Publications by authors named "Louis B Harrison"

122 Publications

Tumor-immune ecosystem dynamics define an individual Radiation Immune Score to predict pan-cancer radiocurability.

Neoplasia 2021 Oct 4;23(11):1110-1122. Epub 2021 Oct 4.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

Radiotherapy efficacy is the result of radiation-mediated cytotoxicity coupled with stimulation of antitumor immune responses. We develop an in silico 3-dimensional agent-based model of diverse tumor-immune ecosystems (TIES) represented as anti- or pro-tumor immune phenotypes. We validate the model in 10,469 patients across 31 tumor types by demonstrating that clinically detected tumors have pro-tumor TIES. We then quantify the likelihood radiation induces antitumor TIES shifts toward immune-mediated tumor elimination by developing the individual Radiation Immune Score (iRIS). We show iRIS distribution across 31 tumor types is consistent with the clinical effectiveness of radiotherapy, and in combination with a molecular radiosensitivity index (RSI) combines to predict pan-cancer radiocurability. We show that iRIS correlates with local control and survival in a separate cohort of 59 lung cancer patients treated with radiation. In combination, iRIS and RSI predict radiation-induced TIES shifts in individual patients and identify candidates for radiation de-escalation and treatment escalation. This is the first clinically and biologically validated computational model to simulate and predict pan-cancer response and outcomes via the perturbation of the TIES by radiotherapy.
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http://dx.doi.org/10.1016/j.neo.2021.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502777PMC
October 2021

American Brachytherapy Society (ABS) consensus statement for soft-tissue sarcoma brachytherapy.

Brachytherapy 2021 Jul 21. Epub 2021 Jul 21.

Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Purpose: Growing data supports the role of radiation therapy in the treatment of soft tissue sarcoma (STS). Brachytherapy has been used for decades in the management of STS and can be utilized as monotherapy or as a boost to external beam radiation. We present updated guidelines from the American Brachytherapy Society regarding the utilization of brachytherapy in the management of STS.

Methods And Materials: Members of the American Brachytherapy Society with expertise in STS and STS brachytherapy created an updated clinical practice guideline including step-by-step details for performing STS brachytherapy based on a literature review and clinical experience.

Results: Brachytherapy monotherapy should be considered for lower-recurrence risk patients or after a local recurrence following previous external beam radiation; a brachytherapy boost can be considered in higher-risk patents meeting implant criteria. Multiple dose/fractionation regimens are available, with determination based on tumor location and treatment intent. Techniques to limit wound complications are based on the type of wound closure; wound complication can be mitigated with a delay in the start of brachytherapy with immediate wound closure or by utilizing a staged reconstruction technique, which allows an earlier treatment start with a delayed wound closure.

Conclusions: These updated guidelines provide clinicians with data on indications for STS brachytherapy as well as guidelines on how to perform and deliver high quality STS brachytherapy safely with minimal toxicity.
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http://dx.doi.org/10.1016/j.brachy.2021.05.011DOI Listing
July 2021

Genomic identification of sarcoma radiosensitivity and the clinical implications for radiation dose personalization.

Transl Oncol 2021 Oct 7;14(10):101165. Epub 2021 Jul 7.

H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, United States. Electronic address:

Background: Soft-tissue sarcomas (STS) are heterogeneous with variable response to radiation therapy (RT). Utilizing the radiosensitivity index (RSI) we estimated the radiobiologic ratio of lethal to sublethal damage (α/β), genomic-adjusted radiation dose(GARD), and in-turn a biological effective radiation dose (BED).

Methods: Two independent cohorts of patients with soft-tissue sarcoma were identified. The first cohort included 217 genomically-profiled samples from our institutional prospective tissue collection protocol; RSI was calculated for these samples, which were then used to dichotomize the population as either highly radioresistant (HRR) or conventionally radioresistant (CRR). In addition, RSI was used to calculate α/β ratio and GARD, providing ideal dosing based on sarcoma genomic radiosensitivity. A second cohort comprising 399 non-metastatic-STS patients treated with neoadjuvant RT and surgery was used to validate our findings.

Results: Based on the RSI of the sample cohort, 84% would historically be considered radioresistant. We identified a HRR subset that had a significant difference in the RSI, and clinically a lower tumor response to radiation (2.4% vs. 19.4%), 5-year locoregional-control (76.5% vs. 90.8%), and lower estimated α/β (3.29 vs. 5.98), when compared to CRR sarcoma. Using GARD, the dose required to optimize outcome in the HRR subset is a BED of 97 Gy.

Conclusions: We demonstrate that on a genomic scale, that although STS is radioresistant overall, they are heterogeneous in terms of radiosensitivity. We validated this clinically and estimated an α/β ratio and dosing that would optimize outcome, personalizing dose.
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http://dx.doi.org/10.1016/j.tranon.2021.101165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274330PMC
October 2021

Forecasting Individual Patient Response to Radiation Therapy in Head and Neck Cancer With a Dynamic Carrying Capacity Model.

Int J Radiat Oncol Biol Phys 2021 Nov 5;111(3):693-704. Epub 2021 Jun 5.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida; Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Electronic address:

Purpose: To model and predict individual patient responses to radiation therapy.

Methods And Materials: We modeled tumor dynamics as logistic growth and the effect of radiation as a reduction in the tumor carrying capacity, motivated by the effect of radiation on the tumor microenvironment. The model was assessed on weekly tumor volume data collected for 2 independent cohorts of patients with head and neck cancer from the H. Lee Moffitt Cancer Center (MCC) and the MD Anderson Cancer Center (MDACC) who received 66 to 70 Gy in standard daily fractions or with accelerated fractionation. To predict response to radiation therapy for individual patients, we developed a new forecasting framework that combined the learned tumor growth rate and carrying capacity reduction fraction (δ) distribution with weekly measurements of tumor volume reduction for a given test patient to estimate δ, which was used to predict patient-specific outcomes.

Results: The model fit data from MCC with high accuracy with patient-specific δ and a fixed tumor growth rate across all patients. The model fit data from an independent cohort from MDACC with comparable accuracy using the tumor growth rate learned from the MCC cohort, showing transferability of the growth rate. The forecasting framework predicted patient-specific outcomes with 76% sensitivity and 83% specificity for locoregional control and 68% sensitivity and 85% specificity for disease-free survival with the inclusion of 4 on-treatment tumor volume measurements.

Conclusions: These results demonstrate that our simple mathematical model can describe a variety of tumor volume dynamics. Furthermore, combining historically observed patient responses with a few patient-specific tumor volume measurements allowed for the accurate prediction of patient outcomes, which may inform treatment adaptation and personalization.
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http://dx.doi.org/10.1016/j.ijrobp.2021.05.132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463501PMC
November 2021

Pretreatment CT and PET radiomics predicting rectal cancer patients in response to neoadjuvant chemoradiotherapy.

Rep Pract Oncol Radiother 2021 25;26(1):29-34. Epub 2021 Feb 25.

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida, United States.

Background: The purpose of this study was to characterize pre-treatment non-contrast computed tomography (CT) and F-fluorodeoxyglucose positron emission tomography (PET) based radiomics signatures predictive of pathological response and clinical outcomes in rectal cancer patients treated with neoadjuvant chemoradiotherapy (NACR T).

Materials And Methods: An exploratory analysis was performed using pre-treatment non-contrast CT and PET imaging dataset. The association of tumor regression grade (TRG) and neoadjuvant rectal (NAR) score with pre-treatment CT and PET features was assessed using machine learning algorithms. Three separate predictive models were built for composite features from CT + PET.

Results: The patterns of pathological response were TRG 0 (n = 13; 19.7%), 1 (n = 34; 51.5%), 2 (n = 16; 24.2%), and 3 (n = 3; 4.5%). There were 20 (30.3%) patients with low, 22 (33.3%) with intermediate and 24 (36.4%) with high NAR scores. Three separate predictive models were built for composite features from CT + PET and analyzed separately for clinical endpoints. Composite features with α = 0.2 resulted in the best predictive power using logistic regression. For pathological response prediction, the signature resulted in 88.1% accuracy in predicting TRG 0 . TRG 1-3; 91% accuracy in predicting TRG 0-1 . TRG 2-3. For the surrogate of DFS and OS, it resulted in 67.7% accuracy in predicting low . intermediate . high NAR scores.

Conclusion: The pre-treatment composite radiomics signatures were highly predictive of pathological response in rectal cancer treated with NACR T. A larger cohort is warranted for further validation.
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http://dx.doi.org/10.5603/RPOR.a2021.0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086711PMC
February 2021

Status of Cancer Care at Network Sites of the Nation's Academic Cancer Centers.

J Natl Compr Canc Netw 2021 Mar 11;19(6):726-732. Epub 2021 Mar 11.

12Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.

Background: Cancer care coordination across major academic medical centers and their networks is evolving rapidly, but the spectrum of organizational efforts has not been described. We conducted a mixed-methods survey of leading cancer centers and their networks to document care coordination and identify opportunities to improve geographically dispersed care.

Methods: A mixed-methods survey was sent to 91 cancer centers in the United States and Canada. We analyzed the number and locations of network sites; access to electronic medical records (EMRs); clinical research support and participation at networks; use of patient navigators, care paths, and quality measures; and physician workforce. Responses were collected via Qualtrics software between September 2017 and December 2018.

Results: Of the 69 responding cancer centers, 74% were NCI-designated. Eighty-seven percent of respondents were part of a matrix health system, and 13% were freestanding. Fifty-six reported having network sites. Forty-three respondents use navigators for disease-specific populations, and 24 use them for all patients. Thirty-five respondents use ≥1 types of care path. Fifty-seven percent of networks had complete, integrated access to their main center's EMRs. Thirty-nine respondents said the main center provides funding for clinical research at networks, with 22 reporting the main center provides all funding. Thirty-five said the main center provided pharmacy support at the networks, with 15 indicating the main center provides 100% pharmacy support. Certification program participation varied extensively across networks.

Conclusions: The data show academic cancer centers have extensive involvement in network cancer care, often extending into rural communities. Coordinating care through improved clinical trial access and greater use of patient navigation, care paths, coordinated EMRs, and quality measures is likely to improve patient outcomes. Although it is premature to draw firm conclusions, the survey results are appropriate for mapping next steps and data queries.
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http://dx.doi.org/10.6004/jnccn.2020.7656DOI Listing
March 2021

Personalizing Radiotherapy Prescription Dose Using Genomic Markers of Radiosensitivity and Normal Tissue Toxicity in NSCLC.

J Thorac Oncol 2021 03 8;16(3):428-438. Epub 2020 Dec 8.

Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Introduction: Cancer sequencing efforts have revealed that cancer is the most complex and heterogeneous disease that affects humans. However, radiation therapy (RT), one of the most common cancer treatments, is prescribed on the basis of an empirical one-size-fits-all approach. We propose that the field of radiation oncology is operating under an outdated null hypothesis: that all patients are biologically similar and should uniformly respond to the same dose of radiation.

Methods: We have previously developed the genomic-adjusted radiation dose, a method that accounts for biological heterogeneity and can be used to predict optimal RT dose for an individual patient. In this article, we use genomic-adjusted radiation dose to characterize the biological imprecision of one-size-fits-all RT dosing schemes that result in both over- and under-dosing for most patients treated with RT. To elucidate this inefficiency, and therefore the opportunity for improvement using a personalized dosing scheme, we develop a patient-specific competing hazards style mathematical model combining the canonical equations for tumor control probability and normal tissue complication probability. This model simultaneously optimizes tumor control and toxicity by personalizing RT dose using patient-specific genomics.

Results: Using data from two prospectively collected cohorts of patients with NSCLC, we validate the competing hazards model by revealing that it predicts the results of RTOG 0617. We report how the failure of RTOG 0617 can be explained by the biological imprecision of empirical uniform dose escalation which results in 80% of patients being overexposed to normal tissue toxicity without potential tumor control benefit.

Conclusions: Our data reveal a tapestry of radiosensitivity heterogeneity, provide a biological framework that explains the failure of empirical RT dose escalation, and quantify the opportunity to improve clinical outcomes in lung cancer by incorporating genomics into RT.
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http://dx.doi.org/10.1016/j.jtho.2020.11.008DOI Listing
March 2021

Pretreatment CT and F-FDG PET-based radiomic model predicting pathological complete response and loco-regional control following neoadjuvant chemoradiation in oesophageal cancer.

J Med Imaging Radiat Oncol 2021 Feb 1;65(1):102-111. Epub 2020 Dec 1.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.

Introduction: To develop a radiomic-based model to predict pathological complete response (pCR) and outcome following neoadjuvant chemoradiotherapy (NACRT) in oesophageal cancer.

Methods: We analysed 68 patients with oesophageal cancer treated with NACRT followed by esophagectomy, who had staging 18F-fluorodeoxyglucose ( F-FDG) positron emission tomography (PET) and computed tomography (CT) scans performed at our institution. An in-house data-chjmirocterization algorithm was used to extract 3D-radiomic features from the segmented primary disease. Prediction models were constructed and internally validated. Composite feature, F  = α * F  + (1 - α) * F , 0 ≤ α ≤ 1, was constructed for each corresponding CT and PET feature. Loco-regional control (LRC), recurrence-free survival (RFS), metastasis-free survival (MFS) and overall survival (OS) were estimated by Kaplan-Meier analysis, and compared using log-rank test.

Results: Median follow-up was 59 months. pCR was achieved in 34 (50%) patients. Five-year RFS, LRC, MFS and OS were 67.1%, 88.5%, 75.6% and 57.6%, respectively. Tumour Regression Grade (TRG) 0-1 indicative of complete response or minimal residual disease was significantly associated with improved 5-year LRC [93.7% vs 71.8%; P = 0.020; HR 0.19, 95% CI 0.04-0.85]. Four sepjmirote pCR predictive models were built for CT alone, PET alone, CT+PET and composite. CT, PET and CT+PET models had AUC 0.73 ± 0.08, 0.66 ± 0.08 and 0.77 ± 0.07, respectively. The composite model resulted in an improvement of pCR predicting power with AUC 0.87 ± 0.06. Stratifying patients with a low versus high radiomic score showed clinically relevant improvement in 5-year LRC favouring low-score group (91.1% vs. 80%, 95% CI 0.09-1.77, P = 0.2).

Conclusion: The composite CT/PET radiomics model was highly predictive of pCR following NACRT. Validation in larger data sets is warranted to determine whether the model can predict clinical outcomes.
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http://dx.doi.org/10.1111/1754-9485.13128DOI Listing
February 2021

Harnessing COVID-Driven Technical Innovations for Improved Multi-Disciplinary Cancer Care in the Post-COVID Era: The Virtual Patient Room.

Cancer Control 2020 Jan-Dec;27(1):1073274820964800

Depatment of Radiation Oncology, 25301H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Emergence of the COVID-19 crisis has catalyzed rapid paradigm shifts throughout medicine. Even after the initial wave of the virus subsides, a wholesale return to the prior status quo is not prudent. As a specialty that values the proper application of new technology, radiation oncology should strive to be at the forefront of harnessing telehealth as an important tool to further optimize patient care. We remain cognizant that telehealth cannot and should not be a comprehensive replacement for in-person patient visits because it is not a one for one replacement, dependent on the intention of the visit and patient preference. However, we envision the opportunity for the virtual patient "room" where multidisciplinary care may take place from every specialty. How we adapt is not an inevitability, but instead, an opportunity to shape the ideal image of our new normal through the choices that we make. We have made great strides toward genuine multidisciplinary patient-centered care, but the continued use of telehealth and virtual visits can bring us closer to optimally arranging the spokes of the provider team members around the central hub of the patient as we progress down the road through treatment.
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http://dx.doi.org/10.1177/1073274820964800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791470PMC
October 2020

Prognostic potential of mid-treatment nodal response in oropharyngeal squamous cell carcinoma.

Head Neck 2020 Sep 21. Epub 2020 Sep 21.

Department of Radiation Oncology, NYU Langone Health, New York, New York, USA.

Background: We examine the prognostic implications of mid-course nodal response in oropharyngeal cancer (OPX) to radiation therapy.

Methods: In 44 patients with node-positive OPX undergoing concurrent chemoradiation, nodal volumes were measured on cone beam CTs from days 1, 10, 20, and 35. Nodal decrease (ND) was based on percent shrinkage from day 1.

Results: At a median follow-up of 17 months, the 2-year disease-free survival (DFS), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) were 87%, 92%, 89%, and 92%, respectively. Patients with ND ≥43% at D20 had improved LRC (100% vs 78.4%, P = .03) compared to D20 ND <43%. On multivariate analysis, D20 ≥43% was independently prognostic for LRC (HR 1.17, P = .05).

Conclusion: Patients with low-risk oropharynx cancer with ND of ≥43% by treatment day 20 had significantly improved LRC. The prognostic benefit of ND may assist in identifying candidates for treatment de-escalation.
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http://dx.doi.org/10.1002/hed.26467DOI Listing
September 2020

CT-based radiomic features to predict pathological response in rectal cancer: A retrospective cohort study.

J Med Imaging Radiat Oncol 2020 Jun 9;64(3):444-449. Epub 2020 May 9.

Radiation Oncology, Moffitt Cancer Center, Tampa, Florida, USA.

Introduction: Innovative biomarkers to predict treatment response in rectal cancer would be helpful in optimizing personalized treatment approaches. In this study, we aimed to develop and validate a CT-based radiomic imaging biomarker to predict pathological response.

Methods: We used two independent cohorts of rectal cancer patients to develop and validate a CT-based radiomic imaging biomarker predictive of treatment response. A total of 91 rectal cancer cases treated from 2009 to 2018 were assessed for the tumour regression grade (TRG) (0 = pathological complete response, pCR; 1 = moderate response; 2 = partial response; 3 = poor response). Exploratory analysis was performed by combining pre-treatment non-contrast CT images and patterns of TRG. The models built from the training cohort were further assessed using the independent validation cohort.

Results: The patterns of pathological response in training and validation groups were TRG 0 (n = 14, 23.3%; n = 6, 19.4%), 1 (n = 31, 51.7%; n = 15, 48.4%), 2 (n = 12, 20.0%; n = 7, 22.6%) and 3 (n = 3, 5.0%; n = 3, 9.7%), respectively. Separate predictive models were built and analysed from CT features for pathological response. For pathological response prediction, the model including 8 radiomic features by random forest method resulted in 83.9% accuracy in predicting TRG 0 vs TRG 1-3 in validation.

Conclusion: The pre-treatment CT-based radiomic signatures were developed and validated in two independent cohorts. This imaging biomarker provided a promising way to predict pCR and select patients for non-operative management.
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http://dx.doi.org/10.1111/1754-9485.13044DOI Listing
June 2020

A Hard Target Needs a Sharper DaRT.

Int J Radiat Oncol Biol Phys 2020 05;107(1):152-153

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address:

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http://dx.doi.org/10.1016/j.ijrobp.2020.01.019DOI Listing
May 2020

Integrating Mathematical Modeling into the Roadmap for Personalized Adaptive Radiation Therapy.

Trends Cancer 2019 08 10;5(8):467-474. Epub 2019 Jul 10.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.

In current radiation oncology practice, treatment protocols are prescribed based on the average outcomes of large clinical trials, with limited personalization and without adaptations of dose or dose fractionation to individual patients based on their individual clinical responses. Predicting tumor responses to radiation and comparing predictions against observed responses offers an opportunity for novel treatment evaluation. These analyses can lead to protocol adaptation aimed at the improvement of patient outcomes with better therapeutic ratios. We foresee the integration of mathematical models into radiation oncology to simulate individual patient tumor growth and predict treatment response as dynamic biomarkers for personalized adaptive radiation therapy (RT).
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http://dx.doi.org/10.1016/j.trecan.2019.06.006DOI Listing
August 2019

Immunologic Consequences of Sequencing Cancer Radiotherapy and Surgery.

JCO Clin Cancer Inform 2019 04;3:1-16

Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Purpose: Early-stage cancers are routinely treated with surgery followed by radiotherapy (SR). Radiotherapy before surgery (RS) has been widely ignored for some cancers. We evaluate overall survival (OS) and disease-free survival (DFS) with SR and RS for different cancer types and simulate the plausibility of RS- and SR-induced antitumor immunity contributing to outcomes.

Materials And Methods: We analyzed a SEER data set of early-stage cancers treated with SR or RS. OS and DFS were calculated for cancers with sufficient numbers for statistical power (cancers of lung and bronchus, esophagus, rectum, cervix uteri, corpus uteri, and breast). We simulated the immunologic consequences of SR, RS, and radiotherapy alone in a mathematical model of tumor-immune interactions.

Results: RS improved OS for cancers with low 20-year survival rates (lung: hazard ratio [HR], 0.88; P = .046) and improved DFS for cancers with higher survival (breast: HR = 0.64; P < .001). For rectal cancer, with intermediate 20-year survival, RS improved both OS (HR = 0.89; P = .006) and DFS (HR = 0.86; P = .04). Model simulations suggested that RS could increase OS by eliminating cancer for a broader range of model parameters and radiotherapy-induced antitumor immunity compared with SR for selected parameter combinations. This could create an immune memory that may explain increased DFS after RS for certain cancers.

Conclusion: Study results suggest plausibility that radiation to the bulk of the tumor could induce a more robust immune response and better harness the synergy of radiotherapy and antitumor immunity than postsurgical radiation to the tumor bed. This exploratory study provides motivation for prospective evaluation of immune activation of RS versus SR in controlled clinical studies.
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http://dx.doi.org/10.1200/CCI.18.00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661069PMC
April 2019

A Deep Dive into the Diagnosis and Management of Regional Lymph Node Metastases.

Semin Radiat Oncol 2019 04;29(2):91-92

Moffitt Cancer Center and Research Institute, Tampa, FL.

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http://dx.doi.org/10.1016/j.semradonc.2018.11.009DOI Listing
April 2019

Novel Genomic-Based Strategies to Personalize Lymph Node Radiation Therapy.

Semin Radiat Oncol 2019 04;29(2):111-125

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL; Departments of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, FL. Electronic address:

Current standard radiotherapy doses have been derived from empiric methods rather than a scientific framework. Subclinical nodal dosing remains relatively uniform across most disease sites, despite heterogeneity in patient and tumor biology. It is now clear that there are subsets of patients who will benefit from genomically-informed radiotherapy planning, and there are increasing efforts toward prescribing radiation dose to match the radiosensitivity of the tumor. By using novel genomic biomarkers to personalize delivery of radiotherapy, there is an opportunity to improve loco-regional control and cure rates. We survey the current landscape of personalized radiation oncology across commonly treated disease sites.
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http://dx.doi.org/10.1016/j.semradonc.2018.11.003DOI Listing
April 2019

Radiotherapy for parapharyngeal space tumors.

Am J Otolaryngol 2019 Mar - Apr;40(2):289-291. Epub 2018 Dec 21.

Coordinator of the International Head and Neck Scientific Group, Padua, Italy.

A wide variety of tumors, both benign and malignant, occur in the parapharyngeal space. Depending on histology and extent, treatment may include surgery and/or radiotherapy (RT). Herein we discuss the role of RT in the management of some of the more commonly encountered neoplasms, including salivary gland tumors, paragangliomas, schwannomas, and soft-tissue sarcomas.
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http://dx.doi.org/10.1016/j.amjoto.2018.12.010DOI Listing
June 2019

Radiotherapy for early stage diffuse large B-cell lymphoma with or without double or triple hit genetic alterations.

Leuk Lymphoma 2019 04 20;60(4):886-893. Epub 2018 Nov 20.

a Department of Radiation Oncology , H. Lee Moffitt Cancer Center and Research Institute, Tampa , FL , USA.

We investigated whether adding radiation (RT) to systemic therapy improved outcomes in early stage diffuse large B-cell lymphoma (DLBCL) patients with or without double- or triple-hit lymphoma (DHL/THL) biology. This analysis included 183 patients profiled with fluorescent in situ hybridization (FISH) for alterations in MYC, BLC2, and/or BCL6. A total of 146 (80%) were non-DHL/THL, 27 (15%) were DHL, and 10 (6%) were THL. Systemic therapy without RT resulted in inferior freedom from relapse (FFR) (HR: 2.28; 95% CI, 1.10-4.77; p = .02). The median FFR for non-DHL/THL was not reached and was 33 and 22.3 months for DHL and THL, respectively; p < .001. Low-risk (R-IPI <2) DHL/THL patients treated with rituximab-based therapy had 3-year FFR rates of 11% and 71% for systemic therapy without and with RT, respectively; p = .04. No differences in overall survival were observed between the treatment groups. Treatment intensification with RT may improve early stage DHL/THL outcomes.
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http://dx.doi.org/10.1080/10428194.2018.1506586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596288PMC
April 2019

Management of Sentinel Lymph Node Metastasis in Merkel Cell Carcinoma: Completion Lymphadenectomy, Radiation, or Both?

Ann Surg Oncol 2019 Feb 11;26(2):379-385. Epub 2018 Oct 11.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Background: Approximately 30% of patients with clinically localized Merkel cell carcinoma (MCC) show nodal involvement on sentinel lymph node biopsy (SLNB). Optimal management of SLNB-positive disease has not been defined. This study compared outcomes after completion lymphadenectomy (CLND), radiation, and combined CLND plus radiation after a positive SLNB.

Methods: All patients treated at a single institution for SLNB-positive MCC (1998-2015) were retrospectively evaluated, with examination of patient demographics, clinicopathologic characteristics, outcomes, and regional toxicity.

Results: The study identified 71 evaluable patients with SLNB-positive disease. The median age of these patients was 76 years, and 76.1% were men. Of the 71 patients, 11 (15.5%) underwent CLND, 40 (56.3%) received radiation, and 20 (28.2%) underwent CLND plus postoperative radiation. Lymphovascular invasion was significantly more common in the radiation-alone cohort (p = 0.04). For the three cohorts, the median percentages of nodal involvement were respectively 2, 10, and 30% (p = 0.06). After a median follow-up period of 22.3 months, four patients had recurrence in their regional nodal basin (3 radiation-alone patients and 1 CLND + radiation patient). The three cohorts did not differ significantly in the development of distant metastases (p = 0.68) or overall survival (p = 0.72). Six patients experienced surgical-site infections (2 CLND and 4 CLND + radiation patients), and three patients experienced symptomatic lymphedema (1 CLND patient and 2 CLND + radiation patients).

Conclusions: Regional failure was infrequent (≤ 10%) regardless of treatment, and morbidity appeared to be low with all approaches. Given that multiple treatment approaches can be successful in treating micrometastatic MCC, future efforts should be directed at refining criteria for allocating patients to a specific method, or possibly no further nodal basin treatment, in an effort to maximize regional control at the lowest cost and morbidity.
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http://dx.doi.org/10.1245/s10434-018-6810-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771265PMC
February 2019

Interferon is associated with improved survival for node-positive cutaneous melanoma: a single-institution experience.

Melanoma Manag 2018 Jun 9;5(1):MMT02. Epub 2018 Apr 9.

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.

Aim: We assessed the role of adjuvant interferon on relapse-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS) in node-positive melanoma patients.

Methods: We retrospectively reviewed 385 node-positive patients without distant metastatic disease treated from 1998 to 2015. The surgery was therapeutic lymph node dissection (LND, n = 86) or sentinel lymph node biopsy ± completion LND (n = 270). 128 patients (33.2%) received adjuvant interferon.

Results: After a median follow-up of 70 months, interferon was associated with improved RFS (hazard ratio [HR]: 0.55; p < 0.001), DMFS (HR: 0.59; p < 0.001) and OS (HR: 0.61; p = 0.003), controlling for tumor and nodal stage, node size, sex, primary site, adjuvant therapy and extracapsular extension. In an exploratory age-matched comparison of patients treated with (n = 67) and without (n = 233) adjuvant immunotherapy, interferon still showed improved RFS, DMFS and OS.

Conclusion: Adjuvant interferon appears to improve OS among node-positive melanoma patients in a modern experience, providing context for comparison in the adjuvant therapy landscape.
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http://dx.doi.org/10.2217/mmt-2017-0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122528PMC
June 2018

Patient choice for high-volume center radiation impacts head and neck cancer outcome.

Cancer Med 2018 10 2;7(10):4964-4979. Epub 2018 Sep 2.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: Studies suggest treatment outcomes may vary between high (HVC)- and low-volume centers (LVC). Radiation therapy (RT) for head and neck cancer (HNC) requires weeks of treatment, the inconvenience of which may influence a patient's choice for treatment location. We hypothesized that receipt of RT for HNC at a HVC would influence outcomes compared to patients evaluated at a HVC, but who chose to receive RT at a LVC.

Methods: From 1998 to 2011, 1930 HNC patients were evaluated at a HVC and then treated with RT at either a HVC or LVC. Time-to-event outcomes and treatment factors were compared.

Results: Median follow-up was 34 months. RT was delivered at a HVC for 1368 (71%) patients and at a LVC in 562 (29%). Patients were more likely to choose HVC-RT if they resided in the HVC's county or required definitive RT (all P < 0.001). HVC-RT was associated with a significant improvement in 3-year LRC (84% vs 68%), DFS (68% vs 48%), and OS (72% vs 57%) (all P < 0.001). On multivariate analysis (MVA), HVC-RT independently predicted for improved LRC, DFS, and OS (all P < 0.05).

Conclusions: In patients evaluated at a HVC, the choice of RT location was primarily influenced by their residing distance from the HVC. HVC-RT was associated with improvements in LRC, DFS, and OS in HNC. As treatment planning and delivery are technically demanding in HNC, the choice to undergo treatment at a HVC may result in more optimal delivered dose, RT duration, and outcome.
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http://dx.doi.org/10.1002/cam4.1756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198196PMC
October 2018

Resection Margins in Merkel Cell Carcinoma: Is a 1-cm Margin Wide Enough?

Ann Surg Oncol 2018 Oct 2;25(11):3334-3340. Epub 2018 Aug 2.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Background: Guidelines regarding specific resection margins for primary Merkel cell carcinoma (MCC) are not well established. The current National Comprehensive Cancer Network (NCCN) guidelines recommend 1- to 2-cm resection margins. This study aimed to determine the impact of margin width on local recurrence (LR), disease-specific survival (DSS), overall survival (OS), and type of wound closure.

Methods: All patients who underwent resection of primary MCC at a single institution from 2000 to 2015 were reviewed. Patient demographics, clinicopathologic characteristics, treatments, and outcomes were reviewed.

Results: A total of 240 patients underwent resection of primary MCC with resection margin width identified in the operative report. The median age was 76 years, and 65.8% of the patients were men. Of the 240 patients, 85 (35.4%) had head and neck primaries, 140 (58.3%) had extremity primaries, and 15 (6.3%) had trunk primaries. In terms of margins, 69 patients (28.8%) had a margin of 1 cm, 36 patients (15%) had a margin of 1.1-1.9 cm, and 135 patients (56.2%) had a margin of 2 cm or more. The median follow-up period was 21 months. The LR rate was 2.9% for a margin of 1 cm, 2.8% for a margin of 1.1-1.9 cm, and 5.2% for a margin of 2 cm or more (p = 0.80). The 5-year OS was 63.6% for a margin of 1 cm, 59.7% for a margin of 1.1-1.9, and 70.7% for a margin of 2 cm or more (p = 0.66). The 5-year DSS was 80.3% for a margin of 1 cm, 66.2% for a margin of 1.1-1.9 cm, and 91.8% for a margin of 2 cm or more (p = 0.28). For wound closure, 43.5, 50, and 65.9% of the patients respectively required a flap or graft with a margin of 1, 1.1-1.9, and 2 cm or more (p = 0.006).

Conclusions: A 1-cm resection margins did not increase the risk of LR. Margin width did not make a significant difference in DSS or OS. Larger resection margins increase the need for a graft or flap closure.
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http://dx.doi.org/10.1245/s10434-018-6688-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771268PMC
October 2018

Immune interconnectivity of anatomically distant tumors as a potential mediator of systemic responses to local therapy.

Sci Rep 2018 06 21;8(1):9474. Epub 2018 Jun 21.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Complex interactions occur between tumor and host immune system at each site in the metastatic setting, the outcome of which can determine behavior ranging from dormancy to rapid growth. An additional layer of complexity arises from the understanding that cytotoxic T cells can traffic through the host circulatory system. Coupling mathematical models of local tumor-immune dynamics and systemic T cell trafficking allows us to simulate the evolution of tumor and immune cell populations in anatomically distant sites following local therapy and thus computationally evaluate immune interconnectivity. Results suggest that the presence of a secondary site may either inhibit or promote growth of the primary, depending on the capacity for immune recruitment of each tumor and the resulting systemic redistribution of T cells. Treatment such as surgical resection and radiotherapy can be simulated to estimate both the decrease in tumor volume at the local treatment-targeted site, and the change in overall tumor burden and tumor growth trajectories across all sites. Qualitatively similar responses of distant tumors to local therapy (positive and negative abscopal effects) to those reported in the clinical setting were observed. Such findings may facilitate an improved understanding of general disease kinetics in the metastatic setting: if metastatic sites are interconnected through the immune system, truly local therapy does not exist.
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http://dx.doi.org/10.1038/s41598-018-27718-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013469PMC
June 2018

2D kV orthogonal imaging with fiducial markers is more precise for daily image guided alignments than soft-tissue cone beam computed tomography for prostate radiation therapy.

Adv Radiat Oncol 2017 Jul-Sep;2(3):420-428. Epub 2017 May 4.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai and Mount Sinai West Hospital, New York, New York.

Purpose: The hypothesis is that 2-dimensional kV orthogonal imaging with fiducial markers (kV-FM) and soft-tissue cone beam computed tomography (ST-CBCT) are equally reproducible for daily positional alignments for image guided (IG) intensity modulated radiation therapy (IMRT) for prostate cancer.

Methods And Materials: Ten patients undergoing definitive treatment for prostate cancer with IG-IMRT were imaged daily with kV-FM and ST-CBCT. For each acquired kV and CBCT image, offline alignments to the digitally reconstructed radiograph or planning CT, respectively, were made twice by the same physician to assess intraobserver test-retest reproducibility. The 256 kV and 142 CBCT images were analyzed, and the test-retest analysis was performed again on a subset of images by another physician to verify the results.

Results: The results demonstrated that kV-FM had better intraobserver test-retest reproducibility in the anterior-posterior (AP; 95% confidence interval [CI] Pearson correlation coefficient [r], 0.987-0.991), left-right (LR; 95% CI r, 0.955-0.969), and superior-inferior (SI; 95% CI r, 0.971-0.980) directions for daily IG alignments compared with ST-CBCT (AP: 95% CI r, 0.804-0.877; LR: 95% CI r, 0.877-0.924; SI: 95% CI r, 0.791-0.869). Errors associated with intraobserver test-retest reproducibility were submillimeter with kV-FM (AP: 0.4 ± 0.7 mm; RL: 0.4 ± 1.0 mm; SI: 0.5 ± 0.7 mm) compared with ST-CBCT (AP: 2.1 ± 2.2 mm; LR: 1.3 ± 1.4 mm; SI: 1.2 ± 1.8 mm). The mean shift differences between kV-FM and ST-CBCT were 0.3 ± 3.8 mm for AP, -1.1 ± 8.5 mm for LR, and -2.0 ± 3.7 mm for SI. Dose-volume histograms were generated and showed that test-retest variability associated with ST-CBCT IG-alignments resulted in significantly increased dose to normal structures and a reduced planning target volume dose in many patients.

Conclusions: The kV-FM-based daily IG alignment for IMRT of prostate cancer is more precise than ST-CBCT, as assessed by a physician's ability to reproducibly align images. Given the magnitude of the error introduced by inconsistency in making ST-CBCT alignments, these data support a role for daily kV imaging of FM to enhance the precision of external beam dose delivery to the prostate.
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http://dx.doi.org/10.1016/j.adro.2017.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605315PMC
May 2017

In Reply to Zhang.

Int J Radiat Oncol Biol Phys 2017 10;99(2):501

Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1016/j.ijrobp.2017.04.038DOI Listing
October 2017

Tumour radiosensitivity is associated with immune activation in solid tumours.

Eur J Cancer 2017 10 29;84:304-314. Epub 2017 Aug 29.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

Purpose: Our goal was to determine whether tumour radiosensitivity is associated with activation of the immune system across all tumour types as measured by two gene expression signatures (GESs).

Methods: We identified 10,240 genomically profiled distinct solid primary tumours with gene expression analysis available from an institutional de-identified database. Two separate GESs were included in the analysis, the radiosensitivity index (RSI) GES (a 10-gene GES as a measure of radiosensitivity) and the 12-chemokine (12-CK) signature (a 12-gene GES as a measure of immune activation). We tested whether the RSI and 12-CK were associated with each other across all tumour samples and, in an exploratory analysis, their prognostic significance in predicting distant metastasis-free survival (DMFS) among a well-characterised, independent cohort of 282 early-stage breast cancer cases treated with surgery and post-operative radiation alone without systemic therapy. The lower the RSI score, the higher the tumour radiosensitivity; whereas, the higher the 12-CK score the higher the immune activation.

Results: Using an RSI cut-point of ≤0.3745, RSI-low tumours (n = 4,291, 41.9%) had a significantly higher median 12-CK GES value (0.54 [-0.136, 1.095]) compared with RSI-high tumours (-0.17 [-0.82, 0.42]; p < 0.001) across all tumour samples, indicating that radiosensitivity is associated with immune activation. In an exploratory analysis of early-stage breast cancer cases, a multivariable model with patient age, RSI and 12-CK provided a strong composite model for DMFS (p = 0.02), with RSI (hazard ratio [HR] 0.63 [95% confidence interval 0.36, 1.09]) and 12-CK (HR 0.66 [0.41, 1.04]) each providing comparable contributions.

Conclusions: Tumour radiosensitivity is associated with immune activation as measured by the two GESs.
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http://dx.doi.org/10.1016/j.ejca.2017.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822441PMC
October 2017

The Impact of Music Therapy on Anxiety in Cancer Patients Undergoing Simulation for Radiation Therapy.

Int J Radiat Oncol Biol Phys 2017 09 8;99(1):103-110. Epub 2017 May 8.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Purpose: Radiation therapy (RT) is associated with high stress levels. The role of music therapy (MT) for patients receiving RT is not well described. This study evaluates the impact of MT on anxiety and distress during simulation in patients with newly diagnosed head and neck or breast cancer.

Methods And Materials: This institutional review board-approved randomized trial of MT versus no MT at the time of simulation included the pre-State-Trait Anxiety Inventory (STAI-S Anxiety) questionnaire and Symptom Distress Thermometer (SDT). Patients randomized to MT received a consultation with a music therapist, during which music of the patients' choice to be played during simulation was selected. The no-MT patients did not receive the MT consultation, nor did they hear prerecorded music during simulation. Subsequent to the simulation, all patients repeated the STAI-S Anxiety questionnaire and the SDT.

Results: Of the 78 patients enrolled (39 in MT group and 39 in no-MT group), 38 had breast cancer and 40 had head and neck cancer. The male-female ratio was 27:51. The overall mean pre- and post-simulation STAI-S scores were 38.7 (range, 20-60) and 35.2 (range, 20-72), respectively. The overall mean pre- and post-simulation SDT scores were 3.2 (range, 0-10) and 2.5 (range, 0-10), respectively. The MT group had mean pre- and post-simulation STAI-S scores of 39.1 and 31.0, respectively (P<.0001), and the mean SDT scores before and after simulation were 3.2 and 1.7, respectively (P<.0001). The no-MT group's mean pre- and post-simulation STAI-S scores were 38.3 and 39.5, respectively (P=.46), and the mean SDT scores were 3 and 3.2, respectively (P=.51).

Conclusions: MT significantly lowered patient anxiety and distress during the simulation procedure on the basis of the STAI-S questionnaire and SDT. Incorporating culturally centered individualized MT may be an effective intervention to reduce stressors. Continued research defining the role of MT intervention in improving the patient experience by reducing anxiety is warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2017.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864375PMC
September 2017

Neoadjuvant radiotherapy of early-stage breast cancer and long-term disease-free survival.

Breast Cancer Res 2017 Jun 30;19(1):75. Epub 2017 Jun 30.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB 4, Tampa, FL, 33612, USA.

Background: Compared with surgery alone, postoperative adjuvant radiotherapy (RT) improves relapse-free survival of patients with early-stage breast cancer. We evaluated the long-term overall and disease-free survival rates of neoadjuvant (presurgical) versus adjuvant RT in early-stage breast cancer patients.

Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database provided by the National Institutes of Health to derive an analytic dataset of 250,195 female patients with early-stage breast cancer who received RT before (n = 2554; 1.02%) or after (n = 247,641; 98.98%) surgery. Disease-free survival, defined as time to diagnosis of a second primary tumor at any location, was calculated from automated patient identification matching of all SEER records.

Results: Partial and complete mastectomies were performed in 94.4% and 5.6% of patients, respectively. In the largest cohort of estrogen receptor-positive women who underwent partial mastectomy, the HR of developing a second primary tumor after neoadjuvant compared with adjuvant RT was 0.64 (95% CI 0.55-0.75; P < 0.0001). Overall survival was independent of radiation sequence (HR 1; P = 0.95). Neoadjuvant RT also resulted in a lower HR for second primary cancer among estrogen receptor-positive patients who underwent mastectomy compared with those who received adjuvant RT (HR 0.48, 95% CI 0.26-0.87; P = 0.0162).

Conclusions: Neoadjuvant RT may significantly improve disease-free survival without reducing overall survival, especially for estrogen receptor-positive patients with early-stage breast cancer. This finding warrants further exploration of potential long-term benefits of neoadjuvant radiotherapy for early-stage breast cancer in a controlled, prospective clinical trial setting, with correlative studies done to identify potential mechanisms of superiority.
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http://dx.doi.org/10.1186/s13058-017-0870-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493088PMC
June 2017

Novel Opportunities to Use Radiation Therapy with Immune Checkpoint Inhibitors for Melanoma Management.

Surg Oncol Clin N Am 2017 07 11;26(3):515-529. Epub 2017 May 11.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Electronic address:

Immunotherapy has revolutionized the systemic management of numerous malignancies. Nowhere has the proven benefit of these agents in clinical practice been more evident than in the management of advanced melanoma. Numerous preclinical studies have revealed the potential benefit of immune-priming radiotherapy in stimulating tumor-specific immune responses. This signal for immune activation may lead to clinically relevant synergy with immune checkpoint inhibitors against malignant cells. In this review, the authors summarize the current data outlining the role radiation therapy may play in the management of advanced melanoma alongside immune checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.soc.2017.01.007DOI Listing
July 2017
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