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Academic Centers Compared With Nonacademic Centers for Patients With International Prognostic Index Risk-stratified Diffuse Large B-cell Lymphoma: A Survival Outcomes Analysis
Journal Pre-proof Academic Centers Compared to Non-Academic Centers in IPI Risk Stratified DLBCL Patients: A Survival Outcomes Analysis Daniel A. Ermann, Victoria A. Vardell, Avyakta Kallam, Peter T. Silberstein, James O. Armitage PII:
S2152-2650(19)32122-6
DOI:
https://doi.org/10.1016/j.clml.2019.11.012
Reference:
CLML 1473
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 24 July 2019 Revised Date:
16 October 2019
Accepted Date: 11 November 2019
Please cite this article as: Ermann DA, Vardell VA, Kallam A, Silberstein PT, Armitage JO, Academic Centers Compared to Non-Academic Centers in IPI Risk Stratified DLBCL Patients: A Survival Outcomes Analysis, Clinical Lymphoma, Myeloma and Leukemia (2019), doi: https://doi.org/10.1016/ j.clml.2019.11.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Published by Elsevier Inc.
Academic Centers Compared to Non-Academic Centers in IPI Risk Stratified DLBCL Patients: A Survival Outcomes Analysis Daniel A. Ermanna, Victoria A. Vardella, Avyakta Kallamb, Peter T. Silbersteinc, and James O. Armitageb
a
Department of Internal Medicine, Creighton University Medical Center, Omaha, NE; 7500 Mercy Rd., Omaha, NE, 68154 United States b
Department of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE; 505 S 45th St, Omaha, NE 68105 United States
c
Department of Hematology/Oncology, Creighton University Medical Center, Omaha, NE; 7500 Mercy Rd., Omaha, NE, 68154 United States Address for correspondence: Victoria A. Vardell, MD, Bergan Mercy Medical Center, 7500 Mercy Rd., Omaha, NE, 68154; (208-610-9131); e-mail: [email protected]
Short title: Academic Centers Survival in IPI Risk Stratified DLBCL Presented in abstract form at the 60th annual meeting of the American Society of Hematology, San Diego, CA, Dec 3rd, 2018 Contribution: D.A.E. and V.A.V. analyzed and interpreted data and wrote the paper; V.A.V. performed statistical analysis and created figures and tables; D.A.E., A.K., P.T.S., and J.O.A. designed the project and edited the paper. Conflicts of Interest: None to report Word Count: 2,667 Tables/Figures: 9
1
MICRO-ABSTRACT Diffuse large B-cell lymphoma is associated with varying outcomes, and disparities exist within high risk disease. Prognostication with the International Prognostic Index anticipates patient outcomes, provides risk stratification, and guides treatment. We utilized a national database to compare academic centers and non-academic centers treatment outcomes. We found that academic centers have improved overall survival in each risk category.
ABSTRACT Introduction Diffuse large B-cell lymphoma (DLBCL) is a heterogenous disease associated with varying outcomes. The International Prognostic Index (IPI) has been the standard for baseline prognostic assessment in these patients. This study aimed to determine the impact of treatment facility on overall survival outcomes in DLBCL patients stratified by IPI risk groups. Methods The National Cancer Database was utilized to identify patients diagnosed with DLBCL between 2004 and 2015. Patients were stratified by IPI risk score from low to high risk disease, and overall survival of those treated at academic centers were compared to those treated at non-academic centers. Results Treatment at academic centers was associated with a significantly improved overall survival for all DLBCL patients (108.3 months) when compared to non-academic centers (74.5 months, p<.001). Median survival for patients with high risk disease treated at academic centers (33.5 months) was more than twice that of high risk patients treated at non-academic centers (14.4 months, p<.001). Median survival for other risk categories was similarly improved, though less pronounced in lower IPI score groups. Long-term overall survival for all DLBCL patients at academic centers was improved at five and ten-years (59% and 43% survival) when compared to those treated at non-academic centers (51% and 35% survival, p<.001). Conclusion DLBCL patients treated at academic centers demonstrated improved survival to those treated at nonacademic centers, especially in high risk disease. Further investigations into the factors contributing to such disparities should be done to help standardize care and improve outcomes.
KEYWORDS: academic centers; DLBCL; lymphoma; survival; high risk; IPI; NCDB; database
2
Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and represents approximately 30%-40% of all newly diagnosed non-Hodgkin lymphoma.1 This is estimated as 5.5 new cases of DLBCL per 100,000 men and women per year in the United States.2 Since the introduction of immunochemotherapy regimens for treatment of this disease, notably the addition of rituximab to an anthracycline-containing chemotherapy regimen, significant improvement in outcomes and long-term survival has been observed.3,4 The standard therapy for DLBCL has become rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and is associated with disease cure in the majority (≥50%) of patients treated.5 Current 5-year relative survival for DLBCL is estimated to be at 62.8% when all stages of disease are combined.2 Despite these advances, DLBCL remains a heterogeneous disease with striking variations in aggressiveness, genetic expression, and clinical outcomes. Several scoring systems have been developed for predicting prognosis and aiding in treatment decisions. The International Prognostic Index (IPI), which was developed over 25 years ago for aggressive B-cell and T-cell lymphoma, has become the standard for baseline prognostic assessment for patients diagnosed with B-cell lymphoma.6,7 Comprised of five adverse prognostic features present at the time of diagnosis, with one point each for age >60 years, Eastern Cooperative Oncology Group performance status ≥2, elevated serum lactate dehydrogenase level, ≥2 extra-nodal sites of disease, and stage III/IV disease. The IPI categorized patients into one of four outcome groups (low, low-intermediate, high-intermediate, and high risk) with five-year survival rates of 73% to 26% for low and high risk disease respectively.8 The IPI has since gained universal acceptance as an assessment tool to effectively risk stratify patients and predict responses to therapy. Even with the emergence of new treatment approaches for DLBCL, and throughout the rituximab era, the prognostic relevance of risk stratification with the IPI has remained valid.9,10 Although the majority of patients diagnosed with DLBCL and treated with standard therapy will reach a favorable outcome, higher risk patients (those with higher IPI score) have consistently shown poorer outcomes. 11,12 Though many clinical factors may contribute in such cases, data concerning influence from the type of facility these patients are treated at are lacking.5 In this study we aimed to determine the impact of treatment facility (academic compared to nonacademic centers) on overall survival outcomes in DLBCL patients, stratified by IPI score risk groups, with a focus on higher risk disease. Materials and Methods The National Cancer Database was utilized for this study. The National Cancer Database is a nationwide, facility-based, comprehensive clinical oncology resource established in 1989. It is a joint project of the American Cancer Society and the Commission on Cancer of the American College of Surgeons. The National Cancer Database encompasses more than 1500 Commission on Cancer accredited treatment facilities and captures an estimated 70% of all newly diagnosed malignancies in the United States annually.13 Data collected by the National Cancer Database include patient demographic features, characteristics of the selected malignancy (including stage, 3
grade, and location), and type of therapy used for treatment (including surgery, radiation, and chemotherapy). However, the identity of specific systemic therapy administered is not included or described in the database. The NDCB also captures other patient factors including facility type, insurance status, and IPI risk score in a subset of all DLBCL cases. The 2018 National Cancer Database participant user file for non-Hodgkin’s lymphoma was used to retrospectively identify patients diagnosed with DLBCL between 2004 and 2015. DLBCL histology codes were defined using the InterLymph Pathology Working Group hierarchical classification of lymphoid neoplasms for epidemiologic research definition of DLBCL, based on the 2008 World Health Organization classification.14 Using this classification, the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) histology codes 9688, 96789684, and 9735-9738 were included, and all other histology codes were excluded. Patients were only included if their IPI at the time of diagnosis was reported. These patients were then stratified based on IPI risk score from low to high risk disease. Four risk groups were formed based on number of adverse prognostic features: low (0-1), low-intermediate (2), highintermediate (3), and high risk (4-5).8 Patient characteristics and disease management was examined for the overall dataset and for each IPI risk group. This included sex, race, age at diagnosis, year of diagnosis, insurance status, facility type, Charlson-Deyo comorbidity score, distance traveled to treatment facility, association with HIV/AIDS, stage of disease, association with B symptoms, sequence number of malignancies, and the use of radiation or chemotherapy in treatment. Race was classified as white, black, or other. Insurance groups include uninsured, private insurance, Medicaid, and Medicare. Facility types available in the National Cancer Database are based on the Commission on Cancer categories. These include community, comprehensive community, integrated, and academic centers.13 The National Cancer Database describes community centers as facilities treating between 100 to 500 newly diagnosed cancer cases each year, and comprehensive centers as community centers that treat more than 500 new cases each year. Community centers may provide a full range of treatment services but may refer patients to other facilities for a portion of diagnoses or treatment, and participation in research and resident physician training is optional. Integrated centers provide comprehensive care as part of a joint venture of multiple facilities, have no minimum caseload, and may or may not participate in research and resident physician training. Academic centers treat more than 500 newly diagnosed cases each year and participate in postgraduate medical training in at least four program areas. These facilities participate directly in clinical cancer research through clinical trial enrollment or by referral to facilities that offer clinical trial enrollment.13 All non-academic centers were combined (community, comprehensive community, and integrated programs) to compare their outcomes directly to those of academic centers. One-way analysis of variance was used to compare mean age, year of diagnosis, and distance traveled to treatment facility between IPI risk groups. Significance was determined by p<0.05 between groups. Kaplan-Meier analysis was used to evaluate survival from all-cause mortality of entire the dataset and within each IPI risk category, and to compare survival within each group between 4
patients treated at academic and non-academic centers. Significance was evaluated using logrank tests to evaluate for significance of p<0.05. Life-tables were also used to compare all-cause five- and ten-year survival between IPI score groups and by treatment at academic and nonacademic centers. Pairwise comparisons using Wilcoxon (Gehan) statistics were used to determine significance of p<0.05. Relative risk reduction and absolute risk reduction was calculated to compare five-year and ten-year survival in academic and non-academic centers. A number needed to treat (NNT) for the additional survival to five-years and ten-years of one patient by treatment at an academic center versus a non-academic center was calculated from this absolute risk reduction. Cox proportional hazards modeling was used for multivariate analysis to analyze mortality benefit of various factors within IPI risk groups. Factors included in multivariate analysis include insurance status, treatment with chemotherapy, treatment at academic centers, race, distance travelled to treatment facility, sex, and year of diagnosis. Factors such as age, stage, and comorbidity were excluded as they are accounted for in IPI score. The presence of systemic B symptoms, association with HIV/AIDS, treatment with radiation, and sequence of malignancy were excluded due to small sample size and low power of results. Results are reported as hazard ratios for all-cause mortality with a 95% CI. Two-sided tests of significance were performed and evaluated for a significance of p<0.05. All analysis was completed using the Statistical Package for Social Sciences (SPSS) software version 25. Results Description of Data Set A total of 27,690 patients were identified. The majority of the patients in the data set were white (89.3%), males (53.7%), averaging 64 years of age (Table 1). Increasing age at diagnosis was associated with higher IPI score. 57.6% of patients were treated at non-academic centers and 42.4% were treated at academic centers. Of the identified cases 34.2% were classified as low risk, 21.8% were low-intermediate risk, 21.4% were high-intermediate risk, and 22.6% were high risk. There is no notable difference in facility choice between IPI risk categories. Government health insurance (Medicare or Medicaid) represented 57.7% of patients. 38.6% of patients had private insurance, and 3.6% were uninsured. Private insurance, Medicaid, or lack of insurance was associated with lower risk disease at diagnosis, where patients with Medicare were more likely to be diagnosed with higher risk disease. The majority of patients in all risk groups had a Charlson-Deyo comorbidity score of 0, indicating no comorbid diseases. Charlson-Deyo scores of 1 or greater are more common in higher IPI risk categories. Only 5% or less of patients of each risk category were diagnosed with HIV/AIDS and there was no notable association with higher or lower IPI risk score. High risk IPI score was most often associated with Stage III/IV disease (93% of cases), whereas low risk disease most often presented as Stage I/II (76.3% of cases). Patients in higher risk categories were more likely to have had prior malignancies, and there was an increasing prevalence of systemic B symptoms in each increasing IPI risk group, from 21.4% in low risk to 49.1% in high risk disease. 5
On analysis of variance there was no significant difference in the mean distance travelled to treatment facility between each IPI risk group (Table 2). Analysis of variance did show a significant increase in mean age and in mean year of diagnosis with increasing IPI score. Survival Analysis On Kaplan-Meyer analysis, treatment at academic centers was associated with a significantly improved overall survival for all DLBCL patients, regardless of IPI score, when compared to survival at non-academic centers (p<.001) (Table 3; Figures 1-5). Median survival for patients with high risk disease treated at academic centers (33.5 months [2.8 years]) was more than twice that of high risk patients treated at non-academic centers (14.4 months [1.2 years] p<.001). Median survival for high-intermediate risk patients at academic centers (87.3. months [7.3 years]) was improved when compared to non-academic centers (49.3 months [4.1 years] p <.001). Low-intermediate risk and low risk disease both demonstrated a median survival advantage at academic centers when compared to non-academic centers (10.2 years versus 7.2 years) and (12.3 years versus 11.0 years) respectively (p<.001). Long-term overall survival for all DLBCL patients at academic centers was improved at five and ten-years (59% and 43% survival) when compared to those treated at non-academic centers (51% and 35% survival). This demonstrated an 8% reduction in long-term absolute risk of death when patients are treated at academic centers (p<.001). Both five-year and ten-year survival were significantly higher for academic centers across all IPI risk categories. Five-year survival at academic centers was most improved in the high risk, high-intermediate, and low-intermediate risk patients (38%, 55%, 65%) when compared to non-academic centers (31%, 44%, 55%) respectively (p<.001). High-intermediate risk patients treated at academic centers (55% five-year survival, 38% tenyear survival) had similar long-term survival to those patients who were diagnosed with lowintermediate risk disease treated at non-academic centers (55% five-year survival, 36% ten-year survival). Those with low risk disease did have improved long-term survival outcomes at academic centers (73% five-year, 57% ten-year) when compared to non-academic centers (67% five-year, 50% ten-year) however the advantage was less pronounced than with higher risk disease. All findings were significant with a p<.001. The most pronounced absolute risk reduction at five-years after treatment at academic centers was seen in the high-intermediate (11%) and low-intermediate (10%) risk groups, followed by high risk (7%) and low risk (6%) when compared to non-academic centers. The greatest absolute risk reduction at ten-years after treatment was seen in the high-intermediate (9%) risk patients and high risk (8%) patients, followed by low-intermediate (7%) and low risk (7%) groups (p<.001). Relative risk reduction in ten-year survival improved with each increasing IPI risk score category from low risk to high risk disease. This was seen as a 33.3% risk reduction in high risk, 23.7% risk reduction in high-intermediate, 23.4% risk reduction in low-intermediate, and 12.3% risk reduction in low risk disease at ten-years when patients are treated at academic centers compared to non-academic centers (p<.001). Five-year survival also showed significant relative risk 6
reduction, which was most notable for high risk (18.4%) and high-intermediate (20%) risk disease. Both low-intermediate (15.4%) and low risk (8.2%) disease had significant, but lower relative risk reduction, at five-years after treatment (p<.001). The number of patients that need to be treated at an academic center to prevent mortality in one patient (NNT) within five-years and ten-years demonstrated the most benefit in the highintermediate (NNT = 9 and 11 respectively) and low-intermediate risk groups (NNT = 10 and 9 respectively). NNT for high risk disease was 14 and 13 patients at five and ten-year time intervals, whereas low IPI score had an NNT of 17 and 14 at five and ten years. NNT for all patients diagnosed with DLBCL, regardless of risk IPI risk group, was 13 for both intervals of long-term follow-up when academic centers are compared to non-academic centers (p<.001). Multivariate Analysis Multivariate analysis was performed to control for race, gender, chemotherapy, distance to treatment facility, year of diagnosis, and primary insurance (Table 4). Treatment at academic centers was an independent factor for improved overall survival across all DLBCL patients (hazard ratio [HR], 0.86; 95% CI, 0.83 – 0.90; p<.001). This effect was significant, but least pronounced in low risk patients (HR, 0.91; 95% CI, 0.83 – 0.96; p=.041). Patients diagnosed with low-intermediate risk DLBCL and treated at academic centers demonstrated the highest mortality benefit (HR, 0.81; 95% CI, 0.73-0.89), followed by high-intermediate risk (HR, 0.825; 95% CI, 0.75-0.89) and high risk (HR, 0.88; 95% CI, 0.81-0.94) when academic centers were compared to non-academic centers (p <.0001). Discussion In this study we were able to compare the survival outcomes of two distinct DLBCL patient cohorts. Receipt of treatment at an academic facility provided an added survival advantage among patients with DLBCL compared to a non-academic facility. This survival advantage was seen among all patients. The overall survival advantage for any patient diagnosed with DLBCL at an academic facility was significant, demonstrating an 8% improvement in survival at five and ten years. When patients are then stratified by IPI risk score, each individual risk group also demonstrates a significant improvement in overall survival. The greatest survival benefit is seen in the high risk group where the overall survival was more than double when patients were treated at academic centers as opposed to non-academic centers. Though there is a significant survival advantage to those treated at academic facilities, the rationale behind the improved outcomes is likely multifactorial and complex. Previous studies have also arrived at similar conclusions.15,16 Considering the standard first line treatment option for most patients across all centers is likely R-CHOP, it may be provider expertise, with more optimal and patient centered treatment regimens that focus on decreased toxicity while maximizing anti-tumor effect. This may be especially true in patients who are refractory to primary therapy, or those whom suffer from relapsed disease. Other considerations include patients undergoing care at academic centers may be more likely to have the option for enrollment in clinical trials. Furthermore, our survival curves demonstrate a decrease in overall survival at non-academic centers earlier in the course of treatment that is not present at academic 7
centers. The reason for this decline in early-on survival is not entirely clear, however it may relate to increased availability of resources such as access to expanded supportive cares, ancillary services, and critical care at academic centers. Limiting our study is that the National Cancer Database does not provide information on disease specific survival, relapsed or refractory disease, or specific chemotherapy regimens. Based on our findings there is an advantage for patients with DLBCL to be managed at academic centers. This is especially true for patients with higher risk disease. Although retrospective in nature and performed within the limits of the NCDB database, this should prompt further investigation in precisely determining factors that may support this significant effect on decreased survival among those treated in the community and help ameliorate this discrepancy.
CLINICAL PRACTICE POINTS
In this study we were able to compare the survival outcomes of two distinct DLBCL patient cohorts. Those treated at academic centers demonstrated a survival advantage to those treated at non-academic centers. There has been other literature that concurs with our findings that academic centers may ultimately result in overall patient outcomes. It is unclear exactly what contributes to these disparities. Given that high risk DLBCL morbidity and mortality is an unmet need, especially in relapsed and refractory settings, these findings may shed light on different treatment practices that can be elucidated with further studies.
Acknowledgements: None to report. 8
References 1) Li S, Young KH, Medeiros LJ. Diffuse large B-cell lymphoma. Pathology. 2018;50(1):7487. 2) National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Diffuse Large B-Cell Lymphoma. https://seer.cancer.gov/statfacts/html/dlbcl.html. Accessed January 2019. 3) Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23(22):5027-33. 4) Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235-42. 5) Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125(1):22-32. 6) Vaidya R, Witzig TE. Prognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era. Ann Oncol. 2014;25(11):2124-33. 7) Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837-42. 8) The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993;329(14):987-94. 9) Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(14):2373-80. 10) Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857-61. 11) Van den neste E, Schmitz N, Mounier N, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant. 2016;51(1):51-7. 12) Nagle SJ, Woo K, Schuster SJ, et al. Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol. 2013;88(10):890-4.
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13) Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol. 2008;15(3):683-90. 14) Turner JJ, Morton LM, Linet MS, et al. InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions. Blood. 2010;116(20):e90-8. 15) Loberiza FR, Cannon AJ, Weisenburger DD, et al. Survival disparities in patients with lymphoma according to place of residence and treatment provider: a population-based study. J Clin Oncol. 2009;27(32):5376-82. 16) Kallam A, Armitage JO, Chen B, Vose JM, Bhatt VR: Center Effect and Socioeconomic Determinants of Overall Survival (OS) of Diffuse Large B Cell Lymphoma (DLBCL). Blood 128:5949, 2016.
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Table 1. Patient, tumor, and treatment characteristics by IPI risk groups. Low Intermediate IPI Score (N=6042)
High Intermediate IPI Score (N=5921)
High IPI Score (N=6262)
(54.3%)
3132
(52.9%)
3278
(52.3%)
2764
(45.7%)
2789
(47.1%)
2984
(47.7%)
(88.5%)
5436
(90.0%)
5313
(89.7%)
5599
(89.4%)
640
(6.8%)
353
(5.8%)
369
(6.2%)
380
(61.0%)
448
(4.7%)
253
(4.2%)
239
(4.0%)
283
(45.0%)
All Risk Groups (N=27690)
Low IPI Score (N=9465)
Male
14858
(53.7%)
5170
(54.6%)
3278
Female
12832
(46.3%)
4295
(45.4%)
White
24725
(89.3%)
8377
Black
1742
(6.3%)
Other Insurance Status (n=27,093)
1223
(4.4%)
994
Gender (n=27,690)
Race (n=27,690)
None
(3.7%)
401
(4.3%)
225
(3.8%)
210
(3.6%)
158
(2.6%)
10463
(38.6%)
4800
(52.2%)
2361
(40.0%)
1823
(31.4%)
1459
(23.8%)
Medicaid
1582
(5.8%)
593
(6.4%)
319
(5.4%)
338
(5.8%)
332
(5.4%)
Medicare
14054
(51.9%)
3426
(37.1%)
3003
(50.8%)
3436
(59.2%)
4189
(68.2%)
13245
(57.6%)
4172
(57.0%)
2953
(58.5%)
2959
(58.0%)
3161
(57.2%)
Academic Charlson-Deyo Score (n=27,690)
9754
(42.4%)
3151
(43.0%)
2094
(41.5%)
2146
(42.0%)
2363
(42.8%)
0
20361
(73.5%)
7573
(80.0%)
4475
(74.1%)
4237
(71.6%)
4076
(65.1%)
1
5107
(18.4%)
1409
(14.9%)
1132
(18.7%)
1118
(18.9%)
1448
(23.1%)
2
Private
Facility Type (n=22,999) Non-Academic
1347
(4.9%)
280
(3.0%)
272
(4.5%)
338
(5.7%)
457
(7.3%)
3+ Association with HIV/AIDS (n=17,775)
875
(3.2%)
203
(2.1%)
163
(2.7%)
228
(3.9%)
281
(4.5%)
HIV negative
16935
(95.3%)
5983
(95.3%)
3594
(95.3%)
3556
(94.9%)
3802
(95.6%)
HIV positive
840
(4.7%)
297
(4.7%)
178
(4.7%)
190
(5.1%)
175
(4.4%)
Stage I
5177
(19.5%)
3799
(42.6%)
892
(15.2%)
333
(5.8%)
153
(2.5%)
Stage II
5372
(20.2%)
3010
(33.7%)
1484
(25.3%)
610
(10.6%)
168
(4.4%)
Stage III
5595
(21.0%)
996
(11.2%)
1727
(29.5%)
1724
(30.0%)
1148
(18.9%)
10450
(39.3%)
1120
(12.5%)
1760
(30.0%)
3072
(53.5%)
4498
(74.1%)
17114
(66.0%)
6969
(78.6%)
3857
(68.2%)
3298
(59.7%)
2990
(50.9%)
Present Sequence of Malignancy (n=27,687)
8807
(34.0%)
1896
(21.4%)
1798
(31.8%)
2223
(40.3%)
2890
(49.1%)
Only
21962
(79.3%)
7762
(82.0%)
4761
(78.8%)
4595
(77.6%)
4844
(77.4%)
1564
(5.6%)
519
(5.5%)
403
(6.7%)
377
(6.4%)
265
(4.2%)
Stage (n=26,594)
Stage IV Systemic Symptoms at Diagnosis (n=25,921) Absent
First of Multiple
11
Subsequent
4161
(15.0%)
1183
(12.5%)
876
(14.5%)
949
(16.0%)
1153
(18.4%)
22051
(80.0%)
6370
(67.7%)
4925
(82.0%)
5149
(87.3%)
5607
(89.9%)
5498
(20.0%)
3041
(32.3%)
1079
(18.0%)
748
(12.7%)
630
(10.1%)
2761
(10.0%)
978
(10.4%)
442
(7.4%)
512
(8.7%)
829
(13.3%)
24726
(90.0%)
8390
(89.6%)
5563
(92.6%)
5376
(91.3%)
5397
(86.7%)
Radiation (n=27,549) None Administered Chemotherapy (n=27,487) None Administered
12
Table 2. Analysis of variance for mean age, year of diagnosis, and distance travelled between IPI risk groups.
Pvalue Age <0.001 Year of Diagnoses <0.001 Distance Traveled 0.737
All Risk Groups (N=27690)
Low IPI Score (N=9465)
LowIntermediate IPI Score (N=6042)
HighIntermediate IPI Score (N=5921)
64.2 (64.0-64.4) 2009.2 (2009.12009.2)
58.5 (58.2-58.8) 2008.8 (2008.82008.9)
64.0 (63.6-64.4) 2009.2 (2009.12009.3)
66.9 (66.5-67.2) 2009.1 (2009.02009.2)
High IPI Score (N=6262) 70.34 (70.070.6) 2009.6 (2009.52009.7)
30.1 (28.8-31.5)
29.7 (27.5-32.0)
29.6 (26.6-32.5)
29.8 (27.1-32.5)
31.5 (28.4-34.6)
13
Table 3. Survival analysis by IPI risk group and facility type. Median Survival* (months) All DLBCL All Facilities Non-Academic Academic Low Risk All Facilities Non-Academic Academic Low Intermediate Risk All Facilities Non-Academic Academic High Intermediate Risk All Facilities Non-Academic Academic High Risk All Facilities Non-Academic
5-year 10-year survival† survival†
95.5 (92.7-98.4) 74.5 (71.3-77.7) 108.3 (102.6-114.1)
56% 51% 59%
37% 35% 43%
141.6 (135.2-148.0) 132.0 (125.0-138.7) 148.1 (NA)
72% 67% 73%
57% 50% 57%
98.9 (93.3-104.6) 86.2 (80.5-91.9) 122.8 (112.3-133.3)
60% 55%
42% 36%
65%
47%
63.5 (58.5-68.5) 49.3 (43.4-55.2) 87.3 (77.1-97.4)
49% 44% 55%
34% 29% 38%
19.1 (16.9-21.3) 34% 20% 14.4 (12.6-16.2) 31% 16% 33.5 (27.1-39.9) Academic 38% 24% Note: Pairwise comparisons between IPI score groups and between facilities within each IPI grouping were all significant with a p<0.001. NA, Not Available. * Median survival by Kaplan Meier analysis; † Cumulative proportion of patients surviving at end of interval.
14
Table 4. Multivariate Cox-Regression by IPI risk category. All Risk Groups (N=27690)
Facility Type NonAcademic Academic
Low IPI Score (N=9465)
Low-Intermediate IPI Score (N=6042) Hazard Ratio P-value
Hazard Ratio
P-value
Hazard Ratio
P-value
*
*
*
*
*
0.041
0.81
*
*
0.866
<0.001
0.911
* <0.001
HighIntermediate IPI Score (N=5921) Hazard PRatio value * 0.825
* <0.001
High IPI Score (N=6262) Hazard Ratio P-value * 0.88
* <0.001
Sex Male Female
* 0.876
* <0.001
* 0.837
<0.001
0.838
* <0.001
* 0.895
* 0.005
* 0.869
* <0.001
Race *
*
*
*
Black
1.155
<0.001
1.294
0.003
1.057
0.601
1.06
0.505
1.021
0.787
Other Insurance Status
0.974
0.622
0.895
0.339
1.088
0.513
0.899
0.341
0.926
0.386
*
*
White
None
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Private
0.715
<0.001
0.621
<0.001
0.63
<0.001
0.871
0.286
1.126
0.372
Medicaid
1.253
0.004
1.313
0.071
0.898
0.544
1.284
0.103
1.519
0.006
Medicare
1.766
<0.001
1.869
<0.001
0.057
1.285
1.539
<0.001
1.789
<0.001
Chemotherapy None Administered Distance Travelled† Year of Diagnosis†
*
*
*
*
*
*
*
*
*
*
0.318
<0.001
0.408
<0.001
0.313
<0.001
0.246
<0.001
0.197
<0.001
1.000
0.07
1.000
0.159
1.000
0.283
1.000
0.126
1.000
0.405
0.963
<0.001
0.94
<0.001
0.955
<0.001
0.957
<0.001
0.947
<0.001
* Reference variable; †Continuous analysis.
15
Figure 1. Kaplan Meier curve for survival of all DLBCL patients treated at academic centers compared to non-academic centers.
16
Figure 2. Kaplan Meier curve for survival of high IPI risk category DLBCL patients treated at academic centers compared to non-academic centers.
17
Figure 3. Kaplan Meier curve for survival of high-intermediate IPI risk category DLBCL patients treated at academic centers compared to non-academic centers.
18
Figure 4. Kaplan Meier curve for survival of low-intermediate IPI risk category DLBCL patients treated at academic centers compared to non-academic centers.
19
Figure 5. Kaplan Meier curve for survival of low IPI risk category DLBCL patients treated at academic centers compared to non-academic centers.
20
S2152-2650(19)32122-6
DOI:
https://doi.org/10.1016/j.clml.2019.11.012
Reference:
CLML 1473
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 24 July 2019 Revised Date:
16 October 2019
Accepted Date: 11 November 2019
Please cite this article as: Ermann DA, Vardell VA, Kallam A, Silberstein PT, Armitage JO, Academic Centers Compared to Non-Academic Centers in IPI Risk Stratified DLBCL Patients: A Survival Outcomes Analysis, Clinical Lymphoma, Myeloma and Leukemia (2019), doi: https://doi.org/10.1016/ j.clml.2019.11.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Published by Elsevier Inc.
Academic Centers Compared to Non-Academic Centers in IPI Risk Stratified DLBCL Patients: A Survival Outcomes Analysis Daniel A. Ermanna, Victoria A. Vardella, Avyakta Kallamb, Peter T. Silbersteinc, and James O. Armitageb
a
Department of Internal Medicine, Creighton University Medical Center, Omaha, NE; 7500 Mercy Rd., Omaha, NE, 68154 United States b
Department of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE; 505 S 45th St, Omaha, NE 68105 United States
c
Department of Hematology/Oncology, Creighton University Medical Center, Omaha, NE; 7500 Mercy Rd., Omaha, NE, 68154 United States Address for correspondence: Victoria A. Vardell, MD, Bergan Mercy Medical Center, 7500 Mercy Rd., Omaha, NE, 68154; (208-610-9131); e-mail: [email protected]
Short title: Academic Centers Survival in IPI Risk Stratified DLBCL Presented in abstract form at the 60th annual meeting of the American Society of Hematology, San Diego, CA, Dec 3rd, 2018 Contribution: D.A.E. and V.A.V. analyzed and interpreted data and wrote the paper; V.A.V. performed statistical analysis and created figures and tables; D.A.E., A.K., P.T.S., and J.O.A. designed the project and edited the paper. Conflicts of Interest: None to report Word Count: 2,667 Tables/Figures: 9
1
MICRO-ABSTRACT Diffuse large B-cell lymphoma is associated with varying outcomes, and disparities exist within high risk disease. Prognostication with the International Prognostic Index anticipates patient outcomes, provides risk stratification, and guides treatment. We utilized a national database to compare academic centers and non-academic centers treatment outcomes. We found that academic centers have improved overall survival in each risk category.
ABSTRACT Introduction Diffuse large B-cell lymphoma (DLBCL) is a heterogenous disease associated with varying outcomes. The International Prognostic Index (IPI) has been the standard for baseline prognostic assessment in these patients. This study aimed to determine the impact of treatment facility on overall survival outcomes in DLBCL patients stratified by IPI risk groups. Methods The National Cancer Database was utilized to identify patients diagnosed with DLBCL between 2004 and 2015. Patients were stratified by IPI risk score from low to high risk disease, and overall survival of those treated at academic centers were compared to those treated at non-academic centers. Results Treatment at academic centers was associated with a significantly improved overall survival for all DLBCL patients (108.3 months) when compared to non-academic centers (74.5 months, p<.001). Median survival for patients with high risk disease treated at academic centers (33.5 months) was more than twice that of high risk patients treated at non-academic centers (14.4 months, p<.001). Median survival for other risk categories was similarly improved, though less pronounced in lower IPI score groups. Long-term overall survival for all DLBCL patients at academic centers was improved at five and ten-years (59% and 43% survival) when compared to those treated at non-academic centers (51% and 35% survival, p<.001). Conclusion DLBCL patients treated at academic centers demonstrated improved survival to those treated at nonacademic centers, especially in high risk disease. Further investigations into the factors contributing to such disparities should be done to help standardize care and improve outcomes.
KEYWORDS: academic centers; DLBCL; lymphoma; survival; high risk; IPI; NCDB; database
2
Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and represents approximately 30%-40% of all newly diagnosed non-Hodgkin lymphoma.1 This is estimated as 5.5 new cases of DLBCL per 100,000 men and women per year in the United States.2 Since the introduction of immunochemotherapy regimens for treatment of this disease, notably the addition of rituximab to an anthracycline-containing chemotherapy regimen, significant improvement in outcomes and long-term survival has been observed.3,4 The standard therapy for DLBCL has become rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and is associated with disease cure in the majority (≥50%) of patients treated.5 Current 5-year relative survival for DLBCL is estimated to be at 62.8% when all stages of disease are combined.2 Despite these advances, DLBCL remains a heterogeneous disease with striking variations in aggressiveness, genetic expression, and clinical outcomes. Several scoring systems have been developed for predicting prognosis and aiding in treatment decisions. The International Prognostic Index (IPI), which was developed over 25 years ago for aggressive B-cell and T-cell lymphoma, has become the standard for baseline prognostic assessment for patients diagnosed with B-cell lymphoma.6,7 Comprised of five adverse prognostic features present at the time of diagnosis, with one point each for age >60 years, Eastern Cooperative Oncology Group performance status ≥2, elevated serum lactate dehydrogenase level, ≥2 extra-nodal sites of disease, and stage III/IV disease. The IPI categorized patients into one of four outcome groups (low, low-intermediate, high-intermediate, and high risk) with five-year survival rates of 73% to 26% for low and high risk disease respectively.8 The IPI has since gained universal acceptance as an assessment tool to effectively risk stratify patients and predict responses to therapy. Even with the emergence of new treatment approaches for DLBCL, and throughout the rituximab era, the prognostic relevance of risk stratification with the IPI has remained valid.9,10 Although the majority of patients diagnosed with DLBCL and treated with standard therapy will reach a favorable outcome, higher risk patients (those with higher IPI score) have consistently shown poorer outcomes. 11,12 Though many clinical factors may contribute in such cases, data concerning influence from the type of facility these patients are treated at are lacking.5 In this study we aimed to determine the impact of treatment facility (academic compared to nonacademic centers) on overall survival outcomes in DLBCL patients, stratified by IPI score risk groups, with a focus on higher risk disease. Materials and Methods The National Cancer Database was utilized for this study. The National Cancer Database is a nationwide, facility-based, comprehensive clinical oncology resource established in 1989. It is a joint project of the American Cancer Society and the Commission on Cancer of the American College of Surgeons. The National Cancer Database encompasses more than 1500 Commission on Cancer accredited treatment facilities and captures an estimated 70% of all newly diagnosed malignancies in the United States annually.13 Data collected by the National Cancer Database include patient demographic features, characteristics of the selected malignancy (including stage, 3
grade, and location), and type of therapy used for treatment (including surgery, radiation, and chemotherapy). However, the identity of specific systemic therapy administered is not included or described in the database. The NDCB also captures other patient factors including facility type, insurance status, and IPI risk score in a subset of all DLBCL cases. The 2018 National Cancer Database participant user file for non-Hodgkin’s lymphoma was used to retrospectively identify patients diagnosed with DLBCL between 2004 and 2015. DLBCL histology codes were defined using the InterLymph Pathology Working Group hierarchical classification of lymphoid neoplasms for epidemiologic research definition of DLBCL, based on the 2008 World Health Organization classification.14 Using this classification, the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) histology codes 9688, 96789684, and 9735-9738 were included, and all other histology codes were excluded. Patients were only included if their IPI at the time of diagnosis was reported. These patients were then stratified based on IPI risk score from low to high risk disease. Four risk groups were formed based on number of adverse prognostic features: low (0-1), low-intermediate (2), highintermediate (3), and high risk (4-5).8 Patient characteristics and disease management was examined for the overall dataset and for each IPI risk group. This included sex, race, age at diagnosis, year of diagnosis, insurance status, facility type, Charlson-Deyo comorbidity score, distance traveled to treatment facility, association with HIV/AIDS, stage of disease, association with B symptoms, sequence number of malignancies, and the use of radiation or chemotherapy in treatment. Race was classified as white, black, or other. Insurance groups include uninsured, private insurance, Medicaid, and Medicare. Facility types available in the National Cancer Database are based on the Commission on Cancer categories. These include community, comprehensive community, integrated, and academic centers.13 The National Cancer Database describes community centers as facilities treating between 100 to 500 newly diagnosed cancer cases each year, and comprehensive centers as community centers that treat more than 500 new cases each year. Community centers may provide a full range of treatment services but may refer patients to other facilities for a portion of diagnoses or treatment, and participation in research and resident physician training is optional. Integrated centers provide comprehensive care as part of a joint venture of multiple facilities, have no minimum caseload, and may or may not participate in research and resident physician training. Academic centers treat more than 500 newly diagnosed cases each year and participate in postgraduate medical training in at least four program areas. These facilities participate directly in clinical cancer research through clinical trial enrollment or by referral to facilities that offer clinical trial enrollment.13 All non-academic centers were combined (community, comprehensive community, and integrated programs) to compare their outcomes directly to those of academic centers. One-way analysis of variance was used to compare mean age, year of diagnosis, and distance traveled to treatment facility between IPI risk groups. Significance was determined by p<0.05 between groups. Kaplan-Meier analysis was used to evaluate survival from all-cause mortality of entire the dataset and within each IPI risk category, and to compare survival within each group between 4
patients treated at academic and non-academic centers. Significance was evaluated using logrank tests to evaluate for significance of p<0.05. Life-tables were also used to compare all-cause five- and ten-year survival between IPI score groups and by treatment at academic and nonacademic centers. Pairwise comparisons using Wilcoxon (Gehan) statistics were used to determine significance of p<0.05. Relative risk reduction and absolute risk reduction was calculated to compare five-year and ten-year survival in academic and non-academic centers. A number needed to treat (NNT) for the additional survival to five-years and ten-years of one patient by treatment at an academic center versus a non-academic center was calculated from this absolute risk reduction. Cox proportional hazards modeling was used for multivariate analysis to analyze mortality benefit of various factors within IPI risk groups. Factors included in multivariate analysis include insurance status, treatment with chemotherapy, treatment at academic centers, race, distance travelled to treatment facility, sex, and year of diagnosis. Factors such as age, stage, and comorbidity were excluded as they are accounted for in IPI score. The presence of systemic B symptoms, association with HIV/AIDS, treatment with radiation, and sequence of malignancy were excluded due to small sample size and low power of results. Results are reported as hazard ratios for all-cause mortality with a 95% CI. Two-sided tests of significance were performed and evaluated for a significance of p<0.05. All analysis was completed using the Statistical Package for Social Sciences (SPSS) software version 25. Results Description of Data Set A total of 27,690 patients were identified. The majority of the patients in the data set were white (89.3%), males (53.7%), averaging 64 years of age (Table 1). Increasing age at diagnosis was associated with higher IPI score. 57.6% of patients were treated at non-academic centers and 42.4% were treated at academic centers. Of the identified cases 34.2% were classified as low risk, 21.8% were low-intermediate risk, 21.4% were high-intermediate risk, and 22.6% were high risk. There is no notable difference in facility choice between IPI risk categories. Government health insurance (Medicare or Medicaid) represented 57.7% of patients. 38.6% of patients had private insurance, and 3.6% were uninsured. Private insurance, Medicaid, or lack of insurance was associated with lower risk disease at diagnosis, where patients with Medicare were more likely to be diagnosed with higher risk disease. The majority of patients in all risk groups had a Charlson-Deyo comorbidity score of 0, indicating no comorbid diseases. Charlson-Deyo scores of 1 or greater are more common in higher IPI risk categories. Only 5% or less of patients of each risk category were diagnosed with HIV/AIDS and there was no notable association with higher or lower IPI risk score. High risk IPI score was most often associated with Stage III/IV disease (93% of cases), whereas low risk disease most often presented as Stage I/II (76.3% of cases). Patients in higher risk categories were more likely to have had prior malignancies, and there was an increasing prevalence of systemic B symptoms in each increasing IPI risk group, from 21.4% in low risk to 49.1% in high risk disease. 5
On analysis of variance there was no significant difference in the mean distance travelled to treatment facility between each IPI risk group (Table 2). Analysis of variance did show a significant increase in mean age and in mean year of diagnosis with increasing IPI score. Survival Analysis On Kaplan-Meyer analysis, treatment at academic centers was associated with a significantly improved overall survival for all DLBCL patients, regardless of IPI score, when compared to survival at non-academic centers (p<.001) (Table 3; Figures 1-5). Median survival for patients with high risk disease treated at academic centers (33.5 months [2.8 years]) was more than twice that of high risk patients treated at non-academic centers (14.4 months [1.2 years] p<.001). Median survival for high-intermediate risk patients at academic centers (87.3. months [7.3 years]) was improved when compared to non-academic centers (49.3 months [4.1 years] p <.001). Low-intermediate risk and low risk disease both demonstrated a median survival advantage at academic centers when compared to non-academic centers (10.2 years versus 7.2 years) and (12.3 years versus 11.0 years) respectively (p<.001). Long-term overall survival for all DLBCL patients at academic centers was improved at five and ten-years (59% and 43% survival) when compared to those treated at non-academic centers (51% and 35% survival). This demonstrated an 8% reduction in long-term absolute risk of death when patients are treated at academic centers (p<.001). Both five-year and ten-year survival were significantly higher for academic centers across all IPI risk categories. Five-year survival at academic centers was most improved in the high risk, high-intermediate, and low-intermediate risk patients (38%, 55%, 65%) when compared to non-academic centers (31%, 44%, 55%) respectively (p<.001). High-intermediate risk patients treated at academic centers (55% five-year survival, 38% tenyear survival) had similar long-term survival to those patients who were diagnosed with lowintermediate risk disease treated at non-academic centers (55% five-year survival, 36% ten-year survival). Those with low risk disease did have improved long-term survival outcomes at academic centers (73% five-year, 57% ten-year) when compared to non-academic centers (67% five-year, 50% ten-year) however the advantage was less pronounced than with higher risk disease. All findings were significant with a p<.001. The most pronounced absolute risk reduction at five-years after treatment at academic centers was seen in the high-intermediate (11%) and low-intermediate (10%) risk groups, followed by high risk (7%) and low risk (6%) when compared to non-academic centers. The greatest absolute risk reduction at ten-years after treatment was seen in the high-intermediate (9%) risk patients and high risk (8%) patients, followed by low-intermediate (7%) and low risk (7%) groups (p<.001). Relative risk reduction in ten-year survival improved with each increasing IPI risk score category from low risk to high risk disease. This was seen as a 33.3% risk reduction in high risk, 23.7% risk reduction in high-intermediate, 23.4% risk reduction in low-intermediate, and 12.3% risk reduction in low risk disease at ten-years when patients are treated at academic centers compared to non-academic centers (p<.001). Five-year survival also showed significant relative risk 6
reduction, which was most notable for high risk (18.4%) and high-intermediate (20%) risk disease. Both low-intermediate (15.4%) and low risk (8.2%) disease had significant, but lower relative risk reduction, at five-years after treatment (p<.001). The number of patients that need to be treated at an academic center to prevent mortality in one patient (NNT) within five-years and ten-years demonstrated the most benefit in the highintermediate (NNT = 9 and 11 respectively) and low-intermediate risk groups (NNT = 10 and 9 respectively). NNT for high risk disease was 14 and 13 patients at five and ten-year time intervals, whereas low IPI score had an NNT of 17 and 14 at five and ten years. NNT for all patients diagnosed with DLBCL, regardless of risk IPI risk group, was 13 for both intervals of long-term follow-up when academic centers are compared to non-academic centers (p<.001). Multivariate Analysis Multivariate analysis was performed to control for race, gender, chemotherapy, distance to treatment facility, year of diagnosis, and primary insurance (Table 4). Treatment at academic centers was an independent factor for improved overall survival across all DLBCL patients (hazard ratio [HR], 0.86; 95% CI, 0.83 – 0.90; p<.001). This effect was significant, but least pronounced in low risk patients (HR, 0.91; 95% CI, 0.83 – 0.96; p=.041). Patients diagnosed with low-intermediate risk DLBCL and treated at academic centers demonstrated the highest mortality benefit (HR, 0.81; 95% CI, 0.73-0.89), followed by high-intermediate risk (HR, 0.825; 95% CI, 0.75-0.89) and high risk (HR, 0.88; 95% CI, 0.81-0.94) when academic centers were compared to non-academic centers (p <.0001). Discussion In this study we were able to compare the survival outcomes of two distinct DLBCL patient cohorts. Receipt of treatment at an academic facility provided an added survival advantage among patients with DLBCL compared to a non-academic facility. This survival advantage was seen among all patients. The overall survival advantage for any patient diagnosed with DLBCL at an academic facility was significant, demonstrating an 8% improvement in survival at five and ten years. When patients are then stratified by IPI risk score, each individual risk group also demonstrates a significant improvement in overall survival. The greatest survival benefit is seen in the high risk group where the overall survival was more than double when patients were treated at academic centers as opposed to non-academic centers. Though there is a significant survival advantage to those treated at academic facilities, the rationale behind the improved outcomes is likely multifactorial and complex. Previous studies have also arrived at similar conclusions.15,16 Considering the standard first line treatment option for most patients across all centers is likely R-CHOP, it may be provider expertise, with more optimal and patient centered treatment regimens that focus on decreased toxicity while maximizing anti-tumor effect. This may be especially true in patients who are refractory to primary therapy, or those whom suffer from relapsed disease. Other considerations include patients undergoing care at academic centers may be more likely to have the option for enrollment in clinical trials. Furthermore, our survival curves demonstrate a decrease in overall survival at non-academic centers earlier in the course of treatment that is not present at academic 7
centers. The reason for this decline in early-on survival is not entirely clear, however it may relate to increased availability of resources such as access to expanded supportive cares, ancillary services, and critical care at academic centers. Limiting our study is that the National Cancer Database does not provide information on disease specific survival, relapsed or refractory disease, or specific chemotherapy regimens. Based on our findings there is an advantage for patients with DLBCL to be managed at academic centers. This is especially true for patients with higher risk disease. Although retrospective in nature and performed within the limits of the NCDB database, this should prompt further investigation in precisely determining factors that may support this significant effect on decreased survival among those treated in the community and help ameliorate this discrepancy.
CLINICAL PRACTICE POINTS
In this study we were able to compare the survival outcomes of two distinct DLBCL patient cohorts. Those treated at academic centers demonstrated a survival advantage to those treated at non-academic centers. There has been other literature that concurs with our findings that academic centers may ultimately result in overall patient outcomes. It is unclear exactly what contributes to these disparities. Given that high risk DLBCL morbidity and mortality is an unmet need, especially in relapsed and refractory settings, these findings may shed light on different treatment practices that can be elucidated with further studies.
Acknowledgements: None to report. 8
References 1) Li S, Young KH, Medeiros LJ. Diffuse large B-cell lymphoma. Pathology. 2018;50(1):7487. 2) National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Diffuse Large B-Cell Lymphoma. https://seer.cancer.gov/statfacts/html/dlbcl.html. Accessed January 2019. 3) Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23(22):5027-33. 4) Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235-42. 5) Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125(1):22-32. 6) Vaidya R, Witzig TE. Prognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era. Ann Oncol. 2014;25(11):2124-33. 7) Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837-42. 8) The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993;329(14):987-94. 9) Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(14):2373-80. 10) Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857-61. 11) Van den neste E, Schmitz N, Mounier N, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant. 2016;51(1):51-7. 12) Nagle SJ, Woo K, Schuster SJ, et al. Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol. 2013;88(10):890-4.
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13) Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol. 2008;15(3):683-90. 14) Turner JJ, Morton LM, Linet MS, et al. InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions. Blood. 2010;116(20):e90-8. 15) Loberiza FR, Cannon AJ, Weisenburger DD, et al. Survival disparities in patients with lymphoma according to place of residence and treatment provider: a population-based study. J Clin Oncol. 2009;27(32):5376-82. 16) Kallam A, Armitage JO, Chen B, Vose JM, Bhatt VR: Center Effect and Socioeconomic Determinants of Overall Survival (OS) of Diffuse Large B Cell Lymphoma (DLBCL). Blood 128:5949, 2016.
10
Table 1. Patient, tumor, and treatment characteristics by IPI risk groups. Low Intermediate IPI Score (N=6042)
High Intermediate IPI Score (N=5921)
High IPI Score (N=6262)
(54.3%)
3132
(52.9%)
3278
(52.3%)
2764
(45.7%)
2789
(47.1%)
2984
(47.7%)
(88.5%)
5436
(90.0%)
5313
(89.7%)
5599
(89.4%)
640
(6.8%)
353
(5.8%)
369
(6.2%)
380
(61.0%)
448
(4.7%)
253
(4.2%)
239
(4.0%)
283
(45.0%)
All Risk Groups (N=27690)
Low IPI Score (N=9465)
Male
14858
(53.7%)
5170
(54.6%)
3278
Female
12832
(46.3%)
4295
(45.4%)
White
24725
(89.3%)
8377
Black
1742
(6.3%)
Other Insurance Status (n=27,093)
1223
(4.4%)
994
Gender (n=27,690)
Race (n=27,690)
None
(3.7%)
401
(4.3%)
225
(3.8%)
210
(3.6%)
158
(2.6%)
10463
(38.6%)
4800
(52.2%)
2361
(40.0%)
1823
(31.4%)
1459
(23.8%)
Medicaid
1582
(5.8%)
593
(6.4%)
319
(5.4%)
338
(5.8%)
332
(5.4%)
Medicare
14054
(51.9%)
3426
(37.1%)
3003
(50.8%)
3436
(59.2%)
4189
(68.2%)
13245
(57.6%)
4172
(57.0%)
2953
(58.5%)
2959
(58.0%)
3161
(57.2%)
Academic Charlson-Deyo Score (n=27,690)
9754
(42.4%)
3151
(43.0%)
2094
(41.5%)
2146
(42.0%)
2363
(42.8%)
0
20361
(73.5%)
7573
(80.0%)
4475
(74.1%)
4237
(71.6%)
4076
(65.1%)
1
5107
(18.4%)
1409
(14.9%)
1132
(18.7%)
1118
(18.9%)
1448
(23.1%)
2
Private
Facility Type (n=22,999) Non-Academic
1347
(4.9%)
280
(3.0%)
272
(4.5%)
338
(5.7%)
457
(7.3%)
3+ Association with HIV/AIDS (n=17,775)
875
(3.2%)
203
(2.1%)
163
(2.7%)
228
(3.9%)
281
(4.5%)
HIV negative
16935
(95.3%)
5983
(95.3%)
3594
(95.3%)
3556
(94.9%)
3802
(95.6%)
HIV positive
840
(4.7%)
297
(4.7%)
178
(4.7%)
190
(5.1%)
175
(4.4%)
Stage I
5177
(19.5%)
3799
(42.6%)
892
(15.2%)
333
(5.8%)
153
(2.5%)
Stage II
5372
(20.2%)
3010
(33.7%)
1484
(25.3%)
610
(10.6%)
168
(4.4%)
Stage III
5595
(21.0%)
996
(11.2%)
1727
(29.5%)
1724
(30.0%)
1148
(18.9%)
10450
(39.3%)
1120
(12.5%)
1760
(30.0%)
3072
(53.5%)
4498
(74.1%)
17114
(66.0%)
6969
(78.6%)
3857
(68.2%)
3298
(59.7%)
2990
(50.9%)
Present Sequence of Malignancy (n=27,687)
8807
(34.0%)
1896
(21.4%)
1798
(31.8%)
2223
(40.3%)
2890
(49.1%)
Only
21962
(79.3%)
7762
(82.0%)
4761
(78.8%)
4595
(77.6%)
4844
(77.4%)
1564
(5.6%)
519
(5.5%)
403
(6.7%)
377
(6.4%)
265
(4.2%)
Stage (n=26,594)
Stage IV Systemic Symptoms at Diagnosis (n=25,921) Absent
First of Multiple
11
Subsequent
4161
(15.0%)
1183
(12.5%)
876
(14.5%)
949
(16.0%)
1153
(18.4%)
22051
(80.0%)
6370
(67.7%)
4925
(82.0%)
5149
(87.3%)
5607
(89.9%)
5498
(20.0%)
3041
(32.3%)
1079
(18.0%)
748
(12.7%)
630
(10.1%)
2761
(10.0%)
978
(10.4%)
442
(7.4%)
512
(8.7%)
829
(13.3%)
24726
(90.0%)
8390
(89.6%)
5563
(92.6%)
5376
(91.3%)
5397
(86.7%)
Radiation (n=27,549) None Administered Chemotherapy (n=27,487) None Administered
12
Table 2. Analysis of variance for mean age, year of diagnosis, and distance travelled between IPI risk groups.
Pvalue Age <0.001 Year of Diagnoses <0.001 Distance Traveled 0.737
All Risk Groups (N=27690)
Low IPI Score (N=9465)
LowIntermediate IPI Score (N=6042)
HighIntermediate IPI Score (N=5921)
64.2 (64.0-64.4) 2009.2 (2009.12009.2)
58.5 (58.2-58.8) 2008.8 (2008.82008.9)
64.0 (63.6-64.4) 2009.2 (2009.12009.3)
66.9 (66.5-67.2) 2009.1 (2009.02009.2)
High IPI Score (N=6262) 70.34 (70.070.6) 2009.6 (2009.52009.7)
30.1 (28.8-31.5)
29.7 (27.5-32.0)
29.6 (26.6-32.5)
29.8 (27.1-32.5)
31.5 (28.4-34.6)
13
Table 3. Survival analysis by IPI risk group and facility type. Median Survival* (months) All DLBCL All Facilities Non-Academic Academic Low Risk All Facilities Non-Academic Academic Low Intermediate Risk All Facilities Non-Academic Academic High Intermediate Risk All Facilities Non-Academic Academic High Risk All Facilities Non-Academic
5-year 10-year survival† survival†
95.5 (92.7-98.4) 74.5 (71.3-77.7) 108.3 (102.6-114.1)
56% 51% 59%
37% 35% 43%
141.6 (135.2-148.0) 132.0 (125.0-138.7) 148.1 (NA)
72% 67% 73%
57% 50% 57%
98.9 (93.3-104.6) 86.2 (80.5-91.9) 122.8 (112.3-133.3)
60% 55%
42% 36%
65%
47%
63.5 (58.5-68.5) 49.3 (43.4-55.2) 87.3 (77.1-97.4)
49% 44% 55%
34% 29% 38%
19.1 (16.9-21.3) 34% 20% 14.4 (12.6-16.2) 31% 16% 33.5 (27.1-39.9) Academic 38% 24% Note: Pairwise comparisons between IPI score groups and between facilities within each IPI grouping were all significant with a p<0.001. NA, Not Available. * Median survival by Kaplan Meier analysis; † Cumulative proportion of patients surviving at end of interval.
14
Table 4. Multivariate Cox-Regression by IPI risk category. All Risk Groups (N=27690)
Facility Type NonAcademic Academic
Low IPI Score (N=9465)
Low-Intermediate IPI Score (N=6042) Hazard Ratio P-value
Hazard Ratio
P-value
Hazard Ratio
P-value
*
*
*
*
*
0.041
0.81
*
*
0.866
<0.001
0.911
* <0.001
HighIntermediate IPI Score (N=5921) Hazard PRatio value * 0.825
* <0.001
High IPI Score (N=6262) Hazard Ratio P-value * 0.88
* <0.001
Sex Male Female
* 0.876
* <0.001
* 0.837
<0.001
0.838
* <0.001
* 0.895
* 0.005
* 0.869
* <0.001
Race *
*
*
*
Black
1.155
<0.001
1.294
0.003
1.057
0.601
1.06
0.505
1.021
0.787
Other Insurance Status
0.974
0.622
0.895
0.339
1.088
0.513
0.899
0.341
0.926
0.386
*
*
White
None
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Private
0.715
<0.001
0.621
<0.001
0.63
<0.001
0.871
0.286
1.126
0.372
Medicaid
1.253
0.004
1.313
0.071
0.898
0.544
1.284
0.103
1.519
0.006
Medicare
1.766
<0.001
1.869
<0.001
0.057
1.285
1.539
<0.001
1.789
<0.001
Chemotherapy None Administered Distance Travelled† Year of Diagnosis†
*
*
*
*
*
*
*
*
*
*
0.318
<0.001
0.408
<0.001
0.313
<0.001
0.246
<0.001
0.197
<0.001
1.000
0.07
1.000
0.159
1.000
0.283
1.000
0.126
1.000
0.405
0.963
<0.001
0.94
<0.001
0.955
<0.001
0.957
<0.001
0.947
<0.001
* Reference variable; †Continuous analysis.
15
Figure 1. Kaplan Meier curve for survival of all DLBCL patients treated at academic centers compared to non-academic centers.
16
Figure 2. Kaplan Meier curve for survival of high IPI risk category DLBCL patients treated at academic centers compared to non-academic centers.
17
Figure 3. Kaplan Meier curve for survival of high-intermediate IPI risk category DLBCL patients treated at academic centers compared to non-academic centers.
18
Figure 4. Kaplan Meier curve for survival of low-intermediate IPI risk category DLBCL patients treated at academic centers compared to non-academic centers.
19
Figure 5. Kaplan Meier curve for survival of low IPI risk category DLBCL patients treated at academic centers compared to non-academic centers.
20