INTRODUCTION
Pancreatic cancer remains a deadly disease, with its mortality rate (n 5 41,780) estimated to approach its incidence rate (n 5 53,070) in 2016. 1 The majority of patients die from metastatic disease, although 30% of patients may die from local tumor progression, providing a potential opportunity for enhanced local control to improve survival in these patients. 2 Advances in chemotherapy (CT) have improved the median survival of patients with metastatic pancreatic cancer 3, 4 and locally advanced pancreatic cancer (LAPC). 5 However, long-term survival remains dismal, and very few patients with LAPC live for more than 5 years. 6 The role of radiotherapy in LAPC, defined as nonmetastatic, unresectable disease, remains a challenge. Results from past randomized clinical trials have been mixed, with the most recent randomized clinical trial, LAP-07, failing to demonstrate a survival benefit for chemoradiation (CRT) compared with CT alone. 7 Criticism of these trials has included the use of single-agent CT, 7, 8 outdated or excessively toxic chemotherapy, [9] [10] [11] [12] antiquated or excessively toxic radiation techniques, 11, 13 and patients with different disease sites and stages. 9 However, retrospective series have reported an improvement in survival when patients receive multiagent induction CT followed by CRT. 14, 15 In this study, we sought to examine whether CRT is associated with a survival benefit compared with CT alone in patients with LAPC. We also examined whether the timing of chemotherapy and radiation (induction followed by concurrent vs concurrent only) and the number of chemotherapy agents (single vs multiple) were relevant to survival. Finally, we sought to quantify the survival of patients with LAPC who undergo surgical resection after either CT alone or CRT. To our knowledge, this is the first study to use aggregated hospital registry data to compare the effects of CT only versus CRT in patients with LAPC.
MATERIALS AND METHODS
Patient data were obtained from the National Cancer Data Base (NCDB), a joint program of the Commission on Cancer and the American Cancer Society, which includes data from approximately 1500 hospitals and clinics in the United States and its territories. This database captures nearly 70% of new cancer diagnoses made in the United States. 16 All NCDB data are de-identified and thus are exempt from institutional review board review.
MATERIALS AND METHODS
The initial query included all patients who were diagnosed with pancreatic cancer between the years 2004 and 2014, which yielded 309,709 patients. Patients were excluded if they were metastatic at presentation, resectable or borderline resectable, or had unknown staging or resectability status (n 5 285,089). To be considered unresectable, both an American Joint Committee on Cancer (AJCC) seventh edition tumor classification of T4 (clinical stage III) and inseparability from the celiac artery, superior mesenteric artery, or more proximal vasculature were required. We further excluded patients with histology other than adenocarcinoma or unknown histology (n 5 2765), those who were lacking information on the receipt of CT (n 5 809) or radiation (n 5 15), and who underwent surgery first or had an unknown surgical sequence (n 5 1020). Patients were excluded if no CT was received (n 5 6159), if the site treated with radiation was not the pancreas (n 5 1124), if the radiation was not external beam alone (n 5 417), and if the dose was 3000 centigray (cGy) (palliative doses) or >7000 cGy (unrealistic doses; n 5 1646). Patients were excluded if survival time was not known or if it was <3 months after diagnosis (n 5 1976).
MATERIALS AND METHODS
The primary outcome variable was survival after the receipt of either CT alone or CRT. Patients in the CT group received CT only as their first course of treatment. Those in the CRT group could receive either induction CT (iCRT), defined as CT that was started 120 to 31 days before CRT, or concurrent chemoradiation (cCRT), defined as CT and radiation starting within 30 days of each other. Chi-square analysis was used to compare demographic, tumor, and treatment characteristics between the 2 groups. The demographic factors examined included sex, age, race, insurance group, facility type, census region, income, percentage of residents without a high school degree, distance from the treatment facility, and urban density. The clinical characteristics examined included Charlson comorbidity score, lymph node status at diagnosis, tumor size, and tumor location. Tumor grade was not reported in 77% of patients, so it was not analyzed as a variable. Treatment characteristics included multiple agents versus single-agent CT, CRT sequence (induction vs concurrent), radiation dose >5400 cGy or <5400 cGy, surgery performed (no surgery or local procedure vs pancreatectomy), margin status (negative, positive microscopic, positive macroscopic), and the number of positive lymph nodes at the time of surgery.
MATERIALS AND METHODS
Univariate and multivariate Cox proportional hazards models were then used to analyze the association between CRT and the risk of death as well as other demographic, tumor, and treatment factors that may be predictive of survival. Factors with P values .2 were included in the multivariate model. A P value .05 was required for significance on multivariate analysis. Propensity score analysis was performed to correct for baseline differences between the CT and CRT groups. [17] [18] [19] [20] A matching algorithm including the variables that differed between the 2 treatment groups was used. Propensity scores were generated, and the measured covariates between the groups were balanced. A shared frailty univariate Cox regression was performed on the matched groups to estimate the benefit of CRT therapy.
MATERIALS AND METHODS
Subgroup analyses were then undertaken to determine whether certain groups had improved survival relative to others. Survival was compared through Cox proportional hazards modeling for patients who underwent surgery versus those who did not and for patients who received different combinations of CRT (induction, concurrent, single agent, multiagent) and CT alone (single, multiagent). Univariate analysis (UVA) and multivariate analysis (MVA) were then repeated for these treatment groups to further verify the survival benefit. All analyses were performed using the STATA 14.0 statistical package (Stata Corporation, College Station, Tex).
RESULTS
After all appropriate exclusions had been made, 8689 patients with unresectable LAPC were available for the current analysis (see Table 1 ). There were 4487 patients in the CT group and 4202 in the CRT group. Patients in the CRT group were more likely to be men (51% vs 48%), aged <70 years (67% vs 58%), and to have a Charlson comorbidity score of 0 (74% vs 71%). Treatment characteristics varied: patients in the CRT group were more likely to receive single-agent CT (55% vs 46%; P < .001) and to undergo surgery after initial treatment (6% vs 2%; P < .001). The CRT group also had a slightly higher rate of negative margins after surgery and negative lymph nodes at the time of resection (see Table 1 ).
RESULTS
Treatment with CRT was associated with a decreased risk of death on both UVA and MVA (hazard ratio 0.76-0.84). Median survival was 13.5 months for the CRT group versus 10.6 months for the CT group (Fig.  1 ). This was confirmed by shared frailty analysis (HR, 0.72; P < .001; 95% CI, 0.67-0.77). The 1-year overall survival rate was 46.2% for CT only (95% CI, 44.7%-47.6%) versus 59% (95% CI, 57.5%-60.5%) for CRT; and the 2-year overall survival rate was 16.7% (95% CI, 15.6%-17.8%) versus 20.6% (95% CI, 19.4%-21.9%), respectively. The 5-year overall survival rate did not differ between the 2 joy03@example.net% (95% CI, 5.6%-7%) versus 5.8% (95% CI, 5.1%-6.6%), respectively.
RESULTS
On MVA, large tumor size (HR, 1.15; P 5 .04; 95% CI, 1.01-1.30) and positive lymph nodes at diagnosis (HR, 1.12; P < .001; 95% CI, 1.06-1.18) were associated with an increased risk of death (see Table 2 ). Multiagent CT was associated with a decreased risk of death compared with single-agent CT (HR, 0.72; P < .001; 95% CI, 0.69-0.76). In the CRT group, iCRT was associated with a decreased risk of death on MVA compared with cCRT (HR, 0.67; P < .001; 95% CI, 0.62-0.72) ( Table 2) . On subgroup analysis, median survival was 12 months for cCRT and 16.6 months for iCRT, and a long-term survival benefit was observed: with 5-year overall survival rates of 9.2% (95% CI, 7.7%-11%) compared with 4.3% (95% CI, 3.6%-5.2%), respectively. Nine percent of patients who received iCRT were able to undergo surgery compared with 4.8% of patients who received cCRT.
RESULTS
Patients were then separated into 6 different cohorts according to radiation administration, timing, and the number of CT agents used (see Table 3 and Fig. 2 ). Multiagent CT (median survival, 12.4 months) was superior to single-agent cCRT (HR, 1.18; P < .001; 95% CI, 1.10-1.26) in terms of both short-term and long-term survival (5 year overall survival, 8.5% vs 4%). Multiagent iCRT was superior to multiagent CT (17.5 vs 12.4 months; HR, 0.80; P < .001) in terms of median and short-term survival (2-year overall survival: 32.9% vs 21.4%), but the CIs overlapped for 5-year overall survival. The strongest predictor for survival was the ability to undergo pancreatectomy compared with either no surgery or a more local procedure (HR, 0.39; P < .001; 95% CI, 0.34-0.46). Patients with LAPC who underwent pancreatectomy had significantly improved survival compared with those who did not (22 vs 10.6 months) (Fig. 3) , with a 1-year overall survival rate of 80.1% (95% CI, 75.9%-83.7%) versus 45.3% (95% CI, 44.4%-46.2%), a 2-year overall survival rate of 50% (95% CI, 44.8%-54.7%) versus 15% (95% CI, 14.7%-16.1%), and a 5-year overall survival rate of 20.6% (95% CI, 16.6%-24.9%) versus 5% (95% CI, 4.6%-5.4%), respectively. Positive pathologic lymph node status in those patients who proceeded to definitive resection was not significantly predictive of survival. Multiagent iCRT improved the resection rate (9.8%) compared with cCRT (5%) or multiagent CT alone (3.3%).
DISCUSSION
The current data indicate that CRT is associated with a survival benefit compared with CT alone in the treatment of LAPC, although the absolute benefit is small. However, an inherent condition to this strategy is that the value of local control is greatest when systemic therapy is maximized and patients who progress distantly through maximized therapy are not treated locally. Thus, the highest median survival occurred when patients received multiagent iCRT. Five-year survivorship was improved in this Abbreviations: cCRT, concurrent chemoradiation; CI, confidence interval; CRT, chemoradiation; CT, chemotherapy alone; HR, hazard ratio; iCRT, induction chemotherapy followed by chemoradiation. group compared with those who received single-agent CT alone and those in both cCRT groups. Conversely, a survival detriment was observed when patients who received cCRT with a single agent were compared with those who received multiagent CT only. Patients who underwent pancreatectomy after receiving either CT or CRT had a 5-year overall survival rate of 20.6%, which was double that of their peers in the most selective cohort (multiagent iCRT). The great majority of those patients underwent complete (R0) resection (85% of patients in the CT group and 87% in the CRT group). Patients were most likely to proceed to pancreatectomy if they received multiagent, induction CRT (9.8%) compared with other cohorts. Taken together, these data suggest that the optimal regimen for LAPC is induction CT with multiple agents followed by CRT. These data are concordant with retrospective analyses from patients with LAPC who received multiagent iCRT in phases 2 and 3 of the French Cooperative Multidisciplinary Oncology Group (GERCOR) study. 14 In both of these studies, patients who had stable disease after induction CT (3 of 4 arms received multiagent CT) could receive CRT or continue CT at the discretion of the treating physician. Patients who received CRT had increased survival compared with those who continued CT (15 vs 11.7 months; P 5 .009).
DISCUSSION
14 The LAP-07 trial failed to demonstrate an improvement in survival when CRT was added to induction CT with only a single agent. 7 Krishnan et al reported that, after induction CT, CRT improved survival compared with CT alone. 15 The increasing benefit observed in patients who received multiagent CT is consistent with the trials demonstrating that multiagent CT (ie, combined folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin [FOLFIRINOX] or gemcitabine and albumin-bound paclitaxel) was superior to single-agent CT in the metastatic setting. 3, 4 Indeed, this hypothesis is currently being tested in Europe in the SCA-LOP2 study (Systemic Therapy and Chemoradiation in Advanced Localized Pancreatic Cancer-2; clinicaltrials. gov identifier NCT02024009).
DISCUSSION
In our analysis, even the most selective CRT cohorts (multiagent iCRT) had a dismal long-term survival, with <10% of patients living beyond 5 years. However, if these patients were able to undergo pancreatectomy, then their survival mirrored that of patients who had early stage pancreatic cancer at 5 and even 10 years, which confirms the possibility of long-term survival. These findings are concordant with the LAP-07 trial, which demonstrated that, of the 4% of patients who were able to undergo pancreatectomy, median survival was double that of patients who did not proceed to surgery. 7 This has also been observed in other reported series. 22 The use of multiagent iCRT improved not only overall survival, presumably through the optimization of distant disease control, but also improved local disease management, ultimately increasing the proportion of patients able to undergo pancreatectomy to 9.8%. This is concordant with retrospective series and past randomized clinical trials, 15, 22 although some retrospective studies have suggested that, with improved systemic regimens, approximately 22% of patients may become resectable. [23] [24] [25] Ferrone et al further raised the issue that imaging alone may not be enough to declare unresectability. 26 Forty patients with unresectable pancreatic cancer who received neoadjuvant, multiagent CT (FOLFIRINOX) and radiation underwent resection with a 92% R0 resection rate, although almost one-half had been deemed unresectable by imaging after initial treatment. Truty et al and Huguet and colleagues reported similar findings with CRT. 27, 28 It is important to note that, in the recently published European Study Group for Pancreatic Cancer-4 (ESPAC-4) study, upfront resection led to positive margins in 60% of patients. 29 The high rates of R0 resection in that analysis are consistent with historical data indicating that <10% of patients have positive margins after receiving neoadjuvant CT or CRT. 30 In a singleinstitutional experience, the rates of resection after preoperative CT increased over time for patients who had borderline and LAPC, although local recurrence rates remained the same, and overall survival improved. 31 These findings taken together suggest a burgeoning role for surgical resection after maximal systemic and local therapy.
DISCUSSION
This study has important limitations inherent to the large, multi-institutional registry data used. Performance status, symptoms, and palliative interventions are not addressed within NCDB. This may introduce selection bias, in that patients with minimal disease burden and those with excellent performance status may have received the most aggressive treatments because of their ability to tolerate them. Therefore, the prolonged survival identified within the more aggressive treatment cohorts (multiagent iCRT) may not be caused by inherent advantages of the treatment delivered but, rather, by patient joy03@example.net. In addition, it is plausible that some patients in the CT group were not deemed candidates for locoregional therapy because of equivocal findings at presentation that were suspicious, but not definitive, for metastatic disease. They may have also had other features indicating an overall poor prognosis, including elevated Figure 2 . Overall survival is illustrated, including (Top) optimal chemotherapy (CT) versus suboptimal chemoradiation (CRT), (Middle) suboptimal CT versus optimal CRT, and (Bottom) optimal CT versus optimal CRT. cCRT indicates concurrent CRT; iCRT, induction CT followed by CRT; MS, median survival; CTM, multi-agent chemotherapy; CTS, single agent chemotherapy; MAI, multiagent induction chemotherapy followed by CRT; SAC, single agent concurrent chemoradiotherapy. 
Cancer
October 1, 2017 levels of cancer antigen 19-9 (CA 19-9), which were not reported in this data set. Elevated levels of CA 19-9 are associated with decreased resectability, a worse response to chemotherapy, and an overall poor prognosis. 32 The NCDB also lacks information on tumor biomarkers such as SMAD family member 4 (SMAD-4), which, when intact, is predictive of a local rather than distant pattern of recurrence compared with patients whose have lost SMAD-4. 33, 34 It is hypothesized that patients with SMAD-4 deletions are less likely to benefit from CRT. However, the predictive value of this biomarker will need to be tested in randomized studies.
Cancer
Finally, a significant proportion of patients, up to 40% in some series, will progress distantly or otherwise decompensate through systemic therapy and thus will not be eligible for locoregional therapy. 7 Although this is accounted for in clinical trials, it is not accounted for in the NCDB, because patients are classified only by their initial disease stage and treatment regimen. Attempts were made to account for early progression and subsequent deterioration, because patients who died <3 months from diagnosis were excluded from the analysis. This exclusion clearly does not account for all cases of early progression and deterioration, and it is likely that the diminished overall survival observed in the CT group was affected by the inclusion of patients who, because of disease progression, were not candidates for consolidative radiation therapy. The opposite is also true, however. Patients who originally were destined for treatment with CT alone may have had local progression requiring the addition of radiation. These patients would ultimately be coded as having received single-agent/multiagent iCRT. The extent to which local progression was the reason patients who initially received CT alone went on to receive CRT is unknown. However, the finding that adding CRT was associated with a benefit indicates that, even with some amount of local progression, the iCRT group had a better prognosis, which further develops the hypothesis that local therapy is still beneficial to those patients who have local progression only.
Cancer
Another limitation of this analysis is that the CT agents are not individually identified within the NCDB. Along these lines, when induction CT is followed by CRT, it is not known whether the same CT was continued through radiation. Challenges also exist in analyzing radiation therapy; although the dose of radiation was specified, it is likely that both target volumes and dose constraints varied from institution to institution and evolved over the 10-year period that these data were gathered. Randomized data seem to support a potentially detrimental impact on overall survival from nonconformal, dose-escalated radiation therapy, 12 and our inability to account for radiation technique may mask a benefit to dose escalation. Toxicity data were not available for either the CT or radiotherapy group, so it is unknown whether the survival benefit came at the cost of substantially increased toxicity. Finally, although the criteria for inclusion were strictly patients who had both AJCC T4 tumors and encasement of major vessels, this assessment was made within individual institutions, and it is probable that some of these patients had disease that more closely resembled borderline resectable pancreatic cancer. Such patients may have comprised the small cohort that subsequently proceeded to pancreatectomy.
Cancer
The strength of this study is 2-fold. First, within the NCDB, LAPC can be specifically identified by the AJCC T4 designation and a subsequent modifier identifying vessel encasement. Second, the study has ample statistical power: we were able to analyze 8689 patients from across the United States, representing multiple different demographics, tumor characteristics, and treatment methods over a 10-year period. These patients were also likely a mix of various symptomatology and performance status and were treated by physicians whose practice patterns and beliefs varied. We believe that, although the unknown variables like performance status and palliative interventions create some uncertainty, the high power and variety of demographic characteristics add to the validity of this study.
CONCLUSION
In this NCDB analysis, CRT was associated with improved survival relative to CT alone in patients with LAPC. The best outcomes were identified in patients who received multiagent iCRT, with superior overall survival and an increased likelihood of proceeding to pancreatectomy. This suggests a role for aggressive, up-front, systemic therapy followed by consolidative local therapy to the primary site in those patients who do not progress distantly through induction CT. Of patients the whose disease became resectable and underwent surgery, outcomes were further improved and paralleled the overall survival outcomes identified in patients with initially resectable disease. Given previously mixed evidence about the role of radiation therapy in the treatment of LAPC, further randomized investigation of its role is warranted given the improved efficacy of current multiagent systemic therapy.
FUNDING SUPPORT
No specific funding was disclosed.

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