Abstract

Introduction: Periampullary adenocarcinoma is one of the most aggressive malignancies, with biological behavior as its most significant predictor of survival. Curative surgical resection is the main contributing factor in the management. Yet, no oncological data exist for patients who underwent curative resection locally in Saudi Arabia. The study aimed to identify the oncological outcomes of curatively resected periampullary adenocarcinoma and the prognostic factors toward survival.

Methods: All patients who underwent surgical intervention for periampullary adenocarcinoma in a single institution between November 2015 to August 2022 were retrospectively reviewed and analyzed. Only patients who underwent curative resection were included for oncological outcomes.

Results: A total of 58 patients underwent surgical intervention for periampullary adenocarcinoma. Of them, 51 patients underwent curative surgical resection. The most common adenocarcinoma origin was ductal (57%), followed by pancreaticobiliary (16%), ampullary (16%), intestinal (10%), and lastly mixed (2%). The distant metastasis rate was 37.3%, with a mean disease-free interval of 15.8 months (SD 18.1). The median overall survival for all patients who underwent curative surgical resection was 44.07 months (95% CI, 19.54-68.59), while the disease-free survival was 24.67 months (95% CI, 15.77-33.56). The predictors of survival on univariate analysis were female gender (P=0.02) and ASA score IV (P=0.01). However, no variables were significant in the multivariate analysis.

Conclusion: Periampullary adenocarcinoma remains to have aggressive behavior despite optimal surgical resection and appropriate adjuvant therapy. As it tends to metastasize systematically with short disease-free intervals. Pancreatic adenocarcinoma is the highest mortality rate among our patients. There is a need for referral centers to increase the volume and improve the outcomes.

Keywords: Oncological outcomes; Overall survival; Periampullary tumors; Prognostic variables.

Citation: Oraini AM, Shammari SA, Rabah RN, Zahrani AM, Swayyed MA, et al. Survival of periampullary adenocarcinoma post curative resection: A tertiary academic center experience. J Gastroenterol Res Pract. 2024; 4(6): 1205.

Introduction

The Periampullary region comprises several organs packed nearby the [1]. Adenocarcinoma of this region includes adenocarcinoma of the pancreatic head, distal common bile duct, ampulla of Vater, and duodenum [2]. Therefore, it might be challenging to determine the primary tumor site in some cases [1]. Epidemiologically, pancreatic cancer is the third leading cause of death in the United States, with a 5-year survival rate of 11% [3]. In addition, the 5-year survival rate for duodenal and ampullary adenocarcinoma is 53% and 38%, respectively [4]. Lastly, the 5-year survival rate of extrahepatic bile duct cancer is 17.6% [5]. The prevalence of periampullary adenocarcinoma increases with age, and risk factors include smoking, alcohol consumption, a history of diabetes, and chronic pancreatitis [6].

Surgical resection is the only potential cure and long-term survival for patients with periampullary tumors [7]. The standard treatment for periampullary tumors consists of either a classic Whipple’s procedure (pancreaticoduodenectomy) or a pylorus-preserving Pancreaticoduodenectomy (PD) [8]. In contrast to the improvement in survival rate post-curative resection, the recurrence rate remained high [9]. Unfortunately, in most patients, the diagnosis is made at a stage where surgical treatment is not curable, and limited effect is provided by other therapies such as chemotherapy and radiation therapy [10].

Factors reported in the literature that influences better prognosis and long-term survival in patients with periampullary adenocarcinomas; degree of differentiation, stage I or II, small tumor size (< 3 cm), no lymph node metastases, negative resection margins, completion adjuvant chemoradiation therapy, low preoperative and post-operative CA19-9 levels, and low Albumin bilirubin ratio [10-14].

Despite the recent advancements in diagnosis, early detection, and therapeutic modalities, the death rate due to periampullary adenocarcinoma has shown minimal improvement [15]. In Saudi Arabia, the incidence of pancreatic cancer showed a 4-fold increase from 1990 to 2016, with the highest incidence in patients above 70 years, with rates significantly higher among males [16,17]. Therefore, this study aims to identify the oncological outcomes of periampullary adenocarcinoma in patients who underwent curative resection.

Materials and methods

Following the approval of the Institutional Review Board (IRB) at King Saud University, we retrospectively collected and reviewed the electronic medical records of all patients with periampullary adenocarcinoma who underwent surgical resection for curative intent from November 2015 to August 2022 at King Saud University Medical City (KSUMC), an academic medical institution in Riyadh, Saudi Arabia.

Periampullary adenocarcinoma was defined as adenocarcinoma of the pancreatic head, distal common bile duct, ampulla of Vater, or duodenum. We included only patients who underwent curative resection with no distant metastasis upon initial presentation. Patients with benign disease, malignancies other than adenocarcinoma, and patients who did not undergo surgical intervention were excluded.

All patients with periampullary carcinoma were admitted to the hepatobiliary surgery unit for workup and therapy. All cases were discussed in the multidisciplinary tumor board meeting. The tumor board members included specialized radiologists, pathologists, surgical oncologists, hepatobiliary surgeons, and medical and radiation oncologists. Qualified specialized hepatobiliary surgeons operated on all cases.

Data collected included baseline demographic, oncological parameters, surgical intervention, histopathological characteristics, neo-adjuvant and adjuvant therapy, tumor board reports, and clinical follow-up reports. Regression test was used to assess prognostic factors toward survival.

Statistical analysis: Data were analyzed using Statistical Package for Social Studies (SPSS 22; IBM Corp., New York, NY, USA). Continuous variables were expressed as mean ± standard deviation when normally distributed, and categorical variables were expressed as percentages. The t-test was used for continuous variables, and the chi-square test was used for categorical variables. Cox proportional hazards regression was performed to estimate Hazard Ratios (HR) (95% CI). Survival curves were estimated by the Kaplan–Meier method. A p-value < 0.05 was considered statistically significant.

Results

Between November 2015 to August 2022, fifty-eight patients with periampullary adenocarcinoma underwent surgical intervention. Seven patients who had aborted surgery due to intraoperative findings of unrespectability or the presence of distant metastasis were excluded from the survival analysis. Patients were followed up for a mean of 15.27 months (±14.13).

The demographics, baseline characteristics, preoperative parameters, and oncological outcomes are presented in Table 1. The mean age of the 58 patients was 60 years (range 33 to 84), with 40 patients being males (69%). The most common presenting signs and symptoms were jaundice (82%), followed by abdominal pain (70%), and weight loss (63%). Preoperative ERCP with stent placement was performed in 62% of the patients. The radiological staging was defined as resectable in 48 of our patients (83%), eight as borderline (14%), and two were unresectable (3%).

Surgical parameters, histopathological characteristics, and adjuvant therapy of fifty-one patients who underwent curative resection are shown in Table 2. All our patients who underwent surgical resection had an open surgery approach. The portal vein was reconstructed in 5 patients (10%). The most common adenocarcinoma origin was ductal (57%), followed by pancreaticobiliary (16%), ampullary (16%), intestinal (10%), and lastly mixed (2%). Moderately differentiated tumors were the most common type (59%). Thirty-six patients had positive lymph nodes (71%) with a lymph node ratio of 0.22. Furthermore, five patients had a positive resected margin (10%). Out of which, two patients received post-op radiation therapy. Twenty-five patients (50%) received adjuvant therapy with a mean initiation duration of 7.76 weeks. Of them, only seven patients received adjuvant therapy within 6 weeks of curative surgery. Additionally, only two patients received and completed neo-adjuvant therapy (4%).

Oncological outcomes are shown in Table 3. Four patients (8%) had a local recurrence, and nineteen had distant metastasis (37%). The overall mortality rate was 26%. Figure 1 shows the cumulative Kaplan Meier 5-year survival curve, the median of overall survival for all patients who underwent curative surgical resection was 44.07 months (95% CI, 19.54-68.59). In respect of the median of disease-free survival was 24.67 months (95% CI, 15.77-33.56) which is shown in Figure 2.

Survival rate correlated significantly with age, gender, and ASA score, as shown in Table 4. In addition, receiving less than four cycles of adjuvant therapy was marginally significant for survival (P=0.05). Moreover, seven patients received adjuvant chemotherapy within six weeks, and all survived (P=0.10). We observed survival difference in the interval between curative resection and local recurrence in deceased patients compared to alive patients, but it was not statistically significant (312.5 vs. 959 days, P=0.46).

On univariate analysis, several significant factors associated with survival were identified (Table 5). These variables included female gender (P=0.02), and ASA score IV (P=0.01). However, on multivariate analysis, no variables were significant.

Table 1: Baseline demographics and preoperative clinical characteristics (n=58).

Data are expressed as numbers (percentages) except †mean (standard deviation). P values < 0.05 were considered statistically significant. ASA: American Society of Anesthesiologists; BMI: Body Mass Index; CA 19-9: Carbohydrate Antigen; CEA: Carcinoembryonic Antigen; ERCP: Endoscopic retrograde cholangiopancreatography; PTC: Percutaneous Transhepatic Cholangiography.

Table 2: Surgical intervention and oncological parameters (n=51).

Data are expressed as numbers (percentages) except †mean (standard deviation). P values < 0.05 were considered statistically significant.

Table 3: Oncological outcomes (n=51).

Data are expressed as numbers (percentages) except †mean (standard deviation). P values < 0.05 were considered statistically significant.

Table 4: Prognostic variables toward survival.

Data are expressed as numbers (percentages) except †mean (standard deviation). P values < 0.05 were considered statistically significant. ASA: American Society of Anesthesiologists; CA 19-9: Carbohydrate Antigen; CBD: Common Bile Duct; CEA: Carcinoembryonic Antigen.

Table 5: Cox proportional-hazards analysis of prognostic factors toward survival.

Data are expressed as numbers. P values < 0.05 were considered statistically significant. ‡Used as a reference.

Discussion

Periampullary adenocarcinoma is one of the worst survival rates among gastrointestinal malignancies [18]. Curative resection is the main factor in achieving better oncological outcomes [7,19]. There is no published data on periampullary adenocarcinoma in Saudi Arabia after curative resection. The primary goal of this study is to identify the oncological outcomes of periampullary adenocarcinoma post-curative resection.

Several studies showed that adenocarcinoma originating from the intestine has the best survival outcomes, followed by ampullary, biliary, and ductal in patients who underwent curative resection [18,20,21]. Hester et al. reported 5‐year survivalrates of 50% for duodenal, 45% for ampullary, 31% for distal bile duct, and 18% for pancreatic head. He et al. showed that the overall estimated 5-year median survival for periampullary adenocarcinoma was 22 months; pancreatic cancer had the worst survival (median survival 19 months), followed by bile duct cancer (median survival 23 months), ampullary cancer (median survival 47 months) and duodenal cancer (median survival 54 months) [18]. Similarly, in a study by Hatzaras et al., pancreatic cancer histology correlated with the shortest median survival (17.1 months), followed by cholangiocarcinoma (17.9 months) and ampullary carcinoma (44.3 months) [22]. In this study, the median overall survival for all patients who underwent curative surgical resection was 44.07 months (95% CI, 19.54-68.59). The mortality rate based on the adenocarcinoma site was pancreas at 34.48%, followed by cholangiocarcinoma, in which we had two patients, and one is deceased. Then, the ampullary adenocarcinoma mortality rate was 11%. Lastly, we had two patients with duodenum cancer, and both are alive. This finding is interesting since periampullary adenocarcinomas are tissues that are packed nearby, sharing the same venous and lymphatic drainage.

In some cases, it’s challenging to differentiate between them on a gross and histological level, yet they have different outcomes [18]. Thus, each type’s “biological behavior” is one of the most important prognostic factors [22]. With the advancement in medicine and more understanding of the histomolecular basis of these tumors, each periampullary adenocarcinoma needs to be recognized as a distinct entity which will enable us to treat each type as a unique entity for a better outcome [23].

Prognostic variables have been investigated in several studies [10-12,20,22,24,25]. Favorable prognostic variables toward survival were well-differentiated histology, duodenal or ampullary adenocarcinoma, early stage, tumor diameter < 2 cm, negative margins, receipt of chemotherapy, and absence of lymph node metastases, perineural or vascular invasion. Interestingly, this study’s demographic factors, such as age, gender, and ASA score, and on univariate analysis, female gender (P=0.02) and ASA score IV (P=0.01) were significantly associated with survival, in contrast to other studies, which showed no relation [24]. None of the pathological factors reached statistical significance, which the small sample size can justify in our study.

Furthermore, supporting that surgical resection is the only potential for cure, a study showed that the median survival was 20.4 months for resectable patients versus 4.5 months for unresectable patients with periampullary adenocarcinoma [24]. Nevertheless, no statistically significant differences were observed between patients who underwent classic Whipple’s or total pancreatectomy nor for those in whom a pylorus-preserving PD was performed. Similar results were documented elsewhere [24,26].

Patients who underwent only surgical resection experienced a 30-50% recurrence rate [27]. Therefore, surgery alone is not enough. Ongoing studies are evaluating the role of neoadjuvant therapy in patients with resectable periampullary tumors. Whereas a few studies have supported its use in the management of pancreatic adenocarcinoma and cholangiocarcinoma with evidence of improved overall survival [28,29]. In this study, only two patients received and completed neo-adjuvant therapy, which limits the interpretation of its effect on oncological outcomes.

Adjuvant therapy mirrors improving survival and reducing recurrence in surgically resected patients, which could represent a superior efficacy of multimodal treatment with combined chemotherapy [20,30-32]. Although not statistically significant, those who received incomplete adjuvant therapy or less than four cycles had 60% and 20% recurrence, respectively. Additionally, out of twenty-five patients who received adjuvant therapy, twenty-one patients survived (55.3%), but this did not yield any statistical significance. While all patients who received adjuvant chemotherapy within six weeks survived, no statistical significance was observed. Justifiably, the small sample size did not allow proper statistical analysis denoting the need for referral centers to increase the volumes and improve outcomes.

As reported in the literature, the most common site of distant metastasis was the liver, regional lymph node, lungs, and peritoneum [19,33]. In this study, the most common site of metastasis was the liver 42.1%, lung 42.1%, and regional lymph node 31.6%.

This study has several limitations. One of these limitations is that this study is a retrospective cohort study; thus, potential bias exists. Another limitation, the sample size is small, which might contribute to the statistical insignificance of different variables. Therefore, multi-center studies with larger sample sizes are warranted to confirm the results.

Conclusion

Periampullary adenocarcinoma remains to have aggressive behavior despite optimal surgical resection and appropriate adjuvant therapy, as it tends to metastasize systematically with short disease-free intervals. However, there is a significant variation in survival based on biological behavior, with pancreatic and common bile duct tumors associated with the worst survival rates. This is evident in our study, as patients with pancreatic adenocarcinoma have the highest mortality rate.

Conflicting interest: The authors have no conflict of interest to disclose.

Acknowledgment: The authors thank Ahmad H. Al-Sharqawi for his statistical analysis.

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