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. 2019 Jan 16;8(3):939–952. doi: 10.1002/cam4.1967

Adjuvant chemotherapy followed by concurrent chemoradiation is associated with improved survival for resected stage I‐II pancreatic cancer

Sung Jun Ma 1, Gregory M Hermann 1, Kavitha M Prezzano 1, Lucas M Serra 2, Austin J Iovoli 2, Anurag K Singh 1,✉
PMCID: PMC6434497  PMID: 30652417

Abstract

Background

This National Cancer Database (NCDB) analysis evaluates the clinical outcomes of postoperative chemotherapy followed by concurrent chemoradiation (C + CRT) compared to concurrent chemoradiation (CRT) alone or adjuvant chemotherapy alone (C) for resected pancreatic cancer.

Methods

The NCDB was queried for primary stage I‐II, cT1‐3N0‐1M0, resected pancreatic adenocarcinoma treated with adjuvant C, CRT, or C + CRT (2004‐2015). Patients treated with C + CRT were compared with those treated with C (cohort C) and CRT (cohort CRT). Baseline patient, tumor, and treatment characteristics were examined. Kaplan‐Meier analysis, multivariable Cox proportional hazards method, forest plot, and propensity score matching were used.

Results

Among 5667 patients, median follow‐up was 34.7, 45.2, and 39.7 months for the C, CRT, and C + CRT cohorts, respectively. By multivariable analysis for all patients, C and CRT had worse OS compared to C + CRT. Treatment interactions were seen among pathologically node‐positive disease. C + CRT was favored in 1‐3 and 4+ positive lymph node diseases when compared to C or CRT alone, but none of the treatment options were significantly favored in node negative disease. Using propensity score matching, 2152 patients for cohort C and 1774 patients for cohort CRT were matched. C + CRT remained significant for improved OS for both cohort C (median OS 23.3 vs 20.0 months) and cohort CRT (median OS 23.4 vs 20.8 months).

Conclusion

This NCDB study using propensity score matched analysis suggests an OS benefit for C + CRT compared to C or CRT alone following surgical resection of pancreatic cancer, particularly for patients with pathologically positive lymph nodes.

Keywords: adjuvant chemoradiation, adjuvant chemotherapy, adjuvant radiation, adjuvant therapy, National Cancer Database, resectable pancreatic cancer

1. INTRODUCTION

Pancreatic adenocarcinoma, the fourth leading cause of cancer death in the United States, is a treatment challenge with a dismal median survival of 12.4 months.1 Surgical resection is considered the only potentially curative approach, though survival rates are modest, with a 5‐year overall survival (OS) of 7%‐17%.2, 3, 4 With local failure rates as high as 73% after surgery,2, 3, 4 various adjuvant therapies, including chemoradiation (CRT), have been investigated in clinical trials and institutional studies as a means to address the poor clinical outcomes in patients with pancreatic adenocarcinoma. Several reports have demonstrated improved OS with the use of adjuvant chemoradiation, with median OS times ranging from 19.5 to 25.2 months.5, 6, 7, 8, 9 Several National Cancer Database (NCDB) studies have similarly shown improved OS with adjuvant CRT.10, 11, 12

Literature for the role of chemotherapy (C) before CRT for resected pancreatic adenocarcinoma is limited. A phase III study of adjuvant fluorouracil vs gemcitabine, given for 3 weeks followed by CRT, and then an additional 3 months of C, found no difference in OS with either agent.13 A NCDB analysis, did however, report a survival benefit with chemotherapy prior to CRT for locally advanced pancreatic cancer.14 Due to a lack of comparative studies, the value of C prior to CRT specifically for early‐stage pancreatic cancer remains unclear.

This study compares the outcomes of patients who received C + CRT vs those who received C or CRT alone for stage I‐II, resected pancreatic cancer.

2. METHODS

2.1. Patient population

The NCDB registry was used to identify patients with pancreatic adenocarcinoma diagnosed between 2004 and 2015 (the most recent dataset available at the time of this study). The NCDB is a nationwide cancer database that captures approximately 70% of newly diagnosed cancer cases in the United States and includes 34 million historical records.15 It provides access to de‐identified datasets from Commission on Cancer‐accredited programs through online application. This study was exempt from institutional review board review.

Our patient selection criteria are shown in Figure 1. We selected from our initial query of patients with stage I‐II, clinical T1‐3N0‐1M0 pancreatic adenocarcinoma who had been treated with curative‐intent resection followed by adjuvant chemotherapy and conventionally fractionated radiation therapy. American Joint Committee on Cancer (AJCC) 6th and 7th editions were used to determine stage I‐II disease in 2004‐2015.

Figure 1.

Figure 1

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CONSORT diagram for patient selection criteria

Whipple surgery was defined as local or partial pancreatectomy and duodenectomy with partial gastrectomy. Whipple‐variant surgery was characterized as partial pancreatectomy with duodenectomy, total pancreatectomy alone, or total pancreatectomy with subtotal gastrectomy or duodenectomy.16 Patients treated with chemotherapy or radiation therapy within 30 days of each other were considered to have received adjuvant CRT alone. Those who were treated with adjuvant chemotherapy within 31‐180 days prior to the radiation therapy were defined as having received C + CRT.14 Patients who received adjuvant chemotherapy more than 180 days prior to adjuvant radiation therapy were excluded.

Patients were excluded if they had incomplete follow‐up data, missing radiation dose or fractionation information, incomplete data on the number of days between diagnosis and treatments, or missing information regarding surgical margins. Patients treated with palliative‐intent or with neoadjuvant chemotherapy or radiation were also excluded. To address immortal time bias, those with postdiagnosis survival duration of <3 months were not included.17

Baseline patient, tumor, and treatment characteristics for analysis included the following: facility type, age, gender, race, insurance type, income level, residential setting, Charlson‐Deyo comorbidity score (CDS), year of diagnosis, primary tumor location within pancreas, tumor grade, tumor size, clinical T and N stages, pathologic T and N stages, number of biopsy‐positive lymph nodes, surgery type, surgical margin, total radiation dose, and chemotherapy use. Surgical margin was categorized as either negative (R0) or positive (R1, R2, positive margin not otherwise specified). Patients were stratified by age ≥66 or <66 years, and tumor size <3.1 or ≥3.1 cm based on their median values. The household income level of each patient's residential area was based on the 2012 American Community Survey data adjusted for inflation (the most recent data at the time of this study) and was stratified above or below the median value of $48 000. CA 19‐9 factor was coded by the NCDB with a cut off of <98 or ≥98 Units/mL, although CA 19‐9 was not used for propensity score matching due to missing data in 3064 (54.1%) of patients. Local and distant failure/progression information is also unable to be analyzed based on data from the NCDB. Important prognostic variables such as the patient's initial performance status, type and duration of chemotherapy received, and toxicity outcomes are unavailable in the NCDB. The primary endpoint was overall survival (OS), time between the diagnosis and the last follow‐up or death.

2.2. Statistical analysis

OS was evaluated using the Kaplan‐Meier method and log‐rank tests. Fisher's exact test and Mann‐Whitney U test were used to compare categorical and continuous variables between two treatment cohorts, respectively. Logistic regression univariable (UVA) and multivariable analyses (MVA) were used to determine potential factors that predicted the use of postoperative chemotherapy and were reported as odds ratio (OR). Cox proportional hazard UVA and MVA were used to determine factors that predict the OS and were reported as hazards ratio (HR). MVA was initially constructed using all statistically significant variables from UVA and was finalized using a backward stepwise elimination. Only patients with complete information on such variables were included. Potential interactions between the treatment and other covariates were examined using Cox MVA by adding interaction terms.18 When the interaction terms were statistically significant, the final Cox MVA model was re‐analyzed for each subgroup of covariates, and a forest plot was constructed to illustrate the direction and magnitude of treatment effects.18

To minimize selection bias, propensity score matching was used. Match‐pairs were constructed by matching baseline patient, tumor, and treatment characteristics. Variables of interest include facility type, year of diagnosis, age, CDS, tumor grade, tumor size, surgery type, chemotherapy use, total radiation dose, pathologic T and N stages, and additional variables that were statistically significant in Cox proportional hazard MVA results for each cohort. All matching was performed in a 1:1 ratio without any replacement and was based on nearest neighbor method with a caliper distance of 0.2 of the standard deviation of the logit of the propensity score.19 Matching was performed using MatchIt package (version 3.0.1). R software (version 3.5.0, R Foundation for Statistical Computing, Vienna, Austria) was used for all aforementioned analyses. All P values were two‐sided. A P value <0.05 was considered statistically significant.

3. RESULTS

A total of 5667 patients with resected clinical stage I‐II, T1‐3N0‐1M0 pancreatic adenocarcinoma were identified for analysis. Of those, adjuvant C, CRT, and C + CRT were delivered to 3031, 1307, and 1329 patients, respectively. Overall follow‐up was 37.4 months (IQR [interquartile range] 24.5‐59.3). The majority of patients had pathologic T3N1 adenocarcinoma of the pancreatic head with negative surgical margins (Tables 1 and 2). Of the 2636 (1307 + 1329) patients who received RT, 2050 (1001 for CRT, 1049 for C + CRT) patients received RT to the pancreas, and 420 (221 for CRT, 199 for C + CRT) patients received RT to the abdomen (not otherwise specified); therefore, 93.7% (2470/2636) of patients received RT to the pancreas or abdomen. A total of 107 (107/1307 = 8.2%) and 106 (106/1329 = 8.0%) patients received <45 Gy in cohort CRT and C + CRT, respectively.

Table 1.

Baseline characteristics for cohort C

Before matching After matching
C C + CRT P C C + CRT P
N % N % N % N %
Facility
Nonacademic 1454 48 789 59 <0.001 622 58 631 59 0.73
Academic 1557 51 521 39 454 42 445 41
NA 20 1 19 1 0 0 0 0
Age
<66 1297 43 762 57 <0.001 620 58 589 55 0.19
≥66 1734 57 567 43 456 42 487 45
NA 0 0 0 0 0 0 0 0
Gender
Female 1497 49 663 50 0.77
Male 1534 51 666 50
NA 0 0 0 0
Race
White 2645 87 1148 86 0.60
Black 270 9 121 9
Other 95 3 49 4
NA 21 1 11 1
Insurance
None 70 2 34 3 <0.001
Nonprivate 1846 61 684 51
Private 1096 36 601 45
NA 19 1 10 1
Income
Above median 1947 64 870 65 0.37 704 65 707 66 0.93
Below median 1053 35 441 33 372 35 369 34
NA 31 1 18 1 0 0 0 0
Residential setting
Metro 2470 81 1086 82 0.84
Urban 410 14 181 14
Rural 49 2 18 1
NA 102 3 44 3
Charlson‐Deyo Score
0‐1 2805 93 1248 94 0.11 1011 94 1008 94 0.86
≥2 226 7 81 6 65 6 68 6
NA 0 0 0 0 0 0 0 0
Year of diagnosis
2004‐2007 195 6 74 6 <0.001 62 6 46 4 0.13
2008‐2011 1376 45 696 52 506 47 543 50
2012‐2015 1460 48 559 42 508 47 487 45
NA 0 0 0 0 0 0 0 0
Primary tumor site
Head 2391 79 1105 83 <0.001
Body 237 8 105 8
Tail 403 13 119 9
NA 0 0 0 0
Tumor grade
Well diff 202 7 112 8 0.024 78 7 91 8 0.083
Mod diff 1450 48 652 49 559 52 566 53
Poor diff 1126 37 448 34 431 40 400 37
Other 30 1 20 2 8 1 19 2
NA 223 7 97 7 0 0 0 0
Tumor size (cm)
<3.1 1466 48 657 49 0.35 526 49 526 49 1
≥3.1 1511 50 636 48 550 51 550 51
NA 54 2 36 3 0 0 0 0
Clinical T stage
1 505 17 195 15 0.15
2 1180 39 509 38
3 1346 44 625 47
NA 0 0 0 0
Clinical N stage
0 2122 70 871 66 0.0036
1 909 30 458 34
NA 0 0 0 0
Pathologic T stage
0 1 0 1 0 0.013 0 0 1 0 0.81
1 158 5 45 3 41 4 37 3
2 404 13 153 12 110 10 123 11
3 2299 76 1056 79 908 84 898 83
4 38 1 22 2 17 2 17 2
Other 1 0 0 0 0 0 0 0
NA 130 4 52 4 0 0 0 0
Pathologic N stage
0 900 30 293 22 <0.001 257 24 256 24 1
1 1988 66 971 73 819 76 820 76
NA 143 5 65 5 0 0 0 0
Number of positive lymph nodes
0 920 30 297 22 <0.001
1‐3 1173 39 585 44
4+ 848 28 415 31
NA 90 3 32 2
Surgery
Whipple variant 941 31 397 30 0.33 364 34 325 30 0.079
Whipple 1409 46 650 49 477 44 528 49
Other 681 22 282 21 235 22 223 21
NA 0 0 0 0 0 0 0 0
Surgical margin
Negative 2429 80 968 73 <0.001 826 77 807 75 0.36
Positive 510 17 336 25 250 23 269 25
NA 92 3 25 2 0 0 0 0
Chemotherapy
Single agent 2376 78 766 58 <0.001 650 60 634 59 0.51
Multi agent 655 22 563 42 426 40 442 41
NA 0 0 0 0 0 0 0 0
Radiation dose (Gy)
Median — 50.4 NA
IQR — 50.0‐50.4
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C, chemotherapy; CRT, chemoradiation; diff, differentiated; IQR, interquartile range; mod, moderately; NA, not available; poor, poorly.

Table 2.

Baseline characteristics for cohort CRT

Before matching After matching
CRT C + CRT P CRT C + CRT P
N % N % N % N %
Facility
Nonacademic 848 65 789 59 0.0085 548 62 539 61 0.70
Academic 452 35 521 39 339 38 348 39
NA 7 1 19 1 0 0 0 0
Age
<66 674 52 762 57 0.0030 472 53 498 56 0.23
≥66 633 48 567 43 415 47 389 44
NA 0 0 0 0 0 0 0 0
Gender
Female 645 49 663 50 0.79
Male 662 51 666 50
NA 0 0 0 0
Race
White 1141 87 1148 86 0.19
Black 119 9 121 9
Other 32 2 49 4
NA 15 1 11 1
Insurance
None 31 2 34 3 0.071
Nonprivate 728 56 684 51
Private 533 41 601 45
NA 15 1 10 1
Income
Above median 733 56 870 65 <0.001 547 62 563 63 0.46
Below median 544 42 441 33 340 38 324 37
NA 30 2 18 1 0 0 0 0
Residential setting
Metro 1023 78 1086 82 0.049
Urban 201 15 181 14
Rural 31 2 18 1
NA 52 4 44 3
Charlson‐Deyo Score
0‐1 1235 94 1248 94 0.56 836 94 841 95 0.68
≥2 72 6 81 6 51 6 46 5
NA 0 0 0 0 0 0 0 0
Year of diagnosis
2004‐2007 210 16 74 6 <0.001 69 8 47 5 0.11
2008‐2011 680 52 696 52 458 52 467 53
2012‐2015 417 32 559 42 360 41 373 42
NA 0 0 0 0 0 0 0 0
Primary tumor site
Head 1076 82 1105 83 0.015
Body 78 6 105 8
Tail 153 12 119 9
NA 0 0 0 0
Tumor grade
Well diff 108 8 112 8 0.64 75 8 79 9 0.13
Mod diff 629 48 652 49 460 52 478 54
Poor diff 455 35 448 34 346 39 315 36
Other 13 1 20 2 6 1 15 2
NA 102 8 97 7 0 0 0 0
Tumor size (cm)
<3.1 575 44 657 49 0.0050 410 46 410 46 1
≥3.1 697 53 636 48 477 54 477 54
NA 35 3 36 3 0 0 0 0
Clinical T stage
1 158 12 195 15 0.15
2 517 40 509 38
3 632 48 625 47
NA 0 0 0 0
Clinical N stage
0 874 67 871 66 0.48
1 433 33 458 34
NA 0 0 0 0
Pathologic T stage
0 1 0 1 0 0.61 1 0 1 0 0.95
1 49 4 45 3 30 3 36 4
2 169 13 153 12 108 12 105 12
3 980 75 1056 79 731 82 729 82
4 22 2 22 2 17 2 16 2
Other 0 0 0 0 0 0 0 0
NA 86 7 52 4 0 0 0 0
Pathologic N stage
0 338 26 293 22 0.0075 228 26 226 25 0.96
1 874 67 971 73 659 74 661 75
NA 95 7 65 5 0 0 0 0
Number of positive lymph nodes
0 363 28 297 22 <0.001
1‐3 585 45 585 44
4+ 324 25 415 31
NA 35 3 32 2
Surgery
Whipple variant 342 26 397 30 0.10 253 29 256 29 0.98
Whipple 668 51 650 49 437 49 436 49
Other 297 23 282 21 197 22 195 22
NA 0 0 0 0 0 0 0 0
Surgical margin
Negative 891 68 968 73 0.012 643 72 637 72 0.79
Positive 386 30 336 25 244 28 250 28
NA 30 2 25 2 0 0 0 0
Chemotherapy
Single agent 824 63 766 58 0.0047 536 60 515 58 0.33
Multi agent 483 37 563 42 351 40 372 42
NA 0 0 0 0 0 0 0 0
Radiation dose (Gy)
Median 50.4 50.4 0.18 50.4 50.4 0.17
IQR 50.0‐54.0 50.0‐50.4 50.0‐54.0 50.0‐50.4
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C, chemotherapy; CRT, chemoradiation; diff, differentiated; IQR, interquartile range; mod, moderately; NA, not available; poor, poorly.

On logistic MVA for all patients, patients with diagnosis between 2008 and 2011 (OR 2.17, P < 0.001) and 2012 and 2015 (OR 1.99, P < 0.001), pathologic nodal diseases (OR 1.37, P < 0.001 for 1‐3 positive nodes; OR 1.32, P = 0.0034 for 4+ positive nodes), positive surgical margin (OR 1.25, P = 0.0062), and receipt of multiagent chemotherapy (OR 2.01, P < 0.001) were more likely to receive C + CRT compared to C or CRT alone. Patients treated at academic facilities (OR 0.73, P < 0.001), older than 66 years old (OR 0.66, P < 0.001), from low‐income regions (OR 0.83, P = 0.0083), with pancreatic tail disease (OR 0.68, P = 0.0011), and poorly differentiated histology (OR 0.74, P = 0.019) were less likely to undergo C + CRT.

On Cox MVA for all patients (Table 3), those older than 66 years old (HR 1.14, P < 0.001), from low‐income regions (HR 1.10, P = 0.0082), with higher CDS (HR 1.23, P = 0.0017), moderately (HR 1.18, P = 0.018) or poorly differentiated (HR 1.51, P < 0.001) disease, tumors larger than 3.1 cm (HR 1.26, P < 0.001), pathologic positive nodal diseases (HR 1.46, P < 0.001 for 1‐3 positive nodes; HR 1.79, P < 0.001 for 4+ positive nodes), high CA 19‐9 (≥98 U/mL) (HR 1.30, P < 0.001), and positive surgical margins (HR 1.47, P < 0.001) were associated with worse mortality. When compared to C + CRT, those treated with C (HR 1.31, P < 0.001) or CRT alone (HR 1.24, P < 0.001) had worse survival outcomes. Improved overall survival was observed in those treated at academic facilities (HR 0.83, P < 0.001) and pathologic T1‐2 diseases (HR 0.87, P = 0.0051).

Table 3.

Cox UVA and MVA for all cohorts

Variable Cox UVA Cox MVA
HR 95% CI P HR 95% CI P
Facility
Nonacademic 1 Ref 1 Ref
Academic 0.88 0.82‐0.93 <0.001 0.83 0.78‐0.89 <0.001
Age
<66 1 Ref 1 Ref
≥66 1.16 1.09‐1.23 <0.001 1.14 1.06‐1.22 <0.001
Gender
Female 1 Ref
Male 1.01 0.95‐1.08 0.64
Race
White 1 Ref
Black 0.98 0.88‐1.10 0.76
Other 0.95 0.79‐1.14 0.55
Insurance
None 1 Ref
Nonprivate 1.15 0.94‐1.42 0.18
Private 0.95 0.77‐1.17 0.64
Income
Above median 1 Ref 1 Ref
Below median 1.14 1.07‐1.21 <0.001 1.10 1.02‐1.18 0.0082
Residential setting
Metro 1 Ref 1 Ref
Urban 1.08 0.99‐1.18 0.086
Rural 1.37 1.10‐1.71 0.0052 1.20 0.94‐1.53 0.15
Charlson‐Deyo score
0‐1 1 Ref 1 Ref
≥2 1.2 1.06‐1.35 0.0033 1.23 1.08‐1.40 0.0017
Year of diagnosis
2004‐2007 1 Ref
2008‐2011 0.97 0.88‐1.08 0.63
2012‐2015 0.90 0.80‐1.00 0.051
Primary tumor site
Head 1 Ref
Body 0.92 0.81‐1.03 0.15
Tail 0.95 0.87‐1.05 0.33
Tumor grade
Well diff 1 Ref 1 Ref
Mod diff 1.22 1.07‐1.38 0.0022 1.18 1.03‐1.35 0.018
Poor diff 1.60 1.41‐1.82 <0.001 1.51 1.32‐1.73 <0.001
Other 1.19 0.86‐1.66 0.30
Tumor size (cm)
<3.1 1 Ref 1 Ref
≥3.1 1.42 1.34‐1.52 <0.001 1.26 1.18‐1.35 <0.001
Pathologic T stage
0‐2 1 Ref 1 Ref
3‐4 0.72 0.66‐0.79 <0.001 0.87 0.79‐0.96 0.0051
Number of positive lymph nodes
0 1 Ref 1 Ref
1‐3 1.61 1.48‐1.74 <0.001 1.46 1.34‐1.59 <0.001
4+ 2.08 1.91‐2.27 <0.001 1.79 1.63‐1.97 <0.001
Surgery
Whipple variant 1 Ref
Whipple 1.04 0.97‐1.12 0.30
Other 1.03 0.94‐1.12 0.51
Surgical margin
Negative 1 Ref 1 Ref
Positive 1.64 1.53‐1.76 <0.001 1.47 1.36‐1.59 <0.001
Chemotherapy
Single agent 1 Ref
Multi agent 1.03 0.96‐1.10 0.47
Radiation dose (Gy)
1 Gy increase 1.00 1.00‐1.00 1
Treatment
C + CRT 1 Ref 1 Ref
CRT 1.19 1.09‐1.30 <0.001 1.24 1.12‐1.37 <0.001
C 1.15 1.07‐1.24 <0.001 1.31 1.20‐1.43 <0.001
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CI, confidence interval; diff, differentiated; HR, hazard ratio; mod, moderately; MVA, multivariable analysis; poor, poorly; Ref, reference; UVA, univariate analysis.

After Cox MVA, treatment interactions were observed in positive nodal disease subgroups (1‐3 positive nodes: HR 0.78, P = 0.020; 4+ positive nodes: HR 0.79, P = 0.041). No other treatment interactions were seen in age (HR 0.94, P = 0.46), CDS (HR 0.98, P = 0.88), years of diagnosis (2008‐2011: HR 1.05, P = 0.76; 2012‐2015: HR 1.05, P = 0.79), tumor size (HR 0.93, P = 0.40), surgical margin (HR 0.89, P = 0.23), or pathologic T stages (HR 1.10, P = 0.40). On subgroup analysis (Figure 2), nodal disease favored C + CRT when compared to C or CRT alone (0 positive node: HR 0.96, P = 0.67; 1‐3 positive nodes: HR 0.74, P < 0.001; 4+ positive nodes: HR 0.75, P < 0.001).

Figure 2.

Figure 2

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Forest plot for subgroup analysis. C, adjuvant chemotherapy; C + CRT, adjuvant chemotherapy followed by chemoradiation; CI, confidence interval; CRT, chemoradiation; HR, hazards ratio; LN, lymph node; No., number of patients

3.1. Cohort C

The C group had a median follow‐up of 34.7 months (IQR 22.9‐54.6), and the C + CRT group had that of 39.7 months (IQR 26.7‐59.5). The median OS was 21.1 months (IQR 12.0‐34.7) for the C group and 23.4 months (IQR 15.6‐39.3) for the C + CRT group (log‐rank P < 0.001). OS at 2 years was 48.8% for the C group and 53.1% for the C + CRT group.

A total of 2152 patients were matched. All variables were well balanced between these two groups (Table 1). The overall median follow‐up for the matched patients was 36.7 months (IQR 24.7‐54.5). The median OS was 20.0 months (IQR 11.5‐33.6) for the C group and 23.3 months (IQR 15.6‐39.2) for the C + CRT group (Figure 3; log‐rank P < 0.001). OS at 2 years was 45.2% for the C group and 52.3% for the C + CRT group.

Figure 3.

Figure 3

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Overall survival for cohort C after matching. P < 0.001. C, adjuvant chemotherapy; C + CRT, adjuvant chemotherapy followed by chemoradiation

3.2. Cohort CRT

The CRT and C + CRT groups had a median follow‐up of 45.2 and 39.7 months, respectively. The median OS was 21.1 months (IQR 12.5‐36.0) for the CRT group and 23.4 months (15.6‐39.3) for the C + CRT group (log‐rank P < 0.001). OS at 2 years was 46.2% and 53.1% for the CRT and C + CRT groups, respectively.

A total of 1774 patients were matched. All variables were well balanced (Table 2). The overall follow‐up was 40.2 months (IQR 26.0‐58.3). The CRT group had a median OS of 20.8 months (IQR 12.5‐34.7) and the C + CRT group had that of 23.4 months (IQR 16.0‐40.0). OS at 2 years was 46.6% for the CRT group and 52.5% for the C + CRT group (Figure 4; log‐rank P < 0.001).

Figure 4.

Figure 4

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Overall survival for cohort CRT after matching. P < 0.001. CRT, adjuvant chemoradiation; C + CRT, adjuvant chemotherapy followed by chemoradiation

4. DISCUSSION

To our knowledge, this is the first study to compare adjuvant C + CRT vs C or CRT alone for stage I‐II resected pancreatic cancer. This study suggests a survival benefit favoring the use of C + CRT for resected pancreatic cancer, specifically in cases of pathologically node‐positive disease.

The C + CRT cohort included over 70% patients with pathologically staged T3 and N1 disease, which are notably associated with worse prognosis.20, 21, 22 Despite this, the C + CRT still had better OS compared to the CRT alone cohort. The median OS was 23 months, which is comparable to or better than previously reported survival outcomes for adjuvant CRT alone.5, 6, 7, 8, 9, 10

The use of adjuvant C in addition to CRT has only been investigated in a few studies.6, 23, 24, 25 RTOG 9704 delivered C before and after adjuvant CRT for resected pancreatic cancer. A large number of included patients had T3‐4N1 disease and positive surgical margins. Median OS was 17.1 months for fluorouracil and 20.5 months for gemcitabine.25 Likely due to the initial publication of RTOG 9704 in 2008, our logistic MVA results demonstrated that those diagnosed between 2008 and 2015 were more likely to receive C + CRT compared to those diagnosed between 2004 and 2007. A prior institutional study showed that delaying CRT until after >1 cycle of adjuvant C is not associated with worse mortality when compared to adjuvant CRT only.24 Our study is the first report showing that delaying CRT until after 30‐180 days of adjuvant C may have survival benefits.

Our Cox MVA results (Table 3) showed that moderately or poorly differentiated tumors, larger tumor size, and pathologic N1 disease were adverse prognostic factors for mortality. This association is consistent with prior studies.26, 27, 28, 29, 30, 31, 32, 33, 34, 35 Older age, more medical comorbidities, low income, and positive surgical margins were also shown to be associated with worse mortality in our study, and this finding is also consistent with other reports.36, 37, 38, 39 In this study, treatment at academic facilities was an independent favorable prognostic factor for OS. This finding is consistent with prior analyses showing improved outcomes at high volume centers related to better surgical outcomes, which may explain why living in a rural area was associated with worse mortality.40, 41, 42 Although additional factors contributing to improved OS at academic facility may include patient self‐selection, higher socioeconomic status and/or performance status.

From our logistic MVA results, patients with pathologic T3‐4N1 diseases and positive surgical margins were more likely to receive C + CRT. A prior study has also shown that patients with a higher disease burden were more likely to receive adjuvant therapies.43

In our study, the use of multiagent chemotherapy was not a favorable prognostic factor for survival. This finding is in contrast to theEuropean Study Group for Pancreatic Cancer‐4 (ESPAC‐4) trial. Despite including 61% of patients with positive surgical margins and 79% with N1 disease in the ESPAC‐4 trial, adjuvant gemcitabine combined with capecitabine significantly improved survival.28 In NCDB, multiagent chemotherapy was recorded as the first course, and it is possible that some chemotherapy regimens were changed during the course of treatments. This change in chemotherapy regimens is not recorded in NCDB, which may explain this discrepancy.

4.1. Limitations

This study has a number of limitations, many of which are inherent to performing a retrospective review. Various potential prognostic factors, such as smoking and alcohol history, performance status, molecular tests, and the type and duration of chemotherapy, are not recorded by the NCDB. Outcomes such as local or distant recurrences, toxicity, and cancer‐specific survival were also unavailable. More than half of the CA 19‐9 values, an important prognostic factor for resectability and survival, were missing from this dataset and could not be included for propensity score matched analysis.27, 44, 45, 46, 47 The NCDB also does not include information on disease progression; therefore, this study cannot address the possibility of a patient received RT for progression of disease on chemotherapy. This limitation is inherent to all NCDB analyses and limit interpretation of our findings. Further, RT may have been palliative‐intent for a minority of the included patients based on site and dose of RT, but since both CRT and C‐CRT had similar numbers of patients receiving <45 Gy, it is unlikely these patients would change the conclusions of this study. Since the NCDB is not a population‐based database, our findings may not be generalized to other patient populations.

Up to 79% of patients in RTOG 9704 experienced chemotherapy‐related toxicity. A meta‐analysis of adjuvant treatments for resected pancreatic adenocarcinoma also showed significant toxicity with the addition of chemotherapy to chemoradiation.48 It is possible that those patients who received C + CRT may have had a better initial performance status in order to tolerate the additional toxicity of chemotherapy, thus leading to better survival outcomes compared to those receiving C or CRT alone.13 This potential confounder may also explain the improved survival seen in other institutional studies.6, 23 However, it is unlikely that improved performance status was the only factor contributing to this overall survival benefit, since patients with node negative diseases would have also favored C + CRT in our study. In addition, no treatment interaction was seen with CDS or with age on Cox MVA in this study, nor were CDS or age predictors on logistic MVA for the receipt of C + CRT. Since all patients in our study underwent adjuvant therapies, the difference in performance status between the C + CRT and other regimens is unlikely to independently explain the survival benefits.

5. CONCLUSION

In summary, this analysis suggests improved survival for adjuvant C + CRT following resected pancreatic cancer with node‐positive disease. More studies may be warranted to investigate the benefit of adding adjuvant chemotherapy to CRT and the ideal sequencing of these regimens.

CONFLICT OF INTEREST

All authors declare that they have no competing interests.

Ma SJ, Hermann GM, Prezzano KM, Serra LM, Iovoli AJ, Singh AK. Adjuvant chemotherapy followed by concurrent chemoradiation is associated with improved survival for resected stage I‐II pancreatic cancer. Cancer Med. 2019;8:939–952. 10.1002/cam4.1967

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