The accurate diagnosis and staging of lung cancer patients is vital for the selection of appropriate treatment. In recent years, 18-fluorodeoxyglucose positron emission tomography (18FDG PET) scanning has emerged as a potential non-invasive imaging technique for the diagnosis and staging of lung cancer. Many studies have evaluated the accuracy of 18FDG-PET in the diagnosis and staging of lung cancer; however, there is limited evidence to determine the impact of PET on clinical management and on patient outcomes.
The majority of studies examining PET have been diagnostic accuracy studies; however, these studies are highly susceptible to bias, which can result in unreliable estimates of accuracy. Diagnostic studies with methodological limitations tend to overestimate the diagnostic performance of the test. In evaluating the evidence for PET in lung cancer, a number of limitations were present in the accuracy studies, including differences in patient selection, the use of different reference standards for verification of results, and biases in the evaluation of test results. These shortcomings in study design can affect the estimates of diagnostic accuracy. In addition, it is not clear how results from diagnostic accuracy studies translate into changes in patient management. The Disease Site Group (DSG) placed considerable weight on the findings of the randomized utility studies for the staging of primary non-small cell lung cancer (NSCLC). For other issues, accuracy of the evidence was used to support what are largely consensus recommendations.
The determination as to whether a solitary pulmonary nodule (SPN) is benign or malignant can be problematic as certain lesions cannot be diagnosed by conventional means other than surgical resection. To ensure that only patients with a potentially resectable lung cancer are taken to thoracotomy, histologic or cytologic evidence of malignancy is needed. For patients with an SPN, percutaneous fine needle aspiration biopsy (FNAB) is usually performed. However, FNAB may be contraindicated because there may be an underlying medical condition, the lesion may be inaccessible to FNAB, prior attempts at FNAB may have failed, or the patient may refuse the procedure.
Meta-analyses of studies evaluating the ability of PET to differentiate benign from malignant lesions have found the sensitivity of PET to range from 96% to 97% and specificity to range from 78% to 86%. Accuracy studies have confirmed that PET appears to have a high sensitivity, and a reasonable specificity for differentiating benign from malignant lesions as small as 1 cm in size. A mass of metabolically active cells is needed for PET to be positive and to suggest that a lesion may be malignant. With current PET scanners, it is difficult to detect malignancy in nodules that are less than 1 cm. Studies suggest that pulmonary nodules less than 1 cm or with faint or ground-glass opacity images on computed tomography (CT) cannot be evaluated accurately by PET and that both CT and PET findings should be considered to determine if surgical biopsy is necessary for small pulmonary nodules. False-negative results can also occur with low-grade malignant tumours such as well-differentiated adenocarcinomas, including bronchoalveolar cell carcinomas, due to their lower metabolic activity. False-positive results can occur in inflammatory conditions such as granulomatous disease due to the increased metabolic activity of inflammatory cells. Infection with histoplasmosis is common in Ontario and could increase the rate of false-positive PET scans.
Based on this evidence, PET is recommended for patients with SPN 1.0 cm or greater in size who cannot undergo FNAB or who have failed a prior attempt at FNAB. If the PET is positive, the probability is high that the lesion is malignant, and the patient should proceed to thoracotomy. A negative PET scan suggests that the lesion is benign but careful follow-up is indicated, as PET can be falsely negative in slow growing adenocarcinomas and bronchoalveolar carcinoma.
One study that did not meet the inclusion criteria for this report reviewed cases of NSCLC solitary extrapulmonary FDG accumulations in patients with NSCLC. Solitary extrapulmonary lesions were found in 72 of 350 patients (21%) with PET-CT imaging. 54% of lesions were solitary metastases and 46% were lesions unrelated to the primary lung tumour. This trial supports the conclusions that SPN require histopathologic diagnosis as up to half solitary extrapulmonary FDG accumulations may represent unrelated malignancies or benign disease.
After lung cancer has been diagnosed, accurate staging is essential for appropriate treatment decisions to be made. Conventional staging procedures are currently imperfect in their ability to spare patients from the morbidity and mortality of stage inappropriate therapies. Health technology assessment reports have concluded that it is difficult to quantify the improvement in diagnostic accuracy of PET in staging NSCLC due to the variations in study quality and the lack of direct evidence on whether PET improves patient outcomes. Meta-analyses found sensitivity to range from 81% to 90% and specificity to range from 89% to 90% for the distinction between N0-1 and N2-3 patients. Accuracy studies had similar results, with PET results found to be superior to CT imaging for mediastinal staging. Studies that interpreted PET images with CT results had higher accuracy than when PET was interpreted independently. Integrated PET-CT scanners also improved accuracy; however, additional studies on this type of imaging are needed as only a few small single-centre prospective studies have evaluated the accuracy of integrated PET-CT scanners, and there are no studies on the impact of PET-CT on patient outcomes. The results from one study suggest that PET is unable to detect metastatic foci smaller than 4 mm. False positives with respect to staging the mediastinum also occur with infection and inflammation. The trials suggest that a positive test result should be confirmed to ensure that patients are not denied potentially curative surgery. False-negative results can occur when the primary tumour obscures mediastinal lymph nodes, as the 18FDG uptake in the lymph nodes may not be distinguished from the avid uptake in the primary tumour. PET has also been used to detect distant metastases, but additional research is needed in this area. PET has been found to have high accuracy (89% to 96%) for detecting distant metastases and has also detected extrathoracic metastases in patients in whom conventional imaging showed no evidence of distant metastases. The role of PET in the evaluation of distant metastases appears to be greatest for adrenal and bone metastases. PET is not useful for detection of brain metastases due to the high glucose uptake of normal brain tissue.
Three randomized controlled trials have evaluated the value of preoperative PET assessment; however, two of these trials had conflicting results. These two trials randomized patients to conventional workup with or without PET. The PET in Lung Cancer Staging (PLUS) trial reported a 51% relative reduction in futile thoracotomies (p=0.003) when PET was added to conventional work up, whereas the Australian trial found no difference in the number of thoracotomies avoided (p=0.2). A number of factors contribute to the apparent discrepancy between these trials. One factor is the difference in the patient populations between the trials. The PLUS trial included patients with suspected or proven NSCLC based on clinical, not surgical staging and as a result included patients with both benign and malignant lesions, whereas the Australian trial only included patients with histologically or cytologically proven NSCLC prior to randomization. However, the reduction in futile thoracotomies was still significant for PET (53% relative reduction, 95% confidence interval [CI] 32% to 88%) when patients with benign lesions were excluded from the analysis in the PLUS study. In addition, 29% of patients in the PLUS trial had clinical stage III disease at baseline, whereas the Australian trial only included patients demonstrating clinical stage I or II disease. Another explanation for the difference in results is that the approach to the management of patients with early stage lung cancer differed. Patients in the Australian trial with stage IIIA disease underwent surgery without further evaluation, while thoracotomy was considered futile in the PLUS trial if the patients had stage IIIA/N2 disease. Finally, the definition of futile thoracotomies (benign disease, exploratory thoracotomy, pathological stage IIIA [mediastinal node positive] or IIIB disease, or postoperative relapse or death within 12 months of randomization) in the PLUS study differed from the Australian trials definition of avoided thoracotomies (patients who were able to avoid thoracotomy as determined by the surgeon). Thus, the different designs of these studies might explain the contradicting results, demonstrating that the impact of PET on patient outcomes depends on the treatment decision-making process.
The recent POORT trial randomized patients with suspected NSCLC to traditional staging workup or up-front PET. PET did not decrease the number of staging tests required, and the agreement between the clinical and final stage were similar for both analyses. PET shortened the time to diagnosis by nine days, decreased the number of mediastinoscopies, and decreased the percentage of patients who needed one or more invasive tests for nodal staging. This is the first trial to compare conventional imaging to PET on clinically important aspects of clinical management.
18FDG-PET has not been studied as extensively in staging patients with small cell lung cancer (SCLC). PET appears to have good accuracy (83% to 99%) in staging extensive versus limited stage disease, but further trials are needed to determine the role of PET in this setting.
Evaluation of new imaging techniques is important as "high costs, increasing demand for healthcare, increasing medical abilities and limited budgets have necessitated prioritization". PET scanning could improve the results of surgical therapy for early stage lung cancer by excluding patients from surgical resection who have evidence of metastatic disease beyond the scope of surgical resection and not evident by standard preoperative staging procedures. Similarly, the results for the management of locally advanced disease might also be expected to improve because of the addition of patients with minimal contralateral nodal disease that precluded surgery. Moreover, if PET imaging spares patients from the potential morbidity and risk of mortality from an unnecessary surgical procedure or chemo-radiotherapeutic intervention, it would not only have a significant impact on individual patients but would allow for more efficient and effective utilization of limited health care resources. Future research is needed to determine not only if PET should be integrated into the standard staging and diagnosis process of lung cancer but also how PET would be incorporated into the diagnostic algorithm. The Ontario Clinical Oncology Group (OCOG) is currently conducting two prospective randomized controlled trials on the use of PET that have been approved by the Ontario Ministry of Health and Long-Term Care and a registry study of PET in patients with SPN. The randomized trials are examining the impact of PET on improving the management of patients with potentially surgically resectable NSCLC and the impact of PET on improving the management of patients with stage III NSCLC.
This systematic review only evaluated the role of 18FDG-PET in lung cancer. There are many other radioisotopes and biological markers that may in the future find utility in lung cancer imaging.
