who received targeted therapy at some time during­ their treatment had a median overall survival of 31.8 months compared to 12.7 months for cytotoxic chemotherapy and 5.1 months for supportive care only [30]. Biomarkers are classi-ed as actionable or prognostic. Actionable biomarkers are the mutations for which treatments have been developed compared to prognostic biomarkers which are indicative of a patient’s survival independent of the treatment received. The NCCN guidelines recommend testing for ALK rearrangements, BRAF mutations, EGFR mutations, METex14 skipping mutations, NTRK1/2/3 gene fusions, RET rearrangements, and ROS1 rearrangements for individuals with advanced NSCLC [7]. Biomarker status should be documented prior to initiation of therapy as patients may be able to receive targeted therapy or immunotherapy with or without chemotherapy. If mutational analysis cannot be performed on a biopsy sample, the patient may need to a repeat procedure/biopsy to obtain tissue solely for molecular analysis. Some patients may not be able to undergo another procedure for molecular analysis. In these instances, a liquid biopsy drawn from a blood sample searching for circulating tumor cell free DNA can be obtained to assess for actionable mutations. If a patient has both a

Fig. 28.4  PET-CT showing a RUL 2.4 cm hypermetabolic nodule with an SUV of 10.1

molecular biomarker and high PD-L1 expression, targeted therapy is usually recommended rst prior to consideration of immunotherapy [7].

Case 1 Concluded

Patient underwent CT-guided biopsy of the adrenal lesion which was diagnostic for adenocarcinoma of the lung and Stage IVB was confrmed. Molecular analysis documented an EGFR mutation and he was referred to Oncology for targeted therapy.

Case 2

A 64-year-old female with a previous smoking history is evaluated in clinic with a 1.8 cm RUL nodule. Due to patient preference, a follow-up CT scan obtained 6 months later showed that the nodule had grown in size. PET-CT was performed (Figs. 28.4 and 28.5) and revealed the nodule was hypermetabolic along with a hypermetabolic right hilar lymph node.

The rst step in deciding which invasive approach to stage the mediastinum is to perform initial radiographic staging (Table 28.1).

Fig. 28.5  PET-CT showed a hypermetabolic right hilar lymph node measuring 2.1 cm with an SUV of 10

Table 28.1  De nition of intrathoracic radiographic categories of lung cancer

Chest X-Ray

Although CXR is a good tool in providing preliminary information such as obvious chest wall and mediastinal invasion in large tumors, it has limited sensitivity to predict T3/T4 disease or metastases to the mediastinum. The patient will

need further imaging for better delineation of the extent of disease prior to consideration of treatment options.

Computerized Tomography

Computerized tomography scan of the chest is the cornerstone of lung cancer imaging on which further management is decided. Ideally, it should be extended to include the liver and adrenal glands to assess for metastatic disease. Based on the intra-thoracic radiographic characteristics (including both the primary tumor and the mediastinum), patients with lung cancer can be separated into four groups, A to D (Table 28.1 and Fig. 28.6). Radiographic group A involves patients with mediastinal in ltration that encircles the vessels and airways, so that the discrete lymph nodes can no longer be discerned or measured. Group B involves patients with enlarged mediastinal node (≥1 cm in short axis diameter) in whom the size of the discrete nodes can be measured. The last two groups involve patients with normal mediastinal nodes. In radiographic group C, the presence of a central tumor or sus-

Fig. 28.6  American College of Chest Physicians intrathoracic radiographic (CT) categories for lung cancer. (a) Mediastinal in ltration by tumor. (b) Enlarged discrete

N2,3 nodes. (c) A central tumor or a tumor with enlarged N1 nodes, but a normal mediastinum. (d) A peripheral small tumor with normal sized lymph nodes

pected N1 disease makes the chance of N2 or N3 nodal involvement relatively high, 20–25%. Despite normal-sized mediastinal lymph nodes, further con rmation is needed. In group D, those with a clinical stage I tumor, the chance of either distant metastases or mediastinal involvement is quite low [12]. The advantage of CT is that it provides accurate anatomic de nition of the tumor within the thorax. For example, it helps us accurately identify T3 or T4 lesions and enlarged lymph nodes which directs tissue biopsy for histopathologic diagnosis and staging.

The major limitation of CT is its low accuracy in the identi cation of mediastinal metastases. The ACCP guidelines published the performance characteristics of CT for staging the mediastinum which involved 35 studies in a meta-analysis. The analysis showed a pooled sensitivity of 51%

(95% CI 47–54%) and a pooled speci city of 86% (95% CI 84–88%) [31]. This limitation is more evident in 5–15% of patients with clinical T1N0 lesions that will be found to have positive lymph node involvement by surgical sampling [32]. It is usually inappropriate to rely solely on chest CT to determine the mediastinal lymph node status; regardless, CT continues to play an important role in the evaluation of patients with either a known or suspected lung cancer who are eligible for treatment [12].

Positive Emission Tomography

The advent of the PET scan has been the single most notable addition to lung cancer staging in recent history. Cancer cells demonstrate increased

cellular uptake of glucose when compared with normal cells. PET scan uses 18-FDG, a radio-­ labeled glucose analogue which undergoes the same cellular uptake as glucose. After phosphorylation, is not further metabolized and becomes trapped in cells. This accumulation of isotope is identi ed by a PET detector [33]. There are no standardized criteria de ning what constitutes a positive PET result and no ideal cutoff point for the standardized uptake value (SUV). However, lymph nodes with FDG uptake greater than that observed in the mediastinal blood pool are highly suspicious for metastatic disease [34].

Whole body PET imaging in preoperative staging of lung cancer has been shown to increase identi cation of patients with mediastinal and extrathoracic disease compared to conventional staging by 20% [35–38]. In addition, PET improves discrimination between N0-1 and N2-3 disease [39]. One systematic review of 45 studies which included 4105 patients reported sensitivity, speci city, positive predictive value (PPV) and negative predictive value (NPV) of 80%, 88%, 75%, and 91%, respectively for mediastinal staging [12]. One limitation of PET scan is the poor anatomic de nition of suspicious lesions. Integrated PET-CT enables the direct correlation of FDG-accumulating lesions with morphological structures. There is an improvement in the number of patients correctly staged with this modality over CT or PET alone, but that has not been shown to improve mortality [40, 41].

There have been 5 randomized controlled trials (RCTs) evaluating the role of PET scan in lung cancer patients all with varying results. While two studies suggest a reduction in the rate of futile thoracotomies with the use of PET as a staging modality [36, 38], three studies suggest no difference in a similar population [35, 37, 42]. This variation was likely due to the signi cant differences among the patients enrolled, their evaluation prior to PET, and the risk for advanced disease. Population-based studies suggest that the use of PET has had increased stage migration from stage III to stage IV, but adds little to the staging of patients with clinical stage I cancer [43]. One of the downsides to increasing sensitivity in detecting occult metastases is incorrectly

upstaging patients and potentially withholding possible curative management [12].

When staging the mediastinum with PET or PET-CT, benign FDG-avid lesions such as infections, infammation, and granulomatous disease can present as false positives. Additionally, lymph nodes <10 mm have a lower chance of detection from PET scan compared to enlarged lymph nodes [44]. In patients without mediastinal lymphadenopathy, a negative PET-CT is highly valid and patients may proceed to surgery unless they have a central tumor. However, the false negative rate is considerable in enlarged lymph nodes without FDG uptake (30%) [39].

Despite its widespread use, there is no consensus regarding the routine use of PET as a staging modality for patients with suspected NSCLC. Con rmation of PET ndings is essential because it also carries a signi cant rate of incorrect upstaging. Needle techniques to assess the mediastinum are the most rational next step. Nevertheless, there are enough data (including RCTs, prospective studies, and population studies) which suggest that the PET-CT is of more bene t than harm [12].

Magnetic Resonance Imaging

Historically, MRI of lung was thought not to be ideal due to low signal-to-noise ratio, which includes susceptibility artifacts caused by multiple air-tissue interfaces and motion artifacts [45]. Currently, MRI is indicated for superior sulcus tumors, such as a Pancoast tumor, and assessment of possible invasion of the spinal cord [46]. Recent improvements in MRI techniques such as short echo times, ultrafast turbo- spin-echo acquisitions, projection reconstruction technique, breath-hold imaging, electrocardiogram triggering, and oxygen enhancement have widened the potential for investigations of pulmonary parenchymal disease [45]. Once radiographic staging has been completed, the physician can select the proper invasive test depending on the location of the target and the performance characteristics of the test selected (Table 28.2) [12].