Accepted Manuscript The Role of Radiation in All Stages of Nodular Lymphocytic Predominant Hodgkin Lymphoma Bismarck Odei, BS, Dustin Boothe, MD, Jonathan Frandsen, MD, Matthew M. Poppe, MD, David K. Gaffney, MD, PhD PII:
S2152-2650(16)30926-0
DOI:
10.1016/j.clml.2017.09.013
Reference:
CLML 1011
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 8 December 2016 Revised Date:
7 September 2017
Accepted Date: 15 September 2017
Please cite this article as: Odei B, Boothe D, Frandsen J, Poppe MM, Gaffney DK, The Role of Radiation in All Stages of Nodular Lymphocytic Predominant Hodgkin Lymphoma, Clinical Lymphoma, Myeloma and Leukemia (2017), doi: 10.1016/j.clml.2017.09.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title:
2 The Role of Radiation in All Stages of Nodular Lymphocytic Predominant Hodgkin
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Lymphoma
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Authors: Bismarck Odei, BSa; Dustin Boothe, MDb; Jonathan Frandsen, MDb; Matthew M.
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Poppe, MDb; David K. Gaffney, MD, PhDb
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aDavid
Geffen School of Medicine UCLA, Los Angeles, CA; bUniversity of Utah Huntsman
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Cancer Institute, Department of Radiation Oncology, Salt Lake City, UT.
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David Geffen School of Medicine UCLA,
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Department of Radiation Oncology,
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200 Suite #B265, Medical Plaza Driveway,
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Los Angeles, CA 90095, USA
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Full Postal Address b:
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Huntsman Cancer Hospital
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University of Utah Dept. of Radiation Oncology
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1950 Circle of Hope Room 1570
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Salt Lake City, UT 84112, USA
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Corresponding Author:
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David K Gaffney
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Huntsman Cancer Hospital
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University of Utah Dept. of Radiation Oncology
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1950 Circle of Hope Room 1570
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Salt Lake City, UT 84112
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o-801-581-2396; f-801-585-3502
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Email:
[email protected]
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Email Address of Authors:
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Bismarck Odei:
[email protected]
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Dustin Boothe:
[email protected]
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Jonathan Frandsen:
[email protected] Matthew M. Poppe:
[email protected]
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David K. Gaffney:
[email protected]
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Conflict of Interests
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in the public, commercial, or not-for-profit sectors.
Financial disclosures: This research did not receive any specific grant from funding agencies
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Conflicts of interest: The authors declare there are no conflicts of interest.
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MicroAbstract
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We assessed the role of radiotherapy (RT) in nodular lymphocytic Hodgkin lymphoma
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(NLPHL), particularly among patients with advanced stage disease, and B symptoms. We
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found that among NLPHL patients, RT had a potential role in advanced-stage disease and
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those with B symptoms, suggesting further exploratory studies.
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Abstract
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Background: The goal of this study was to assess the survival differences seen in early-stage
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and advanced-stage nodular lymphocytic predominant Hodgkin lymphoma (NLPHL) based
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on treatment modality.
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Patients and Methods: The National Cancer Database (NCDB) was queried to identify
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patients diagnosed with NLPHL between 2004-2012. Overall survival (OS) was determined
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using univariate and multivariate Cox regression analysis. Kaplan-Meier and log-rank
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analysis were used to estimate differences in OS between treatment groups.
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Results: A total of 1,968 patients were identified for analysis, consisting of stage I (40.4%),
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stage II (29.3%), stage III (22.3%,) and stage IV (8.0%) disease. The median age of patients
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was 46 years. The following factors were predictive of radiotherapy (RT) omission in
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treatment: increasing age, black race, Medicare insurance, chemotherapy use, stage II-IV
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disease, and the presence of B-symptoms. On survival analysis, RT was associated with
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prolonged OS in all stages of NLPHL (50.1 versus [vs.] 42.4 months, p<0.01). The OS benefit
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of RT persisted on multivariate analysis (HR 0.37, p<0.01). On subset analysis, RT was
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associated with prolonged OS in early disease (49.8 vs. 45.5 months, p<0.01), while a trend
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towards an OS benefit was observed in advanced-stage (54.1 vs. 39.6 months, p=0.06)
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NLPHL. Radiotherapy was also associated with prolonged OS among patients with B-
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symptoms (49.0 vs. 42.6 months, p<0.01).
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Conclusion: The use of RT in NLPHL is less likely among those with advanced-stage and B-
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symptoms. However, we found RT to be associated with prolonged OS in all stages of
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NLPHL, including those with B-symptoms.
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Keywords: Hodgkin lymphoma; Nodular lymphocytic Hodgkin lymphoma (NLPHL);
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Advanced Staged; B symptoms
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Introduction1
95 Nodular lymphocytic predominant Hodgkin lymphoma (NLPHL) is a rare variant of Hodgkin
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lymphoma (HL), accounting for only 3% to 8% of HL patients.1,2 Immunophenotyping
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differentiates NLPHL from classical HL in that NLPHL cells express CD20 and do not express
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CD15 and CD30.3 This immunophenotype is similar to non-hodgkin lymphoma. Nodular
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lymphocytic predominant Hodgkin lymphoma is associated with a good prognosis in which
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70%-80% of patients present with stage I or II disease and experience a 10-year overall
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survival (OS) of 71% to 100%.2,4-8 Advanced stage disease carries a worse prognosis. Diel et
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al. evaluated outcomes among 271 patients with stage IV disease, reporting an 8-yr disease
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specific survival of 41%.9
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Treatment of NLPHL is controversial. Due to the rare nature of NLPHL, treatment guidelines
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are based on conclusions derived from limited retrospective studies. Treatment options for
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NLPHL include observation, radiotherapy (RT), chemotherapy (CT), a combination of
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chemotherapy and radiation (CRT), or rituximab alone.10-15 For early stage disease, the use
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of RT has demonstrated a significant progression-free survival benefit, while the
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substitution or addition of chemotherapy has not.8,16-18 For advanced NLPHL, systemic
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therapy is the mainstay of treatment, while the role of RT is unclear.9,18,19
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Abbreviations: NLPHL, nodular lymphocytic predominant Hodgkin lymphoma; HL, Hodgkin lymphoma; OS, overall survival; RT, radiotherapy; CT, chemotherapy; CRT, combination of chemotherapy and radiotherapy; NCDB, National Cancer Data Base; CoC, Commission on Cancer; OR, odds ratio; HR, hazard ratio; OS, overall survival; PET, positron emission tomography.
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A recent study utilizing the National Cancer Database (NCDB) demonstrated that RT was
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associated with an OS benefit among early-stage patients. Our goal was to add to the
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existing registry data, by investigating the role of RT among all stages of NLPHL within the
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NCDB.
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Patients and Methods
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The NCDB is a joint project of the Commission on Cancer (CoC) of the American College of
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Surgeons and the American Cancer Society. It is estimated that the NCDB captures 70% of
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new cancer diagnoses from over 1,500 CoC-accredited hospitals and clinics in the United
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States and Puerto Rico. An application was submitted to gain access to the NCDB participant
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user files, limited to NLPHL diagnosed between 2004 and 2012. This was subsequently
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approved by our institutional internal review board. The data used in the study are derived
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from a de-identified NCDB file. The American College of Surgeons and the Commission on
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Cancer have not verified and are not responsible for the analytic or statistical methodology
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employed, or the conclusions drawn from these data by the investigator.
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To address our proposed clinical question, we applied specific inclusion and exclusion
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criteria. Only patients with NLPHL histology were included. Patients under age 18, or those
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with absent or unknown chemotherapy, radiotherapy, or staging information were
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excluded. Those with unknown survival time or with a survival time of less than three
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months from diagnosis were also excluded from analysis. The following demographic
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variables were collected for patterns-of-care and survival analysis: age, race, insurance
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status, treatment facility type, and modified Charlson-Deyo comorbidity score. The modified
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Charlson-Deyo comorbidity score represents the presence of up to 15 potential
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comorbidities (heart disease, diabetes, AIDS, etc.) with higher scores associated with more
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burdensome diagnoses 20. We also analyzed a variety of clinical data including stage and
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presence of B-symptoms. Surgical resection was not included due to the suspicion that
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excisional biopsies were underreported in this dataset. Staging was according to the Ann
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Arbor staging system. Information on presence or absence of bulky disease is not available
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in the NCDB dataset.
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Univariate and multivariate logistical regression were applied to identify predictors of RT
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use. Variables predictive of RT with a p-value of less than 0.20 were included in our
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multivariate model. All other variables were added to the multivariate model in a step-wise
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fashion and were analyzed to see if the odds ratio (OR) or hazard ratio (HR) of the variable
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of interest changed by greater than 10% 21. To determine the effect of therapy on overall
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survival (OS), Kaplan-Meier, as well as log-rank analysis, was performed. Multivariate Cox
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regression analysis was performed to assess for the impact of treatment modality on OS
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while controlling for additional demographic and clinical factors. All statistical analyses
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were performed using STATA 14.0 (Austin, TX).
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Results
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A total of 1,968 patients were identified for analysis. Median age at diagnosis was 46 years.
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The predominant race was Caucasian (69.3%). The majority of patients were privately
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insured (68.0%), while less than half of patients were treated at a comprehensive cancer
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center (48%). Most patients had a Charlson comorbidity score of zero (87.5%) and lacked B-
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symptoms (83.6%). Additionally, stage I was the most common stage at presentation
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(40.6%) (see Table 1).
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On multivariate analysis, increasing stage was associated with RT omission: stage II (OR
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0.74, p=0.02), stage III (OR 0.03, p<0.01), and stage IV (OR 0.11, p<0.01). Additionally, the
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following were predictors for omission of RT: increasing age (OR 0.83, p=0.01), B-symptoms
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(OR 0.62, p=0.01), Medicare insurance (OR 0.67, p=0.04), black race (OR 0.67, p=0.01),
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chemotherapy use (OR 0.34, p=<0.01), and Charlson Comorbidity score of one (OR 0.61,
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p=0.02) (see Table 2).
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Radiation therapy use was associated with prolonged survival in NLPHL patients of all
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stages, 50.1 versus (vs.) 42.4 months (p<0.01) (see Figure 1a). We further examined the
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association of RT with survival among early and late-stage patients. Receipt of RT in early-
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stage patients was associated with a statistically significant improved median survival, 49.8
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vs. 45.5 months (p<0.01) (see Figure 1b). A trend towards a survival benefit was seen
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among advanced-stage patients, 54.1 vs. 39.6 months (p=0.06) (see Figure 1c). Also, a sub-
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group analysis was done on all patients presenting with B-symptoms. Interestingly, patients
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with B-symptoms also experienced a survival prolongation with RT, 49.0 vs. 42.6 months
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(p<0.01) (see Figure 2).
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Multivariate analysis of the entire cohort revealed that receipt of RT was associated with a
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decreased risk of death (HR 0.37, p<0.01). Other predictors of an increased risk of death in
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multivariate analysis included: Medicaid insurance (HR 2.48, p<0.01), B-symptoms (HR
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1.78, p<0.01), and Charlson comorbidity of 1 (HR 2.43, p<0.01). Increasing stage was also
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associated with an increased risk of death: stage III (HR 1.68, p=0.05), and stage IV (HR 2.37,
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p=0.01).When assessing the entire cohort, regardless of disease stage,, chemotherapy use
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was not associated with a survival benefit (HR 0.83, p=0.36) (see Table 3). However, on
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subset analysis, chemotherapy was associated with a survival benefit among those with
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stage III or IV, 42.1 vs. 34.7 months (p<0.01). Only 72 of the 581 (12.4%) patients with
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advanced stage disease did not receive chemotherapy.
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Discussion
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The present study reports on 1,968 patients with both early and advanced stage NLPHL
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from the NCDB (2004-2012). Our study builds on the recent study by Parikh et al., which
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revealed the patterns-of-care and the association of RT with prolonged survival among
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patients with stage I or II NLPHL only.18 In our expanded cohort analysis (including
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advanced stage disease), we found B-symptoms and advanced stage disease to be associated
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with omission of RT. In patients with advanced stage disease, we observed a trend toward
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improved survival with the addition of RT (p=0.06). Additionally, subgroup analysis of
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patients with B-symptoms demonstrated RT to be associated with a prolonged OS.
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In our analysis, we noted a trend towards significance for RT in advanced-stage NLPHL. To
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date, no published studies have investigated the role of RT in advanced NLPHL.
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Unfortunately, the largest studies involving stage III and IV disease primarily focus on
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differences between classical HL and NLPHL, rather than treatment outcomes.9,22 In a case-
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matched analysis, Xing et al. compared classical HL and NLPHL and found NLPHL to have
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similar rates of treatment failure and survival 23. Therefore, an explanation of the OS benefit
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seen with RT among advanced NLPHL patients could be drawn from outcomes in patients
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with classical HL.24-26 Proponents of consolidative RT in classical HL utilize RT to improve
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local recurrence, often in the setting of bulky disease or residual positron emission
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tomography (PET) avidity.24,25 Patients with advanced NLPHL may similarly benefit from
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RT; however, NLPHL studies to date have not identified patterns of recurrence or risk
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factors predictive of local recurrence that would support this hypothesis.
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Our analysis also demonstrated a survival benefit for receipt of RT in the setting of B-
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symptoms in patients with NLPHL. Among those with early stage NLPHL, B-symptoms have
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been associated with poor survival, which is concordant with our results.27 Consequently,
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more aggressive treatment involving CRT with the option of rituximab has been
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recommended.19 However, as seen by our patterns-of-care analysis, patients with B-
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symptoms often do not receive RT.
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Our study supports the role of CT for those with advanced disease. Multiple studies describe
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the role of CT in advanced staged NLPHL.23,28 Fanale et al. assessed a subset of 11 patients
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with stage III or IV disease treated with R-CHOP and reported no relapse at a median follow-
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up of 42 months (range 8-111 months).28 Xing et al. found NLPHL patients receiving ABVD-
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like chemotherapy had an associated 10-year freedom from failure of 75%.23 More studies
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are needed to evaluate the clinical application of our findings and to assess the comparative
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benefits of CT, rituximab, RT, and CRT in advanced-stage disease.
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The presented patterns-of-care analysis showed the following factors to be predictive of the
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omission of RT in the treatment of all stages of NLPHL: stage II-IV, younger age, and B-
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symptoms. The rationale for the omission of RT in treating younger patients might be due to
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concerns for secondary malignancy, and late toxicities associated with RT. To mitigate such
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adverse effects, smaller RT fields and lower doses are now used in lieu of wider fields and
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higher doses.29
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Our NCDB study has multiple limitations. The retrospective nature of the study increases
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the likelihood of introducing confounders and selection bias. It is possible that there were
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unmeasured confounding variables resulting in a bias towards improved OS with RT.
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Multiple clinical factors important to patient survival and decision making are either
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incomplete or excluded from the NCDB, such as performance status, and tumor size. The
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omission of these factors limits the effectiveness and widespread applicability of our study.
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Treatment details in the NCDB are also limited to the first course of therapy only. This is a
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significant limitation with NLPHL given the often relapsing and remitting course.
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Conclusion
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This study is the largest retrospective analysis examining the effect of RT in patients with
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advanced and limited stage NLPHL. We found that the addition of RT to the first course of
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therapy improves survival. On subgroup analysis, this survival improvement persisted for
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patients with early stage disease and for individuals with B-symptoms. For patients with
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advanced stage disease, RT is associated with a trend towards improved survival. Further
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research is needed to further characterize appropriate treatments for this patient
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population.
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Clinical Practice Points: •
Currently among patients with NLPHL with advanced-stage disease or early-staged with B-symptoms, radiotherapy is not predominantly utilized as definitive or adjunct
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treatment.
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Our preliminary study suggests that there might be a role for radiotherapy in such settings.
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11 48 35 7 41 29 22 8 84 16 12 27 41 20
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N Age 18-29 377 30-49 766 50-64 508 Older than 65 317 Race Caucasian 1,348 Black 446 Hispanic 117 Other 46 Insurance Private Insurance 1,314 No Insurance 94 Medicaid 166 Medicare 347 Charlson Comorbidity 0 1,725 1 188 2+ 55 Facility Type Community 137 Comprehensive 589 Academic Program 428 Integrated 84 Stage I 802 II 575 III 437 IV 154 B-symptoms No 1,477 Yes 287 Adjuvant Treatment None 235 Radiation 511 Chemotherapy 789 Chemoradiation 383 Abbreviations: N=number
EP
370 371 372
Table 1. Study Demographics
AC C
369
ACCEPTED MANUSCRIPT
373
Table 2. Predictors of radiotherapy use Univariate 95% CI 0.75,0.91
P <0.01
OR 0.83
Multivariate 95% CI 0.71,0.96
P Age 0.01 Race Caucasian Black 0.77 0.62,0.96 0.02 0.67 0.50,0.91 0.01 Hispanic 1.27 0.87,1.86 0.21 0.99 0.59,1.67 0.97 Other 0.92 0.51,1.65 0.77 0.90 0.40,2.00 0.79 Insurance Private Insurance No Insurance 0.85 0.56,1.29 0.43 1.07 0.59,1.92 0.83 Medicaid 0.60 0.43,0.84 <0.01 0.72 0.45,1.13 0.15 Medicare 0.55 0.43,0.71 <0.01 0.67 0.46,0.99 0.04 Charlson Comorbidity 0 1 0.76 0.56,1.03 0.08 0.61 0.41,0.92 0.02 2+ 0.63 0.36,1.09 0.10 1.29 0.60,2.79 0.52 Facility Type Community Program Comprehensive Program 1.21 0.83,1.76 0.32 Academic Program 1.06 0.72,1.56 0.78 Integrated 1.50 0.87,2.59 0.15 AJCC Stage I II 0.61 0.49,0.76 <0.01 0.74 0.57,0.96 0.02 III 0.03 0.02,0.04 <0.01 0.03 0.02,0.06 <0.01 IV 0.06 0.04,0.11 <0.01 0.11 0.06,0.19 <0.01 B-symptoms No Yes 0.40 0.31,0.53 <0.01 0.62 0.45,0.87 0.01 Chemotherapy No Yes 0.22 0.18,0.27 <0.01 0.34 0.26,0.44 <0.01 Abbreviations: OR=odds ratio; HR=hazard ratio; CI=confidence interval; AJCC=American Joint Committee on Cancer.
TE D EP AC C
374 375 376
M AN U
SC
RI PT
OR 0.83
ACCEPTED MANUSCRIPT
Table 3. Predictors of overall survival Multivariate 95% CI
P
<0.01 <0.01
0.37 2.22
0.23,0.60 1.72,2.87
<0.01 <0.01
0.94 <0.01 <0.01
1.22 2.48 1.41
0.49,3.07 1.41,4.35 0.88,2.27
0.67 <0.01 0.16
<0.01 <0.01
2.43 1.69
1.63,3.61 0.81,3.50
0.81 0.45 0.52
0.19 0.48 0.23
RI PT
HR
<0.01 0.16
0.03 <0.01 <0.01
1.26 1.68 2.37
0.76,2.09 1.00,2.84 1.29,4.33
0.37 0.05 0.01
<0.01
1.78
1.21,2.62
<0.01
0.10
0.83
0.55,1.24
0.36
TE D
EP AC C
378 379 380 381
Radiation None Radiation 0.22 0.15,0.33 Age 2.50 2.11,2.97 Race Caucasian Black 0.95 0.66,1.38 Hispanic 0.75 0.35,1.60 Other 1.34 0.55,3.29 Insurance Private Insurance No Insurance 1.04 0.42,2.58 Medicaid 2.93 1.77,4.83 Medicare 5.07 3.64,7.06 Charlson Comorbidity 0 1 2.96 2.04,4.29 2+ 3.97 2.19,7.19 Facility Type Community Program Comprehensive Program 1.46 0.83,2.56 Academic Program 0.80 0.43,1.49 Integrated 0.53 0.19,1.48 AJCC Stage I II 1.63 1.05,2.54 III 3.47 2.30,5.25 IV 5.25 3.26,8.46 B-symptoms No Yes 2.27 1.59,3.23 Chemotherapy No Yes 1.31 0.95,1.82 Abbreviations: HR=hazard ratio; CI=confidence interval
P
SC
Univariate 95% CI
HR
M AN U
377
ACCEPTED MANUSCRIPT
Figure Legends
383
Figure 1. Survival analysis by stage: all stages (panel A), stages I & II (panel B), and stages III
384
& IV (panel C).
385 386
Figure 2. Survival analysis among patients with B-symptoms.
387
SC
388
RI PT
382
AC C
EP
TE D
M AN U
389
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT