Non-small cell lung cancer
- Non-Small Cell Lung Cancer (NSCLC)
What every physician needs to know:
- Are you sure your patient has non-small cell lung cancer? What should you expect to find?
Should I screen patients for non-small cell lung cancer?
- Beware of other conditions that can mimic non-small cell lung cancer
- Which individuals are most at risk for developing non-small cell lung cancer?
- 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?
What therapies should you initiate immediately i.e., emergently?
- What should the initial definitive therapy for the cancer be?
- What other therapies are helpful for reducing complications?
What should you tell the patient and the family about prognosis?
- What if scenarios.
Follow-up surveillance and therapy/ management of recurrences.
What's the evidence?
Non-Small Cell Lung Cancer (NSCLC)
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 2010, there were an estimated 224,210 new cases and 159,260 deaths due to the disease, representing approximately 28% 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 erlotinib and afatanib, and the anaplastic lymphoma kinase (ALK) inhibitors crizotinib and ceritinib. Several others are under clinical investigation.
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 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.
Cushings 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
"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:
Primary lung cancer
Metastatic cancer (most commonly breast, colorectal, renal cell, germ cell, melanoma, and sarcoma)
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. (
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?
Smoking is associated with approximately 85% of lung cancer cases. 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.
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.
Radon (occurring naturally in the soil), uranium, arsenic, nickel-cadmuim, chromium, chloromethyl ether.
Lung cancer may arise at the site of prior tuberculosis infection or other lung injury.
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.
The principal histologic subtypes of NSCLC are adenocarcinoma (
In addition to histopathologic appearance, immunohistochemistry (IHC) may aid in the diagnosis of NSCLC. See
It is estimated that up to 50% of NSCLC harbor "driver mutations," however FDA approved therapies are only available for approximately 15-20% of patients at this time. (see
Selected molecular subsets of NSCLC are described below.
EGFR mutations occur in approximately 10% of all NSCLC patients. The most common EGFRmutations are exon 19 in-frame deletions of amino acids 747-750 and exon 21 L858R substitutions. Clinicopathologic features associated with EGFRmutations 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-based direct gene sequencing).
All methods require adequate tissue (excisional or core biopsy preferred to cytology), proper tissue handling, and standardization of laboratory techniques. Of any biomarker, EGFR mutations have the clearest association with tumor sensitivity to EGFR tyrosine kinase inhibitors and are the preferred assay.
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.
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) and IHC. ALK gene alterations may also be detected by 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.
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 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 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 ALK inhibitors.
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 appear promising for 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.
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.
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.
In contrast to breast cancer and gastric cancer, in lung cancer HER2 amplification does not 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 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), is associated with poor prognosis, and may confer sensitivity to MET inhibitors (including the ALK/ROS1/MET inhibitor crizotinib).
Given the challenges of tissue acquisition, the cost of mutational analysis, and the rarity of EGFR mutations and ALKrearrangements in NSCLC, 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, may lead 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, and some studies have suggested a detrimental effect of EGFR inhibitors for treating earlier stage and locally advanced tumors.
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 should be considered 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.
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
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 45mm 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.
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.
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 (> 7cm), chest wall invasion, or location in the superior sulcus (Pancoast tumor).
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.
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.
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.
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.
Radiofrequency ablation (RFA) and cryoablation have been used to treat small lung tumors in patients not candidates for surgery.
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 vivochemosensitivity, 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. Commonly used adjuvant regimens are displayed in
Currently, there is no established role for EGFR inhibitors or ALK inhibitors for early stage NSCLC (stage I-III). Clinical trials are ongoing.
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 50mg/m2 days 1 and 8 and etoposide 50mg/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 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:
Cisplatin: 50mg/m2 IV days 1, 8, 29, 36.
Etoposide: 50mg/m2 IV days 1-5, 29-33 during radiation therapy.
Carboplatin: AUC 2 IV weekly.
Paclitaxel: 45mg/m2 IV weekly during radiation therapy, followed by 2 cycles consolidation chemotherapy.
Carboplatin: AUC 6 IV day 1.
Paclitaxel: 200mg/m2 IV day 1 every 21 days.
Cisplatin 75mg/m2 or Carboplatin AUC 6.
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 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) alone. Possible exceptions ("oligometastatic" disease, multiple lung lesions) are discussed in the "What if scenarios" section below.
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 antibody cetuximab in addition to chemotherapy.
Patients who are not candidates for doublet chemotherapy may be treated with single-agent regimens.
Patients with tumors harboring activating EGFRmutations may be preferentially treated with an EGFR tyrosine kinase inhibitor (Erlotinib 150mg daily, Gefitinib 250mg, or Afatinib 40mg daily) in the first-line setting.
Patients with tumors harboring ALK rearrangements may be preferentially treated with an ALK tyrosine kinase inhibitor (Crizotinib 250mg 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.
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.(
"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.
At present, only three drugs are FDA approved for second-line therapy in NSCLC patients in the US. These are docetaxel, pemetrexed and erlotinib. All three agents have response rates of approximately 10% and yield median survival of approximately 6-8 months. 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. (
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 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 include bleeding, clotting, hypertension, proteinuria, wound healing complications, gastrointestinal perforation, and increased myelosuppression when added to chemotherapy. Bevacuzimab 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 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 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.
The selection of patients for EGFR molecular testing and treatment with EGFR inhibitors is complex. The following points should be considered:
In unselected patient populations, EGFR TKIs provide a survival benefit in second and third-line therapy.
Even in highly clinically enriched populations (eg, never/oligo-smoking East Asians), EGFR mutations occur in only 60% of patients.
In those patients with tumors harboring EGFR mutations, response rates are similar if an EGFR TKI is administered as first, second, or third-line therapy. However quality of life appears improved if EGFR TKIs are administered first-line, an important consideration in patients with stage IV disease.
In the first-line setting, patients with EGFR wild type tumors have superior outcomes with conventional chemotherapy compared to EGFR TKIs.
In the second-line setting, unselected patients appear to have similar outcomes with conventional chemotherapy and with EGFR TKIs, although some recent clinical trials suggest inferior outcomes with EGFR TKIs in populations known to be EGFR wild type.
VeriStrat is a serum proteomic assay that may predict benefit from erlotinib in previously treated advanced NSCLC patients. Patients with a VeriStrat "good" result (generally ~65% of patients) may have similar overall survival with erlotinib and conventional single-agent cytotoxic chemotherapy, whereas patients with a VeriStrat "poor" result (generally about ~35% of patients) appear to have inferior overall survival with erlotinib compared to conventional single-agent cytotoxic chemotherapy. The VeriStrat result may change over time, so the test is probably best ordered within 2 weeks of planned treatment initiation.
Plasma levels of EGFR inhibitors are subject to factors influencing absorption and metabolism:
Drug 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.
Cigarette smoking reduces drug plasma concentrations.
Erlotinib is primarily metabolized by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP1A2 (see
). Table IX
Erlotinib may also cause INR changes in patients taking concomitant warfarin.
Currently there are three generations of EGFR inhibitors in clinical use and/or development:
First-generation (eg, erlotinib, gefitinib): reversible binding to EGFR molecule.
Second-generation (eg, afatinib): irreversible (covalent) binding to EGFR molecule; similar spectrum of toxicities as first-generation EGFR inhibitors (predominantly dermatologic, gastrointestinal) but possibly increased prevalence and severity. Unclear if improved efficacy against resistance (eg, T790M) EGFR mutations compared to first-generation EGFR inhibitors.
Third-generation (eg, CO-1686, AZD9291): preferential binding to mutant form of EGFR molecule; may have improved efficacy in patients with T790M as their mechanism of acquired resistance to EGFR inhibitors; different toxicity profile (eg, hyperglycemia with CO-1686) 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.
Whether or not EGFR inhibitors should be continued after disease progression (eg, 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.
In contrast to EGFR inhibitors, ALK inhibitors are indicated for use only in ALK-positive lung cancer. In this population, ALK inhibitors are associated with radiographic response rates exceeding 60%, disease control rates exceeding 90%, and median progression-free survival ranging 10-12 months.
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 second-generation ALK inhibitor ceritinib is FDA approved and associated with high rates of clinical benefit albeit with significant gastrointestinal toxicities. Other second generation ALK inhibitors are in clinical development.
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 1mg/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
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
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.
ALK tyrosine kinase inhibitors:
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 (eg, 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.
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.
Over time, prolonged exposure to crizotinib may also lead to peripheral edema, orthostatic hypotension, hepatitis, and renal insufficiency.
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.
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 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.
Diarrhea occurs in approximately 50% of patients treated with EGFR inhibitors. Most cases are mild and respond to symptomatic measures such as loperamide (Imodium) and diphenoxylate hydrochloride/atropine sulfate (Lomotil).
Rare cases (<1%) of serious, including fatal, interstial 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.
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). 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.
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 (
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.
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.
What's the evidence?
Screening for lung cancer and approach to the solitary pulmonary nodule
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