Surgical treatment is the only potentially curative treatment for patients with pancreatic cancer that present at a resectable stage and it may be substantially underutilized even in countries with sufficient medical resources [20]. Hence the importance of reporting long term results of surgical treatment of this disease. In addition, little evidence has been published from Argentina and from Latin America about long term oncological outcomes of multidisciplinary treatment of pancreatic cancer. When we analyze the overall survival in this cohort of 10 years of consecutive pancreatectomies for PDAC in a single center, we find that results are similar to international standards. For example, in a recent manuscript from Heidelberg University, 937 patients were included that received pancreatic surgery over the first decade of this millennium and they obtained a median actual overall survival of 22.1 months and 5-year survival rate of 17% [7]. Whereas in this cohort estimated overall survival was 22.8 months and 5-year survival rate was 20.8%.
Perineural invasion is a major pathway by which tumors progress and spread to the adjacent tissue. Furthermore, it has been shown to be an important prognostic factor in many types of human malignancies [21]. The pancreas is an organ that is highly innervated by sympathetic and parasympathetic nerves from ganglia around the celiac and superior mesenteric artery [22]. As mentioned before, recent studies have proposed a major role of PNI in cancer progression, to the point that in animal models of PDAC the ablation of sympathetic nerves resulted in the inhibition of cancer progression [23]. The aggressiveness of PNI cancer cell invasion has been related to neuropathic changes, desmoplasia, and pain. Severe and enduring pain has been strongly associated with poor prognosis in PDAC [8, 24]. In our study we have found using multivariable analysis, that presence of PNI was an independent prognostic factor for worse OS, with an HR of 1.94. These results are consistent with findings reported by a recent multicenter study which included 778 patients from different world wide known pancreas centers. They found that PNI was an independent predictor of survival with a HR of 1.6, and median OS was 50 months in patients without PNI compared with 27 months in those with PNI. We concur with the authors that perineural invasion plays a major role in disease recurrence and survival after pancreatectomy for pancreatic head ductal adenocarcinoma, especially in early stage disease [25].
The presence or absence of lymph node metastases is an established prognostic factor in patients with resected adenocarcinoma of the pancreas. In a reported experience from Johns Hopkins University of 905 patients that underwent pancreaticoduodenectomy for pancreatic adenocarcinoma from 1995 to 2005, they obtained a median survival for all patients of 17.4 months, and the 5-year actuarial survival rate was 16.1%. Demographics, operative data, number of lymph nodes evaluated, number of lymph nodes with metastatic carcinoma, LN ratio, pathologic margin status, and long-term survival were analysed. In that cohort it was found that LN ratio was one of the most powerful predictors of survival [26]. In our study LN ratio was also a significant finding in bivariate analysis but was not significant after adjusting for the other factors.
Systemic inflammation is a well-established physiopathological factor in neoplastic condition. Neutrophilia reflects an underlying neoplastic inflammatory syndrome and is usually accompanied by a variable degree of lymphopenia. Therefore, neutrophil lymphocyte ratio (NLR) is an accessible marker of systemic inflammation. The balance between the negative effects of neutrophilia and the positive effects of lymphocyte-mediated immunity is an interesting line of research. There are meta-analyses that have validated pretreatment NLR as a prognostic factor, and high NLR values have been linked to poor outcomes in numerous types of solid tumors [27]. In metastatic pancreatic adenocarcinoma, a high neutrophil lymphocyte ratio at diagnosis is a marker of poor prognosis. In addition, a high preoperative NLR indicates a worse prognosis than in patients with a low NLR according to another meta-analysis [28]. Furthermore, the prognostic role of baseline NLR and NLR variation after surgery is a novel approach that, to our knowledge, has not been studied before. Therefore, we included this variable in the analysis with special interest, but an association with survival was not found in this cohort. Nevertheless, prospective studies would be appropriate to validate this finding due to the possibility of information bias related to the retrospective nature of this work.
Different authors have found a significantly lower rate of PNI in patients receiving preoperative chemotherapy/chemoradiation (50-70%) compared with those undergoing immediate resection (80-90%) [29, 30]. In our cohort only 8 patients (3.3%) of the surgically resected patients received neoadjuvant therapy. We could not find a statistically significant difference between groups but, due to the low number of patients in the neoadjuvant arm, it is not proper to draw conclusions about the effect of neoadjuvant treatment on PNI. Whereby in our institution neoadjuvant therapy approach is reserved for borderline and locally advanced tumors, previously discussed in a multidisciplinary tumor board. Interestingly, recent evidence on this topic has been revealed in the PREOPANC Trial, which was a randomized phase III trial in 16 centers from Netherlands where they compared patients with resectable or borderline resectable pancreatic cancer that were randomly assigned to receive preoperative chemoradiotherapy versus immediate surgery and 6 courses of adjuvant gemcitabine. The patients that underwent upfront surgery showed a median overall survival of 16 months vs 14.3 months for the neoadjuvant arm (P=0.096). Even though they didn’t reach statistical significance in the primary endpoint that was overall survival, a significantly higher proportion of patients reached R0 resections in the neoadjuvant arm (71% vs 40%, P<0.001) and also a lower rate of perineural invasion [31]. In a posterior long-term analysis from this trial, three- and five-year overall survival (intention-to-treat) was 27.7% and 20.5% after preoperative CRT versus 16.5% and 6.5% after immediate surgery (HR 0.73; 95% CI 0.56 to 0.96; p = 0.025), which becomes an important evidence towards neoadjuvant approach in this group [32].
This study is not free from limitations. Its retrospective nature makes it susceptible to information bias. Some of the follow up data is also a problem with these patients, especially in our center. Being a referral center for pancreatic diseases for patients all over Argentina, many patients receive surgery in our institution but afterwards they must continue their follow-up in their home towns or cities, accounting for loss of some oncological outcomes such as recurrence. On the other hand, information about death could be recovered by different means, such as telephonic interviews and public registries making practically a complete registry of this outcome. Furthermore, to the best of our knowledge, there is no previous evidence of the study of variation of neutrophil-lymphocyte ratio in pancreatic cancer surgery survival. Finally, the main use of these results for our daily practice is related to the awareness of physicians and patients about the prognostic factors that may lead to long term survival after surgery.