Close-up On Pancreatic Disease: How Do We Improve The Odds?

Risk of Malignancy in Resected Cystic Tumors of the Pancreas <3 cm in Size: Is it Safe to Observe Asymptomatic Patients?

Surgeons and gastroenterologists often use the size of a discovered cystic tumor as a parameter for their treatment decisions; the smaller the size, the less likely they are to take immediate invasive action. But especially in pancreatic cancer, when tumors can grow aggressively, it is critically important to watch for any signs of growth or change. Recent international guidelines have suggested that all cystic pancreatic tumors less than three centimeters (cm) in asymptomatic patients with no radiographic features concerning for malignancy are safe to observe, but there is little published data supporting this guideline.

This study reviewed the incidence of malignancy in small tumors (less than or equal to three cm) to determine the most important criteria for either continued observation or immediate action using pancreatic resection databases from five high-volume pancreatic centers between 1998 and 2006. A total of 166 pancreatic neoplasm resections less than three cm in size were identified and reviewed for clinical, radiographic and pathological data. The team identified predictors of malignancy such as age, gender and symptoms (abdominal pain, nausea and vomiting, jaundice, presence of pancreatitis, unexplained weight loss, anorexia) and radiographic features from CT, MRI or EUS (presence of a mass, lymphadenopathy or dilated main pancreatic or common bile ducts).

Of the 166 cases, 135 cases were benign [38 serous cystadenomas, 35 mucinous cystic neoplasms, 60 intraductal papillary mucinous neoplasms (IPMN), one cystic papillary tumor, one cystic islet cell tumor] and 31 were malignant (14 mucinous cystic adenocarcinomas, 17 invasive carcinomas in IPMN). Male gender seemed to predict malignancy (19/67, 28%) compared to females (12/99, 12%), as did older age (average 67 years for malignancy vs. 62 years for benign lesions). Most patients with malignancy displayed symptoms (28/31, 96%), with abdominal pain being the most common symptom (55%), followed by weight loss (35%), jaundice and pancreatitis. In addition, most patients with malignancy had at least one radiographic feature indicating as such (87%). Of the patients who had no symptoms but did have concerning radiographic features for malignancy (30 patients), one patient had a malignant tumor.

"Decision-making on the management of small cystic pancreatic neoplasms is currently difficult based on the absence of good, long-term natural history data on the behavior of these lesions. We are confident that based on these results, very small tumors with no other symptoms or radiographic indicators have a very low-risk of malignancy, and enrollment in a surveillance program for monitoring may be a more appropriate management scheme rather than initial surgical resection," said Diane M. Simeone, M.D., of the University of Michigan in Ann Arbor, Mich., and lead investigator of the multi-institutional report. "We hope that as we continue to improve imaging modalities and find better biomarkers in cyst fluid, we will have even more accurate descriptors for patients who need immediate treatment."

Endoscopic Ultrasound and Computed Tomography Predictors of Pancreatic Cancer Resectability

Studies have shown that the best opportunity for long-term survival in patients with pancreatic cancer (PC) is with surgical removal of the tumor during pancreaticoduodenectomy (PD). To determine if patients are candidates for surgery, physicians rely on imaging technologies, such as endoscopic ultrasound (EUS) and computed tomography (CT), to determine the location and size of the tumor as well as its relation to surrounding structures. For example, if the mass is connected to a major blood vessel, it may be more difficult to safely resect the entire tumor.

After surgery, doctors look for other features, such as positive margins (meaning that some cancer cells remain at the edge of the tissues removed) and positive lymph nodes (in which cells have spread beyond the immediate tissue to nearby nodes or glands), which indicate poorer survival rates. The study investigated EUS and CT accuracy in predicting margins and node status as well as the need for more extensive venous resection in patients undergoing pancreaticoduodenectomy.

A total of 107 patients with pancreatic head adenocarcinoma who underwent palliative or curative resection during the last five years were analyzed in the study, comparing preoperative imaging results to intraoperative findings and final pathology. Of the 61 patients who underwent potentially curative PD, 17 (28%) required mesenteric vein resection, a significant indicator of poor survival among PC patients. About one-fourth of patients (n=15) had an R0, LN-resection (a complete resection with clear margins, node-negative), 26 patients had an R0, LN+ (node-positive) resection, three had an R1, LN-resection (involved margins), and 17 had an R1, LN+ resection. Of the 46 unresectable patients, 26 had been estimated resectable by preoperative imaging.

The most significant predictor of unsuccessful R0 resection was superior mesenteric vein (SMV) involvement on CT (OR 0.29) and the only significant predictor of unresectability on CT was periportal adenopathy (OR 3.42). No imaging features predicting node-positivity or vein resection were statistically significant and adding EUS to CT did not improve the accuracy in predicting outcomes.

"We are continually trying to find better ways to choose which patients may benefit most from surgery versus other modalities, such as chemotherapy, particularly with pancreatic cancer, and this study gives us more information about how this staging process is influenced by the current state of the art in imaging," said Philip Bao, M.D., of Vanderbilt University Medical Center in Nashville, Tenn., and lead investigator of the study. "CT imaging appears to be the most valuable strategy to predict resectability of pancreatic cancer compared to EUS, so we will continue to look at imaging quality to support our surgical procedures in order to improve overall survival."

Digital Image Analysis of EUS Images Accurately Differentiates Pancreatic Cancer  from Chronic Pancreatitis

One of the most significant challenges in treating pancreatic cancer is gaining a clear diagnosis at an early stage. Imaging technologies have improved drastically during the past decade, but are still limited in terms of image clarity and ability to differentiate among similar conditions. Because changes in chronic pancreatitis (CP) can affect the accuracy of EUS in diagnosing pancreatic cancer, researchers at the Mayo Clinic sought to determine how digital image analysis (DIA) of endoscopic ultrasound (EUS) images would help better differentiate between pancreatic cancer patients and those with CP, a chronic inflammation of the pancreas.

Specific regions of interest were selected from EUS images of patients with normal pancreas readings (group one, n=110), established CP (group two, n=99), or confirmed PC (group three, n=110) and analyzed using DIA. The team performed a variety of digital image analyses to determine changes in texture, from which a predictive model was built and validated using the extracted texture features for classification. Several of these specific measures had high discriminatory power in defining changes seen on the EUS. Overall, the neural network based model was very accurate in classifying pancreatic cancer, with an area under ROC curve of 0.93.

"According to these results, DIA of the texture changes seen on EUS images is quite accurate in differentiating pancreatic cancer from chronic pancreatitis," said Ananya Das, M.D., of the Mayo Clinic in Scottsdale, Ariz., and senior study author of this study. "Using mathematical models and texture analyses, we can effectively enhance the value of imaging techniques to provide a more accurate diagnosis of pancreatic cancer potentially without the need for invasive diagnostic procedures."

Antioxidant Supplementation for Pain Relief in Chronic Pancreatitis

As we continue to advance our understanding of oxidative stress and its relationship to a variety of diseases, researchers are encouraged about the potential therapeutic role for antioxidants. In this study, a team from the All India Institute of Medical Sciences in New Delhi, India, found that antioxidants may offer relief from the painful symptoms of chronic pancreatitis (CP), an ongoing inflammation of the pancreas that can lead to severe GI complications.

To study the effect of antioxidant supplementation on pain relief, oxidative stress and antioxidant status in CP, the team randomized patients with CP and abdominal pain to receive either placebo (n=56) or antioxidants (n=71) (600�g selenium, 0.54g vitamin C, 9000IU �-carotene, 270IU vitamin E, 2g methionine) daily for six months between October 2003 through January 2006 in a double blind trial. Patients were then evaluated for pain relief using variables such as the number of painful days per month, number of oral and IV analgesics required per month, number of hospitalization episodes per month and percentage of patients who were pain free. The team also assessed markers of oxidative stress [thiobarbituric acid reactive substances (TBARS), serum superoxide dismutase (s-SOD)] and antioxidant status [ferric reducing ability of plasma (FRAP), vitamins A, C and E, erythrocyte SOD (e-SOD), erythrocyte total glutathione (E-TGSH)].

According to the study results, antioxidant supplementation was effective in relieving pain related to CP, with reduced levels of oxidative stress and increases in antioxidant status. In particular, the number of painful days per month was 1.68 after supplementation compared to 3.4 in the placebo group, while the percent of pain-free patients rose from 13 percent in the placebo group to 33 percent in the treated group. Vitamin C and E levels were higher in the treated group, along with other important markers of antioxidant status (FRAP, e-SOD, E-TGSH). Importantly, measures of oxidative stress (TBARS, s-SOD) were reduced in the treated group. Overall, the team found that antioxidant supplementation was the only independent predictor of response.

"We continue to find new beneficial properties of antioxidants and studies like these offer clinical evidence of their important role in maintaining health among patients who have experienced oxidative stress," said Payal Bhardwaj, Ph.D., of the All India Institute of Medical Sciences, and lead investigator of the trial. "We hope that continued research will determine the best combination of antioxidants at the best dose to provide effective supplemental treatment and possibly one day, prevention."

Pancreatic Cancer ErbB3 Pathway Activation is Associated with Erlotinib Sensitivity in Vitro and Improved Postoperative Patient Survival

As targeted therapies become more reliable, researchers are searching for additional prognostic factors as therapeutic targets, with the concept of tailoring therapies to patients who will respond better to certain regimens. Epidermal growth factor receptor (or EGFR) is a major target for novel therapies such as erlotinib and ErbB3 is a specific cell receptor that is stimulated by neuregulin (NRG) and interacts with EGFR � both receptors are often expressed in pancreatic cancer. In this study, a team of researchers from the University of Alabama at Birmingham in Alabama evaluated the relationship of NRG-associated ErbB3 pathway activation to pancreatic cancer prognosis and erlotinib sensitivity in vitro.

To assess these two factors, researchers examined the influence of EGFR/ErbB3 expression and NRG stimulation on the anti-proliferative effects of erlotinib in nine pancreatic cancer cell lines. The expression of EGFR, ErbB3 and NRG was also evaluated in 31 postoperative pancreatic cancer specimens and correlated with patient overall survival.

The team found that higher pancreatic cancer ErbB3 levels correlated with improved sensitivity to erlotinib treatment in vitro. Importantly, among the resected pancreatic cancer specimens, the ErbB3 ligand NRG-� was present in 86 percent of tumors. Elevated expression of NRG-� was found to be the only parameter associated with improved postoperative pancreatic cancer patient survival (median 24.7 vs. 13.7 months).

"Increased levels of ErbB3 receptor-mediated signaling seem to be associated with improved sensitivity to erlotinib in vitro and NRG-dependent activation of the ErbB3 pathway seems to have prognostic significance among pancreatic cancer patients," said Juan Pablo Arnoletti, M.D., of the University of Alabama at Birmingham, and lead author of the study. "What's important about this study is our ability to improve the understanding of the mechanisms that govern pancreatic cancer cell dependence on the ErbB signaling pathways. This understanding may lead to improved patient selection strategies for EGFR-targeted therapies, ultimately impacting patients' odds for survival following treatment."

These research findings were presented at Digestive Disease Week 2007 on May 22.