Our retrospective decision-tree analysis suggests that, in those with NSCLC and without evidence of stage IV disease on baseline CT chest, a diagnostic and staging approach starting with whole body FDG-PET/CT is less likely to require more than one biopsy attempt than an approach that utilises FDG-PET/CT after pathological confirmation or failed biopsy attempt. This results supports Australian and international guidelines that suggest FDG-PET/CT prior to initial biopsy [9, 10]. Extrapolating the result implies that approximately one out of 14 people with NSCLC would avoid additional biopsy if FDG-PET/CT was used prior to initial biopsy. The clinical significance of this result is uncertain. The potential benefit comes at the expense of additional FDG-PET/CT scans performed on individuals with baseline imaging of suspected lung cancer who subsequently are confirmed to have benign or non-NSCLC malignant diagnoses. In our cohort, 28% of patients fit into this category, who may have undergone low-value FDG-PET/CT scans.
FDG-PET/CT is more accurate than other modalities for the detection of metastatic disease with pooled sensitivity and specificity of 0.77 (95% CI: 0.47–0.93) and 0.95 (95% CI: 0.92–0.97) respectively [17]. The rate of CT-Chest occult metastatic disease identified on FDG-PET/CT in our cohort was 12.2%, lower than previously described in a similar Australian cohort who were undergoing radiotherapy (19%, p = 0.002), yet similar to other prospective studies [18,19,20]. While this is clinically important in the pre-treatment assessment of NSCLC for accurate clinical staging, the hypothesised benefit of FDG-PET/CT in pre-diagnosis assessment is to guide biopsy of the most distant site of suspected disease—an approach that simultaneously confirms diagnosis and staging. Approximately one third (5/14) of CT Chest-occult metastatic lesions were not amenable to percutaneous biopsy, reducing the value pre-diagnosis FDG-PET/CT to guide biopsy approach.
Herder et al. performed a prospective randomised-control trial in individuals with CXR abnormalities suggestive of lung cancer in which a diagnosis and staging approach using initial FDG-PET without CT was compared to traditional work-up (TWU). There was no difference in the primary outcome of total number of tests and procedures to finalize staging and define operability (mean 7.90 for initial FDG-PET vs 7.88 for TWU). There was also no difference the number of invasive tests (mean 0.85 vs 0.96, p = 0.18), but there were fewer tests requiring general anaesthesia (mean 0.59 vs 0.78, p = 0.0074). Costs of staging investigations were similar in both study arms. Factors that may reduce the generalizability to current practice include FDG-PET scans being performed without concurrent CT scanning, inclusion criteria being based on CXR abnormalities suggestive of lung cancer and the widespread introduction of endobronchial ultrasound technology to perform mediastinal sampling.
Other prospective randomised-control trials have investigated the role of FDG-PET in avoiding futile thoracotomy, defined as a composite endpoint of thoracotomy for benign disease, pathologicaly proven mediastinal lymph node involvement, explorative thoracotomy or recurrent disease or death within one year. The PLUS study suggested standalone FDG-PET reduced futile thoracotomy from 41 to 21% (p = 0.003) translating to one patient avoiding futile thoracotomy for every five patient undergoing FDG-PET (95%CI 3–14) [19]. Costs were reduced given fewer thoracotomies and associated hospital bed-days [21]. This result was repeated by Fisher et al. who reported that FDG-PET/CT reduced futile thoracotomy from 52 to 35% (p = 0.05) [22]. The number of individual invasive investigations prior to treatment were similar between the two groups.
Mac Manus et al. performed a similar study where 167 patient with confirmed NSCLC with Stage I-III disease based on CT were allocated clinical staging with or without FDG-PET/CT [18]. The proportion of CT-occult distant metastasis increased with FDG-PET/CT staging, but the impact on biopsy approach was not discussed. The ongoing “PET/CT FIRST” study is using a similar matched study design where the recommended biopsy test will be based on the pre- and post-FDG-PET/CT clinical information [23].
The aims and contextual rationale for our study is framed by current regulatory funding in Australia for FDG-PET/CT scans, which may not apply in other jurisdictions. In Australia, the Medicare Benefits Schedule (MBS) provides criteria for government subsidy of medical investigations and non-pharmaceutical treatment. The current MBS criteria for FDG-PET/CT in lung cancer are for (i) evaluation of a solitary pulmonary nodule where the lesion is considered unsuitable for transthoracic fine needle aspiration biopsy, or for which an attempt at pathological characterisation has failed or (ii) the staging of proven NSCLC, where curative surgery or radiotherapy is planned [11]. FDG-PET/CT scanning performed to guide initial biopsy in suspected lung cancer is not specifically subsidised. More robust, prospective evidence, accompanied by cost-utility analysis will be required to update MBS FDG-PET/CT scan criteria to include pre-biopsy in those with suspected lung cancer, but the feasibility of such a study is unclear. A sample size calculation using data from the current study for the primary outcome of the proportion who people needing more than one invasive investigation would require a minimum of 836 participants (19% vs 12%, power 0.80, alpha 0.05). There may be additional benefits of pre-biopsy FDG-PET/CT, such as reduced time to treatment, but faster treatment may not necessarily be associated with improved outcomes and this needs to be balanced by the additional cost and radiation exposure of FDG-PET/CT on individuals who do not have NSCLC [24]. Clinicians who practice outside of current Australian funding requirements may use these results to weigh potential benefits of FDG-PET/CT prior to initial biopsy, such as fewer repeat biopsies on individuals with NSCLC with potential downsides including cost and radiation exposure of FDG-PET/CT scans on individuals without malignancy.
Many limitations of the current study need acknowledging. These include the retrospective nature and lack of a pre-determined sample size. Most individuals (62.6%) had early stage (I or II) NSCLC, which may have reduced the probability of FDG-PET/CT detected accessible metastatic disease. An alternative inclusion criteria such as baseline CT-Chest evidence of stage II or III disease may lead to an enriched population where FDG-PET/CT prior to biopsy may have more benefit at reducing repeated biopsy attempts. We assumed that all participants would have been suitable for all recommended invasive investigations, yet our known real-world experience is that individual patients may have varied diagnostic pathways due to technical and patient-related factors that were not accounted for in our study. For example, all pulmonary nodules/masses were deemed suitable for CT-guided transthoracic biopsy. Additionally, our clinical decision tree used the HAL model to guide need for systematic pre-operative mediastinal. The 10% probability for detecting N2/3 lymph node involvement with EBUS threshold suggested by the HAL model authors has (i) not been prospectively validated, (ii) compared to existing recommended criteria for systematic mediastinal staging or (iii) incorporated into clinical practice guidelines. The choice of primary outcome was a pragmatic decision that balanced feasibility of statistical analysis using a simple decision tree with clinical relevance, but the real-world importance of patients needing more than one invasive biopsy requires further consideration.
