Although adjuvant chemotherapy in resected PDAC patients can significantly improve overall survival in comparison with observation, the majority of these patients would eventally develop local recurrence with or without distant metastasis. Since not all PDAC patients recur in the same manner, understanding the pattern, timing, and implications of recurrence is critical to the planning of adjuvant strategies. In addition, clinicopathologic risk factors for predicting failure patterns could potentially allow individualized and more effective adjuvant therapy strategies[17, 18]. However, to our best knowledge, there is no published studies to specially investigate the risk predictor factors for isolated LRR in PDCA patients by using competing risk regression model, and the patterns of local regional recurrence of lymph node are remains undetermined. As a result, we conduct the present study to clearly define the patterns of recurrence and identify the risk factors for isolated LRR, in order to optimize the irradiation volume and perform individualized treatments.
A total of 114 patients are included for analysis. In consistent with previously published data, 95 of 114 patients (83.3%) develop recurrence after a median follow-up of 42 months, and the isolated local recurrence is observed in 23 patients(24.2%). Previously published data also demonstrated that the prognosis of patients with local recurrence is better than that of distant metastasis [19–21]. In the present study, we also found that the interval of patients developing isolated LRR is significantly longer than those recurred with any DM after the adjuvant chemotherapy. This may be explained for this finding is that micro-metastasis might exist before the surgical resection of primary tumor [22–24]. As a result, local treatment options such as re-resection and radiotherapy could be considered to for those isolated LRR patients to improve the survival.
Adjuvant chemotherapy can also improve the local control rate[25, 26]. However, with the completion of the chemotherapy, it is hypothesized that the local-regional problem will emerge as the main challenge. In consistent with this hypothesis, our study demonstrates that the incidence of isolated LRR is significantly higher than that of DM after completion of adjuvant chemotherapy. Although most patients with PDAC would die from distant metastases, the mortality after local recurrence is still 20%. And the natural evolution is the development of hepatic metastases after the local recurrence. Therefore, the avoiding of the LRR becoming a secondary source of DM, it may be an important reason for application radiochemotherapy following adjuvant chemotherapy after curative surgery.
In order to reduce post-operative recurrence, increasingly radical surgery with extended lymph node dissection and combined with vascular resection has been explored but the efficacy is debated [28–31]. The combination with vascular resection improved the prognosis of patients in comparison with not resected tumors [32, 33]. This surgery is associated with higher probability of positive surgical margins [34–36]. Furthermore, tumor involving arterial structures (especially T4 tumor ) recur rapidly, even after an apparent R0 resection. In our series, the vascular resection is associated with a higher risk of isolated LRR as previously reported in the literature [37, 38]. However, this phenomenon is masked by the decline of distant metastasis rate after vascular resection when analyzed by the cox regression model. There are two types of vascular involvement after vascular resection: neoplastic vessel invasion on histopathology and inflammatory adhesion. Mierke et. al. reported that patients who had inflammatory adhesion has a lower distant metastasis rate than those who had tumor infiltration and those without vascular resection. Thus, the involvement of peripancreatic vessels seems to be an indicator of unfavorable tumor topography . One of the limitations of our retrospective study is that it can not provide the proportion of inflammatory adhesion in those patients with vascular resection.
Positive surgical margin (R1 resection) is a major adverse prognostic factor of disease-free survival(DFS) for resectable PDAC[27, 41, 42] though lack of consensus on definition of margin status. The definition of positive margin in our institution is the directed involvement of tumor at any of the edges of the resection specimen. In our study, R1 resection rate was about 20% and R1 status was a significant predictor of isolated LRR but not significantly increase rates of any DM in PDAC patients after received adjuvant chemotherapy. Systemic chemotherapy was still effective for decreasing recurrence in R1 patients, with small benefit as previously reported . Our study shows that after chemotherapy, local-regional problems become the focus of attention in patients with R1 resection. Therefore the idea of this work is that the loco regional radiotherapy with careful volume definition and delineation after attentive analysis of the patterns could be alternative for this population of patients. We have shown that the remnant pancreas or tumor bed was the common site of recurrence (23.7%) and it must be included in the target volume of irradiation. Miyazaki et al. reported 13/67(19%) patients with isolated local recurrence in the remnant pancreas. Of the many major vessels near the pancreas, the most likely to relapse is the SMA and the CA. This occurs not only due to their features easy to directly involved from the primary tumor but also the practical difficulties for surgical clearance, and radiation oncologists have attached vital importance to them from the era of two dimensional radiotherapy treatment to modern radiotherapy[46–48].
So far, several studies optimizing the adjuvant radiotherapy field for pancreatic cancer have been published [47–49]. However, these studies generally use the Cox regression model to identify the risk factors for LRR. In the present study, we use the competing risks regression model to define the risk factors and comprehensively investigate the recurrence patterns of regional lymph nodes. We believe that the understanding based on vascular anatomy may make easier to delineate, however, for the analysis of lymph node metastasis, there is a lack of uniformity. Thus, we used JPS stage system to study the recurrence of the peritoneal lymph nodes, and we find that nodal metastasis is commonly involved in No.14p, No.16b1, No. 9 and No. 12p. The outcome is consistent with the pathological results after surgery, besides the lymph nodes around the pancreas, the regional lymph nodes are mainly involved in group No.9, No.12 group, No.14 group. Furthermore, para-aortic lymph node (No.16) metastasis, regarded as distant metastasis rather than regional lymph node and classified as pM1 stage, is found in 37 of 114 patients (32.4% ) after adjuvant chemotherapy, which approximately involved 14–18% at the time of resection[51–54]. No.16 is classified into four groups according to JPS system (16a1, 16a2, 16b1, 16b2). In the present study, No.16b1 is frequently involved (27.4% of all recurrences). Especially, in any DM group, No.16b1 is involved more frequently with the recurrence of tumor bed apparently decreased (2.8%) compared to the isolated group. A recent meta-analysis also confirmed that the status of lymph node para-aortic (No.16) metastases had a significant prognostic value. Our study suggests that the optimal radiotherapy volume may include not only the tumor bed and vessels but also involved regional nodes including partially the region No.16 (Figure. 4).
The findings of present study should be interpreted with some caution due to the following limitations: (1) first of all, our study is a single institute retrospective studies, and selection bias is unavoidable, the true impact of adjuvant chemotherapy on recurrence patterns of pancreatic cancer could be underestimated in this study; (2) secondly, the sample size for our study might be relatively small to evaluate all patterns of recurrences, although the median follow-up time is longer than three years. The stength of this study is that we only include resectable pancreatic cancer received with adjuvant chemotherapy, and patients, who initially diagnosed with “ borderline resectable” pancreatic cancer and received neoadjuvant therapy, are excluded for analysis, while this patient cohort is generally included for analysis in several published studies [11, 33–36], as a result, the clinical heterogeneities of the present is relative small than previous publication.