Publications by authors named "Joshua E Meyer"

54 Publications

The American Brachytherapy Society consensus statement for permanent implant brachytherapy using Yttrium-90 microsphere radioembolization for liver tumors.

Brachytherapy 2022 May 19. Epub 2022 May 19.

Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE; Department of Radiation Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA. Electronic address:

Purpose: To develop a multidisciplinary consensus for high quality multidisciplinary implementation of brachytherapy using Yttrium-90 (Y) microspheres transarterial radioembolization (Y TARE) for primary and metastatic cancers in the liver.

Methods And Materials: Members of the American Brachytherapy Society (ABS) and colleagues with multidisciplinary expertise in liver tumor therapy formulated guidelines for Y TARE for unresectable primary liver malignancies and unresectable metastatic cancer to the liver. The consensus is provided on the most recent literature and clinical experience.

Results: The ABS strongly recommends the use of Y microsphere brachytherapy for the definitive/palliative treatment of unresectable liver cancer when recommended by the multidisciplinary team. A quality management program must be implemented at the start of Y TARE program development and follow-up data should be tracked for efficacy and toxicity. Patient-specific dosimetry optimized for treatment intent is recommended when conducting Y TARE. Implementation in patients on systemic therapy should account for factors that may enhance treatment related toxicity without delaying treatment inappropriately. Further management and salvage therapy options including retreatment with Y TARE should be carefully considered.

Conclusions: ABS consensus for implementing a safe Y TARE program for liver cancer in the multidisciplinary setting is presented. It builds on previous guidelines to include recommendations for appropriate implementation based on current literature and practices in experienced centers. Practitioners and cooperative groups are encouraged to use this document as a guide to formulate their clinical practices and to adopt the most recent dose reporting policies that are critical for a unified outcome analysis of future effectiveness studies.
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http://dx.doi.org/10.1016/j.brachy.2022.04.004DOI Listing
May 2022

Delineating The RAS Conformational Landscape.

Cancer Res 2022 May 10. Epub 2022 May 10.

Fox Chase Cancer Center, Philadelphia, PA, United States.

Mutations in RAS isoforms (KRAS, NRAS, and HRAS) are among the most frequent oncogenic alterations in many cancers, making these proteins high priority therapeutic targets. Effectively targeting RAS isoforms requires an exact understanding of their active, inactive, and druggable conformations. However, there is no structural catalog of RAS conformations to guide therapeutic targeting or examining the structural impact of RAS mutations. Here we present an expanded classification of RAS conformations based on analyses of the catalytic switch 1 (SW1) and switch 2 (SW2) loops. From 721 human KRAS, NRAS, and HRAS structures available in the Protein Data Bank (206 RAS-protein co-complexes, 190 inhibitor-bound, and 325 unbound, including 204 WT and 517 mutated structures), we created a broad conformational classification based on the spatial positions of Y32 in SW1 and Y71 in SW2. Clustering all well-modeled SW1 and SW2 loops using a density-based machine learning algorithm defined additional conformational subsets, some previously undescribed. Three SW1 conformations and nine SW2 conformations were identified, each associated with different nucleotide states (GTP-bound, nucleotide-free, and GDP-bound) and specific bound proteins or inhibitor sites. The GTP-bound SW1 conformation could be further subdivided based on the hydrogen bond type made between Y32 and the GTP γ-phosphate. Further analysis clarified the catalytic impact of G12D and G12V mutations and the inhibitor chemistries that bind to each druggable RAS conformation. Overall, this study has expanded our understanding of RAS structural biology, which could facilitate future RAS drug discovery.
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http://dx.doi.org/10.1158/0008-5472.CAN-22-0804DOI Listing
May 2022

Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers.

Nat Commun 2022 03 25;13(1):1618. Epub 2022 Mar 25.

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS, APC, TP53, and PIK3CA. These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts.
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http://dx.doi.org/10.1038/s41467-022-29227-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956741PMC
March 2022

Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology.

Cancer Treat Rev 2022 Mar 5;104:102337. Epub 2022 Jan 5.

Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, United States; Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States. Electronic address:

DNA repair vulnerabilities are present in a significant proportion of cancers. Specifically, germline alterations in DNA repair not only increase cancer risk but are associated with treatment response and clinical outcomes. The therapeutic landscape of cancer has rapidly evolved with the FDA approval of therapies that specifically target DNA repair vulnerabilities. The clinical success of synthetic lethality between BRCA deficiency and poly(ADP-ribose) polymerase (PARP) inhibition has been truly revolutionary. Defective mismatch repair has been validated as a predictor of response to immune checkpoint blockade associated with durable responses and long-term benefit in many cancer patients. Advances in next generation sequencing technologies and their decreasing cost have supported increased genetic profiling of tumors coupled with germline testing of cancer risk genes in patients. The clinical adoption of panel testing for germline assessment in high-risk individuals has generated a plethora of genetic data, particularly on DNA repair genes. Here, we highlight the therapeutic relevance of germline aberrations in DNA repair to identify patients eligible for precision treatments such as PARP inhibitors (PARPis), immune checkpoint blockade, chemotherapy, radiation therapy and combined treatment. We also discuss emerging mechanisms that regulate DNA repair.
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http://dx.doi.org/10.1016/j.ctrv.2021.102337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016579PMC
March 2022

Initial Clinical Experience With Novel Directional Low-Dose Rate Brachytherapy for Retroperitoneal Sarcoma.

J Surg Res 2021 12 17;268:411-418. Epub 2021 Aug 17.

Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois.

Background: A novel Palladium-103 low-dose rate (LDR) brachytherapy device was developed to provide dose-escalation to the tumor bed after resection while shielding adjacent tissues. This multicenter report describes the initial experience with this device in patients with retroperitoneal sarcoma (RPS).

Materials And Methods: Patients with recurrent RPS, prior radiotherapy, and/or concern for positive margins were considered. An LDR brachytherapy dose of 20-60 Gy was administered, corresponding to biologically effective dose values of 15-53 Gy and equivalent dose values of 12-43 Gy.

Results: Six patients underwent implantation at four institutions. Of these, five had recurrent disease in the retroperitoneum or pelvic sidewall, one had untreated locally advanced leiomyosarcoma, two had prior external beam radiation therapy at the time of initial diagnosis, and four received neoadjuvant external beam radiation therapy plus brachytherapy. The device was easily implanted and conformed to the treatment area. Median follow-up was 16 mo; radiation was delivered to the at-risk margin with minimal irradiation of adjacent structures. No local recurrences at the site of implantation, device migration, or radiation-related toxicities were observed.

Conclusions: The novel LDR directional brachytherapy device successfully delivered a targeted dose escalation to treat RPS high-risk margins. Lack of radiation-related toxicity demonstrates its safety.
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http://dx.doi.org/10.1016/j.jss.2021.06.080DOI Listing
December 2021

Neoadjuvant Chemoradiation Impacts the Prognostic Effect of Surgical Margin Status in Pancreatic Adenocarcinoma.

Ann Surg Oncol 2022 Jan 10;29(1):354-363. Epub 2021 Jun 10.

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Background: Many studies show significantly improved survival after R0 resection compared with R1 resection in pancreatic adenocarcinoma (PAC); however, the effect of neoadjuvant chemoradiation (NACRT) on this association is unknown.

Objective: The aim of this study was to evaluate the prognostic significance of positive surgical margins (SMs) after NACRT compared with upfront surgery + adjuvant therapy in PAC.

Methods: All cases of surgically resected PAC at a single institution were reviewed from 1996 to 2014; patients treated with palliative intent, metastatic disease, and biliary/ampullary tumors were excluded. The primary endpoint was overall survival (OS).

Results: Overall, 300 patients were included; 134 patients received NACRT with concurrent 5-fluorouracil or gemcitabine followed by surgery, and 166 patients received upfront surgery (+ adjuvant chemotherapy in 72% of patients and RT in 65%); 31% of both groups had a positive SM (+SM). The median OS for patients with a +SM or negative SM (-SM) was 26.6 and 31.6 months, respectively for NACRT, and 12.0 and 24.5 months, respectively, for upfront surgery. OS was significantly improved with -SM compared with +SM in both groups (p = 0.006). When resection yielded +SM, NACRT patients had improved OS compared with upfront surgery patients (p < 0.001). On multivariable analysis, +SM in the upfront surgery group (hazard ratio [HR] 2.94, 95% confidence interval [CI] 2.04-4.24; p < 0.001) and older age (HR 1.01, 95% CI 1.00-1.03, per year; p = 0.007) predicted worse OS. +SM in the NACRT group was not associated with worse OS (HR 1.09, 95% CI 0.72-1.65; p = 0.70).

Conclusion: Patients with a positive margin after NACRT and surgery had longer survival compared with patients with a positive margin after upfront surgery. NACRT should be strongly considered for patients at high risk of R1 resections.
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http://dx.doi.org/10.1245/s10434-021-10219-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660918PMC
January 2022

ASO Author Reflections: Neoadjuvant Chemoradiation Impacts the Prognostic Effect of Surgical Margin Status in Pancreatic Adenocarcinoma.

Ann Surg Oncol 2022 01 5;29(1):364-365. Epub 2021 Jun 5.

Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

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http://dx.doi.org/10.1245/s10434-021-10230-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036528PMC
January 2022

Pancreatic cancer in the era of COVID-19 pandemic: Which one is the lesser of two evils?

World J Clin Oncol 2021 Feb;12(2):54-60

Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA 19111, United States.

Pancreatic adenocarcinoma remains one of the deadliest malignancies affecting the older population. We are experiencing a paradigm shift in the treatment of pancreatic cancer in the era of coronavirus disease 2019 (COVID-19) pandemic. Utilizing neoadjuvant treatment and further conducting a safe surgery while protecting patients in a controlled environment can improve oncological outcomes. On the other hand, an optimal oncologic procedure performed in a hazardous setting could shorten patient survival if recovery is complicated by COVID-19 infection. We believe that oncological treatment protocols must adapt to this new health threat, and pancreatic cancer is not unique in this regard. Although survival may not be as optimistic as most other malignancies, as caregivers and researchers, we are committed to innovating and reshaping the treatment algorithms to minimize morbidity and maximize survival as caregivers and researchers.
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http://dx.doi.org/10.5306/wjco.v12.i2.54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918523PMC
February 2021

Feasibility of Fitness Tracker Usage to Assess Activity Level and Toxicities in Patients With Colorectal Cancer.

JCO Clin Cancer Inform 2021 01;5:125-133

Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA.

Purpose: Performance status (PS) is a subjective assessment of patients' overall health. Quantification of physical activity using a wearable tracker (Fitbit Charge [FC]) may provide an objective measure of patient's overall PS and treatment tolerance.

Materials And Methods: Patients with colorectal cancer were prospectively enrolled into two cohorts (medical and surgical) and asked to wear FC for 4 days at baseline (start of new chemotherapy [± 4 weeks] or prior to curative resection) and follow-up (4 weeks [± 2 weeks] after initial assessment in medical and postoperative discharge in surgical cohort). Primary end point was feasibility, defined as 75% of patients wearing FC for at least 12 hours/d, 3 of 4 assigned days. Mean steps per day (SPD) were correlated with toxicities of interest (postoperative complication or ≥ grade 3 toxicity). A cutoff of 5,000 SPD was selected to compare outcomes.

Results: Eighty patients were accrued over 3 years with 55% males and a median age of 59.5 years. Feasibility end point was met with 68 patients (85%) wearing FC more than predefined duration and majority (91%) finding its use acceptable. The mean SPD count for patients with PS 0 was 6,313, and for those with PS 1, it was 2,925 (122 and 54 active minutes, respectively) ( = .0003). Occurrence of toxicity of interest was lower among patients with SPD > 5,000 (7 of 33, 21%) compared with those with SPD < 5,000 (14 of 43, 32%), although not significant ( = .31).

Conclusion: Assessment of physical activity with FC is feasible in patients with colorectal cancer and well-accepted. SPD may serve as an adjunct to PS assessment and a possible tool to help predict toxicities, regardless of type of therapy. Future studies incorporating FC can standardize patient assessment and help identify vulnerable population.
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http://dx.doi.org/10.1200/CCI.20.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189607PMC
January 2021

Impact of Clinical Markers of Nutritional Status and Feeding Jejunostomy Use on Outcomes in Esophageal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.

Nutrients 2020 Oct 17;12(10). Epub 2020 Oct 17.

Fox Chase Cancer Center, Department of Hematology/Oncology, Philadelphia, PA 19111-2497, USA.

Background: Patients with esophageal cancer (EC) have high rates of malnutrition due to tumor location and treatment-related toxicity. Various strategies are used to improve nutritional status in patients with EC including oral and enteral support.

Methods: We conducted a retrospective analysis to determine the impact of malnutrition and prophylactic feeding jejunostomy tube (FJT) placement on toxicity and outcomes in patients with localized EC who were treated with neoadjuvant chemoradiation therapy (nCRT) followed by esophagectomy.

Results: We identified 125 patients who were treated with nCRT between 2002 and 2014. Weight loss and hypoalbuminemia occurred frequently during nCRT and were associated with multiple adverse toxicity outcomes including hematologic toxicity, nonhematologic toxicity, grade ≥3 toxicity, and hospitalizations. After adjusting for relevant covariates including the specific nCRT chemotherapy regimen received and the onset of toxicity, there were no significant associations between hypoalbuminemia, weight loss, or FJT placement and relapse-free survival (RFS) or overall survival (OS). FJT placement was associated with less weight loss during nCRT ( = 0.003) but was not associated with reduced toxicity or improved survival.

Conclusions: Weight and albumin loss during nCRT for EC are important factors relating to treatment toxicity but not RFS or OS. While pretreatment FJT placement may reduce weight loss, it may not impact treatment tolerance or survival.
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http://dx.doi.org/10.3390/nu12103177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602938PMC
October 2020

Patterns of Failure and Need for Biliary Intervention in Resected Biliary Tract Cancers After Chemoradiation.

Ann Surg Oncol 2020 Dec 17;27(13):4867-4869. Epub 2020 Aug 17.

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

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http://dx.doi.org/10.1245/s10434-020-09014-3DOI Listing
December 2020

Pelvic Reirradiation Utilizing Pulsed Low-dose Rate Radiation Therapy.

Am J Clin Oncol 2020 10;43(10):748-751

Departments of Radiation Oncology.

Pulsed low-dose rate radiation therapy has been shown to reduce normal tissue damage while decreasing DNA damage repair in tumor cells. In a cohort of patients treated with palliative or definitive pelvic reirradiation using pulsed low-dose rate radiation therapy, we observed substantial local control and low rates of toxicity.
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http://dx.doi.org/10.1097/COC.0000000000000741DOI Listing
October 2020

Toxicity and outcomes in older versus younger patients treated with trimodality therapy for locally advanced rectal cancer.

J Geriatr Oncol 2020 11 4;11(8):1331-1334. Epub 2020 May 4.

Departments of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.jgo.2020.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606716PMC
November 2020

Predictors of Distant Recurrence Following Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer.

Am J Clin Oncol 2020 04;43(4):243-248

Departments of Radiation Oncology.

Objective: The objective of this study was to characterize patients at an increased risk of distant metastasis (DM) following stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC).

Materials And Methods: We identified patients undergoing SBRT for stage I NSCLC between 2005 and 2016. Patients with a prior lung cancer diagnosis, receiving a biological effective dose <100 Gy, or receiving chemotherapy were excluded. Patients underwent pretreatment staging and were classified according to the American Joint Committee for Cancer (AJCC) 8th edition staging. The primary endpoint was DM. The Kaplan-Meier method and the Cox proportional hazards model were used for survival analysis and to identify predictors of DM.

Results: A total of 174 patients were included, with a median age 75 years (range, 49 to 96 y) and a median follow-up of 24 months (range, 3 to 123 mo). The 2- and 4-year cumulative incidences of DM were 14.2% and 19.1%, respectively. Patients who developed DM had worse overall survival versus patients developing a locoregional recurrence (P=0.023). On multivariable analysis, having stage IB disease (hazard ratio: 2.95; 95% confidence interval: 1.06-8.23; P=0.039) or a lower/middle lobe tumor (hazard ratio: 2.67; 95% confidence interval: 1.07-6.69; P=0.036) was associated with increased risk of DM. The 2-year cumulative incidences of DM were 10.9% and 35.7% (P=0.002) for patients with stage IA versus IB tumors, respectively, and 11.3% and 19.7% (P=0.049) for patients with upper lobe versus lower/middle lobe tumors, respectively.

Conclusions: Patients with stage IB disease or lower/middle lobe tumors may have an increased risk of DM following SBRT. Randomized controlled trials are needed to further identify patients who may benefit from adjuvant systemic therapy after SBRT for stage I NSCLC.
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http://dx.doi.org/10.1097/COC.0000000000000662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103551PMC
April 2020

Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients.

Nat Commun 2019 08 19;10(1):3722. Epub 2019 Aug 19.

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Colorectal cancer (CRC) is increasingly appreciated as a heterogeneous disease, with factors such as microsatellite instability (MSI), cancer subsite within the colon versus rectum, and age of diagnosis associated with specific disease course and therapeutic response. Activating oncogenic mutations in KRAS and NRAS are common in CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. The RAS mutational spectrum differs substantially between tumors arising from distinct tissues. Structure-function analysis of relatively common somatic RAS mutations in G12, Q61, and other codons is characterized by differing potency and modes of action. Here we show the mutational profile of KRAS, NRAS, and the less common HRAS in 13,336 CRC tumors, comparing the frequency of specific mutations based on age of diagnosis, MSI status, and colon versus rectum subsite. We identify mutation hotspots, and unexpected differences in mutation spectrum, based on these clinical parameters.
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http://dx.doi.org/10.1038/s41467-019-11530-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700103PMC
August 2019

Treatment-related toxicity and outcomes in older versus younger patients with esophageal cancer treated with neoadjuvant chemoradiation.

J Geriatr Oncol 2020 05 28;11(4):668-674. Epub 2019 Jun 28.

Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States of America.

Background: Neoadjuvant chemoradiation (nCRT) followed by esophagectomy is the standard treatment for locally advanced esophageal cancer. Older patients are often felt to be poor candidates for nCRT. Limited data is available to guide the use of nCRT in this population.

Methods: A retrospective review of patients treated at a tertiary cancer center between 2002 and 2014 was conducted grouping patients by age (≥ 65 or < 65) for evaluation of differences in toxicity and outcomes. Evaluation of pre-treatment platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) was also performed. Univariate (UVA) and multivariate analyses (MVA) determined associations between age, toxicities and outcomes. The Kaplan-Meier method (KM) assessed overall survival (OS) and relapse free survival (RFS).

Results: 125 patients were identified for this study (67 aging <65, and 58 ≥ 65). In the UVA, advanced age was only associated with increased hematologic toxicity (p = .04). After adjusting for covariates in the MVA, there were no significant differences in toxicity between older and younger patients. There were also no differences between overall survival and relapse free survival between age groups. Increased pre-treatment NLR was strongly correlated with advanced age (p = .01), increased hospitalizations (p = .04), and decreased RFS (p = .002).

Conclusions: Older patients who underwent nCRT followed by esophagectomy had similar toxicities and outcomes as younger patients suggesting that nCRT before esophagectomy is safe in select older adults with esophageal cancer. PLR and NLR may serve as prognostic markers of aging, toxicity, and outcomes. Further research is warranted to optimize the therapy of older patients with this disease.
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http://dx.doi.org/10.1016/j.jgo.2019.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751616PMC
May 2020

Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer.

Clin Cancer Res 2019 10 26;25(19):5852-5858. Epub 2019 Jun 26.

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Purpose: The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer.

Experimental Design: DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established.

Results: Overall genomic alteration rates in the younger (<40) and older (≥50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, (FDR < 0.01) and (FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and (FDR < 0.01), (FDR < 0.01), (FDR < 0.01), and (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in (FDR < 0.01), (FDR < 0.01), and KRAS (FDR < 0.01).

Conclusions: Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774873PMC
October 2019

Impact of PET/CT for Restaging Patients With Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiation.

J Surg Res 2019 11 21;243:242-248. Epub 2019 Jun 21.

Department of Surgical Oncology, Intermountain Health, Salt Lake City, Utah. Electronic address:

Background: A major challenge in identifying candidates for nonoperative management of locally advanced rectal cancer is predicting pathologic complete response (pCR) following chemoradiation. We evaluated pre- and post-CRT PET-CT imaging to predict pCR and prognosis in this set of patients undergoing resection after neoadjuvant therapy.

Methods: We retrospectively identified patients from 2002 to 2015 with locally advanced rectal cancer who underwent CRT, pre- and post-CRT PET-CT imaging, and resection. Univariate and multivariate analysis was performed and receiver operating characteristic (ROC) curves were generated to evaluate the association of PET-CT characteristics with pCR and survival. ROC curves were generated to define optimal cutoff points for predictive PET-CT characteristics.

Results: 125 patients were included. pCR rate was 28%, and follow-up was 48 mo. On multivariable analysis, patients who had a pCR had lower median post-CRT maximal standardized uptake value (SUV) (3.2 versus 5.2, P = 0.009) and higher median %SUV decrease (72 versus 58%, P = 0.009). ROC curves were generated for %SUV decrease (AUC = 0.70) and post-CRT SUV (AUC = 0.69). Post-CRT SUV <4.3 and %SUV decrease of >66% were equally predictive of pCR with a sensitivity of 65%, specificity of 72%, PPV of 44%, and NPV of 86%. Median 5-y overall and relapse-free survival were improved for patients with post-CRT SUV <4.3 (OS: 86 versus 66%, P = 0.01; RFS: 75 versus 52%, P = 0.01) or %SUV decrease of >66% (OS, 82 versus 66%, P = 0.05; RFS, 75 versus 54%, P = 0.01).

Conclusions: PET/CT may be useful in identifying patients who did not achieve pCR, as well as overall survival in patients undergoing CRT for rectal cancer. Patients with a post-CRT SUV of >4.3 should be considered for operative management, as an estimated 86% of these patients will not have a pCR.
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http://dx.doi.org/10.1016/j.jss.2019.04.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751164PMC
November 2019

External beam radiation therapy (EBRT) for asymptomatic bone metastases in patients with solid tumors reduces the risk of skeletal-related events (SREs).

Ann Palliat Med 2019 Apr 6;8(2):159-167. Epub 2018 Nov 6.

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Background: The potential benefit of administering external beam radiation therapy (EBRT) to patients with asymptomatic bone metastases has rarely been addressed in clinical investigations. The aim of this study was to determine if cancer patients who were treated with EBRT for asymptomatic bone metastases experienced later onset of pain and skeletal-related events (SREs) than those who were untreated.

Methods: A retrospective chart review was conducted for prostate, breast, and lung cancer patients with asymptomatic bone metastases treated at a single cancer center from 2007 to 2017. Patients who received EBRT for asymptomatic bone metastases were compared to those who received medical or supportive therapy only.

Results: When all cancer groups were combined, the median time from the diagnosis of asymptomatic bone metastases to either moderate-to-severe pain or an SRE was 25 months for the untreated patients and 81 months for the patients receiving EBRT (P<0.001). The delay in the first occurrence of pain or an SRE following EBRT was observed for patients with prostate cancer (P=0.025) and lung cancer (P=0.029) but not for patients with breast cancer. In a multivariate analysis, EBRT was again shown to reduce the risk of developing pain or an SRE when all cancer types were combined (P=0.006). OS was not altered by EBRT.

Conclusions: EBRT administered to a group of prostate, lung, and breast cancer patients with asymptomatic bone metastases was associated with an increase in time to the first occurrence of either pain or an SRE. These data demonstrate that there may be clinical settings in which EBRT should be used to delay or prevent late complications of bone metastases that are asymptomatic at the time of diagnosis.
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http://dx.doi.org/10.21037/apm.2018.10.04DOI Listing
April 2019

Predictive Value of Leukocyte- and Platelet-Derived Ratios in Rectal Adenocarcinoma.

J Surg Res 2018 12 14;232:275-282. Epub 2018 Jul 14.

Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Background: Advances in treatment of rectal cancer have improved survival, but there is variability in response to therapy. Recent data suggest the utility of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in predicting survival. Our aim was to examine these ratios in rectal cancer patients and determine whether any association exists with overall survival (OS).

Methods: Using prospectively maintained institutional data, a query was completed for clinical stage II-III rectal adenocarcinoma patients treated from 2002 to 2016. We included patients who had a complete blood count collected before neoadjuvant chemoradiation (pre-CRT) and again before surgery (post-CRT). The LMR, NLR, and PLR were calculated for the pre-CRT and post-CRT time points. Potential cutpoints associated with OS differences were determined using maximally selected rank statistics. Survival curves were compared using log-rank tests and were adjusted for age and stage using Cox regression.

Results: A total of 146 patients were included. Cutpoints were significantly associated with OS for pre-CRT ratios but not for post-CRT ratios. Within the pretreatment group, a "low" (<2.86) LMR was associated with decreased OS (log-rank P = 0.004). In the same group, a "high" (>4.47) NLR and "high" PLR (>203.6) were associated with decreased OS (log-rank P < 0.001). With covariate adjustment for age, and separately for final pathologic stage, the associations between OS and LMR, NLR, and PLR each retained statistical significance.

Conclusions: If obtained before the start of neoadjuvant chemoradiation, LMR, NLR, and PLR values are accurate predictors of 5-y OS in patients with locally advanced rectal adenocarcinoma.
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http://dx.doi.org/10.1016/j.jss.2018.06.060DOI Listing
December 2018

Concurrent chemoradiation for resected gall bladder cancers and cholangiocarcinomas.

J Gastrointest Oncol 2018 Aug;9(4):762-768

Department of Radiation Oncology, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA.

Background: Gallbladder cancer (GBC) and cholangiocarcinoma (CCA) are rare entities with relatively poor prognoses. We compared treatment outcomes of definitive resection with or without neoadjuvant therapy in GBC and CCA patients.

Methods: All non-metastatic GBC and CCA patients at a single institution who underwent definitive resection from 1992-2016 were analyzed. We compared overall survival (OS), locoregional failure (LRF) and distant failure (DF) in patients who received neoadjuvant therapy (chemotherapy and/or radiation) versus those who did not receive neoadjuvant treatment. OS was analyzed using the Kaplan-Meier method and log rank tests. Cox proportional hazard models were used to analyze time to recurrence.

Results: Out of 128 patients, 90 had GBC and 38 had CCA, 25 patients (27%) among GBC and 8 patients (21%) with CCA were T3, T4 or node positive. Overall, 52 (40%) GBC and 25 (20%) CCA patients received neoadjuvant treatment, chemotherapy alone 60 patients (47%) or radiation with or without chemotherapy 17 patients (13%). Chemotherapy was single agent in 44 patients (34%) and multi-agent in 25 (20%). The median OS for GBC patients was 3.1 years with 2.6 years for no neoadjuvant group and 3.1 years for neoadjuvant group (P=0.6786). Median OS was 2.6 years for CCA patients, 3.6 years for no neoadjuvant therapy versus 2.0 years for neoadjuvant group (P=0.1613). There was a trend towards increased DF in patients with CCA and GBC receiving neoadjuvant therapy: HR 2.74, 95% CI, 0.73-10.3, P=0.14 and 0.92, 95% CI, 0.44-1.93, P=0.82 respectively. The hazard ratio for time to LRF in CCA patients receiving neoadjuvant treatment was 3.17, 95% CI, 0.62-16.31, P=0.16 whereas HR was 0.15, 95% CI, 0.10-1.76, P=0.23 for GBC patients. Among GBC patients, the pattern of first failure was locoregional in 8 (10%) having 3 LRF in neoadjuvant group (2 with chemotherapy, 1 with CRT, 0 with RT alone) as compared to 5 in adjuvant group. Among 28 (35%) patients with DF first, 15 patients received neoadjuvant therapy versus 13 patients in non-neoadjuvant group. In CCA patients, LRF occurred first in 6 patients receiving neoadjuvant treatment (3 with chemotherapy, 1 with CRT, 2 with RT alone) as compared to 2 patients who were treated with non-neoadjuvant CRT. DF was the first site of failure in 9 patients treated with neoadjuvant CRT (8 with chemotherapy, 0 with CRT and 1 with RT alone) as compared to 4 patients without neoadjuvant treatment.

Conclusions: In this retrospective data set, a trend towards better survival was seen in adjuvantly treated CCA patients, but not in GBC patients. Recurrence patterns also appear different among the two, which might be attributed to treatment modality used, patient selection or unmeasured factors.

Keywords: Gallbladder cancer (GBC); cholangiocarcinoma (CCA); neoadjuvant; resection; chemoradiation; chemotherapy.
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http://dx.doi.org/10.21037/jgo.2018.05.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087856PMC
August 2018

Dose Escalation in Stereotactic Body Radiation Therapy for Pancreatic Cancer: A Meta-Analysis.

Am J Clin Oncol 2019 01;42(1):46-55

Department of Radiation Oncology.

Objective: To determine whether increasing biologically effective dose (BED) with stereotactic body radiation therapy (SBRT) is associated with improved local control (LC) or toxicities in patients with locally advanced pancreatic cancer.

Methods: A PICOS/PRISMA/MOOSE selection protocol was used to identify 15 studies across 12 institutions in 5 countries where patients received definitive SBRT for nonmetastatic disease. Biologically equivalent doses were calculated with an α/β of 10 (ie, BED10) for LC and acute toxicity and 3 (ie, BED3) for late toxicity. Fixed and random effects models were used to characterize LC and grade 3/4 toxicities by BED.

Results: There were 508 patients included with a median follow-up time of 9.1 months. The median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. There was no significant difference in LC rates at 1 year between the BED10<70 Gy versus ≥70 Gy groups, with an estimate of 0.60 (95% confidence interval [CI], 0.36-0.81) versus 0.83 (95% CI, 0.63-0.97), respectively. There was no significant difference in acute toxicity rates between the BED10<70 Gy versus ≥70 Gy groups, with an estimate of 0.02 (95% CI, 0.00-0.08) versus 0.05 (95% CI, 0.00-0.22), respectively. Given the dose distribution across studies, 3 intervals were used to characterize BED3. There were no significant differences in late toxicity among those receiving BED3<100, 100 to 200, or >200 Gy.

Conclusions: SBRT for pancreatic cancer results in LC rates of 60% to 83% and clinically significant toxicity of <7%. Increasing BED10 beyond 70 Gy was not associated with increased rates of 1-year LC or acute toxicity. Increasing BED3 beyond 100 Gy was not associated with increased rates of late toxicity.
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http://dx.doi.org/10.1097/COC.0000000000000472DOI Listing
January 2019

Postresection CA19-9 and margin status as predictors of recurrence after adjuvant treatment for pancreatic carcinoma: Analysis of NRG oncology RTOG trial 9704.

Adv Radiat Oncol 2018 Apr-Jun;3(2):154-162. Epub 2018 Feb 9.

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

Purpose: NRG Oncology RTOG 9704 was the first adjuvant trial to validate the prognostic value of postresection CA19-9 levels for survival in patients with pancreatic carcinoma. The data resulting from this study also provide information about predictors of recurrence that may be used to tailor individualized management in this disease setting. This secondary analysis assessed the prognostic value of postresection CA19-9 and surgical margin status (SMS) in predicting patterns of disease recurrence.

Methods And Materials: This multicenter cooperative trial included participants who were enrolled as patients at oncology treatment sites in the United States and Canada. The study included 451 patients analyzable for SMS, of whom 385 were eligible for postresection CA19-9 analysis. Postresection CA19-9 was analyzed at cut points of 90, 180, and continuously. Patterns of disease recurrence included local/regional recurrence (LRR) and distant failure (DF). Multivariable analyses included treatment, tumor size, and nodal status. To adjust for multiple comparisons, a value of ≤ .01 was considered statistically significant and > .01 to ≤ .05 to be a trend.

Results: For CA19-9, 132 (34%) patients were Lewis antigen-negative (no CA19-9 expression), 200 (52%) had levels <90, and 220 (57%) had levels <180. A total of 188 patients (42%) had negative margins, 152 (34%) positive, and 111 (25%) unknown. On univariate analysis, CA19-9 cut at 90 was associated with increases in LRR (trend) and DF. Results were similar at the 180 cut point. SMS was not associated with an increase in LRR on univariate or multivariate analyses. On multivariable analysis, CA19-9 ≥ 90 was associated with increased LRR and DF. Results were similar at the 180 cut point.

Conclusions: In this prospective evaluation, postresection CA19-9 was a significant predictor of both LRR and DF, whereas SMS was not. These findings support consideration of adjuvant radiation therapy dose intensification in patients with elevated postresection CA19-9.
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http://dx.doi.org/10.1016/j.adro.2018.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000159PMC
February 2018

Trends in intensity modulated radiation therapy use for locally advanced rectal cancer at National Comprehensive Cancer Network centers.

Adv Radiat Oncol 2018 Jan-Mar;3(1):34-41. Epub 2017 Oct 12.

Department of Radiation Oncology, University of Colorado Cancer Center, Aurora, Colorado.

Purpose: Intensity modulated radiation therapy (IMRT) has been rapidly incorporated into clinical practice because of its technological advantages over 3-dimensional conformal radiation therapy (CRT). We characterized trends in IMRT utilization in trimodality treatment of locally advanced rectal cancer at National Comprehensive Cancer Network cancer centers between 2005 and 2011.

Methods And Materials: Using the prospective National Comprehensive Cancer Network Colorectal Cancer Database, we determined treatment patterns for 976 patients with stage II-III rectal cancer who received pelvic radiation therapy at contributing centers between 2005 and 2011. Multivariable logistic regression was used to identify factors associated with IMRT versus 3-dimensional CRT. Radiation therapy compliance and time to completion were used to compare acute toxicity.

Results: A total of 947 patients (97%) received 3-dimensional CRT (80%) or IMRT (17%). Ninety-eight percent of these patients received radiation therapy preoperatively, and 81% underwent definitive resection. IMRT use increased from <13% pre-2009 to >30% in 2010 and thereafter, with significant variability among institutions (range, 0%-43%). Other factors associated with IMRT use included age ≥65 years, dose >50.4 Gy, African-American race, and no transabdominal surgery. Rates of and time to radiation therapy completion were similar between the groups.

Conclusions: Although most patients with stage II-III rectal cancer at queried National Cancer Institute-designated cancer centers between 2005 and 2011 received 3-dimensional CRT, significant and increasing numbers received IMRT. IMRT utilization is highly variable among institutions and not uniform among sociodemographic groups but may be more consistently embraced in specific clinical settings. Given this trend, comparative-effectiveness research is needed to evaluate the benefits of IMRT for rectal cancer.
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http://dx.doi.org/10.1016/j.adro.2017.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856979PMC
October 2017

Local Control and Toxicity of External Beam Reirradiation With a Pulsed Low-dose-rate Technique.

Int J Radiat Oncol Biol Phys 2018 03 23;100(4):959-964. Epub 2017 Dec 23.

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Electronic address:

Purpose: To evaluate the efficacy and toxicity of external beam reirradiation using a pulsed low-dose-rate (PLDR) technique.

Methods And Materials: We evaluated patients treated with PLDR reirradiation from 2009 to 2016 at a single institution. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0, and local control was assessed using the Response Evaluation Criteria In Solid Tumors, version 1.1. On univariate analysis (UVA), the χ and Fisher exact tests were used to assess the toxicity outcomes. Competing risk analysis using cumulative incidence function estimates were used to assess local progression.

Results: A total of 39 patients were treated to 41 disease sites with PLDR reirradiation. These patients had a median follow-up time of 8.8 months (range 0.5-64.7). The targets were the thorax, abdomen, and pelvis, including 36 symptomatic sites. The median interval from the first radiation course and reirradiation was 26.2 months; the median dose of the first and second course of radiation was 50.4 Gy and 50 Gy, respectively. Five patients (13%) received concurrent systemic therapy. Of the 39 patients, 9 (23%) developed grade ≥2 acute toxicity, most commonly radiation dermatitis (5 of 9). None developed grade ≥4 acute or subacute toxicity. The only grade ≥2 late toxicity was late skin toxicity in 1 patient. On UVA, toxicity was not significantly associated with the dose of the first course of radiation or reirradiation, the interval to reirradiation, or the reirradiation site. Of the 41 disease sites treated with PLDR reirradiation, 32 had pre- and post-PLDR scans to evaluate for local control. The local progression rate was 16.5% at 6 months and 23.8% at 12 months and was not associated with the dose of reirradiation, the reirradiation site, or concurrent systemic therapy on UVA. Of the 36 symptomatic disease sites, 25 sites (69%) achieved a symptomatic response after PLDR, including 6 (17%) with complete symptomatic relief.

Conclusion: Reirradiation with PLDR is effective and well-tolerated. The risk of late toxicity and the durability of local control were limited by the relatively short follow-up duration in the present cohort.
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http://dx.doi.org/10.1016/j.ijrobp.2017.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537409PMC
March 2018

Deviations From Standard Chemoradiation Among Early-Stage Anal Cancer Patients.

Int J Radiat Oncol Biol Phys 2018 03 16;100(4):945-949. Epub 2017 Dec 16.

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.ijrobp.2017.12.003DOI Listing
March 2018

Mismatch Repair Deficiency Testing in Patients With Colorectal Cancer and Nonadherence to Testing Guidelines in Young Adults.

JAMA Oncol 2018 Feb 8;4(2):e173580. Epub 2018 Feb 8.

Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Importance: Mismatch repair (MMR) deficiency of DNA has been observed in up to 15% of sporadic colorectal cancers (CRCs) and is a characteristic feature of Lynch syndrome, which has a higher incidence in young adults (age, <50 years) with CRC. Mismatch repair deficiency can be due to germline mutations or epigenetic inactivation, affects prognosis and response to systemic therapy, and results in unrepaired repetitive DNA sequences, which increases the risk of multiple malignant tumors.

Objective: To evaluate the utilization of MMR deficiency testing in adults with CRC and analyze nonadherence to long-standing testing guidelines in younger adults using a contemporary national data set to help identify potential risk factors for nonadherence to newly implemented universal testing guidelines.

Design, Setting, And Participants: Adult (age, <30 to ≥70 years) and, of these, younger adult (<30 to 49 years) patients with invasive colorectal adenocarcinoma diagnosed between 2010 and 2012 and known MMR deficiency testing status were identified using the National Cancer Database. The study was conducted from March 16, 2016, to March 1, 2017.

Exposures: Patient sociodemographic, facility, tumor, and treatment characteristics.

Main Outcomes And Measures: The primary outcome of interest was receipt of MMR deficiency testing. Multivariable logistic regression was used to identify independent predictors of testing in adult and/or young adult patients.

Results: A total of 152 993 adults with CRC were included in the study (78 579 [51.4%] men; mean [SD] age, 66.9 [13.9] years). Of these patients, only 43 143 (28.2%) underwent MMR deficiency testing; the proportion of patients tested increased between 2010 and 2012 (22.3% vs 33.1%; P<.001). Among 17 218 younger adult patients with CRC, only 7422 (43.1%) underwent MMR deficiency testing; the proportion tested increased between 2010 and 2012 (36.1% vs 48.0%; P < .001). Irrespective of age, higher educational level (OR, 1.38; 95% CI, 1.15-1.66), later diagnosis year (OR, 1.81; 95% CI, 1.65-1.98), early stage disease (OR, 1.24; 95% CI, 1.18-1.30), and number of regional lymph nodes examined (≥12) (OR, 1.44; 95% CI, 1.34-1.55) were independently associated with MMR deficiency testing, whereas older age (OR, 0.31; 95% CI, 0.26-0.37); Medicare (OR, 0.89; 95% CI, 0.84-0.95), Medicaid (OR, 0.83; 95% CI, 0.73-0.93), or uninsured (OR, 0.78; 95% CI, 0.66-0.92) status; nonacademic vs academic/research facility type (OR, 0.44; 95% CI, 0.34-0.56); rectosigmoid or rectal tumor location (OR, 0.76; 95% CI, 0.68-0.86); unknown grade (OR, 0.61; 95% CI, 0.53-0.69); and nonreceipt of definitive surgery (OR, 0.33; 95% CI, 0.30-0.37) were associated with underuse of MMR deficiency testing.

Conclusions And Relevance: Despite recent endorsement of universal use of MMR deficiency testing in patients with CRC and well-established guidelines aimed at high-risk populations, overall utilization of testing is poor and significant underuse of testing among young adults persists. Interventions tailored to groups at risk for nonadherence to guidelines may be warranted in the current era of universal testing.
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http://dx.doi.org/10.1001/jamaoncol.2017.3580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838708PMC
February 2018

Optimal Use of Combined Modality Therapy in the Treatment of Esophageal Cancer.

Surg Oncol Clin N Am 2017 07 11;26(3):405-429. Epub 2017 May 11.

Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Electronic address:

Esophageal cancer is associated with a poor prognosis with 5-year survival rates of approximately 15% to 20%. Although patients with early stage disease may adequately be treated with a single modality, combined therapy typically consisting of neoadjuvant chemoradiation followed by esophagectomy is being adopted increasingly in patients with locally advanced disease. In patients who are not surgical candidates, definitive chemoradiation is the preferred treatment approach. All patients with newly diagnosed esophageal cancer should be evaluated in the multidisciplinary setting by a surgeon, radiation oncologist, and medical oncologist owing to the importance of each specialty in the management of these patients.
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http://dx.doi.org/10.1016/j.soc.2017.01.009DOI Listing
July 2017

Tissue TGF-β expression following conventional radiotherapy and pulsed low-dose-rate radiation.

Cell Cycle 2017 Jun 9;16(12):1171-1174. Epub 2017 May 9.

b Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program , Fox Chase Cancer Center , Philadelphia , Pennsylvania.

The release of inflammatory cytokines has been implicated in the toxicity of conventional radiotherapy (CRT). Transforming growth factor β (TGF-β) has been suggested to be a risk marker for pulmonary toxicity following radiotherapy. Pulsed low-dose rate radiotherapy (PLDR) is a technique that involves spreading out a conventional radiotherapy dose into short pulses of dose with breaks in between to reduce toxicities. We hypothesized that the more tolerable toxicity profile of PLDR compared with CRT may be related to differential expression of inflammatory cytokines such as TGF-β in normal tissues. To address this, we analyzed tissues from mice that had been subjected to lethal doses of CRT and PLDR by histology and immunohistochemistry (IHC). Equivalent physical doses of CRT triggered more cellular atrophy in the bone marrow, intestine, and pancreas when compared with PLDR as indicated by hematoxylin and eosin staining. IHC data indicates that TGF-β expression is increased in the bone marrow, intestine, and lungs of mice subjected to CRT as compared with tissues from mice subjected to PLDR. Our in vivo data suggest that differential expression of inflammatory cytokines such as TGF-β may play a role in the more favorable normal tissue late response following treatment with PLDR.
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http://dx.doi.org/10.1080/15384101.2017.1317418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499842PMC
June 2017
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