11 Lung Cancer (Non–Small Cell)
Epidemiology
Lung cancer is the most common cause of cancer death worldwide. It is associated with smoking, but over half the cases in the United States are diagnosed in patients who never smoked or quit many years earlier. Also, asbestos, beryllium, cadmium, chromium, radon gas, nickel, and vinyl chloride, which the patients are exposed to at the workplace and in the environment, are causative agents. 1 – 3
Pathology
Adenocarcinoma is the dominant type, followed by squamous cell.
Genetics
Carcinogens in smoking are responsible for deoxyribonucleic acid (DNA) adduct formation and DNA mutations that activate the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene seen in 25% of patients. 4 , 5 Nonsquamous mutations include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) rearrangement, ROS1 rearrangement, human epidermal growth factor receptor 2 (HER2) mutation, v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation, rearranged during transfection (RET) rearrangement, KRAS, mesenchymal–epithelial transition (MET) mutation, MEK1 mutation, PIK3CA mutation. This plethora of gene mutations has led to the development of targeted agents. The first four mutations have agents that have been approved by the Food and Drug Administration (FDA). These include gefitinib (EGFR inhibitor), erlotinib (EGFR inhibitor), afatinib (EGFR inhibitor, HER2 inhibitor), crizotinib (ALK inhibitor, ROS1 inhibitor), and ceritinib (ALK inhibitor). 6 Multiple companies are now providing gene sequencing services to detect the mutations that can have drugs targeted to them. Practically, for the interventional radiology, this requires a larger biopsy specimen, usually cores, which will increase the likelihood of a pneumothorax in an already at-risk population due to chronic obstructive pulmonary disease or emphysema caused by smoking.
Staging 7
Tumor
T1a = Primary tumor is 2 cm or less in diameter.
T1b = Primary tumor is greater than 2 but less than 3 cm in diameter.
T2a = Primary tumor is greater than 3 but less than 5 cm in diameter.
T2b = Primary tumor is greater than 5 but less than 7 cm in diameter.
T3 = Primary tumor is greater than 7 cm in diameter.
T3 invasive = Invades chest wall, diaphragm, phrenic nerve, mediastinal pleura, or pericardium.
T3 central = Primary tumor is less than 2 cm to the carina or atelectasis of an entire lung.
T3 satellite = Any size primary tumor with additional tumor nodules in the same ipsilateral lobe.
T4 invasive = Any size tumor that invades heart, great vessels, esophagus, trachea, vertebral body, carina.
T4 ipsilateral nodules = Separate tumor nodule in a different ipsilateral lobe.
Lymph Nodes
The lymph nodes in the chest are divided into levels so that communication about positive nodal spread can be uniform.
Level 1 = Highest mediastinal nodes at the upper rim of the brachiocephalic vein where it crosses anteriorly to the trachea.
Level 2 = Upper paratracheal nodes.
Level 3 = Prevascular and retrotracheal nodes.
Level 4 = Lower paratracheal nodes.
Level 5 = Aortopulmonary window nodes.
Level 6 = Para-aortic nodes near the ascending aorta or phrenic nerve.
Level 7 = Subcarinal nodes.
Level 8 = Paraesophageal nodes below the carina.
Level 9 = Pulmonary ligament nodes.
Level 10 = Hilar nodes.
Level 11 = Interlobar nodes.
Level 12 = Lobar nodes.
Level 13 = Segmental nodes.
Level 14 = Subsegmental nodes.
These levels are preceded by an R or L designating the side, as in R10 node. 8
The staging for nodal extension is as follows:
N0 = No nodal metastases.
N1 = Nodal metastases in ipsilateral hilar, peribronchial, or pulmonary nodes.
N2 = Nodal metastases in ipsilateral mediastinal or subcarinal nodes.
N3 = Metastases in contralateral nodes.
Metastases
M0 = No distant metastases.
M1 = Metastases in contralateral lobe, pleural nodules, or malignant pleural effusion.
M2 = Distant metastases.
Stages
Stage 0 = Carcinoma in situ.
Stage I = T1a/b, T2a; N0, M0.
Stage IIA = T1, T2a; N1, M0 or T2b, N0, M0.
Stage IIB = T2b, N1, M0 or T3, N0, M0.
Stage IIIA = T1, T2, T3; N2, M0 or T3, T4; N1, M0 or T4, N0 or N1, M0.
Stage IIIB = Any T, N3, M0 or T4, N2, M0.
Stage IVA = Any T, Any N, M1.
Stage IVB = Any T, Any N, M2.
If there are no distant metastases, it becomes crucial to know the status of the mediastinal lymph nodes. A fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scan will demonstrate any node greater than 1 cm in diameter is likely involved with tumor. However, nodes that are suspicious on CT need to be biopsied via either bronchoscopy or mediastinoscopy.
Treatment
Surgery
Minimally invasive resection using video-assisted thoracic surgery (VATS) has dramatically decreased the morbidity of lung cancer surgery, allowing more fragile patients to have the tumor excised.
The treatment of non–small cell lung cancer (NSCLC) requires a combination of surgery, chemotherapy, and radiation that is personalized for each patient considering their comorbidities and the stage of the disease. The recommended treatments for each stage are as follows:
Stage I: A minimally invasive, for example, VATS, lobectomy is recommended without adjuvant chemotherapy or radiation for patients who can tolerate the surgery with a 5-year survival of 60 to 80%. In compromised patients, the use of Stereotactic Body Radiation Therapy (SBRT) can be substituted for surgery with a 2-year survival of 60 and 45% at 5 years. Disease control at the primary site is accomplished with SBRT in 80 to 100% at 2 years.
Stage II: Resection followed by adjuvant chemotherapy is the standard of care, with survival at 5 years of 45%, and most deaths (75%) are caused by recurrence. The chemotherapy recommended is a doublet that includes cisplatin. Often used for the other half of the doublet are vinorelbine or etoposide. In locally invasive T3N0M0 tumors, an en bloc resection is recommended. If all the tumor is removed, a 50 to 60% 5-year survival is expected. If less than an R0 resection is performed, the survival is less than 5% at 5 years, with or without radiotherapy. For central T3N0 tumors, even with R0 resection the survival is 25 to 30% at 5 years. 8 , 9
Pancoast tumors are a subset of T3 tumors. These occur at the apex of the lung and invade the thoracic inlet effecting the first rib, brachial plexus, subclavian artery and vein, and thoracic spine. Neoadjuvant chemoradiation utilizing a cisplatin doublet and at least 45 Gy of external beam radiation therapy (EBRT) is recommended. Surgery is performed for cure and, if an R0 resection is performed, 5-year survival is approximately 55% with a recurrence rate of 6%. However, if such a resection cannot be accomplished, chemoradiation should be performed for cure with a 5-year survival of 28%. 10 , 11
Stage III is conveniently subdivided into three clinical subgroups:
Where there is unsuspected N2 disease prior to surgery.
Adjuvant chemotherapy with a cisplatin doublet extended overall survival (OS) to 20% at 5 years. When radiation is added postoperatively, the OS rises to 27 to 33%. If combined with cisplatin doublet, chemoradiation has a higher toxicity than when given sequentially. Adjuvant radiation should be considered if an incomplete resection is performed. If an R0 resection is performed, no adjuvant therapy is recommended. 12 , 13
Where there is discrete nodal involvement detected on CT or PET/CT prior to surgery. Mediastinoscopy with nodal sampling should be performed at the time of initial surgery. Meta-analyses of intent to treat studies have suggested that the outcomes are better after neoadjuvant chemotherapy. 9 , 14 Several randomized clinical trials compared neoadjuvant therapy followed by surgery to chemotherapy alone and found no significant difference. 14 Chemoradiotherapy using a cisplatin doublet with 45 Gy of EBRT concurrently resulted in better outcomes than chemotherapy alone with higher rates of mediastinal downstaging, higher rates of near pathologic complete response, and lower rates of incomplete resection. 9 , 14
Where there is infiltrative tumor or matted lymph nodes defined in CT or PET/CT. Radiation alone has been the historical modality used to control the tumor in this case with an OS of 22% at 5 years. 15 With the advent of combined modality therapy, chemoradiation is recommended with a cisplatin doublet. Using this therapy, there is a 30% reduction in mortality at 2 years when compared with radiation alone. 16 Use of cisplatin and pemetrexed disodium offers a lower toxicity profile than cisplatin and etoposide with 63 Gy of EBRT, but there is no improvement in survival with OS of 25 months. 17
Stage IV: Patients with this level of advanced disease are often symptomatic and are more concerned with quality of life than undergoing toxic chemotherapy. However, it has been shown that patients live longer with the administration of chemotherapy than by the use of best supportive care, and the toxicity of this chemotherapy is less than grade III. 18 It is recommended that patients with stage IV NSCLC be treated with chemotherapy with a platinum doublet avoiding pemetrexed, if squamous, then maintain with erlotinib. If nonsquamous, the patients should have genetic testing to determine if a genetic alteration conforming to the requirements of a specific targeted drug is present. If the mutation is present, treat with the specific drug. If not, treat with a platinum doublet and bevacizumab if possible. Then maintain with bevacizumab (if eligible), erlotinib, or pemetrexed. 9 If patients are treated with targeted therapy, their survival ranges from 20 to 36 months with an overall response rate of 25 to 74%. The use of maintenance chemotherapy extends the survival from 10 to 12 months. 19
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