Monday, December 24, 2012

Improved Understanding and Management of Pancreatic Cancer

Advances, Winter 2013


Despite improved surgical outcomes in localized pancreatic cancer, more effective treatment approaches are needed for locally advanced and metastatic disease. In the diagnostics arena, improvements in imaging techniques have resulted in the detection of an increased number of pancreatic cysts, leading to the need for more refined approaches to distinguishing low-risk pancreatic cysts from those that require more aggressive intervention. Efforts at Massachusetts General Hospital to address these needs include offering proton beam therapy, which increases the chance of a margin-negative resection while reducing radiation time from six weeks to five days, and combining proton beam therapy with standard and novel chemotherapies, including FOLFIRINOX. Clinical and laboratory studies at Mass General utilize the resources of a robust database and extensive tissue laboratory to identify new targets for small molecule development and to develop minimally invasive tests to help predict the malignant potential of cysts.

Currently, surgical resection offers patients with pancreatic cancer the only chance of cure. The dearth of early screening and diagnostic techniques for pancreatic cancer, however, means that the disease is frequently advanced at the time of diagnosis, complicating surgery and, in many cases, rendering the tumor inoperable. Over the past few decades, says Keith D. Lillemoe, MD, chief of surgery at Massachusetts General Hospital, surgical outcomes at high-volume surgical centers like Mass General have improved dramatically as a result of technical expertise and improved perioperative care. However, new treatment approaches are needed for this challenging disease.

Pancreas specialists at Mass General are pioneering myriad approaches to managing pancreatic cancer at all stages, including efforts to determine which patients need surgery first and which need preoperative therapy to convert unresectable, locally advanced tumors to ones that can be safely resected. These efforts are aimed at biopsy-confirmed pancreatic adenocarcinomas; malignant neuroendocrine tumors of the pancreas have a different biology and are treated under different protocols.

Proton Beam Cuts Radiation to Five Days

Mass General physicians have long been at the forefront in the evaluation of radiation and chemoradiation to improve outcomes. As one of the few centers in the U.S. offering proton beam therapy (PBT) for pancreatic cancer, Mass General is now the site of studies aimed at combining the tissue-sparing advantages of proton beam therapy with standard and emerging chemotherapies to safely maximize the chance of a margin-negative resection while reducing radiation time.

Current treatment for patients with pancreatic cancer involves surgery and a six-week course of photon radiation in combination with capecitabine. This approach places considerable burden on patients, particularly in light of the shortened life expectancy associated with this disease. Recent studies conducted by Mass General physicians, including radiation oncologist Theodore S. Hong, MD; medical oncologistDavid P. Ryan, MD; gastrointestinal surgeonCarlos Fernandez-del Castillo, MD; and others examined the safety and efficacy of preoperative short-course PBT and capecitabine followed by early surgery for localized, resectable pancreatic cancer of the head. PBT has the advantages of delivering the maximum therapeutic dose in five days with minimal destruction of normal tissue. These phase 1 and phase 1/2 studies indicate that preoperative chemoradiation with one week of PBT and capecitabine followed by early surgery is well-tolerated and associated with favorable local control.

Representative dosimetry for: 1) three-field, proton plan; and 2) seven-field, intensity-modulated radiotherapy plan with axial, coronal, and sagittal views.

Converting Unresectable Tumors to Resectable

Dr. Hong and his colleagues are leveraging the advantages of PBT in combination with other agents to improve tumor response in the presurgical setting. A phase 2 study, for example, examines progression-free survival in patients receiving preoperative PBT for five days plus capecitabine and the antimalarial drug hydroxychloroquine. Hydroxychloroquine, says Dr. Hong, shrinks or slows the growth of pancreatic tumors in preclinical models. Patients undergo surgery between weeks five and nine following PBT and resume hydroxychloroquine after surgery until the study ends.

Borderline resectable pancreas.

A European study found the drug regimen known as FOLFIRINOX (fluorouracil, irinotecan, oxaliplatin, andleucovorin) reduced metastatic lesion size in about one-third of patients. Recently, Mass General physicians presented preliminary results of FOLFIRINOX in patients with locally advanced pancreatic cancer, indicating that the approach is safe and feasible in this patient population. Current work involves using FOLFIRINOX to shrink tumors away from major blood vessels located near the pancreas, thus converting patients with locally advanced disease from unresectable to resectable.

One drawback to FOLFIRINOX, says Dr. Ryan, is that it is highly myelosuppressive. Combining the regimen with subsequent chemoradiation may cause overwhelming damage to bone marrow. Since PBT reduces the duration of radiation treatment from six weeks to five days, it offers an appealing way of delivering the beneficial effects of radiation while reducing collateral damage to bone marrow activity. This study—FOLFIRINOX followed by PBT—for patients with borderline resectable pancreatic cancer is now recruiting at Mass General.

Another difficulty with FOLFIRINOX and all chemotherapy regimens used in the treatment of pancreatic cancer is the protective effect of the inflammatory response surrounding these tumors. This fibrotic response may block or impede the penetration of chemotherapy, shielding malignant cells from therapy. Rakesh K. Jain, MD, director of the Edwin L. Steele Laboratory for Tumor Biology at Mass General, recently demonstrated that losartan, commonly used for hypertension management, inhibited collagen synthesis by cancer-associated fibroblasts in preclinical models. Based on that work, Mass General clinical researchers under the guidance of Dr. Hong have launched a phase 1/2 study of losartan plus FOLFIRINOX in patients with locally advanced pancreatic cancer.

Headway in Developing Targeted Therapies

Key Points

  • Preoperative proton beam therapy reduces radiation time and spares normal tissue compared to photon radiotherapy in patients with pancreatic cancer.
  • Combining presurgical proton beam therapy with established and emerging chemotherapy regimens may shrink pancreatic tumors, increasing the possibility of curative resection.
  • Clinical trials study novel targets, dual pathway inhibitors, and FOLFIRINOX in locally advanced pancreatic cancer.
  • Circulating Tumor Cell technology captures pancreatic cancer cells with metastasisenhancing properties.
  • Novel imaging modalities and data analysis help distinguish high-risk and low-risk mucinous cysts.

Pancreatic cancer is inoperable at diagnosis in 90 percent of patients, rendering chemotherapy the only therapeutic option for these individuals. While FOLFIRINOX provides the most significant survival benefit of any treatment introduced to the clinics in more than 20 years, this new regimen yields only a four-month survival benefit. Clinical studies—many of them based on discoveries in Mass General’s research labs—continue to open the door to improved therapies for local and metastatic disease.

Fundamental to these efforts are the Circulating Tumor Cell (CTC) chip technology, developed by scientists in the Mass General Hospital Cancer Center in collaboration with the Mass General Center for Engineering in Medicine; a comprehensive pancreatic tissue library with fully annotated clinical data that has been compiled over more than a decade; routine genotyping of all pancreatic cancers treated at Mass General; and a fully integrated multidisciplinary approach involving experienced specialists and subspecialists. These unique resources allow Mass General clinical researchers to examine the molecular underpinning of pancreatic cancer and the efficacy of potential therapeutics in unique preclinical models, as well as allow physicians to direct patients to trials appropriate for the specific molecular fingerprint of their tumors.

In a recent study published in Nature, senior author Daniel A. Haber, MD, PhD, director of the Mass General Cancer Center, and colleagues showed that the WNT2 protein is over-expressed in CTCs captured in mouse models of metastatic pancreatic cancer and in human patients, whereas WNT2 is rare in primary tumors. The investigators identified factors at work in WNT2-expressing cells that increase metastatic propensity; targeting a key step in this pathway could control pancreatic cancer metastasis. Ongoing work is aimed at developing such a therapy for clinical testing.

For the past 40 years, clinical and basic scientists in the Pancreatic Biology Laboratory have conducted studies designed to understand the biologic mechanisms involved in the initiation, progression, and maintenance of pancreatic disease and cancer. Ongoing work, performed under the leadership ofSarah P. Thayer, MD, PhD, director of the lab, focuses on cancer stem cells and developmental genes and on participation in a worldwide collaboration aimed at sequencing 500 pancreatic cancer genomes and their normal matched controls.

Approximately 70 percent of individuals with pancreatic cancer have a KRAS mutation. Although no targeted therapy has yet been found for pancreatic cancer, experience with other cancer types indicates that targeted therapies—while initially effective—are not long-term solutions. Scientists are now investigating ancillary pathways used to overcome the effects of single-target drugs. Work in the laboratory ofJeffrey A. Engelman, MD, PhD, demonstrated inhibition of both the PI3K pathway and the RAF pathway is required to kill KRAS mutant cancer cells. A phase 1 study of a dual-pathway inhibitor is open to qualifying patients at Mass General.Nabeel M. Bardeesy, PhD, has developed a series of cancer cell lines and genetically engineered mouse models to help elucidate the functional interactions of key cancer genes in both pancreatic and biliary cancers. This work includes focus on epigenetic regulators such as chromatin-modifying enzymes that are deregulated in pancreatic cancer progression as well as on signaling pathways implicated in tumorigenesis and cancer progression. In an effort to help physicians identify pancreatic cancer early, while it is still operable, Dr. Bardeesy has identified biomarkers relevant to the detection of human disease. Current efforts are aimed at validating these markers and identifying new ones.

Improved Methods for Evaluating Cysts

Enhanced imaging has led to the detection of an increased number of pancreatic cysts, yet not all cysts require active treatment. Mass General researchers described distinctions between mucinous cystadenomas, which tend to progress to pancreatic cancer, and serous cystadenomas, which are more likely to be benign. They then developed endoscopic ultrasound fine needle aspiration (EUS-FNA), a technology that provides visual data about the cyst as well as fluid samples. These samples are analyzed for gene changes and levels of carcinoembryonic antigen (CEA). CEA levels are elevated in patients with mucinous cystadenoma but not in patients with serous cystadenoma. This test is now used routinely in medical centers.

Under the direction ofWilliam R. Brugge, MD, director of gastrointestinal endoscopy in Mass General’s Digestive Healthcare Center, the pancreas team is investigating the use of a novel imaging technique, optical coherence tomography (OCT) in combination with EUS-FNA, in an in vivo model to help further distinguish low-risk pancreatic cysts from higher-risk cysts. Whenever possible, Mass General surgeons remove higher-risk cysts located in the pancreatic tail using laparoscopic surgery. Cysts located in the middle of the pancreas may be removed using a parenchyma-sparing technique pioneered at Mass General. This approach is aimed at reducing the risk of postoperative exocrine and endocrine insufficiency.

In a more recent study, Mass General physicians looked at both preoperative clinical and cyst characteristics at the time of endoscopic ultrasound and discovered that older age, male gender, and malignant cytology were independent predictors of malignancy. Patients with these risk factors may benefit from more aggressive management of cysts.

Ongoing research in laboratories associated with theAndrew L. Warshaw, MD, Institute for Pancreatic Research continues to bring together gastrointestinal subspecialists to further distinguish subtypes of mucinous tumors. According to Dr. Warshaw, tumors developing in the branch duct are less likely to develop into invasive cancer, yet when they do, they are highly aggressive. Papillary mucinous cancer developing first in the main duct, like its branch-duct cousin and other mucinous cystic tumors, can be invasive and lethal, but the five-year survival of this class of cancers is more than double that of the more common ductal adenocarcinoma. Work in the Warshaw Institute, spearheaded by Mass General gastroenterologic pathologistMari Mino-Kenudson, MD, has helped characterize different cell types in the two types of mucinous cysts. Analysis of these cell types will help clinicians determine the level of cancer risk in patients with pancreatic cysts.

Meanwhile, with the aid of resources like the tissue laboratory, Mass General researchers are continuing to study the role of gene mutations associated with pancreatic cancer, uncovering variations in these mutations that could have implications in both diagnosis and treatment planning. These laboratory efforts, which are closely tied to an active clinical trial program, support pancreatic cancer physicians in prolonging the lives of patients with this challenging disease.

Selected References

Diop-Frimpong B, et al. (2011). Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. PNAS, 108(7): 2909-14.

Hong TS, et al. (2012). Phase I/II study of preoperative (pre-op) short course chemoradiation (CRT) with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma of the head. J Clin Oncol, abstr 4021. Poster Discussion Session, Gastrointestinal (Noncolorectal) Cancer, presented at 2012 ASCO Annual Meeting.

Huang ES, et al. (2010). Pancreatic cystic lesions: clinical predictors of malignancy in patients undergoing surgery. Aliment Pharmacol Ther, 31(2): 285-94.

Thayer SP, et al. (2003). Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature, 425(6960): 851-56.

Willett CG, et al. (2005). Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer. Ann Surg, 241: 295-99.

Yu M, et al. (2012). RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature, 487: 510-13.


Theodore S. Hong, MD

  • Director, Gastrointestinal Service, Department of Radiation Oncology,Massachusetts General Hospital
  • Associate Clinical Director, Department of Radiation Oncology, Massachusetts General Hospital
  • Assistant Professor of Radiation Oncology, Harvard Medical School
  • Co-director, Tucker Gosnell Center for Gastrointestinal Cancers,Massachusetts General Hospital
Keith D. Lillemoe, MD

  • Chief of Surgery, Massachusetts General Hospital
  • W. Gerald Austen Professor of Surgery, Harvard Medical School
David P. Ryan, MD

  • Chief of Hematology/Oncology, Massachusetts General Hospital
  • Associate Professor of Medicine, Harvard Medical School
Andrew L. Warshaw, MD

  • Senior Consultant, International and Regional Clinical Relations, Massachusetts General Hospital and Partners Healthcare
  • W. Gerald Austen Distinguished Professor of Surgery, Harvard Medical School
  • Surgeon-in-Chief, Emeritus, Massachusetts General Hospital


An integral part of one of the world’s most distinguished academic medical centers, the Massachusetts General Hospital Cancer Center is among the leading cancer care providers in the U.S. Known for providing customized, innovative treatments and compassionate care to both adults and children, the Cancer Center comprises 23 fully integrated, multidisciplinary clinical programs and a vast array of support and educational services. Its network of affiliations extends throughout New England and the southeastern U.S. The Cancer Center’s commitment to eradicating cancer is fueled by scientific investigation conducted as part of one of the largest hospital-based research programs in the nation. Through a powerful synergy between laboratory scientists and bedside physicians, the Mass General Cancer Center fosters innovation in all phases of cancer research. Physician investigators conduct nearly 400 clinical trials annually.

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