18F-FDG PET Breaks New Ground in Small Cell Lung Cancer Imaging
In the past few years, the literature has shown that 18F-FDG PET is ideal for the evaluation, staging and management of patients with lung cancer. Recent data show that this may not only reduce unnecessary surgeries for widespread metastatic disease, but also could be an added benefit for the diagnosis and initial staging of small cell lung cancer, as well as for radiotherapy planning and monitoring.
PET/CT with 18F-FDG has become an essential tool for staging of lung cancer patients, particularly that of the mediastinum. Andrew C. Chang, MD, a general thoracic surgeon at the University of Michigan Medical Center in Ann Arbor, Mich., says PET/CT imaging for lung cancer has not so much changed preoperative planning as much as it has changed the determination of whether a patient is a good candidate for surgery.
"PET is helpful in identifying the extent of disease," he says. "About two-thirds of patients who present with lung cancer have cancer that goes beyond what we are capable of curing with a lobectomy or segmentectomy."
Chang suggests that unless there are peripheral tumors smaller than 2 cm and no sign of lymph node disease exhibited on CT or PET, a mediastinoscopy should be performed for every patient to determine the extent of the disease.
In the study, of the patients who underwent both conventional staging and PET/CT, 61 percent underwent surgery. For patients who underwent only conventional staging, 80 percent underwent the procedure. The frequency of surgery was reduced 19 percent. In the latter group, 42 percent were later shown to have undergone a "futile thoracotomy," where the surgery did not benefit the patient with regard to survival. For the first group who received PET/CT staging, this was halved to 21 percent (N Engl J Med 2009;361:32-39).
"To measure the clinical impact of PET/CT, we chose the number and frequency of unnecessary surgeries as the primary endpoint," she says. "Our study results demonstrate that by including PET/CT staging for lung cancer patients, you can significantly reduce the total number of thoracotomies as well as the number of unnecessary surgeries without affecting the overall survival of the patients."
The benefit of using 18F-FDG PET for non-small cell lung cancer is well documented, but in the past few years, researchers have explored the potential benefit of 18-FDG PET for small cell lung carcinoma.
"In 2009, Medicare started covering small cell lung cancer routinely based on the data in the 2006 National Oncologic PET Registry [NOPR], as well as other studies," says R. Edward Coleman, MD, director of nuclear medicine at Duke University Medical Center in Durham, N.C.
Still, the use of 18F-FDG PET for small cell lung carcinoma remains somewhat controversial. "We conducted some of the first studies using PET/CT to manage small cell lung cancer," says Fischer. "There is no doubt that PET/CT can be used in small cell lung cancer, but the clinical relevance unfortunately is still limited due to two major differences in the management of non-small cell and small cell lung cancer—complexity of staging and number of treatment options."
Staging for patients with non-small cell lung cancer is categorized in seven stages that determine the appropriate course of treatment, whether surgery, radiotherapy, chemotherapy, targeted therapy or a combination. In contrast, staging patients with small cell lung cancer is delineated into two categories based on the extent of disease, either limited or extensive. Patients categorized as limited stage receive a combination of chemotherapy and radiotherapy, whereas those categorized as having extensive disease receive palliative therapy, leading some to question the use of FDG-PET for the latter.
Treatment planning prior to radiotherapy is one application that can be used for both non-small and small cell carcinoma. "The use of PET/CT in radiotherapy planning is rapidly increasing," says Fischer. "It has been shown in several studies that the use of PET/CT significantly changes the target volume in up to 50 percent of patients."
PET/CT also can detect metastases in mediastinal lymph nodes that may not be apparent on CT alone. "If these lymph nodes are included in the radiation field, the risk of relapse is decreased and the chance of cure improved," says Fischer.
"Tumor growth and prognosis may vary depending on cell type, cell proliferation and the microenvironment due to factors such as hypoxia," says Nghi C. Nguyen, MD, PhD, assistant professor of radiology at St. Louis University Hospital in St. Louis. "A high uptake of 18F-FDG in tumors is accomplished primarily by excessive glycolysis by activation of the glucose transporter and hexokinase, which is the major rate-limiting step of FDG uptake in tumors. Some of the glucose metabolism may be partially due to increased activity of the pentose phosphate shunt for increased DNA synthesis, as may be the case in non-small cell lung cancer."
"At Duke, lung cancer is the most common reason for doing a PET/CT scan," says Coleman. "While other agents have compared with FDG for use in evaluation of lung cancer, none of them have been demonstrated to be as good as FDG at this time."
18F FDG-PET is superior for imaging single pulmonary nodules and metastatic lung disease for non-small and small cell lung carcinoma, and it also reveals infectious and inflammatory diseases.
"However, one limitation with FDG is that certain infectious processes, particularly granulomatous infections, will look like cancer on both a CT and a PET scan," says Coleman. "There are some false positives with FDG-PET. That being said, if a patient has a positive PET scan, you always need to biopsy to document that it is cancer and not a false positive."
Future studies will continue to evaluate the use of 18F-FDG PET for lung cancer, staging and therapy monitoring until such time that a more lung-cancer specific agent emerges to take its place.
Stark statistics
Lung cancer remains the most commonly diagnosed cancer, with 1.2 million new cases diagnosed worldwide every year, according to the World Health Organization. Lung cancer is still one of the deadliest forms of cancer, with researchers estimating that the likelihood of developing distant metastases could be as great as 50 percent for patients with non-small cell lung carcinoma. If the disease is caught in its earliest stages, patients are still eligible for curative thoracic surgery, but the procedure is not only costly but invasive and only should be performed if the potential benefit outweighs the risk associated with surgery. Thus, correct identification of surgical candidates is of great importance in managing lung cancer patients.PET/CT with 18F-FDG has become an essential tool for staging of lung cancer patients, particularly that of the mediastinum. Andrew C. Chang, MD, a general thoracic surgeon at the University of Michigan Medical Center in Ann Arbor, Mich., says PET/CT imaging for lung cancer has not so much changed preoperative planning as much as it has changed the determination of whether a patient is a good candidate for surgery.
"PET is helpful in identifying the extent of disease," he says. "About two-thirds of patients who present with lung cancer have cancer that goes beyond what we are capable of curing with a lobectomy or segmentectomy."
Chang suggests that unless there are peripheral tumors smaller than 2 cm and no sign of lymph node disease exhibited on CT or PET, a mediastinoscopy should be performed for every patient to determine the extent of the disease.
Approaching definitive proof
Barbara Fischer, MD, PhD, a lead researcher of clinical physiology, nuclear medicine and PET at Rigshospitalet, Copenhagen University Hospital in Copenhagen, Denmark, has been involved in critical studies that have shown that 18F-FDG PET helps to reduce unnecessary surgeries.In the study, of the patients who underwent both conventional staging and PET/CT, 61 percent underwent surgery. For patients who underwent only conventional staging, 80 percent underwent the procedure. The frequency of surgery was reduced 19 percent. In the latter group, 42 percent were later shown to have undergone a "futile thoracotomy," where the surgery did not benefit the patient with regard to survival. For the first group who received PET/CT staging, this was halved to 21 percent (N Engl J Med 2009;361:32-39).
"To measure the clinical impact of PET/CT, we chose the number and frequency of unnecessary surgeries as the primary endpoint," she says. "Our study results demonstrate that by including PET/CT staging for lung cancer patients, you can significantly reduce the total number of thoracotomies as well as the number of unnecessary surgeries without affecting the overall survival of the patients."
Expansion of PET for small cell lung cancer
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| A 64-year-old man with no prior history of smoking was found to have a right perihilar mass and enlargement of bilateral mediastinal lymph nodes at diagnostic CT. Subsequent FDG PET/CT showed intense FDG avidity within these lesions. Source: Nghi C. Nguyen, MD, PhD, assistant professor of radiology, St. Louis Hospital, St. Louis. |
"In 2009, Medicare started covering small cell lung cancer routinely based on the data in the 2006 National Oncologic PET Registry [NOPR], as well as other studies," says R. Edward Coleman, MD, director of nuclear medicine at Duke University Medical Center in Durham, N.C.
Still, the use of 18F-FDG PET for small cell lung carcinoma remains somewhat controversial. "We conducted some of the first studies using PET/CT to manage small cell lung cancer," says Fischer. "There is no doubt that PET/CT can be used in small cell lung cancer, but the clinical relevance unfortunately is still limited due to two major differences in the management of non-small cell and small cell lung cancer—complexity of staging and number of treatment options."
Staging for patients with non-small cell lung cancer is categorized in seven stages that determine the appropriate course of treatment, whether surgery, radiotherapy, chemotherapy, targeted therapy or a combination. In contrast, staging patients with small cell lung cancer is delineated into two categories based on the extent of disease, either limited or extensive. Patients categorized as limited stage receive a combination of chemotherapy and radiotherapy, whereas those categorized as having extensive disease receive palliative therapy, leading some to question the use of FDG-PET for the latter.
Treatment planning prior to radiotherapy is one application that can be used for both non-small and small cell carcinoma. "The use of PET/CT in radiotherapy planning is rapidly increasing," says Fischer. "It has been shown in several studies that the use of PET/CT significantly changes the target volume in up to 50 percent of patients."
PET/CT also can detect metastases in mediastinal lymph nodes that may not be apparent on CT alone. "If these lymph nodes are included in the radiation field, the risk of relapse is decreased and the chance of cure improved," says Fischer.
Just the right mechanism
The superiority of 18F-FDG as an agent lies in its unique uptake by cancer cells. The mechanism by which tumors utilize the agent is complex and nonselective."Tumor growth and prognosis may vary depending on cell type, cell proliferation and the microenvironment due to factors such as hypoxia," says Nghi C. Nguyen, MD, PhD, assistant professor of radiology at St. Louis University Hospital in St. Louis. "A high uptake of 18F-FDG in tumors is accomplished primarily by excessive glycolysis by activation of the glucose transporter and hexokinase, which is the major rate-limiting step of FDG uptake in tumors. Some of the glucose metabolism may be partially due to increased activity of the pentose phosphate shunt for increased DNA synthesis, as may be the case in non-small cell lung cancer."
Mixed signals
One of the limiting factors of 18F-FDG PET is its tendency to indicate metabolic abnormalities involved in more than just tumor processes."At Duke, lung cancer is the most common reason for doing a PET/CT scan," says Coleman. "While other agents have compared with FDG for use in evaluation of lung cancer, none of them have been demonstrated to be as good as FDG at this time."
18F FDG-PET is superior for imaging single pulmonary nodules and metastatic lung disease for non-small and small cell lung carcinoma, and it also reveals infectious and inflammatory diseases.
"However, one limitation with FDG is that certain infectious processes, particularly granulomatous infections, will look like cancer on both a CT and a PET scan," says Coleman. "There are some false positives with FDG-PET. That being said, if a patient has a positive PET scan, you always need to biopsy to document that it is cancer and not a false positive."
Future studies will continue to evaluate the use of 18F-FDG PET for lung cancer, staging and therapy monitoring until such time that a more lung-cancer specific agent emerges to take its place.