Pancreatic Cancer: Molecular Imaging’s Increasing Role

Currently ranked the fourth-leading cause of cancer-related deaths in the U.S. and slated to move up the list to No. 2 in the next few years, pancreatic cancer has the highest mortality rate and among the poorest prognoses of all major cancers. The deadliness is largely due to late diagnosis. Some 94 percent of pancreatic patients die within five years of diagnosis.

Molecular imaging, including FDG-PET and other techniques, is assuming an increasing role in efforts aimed at earlier diagnosis and effective treatment monitoring—treatments such as targeted radioimmunotherapy, which is leading the way to better health outcomes for pancreatic cancer patients.

Diagnosis and staging

Non-molecular imaging modalities—specifically, state-of-the-art CT/CT angiography and/or contrast-enhanced MRI/MRCP—currently are regarded as the best options for detecting the primary tumor and assessing whether the degree of disease renders pancreatic resection a viable course of action. This is the case primarily because both CT/CT angiography and contrast-enhanced MRI/MRCP offer appropriate spatial resolution, contrast resolution and the ability to assess vascular involvement. Conversely, PET imaging does not provide the anatomic detail needed to accurately assess patients for locally advanced disease.

However, molecular imaging is playing a role in the diagnosis and staging of pancreatic adenocarcinoma. Case in point: “If initial CT or MRI exams fail to detect the primary tumor, or if CT or MRI are negative or equivocal for metastatic tumor, FDG-PET may be of significant value in detecting and localizing a pancreatic tumor or detecting distant metastases,” observes Paul B. Shyn, MD, a member of the research faculty and an associate radiologist with Brigham and Women’s Hospital in Boston. Shyn, who also serves as an assistant professor of radiology at Harvard Medical School, says it should be noted that endoscopic ultrasound (EUS) is commonly performed to assess the pancreatic tumor. Its chief advantage is that it is used to biopsy the mass and thus confirm the diagnosis. However, it is less helpful in assessing resectability. Thus, in the initial workup of pancreatic cancer, FDG-PET and PET/CT tend to be used as problem-solving tools when initial MRI, CT, or EUS leave unanswered questions.

FDG-PET is especially helpful in assessing the spread of disease. “We are seeing that FDG-PET, in particular, works well in determining the presence of metastatic disease outside of the CT scan, and in identifying the manner in which those tumors spread,” states Alexander “Sandy” McEwan, MD, professor and chair of the department of oncology at the University of Alberta in Edmonton and medical director of the Cross Cancer Institute, also in Alberta.

There may be added horsepower when contrast is part of pancreatic staging. In a study published in the October issue of the European Journal of Radiology, Yoneyama et al, aimed to clarify the diagnostic impact of contrast-enhanced FDG PET/CT for staging of pancreatic cancer compared to non-contrast-enhanced PET/CT. Over a period of three years and seven months, the team from Yokohama Graduate School of Medicine at Yokohama University in Yokohama, Japan, administered FDG PET/CT examinations to a total of 95 patients from 36 to 83 years old with primary pancreatic cancer as a means of comparing diagnostic accuracy achieved with contrast-enhanced and non-contrast-enhanced PET/CT exams. Two blind reviewers analyzed images culled from the exams, both visually and quantitatively; the reference standard was histological examination in 48 patients (51 percent of participants) and/or confirmation of an obvious progression in number and/or size of lesions on follow-ups CT examinations of 47 patients (49 percent of study subjects).

For T-staging, both modalities were found to have correctly dosed invasion of the duodenum in 20 cases (20 percent); mesentery in 12 (13 percent); and 13 (14 percent) in the retroperitoneum. A statistical analysis revealed that certain measures of disease in the celiac artery, common hepatic artery, splenic artery and superior mesenteric vein invasion were significantly higher in the contrast-enhanced PET/CT group for both readers. The latter correctly diagnosed nodal metastasis in 38 patients (88 percent); non-contrast-enhanced PET/CT did the same in 45 patients (87 percent).

Further, via contrast-enhanced PET/CT, distant metastasis, scalene node metastasis, and peritoneal dissemination were correctly assigned in 39 patients (91 percent), while interpretation based on non-contrast-enhanced PET/CT revealed distant metastasis, scalene node metastasis, and peritoneal dissemination in 42 patients (81 percent). Diagnostic accuracy of distant metastasis, scalene node metastasis, and peritoneal dissemination with contrast-enhanced PET/CT was significantly higher than that of non-CE PET/CT.

“Contrast-enhanced PET/CT allows a more precise assessment of distant metastasis, scalene node metastasis, and peritoneal dissemination in patients with pancreatic cancer,” according to the authors.

Just as significantly, FDG PET/CT has been found to have merit when it comes to the re-staging of patients in whom limited locally advanced tumors are addressed with neoadjuvant chemoradiation therapy. Following such treatment, soft tissue planes around the pancreas are frequently obscured, making it difficult for clinicians to interpret CT or MRI scans for response to the therapy or further progression of disease. However, once any initial inflammation related to chemoradiation has subsided (at about the six-week mark), FDG-PET can yield a better assessment for residual viable tumor, significantly aiding in decision-making regarding surgical resection, asserts Shyn.

“In general, FDG-PET images are excellent for pancreatic cancer treatment stratification—to ensure that the right patient receives the right treatment at the right time, with the image serving as a biomarker to guide that stratification,” McEwan says. “And there is strong evidence that the degree to which FDG changes after treatment dictates treatment response.”

He adds that FLT-PET may serve to help clinicians predict which patients will respond to neucleocide-based chemotherapy and which will not, as neucleocide transporters appear to take the imaging agent into malignant cells in the pancreas. Upcoming clinical trials will investigate this hypothesis.

Biomarkers and companion diagnostics

Moving beyond PET, researchers have recently begun to focus on using a combination of biomarker identification and molecular imaging as a vehicle for detecting pancreatic ductal adenocarcinoma in its earliest stages, when surgical resection to increase patient survival times is still possible. “Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be identified by ultrasound molecular imaging, which leads to accurate detection of small lesions,” says Juergen K. Willmann, MD, associate professor of radiology at Stanford University School of Medicine and principal investigator of the institution’s Translational Molecular Imaging Laboratory.

In a recent study, Willmann and his colleagues leveraged ultrasound molecular imaging to search for new markers of neovasculature in pancreatic ductal adenocarcinoma and to assess the potential of those markers for tumor detection. Proteomic analysis was used to identify Thymocyte Differentiation Antigen 1 (Thy 1) as a specific biomarker of pancreatic ductal adenocarcinoma neovasculature. To validate up-regulation, the researchers conducted immunohistochemical analyses of pancreatic tissue samples from 28 healthy subjects, 15 patients with primary chronic pancreatitis tissues, and 196 patients who had been diagnosed with pancreatic ductal adenocarcinoma. The binding of Thy1-targeted contrast micro-bubbles was assessed in cultured cells and animal models.

Immunohistochemical analyses revealed that Thy1 levels were significantly higher in the vascular of pancreatic ductal adenocarcinoma patients than in the vascular of those with chronic pancreatitis and in normal tissue samples. Additionally, molecular ultrasound imaging accurately detected human Thy-1 positive pancreatic ductal adenocarcinoma xenografts in mice, along with pancreatic ductal adenocarcinomas that expressed endogenous Thy1 (Gastroenterology. 2013; 145 (4): 885-894 e3).

“Through this study, we have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice,” Willmann asserts, adding that developing a specific imaging agent and identifying Thy1 as a new biomarker has the potential to aid not only in the diagnosis of pancreatic cancer, but also in the management of patients throughout the course of the disease.

The monitoring of chemotherapy effectiveness constitutes yet another application of molecular imaging in patients with pancreatic adenocarcinoma. According to both Shyn and McEwan, obtaining a baseline FDG-PET before treatment with chemotherapy and comparing it to a repeat scan several days to several weeks later has the potential to afford clinicians a better assessment of response to chemotherapy than do either CT or MRI. Their rationale: On the latter two modalities, anatomic changes may be minimal, whereas metabolic changes may be substantial.

Moreover, Shyn and McEwan deem the combination of FDG-PET and contrast-enhanced CT/CT angiography during PET scanning very appealing as a single-imaging test approach. However, it is presently not in widespread use due to cost and reimbursement issues.

Beyond diagnostics and follow-up

Radioimmunotherapy is one of the newest developments in pancreatic cancer therapy. At an American Association for Cancer Research (AACR) special conference held this past May, Vincent J. Picozzi Jr., MD, director of the Pancreatic Center of Excellence at the Virginia Mason Medical Center Digestive Disease Institute in Seattle, presented phase Ib clinical trial data demonstrating that a combination of several small doses of an investigational radioimmunotherapy and the chemotherapy drug gemcitabine yield superior outcomes compared with radioimmunotherapy alone in patients with metastatic pancreatic ductal cancer.

“An antibody that can recognize a target found only on most pancreatic cancer cells and that can carry a radioactive source with it has the potential to kill cancer cells throughout the body, as opposed to conventional radiation therapy, which is delivered as a ‘beam’ to a specific area of the body,” Picozzi notes.

The radioimmunotherapy used in the trial was Y-90 clivatuzumab tetraxetan with the antibody PAM4. “The antibody binds to a protein called MUC5ac, which is a protein found on the surface of most pancreatic cancer cells, but not normal cells,” explained Picozzi.

In the trial, 58 patients were randomly assigned to one of two treatment arms, each comprised of 29 subjects. Patients from both arms received 6.5 mCi/m2 Y-90 clivatuzumab tetraxetan, divided into multiple smaller doses per cycle, for three weeks. Patients from arm A also received low-dose gemcitabine for one week and then in combination with the radioimmunotherapy for three weeks in each cycle. Treatment was administered for up to nine cycles, separated by four-week delays.

Twenty-seven patients from arm A and 26 patients from arm B completed at least one cycle of treatment. Patients terminated treatment due to disease progression or clinical deterioration, but 12 and 11 patients from arms A and B, respectively, completed two or more cycles of treatment. Patients from arm A were found to be 45 percent more likely to live longer, compared with patients from arm B. For patients who received only one treatment cycle, there was little survival difference between arm A and arm B.

“We found that Y-90 clivatuzumab tetraxetan, when used with low-dose gemcitabine, is a safe, low-side-effect therapy that can prolong survival for at least some patients with metastatic pancreatic cancer, even when no chemotherapy options exist,” Picozzi adds. “Our studies imply that radiolabelled antibodies are safe to use in advanced pancreatic cancer, and that it may be possible to attach other anticancer agents besides Y-90 to clivatuzumab tetraxetan to fight pancreatic cancer.”

A larger, randomized phase III trial to confirm these results is now underway, which should provide new insight  into how to manage care for pancreatic cancer patients.

“Pancreatic cancer and cancer treatment are moving targets,” McEwan concludes. “Whether for treatment planning, gauging treatment response, or something else, molecular imaging will continue to play a role in hitting those targets.”