Chi-square tests analyses were used to assess factors that were associated with QA inclusion in RT trials.

Results: Forty-two RCTs with RT as the primary intervention or as a mandatory component of the protocol were analyzed; the earliest was started in 1994 and one trial was still active though not recruiting. Twenty-nine (69%) trials mandated RT quality assurance (RTQA) practices as part of the trial protocol, with 19 (45%) trials requiring institutional credentialing. Twenty-one (50%) trials published protocol deviation outcomes. Clinical trials involving advanced radiation techniques (IMRT, VMAT, SRS, SBRT) did not include more RTQA than trials without these advanced techniques (73% vs. 65%, p = 0.55). Trials that reported protocol deviation outcomes were associated with mandating RTQA in their protocols as compared to trials that did not report these outcomes (100% vs. 38%, p < 0.001).

Conclusions: There is a lack of RTQA utilization and transparency in RT clinical trials. It is imperative for RT trials to include increased QA for safe, consistent, and high-quality RT planning and delivery.
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http://dx.doi.org/10.1016/j.radonc.2021.11.018DOI Listing
November 2021

Design and validation of a synchrotron proton beam line for FLASH radiotherapy preclinical research experiments.

Med Phys 2022 Jan 10;49(1):497-509. Epub 2021 Dec 10.

Department of Radiation Physics, M.D. Anderson Cancer Center, University of Texas, Houston, Texas.

Purpose: The main purpose of this work was to generate and validate the dosimetric accuracy of proton beams of dimensions that are appropriate for in vivo small animal and in vitro ultrahigh dose rate (FLASH) radiotherapy experiments using a synchrotron-based treatment delivery system. This study was performed to enable future investigations of the relevance of a spread-out Bragg peak (SOBP) under FLASH conditions.

Methods: The spill characteristics of the small field fixed horizontal beam line were modified to deliver accelerated protons in times as short as 2 ms and to control the dose delivered. A Gaussian-like transverse beam profile was transformed into a square uniform one at FLASH dose rates, while avoiding low-dose regions, a crucial requirement to protect normal tissue during FLASH irradiation. Novel beam-shaping devices were designed using Monte Carlo techniques to produce up to about 6 cm of uniform dose in SOBPs while maximizing the dose rate. These included a scattering foil, a conical flattening filter to maximize the flux of protons into the region of interest, energy filters, range compensators, and collimators. The shapes, sizes, and positions of the components were varied to provide the required field sizes and SOBPs.

Results: The designed and fabricated devices were used to produce 10-, 15-, and 20-mm diameter, circular field sizes and 10-, 15-, and 20-mm SOBP modulation widths at uniform physical dose rates of up to 375 Gy/s at the center of the SOBP and a minimum dose rate of about 255 Gy/s at the entrance, respectively, in cylindrical volumes. The flatness of lateral dose profiles at the center could be adjusted to within ±1.5% at the center of the SOBP. Assessment of systematic uncertainties, such as impact of misalignments and positioning uncertainties, was performed using simulations, and the results were used to provide appropriate adjustments to ensure high-accuracy FLASH beam delivery for both in vitro and in vivo preclinical experiments.

Conclusions: It is feasible to use synchrotron-generated proton beams of sufficient dimensions for FLASH radiobiology experiments. We expect to use the system we developed to acquire in vitro and in vivo small animal FLASH radiobiology data as a function of dose, dose rate, oxygen content, and linear energy transfer to help us understand the underlying mechanisms of the FLASH phenomenon.
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http://dx.doi.org/10.1002/mp.15370DOI Listing
January 2022

Benchmarking Outcomes for Definitive Treatment of Young-Onset, Locally Advanced Rectal Cancer.

Clin Colorectal Cancer 2021 Oct 9. Epub 2021 Oct 9.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Purpose: There has been an increase in the incidence of rectal cancer diagnosed in young adults (age < 50 years). We evaluated outcomes among young adults treated with pre-operative long course chemoradiation (CRT) and total mesorectal excision (TME).

Methods: The medical records of 219 patients, age 18-49, with non-metastatic, cT3-4, or cN1-2 rectal adenocarcinoma treated from 2000 to 2017 were reviewed for demographic and treatment characteristics, as well as pathologic and oncologic outcomes. The Kaplan-Meier test, log-rank test, and Cox regression analysis were used to evaluate survival outcomes.

Results: The median age at diagnosis was 44 years. CRT followed by TME and post-operative chemotherapy was the most frequent treatment sequence (n = 196), with FOLFOX (n = 115) as the predominant adjuvant chemotherapy. There was no difference in sex, stage, MSS/pMMR, or pCR by age (< 45 years [n = 111] vs. ≥ 45 years [n = 108]). The 5-year rates of DFS were 77.2% for all patients, 69.8% for age < 45 years and 84.7% for age ≥ 45 years (P = .01). The 5-year rates of OS were 89.6% for all patients, 85.1% for patients with age < 45 years and 94.3% for patients with age ≥ 45 years (P = .03). Age ≥ 45 years was associated with a lower risk of disease recurrence or death on multivariable Cox regression analysis (HR = 0.55, 95% CI 0.31-0.97, P = .04).

Conclusion: Among young adults, patients with age < 45 years had lower rates of DFS and OS, compared to those with age ≥ 45 years. These outcomes could serve as a benchmark by which to evaluate newer treatment approaches.
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http://dx.doi.org/10.1016/j.clcc.2021.09.012DOI Listing
October 2021

Prognostic impact of lymphopenia and neutrophil-lymphocyte ratio for patients with anal squamous cell carcinoma.

J Gastrointest Oncol 2021 Oct;12(5):2412-2422

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Outcomes after definitive chemoradiation for squamous cell carcinoma are generally favorable. However, biomarkers to further yield prognostic information are desired. Treatment-related lymphopenia as well as an elevated baseline neutrophil-lymphocyte ratio have been associated with worse survival in several cancer types. We evaluated absolute lymphocyte count and neutrophil-lymphocyte ratio at baseline and at treatment-related nadir in patients with anal cancer for associations with oncologic endpoints.

Methods: We conducted a retrospective analysis of 428 consecutive patients with non-metastatic anal cancer treated with definitive, intensity-modulated radiation therapy-based chemoradiation. We analyzed absolute neutrophil and lymphocyte counts at several timepoints: pretreatment, weekly during treatment, and in the six weeks following treatment completion. Neutrophil-lymphocyte ratio was calculated at baseline and treatment-related nadir. We estimated oncologic endpoints using life tables and compared them using the log-rank test. We conducted univariate and multivariable time-to-event analyses using Cox proportional hazards.

Results: Median absolute lymphocyte count at baseline and nadir were 1.80 [interquartile range (IQR), 1.45-2.32] k/µL and 0.26 (IQR, 0.18-0.36) k/µL, respectively, and 31% developed treatment-related grade 4 lymphopenia. Median neutrophil-lymphocyte ratio at baseline and nadir were 2.34 (IQR, 1.68-3.30) and 8.80 (IQR, 5.86-12.68), respectively. Estimates of overall survival, local failure-free survival, distant metastasis-free survival (DMFS), and freedom from colostomy at 5 years were 87%, 86%, 82%, and 88%, respectively. Baseline and nadir absolute lymphocyte count were not associated with selected outcomes on univariate analysis. On multivariable analysis, factors independently associated with death included T3-T4 disease, HIV-positive status, treatment break, and baseline neutrophil-lymphocyte ratio >3. Baseline neutrophil-lymphocyte ratio showed a trend toward association with distant progression or death (P=0.07). The 5-year overall survival estimates for patients with baseline neutrophil-lymphocyte ratios ≤3 and >3 were 92.3% and 80.6%, respectively.

Conclusions: Lymphopenia during and after chemoradiation for anal cancer is common but does not appear to be associated with worse survival, recurrence, or metastases. However, elevated baseline neutrophil-lymphocyte ratio was independently associated with overall survival, local recurrence-free survival, and DMFS. Further studies are needed to determine the clinical utility of baseline neutrophil-lymphocyte ratio to guide treatment and follow-up.
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http://dx.doi.org/10.21037/jgo-21-323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576202PMC
October 2021

A Machine Learning Model Approach to Risk-Stratify Patients With Gastrointestinal Cancer for Hospitalization and Mortality Outcomes.

Int J Radiat Oncol Biol Phys 2021 09 29;111(1):135-142. Epub 2021 Apr 29.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Purpose: Patients with gastrointestinal (GI) cancer frequently experience unplanned hospitalizations, but predictive tools to identify high-risk patients are lacking. We developed a machine learning model to identify high-risk patients.

Methods And Materials: In the study, 1341 consecutive patients undergoing GI (abdominal or pelvic) radiation treatment (RT) from March 2016 to July 2018 (derivation) and July 2018 to January 2019 (validation) were assessed for unplanned hospitalizations within 30 days of finishing RT. In the derivation cohort of 663 abdominal and 427 pelvic RT patients, a machine learning approach derived random forest, gradient boosted decision tree, and logistic regression models to predict 30-day unplanned hospitalizations. Model performance was assessed using area under the receiver operating characteristic curve (AUC) and prospectively validated in 161 abdominal and 90 pelvic RT patients using Mann-Whitney rank-sum test. Highest quintile of risk for hospitalization was defined as "high-risk" and the remainder "low-risk." Hospitalizations for high- versus low-risk patients were compared using Pearson's χ test and survival using Kaplan-Meier log-rank test.

Results: Overall, 13% and 11% of patients receiving abdominal and pelvic RT experienced 30-day unplanned hospitalization. In the derivation phase, gradient boosted decision tree cross-validation yielded AUC = 0.823 (abdominal patients) and random forest yielded AUC = 0.776 (pelvic patients). In the validation phase, these models yielded AUC = 0.749 and 0.764, respectively (P < .001 and P = .002). Validation models discriminated high- versus low-risk patients: in abdominal RT patients, frequency of hospitalization was 39% versus 9% in high- versus low-risk groups (P < .001) and 6-month survival was 67% versus 92% (P = .001). In pelvic RT patients, frequency of hospitalization was 33% versus 8% (P = .002) and survival was 86% versus 92% (P = .15) in high- versus low-risk patients.

Conclusions: In patients with GI cancer undergoing RT as part of multimodality treatment, machine learning models for 30-day unplanned hospitalization discriminated high- versus low-risk patients. Future applications will test utility of models to prompt interventions to decrease hospitalizations and adverse outcomes.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.019DOI Listing
September 2021

Impact of Fiducial Marker Placement Before Stereotactic Body Radiation Therapy on Clinical Outcomes in Patients With Pancreatic Cancer.

Adv Radiat Oncol 2021 Mar-Apr;6(2):100621. Epub 2020 Nov 23.

University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Localized pancreatic cancer is commonly treated with stereotactic body radiation therapy (SBRT), which often requires the placement of fiducial markers. We compared the clinical outcomes of patients with and without fiducial markers.

Methods And Materials: We retrospectively collected data on patients with pancreatic cancer treated with neoadjuvant SBRT at a single institution. Patients were divided into 2 groups based on the placement of a fiducial marker. Local recurrence was the primary outcome. Time to event endpoints were analyzed using COX regression.

Results: We included 96 patients with unresectable pancreatic cancer: 46 patients (47.9%) did not have a fiducial marker, and 50 patients (52.1%) had a fiducial placed. Patients in the fiducial group were older and had more locally advanced pancreatic cancer compared with those who did not have a fiducial placed. Most patients in both groups (92.7%) received chemotherapy before SBRT treatment. SBRT was delivered to a median of 36 Gy over 5 fractions in the no-fiducial group, and 38 Gy over 5 fractions in the fiducial group. At a median follow-up of 20 months, local recurrence was similar irrespective of fiducial placement (adjusted hazard ratio [aHR] 0.6, 95% CI 0.3-1.3, = .59). Furthermore, no difference in overall survival was noted between the 2 groups (aHR 0.8, 95% CI 0.3-1.9, = .65). In patients who eventually underwent surgery post-SBRT, no difference in surgical margins ( = .40) or lymphovascular invasion ( = .76) was noted between the 2 groups. No patient developed acute pancreatitis after fiducial placement.

Conclusions: Our data suggest that the use of fiducial markers does not negatively affect clinical outcomes in patients with localized pancreatic cancer. Prospective confirmation of our results is still needed.
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http://dx.doi.org/10.1016/j.adro.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071717PMC
November 2020

Early and Midtreatment Mortality in Palliative Radiotherapy: Emphasizing Patient Selection in High-Quality End-of-Life Care.

J Natl Compr Canc Netw 2021 04 20;19(7):805-813. Epub 2021 Apr 20.

Department of Radiation Oncology, and.

Background: Palliative radiotherapy (RT) is effective, but some patients die during treatment or too soon afterward to experience benefit. This study investigates end-of-life RT patterns to inform shared decision-making and facilitate treatment consistent with palliative goals.

Materials And Methods: All patients who died ≤6 months after initiating palliative RT at an academic cancer center between 2015 and 2018 were identified. Associations with time-to-death, early mortality (≤30 days), and midtreatment mortality were analyzed.

Results: In total, 1,620 patients died ≤6 months from palliative RT initiation, including 574 (34%) deaths at ≤30 days and 222 (14%) midtreatment. Median survival was 43 days from RT start (95% CI, 41-45) and varied by site (P<.001), ranging from 36 (head and neck) to 53 days (dermal/soft tissue). On multivariable analysis, earlier time-to-death was associated with osseous (hazard ratio [HR], 1.33; P<.001) and head and neck (HR, 1.45; P<.001) sites, multiple RT courses ≤6 months (HR, 1.65; P<.001), and multisite treatments (HR, 1.40; P=.008), whereas stereotactic technique (HR, 0.77; P<.001) and more recent treatment year (HR, 0.82; P<.001) were associated with longer survival. No difference in time to death was noted among patients prescribed conventional RT in 1 to 10 versus >10 fractions (median, 40 vs 47 days; P=.272), although the latter entailed longer courses. The 30-day mortality group included 335 (58%) inpatients, who were 27% more likely to die midtreatment (P=.031). On multivariable analysis, midtreatment mortality among these inpatients was associated with thoracic (odds ratio [OR], 2.95; P=.002) and central nervous system (CNS; OR, 2.44; P=.002) indications, >5-fraction courses (OR, 3.27; P<.001), and performance status of 3 to 4 (OR, 1.63; P=.050). Conversely, palliative/supportive care consultation was associated with decreased midtreatment mortality (OR, 0.60; P=.045).

Conclusions: Earlier referrals and hypofractionated courses (≤5-10 treatments) should be routinely considered for palliative RT indications, given the short life expectancies of patients at this stage in their disease course. Providers should exercise caution for emergent thoracic and CNS indications among inpatients with poor prognoses due to high midtreatment mortality.
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http://dx.doi.org/10.6004/jnccn.2020.7664DOI Listing
April 2021

A multi-scale integrated analysis identifies KRT8 as a pan-cancer early biomarker.

Pac Symp Biocomput 2021 ;26:297-308

Biophysics Program, Department of Medicine, Stanford University, Stanford, CA, USA,

An early biomarker would transform our ability to screen and treat patients with cancer. The large amount of multi-scale molecular data in public repositories from various cancers provide unprecedented opportunities to find such a biomarker. However, despite identification of numerous molecular biomarkers using these public data, fewer than 1% have proven robust enough to translate into clinical practice. One of the most important factors affecting the successful translation to clinical practice is lack of real-world patient population heterogeneity in the discovery process. Almost all biomarker studies analyze only a single cohort of patients with the same cancer using a single modality. Recent studies in other diseases have demonstrated the advantage of leveraging biological and technical heterogeneity across multiple independent cohorts to identify robust disease biomarkers. Here we analyzed 17149 samples from patients with one of 23 cancers that were profiled using either DNA methylation, bulk and single-cell gene expression, or protein expression in tumor and serum. First, we analyzed DNA methylation profiles of 9855 samples across 23 cancers from The Cancer Genome Atlas (TCGA). We then examined the gene expression profile of the most significantly hypomethylated gene, KRT8, in 6781 samples from 57 independent microarray datasets from NCBI GEO. KRT8 was significantly over-expressed across cancers except colon cancer (summary effect size=1.05; p < 0.0001). Further, single-cell RNAseq analysis of 7447 single cells from lung tumors showed that genes that significantly correlated with KRT8 (p < 0.05) were involved in p53-related pathways. Immunohistochemistry in tumor biopsies from 294 patients with lung cancer showed that high protein expression of KRT8 is a prognostic marker of poor survival (HR = 1.73, p = 0.01). Finally, detectable KRT8 in serum as measured by ELISA distinguished patients with pancreatic cancer from healthy controls with an AUROC=0.94. In summary, our analysis demonstrates that KRT8 is (1) differentially expressed in several cancers across all molecular modalities and (2) may be useful as a biomarker to identify patients that should be further tested for cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958996PMC
April 2021

Radiation-Associated Lymphopenia and Outcomes of Patients with Unresectable Hepatocellular Carcinoma Treated with Radiotherapy.

J Hepatocell Carcinoma 2021 3;8:57-69. Epub 2021 Mar 3.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC).

Patients And Methods: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan-Meier method. Univariable and multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy.

Results: Of 143 patients identified, the median age was 66 (range, 19-90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13-25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/µL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.

Conclusion: Grade 3 or higher lymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.
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http://dx.doi.org/10.2147/JHC.S282062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937383PMC
March 2021

Implementation of a stereotactic body radiotherapy program for unresectable pancreatic cancer in an integrated community academic radiation oncology satellite network.

Clin Transl Radiat Oncol 2021 Mar 12;27:147-151. Epub 2021 Feb 12.

Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, United States.

With increasing interest in stereotactic body radiotherapy (SBRT) for unresectable pancreatic cancer, quality improvement (QI) initiatives to develop integrated clinical workflows are crucial to ensure quality assurance (QA) when introducing this challenging technique into radiation practices.

Materials/methods: In 2017, we used the Plan, Do, Study, Act (PDSA) QI methodology to implement a new pancreas SBRT program in an integrated community radiation oncology satellite. A unified integrated information technology infrastructure was used to virtually integrate the planned workflow into the community radiation oncology satellite network (P - Plan/D - Do). This workflow included multiple prospective quality assurance (QA) measures including multidisciplinary evaluation, prospective scrutiny of radiation target delineation, prospective radiation plan evaluation, and monitoring of patient outcomes. Institutional review board approval was obtained to retrospectively study and report outcomes of patients treated in this program (S - Study).

Results: There were 12 consecutive patients identified who were treated in this program from 2017 to 2020 with a median follow-up of 27 months. The median survival was 13 months, median local failure free survival was 12 months and median progression free survival was 6 months from SBRT. There were no acute or late Common Terminology Criteria for Adverse Effects (CTCAE) version 5 toxicities ≥ Grade 3.

Conclusion: We report the successful implementation of a community pancreas SBRT program involving multiple prospective QA measures, providing the groundwork to safely expand access to pancreas SBRT in our community satellite network (A - Act).
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http://dx.doi.org/10.1016/j.ctro.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907676PMC
March 2021

Detecting the Dark Matter of Unpublished Clinical Cancer Studies: An Analysis of Phase 3 Randomized Controlled Trials.

Mayo Clin Proc 2021 02;96(2):420-426

The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Unpublished randomized controlled trial (RCT) frequency, correlates, and financial impact are not well understood. We sought to characterize the nonpublication of peer-reviewed manuscripts among interventional, therapeutic, multi-arm, phase 3 oncology RCTs. Trials were identified by searching ClinicalTrials.gov, while publications and abstracts were identified through PubMed and Google Scholar. Trial data were extracted from ClinicalTrials.gov and individual publications. Publication was defined as a peer-reviewed manuscript addressing the primary endpoint. Patient accrual cost was extrapolated from experimental data; investigators/sponsors were contacted to determine nonpublication reasons. Six hundred eighty-four completed RCTs met inclusion criteria, which accrued 434,610 patients from 1994 to 2015; 638 were published (93.3%) and 46 were unpublished (6.7%). Among the unpublished trials, the time difference from primary endpoint maturity to data abstraction was a median of 6 years (interquartile range, 4 to 8 years). On multiple binary logistic regression analysis, factors associated with unpublished trials included lack of cooperative group sponsorship (odds ratio, 5.91, 95% CI, 1.35 to 25.97; P=.019) and supportive care investigation (odds ratio, 2.90; 95% CI, 1.13 to 7.41; P=.027). The estimated inflation-adjusted average cost of patient accrual for all unpublished trials was $113,937,849 (range, $41,136,883 to $320,201,063). Direct contact with sponsors/investigators led to a 50.0% response rate (n=23 of 46); manuscript in preparation and/or in submission (n=10 of 23) was the most commonly cited reason for nonpublication. In conclusion, approximately 1 in 15 clinical oncology RCTs are unpublished and this has a profound impact on the research enterprise. The cooperative group infrastructure may serve as a blueprint to reduce nonpublication.
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http://dx.doi.org/10.1016/j.mayocp.2020.08.015DOI Listing
February 2021

Radiotherapy clinical trial enrollment during the COVID-19 pandemic.

Acta Oncol 2021 Mar 28;60(3):312-315. Epub 2020 Dec 28.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1080/0284186X.2020.1865564DOI Listing
March 2021

Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice.

Sci Rep 2020 12 10;10(1):21600. Epub 2020 Dec 10.

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.
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http://dx.doi.org/10.1038/s41598-020-78017-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728763PMC
December 2020

Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer.

Clin Cancer Res 2021 02 1;27(4):1069-1081. Epub 2020 Dec 1.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Purpose: Although abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress antitumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood.

Experimental Design: To generate spatially resolved tumor and immune cell data at single-cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, IFN regulatory factor 5, MRC1 (CD206)] in the PDAC tumor microenvironment. Spatial point pattern analyses were conducted to assess the degree of colocalization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes.

Results: In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, and differed by somatic genotype. High densities of CD15ARG1 immunosuppressive granulocytic cells and M2-polarized macrophages were associated with worse patient survival. Moreover, beyond cell density, closer proximity of M2-polarized macrophages to tumor cells was strongly associated with disease-free survival, revealing the clinical significance and biologic importance of immune cell localization within tumor areas.

Conclusions: A diverse set of myeloid cells are present within the PDAC tumor microenvironment and are distributed heterogeneously across patient tumors. Not only the densities but also the spatial locations of myeloid immune cells are associated with patient outcomes, highlighting the potential role of spatially resolved myeloid cell subtypes as quantitative biomarkers for PDAC prognosis and therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345232PMC
February 2021

Gastrointestinal malignancies and supportive care trials: a snapshot of the last two decades.

BMJ Support Palliat Care 2020 Sep 17. Epub 2020 Sep 17.

Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: Patients with gastrointestinal (GI) cancers experience a high symptom burden due to the effects of both cancer and treatment. As such, trials assessing symptom burden and supportive interventions are crucial. Here, we characterise the landscape of phase III GI cancer clinical trials and explore study outcomes centred on the patient's quality of life (QoL).

Methods: We searched ClinicalTrials.gov for phase III randomised controlled trials (RCTs) registered between 2000 and 2017 that are assessing a therapeutic intervention in adult patients with cancer and grouped trials by GI disease sites.

Results: Overall, we identified 76 phase III trials specific to GI cancers that enrolled a total of 53 725 patients. When analysing the primary outcomes measured, the vast majority of studies (n=71, 86%) measured disease-related endpoints such as progression-free survival or overall survival. All trials had a secondary endpoint that measured adverse events, but only 30 trials (39%) included QoL measures as secondary endpoints. Of the 30 trials that included QoL secondary endpoints, only 16 (53%) reported these results. Only five trials (7%) assessed interventions aimed at supportive measures impacting disease-related or treatment-related toxicity. None of the supportive trials included QoL as a primary endpoint and only two of these trials (40%) included QoL as a secondary endpoint.

Conclusions: Most GI cancer trials failed to incorporate patient-centred outcomes or QoL measures when studying new interventions. These findings call for greater integration of patient-reported metrics, which may lead to better care and outcomes for patients with GI malignancies.
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http://dx.doi.org/10.1136/bmjspcare-2020-002538DOI Listing
September 2020

Telemedicine for Radiation Oncology in a Post-COVID World.

Int J Radiat Oncol Biol Phys 2020 10;108(2):407-410

Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1016/j.ijrobp.2020.06.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462809PMC
October 2020

Understanding the Intersection of Working from Home and Burnout to Optimize Post-COVID19 Work Arrangements in Radiation Oncology.

Int J Radiat Oncol Biol Phys 2020 Oct;108(2):370-373

The University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Houston, Texas.

Purpose: To evaluate burnout in an academic radiation oncology program after the workforce shifted to working from home all or part of the time to better understand the impact of remote work and if it is sustainable after the COVID-19 virus abates.

Methods And Materials: In May 2020, in the midst of work-safe policies in the state and stabilizing COVID-19 case numbers, the Qualtrics-based MiniZ burnout survey was amended to include questions related to COVID-19 and working from home and was emailed to all radiation oncology employees across 3 departments: radiation oncology, radiation physics, and experimental radiation oncology. Descriptive and χ statistics were calculated within Qualtrics using StatIQ to evaluate factors associated with burnout and positive work from home experience.

Results: Five hundred seventy-five employees completed the survey. Aggregating 3 responses that indicate having some degree of burnout, the rate of burnout across the cohort was 32%. For the same survey questions administered a year earlier, burnout rate was reported to be 40%. In the current survey, radiation oncology faculty and therapists had the highest reported burnout rates, at 47% and 44%, respectively (P = .031). The majority of employees working from home at least part of the time reported the experience was positive (74%, 323/436), and feeling positive about working from home was associated with reduced burnout (P = .030). Qualitative data review suggested the main drivers of unfavorable work-from-home responses were child/family care issues and information technology issues.

Conclusions: Burnout was not increased during the emerging COVID-19 period compared with pre-COVID data. The shift to working from home was positive for most of the workforce and a potential benefit in reducing burnout for many staff groups. Maintaining work-from-home options post COVID-19 may help reduce burnout long term. It is important to personalize options for those unable to work effectively from home and to resolve information technology challenges to ensure functionality.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462773PMC
October 2020

Radiation for Glioblastoma in the Era of Coronavirus Disease 2019 (COVID-19): Patient Selection and Hypofractionation to Maximize Benefit and Minimize Risk.

Adv Radiat Oncol 2020 Jul-Aug;5(4):743-745. Epub 2020 May 27.

Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

We describe the institutional guidelines of a major tertiary cancer center with regard to using hypofractionated radiation regimens to treat glioblastoma as a measure to minimize exposure to coronavirus disease 2019 (COVID-19) while not sacrificing clinical outcomes. Our guidelines review level one evidence of various hypofractionated regimens, and recommend a multidisciplinary approach while balancing the risk of morbidity and mortality among individuals at high risk for severe illness from COVID-19 infection. We also briefly outline strategies our department is taking in mitigating risk among our cancer patients undergoing radiation.
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http://dx.doi.org/10.1016/j.adro.2020.04.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251361PMC
May 2020

Radiation Oncology Strategies to Flatten the Curve During the Coronavirus Disease 2019 (COVID-19) Pandemic: Experience From a Large Tertiary Cancer Center.

Adv Radiat Oncol 2020 Jul-Aug;5(4):567-572. Epub 2020 May 21.

Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

During the coronavirus disease 2019 pandemic, minimizing exposure risk for patients with cancer and health care personnel was of utmost importance. Here, we present steps taken to date to flatten the curve at the radiation oncology division of a tertiary cancer center with the goal of mitigating risk of exposure among patients and staff, and optimizing resource utilization. Response to the coronavirus disease 2019 pandemic in this large tertiary referral center included volume reduction, personal protective equipment recommendations, flexible clinic visit interaction types dictated by need and risk reduction, and numerous social distancing strategies. We hope these outlined considerations can assist the wider radiation oncology community as we collectively face this ongoing challenge.
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http://dx.doi.org/10.1016/j.adro.2020.04.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240274PMC
May 2020

Intensified systemic therapy and stereotactic ablative radiotherapy dose for patients with unresectable pancreatic adenocarcinoma.

Radiother Oncol 2020 11 5;152:63-69. Epub 2020 Aug 5.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.radonc.2020.07.053DOI Listing
November 2020

IMRT Reduces Acute Toxicity in Patients Treated With Preoperative Chemoradiation for Gastric Cancer.

Adv Radiat Oncol 2020 May-Jun;5(3):369-376. Epub 2019 Nov 28.

Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Preoperative chemoradiation is being currently evaluated in 2 randomized international trials. However, chemoradiation for gastric cancer can be associated with relatively high rates of acute toxicity. We compared rates of toxicity, toxicity-related events, and oncologic outcomes in patients treated with intensity modulated radiation therapy (IMRT) and those treated with 3-dimensional conformal radiation therapy (3DCRT).

Methods And Materials: We retrospectively reviewed records of 202 patients with consecutive gastric cancer treated with preoperative intent radiation therapy at our institution from 1998 to 2018. Patients with gastroesophageal junction involvement and those with metastatic disease were excluded. Eighty-two patients received 3DCRT, and 120 patients received IMRT. The median radiation dose was 45 Gy, and 99% received concurrent chemotherapy.

Results: There were no significant differences between the 3DCRT and IMRT groups regarding sex, race, histology, tumor location, histology, or nodal stage. The rate of grade 3 to 4 acute toxicity was significantly lower in patients treated with IMRT compared with 3DCRT (49% vs 70%, = .004). The composite rate of toxicity-related events (hospitalization, feeding tube use, intravenous rehydration, or radiation therapy breaks) was also significantly lower in patients treated with IMRT compared with 3DCRT (56% vs 85%, <.001). In addition, 68% of patients who received IMRT and 73% of patients who received 3DCRT underwent subsequent surgical resection ( = .245). Among patients who underwent surgery, the 3-year overall survival rates were not significantly different between those treated with IMRT and 3DCRT (71% vs 69%,  = .786). Patients receiving IMRT had a significantly higher absolute nadir lymphocyte count compared with patients receiving 3DCRT (median, 0.21 vs 0.16 K/UL; = .047).

Conclusions: Our study suggests that IMRT might significantly reduce rates of grade 3 to 4 acute toxicity and toxicity-related events compared with 3DCRT, with no significant difference in oncologic outcomes. IMRT is an appropriate and possibly preferable radiation modality in patients treated with preoperative chemoradiation for gastric cancer.
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http://dx.doi.org/10.1016/j.adro.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276694PMC
November 2019

Mitigating the impact of COVID-19 on oncology: Clinical and operational lessons from a prospective radiation oncology cohort tested for COVID-19.

Radiother Oncol 2020 07 29;148:252-257. Epub 2020 May 29.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.

Background And Purpose: The COVID-19 pandemic warrants operational initiatives to minimize transmission, particularly among cancer patients who are thought to be at high-risk. Within our department, a multidisciplinary tracer team prospectively monitored all patients under investigation, tracking their test status, treatment delays, clinical outcomes, employee exposures, and quarantines.

Materials And Methods: Prospective cohort tested for SARS-COV-2 infection over 35 consecutive days of the early pandemic (03/19/2020-04/22/2020).

Results: A total of 121 Radiation Oncology patients underwent RT-PCR testing during this timeframe. Of the 7 (6%) confirmed-positive cases, 6 patients were admitted (4 warranting intensive care), and 2 died from acute respiratory distress syndrome. Radiotherapy was deferred or interrupted for 40 patients awaiting testing. As the median turnaround time for RT-PCR testing decreased from 1.5 (IQR: 1-4) to ≤1-day (P < 0.001), the median treatment delay also decreased from 3.5 (IQR: 1.75-5) to 1 business day (IQR: 1-2) [P < 0.001]. Each patient was an exposure risk to a median of 5 employees (IQR: 3-6.5) through prolonged close contact. During this timeframe, 39 care-team members were quarantined for a median of 3 days (IQR: 2-11), with a peak of 17 employees simultaneously quarantined. Following implementation of a "dual PPE policy," newly quarantined employees decreased from 2.9 to 0.5 per day.

Conclusion: The severe adverse events noted among these confirmed-positive cases support the notion that cancer patients are vulnerable to COVID-19. Active tracking, rapid diagnosis, and aggressive source control can mitigate the adverse effects on treatment delays, workforce incapacitation, and ideally outcomes.
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http://dx.doi.org/10.1016/j.radonc.2020.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256609PMC
July 2020

Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1586-1595. Epub 2020 May 28.

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes.

Methods: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors.

Results: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; = 0.032). -mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, < 0.001).

Conclusions: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC.

Impact: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415636PMC
August 2020

Deep learning for identification of critical regions associated with toxicities after liver stereotactic body radiation therapy.

Med Phys 2020 Aug 3;47(8):3721-3731. Epub 2020 Jun 3.

Department of Oncology, Faulty of Health & Medical Sciences, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1002/mp.14235DOI Listing
August 2020
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