Non-Small Cell Lung Cancer

What every physician needs to know:

Lung cancer is the second most common cancer diagnosed in both men and women in the United States, and the leading cause of cancer related mortality. In 2017, there were an estimated 222,500 new cases and 155,870 deaths due to the disease, representing approximately 25.9% of all cancer related deaths, and 6% of all deaths in the U.S. Deaths from lung cancer exceed the combined deaths from breast, prostate, and colorectal cancer. The average age at diagnosis is 70 years.

The poor outcomes from lung cancer reflect relative resistance to medical therapies, patient comorbidites and presentation at locally advanced or metastatic stages at the time of diagnosis. However, recent data suggesting decreased mortality from computed tomography (CT)-based lung cancer screening has resulted in implementation of screening programs across the country.

Lung cancer is divided into two major histological subtypes; non-small cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer cases and includes adenocarcinoma, squamous cell carcinoma and large cell carcinoma and small cell lung cancer accounting for the other 15%. The proportion of patients with small cell lung cancer in North America has decreased over time due to the decline in cigarette consumption.

The principal histologic subtypes of NSCLC in the United States are adenocarcinoma (40%), squamous cell carcinoma (25%), large cell carcinoma (10%), and undifferentiated (25%). Characteristically, adenocarcinoma tumors and large cell tumors are peripheral lesions and tend to metastasize early in the clinical course. By contrast, squamous tumors tend to be central, have the highest rates of cavitation, and metastasize late.

Adenocarcinoma with lepidic growth pattern (formerly known as bronchioloalveolar cancer (BAC), more recently termed Adenocarcinoma in situ) is a subtype of adenocarcinoma. This histological type spreads via small airways, does not have any invasive component, does not involve regional lymph nodes, and does not spread hematogenously.

Historically, the histologic subtype of NSCLC was not considered in selecting therapy as it was not thought to impact patient outcomes. However, differential safety and efficacy results with specific therapies for advanced NSCLC have recently led to distinct treatment recommendations for non-squamous and squamous cell tumors. In addition, specific molecular mutations have been found to be present in non-squamous cell NSCLC tumors and should be considered when selecting therapy.

Approximately 50% of NSCLC harbor molecular aberrations in activating “driver” kinases. A number of agents that specifically target some of these alterations are FDA approved, such as the epidermal growth factor receptor (EGFR) inhibitors gefitinib, erlotinib and afatanib, and the anaplastic lymphoma kinase (ALK) inhibitors crizotinib, alectinib, brigatinib and ceritinib, the ROS1 inhibitor crizotinib and the BRAF inhibitors dabrabenib (with or without trametinib) and vemurafenib. Several others are under clinical investigation.

Recently, immunotherapy has emerged as a promising treatment for advanced NSCLC. Immune checkpoint inhibitors are currently approved in the first and second-line setting.

Are you sure your patient has non-small cell lung cancer? What should you expect to find?

NSCLC may present with signs or symptoms related to the primary tumor, local growth or invasion, distant metastases, or paraneoplastic syndromes.

Thoracic signs and symptoms

Bronchial obstruction: cough, dyspnea, hypoxia, hemoptysis, wheezing, post-obstructive pneumonia or pneumonitis.
Chest wall invasion: pain or palpable mass.
Tumor compression of local structures: superior vena cava [SVC] syndrome, dysphagia due to esophageal compression or cardiac symptoms.
Pleural or pericardial effusion: pain, dyspnea, tamponade, or arrhythmias.
Nerve entrapment: Horner’s Syndrome due to invasion of sympathetic chain, diaphragmatic paralysis due to phrenic nerve palsy, hoarseness due to involvement of recurrent laryngeal nerve, ulnar pain and vasomotor changes from involvement of 8th cervical and 1st thoracic nerves.

Features of metastatic disease

Bone: pain, fracture, spinal cord or nerve root compression.
Brain: headache, dizziness, nausea/emesis, seizures, or focal neurologic deficits.
Liver: anorexia, RUQ pain, jaundice, or weight loss.
Bone marrow: cytopenias, or leukoerythroblastic features.
Adrenal metastases: rarely cause symptoms but may cause pain or adrenal insufficiency.

Paraneoplastic syndromes

Paraneoplastic syndromes are common in patients with lung cancer and are more commonly seen in patients with SCLC than NSCLC. They may be the presenting finding or a symptom of disease recurrence. Often the paraneoplastic syndrome may improve with treatment of the primary tumor.

Hypercalcemia: due to secretion of parathyroid hormone-related peptide (PTH-RP) most commonly seen with squamous cell carcinoma.
Hyponatremia: due to syndrome of inappropriate antidiuretic hormone (SIADH) most commonly seen with SCLC.
Cushing’s syndrome: due to ectopic production of ACTH most commonly seen with SCLC and pulmonary carcinoids.
Eaton Lambert myasthenic syndrome: seen most commonly in SCLC.
Hypertrophic osteoarthropathy: most commonly seen in adenocarcinoma.

Should I screen patients for non-small cell lung cancer?

The clinical outcome for a patient diagnosed with NSLC is related to the stage at the time of diagnosis. Two-thirds of patients diagnosed with lung cancer present with locally advanced or metastatic disease and it is presumed that early detection would lead to improved patient outcomes.

In 2013, the United States Preventive Services Task Force (USPSTF) endorsed computed tomography (CT)-based lung cancer screening for high-risk individuals. Specifically, the USPSTF recommends annual low-dose CT screening for individuals who meet the following criteria:

Age 55-80 years
>30 pack-year smoking
If former smoker, quit within past 15 years

This recommendation was based on the positive results of the National Lung Screening Trial (NLST), which compared yearly chest x-ray to spiral CT scan for 3 years in 53,454 individuals age 55-74 years with 30-plus pack-years smoking. This trial reported a 20% reduction in lung cancer mortality in individuals randomized to CT scan compared to chemotherapy and a 6.7% reduction in all-cause mortality. This translated to a number needed to screen to prevent one lung cancer death (NNS) of 320, which compares favorably with NNS for other screening modalities such as mammography for breast cancer (NNS 377-1,139, depending on age) and fecal occult blood testing for colorectal cancer (NNS 1,250).

Importantly, in the NLST, up to 40% of participants over time had a “positive” CT screen, broadly defined as a non-calcified nodule >4 mm or other concerning radiographic findings. Of these, only about 4% were found to be lung cancer, suggesting that screening programs will need to have a multidisciplinary approach that includes algorithms and counselling services to navigate patients through the process.

“Low-dose CT” refers to studies that are generally performed in a single breath hold, without IV contrast, and convey less than one-third the radiation exposure of a standard diagnostic chest CT.

Beware of other conditions that can mimic non-small cell lung cancer

The solitary pulmonary nodule is defined as a single density, with well circumscribed margins, surrounded by normal pulmonary parenchyma, measuring 1-6cm in greatest diameter. The differential diagnosis of a pulmonary nodule includes the following:

Malignant

Primary lung cancer
Bronchial carcinoid
Metastatic cancer (most commonly breast, colorectal, renal cell, germ cell, melanoma, and sarcoma)

Benign

Infectious
Granulomatous disease
Hamartoma
Abscess
Vascular

The approach to a patient with a solitary pulmonary nodule is derived from an estimate of the probability of cancer based on the nodule’s size and characteristics and the patient’s age and smoking status. (Table I)

Table I.

	Increased probability of malignant	Increased probability of benign
General appearance	Corona radiata sign; spiculated	Smooth; scalloped border

Calcification	Absent	Present
Nodule size	<1.5cm	>=2.3cm
Growth rate on high-resolution CT scan		Stable > 2 years

If possible, the first step is to obtain prior radiographs for comparison. This would allow a determination of whether the nodule is indeed new and an estimation of its growth rate.

The optimal frequency of follow-up imaging remains controversial. If using high-resolution CT scans, follow-up imaging should be considered at 3 months after the nodule is initially detected and then every 3-6 months to assess the growth pattern of the lesion.

For lesions that are larger, or equal to, 1cm at the time of detection, a PET scan may be helpful. However, a nodule may be positive on PET scan in patients with infections or granulomatous disease. A positive PET scan requires tissue sampling to confirm a diagnosis in all patients with suspected lung cancer.

As CT scans have improved, so has the detection of smaller lesions including small “ground glass” opacities (GGOs). Many of these GGOs, when biopsied, are found to be adenocarcinoma with lepidic growth pattern. GGOs may appear as semiopaque nodules and referred to as “partial” GGOs and are often more slowly growing. By contrast, “solid” GGOs have faster growth rates and are usually typical adenocarcinoma histologically.

Which individuals are most at risk for developing non-small cell lung cancer?

Cigarette smoking

Smoking is associated with approximately 85% of lung cancer cases in the U.S. The risk of developing lung cancer increases with duration and intensity of smoking. An individual who smokes one pack of cigarettes daily has a 20-fold increased risk of lung cancer compared with a never smoker. The risk of lung cancer declines but persists after smoking cessation; 15 years after quitting, the risk is still 4 times higher than in a never smoker.

Half of all patients diagnosed with lung cancer are former smokers and approximately 15% of patients are never smokers. Women may be at greater risk for lung cancer for a given degree of tobacco exposure, which may reflect differences in carcinogen metabolism, DNA repair, or tumor promoter effects of hormones.

Environmental tobacco smoke (ETS)

Individuals who live in a household with a smoker have a 30% increase in the risk of lung cancer compared to never smokers who do not live in such an environment. Passive smoking accounts for 3-5% of lung cancer cases.

Asbestos exposure

Cigarette smokers exposed to asbestos have a 50-90-fold increase in lung cancer (particularly adenocarcinoma) compared with unexposed individuals. Among non-smokers, asbestos exposure increases the risk of lung cancer 5-fold.

Other exposures

Radon (occurring naturally in the soil) is the second most common cause of lung cancer, and the leading cause among non-smokers, accounting for an estimated 21,000 cases every year, of which 15% are non-smokers. Exposure to uranium, arsenic, nickel-cadmuim, chromium, or chloromethyl ether is also associated with lung cancer.

"Scar carcinoma"

Lung cancer may arise at the site of prior tuberculosis infection or other lung injury.

Germline mutations

Genetic polymorphisms of the cytochrome P450 enzyme system, specifically CYP1A1 and chromosome fragility are associated with increased risk of lung cancer in conjunction with environmental exposures.

First degree relatives of lung cancer probands have a 2-3-fold increased risk of lung cancer development suggesting genetic variants that may contribute to lung cancer susceptibility. However, very few genes have been identified and are still under exploration. A rare germline mutation (T790M) in the epidermal growth factor receptor (EGFR) gene is associated with lung cancer susceptibility.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.)? How should you interpret the results and use them to establish prognosis and plan initial therapy?

Obtaining a tissue diagnosis

Tissue sampling is required to confirm a diagnosis in all patients with suspected lung cancer.

Central lung lesions may be sampled during bronchoscopy via transbronchial biopsy, endobronchial ultrasound (EBUS), or blind biopsy. Bronchial brushings, washings, and bronchoalveolar lavage together have a sensitivity of approximately 80% that increases to 85-90% when tissue is obtained.

Bronchoscopic techniques that may improve detection of cancer include autofluorescence bronchoscopy, high-resolution bronchoscopy with narrow band imaging, electromagnetic guidance, virtual navigation, and endobronchial ultrasound.

Peripheral lung lesions may be sampled via CT-guided transthoracic biopsy.

Lymph nodes may be sampled via blind biopsy, EBUS or transesophageal ultrasound (EUS). Palpable lymph nodes may be sample by fine needle aspiration.

If a lesion is not amenable to minimally invasive approaches, a thoracotomy or video-assisted thoracic surgery (VATS) may be required for sampling of lung nodules. A mediastinoscopy may be required for sampling of suspicious lymph nodes.

Biopsy of a radiographically evident distant site of disease is often preferred if present as it may accomplish tissue diagnosis and staging simultaneously.

Pathologic analysis

The principal histologic subtypes of NSCLC are adenocarcinoma (Figure 1), squamous cell carcinoma (Figure 2), and large cell carcinoma (Figure 3). Adenocarcinoma in situ (AIS) (previously termed bronchioloalveolar cancer [BAC]) (Figure 4) is a subtype of adenocarcinoma that is associated with never smoking status, high rate of EGFR mutations, and low likelihood of lymphatic or hematogenous spread.

Adenocarcinoma in situ (previously termed bronchioloalveolar cancer)

In addition to histopathologic appearance, immunohistochemistry (IHC) may aid in the diagnosis of NSCLC. See Table II.

Table II.

Histology	Positive immunohistochemical markers
Squamous cell carcinoma^§	Cytokeratin (CK) cocktail, e.g. AE1/AE3CK 5/6p63ThrombomodulineCK7 rare
Adenocarcinoma	Cytokeratin (CK) cocktail, e.g. AE1/AE3CK7TTF-1*Napsin ANeuroendocrine markers rare, e.g. CD56, NSE
Large cell carcinoma	CytokeratinTTF-1 rareNeuroendocrine markers rare, e.g. CD56, NSE
Large cell neuroendocrine carcinoma	Cytokeratin (CK) cocktail, e.g. AE1/AE3TTF-1CD56ChromograninSynaptophysin

*TTF-1 is positive in 80% of NSCLC adenocarcinoma. The frequency of TTF-1 positivity in extrapulmonary adenocarcinomas (excepting thyroid) is so low (1%) that TTF-1 positivity may interpreted as definitive evidence that the tumor is a lung primary. If needed, a thyroglobulin stain can distinguish between NSCLC (negative) and thyroid cancer (positive).

§IHC analysis does not reliably distinguish between a primary lung squamous cell cancer or a metastasis from an extrapulmonary squamous cell cancer (e.g., head and neck primary).

Molecular profiling

It is estimated that up to 50% of NSCLC harbor “driver mutations.” However, FDA approved targeted therapies are only available for approximately 15-20% of patients at this time (see Figure 5
). Currently, FDA approved molecularly targeted therapies are available for four subsets: EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) rearrangements, ROS1 rearrangements, and BRAF mutations. An additional three alterations may be treated with clinically available therapies approved for other indications: HER2 mutations (in contrast to the HER2 expression or amplification used as clinical biomarkers in breast and gastroesophageal cancer), RET rearrangements, and MET exon 14 mutations.

Frequency of oncogenic alterations in non-small cell lung cancer. (A) adenocarcinoma. (B) squamous cell carcinoma.

The majority of actionable genomic alterations in lung cancer occur in non-squamous NSCLC and are over-represented in never- or oligo-smokers. KRAS mutations represent the most common genomic alteration in lung cancer (approximately 25% of adenocarcinoma cases). Currently, there are no available direct KRAS inhibitors.

Selected molecular subsets of NSCLC are described below.

EGFR

EGFR mutations occur in approximately 10% of all NSCLC patients in the U.S., with higher incidence in Asian countries. The most common EGFR mutations are exon 19 in-frame deletions of amino acids 747-750 and exon 21 L858R substitutions. Clinicopathologic features associated with EGFR mutations include never-smoking history, East Asian ethnicity, adenocarcinoma histology, and female gender.

Tumor EGFR status may be characterized by protein expression (using IHC), gene amplification and copy number (using fluorescence in situ hybridization [FISH]), or mutation (using PCR- or NGS-based direct gene sequencing).

All methods require adequate tissue (excisional or core biopsy preferred to cytology), proper tissue handling, and standardization of laboratory techniques. Plasma-based assays are now approved for detection of exon 19 deletions and the exon 21 L858R substitution mutations, as well as exon 20 T790M resistance mutations.

The majority of activating EGFR mutations are associated with high response and disease control rates from EGFR inhibitors. Treatment of EGFR mutant lung cancer is described in detail in the “Use of EGFR tyrosine kinase inhibitors (TKIs)” section.

ALK

In a rare subset (<5%) of NSCLC, ALK gene fusions occur. Most common is an interstitial deletion and inversion within chromosome 2p resulting in fusion of the N-terminal portion of the protein encoded by the EML4 (echinoderm microtubule-like 4) gene with the intracellular signaling portion of the ALK (anaplastic lymphoma kinase) receptor tyrosine kinase.

Clinicopathologic features associated with EML4-ALKrearrangements include younger age, never-smoking history and adenocarcinoma histology (particularly signet-ring cell type with abundant intracellular mucin). In contrast to EGFR mutant NSCLC, there does not appear to be a clear association with patient ethnicity or gender.

ALK testing is most commonly performed by FISH (Figure 6), IHC, and Next Generation sequencing. FISH employs differently labeled break-apart (split-signal) probes on the 5′ and 3′ ends of the ALK gene. In normal cells the signals appear as fused/adjacent orange/green (hence yellow) signals. When a rearrangement involving the ALK gene is present such as in the case of the inversion of chromosome 2p involving the EML4 gene then the fusion signal will split, leading to the orange and green separate signals. The unaffected ALK gene on the other remaining chromosome 2 stays as the yellow fusion. Thus, a “positive” cell will show 1 orange, 1 green and one fusion signal. Normal cells will show 2 fusion (yellow) signals indicating that the two copies of ALK are not involved in a rearrangement. The probe will also detect copy number increase or loss, which are seen as multiple fusion signals or only one fusion signal (see Figure 6).

ALK protein expression is correlated with ALK gene rearrangements. While FISH remains the most commonly used biomarker, one recently proposed approach is to evaluate with IHC and employ FISH for further characterization of tumors with intermediate ALK expression, analogous to HER2 testing in breast cancer. Additionally, ALK alterations may be detected by Next Generation (NextGen) sequencing. Of note, cases that are ALK-positive by IHC and/or NextGen sequencing but negative by FISH may still respond to ALK inhibitors.

ALK rearrangements are associated with high response and disease control rates from ALK inhibitors. Treatment of ALK positive lung cancer is described in detail in the “Use of ALK tyrosine kinase inhibitors (TKIs)” section.

KRAS

KRAS mutations occur in 25-30% of lung adenocarcinoma, are associated with smoking, and are mutually exclusive of EGFR mutations and ALK rearrangements. To date, KRAS has been considered a non-druggable target that predicts poor response to standard and targeted therapies. Therapeutic strategies currently under clinical investigation focus primarily on interfering with signal transduction of downstream pathways such as PI3K, MEK, and focal adhesion kinase (FAK). Recently, direct KRAS inhibitors have been described, but such drugs are likely years away from clinical use.

ROS1

ROS1 rearrangements occur in approximately 1-2% of NSCLC. ROS1 shares greater than 50% homology with ALK. Clinicopathologic features of ROS1-positive cases resemble those of ALK-positive NSCLC and include younger age, never/oligo-smokers, and adenocarcinoma histology. The majority of these cases respond to selected, but not all, ALK inhibitors. For instance, crizotinib, ceritinib, and brigatinib have activity against ROS1. Alectinib does not.

BRAF

BRAF mutations occur in 1-4% of lung adenocarcinoma and are associated with smoking. In contrast to melanoma (in which almost all BRAF mutations are V600E), a number of BRAF mutations have been identified in NSCLC: V600E (50%), G469A (40%), D594G (11%). Mutation-specific BRAF inhibitors (with or without concurrent MEK inhibitors) have activity and are approved in V600E cases. For tumors harboring non-V600E BRAF mutations, for which V600E-specific mutations are unlikely to be effective, inhibitors of downstream targets such as MEK are being explored.

DDR2

Discoidin death receptor 2 (DDR2) is a receptor tyrosine kinase activated by collagen that may signal via the SRC and signal transducer and activator of transcription (STAT) pathways. DDR2 mutations occur in 4% of squamous NSCLC and in <1% non-squamous cases. The multitargeted kinase inhibitor dasatinib inhibits DDR2 in preclinical models and cases of clinical response have been reported.

FGFR

The fibroblast growth factor receptor (FGFR) family includes four receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, FGFR4). FGFR1 amplifications occur in approximately 20% of squamous NSCLC but in <2% of adenocarcinomas. FGFR mutations have also been described. Studies of FGFR inhibitors for NSCLC therapy are underway.

HER2

In contrast to breast cancer and gastric cancer, in lung cancer HER2 amplification does not itself appear to have a prognostic or predictive role. However, HER2 mutations (predominantly in-frame insertions in exon 20) have been associated with some degree of disease control (unfortunately not as robust as observed in other oncogene-driven tumors treated with TKIs) with therapies with HER2 activity, such as the dual EGFR/HER2 inhibitors neratinib, dacomitinib, and afatinib. HER2 mutations are detected in 2-4% of NSCLC, most commonly in never smokers and adenocarcinoma histology.

MET

MET is a receptor tyrosine kinase activated by binding of its ligand hepatocyte growth factor (HGF), which is also known as scatter factor (SF). MET protein overexpression occurs in 25-75% of NSCLC and is associated with poor prognosis. Amplification of the MET gene occurs in 2-4% of both squamous and non-squamous NSCLC (up to 20% of EGFR mutant NSCLC with acquired resistance to EGFR inhibitors) and is associated with poor prognosis.

The most clinically relevant biomarker is MET exon 14 mutation, which predicts response to the ALK/ROS1/MET inhibitor crizotinib and other MET inhibitors in clinical development.

Approach to molecular profiling

Given the challenges of tissue acquisition, the cost of mutational analysis, selection of patients for molecular testing requires careful consideration. Most expert guidelines recommend focusing testing on patients with non-squamous histology. However, the growing availability of “Next Generation” multiplex testing – which can provide rapid analysis of multiple genes quickly and with relatively little tissue – and identification of druggable molecular targets in squamous tumors (such as BRAF and MET exon 14 mutations), has led to broader application.

Molecular testing may be performed at any disease stage and at any point in therapy. However, currently there is no established role for EGFR or ALK inhibitors outside the advanced disease (stage IV) setting.

Recently, blood-based assays of circulating cell-free DNA have permitted the non-invasive assessment of tumor genomic alterations in lung cancer and other malignancies. Depending on the specific biomarker, the sensitivity and specificity of this approach can be quite high. Cases with positive results by blood-based assay but negative results by tissue testing generally respond as expected to molecularly targeted therapies, suggesting false negative tissue results rather than false positive blood-based test results.

Imaging studies

PET-CT

To evaluate for nodal and distant disease, PET-CT is recommended. If PET-CT is not available, CT of chest/abdomen/pelvis plus nuclear bone scan may be employed. The widespread use of PET-CT has been shown to decrease the number of futile thoracotomies performed and may result in stage migration. PET-CT has a sensitivity of approximately 90% (slower-growing tumors may not be FDG-avid) and a specificity of approximately 80% (granulomas and infections may be FDG-avid).

If distant disease is suspected based on PET-CT, a confirmatory biopsy is recommended prior to deeming a person to have stage IV disease. PET-CT may remain abnormal for months after surgery or radiation therapy. The role of PET-CT during and after lung cancer treatment is not established.

Brain magnetic resonance imaging or computed tomography

Due to the accumulation of FDG in normal brain tissue, PET-CT is relatively insensitive for the detection of brain metastases. In the absence of other metastatic sites, or in the presence of CNS symptoms, brain imaging is indicated, preferably with an MRI. CT scan may be used in patients with contraindication to MRI.

Pleural effusions

A malignant effusion is considered stage IVA disease. Due to the relatively low sensitivity of cytologic analysis, effusions are considered malignant if they have positive cytology, are hemorrhagic or are exudative (effusion LDH:serum LDH ratio >=0.6; effusion albumin:serum albumin ratio >=0.5). Exceptions would be a clear alternative explanation, such as pneumonia associated with an exudative effusion.

Mediastinal lymph node sampling

In the absence of extrathoracic disease or a malignant effusion, mediastinal lymph node sampling is recommended because the presence of nodal metastases is a key factor in determining tumor resectability. Stations 2-9 are mediastinal (N2 or N3) nodes. Stations 10-14 are hilar (N1) nodes. Generally accepted criteria for mediastinal sampling include the following:

Clinical stage II disease (i.e. enlarged N1 hilar lymph nodes).
Enlarged (>1cm in short axis) mediastinal nodes on CT.
FDG-avid nodes on PET.

Mediastinal sampling procedures include cervical mediastinal exploration (CME), EBUS, EUS, VATS and Chamberlain procedure (anterior mediastinotomy). CME, EBUS, and EUS generally provide access to mediastinal lymph node stations other than stations 5 and 6 (the aortopulmonary window), which are common sites of spread for left-sided lesions.

Access to the AP window nodes requires an additional procedure, such as VATS or Chamberlain. Mediastinal sampling may be performed at the time of resection as a single operation or prior to resection as two separate procedures.

Assessment of patient fitness for therapy

Early stage and locally advanced disease

For consideration of surgery or radiation therapy, patient must have adequate pulmonary reserve demonstrated by pulmonary function tests (PFTs) and arterial blood gas (ABG). Typical requirements for resection include the following criteria:

Predicted post-operative 1-second forced expiratory volume (FEV1) greater than 0.8-1.0 liters.
Preoperative maximum voluntary ventilation (MVV) greater than 35% of predicted.
Carbon monoxide diffusing capacity (DLCO) greater than 60% of predicted.
Arterial oxygen pressure (PO2) greater than 60mm Hg and carbon dioxide pressure (PCO2) of less than 45 mm Hg.

These criteria roughly correspond to the ability to walk up more than one flight of stairs without stopping. Split PFTs or nuclear ventilation scans may be employed to determine the individual capacity of each lung.

For definitive radiation therapy in patients with locally advanced disease, an FEV1 larger than 1-1.5 liters is a commonly used criterion. For both surgery and radiation therapy, ongoing smoking is associated with substantial increased risk of complications.

Advanced (stage IV) disease

For patients with advanced (stage IV) disease, chemotherapy is recommended for patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-2. A possible exception is patients with tumors harboring activating epidermal growth factor (EGFR) mutations, who have a high likelihood of responding to treatment with well tolerated oral EGFR tyrosine kinase inhibitors (TKIs).

Advanced age alone in an individual with good functional status should not limit therapeutic considerations. Routine laboratory testing (complete blood count with differential and comprehensive metabolic panel) is sufficient to determine adequacy of bone marrow, renal, and hepatic function for chemotherapy.

Staging

Table III. TNM staging of lung cancer.

What therapies should you initiate immediately i.e., emergently?

Most cases of NSCLC do not require urgent initiation of treatment. However, a number of disease-related complications may need to be addressed emergently. These complications may occur at any point in the disease course.

Hypercalcemia: treat with intravenous fluids and bisphosphonates; use of diuretics is generally discouraged, particularly in the setting of volume depletion.
Spinal cord compression: initiate corticosteroids (e.g., dexamethasone 10mg IV then 4mg IV q 6 hours); treat with radiation therapy and/or surgery.
Cardiac tamponade: treat with pericardiocentesis +/- pericardiotomy (“pericardial window”).
SVC syndrome: consider steroids, radiation therapy and possible stent.
Bronchial compression: treat with endobronchial stent or radiation therapy.
Hemoptysis: treat with radiation therapy or endobronchial ablative techniques.
Brain metastases: initiate steroids and treat with whole-brain radiation therapy, stereotactic radiation, surgical resection, or a combination of these modalities.

What should the initial definitive therapy for the cancer be?

Stage I and II

Stage I accounts for approximately 25% of NSCLC diagnoses. Stage I encompasses TNM stages T1 and T2aN0M0. These are small tumors with no lymph node involvement.

Stage II NSCLC represents 10-15% of NSCLC and encompasses tumors with hilar node (N1) involvement, large primaries (> 7 cm), chest wall invasion, or location in the superior sulcus (Pancoast tumor).

Surgery

Surgical resection is the mainstay of treatment for stage I and II NSCLC, with cure rates of 60-80% for stage I disease. For stage II NSCLC, surgery results in 5-year survival rates ranging 25-50%. The preferred operation is a lobectomy, rather than a segmentectomy or wedge resection.

Hilar and mediastinal (if not sampled pre-operatively) lymph nodes should be sampled at the time of surgery. For right sided tumors, it is generally recommended that lymph node stations 4, 7, and 10 be sampled; for left-sided tumors, stations 5, 6 and 7.

Lobectomy may be performed via thoracotomy or video-assisted thoracic surgery (VATS), a minimally invasive approach. Single-arm and retrospective studies suggest that VATS may achieve similar outcomes as thoracotomy in stage I and II NSCLC. VATS may provide particular advantage in elderly, frail, or high-risk patients. Compared to open thoracotomy, VATS is associated with:

Reduced post-operative morbidity.
Improved post-operative pulmonary function.
Less post-operative pain.
Shorter chest tube duration.
Shorter length of stay.

Limited (sublobar) resection consists of the removal of one or more anatomical segment(s) (segmentectomy) or a non-anatomical wedge resection. In the Lung Cancer Study Group trial 801, 276 patients with stage IA (T1N0) peripheral NSCLC were randomized to lobectomy or a more sublobar resection. Local recurrence was increased threefold and mortality was increased by 30% in the sublobar resection arm.

Nevertheless, sublobar resection may be considered for those patients rather than lobectomy, particularly for small primary tumors.

Proximal lesions

For proximal lesions, lobectomy may not result in complete tumor resection. Surgical options include pneumonectomy and sleeve resection. Sleeve resection is associated with better preservation and fewer complications. In selected cases, it may also provide equivalent oncologic results.

Positive surgical margins

If surgical margins are involved by cancer, re-resection is recommended or radiation therapy (with or without chemotherapy) can be considered when additional surgery is not possible.

Radiation therapy

For patients with contraindications to surgery, conventional fractionated radiation therapy offers 15-20% 5-year survival rates, a statistic that reflects both the inferior efficacy of this modality compared to surgical resection and the inherent poor prognosis of the patient population. A typical treatment plan:

200 cGy/day administered 5 days/week x 6 weeks to a total of 6000 cGy.

Recently, the advent of stereotactic body radiation therapy (SBRT) has permitted the delivery of higher, “ablative” radiation doses over a small number of fractions. Disease control rates with SBRT appear far superior to those obtained with conventional fractionated radiation therapy.

The targeted radiation of SBRT has become feasible through improvements in patient immobilization, imaging, and radiation beam contouring. SBRT is considered for relatively small tumors (usually < 5cm) that are not adjacent to the proximal bronchial tree or in the central chest region. Typical SBRT treatment plans:

1200 – 2000 cGy/day x 3 – 5 days (administered every 2nd or 3rd day) to a total of up to 6000 cGy.

While the total radiation dose is comparable to that of conventional radiation, the high-dose hypofractionated schedule results in a substantially more biologically potent treatment. To date, outcomes with this technique appear quite promising, with 2-year local control rates in excess of 90%. However, longer term follow-up is not yet available, and SBRT has not been directly compared to surgery or conventional radiation therapy.

After resection, post-operative radiation therapy (PORT) is not recommended for stage I or II NSCLC unless there are positive surgical margins.

Other local therapies

Radiofrequency ablation (RFA) and cryoablation have been used to treat small lung tumors in patients not candidates for surgery.

Chemotherapy

Adjuvant (post-operative) chemotherapy is routinely recommended after resection of stage II and III NSCLC. Additionally, based on a subset analysis of a single randomized clinical trial, adjuvant chemotherapy appears to offer a survival benefit for stage I patients with tumors larger than, or equal to, 4 cm in diameter.

Adjuvant chemotherapy is not recommended for smaller stage I tumors. Adjuvant chemotherapy is generally started 6-12 weeks after surgery and administered for up to 4 cycles. In appropriate patients, (good functional status, creatinine clearance >= 60 and neuropathy <= grade 1) cisplatin doublet therapy is recommended. Carboplatin may be substituted in select patients.

The major adjuvant chemotherapy clinical trials (IALT, ANITA, NCIC BR-10 and CALGB9633) demonstrate a 5-year survival benefit of approximately 5%. The greatest benefit is seen in patients with higher stage disease (15% for stage III, 12% for stage II, 2% for stage I). The regimen for which the greatest investigational experience is available, and which demonstrates the greatest survival advantage in meta-analysis, is cisplatin-vinorelbine.

In some circumstances, neoadjuvant (pre-operative) chemotherapy may be administered. Compared to adjuvant chemotherapy, it offers the potential advantages of reducing tumor volume before surgery (which might simplify resection), demonstrating in vivo chemosensitivity, addressing micrometastatic disease earlier, and possibly being better tolerated.

Although phase 3 trials comparing neoadjuvant platinum-based regimens with surgery alone have demonstrated the feasibility of this approach, there is no data showing a benefit for neoadjuvant compared to adjuvant chemotherapy, which remains the standard approach.

A number of adjuvant chemotherapy regimens are employed. Although the principal adjuvant chemotherapy trials employed cisplatin combined with either vinorelbine, vindesine, vinblastine, or etoposide, or carboplatin-paclitaxel, data for other agents from the advanced disease setting has been extrapolated to the adjuvant setting. ECOG E1505 trial results suggest that cisplatin combinations with vinorelbine, pemetrexed, docetaxel, or gemcitabine have similar outcomes. Commonly used adjuvant regimens are displayed in Table IV.

Table IV.

Chemotherapy	Squamous	Non-Squamous
Cisplatin 75mg/m² day 1Vinorelbine 30 mg/m² days 1 and 8	X	X
Cisplatin 75mg/m² IV day 1Docetaxel 75mg/m² IV day 1	X	X
Cisplatin 75mg/m² IV day 1Gemcitabine1200mg/m2 IV days 1 and 8	X	X
Cisplatin 75mg/m² IV day 1Pemetrexed 500mg/m² IV day 1		X
Carboplatin * AUC 6 IV day 1Paclitaxel 200mg/m² IV day 1	X	X

*For patients not candidates for cisplatin

Molecularly targeted therapies

Currently, there is no established role for EGFR inhibitors, ALK inhibitors, or other molecularly targeted therapies for early stage NSCLC (stage I-III). Clinical trials are ongoing.

Superior sulcus (pancoast tumors)

Superior sulcus (pancoast) tumors adjoin the brachial plexus. They are frequently associated with Horner’s Syndrome or shoulder/arm pain. They are typically treated with combined modality therapy; concurrent chemoradiation followed by surgery and additional chemotherapy. Cisplatin 50 mg/m² days 1 and 8 and etoposide 50 mg/m² days 1 to 5 every 28 days is the recommended therapy for 4 cycles (2 during concurrent chemoradiation therapy and two after surgery).

Stage III

Stage III or locally advanced NSCLC is a heterogeneous disease category that comprises tumors with mediastinal nodal involvement or direct mediastinal invasion. Five-year survival is 15-25%. There is no clear consensus on treatment for these patients, though it is generally agreed that therapy should include both a local (surgery, radiation therapy, or both) and systemic (chemotherapy) modality.

"Non-bulky" stage IIIA

These tumors generally involve a single mediastinal nodal station and have no T4 mediastinal invasion. Possible approaches include:

Neoadjuvant chemotherapy followed by surgery.
Surgery followed by adjuvant chemotherapy (+/- sequential post-operative radiation therapy [PORT] to the mediastinum).
Radiation therapy plus chemotherapy (either concurrent or sequential).
A trimodality approach.

Concurrent chemoradiation is preferred to sequential treatment in suitable candidates. If surgery is planned thereafter, radiation doses generally do not exceed 4500 cGy. If surgery is not planned, radiation doses up to 6000-7200 cGy are employed. There are two commonly used chemotherapy regimens that may be administered with radiation therapy:

Concurrent chemoradiation regimens

1. Cisplatin-etoposide

Cisplatin: 50 mg/m² IV days 1, 8, 29, 36.
Etoposide: 50 mg/m² IV days 1-5, 29-33 during radiation therapy.

2. Carboplatin-paclitaxel

Carboplatin: AUC 2 IV weekly.
Paclitaxel: 45 mg/m² IV weekly during radiation therapy

followed by 2 cycles consolidation chemotherapy.

Carboplatin: AUC 6 IV day 1.
Paclitaxel: 200 mg/m² IV day 1 every 21 days.

3. Platinum-pemetrexed

Cisplatin 75 mg/m² or Carboplatin AUC 6 day 1.
Pemetrexed 500 mg/m² day 1 every 21 days.

Trimodality approaches have been shown to prolong disease control rates but not overall survival. They are associated with considerable morbidity and mortality. In patients treated with this approach, the benefit of surgery appears greatest for patients who “clear” the mediastinum after induction therapy; the toxicity of therapy appears greatest for patients who require a pneumonectomy.

"Surprise" stage IIIA (N2 disease)

Occasionally, despite pre-operative staging, patients thought to have stage I or II disease are found to have N2 nodal involvement at the time of surgery. For these patients, post-operative radiation therapy (PORT) (50-54 Gy) may be considered, preferably after completion of adjuvant chemotherapy.

"Bulky" stage III

These tumors are characterized by any of the following:

Large mediastinal nodes.
Involvement of multiple mediastinal lymph node stations.
Involvement of contralateral (N3) mediastinal lymph nodes.
T4 tumors directly invading the mediastinum.

These cases are treated with concurrent or sequential chemoradiation (as described above), without surgery.

Stage IV

Stage IV NSCLC encompasses patients with distant disease (IVB), bilateral lung involvement (IVA), or malignant effusions (IVA). Five-year survival rates are less than 5%. Treatment generally entails medical therapies (chemotherapy, molecular targeted therapies, immunotherapy) alone. Possible exceptions (“oligometastatic” disease, multiple lung lesions) are discussed in the “What if scenarios” section below.

Chemotherapy

Chemotherapy has been shown to increase survival and quality of life in patients with stage IV NSCLC.

In general, first-line treatment entails up to 4-6 cycles of “platinum doublet” chemotherapy, with radiographic response assessed every two to three cycles.
Selected patients may be treated with a biologic agent (the anti-vascular endothelial growth factor [VEGF] monoclonal antibody bevacizumab or the anti-epidermal growth factor receptor [EGFR] monoclonal antibodies cetuximab or necitumumab in addition to chemotherapy.
Patients who are not candidates for doublet chemotherapy may be treated with single-agent regimens.
Patients whose tumors express > 50% programed death-ligand 1 (PD-L1) have a progression free survival benefit from front-line immune check-point inhibitor therapy with the anti- programed death (PD-1) antibody pembrolizumab verses a platinum-based chemotherapy doublet.
Combination carboplatin-pemetrexed plus pembrolizumab is well tolerated and associated with improved response rate and progression-free survival compared to carboplatin-pemetrexed. This regimen is approved as first-line treatment for advanced non-squamous NSCLC regardless of tumor PD-L1 expression.
Patients with tumors harboring activating EGFR mutations may be preferentially treated with an EGFR tyrosine kinase inhibitor (Erlotinib 150 mg daily, Gefitinib 250 mg daily, or Afatinib 40 mg daily) in the first-line setting.
Patients with tumors harboring ALK rearrangements may be preferentially treated with an ALK tyrosine kinase inhibitor (Crizotinib 250 mg twice daily, Ceritinib 750 mg daily, Alectinib 600 mg twice daily) in the first-line setting.
After completion of first-line therapy, patients may receive immediate further therapy (maintenance chemotherapy) or watchful waiting until disease progression, at which point they may be offered second-line chemotherapy.
Radiographic response rates range 20-35% with first-line chemotherapy and are approximately 10% with second-line therapy.
Immune checkpoint inhibitors are approved for previously treated advanced NSCLC and appear to have greater efficacy and more favorable toxicity profiles than conventional chemotherapy in that setting

Commonly used chemotherapy regimens (Table V) (Table VI)

Table VI.

Chemotherapy	Squamous	Non-Squamous
Cisplatin 75mg/m² IV day 1Pemetrexed † 500mg/m² IV day 1		X
Cisplatin 75mg/m2 IV day 1Paclitaxel 175mg/m2 IV day 1	X	X
Cisplatin 75mg/m² IV day 1Gemcitabine 1000mg/m² IV days 1 and 8	X	X
Cisplatin 75mg/m² IV day 1Docetaxel 75mg/m² IV day 1	X	X
Cisplatin 80mg/m² IV day 1Vinorelbine 25mg/m² IV days 1 and 8 Cetuximab 400mg/m² IV day 1 then 250mg/m² weekly	X	X

*All regimens are administered every 21 days for 4-6 cycles

†Pemetrexed may be continued until disease progression

Maintenance therapy

Maintenance chemotherapy refers to continuation of chemotherapy after the initial 4 to 6 cycles of platinum based-doublet therapy has been administered. The platinum is generally discontinued. There are two types of maintenance chemotherapy that are administered, “switch” and “continuation” maintenance. (Table VII)

“Switch maintenance” refers to switching the non-platinum chemotherapy to an agent not initially used in the first few cycles of chemotherapy for example switching from carboplatin and paclitaxel after 4 to 6 cycles to pemetrexed. “Continuation maintenance” refers to continuing the non-platinum chemotherapy, for example continuing single agent bevacizumab after 4 to 6 cycles of carboplatin, paclitaxel and bevacizumab.

Second-line therapy

At present, six drugs are FDA approved for second-line therapy in NSCLC patients in the US. These are docetaxel, pemetrexed, nivolumab, pembrolizumab, atezolizumab, and ramucirumab (an anti-VEGF receptor 2 [VEGFR2] monoclonal antibody administered with docetaxel. Docetaxel and pemetrexed, and erlotinib have response rates of approximately 10% and yield median survival of approximately 6-8 months. Compared to docetaxel, outcomes with nivolumab, atezolizumab in all patients and pembrolizumab in patients with tumors that are ≥ 1% PD-L1 positive are superior. Other single-agent regimens that are also used are listed below. Each agent has a distinct toxicity profile and should be considered based on the patient’s prior chemotherapy regimen and performance status. (Table VIII)

Considerations for selection of chemotherapy for stage IV NSCLC:

Choice of platinum agent

Given the relative ease of administration, favorable toxicity profile, and non-curative treatment paradigm, in the US carboplatin is used more frequently than cisplatin for stage IV disease.

Use of pemetrexed

This multitargeted antifolate agent is approved for use in non-squamous NSCLC only due to lack of efficacy against squamous tumors. This is attributed to relatively higher levels of thymidylate synthase, an enzyme inhibited by pemetrexed, in squamous NSCLC.

Addition of bevacizumab

This anti-vascular endothelial growth factor receptor (VEGF) monoclonal antibody inhibits angiogenesis, or new blood vessel formation.

Therapeutic effects

Therapeutic effects are attributed to a reduced delivery of oxygen and nutrients to the tumors, and “normalization” of inherently tortuous tumor vasculature, resulting in improved delivery of chemotherapy.

Toxicities

Toxicities include bleeding, clotting, hypertension, proteinuria, wound healing complications, gastrointestinal perforation, and increased myelosuppression when added to chemotherapy. Bevacizumab should not be administered within 4-8 weeks of major surgery or until the surgical incision is fully healed. Administration of bevacizumab within 7 days of a minor procedure, such as insertion of vascular access devices, does not appear to increase complication rates.

Patient monitoring

Patient monitoring includes routine assessment of blood pressure and urine dipstick for protein. If dipstick 2+ of greater (≥ 100 mg/dl), a 24-hour urine collection for protein should be performed. Bevacizumab should be interrupted until 24-hour urine protein is under 2g. If grade 4 proteinuria (nephrotic syndrome) develops, bevacizumab should be permanently discontinued.

Contraindications

Contraindications include squamous histology due to the occurrence of severe hemoptysis in these patients in clinical trials. Caution is recommended if there is radiographic evidence of tumor cavitation or vessel invasion by tumor. Bevacizumab use appears safe in patients with brain metastases previously treated with surgery, radiation therapy, or both. There is less experience with the use of bevacizumab in patients receiving concomitant therapeutic anticoagulation, though it may be considered with careful monitoring.

Addition of ramucirumab

Ramucirumab is an anti-VEGFR2 monoclonal antibody with antiangiogenic effects. In contrast to bevacizumab, it is approved in squamous as well as non-squamous NSCLC. Whether the apparent safety of this agent in squamous tumors reflects differences between the drugs or differences in the clinical setting (bevacizumab is often given as a component of initial therapy, whereas ramucirumab is approved for previously treated cases) is not clear.

Use of EGFR tyrosine kinase inhibitors (TKIs)

The EGFR TKIs erlotinib, gefitinib, and afatinib are restricted to patients with tumors harboring activating EGFR mutations (i.e., EGFR exon 19 deletions or exon 21 L858R substitution mutations). Tumor testing for these alterations is necessary because clinical factors are unreliable for their detection – even in highly clinically enriched populations (e.g., never/oligo-smoking East Asians), EGFR mutations occur in only 60% of patients. Conversely, EGFR mutations may occur in patients without typical clinical features.

Plasma levels of EGFR inhibitors are subject to factors influencing absorption and metabolism:

Afatinib and erlotinib should be taken on an empty stomach, at least 1 hour before or 2 hours after eating. Concomitant food intake may result in increased drug absorption and enhanced toxicities. Gefitinib may be taken with or without food
Cigarette smoking reduces erlotinib plasma concentrations.

Erlotinib is primarily metabolized by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP1A2 (see Table IX).

Table IX.

Selected CYP3A4 inhibitors and inducers.

Class	Examples	Effect
Strong CYP 3A4 inhibitors	Protease inhibitors, azole antifungals, macrolide antibacterials, grapefruit/grapefruit juice	Increased erlotinib levels
CYP3A4 and CYP1A2 inhibitors	Ciprofloxacin	Increased erlotinib levels
CYP3A4 inducers	Antiepileptic agents (carbamazepine, phenobarbital, phenytoin), rifampin, St John’s wort	Reduced erlotinib levels

Erlotinib may also cause INR changes in patients taking concomitant warfarin.
Neutralization of gastric acidity, as occurs with concurrent administration of proton pump inhibitors, may decrease erlotinib absorption. Temporal separation of the drugs or use instead of H2 blockers may decrease this effect. Conversely, administration of cola products may increase absorption.

Currently there are three generations of approved EGFR inhibitors:

First-generation (e.g., erlotinib, gefitinib): reversible binding to EGFR molecule.
Second-generation (e.g., afatinib): irreversible (covalent) binding to EGFR molecule, as well as to HER2; similar spectrum of toxicities as first-generation EGFR inhibitors (predominantly dermatologic, gastrointestinal) but possibly increased prevalence and severity. There does not appear to be meaningful improved efficacy against resistance (e.g., T790M) EGFR mutations compared to first-generation EGFR inhibitors.
Third-generation (e.g., osimertinib): preferential binding to mutant form of EGFR molecule; have improved efficacy in patients with T790M as their mechanism of acquired resistance to EGFR inhibitors; different toxicity profile (e.g., cardiac effects, QTc prolongation) and less rash and diarrhea compared to first- and second-generation EGFR inhibitors.

Resistance to EGFR inhibitors generally develops within 10-12 months. Molecular mechanisms of resistance include development of an acquired gatekeeper resistance mutation (Exon 20 T790M) (up to 50% of cases), MET amplification, PIK3CA mutation, histologic transformation to small cell lung cancer (<10% of cases), and epithelial-to-mesenchymal transition. In the setting of T790M mutation, the third-generation EGFR inhibitor osimertinib is FDA approved and associated with response rates of approximately 60% and median PFS of approximately 10 months.

Whether or not EGFR inhibitors should be continued after disease progression (e.g., in combination with subsequently administered chemotherapy) remains a point of active discussion. Some studies have suggested that there is no additional clinical benefit provided, while other series have raised concerns about the possibility of “tumor flare” at the time of EGFR inhibitor discontinuation. A common recommendation is to continue an EGFR inhibitor until the day of chemotherapy initiation or for a few days after starting chemotherapy to limit the risk of tumor flare.

Use of ALK tyrosine kinase inhibitors (TKIs)

ALK inhibitors are indicated for use in ALK-positive positive lung cancers. In this population, ALK inhibitors are associated with radiographic response rates exceeding 60% and disease control rates exceeding 90%. Depending on the specific agent, median progression-free survival may range from 10-12 months (crizotinib) to greater than 18 months (ceritinib, alectinib, brigatinib).

In up to 40% of cases, disease progression occurs in central nervous system sites, suggesting pharmacokinetic (drug-delivery) limitations. Molecular mechanisms of resistance to first-generation ALK inhibitors include secondary ALK mutations and development of other oncogenic alterations. After failure of crizotinib, the later-generation ALK inhibitors ceritinib, alectinib, and brigatinib are currently FDA approved and associated with high rates of clinical benefit. Gastrointestinal side effects including nausea, vomiting, and diarrhea are increased with ceritinib, whereas liver function testing abnormalities and dyspnea were more common with alectinib.

Certain ALK inhibitors also have activity against other NSCLC subsets. For instance, crizotinib is also approved for ROS1-positive NSCLC and has activity against NSCLC harboring c-MET exon 14 mutations as well. By contrast, alectinib has no activity against these tumors.

Use of BRAF/MEK inhibitors

The combination of the oral BRAF inhibitor dabrafenib and the MEK inhibitor trametinib is approved for use in patients with BRAF V600E mutations. Both treatment-naïve and pretreated patients (including patients who had received single-agent dabrafenib) achieve clinical benefit with an ORR of 63%, and median duration of response of 12.3 months. There are no approved targeted therapies for patients with non-V600E BRAF mutations at this time.

Use of immune checkpoint inhibitors

Currently, there are three immune checkpoint inhibitors FDA approved for the treatment of advanced NSCLC. The anti- programmed death 1 (PD1) antibody nivolumab and the programmed death-ligand 1 (PD-L1) blocking antibody atezolizumab are approved for previously treated advanced NSCLC. The anti- programmed death 1 (PD1) antibody pembrolizumab is approved for first-line and in previously treated programmed death ligand 1 (PD-L1)-positive advanced NSCLC. In these indications, PD-L1 positivity has different definitions (≥50% in first-line; ≥1% in second-line). Additionally, pembrolizumab is approved in combination with carboplatin-pemetrexed as first-line therapy for non-squamous NSCLC regardless of tumor PD-L1 expression.

Cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD1), and programmed death ligand 1 (PDL1) are so-called immune checkpoints. Most relevant to lung cancer therapy, PD1 molecules on T cells interact with PDL1 molecules on tumor cells to suppress anti-tumor immune responses. PD1 and PDL1 inhibitors work to overcome this suppression, thereby enhancing anti-tumor immune effects. A number of these drugs (all of which are monoclonal antibodies) are under development.

Compared to docetaxel chemotherapy, nivolumab, atezolizumab and pembrolizumab yield improved response rates and overall survival in both squamous and non-squamous NSCLC. In the first line setting, the approval of pembrolizumab was based on superior PFS compared to platinum-doublet chemotherapy in (≥50% PDL1-positive cases. The approval of pembrolizumab in combination with carboplatin-pemetrexed in non-squamous NSCLC was based on demonstration of improved progression-free survival (and response rate) compared to carboplatin-pemetrexed.

A key question surrounding use of this class of drugs in NSCLC and other malignancies is the role of predictive biomarkers. Thus far, the most promising candidates are tumor PDL1 expression, tumor-infiltrating lymphocytes, and tumor mutational burden. A number of trials have demonstrated that tumor PDL1 appears to predict benefit from PD1 and PDL1 inhibitors. Indeed, the FDA approval of pembrolizumab is currently limited to PDL1-positive cases (tumor proportion score [TPS] ≥50% expression for first-line, ≥1% expression after progression on prior platinum chemotherapy), as determined by an FDA approved companion diagnostic test. Nevertheless, there remains considerable discussion as to what assay and cut-point should be used to define PDL1-positive cases, whether PDL1 expression differs within and among sites of disease, and whether PDL1 expression changes over time. Furthermore, some trials have suggested that, for PDL1-negative tumors, immunotherapy may not be better than chemotherapy, but is not necessarily worse.

The association between mutational burden and response to immunotherapy likely reflects the associated increase in tumor antigenicity, hence priming the tumor for immune attack. This phenomenon is also thought to explain why patients with lung cancer who have the greatest smoking history appear to benefit the most from immunotherapy.

Some patients treated with immune checkpoint inhibitors may develop pseudoprogression, although the frequency of this is likely < 5%. With pseudoprogression, clinical or radiographic enlargement of tumor masses—or even the appearance of new lesions—is attributed to the influx of immune cells rather than to cancer growth. In these cases, continued treatment with immunotherapy may result in subsequent radiographic improvement and clinical benefit. How to distinguish between pseudoprogression and true progression when treating a symptomatic visceral disease such as lung cancer remains a complex consideration.

Due to concerns for enhanced autoimmunity (see “Toxicities” below), immune checkpoint inhibitors are prohibited in patients with active autoimmune disease and patients requiring chronic systemic steroids.

What other therapies are helpful for reducing complications?

Toxicities of radiation therapy

Depending on tumor location and radiation technique, toxicities include skin changes, esophagitis, cardiac effects (including coronary artery disease and cardiomyopathy), and lung effects:

Radiation pneumonitis: occurs 4-12 weeks after radiation therapy.
Radiation fibrosis: occurs 6-12 months after radiation therapy.

Clinical features of radiation pneumonitis and fibrosis overlap considerably and include cough, dyspnea, fever (more commonly seen with pneumonitis), chest pain, rales, and hypoxemia. Radiographic findings include volume loss, patchy infiltrates, and the straight line effect (denoting the radiation treatment field).

Radiographic changes are not specific for radiation pneumonitis or fibrosis: they occur in up to 65% of patients treated with radiation therapy for lung cancer, while the clinical syndromes occur in only 5-15% of patients. The volume of normal lung irradiated is the greatest predictor of pulmonary toxicity. It is recommended that the V20 (volume of normal lung receiving more than 2000 cGy) be no more than 30-35%.

Radiation pneumonitis is treated with corticosteroids, starting dose of prednisone is 1 mg/kg for several weeks followed by a slow taper.

Esophagitis is treated with proton pump inhibitors, a combination of topical lidocaine and antifungals and narcotic pain medications. The symptoms generally peak in the third week of radiation therapy and improve about three weeks after radiation therapy is complete.

Toxicities of chemotherapy

All chemotherapy agents may cause cytopenias, electrolyte and liver function abnormalities and blood work should be routinely monitored.

Bevacizumab may cause hypertension and hypoalbuminemia and a spot urine protein; creatinine should be done prior to each cycle. Patients with uncontrolled hypertension should not receive the drug. Bleeding and thrombosis (vascular and arterial) have also been reported and bevacizumab should not be given to patients with a history of recent hemorrhage or hemoptysis as well as heart attack, stroke or thrombus. Bevacizumab can affect wound healing and should not be given within 28 days of a procedure, it has also been known to cause gastrointestinal perforation.

Platinum based agents, particularly cisplatin may cause neuropathy, ototoxicity and nephropathy. Carboplatin is preferred in patients with baseline hearing impairment, neuropathy, greater than grade 1 or poor renal function. All symptoms should be monitored prior to each cycle of chemotherapy.

Taxanes may also cause neuropathy. Patients may have allergic reactions to taxanes and steroid pre-medications are required prior to each cycle.

Steroids are prescribed for patients prior to the administration pemetrexed to prevent a rash. Patients receiving pemetrexed should also be prescribed folic acid 1mg daily and B12 1000 mcg every 9 weeks, starting a week before chemotherapy.

Toxicities of molecular targeted therapies

EGFR tyrosine kinase inhibitors:

Dermatologic

Acneiform rash occurs in up to 75% of patients. It usually starts within 8-10 days after initiating therapy and usually resolves within weeks of discontinuing therapy. Less commonly, patients may develop conjunctival irritation, as well as mucosal, nail, and hair changes. Management of these toxicities is detailed in Table X.

Table X.

Rash severity	Description	Treatment
Mild	minimally symptomatic no effect on activities of daily living no evidence of superinfection	Continue EGFR inhibitor at current dose. Consider pulsed topical steroids (e.g. hydrocortisone 1% or 2.5% cream) and/or topical antibacterials (e.g. clindamycin 1% gel). If no improvement after 2 weeks, institute moderate rash management.
Moderate	generalized mild symptoms (pruritus, tenderness) minimal impact on activities of daily living no evidence of superinfection	Continue EGFR inhibitor at current dose. Administer pulsed topical steroids (e.g. hydrocortisone 1% or 2.5% cream) and/or topical antibacterials (e.g. clindamycin 1% gel). Give systemic antibacterials (e.g. doxycycline 100 mg PO bid or minocycline 100mg PO bid) (tetracyclines are preferred due to their anti-inflammatory as well as anti-bacterial properties). If no improvement after 2 weeks, institute severe rash management.
Severe	generalized severe symptoms (pruritus, tenderness) significant impact on activities of daily living potential for or evidence of superinfection	Reduce EGFR inhibitor dose (e.g. from erlotinib 150mg PO daily to 100mg PO daily and possibly to 50mg PO daily). Administer pulsed topical steroids (e.g. hydrocortisone 1% or 2.5% cream) and/or topical antibacterials (e.g. clindamycin 1% gel). Give systemic antibacterials (e.g. doxycycline 100mg PO bid or minocycline 100mg PO bid) (tetracyclines are preferred due to their anti-inflammatory as well as anti-bacterial properties). If no improvement after 2 weeks, consider a dose interruption or discontinuation.

Gastrointestinal

Up to 50% of patients may experience diarrhea when treated with first and second generation EGFR inhibitors. In most cases, this is readily managed with antidiarrheal agents.

Paronychia (a painful periungual inflammation and fissuring affecting the fingernails and toenails) occurs in approximately 15% of patients receiving EGFR inhibitors:

Application of petroleum jelly to the periungual area may prevent paronychia.
Treatment includes daily soaks (vinegar, Burrows solution, or bleach) and silver nitrate.

Hair abnormalities are reported by approximately 30% of patients receiving EGFR inhibitors for over 3 months. These include scalp and body alopecia, and changes in texture. These changes do not always revert after treatment discontinuation.

Ocular

Ocular toxicities develop in up to one-third of patients. These include dry eyes, conjunctivitis, blepharitis (inflammation of the lid margin), trichomegaly (increased growth of eye lashes), and corneal erosions.

Prompt ophthalmologic evaluation is warranted, although these changes are generally not vision-threatening.
Treatments include artificial tears, short-term ophthalmic steroids, warm compresses, and eyelash clipping.

Pulmonary

Rare cases (<1%) of serious, including fatal, interstitial lung disease (ILD)-like events have been reported in patients receiving EGFR inhibitors. If a patient develops new or progressive unexplained pulmonary symptoms (e.g., dyspnea, cough, fever), EGFR inhibitor therapy should be interrupted pending diagnostic evaluation. Dyspnea is also the most common grade 3-4 toxicity reported with alectinib.

In some cases, combination therapy regimens may yield synergistic toxicities. While the EGFR inhibitor osimertinib and the PD-L1 inhibitor durvalumab each have pulmonary toxicity rates <5%, combination therapy resulted in a >60% rate of ILD-like events.

Other supportive measures

For pruritus: consider systemic antihistamines, cool compresses, topical menthol lotions.
For xerosis (dry skin): avoid alcohol-based lotions and antibacterial soaps; use emollients (e.g., zinc oxide, petroleum jelly, Aquaphor, Aveeno, Cetaphil, Eucerin).
Given the risk of conjunctival involvement, avoid contact lens use in individuals with EGFR inhibitor rashes.
Consider early referral to a dermatologist in the case of substantial skin toxicity.

ALK tyrosine kinase inhibitors:

Ophthalmologic

Over half of patients treated with crizotinib may develop visual changes early in treatment. These are often described as “floaters” or “shadows”, especially when going from a dark to light environment (e.g., turning on the lights in the morning, driving at night), do not affect visual acuity, and improve or even resolve spontaneously despite ongoing dosing in most cases.

Gastrointestinal

Nausea and vomiting (usually low grade) may occur with all ALK inhibitors. Anti-emetics and taking medication with light food such as crackers may be beneficial.

Diarrhea and transaminitis are most common with the second generation ALK inhibitor ceritinib and may require dose modification. By contrast, alectinib may be associated with constipation.

Other toxicities

Over time, prolonged exposure to crizotinib may also lead to peripheral edema, orthostatic hypotension, hepatitis, and renal insufficiency. Brigatinib may be associated with pulmonary toxicity, particularly early in treatment.

BRAF/MEK inhibitors:

Skin

A propensity for the development of cutaneous squamous cell carcinomas (up to 19%) has been noted with unopposed BRAF inhibition, although this is largely ameliorated when used in combination with a MEK inhibitor due to its downstream effects in the MAPK pathway. Rash and photosensitivity are also reported.

Pyrexia

Pyrexia is very common with BRAF inhibition (up to 50%) and can typically be managed with supportive care. However, for particularly difficult cases antipyretics such as acetaminophen or low-dose steroids may be employed. In severe cases, pyrexia can be associated with hypotension and malaise/lethargy, which should be urgently evaluated to exclude the possibility of febrile neutropenia (a rare but reported toxicity with this treatment).

Other toxicities

Common toxicities with the combination include diarrhea, electrolyte abnormalities, hyperglycemia, fatigue, nausea/vomiting, hypertension, and liver function abnormalities. Additionally, reduced left ventricular ejection fraction has been reported and should be investigated if patients develop clinical signs of heart failure.

Monoclonal antibodies

Infusion reactions are more common with cetuximab (a chimeric antibody of 35% mouse protein and 65% human protein) than with bevacizumab (a humanized antibody of 5% mouse protein, 95% human protein) or nivolumab (a 100% human protein). These events may be broadly characterized as cytokine-dependent or hypersensitivity reactions.

Clinical features include bronchospasm, dyspnea, tachycardia, hypotension, urticaria, angioedema, and fever.

Management of acute infusion reactions includes the following:

stop infusion immediately;
medical measures may include diphenhydramine, corticosteroids, aceteminophen, meperidine, epinephrine, and supplemental oxygen;
for minor-moderate reactions, consider resuming treatment with 50% reduced infusion rate;
for severe reactions, treatment should be permanently discontinued.

Cetuximab may also cause a rash that should be managed similar to described above for EGFR TKIs.

Toxicities of immune checkpoint inhibitors

The most common adverse events of immune checkpoint inhibitors are fatigue, low-grade nausea, and anorexia. No standard premedication is given.

In a minority of cases, patients may develop autoimmune toxicities affecting specific organs. Clinical syndromes include pneumonitis, thyroiditis, colitis, hepatitis, dermatitis, nephritis, hypophysitis, endophthalmitis, and others.

Depending on the severity of the toxicity, treatment is either withheld or permanently discontinued. There are no dose reductions. The mainstay of management is corticosteroids. A typical approach might be prednisone 1 mg/kg equivalent daily. Once toxicity has improved to grade 1 in severity, a 4-6 week taper is initiated. Only if symptoms remain improved after taper completion is the immunotherapeutic agent re-initiated. In some instances, other immune-modulating agents such as TNF inhibitors may be warranted. Consultation with appropriate medical services (endocrinology, pulmonary medicine, gastroenterology, nephrology) for assistance with diagnosis and treatment may be considered. For patients with treatment-related hypothyroidism and adrenal insufficiency, replacement with levothyroxine and hydrocortisone is given.

What should you tell the patient and the family about prognosis?

Lung cancer survival rates vary depending on the type of cancer and the stage at diagnosis (Table XI).

Table XI.

Stage	Survival
I	60-80%
II	25-50%
III	15-25%
IV	<5%

The goal of any therapy in patients with stage IV disease is to improve survival, palliative symptoms and improve quality of life. Therapy should be considered if patients have a good performance status and desire for treatment exists.

What if scenarios.

"Oligometastatic" disease

Patients with limited thoracic disease and limited distant disease may be considered for local therapies to each disease site with curative intent. This oligometastatic treatment paradigm has been applied to patients with single brain and adrenal metastases, but not to other sites of disease such as liver or bone metastases.

The best outcomes have been seen in patients with a stage I lung tumor and a single brain metastasis. Resection of the lung tumor and resection (or possibly stereotactic radiation therapy) of the brain metastasis appears to result in overall survival comparable to patients with stage I NSCLC without brain metastases. In appropriate cases, stereotactic radiation may offer outcomes similar to craniotomy. The benefit of such an approach declines with increased number of brain metastases or higher stage thoracic disease.

Outcomes from an oligometastatic approach to adrenal metastases are generally poorer than those seen for brain metastases. Patients with metachronous adrenal metastases have improved survival compared to those with synchronous adrenal metastases.

Multiple lung lesions

It is often difficult to determine if multiple lung lesions represent multiple primary tumors or hematogenous spread. In the absence of nodal involvement, it is reasonable to consider contralateral lung tumors as two separate primaries and consider resection in patients with adequate pulmonary reserve.

Management of malignant effusions

Therapeutic thoracentesis should be performed for symptomatic pleural effusions. For long-term control, indwelling pleural catheter is preferred to pleurodesis. Moderate, large-sized or symptomatic pericardial effusions should be characterized by echocardiography. If cardiopulmonary compromise (tamponade) is present, pericardiocentesis and possibly pericardial drain placement or pericardotomy (“window”) are indicated.

Follow-up surveillance and therapy/ management of recurrences.

Patients diagnosed with early stage disease and treated with definitive therapy should be monitored both for risk of disease recurrence and development of a second primary. The frequency of monitoring may depend on the stage at diagnosis and treatment administered. A common recommendation after definitive treatment of stage I-III lung cancer is clinical and radiographic surveillance (typically CT chest with or without IV contrast) every 4-6 months for two years, then every 12 months for years 2-5.

For patients with suspected recurrence on imaging, biopsy should be considered to definitively document recurrent disease. Therapy will depend on the site of recurrence.

No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.

Jump to Section