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Five-year actual survival after pancreatoduodenectomy for pancreatic head cancer Iraklis Perysinakis, Spyridon Avlonitis, Despoina Georgiadou, Hercules Tsipras and Ilias Margaris 3rd Surgical Department, George Gennimatas General Hospital of Athens, Athens, Greece

Key words curative resection, long-term outcome, pancreatic cancer, pancreatoduodenectomy, prognostic factor. Correspondence Mr Iraklis Perysinakis, 3rd Surgical Department, George Gennimatas General Hospital of Athens, Kountouriotou 46, Holargos, 15562 Athens, Greece. Email: [email protected] I. Perysinakis MD; S. Avlonitis MD; D. Georgiadou MD; H. Tsipras MD, PhD; I. Margaris MD, PhD. Accepted for publication 15 September 2013. doi: 10.1111/ans.12422

Abstract Background: The aim of this study was to analyse retrospectively the long-term results of patients who were operated for adenocarcinoma of the pancreatic head and identify significant prognostic factors. Methods: Eighty patients who were surgically treated for adenocarcinoma of the pancreatic head between 1995 and 2006 met the inclusion criteria and were subject to retrospective analysis. Possible prognostic factors were evaluated and independent predictors of survival were determined. Results: A classic Whipple procedure was performed in 47 patients and a pyloruspreserving pancreatoduodenectomy in 32 patients; one patient underwent total pancreatectomy. Five-year survival rate in this group of patients was 13.6%. Median survival time was 24 months. Univariable analysis demonstrated stage of disease, tumour size and grade and nodal status as significant predictive factors of survival. Multivariable analysis indicated tumour size, nodal status and disease stage as significant prognostic indicators in terms of survival. Conclusions: Long-term survival in pancreatic cancer is still very low. Prognostic factors include differentiation of the tumour, disease stage and nodal status. So far, there has been no reliable method that can accurately predict which patient will mostly benefit from surgical resection. This means that pancreatic cancer resection should nearly always be attempted.

Introduction Pancreatic cancer is one of the most lethal and aggressive malignancies; it is the 11th most common cancer and it is also the fourth cause of cancer-related death in the United States.1 At the time of diagnosis, more than 85% of the tumours have extended beyond the pancreas or liver metastasis is present. The chance of a curative resection is possible in no more than 10% of all cases. The closer the tumour lies to the ampulla, the more likely is its early detection, due to the presence of obstructive jaundice.2 Pancreatoduodenectomy (PD), although it is considered to be one of the most complicated operations of the alimentary tract, it is the primary treatment for the cancer of the head of the pancreas and can offer long-term survival in a subset of patients, particularly in early stage disease.3 The aim of this study was to identify possible prognostic factors that may influence patients’ long-term outcome.

Methods Between 1995 and 2006, a total of 86 patients were diagnosed with adenocarcinoma of the head of the pancreas and underwent a © 2013 Royal Australasian College of Surgeons

curative classic Whipple or a pylorus-preserving pancreatoduodenectomy (PPPD). All operative specimens were re-evaluated by pathologists to confirm the diagnosis. Histopathologic re-evaluation also included assessment of the degree of differentiation, presence of neural and vascular invasion and degree of pancreatic intraepithelial neoplasia in the specimens. Disease stage for all patients was defined by the tumour-node-metastasis classification of the American Joint Committee on Cancer (7th edition). The follow-up interval was calculated in months and defined as the time between the surgical resection and either the date of death or the last follow-up which was set at 60 months. Patients who died during the first month after the operation were also excluded from the analysis. Survival analysis was performed for the determination of the survival predictors. More specifically, factors related to the event (death) were evaluated by Kaplan–Meier method and the log– rank test for categorical variables. After univariable analysis, independent predictors of survival were determined using multivariable Cox regression analysis. Statistical analysis was performed using SPSS 20.0 software (IBM SPSS Inc., Chicago, IL, USA); a P-value of less than 0.05 was considered statistically significant in all tests. ANZ J Surg 85 (2015) 183–186

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Table 1 Main clinical and pathological characteristics of 80 patients with resected pancreatic cancer included in the study group and their impact on survival according to univariate analysis

Table 2 Medians for survival time by stage Stage

Median Estimate

Parameters Age Cut point 60 years Cut point 65 years Cut point 70 years Mean (SD) Min–Max Gender Male Female Tumour size (cm) Mean (SD) Min–Max Grade High Medium Low Infiltrated lymph nodes 0 1,2,3 >3 Stage IA IB IIA IIB Type of surgery Whipple PPPD

Values

Standard error

P value

0.578 0.954 0.364 64.5 (11.0) 34–80

IA IB IIA IIB Overall

59.000 18.000 48.000 18.000 24.000

— 18.166 9.165 2.620 3.902

95% Confidence interval Lower bound

Upper bound

— 0.000 30.036 12.864 16.352

— 53.605 65.964 23.136 31.648

0.887 52 (65.0%) 28 (35.0%) 0.003 3.0 (1.4) 0.8–7.5 34 (42.5%) 28 (35.0%) 18 (22.5%)

0.006 0.278 0.206 0.002

26 (32.5%) 26 (32.5%) 28 (35.0%) 10 (12.5%) 11 (8.8%) 7 (13.8%) 52 (65.0%)

0.019 0.0 0.05 0.750

47 (58.8%) 32 (40.0%)

Max, maximum; Min, minimum; PPPD, pylorus-preserving pancreatoduodenectomy; SD,standard deviation.

Results During the study period, 144 patients underwent PD in our institution for malignant and benign diseases of the head of the pancreas. The pathology specimen was available in all patients and the diagnosis of ductal adenocarcinoma was documented in 86 patients. Three out of the 86 patients with adenocarcinoma who were lost during follow-up as well as three others who died in the immediate post-operative period were excluded from the study. The 80 remaining patients were subject to further analysis. The study group consisted of 52 males and 28 females at an average age of 64.5 years (range 46, 34–80, standard deviation = 11.16) (Table 1). A classic Kausch–Whipple procedure was performed in 47 patients (59%) and a PPPD in 32 patients (41%); one patient underwent total pancreatectomy due to locally extended disease. Portal vein resection en block with the pancreatic specimen was carried out in two cases in order to achieve a R0 resection. Operative time ranged between 240 and 530 min (mean time 350 min). Estimated blood loss during the operation or in the immediate post-operative period was 950 ± 230 mL. In hospital morbidity was 42% and in hospital mortality 3.5% (three patients died). Causes of in hospital death in the two patients were sepsis due to pancreatic anastomosis breakdown and in one patient pulmonary embolism. Major postoperative complications (apart from the aforementioned three patients) were eight cases of sepsis due to pancreatic anastomosis dehiscence, four cases of intraoperative haemorrhage, two cases of

post-operative haemorrhage due to pancreatic anastomosis dehiscence and three cases of respiratory complications. The mean duration of hospital stay was 18 ± 2 days. All the operations were performed by two senior staff surgeons. The neoplasm was located to the head, uncinate process or the neck of the pancreas in 90, 8 and 2% of patients, respectively. In seven patients, the cancer extended beyond the pancreas invading the duodenum in two cases, the distal common bile duct in three cases and the confluence of the portal vein in two cases. Main clinical and pathological characteristics of patients included in the study group are presented in Table 1. Five-year survival rate in this series of patients was 13.6% while 2-year survival rate was 50.0%. The median survival time was 24 months (standard error = 3.9 months, 95% confidence interval = 16.35–31.65). Medians for survival time by stage are presented in Table 2. Univariable analysis demonstrated significant differences in survival rates between patients with different tumour size (Fig. 1a), high grade, stage of disease (Fig. 1b) and number of infiltrated lymph nodes (Fig. 1c). Results are shown in Table 1. A multivariate forward stepwise likelihood ratio Cox regression indicated tumour size, infiltrated lymph nodes and stage of the tumour as significant prognostic indicators in terms of survival after curative resection (R0) of pancreatic cancer (Table 3).

Discussion Nowadays, operative mortality after PD in centres experienced in pancreatic surgery has dropped below 5%. It was the progress made during the 1980s which forced the surgical community to confront the nihilistic approach that advocated palliative non-resectional treatment even for operable lesions.4–6 In recent years, there have been several studies reporting improved long-term survival after PD. Actuarial 5-year survival rates of 24% have been achieved in patients with curative resections. Even better, 5-year survival rates exceeding 30% should be expected in patients without lymph nodes metastasis.7–10 Although the reasons for this improvement are not clear enough, it seems that low operative mortality and increasing resectability rate that have been achieved in tertiary centres by surgeons with particular interest in pancreatic cancer, have the most important positive impact.11,12 Unfortunately all these encouraging results based on actuarial survival evaluation have not been confirmed by long-term studies. Reports of actual long-term survival after pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas have produced disappointing results.7,10,13,14 © 2013 Royal Australasian College of Surgeons

Pancreatic head cancer: long term outcome

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Fig. 1. Impact of (a) tumour size, (b) disease stage and (c) nodal status on cumulative survival of 80 patients after pancreaticoduodenectomy for pancreatic cancer with curative intent.

Table 3 Risk factors for overall survival after curative resection (R0) of pancreatic cancer (Cox regression model)

(a) Tumour Stage IA IB IIA IIB (b) Tumour size ≤3cm >3cm Infiltrated lymph nodes 0 1,2,3 >3

Hazard ratio

95% CI

P

0.220 0.656 0.447 Reference

0.086–0.563 0.327–1.317 0.189–1.057

0.002 0.236 0.067

0.593 Reference

0.359–0.977

0.040

0.379 0.670 Reference

0.205–0.700 0.380–1.181

0.002 0.166

CI, confidence interval.

This difference between actuarial and actual patients’ survival is attributed to the statistical method used for the analysis. The Kaplan–Meier method that many studies use to calculate the overall survival produces results that may be overestimated due to cases with short-term follow-up included in the analysis as well as patients lost during follow-up.4,13 In order to address this problem properly, actual instead of actuarial survival should be the gold standard for evaluating operative success and long-term survival. In this study, only patients who had undergone PD for adenocarcinoma of the head of the pancreas at least 5 years before were included. The cumulative 5-year survival rate of these patients was 13.6%. Our results are in accordance with other recent reports and suggest clearly that pancreatic cancer carries a bad prognosis and only in eight patients will survive more than 5 years.5,8–10,15 The characteristics of long-term survivors are not well defined. Reviewing several reports dealing with this issue, we were surprisingly confused by the heterogenicity of clinicopathologic characteristics found in long-term survivors.16–18 In our study, there are five patients with poor prognostic factors such as T3 tumours and positive lymph nodes who remain alive more than 5 years after the © 2013 Royal Australasian College of Surgeons

operation. Although the number of these patients is small, it must be pointed out that two of them continue to live free of disease for 8 and 12 years, respectively after the surgical resection. The remaining three died with recurrent disease 6, 7 and 8 years, respectively after the operation. Based on reports which point out the difficulty to distinguish pancreatic ductal adenocarcinoma from non-ductal adenocarcinoma and adenocarcinomas of adjacent organs, we reviewed the histological characteristics of our own long-term survivors.19,20 The results of this re-evaluation did not change our survival data. It is our opinion that careful review of the pathological subtypes of pancreatic cancer should be an important step before reporting final survival data. Furthermore, patients who died more than 5 years postoperatively did so from recurrent disease. This pattern of late recurrence has also been shown by Colnon and Trede. Five-year survival is not synonymous with cure. The causes of these late recurrences are not yet clear.21,22 Riall et al. suggested that nodal status, tumour size and differentiation are factors that should be taken into account when predicting long survival.23 Indeed our results show clearly that negative nodal status, well-differentiated tumours and tumours less than 3 cm in size are associated with better prognosis.23–25 Tumours more than 3 cm in size adversely affect survival but do not preclude long survival. In effect, clinicians should not exclude patients with large tumours from having surgical treatment. Metastatic spread to regional lymph nodes is considered to be the most powerful prognostic factor of survival in patients who have been operated with curative intent.21,22,25,26 We also confirmed that lymph node involvement affects long-term survival adversely. However, there are two patients with positive lymph nodes among long survivors, who are still alive 6 and 12 years, respectively after the operation. The outcomes reported in this study represent results obtained using standard classic Whipple or PPPD resection without extensive retroperitoneal lymph node dissection. Although some authors have advocated such a radical procedure, the accumulated data have failed to demonstrate a benefit in terms of survival.27–29 According to Howard et al., the surgeon’s role in curing pancreatic ductal

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adenocarcinoma is limited to ‘a margin negative resection, accomplished with minimal postoperative complications’.30,31 Due to the aggressive behaviour of pancreatic cancer, long-term survival is still very low and this neoplasm frequently recurs even beyond a long disease-free period. Taking into consideration that there is no other effective treatment apart from surgery, it can be concluded that resection of the pancreatic cancer should nearly always be attempted. A truly curative approach must await major improvements in adjuvant therapy, molecular biology and genetic manipulations.

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© 2013 Royal Australasian College of Surgeons

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Five-year actual survival after pancreatoduodenectomy for pancreatic head cancer.

The aim of this study was to analyse retrospectively the long-term results of patients who were operated for adenocarcinoma of the pancreatic head and...
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