Journal of Pancreatic Cancer and Treatment

Surgical Therapy of Ductal Adenocarcinoma of the Pancreas Head: Real World Data from an Excellence Center

Abstract

Introduction: The 5-year survival rates of surgical therapy in adenocarcinoma of the pancreas (PHAC) head varies widely, in the last years many studies showed partial astounding improvement in survival by more radical and/or concomittant systemic therapies. 167 patients with PHAC with and without systemic treatment were operated by Whipple- or pylorus - preserving procedures in our Center of Excellence. These “Real- World-Data“ may help to identfy the significance of surgical therapy within present pancreas carcinoma therapy options.

Methods and results: 167 patients with PHAC underwent surgery in Munich at Clinic and Polyclinic of Surgery of the Technical University, Clinical Center “Rechts der Isar“ from August 2014 to June 2023. These prolective collected data were retrospectively evaluated by a multivariate analysis. The different parameters were independently associated with overall survival. Median age at surgery was 70 years and 53.9% were male and 46.1% were female. Systemic therapy was additionally performed in 71.3% of all patients. The median overall survival (OS) of the entire population was 19.4 months. For patients who received systemic therapy the median OS was 23 months. Significant predictors of survival were the resection status (R0/R1), lymphe node involvement (N0/ypN0/N1/ypN1/pN2/ypN2), distant metastasis (M0/M1), CRM-status (CRM-/CRM+), tumor stage (IA/IV), lymphnode invasion, vascular infiltration (venous/arterial) and resection of the V. mesenterica. Tumor progress or relapse were found in most cases locally (66.9%) and/or in the liver (40%). The median time to tumor progression was 6.4 months and was diagnosed in 43% at 12 months and in 74% at 24 months. The 5-year OS was 10.1% and the 1-year survival was 67.4% for all patients with surgical resection, respectively 6.7% and 72.5% for patients with systemic therapy and resection.

Conclusion: Despite varoius systemic therapies and more locally radical operation procedures the value of surgical therapy could improve the prognosis only in few patients for a limitited period. Even more radical surgical therapy was not able to decrease effectively significant risk factors for local recurrence like CRM-involvement, R-status or lymphnode involvement. Most of the patients developed local recurrence after a short postoperative time interval. In our study systemic therapy and resection had an short-time effect for survival, after 2 years there was no difference between resected and resected and systemic treated patients. The question if radical surgery may improve the patients prognosis stays at least open, local predictive factors still significantly influence the overall survival despite multimodal treatment options and for superior results compared to the natural course of the disease. Furthermore, the comorbidity and side effects of the current systemic and surgical treatment modalities are not shown in most of the studies. They affect essential the patients quality of life in his remainig days and shoud be more taken in consideration before indicating surgical resection at advanced tumor stages.

Keywords

Adenocarcinoma of the pancreatic head, Significance of surgical therapy

Introduction

For most patients ductal pancreatic cancer type is refractory to most treatments and the general 5-year survival rate for all patients approached 1-12% depending on tumor stage [1-7]. The survival improvements are modest and attributed to more radical operation procedures and systemic therapies [5,8-10]. In absence of metastatic disease surgery offers the chance of improved 5 year survival after curative resection with 3% mortality in high volume centers [4,9,10]. Correct preoperative staging and the comorbidity of the patients have major influence for the indication of tumor resection and the outcome after resection. In the last years extended surgical resection like arterial and venous resection or the "TriangleOperation“ showed in some patients promising results, but the procedure and the outcome is still under debate [8-11]. Furthermore in most studies the anatomic localization of the tumor may have prognostic impact but this feature will not take in account in most of the studies [12-14].

Therefore the presentation of real world data from a pancreas center of excellence for carcinoma treatment may help to define the significance and status of surgical resection in the therapy of adenocarcinoma of the pancreas head.

Methods

167 patients underwent in our center resection of the pancreatic head by classic Whipple or pylorus preserving Whipple procedure between August 2014 and July 2023 in curative intention. 120 (72.3%) patients received concomittant systemic chemotherapy. Exclusion citeria were other histological types than adenocarcinoma of the pancreas, secondary tumors, bile duct carcinomas or previous pancreas surgery. Follow-up and data collection was finished in July 2023. Patients demographics and clinical characteristics were shown in Table 1.

After surgery all specimens underwent histopathological review and were classified according to the TNM-system. Tumor grading, circumferential resection margin (CMR), resection margin involvement (R-status), resected and involved lymphnodes, arterial and/or venous vessel involvement, infiltration of the perineural sheath and lymphatic vessel invasion were analyzed. Tumor progression and tumor relapse were diagnosed as clinical and radiological evidence at the date of new tumor mass in lymphnodes, liver, lung or locally at the resection side with detoriation of the general condition.

For statistical analysis continous variables were summarized using median and range. All data were prolectively collected and retrospectively analyzed. Categorical variables were summarized using frequency and percentage. Patients who were alive at last follow-up were censored at date of last follow-up. The median OS was estimated using the Kaplan-Meier method. For differences in survival curves the log-rank test was used, uni- and multivariable anlyses were performed using the Cox proportional hazard model. For multivariable analysis, variable selection was performed using a forward selection procedure. The proportional hazard assumption was tested on the final multivariable model using a test basing on Schoenfeld residuals. A P-value of less than 0.05 was taken as statistically significant in the univariate analyses. For the forward selection, a P-value of less than 0.1 was used for addition of variables into the multivariate model. P-values for Cox models were calculated using the likelihood ratio test.

Results

167 patients with adenocarcinoma of the pancreas head with an median age of 70 years, 53.9% male and 46.1% female, were resected between August 2014 and June 2023 by Whipple operation (37.1%) or pylorus-preserving pancreaticoduodenectomy (62.9%). In average 36 (7-83) lymph nodes were removed, about what in average 3 lymph nodes (0-43) showed infiltration of tumor. 66.5% of the patients underwent curative resection and 71.3% received concomittant systemic treatment. Most of them received adjuvant treatment (38.3%), 17.4% only neoadjuvant therapy and 5.4% perioperative chemotherapy. 68% of the patients died during the observation time, 6% was the hospital mortality, whereas in over 80% the death was tumor-related. The median time to tumor progression was 6.4 months and was diagnosed in 43% at 12 months and in 74% at 24 months. The 5-year OS was 10.1% and the 1-year survival was 67.4% for all patients with surgical resection, respectively 6.7% and 72.5% for patients with systemic therapy and resection. The most common side of recurrence was located in the operation field (67.2%), distant metastases were found in the liver (26.8%) and in 23.7% in the lung. Patient demographic and clinicopathological results of the study are detailed described in Table 1.

The multivariable model revealed significant results for negative predictores in overall survival for pN-stage (p < 0.00013), positive resection margin (CRM)-status (p < 0.00048), tumor stage (p < 0.0015), lymphatic vessel invasion (p < 0.0027), R-stage (p < 0.0055), distant metastasis (p < 0.0093), vascular infiltration (p < 0.011) and resection of the vena mesenterica (p < 0.025).

The OS for all patients is shown in Figure 1, the results of all significant predictors influenzing OS were presented in Figure 2, Figure 3, Figure 4, Figure 5 and Figure 6.

Discussion

In this analysis of a heteregenous patient population with PHAC the median survival was 19.4 months and the 5-years survival was 10.7%. That is comparable to the results of most of the specialized centers in Western countries showing OS from 12 to 25 months and 5 year-survival rates between 3% and 28% after surgery [1,4,5,13,15,16]. 71.3% of all patients received any form of systemic treatment without any significant influence on patients OS. There seems to be a short-time effect, but no favourable significant influence on longer survival or patients quality of life.

The pattern of recurence in our study is similar to the reported literature, whereas 67.3% were found in region of the operation field [17]. Local predictive factors for radical surgery like pN-stage (p < 0.00013), positive resection margin (CRM)-status (p < 0.00048), tumor stage (p < 0.0015), lymphatic vessel invasion (p < 0.0027), R-stage (p < 0.0055), distant metastasis (p < 0.0093), vascular infiltration (p < 0.011) and resection of the vena mesenterica (p < 0.025) could be influenced by the surgeon, but the results are disappointing [1,5,8,16,18].

Patients with recurrence of PHAC the OS is around 8% [19]. The group of patients with pancread head cancer showed in this study higher rates of local recurrence than those with body and tail cancer. Aside from that the rate of local recurrence was the highest in the region of the hepatoduodenal ligament/common hepatic artery [19]. The anatomic location of pancreatic cancer as prognostic factor is still under debate [12-14,20].

Several robust randomized control trials suggests no difference in survival of patients with PHAC between standard and extended lymphadenectomy [21]. In contrast lymphatic vessel invasion represents a decisive factor of tumor recurrence and poor survival, even in early stage patients [16].

Our results showed like those from several other studies strong limitations for patient´s survival. Even the short time of 6 months of clinical and radiological signs of tumor progression like in many other analyses prove the short-time effect of surgery in PHAC surgery [2,11,22]. That raise the question of patients benefits and high perioperative expense resulting in poor outcomes and quality of life for these patients.

Systemic therapy offers the possibility for more radical tumor removal after neoadjuvant therapy and to ensure the sucess of locally radical resection with adjuvant therapy [4,10,12]. Of interest may be the question to resect the mesenteric vein, that should increase the local radicality of tumor removal. Our results similar as many other studies showed no survival benefit from resection of the mesenteric vein, but in general patients with infiltration of the vein present higher tumor stages [23,24]. The benefit of locally radical and vessel-orientated pancreatic surgery in PHAC patients should be evaluated against enhanced postoperative complications, detoriation of quality of life and gained lifetime [6,8,9,14]. In all concepts of locally more radical surgery for PAHC patients you should never forget that it is a matter of systemic disease with an unfavourable location of the primary tumor for surgical resection. For exact examination and determination for pathohistological prognostic factors found at the specimen from patients with PHAC, standardized protocols and experienced pathologists are necessary to prove the quality of adequate surgical therapy and to optimize future treatment strategies [17,22].

In conclusion, the survival data of European patients with resectable PHAC who received similar therapies is comparable to reported randomized trials [1,6,11,13]. Maximum 20% of PHAC patients were diagnosed with localized resectable disease. Therefore surgical therapy in stage III PHAC patients despite great efforts remains always palliative proving what five-year survival rates are still 5% to 10% with low quality of life [5,8,10,12,13]. In comparison to that the natural course of disease, for all patients with the diagnose of pancreatic cancer the 5-year showed survival rates about 12% [1,4,6,12].

So far data on quality of life for patients with PAHC are not or insufficient available and should be as well part of interdisciplinary multimodal therapy decision concepts as radical surgery and/or systemic therapies. Moreover, it remains a skill and requires much experience to make the right indication for operation in PAHC patients and not to serve the surgeons enjoyment.

Conflict of Interest Statement

None declared.

Acknowledgements

Dedicated to H. Friess, in gratitude for his respect and relief to my work.

The author thanks Bernhard Haller, Institute for AI and Medical Informatic, Technische University of Munich, for performing the statistical analysis.

References

1. Birkmeyer JD, Siewers AE, Finlayson EVA, et al. (2002) Hospital volume and surgical mortality in the United States. N Engl J Med 346: 1128-1137.
2. McPhee JT, Hill JS, Whalen GF, et al. (2007) Perioperative mortality for pancreatectomy: A national perspective. Ann Surg 246: 246-253.
3. Hackert T, Schneider L, Büchler MW (2015) Current state of vascular resections in pancreatic cancer surgery. Gastroenterol Res Pract 2015: 120207.
4. Hackert T, Klaiber U, Pausch T, et al. (2020) Fifty years of surgery for pancreatic cancer. Pancreas 49: 1005-1013.
5. Strobel O, Neoptolemos J, Jäger D, et al. (2019) Optimizing the outcomes of pancreatic surgery. Nat Rev Clin Oncol 16: 11-26.
6. Park W, Chawla A, O´Reilly EM (2021) Pancreatic cancer: A Review. JAMA 326: 851-862.
7. Goess R, Friess H (2018) A look at the progress of treating pancreatic cancer over the past 20 years. Expert Rev Anticancer Ther 18: 295-304.
8. Schneider M, Strobel O, Hackert T, et al. (2019) Pancreatic resection for cancer-the Heidelberg technique. Langenbecks Arch Surg 404: 1017-1022.
9. Schneider M, Hackert T, Strobel O, et al. (2021) Technical advances in surgery for pancreatic cancer. Br J Surg 108: 777-785.
10. Hackert T, Strobel O, Michalski CW, et al. (2017) The TRIANGLE operation - radical surgery after neoadjuvant treatment for advanced pancreatic cancer: A single arm observation study. HPB 19: 1001-1007.
11. Wang X, Demir IE, Schorn S, et al. (2019) Venous resection during pancreatectomy for pancreatic cancer: A systematic review. Transl Gastroenterol Hepatol 4: 46-52.
12. Takeda T, Sasaki T, Mie T, et al. (2021) The prognostic impact of tumour location and firstline chemotherapy regimen in locally advanced pancreatic cancer. J Clin Oncol 51: 728-736.
13. Lau MK, Davila JA. Shaib YH (2010) Incidence and survival of pancreatic head and body and tail cancers: A population-based study in the United States. Pancreas 39: 458-462.
14. Artinyan A, Soriano PA, Prendergast C, et al. (2008) The anatomic location of pancreatic cancer is a prognostic factor for survival. HPB 10: 371-376.
15. Luu AM, Braumann C, Belyaev O, et al. (2021) Long-term survival after pancreaticoduodenectomy in patients with ductal adenocarcinoma of the pancreas head. Hepatobiliary Pancreat Dis Int 20: 271-278.
16. Crippa S, Pergolini I, Javed AA, et al. (2022) Implications of perineural invasion on disease recurrence and survival after pancreatectomy for pancreatic head ductal adenocarcinoma. Ann Surg 276: 378-385.
17. Esposito I, Kleef J, Bergmann F, et al. (2008) Most pancreatic cancer resections are R1 resections. Ann Surg Oncol 15: 1651-1660.
18. Chatterjee D, Katz MH, Rashid A, et al. (2012) Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma. Am J Surg Pathol 36: 409-417.
19. Kim JR, Kim H, Kwon W, et al. (2021) Pattern of local recurrence after curative resection in pancreatic ductal adenocarcinoma according to the initial location of the tumor. Hepatobiliary Pancreat Sci 28: 105-114.
20. Mackay TM, Van Erning FN, van der Geest LGM, et al. (2019) Association between primary origin (head, body, and tail) of metastasised pancreatic durctal adenocarcinoma and oncologic outcome: A population-based analysis. Eur J Cancer 106: 99-105.
21. Kotb A, Hajibandeh S, Hajibandeh S, et al. (2021) Metaanalysis and trial sequential analysis of randomised controlled trials comparing standard versus extended lymphadenectomy in pancreatoduodenectomy for adenocarcinoma of the head of pancreas. Langenbecks Arch Surg 406: 547-561.
22. Hishinuma S, Ogata Y, Tomikawa M, et al. (2006) Patterns of recurrence after curative resections of pancreatic cancer, on autopsy findings. J Gastrointest Surg 10: 511-518.
23. Müller SA, Hartel M, Mehrabia A, et al. (2009) Vascular resection in pancreatic cancer surgery: Survival determinants. J Gastrointest Surg 13: 784-792.
24. Tseng JF, Tamm ER, Lee JE, et al. (2006) Venous resection in pancreatic cancer surgery. Best Pract Res Clin Gastroenterol 20: 349-364.