Date Published: February 9, 2017
Publisher: Public Library of Science
Author(s): Ronald Walker, Stephen Deppen, Gary Smith, Chanjuan Shi, Jonathan Lehman, Jeff Clanton, Brandon Moore, Rena Burns, Eric L. Grogan, Pierre P. Massion, Byeong-Cheol Ahn.
18F-FDG PET/CT is widely used to evaluate indeterminate pulmonary nodules (IPNs). False positive results occur, especially from active granulomatous nodules. A PET-based imaging agent with superior specificity to 18F-FDG for IPNs, is badly needed, especially in areas of endemic granulomatous nodules. Somatostatin receptors (SSTR) are expressed in many malignant cells including small cell and non-small cell lung cancers (NSCLCs). 68Ga-DOTATATE, a positron emitter labeled somatostatin analog, combined with PET/CT imaging, may improve the diagnosis of IPNs over 18F-FDG by reducing false positives. Our study purpose was to test this hypothesis in our region with high endemic granulomatous IPNs.
We prospectively performed 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT scans in the same 30 patients with newly diagnosed, treatment-naïve lung cancer (N = 14) or IPNs (N = 15) and one metastatic nodule. 68Ga-DOTATATE SUVmax levels at or above 1.5 were considered likely malignant. We analyzed the scan results, correlating with ultimate diagnosis via biopsy or 2-year chest CT follow-up. We also correlated 68Ga-DOTATATE uptake with immunohistochemical (IHC) staining for SSTR subtype 2A (SSTR2A) in pathological specimens.
We analyzed 31 lesions in 30 individuals, with 14 (45%) being non-neuroendocrine lung cancers and 1 (3%) being metastatic disease. McNemar’s result comparing the two radiopharmaceuticals (p = 0.65) indicates that their accuracy of diagnosis in this indication are equivalent. 68Ga-DOTATATE was more specific (94% compared to 81%) and less sensitive 73% compared to 93%) than 18F-FDG. 68Ga-DOTATATE uptake correlated with SSTR2A expression in tumor stroma determined by immunohistochemical (IHC) staining in 5 of 9 (55%) NSCLCs.
68Ga-DOTATATE and 18F-FDG PET/CT had equivalent accuracy in the diagnosis of non-neuroendocrine lung cancer and 68Ga-DOTATATE was more specific than 18F-FDG for the diagnosis of IPNs. IHC staining for SSTR2A receptor expression correlated with tumor stroma but not tumor cells.
There were an estimated 221,000 newly diagnosed cases of lung cancer in the US in 2014, with an estimated 158,000 deaths. Lung cancer is the leading cause of cancer death in the US and worldwide. The five-year relative cancer survival of all stages and all types of lung cancer combined (2002–2008) is 17%. While 18F-fluorodeoxyglucose (18F-FDG) PET/CT is approved and widely used for staging of lung cancer, and for initial diagnosis of an indeterminate pulmonary nodule (IPN), the accuracy of 18F-FDG PET/CT for diagnosis of IPNs depends on many factors, including regional exposures and infectious lung diseases. Regionality can result in variable test accuracy by influencing false positive (FP) and false negative (FN) results.[2, 3] Lesion size below 1 cm and low proliferative lung cancers can lead to FN results from low metabolic uptake.[4, 5] FP results occur from infectious or inflammatory foci, most infamously granulomatous nodules. Granulomatous nodules occur in much of the United States (US), especially the Ohio/Mississippi River Valley and the Southwestern US. These benign nodules arise from a variety of soil fungi, such as Histoplasma capsulatum, endemic in our region. We have reported  that 18F-FDG PET/CT is very sensitive (92% true positive, TP) for the diagnosis of IPNs in our region, but with a specificity (true negative, TN) of only 40%, mostly due to FPs from granulomatous nodules, with similar results from others.[2, 7] Given our 40% regionally low specificity of 18F-FDG PET/CT for IPNs, many clinicians have chosen serial CT exams to follow IPNs with Fleischner guidelines. Using either Fleischner criteria for a prevalent nodule, or Lung-RADS criteria for a screening-detected nodule, a solid IPN must show no growth for 2 years by CT to be considered benign.[9, 10]
This investigation was performed with VATVHS IRB approval (#974), and with oversight of the VATVHS Radioactive Drug Research Committee. All subjects gave their own written informed consent. Consents were recorded in the subjects’ electronic healthcare record. All consents were obtained with IRB review and approval. 68Ga-DOTATATE imaging was for correlation of tumor or nodule uptake with final diagnosis via tissue diagnosis or 2-year follow-up in all 30 subjects, but not for altering standard of care management. Our measured dosimetry of 68Ga-DOTATATE is previously reported, with similar results reported by others.[19, 20]
There were no observed serious adverse events from 68Ga-DOTATATE. Long term follow-up of lab values from routine medical care, when available, revealed no evidence of delayed toxicity.
This study uniquely reports the results of a prospective trial comparing 18F-FDG with 68Ga-DOTATATE PET/CT in patients with newly diagnosed lung cancer or IPNs in patients at high risk for lung cancer. Importantly, we performed our investigation in a region with high endemic granulomatous nodules, a confounder of 18F-FDG PET imaging. Our investigation demonstrates that 68Ga-DOTATATE is equivalent in accuracy to 18F-FDG PET/CT for diagnosis of a malignant IPN, and, in most cases, for diagnosis and staging of NSCLC (Table 1). Since 68Ga is a generator-based product, the equivalent accuracy of 68Ga-DOTATATE vs. 18F-FDG PET/CT suggests that, upon validation in a larger cohort, 68Ga-DOTATATE PET/CT could be an alternative to 18F-FDG PET/CT in areas where 18F-FDG is not available, which would include isolated areas of the US (Rocky Mountain states such as Idaho, Montana, or Wyoming) or developing countries, where access to a medical cyclotron is still limited.