CONTENTS

• Lung cancer screening
• Epidemiology
• Types of lung cancer
  • NSCLC (non-small cell lung cancer)
    • Adenocarcinoma
      • Lepidic predominant adenocarcinoma
    • Squamous cell carcinoma
    • Large cell carcinoma
• Clinical presentation
• Management of NSCLC
  • Staging
  • Discussion of specific therapies:
    • Radiotherapy
    • Targeted therapy
      • EGFR mutations
      • ALK fusion gene
    • Chemotherapy
  • Integration of therapies to manage specific situations:
    • Stage I-III: Surgery +/- adjuvant chemotherapy
    • Stage III: Definitive chemoradiation (+/- immunotherapy)
    • Stage IV
• SCLC (small cell lung cancer)
  • Presentation
  • Staging
  • Management
• Related topics
  • Lung cancer in HIV ➡️
• Questions & discussion

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lung cancer screening

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The USPSTF (US Preventive Services Task Force) recommends lung cancer screening with annual low-dose CT scan for people meeting all of the following criteria: 🌊

• 50-80 years old.
• ≧20-pack-year smoking history.
• Currently smoking, or quit within the past 15 years.
• Does not have a health problem that substantially limits life expectancy.
• Is willing and able to undergo curative lung surgery.

💡 Patients diagnosed with DVT and/or PE should be considered for lung cancer screening if they meet the above criteria. Such patients don't necessarily benefit from an extensive search for malignancy, but they should receive age-appropriate cancer screening.

approach to lung nodules:

• Found upon screening CT scan: American College of Radiology LUNG-RAD system.
• Found incidentally: Fleischner Society Guidelines 2017 (below). Low versus high risk is defined in terms of the patient's epidemiology (e.g., age, smoking history). 📄
• Features of lung nodules associated with malignancy include:
  • Larger size.
  • Subsolid nodules (ground-glass or partly solid appearance)
  • Spiculation.
  • Upper lobe location.
  • A PET scan shows SUVmax of ≧2.5 and higher SUV than mediastinal lymph nodes.  (de Moraes 2024)

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epidemiology

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statistics

• Lung cancer is the leading cause of cancer-related mortality.

common risk factors

• Smoking:
  • Involved in ~85% of lung cancer, usually >20-30 pack years.
  • Smoking is most closely related to SCLC (small-cell lung cancer), as well as squamous cell carcinoma. Nearly all patients with small-cell lung cancer have a smoking history.
• Asbestos exposure (synergistic with smoking).
• Radon exposure (~5% of lung cancer).
• Therapeutic radiotherapy to the chest (e.g., for lymphoma or breast cancer).

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types of lung cancer

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The more common types of lung cancer may be classified as follows. Treatment of various types of NSCLC tends to be similar. 

• Non-small cell lung cancer (NSCLC): 85% of all lung cancer.
  • Adenocarcinoma.
    • Lepidic predominant adenocarcinoma (aka pneumonic-type adenocarcinoma, bronchoalveolar carcinoma).
  • Squamous cell carcinoma (~20% of NSCLC).
  • Large cell carcinoma.
• Small-cell lung cancer (SCLC): 15% of all lung cancers.

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adenocarcinoma

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epidemiology

• Adenocarcinoma is the most common form of lung cancer, accounting for >50%. (Cecil 27th ed)
• Adenocarcinoma is the least associated with smoking:
  • Up to 50% of patients with adenocarcinoma lack a smoking history.
  • Never-smokers who develop lung cancer usually have adenocarcinoma. (Cecil 27th ed)
• Pulmonary fibrosis is a risk factor. (Shepard 2019)

presentation

• Adenocarcinoma often presents as a peripheral lung nodule. Expansion may lead to chest wall invasion or malignant pleural effusion.
• Clubbing is more commonly seen in adenocarcinoma than in other types of lung cancer.
• Adenocarcinoma may spread via the alveoli (lepidic predominant adenocarcinoma, aka pneumonic-type adenocarcinoma, previously termed “bronchoalveolar carcinoma”).
  • Radiographically, this may cause consolidation (mimicking pneumonia).
  • Clinically, patients may present with hypoxemia or a cough productive of salty sputum (bronchorrhea).

radiology

• Adenocarcinoma tends to be peripherally located.
• (1) Usually solitary nodule or mass: (Shepard 2019)
  • Spiculated, lobulated, or ill-defined border.
  • May have air bronchograms.
  • Density ranges from solid, ground-glass, or mixed attenuation.
• (2) Consolidation may occur due to lepidic spread.
• (3) Multiple nodules can occur.

behavior

• Metastasis occurs readily and early via a vascular route (often to the brain or bone).
• Invasion of the pleura and mediastinal lymph nodes is common.
• Patients who have a purely lepidic pattern (which may appear radiographically as a ground-glass nodule without any solid component) may have a more favorable prognosis.

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lepidic predominant adenocarcinoma (LPA)

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Lepidic predominant adenocarcinoma (LPA) refers to adenocarcinomas which grow along the alveoli, potentially mimicking pneumonia. Most are nonmucinous, but ~25% are mucinous (which may lead to bronchorrhea and distinctive low-density consolidations on CT scan). 

epidemiology of LPA

• LPA is the most common type of lung cancer among nonsmokers.
• It is associated with female sex and Asian ancestry.

symptoms of LPA 

• May include constitutional symptoms, cough, dyspnea, and/or hemoptysis.
• Two uncommon presentations may occur:
  • Bronchorrhea (~20% of patients) – Expectoration of >100 ml/day watery sputum (which may have a salty taste). This may be life-threatening, due to respiratory dysfunction and electrolyte imbalances. Other causes of bronchorrhea include tuberculosis, chronic bronchitis, and bronchiectasis. (29223274)
  • Hypoxemia due to extensive airspace involvement. This may cause subacutely progressive hypoxemic respiratory failure that is refractory to treatment.
• Metastasis can occur (most often to the bone, adrenal gland, or brain).

radiology: LPA causing solitary nodule (~40%)

• Solitary nodules are usually asymptomatic and slow-growing.
• These may have a ground-glass appearance on CT scan.
• The nodule often contains an air bronchogram. Similarly, the nodule may contain bubble-like pseudocavitation (patent bronchi or air-containing cystic spaces).

radiology: LPA causing consolidative appearance 

• More advanced lesions may cause focal or multifocal airspace consolidation (which may be segmental, lobar, or multilobar).
• Mucoid tumors may cause a low-density consolidation, leading to a “CT angiogram sign.” 📖
• Features that may favor LPA (as opposed to pneumonia):
  • Multiple small, low-attenuation areas occur within the lesion.
  • Nodular sphericity.
  • Bulging of the interlobar fissure.
  • Air bronchograms are stretched, squeezed, or show widening of the branching angle. (36894266)

management of LPA 

• Overall management follows the same general principles as outlined for NSCLC (below).
• There is a high rate of EGFR (epidermal growth factor receptor) mutations among non-mucinous tumors (which constitute ~65% of lepidic predominant adenocarcinomas).
• Management of bronchorrhea:
  • Octreotide has been reported to be rapidly effective. (29223274) 
  • EGFR-inhibitors may improve bronchorrhea as well. These may require more time to work, but could be a superior long-term solution.

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squamous cell carcinoma

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epidemiology

• This is the second most common type of lung carcinoma (~35% of all malignant tumors).
• 95% of patients with squamous cell carcinoma have a history of smoking.

presentation

• Squamous cell carcinoma usually presents with a central lesion with bronchial involvement (e.g., cough; hemoptysis; atelectasis, perhaps with postobstructive pneumonia).
• ~10% are cavitated at presentation. These may become infected, potentially mimicking a lung abscess.
• Peripheral squamous cell carcinoma is the most common type of lung cancer to cause Pancoast syndrome (an apical lung cancer that causes Horner's syndrome, shoulder and arm pain, and atrophy of hand muscles).
• Hypercalcemia is a common feature. Squamous cell carcinoma is the type of cancer most frequently associated with hypercalcemia due to elevated PTHrP (PTH related protein) production. (Shepard 2019)

radiology

• (1) Location is generally central, and often endobronchial.
  • Central necrosis with cavitation may occur.
  • Spread occurs to local lymph nodes.
• (2) Peripheral location occurs in ~1/3 of patients. This typically produces a cavitary lesion with a thick wall (2-10 mm).

behavior

• Local spread is common, but widespread metastatic spread occurs relatively late.
• Recurrence tends to occur locally.

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large cell carcinoma

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epidemiology

• Relatively uncommon (accounting for 5-10% of lung cancers).
• Associated with smoking in 90% of patients.

clinical attributes

• Often presents as a large, peripheral lesion (with cavitation in 15% of cases).
• Large cell carcinoma usually has a behavior similar to that of adenocarcinoma, but it tends to be more aggressive. Clinical course is often marked by rapid growth and early metastasis. Tissue diagnosis may be challenging due to a high degree of necrosis. (Cecils 27th ed)

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clinical presentation of lung cancer

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Presentation is highly variable, depending on the type, stage, and location of the malignancy. Some more common presentations are listed below.

clinical findings from locoregional disease in the chest 

• Cough (including hemoptysis or bronchorrhea).
• Dyspnea.
• Endobronchial obstruction:
  • Postobstructive pneumonia or atelectasis.
  • Focal wheezing, cough, hemoptysis.
• Pleuritic chest pain (due to invasion beyond the lung).
• Pancoast syndrome may involve:
  • Shoulder pain that may radiate into the ulnar distribution.
  • Hand muscle atrophy.
  • Horner's syndrome 📖.
• Hoarseness (due to involvement of the recurrent laryngeal nerve).
• Superior vena cava syndrome.
• Supraclavicular lymphadenopathy.

metastatic disease

• Bone pain.
• Spinal cord compression.
• Brain metastases may cause: 📖
  • Headache.
  • Nausea and vomiting.
  • Seizures.
  • Focal neurologic deficits.
• Skin nodule(s) – painless subcutaneous or intramuscular masses, most often on the chest wall, scalp, or back.
• Adrenal insufficiency.

paraneoplastic syndromes

• Digital clubbing +/- hypertrophic osteoarthropathy. 📖
• Endocrine:
  • Hypercalcemia (either due to bone metastasis or ectopic secretion of PTH-related peptide).
  • Hyponatremia due to SIADH.
  • Cushing syndrome (hyperkalemia, edema, hypertension).
• Neurologic
  • Lambert-Eaton myasthenic syndrome (LEMS).
  • Peripheral or autonomic neuropathy.
  • Limbic encephalitis.
  • Cerebellar degeneration.
• Other:
  • Dermatomyositis.
  • Hematologic manifestations (anemia, leukocytosis, thrombocytosis). (ERS handbook 3rd ed.)
  • Hypercoagulability.

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staging

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some general principles:

• The most distant tissue should ideally be biopsied first (e.g., a lesion suspicious for distal metastasis). If positive for malignancy, this may provide a diagnosis and staging (thereby rendering additional biopsies of tissue closer to the cancer unnecessary).

brain imaging

• Indicated for:
  • Patients with neurological signs or symptoms concerning for metastasis.
  • Stage II or higher lung cancer, regardless of neurological symptoms (based on the National Comprehensive Cancer Network guidelines). (35540711)
• MRI with contrast is preferred. However, a contrast CT scan may be used if MRI isn't feasible.

PET-CT scan

• Role of PET scan:
  • Provides a useful survey for metastatic or nodal involvement (especially if it identifies an unexpected distant metastasis).
  • PET scanning is recommended for all patients with lung cancer, except for ground-glass nodules and peripheral stage IA tumors.
• Sensitivity is ~80%
  • Thus, many patients with negative PET scan should still undergo EBUS staging of the mediastinum (discussed further below).
  • Causes of false-negatives include lesions <8 mm, diabetes, or slow-growing tumors. (Harrisons 21st ed.)
• Specificity is ~85%
  • Standardized uptake value (SUV) >2.5 is highly suspicious for malignancy. (Harrisons 21st ed.)
  • False-positive results may occur due to infectious, inflammatory, or granulomatous processes (e.g., sarcoid-like reaction to malignancy).
  • ⚠️ Positive finding on PET scan should be confirmed with tissue sampling.
• (Note that CT scanning alone (without PET) has even worse performance, with a sensitivity of ~55% and specificity of ~80% for nodal involvement). (Murray 2022)

EBUS-TBNA (endobronchial ultrasound-guided transbronchial needle aspiration)

• EBUS-TBNA is generally the preferred technique for staging the mediastinal lymph nodes. Esophageal ultrasound is required to access lymph node stations #8-9, but it is extremely rare that involvement of these lymph nodes would affect staging. Thus, EBUS-TBNA is generally adequate for staging the mediastinum. (Murray 2022)
• Invasive mediastinal staging is needed, unless one of the following conditions occurs:
  • (1) Patient isn't a candidate for surgical resection (e.g., distant metastatic disease, poor surgical candidate).
  • (2) Peripheral lesion, <1-3* cm in size, and no evidence of lymph node involvement on PET/CT scan. (Fishman 2023)
    • (*CHEST guidelines recommend EBUS for patients with tumors >3 cm, whereas NCCN guidelines recommend EBUS for tumors >1 cm.)

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TNM staging system

t: tumor stage

• T0 = No evidence of primary tumor.
  • Tis = Carcinoma in situ (squamous or adenocarcinoma)
• T1 = <3 cm and doesn't invade things.
  • T1a (mi) = minimally invasive (adenocarcinoma only)
  • T1a (ss) = superficial spreading tumor in central airways, confined to tracheal or bronchial wall.
  • T1a = <1 cm.
  • T1b = 1-2 cm.
  • T1c = 2-3 cm.
• T2 = 3-5 cm -OR- <3 cm with involvement of visceral pleura, or main bronchus (excluding carina) with atelectasis to the hilum.
  • T2a = Tumor 3-4 cm.
  • T2b = Tumor 4-5 cm.
• T3: Any of the following:
  • Tumor is 5-7 cm.
  • Separate tumor nodule(s) in the same lobe.
  • Invasion of the chest wall, pericardium, or phrenic nerve.
• T4: Any of the following features (usually inoperable):
  • >7 cm.
  • Tumor nodule(s) in a different ipsilateral lobe.
  • Invasion of any of the following structures:
    • Heart or great vessels.
    • Recurrent laryngeal nerve.
    • Carina, trachea.
    • Esophagus.
    • Spine.
    • Mediastinum.
    • Diaphragm.
• Tx = T status unable to be assessed.

n: nodal stage

• N0 = No lymph node involvement.
• N1 = Ipsilateral intrapulmonary or hilar nodes (Stations 10-14; figure below).
• N2 = Ipsilateral mediastinal or subcarinal nodes.
• N3 = Any of the following (usually inoperable):
  • Contralateral hilar, peribronchial, or mediastinal lymph nodes.
  • Scalene or supraclavicular lymph nodes (either ipsilateral or contralateral).
• Nx = N status cannot be assessed.

m: metastasis

• M0 = No distant metastases.
• M1a =
  • Malignant pleural/pericardial effusion or nodules.
  • Separate tumor nodule(s) in CONTRAlateral lobe.
• M1b = Single extrathoracic metastasis (oligometastasis).
• M1c = Multiple extrathoracic metastases.

overall staging

• Generally operable: 
• Stage IA1     T1a     N0      M0
• Stage IA2     T1b     N0      M0
• Stage IA3     T1c     N0      M0
• Stage IB       T2a     N0      M0
• Stage IIA     T2b      N0      M0
• Stage IIB     T1-2     N1      M0
• Stage IIB     T3        N0      M0
• Stage IIIA    T3       N1       M0
• Operability controversial:
• Stage IIIA    T4        N0-1   M0
• Stage IIIA    T1-2     N2      M0
• Generally inoperable: 
• Stage IIIB    T1-2    N3       M0
• Stage IIIB    T3-4    N2       M0
• Stage IIIC    T3-4    N3       M0
• Stage IVA    any     any      M1a-M1b
• Stage IVB    any     any      M1c

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radiotherapy

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general concepts

• Radiotherapy management doesn't distinguish between various types of NSCLC tumor histology (e.g., adenocarcinoma versus squamous cell cancers are treated similarly).
• Radiotherapy is typically provided either with curative intent (“definitive” radiotherapy) or palliative intent. Definitive radiotherapy involves higher doses, with a higher risk of side effects.

overview of various roles of radiotherapy for NSCLC

• Definitive (curative intent):
  • Definitive radiotherapy for medically inoperable early stage cancer (SABR). 📖
  • Definitive chemoradiation for locally advanced cancer (Stage III). 📖
• Palliative thoracic radiotherapy (Stage III-IV): 📖
• Oligometastatic disease:
  • Radiotherapy may be quasi-definitive (with utilization of stereotactic ablative radiotherapy).
  • Alternatively, in some cases a single 10-gray fraction may be sufficient for palliative purposes.
• Pre/postoperative neoadjuvant/adjuvant radiotherapy may be used for select Stage IIIa tumors.

relative contraindications to definitive radiotherapy 

• Prior radiotherapy in an overlapping field (tissue can tolerate only a fixed amount of radiation).
• Active autoimmune lung disease or idiopathic pulmonary fibrosis.
• Tracheoesophageal fistula.
• Tumor is so large that the radiation field would be >37% of the lung volume.
• Tumor is so large that the radiation field would involve >50% of the heart.
• Performance status of 3-4. (Fishman 2023)

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stereotactic ablative radiotherapy (SABR), aka stereotactic body radiation therapy (SBRT)

basics

• This is modeled after stereotactic radiosurgery (SRS) for brain lesions.
• The goal is to ablate all tissue within a small area (<5 cm lesion), using very few sessions of focused radiation. This is in contrast to conventional radiotherapy (wherein the goal is to damage cancer cells, without causing harm to normal tissue).
• SABR has been shown to extend survival, as compared to conventional radiotherapy. (34273294) 

indications

• (1) Treatment of primary cancer:
  • Patients with Stage I disease, or selected patients with node-negative stage II disease (e.g., T3N0).
  • Not a candidate for surgery (e.g., due to lung disease or other comorbidities).
  • Peripheral lesions are easier to target, with lower risk of harming vital organs.
• (2) Treatment of oligometastatic or oligoprogressive disease.

technique

• High dose per fraction (~7.5-20 Gray).
• Relatively few fractions (e.g., 1-8 fractions, delivered within <2 weeks).
• Within the target area, the amount of radiation deployed is high (e.g., ~60-100 Gray).
• Currently there is no evidence to support (neo)adjuvant systemic therapy (chemotherapy or immunotherapy) in combination with SABR.

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palliative radiotherapy for advanced stage NSCLC 

basics

• Palliative radiotherapy is generally utilized for Stage IV disease, or selected patients with stage III disease.
• Radiotherapy may be utilized concurrently with immunotherapy.
• A common regimen is ~30 Gray divided in ten 3-Gray fractions, although this may vary depending on the lesion. Lower dosing compared to definitive chemoradiation reduces the likelihood of severe toxicity.

response rate to radiotherapy for common thoracic symptoms

• Hemoptysis: ~80%; low or moderate severity hemoptysis is most likely to respond.
• Pain: ~70%
• SVC syndrome: ~60%
• Cough: ~50%
• Dyspnea: ~40%
• Weight loss/anorexia: ~30%
• Atelectasis: ~20%
• Vocal cord paralysis: ~5% (Fishman 2023)

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targeted therapy

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basics of targeted therapy

• Targeted therapy involves small-molecule inhibitors that suppress tumor growth by interfering with specific tumor proteins. These therapies are often well tolerated and initially effective, but tumor resistance inevitably develops over time. Targeted therapy is most often used for stage IV disease.
• Targeted therapy is useful for tumors with driver mutations, which result in the tumor being heavily dependent on a single pathway to drive proliferation. Driver mutations are mutually exclusive of one another, so a tumor will usually have only one driver mutation.
• Driver mutations are found among ~64% of genotyped non-small cell lung cancers. They are more likely to occur in adenocarcinoma, and among patients with little or no smoking history. (Murray 2022)

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EGFR mutations (epidermal growth factor receptor)

basics

• EGFR mutations are by far the most commonly encountered form of targeted therapy, occurring with a frequency of ~15%. (34273294) Factors associated with EGFR mutations include:
  • Female sex.
  • Lack of tobacco exposure.
  • Adenocarcinoma.
  • Asian ethnicity. (ERS handbook 3rd ed.)
• Targeted therapy for these patients is often superior to chemotherapy (with main side effects of rash or diarrhea).
• The combination of targeted therapy with chemotherapy may extend survival for some patients.

different EGFR mutations:

• EGFR exon 19 deletion, and exon 21 Leu858Arg mutation predict sensitivity to EGFR tyrosine kinase inhibitors. (34273294)
• EGFR exon 20 insertions result in resistance to most EGFR tyrosine kinase inhibitors. (34273294)
• EGFR T790M mutations associate with resistance to first-generation tyrosine kinase inhibitors, but this may be overcome with third-generation tyrosine kinase inhibitors. (ERS handbook 3rd ed.)

different EGFR tyrosine kinase inhibitors:

• First generation (erlotinib, gefitinib) bind reversibly to the tyrosine kinase.
• Second generation (afatinib, dacomitinib) bind irreversibly to tyrosine kinase.
• 🏆 Third generation (osimertinib) binds irreversibly with a broader spectrum of activity:
  • Patients who progress despite erlotinib therapy have developed a T790M mutation about half of the time. (34273294) These tumors remain sensitive to osimertinib.
  • Osimertinib has also demonstrated superiority to other EGFR tyrosine kinase inhibitors for treatment-naive EGFR-positive NSCLC. (34273294)
  • Osimertinib may be effective against brain metastases.
  • Currently, osimertinib is recommended as the front-line tyrosine kinase inhibitor for patients with EGFR mutations.
  • Unfortunately, almost all tumors eventually acquire mutations causing resistance.
  • Osimertinib-induced pneumonitis occurs in ~3% of patients. Most cases are not severe and may improve following discontinuation of osimertinib and therapy with steroid. (35680315) 

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ALK fusion gene (anaplastic lymphoma kinase)

• ALK-positive lung cancer:
  • ~4% of patients with NSCLC are positive for ALK gene rearrangements. This predicts response to ALK tyrosine kinase inhibitors.
  • Patients are often relatively young, with less tobacco exposure than those with other types of lung cancer.
  • ALK-positive lung cancer may have a high potential for metastatic spread (including a high rate of brain metastasis). (34295416)
• 1st Generation: Crizotinib is a first-generation ALK tyrosine kinase inhibitor. It has been shown to be superior to chemotherapy in first-line and second-line settings. (34273294) However, crizotinib has been superseded by subsequent generations of ALK inhibitors, so is no longer a preferred agent.
• 2nd Generation: Alectinib, brigatinib, ceritinib, and ensartinib are second-generation ALK tyrosine inhibitors that have improved CNS penetration. Alectinib, brigatinib, and ensartinib have been shown to be superior to crizotinib as first-line therapy. (34273294)
• 3rd Generation: lorlatinib is a third-generation ALK tyrosine kinase inhibitor that can penetrate the CNS and act broadly against ALK-resistance mutations (including ALK Gly1202Arg, which causes resistance to first- and second-generation inhibitors). (34273294)

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ROS1 translocation

• ROS1 translocation is found in ~1-2% of NSCLC.
• This predicts responsiveness to some ALK tyrosine kinase inhibitors (crizotinib and ceritinib).
• Entrectinib inhibits neurotrophic tropomyosin receptor tyrosine kinases (NTRKs), ROS1, and ALK. This has been shown to be effective against NSCLC with ROS1 translocation.
• Lorlatinib may be used for mutations resistant to other agents.

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BRAF Val600Glu (BRAFV600E)

• This is present in ~2% of NSCLC (including both squamous and nonsquamous types).
• This predicts responsiveness to the combination of BRAF and MEK (aka MAPK kinase) inhibitors, such as dabrafenib and trametinib.

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MET exon 14 skipping mutations

• MET exon 14 mutations may occur in either squamous or nonsquamous types of NSCLC.
• Capmatinib and tepotinib are MET inhibitors with intracranial activity.
• Crizotinib may also have activity.

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RET rearrangements

• These are found in 1-2% of lung adenocarcinomas.
• Various multikinase inhibitors may be effective (e.g., selpercatinib, pralsetinib, cabozantinib, vandetanib).

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NTRK (neurotrophic tyrosine receptor kinase)

• This is present in ~1% of NSCLC.
• Two NTRK inhibitors may be effective for these patients (larotrectinib and entrectinib).

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chemotherapy: general comments

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notes on commonly utilized chemotherapeutics

• Cisplatin:
  • Highly emetogenic.
  • Nephrotoxic (avoid in patients with reduced GFR; pre-hydration may reduce risk) and neurotoxic.
  • Contraindications may include: reduced renal function, baseline neuropathy, or hearing impairment.
• Carboplatin:
  • Alternative to cisplatin, with better tolerance.
  • Consider for patients who are at increased risk of complications from cisplatin, due to:
    • Older age or frailty (e.g., carboplatin is often preferred over cisplatin for palliative chemotherapy).
    • Renal insufficiency.
    • Increased risk of hearing loss.
  • The dose-limiting toxicity is usually thrombocytopenia. (Cecils 27th ed)
• Vinorelbine:
  • May cause neuropathy or neutropenia.
  • Available in pill form.
  • Supported by greatest volume of data for adjuvant chemotherapy following surgery (in combination with a platinum agent).
• Pemetrexed:
  • Effective in nonsquamous NSCLC (e.g., adenocarcinomas and large cell NSCLC).
  • Better tolerated than vinorelbine.
  • May be utilized for definitive chemoradiation, or palliative chemotherapy for nonsquamous NSCLC (in combination with a platinum agent).
• Paclitaxel, docetaxel:
  • Premedication with dexamethasone is required to prevent allergic reaction. (ERS handbook 3rd ed.)
  • These may be utilized for definitive chemoradiation (in combination with a platinum agent).
  • May cause neuropathy.
• Gemcitabine:
  • Avoid the combination of gemcitabine with radiotherapy, due to increased side effects. (ERS handbook 3rd ed.)
  • Gemcitabine may be utilized for palliative chemotherapy of squamous NSCLC (in combination with a platinum agent).

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surgery

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Complete surgical resection is ideal for adequately selected patients. Surgery typically has the greatest likelihood of achieving cure.

potentially resectable lesions

• Stage I-II disease (tumor location and involvement of hilar lymph nodes determine whether lobectomy or pneumonectomy is required).
• Some IIIa disease (e.g., T3N1). Some T4N0 (e.g., Pancoast tumors) may be resectable with favorable prolonged survival.
• Stage IIIa due to N2 disease is controversial, but could be considered in some situations, following neoadjuvant chemoradiotherapy plus immunotherapy.
  • Abain et al 2009 (19632716): 202 patients were initially treated with chemo-radiotherapy and then randomized to surgery versus additional radiotherapy. There was no difference in overall survival. However, not all of these patients are necessarily comparable. Microscopic metastasis in a single N2 node may carry a more favorable outcome with surgery. (ERS handbook 3rd ed.) Alternatively, the following features argue against surgery: bulky lymphadenopathy (>2 cm), multistation adenopathy, or patients requiring a pneumonectomy.
  • Neoadjuvant immunotherapy with nivolumab may improve event-free survival and pathological complete response rate. The benefit is greatest when PD-L1 expression is 1% or greater.
• Stage IV with a single metastatic lesion in the adrenal gland or brain may potentially be resected with curative intent (but only if there isn't involvement of the hilar or mediastinal lymph nodes). The evidence level is weak (mostly case series), with long-term survival of ~15% reported.

physiological candidacy for surgery

• Surgery requires a combination of resectable disease plus a patient who is physiologically fit enough to tolerate such a resection.
• Physiologic clearance for surgery is beyond the scope of this chapter, but the figure below provides a general concept regarding this.
• Predicted postoperative values for DLCO and FEV1 may be calculated by counting segments (#1 below) or by using quantitative perfusion imaging (#2 below)
  • Predicted Postoperative value = (Preoperative value)(19 total segments – number of segments resected)/19
  • Predicted Postoperative value = (Preoperative value)(100 – % perfusion to the region to be resected)/100

follow-up after surgery

• Adjuvant therapies:
  • (a) Adjuvant chemotherapy is discussed in the section below.
  • (b) Adjuvant radiotherapy is generally not utilized. However, adjuvant radiotherapy may be used in patients with positive surgical margins (indicative of residual tumor).
• Surveillance for relapse:
  • Risk of relapse is greatest within the first two years post-operatively. Relapse is most often due to distant metastases, rather than local recurrence.
  • Risk of relapse decreases and is nearly absent after five years. (ERS handbook 3rd ed.)

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adjuvant chemotherapy following surgery

summary

• Chemotherapy following surgical resection may be beneficial among patients with stage II, stage III, and possibly stage IB tumors >4 cm.
• 3-4 cycles of cisplatin-based doublet chemotherapy are utilized:
  • Platinum agent: More data with cisplatin, but carboplatin may be utilized if there is a contraindication to cisplatin.
  • 2nd agent: More data with vinorelbine, but pemetrexed is better tolerated.
• For patients with EGFR mutations, the addition of osimertinib improves outcomes. (32955177)
• Patients with performance status 0-1 benefit the most (whereas among patients with performance status of 2, chemotherapy may be detrimental; see the LACE meta-analysis below).
• The primary literature that this is based upon is below:

International Adjuvant Lung Cancer Trial (2004)(14736927)

• 1867 patients with stage I, II, or III NSCLC randomized to surgery +/- adjuvant chemotherapy (cisplatin plus etoposide, vinblastine, vinorelbine, or vindesine; about half of patients received cisplatin plus etoposide).
• Survival after five years was improved from 40.4% to 44.5%.

NCIC JBR 10 (2005)(15972865)

• 482 patients with IB or II NSCLC randomized to surgery +/- 4 cycles of chemotherapy with cisplatin plus vinorelbine.
• Chemotherapy caused an improvement in 5-year survival (69% vs. 54%).

ANITA (2006)(16945766)

• 840 patients with stage IB, II, or IIIA NSCLC randomized to surgery +/- 4 cycles of cisplatin and vinorelbine.
• Chemotherapy caused an 8.6% absolute improvement in survival after five years.
• Benefit seemed to be primarily among patients with Stage II and IIIA disease.

LACE meta-analysis (2008) (18506026) 📄

• Pooled analysis involving 4584 patients enrolled in RCTs investigating the utility of cisplatin-based adjuvant chemotherapy.
• Adjuvant therapy caused an overall 5.4% absolute improvement in 5-year survival.
• Outcomes were most favorable for carboplatin + vinorelbine.
• Patients with highest performance status benefitted the most.
• Chemotherapy was most beneficial among stage II or III cancer, whereas the benefit was unclear among patients with stage IB cancer.

CALBG 9633 (2008)(18809614) 📄

• 344 patients with IB cancer investigating the use of carboplatin-paclitaxel adjuvant therapy.
• No difference in survival was found. However, a subgroup of patients with tumors >4 cm did appear to obtain survival benefit.

TREAT (2013)(23161898) 📄

• 143 patients with stage IB, IIA, or IIB were randomized to cisplatin-pemetrexed versus cisplatin-vinorelbine.
• Pemetrexed was better tolerated.
• There was no difference in progression-free survival. However, the study is relatively underpowered, so it's not entirely clear that pemetrexed is equally as effective as vinorelbine.

ADAURA trial (2020) (32955177)

• Subjects: 682 patients with EGFR-positive, nonsquamous NSCLC, status post complete resection who were receiving adjuvant chemotherapy.
• Intervention: Randomized to placebo versus osimertinib daily for three years (an EGFR tyrosine kinase inhibitor).
• Outcomes from osimertinib:
  • Improved disease-free survival among patients with IB-IIIa disease.
  • Reduced the development of CNS metastases.

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definitive chemoradiation (+/- immunotherapy)

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Definitive chemoradiation (with curative intent) may be utilized for patients with stage III disease who cannot be resected and have a good performance status (ECOG 0-1). Simultaneous chemotherapy and radiotherapy may optimize efficacy (since chemotherapy may cause some cancer cells to be more radiosensitive). 

radiotherapy

• Typically ~60 Gray is administered in thirty 2-Gray fractions, over six weeks.
• An RCT showed that higher doses of radiation (74 Gray in 37 fractions) actually worsened survival. (25601342)

chemotherapy

• Usual therapy involves a combination of cisplatin/carboplatin plus a third-generation agent (e.g., pemetrexed, paclitaxel, or vinorelbine). (ERS handbook 3rd edition)

consolidation immunotherapy: PACIFIC trial (2017)

• Subjects:
  • 713 patients with stage III NSCLC, without disease progression following definitive chemoradiation.
  • Patients were enrolled only if they were doing well after chemoradiation (without any major pulmonary toxicity or early disease progression). (Fishman 2023)
• Intervention: Patients were randomized to durvalumab (anti-PD-L1 antibody) every two weeks for a year.
• Effects of durvalumab:
  • Increase in median progression-free survival from 6 months to 17 months.
  • Improved overall survival (hazard ratio for death 0.69, CI 0.55-0.86). (28885881, 31622733)

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management of stage IV NSCLC

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overview: systemic therapy for stage IV NSCLC

• If a driver mutation is present → then targeted therapy is preferred. ⚡️
• If a driver mutation is absent and PD-L1 expression is >50% → checkpoint therapy alone is preferred. ⚡️
• If a driver mutation is absent and PD-L1 expression is 1-50% → dual immunotherapy may be used, or chemotherapy plus immunotherapy.
• If a driver mutation is absent and PD-L1 expression is <1% → chemotherapy is the cornerstone of treatment (often with adjunctive immunotherapy).

oligometastatic stage IV NSCLC

• Oligometastatic disease is vaguely defined as a primary lesion with a small number of metastatic lesions (studies have included ≦3 or ≦5).
• In patients with fewer metastatic lesions (especially just one), there may be benefit in more aggressive local treatment of both the primary and metastatic lesion(s). Treatment may involve systemic therapies as well as local treatment for the primary lesion and the metastatic lesion (e.g., resection and/or local ablative radiotherapy). In this context, surgery hasn't been shown to be more effective than radiotherapy for local disease control. (de Moraes 2024)

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immunotherapy without chemotherapy for Stage IV NSCLC 

candidates for immunotherapy alone

• Not candidates for targeted therapy (most studies on immunotherapy alone have excluded patients with EGFR or ALK mutations, as these tumors may seem to be less responsive to immunotherapy).
• At least >1% expression of PD-L1: 
  • PD-L1 expression >50%: single agent immunotherapy may be used.
  • PD-L1 expression 1-50%: dual agent immunotherapy may be used.

evidentiary basis

• Several RCTs have demonstrated that a checkpoint inhibitor may lead to superior overall survival as compared to standard chemotherapy, for example:
• Keynote 042 and keynote 024 (pembrolizumab vs. chemotherapy, among patients with PD-L1 expression on >50% of tumor cells). (30955977) 
• Checkmate 227 (nivolumab+ipilimumab vs. nivolumab vs. chemotherapy). Among patients with PD-L1 expression >1%, the combination of nivolumab+ipilimumab was more effective than chemotherapy.
• IMpower 110 (atezolizumab vs. chemotherapy).

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chemotherapy for Stage IV NSCLC 

potential candidates for chemotherapy:

• Lack of more attractive options:
  • No mutations in EGFR or ALK genes.
  • Lower levels of PD-L1 staining, suggesting less responsiveness to checkpoint inhibitors.
• Lack of significant comorbidities.
• Good performance status (ECOG 0-2; patients should be ambulatory, capable of carrying out self-care, and up and about most of the day).
  • For patients who are ECOG-3 (capable of only limited self-care, confined to a bed or chair most of the day), chemotherapy is not recommended.

initial regimen: usually platinum doublet backbone

• Common choices might be:
  • Nonsquamous histology: Cisplatin/carboplatin plus pemetrexed
  • Squamous cell cancers: Cisplatin/carboplatin plus gemcitabine.
  • Carboplatin is often favored for palliation due to superior tolerability.
  • For example, 4-6 cycles of chemotherapy may extend median survival by ~1-4 months.
• Evidentiary basis:
  • Schiller et al. 2002: 1,207 patients randomized to cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, or carboplatin/paclitaxel. There was no impact on mortality, regardless of the regimen. (11784875)
  • Scagliotti GV et al. 2008: 1,725 patients randomized to cisplatin/pemetrexed or cisplatin/gemcitabine. There was no difference in overall survival. However, pemetrexed was superior to gemcitabine among patients with nonsquamous histology (and inferior to gemcitabine among patients with squamous histology). Pemetrexed caused fewer cytopenias. (18506025)
  • Treat JA et al. 2010: 1,135 patients were randomized to carboplatin-gemcitabine, carboplatin/paclitaxel, or gemcitabine/paclitaxel. There were no differences in outcomes. The gemcitabine/paclitaxel arm caused more hematologic toxicity, but lower rates of neurotoxicity or alopecia. (19833819)

initial regimen: addition of bevacizumab

• Bevacizumab is a monoclonal antibody that inhibits VEGF-R (vascular endothelial growth factor receptor).
• Bevacizumab may cause severe hemoptysis. Potential contraindications to bevacizumab may include: (ERS handbook 3rd ed.)
  • 🩸 Squamous cell cancer.
  • 🩸 Brain metastases.
  • 🩸 History of hemoptysis.
  • 🩸 Cavitary lung lesions.
  • 🩸 Concurrent anticoagulation.
• Bevacizumab may extend survival among patients with nonsquamous histology by ~2 months (when combined with combination chemotherapy as discussed above).
• Bevacizumab may have several unique side effects:
  • Hemoptysis.
  • Hypertension, proteinuria.
  • Neutropenia. (Cecils 27th ed)

initial regimen: addition of a checkpoint inhibitor

• Numerous RCTs have demonstrated improved endpoints when a checkpoint inhibitor is added to standard chemotherapy, for example:
  • Keynote 189: Pembrolizumab improved survival when added to carboplatin/cisplatin plus pemetrexed. Initial combination therapy was followed by maintenance therapy with either pemetrexed alone, or pemetrexed plus pembrolizumab.
  • Keynote 407: Pembrolizumab improved survival when added to carboplatin plus (nab) paclitaxel, among patients with squamous cell carcinoma.
  • IMpower 130: Atezolizumab improved survival when added to carboplatin plus (nab) paclitaxel.
  • IMpower 150: Atezolizumab improved survival when added to carboplatin/paclitaxel and bevacizumab.
• Improved outcomes occur regardless of tumor histology, or the level of PD-L1 expression.

maintenance therapy

• Maintenance therapy may be utilized with relatively well tolerated treatments (pemetrexed, immunotherapy, and/or bevacizumab).
• (1) Checkpoint inhibitors are generally continued as maintenance therapy, following completion of combination chemotherapy.
• (2) Pemetrexed and/or bevacizumab maintenance may be used for patients with nonsquamous tumors who achieve disease control with platinum-based chemotherapy and have good performance status (ECOG 0-1; ambulatory and able to carry out light work).

second-line options

• These treatments may be considered for patients with disease progression and good performance status (0-2). (Murray 2022) In some cases, combinations may be utilized (e.g., immunotherapy plus chemotherapy). 
• Chemotherapy:
  • Docetaxel +/- ramucirumab (a monoclonal antibody against vascular endothelial growth factor receptor 2) may be used for any histology. This may be useful for early or rapidly progressing tumors. (ERS handbook 3rd ed.)
  • Pemetrexed may be used for nonsquamous histology. Compared to docetaxel, pemetrexed has the advantage of similar efficacy with less toxicity. (Cecils 27th ed).
• Targeted therapy:
  • Afatinib (a tyrosine kinase inhibitor) may be used for squamous histology.
  • Erlotinib may be an option, especially for patients unable to tolerate chemotherapy.
• Immunotherapy:
  • May cause improved outcomes, as compared to docetaxel.
  • Immunotherapy is usually preferred for patients without early/rapid recurrence. (ERS handbook 3rd ed.)

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small cell lung cancer (SCLC)

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general

• SCLC is composed of small cells that have a very rapid turnover rate (unlike other lung tumors that are derived from epithelial tissue, SCLC is derived from neuroendocrine tissue).
• SCLC tends to spread early, limiting its ability to be surgically resected.

epidemiology

• SCLC accounts for 13% of lung cancer.
• SCLC is nearly always (98%) encountered in patients with a history of smoking. In the absence of a smoking history, this diagnosis should be questioned.
• Radon exposure is also a risk factor.

clinical attributes

• The original tumor usually presents with prominent and rapidly enlarging thoracic lymphadenopathy (without any identifiable primary lesion).
  • Superior vena cava syndrome is common.
  • Airway compression with atelectasis may occur.
  • Compression of the recurrent laryngeal nerve may cause hoarseness. (de Moraes 2024)
• Paraneoplastic syndromes are frequent because SCLC is derived from neuroendocrine tissue. These may result from hormone secretion by the tumor, or from immune activation against neural tissue antigens. Some examples include:
  • SIADH (due to ADH secretion).
  • Hypercalcemia due to the secretion of parathyroid hormone-related protein.
  • Cushing syndrome (due to secretion of adrenocorticotropic hormone).
  • Paraneoplastic neurologic syndromes, including:
    • LEMS (Lambert-Eaton myasthenic syndrome).
    • Limbic encephalitis. 📖
    • Cerebellar degeneration / cerebellitis. 📖
    • Subacute (peripheral) sensory neuropathy.
    • Optic neuropathy.
    • Autonomic neuropathy.
• Brain metastasis is especially common. Among patients who respond to initial induction chemotherapy, prophylactic whole-brain radiation may be used to reduce the risk of brain metastasis.

radiology

• The primary tumor is often in a central location. However, the primary tumor may be dwarfed by massive lymphadenopathy, which may be bilateral.
• Lymphadenopathy may compress various structures, for example:
  • Lobar collapse can occur.
  • Superior vena cava syndrome may occur.
• Cavitation is rare. If seen, this suggests an alternative diagnosis (e.g., squamous cell carcinoma). (Fishman 2023)
• (Very rarely, SCLC can present as a peripheral nodule.)

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staging for SCLC

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staging evaluation

• Noninvasive imaging is usually sufficient for staging, as most patients will require systemic therapy.
• Key tests include:
  • [1] Whole body PET scanning (this has supplanted bone scanning at most centers).
  • [2] Brain MRI (asymptomatic brain metastasis may be present in ~5% of patients).
  • (Bone marrow biopsy could be considered for patients with limited-stage disease and abnormal blood counts, but isolated metastasis to the bone marrow is overall unlikely.)

early-stage disease (“peripheral SCLC” – very rare)

• This refers to a peripheral tumor without mediastinal lymph node involvement.
• This is rarely seen, given the high tendency of SCLC for early dissemination.
• Treatment:
  • Surgery is controversial, given the high likelihood that some tumor cells have already disseminated elsewhere in the body. Surgery may be an option for some patients.
  • Even if surgery is performed, chemoradiation should still be pursued (given the high likelihood of residual disease).

limited-stage disease (~30% of patients)

• Limited-stage disease is defined as being contained within one hemithorax (including, at most, one hemithorax, the mediastinum, and ipsilateral supraclavicular lymph nodes). (Fishman 2023)
• Limited-stage disease is sufficiently confined so that it can be treated with radiotherapy. The treatment of limited-stage disease is typically a combination of chemotherapy plus radiation.

extensive disease (~70% of patients)

• Extensive disease is defined by extension beyond one hemithorax. This includes: (Fishman 2023)
  • Malignant pleural or pericardial effusion.
  • Contralateral hilar or supraclavicular lymph nodes.
  • Distant metastases.
• The initial treatment is chemotherapy alone.

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management of limited or extensive stage SCLC

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SCLC involves cells that are growing very rapidly. Unfortunately, this leads to early metastasis, so surgical resection is rarely possible. However, the rapid growth rate makes SCLC highly sensitive to chemotherapy and radiotherapy. A complete response to induction therapy is often achievable, which buys the patient time. Unfortunately, eventual relapse is the rule.

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induction therapy for SCLC

Chemotherapy (+/- radiotherapy) is often successful at initially inducing a cancer remission. 

[1/3] induction chemotherapy

• Standard therapy is 4-6 cycles of doublet chemotherapy with cisplatin/carboplatin plus etoposide over 4-5 months.
• Response rates are high.

[2/3] addition of checkpoint inhibitor to induction therapy 

• Adding anti-PD or anti-PD-L antibody to chemotherapy for extensive-stage SCLC improves overall survival. Studies have validated the use of atezolizumab (IMPOWER 133) or durvalumab (CASPIAN).
• Few cases of SCLC are PD-L1 positive. However, PD-L1 positivity of tumor cells doesn't appear to predict responsiveness to checkpoint inhibitors in the context of SCLC. (34273294)
• Checkpoint inhibitor therapy is generally continued as maintenance therapy until disease progression or intolerable toxicity. (Fishman 2023)

[3/3] role of radiation

• [1] Induction chemoradiation for limited-stage disease:
  • Combined chemoradiation improves the durability of cancer remission. The addition of radiotherapy may increase overall survival by ~5%.
  • 45 Gray is often used (e.g., twice daily fractions of 1.5 Gray, for three weeks).
• [2] Advanced-stage disease: radiation is not initially utilized.  If the tumor responds well to induction chemotherapy, radiotherapy may subsequently be considered.
• [3] Prophylactic cranial irradiation?
  • Patients with limited or extensive disease who achieve a complete response to front-line therapy may benefit from prophylactic cranial irradiation.
  • Whole brain irradiation may reduce the incidence of brain metastases by about 50%. It has also been shown to improve the absolute survival. However, a recent study showed that serial surveillance MRI without prophylactic cranial irradiation may result in similar outcomes. (28343976)

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relapsed SCLC

relapse is nearly inevitable

• Following relapse, the median survival historically has been ~3-4 months.
• Relapsed SCLC is usually refractory to chemotherapy.
• The prognosis depends on the time to relapse:
  • Relapse within <3 months implies platinum-resistant disease (worse prognosis).
  • Relapse after >3 months suggests platinum-sensitive disease.

chemotherapy for relapsed SCLC 

• Patients with platinum-sensitive disease may be rechallenged with the original chemotherapeutic regimen if possible (platinum doublet chemotherapy, as discussed above).
  • Response rates are ~1/3.
• Patients with platinum-resistant disease and satisfactory performance status may be offered second-line therapy. Unfortunately, response rates are low.
  • Options include single-agent topotecan or combination chemotherapy with cyclophosphamide, doxorubicin, and vincristine.
• (Immunotherapy: To date, checkpoint inhibitors have not been shown to be effective in combination with second-line chemotherapy.)

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questions & discussion

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