To date, the survival outcome of metachronous metastasized PDAC has never been evaluated in regard to the different relapse compartments (local, hepatic, pulmonary) in one single centre cohort. In previous studies, only one specific relapse compartment was investigated (15-18). In our study, we could show for the first time that DFS was longer in patients with isolated pulmonary metastases when compared to patients with metachronous hepatic metastases and local recurrence. Relapse surgery significantly improved survival of patients with isolated pulmonary metastases and local recurrence, when compared to patients treated only with chemotherapy. Long-term survivors (>5 years) were, however, only found in patients receiving surgery for local recurrence, despite the dismal disease free survival of this subgroup.
Over the past decade, the role of metastasectomy for localized pulmonary metastases in PDAC was elucidated. It was reported that long-term survivors of PDAC and patients with a superior DFS were often the patients suffering from isolated pulmonary disease. Our findings are in-line with these previous observations (15, 16, 19). The DFS of the isolated pulmonary metastasis group was significantly longer, compared to the hepatic metastasis and local recurrence groups. Survival before diagnosis of the local recurrence and hepatic metastasis groups was comparably poor. However, interestingly, survival following surgery for isolated local recurrence and pulmonary metastases were similar and, importantly, in both cases longer, compared to patients following surgery for hepatic metastases. Very-long-term survivors were only found in the subgroup receiving surgery for local recurrence. Thus, local recurrence presumably reflected insufficient tumor clearance during primary surgery in a tumor with a less adverse systemic cancer biology (20). This indicates that a surgical approach for local recurrence is feasible, if resectability is provided as described by Strobel et al (17). Thus, even a very early diagnosis of local relapse should not preclude relapse surgery, as long term survival seems still possible.
In two recent meta-analyses from 2017 by Groot et al and from 2019 by Moletta et al, the authors investigated the survival difference by different therapeutic approaches for local recurrence (21, 22). In summary, both analyses showed that surgery is feasible and does prolong survival. However, both meta-analyses showed a certain degree of heterogeneity due to multiple interdisciplinary approaches. In some studies, adjuvant therapy was administered after the initial operation (23). Others have offered adjuvant therapy after both initial and relapse operation (18, 24-27). Neoadjuvant therapy prior to the relapse operation was only applied in two studies (17, 28). Our data clearly revealed, if resectability is provided, upfront relapse surgery in patients with isolated local recurrence after multimodal therapy does significantly prolong survival, compared to patients who received chemotherapy alone. 45% of all patients receiving surgery for isolated local recurrence were still alive at the conclusion of our study period and presented with no further relapse in follow-up investigations over a duration of 102 months. Hence, this excellent survival outcome presumably reflects a less adverse tumor biology in this subgroup despite the relatively short DFS. In conclusion, this emphasizes a primary radical degree of surgery in order to prevent margin positive resections and thus local relapse in follow-up, with a further burden of surgical re-exploration (29, 30).
Since the DFS of the surgery subgroup of the pulmonary metastasis group was significantly longer compared to the chemotherapy alone subgroup, our study was limited in terms of selection bias. Thus, the post relapse survival after surgery for isolated pulmonary metastases has to be considered with certain precautions. However, it is a well-established observation that a superior DFS is mostly found in patients with pulmonary metastases (19, 31-33). This is in-line with a recent SEER analysis from Liu et al, who demonstrated that resection in highly selected patients with either isolated synchronous or metachronous pulmonary metastases is correlated with a significant survival benefit in PDAC (34). Furthermore, no advice can be given on the setting of multimodality for metachronous disease (preoperative vs. postoperative vs. perioperative), as all patients received upfront surgery with adjuvant therapy compared to patients with only chemotherapy.
Isolated resectable relapse is rare in patients with prior therapy for PDAC. Thus, no larger case series exist in the literature and randomized control studies are not available. In selected patients, however, we and others have shown that metastasis surgery followed by adjuvant chemotherapy is feasible (17).
One weakness of this study is the relatively prolonged study period of 9 years. Hence, during this time, adjuvant treatment protocols following primary surgery have changed. However, due to our focus on post relapse survival, it seems reasonable to assume that an adjuvant treatment following the primary surgery only has a limited effect on the survival after relapse diagnosis and treatment. To date, no multicenter studies exist which elucidate the survival effect of FOLFIRINOX in patients with metachronous relapse. For this matter, future multicenter studies are needed to clarify the impact of different chemotherapeutic therapies on survival outcome. To further select patients who most likely benefit from relapse surgery or chemotherapy for prolonged survival, enhanced preoperative diagnostics are clearly needed. Thus, future studies should investigate the genomic information of the primary tumor and the metastasis to detect mutational changes for targeted therapies. Furthermore, sensitive detection methods to identify circulating tumor cells to estimate the presumed tumor load and identify auxiliary genomic subgroups should be evaluated and might help to detect patients at increased risk of relapse (35).