Pamela J. Hodul

Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated.

PURPOSE Stereotactic body radiation therapy (SBRT) provides high rates of local control (LC) and margin-negative (R0) resections for locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC), respectively, with minimal toxicity. METHODS AND MATERIALS A single-institution retrospective review was performed for patients with nonmetastatic pancreatic cancer treated with induction chemotherapy followed by SBRT. SBRT was delivered over 5 consecutive fractions using a dose painting technique including 7-10 Gy/fraction to the region of vessel abutment or encasement and 5-6 Gy/fraction to the remainder of the tumor. Restaging scans were performed at 4 weeks, and resectable patients were considered for resection. The primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS Seventy-three patients were evaluated, with a median follow-up time of 10.5 months. Median doses of 35 Gy and 25 Gy were delivered to the region of vessel involvement and the remainder of the tumor, respectively. Thirty-two BRPC patients (56.1%) underwent surgery, with 31 undergoing an R0 resection (96.9%). The median OS, 1-year OS, median PFS, and 1-year PFS for BRPC versus LAPC patients was 16.4 months versus 15 months, 72.2% versus 68.1%, 9.7 versus 9.8 months, and 42.8% versus 41%, respectively (all P>.10). BRPC patients who underwent R0 resection had improved median OS (19.3 vs 12.3 months; P=.03), 1-year OS (84.2% vs 58.3%; P=.03), and 1-year PFS (56.5% vs 25.0%; P<.0001), respectively, compared with all nonsurgical patients. The 1-year LC in nonsurgical patients was 81%. We did not observe acute grade ≥3 toxicity, and late grade ≥3 toxicity was minimal (5.3%). CONCLUSIONS SBRT safely facilitates margin-negative resection in patients with BRPC pancreatic cancer while maintaining a high rate of LC in unresectable patients. These data support the expanded implementation of SBRT for pancreatic cancer.

A Comparison of Pancreaticogastrostomy and Pancreaticojejunostomy Following Pancreaticoduodenectomy

This retrospective study compares the results of pancreaticogastrostomy (PG) and pancreaticojejunostomy (PJ) in our institution, which has extensive experience in both techniques. Between the years of June 1995 and June 2001, 214 patients underwent pancreaticoduodenectomy (PD) at our institution. Of these 177 had PG and 97 had pancreatojejunostomy (PJ). There were 117 (54.6%) males and 97 (45.3%) females with a mean age of 64.2 ± 12.4 years. Indications for surgery were pancreatic adenocarcinoma in 101 (47.2%), ampullary adenocarcinoma in 36 (16.9%), distal bile duct adenocarcinoma in 22 (10.2%), duodenal adenocarcinoma in 9 (4.2%), and miscellaneous causes in 46 (21.4%) of patients. Preoperatively, significant differences in the groups were that the patients undergoing PJ were significantly younger than those undergoing PG. Also noted preoperatively, was that the patients undergoing PG had a significantly lower direct bilirubin than those undergoing PJ. With regard to intraoperative parameters, operative time was significantly shorter in the PJ group when compared to the PG group. When the patients who did not develop fistula (N = 186) were compared to those who developed fistula (N = 28) the significant differences were that the patients who developed fistula were more likely to have hypertension preoperatively and a higher alkaline phosphatase. They also showed a significantly higher drain amylase and were likely to have surgery for ampullary, distal bile duct or duodenal carcinoma rather than pancreatic adenocarinoma. In addition, those patients who developed fistula had a significantly longer postoperative stay, a larger number of intraabdominal abscesses and leaks at the biliary anastomosis. Thirty-day mortality was significantly higher in the PJ group compared to the PG (4 vs. 0, P = 0.041). There was a significantly larger number of bile leaks in the PJ group when compared to the PG (6 vs. 1, P = 0.048). In addition, the PJ group required a significantly larger number of new CT guided drains to control infection (8 vs. 2,P = 0.046) and the PJ group required a larger number of re-explorations to control infection or bleeding (5 vs. 0, P = 0.018). However, the pancreatic fistula rate was not different between the two groups (12% [PG] vs. 14% [PJ]). This retrospective analysis shows that safety of PG can be performed safely and is associated with less complications than PJ and proposes PG as a suitable and safe alternative to PJ for the management of the pancreatic remnant following PD.

Neoadjuvant GTX Chemotherapy and IMRT-Based Chemoradiation for Borderline Resectable Pancreatic Cancer

To improve the likelihood of achieving a margin‐free resection, neoadjuvant induction chemotherapy with GTX (gemcitabine, docetaxel, and capecitabine) followed by 5‐FU‐IMRT was administered to patients with borderline resectable pancreatic cancer. The utility of computed tomography (CT), endoscopic ultrasound (EUS), positron emission tomography (PET), and CA 19‐9 during diagnostic workup and assessment of response was also examined.

Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma

Abstract Purpose. Limited data are available to guide neoadjuvant treatment of borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer. Material and methods. We updated our institutional outcomes with a neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT) approach. An IRB-approved analysis was performed of all BRPC and LAPC patients treated with our departmental treatment protocol. After staging, medically fit patients underwent chemotherapy for 2–3 months, with regimen at the discretion of the treating medical oncologist. Patients then received SBRT delivered in five consecutive daily fractions with median total radiation doses of 30 Gy to tumor and 40 Gy dose painted to tumor-vessel interfaces. This was followed by restaging imaging for possible resection. Overall survival (OS), event free survival (EFS), and locoregional control (LRC) rates were estimated and compared by Kaplan-Meier and log-rank methods. Results. We identified 159 patients, 110 BRPC and 49 LAPC, with 14.0 months median overall follow-up. The resection and margin negative (R0) rate for BRPC patients who completed neoadjuvant therapy was 51% and 96%, respectively. Estimated median OS was 19.2 months for BRPC patients and 15.0 months for LAPC patients (p = 0.402). Median OS was 34.2 months for surgically resected patients versus 14.0 months for unresected patients (p < 0.001). Five of 21 (24%) LAPC patients receiving FOLFIRINOX chemotherapy underwent R0 resection. In LAPC, FOLFIRINOX recipients underwent R0 resection more often than other chemotherapy recipients (5 of 21 vs. 0 of 28, p = 0.011). There was a trend for improved survival in those resected LAPC patients (p = 0.09). For those not undergoing resection, one year LRC was 78%. Any grade ≥ 3 potentially radiation-related toxicity rate was 7%. Conclusions. These data underscore the feasibility, safety, and effectiveness of neoadjuvant SBRT and chemotherapy for BRPC and LAPC.

Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer.

Objectives: Few genetic mutations have been identified in pancreatic adenocarcinoma, whereas epigenetic changes that lead to gene silencing are known in several genes. Because SLC5A8 is regarded as a potential tumor suppressor gene that is down-regulated by epigenetic changes in several other cancers, we sought to characterize promoter methylation status and its relationship to SLC5A8 expression in pancreatic cancer. Methods: Promoter methylation and expression of SLC5A8 were evaluated in pancreatic cancer cell lines, tumor, and adjacent nontumor tissues from pancreatic cancer patients using methylation-specific polymerase chain reaction analysis, quantitative real-time and semiquantitative reverse transcriptase-polymerase chain reaction, and bisulfate-modified sequencing. Results: Complete or partial loss of SLC5A8 expression was observed in all tumor tissues. Bisulfite sequencing analysis on pancreatic cancer cell lines that did not express SLC5A8 detected dense methylation of the promoter region. SLC5A8 expression was reactivated by treatment with aza-deoxycytidine or trichostatin A. Methylation-specific polymerase chain reaction detected methylation in 7 of 10 pancreatic tumor tissues, whereas in only 3 of 28 adjacent nontumor tissues (P < 0.001). Conclusions: Our findings indicate loss of SLC5A8 expression as a result of aberrant promoter methylation in pancreatic adenocarcinoma. We suggest that SLC5A8 may function as a tumor suppressor gene whose silencing by epigenetic changes may contribute to carcinogenesis and progression of pancreatic cancer.Abbreviations: SLC5A8 - solute carrier family 5 (iodide transporter) member 8, SMCT - Na(+)/monocarboxylate transporter, HDAC - histone deacetylase, 5-aza - 5-azacytidine, TSA - trichostatin A, MSP - methlyation-specific PCR, COBRA - combined bisulfite restriction analysis

Defining a role for endoscopic ultrasound in staging periampullary tumors

BACKGROUND The goal of the preoperative workup in patients with suspected periampullary carcinoma is to establish the diagnosis with a high degree of certainty. In this study we compared endoscopic ultrasonography (EUS) and computed tomography (CT) scans for the detection of tumor, lymph node metastasis, and vascular invasion in patients with suspected periampullary carcinoma in order to define a role for EUS in the preoperative staging of these patients. METHODS Thirty-seven consecutive patients received EUS and CT scanning followed by operation for presumed periampullary carcinoma during a 30-month period. Both imaging modalities were reviewed in a blinded fashion and the results compared with pathology and operative reports on all patients. RESULTS Sensitivity, specificity, positive predictive value, and negative predictive value for tumor detection by EUS were 97%, 33%, 94%, and 50%, respectively, compared with 82%, 66%, 97%, and 25% for CT scan. For lymph nodes the values were 21%, 80%, 57%, and 44%, respectively, for EUS compared with 42%, 73%, 67%, and 50% for CT. For vascular invasion, the values were 20%, 100%, 100%, and 89%, respectively, for EUS, compared with 80%, 87%, 44%, and 96% for CT. CONCLUSIONS CT is the initial study of choice in patients with suspected periampullary tumors. EUS is superior for detecting tumor and for predicting vascular invasion. Therefore, EUS should be used for patients in whom CT does not detect a mass and for those with an identifiable mass on CT in whom vascular invasion cannot be ruled out.

Aggressive Surgical Resection in the Management of Pancreatic Neuroendocrine Tumors: When Is It Indicated?

BACKGROUND Pancreatic neuroendocrine tumors (PNETs) comprise a heterogeneous group of neoplasms for which treatment is variable, depending on the clinical stage. Despite this diversity, surgery remains the gold standard in the management of PNETs. This paper discusses whether aggressive surgical intervention is indicated for PNETs and investigates what prognostic factors may assist in predicting which patients with invasive disease will benefit most from surgical intervention. METHODS A review was conducted of large surgical series reported in the English literature over the last 10 years as they pertain to current surgical intervention in PNETs and of prognostic factors related to surgical outcome and survival. RESULTS Improved survival can be achieved with aggressive surgical management of PNETs. The presence of hepatic metastases is not a contraindication to surgical resection of the primary PNET. Results of series that reported prognostic factors are heterogeneous. CONCLUSIONS Aggressive surgical resection for selected individuals with PNETs can be performed safely and may improve both symptomatic disease and overall survival. Consideration for resection of primary PNETs should be given to patients with treatable hepatic metastases. Prognostic indices such as tumor differentiation and ability to achieve R0/R1 resection have been linked to survival outcome in PNETs and should be considered when planning aggressive surgical management for this disease.

Vitamin E δ-Tocotrienol Induces p27Kip1-Dependent Cell-Cycle Arrest in Pancreatic Cancer Cells via an E2F-1-Dependent Mechanism

Vitamin E δ-tocotrienol has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we demonstrated that δ-tocotrienol exerted significant cell growth inhibition pancreatic ductal cancer (PDCA) cells without affecting normal human pancreatic ductal epithelial cell growth. We also showed that δ-tocotrienol-induced growth inhibition occurred concomitantly with G1 cell-cycle arrest and increased p27Kip1 nuclear accumulation. This finding is significant considering that loss of nuclear p27Kip1 expression is a well-established adverse prognostic factor in PDCA. Furthermore, δ-tocotrienol inactivated RAF-MEK-ERK signaling, a pathway known to suppress p27Kip1 expression. To determine whether p27Kip1 induction is required for δ-tocotrienol inhibition of PDCA cell proliferation, we stably silenced the CDKN1B gene, encoding p27Kip1, in MIAPaCa-2 PDCA cells and demonstrated that p27Kip1 silencing suppressed cell-cycle arrest induced by δ-tocotrienol. Furthermore, δ-tocotrienol induced p27Kip1 mRNA expression but not its protein degradation. p27Kip1 gene promoter activity was induced by δ-tocotrienol through the promoters E2F-1 binding site, and this activity was attenuated by E2F-1 depletion using E2F-1 small interfering RNA. Finally, decreased proliferation, mediated by Ki67 and p27Kip1 expression by δ-tocotrienol, was confirmed in vivo in a nude mouse xenograft pancreatic cancer model. Our findings reveal a new mechanism, dependent on p27Kip1 induction, by which δ-tocotrienol can inhibit proliferation in PDCA cells, providing a new rationale for p27Kip1 as a biomarker for δ-tocotrienol efficacy in pancreatic cancer prevention and therapy.

The role of cytoreductive hepatic surgery as an adjunct to the management of metastatic neuroendocrine carcinomas.

BACKGROUND Patients with metastatic neuroendocrine cancers to the liver often present with disabling endocrinopathies and pain associated with bulky disease. Quality of life for these patients is poor and can require long-term therapy with somatostatin analogs for control of their symptoms. Alternative therapies to decrease tumor burden and subsequent hormone release have been investigated. Of these, cytoreductive surgery was found to have the most consistent and profound impact on symptom regression and overall survival. METHODS Several cases are reported that illustrate an aggressive multimodality approach in the treatment of metastatic neuroendocrine cancers to the liver. The literature is reviewed and the role of cytoreductive surgery in the management of hepatic neuroendocrine metastases is discussed. RESULTS Cytoreductive surgery can be performed safely with minimal morbidity and mortality. Regression of symptoms occurs in the majority of patients and survival is prolonged. CONCLUSIONS Surgical intervention as part of an aggressive multimodality treatment plan results in improved outcomes for patients with advanced hepatic metastases of neuroendocrine origin. Future directions may include earlier surgical intervention with adjuvant therapies reserved for aggressive recurrent disease.

Outcomes following resection of pancreatic adenocarcinoma: 20-year experience at a single institution.

BACKGROUND Pancreatectomy for ductal adenocarcinoma has been performed with increasing frequency since the late 1980s as postoperative mortality decreased and long-term survival became more common. However, the belief persists among some clinicians that pancreatectomy offers little survival benefit. This report reviews our institutional experience with pancreatectomy for pancreatic adenocarcinoma and provides a critical overview of the controversies regarding the benefits of surgical intervention for patients who are candidates for curative resection. METHODS We determined the survival of 142 patients who underwent pancreatectomy for ductal adenocarcinoma with curative intent (stage IA-IIB) at Moffitt Cancer Center during the last two decades by using data obtained from review of the medical record, the Moffitt Cancer Registry, and the Social Security Death Index. Histologic diagnosis was confirmed by expert review of stained sections cut from fixed surgical specimens. RESULTS In the 137 patients who survived at least 30 days after surgery, the median survival was 21.2 months after resection, with Kaplan-Meier 3- and 5-year disease-specific survival rates of 36% and 32%, respectively. One patient has survived without evidence of recurrent disease for more than 15 years after pancreatectomy. Survival for patients greater than 75 year of age did not differ from that of younger patients. The postoperative mortality rate was 1.5% during the most recent years of highest operative volume (2003 to 2006) and 3.5% for the entire patient cohort. CONCLUSIONS Review of our 20-year experience with resection of pancreatic adenocarcinoma indicates that pancreatectomy with curative intent offers a real chance of long-term survival to patients with this highly lethal disease for which there is no other curative modality.