The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system.

OBJECTIVE: The 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer changed from a clinical system to a clinical/pathologic/radiologic system with stages IIIC1 and IIIC2 indicating positive pelvic and para-aortic lymph nodes, respectively. We evaluated the National Cancer Database (NCDB) for the impact on survival of lymph node metastases (LNM). METHODS: The NCDB from 2004 to 2015 was queried for patients with cervical cancer, yielding 115,819 patients. Patients with FIGO IVB (22,569), non-adeno/squamous cell histologies (5,909), unknown nodal status (60,695), or unknown survival time (9,473) were excluded. Survival was compared using Cox proportional hazard model based on nodal status. Univariate (UVA) and multivariate analyses (MVA) were done for the overall cohort, followed by UVA by individual stage. RESULTS: In 17,173 eligible patients, LNM negatively affected survival (UVA IIIC1 Hazard Ratio [HR] 2.0, p < 0.001, IIIC2 HR 3.9, p < 0.001, MVA IIIC1 HR 1.36, p < 0.001, IIIC2 HR 2.14, p < 0.001). In T1B, the effect of IIIC2 was most pronounced (HR 5.38, p < 0.001 versus HR 1.5 p = 0.001 for IIIC1 disease). In T3, the effect of LNM was markedly less: (HR 1.7, p < 0.001 for IIIC2 versus HR 1.2 p = 0.02 for IIIC1). Within T1B, there was no difference in survival for IIIC1 for the smaller T stages (IB1-2). CONCLUSION: In this study, LNM negatively affects prognosis in cervical cancer. The impact on survival varies by T stage with the greatest effect seen in stage T1B with IIIC2 disease.

Correlates of Refusal of Surgery in the Treatment of Non-metastatic Pancreatic Adenocarcinoma.

BACKGROUND: Surgical resection is the most important therapeutic intervention for eligible patients with pancreatic cancer; however, a majority of patients never receive surgery for a variety of reasons, including patient refusal. Utilizing the National Cancer Database, we investigated the associated sociodemographic and clinical factors for those patients who refused surgery, and the impact of this decision on overall survival (OS). METHODS AND MATERIALS: We analyzed adult patients with non-metastatic adenocarcinoma of the pancreas diagnosed from 2004 to 2013. Univariate and multivariate logistic regression modeling was used to identify factors predictive of refusing surgery, and Kaplan-Meier and log-rank analysis was performed to investigate the effect on OS. RESULTS: A total of 48,902 patients were identified: 47,107 received surgery (96.3%) and 1795 were offered surgery but refused (3.7%). Factors associated with refusing surgery include both sociodemographic factors [age > 50 years, female sex, Black race, non-private insurance, treatment at a non-academic institution or non-metro facility, Carlson Comorbidity Index of 2 + (p ≤ 0.01)], and clinical factors [advanced clinical T (tumor) category and tumor size > 20 cm (p ≤ 0.01)]. Patients who refused surgery and received no treatment at all experienced a median survival of 5.1 months, while those who refused surgery but received chemoradiotherapy experienced a median survival of 11.2 months. As an index for comparison, those who received surgery had a median survival of 20.5 months. CONCLUSION: Refusing surgery is an understudied phenomenon associated with several sociodemographic and clinical factors. The expected prognosis for patients who refuse surgery is presented.

Multiagent induction chemotherapy followed by chemoradiation is associated with improved survival in locally advanced pancreatic cancer.

BACKGROUND: The role of chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC) is uncertain after multiple randomized clinical trials have yielded mixed results. The authors used the National Cancer Data Base (NCDB) to determine whether CRT yields a survival benefit compared with chemotherapy alone (CT). METHODS: Patients with nonmetastatic LAPC diagnosed during 2004 through 2014 were identified in the NCDB. Patients who received CT were compared with those who received CRT using chi-square analysis. Univariate and multivariate Cox regression analyses were used to compare demographic, clinical, and treatment characteristics that were predictive of survival. Propensity score matching and shared frailty analysis were done. Subgroup analyses were undertaken to examine patients who underwent pancreatectomy and cohorts of patients who received different CT or CRT regimens. RESULTS: In total, 8689 patients with LAPC were identified. CRT was associated with improved survival (median survival [MS], 13.5 months) compared with CT (MS, 10.6 months) on multivariate analysis (hazard ratio [HR], 0.80; P < .001). Induction chemotherapy before CRT (HR, 0.67; P < .001) and multiagent chemotherapy (HR, 0.72; P < .001) were also identified as independent predictors of survival compared with concurrent CRT and single-agent CT, respectively. Patients in the CRT group who received multiagent induction chemotherapy had superior MS and pancreatectomy rates (MS, 17.5 months; HR, 0.70; P < .001; pancreatectomy rate, 10%) compared with those who received multiagent CT alone (MS, 12.4 months; pancreatectomy rate, 3.3%). Patients who underwent pancreatectomy experienced improved survival (MS, 22 vs 10.6 months; HR, 0.39; P < .001). CONCLUSIONS: In this NCDB analysis, maximizing systemic chemotherapy before CRT improved survival compared with CT alone in patients with LAPC. Continued analysis of CRT in properly selected patients after maximized systemic therapy is needed. Cancer 2017;123:3816-24. © 2017 American Cancer Society.

Chemoradiation Therapy for Unresected Extrahepatic Cholangiocarcinoma: A Propensity Score-Matched Analysis.

BACKGROUND: Unresected extrahepatic cholangiocarcinoma (uEHCC) remains a deadly disease. Guidelines for uEHCC recommend either chemotherapy alone (CT) or chemoradiotherapy (CRT). This study used the National Cancer Database (NCDB) to compare outcomes for patients treated with CT and those who underwent CRT. METHODS: Patients with initially diagnosed non-metastatic uEHCC from 2004 to 2014 were identified. Using Chi square analysis, patients who underwent CT were compared with those who received CRT. Uni- and multivariate Cox regression analyses were used to compare characteristics related to survival. Propensity score matching and shared frailty analysis were undertaken to correct for baseline differences between the two groups. Additional analyses were performed to compare survival for the minority of patients who underwent surgery and advanced-stage patients. RESULTS: The study identified 2996 patients with uEHCC. Chemoradiation was associated with better survival (median survival [MS], 14.5 months; hazard ratio [HR] 0.84; p < 0.001) than CT alone (MS, 12.6 months). Induction of CT before CRT was associated with a trend toward decreased risk of death compared with concurrent CRT (HR 0.81; p = 0.051). For the patients able to undergo surgery after initial treatment, MS was 24.5 months (HR 0.38; p < 0.001) versus 12.2 months for those who had no surgery. For these patients, CRT also was associated with better survival (MS, 31.2 months; HR 0.66; p = 0.001) than CT (MS, 22.1 months). Positive margins at surgery yielded survival equivalent to that with no surgery. CONCLUSION: Although CRT may be associated with slightly better survival in uEHCC than CT alone, the majority of the benefit was observed for patients able to undergo eventual surgery.

Disparities in care for elderly women with endometrial cancer adversely effects survival.

PURPOSE: Elderly women with endometrial cancer are at increased risk of local recurrence and cancer-specific death compared to younger women. We sought to investigate adjuvant radiotherapy (RT) practice patterns and effects on survival in elderly women with endometrial cancer. METHODS: Women from the National Cancer Data Base (NCDB) with FIGO IA grade 3 to FIGO IVA endometrial cancer diagnosed from 2004-2013 were included. Chi square analysis was used to compare the elderly (80+) and non-elderly women (18-79) and women who received RT and those that did not. Univariate and multivariate logistic regression were used to determine predictors of receipt of oncologic surgery and adjuvant RT. Univariate and multivariate Cox survival analyses were performed to examine the effect of radiotherapy on survival. Propensity score matching and shared frailty analysis were done in the elderly cohort. RESULTS: We identified 48,871 women for analysis. Rates of oncologic surgery were higher in the women 80+ compared with rates of adjuvant RT (95% versus 34%). Rates of RT receipt were higher in non-elderly women (48% versus 34%, p<0.001). Age over 80 was a negative predictive factor (OR 0.62, p<0.001) for receipt of adjuvant RT and oncologic surgery (OR 0.81, p=0.03). Adjuvant RT was associated with a decreased risk of death in elderly (HR 0.79, p<0.001) and non-elderly women (HR 0.77, p<0.001). CONCLUSION: Endometrial cancer patients over age 80 have similar rates of oncologic surgery as younger women but are significantly less likely to receive adjuvant RT, and this negatively impacts their survival.

Early-Stage Non-Small Cell Lung Cancer Stereotactic Body Radiation Therapy (SBRT) Outcomes in an Equal Access Military Setting.

Introduction Lung stereotactic body radiation therapy (SBRT) is a first-line treatment for early-stage lung cancer in non-surgical candidates or those who refuse surgery. We compared our institutional outcomes from a unique patient population with decreased barriers to care with a recently published prospective series. Materials and methods  We retrospectively reviewed all patients who received definitive lung SBRT at the Walter Reed National Military Medical Center from 2015 to 2020. All patients underwent a positron emission tomography-computed tomography (PET-CT) and all were presented at a multidisciplinary tumor board. Patients were treated on a Trubeam linear accelerator (LINAC)-based system with daily cone-beam CT. The results were qualitatively compared to outcomes from prospective studies including RTOG 0236 and RTOG 0618. Results A total of 105 patients with 114 lesions were included. Median age was 77 years and 54.7% had ≥ 40-pack year smoking history. 36.8% did not have pathologic confirmation. With a median follow-up of 24 months, three-year local control (LC), disease-free survival (DFS) and overall survival (OS) rates were 92.4%, 81.0%, and 80.0%, respectively. Rates of Grade 1 and 2 toxicity were 21.9% and 6.7% and no patients experienced Grade ≥ 3 toxicity. Conclusions In our military setting with universal coverage and routine multidisciplinary care, lung SBRT provides outcomes comparable to prospective studies conducted at high-volume academic centers. More than one-third of patients were treated empirically without pathologic confirmation of disease, demonstrating a difference between clinical trials and community practice. Further investigation is warranted to integrate multidisciplinary management and achieve equal access to care to bridge existing health disparities in the community setting.

Factors associated with the refusal of surgery and the associated impact on survival in patients with rectal cancer using the National Cancer Database.

BACKGROUND: Surgical resection is an integral component of the curative-intent treatment for most patients with non-metastatic rectal cancer. However, some patients refuse surgery for a number of reasons. Utilizing the National Cancer Database (NCDB), we investigated the sociodemographic and clinical factors associated with patients who were coded as having been offered but refused surgery, and the factors affecting overall survival (OS) in these patients. METHODS: Adult patients with adenocarcinoma of the rectum (excluding T1N0M0 and M1 disease) diagnosed from 2004 to 2015 were analyzed in this retrospective cohort study. Logistic regression was performed to identify factors associated with refusal of surgery. OS of patients refusing surgery was compared using Kaplan-Meier estimate, log-rank test, propensity score matching, and proportional hazards regression. RESULTS: A total of 55,704 patients were identified: 54,266 received definitive surgery (97.4%) and 1,438 refused (2.6%). Of patients refusing surgery, 135 (9.4%) were stage I, 709 (49.3%) were stage II, and 594 (41.3%) were stage III. Patients were more likely to refuse surgery as the study period progressed (P<0.01). Factors associated with refusal of surgery on multivariate analysis include: age ≥70 years, Black race, non-private insurance, and tumor size greater than 2 cm (all values P≤0.01). The 5-year OS was 61.6% for the surgery cohort and 35.7% for the refusal cohort. In the propensity matched groups, median survival was 84.2 months in patients who received definitive surgery compared to 43.7 months in patients who refused surgery. As an index for comparison, patients who refused surgery but received both radiotherapy and chemotherapy had a median survival of 48.5 months. Among patients that refused surgery, those that received radiotherapy alone, chemotherapy alone, or radiotherapy and chemotherapy (compared to no treatment) experienced a survival benefit (all values P≤0.01). CONCLUSIONS: In patients with non-metastatic adenocarcinoma of the rectum reported in the NCDB, age, race, and insurance status were associated with refusal of surgery. Refusal of surgery was more common in the later years of the study. Survival is poor in patients who refused surgical resection.

Impact of Brachytherapy Boost and Dose-escalated External Beam Radiotherapy in Margin Positive Cervical Cancer Treated With Chemotherapy and Radiation.

OBJECTIVES: We examined the impact of brachytherapy boost (BB) and external beam radiotherapy (EBRT) dose-escalation on overall survival (OS) for women with cervical cancer receiving postoperative chemotherapy and radiation (CRT) for a positive margin following hysterectomy. MATERIALS AND METHODS: The National Cancer Database (NCDB) was queried from 2004 to 2015 for women with nonmetastatic squamous cell carcinoma or adenocarcinoma of the cervix who had a positive margin following hysterectomy and received postoperative CRT. Patient and treatment characteristics were assessed with multivariate logistic regression. Survival analyses were performed with univariate Cox regression and Kaplan-Meier analyses. Propensity-score weighted cohorts were generated with inverse probability of treatment weighting via generalized boosted regression modeling. RESULTS: Of 630 women receiving CRT, 331 (53%) received EBRT alone and 299 (47%) received EBRT+BB. Eighty-two percent had chemotherapy initiation within 2 weeks of radiation, suggesting concurrent delivery. Median EBRT dose was 5040 cGy. Intracavitary high-dose rate was the most common BB (67%). Inclusion of BB was more likely with larger tumor sizes (odds ratio=1.03, P=0.002). Women receiving EBRT+BB had improved OS compared to EBRT alone for both unweighted (hazard ratio [HR], 0.72; P=0.020) and propensity-score weighted cohorts (HR, 0.70; P=0.017), and this finding was consistent across multiple patient subsets. EBRT dose-escalation >5040 cGy was not found to be associated with OS (unweighted HR, 1.38; P=0.065 and weighted HR, 1.16; P=0.450). CONCLUSION: The addition of BB to standard CRT improved OS for women with cervical cancer and a positive margin after hysterectomy. No consistent survival benefit was seen to EBRT dose-escalation beyond 5040 cGy.

Large database utilization in health outcomes research in pancreatic cancer: an update.

We sought to review published aggregate dataset studies on pancreatic cancer in the national and international settings, discuss the advantages and disadvantages these datasets possess, and possible future directions. A combination of Google Scholar, PubMed, and MEDLINE were used with search terms "pancreatic cancer" + "resectable" + "national cancer database", "pancreatic cancer" + "unresectable" + "national cancer database" and more broadly "borderline resectable pancreatic cancer", "locally advanced pancreatic cancer", "unresectable pancreatic cancer", and "resectable pancreatic cancer". Original articles and abstracts from this search were included, including data from the Surveillance, Epidemiology, and End Results (SEER) database, National Cancer Database (NCDB), and SEER-Medicare within the United States (US), as well as international database studies. Multiple database studies have been published regarding the role for radiotherapy in resected pancreatic cancer (n=6), the timing of additional therapy in resectable pancreatic cancer (n=4), and the role for radiotherapy and resection in locally advanced pancreatic cancer (LAPC) (n=4). Studies from both SEER and NCDB found a survival benefit to post-operative radiotherapy. In resectable pancreatic cancer, neoadjuvant treatment was found to be superior to adjuvant (NCDB). Chemoradiotherapy was found to be more beneficial than chemotherapy alone in LAPC, and patients who received highly-conformal or stereotactic body radiotherapy (SBRT) had improved survival compared to either conformal radiotherapy or chemotherapy alone. These studies also found that up to 10% of patients underwent resection, with a 90% margin-negative rate, and either one-half to one-third the risk of death of non-surgical patients. Criticism of large datasets includes lack of granularity of performance status, diagnosis, treatment, and outcomes-related data compared to properly administered prospective trials, as well as cross-over between treatment arms that cannot be accounted for, and concerns over quality of data represented. The US has witnessed a growing number of comparative effectiveness studies in pancreatic cancer. When taken together, certain themes emerge that are consistent with both single-institution data and clinical trials. These studies have also provided insight into questions not readily answerable by clinical trials. However, they require caution in interpretation.

Combination immunotherapy and radiation therapy strategies for pancreatic cancer-targeting multiple steps in the cancer immunity cycle.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, with its mortality rate approaching its incidence rate every year. Accordingly, much interest has been generated in harnessing the immune system in order to improve survival outcomes for these patients. Pancreatic cancer is not thought to be as immunogenic as other cancers that have seen promising results with immune checkpoint inhibitors alone, therefore likely several targets within the cancer-immunity cycle will need to be employed for successful treatment. We sought to investigate both the current state of the field in immunotherapy in PDAC with a special emphasis on combined approaches with radiation therapy (RT). We also summarized ongoing clinical trials that are examining the use of radiotherapy with other immune-stimulating agents in the treatment of PDAC. A PubMed and clinicaltrials.gov search was conducted using the following search terms, either alone or in combination: "pancreatic cancer", "immunotherapy", and "abscopal effect". Open clinical trials were reviewed and included if they involved both RT and other immune-stimulating agents. Pancreatic cancers tend to reside within immune-suppressive tumor microenvironments (TME), express PD-L1, and secrete several immuno-suppressive agents, such as TGF-B, IL-10, indoleamine 2,3-dioxygenase, galectin-1. Whole-cell vaccine therapies, peptide and protein vaccines, dendritic cell vaccines, and vaccines with micro-organisms have been investigated by themselves with promising results. Open clinical trials are currently investigating the use of these vaccines, which increase antigen presentation, with treatments that stimulate release of tumor antigens including RT. There are currently at least 21 open clinical trials investigating the combination of RT with other immune-stimulating agents. The combination of RT and immunotherapy may be a promising avenue for PDAC treatment and deserves further research.

Value of surgical resection and timing of therapy in patients with pancreatic cancer at high risk for positive margins.

BACKGROUND: Surgical resection remains the best chance at long-term survival in pancreatic cancer, though margin-positive resections are associated with diminished survival. We examined the effect of margin-positive resection on survival, as well as the role and timing of additional therapies through the National Cancer Database (NCDB). PATIENTS AND METHODS: Patients with stage IIA-III pancreatic adenocarcinoma diagnosed from 2004 to 2013 were identified in NCDB. Survival was compared using univariate and multivariate Cox proportional hazards modelling for patients who underwent surgery with negative (R0), microscopically positive (R1) and macroscopically positive (R2) margins or non-surgical treatment. We further analysed patients by margin status, timing of additional therapy (neoadjuvant therapy (NAT) vs adjuvant therapy (AT) vs none) and clinical stage. RESULTS: We analysed 44 852 patients. Median survival (MS) for patients who did not undergo surgery was 10.3 months, compared with 19.7 months for R0 (P<0.001), 14.3 months for R1 (P<0.001) and 9.8 months (P=0.07) for R2 resections. NAT (MS 23.2 months) was associated with improved survival compared with AT (MS 21.5 months) in negative-margin patients and equivalent (MS 17.6 months) to AT (MS 16.8 months) in positive-margin patients. Survival for stage III NAT positive-margin patients (MS 19.8 months) was equivalent to AT after negative margins (MS 18.4 months, P=1.00). Improved R0 rates were seen with NAT (88% vs 81%, P<0.001), especially in stage III patients (85% vs 59%, P<0.001). CONCLUSION: R1 resections portend poorer survival than R0 but do not negate the benefit of surgery when additional therapy is given. NAT was associated with improved R0 rates and improved survival for stage III positive-margin patients.

Hypoxia imaging in upper gastrointestinal tumors and application to radiation therapy.

Survival for upper gastrointestinal tumors remains poor, likely in part due to treatment resistance associated with intratumoral hypoxia. In this review, we highlight advances in nuclear medicine imaging that allow for characterization of in vivo tumor hypoxia in esophageal, pancreatic, and liver cancers. Strategies for adaptive radiotherapy in upper gastrointestinal tumors are proposed that would apply information gained through hypoxia imaging to the creation of personalized radiotherapy treatment plans able to overcome hypoxia-induced treatment resistance, minimize treatment-related toxicities, and improve patient outcomes.