L. William Traverso

Pretreatment Assessment of Resectable and Borderline Resectable Pancreatic Cancer: Expert Consensus Statement

Preoperative Staging and Defining Resectability From a surgical perspective, the first objective in the management of suspected or confirmed pancreatic cancer is to determine the potential for resection. Routine exploratory laparotomy for the purpose of operatively determining resectability has been diminished by modern 3-D radiographic imaging, along with effective and sustainable nonoperative methods of palliation. Careful correlation between preoperative CT findings and surgical results has better-defined CT criteria for resectability. The critical aspects that need be evaluated in a thorough radiographic assessment are the presence or absence of peritoneal or hepatic metastases; the potential involvement of the SMV and portal vein and the relationship of these vessels and their tributaries to the tumor; the relationship of the tumor to the SMA, celiac axis, hepatic artery, and gastroduodenal artery; and the presence of any aberrant vascular anatomy. Unequivocal radiographic findings contraindicating resection include distant metastases, major venous thrombosis of the portal vein or SMV extending for several centimeters, and circumferential encasement of the SMA, celiac axis or proximal hepatic artery. Recent revisions of the National Comprehensive Cancer Network (NCCN) guidelines were an attempt to distinguish locally advanced unresectable tumors from potentially resectable tumors.22 Ambiguity exists in these guidelines because of the lack of clarity in defining clearly resectable situations from “borderline resectable” tumors and because of the subjective criteria used to define “borderline” tumors relative to locally advanced, unresectable lesions. The NCCN guidelines do offer a definition of what should be considered a radiographically resectable tumor. Patients without distant metastases and no evidence of tumor extension to the SMV and portal vein and clear fat planes around the celiac axis, the hepatic artery, and SMA should be categorized as having localized and resectable cancers. More refined and objective criteria have been proposed by the M. D. Anderson Cancer Center Pancreas Cancer Group in an attempt to better define the term “borderline resectable” and to guide treatment decisions regarding the use of neoadjuvant therapy and the high likelihood of vein resection and reconstruction as a means to improve the rate of a complete and margin-negative resection.23 Radiographic findings of tumor abutment on the portal vein or SMV with or without venous deformity, and limited encasement of the mesenteric vein and portal vein (i.e., short segment occlusion with suitable vessel for anastomosis above and below) represent the extent of venous involvement that would categorize a tumor as borderline resectable. Radiographic findings suggesting borderline arterial involvement as defined by M. D. Anderson Cancer Center include encasement of a short segment of the hepatic artery, without evidence of tumor extension to the celiac axis and/or tumor abutment of the SMA involving < 180° of the artery circumference. In patients without clinically important major comorbidities, and in the absence of radiographic findings to suggest metastatic disease or locally advanced unresectable disease as outlined above, surgical resection should be considered feasible and likely to be achievable. Whether these resections would result in a higher-than-expected rate of margin-positive resections, and whether such resections would affect survival would best be determined by careful examination of outcomes relative to extent of vascular involvement using objective criteria to determine categorization of extent of disease. Consensus Statement 1. Tumors considered localized and resectable should demonstrate the following: a. No distant metastases. b. No radiographic evidence of SMV and portal vein abutment, distortion, tumor thrombus, or venous encasement. c. Clear fat planes around the celiac axis, hepatic artery, and SMA. 2. Tumors considered borderline resectable include the following: a. No distant metastases. b. Venous involvement of the SMV/portal vein demonstrating tumor abutment with or without impingement and narrowing of the lumen, encasement of the SMV/portal vein but without encasement of the nearby arteries, or short segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction. c. Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis. d. Tumor abutment of the SMA not to exceed >180° of the circumference of the vessel wall.

Endoscopic transpapillary therapy for disrupted pancreatic duct and peripancreatic fluid collections

Eighteen patients with active pancreatic ductal disruptions, including 14 with definable fluid collections, were treated with transpapillary pancreatic duct drains or stents. Twelve of these patients had undergone a previous percutaneous or surgical pancreatic drainage procedure or both, and 8 had long-term drainage tubes in chronic fistulous tracts. Transpapillary catheters could be placed across the ductal disruption or directly into the fluid collection in each case, and 16 of 18 patients had resolution of the disrupted pancreatic duct. Twelve of 14 fluid collections resolved. Complications were limited to mild exacerbation of pancreatitis symptoms in 2 patients and 2 patients who developed subsequent stent occlusion leading to recurrent pancreatitis (1 patient) or recurrent duct blowout with pseudocyst (1 patient). Nine patients had variably significant ductal changes attributable to pancreatic duct stents. At a median follow-up of 16 months, 7 patients ultimately required surgery for ongoing pancreatic pain or residual/recurrent fluid collection. The transpapillary treatment of ongoing pancreatic ductal disruption with or without fluid collection has the potential to obviate surgery in some patients, change an urgent surgical procedure into an elective one, or even assist the surgeon in the performance of intraoperative pancreatography. Further study of this technique appears warranted and must be placed into the perspective of current therapies.

Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma

BACKGROUND Patients with cancer who undergo pancreaticoduodenectomy (PD) followed by radiation and 5-fluorouracil (5-FU) therapy have experienced median overall survival from 18 to 24 months and an actuarial 2-year overall survival from 34% to 48%. We previously reported an 84% 2-year survival using a novel adjuvant chemoradiation protocol that included alpha interferon. This report describes the continued observations regarding this methodology with longer follow-up and more than twice the number of patients as the original report. METHODS From July 1995 to May 2002, 43 patients with adenocarcinomas in the pancreatic head underwent PD at our institution. The mean age was 62 years (range 29 to 77) and 60% were men. Final pathologic findings were stage I (2%), II (12%), III (72%), and IVa (14%) while 84% had positive lymph nodes (average number of nodes positive was 3.2 nodes, (range 0 to 13). Tumor extended through the capsule of the surgical specimen in 70%. These patients then received our investigational protocol consisting of external-beam irradiation at a dose of 4,500 to 5,400 cGy (25 fractions over 5 weeks) and three-drug chemotherapy: continuous infusion 5-FU (200 mg/m(2) daily, days 1 to 35), weekly intravenous bolus cisplatin (30 mg/m(2) daily, days 1,8,15,22,29), and subcutaneous alpha, interferon (3 x 10(6) units, days 1 to 35). This chemoradiation was followed by continuous infusion 5-FU (200 mg/m(2) daily, weeks 9 to 14 and 17 to 22). Chemoradiation was generally initiated between 6 and 8 weeks after surgery. RESULTS All patients completed radiation therapy. There were no deaths due to chemoradiation but 42% were hospitalized during chemoradiation, virtually all due to gastrointestinal toxicity. With a mean follow-up time of 31.9 months, 67% of the patients are alive. Therefore, the median survivorship has not been reached. Actuarial overall survival for the 1-, 2-, and 5-year periods was 95% (confidence interval [CI] = 91% to 98%), 64% (CI = 56% to 72%), and 55% (CI = 46% to 65%), respectively. CONCLUSIONS This follow-up report further suggests overall survival may be improved for patients with adenocarcinoma in the pancreatic head using an adjuvant interferon-based chemoradiation protocol. These results are obtained despite a high incidence of node involvement and advanced tumor stage. From this limited patient series, the actuarial 2-year and 5-year overall survival rates suggest a potential for improved long-term survival. Further study of this regimen in a multiinstitutional setting is needed.

Diagnosis and staging of pancreatic adenocarcinoma with dynamic computed tomography

We assessed the accuracy of dynamic contrast-enhanced computed tomography (CT) in the diagnosis and staging of 213 patients with pancreatic carcinoma and compared it with the accuracy of angiography and surgery. A correct CT diagnosis of pancreatic carcinoma was made in 207 of 213 (97%) patients. Tumors were located in the pancreatic head in 64%, the body in 22%, and the tail in 10%, and enlarged the pancreas diffusely in 4%. CT staged 25 (12%) patients as having potentially resectable tumors and 188 (88%) as having unresectable tumors on the basis of local extension (72%), contiguous organ invasion (43%), vascular invasion (82%), and distant metastases (50%). Compared with angiography in 60 patients, CT detected vascular invasion missed on angiography in 20%, and angiography detected invasion missed by CT in 5%. In these latter cases, other CT criteria of unresectability were present, and angiography provided no significant staging information. Compared with surgery in 71 patients, CT accurately predicted unresectable tumors in 100% of patients and resectable tumors in 72% of patients. Eleven of the patients with CT-resectable tumors underwent resection. Median survival was 22.7 months, with four patients alive at a median of 15.5 months postoperatively. Palliative resections were performed in six patients, and median survival was 14.4 months.

Characteristics of biliary tract complications during laparoscopic cholecystectomy: A multi-institutional study

We collected the records of 81 patients with biliary tract injuries occurring during laparoscopic cholecystectomy (LC) who were referred to 3 referral centers during a 33-month (May 1990 to March 1993) period. All records were reviewed to provide data concerning the anatomy of the lesion induced, method of injury, timing of injury detection, role of intraoperative cholangiography (IOC), methods of treatment, and outcome of these injuries. Injuries were classified by our own method as follows: (1) cystic duct leaks (n = 15), (2) bile leaks and/or ductal strictures (n = 27), and (3) ductal transections or excisions (n = 39). Peak occurrence by quarter of the year was 4th quarter, 1990 (Lahey), and 3rd quarter, 1991 (Mason), and 1st quarter, 1992 (Mayo). The majority (62%) of the injuries were recognized after LC. At the time of LC, 31 of 81 (38%) injuries were recognized and converted to open procedures. Data regarding IOC were available in 63 of 81 (78%) cases. In patients in whom IOC was not performed, 14 of 38 (37%) operations were converted; if an IOC was obtained and interpreted correctly, 13 of 21 (62%) operations were converted. Primary repair was attempted in 11 leaks and/or strictures, but 36% required additional treatment. Primary repair was used in six transections or excisions, and 17% have required further intervention. In patients who had biliary-enteric bypass (BEB) performed outside (17) versus at the referral institution (29), 94% (16 patients) versus 0%, respectively, required additional operative (e.g., revision of a hepaticojejunostomy) or nonoperative (e.g., radiologic or endoscopic stenting or balloon dilation) procedures. When used as initial therapy or after a primary ductal repair, stents (with or without balloon dilation) resolved 100% of simple cystic duct leaks and 91% of leaks and/or strictures. In conclusion, the peak incidence of LC-related biliary injuries appears to have passed. A completed and correctly interpreted IOC increases the chance of detection of biliary injuries intraoperatively and should assist surgeons who use routine IOC. Nonsurgical techniques allow treatment of most simple cystic duct leaks, major ductal leaks and/or strictures, and postoperative BEB strictures, although follow-up is limited. The poor results of pre-referral BEB is not surprising since all of these patients were selected for referral because their treatments had not been successful.

Mucus is a predictor of better prognosis and survival in patients with intraductal papillary mucinous tumor of the pancreas

The aim of our study was to examine the case histories of patients with intraductal papillary mucinous tumor (IPMT) treated with resection to determine predictors of prognosis. Between 1989 and 2000, all patients treated with pancreatic resection for IPMT (n = 63) were analyzed. The diagnosis of IPMT was made using the surgical specimen and the World Health Organization definition. Predictors were determined using univariate and multivariate analysis. The pathologic findings were benign (n = 30), carcinoma in situ (CIS; n = 5), and invasive carcinoma (n = 28). After univariate analysis, predictors of malignancy (invasive plus CIS) were jaundice (odds ratio = 10.32), elevated serum CA19-9 (odds ratio = 15.0), any abnormal liver function test (odds ratio = 7.69), and p53 overexpression. The only predictor of benign disease was gross mucus observed during endoscopy (odds ratio = 4.35). After multivariate analysis, predictors of malignancy were any abnormal liver function test (odds ratio = 5.09) and p53 overexpression, whereas the only predictor of benign disease was still gross mucus (odds ratio = 5.88). Actuarial 3- and 5-year survival for benign disease was 95% and 83% and for malignant disease 52% and 44%, respectively (P = 0.0048). Survival curves also favored p53-negative tumors vs. p53 -positive tumors (P = 0055). In the 33 patients with malignant disease (mean follow-up time =35 months), the presence of gross mucus was a predictor of prolonged survival after univariate and multivariate analysis (odds ratio = 4.34 and 4.55, respectively), whereas alcohol abuse was a predictor of poor survival (odds ratio = 3.41 and 3.60, respectively). Gross mucus observed during endoscopy is a predictor of benign IPMT and, within the group with malignant IPMT; the presence of gross mucus was associated with better survival. Survival was also strongly associated with either benign IPMT or negative staining for p53 overexpression.

Interferon-based adjuvant chemoradiation therapy improves survival after pancreaticoduodenectomy for pancreatic adenocarcinoma.

BACKGROUND Based on a 2-year survival of 43%, the Gastrointestinal Tumor Study Group (GITSG) recommended adjuvant 5-FU-based chemoradiation for resected patients with adenocarcinoma of the pancreatic head. Here we report improved survival over the GITSG protocol with a novel adjuvant chemoradiotherapy based on interferon-alpha (IFNalpha). METHODS From July 1993 to September 1998, 33 patients with adenocarcinoma of the pancreatic head underwent pancreaticoduodenectomy (PD) and subsequently went on to adjuvant therapy (GITSG-type, n = 16) or IFNalpha-based (n = 17) typically given between 6 and 8 weeks after surgery. The latter protocol consisted of external-beam irradiation at a dose of 4,500 to 5,400 cGy (25 fractions per 5 weeks) and simultaneous three-drug chemotherapy consisting of (1) continuous infusion 5-FU (200 mg/m2 per day); (2) weekly intravenous bolus cisplatin (30 mg/m2 per day); and (3) IFNalpha (3 million units subcutaneously every other day) during the 5 weeks of radiation. This was then followed by two 6-week courses of continuous infusion 5-FU (200 mg/m2 per day, given weeks 9 to 14 and 17 to 22). Risk factors for recurrence and survival were compared for the two groups. RESULTS A more advanced tumor stage was observed in the IFNalpha-treated patients (positive nodes and American Joint Committee on Cancer [AJCC] stage III = 76%) than the GITSG group (positive nodes and stage III = 44%, P = 0.052). The 2-year overall survival was superior in the IFNalpha cohort (84%) versus the GITSG group (54%). With a mean follow-up of 26 months in both cohorts, actuarial survival curves significantly favored the IFNalpha group (P = 0.04). CONCLUSIONS With a limited number of patients, this phase II type trial suggests better survival in the interferon group as compared with the GITSG group even though the interferon group was associated with a more extensive tumor stage. The 2-year survival rate in the interferon group is the best published to date for resected pancreatic cancer. The interferon/cisplatin/5-FU-based adjuvant chemoradiation protocol appears to be a promising treatment for patients who have undergone PD for adenocarcinoma of the pancreatic head.

Expandable metallic prostheses for malignant obstructions of gastric outlet and proximal small bowel

BACKGROUND Data are limited on use of expandable metal stents for treatment of malignant gastric outlet obstruction. Accordingly, we report our experience using these stents to palliate malignant obstructions of the gastric outlet, duodenum, and proximal jejunum. METHODS Eight patients with malignant strictures causing gastric obstruction underwent endoscopy with fluoroscopic guidance to delineate tumor borders and length followed by expandable metallic prosthesis placement (Wallstent, Z-Stent, Ultraflex, and Endocoil). RESULTS Symptoms were relieved in seven patients, five of whom had previous surgeries (Whipple, Billroth II, esophagojejunostomy, and gastrojejunostomy) for malignancy. One patient underwent surgical resection of a presumed malignant stricture containing a previously placed Wallstent after a 45-pound weight gain. CONCLUSIONS Expandable metallic prostheses placed in patients with malignant obstruction of the gastric outlet, duodenum, or proximal jejunum, before or after surgery, effectively palliate obstructive symptoms and may also serve to improve nutrition.

Computed tomography severity index is a predictor of outcomes for severe pancreatitis.

BACKGROUND In a small group of patients with acute pancreatitis, Balthazar and Ranson demonstrated the applicability of computed tomography (CT) criteria to predict mortality. Building upon their work with a larger group of patients with acute pancreatitis, we set out not only to demonstrate that the CT severity index can predict death, but also length of hospital stay and need for necrosectomy. METHODS We reviewed all patients admitted to our hospital in the years 1992 to 1997 with a primary diagnosis of acute pancreatitis. Entrance criteria required that a CT scan had been performed during the hospitalization. The index CT scan was used to determine a CT severity index (the CTSI of Balthazar and Ranson). Outcomes measured were death, length of stay (LOS), and need for necrosectomy (NEC). Statistical analysis was performed using Fishers exact and chi-square tests where appropriate. RESULTS Between the years 1992 to 1997, 886 patients had 1,774 admissions for acute pancreatitis, of which 268 had a CT scan performed and were entered into our study. These 268 patients had a mean age of 57 years, a mean LOS of 16 days (1 to 118), and a mean CTSI of 3.9 (0 to 10). Overall mortality was 4% (n = 11). A CTSI >5 significantly correlated with death (P = 0.0005), prolonged hospital stay (P <0.0001), and need for necrosectomy (P <0.0001). Patients with a CTSI >5 were 8 times more likely to die, 17 times more likely to have a prolonged hospital course, and 10 times more likely to undergo necrosectomy than their counterparts with CT scores <5. CONCLUSIONS These data show that the CTSI is an applicable and comparable predictor of outcomes in severe pancreatitis.

Endoscopic pancreatic duct sphincterotomy: Indications, technique, and analysis of results

Fifty-six patients, 54 of whom had chronic pancreatitis, underwent endoscopic pancreatic duct sphincterotomy during a 4-year period from 1988 to 1992. Acute complications noted in 10% of patients included exacerbation of pancreatitis (4) and cholangitis (2). Chronic complications included induction of asymptomatic ductal changes in 16%, thought to be related to endoprosthesis placement, and stenosis of the sphincterotomy site in 14%, requiring repeated endoscopic or surgical sphincter section. When combined with a number of ancillary procedures, including removal of obstructing ductal calculi and stent placement for ductal disruption or stenosis, pancreatic duct sphincterotomy was associated with amelioration of chronic pain or decreased number of clinical attacks of pancreatitis in a subset of patients. The authors conclude that endoscopic pancreatic duct sphincterotomy enlarges our endotherapeutic armamentarium and deserves additional evaluation.