Tella, Sri Harsha

Aspirin and statin drugs have been associated with reduced risk of several gastrointestinal cancers, but their association with gallbladder cancer (GBC) has not been well established. We evaluated the association of aspirin and statins with the risk of GBC. Patients with GBC managed at Mayo Clinic between 2000 and 2019 were matched 1:2 with a general patient pool by age and sex. Univariable and multivariable logistic regression models were used to assess associations between GBC and aspirin or statin use. The analysis included 795 cases and 1590 controls, with a median age of 67 years. Aspirin or statin use alone or in combination was higher in controls (p < 0.001). Univariate analysis showed that the use of aspirin [odds ratio (OR): 0.11; 95%CI: 0.08–0.15] or statins (OR: 0.29; 95%CI: 0.20–0.40) and their combined use (OR: 0.18; 95%CI: 0.13–0.24) was associated with lower risk of GBC. Multivariable analysis revealed that aspirin (OR: 0.12; 95%CI: 0.09–0.16) and combined statins and aspirin (OR: 0.46; 95%CI: 0.31–0.67) were associated with lower risk of GBC. Aspirin alone or in combination with statins is associated with a strongly reduced risk of GBC. Further prospective studies are needed to confirm these results and to elucidate their mechanisms.

Background: National Comprehensive Cancer Network (NCCN) guidelines are the most comprehensive and widely used standard for clinical care in malignant hematology by clinicians and payers in the US. The level of scientific evidence in NCCN guidelines for malignant hematological conditions has not been recently investigated. We describe the distribution of categories of evidence and consensus (EC) among the 10 most common hematologic malignancies with regard to recommendations for staging, initial and salvage therapy, and surveillance. Methods: NCCN uses a system of guideline development distinct from other major professional organizations. The NCCN definitions for EC are: category I, high level of evidence such as randomized controlled trials with uniform consensus; category IIA, lower level of evidence with uniform consensus; category IIB, lower level of evidence without a uniform consensus but with no major disagreement; and category III, any level of evidence but with major disagreement. We compared our results with previously published results from 2011 guidelines. Results: Total recommendations increased by 16.6% from 1160 (2011) to 1353 (2020). Of the 1353 recommendations, Category 1, 2A, 2B and 3 EC were 5%, 91%, 4%, 1% while in 2011 they were 3%, 93%, 4% and 0% respectively. Recommendations with category 1 EC were found in all guidelines, except for Burkitt's Lymphoma. 6.3% of therapeutic recommendations were category 1 EC with the majority (56.4%) pertaining to initial therapy. Guidelines with highest proportions of therapeutic recommendations with category 1 EC were Multiple Myeloma (12.4%), CLL/SLL (6.9%) and AML (5.6%). Between 2011 and 2020, the proportion of category I recommendations increased significantly only in Follicular lymphoma and CLL/SLL. No category 1 EC recommendations existed in staging or surveillance. Conclusion: Recommendations issued in the 2020 NCCN guidelines are largely developed from lower levels of evidence but with uniform expert opinion. Despite the major advances in hematology in the past decade, this is largely unchanged. Our study underscores the urgent need and available opportunities to expand the current evidence base in malignant hematological disorders which forms the platform for clinical practice guidelines. Figure Disclosures No relevant conflicts of interest to declare.

e19523 Background: Previous studies have shown a disparity in outcomes of MM between clinical trials and real-world practice. This could be partly due to clinical trial exclusion of patients who need urgent treatment due to high burden of disease or significant illness. In this study, we aim to analyze the impact of time to initiation of systemic therapy for MM on overall survival (OS). Methods: We included MM patients reported to National Cancer Data Base (2004-2014). We excluded 2,860 patients with suspected smoldering MM due to initial treatment beyond 120 days. Relative risk of delayed time to systemic therapy was assessed by logistic regression model. Kaplan-Meier method and Cox multivariate analysis were used to evaluate the association between time to therapy and OS. Results: A total of 53, 519 MM patients were included. Median time to systemic therapy in our cohort was 18 days (range 0-120). Of the entire cohort, 24% patients received systemic therapy for MM < 7 days from diagnosis, and 32% received it after 30 days. Factors associated with time to systemic therapy > 30 days were Black race (OR 1.12, CI 1.07-1.16), female sex (OR 1.10, CI 1.06-1.14), lower Charlson comorbidity score (OR 1.36, CI 1.28-1.45), and academic facility (OR 1.18, CI 1.13-1.24). The median OS for patients who initiated therapy > 30 days after diagnosis was longer than those who received it within 7 days (37 vs. 29 month, p < 0.001). Similarly, on multivariate analysis, patients who received treatment > 30 days after diagnosis were found to have a lower mortality as compared to those who initiated treatment < 7 days (HR 0.81, CI 0.79-0.83; Table). Conclusions: In our study, time to initiation of systemic therapy was an independent prognostic factor in MM. This could be related to the high-risk nature of disease of patients treated within a short duration of diagnosis. These findings have implications for future clinical trial design, which should allow for a pragmatic approach toward enrollment of these high-risk patients to improve external validity. [Table: see text]

BackgroundPrior studies in oncology have shown that a higher annual facility patient volume is associated with reduced mortality. Because classic Hodgkin lymphoma is uncommon but highly curable, this study used the National Cancer Database (2003‐2014) to analyze whether such a relationship exists for this disease.MethodsThe facilities were classified by quartiles, and random intercepts were used to account for clustering of patients within facilities. A Cox regression model was used to determine the volume‐outcome relationship.ResultsThere were 47,633 patients with classic Hodgkin lymphoma treated at 1310 facilities. The first quartile (Q1), which included 58.4% of the facilities, treated 3 or fewer patients per year, whereas the fourth quartile (Q4), which included 5.9% of the facilities, treated more than 9 patients per year. Compared with the patients treated at Q4 facilities, those treated at lower quartile facilities had a higher risk of death (hazard ratio for the third quartile [HR], 1.19; 95% confidence interval [CI], 1.1‐1.29; HR for the second quartile, 1.28; 95% CI, 1.19‐1.38; HR for Q1, 1.29; 95% CI, 1.2‐1.39) after adjustments for all other factors (P < .0001). Compared with facilities treating 10 patients per year, facilities treating 40 patients per year had approximately 27% lower overall mortality rates.ConclusionsPatients with classic Hodgkin lymphoma treated at high‐volume centers had lower overall mortality than those treated at lower volume centers. Because this is a highly curable malignancy, such differences may suggest a benefit from referral to higher volume facilities or the emulation of their care models.

Abstract Introduction: Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, with ~21,000 estimated new cases in 2018. Prior retrospective studies have suggested an increased risk of second primary malignancies (SPMs) in CLL patients. Population-based studies on the risk of SPMs in CLL are limited, especially in the last decade with improvements in prognostic and therapeutic tools over the last decade. As the survival of CLL patient improves, it may lead to more survivors who are at risk of developing SPMs. In this study, we sought to evaluate the risk of development of SPMs among CLL patients diagnosed from 2000-2014. Methods: We used the SEER 18 registries for the calculation of risk of SPMs and included CLL cases that were confirmed histologically between 2000-2014 (https://seer.cancer.gov/). SPMs diagnosed within 2 months of primary CLL diagnosis were excluded. Time to SPM was calculated by subtracting second malignancy survival/follow-up time from CLL survival/follow-up time. The SEER*Stat Multiple Primary-SIR tool was used to calculate SIRs for secondary malignancies by comparing these patients' subsequent cancer experience with the number of cancers that would be expected based on incidence rates for the general U.S. population. These analyses were adjusted for age, gender, race, and year of CLL diagnosis. Multivariate logistic regression was performed to identify factors associated with development of SPM. Results: The study cohort included 46,164 patients with CLL. After a median follow up of 50 months (range 1-179), 5220 (11.3%) patients developed a total of 5,738 subsequent malignancies. As compared to that of general population, CLL patients had a higher risk of developing SPMs (SIR: 1.40 [95%CI:1.37-1.44]) and the risk was much higher for hematologic malignancies (SIR: 2.63 [95%CI:2.47-2.80]) as compared to solid organ malignancies (SIR: 1.25 [95%CI: 1.22-1.29]). In addition to known common SPMs in CLL (lymphoma, melanoma, lung cancer, and prostate cancer), there was an elevated risk of developing acute lymphoblastic leukemia (SIR 5.43), chronic myeloid leukemia (SIR 2.18), thyroid cancer (SIR 2.09), and kidney cancer (SIR 1.70) (Table). Out of the 5220 patients who developed SPMs, 437 (8.3%) patients developed two subsequent second primary malignancies, and 81 (1.5%) patients developed > 2 subsequent primary cancers, which was significantly more than the endemic rate (SIR, 1.40; p <.05). Of the 5738 SPMs, 1095 (19%) occurred in 2-11 months, 2822 (49%) in 1-5 years, 1499 (26%) in 6-10 years and 321 (6%) beyond 10 years of CLL diagnosis (Figure). On logistic regression, males had higher odds of developing SPMs than females (OR: 1.46 [95% CI: 1.38-1.56], p<0.0001) and the patients diagnosed with from 2000-2007 had higher odds of developing SPMs as compared to those diagnosed from 2007-2014 (OR: 2.28 [95%CI: 2.15-2.42], p<0.0001]. The risk of developing SPM did not differ based on the age, race and between the patients who received first line therapy and no initial therapy. CLL patients who developed SPMs had significantly less median overall survival as compared to that of patients who did not develop SPMs (93 vs 109 months, p<0.05). Conclusion: In this large population-based study, CLL patients had an elevated risk of developing second primary hematologic and solid malignancies. The specific types of SPMs were varied, ranging from common ones such as lymphoma, lung cancer, prostate cancer, to uncommon ones such as thyroid cancer, kidney cancer, and chronic myeloid leukemia. The patients who were diagnosed after 2007 had a lower risk of developing SPMs as compared to those diagnosed before. There is a need for studies evaluating immunological repertoire of CLL and its impact on development of SPMs. Knowledge of these SPMs may help physicians with their early detection. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Early integration of Palliative Care (PC) have shown to improve survival in some solid malignancies such as lung and colon cancers. In this study we sought to analyze the PC utilization in acute myeloid leukemia (AML) patients. Methods: Using the National Cancer Data Base (NCDB) Participant User File, we extracted patient-level data of patients with AML reported between 2004 to 2015.Patients who received pain management and/or other palliative procedures were considered as PC utilizers. After excluding the cases with acute promyelocytic leukemia t (15, 17) (given its excellent prognosis), we classified the AML into three groups- AML with genetic abnormalities, therapy related AML and AML with dysplasia. Other co-variates included in the analysis were age, sex, race, origin, Charlson-Deyo comorbidity score, insurance status, household income, educational status, facility type (academic vs non-academic) and year of diagnosis. Multivariate logistic regression was performed to identify the predictors of palliative care utilization. Statistical analysis was done using PC SPSS v24.0. Results: Of 102,778 patients, 3.4% (n=3504) received PC as initial treatment. PC utilization increased significantly from 2004-2006 to 2013-2015 (2.5% vs 3.9%, p < 0.001). Individuals of non-Hispanic origin (as compared to that of Hispanics) are more likely to receive PC as compared to that of non-Hispanics. (3.5 vs 1.8%, p<0.001). The patterns of PC utilization at non-academic centers were much higher than that of academic centers (4.4% vs 2.9%, p<0.001). As compared to that of AML, not otherwise specified subtype (3.3%), therapy-related AML (4%) and AML with dysplasia (4.3%) had higher rates of PC utilization, whereas individuals with AML with genetic abnormalities have lesser rates of PC utilization (1.9%) (p<0.001, all comparisons). Significant predictors of PC on multivariable regression are listed in the Table and forest plot. Conclusions: We noticed a differential utilization of palliative care based on the histological subtype of AML. The lesser utilization of PC in AML with certain genetic abnormalities may be attributed to their better overall survival outcomes. Though we noticed an increased trend in PC utilization over the past decade, the overall PC utilization in AML is markedly low and plagued by origin and socio-economic status. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Langerhans cell sarcoma (LCS) is a rare malignant neoplasm of Langerhans cells characterized by multi-organ involvement and an aggressive clinical course.Given the rarity of the disease, the true epidemiological data on LCS are lacking, and most of our knowledge is obtained from institutional case series. In this study, we utilized two national databases- the Surveillance, Epidemiology, and End Results (SEER) Program database (https://seer.cancer.gov/) and National Cancer Data Base (NCDB) to study the incidence, clinical presentation, and outcomes of LCS. Methods: We calculated LCS incidence (cases/10, 000, 000 individuals) from SEER database using SEER*Stat (v 8.3.4; https://seer.cancer.gov/seerstat/) statistical software. SEER is a population-based registry program of the United States National Cancer Institute that covers approximately 28% of the population. We identified LCS cases that were confirmed histologically using International Classification of Diseases for Oncology edition 3 (ICD-0-3) histology code 9756/3 from SEER 18 (2000-2014) registry. As the disease was mandatory reportable only after 2001, we included cases that were diagnosed after 2001 in the analysis. Demographic patterns, clinical presentation, and overall survival (OS) were calculated utilizing the patient level data from the NCDB Participant User File. NCDB is a joint program by the American College of Surgeons and American Cancer Society that represents approximately 70% of newly diagnosed cancer cases in the nation. All patients aged > 18 years with a diagnosis LCS (ICD-0-3 Code 9756/3) from 2004 to 2015 were included. To ensure accuracy of follow-up, we excluded the patients that were not treated at the same facility of diagnosis from survival analysis. Results: A total of 25 cases of LCS were reported to SEER between 2000 and 2014. The overall incidence of the disease was 0.2 per 10,000,000 [95% CI:0.1-0.3] and was similar among males and females (p=0.33). The incidence of the disease did not differ significantly among different races (whites, blacks and other races) (p=0.56). Between 2004 and 2015, 52 patients with newly diagnosed LCS were identified from NCDB and 60% were males. The median age of diagnosis was 62 (range, 19-90 years). The most common sites of the presentation were connective tissue (29%; n=15), reticuloendothelial system (RES) and hematopoietic system (25%; n=13), skin (19%, n=10), gastrointestinal (10%, n=5), bones and joints (8%, n=4), brain (2%, n=1) and breast (2%, n=1). Site specific details were missing in 27% (n=14) of cases. Out of the 52 patients, twenty patients (39%) received chemotherapy as first-line therapy, while 24 (46%) received surgery and 15 (29%) received radiation therapy. After a median follow up of 18 (range, 1-144) months, 27 patients (52%) had died. The one- year survival rate was 62%, and the median OS was 19 months (Fig. 1A). We also calculated the 1-year disease-specific survival and OS using SEER database, and was 74% and 63%, respectively. After censoring the patients with hematopoietic and RES involvement, the patients who were managed with radiation therapy (median dose 3960 cGy, range 750-6400) had a better OS as compared to those who received no radiation therapy (p=0.03, Fig. 1B). On the contrary, after excluding the patients with hematopoietic and RES as primary site, no significant difference in OS was noted between the patients who were managed with and without surgery (17 vs 21 months; p = 0.75; Fig. 1C). In addition, post-surgical radiation or chemotherapy had no significant benefit in median OS (p=0.25). Among patients with hematopoietic and RES involvement, there was no association between OS and receipt of chemotherapy (p = 0.16; Fig. 1D); however, the number of patients who received chemotherapy was small (n=6). Conclusion: This dual-national registry study shows that LCS is extremely rare, and has a poor prognosis. Although the data regarding optimal management of LCS are limited, our study demonstrates that radiation therapy may offer survival advantage in patients without hematopoietic and RES involvement. Disclosures No relevant conflicts of interest to declare.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with dismal prognosis when diagnosed at advanced stages. Surgical resection of the primary tumor or orthotropic liver transplantation serves as a potential curative option. However, this approach is highly dependent on the hepatic reserve and baseline functional status of the patient. Liver directed therapies such as portal vein embolization (PVE), trans-arterial chemoembolization (TACE), and systemic chemotherapy are employed in non-surgical candidates. Sorafenib was the only approved systemic therapeutic agent for almost a decade until the recent approval of lenvatinib by the United States Food and Drug Administration (FDA) as an alternate first-line agent. Regorafenib, nivolumab, pembrolizumab and cabozantinib are approved by the FDA as second-line agents in patients who failed or could not tolerate sorafenib. Ramucirumab was recently FDA approved for the subset of patients that have high alfa-fetoprotein levels (>400 ng/mL). A better understanding of tumorigenesis and encouraging clinical trial results that evaluated immune-checkpoint inhibitors opened doors for immunotherapy in HCC. Immune checkpoint inhibitors have demonstrated a prolonged median overall and progression-free survival in a subset of patients with HCC. On-going translational and clinical research will hopefully provide us with a better understanding of tumor markers, genetic aberrations and other factors that determine the immunotherapy response in HCC. In this review, we sought to summarize the potential role and future directions of immunotherapy in the management of HCC.

4091 Background: Optimal management of ECCA patients with elevated CA19-9 remains undefined. We hypothesized CA 19-9 elevation as a marker of aggressive biology in ECCA and that inclusion of CA 19-9 in the staging may improve OS discrimination. Methods: Patients with ECCA with CA 19-9 levels reported to the National Cancer Database (years 2004-2015) were included. The patients were classified based on their CA19-9 levels and a new staging system was proposed. Based on the current knowledge, we considered 37 U/ml as our cut off. Kaplan Meier method was used to compare OS between the groups. The net reclassification improvement (NRI) model was used to assess the predictive improvement in the proposed survival model. Results: A total of 2100 patients met the inclusion criteria: 601 (32%) and 1436 (68%) had normal and elevated CA19-9 levels, respectively. Rates of chemo (p=0.16) and radiation therapy (p=0.07) were similar between groups, but patients with elevated CA19-9 were less likely to undergo resection. Resected patients with CA19-9 elevation had higher 30-day mortality (p=0.02) and lower median OS (p<0.01). Patients with elevated CA 19-9 levels had decreased stage-specific survival in all stages (p<0.01). On adjusted analysis, CA19-9 elevation independently predicted poor OS (HR: 1.67 [1.42-1.97]) with impact resembling nodal metastasis, positive resection margin, lymphovascular invasion, and non-receipt of surgery or chemotherapy (p<0.01). CA 19-9 included proposed staging system (Table) had a better OS discrimination over AJCC 7th edition. The new staging system had a concordance of 60% as opposed to 58% for the AJCC staging, leading to an improvement of 2% (p<0.01). NRI of 46% (95% CI: 39-57) indicates that the new staging system is substantially effective at re-classifying events at 12 months as compared to AJCC staging. Conclusions: Elevated CA19-9 was found to be an independent risk factor for mortality in ECCA and its inclusion in the newly proposed staging system markedly improved OS discrimination.[Table: see text]

672 Background: Rectal squamous cell carcinoma (RSCC) is a rare form of gastrointestinal malignancy. Using the NCDB, we determined the prognostic factors and survival outcomes of RSCC in the United States. Methods: We identified histologically confirmed cases of RSCC from the National Cancer Data Base (2004-2015). Univariate and multivariable methods were used to assess factors associated with survival. Kaplan-Meier method and log-rank test were used to perform overall survival (OS) analysis. Results: Of the 5,527 cases included in our analysis, 67% were female. Median age at diagnosis was 61 years and did not differ by sex. The proportion of patients with stage 1, 2, 3 and 4 diseases were 22%, 16%, 20%, and 11%, respectively (30% unknown stage). Among the ones who received surgical resection of primary tumor, 41%, 30%, 20% and 8% are of stages 1, 2, 3 and 4 respectively. The rate of R0 resection was 54%, 63%, 55% and 38% in stage 1, 2, 3 and 4, respectively. The R0 resection rate was much higher in patients who received neoadjuvant chemo or radiation therapy or both (87%, 78%, 74%, and 57% in stages I, 2, 3 and 4, respectively) as compared to that of their counterparts. On stage wise sub-group OS analysis, stage 1-3 patients had OS benefit from surgery (as compared to no-surgery) (145 vs 90 months, p<0.001) as opposed to 4 disease (16 vs 11 months, p=0.06). Adjuvant radiation therapy improved the median OS in stage 1-3 patients (as compared to no-adjuvant radiation) in patients with positive surgical margins (not reached vs 40 months, p<0.0001). Patients with stage 4 disease treated with radiation therapy had a better median OS than those without (16 vs 6 months, p<0.0001). On therapy wise sub-group analysis, the patients who received surgery only had a median OS of 145 months; surgery + chemoradiation (adjuvant and neoadjuvant) = not reached; whereas patients with chemoradiation only had median OS of 80 months. Conclusions: This is the largest registry-based study on RSCC to date. RSCC had a diverse OS varied significantly according to stage of the disease at presentation and therapy received. Surgical resection of primary tumor was associated with improved OS as compared to that of patients who received chemoradiation.