Resection of pancreatic ductal adenocarcinoma with synchronous distant metastasis: is it worthwhile?

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States and the sixth in Europe and Japan [1]. Surgery remains the only chance of cure and should be performed when involvement is limited to the pancreatic gland. In cases of advanced disease, such as major vascular involvement, peritoneal carcinomatosis or distant metastasis, palliative treatment is mandatory because surgery is of no benefit while incurring a high risk of complications and patient discomfort [2]. Despite aggressive surgical therapy, only 10 to 15% of patients are eligible for curative resection, which provides a long term survival rarely exceeding 20% at 5 years [3]. The high rate of recurrence after curative resection suggests frequent occult disease or micrometastasis at the time of surgery [4]. For this reason, adjuvant gemcitabine-based chemotherapy has become a standard treatment following resection of PDAC, although the FOLFIRINOX regimen has been recently approved as a new alternative in selected patients [5].

Surgical resection of PDAC with synchronous distant metastases is not mandatory since median survival time is equivalent to that of chemotherapy alone [6]. However, several publications have reported successful resection of PDAC with distant metastases and long-term survival [7‐10]. In these observations, neoadjuvant systemic chemotherapy or chemoradiation was administered initially because the disease was considered to be palliative. However, objective response based on imagery and blood markers suggested that occult disease had disappeared, so we decided to perform laparotomy and resection.

Herein, we present a series of three patients with PDAC and distant metastases who underwent pancreaticoduodenectomy (PD) following objective response to neoadjuvant chemotherapy.

Between January 2009 and August 2013, 689 patients were investigated in our unit for PDAC. Management of PDAC in our tertiary center is consistent with international recommendations [11].

Two hundred eighty-four patients (41.2%) had metastatic disease (199 to the liver, 90 to the peritoneum, 60 to the lung, 42 to the lymph nodes and 36 elsewhere), 261 (37.9%) had locally advanced disease, and 144 (20.9%) were resectable (Table 1). Of the patients with metastatic disease, 3 (1.0%) underwent resection of both the primary tumor and metastases. Clinical and perioperative data are summarized in Table 2.

PDAC with synchronous distant metastases has a very poor prognosis and in cohort studies median survival rarely exceeds 6 months [14‐16]. New regimens of chemotherapy and radiotherapy has improved the prognosis of metastatic and/or locally advanced PDAC [17, 18], but the benefit of surgery in such cases is still a matter of debate. However, there is robust evidence that some patients with locally advanced or metastatic disease can be cured following aggressive therapy. In the study of Adham and coworkers concerning prolonged survival after resection of PDAC, six patients had advanced disease and one had metastatic disease [19]. Bachellier and coworkers showed that initially advanced disease could be down staged by neoadjuvant chemotherapy, and that in such cases, resection offered a significant prolonged survival, as in patients with initially resectable PDAC [20]. In contrast, Gleisner and coworkers in 2007 reported a series of patients with concomitant resection of pancreatic cancer and liver metastasis [6]. In their series, 17 patients had PDAC, most of them with a single liver metastasis. The authors concluded that there was no benefit to resection of liver metastases compared to palliative care, although 3 year-survival was higher in resected patients (6.7% versus 0%). Finally, it is likely that some patients with metastatic and/or locally advanced PDAC have good molecular behavior and can benefit from aggressive resection. However, the ability to select such patients is currently not possible with standard molecular biomarkers. Furthermore, standard imaging still fails to detect millimetric metastasis that could improve preoperative staging and thus avoid unnecessary resections. In this setting, preoperative chemotherapy acts as a ‘test-of-time’ and can help to select patients with less aggressive PDAC that could benefit from radical surgery, even in case of limited metastatic disease.

Consequently, resection of metastatic PDAC remains challenging and raises three important questions. First, do all types of distant metastases (for example, liver, nodal, and peritoneal) have the same prognosis? PDAC with distant metastases is usually estimated as definitively nonresectable and thus palliative chemotherapy is administered. The results of series of metastatic PDAC have shown such a poor prognosis that the impact of the type of metastasis has been rarely investigated [6]. The AJCC-UICC staging system attributes the item ‘M’ for metastatic disease, but does not take into account the location of the metastases. This problem is the same with the item ‘N’, for which it has been shown that prognosis differs according to the type of lymph node metastases (peripancreatic or mesenteric) [21]. Given that distant metastases have a very poor prognosis, the metastatic site has little impact on therapeutic management. Distant metastases in PDAC are most of the time visceral (liver, lung) or nodal (interaorticaval) [8]. However, despite no survival benefit of extended lymphadenectomy in PDAC [22], metastatic interaortocaval lymph nodes seem to have a better prognosis than metastases in other organs such as the liver and peritoneum [23, 24]. Similarly, local recurrence after initial resection seems to have a better prognosis than metastatic recurrence, and can be managed by surgery with survival benefit in selected patients [25]. Thus, in the event of objective response to chemotherapy, the type of distant metastases should be considered, as in our patient number 2. In such cases, PD with systematic en bloc interaorticaval lymphadenectomy can be proposed since interaorticaval lymphadenectomy does not increase postoperative morbidity [26].

Second, is the number of metastases important? In patients number 1 and number 3 in our series, laparotomy disclosed single liver metastases undetected by preoperative imaging. Prognosis of PDAC with single liver metastases is better than with multiple liver metastases, [27] and a meta-analysis has shown that resection of PDAC with single liver metastases was comparable to resection of PDAC with no evidence of liver metastases [28]. As in our study, documented reports of prolonged survival after resection of liver metastases from PDAC involved single and small metastases, incidentally discovered at laparotomy [6, 7, 19]. PD may sometimes be performed although there are concomitant single liver metastases that were undetectable because of limited exploration of the whole liver. This is consistent with the rapid time of liver recurrence in PDAC after PD [6, 27, 29]. Given that liver metastases have better prognosis than metastases in other sites (locoregional or peritoneal) [30], single and small liver metastases may indicate a low metastatic volume, as in metastatic colorectal cancer [31] and do not have to be considered as definitely palliative, especially in the event of objective response to chemotherapy.

Third, can we manage liver metastases surgically without previous neoadjuvant therapy? In comparison to colorectal liver metastases (CRLM), concomitant resection of single liver metastases with PDAC has two drawbacks: adjuvant chemotherapy in PDAC is not as efficient as in CRLM, and PD is a major procedure with a high risk of morbidity - in particular pancreatic fistula - that increases the risk of recurrence and reduces the likelihood of receiving adjuvant chemotherapy [32]. However, as indicated above, liver metastases in PDAC may not necessarily be a contraindication to surgery. Laurent and coworkers demonstrated that non-colorectal metachronous liver metastases could justify resection leading to increased survival [33]. In contrast, Gleisner and coworkers in 2007 found no benefit of concomitant resection of PDAC with single liver metastases compared to a palliative procedure [6]. Likewise, Takada and coworkers showed no improvement of survival despite aggressive surgery of PDAC with multiple liver metastases [29]. However, in these two latter studies liver resection of synchronous metastases was performed without neoadjuvant chemotherapy, and recurrence occurred less than 4 months after surgery, suggesting a non-controlled disease [6]. As in CRLM, management of liver metastases needs a ‘test-of-time’, to ensure the control of the disease [34]. In this setting, the FOLFIRINOX regimen showed very promising results compared to the low rate of objective response of a gemcitabine-based regimen [17, 35‐37]. Additionally, the cost-effectiveness of neoadjuvant treatment seems to be superior to that of a surgery-first approach [38]. Thus, simultaneous resection of PDAC with single liver metastasis - and by extension all types of distant metastases - should be considered in the setting of neoadjuvant chemotherapy, first to assess the response to chemotherapy and second to assess the aggressiveness of the disease. In the event of objective response, surgical resection can be considered in selected patients with low-volume metastatic liver disease and very good general health status.

Our short series of three observations shows that R0 resection of PDAC with single distant metastases can offer prolonged survival after selection by neoadjuvant chemotherapy. Only patient number 1 experienced recurrence, but this patient had a T4 tumor with a high risk of local recurrence, and subsequent development of liver metastases that occurred far from the initial site of recurrence. The high rate of recurrence of PDAC raises the question of selecting good responders before resection of PDAC on the basis of systematic neoadjuvant chemotherapy in order to improve long-term survival.