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Systematic Review and Meta-Analysis Comparing the Surgical Outcomes of Invasive Intraductal Papillary Mucinous Neoplasms and Conventional Pancreatic Ductal Adenocarcinoma

  • Pancreatic Tumors
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Abstract

Objective

The aim of this study was to summarize the current literature comparing the surgical outcomes of invasive intraductal papillary mucinous neoplasms (IPMNINV) and conventional pancreatic ductal adenocarcinomas (PDAC) in order to determine the differences in disease characteristics and prognosis.

Methods

Systematic review of the literature yielded 12 comparative studies reporting the clinicopathological characteristics and overall survival (OS) of 1,450 patients with IPMNINV with 19,304 patients with conventional PDAC.

Results

IPMNINV had a significantly lower likelihood of tumors extending beyond the pancreas [27.6 vs. 94.3 %; T4 vs. T1: odds ratio (OR) 0.111, 95 % confidence intervals (CI) 0.057–0.214], nodal metastasis (45.4 vs. 62.9 %: OR 0.507, 95 % CI 0.347–0.741), positive margin (14.2 vs. 28.3 %; OR 0.438, 95 % CI 0.322–0.596), perineural invasion (49.2 vs. 76.5 %; OR 0.304, 95 % CI 0.106–0.877) and vascular invasion (25.2 vs. 45.7 % OR 0.417, 95 % CI 0.177–0.980) when compared with PDAC. The 5-year OS of IPMNINV was significantly better than PDAC [31.4 vs. 12.4 %: hazard ratio (HR) 0.659, 95 % CI 0.574–0.756]. The tubular subtype had a poorer 5-year OS and demonstrated significantly more aggressive features such as nodal metastases, vascular invasion, and perineural invasion compared with the colloid subtype.

Conclusion

IPMNINV were significantly more likely to present at an earlier stage and were less likely to demonstrate nodal involvement, perineural invasion and vascular invasion. When controlled for stage, IPMNINV had an improved OS when compared with PDAC in the early stages.

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Correspondence to Brian K. P. Goh MBBS, MMed, MSc, FRCS.

Appendices

Appendix 1. Statistical Analyses

To facilitate the pooling of results across studies in the meta-analysis, the number of individuals with or without the event of interest in the IPMN and PDAC groups was used for dichotomous outcomes. The Mantel–Haenszel (MH) method was used to pool the OR across studies. A Woolf–Haldane continuity correction of 0.5 was used when the number of events for one of the groups was zero.22 Studies in which there was no event in an outcome of interest for both groups were excluded.

Four studies reported tumor size as a continuous outcome,13,15,23,24 while four others reported it as a dichotomized outcome.14,16,25,26 ORs were transformed into effect sizes allowing the pooling of results as effect measures for continuous outcomes by using the inverse-variance (IV) approach.27

Analysis of the 5-year OS was performed by computing the p value for the test of survival difference between the two groups, the number of events in each group, and the number of patients in each group. These statistics were used to compute the HR and its corresponding variance for each study. The HRs and variances from the 11 studies were, in turn, pooled together via the IV approach.28

Heterogeneity between the studies was evaluated using the Chi squared test of heterogeneity. If there was limited evidence supporting the assumption of homogeneity of studies for an outcome (i.e. the p value of the heterogeneity Chi squared test was <0.1), a random effects model was used;29 otherwise, a fixed effects model was used. Two separate sets of sensitivity analyses were performed: (1) excluding each study individually; and (2) excluding studies with a sample size fewer than 20 patients in each group, from the analysis of each outcome. Pooled results from these subgroups were computed and compared with the pooled results from the set of studies without these exclusion criteria. The meta-analysis was conducted using STATA SE 10 (StataCorp. LP, College Station, TX, USA).

Appendix 2

See Fig. 3.

Fig. 3
figure 3

Results of a systematic search of the literature

Appendix 3

See Fig. 4.

Fig. 4
figure 4figure 4

Forest plots illustrating the results of a meta-analysis comparing pathological characteristics in invasive IPMN and conventional PDAC. Pooled ORs or weighted mean differences (WMDs) with 95 % CIs were calculated using the fixed effects or random effects* model where appropriate. a Tumor size; b margin status; c lymphatic invasion; d tumor grade

Appendix 4

See Fig. 5.

Fig. 5
figure 5figure 5figure 5

Forest plots illustrating the results of a meta-analysis comparing clinical characteristics in invasive IPMN and conventional PDAC. Pooled ORs with 95 % CIs are calculated using the fixed effects or random effects* model where appropriate. a Location; b surgical type: distal vs. Whipple, and c total vs. Whipple; d local spread: T2 vs. T1, e T3 vs. T1, and f T4 vs. T1; g tumor stage: TNM2 vs. TNM1, hTNM3 vs. TNM1, and iTNM4 vs. TNM1

Appendix 5

Sensitivity analyses were carried out by excluding each study individually from the analysis of each outcome (Appendix 6). Among outcomes with a p value less than 0.05 in Table 3, location, surgical type, local spread, tumor stage, nodal metastasis, and margin status had consistent findings in the sensitivity analyses. Although surgical type, perineural invasion, and vascular invasion had p-values exceeding 0.05 in the sensitivity analyses, the ORs were in the same consistent direction as those in Table 3. Among outcomes with a p value more than 0.05 in Table 3, local spread (T2 vs. T1), tumor stage (TNM stage 4 vs. TNM stage 1), lymphatic invasion, and tumor size had p-values lower than 0.05 in the sensitivity analyses. The ORs and effect sizes were consistent with those in Table 3.

Additional sensitivity analyses were performed by including those studies with more than 20 patients in each group (Appendix 7). The exclusion of studies with small sample sizes reduces heterogeneity across the studies and did not change the conclusion for all outcomes. This suggests that the findings based on all available studies shown were robust.

Appendix 6

See Table 6.

Table 6 Results of sensitivity analysis by excluding each study individually from all available studies for each outcome (where the reference group is conventional PDAC)

Appendix 7

See Table 7.

Table 7 Results of sensitivity analysis by excluding studies with a sample size fewer than 20 patients in either, or both, IPMN and PDAC for each outcome (where the reference group is conventional PDAC)

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Koh, YX., Chok, AY., Zheng, HL. et al. Systematic Review and Meta-Analysis Comparing the Surgical Outcomes of Invasive Intraductal Papillary Mucinous Neoplasms and Conventional Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol 21, 2782–2800 (2014). https://doi.org/10.1245/s10434-014-3639-0

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