Systemic Therapy and Radiation Therapy in Lung Cancer

Introduction

Lung cancer is the most common cause of cancer-related death in both men and women around the world. Given that lung cancer can remain asymptomatic when it presents with a low disease burden in its early stages, it is usually discovered only after it has progressed to an advanced stage. Nonsmall cell lung cancer (NSCLC) accounts for about 85% of lung cancer cases. Screening with low-dose computed tomography (CT) has recently been shown to have a mortality benefit in high-risk patients (i.e., 50 years and older, 20 or more pack-year smoking history, exposure to radon and asbestos, family history of lung cancer), and its use is increasing given its incorporation into national guidelines. However, the majority of patients come in for diagnostic evaluation of specific symptoms or because of an unexpected finding on chest imaging (not performed during screening assessment). The goal of the initial examination is to gather enough clinical and radiologic information to guide diagnostic tissue biopsy, complete staging, and determine a treatment plan. Treatment is governed by the cancer's subtype and stage, and there are now several personalized treatments that were previously unavailable based on the molecular profile of the disease. In general, the role of multidisciplinary teams to optimize treatment is crucial, especially as patients receive multimodal therapies.

Epidemiology of Lung Cancer

Lung cancer caused an estimated 1.8 million deaths in 2020 worldwide. In the United States, it causes about 230,000 new cases and 130,000 deaths per year. ^, Due to advancements in systemic therapies, such as the development of newer targeted agents against specific actionable molecular alterations, as well as the introduction of immunotherapeutics into the treatment space, improvements in survival have been observed in recent population-based analyses. ^, Before the fifth decade of life, lung cancer is quite uncommon; after that, the risk increases with age. Men are generally more affected than women. Lung cancer deaths are slowly declining, largely due to cessation in smoking as it reduces lung cancer risk. Even reducing the number of cigarettes smoked daily has shown to be beneficial. In general, any form of smoking, including secondhand smoke, cigars, and pipes, raises the risk of lung cancer. Due to inconsistent results, the link between marijuana and e-cigarettes is less apparent with lung cancer that traditional tobacco exposures. Radon exposure and select types of interstitial lung disease are other risk factors. Lung cancer is also linked to chronic obstructive pulmonary disease and prior family history.

The most common presenting manifestations in lung cancer include cough, hemoptysis, dyspnea, and chest pain. Patients with these symptoms often undergo a chest radiograph at initial presentation due to the low radiation exposure and ease of testing. An enlarged hilar or paratracheal node, an endobronchial lesion, postobstructive pneumonia, or segmental or lobar atelectasis can all be seen on a chest radiograph. Additional testing with a contrast-enhanced chest CT can be performed based on suspicious radiograph findings. A solitary lung nodule, uneven or spiculated margins, and thick-walled cavitation on CT are potential indicators of malignancy. On the other hand, lung cancer is highly unlikely to be represented by solid-appearing lesions on chest CTs that have remained consistent in size for at least 2 years. Asymptomatic patients may have incidental findings during routine screening.

Staging for Lung Cancer

Whether lung cancer is localized in the lungs or has extended to regional lymph nodes or other organs determines the stage. Tumors can grow in the lungs for a long period before being discovered. As a result, it is difficult to diagnose lung cancer in its early stages (stages I and II). A positron emission tomography (PET/CT) is recommended for extracranial systemic staging and magnetic resonance imaging (MRI) of the brain for those with Stage II–IV NSCLC and any patient diagnosed with small cell lung cancer (SCLC).

The Tumor, Node, Metastasis (TNM) stage at presentation is the most important factor in determining the prognosis in individuals with NSCLC. Currently, the American Joint Committee on Cancer (AJCC) eighth edition is in use for staging of NSCLC (see Table 2.1 ). The various stages for NSCLC are as follows:

Stage I - A tumor that has not spread to any lymph nodes. Stage I is further divided into subcategories based on the tumor's size: Stage IA cancers are 3 cm or less in size, and are further split into IA1, IA2, and IA3 (depending on size). Tumors in stage IB are greater than 3 cm but less than 4 cm in diameter.
Stage II - It is subdivided into two stages: Stage IIA lung cancer is defined as a tumor that is larger than 4 cm but smaller than 5 cm and has not spread to adjacent lymph nodes. Stage IIB lung cancer is defined as a tumor that is smaller than 5 cm in diameter and has progressed to the lymph nodes.
Stage III - They are further classified as stage IIIA, IIIB, or IIIC and is determined by the size of the tumor and the number of lymph nodes to which the malignancy has spread.
Stage IV - It indicates that the cancer has spread to other parts of the body, such as the other lung, pleural effusion, pericardial effusion, or distant areas of the body, via the bloodstream. Based on the extent of the disease, stage IV NSCLC is further classified into stage IVA, IVB, or IVC.

Table 2.1

TNM Staging of Lung Cancer.

T: Primary tumor
Tx		Primary tumor cannot be assessed or tumor proven by presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0		No evidence of primary tumor
Tis		Carcinoma in situ
T1		Tumor ≤3 cm in greatest dimension surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus
T1a(mi)		Minimally invasive adenocarcinoma
T1a		Tumor ≤1 cm in greatest dimension
T1b		Tumor >1 cm but ≤2 cm in greatest dimension
T1c		Tumor >2 cm but ≤3 cm in greatest dimension
T2		Tumor >3 cm but ≤5 cm or tumor with any of the following features:- Involves main bronchus regardless of distance from the carina but without involvement of the carina- Invades visceral pleura- Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, Involving part or all of the lung
T2a		Tumor >3 cm but ≤4 cm in greatest dimension
T2b		Tumor >4 cm but ≤5 cm in greatest dimension
T3		Tumor >5 cm but ≤7 cm in greatest dimension or associated with separate tumor nodule(s) in the same lobe as the primary tumor or directly invades any of the following structures: Chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, parietal pericardium
T4		Tumor >7 cm in greatest dimension or associated with separate tumor nodule(s) in a different ipsilateral lobe than that of the primary tumor or invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina
N: Regional lymph node involvement
Nx		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1		Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2		Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3		Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M: Distant metastasis
M0	No distant metastasis
M1	Distant metastasis present
M1a	Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodule(s) or malignant pleural or pericardial effusion
M1b	Single extrathoracic metastasis
M1c	Multiple extrathoracic metastases in one or more organs

Treatment Options

Basics of Surgery

For stage I and II NSCLC, surgery is the treatment of choice. ^, The different types of surgery for NSCLC include the following:

Pneumonectomy: The entire lung, as well as its lymph nodes, is removed during this procedure and it is usually indicated for tumors that are centrally located.
Lobectomy: During this treatment, an entire lung lobe is removed along with the regional lymph nodes.
Segmentectomy: Only a portion of the lung is removed, not the complete lobe. Usually indicated if the patient's normal lung function is insufficient to sustain the removal of the entire lobe. This procedure may be performed via a video-assisted thoracoscopic surgery (VATS) or robotic-assisted thoracoscopic surgery (RATS).
Wedge resection: This procedure involves removal of a small nonanatomic wedge of the affected lung. This is typically performed with VATS or RATS techniques. These strategies have been shown to reduce surgical morbidity, including perioperative discomfort, and appear to be especially beneficial for patients with comorbidities.

Despite the fact that surgical decisions are made based on provider and institution preferences, recent studies support the use of VATS procedures. For example, in a randomized study of VATS versus open thoracotomy, VATS procedures were linked to a reduction in operation time, blood loss, and hospital stays, as well as less postoperative pain and better quality of life.

Radiation Therapy

In general, radiation therapy (RT) is often used either in a curative sense or for those needing palliation for metastatic disease. Patients who are unable to have surgery due to comorbidities or who refuse resection may be treated with definitive RT. It may be utilized depending on the stage of NSCLC and other factors: for patients with early-stage disease, as a first-line treatment, occasionally in combination with chemotherapy, especially if the lung tumor cannot be removed, or if the patient refuses surgery in those with locally advanced disease. RT can also be used after surgery (along with chemotherapy) for patients who have resected tumors with positive margins. RT can also be used before surgery (usually along with chemotherapy) to make it easier to operate on a lung tumor by reducing the size and extent of disease. RT is also often used to treat areas of metastatic disease to the brain or bones and can also be used to relieve pain, bleeding, and cough associated with growth of the primary disease.

The various types of RT techniques used are as follows:

Three-dimensional conformal radiation therapy (3D-CRT): RT beams are shaped and focused from a variety of angles on the tumor, reducing the risk of injury to healthy tissues.
Intensity-modulated radiation therapy (IMRT): Sophisticated inverse planning and computational algorithms are used to maximize RT delivery to the treatment volume while minimizing RT to normal tissue outside of the target. When tumors are in close proximity to critical structures, such as the spinal cord, this approach is useful.
Stereotactic body radiation therapy (SBRT): It employs concentrated high-dose RT beams that are delivered in five or fewer treatments. Several beams are targeted at the tumor from various angles. SBRT is usually recommended for lesions less than 5 cm in diameter.
Particle therapy: Patients with stage I NSCLC have received proton beam and carbon ion therapy, with similar outcomes to SBRT. Particle therapy's unique depth-dose characteristics allow for dose escalation to tumors while sparing normal tissues and enhancing quality of life.
Brachytherapy: Radioactive material (typically in the form of small pellets/seeds) is placed directly into the tumor or the airway next to it via a bronchoscope or surgery. The radiation only travels a short distance from the source, minimizing the impact on healthy tissues in the area.

Chemotherapy/Systemic Therapy

Chemotherapy may be suggested in a variety of settings for patients with NSCLC, depending on the tumor stage. Neoadjuvant chemotherapy is used to try to reduce a tumor so that it can be removed with less extensive surgery. Adjuvant chemotherapy is used to try to destroy any residual cancer cells or any subclinical microscopic clinical disease not visible on imaging studies. For locally advanced lung disease, chemotherapy coupled with RT is the preferred treatment. Chemotherapy is used to treat lung cancer that has progressed to other organs such as the bones, liver, or brain. Cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed are the most often utilized chemotherapeutic drugs for NSCLC.

Targeted therapies differ from conventional chemotherapy drugs in their administration, side effect profile, and disease response. Patients who have certain molecular characteristics are frequently treated with specific targeted therapies:

Patients with activating mutations in the epidermal growth factor receptor (EGFR) gene are more likely to be never smokers, women, and Asian in origin. Patients that have EGFR mutations have a much better prognosis and respond to EGFR tyrosine kinase inhibitors such as erlotinib, osimertinib, gefitinib, and afatinib.
Other NSCLC subtypes are identified by the presence of ROS1 or EML4-ALK fusion oncogenes, which are more common in former smokers and appear earlier in life. Anaplastic lymphoma kinase (ALK) inhibitors [i.e., crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib] have high response rates in these select patients.
Less common driver mutations and corresponding targeted drugs include BRAF [dabrafenib, trametinib], Kirsten rat sarcoma viral oncogene homolog [sotorasib], ROS1 [crizotinib, ceritinib, lorlatinib], neurotrophic receptor tyrosine kinase [larotrectinib, entrectinib], MET [capmatinib, tepotinib], and RET [selpercatinib, pralsetinib]. Whole-genome testing is needed to discover the presence of these rare potential targets.
Programmed death-ligand 1 (PD-L1) tumor expression can help guide treatment decisions in both first-line and second-line settings by predicting response to various immunotherapies. ^, Various checkpoint inhibitors used in the treatment of NSCLC are anticytotoxic T-lymphocyte antigen 4 (CTLA-4) [ipilimumab], antiprogrammed cell death protein-1 (PD1) [pembrolizumab, nivolumab], and anti-PD-L1 [durvalumab, atezolizumab].

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here