Lung cancer is the most common cause of cancer-related death in Western countries. In the last several years, a number of new drugs have revolutionized systemic therapy in lung cancer. These new therapies can be divided into two major groups, the targeted therapies and the immunotherapies. Targeted therapies, such as EGFR tyrosine kinase inhibitors, or ALK inhibitors, are a class of drugs that specifically target a well-defined molecular pathway. They have been shown to be more effective than classic chemotherapies in patients who harbor the specific mutation and are associated with fewer toxicities. As these drugs target molecules with a specific mutation, patients who harbor this specific mutation need to be identified. In addition to bronchoscopy, image-guided biopsies are the main modality for obtaining tissue for molecular analysis. Imaging may have a potential role in identifying tumors that harbor a specific mutation, and thus, in guiding further pathologic and genetic work-up. Immunotherapy, however, targets immunological pathways to induce an immunological response against tumors. Immunotherapy has been shown to be a very effective treatment in a subset of patients with non-small cell cancer. Imaging plays a major role in the follow-up evaluation of patients undergoing immunotherapy, as immune reactions must be differentiated from disease progression.
1. To be aware of the importance of detecting EFGR mutation.
2. To learn about demographic and CT features suggestive of EGFR mutation.
3. To learn about the various initial and follow-up CT features.
Adenocarcinoma is the most prevalent type of lung cancer, showing a large spectrum of genetics, histologic subtype, CT appearance, clinical behavior and prognosis. Activating mutations of EGFR are found in 30%-50% of lung adenocarcinomas in East Asian patients and approximately 15% in Caucasian patients. EGFR mutation status is correlated with nonsmoking status, female sex, lepidic subtype, and high response rate to EGFR tyrosine kinase inhibitors (TKI). Some CT findings have shown to be associated with EGFR mutation such as nonsolid or mixed ground-glass opacity, air bronchogram, smaller and peripheral tumors, and pleural retraction. Furthermore, non-smoking patients presenting with diffuse miliary metastatic disease at diagnosis may be diagnosed with adenocarcinoma harboring EFGR mutation and may show dramatic response to EGFR-TKI. The most common resistance mechanism to EGFR-TKI is the T790M mutation, against which new irreversible TKIs have been found to be clinically effective, thus increasing demand for rebiopsy in progressive NSCLC to analyze mutational status. Rebiopsies are feasible and informative in most of patients with acceptable rates of complications. Furthermore, continued EGFR-TKI therapy may be indicated beyond RECIST progression, because these tumors grow slowly and some tumor cells remain sensitive to EGFR-TKI. Radiologists should also be aware of the risk of class-effect toxicity of EGFR-TKI, in particular pneumonitis with an incidence rate of 4-5% in the Japanese population. Finally, European radiologists should keep in mind that a majority of studies dealing with EGFR mutations in adenocarcinomas arise from Asian countries with results that might not be transposable to Caucasian populations.
1. To learn about clinicopathologic features characterising ALK-rearrangement.
2. To understand the impact of ALK rearrangement on the prognosis of non-small cell lung cancer.
3. To see some illustrative cases.
The 2-7% of non-small cell lung cancers (NSCLC) harbor the rearrangement of anaplastic lymphoma kinase (ALK) - an oncogene related to a tyrosine kinase pathway - notably in adenocarcinoma histology and in non-smokers (about 60% of all ALK-rearranged NSCLC). Target therapy by tyrosine kinase inhibitors (TKI) is clinically available for ALK-positive advanced NSCLC and improves progression-free survival (PFS) compared with previous reference chemotherapy. Hence, testing for mutations is paramount for optimal planning of medical treatment of advanced NSCLC. In the face of a better disease control by TKI, however, it happens that ALK-positive tumors are prone to driver mutation with resistance to first-line TKI, in the first months of therapy. In clinical practice, diagnostic imaging, notably computed tomography (CT), has high yield in the management of patients under target therapy. The CT evidence of disease progression, either local or systemic (note: brain metastases are relatively common because first-line TKIs have low trespassing coefficient through emato-encephalic barrier) is paramount for timely adaptation of therapy. Rapid radiologic progression demands prompt TKI swap towards second-line (e.g., ceritinib, brigatinib, or alectinib) or third-line target therapy (e.g., lorlatinib) or otherwise. Re-biopsy is suggested to pitch the optimal second (or further) line therapy by continuous molecular testing. In clinical trials, again, diagnostic imaging has high yield in the assessment of target therapies, namely for definition of PFS. Adverse events occur in a minority of patients under TKI (1% incidence of lung toxicity). Therapy discontinuation is usually sufficient to reduce toxic effects, with only 3-6% of cases lingering after therapy withdrawal.
1. To know about the impact of PD-L1 positivity.
2. To know how to evaluate the tumour response after immunotherapeutics.
3. To be aware of the imaging features of immune therapy complications.
Immune checkpoint inhibitors (ICI) are effective in the treatment of many cancers, blocking immunosuppressive pathways; they play a increasing role in the first-line treatment of lung-cancers. This is particularly true when there is evidence for a significant pretreatment tumor lymphocytic infiltration and/or tumors exhibit a positive staining for PD-L1. As ICIs work through a different mode of action there is good reason to use therapy response criteria other than RECIST. In contrast to cytotoxic agents anti-tumour response in immunotherapy may take longer and in the initial phase the response to immune therapies can manifest in a morphologic “progressive disease”, therefore, called “pseudoprogression”. In this situation a early discontinuation of the treatment would not be appropriate, unless PD is confirmed. “Clinically insignificant” PD may even include the detection of new lesions ("unconfirmed progression") that may not lead immediately to a discontinuation of the oncologic regiment and has to be reevaluated. As ICIs act through a different mechanism than cytotoxic agents or tyrosine inhibitors, deblocking the immune system a broad spectrum of auto immune diseases can be triggered. Imaging characteristics of frequent and serious immune-related adverse events (irAEs) will be discussed.