This cohort study describes patterns of adjuvant chemotherapy use in patients 80 years and older following surgical resection of pancreatic ductal adenocarcinoma and to compare overall survival of patients who received AC vs those who did not.
Key Points
Question
Among patients 80 years and older, is adjuvant chemotherapy following pancreaticoduodenectomy for pancreatic cancer associated with better survival?
Finding
In this cohort study of 2569 patients 80 years and older who underwent pancreaticoduodenectomy for pancreatic cancer between 2004 and 2016, 47.4% received adjuvant chemotherapy. Median overall survival was significantly longer in the adjuvant chemotherapy group across the overall cohort, the propensity-matched cohort, and all subgroups.
Meaning
Adjuvant treatment paradigms need to be further explored for patients 80 years and older with PDAC, as there seems to be a group of patients who could benefit from curative intent with surgery and chemotherapy.
Abstract
Importance
Patients 80 years and older with pancreatic ductal adenocarcinoma (PDAC) have not consistently received treatments that have established benefits in younger older adults (aged 60-79 years), yet patients 80 years and older are increasingly being offered surgery. Whether adjuvant chemotherapy (AC) provides additional benefit among patients 80 years and older with PDAC following surgery is not well understood.
Objective
To describe patterns of AC use in patients 80 years and older following surgical resection of PDAC and to compare overall survival between patients who received AC and those who did not.
Design, Setting, and Participants
Retrospective cohort study among patients 80 years or older diagnosed with PDAC (stage I-III) between 2004 to 2016 who underwent a pancreaticoduodenectomy at hospitals across the US reporting to the National Cancer Database.
Exposures
AC vs no AC 90 days following diagnosis of PDAC.
Main Outcomes and Measures
The proportion of patients who received AC was assessed over the study period. Overall survival was compared between patients who received AC and those who did not using Kaplan-Meier estimates and multivariable Cox proportional hazards regression. A landmark analysis was performed to address immortal time bias. A propensity score analysis was performed to address indication bias. Subgroup analyses were conducted in node-negative, margin-negative, clinically complex, node-positive, and margin-positive cohorts.
Results
Between 2004 and 2016, 2569 patients 80 years and older (median [IQR] age, 82 [81-84] years; 1427 were women [55.5%]) underwent surgery for PDAC. Of these patients, 1217 (47.4%) received AC. Findings showed an 18.6% (95% CI, 8.0%-29.0%; P = .001) absolute increase in the use of AC among older adults who underwent a pancreaticoduodenectomy comparing rates in 2004 vs 2016. Receipt of AC was associated with a longer median survival (17.2 months; 95% CI, 16.1-19.0) compared with those who did not receive AC (12.7 months; 95% CI, 11.8-13.6). This association was consistent in propensity and subgroup analyses. In multivariable analysis, receipt of AC (hazard ratio [HR], 0.72; 95% CI, 0.65-0.79; P < .001), female sex (HR, 0.88; 95% CI, 0.80-0.96; P < .001), and surgery in the more recent time period (≥2011) (HR, 0.90; 95% CI, 0.82-0.99; P = .02) were associated with a decreased hazard of death. An increased hazard of death was associated with higher pathologic stage (stage II: HR, 1.68; 95% CI, 1.43-1.97; P < .001; stage III: HR, 2.39; 95% CI, 1.88-3.04; P < .001), positive surgical margins (HR, 1.49; 95% CI, 1.34-1.65; P < .001), length of stay greater than median (10 days) (HR, 1.17; 95% CI, 1.07-1.28; P < .001), and receipt of oncologic care at a nonacademic facilities (Community Cancer Program: HR, 1.20; 95% CI, 1.07-1.35; P < .001; Integrated Network Cancer Program: HR, 1.25; 95% CI, 1.07-1.46; P < .001).
Conclusions and Relevance
In this cohort study, the use of AC among patients who underwent resection for PDAC increased over the study period, yet it still was administered to fewer than 50% of patients. Receipt of AC was associated with a longer median survival.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths in the US, with an overall 5-year survival rate of 8% to 10%.1,2 Older adults are the fastest growing demographic in the US, with adults aged 65 years and older predicted to account for more than 20% of the population by 2040.3 This demographic shift will exponentially increase the number of newly diagnosed patients 80 years and older with cancer and cancer survivors.4 It is imperative that our treatment approach considers this growing population of patients with pancreatic cancer, as well as their evolving ability to tolerate therapy.
Surgical resection remains the only potential cure for PDAC; however, less than 15% to 25% of patients present with resectable disease. Historically, surgery was not offered to patients 80 years and older. Less than 20% to 35% of older patients with resectable tumors had curative surgery, and those who did undergo surgery had increased perioperative morbidity.5,6,7 In the past 2 decades, there have been significant reductions in perioperative morbidity and mortality for all patients following pancreaticoduodonectomy.8,9,10,11,12,13 Chemotherapy options have also improved, with several randomized clinical trials showing a survival benefit of adjuvant chemotherapy (AC) for resectable PDAC.12,13,14,15 While some of these trials describe the proportion of patients older than 65 years, ie, 62% in the CONKO-001 phase 3 trial,14 the representation of patients 80 years and older is not well described. Furthermore, national rates of AC use remain about 60% for all patients with PDAC16 and are even lower for those older than 80 years (approximately 30%-40%).17,18
Given the paucity of data, understanding national patterns and outcomes of AC use in patients 80 years and older can help inform future treatment strategies. Using the National Cancer Database (NCDB), we sought to answer 3 key questions. First, what are the trends in AC use among patients 80 years and older who underwent surgery for pancreatic cancer? Second, what are the characteristics of patients who underwent AC? Finally, was the use of AC associated with a survival benefit among patients 80 years and older who underwent surgery?
Methods
Cohort Selection
The NCDB is a collaboration between the American Cancer Society and the American College of Surgeons’ Commission on Cancer established in 1989. It captures approximately 70% of new cancer diagnoses in the US from 1500 Commission on Cancer–approved facilities. Data from 2004 to 2016 were obtained from the NCDB pancreas participant use file. This study was deemed exempt by the Brigham and Women’s Hospital Institutional Review Board (IRB2017P000360) because the data were deidentified, and thus the need for consent was also waived.
Study Population
Patients 80 years or older diagnosed with PDAC (International Classification of Diseases for Oncology, Third Edition [ICD-O-3] histology codes 8140 and 8500)19 who underwent a pancreaticoduodenectomy as designated in the NCDB primary surgical site variable (rx_summ_surg_prim_site: C35-C37 and C70) for American Joint Committee on Cancer 8th edition pathologic stage I to III disease were identified.20 Patients were excluded if they received neoadjuvant chemotherapy and if they initiated chemotherapy after 6 months of diagnosis, to identify primary rather than salvage chemotherapy (Figure 1).
Figure 1. CONSORT Diagram of the Study Population.
PDAC indicates pancreatic ductal adenocarcinoma.
Variables
To address our first question, the number of patients 80 years and older who underwent pancreaticoduodenectomy for PDAC and the proportion of patients who underwent AC were identified. To address our second and third question, our predictor variable was AC defined as single-agent or multiagent therapy within the NCDB. Our primary outcome was overall survival, which was calculated as time from 90 days after diagnosis until death or last known follow-up. Using this landmark time point of 90 days and excluding patients who died within 90 days of diagnosis enabled accounting for immortal time bias.21 The 90-day landmark was chosen because most patients have recovered from surgery at this time point and are candidates for initiation of adjuvant therapy.22,23 The 90-day landmark is accounted for in the overall, median, and 5-year survival estimates reported.
Additional demographic and clinical covariates were examined to adjust for confounding: age at diagnosis, sex, race, ethnicity, income (dichotomized as less than or equal to the median income for each patient’s area of residence in the year of diagnosis or those greater than the median income), insurance status, Charlson/Deyo24 comorbidity score (dichotomized as patients with <1 reported mapped comorbid condition or those with ≥1 mapped comorbid conditions), length of stay (LOS) on index surgical admission (dichotomized as less than or equal to the median or greater than the median), American Joint Committee on Cancer tumor stage (8th edition),20 facility location, facility type, and time period of surgery (dichotomized as before 2011 or after and including 2011).
Statistical Analysis
The use of AC among patients 80 years and older with resected PDAC was examined. Characteristics of patients who had AC were compared with those who did not, using the Fisher exact test or 2-sided t test for categorical and continuous variables, respectively. Kaplan-Meier estimates and Cox proportional hazards regression models were used for survival analyses. Covariates for our multivariable model were selected based on clinical relevance and those that had P < .10 on the univariate analysis. Goodness of fit of the final multivariable Cox model was verified with Cox-Snell residuals.25
A propensity score analysis was performed to address indication bias associated with receipt of chemotherapy (eMethods in the Supplement). After propensity score matching, the association of chemotherapy and overall survival was examined with Kaplan-Meier estimates and Cox multivariable regression models.
Subgroup analyses were conducted in a pathologically less advanced cohort, a clinically complex cohort, and a pathologically advanced cohort (eMethods in the Supplement). The association between chemotherapy and survival was also explored using a time-varying covariate Cox multivariable regression model; P values less than .05 were considered significant. Data were analyzed using Stata, version 16.0 (StataCorp LLC). This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Results
Between 2004 and 2016, 2569 patients 80 years and older (median [IQR] age, 82 [81-84] years; 1427 were women [55.5%]) underwent a pancreaticoduodenectomy for PDAC. Of these patients, 1217 (47.4%) received AC. Findings showed an 18.6% (95% CI, 8.0%-29.0%; P = .001) absolute increase in the use of AC among older adults who underwent a pancreaticoduodenectomy comparing rates in 2004 vs 2016 (Figure 2). Of the patients who had AC, 906 (74.4%) had single-agent chemotherapy therapy, 214 (17.6%) had multiagent therapy, and 97 (8.0%) had unknown regimens.
Figure 2. Patterns of Adjuvant Chemotherapy Use Among Patients 80 Years and Older Who Underwent Surgery for PDAC (2004-2016).
PDAC indicates pancreatic ductal adenocarcinoma.
Association Between AC and Overall Survival in the Overall Cohort
Patients who received AC were less likely to be female (51.4% vs 59.3; P < .001), had higher pathological stage (stage IIB: 68.1% vs 56.7%; P < .001; stage III: 5.3% vs 4.2%; P < .001), more likely to have positive surgical margins (24.2% vs 20.1%; P = .03), less likely to have an index surgical admission LOS greater than the median (10 days) (31.7% vs 51.6%; P < .001), and more likely to receive treatment in the Mid-Atlantic region (24.4% vs 21.1%; P < .001) compared with those who did not receive chemotherapy (Table; eTable 1 in the Supplement). Median number of days from diagnosis to start of chemotherapy was 82 days (95% CI, 79-84). Of the 1217 patients who received chemotherapy, 43.7% (532) initiated chemotherapy after 90 days from diagnosis. At a median follow-up of 14.4 months, the median overall survival of the cohort was 15.0 months (95% CI, 14.1-15.7). Receipt of AC was associated with a longer median survival (17.2 months; 95% CI, 16.1-19.0) compared with those who did not receive chemotherapy (12.7 months; 95% CI, 11.8-13.6; log-rank P < .001) (Table, Figure 3A). Five-year overall survival rate was also increased, 15.2% vs 10.9% for patients who received AC vs those who did not receive chemotherapy (log-rank P < .001).
Table. Characteristics of Patients 80 Years and Older Who Underwent Surgery for Pancreatic Adenocarcinoma (2004-2016).
| Characteristic | Overall cohort | Propensity-matched cohort | ||||
|---|---|---|---|---|---|---|
| No chemotherapy (n = 1352 [52.6%]) | Chemotherapy (n = 1217 [47.4%]) | P value | No chemotherapy (n = 934 [50%]) | Chemotherapy (n = 934 [50%]) | P value | |
| Age, median (IQR), y | 82 (81-85) | 82 (81-83) | <.001 | 82 (81-84) | 82 (81-84) | .08 |
| Sex | ||||||
| Female | 802 (59.3) | 625 (51.4) | <.001 | 519 (55.6) | 535 (57.3) | .46 |
| Male | 550 (40.7) | 592 (48.6) | 415 (44.4) | 399 (42.7) | ||
| Race and ethnicity | ||||||
| Asian | 40 (3.0) | 29 (2.4) | .46 | 30 (3.2) | 26 (2.8) | .75 |
| Black | 129 (9.5) | 111 (9.1) | 85 (9.1) | 94 (10.1) | ||
| Hispanic | 52 (3.9) | 40 (3.3) | 27 (2.9) | 32 (3.4) | ||
| White | 1107 (81.9) | 1021 (83.9) | 776 (83.1) | 772 (82.7) | ||
| Othera | 8 (0.6) | 9 (0.7) | 6 (0.6) | 3 (0.3) | ||
| Missing | 16 (1.2) | 7 (0.6) | 10 (1.1) | 7 (0.8) | ||
| Charlson/Deyo score | ||||||
| 0 | 862 (63.8) | 799 (65.7) | .32 | 595 (63.7) | 597 (63.9) | .92 |
| ≥1 | 490 (36.2) | 418 (34.4) | 339 (36.3) | 337 (36.1) | ||
| Length of stay | ||||||
| <Median (10 d) | 560 (41.4) | 674 (55.4) | <.001 | 460 (49.3) | 481 (51.5) | .31 |
| ≥Median | 697 (51.6) | 386 (31.7) | 388 (41.5) | 384 (41.1) | ||
| Missing | 95 (7.0) | 157 (12.9) | 86 (9.2) | 69 (7.4) | ||
| AJCC stage | ||||||
| Stage I | 170 (12.5) | 63 (5.2) | <.001 | 66 (7.1) | 63 (6.8) | .65 |
| IA | 68 (5.0) | 18 (1.5) | 30 (3.2) | 18 (1.9) | ||
| IB | 102 (7.5) | 45 (3.7) | 36 (3.9) | 203 (21.7) | ||
| Stage II | 1125 (83.2) | 1089 (89.5) | 819 (87.7) | 830 (88.9) | ||
| IIA | 359 (26.6) | 260 (21.4) | 266 (28.4) | 203 (21.7) | ||
| IIB | 766 (56.7) | 829 (68.1) | 553 (59.3) | 627 (67.1) | ||
| Stage III | 57 (4.2) | 65 (5.3) | 49 (5.3) | 41 (4.4) | ||
| Margin | ||||||
| R0 | 1055 (78.0) | 896 (73.6) | .03 | 703 (75.3) | 711 (76.1) | .73 |
| R1 or R2 | 272 (20.1) | 295 (24.2) | 217 (23.2) | 206 (22.1) | ||
| Missing | 25 (1.9) | 26 (2.1) | 14 (1.5) | 17 (1.8) | ||
| Time period 2011 or later | 711 (52.6) | 720 (59.2) | .001 | 511 (54.7) | 522 (55.9) | .61 |
Abbreviation: AJCC, American Joint Committee on Cancer.
Other includes Pacific Islander, American Indian, and NOS (not otherwise specified).
Figure 3. Survival Differences Associated With the Use of Adjuvant Chemotherapy in Patients 80 Years and Older Following Surgery for PDAC (2004-2016).
HR indicates hazard ratio; mOS, median overall survival; OS, overall survival; PDAC, pancreatic ductal adenocarcinoma.
In multivariable analysis, receipt of AC (hazard ratio [HR], 0.72; 95% CI, 0.65-0.79; P < .001), female sex (HR, 0.88; 95% CI, 0.80-0.96; P < .001), and surgery in the more recent time period (≥2011) (HR, 0.90; 95% CI, 0.82-0.99; P = .02) were associated with a decreased hazard of death. An increased hazard of death was associated with higher pathologic stage (stage II: HR, 1.68; 95% CI, 1.43-1.97; P < .001; stage III: HR, 2.39; 95% CI, 1.88-3.04; P < .001), positive surgical margins (HR, 1.49; 95% CI, 1.34-1.65; P < .001), LOS greater than median (10 days) (HR, 1.17; 95% CI, 1.07-1.28; P < .001), and receipt of oncologic care at a nonacademic facilities (Community Cancer Program: HR, 1.20; 95% CI, 1.07-1.35; P < .001; Integrated Network Cancer Program: HR, 1.25; 95% CI, 1.07-1.46; P < .001) (eTable 2 in the Supplement). The plot of the cumulative hazard vs Cox-Snell residual approximates a straight line, indicating a good fit.
Association Between AC and Overall Survival in the Matched Cohort
The propensity-matched cohort included 1868 patients, of which 934 (50%) received AC. Previously observed differences between patients who did not receive AC and those who did receive AC with respect to age, sex, income, index surgery LOS, pathologic stage, margin status, region, and time period of therapy were successfully balanced between groups after matching (Table; eFigure 1 in the Supplement). The low number of patients who received radiation therapy among patients who did not receive chemotherapy precluded balancing between groups without losing a large amount of the sample. However, given that a survival benefit has not been reliably associated with radiation therapy in localized PDAC, we do not believe this will influence our results.26,27,28
At a median follow-up of 14.6 months, the median overall survival of the propensity-matched cohort was 15.3 months (95% CI, 14.2-16.1). Receipt of AC was associated with a longer median survival (17.2 months; 95% CI, 16.0-19.2) compared with those who did not receive AC (12.8 months; 95% CI, 11.7-14.1; log-rank P < .001) (Figure 3B) and an increased 5-year overall survival rate, 14.6% vs 11.0% for patients who received AC vs those who did not receive chemotherapy, respectively (log-rank P < .001).
In multivariable analysis, results in the propensity-matched cohort were similar to the overall cohort; receipt of chemotherapy (HR, 0.74; 95% CI, 0.67-0.83; P < .001) and female sex were associated with a decreased hazard of death (HR, 0.85; 95% CI, 0.77-0.94; P < .001). Similarly, higher pathologic stage (stage II: HR, 1.89; 95% CI, 1.52-2.35; P < .001; stage III: HR, 2.65; 95% CI, 1.96-2.65; P < .001), positive margins (HR, 1.53; 95% CI, 1.36-1.73; P < .001), and receipt of oncologic care at a nonacademic facilities (Community Cancer Program: HR, 1.20; 95% CI, 1.07-1.35; P < .001; Integrated Network Cancer Program: HR, 1.25; 95% CI, 1.07-1.46; P < .001) were associated with an increased hazard of death (eTable 3 in the Supplement).
Sensitivity Analysis
Similar findings were seen in the subgroup analyses; receipt of AC was associated with a decreased hazard of death and a longer median survival among the node-negative, margin-negative, clinically complex, node-positive, and margin-positive cohort of patients (Figure 4; eFigures 2-6 in the Supplement). The log-log plot of survival shows that around 7 months, the chemotherapy and no-chemotherapy curves converge but do not cross, which indicates that after 7 months, compared with no chemotherapy, the benefit of chemotherapy remained present but at a reduced magnitude (eFigure 7 in the Supplement). Chemotherapy was added to the overall multivariable Cox regression as a time-varying covariate, allowing for a different effect after 7 months than before 7 months. The effect of chemotherapy before 7 months resulted in a 51% reduction in the hazard of death (HR, 0.49; P < .001), while the effect after 7 months resulted in only a 16% reduction in the hazard of death (HR, 0.84; P = .002).
Figure 4. Subgroup Analyses Examining the Association of Adjuvant Chemotherapy With Overall Survival Among Patients 80 Years and Older Who Underwent Surgery for PDAC (2004-2016).
HR indicates hazard ratio; PDAC, pancreatic ductal adenocarcinoma.
aHazard ratios derived from multivariable models.
Discussion
To our knowledge, this is the first national study examining AC use among patients 80 years and older who underwent pancreaticoduodenectomy for PDAC. The use of AC increased among patients with resected PDAC from 2004 to 2016 and was associated with longer overall survival. This association was consistent across our propensity-matched cohort and subgroup analyses. These results suggest that adjuvant treatment protocols for patients 80 years and older with PDAC should be further investigated because there may be a subset of patients who benefit from treatment.
Adjuvant chemotherapy for resected PDAC became standard of care after phase 3 trials found a survival benefit associated with chemotherapy following surgical resection.12,13,14,15,29,30 This treatment standard has not been expanded to patients 80 years and older owing to a paucity of randomized clinical trials in older adults, coupled with concerns for limited life expectancy, their fitness to withstand curative therapy, and age-related changes in pharmacodynamics of chemotherapy leading to increased toxic complications.31 We initially hypothesized that we would find a detrimental effect of chemotherapy in the clinically complex cohort and that any potential survival association with chemotherapy would be most pronounced in the pathologically advanced cohort, which has been reported in prior retrospective studies.32,33,34 The consistent association of AC with prolonged survival across a spectrum of patients 80 years and older—clinically complex patients, those with pathologically advanced disease (margin-positive, node-positive), and those with less pathologically advanced disease (margin-negative, node-negative)—challenges us to rethink whether we are being inclusive enough with curative intent for patients 80 years and older with PDAC. Furthermore, when we created a propensity-matched cohort of patients who did not have differences across stage, comorbidities, and LOS, we still found a significant association with AC and longer median survival.
While our study highlights that age alone should not preclude consideration for curative intent with surgery and AC among older adults with resectable PDAC, there are several key questions that remain unanswered. Does a difference in median survival confer a quality-of-life benefit, and how best do we assess functional status and use it as a criterion for treatment decisions? Gerstenhaber et al35 assessed quality of life after pancreaticoduodenectomy in patients 70 years and older using a single-institution prospective pancreatic cancer database and found that global quality-of-life scores at 3 and 12 months after surgery were 68% and 73%, respectively, and that scores were comparable with those of matched individuals undergoing laparoscopic cholecystectomy. Research that deepens our understanding of how patients 80 years and older recover from surgery and incorporates validated functional assessment tools is key to identifying frail patients and informing multimodality treatment decisions.36,37 Unfortunately, real-world integration of these measures into practice has not been realized, nor have they been incorporated into clinical trial protocols. A recent study examining the timing of adjuvant therapy among older adults with resected PDAC22 found improved survival when therapy was initiated 28 to 59 days after surgery. This survival benefit persisted even when therapy was initiated more than 12 weeks after the procedure, challenging the notion that delayed recovery from surgery should preclude consideration for AC.
Our study adds to a body of work examining AC in older adults with PDAC. Prior single-institutional studies have demonstrated underutilization of AC among older adults. Nagrial et al18 examined a cohort of patients who underwent operative resection for PDAC and found that 30% of older patients received adjuvant therapy and the absence of chemotherapy was associated with worse survival (median overall survival: 13.1 months vs 21.8 months for treated patients). King et al17 found that chemotherapy in addition to surgery resulted in a survival association similar to those seen in a younger cohort (median overall survival: 20.3 months). A recent analysis comparing treatment patterns and outcomes in stage I to III pancreatic cancer between patients 80 years and older and adults younger than 80 years found that 44.5% of patients 80 years and older received cancer-directed therapy compared with 78.7% patients younger than 80 years (P < .001), and that after propensity score matching, cancer-directed treatment remained associated with improved survival for patients 80 years and older (HR, 0.42; 95% CI, 0.41-0.43; P < .001).38 When we account for the landmarked time point of entry, the median survival rates among patients 80 years and older in our overall cohort is comparable to rates seen across all patients in similar studies.39 Our study is novel in that it examines a larger national cohort during a more recent time period—in which several advances in PDAC chemotherapy were made—and it examines a wide spectrum of patients 80 years and older.
Limitations
Our study has limitations. First, it is a retrospective, observational study subject to unmeasured confounding and indication bias. We worked to partially address this through our propensity score analysis, yet this cannot account fully for unmeasured confounding. Second, we did not have data on specific chemotherapy regimens the patients underwent, to what extent they completed their intended cycles, and chemotherapy-related toxic effects. Third, frailty and measures of functional status were not available in the NCDB. Furthermore, we did not have details on cause of death or have the ability to assess other cancer-specific outcome measures, such as cancer-specific mortality, disease-free survival, or quality of life. It is plausible that the survival advantage observed is attributable to selection. However, notably, all participants were deemed fit enough to undergo pancreaticoduodenectomy and survive the 90-day postoperative period, which mitigates the likelihood that preexisting frailty and unmeasured comorbid illnesses account for the observed survival differences.
Conclusions
In this cohort study of patients older than 80 years who underwent pancreaticoduodenectomy for pancreatic cancer, findings suggest that age alone should not preclude patients from curative intent with surgery and chemotherapy. It is imperative that we shift our treatment paradigm from one that reserves curative intent for a minority of patients 80 years and older to one that is centered on evidence-based criteria and considers individual risk and preference, beyond chronologic age.
eMethods. Propensity-Matched and Subgroup Analyses
eTable 1. Additional Characteristics of Octogenarians that Underwent Surgery for PDAC (2004-2016)
eTable 2. Multivariable Cox Hazard Regression of Octogenarians that Underwent Surgery for PDAC (2004-2016)
eTable 3. Multivariable Cox Hazard Regression of Octogenarians that Underwent Surgery for PDAC in Propensity Matched Cohort (2004-2016)
eFigure 1. Balance of Propensity Scores Before and After Matching Among Octogenarians that Underwent Surgery for PDAC (2004-2016)
eFigure 2. Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Surgery for PDAC in the Node-Negative Cohort (2004-2016)
eFigure 3. Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Surgery for PDAC in the Margin-Negative Cohort (2004-2016)
eFigure 4. Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Surgery for PDAC in the Clinically Complex Cohort (2004-2016)
eFigure 5. Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Curative Resection in the Node-Positive Cohort (2004-2016)
eFigure 6. Survival Differences Associated with the Use of Chemotherapy in Octogenarians Following Curative Resection (2004-2016) in the Margin-Positive Cohort
eFigure 7. Log-Log Plot of Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Surgery for PDAC in the Overall Cohort (2004-2016)
References
- 1.Riall TS. What is the effect of age on pancreatic resection? Adv Surg. 2009;43:233-249. doi: 10.1016/j.yasu.2009.02.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. doi: 10.3322/caac.21442 [DOI] [PubMed] [Google Scholar]
- 3.Ortman JM, Velkoff VA, Hogan H. An aging nation: the older population in the United States [Current Population Reports, P25-1140]. Accessed October 28, 2021. https://www.census.gov/prod/2014pubs/p25-1140.pdf
- 4.Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27(17):2758-2765. doi: 10.1200/JCO.2008.20.8983 [DOI] [PubMed] [Google Scholar]
- 5.Oliveira-Cunha M, Malde DJ, Aldouri A, Morris-Stiff G, Menon KV, Smith AM. Results of pancreatic surgery in the elderly: is age a barrier? HPB (Oxford). 2013;15(1):24-30. doi: 10.1111/j.1477-2574.2012.00549.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Riall TS, Reddy DM, Nealon WH, Goodwin JS. The effect of age on short-term outcomes after pancreatic resection: a population-based study. Ann Surg. 2008;248(3):459-467. doi: 10.1097/SLA.0b013e318185e1b3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Finlayson E, Fan Z, Birkmeyer JD. Outcomes in octogenarians undergoing high-risk cancer operation: a national study. J Am Coll Surg. 2007;205(6):729-734. doi: 10.1016/j.jamcollsurg.2007.06.307 [DOI] [PubMed] [Google Scholar]
- 8.Winter JM, Cameron JL, Campbell KA, et al. 1423 Pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg. 2006;10(9):1199-1210. doi: 10.1016/j.gassur.2006.08.018 [DOI] [PubMed] [Google Scholar]
- 9.Mayo SC, Gilson MM, Herman JM, et al. Management of patients with pancreatic adenocarcinoma: national trends in patient selection, operative management, and use of adjuvant therapy. J Am Coll Surg. 2012;214(1):33-45. doi: 10.1016/j.jamcollsurg.2011.09.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hatzaras I, Schmidt C, Klemanski D, et al. Pancreatic resection in the octogenarian: a safe option for pancreatic malignancy. J Am Coll Surg. 2011;212(3):373-377. doi: 10.1016/j.jamcollsurg.2010.10.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Sperti C, Moletta L, Pozza G. Pancreatic resection in very elderly patients: a critical analysis of existing evidence. World J Gastrointest Oncol. 2017;9(1):30-36. doi: 10.4251/wjgo.v9.i1.30 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Neoptolemos JP, Stocken DD, Tudur Smith C, et al. Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br J Cancer. 2009;100(2):246-250. doi: 10.1038/sj.bjc.6604838 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Psarelli EE, Jackson R, Neoptolemos JP, et al. Beyond ESPAC-4: better surgery and systemic therapy. Lancet. 2017;389(10078):1517-1518. doi: 10.1016/S0140-6736(17)30947-9 [DOI] [PubMed] [Google Scholar]
- 14.Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297(3):267-277. doi: 10.1001/jama.297.3.267 [DOI] [PubMed] [Google Scholar]
- 15.Conroy T, Hammel P, Hebbar M, et al. ; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group . FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379(25):2395-2406. doi: 10.1056/NEJMoa1809775 [DOI] [PubMed] [Google Scholar]
- 16.Bertens KA, Massman JD III, Helton S, et al. Initiation of adjuvant therapy following surgical resection of pancreatic ductal adenocarcinoma (PDAC): are patients from rural, remote areas disadvantaged? J Surg Oncol. 2018;117(8):1655-1663. doi: 10.1002/jso.25060 [DOI] [PubMed] [Google Scholar]
- 17.King JC, Zenati M, Steve J, et al. Deviations from expected treatment of pancreatic cancer in octogenarians: analysis of patient and surgeon factors. Ann Surg Oncol. 2016;23(13):4149-4155. doi: 10.1245/s10434-016-5456-0 [DOI] [PubMed] [Google Scholar]
- 18.Nagrial AM, Chang DK, Nguyen NQ, et al. ; Australian Pancreatic Cancer Genome Initiative . Adjuvant chemotherapy in elderly patients with pancreatic cancer. Br J Cancer. 2014;110(2):313-319. doi: 10.1038/bjc.2013.722 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Fritz A, Percy C, Jack A, et al. , eds. International Classification of Diseases for Oncology (ICD-O-3). 3rd ed. World Health Organization; 2000. Accessed October 12, 2019. https://www.who.int/publications/i/item/international-classification-of-diseases-for-oncology [Google Scholar]
- 20.Chun YS, Pawlik TM, Vauthey JN. 8th Edition of the AJCC cancer staging manual: pancreas and hepatobiliary cancers. Ann Surg Oncol. 2018;25(4):845-847. doi: 10.1245/s10434-017-6025-x [DOI] [PubMed] [Google Scholar]
- 21.Giobbie-Hurder A, Gelber RD, Regan MM. Challenges of guarantee-time bias. J Clin Oncol. 2013;31(23):2963-2969. doi: 10.1200/JCO.2013.49.5283 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Ma SJ, Oladeru OT, Miccio JA, Iovoli AJ, Hermann GM, Singh AK. Association of timing of adjuvant therapy with survival in patients with resected stage I to II pancreatic cancer. JAMA Netw Open. 2019;2(8):e199126. doi: 10.1001/jamanetworkopen.2019.9126 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Park HS, Gross CP, Makarov DV, Yu JB. Immortal time bias: a frequently unrecognized threat to validity in the evaluation of postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2012;83(5):1365-1373. doi: 10.1016/j.ijrobp.2011.10.025 [DOI] [PubMed] [Google Scholar]
- 24.Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45(6):613-619. doi: 10.1016/0895-4356(92)90133-8 [DOI] [PubMed] [Google Scholar]
- 25.Nardi A, Schemper M. New residuals for Cox regression and their application to outlier screening. Biometrics. 1999;55(2):523-529. doi: 10.1111/j.0006-341X.1999.00523.x [DOI] [PubMed] [Google Scholar]
- 26.Khanna A, Walker GR, Livingstone AS, Arheart KL, Rocha-Lima C, Koniaris LG. Is adjuvant 5-FU-based chemoradiotherapy for resectable pancreatic adenocarcinoma beneficial? a meta-analysis of an unanswered question. J Gastrointest Surg. 2006;10(5):689-697. doi: 10.1016/j.gassur.2005.11.006 [DOI] [PubMed] [Google Scholar]
- 27.Stocken DD, Büchler MW, Dervenis C, et al. ; Pancreatic Cancer Meta-analysis Group . Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer. Br J Cancer. 2005;92(8):1372-1381. doi: 10.1038/sj.bjc.6602513 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Liao WC, Chien KL, Lin YL, et al. Adjuvant treatments for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14(11):1095-1103. doi: 10.1016/S1470-2045(13)70388-7 [DOI] [PubMed] [Google Scholar]
- 29.Evans DB, Hess KR, Pisters PW. ESPAC-1 trial of adjuvant therapy for resectable adenocarcinoma of the pancreas. Ann Surg. 2002;236(5):694. doi: 10.1097/00000658-200211000-00023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Valle JW, Palmer D, Jackson R, et al. Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. J Clin Oncol. 2014;32(6):504-512. doi: 10.1200/JCO.2013.50.7657 [DOI] [PubMed] [Google Scholar]
- 31.Hurria A, Lichtman SM. Clinical pharmacology of cancer therapies in older adults. Br J Cancer. 2008;98(3):517-522. doi: 10.1038/sj.bjc.6604201 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Corsini MM, Miller RC, Haddock MG, et al. Adjuvant radiotherapy and chemotherapy for pancreatic carcinoma: the Mayo Clinic experience (1975-2005). J Clin Oncol. 2008;26(21):3511-3516. doi: 10.1200/JCO.2007.15.8782 [DOI] [PubMed] [Google Scholar]
- 33.Vanderveen KA, Chen SL, Yin D, Cress RD, Bold RJ. Benefit of postoperative adjuvant therapy for pancreatic cancer: a population-based analysis. Cancer. 2009;115(11):2420-2429. doi: 10.1002/cncr.24269 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Herman JM, Swartz MJ, Hsu CC, et al. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J Clin Oncol. 2008;26(21):3503-3510. doi: 10.1200/JCO.2007.15.8469 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Gerstenhaber F, Grossman J, Lubezky N, et al. Pancreaticoduodenectomy in elderly adults: is it justified in terms of mortality, long-term morbidity, and quality of life? J Am Geriatr Soc. 2013;61(8):1351-1357. doi: 10.1111/jgs.12360 [DOI] [PubMed] [Google Scholar]
- 36.Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations. Ann Oncol. 2015;26(2):288-300. doi: 10.1093/annonc/mdu210 [DOI] [PubMed] [Google Scholar]
- 37.Macchini M, Chiaravalli M, Zanon S, et al. Chemotherapy in elderly patients with pancreatic cancer: efficacy, feasibility and future perspectives. Cancer Treat Rev. 2019;72:1-6. doi: 10.1016/j.ctrv.2018.10.013 [DOI] [PubMed] [Google Scholar]
- 38.Li R, Vazquez J, Novak J, et al. Patterns of care and treatment outcomes in patients age 80 or older with non-metastatic pancreatic cancer. J Geriatr Oncol. 2020;11(4):652-659. doi: 10.1016/j.jgo.2019.12.006 [DOI] [PubMed] [Google Scholar]
- 39.Kagedan DJ, Raju RS, Dixon ME, et al. The association of adjuvant therapy with survival at the population level following pancreatic adenocarcinoma resection. HPB (Oxford). 2016;18(4):339-347. doi: 10.1016/j.hpb.2015.12.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
eMethods. Propensity-Matched and Subgroup Analyses
eTable 1. Additional Characteristics of Octogenarians that Underwent Surgery for PDAC (2004-2016)
eTable 2. Multivariable Cox Hazard Regression of Octogenarians that Underwent Surgery for PDAC (2004-2016)
eTable 3. Multivariable Cox Hazard Regression of Octogenarians that Underwent Surgery for PDAC in Propensity Matched Cohort (2004-2016)
eFigure 1. Balance of Propensity Scores Before and After Matching Among Octogenarians that Underwent Surgery for PDAC (2004-2016)
eFigure 2. Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Surgery for PDAC in the Node-Negative Cohort (2004-2016)
eFigure 3. Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Surgery for PDAC in the Margin-Negative Cohort (2004-2016)
eFigure 4. Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Surgery for PDAC in the Clinically Complex Cohort (2004-2016)
eFigure 5. Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Curative Resection in the Node-Positive Cohort (2004-2016)
eFigure 6. Survival Differences Associated with the Use of Chemotherapy in Octogenarians Following Curative Resection (2004-2016) in the Margin-Positive Cohort
eFigure 7. Log-Log Plot of Survival Differences Associated with the Use of Adjuvant Chemotherapy in Octogenarians Following Surgery for PDAC in the Overall Cohort (2004-2016)