On the Verge: Inside Clinical Trials that Could Change Patient Care

	Coronal FDG PET images of patient with carcinoma of left lung. Images before (A) treatment with erlotinib, showing reduction in uptake, and increase in necrosis of primary tumor after 7 days (B) of treatment with erlotinib. This early effect also is observed on transversal PET/CT fusion images before (C) and after 7 days (D) of treatment with erlotinib. Source: SNM

PET imaging is effective in staging, restaging, detecting recurrence and treatment monitoring across a wide range of cancers. This feature discusses updates on important PET imaging clinical trials in cancer care by the American College of Radiology Imaging Network and National Cancer Institute and focuses on improving cancer staging and predicting response to therapy. The National Oncology PET Registry (NOPR) recently published the results of the impact of dedicated brain PET on intended patient management and opened a registry for 18F-sodium fluoride PET to identify bone metastasis. The Cancer and Leukemia Group B (CALGB) sponsored by the NCI is another group conducting clinical trials in cancer, yet PET trials are still few.

Cancer staging…better

The American College of Radiology Imaging Network (ACRIN) trials 6685 and 6671 are examples of clinical trials focused on improving cancer staging. ACRIN 6685 is a multicenter trial of 2-deoxy-2-[18]F-fluoro-D-glucose (FDG)-PET/CT staging of head and neck cancer. The trial looks at evaluation of cervical lymph nodes in patients with head and neck cancer to see if potentially a regular PET scan in a patient with a clinically negative neck could obviate neck dissection on that side of the neck, notes Barry A. Siegel, MD, professor of radiology and medicine, chief of division of nuclear medicine, Washington University School of Medicine, St. Louis. Since it is ongoing, data are yet to be available.
Another ACRIN staging trial that is doing well, according to Siegel, is ACRIN 6671. The trial looks at the use of FDG-PET/CT for staging regional lymph lodes in cervical cancer and endometrial cancers.

Predicting response to therapy

One of the major response biomarker trials is ACRIN 6678 which includes patients with advanced non-small cell lung cancer undergoing chemotherapy. The trial looks at two things—the reproducibility of FDG-PET/CT and whether the change in FDG uptake at the end of the first cycle of chemotherapy predicts progression and overall survival in those patients, shares Siegel.

Because of its sensitivity, low background uptake in many tissues, and the fact that so many tumors exhibit elevated glucose utilization, FDG-PET is typically a better molecular imaging metric for detection of tumors, with a few notable exceptions. However, since 3'-deoxy-3'-[18]F-fluorothymidine (FLT) more specifically measures cellular proliferation, this metric may be better for looking at response to therapy, says H. Charles Manning, PhD, assistant professor of radiology and director of molecular imaging research, Vanderbilt-Ingram Cancer Center in Nashville, Tenn. Manning is the principal investigator of an National Cancer Institute (NCI) RC1 challenge grant funded trial which looks to determine if it is possible to predict how well tumor(s) might respond to treatment with FLT-PET imaging in patients with advanced colorectal cancer. In these studies, FLT-PET scans are performed as many as three times during the trial—once before beginning treatment, once during the course of treatment (approximately four weeks), and once after treatment is complete but prior to surgery.

Another NCI funded phase II trial compares FLT and FDG-PET in the evaluation of response to cetuximab, cisplatin and radiation therapy in advanced head and neck cancers. Patients undergo FLT and FDG-PET scans at baseline, after the second dose of cetuximab and, after 20 to 30 Gy of radiotherapy and FDG-PET scans alone at six weeks and six months after completion of radiotherapy in the trial. The goal is twofold, says Jann N. Sarkaria, MD, associate professor of radiation oncology at Mayo Clinic, Rochester, Minn., and investigator of the trial. One is to understand if either FDG or FLT-PET can detect response to cetuximab therapy alone, and the second goal is to figure out if FLT or FDG-PET imaging-based response early during radiotherapy is predictive of disease control at six months after completion of therapy.

Two more ACRIN trials are focusing on FLT-PET. ACRIN 6688, a phase II study, evaluates the relationship between FLT uptake parameters and pathologic complete response to neoadjuvant therapy of the primary tumor in patients with locally advanced breast cancer. “We are going to acquire FLT images before and after a single cycle of chemotherapy and then compare it to pathological response at the end of the treatment,” says David Mankoff, MD, PhD, professor of radiology, medicine and bioengineering at University of Washington in Seattle and principal co-investigator of the trial.  

ACRIN 6689 is another trial just getting started and is being carried out in conjunction with a therapy trial from radiation therapy oncology group (RTOG). The trial assesses therapy response in patients with glioblastoma. It’s an example of an imaging trial being paired with a therapy trial, adds Mankoff. The RTOG trial is a trial of cediranib, an antiangiogenesis agent being tested in the treatment of brain tumors. FLT-PET scan is an exploratory imaging end point being tested to assess the response to therapy that includes cediranib and the idea is that if the treatment is effective, we would see changes in the FLT retention in the brain tumor early, shares Mankoff.

National Oncologic PET Registry Update: Impact of Dedicated Brain PET

Barry A. Siegel, MD, Professor of Radiology and Medicine, Chief of Division of Nuclear Medicine, Washington University School of Medicine, St. Louis Since 2006, the National Oncologic PET Registry (NOPR) has collected data on Medicare beneficiaries with known or suspected cancers undergoing PET studies for a wide variety of uncommon cancer types under a U.S. Centers for Medicare & Medicaid Services (CMS) policy called coverage with evidence development. NOPR in October 2010 published online the results of the impact of dedicated brain PET on intended patient management in Molecular Imaging and Biology. Previous NOPR published results have shown the effect of PET on changing intended management was 38 percent by using PET or PET/CT and the frequencies ranged from 48.7 percent for myeloma to 31.4 percent for non-melanoma skin cancer. The new report included data from 509 dedicated brain PET scans performed between December 1, 2006, and April 3, 2009, on 479 patients—367 for suspected or proven primary brain tumors and 142 for brain metastases. Compared with the overall NOPR cohort, subjects in the dedicated brain cohort were younger and more frequently had functional limitations from their cancers. Although brain metastases outnumber primary neoplasms, the use of dedicated brain PET in NOPR to evaluate suspected metastases was infrequent and less common than for primary brain tumors. This suggests that referring physicians were highly selective in their use of dedicated brain PET among patients with metastatic cancer, which in turn may reflect the known relatively poor sensitivity of FDG-PET for detection of brain metastases, the NOPR investigators noted. In general the direction and magnitude of impact of PET on management was similar between groups. Overall, dedicated brain PET is used very selectively among participants of NOPR. “We also are proposing to use claims data as a way to show the improved outcomes of Medicare patients enrolled in the registry because appropriate decisions get made, for example, to stop active treatments and move the patient to palliative care simply because their disease is no longer responsive to therapy,” Siegel says. Another milestone came in February when the CMS began reimbursing for F18 sodium fluoride (NaF) PET scans at sites participating in NOPR. This widens coverage for Medicare patients with known or suspected cancer metastatic to bone to help physicians formulate treatment plans.