Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Equipping the American Joint Committee on Cancer Staging for Resectable Pancreatic Ductal Adenocarcinoma with Tumor Grade: A Novel Staging System

Equipping the American Joint Committee on Cancer Staging for Resectable Pancreatic Ductal... Hindawi Journal of Oncology Volume 2020, Article ID 9093729, 9 pages https://doi.org/10.1155/2020/9093729 Research Article Equipping the American Joint Committee on Cancer Staging for Resectable Pancreatic Ductal Adenocarcinoma with Tumor Grade: A Novel Staging System 1 1 1 1 1 Hu Ren, Chao-Rui Wu, Guo-Tong Qiu, Li-Peng Zhang, Saderbieke Aimaiti, 1,2 and Cheng-Feng Wang Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China Correspondence should be addressed to Cheng-Feng Wang; ywwangchengfeng@163.com Received 15 February 2020; Revised 29 August 2020; Accepted 5 September 2020; Published 21 September 2020 Academic Editor: Reza Izadpanah Copyright © 2020 Hu Ren et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. -e 8th American Joint Committee on Cancer (AJCC) staging system for pancreatic ductal adenocarcinoma (PDAC) outperforms its previous version in reproducibility but not in survival discrimination. Tumor grade, an indicator of the aggressive biology of PDAC, has been suggested as a reliable prognostic factor. -is study aimed to construct a novel staging system with greater prognostication for resectable PDAC by incorporating tumor grade into the 8th AJCC system. Methods. A total of 9966 patients with resectable PDAC from the Surveillance Epidemiology and End Results (SEER) database were randomly separated into training and interval validation sets. Another 324 patients from our center were included as an external validation set. We proposed a novel staging system by sorting the substages yielded by a combination of T, N, and tumor grade based on their overall survival (OS) and grouping them into several stages. Prognostic homogeneity and discrimination were determined using the 2 2 likelihood ratio χ and the linear trend χ test, respectively. Prognostic accuracies were evaluated by the area under the receiver operating characteristics curve (AUC). Results. Using the 8th AJCC system, the prognosis of patients within the same stage was quite heterogeneous among different substages. -e multivariate Cox model identified the tumor grade (hazard ratio 1.333, 95% confidence interval 1.250–1.423, p< 0.001) was an independent prognostic factor of the OS. In the training set, the AUC, homogeneity, and discriminatory ability were superior for the novel staging system than for the 8th AJCC system (0.642 vs. 0.615, 403.4 vs. 248.6, and 335.1 vs. 218.0, respectively). Similar results were observed in the internal and external validation sets. Conclusions. -e novel staging system incorporating tumor grade into the 8th AJCC system was associated with better prognostic accuracy, homogeneity, and discriminatory ability among resectable PDAC patients. Moreover, the novel staging system also allowed possibly adjuvant chemotherapy decisions. -e American Joint Committee on Cancer (AJCC) 1. Introduction staging system, which includes the depth of tumor invasion Pancreatic ductal adenocarcinoma (PDAC) remains one of (T) and nodal status (N), was the most frequently used the most lethal human malignancies, with little improve- prognosticator for PDAC patients. -e 8th AJCC staging ment in survival over the past decades [1]. -e five-year system has introduced major revisions to its previous ver- survival rate of PDAC is extremely low (approximately 8%), sion, including changes to T and N definitions [4]. -e new and PDAC is projected to be the second leading cause of T1–T3 definitions completely depend on tumor size, and T4 cancer mortality in the next decade [2, 3]. refers to tumors that involved the celiac axis, the superior 2 Journal of Oncology mesenteric artery, and/or common hepatic artery. Addi- 2.2. Data Collection. Demographic and clinicopathological tionally, node-positive disease (previous N1) was further variables extracted for each patient were as follows: age at diagnosis, year of diagnosis, gender, tumor size, tumor categorized into N1 (1–3 positive nodes) and N2 (≥4 positive nodes). However, although the reproducibility of the 8th extent, tumor location (head, body, tail, and others), tumor AJCC staging system was superior, it did not outperform grade (well-differentiated, moderately differentiated, poorly previous versions in terms of survival discrimination [5, 6]. differentiated, and undifferentiated), nodal status (number Survival curves of resectable stages IB, IIA, or IIB disease are of examined lymph nodes and number of positive lymph not well-separated. nodes), the 7th AJCC stage, and survival months. With With the evolving understanding of PDAC biology, the staging information inferred from the 7th AJCC stage, spectrum of biologic factors that are predictive of prognosis patients enrolled in the current study were restaged in and treatment response was rapidly expanding [7, 8]. In compliance with new T, N definitions introduced to the 8th addition to tumor size and lymph node status, those emerging AJCC staging system. Tumor differentiation refers to the biologic factors should also be incorporated into the existing extent to which a tumor cell morphologically and func- tionally resembles a normal cell from the same tissue. -e staging system for more accurate survival prediction [9–12]. Tumor grade, which represents the aggressive biology of the extent of glandular differentiation dictates the histologic tumor itself, has been widely confirmed as a prognostic factor grade of PDAC. A tumor with unrecognizable tissue of in PDAC [13]. Wasif et al. [14] proposed a new staging system origin was graded as undifferentiated, < 50% of its com- by combining the tumor grade and the 7th AJCC stage, which ponents being gland as poorly differentiated, 50%–95% as significantly optimized survival discrimination. However, this moderately differentiated, and > 95% as well-differentiated. proposed staging scheme arbitrarily upstaged patients with In this study, to minimize interinstitution and interobserver high tumor grade and downstaged patients with low tumor variance in the pathological assessment of tumor grade, grade, which was methodologically questionable. Chen et al. tumor grade was dichotomously subdivided into the low [15] have combined tumor grade and the 8th AJCC staging grade (well to moderately differentiated, G1) and the high system into a novel staging system using the SEER database. grade (poorly to undifferentiated, G2). Liu et al. [16] also proposed a novel one by integrating the tumor grade and postoperative CA19-9 levels with the 8th 2.3. Statistical Analysis. OS, the primary endpoint in this AJCC staging system in their single-institutional dataset. study, was defined as the duration from the date of initial However, neither of them had attempted to cross-validate diagnosis to the date of death or last follow-up (updated on their staging schemes. June 1, 2019). -e univariate and multivariate Cox propor- -is study aimed to assess the performance of the 8th tional hazard regression analysis was performed to identify AJCC staging system and the impact of tumor grade on the independent prognostic predictors for the OS. -e OS was overall survival (OS). We sought to incorporate tumor grade analyzed by the Kaplan–Meier survival curves, and log-rank into the 8th AJCC system to form a novel staging system and tests were utilized to evaluate the staging systems. -e per- validate it both internally and externally. formance of these staging systems was graded based on the area under the curve (AUC), homogeneity, and discrimina- tory ability. -e AUC was compared between the two staging 2. Materials and Methods systems using DeLong’s method. Homogeneity, a measure of differences in OS among patients with the same stage within 2.1. Study Cohort. -e National Cancer Institute’s Sur- each staging system, was calculated using the likelihood ratio veillance, Epidemiology, and End Results (SEER) database, χ2 through the Cox regression model [17]. Discriminatory which collects cancer incidence, treatment, and survival ability, a measure of differences in OS among patients in data from 18 population-based cancer registries in the US, different stages within each staging system, was calculated was used to establish the novel staging system for resectable using the linear trend χ test [18]. All tests were 2-sided, and PDAC. We identified patients with locally resectable PDAC p< 0.05 was considered statistically significant. Statistical (ICD-O-3 codes 8500/3 and 8140/3, respectively) from analyses were performed using SPSS software version 25.0 2004 to 2015. Cases with locally unresectable tumor (PDAC (SPSS Inc., Chicago, IL, USA). with unreconstructable SMV or PV occlusion, and clas- sified as T4 by the 8th AJCC staging system), distant metastasis, history of prior malignancy, age at diagnosis 3. Results and Discussion younger than 18 years, and missing information regarding tumor grade, tumor size, tumor extent, and nodal status or 3.1. Baseline Characteristics. A total of 9966 patients with OS were excluded. Finally, a total of 9966 patients with resectable PADC from the SEER database (2004–2015) were resectable PDAC were eligible, which were randomly enrolled, which was split equally into a training set partitioned into disjoint datasets for model training (n � 4983) and an internal validation set (n � 4983). In ad- (n � 4983) and internal validation (n � 4983). To validate dition, a total of 324 patients with resectable PDAC diag- the novel staging system, 324 patients with resectable nosed from 2010 to 2017 at the China National Cancer PDAC that matched the inclusion criteria at the China Center were enrolled as an external validation set. -e National Cancer Center between January 2010 and October detailed patients’ characteristics of the three cohorts are 2017 were included as an external validation set. shown in Table 1. All clinicopathological characteristics were Journal of Oncology 3 Table 1: Baseline clinicopathologic characteristics. Training set (n � 4983) Internal validation set (n � 4983) External validation set (n � 324) Characteristics (%) (%) (%) Age, yrs <65 2172 (43.6) 2185 (43.8) 212 (65.4) ≥65 2811 (56.4) 2798 (56.2) 112 (34.6) Sex Male 2461 (49.4) 2478 (49.7) 136 (42.0) Female 2522 (50.6) 2505 (50.3) 188 (58.0) Location Head 3832 (76.8) 3842 (77.1) 161 (49.7) Body and tail 704 (14.2) 717 (14.4) 163 (50.3) Other 447 (9.0) 424 (8.5) 0 (0) Year of diagnosis 2004–2009 2049 (41.1) 2010 (40.3) — 2010–2015 2934 (58.9) 2973 (59.7) — Grade Low grade 3063 (61.5) 3115 (62.5) 165 (50.9) High grade 1920 (38.5) 1868 (37.5) 159 (49.1) Examined lymph nodes <15 2187 (46.1) 2221 (46.6) 183 (56.5) ≥15 2558 (53.9) 2547 (53.4) 141 (43.5) 7th AJCC stage IA 188 (3.8) 192 (3.9) 7 (2.2) IB 270 (5.4) 292 (5.9) 36 (11.1) IIA 1105 (22.2) 1081 (21.7) 130 (40.1) IIB 3418 (68.6) 3417 (68.5) 151 (46.6) 8th T stage T1 833 (16.7) 801 (16.1) 44 (13.5) T2 2928 (58.8) 3023 (60.7) 179 (54.9) T3 1222 (24.5) 1159 (23.3) 103 (31.6) 8th N stage N0 1610 (32.3) 1591 (31.9) 180 (55.2) N1 2084 (41.8) 2114 (42.4) 112 (34.4) N2 1289 (25.9) 1278 (25.6) 34 (10.4) Extrapancreatic invasion 8th AJCC 4106 (82.4) 4100 (82.3) 250 (76.7) stage IA 393 (7.9) 379 (7.6) 24 (7.4) IB 886 (17.8) 885 (17.8) 97 (29.9) IIA 331 (6.6) 327 (6.6) 58 (17.9) IIB 2084 (41.8) 2114 (42.4) 111 (34.3) III 1289 (25.9) 1278 (25.6) 34 (10.5) Median OS (95% CI) 19 (18.4–19.6) 19.0 (18.4–19.6) 23.6 (19.4–27.8) Values in parentheses are percentages. comparable between the training set and the internal vali- (p< 0.001), year of diagnosis (p< 0.001), tumor grade dation set. Compared with the training set and internal (p< 0.001), number of examined lymph nodes (p< 0.001), validation set, the external validation set was associated with extrapancreatic invasion (p< 0.001), tumor size (p< 0.001), a higher proportion of female patients, patients with age at and number of metastatic lymph nodes (p< 0.001) were diagnosis <65 years, tumors located at the body and tail of identified as independent prognostic factors for OS. pancreas, higher tumor grade, less than 15 harvested lymph nodes, tumor located within pancreas, less advanced path- 3.3. Development of a Novel Staging System in the Training Set. ological N stage, less advanced 7th AJCC, and less advanced To evaluate the accuracy and appropriateness of the 8th 8th AJCC stage. -e median OS of the training set, internal AJCC staging system, the median OS of each substage from validation set, and external validation set were 19.0, 19.0, and the training set was calculated. Even within the same tumor 23.6 months, respectively. stage, the median OS was quite heterogeneous across dif- 3.2. Independent Prognostic Factors of Survival in the Training ferent substages (Figure 1(a)). For example, within stage ?, Set. -e univariate and multivariate analysis results are the median OS for T1N2M0, T2N2M0, and T3N2M0 was shown in Table 2. In the training set, age at diagnosis 18.5, 14.0, and 11.3 months, respectively (p< 0.001). 4 Journal of Oncology Table 2: Univariate and multivariate analysis for overall survival of patients in the training set. Multivariate analysis Characteristics Univariate analysis p value HR (95% CI) p value Age, yrs (<65) ≥65 <0.001 1.175 (1.102–1.254) <0.001 Sex (male) Female 0.507 Location (head) Body and tail 0.088 Other 0.608 Year of diagnosis (2004–2009) 2010–2015 <0.001 0.638 (0.597–0.681) <0.001 Grade (low grade) High grade <0.001 1.333 (1.250–1.423) <0.001 Examined lymph nodes (<15) ≥15 <0.001 0.800 (0.748–0.856) <0.001 Extrapancreatic invasion 8th T stage (T1) <0.001 1.199 (1.097–1.310) <0.001 T2 <0.001 1.340 (1.200–1.473) <0.001 T3 <0.001 1.549 (1.394–1.722) <0.001 8th N stage (N0) N1 <0.001 1.336 (1.235–1.445) <0.001 N2 <0.001 1.793 (1.639–1.961) <0.001 7th AJCC stage (IA) IB <0.001 IIA <0.001 IIB <0.001 Abbreviations: HR, hazard ratio; CI, confidence interval. Moreover, patients with stage IIB T1N1M0 tumors survived by the novel system, respectively. -e proportion of stage IIA longer than patients with stage IIA T3N0M0 tumors (me- disease by the novel stage was much higher than that of stage dian OS: 20.8 vs 17.8 months; p< 0.001). Similarly, patients IIA disease by the 8th AJCC system in the three cohorts. with stage III T1N2M0 tumors survived longer than patients Suggested by the well-separated survival curves for the with stage IIB T3N1M0 tumors (median OS: 18.5 vs 13.9 three cohorts (Figure 1(d), Figures 3(b) and 3(d)), the novel months; p< 0.001). Based on the results of multivariate staging system showed better prognostic discrimination analysis, the tumor grade was incorporated into the 8th compared with the 8th AJCC staging system (Figure 1(c) and Figures 3(a) and 3(c)). A good separation of survival curves AJCC system to form a novel staging system, which resulted in 18 substages. According to the median OS of each sub- between stages IIA and IIB disease was also noticed. -e results stage, these substages were regrouped into five stage groups, of performance evaluation for the three staging systems are including novel IA (G1T1N0), novel IB (G1T1N1, G1T2N0, shown in Table 3. In the training set, the respective 3-year and G2T1N0), novel IIA (G1T1N2, G1T2N1, G1T3N0, AUCs of the 8th AJCC and the novel staging system were G2T1N1, and G2T2N0), novel IIB (G1T2N2, G1T3N1, 0.615, and 0.642, respectively (p< 0.001). -e likelihood ratios G1T3N2, G2T1N2, G2T2N1, and G2T3N0), and novel III χ , which was a measure of homogeneity, of the 8th AJCC and (G2T2N2, G2T3N1, and G2T3N2) (Figure 1(b)). the novel staging system was 248.6 and 403.4, respectively. -e discriminatory ability of each system from the linear trend χ test was 218.0 and 335.1, respectively. Similar results were 3.4. Comparison between the 8th AJCC and the Novel Staging observed in the internal and external validation sets. System. A histogram showing the distribution of patients across different substages within in the three cohorts are shown (Figure 2). In the training set, 7.9%, 17.8%, 6.6%, 41.8%, and 3.5. 6is Novel Staging System Predicted Survival Benefits from 25.9% of the patients were assigned to stage IA, IB, IIA, IIB, and Adjuvant Chemotherapy. Analysis of the external validation III (T1-3N2M0) tumors by the 8th AJCC staging system, re- set showed that the median OS was prolonged by adjuvant spectively, while 5.9%, 29.8%, 48.8%, 31.9%, and 15.1% of the chemotherapy (31.2 versus 16.8 months, p � 0.005). -e patients were assigned to stages IA, IB, IIA, IIB, and III (T1- adjuvant chemotherapy benefit was subsequently deter- 3N2M0) tumors by the novel staging system, respectively. As to mined in each stage within the 8th AJCC and the novel the external validation set, 7.4%, 29.8%, 18.1%, 34.4%, and staging system. In the subgroup of patients with novel stage 10.4% of the patients were assigned to stages IA, IB, IIA, IIB, and IA- IIA disease, there was no significant difference in median III (T1-3N2M0) tumors by the 8th AJCC system, respectively, OS between patients who received adjuvant chemotherapy while 6.1%, 21.2%, 32.8%, 26.4%, and 13.5% of the patients were and patients who did not (35.4 versus 30.4 months, assigned to stages IA, IB, IIA, IIB, and III (T1-3N2M0) tumors p � 0.740, Figure 4(a)). Patients with 8th AJCC stage IA- IIA Journal of Oncology 5 8th AJCC Novel staging system G1T1N0 IA T1N0 IA G1T1N1 IB G1T2N0 IB T2N0 G2T1N0 IIA G1T1N2 T3N0 G1T2N1 IIA G1T3N0 T1N1 G2T1N1 IIB G2T2N0 T2N1 G1T2N2 G1T3N1 T3N1 G1T3N2 IIB G2T1N2 T1N2 G2T2N1 III G2T3N0 T2N2 G2T2N2 G2T3N1 III T3N2 G2T3N2 010 20 30 40 010 20 30 40 Median overall survival (months) Median overall survival (months) (a) (b) 8th AJCC Novel staging system 100 100 P < 0.0001 P < 0.0001 80 80 60 60 40 40 020 40 60 020 40 60 Time (months) Time (months) IA IIB IA IIB IB III IB III IIA IIA (c) (d) Figure 1: Staging system and corresponding Kaplan-Meier survival curves for the training set; TN stages and survival duration using the 8th AJCC staging system (a), G (grade)-TN stages and survival duration using the novel staging system (b), Kaplan-Meier survival curves for the patients using the 8th AJCC staging system (c), or novel staging system (d). disease had a similar result (31.2 versus 31.4, p � 0.144, revised the existing parameters might fail to gain a satisfying performance of survival discrimination. Figure 4(c)). Whereas in the subgroup of patients with the novel or 8th AJCC stage IIB-III disease, there was a survival In the novel staging system, a moderate improvement in benefit in patients who received adjuvant chemotherapy survival discrimination was demonstrated by the elevated (novel stage IIB-III, median OS, 20.7 versus 9.3 months, AUCs of survival prediction. A good separation of survival p< 0.001, Figure 4(b); 8th AJCC stage IIB-III, median OS, curves between stages IIA and IIB disease was also noticed. 24.9 versus 11.1 months, p< 0.001, Figure 4(d)). Prognostic homogeneity and discriminatory ability were also significantly optimized by the novel staging system. Furthermore, we found that this novel staging system had 4. Discussion another role in addition to the prediction of survival for Supported by the previous studies [5, 6, 19, 20], a moderate resectable PDAC. Although chemotherapy remained the improvement in the accuracy of prediction was yielded by only effective option of systemic therapy, the survival benefit it offered was quite limited, and only a few patients would the 8th AJCC staging system. Nevertheless, the survival curves for stages IIA and IIB disease were not clearly sep- respond to chemotherapy [21]. So far, there is a paucity of arated in the 8th AJCC system, and the overall discrimi- tools to select the subset of patients who would benefit from nation was only marginally enhanced compared with the 7th adjuvant chemotherapy [22]. In the current study, only AJCC system. -us, the 8th AJCC system for resectable patients with the 8th AJCC and novel stages IIB or III disease PDAC is far from accurate, and improvement should be could benefit from adjuvant chemotherapy, which suggested considered. So far, revisions of the AJCC staging system for that the tumor grade as well as the tumor stage were reliable PDAC largely relied on changes to T and N definitions [4], indicators of the tumor burden. As shown in Figure 1, the leading us to consider that a staging system that merely novel staging system can provide more accurate survival TN stage Percent survival (%) G-TN stage Percent survival (%) 6 Journal of Oncology Training set Internal validation set 2000 2000 1500 1500 500 500 0 0 IA IB IIA IIB III IA IB IIA IIB III 8th AJCC staging system 8th AJCC staging system Novel staging system Novel staging system (a) (b) External validation set IA IB IIA IIB III 8th AJCC staging system Novel staging system (c) Figure 2: -e histogram showing the distribution of patients across different substages within the 8th AJCC or novel staging system. prediction for resectable PDAC by incorporating tumor Most researchers performed an initial analysis in their grade into the 8th AJCC system. -e information on tumor single-institution dataset before seeking validation within a grade could inform the efficacy of adjuvant chemotherapy larger multi-institution dataset, hoping the analysis can be for patients within the same 8th AJCC staging system. We equally effective in other centers [6, 19, 23], while in the think the novel staging system may be a simple and feasible current study, we utilized the SEER database as the training supplement for the 8th AJCC system to identify patients who set rather than our institution’s patients. -e sample of our would benefit from adjuvant chemotherapy. single-institution cohort was not adequate enough to es- Chen et al. [15] have combined tumor grade and the 8th tablish a reliable staging system. -e sample size of the SEER database was adequate while it only included patients from AJCC staging system into a novel staging system using the SEER database. Liu et al. [16] also proposed a novel one by the USA. Moreover, the characteristics were significantly different between the SEER database and the external cohort, integrating the tumor grade and postoperative CA19-9 levels with the 8th AJCC staging system in their single-institu- which was possibly reflective of the difference between the tional dataset. However, the external validations of their western and eastern PDAC patients. -erefore, we decided staging schemes were lacking in their studies. In contrast, the to establish a novel staging system from the SEER database newly proposed staging system described in this study has and validate it in an external cohort to evaluate its appli- been cross-validated in both the SEER database and our cability in eastern patients. center. Furthermore, lots of nomograms in which diverse In the current study, we observed that the nodal status prognostic factors were included have been developed to was less advanced in the external dataset, but there was no yield absolute prediction [10–12]. However, both patients significant difference in tumor size between the SEER data and the external dataset. A smaller proportion of patients and clinicians were reluctant to use these nomograms, mostly because of their complexity and the difficulty of using with a tumor located at the head of pancreas in the external dataset may account for the smaller number of harvested and them. In contrast, our proposed staging system only in- cluded three components and was subdivided into five stage metastatic lymph nodes. Furthermore, the interinstitutional groups, which was simpler than nomograms. -e tumor variance also accounts for the discrepancy in part. grade was easy to obtain, which was routinely reported by -is novel staging system tends to downstage node- pathologists. Although the incorporation of the tumor grade positive disease (T1N1, T2N1, T1N2, and T2N2) regardless complicated the staging system, it significantly optimized the of grade classification. A recent study by Shi et al. [19] prediction accuracy of the existing AJCC staging system. demonstrated that the median OS of patients in the same 8th Journal of Oncology 7 8th AJCC Novel staging system P < 0.0001 P < 0.0001 40 40 20 20 0 20 40 60 0 20 40 60 Time (months) Time (months) IA IIB IA IIB IB III IB III IIA IIA (a) (b) 8th AJCC Novel staging system 100 100 P = 0.0011 P < 0.0001 80 80 60 60 40 40 20 20 0 0 0 20 40 60 0 20 40 60 Time (months) Time (months) IA IIB IA IIB IB III IB III IIA IIA (c) (d) Figure 3: Kaplan-Meier survival curves for the internal validation set using the 8th AJCC staging system (a) or novel staging system (b). Kaplan-Meier survival curves for the external validation set using the 8th AJCC staging system (c) or novel staging system (d). Table 3: Performance evaluation of the 8th AJCC and the novel staging system. Staging system AUC for 3-year OS (95% CI) p value Homogeneity (likelihood ratio χ ) Discriminatory ability (linear trend χ2) Training set 8th AJCC 0.615 (0.598–0.633) 248.6 218.0 Novel 0.642 (0.624–0.659) <0.001 403.4 335.1 Internal validation set 8th AJCC 0.603 (0.585–0.621) 182.6 154.7 Novel 0.621 (0.604–0.639) <0.001 261.9 218.2 External validation set 8th AJCC 0.596 (0.523–0.670) 15.2 24.6 Novel 0.658 (0.590–0.727) 0.008 33.8 35.7 Higher AUC, discriminatory ability, and homogeneity indicate better performance of the staging system. Abbreviations: AUC, area under the curve. CI, confidence interval. AJCC stage varied widely among the different substages, and survival duration than other substages within the same stage, they proposed a modified staging system by regrouping the which was in accordance with our results. substages. In their proposed staging system, T1N1, T2N1, Some limitations should not be ignored. First, despite T1N2, and T2N2 were downstaged as a result of longer a superior performance of the novel staging system, the Percent survival (%) Percent survival (%) Percent survival (%) Percent survival (%) 8 Journal of Oncology 100 100 80 80 P = 0.740 P < 0.001 60 60 40 40 20 20 0 0 0 20 40 60 0 20 40 60 Time (months) Time (months) No chemotherapy No chemotherapy Chemotherapy Chemotherapy (a) (b) 100 100 80 80 P = 0.144 P < 0.001 60 60 40 40 20 20 0 0 0 20 40 60 80 100 0 20 40 60 80 Time (months) Time (months) No chemotherapy No chemotherapy Chemotherapy Chemotherapy (c) (d) Figure 4: Kaplan-Meier curves showed the response to chemotherapy classified by the novel staging system (stages IA-IIA (a) and stages IIB-III (b)), and the 8th AJCC staging system (stages IA-IIA (c) and stage IIB-III (d)) in the external validation set. Survival curves of the training set and internal validation set are not shown as there was a lack of chemotherapy information in the SEER database. addition of tumor grade created a more complicated 5. Conclusions system than the AJCC 8th system. Second, the period of In conclusion, our newly proposed staging system was as- the current study was more limited as the preoperative sociated with better prognostic accuracy, homogeneity, and radiographic assessment and postoperative adjuvant discriminatory ability among PDAC patients after pancre- therapies of the included patients would be more uniform. atectomy compared with the 8th AJCC staging system. -ird, we cannot eliminate interinstitution and interob- Moreover, the novel staging system also allows possible server variance in protocols for pathological assessment of adjuvant chemotherapy decisions. We believe that the su- tumor grade. -e two-tiered grading system adopted in periority of this staging system stems from new revisions to this study which divided the grade into high and low could the 8th AJCC Tand N definitions and the inclusion of tumor partially minimize that variance. Fourthly, the external grade that reflects the aggressive behavior of PDAC. validation set has a significantly higher OS compared with However, external validation from other populations is the two other sets from the SEER database, which may necessary. undermine the efficacy of validation. Finally, the survival discrimination was only moderately improved by the proposed staging system, which owns to insufficient in- Data Availability clusion of predictive factors needed for absolute predic- tion. For example, although the prognostic value of -e data used to support the findings of this study are various clinicopathological factors, such as preoperative available from the corresponding author upon request. CA19-9 level, resection margin status, lymphovascular invasion, nerve invasion, and adjuvant chemotherapy Conflicts of Interest have already been validated by previous studies [16, 21], they were not included as a lack of these information in -e authors declare that there are no conflicts of interest SEER database. regarding the publication of this paper. Percent survival (%) Percent survival (%) Percent survival (%) Percent survival (%) Journal of Oncology 9 pancreatic cancer treated with chemoradiotherapy,” Radio- Authors’ Contributions therapy and Oncology, vol. 129, no. 2, pp. 340–346, 2018. [13] M. Strijker, J. W. Chen, T. H. Mungroop et al., “Systematic Hu Ren Chao-Rui Wu contributed equally to this work. review of clinical prediction models for survival after surgery for resectable pancreatic cancer,” British Journal of Surgery, Acknowledgments vol. 106, no. 4, pp. 342–354, 2019. [14] N. Wasif, C. Y. Ko, J. Farrell et al., “Impact of tumor grade on -is work was supported by the CAMS Innovation Fund for prognosis in pancreatic cancer: should we include grade in Medical Sciences (CIFMS) (grant number: 2016-I2M-1-001). AJCC staging?” Annals of Surgical Oncology, vol. 17, no. 9, -e authors thank the SEER program for providing open pp. 2312–2320, 2010. access to the database. [15] Y.-T. Chen, Z.-P. Huang, Z.-W. Zhou, and M.-M. He, “Equipping the American Joint Committee on Cancer staging for resectable pancreatic ductal adenocarcinoma with tumor References grade: a recursive partitioning analysis,” Medical Oncology, vol. 33, no. 11, pp. 1–8, 2016. [1] A. McGuigan, P. Kelly, R. C. Turkington, C. Jones, [16] L. Liu, H.-X. Xu, M. He et al., “A novel scoring system predicts H. G. Coleman, and R. S. McCain, “Pancreatic cancer: a postsurgical survival and adjuvant chemotherapeutic benefits review of clinical diagnosis, epidemiology, treatment and in patients with pancreatic adenocarcinoma: implications for outcomes,” World Journal of Gastroenterology, vol. 24, no. 43, AJCC-TNM staging,” Surgery, vol. 163, no. 6, pp. 1280–1294, pp. 4846–4861, 2018. [2] L. Rahib, B. D. Smith, R. Aizenberg, A. B. Rosenzweig, [17] D. W. Hosmer, T. Hosmer, S. Le Cessie, and S. Lemeshow, “A J. M. Fleshman, and L. M. Matrisian, “Projecting cancer in- comparison of goodness-of-fit tests for the logistic regression cidence and deaths to 2030: the unexpected burden of thyroid, model,” Statistics in Medicine, vol. 16, no. 9, pp. 965–980, liver, and pancreas cancers in the United States,” Cancer Research, vol. 74, no. 11, pp. 2913–2921, 2014. [18] A. R. Feinstein, “XVI. -e process of prognostic stratification [3] V. L. Gordon-Dseagu, S. S. Devesa, M. Goggins, and (Part 2),” Clinical Pharmacology & 6erapeutics, vol. 13, no. 4, R. Stolzenberg-Solomon, “Pancreatic cancer incidence trends: pp. 609–624, 1972. evidence from the Surveillance, Epidemiology and End Re- [19] S. Shi, J. Hua, C. Liang et al., “Proposed modification of the sults (SEER) population-based data,” International Journal of 8th edition of the AJCC staging system for pancreatic ductal Epidemiology, vol. 47, no. 2, pp. 427–439, 2018. adenocarcinoma,” Annals of Surgery, vol. 269, no. 5, [4] M. B. Amin, S. Edge, F. Greene et al., AJCC Cancer Staging pp. 944–950, 2019. Manual, Springer, Berlin, Germany, 8th edition, 2017. [20] P. J. Allen, D. Kuk, C. F.-d. Castillo et al., “Multi-institutional [5] A. M. Schlitter, M. Jesinghaus, C. Jager ¨ et al., “pT but not pN validation study of the American Joint commission on cancer stage of the 8th TNM classification significantly improves (8th edition) changes for T and N staging in patients with prognostication in pancreatic ductal adenocarcinoma,” Eu- pancreatic adenocarcinoma,” Annals of Surgery, vol. 265, ropean Journal of Cancer, vol. 84, pp. 121–129, 2017. no. 1, pp. 185–191, 2017. [6] S. van Roessel, G. G. Kasumova, J. Verheij et al., “International [21] H. Oettle, P. Neuhaus, A. Hochhaus et al., “Adjuvant che- validation of the eighth edition of the American Joint com- motherapy with gemcitabine and long-term outcomes among mittee on cancer (AJCC) TNM staging system in patients with patients with resected pancreatic cancer,” JAMA, vol. 310, resected pancreatic cancer,” JAMA Surgery, vol. 153, no. 12, no. 14, pp. 1473–1481, 2013. Article ID e183617, 2018. [22] P. Martinelli, E. Carrillo-de Santa Pau, T. Cox et al., “GATA6 [7] Y. R. Lawrence, J. Moughan, A. M. Magliocco et al., “Ex- regulates EMT and tumour dissemination, and is a marker of pression of the DNA repair gene MLH1 correlates with response to adjuvant chemotherapy in pancreatic cancer,” survival in patients who have resected pancreatic cancer and Gut, vol. 66, no. 9, pp. 1665–1676, 2017. have received adjuvant chemoradiation: NRG Oncology [23] M. Song, S. B. Yoon, I. S. Lee et al., “Evaluation of the RTOG Study 9704,” Cancer, vol. 124, no. 3, pp. 491–498, 2018. prognostic value of the new AJCC 8th edition staging system [8] D. Liang, S. Shi, C. Liang et al., “Mismatch repair status as a for patients with pancreatic adenocarcinoma; a need to beneficial predictor of fluorouracil-based adjuvant chemo- subclassify stage III?” European Journal of Cancer, vol. 104, therapy for pancreatic cancer,” Surgery, vol. 163, no. 5, pp. 62–69, 2018. pp. 1080–1089, 2018. [9] M. M. Rochefort, J. S. Ankeny, B. E. Kadera et al., “Impact of tumor grade on pancreatic cancer prognosis: validation of a novel TNMG staging system,” Annals of Surgical Oncology, vol. 20, no. 13, pp. 4322–4329, 2013. [10] Y.-N. Shen, X.-L. Bai, G. Jin et al., “A preoperative nomogram predicts prognosis of up front resectable patients with pan- creatic head cancer and suspected venous invasion,” Hpb, vol. 20, no. 11, pp. 1034–1043, 2018. [11] J. Hang, L. Wu, L. Zhu et al., “Prediction of overall survival for metastatic pancreatic cancer: development and validation of a prognostic nomogram with data from open clinical trial and real-world study,” Cancer Medicine, vol. 7, no. 7, pp. 2974–2984, 2018. [12] S. H. Choi, S. W. Park, and J. Seong, “A nomogram for predicting survival of patients with locally advanced http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Oncology Hindawi Publishing Corporation

Equipping the American Joint Committee on Cancer Staging for Resectable Pancreatic Ductal Adenocarcinoma with Tumor Grade: A Novel Staging System

Loading next page...
 
/lp/hindawi-publishing-corporation/equipping-the-american-joint-committee-on-cancer-staging-for-EENlGV00DG

References (25)

Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2020 Hu Ren et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
1687-8450
eISSN
1687-8469
DOI
10.1155/2020/9093729
Publisher site
See Article on Publisher Site

Abstract

Hindawi Journal of Oncology Volume 2020, Article ID 9093729, 9 pages https://doi.org/10.1155/2020/9093729 Research Article Equipping the American Joint Committee on Cancer Staging for Resectable Pancreatic Ductal Adenocarcinoma with Tumor Grade: A Novel Staging System 1 1 1 1 1 Hu Ren, Chao-Rui Wu, Guo-Tong Qiu, Li-Peng Zhang, Saderbieke Aimaiti, 1,2 and Cheng-Feng Wang Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China Correspondence should be addressed to Cheng-Feng Wang; ywwangchengfeng@163.com Received 15 February 2020; Revised 29 August 2020; Accepted 5 September 2020; Published 21 September 2020 Academic Editor: Reza Izadpanah Copyright © 2020 Hu Ren et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. -e 8th American Joint Committee on Cancer (AJCC) staging system for pancreatic ductal adenocarcinoma (PDAC) outperforms its previous version in reproducibility but not in survival discrimination. Tumor grade, an indicator of the aggressive biology of PDAC, has been suggested as a reliable prognostic factor. -is study aimed to construct a novel staging system with greater prognostication for resectable PDAC by incorporating tumor grade into the 8th AJCC system. Methods. A total of 9966 patients with resectable PDAC from the Surveillance Epidemiology and End Results (SEER) database were randomly separated into training and interval validation sets. Another 324 patients from our center were included as an external validation set. We proposed a novel staging system by sorting the substages yielded by a combination of T, N, and tumor grade based on their overall survival (OS) and grouping them into several stages. Prognostic homogeneity and discrimination were determined using the 2 2 likelihood ratio χ and the linear trend χ test, respectively. Prognostic accuracies were evaluated by the area under the receiver operating characteristics curve (AUC). Results. Using the 8th AJCC system, the prognosis of patients within the same stage was quite heterogeneous among different substages. -e multivariate Cox model identified the tumor grade (hazard ratio 1.333, 95% confidence interval 1.250–1.423, p< 0.001) was an independent prognostic factor of the OS. In the training set, the AUC, homogeneity, and discriminatory ability were superior for the novel staging system than for the 8th AJCC system (0.642 vs. 0.615, 403.4 vs. 248.6, and 335.1 vs. 218.0, respectively). Similar results were observed in the internal and external validation sets. Conclusions. -e novel staging system incorporating tumor grade into the 8th AJCC system was associated with better prognostic accuracy, homogeneity, and discriminatory ability among resectable PDAC patients. Moreover, the novel staging system also allowed possibly adjuvant chemotherapy decisions. -e American Joint Committee on Cancer (AJCC) 1. Introduction staging system, which includes the depth of tumor invasion Pancreatic ductal adenocarcinoma (PDAC) remains one of (T) and nodal status (N), was the most frequently used the most lethal human malignancies, with little improve- prognosticator for PDAC patients. -e 8th AJCC staging ment in survival over the past decades [1]. -e five-year system has introduced major revisions to its previous ver- survival rate of PDAC is extremely low (approximately 8%), sion, including changes to T and N definitions [4]. -e new and PDAC is projected to be the second leading cause of T1–T3 definitions completely depend on tumor size, and T4 cancer mortality in the next decade [2, 3]. refers to tumors that involved the celiac axis, the superior 2 Journal of Oncology mesenteric artery, and/or common hepatic artery. Addi- 2.2. Data Collection. Demographic and clinicopathological tionally, node-positive disease (previous N1) was further variables extracted for each patient were as follows: age at diagnosis, year of diagnosis, gender, tumor size, tumor categorized into N1 (1–3 positive nodes) and N2 (≥4 positive nodes). However, although the reproducibility of the 8th extent, tumor location (head, body, tail, and others), tumor AJCC staging system was superior, it did not outperform grade (well-differentiated, moderately differentiated, poorly previous versions in terms of survival discrimination [5, 6]. differentiated, and undifferentiated), nodal status (number Survival curves of resectable stages IB, IIA, or IIB disease are of examined lymph nodes and number of positive lymph not well-separated. nodes), the 7th AJCC stage, and survival months. With With the evolving understanding of PDAC biology, the staging information inferred from the 7th AJCC stage, spectrum of biologic factors that are predictive of prognosis patients enrolled in the current study were restaged in and treatment response was rapidly expanding [7, 8]. In compliance with new T, N definitions introduced to the 8th addition to tumor size and lymph node status, those emerging AJCC staging system. Tumor differentiation refers to the biologic factors should also be incorporated into the existing extent to which a tumor cell morphologically and func- tionally resembles a normal cell from the same tissue. -e staging system for more accurate survival prediction [9–12]. Tumor grade, which represents the aggressive biology of the extent of glandular differentiation dictates the histologic tumor itself, has been widely confirmed as a prognostic factor grade of PDAC. A tumor with unrecognizable tissue of in PDAC [13]. Wasif et al. [14] proposed a new staging system origin was graded as undifferentiated, < 50% of its com- by combining the tumor grade and the 7th AJCC stage, which ponents being gland as poorly differentiated, 50%–95% as significantly optimized survival discrimination. However, this moderately differentiated, and > 95% as well-differentiated. proposed staging scheme arbitrarily upstaged patients with In this study, to minimize interinstitution and interobserver high tumor grade and downstaged patients with low tumor variance in the pathological assessment of tumor grade, grade, which was methodologically questionable. Chen et al. tumor grade was dichotomously subdivided into the low [15] have combined tumor grade and the 8th AJCC staging grade (well to moderately differentiated, G1) and the high system into a novel staging system using the SEER database. grade (poorly to undifferentiated, G2). Liu et al. [16] also proposed a novel one by integrating the tumor grade and postoperative CA19-9 levels with the 8th 2.3. Statistical Analysis. OS, the primary endpoint in this AJCC staging system in their single-institutional dataset. study, was defined as the duration from the date of initial However, neither of them had attempted to cross-validate diagnosis to the date of death or last follow-up (updated on their staging schemes. June 1, 2019). -e univariate and multivariate Cox propor- -is study aimed to assess the performance of the 8th tional hazard regression analysis was performed to identify AJCC staging system and the impact of tumor grade on the independent prognostic predictors for the OS. -e OS was overall survival (OS). We sought to incorporate tumor grade analyzed by the Kaplan–Meier survival curves, and log-rank into the 8th AJCC system to form a novel staging system and tests were utilized to evaluate the staging systems. -e per- validate it both internally and externally. formance of these staging systems was graded based on the area under the curve (AUC), homogeneity, and discrimina- tory ability. -e AUC was compared between the two staging 2. Materials and Methods systems using DeLong’s method. Homogeneity, a measure of differences in OS among patients with the same stage within 2.1. Study Cohort. -e National Cancer Institute’s Sur- each staging system, was calculated using the likelihood ratio veillance, Epidemiology, and End Results (SEER) database, χ2 through the Cox regression model [17]. Discriminatory which collects cancer incidence, treatment, and survival ability, a measure of differences in OS among patients in data from 18 population-based cancer registries in the US, different stages within each staging system, was calculated was used to establish the novel staging system for resectable using the linear trend χ test [18]. All tests were 2-sided, and PDAC. We identified patients with locally resectable PDAC p< 0.05 was considered statistically significant. Statistical (ICD-O-3 codes 8500/3 and 8140/3, respectively) from analyses were performed using SPSS software version 25.0 2004 to 2015. Cases with locally unresectable tumor (PDAC (SPSS Inc., Chicago, IL, USA). with unreconstructable SMV or PV occlusion, and clas- sified as T4 by the 8th AJCC staging system), distant metastasis, history of prior malignancy, age at diagnosis 3. Results and Discussion younger than 18 years, and missing information regarding tumor grade, tumor size, tumor extent, and nodal status or 3.1. Baseline Characteristics. A total of 9966 patients with OS were excluded. Finally, a total of 9966 patients with resectable PADC from the SEER database (2004–2015) were resectable PDAC were eligible, which were randomly enrolled, which was split equally into a training set partitioned into disjoint datasets for model training (n � 4983) and an internal validation set (n � 4983). In ad- (n � 4983) and internal validation (n � 4983). To validate dition, a total of 324 patients with resectable PDAC diag- the novel staging system, 324 patients with resectable nosed from 2010 to 2017 at the China National Cancer PDAC that matched the inclusion criteria at the China Center were enrolled as an external validation set. -e National Cancer Center between January 2010 and October detailed patients’ characteristics of the three cohorts are 2017 were included as an external validation set. shown in Table 1. All clinicopathological characteristics were Journal of Oncology 3 Table 1: Baseline clinicopathologic characteristics. Training set (n � 4983) Internal validation set (n � 4983) External validation set (n � 324) Characteristics (%) (%) (%) Age, yrs <65 2172 (43.6) 2185 (43.8) 212 (65.4) ≥65 2811 (56.4) 2798 (56.2) 112 (34.6) Sex Male 2461 (49.4) 2478 (49.7) 136 (42.0) Female 2522 (50.6) 2505 (50.3) 188 (58.0) Location Head 3832 (76.8) 3842 (77.1) 161 (49.7) Body and tail 704 (14.2) 717 (14.4) 163 (50.3) Other 447 (9.0) 424 (8.5) 0 (0) Year of diagnosis 2004–2009 2049 (41.1) 2010 (40.3) — 2010–2015 2934 (58.9) 2973 (59.7) — Grade Low grade 3063 (61.5) 3115 (62.5) 165 (50.9) High grade 1920 (38.5) 1868 (37.5) 159 (49.1) Examined lymph nodes <15 2187 (46.1) 2221 (46.6) 183 (56.5) ≥15 2558 (53.9) 2547 (53.4) 141 (43.5) 7th AJCC stage IA 188 (3.8) 192 (3.9) 7 (2.2) IB 270 (5.4) 292 (5.9) 36 (11.1) IIA 1105 (22.2) 1081 (21.7) 130 (40.1) IIB 3418 (68.6) 3417 (68.5) 151 (46.6) 8th T stage T1 833 (16.7) 801 (16.1) 44 (13.5) T2 2928 (58.8) 3023 (60.7) 179 (54.9) T3 1222 (24.5) 1159 (23.3) 103 (31.6) 8th N stage N0 1610 (32.3) 1591 (31.9) 180 (55.2) N1 2084 (41.8) 2114 (42.4) 112 (34.4) N2 1289 (25.9) 1278 (25.6) 34 (10.4) Extrapancreatic invasion 8th AJCC 4106 (82.4) 4100 (82.3) 250 (76.7) stage IA 393 (7.9) 379 (7.6) 24 (7.4) IB 886 (17.8) 885 (17.8) 97 (29.9) IIA 331 (6.6) 327 (6.6) 58 (17.9) IIB 2084 (41.8) 2114 (42.4) 111 (34.3) III 1289 (25.9) 1278 (25.6) 34 (10.5) Median OS (95% CI) 19 (18.4–19.6) 19.0 (18.4–19.6) 23.6 (19.4–27.8) Values in parentheses are percentages. comparable between the training set and the internal vali- (p< 0.001), year of diagnosis (p< 0.001), tumor grade dation set. Compared with the training set and internal (p< 0.001), number of examined lymph nodes (p< 0.001), validation set, the external validation set was associated with extrapancreatic invasion (p< 0.001), tumor size (p< 0.001), a higher proportion of female patients, patients with age at and number of metastatic lymph nodes (p< 0.001) were diagnosis <65 years, tumors located at the body and tail of identified as independent prognostic factors for OS. pancreas, higher tumor grade, less than 15 harvested lymph nodes, tumor located within pancreas, less advanced path- 3.3. Development of a Novel Staging System in the Training Set. ological N stage, less advanced 7th AJCC, and less advanced To evaluate the accuracy and appropriateness of the 8th 8th AJCC stage. -e median OS of the training set, internal AJCC staging system, the median OS of each substage from validation set, and external validation set were 19.0, 19.0, and the training set was calculated. Even within the same tumor 23.6 months, respectively. stage, the median OS was quite heterogeneous across dif- 3.2. Independent Prognostic Factors of Survival in the Training ferent substages (Figure 1(a)). For example, within stage ?, Set. -e univariate and multivariate analysis results are the median OS for T1N2M0, T2N2M0, and T3N2M0 was shown in Table 2. In the training set, age at diagnosis 18.5, 14.0, and 11.3 months, respectively (p< 0.001). 4 Journal of Oncology Table 2: Univariate and multivariate analysis for overall survival of patients in the training set. Multivariate analysis Characteristics Univariate analysis p value HR (95% CI) p value Age, yrs (<65) ≥65 <0.001 1.175 (1.102–1.254) <0.001 Sex (male) Female 0.507 Location (head) Body and tail 0.088 Other 0.608 Year of diagnosis (2004–2009) 2010–2015 <0.001 0.638 (0.597–0.681) <0.001 Grade (low grade) High grade <0.001 1.333 (1.250–1.423) <0.001 Examined lymph nodes (<15) ≥15 <0.001 0.800 (0.748–0.856) <0.001 Extrapancreatic invasion 8th T stage (T1) <0.001 1.199 (1.097–1.310) <0.001 T2 <0.001 1.340 (1.200–1.473) <0.001 T3 <0.001 1.549 (1.394–1.722) <0.001 8th N stage (N0) N1 <0.001 1.336 (1.235–1.445) <0.001 N2 <0.001 1.793 (1.639–1.961) <0.001 7th AJCC stage (IA) IB <0.001 IIA <0.001 IIB <0.001 Abbreviations: HR, hazard ratio; CI, confidence interval. Moreover, patients with stage IIB T1N1M0 tumors survived by the novel system, respectively. -e proportion of stage IIA longer than patients with stage IIA T3N0M0 tumors (me- disease by the novel stage was much higher than that of stage dian OS: 20.8 vs 17.8 months; p< 0.001). Similarly, patients IIA disease by the 8th AJCC system in the three cohorts. with stage III T1N2M0 tumors survived longer than patients Suggested by the well-separated survival curves for the with stage IIB T3N1M0 tumors (median OS: 18.5 vs 13.9 three cohorts (Figure 1(d), Figures 3(b) and 3(d)), the novel months; p< 0.001). Based on the results of multivariate staging system showed better prognostic discrimination analysis, the tumor grade was incorporated into the 8th compared with the 8th AJCC staging system (Figure 1(c) and Figures 3(a) and 3(c)). A good separation of survival curves AJCC system to form a novel staging system, which resulted in 18 substages. According to the median OS of each sub- between stages IIA and IIB disease was also noticed. -e results stage, these substages were regrouped into five stage groups, of performance evaluation for the three staging systems are including novel IA (G1T1N0), novel IB (G1T1N1, G1T2N0, shown in Table 3. In the training set, the respective 3-year and G2T1N0), novel IIA (G1T1N2, G1T2N1, G1T3N0, AUCs of the 8th AJCC and the novel staging system were G2T1N1, and G2T2N0), novel IIB (G1T2N2, G1T3N1, 0.615, and 0.642, respectively (p< 0.001). -e likelihood ratios G1T3N2, G2T1N2, G2T2N1, and G2T3N0), and novel III χ , which was a measure of homogeneity, of the 8th AJCC and (G2T2N2, G2T3N1, and G2T3N2) (Figure 1(b)). the novel staging system was 248.6 and 403.4, respectively. -e discriminatory ability of each system from the linear trend χ test was 218.0 and 335.1, respectively. Similar results were 3.4. Comparison between the 8th AJCC and the Novel Staging observed in the internal and external validation sets. System. A histogram showing the distribution of patients across different substages within in the three cohorts are shown (Figure 2). In the training set, 7.9%, 17.8%, 6.6%, 41.8%, and 3.5. 6is Novel Staging System Predicted Survival Benefits from 25.9% of the patients were assigned to stage IA, IB, IIA, IIB, and Adjuvant Chemotherapy. Analysis of the external validation III (T1-3N2M0) tumors by the 8th AJCC staging system, re- set showed that the median OS was prolonged by adjuvant spectively, while 5.9%, 29.8%, 48.8%, 31.9%, and 15.1% of the chemotherapy (31.2 versus 16.8 months, p � 0.005). -e patients were assigned to stages IA, IB, IIA, IIB, and III (T1- adjuvant chemotherapy benefit was subsequently deter- 3N2M0) tumors by the novel staging system, respectively. As to mined in each stage within the 8th AJCC and the novel the external validation set, 7.4%, 29.8%, 18.1%, 34.4%, and staging system. In the subgroup of patients with novel stage 10.4% of the patients were assigned to stages IA, IB, IIA, IIB, and IA- IIA disease, there was no significant difference in median III (T1-3N2M0) tumors by the 8th AJCC system, respectively, OS between patients who received adjuvant chemotherapy while 6.1%, 21.2%, 32.8%, 26.4%, and 13.5% of the patients were and patients who did not (35.4 versus 30.4 months, assigned to stages IA, IB, IIA, IIB, and III (T1-3N2M0) tumors p � 0.740, Figure 4(a)). Patients with 8th AJCC stage IA- IIA Journal of Oncology 5 8th AJCC Novel staging system G1T1N0 IA T1N0 IA G1T1N1 IB G1T2N0 IB T2N0 G2T1N0 IIA G1T1N2 T3N0 G1T2N1 IIA G1T3N0 T1N1 G2T1N1 IIB G2T2N0 T2N1 G1T2N2 G1T3N1 T3N1 G1T3N2 IIB G2T1N2 T1N2 G2T2N1 III G2T3N0 T2N2 G2T2N2 G2T3N1 III T3N2 G2T3N2 010 20 30 40 010 20 30 40 Median overall survival (months) Median overall survival (months) (a) (b) 8th AJCC Novel staging system 100 100 P < 0.0001 P < 0.0001 80 80 60 60 40 40 020 40 60 020 40 60 Time (months) Time (months) IA IIB IA IIB IB III IB III IIA IIA (c) (d) Figure 1: Staging system and corresponding Kaplan-Meier survival curves for the training set; TN stages and survival duration using the 8th AJCC staging system (a), G (grade)-TN stages and survival duration using the novel staging system (b), Kaplan-Meier survival curves for the patients using the 8th AJCC staging system (c), or novel staging system (d). disease had a similar result (31.2 versus 31.4, p � 0.144, revised the existing parameters might fail to gain a satisfying performance of survival discrimination. Figure 4(c)). Whereas in the subgroup of patients with the novel or 8th AJCC stage IIB-III disease, there was a survival In the novel staging system, a moderate improvement in benefit in patients who received adjuvant chemotherapy survival discrimination was demonstrated by the elevated (novel stage IIB-III, median OS, 20.7 versus 9.3 months, AUCs of survival prediction. A good separation of survival p< 0.001, Figure 4(b); 8th AJCC stage IIB-III, median OS, curves between stages IIA and IIB disease was also noticed. 24.9 versus 11.1 months, p< 0.001, Figure 4(d)). Prognostic homogeneity and discriminatory ability were also significantly optimized by the novel staging system. Furthermore, we found that this novel staging system had 4. Discussion another role in addition to the prediction of survival for Supported by the previous studies [5, 6, 19, 20], a moderate resectable PDAC. Although chemotherapy remained the improvement in the accuracy of prediction was yielded by only effective option of systemic therapy, the survival benefit it offered was quite limited, and only a few patients would the 8th AJCC staging system. Nevertheless, the survival curves for stages IIA and IIB disease were not clearly sep- respond to chemotherapy [21]. So far, there is a paucity of arated in the 8th AJCC system, and the overall discrimi- tools to select the subset of patients who would benefit from nation was only marginally enhanced compared with the 7th adjuvant chemotherapy [22]. In the current study, only AJCC system. -us, the 8th AJCC system for resectable patients with the 8th AJCC and novel stages IIB or III disease PDAC is far from accurate, and improvement should be could benefit from adjuvant chemotherapy, which suggested considered. So far, revisions of the AJCC staging system for that the tumor grade as well as the tumor stage were reliable PDAC largely relied on changes to T and N definitions [4], indicators of the tumor burden. As shown in Figure 1, the leading us to consider that a staging system that merely novel staging system can provide more accurate survival TN stage Percent survival (%) G-TN stage Percent survival (%) 6 Journal of Oncology Training set Internal validation set 2000 2000 1500 1500 500 500 0 0 IA IB IIA IIB III IA IB IIA IIB III 8th AJCC staging system 8th AJCC staging system Novel staging system Novel staging system (a) (b) External validation set IA IB IIA IIB III 8th AJCC staging system Novel staging system (c) Figure 2: -e histogram showing the distribution of patients across different substages within the 8th AJCC or novel staging system. prediction for resectable PDAC by incorporating tumor Most researchers performed an initial analysis in their grade into the 8th AJCC system. -e information on tumor single-institution dataset before seeking validation within a grade could inform the efficacy of adjuvant chemotherapy larger multi-institution dataset, hoping the analysis can be for patients within the same 8th AJCC staging system. We equally effective in other centers [6, 19, 23], while in the think the novel staging system may be a simple and feasible current study, we utilized the SEER database as the training supplement for the 8th AJCC system to identify patients who set rather than our institution’s patients. -e sample of our would benefit from adjuvant chemotherapy. single-institution cohort was not adequate enough to es- Chen et al. [15] have combined tumor grade and the 8th tablish a reliable staging system. -e sample size of the SEER database was adequate while it only included patients from AJCC staging system into a novel staging system using the SEER database. Liu et al. [16] also proposed a novel one by the USA. Moreover, the characteristics were significantly different between the SEER database and the external cohort, integrating the tumor grade and postoperative CA19-9 levels with the 8th AJCC staging system in their single-institu- which was possibly reflective of the difference between the tional dataset. However, the external validations of their western and eastern PDAC patients. -erefore, we decided staging schemes were lacking in their studies. In contrast, the to establish a novel staging system from the SEER database newly proposed staging system described in this study has and validate it in an external cohort to evaluate its appli- been cross-validated in both the SEER database and our cability in eastern patients. center. Furthermore, lots of nomograms in which diverse In the current study, we observed that the nodal status prognostic factors were included have been developed to was less advanced in the external dataset, but there was no yield absolute prediction [10–12]. However, both patients significant difference in tumor size between the SEER data and the external dataset. A smaller proportion of patients and clinicians were reluctant to use these nomograms, mostly because of their complexity and the difficulty of using with a tumor located at the head of pancreas in the external dataset may account for the smaller number of harvested and them. In contrast, our proposed staging system only in- cluded three components and was subdivided into five stage metastatic lymph nodes. Furthermore, the interinstitutional groups, which was simpler than nomograms. -e tumor variance also accounts for the discrepancy in part. grade was easy to obtain, which was routinely reported by -is novel staging system tends to downstage node- pathologists. Although the incorporation of the tumor grade positive disease (T1N1, T2N1, T1N2, and T2N2) regardless complicated the staging system, it significantly optimized the of grade classification. A recent study by Shi et al. [19] prediction accuracy of the existing AJCC staging system. demonstrated that the median OS of patients in the same 8th Journal of Oncology 7 8th AJCC Novel staging system P < 0.0001 P < 0.0001 40 40 20 20 0 20 40 60 0 20 40 60 Time (months) Time (months) IA IIB IA IIB IB III IB III IIA IIA (a) (b) 8th AJCC Novel staging system 100 100 P = 0.0011 P < 0.0001 80 80 60 60 40 40 20 20 0 0 0 20 40 60 0 20 40 60 Time (months) Time (months) IA IIB IA IIB IB III IB III IIA IIA (c) (d) Figure 3: Kaplan-Meier survival curves for the internal validation set using the 8th AJCC staging system (a) or novel staging system (b). Kaplan-Meier survival curves for the external validation set using the 8th AJCC staging system (c) or novel staging system (d). Table 3: Performance evaluation of the 8th AJCC and the novel staging system. Staging system AUC for 3-year OS (95% CI) p value Homogeneity (likelihood ratio χ ) Discriminatory ability (linear trend χ2) Training set 8th AJCC 0.615 (0.598–0.633) 248.6 218.0 Novel 0.642 (0.624–0.659) <0.001 403.4 335.1 Internal validation set 8th AJCC 0.603 (0.585–0.621) 182.6 154.7 Novel 0.621 (0.604–0.639) <0.001 261.9 218.2 External validation set 8th AJCC 0.596 (0.523–0.670) 15.2 24.6 Novel 0.658 (0.590–0.727) 0.008 33.8 35.7 Higher AUC, discriminatory ability, and homogeneity indicate better performance of the staging system. Abbreviations: AUC, area under the curve. CI, confidence interval. AJCC stage varied widely among the different substages, and survival duration than other substages within the same stage, they proposed a modified staging system by regrouping the which was in accordance with our results. substages. In their proposed staging system, T1N1, T2N1, Some limitations should not be ignored. First, despite T1N2, and T2N2 were downstaged as a result of longer a superior performance of the novel staging system, the Percent survival (%) Percent survival (%) Percent survival (%) Percent survival (%) 8 Journal of Oncology 100 100 80 80 P = 0.740 P < 0.001 60 60 40 40 20 20 0 0 0 20 40 60 0 20 40 60 Time (months) Time (months) No chemotherapy No chemotherapy Chemotherapy Chemotherapy (a) (b) 100 100 80 80 P = 0.144 P < 0.001 60 60 40 40 20 20 0 0 0 20 40 60 80 100 0 20 40 60 80 Time (months) Time (months) No chemotherapy No chemotherapy Chemotherapy Chemotherapy (c) (d) Figure 4: Kaplan-Meier curves showed the response to chemotherapy classified by the novel staging system (stages IA-IIA (a) and stages IIB-III (b)), and the 8th AJCC staging system (stages IA-IIA (c) and stage IIB-III (d)) in the external validation set. Survival curves of the training set and internal validation set are not shown as there was a lack of chemotherapy information in the SEER database. addition of tumor grade created a more complicated 5. Conclusions system than the AJCC 8th system. Second, the period of In conclusion, our newly proposed staging system was as- the current study was more limited as the preoperative sociated with better prognostic accuracy, homogeneity, and radiographic assessment and postoperative adjuvant discriminatory ability among PDAC patients after pancre- therapies of the included patients would be more uniform. atectomy compared with the 8th AJCC staging system. -ird, we cannot eliminate interinstitution and interob- Moreover, the novel staging system also allows possible server variance in protocols for pathological assessment of adjuvant chemotherapy decisions. We believe that the su- tumor grade. -e two-tiered grading system adopted in periority of this staging system stems from new revisions to this study which divided the grade into high and low could the 8th AJCC Tand N definitions and the inclusion of tumor partially minimize that variance. Fourthly, the external grade that reflects the aggressive behavior of PDAC. validation set has a significantly higher OS compared with However, external validation from other populations is the two other sets from the SEER database, which may necessary. undermine the efficacy of validation. Finally, the survival discrimination was only moderately improved by the proposed staging system, which owns to insufficient in- Data Availability clusion of predictive factors needed for absolute predic- tion. For example, although the prognostic value of -e data used to support the findings of this study are various clinicopathological factors, such as preoperative available from the corresponding author upon request. CA19-9 level, resection margin status, lymphovascular invasion, nerve invasion, and adjuvant chemotherapy Conflicts of Interest have already been validated by previous studies [16, 21], they were not included as a lack of these information in -e authors declare that there are no conflicts of interest SEER database. regarding the publication of this paper. Percent survival (%) Percent survival (%) Percent survival (%) Percent survival (%) Journal of Oncology 9 pancreatic cancer treated with chemoradiotherapy,” Radio- Authors’ Contributions therapy and Oncology, vol. 129, no. 2, pp. 340–346, 2018. [13] M. Strijker, J. W. Chen, T. H. Mungroop et al., “Systematic Hu Ren Chao-Rui Wu contributed equally to this work. review of clinical prediction models for survival after surgery for resectable pancreatic cancer,” British Journal of Surgery, Acknowledgments vol. 106, no. 4, pp. 342–354, 2019. [14] N. Wasif, C. Y. Ko, J. Farrell et al., “Impact of tumor grade on -is work was supported by the CAMS Innovation Fund for prognosis in pancreatic cancer: should we include grade in Medical Sciences (CIFMS) (grant number: 2016-I2M-1-001). AJCC staging?” Annals of Surgical Oncology, vol. 17, no. 9, -e authors thank the SEER program for providing open pp. 2312–2320, 2010. access to the database. [15] Y.-T. Chen, Z.-P. Huang, Z.-W. Zhou, and M.-M. He, “Equipping the American Joint Committee on Cancer staging for resectable pancreatic ductal adenocarcinoma with tumor References grade: a recursive partitioning analysis,” Medical Oncology, vol. 33, no. 11, pp. 1–8, 2016. [1] A. McGuigan, P. Kelly, R. C. Turkington, C. Jones, [16] L. Liu, H.-X. Xu, M. He et al., “A novel scoring system predicts H. G. Coleman, and R. S. McCain, “Pancreatic cancer: a postsurgical survival and adjuvant chemotherapeutic benefits review of clinical diagnosis, epidemiology, treatment and in patients with pancreatic adenocarcinoma: implications for outcomes,” World Journal of Gastroenterology, vol. 24, no. 43, AJCC-TNM staging,” Surgery, vol. 163, no. 6, pp. 1280–1294, pp. 4846–4861, 2018. [2] L. Rahib, B. D. Smith, R. Aizenberg, A. B. Rosenzweig, [17] D. W. Hosmer, T. Hosmer, S. Le Cessie, and S. Lemeshow, “A J. M. Fleshman, and L. M. Matrisian, “Projecting cancer in- comparison of goodness-of-fit tests for the logistic regression cidence and deaths to 2030: the unexpected burden of thyroid, model,” Statistics in Medicine, vol. 16, no. 9, pp. 965–980, liver, and pancreas cancers in the United States,” Cancer Research, vol. 74, no. 11, pp. 2913–2921, 2014. [18] A. R. Feinstein, “XVI. -e process of prognostic stratification [3] V. L. Gordon-Dseagu, S. S. Devesa, M. Goggins, and (Part 2),” Clinical Pharmacology & 6erapeutics, vol. 13, no. 4, R. Stolzenberg-Solomon, “Pancreatic cancer incidence trends: pp. 609–624, 1972. evidence from the Surveillance, Epidemiology and End Re- [19] S. Shi, J. Hua, C. Liang et al., “Proposed modification of the sults (SEER) population-based data,” International Journal of 8th edition of the AJCC staging system for pancreatic ductal Epidemiology, vol. 47, no. 2, pp. 427–439, 2018. adenocarcinoma,” Annals of Surgery, vol. 269, no. 5, [4] M. B. Amin, S. Edge, F. Greene et al., AJCC Cancer Staging pp. 944–950, 2019. Manual, Springer, Berlin, Germany, 8th edition, 2017. [20] P. J. Allen, D. Kuk, C. F.-d. Castillo et al., “Multi-institutional [5] A. M. Schlitter, M. Jesinghaus, C. Jager ¨ et al., “pT but not pN validation study of the American Joint commission on cancer stage of the 8th TNM classification significantly improves (8th edition) changes for T and N staging in patients with prognostication in pancreatic ductal adenocarcinoma,” Eu- pancreatic adenocarcinoma,” Annals of Surgery, vol. 265, ropean Journal of Cancer, vol. 84, pp. 121–129, 2017. no. 1, pp. 185–191, 2017. [6] S. van Roessel, G. G. Kasumova, J. Verheij et al., “International [21] H. Oettle, P. Neuhaus, A. Hochhaus et al., “Adjuvant che- validation of the eighth edition of the American Joint com- motherapy with gemcitabine and long-term outcomes among mittee on cancer (AJCC) TNM staging system in patients with patients with resected pancreatic cancer,” JAMA, vol. 310, resected pancreatic cancer,” JAMA Surgery, vol. 153, no. 12, no. 14, pp. 1473–1481, 2013. Article ID e183617, 2018. [22] P. Martinelli, E. Carrillo-de Santa Pau, T. Cox et al., “GATA6 [7] Y. R. Lawrence, J. Moughan, A. M. Magliocco et al., “Ex- regulates EMT and tumour dissemination, and is a marker of pression of the DNA repair gene MLH1 correlates with response to adjuvant chemotherapy in pancreatic cancer,” survival in patients who have resected pancreatic cancer and Gut, vol. 66, no. 9, pp. 1665–1676, 2017. have received adjuvant chemoradiation: NRG Oncology [23] M. Song, S. B. Yoon, I. S. Lee et al., “Evaluation of the RTOG Study 9704,” Cancer, vol. 124, no. 3, pp. 491–498, 2018. prognostic value of the new AJCC 8th edition staging system [8] D. Liang, S. Shi, C. Liang et al., “Mismatch repair status as a for patients with pancreatic adenocarcinoma; a need to beneficial predictor of fluorouracil-based adjuvant chemo- subclassify stage III?” European Journal of Cancer, vol. 104, therapy for pancreatic cancer,” Surgery, vol. 163, no. 5, pp. 62–69, 2018. pp. 1080–1089, 2018. [9] M. M. Rochefort, J. S. Ankeny, B. E. Kadera et al., “Impact of tumor grade on pancreatic cancer prognosis: validation of a novel TNMG staging system,” Annals of Surgical Oncology, vol. 20, no. 13, pp. 4322–4329, 2013. [10] Y.-N. Shen, X.-L. Bai, G. Jin et al., “A preoperative nomogram predicts prognosis of up front resectable patients with pan- creatic head cancer and suspected venous invasion,” Hpb, vol. 20, no. 11, pp. 1034–1043, 2018. [11] J. Hang, L. Wu, L. Zhu et al., “Prediction of overall survival for metastatic pancreatic cancer: development and validation of a prognostic nomogram with data from open clinical trial and real-world study,” Cancer Medicine, vol. 7, no. 7, pp. 2974–2984, 2018. [12] S. H. Choi, S. W. Park, and J. Seong, “A nomogram for predicting survival of patients with locally advanced

Journal

Journal of OncologyHindawi Publishing Corporation

Published: Sep 21, 2020

There are no references for this article.