Much of the IPMN literature has sought to outline the natural history of the disease and determine prognostic factors for recurrence or distant metastasis.4,6–13
Overall survival is worse for malignant disease than for adenoma6–9,13
and worse for invasive tumors when compared to in situ disease.8
and positive margins4
have also been associated with worse outcome. In addition to assessing prognostic factors associated with a carcinoma arising within an IPMN, this series addresses the use of adjuvant therapy in these patients.
PDAC arising within an IPMN appears to have a different prognosis compared with PDAC arising from pancreatic intraepithelial neoplasia (PanIN). Unfortunately, there are little data available to address the role for adjuvant therapy in patients with PDAC arising in IPMN. Further confounding treatment decisions is the fact that an adequate stage-by-stage evaluation of invasive IPMN and classical PDAC has not yet been done. For this reason, treatment decisions frequently extrapolate from the PDAC literature where three randomized control trials have produced conflicting results.
The GITSG and EORTC trials showed or suggested a benefit to adjuvant therapy for pancreatic adenocarcinoma, while ESPAC-1 suggested a discrepant effect of chemoradiotherapy and chemotherapy.14–17
CONKO showed a benefit to adjuvant gemcitabine chemotherapy without the use of radiotherapy.18
Growing evidence suggests, however, that IPMN is associated with markedly different genetic alterations than pancreatic adenocarcinoma and therefore may represent a biologically distinct entity.2,3,5,10
Thus, the extensive clinical experience with pancreatic adenocarcinoma may imperfectly guide the management of patients with PDAC arising in IPMN.
In our study, there were a number of factors that were found to be prognostic for overall and cancer-specific survival. Higher stage, nodal involvement, elevated CA 19-9, LVI, and PNI were all associated with higher risk of death from cancer. Overall, patients with PDAC arising in IPMN in our series presented at an earlier stage than those with classic PDAC, likely reflecting the natural history of the premalignant lesion, which may grow to a large size and become readily apparent on radiography prior to dissemination. This presentation at earlier stage was also shown in a series from Johns Hopkins University, with 64% of patients presenting with stage II disease and only one of 70 patients presenting with stage III disease.19
Patients receiving adjuvant CRT or chemotherapy were more likely to have nodal involvement and higher stage disease and, therefore, a worse prognosis. On univariate analysis, adjuvant therapy was not associated with improved survival, perhaps because of the excellent 5-year survival for patients with node-negative disease. Of the patients with positive nodes, the cohort that received adjuvant therapy had a 16.5-month median cancer-specific survival advantage. While the contribution of selection bias and small numbers complicate interpretation, this result is intriguing.
Our findings of an association of adjuvant radiation with poorer prognostic factors as well as the benefit of adjuvant CRT in patients with high-risk disease was also shown in the Johns Hopkins series.19
In that series, Swartz et al showed that for patients with positive margins or node positive disease, adjuvant CRT was associated with improved survival. However, as in our series, patients who received adjuvant treatment exhibited a significant selection bias, with more stage II–III disease or node positive disease.19
It is likely that this selection bias in the both series led to the finding of no significant benefit to adjuvant CRT in the overall cohorts.
If the patients who did not receive adjuvant therapy were “sicker” or more likely to die, they still required a rapid recurrence of disease to be counted as a cancer-specific death with a median survival of 3.3 months. Indeed, rapid disease progression is the most likely reason that these patients did not receive adjuvant therapy. However, it is impossible to draw any conclusions with only 14 node-positive patients. It is still striking, though, that the node positive patients who received adjuvant therapy had almost a 2-year median survival. Whether the favorable median survival is due to therapy, a favorable genotype, or a combination is unclear. Clearly, any definitive conclusions regarding the role of adjuvant therapy are limited by the small numbers and retrospective nature of this study. Furthermore, in any retrospective study, selection bias can play a significant role in showing benefit for an intervention.
PDAC arising in IPMN appears to represent a distinct neoplastic progression to pancreatic adenocarcinoma compared to PanIN. Our series suggests that patients with PDAC arising in IPMN present with earlier stage disease (30% with node-positive disease) than in classic PDAC series, for which ~70% of resected patients have node-positive disease.14,16–18
Node-negative patients in the current series had an excellent cancer-specific and overall survival, while patients with more advanced stage disease had a much poorer prognosis, consistent with classic PDAC. Adjuvant therapy for patients with positive nodes may provide overall and cancer-specific survival benefits in patients with PDAC arising in IPMN. Future studies of pancreatic cancer should focus on clarifying the prognosis of invasive IPMN and PDAC in a stage-by-stage analysis, as well as further prognostic stratification by histologic subtype and genotyping.