Site of Relapse of the Ductal Adenocarcinoma of the Pancreas affects Survival after Multimodal Therapy

doi:10.21203/rs.3.rs-44866/v1

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Research article

Site of Relapse of the Ductal Adenocarcinoma of the Pancreas affects Survival after Multimodal Therapy

https://doi.org/10.21203/rs.3.rs-44866/v1

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published 03 Mar, 2021

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Background

The ductal adenocarcinoma of the pancreas (PDAC) remains one of the most lethal malignancies. To date, no guidelines exists for isolated resectable metachronous disease. It is still unclear, which patients may benefit from relapse surgery. The aim of our study was to compare disease free survival (DFS) and relapse specific survival (RSS) in patients with isolated local recurrence, metachronous hepatic or pulmonary metastases.

Methods

Patients with isolated resectable metachronous disease of either local recurrence, hepatic or pulmonary metastases were included for survival analyses. RSS of surgically treated patients (local (n = 11), hepatic (n = 6) and pulmonary metastases (n = 11)) were compared to conservative treated patients (local (n = 20), hepatic (n = 49) and pulmonary metastases (n = 14)).

Results

Patients with isolated metachronous hepatic metastases showed a higher T-stage and hepatic M-stage in the primary staging of the previous resected PDAC when compared to the other patients. DFS before diagnosed pulmonary metastases was longer compared to DFS before diagnosed hepatic metastases or local recurrence. Surgical resection only significantly improved RSS in patients with local recurrence or pulmonary metastases, when compared to patients after chemotherapy. Long-term survivors (> 5 years) were only detected after surgery for isolated local recurrence and 45% of these patients were still alive in our study.

Conclusion

Although DFS before diagnosed isolated local recurrence was dismal and comparable to patients with isolated hepatic metastases, long-term survivors were only detected in this group, recommending a surgical approach if resectability is provided.

Surgery

General Surgery

PDAC

ductal adenocarcinoma of the pancreas

oligometastatic

survival outcome

pulmonary metastases

local recurrence

hepatic metastases

The ductal adenocarcinoma of the pancreas (PDAC) has a dismal prognosis with an, over the past decade, unchanged median overall survival of ~ 6 months. Thus, oncological advances for PDAC have been slow [1]. By 2030, it is estimated to become the second leading cause of cancer-related death in the United States and also in Germany [2, 3]. To date, the only curative therapy remains the margin-negative oncological resection with an adjuvant treatment regime starting within 6 weeks after the operation [4, 5].

The PDAC metastasizes primarily peritoneal, hepatic and pulmonary [6]. At PDAC diagnosis, 50% of the patients have already metastasized synchronously and further 30% present with locally advanced disease, not approachable for surgery. Thus, only 20% of the patients with a PDAC receive curative intended surgery. Therefore, it is still regarded as one of the most lethal cancers indicated by a very high mortality-to-incidence ratio [1, 7].

For localized cases of primary resectable pancreatic cancers, treatment options are in the meanwhile clarified and standardized. Thus, upfront surgery and adjuvant chemotherapy are indispensably in the treatment for PDAC [8]. However, during follow-up investigations no guidelines exist for metachronous disease; treatment options are hereby individualized. Decision making is dependent on the patients’ performance status, staging of the primary tumor, tumor load and location of metastases and disease free survival. To stratify patients for an individualized treatment concept, genomic sequencing of the primary tumor and metastases are lately getting attention for the PDAC as well, and are used for other tumor entities in a standardized approach [9–11].

Chemotherapy with palliative intent or best supportive care is the standard for patients with metastasized PDAC [12, 13]. Hence, to date no standardized surgical treatment exists for patients with metachronous isolated disease. Therefore, in current clinical practice, unlike in other malignancies, metachronous metastasectomy has barely been performed. In these patients, chemotherapy are possible treatment options for metastasized PDAC. Hence, therapeutic regimes, such as FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin), have very recently been established as primary treatment options, but are bearable to most patients with an adequate clinical condition [13, 14]. To date, it remains indefinite which patients may benefit from surgical resection. Yet, it is unclear whether chemotherapy-naive patients with resectable relapse burden, patients with a stable relapse or patients with relapse regress after chemotherapy will benefit from a surgical approach.

The aim of our study was to analyze patients who received surgery in our department for isolated pulmonary or hepatic metastases as well as local recurrence and to compare those to patients with conservative therapy for metastasized disease similar in localization and resectability.

Patient selection and clinicopathological data

Patients with a ductal adenocarcinoma of the pancreas who consecutively received surgery between September 2003 and December 2019 at the Heinrich Heine University Hospital of Duesseldorf were included in the study. Exclusion criteria were patients with (1) malignancies of the pancreas other than ductal adenocarcinoma, (2) TNM staging without information of lymphatic, perineural and venous invasion (Lx, Pnx, Vx), (3) patients with insufficient information of the follow-up, (4) palliative treatment (5), and patients who succumbed within the 30-days mortality. Clinical data of these consecutive treated patients collected from patient’s medical records was compiled into an Excel®-file database and analyzed retrospectively.

Information of the TNM staging system (size of tumor / involvement of adjacent arteries, lymph node status and status on distant metastasis), along with grading, perineural invasion, lymphatic and venous invasion was retrospectively collected from the original histopathological reports for each patient. The TNM staging system, if applicable, was updated to the 8th Edition of the UICC TNM classification of malignant tumors [17]. Clinicopathological data (gender, age at the time of surgery, overall survival (OS) and results of follow-up examinations including time of diagnosis of metastases and sight of metastases) were retrieved. In order to evaluate disease free survival (DFS) of the studied cohort, all lesions of suspected metachronous disease detected by any diagnostic imaging were included into the survival analysis. Furthermore, relapse specific survival (RSS), survival from date of relapse diagnosis until death, was calculated.

Patients were stratified according to only isolated and resectable metastases from the total study cohort. Only cases, in which surgical resectable relapse was diagnosed, isolated in either one of the three studied compartments were included for analysis. Tumor relapse including local recurrence or hepatic and pulmonary metastases were included. Exclusion criteria were hereby patients with diffuse formation of metastases not accessible for surgery, metastases located in multiple compartments, poor ECOG performance score, best supportive care and loss of follow-up after diagnoses of relapse. Therefore, from the total studied cohort, patients who received surgery or chemotherapeutic therapy for relapse were identified and included. In the conservative chemotherapeutic therapy group, only patients with a homogenous distribution of amount, size and location of local recurrence, metachronous hepatic and pulmonary metastases were included.

Six groups were generated for the analysis of metachronous disease: patients who approved an individualized approach and received surgery for either (4) local recurrence (surglocal), (5) hepatic (surghep) or (6) pulmonary (surgpul) metastases. Patients who disagreed to surgery and received chemotherapy for (7) local recurrence (chemlocal) or metachronous (8) hepatic (chemhep) or (9) pulmonary (chempul) metastases.

The analysis was performed in conformity to the Declaration of Helsinki and to good Clinical Practice. Furthermore, a positive vote of the Institutional Review Board (IRB) of the Ethics Committee, Heinrich Heine University Duesseldorf (IRB-no. 2019 − 473) was retrieved.

Statistical analysis

The Wilcoxon test was used to analyze differences in clinicopathological data between the three subgroups. The Mann-Whitney U test was used to examine numerical data and to correlate between clinicopathological variables. For categorical data, the chi-square test was applied. DFS and RSS were included for outcome measures. Disease free survival described the period from the date of primary surgery until the date of diagnosed metachronous metastases or local recurrence. Relapse specific survival included the period between relapse diagnoses and death or last follow-up. Kaplan-Meier curves were generated and analyzed using the log-rank (Mantel Cox) test. Analyses were performed using SPSS® statistics for Windows (version 25.0; SPSS, Inc., Chicago, IL, USA). P < 0.05 was considered to indicate a statistically significant difference.

Clinicopathological data for metachronous disease

Out of the 346 primarily operated patients, 111 patients met our pre-defined inclusion criteria for analysis of isolated resectable metachronous disease during follow-up investigations (Table 1). In 102 patients, the primary PDAC was located in the pancreas head (91.9%) while in nine patients (8.1%) the tumor originated from the pancreatic tail (Table 1). In our total cohort of patients, the mean follow-up period was 10.1 months (range: 1-102.1 months). The median age of all 111 patients at the time of primary surgery was 69 years (range 41–95 years). Our collective consisted of 64 males (57.7%) and 47 females (42.3%). In correlation analysis of TNM staging of the primary tumor and site of metachronous disease, T- and N-stage, tumor grading, positive perineural and lymphatic invasion did not correlate with site of metachronous disease. However, patients with resected synchronous hepatic metastases (M1) and patients with positive venous invasion (V1) rater succumbed to metachronous hepatic metastases. (Table 1).

Surgical therapy and chemotherapy

Out of the total study collective, 31 patients received therapy for isolated local recurrence (group surglocal n = 11; chemlocal n = 20). Further 25 patients were treated for isolated metachronous pulmonary metastases (group surgpul n = 11; chempul n = 14) and 55 patients received therapy for isolated metachronous hepatic metastases (group surghep n = 6; chemhep n = 49) (Table 2).

For hepatic metastases, one right hemi-hepatectomy and five atypical non-anatomical resections were performed. For pulmonary metastases, five right and six left atypical resections via video-assisted thoracoscopy (VATS) were done. For local recurrence, one gastrectomy with atypical resection of the left diaphragm, nine salvage-pancreatectomies with simultaneous right hemicolectomies and one partial psoas muscle resection were performed (Fig. 1, Table 2). In all 28 patients, margin negative resections were achieved. Out of the 83 conservatively treated patients, 45 patients (54.2%) received gemcitabine mono, while a combination therapy with gemcitabine was administered in 19 patients (22.9%). In 5 patients (6.0%), FOLFIRINOX was applied.

Disease free survival and relapse specific survival

Median survival data is summarized in Table 3. The median disease free survival was with 18.15 months longer in patients before diagnosed pulmonary metastases when compared to patients before diagnosed isolated local recurrence or metachronous hepatic metastases (p = 0.029) (Table 3, Fig. 2A). The median DFS with 8.52 months before diagnosed local recurrence was similar to the median DFS with 6.77 months in patients before diagnosed hepatic metastases (p = 0.180) (Table 3, Fig. 2A).

In order to exclude selection bias and differences in tumor biology between the applied treatment modalities for metachronous disease, DFS before secondary relapse treatment initiation was stratified according to the treatment modality applied (Table 3). The median DFS before secondary therapy initiation was similar in patients with isolated hepatic metastases or local recurrence between both treatment modalities (surgery and chemotherapy) (p = 0.927 for surghep vs. chemhep and p = 0.666 for surglocal vs. chemlocal) (Table 3). However, DFS in patients before surgery for isolated pulmonary metastases was significantly longer when compared to patients who only received chemotherapy (p = 0.004) (Table 3). Hence a selection bias was detected only in patients with isolated pulmonary metastases.

To further elucidate a survival benefit between surgery and conservative treatment, the relapse specific survival for each analyzed relapse compartment was evaluated after therapy initiation. Surgical therapy significantly improved survival in patients with isolated local recurrence or pulmonary metastases, when compared to chemotherapy (p = 0.002 for surgpul vs. chempul; p = 0.011 for surglocal vs. chemlocal and p = 0.545 for surghep vs. chemhep) (Fig. 2B-D). Although the median RSS was similar in patients after diagnosed isolated pulmonary metastases and in patients after diagnosed local recurrence, a true cure from disease however was not established in patients with isolated pulmonary metastases as all patients succumbed after secondary therapy in our study (Table 3, Fig. 2B). Five from the 11 patients after surgically resected isolated local recurrence were still alive in our study 102 months after relapse surgery. In spite of a dismal median DFS in patients before diagnosed local recurrence, which was similar to patients with diagnosed hepatic metastases, long-term survivors (> 5 years) were found only in patients after surgically resected isolated local recurrence (Fig. 2D).

To date, the survival outcome of metachronous metastasized PDAC has never been evaluated in regard to the different relapse compartments (local, hepatic, pulmonary) in only one patient collective. Thus, in previous studies only one specific relapse compartment was investigated [15–18]. In our study, we could show for the first time that survival before relapse diagnoses was longer in patients with isolated pulmonary metastases when compared to patients with hepatic metastases and local recurrence. Survival after relapse surgery was significantly improved in 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 after surgery for local recurrence, despite the dismal disease free survival before relapse diagnosis.

Over the past decade, the role of metastasectomy only for localized pulmonary metastases was clarified. This was reasoned since long-term survivors of PDAC and patients with a superior DFS were rather diagnosed with isolated pulmonary disease. Our findings are in-line with these previous literature. [19, 16, 15]. The DFS in patients before diagnosis of isolated pulmonary metastases was significantly longer compared to patients with isolated hepatic metastases and local recurrence. Survival before diagnosis of isolated local recurrence was poor and similar to patients with isolated hepatic metastases. However survival after surgery for isolated local recurrence and pulmonary metastases interestingly were similar and importantly both longer compared to patients after surgery for hepatic metastases. Very long-term survivors were only found after surgery for local recurrence. Thus local recurrence presumably reflected insufficient tumor clearance during primary surgery in a tumor with a less adverse systemic cancerous biology [20]. In our opinion, a surgical approach for local recurrence is feasible, if resectability is provided as described by Strobel et al [17]. Thus, we concluded no contraindication for relapse surgery, even in patients with an very early diagnosis of local relapse.

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, the studies of 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 re-operation [18, 24–27]. Neoadjuvant therapy prior to the re-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 for the initial PDAC, does significantly prolong survival compared to patients who received chemotherapy. 45% of all patients after surgery for isolated local recurrence were still alive in our study 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 survival before relapse diagnosis. 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 before relapse surgery in patients with isolated pulmonary metastases was significantly longer compared to patients before relapse chemotherapy, our study was limited in terms of selection bias. Thus, the relapse specific survival after surgery for isolated pulmonary metastases has to be considered with certain precautions. However, it is a well established observation that a superior survival until relapse diagnosis 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 [34]. Furthermore, no advice can be given on the setting of multimodality for metachronous disease 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 exists in the literature and randomized control studies are not available. In selected patients however, we and others have shown that primary surgery followed by adjuvant chemotherapy is feasible [17]. Further studies are needed to clarify the regimes of chemotherapeutic therapies and survival outcome. To further select patients who most likely benefit from relapse surgery or chemotherapy for prolonged survival, further enhanced preoperative diagnostics are clearly needed. Thus, future studies should further investigate genomic sequencing of the primary tumor and the metastasis to detect mutational changes for future targeted therapies. Furthermore, sensitive detection methods for circulating tumor cells to estimate the presumed patients tumor load should be evaluated and thus enhance patient selection prior to relapse therapy [35].

In summary, selected patients suffering from isolated local recurrence potentially benefit from relapse surgery despite a dismal survival before relapse diagnosis with an acceptable hospital stay and rate of morbidity. Very long term survivors were only found in this group of patients. Thus, a dismal survival before relapse diagnosis should still encourage surgical exploration if resectability is provided. Survival before diagnosis of isolated pulmonary metastases was however longer compared to the other patients and surgical resection should also be considered as well. Patient selection is indispensable as long-term survival is achieved by an adequate multimodal therapy approach. In order to provide a clearer view for survival outcome from relapse surgery, prospective multi-center trials are clearly warranted, in which the setting of multimodality is studied in a much numerous study collective.

Chem chemotherapy

CI confidence interval

CTX chemotherapy

DFS disease free survival

FOLFIRINOX folinic acid, fluororuracil, irinotecan, oxaliplatin,

Hep Hepatic

HR hazard ratio

Meta metachronous/metachronously

OS overall survival

Pall palliative

PDAC pancreatic ductal adenocarcinoma

Pul pulmonary

RSS relapse specific survival

Surg surgical

syn synchronous/synchronously

UICC Union for international cancer control

Ethics approval and consent to participate

This study was approved by the local institutional review board (Heinrich Heine University, Duesseldorf, Germany; study-no.: 2019-473-2). All procedures performed in this study were in accordance with the ethical standards in the 1964 Declaration of Helsinki and its later amendments. Informed consent was waived because no data regarding the cases were disclosed.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Table 1

Demographic table of study collective and correlation analysis between relapse compartment and clinicopathological variables from primary PDAC n = 111. Only M-stage and venous invasion correlated with metachronous hepatic metastases. Pearson Test and Mann-Whitney U test were used to test for statistical significance. p-value ≤ 0.05 indicates significance.

Table 2

Correlation analysis between relapse compartment and survival time stratified according to secondary therapy, n = 111. Pearson test was used to test for statistical significance. p-value ≤ 0.05 indicates significance.

Table 3

Survival data stratified according to relapse location and treatment modality, n = 111. Patients with isolated pulmonary metastases showed the best DFS. Surgery significantly influenced RSS in patients with isolated pulmonary metastases and local recurrence.

Funding

No funding was obtained for this study.

Author contributions:

Study conception, design, data acquisition and overall analysis and interpretation of data and drafting of the manuscript (S.A.S; N.L.), manuscript preparation (S.A.S, N.L., W.T.K.), conceptual contributions and manuscript revision (A.R., L.H., V.K., W.T.K.).

Acknowledgements

Not applicable

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Table 1: Demographic table of study collective and correlation analysis between relapse compartment and clinicopathological variables from primary PDAC n=111. Only M-stage and venous invasion correlated with metachronous hepatic metastases. Pearson Test and Mann-Whitney U test were used to test for statistical significance. p-value ≤0.05 indicates significance.

Table 2: Correlation analysis between relapse compartment and survival time stratified according to secondary therapy, n=111. Pearson test was used to test for statistical significance. p-value ≤0.05 indicates significance.

Table 3: Survival data stratified according to relapse location and treatment modality, n=111. Patients with isolated pulmonary metastases showed the best DFS. Surgery significantly influenced RSS in patients with isolated pulmonary metastases and local recurrence.

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Editorial decision: Major revision
26 Aug, 2020
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Reviewer #1 agreed at journal
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Site of Relapse of the Ductal Adenocarcinoma of the Pancreas affects Survival after Multimodal Therapy

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