Surgical Resection For Pancreatic Cancer Research Articles

A molecular prognostic nomogram for resectable pancreatic cancer.

154 Background: Defining clinically and biologically relevant phenotypes in other cancers has led to substantial improvements in the overall outcomes, but as yet none have been defined for pancreatic cancer (PC). About 80% of patients with pancreatic cancer succumb to the disease despite curative resection, many of whom within 6 months of surgery. There is a clear need to better define the biology and clinical behaviour of PC. This study aimed to evaluate the potential clinical utility of biologically relevant molecules as prognostic factors in resected PC. Methods: We assessed the relationship of aberrant S100A4 calcium-binding protein expression with survival in a cohort of 372 patients who underwent surgical resection for PC and derived a nomogram using clinicopathologic variables and aberrant expression of S100A4 and S100A2. Results: High S100A4 expression was an independent poor prognostic factor in both the training (n = 76; HR = 5.00, 95% CI = 2.29 – 10.9; p < 0.0001) and validation sets (n = 296; HR = 1.78, 95% CI = 1.29 – 2.46; p = 0.0004). Incorporating previously published data on S100A2, demonstrated that high expression of S100A4 was still an independent prognostic factor. Aberrant expression of these proteins stratified the cohort into three distinct prognostic groups. A preoperative nomogram using only variables that could be measured preoperatively (tumor size and molecular biomarkers), predicted survival better than nomograms derived from using clinicopathologic variables, which are only determined after examination of the resected specimen. Conclusions: Aberrant expression of S100A4 and S100A2 stratifies PC into distinct prognostic groups and improves the accuracy of prognostic nomograms using variables that can be determined preoperatively. The development and application of such nomograms in routine clinical practice has the potential to improve patient selection and as a consequence overall outcomes for PC. No significant financial relationships to disclose.

Factors affecting long-term survival after surgical resection of pancreatic ductal adenocarcinoma

PurposeSome patients who undergo surgical resection of pancreatic cancer survive longer than other patients. The purpose of this study was to identify the factors that affect long-term survival after resection of histopathologically confirmed pancreatic ductal adenocarcinoma.MethodsA single-center, retrospective study was conducted among 164 patients who underwent surgical resection of pancreatic cancer, between May 1995 and December 2004. The patient follow-up process was conducted via telephone survey and review of electronic medical records for at least 5 years or until death.ResultsWe compared patients with long-term (≥60 months, n = 19) and short-term survival (<60 months, n = 145). Resection margin status, differentiation of the tumor, tumor stage, pre-operative serum level of albumin, total bilirubin and carbohydrate antigen (CA) 19-9 level are related with survival difference (all factors, P < 0.05). Multivariate analysis revealed that a pre-operative serum total bilirubin level <7 mg/dL and a pre-operative serum CA19-9 level <37 U/mL is a statistically significant prognostic factor for long-term survival.ConclusionThe preoperative serum total bilirubin and serum CA19-9 levels are associated with long-term survival after surgical resection of pancreatic cancer.

Prognostic Impact of Perioperative Serum CA 19-9 Levels in Patients with Resectable Pancreatic Cancer

Pancreatic cancer is one of the most deadly cancers, and serum carbohydrate antigen 19-9 (CA19-9) level has been reported to be a useful prognostic marker in pancreatic cancer. The purpose of this study was to determine which prognostic factor (preoperative or postoperative serum CA19-9 level) is more useful. Pre- and postoperative serum CA19-9 levels were measured in 109 patients who underwent surgical resection for pancreatic cancer between 1998 and 2009, and their relationships to clinicopathological factors and overall survival were analyzed with univariate and multivariate methods. In univariate analysis, tumor location (P = 0.019), postoperative adjuvant chemotherapy (P < 0.001), residual tumor factor status (P < 0.001), UICC pT stage (P = 0.004), lymph node metastasis (P = 0.015), and UICC final stage (P = 0.015) were significantly associated with overall survival. Differences in overall survival were significant between groups divided on the basis of four postoperative CA19-9 cutoff values (37, 100, 200, and 500 U/ml) but not significant between groups divided on the basis of the same four preoperative CA19-9 cutoff values. Pre- to postoperative increase in CA19-9 level also was significantly associated with poor prognosis. In multivariate analysis, postoperative adjuvant chemotherapy (hazard ratio, 1.59; P = 0.004) and postoperative CA19-9 cutoff value of 37 U/ml (HR, 1.64; P = 0.004) remained independent predictors of prognosis. Postoperative CA19-9 level is a better prognostic factor than preoperative CA19-9 level, and curative surgery for resectable pancreatic cancer should be tried regardless of the preoperative CA19-9 level.

6601 Long term analysis of Gemcitabine based chemoradiation after surgical resection for pancreatic cancer

6601 Long term analysis of Gemcitabine based chemoradiation after surgical resection for pancreatic cancer

Benefit of postoperative adjuvant therapy for pancreatic cancer

Despite the recent completion of several trials of adjuvant therapy after resection for pancreatic adenocarcinoma, the absolute impact on survival and the identification of appropriate patients for treatment has remained controversial. In the current study, the authors sought to identify the impact of adjuvant therapy and factors associated with any improvement in survival after resection of pancreatic cancer. Through the California Cancer Registry, all California residents diagnosed with pancreatic cancer between 1994 and 2002 were identified. Factors potentially impacting survival were analyzed, including patient demographics, tumor characteristics, and treatment provided. Univariate and multivariate survival analyses were performed by Kaplan-Meier and Cox regression methods. A total of 26,518 patients were identified; 3196 (12.1%) underwent resection as their primary treatment. The median overall survival was 16 months for patients who underwent resection. Prognostic factors associated with better survival included negative lymph node status, well-differentiated tumors, younger age, female sex, and the receipt of any adjuvant therapy. On multivariate analysis, adjuvant therapy demonstrated a statistically significant, although modest, impact on survival, with a hazards ratio of 0.79 (95% confidence interval, 0.72-0.87; P < .001). The benefit of adjuvant therapy was only apparent in those patients with lymph node-positive or poorly differentiated tumors. Adjuvant therapy provided for a modest improvement in overall survival after surgical resection of pancreatic cancer. The absolute effect was most pronounced in those patients with poor prognostic indicators. To identify effective systemic therapy for this deadly cancer, future clinical trials of adjuvant therapy should focus on these groups of patients.

To deny or not to deny surgical resection for pancreatic cancer to elderly patients?

To deny or not to deny surgical resection for pancreatic cancer to elderly patients?

Utilization and Determinants of Adjuvant Therapy Among Older Patients Who Receive Curative Surgery for Pancreatic Cancer

We conducted a population-based study to describe the utilization, determinants, and survival effects of adjuvant therapies after surgery among older patients with pancreatic cancer. Using Surveillance, Epidemiology, and End Results-Medicare data, we identified patients older than 65 years who received surgical resection for pancreatic cancer during 1992-2002. We constructed multiple logistic regression models to examine patient, clinical, and hospital factors associated with receiving adjuvant therapy. Cox proportional hazards models were used to examine the effect of therapy on survival. Approximately 49% of patients received adjuvant therapy after surgery. Patient factors associated with increased receipt of adjuvant therapy included more recent diagnosis, younger age, stage II disease, higher income, and geographic location. Hospital factors associated with increased receipt of adjuvant therapy included cooperative group membership and larger size. Adjuvant treatments associated with a significant reduction in 2-year mortality (relative to surgery alone) were chemoradiation or radiation alone but not chemotherapy alone. Our findings suggest that adjuvant chemoradiation and, to a lesser degree, radiation only are associated with a reduction in the risk of mortality among older patients who undergo surgery for pancreatic cancer. However, receipt of adjuvant therapy varied by period and geography as well as by certain patient and hospital factors.

M2024 Surgical Resection for Pancreatic Cancer: An Estimation of the Number Needed to Treat

M2024 Surgical Resection for Pancreatic Cancer: An Estimation of the Number Needed to Treat

Prognostic Implication of Para‐aortic Lymph Node Metastasis in Resectable Pancreatic Cancer

The survival curve of patients who undergo surgical resection of pancreatic cancer displays a steep decline within 1 year and a relatively slow decline thereafter. The patients with a short survival time may have identifiable clinicopathologic factors that lead to rapid relapse. We analyzed clinicopathologic factors in 133 patients who underwent margin-negative pancreatoduodenectomy with extended radical lymphadenectomy for invasive ductal carcinoma of the pancreas to detect factors that could be responsible for the short survival. Tumor size, invasion of the anterior pancreatic capsule, retroperitoneal invasion, portal venous invasion, major arterial invasion, and metastasis to the para-aortic lymph nodes were variables associated with survival time in univariate analysis. Metastasis to the para-aortic lymph nodes was the single independent factor with a significant association with mortality in multivariate analysis. Some 84% of the patients who had positive para-aortic lymph nodes died within 1 year, versus 46% of the patients with negative nodes. Although tumors that involve the para-aortic lymph nodes may technically be resectable, the expected postoperative survival time for most patients is less than 1 year. If para-aortic nodal metastasis is detected, alternative treatment strategies should be considered.

MAGNETIC RESONANCE IMAGING AFTER ADMINISTRATION OF FERUMOXTRAN-10 FOR EVALUATION OF PARAAORTIC LYMPH NODE METASTATASIS IN PATIENTS WITH PANCREATIC CANCER

Background: Presence or absence of paraaortic lymph node metastasis is one of the most critical factors to decide indication for surgical resection of pancreatic cancer. However, conventional imaging studies such as computed tomography (CT) and magnetic resonace imaging (MRI) often fail to make a correct diagnosis of paraaortic lymph node metastasis, because paraaortic lymph nodes can be enlarged even without metastasis and because size criteria alone is not good enough to discriminate metastatic lymph nodes from non-metastatic lymph nodes with nonspecific enlargement. Therefore, we have evaluated the paraaortic lymph nodes in six patients with pancreatic cancer by MRI after administration of ferumoxtran-10 (Combidex, Advanced Magnetics, Cambridge, MA), a dextran-coated ultrasmall superparamagnetic iron oxide particle that functions as a contrast agent for lymphatic tissue. Patients and Methods: Six patients with pancreatic cancer who were scheduled for surgical resection were enrolled. All patients underwent MRI scanning 24 hours after the intravenous administration of ferumoxtran-10 as well as multi-detector CT scanning. The presence or absence of metastasis in lymph nodes was assessed on the basis of their enhancement patterns. Briefly, non-malignant nodes contain macrophages that phagocytosed ferumoxtran-10 while, due to a decrease in phagocytic activity, metastaic nodes exhibit little or no uptake of ferumoxtran-10. As a consequence, negative nodes show low signal intensity and positive nodes show partial or entire high signal intensity. The results of MRIafter ferumoctran-10 administartion were compared with those of MD-CT and with the final histopathologic diagnosis. Results: In five of the six patients, surgical resctions either by pancreaticoduodenectomy or distal pancreatectomy were carried out. Histopathologic diagnosis of the paraaortic lymph nodes was all negative for metastasis in these patients. In contrast, intraoperative histopathological study of frozen sections resulted in a diagnsosis of metastasis to paraaortic lymph nodes and by-pass operation was performed in the remining one patient. Sensitivity, specificity, and accuracy of MD-CT were 100%, 25%, and 50%, respectively when enlarged paraaortic lymph nodes > 5 mm were considered positive. Sensitivity, specificity, and accuracy of MRI after ferumoxtran-10 infusion were all 100%. Conclusions: MRI after intravenous administration of ferumoxtran-10 is useful for evaluation of paraaortic lymph node metastasis in patients with pancreatic cancer.

Surgical resection for pancreatic cancer: Correlates of margin positivity

4097 Background: Positive surgical margins (PSMs) occur in 20–40% of pancreatic cancer cases treated surgically. PSMs are associated with local recurrence and poor survival. Objectives: Correlate clinicopathological parameters with PSMs in pancreatic cancer patients (pts) undergoing surgical resection. Methods: Clinicopathological data for 71 pts who underwent surgical resection for pancreatic cancer from 1999–2005 were obtained. Data including location, AJCC stage, tumor size, type of resection, use of neoadjuvant therapy, grade, morphology, perineural and angiolymphatic invasion were correlated with PSMs and survival using logistic regression, Fisher-exact test and log-rank test. Results: There were 29 males; median age was 65 years and median follow-up 14 months. Histologies were: adenocarcinoma (n = 67), sarcomatoid (n = 2), adenosquamous (n = 1) and mucinous cystadenocarcinoma (n = 1). Sites of disease were: head only (n = 56), head/uncinate (n = 7) and body/tail (n = 8). Surgical treatments included Whipple (n = 43), pylorus preserving Whipple (n = 18) distal pancreatectomy (n = 8) and total pancreatectomy (n = 2). Pathological AJCC stages were: ΙA (n = 4), ΙB (n = 2), ΙΙA (n = 14), ΙΙB (n = 48), and ΙΙΙ (n = 3). Neoadjuvant chemoradiation (CRT) was administered in 10 cases; 38 other pts received postoperative adjuvant therapy including CRT (n = 36)/chemotherapy only (n = 2). Overall median survival was 30 months and disease free survival 18.6 months. Nineteen cases (27%) had PSMs. PSMs were pancreatic transection line (n = 11), retroperitoneal margin (n = 9), bile duct (n = 1) and peripancreatic soft tissue (n = 2). On univariate analysis, PSM was associated with advanced AJCC stage (p = 0.02) and tumor location other than pancreatic head (p = 0.02). PSM rate was 10% (1/10) and 31% (18/61) for pts with/without neoadjuvant therapy, respectively (p = 0.27). On multivariate analysis, PSM correlated with AJCC stage (p = 0.04) and tumor location (p = 0.05). PSMs were not significantly related to survival or recurrence (p = 0.09). Conclusions: Advanced AJCC stage and tumor in pancreatic body/tail or uncinate are associated with PSMs following pancreatic cancer resection. Strategies to “downstage” with novel therapies prior to surgery should be investigated to facilitate a complete surgical resection. [Table: see text]

Analysis of Long-term Survivors After Surgical Resection for Pancreatic Cancer

The purpose of this study was to determine the outcome of surgical resection for pancreatic cancer and to characterize the clinicopathologic features of actual long-term survivors. Of the 789 pancreatic cancer patients, we retrospectively analyzed 242 patients who underwent an operation between 1985 and 1999. Surgical resection with curative intent was performed in 123 patients. We analyzed the overall results of surgical treatment, compared the clinicopathologic features between long-term and short-term survivors, and reevaluated the histological slides of the long-term survivors. Median survival and cumulative 5-year survival rate after surgical resection were 14.8 months and 12.1%. Tumor size, American Joint Committee on Cancer stage, resection margin involvement, and lymph node metastases were the significant prognostic factors. Eleven patients survived for more than 5 years. Some patients with poor prognostic factors such as lymph node metastasis and big tumor size survived for more than 5 years. Histological reevaluation in the long-term survivors revealed 4 cases of variant adenocarcinoma (anaplastic carcinoma, mucinous noncystic adenocarcinoma [n = 2], and undifferentiated carcinoma). Active surgical resection should be attempted even in patients with poor prognostic factors. As there were various types of pathology among the long-term survivors, typical ductal adenocarcinoma of the pancreas might have a poorer survival rate.

Identification of Prognostic Factors Associated with Early Mortality after Surgical Resection for Pancreatic Cancer—Under‐analysis of Cumulative Survival Curve

The cumulative survival curve after surgery for advanced pancreatic cancer is characterized by a steep downward slope in the early postoperative period. The aim of this investigation was to identify the characteristics associated with early mortality in patients undergoing pancreatic resection for pancreatic cancer. Thirty-seven patients with extended radical pancreatectomy combined with intraoperative radiation therapy were studied. The cumulative survival curve in this series was depicted using the Kaplan-Meier method. Assuming that there were two distinct survival curves, below and above the breakpoint, each part of the curve was modeled as an exponential distribution. Three parameters, the breakpoint, the high hazard rate below the breakpoint, and the low hazard rate above the breakpoint were estimated by the maximum likelihood method. Prognostic factors associated with early mortality after surgery were evaluated using univariate and multivariate Cox proportional hazards regression analyses. The breakpoint of the survival curve was estimated at 41 months. The short-survival group (SSG) was defined as deceased earlier than 41 months after surgery, and included 31 patients (83.8 %). The long-survival patient group (LSG) consisted of 6 patients who were alive more than 41 months after surgery. Eighteen SSG patients (58.1 %) died of hepatic metastases, whereas no LSG patients died of hepatic metastases. Abdominal pain and/or back pain during clinical course was identified by multivariate analysis as a prognostic factor for patients undergoing pancreatic resection. The high hazard rate in the early postoperative period was closely linked with death due to liver metastases. The preoperative presence of local pain was a prognostic factor associated with early mortality.

Systemic treatment of pancreatic cancer.

Patients with pancreatic cancer have a poor prognosis although systemic treatment has slightly improved the outcome for those with advanced pancreatic cancer, The approach to a patient with pancreatic cancer remains a great challenge. Patients often present with advanced disease and many are already in poor general condition at the time of diagnosis. Today, surgery remains the only curative therapeutic option. A small number of pancreatic adenocarcinomas, however, are resectable and relapses after surgery are very frequent. The reference treatment in patients with metastatic pancreatic cancer is gemcitabine. The median survival of patients with advanced pancreatic cancer who are treated with gemcitabine is approximately 6 months and only approximately 20% of patients will be alive at 1 year. Combinations of gemcitabine with new cytotoxic agents and with novel targeted agents hold the promise for improving the outcome. Randomized phase III studies are, however, still ongoing. Since most patients will relapse after complete surgical resection of pancreatic cancer, a search for a better adjuvant or neoadjuvant treatment is important. Although several randomized studies have suggested an improved outcome for a postoperative chemoradiotherapy or chemotherapy, the role of an adjuvant treatment remains today controversial. Randomized phase III studies are ongoing. A neoadjuvant strategy might therefore also play a role, but phase III studies are lacking. The systematic evaluation of new drugs in well designed clinical trials and the search for new molecular targets for treatment are crucial in our aim to improve the outcome for patients with pancreatic cancer.

Adjuvant Therapy After Pancreatic Cancer Resection

Some data suggest that adjuvant therapy after surgical resection for pancreatic cancer may improve long-term survival, but it is not used routinely because evidence from randomized studies is inconclusive. The European Study Group for Pancreatic Cancer randomly assigned 289 patients who had undergone complete macroscopic resection of histologically proven pancreatic ductal adenocarcinoma to receive postoperative chemoradiotherapy alone, chemotherapy alone, combination chemoradiotherapy and chemotherapy, or neither treatment (observation). Clinical features and characteristics of the tumors were similar among groups. After a median follow-up of 47 months, …

OPINIONS AND COMMENTARY ON TREATING PANCREATIC CANCER

Over the past 2 decades, major progress has been made in the perioperative and surgical management of pancreatic cancer. These advances have resulted in improved long-term results after surgical resection for pancreatic cancer. There are still many controversies surrounding the optimal management of this disease, however, resulting in wide variations in perioperative and operative care at different centers.

Endoscopic Ultrasound in the Clinical Staging and Management of Pancreatic Cancer: Its Impact on Cost of Treatment

Surgical resection for pancreatic cancer carries a 5% 5-year survival rate. Most conventional methods of imaging do not detect small pancreatic tumors and do not accurately stage pancreatic neoplasms. There is a significant impact on medical resources despite the relatively small number of patients affected. For these reasons, careful selection of patients for surgical resection is necessary. Endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) have been developed to overcome limitations of conventional staging. We address the issues of how EUS may provide cost-effective treatment in the patient with pancreatic cancer. EUS produces high-resolution images of the pancreas, which can detect small pancreatic tumors and accurately stage pancreatic neoplasms. Evaluation with EUS-guided FNA selects patients who would benefit most from surgical resection. EUS also can be used to deliver palliative treatment for pain at the initial time of staging. EUS with FNA identifies patients most likely to benefit from surgical resection and thus channels health care resources more appropriately. Defining this patient population helps to reduce direct medical care costs in pancreatic cancer. However, prospective data are lacking in this regard and will need to be addressed in the future. When palliative care is the goal for patients, EUS-guided fine-needle injection techniques can be used for celiac neurolysis and possibly in the future use of antitumor agents.

New treatment possibilities for pancreatic and biliary tumours.

Pancreatic adenocarcinoma is one of the most lethal cancers in the Western world with a median survival of approximately 3 months. Patient survival depends on the extent of disease and performance status at diagnosis. The extent of disease is best categorised as resectable, locally advanced or metastatic. Surgery is the only curative treatment. It is, however, an option in only 10-20% of patients. Long-term survival after surgical resection of pancreatic cancer is less than 20%. Local recurrence occurs in up to 85% of patients who undergo surgery alone. Local-regional tumour control is maximised with combined modality therapy in the form of chemoradiation and surgery. With improved therapy for local-regional disease, liver metastases become the predominant form of tumour recurrence and occur in 50 to 70% of patients following potential curative combined modality treatment. At the time of diagnosis, 40% of patients have locally advanced disease and more than 40% have visceral metastases, most frequently in the liver. Therefore, with new surgical and radiotherapeutic techniques improving locoregional control, we will face distant metastases being responsible for therapy failure more often and effective systemic treatment will become even more important for prolonging survival. Unfortunately results obtained with chemotherapy failed to have an important impact on the final outcome and have been the reason for scepticism among clinicians and oncologists for many years. However, a totally fatalistic approach is not justified, because a significant proportion of patients do achieve benefit from chemotherapy. Several new and innovative therapeutic modalities are in development and offer hope for an improved outcome for patients with pancreatic cancer in the future.

Antimetastatic efficacy of adjuvant gemcitabine in a pancreatic cancer orthotopic model.

Gemcitabine is a promising new agent that has been recently studied for palliation of advanced (stage IV) unresectable pancreatic cancer. We hypothesized that adjuvant gemcitabine would reduce recurrence and metastases following surgical resection of pancreatic cancer. To test this hypothesis, we evaluated gemcitabine on a green fluorescent protein (GFP) transductant of the human pancreatic cancer cell line BxPC-3 (BxPC-3-GFP) using surgical orthotopic implantation (SOI) in nude mice. GFP enabled high resolution fluorescent visualization of primary and metastatic growth. Five weeks after SOI, the mice were randomized into three groups: Group I received exploratory laparotomy only. Group II underwent surgical resection of the pancreatic tumor without further treatment. Group III underwent tumor resection followed by adjuvant treatment with gemcitabine, 100 mg/kg every three days for a total of four doses, starting two days after resection. The mice were sacrificed at thirteen weeks following implantation and the presence and location of recurrent tumor was recorded. Gemcitabine reduced the recurrence rate to 28.6% compared to 70.6% with resection only (P = 0.02) and reduced metastatic events 58% in the adjuvant group compared to resection only. This study, demonstrating that gemcitabine is effective as adjuvant chemotherapy post-pancreatectomy, suggests this new indication of the drug clinically.

Aberrant p16INK4 expression related to clinical stage and prognosis in patients with pancreatic cancer.

The p16 tumor suppressor gene is thought to play an important role in cell cycle regulation by encoding for protein products that can inhibit the progression from G1 to S phase in the cell cycle. Recently, the p16 gene has been found to be mutated or deleted in a variety of different types of primary human malignant tumors and human-derived malignant tumor cell lines. In this study, primary ductal pancreatic adenocarcinomas from 32 human patients were analyzed immunohistochemically for expression of p16 protein, with emphasis on the role of abberant p16 protein expression as a prognostic indicator. In addition, the same tumors were also assessed for p53 protein expression, AgNOR counts, and DNA ploidy. Nineteen out of the 32 cases (59%) showed positive immunoreactivity for p16 protein in their tumors and a significant association was found between lack of p16 protein expression, and both advancing clinical stage classification of disease, and poorer survival (p<0.05). The rate of positive immunoreactivity for p53 protein expression was 59%, however, no clear association was found between p53 protein expression, and either clinical stage of disease, or survival. These findings suggest that alteration of the p53 gene may be a relatively early event in pancreatic tumorigenesis, whereas alteration of the p16 gene is more likely to be correlated with tumor progression in pancreatic malignancies. Further survival analysis revealed that all five of the 32 cases that survived for three years or longer had positive immunostaining for p16 protein, and a relatively low level of AgNOR counts. In four out of five of these patients, the tumors also exhibited negative immunostaining for p53 protein and DNA diploidy. These findings suggest that molecular analysis of patient tumor sections may yield potentially useful prognostic indicators for patients undergoing surgical resection for pancreatic cancer.