Lung Cancer: Diagnosis, Treatment Principles, and Screening

Jeffrey Kim; Hobart Lee; Brian W. Huang

JEFFREY KIM, MD, HOBART LEE, MD, AND BRIAN W. HUANG, MD

Am Fam Physician. 2022;105(5):487-494

Patient information: See related handout on lung cancer, written by the authors of this article.

Published online April 1, 2022.

Author disclosure: No relevant financial relationships.

Lung cancer is the second most common cancer in men and women in the United States; however, it remains the leading cause of cancer-related death in the United States and worldwide. The most common but nonspecific symptom of lung cancer is cough. Associated symptoms, including hemoptysis or shortness of breath, or systemic symptoms, including anorexia or weight loss, greatly increase the likelihood of having lung cancer. Referral to a multidisciplinary lung cancer team, imaging, and confirmation through sputum cytology, thoracentesis, fine-needle aspiration, or mediastinoscopy are recommended. If lung cancer is confirmed, treatment options vary based on staging, histology, immunotherapy biomarker testing, and patient health status. Treatments include surgical resection, immunotherapy, chemotherapy, and/or radiotherapy. Family physicians should focus on primary prevention of lung cancer by encouraging tobacco cessation and early recognition by screening at-risk individuals and following guidelines for pulmonary nodules. As of 2021, the U.S. Preventive Services Task Force recommends annual lung cancer screening using low-dose computed tomography starting at 50 years of age in patients with a 20 pack-year history.

Lung cancer remains the leading cause of cancer-related death in the United States and worldwide; in the United States, it is the second most common cancer among men and women.^1,2 The majority of lung cancers are divided into two histologic types: non–small cell lung cancer (NSCLC; 84%) and small cell lung cancer (SCLC; 13%), which helps guide treatment.³ Smoking is closely linked to 80% to 90% of lung cancer deaths, whereas radon exposure is a leading cause of nonsmoking-related lung cancer.⁴ Several guidelines address the management of lung cancer, with the goal of improving patient outcomes.⁵ In the United Kingdom, the National Institute for Health and Care Excellence has developed clinical pathways that were last updated in 2019, whereas in the United States, the most recent comprehensive lung cancer guideline from the American College of Chest Physicians was last updated in 2013, with more recent treatment recommendations from the National Comprehensive Cancer Network.^2,6–8

Clinical recommendation	Evidence rating	Comments
The initial evaluation for lung cancer begins with laboratory testing, including a complete blood count, serum chemistries, calcium levels, liver function tests, and chest radiography; CT of the chest with intravenous contrast media should be performed when there is a high level of suspicion, even if radiographic results are normal.^{2,9,10,13–15}	C	Practice guidelines, expert opinion, disease-oriented studies
Adults 50 to 80 years of age who have a 20 pack-year smoking history and currently smoke or have quit smoking within the past 15 years should undergo annual low-dose CT screening.^36,40,44	B	USPSTF and AAFP guidelines and limited evidence from one large, randomized controlled trial showing moderate benefit
Patients with lung cancer should be offered smoking cessation interventions.⁴⁵	B	Cochrane review that shows reduction in morbidity and mortality; no randomized controlled trials to identify specific smoking cessation interventions are recommended
Patients with lung cancer can improve symptoms with exercise training and nurse counseling.^46,47	B	Cochrane reviews, with studies limited by heterogeneity, small sample sizes, and high risk of bias

Recommendation	Sponsoring organization
Do not perform CT screening for lung cancer among patients at low risk of lung cancer.	American College of Chest Physicians/American Thoracic Society
Do not recommend screening for breast, colorectal, prostate, or lung cancers without considering life expectancy and the risks of testing, overdiagnosis, and overtreatment.	American Geriatrics Society
Do not perform CT surveillance for evaluation of indeterminate pulmonary nodules at more frequent intervals or for a longer period of time than recommended by established guidelines.	American College of Chest Physicians/American Thoracic Society

Clinical Presentation and Diagnosis

IN-OFFICE EVALUATION

When evaluating a patient for lung cancer, a detailed history and physical examination should be performed, including environmental and work exposures. Current smoking or history of smoking is the single most important risk factor for all types of lung cancer.^9,10 Concomitant chronic lung disease or exposure to radon or asbestos may increase the risk of lung cancer.¹⁰

Patients with lung cancer typically present with symptoms,¹¹ the most common of which is cough.^9,11 Hemoptysis in combination with weight loss, loss of appetite, or shortness of breath increases the likelihood of lung cancer.¹¹ Table 1 provides signs and symptoms of lung cancer due to local effects,¹² and Table 2 and Table 3 show, respectively, advanced disease–displaying symptoms of distant metastases and paraneoplastic syndromes associated with lung cancer.¹²

Sign/symptom of the primary tumor*	LR+	LR–
Digital clubbing	55.0	0.96
Hemoptysis	13.2	0.81
Weight loss	6.2	0.76
Loss of appetite	4.8	0.84
Dyspnea	3.6	0.52
Chest or rib pain	3.3	0.68
Fatigue	2.3	0.76
First visit for cough	2.2	0.50
Second visit for cough	3.2	0.66
Third visit for cough	4.2	0.77
Sign/symptom of intrathoracic spread	Clinical context

Decreased breath sounds and dyspnea	Malignant pleural effusion
Decreased heart sounds and enlarged cardiac silhouette	Malignant pericardial effusion
Dysphagia	Esophageal invasion
Elevated hemidiaphragm	Phrenic nerve paralysis
Facial swelling, plethora, and upper extremity edema	Superior vena cava syndrome
Hoarseness, weak cough	Recurrent laryngeal nerve palsy
Pleuritic chest pain	Chest wall invasion
Ptosis, miosis, facial anhidrosis	Horner syndrome (sympathetic chain compression)
Shoulder pain and muscle wasting along C8-T3 nerve root	Pancoast tumor (superior sulcus tumor)

Site	Sign or symptom	Frequency (%)
Any	Any sign or symptom	33
Liver	Weakness, weight loss, anorexia, hepatomegaly	Up to 60
Bone	Pain, fracture, elevated alkaline phosphatase	Up to 25
Lymphatics	Lymphadenopathy	15 to 20
Brain	Headaches, seizures, nausea and vomiting, mental status changes	Up to 10
Adrenals	Adrenal insufficiency	Rare
Skin	Subcutaneous nodules	Rare

Syndrome	Frequency (%)	Comments
Systemic (anorexia, cachexia, weight loss, fatigue, fever)	0 to 68	May be readily apparent and striking
Digital clubbing	29	More common with non–small cell lung cancer
Hypercalcemia	10 to 20	Ectopic production of parathyroid hormone–related peptide; may be life-threatening
Hyponatremia	1 to 5	Syndrome of inappropriate antidiuretic hormone or ectopic production of atrial natriuretic peptide
Paraneoplastic encephalitis	0.2	Mental status changes
Cushing syndrome	Rare	Ectopic production of adrenocorticotropic hormone
Hypertrophic osteoarthropathy	Rare	Triad of clubbing, arthralgias, and ossifying periostitis
Muscular weakness	Rare	Lambert-Eaton myasthenic syndrome

The initial evaluation for patients with a suspicion for lung cancer begins with laboratory testing, including a complete blood count, serum chemistries, calcium levels, and liver function tests, with chest radiography.^2,9 A normal chest radiograph alone should not be used to rule out lung cancer because just under 20% to 25% of normal chest radiographs may miss the disease.^13,14 Patients who have a high level of suspicion for lung cancer based on clinical assessment or initial chest radiography findings should receive computed tomography (CT) of the chest with intravenous contrast media, ideally to include the liver and adrenals.^2,15

PULMONARY NODULE FOLLOW-UP

Among patients presenting with incidental nodules found on radiographic imaging, follow-up for those older than 35 years is assessed based on features and risk categorization, as recommended by the Fleischner Society, updated in 2017 (Table 4).^16,17 New studies are emerging on the use of genomic classifiers and artificial intelligence to help facilitate clinical management of incidental nodules.^18,19 For patients meeting high-risk criteria and undergoing lung cancer screening, appropriate follow-up recommendations should be determined by the 2019 Lung-RADS guidelines²⁰ (eTable A).

Solid nodules*

Nodule type	Size			Comments

	< 6 mm (< 100 mm³)	6 to 8 mm (100 to 250 mm³)	> 8 mm (> 250 mm³)
Single
Low risk†	No routine follow-up	Follow-up CT at 6 to 12 months, then consider follow-up CT at 18 to 24 months	Consider PET/CT, tissue sampling, or follow-up CT at 3 months	Nodules < 6 mm do not require routine follow-up in low-risk patients (recommendation 1A)
High risk†	Optional follow-up CT at 12 months	Follow-up CT at 6 to 12 months and at 18 to 24 months	Consider PET/CT, tissue sampling, or follow-up CT at 3 months	Certain patients at risk with suspicious nodule morphology, upper lobe locations, or both may warrant 12-month follow-up (recommendation 1A)
Multiple
Low risk†	No routine follow-up	Follow-up CT at 3 to 6 months, then consider follow-up CT at 18 to 24 months	Follow-up CT at 3 to 6 months, then consider follow-up CT at 18 to 24 months	Use most suspicious nodule to guide management; follow-up intervals may vary according to size of nodule and risk (recommendation 2A)
High risk†	Optional follow-up CT at 12 months	Follow-up CT at 3 to 6 months and at 18 to 24 months	Follow-up CT at 3 to 6 months and at 18 to 24 months	Use most suspicious nodule to guide management; follow-up intervals may vary according to size of nodule and risk (recommendation 2A)

Category descriptor	Lung-RADS score	Findings	Management	Risk of malignancy	Estimated population prevalence
Incomplete	0	Prior chest CT examination(s) being located for comparison Part or all of lungs cannot be evaluated	Additional lung cancer screening CT images and/or comparison to prior chest CT examinations is needed	NA	1%
Negative: no nodules and definitely benign nodules	1	No lung nodules Nodule(s) with specific calcifications: complete, central, popcorn, concentric rings and fat-containing nodules	Continue annual screening with low-dose CT in 12 months	< 1%	90%
Benign appearance or behavior: nodules with a very low likelihood of becoming a clinically active cancer due to size or lack of growth	2	Perifissural nodule(s)* < 10 mm (524 mm³) Solid nodule(s) < 6 mm total diameter (< 113 mm³) New < 4 mm (< 34 mm³) Part-solid nodule(s) < 6 mm total diameter (< 113 mm³) on baseline screening Nonsolid nodule(s) (ground-glass nodules) < 30 mm (< 14,137 mm³) or ≥ 30 mm (≥ 14,137 mm³) and unchanged or slowly growing Category 3 or 4 nodules unchanged for ≥ 3 months	Continue annual screening with low-dose CT in 12 months	< 1%	90%
Probably benign finding(s): short-term follow-up suggested; includes nodules with a low likelihood of becoming a clinically active cancer	3	Solid nodule(s) ≥ 6 mm to < 8 mm (≥ 113 mm³ to < 268 mm³) at baseline or New 4 mm to < 6 mm (34 mm³ to < 113 mm³) Part-solid nodule(s) ≥ 6 mm total diameter (≥ 113 mm³) with solid component < 6 mm (< 113 mm³) or New < 6 mm total diameter (< 113 mm³) Nonsolid nodule(s) Ground-glass nodule ≥ 30 mm (≥ 14,137 mm³) on baseline CT or new	6-month low-dose CT	1% to 2%	5%
Suspicious: findings for which additional diagnostic testing is recommended	4A	Solid nodules ≥ 8 mm to < 15 mm (≥ 268 mm³ to < 1,767 mm³) at baseline or Growing < 8 mm (< 268 mm³) or New 6 mm to < 8 mm (113 mm³ to < 268 mm³) Part-solid nodules ≥ 6 mm (≥ 113 mm³) with solid component ≥ 6 mm to < 8 mm (113 mm³ to 268 mm³) or With new or growing < 4 mm (< 34 mm³) solid component Endobronchial nodule	3-month low-dose CT; PET/CT may be used when there is a ≥ 8 mm (≥ 268 mm³) solid component	5% to 15%	2%
Very suspicious: findings for which additional diagnostic testing and/or tissue sampling is recommended	4B	Solid nodule(s) ≥ 15 mm (≥ 1,767 mm³) or New or growing, and ≥ 8 mm (268 mm³) Part-solid nodule(s) with: A solid component ≥ 8 mm (≥ 268 mm³) or A new or growing ≥ 4 mm (≥ 34 mm³) solid component	Chest CT with or without contrast media, PET/CT, and/or tissue sampling depending on the probability of malignancy and comorbidities.† PET/CT may be used when there is a ≥ 8 mm (≥ 268 mm³) solid component.	> 15%	2%
	4X	Category 3 or 4 nodules with additional features or imaging findings that increase the suspicion of malignancy	For new large nodules that develop on an annual repeat-screening CT, a 1-month low-dose CT may be recommended to address potentially infectious or inflammatory conditions
Other: clinically significant or potentially clinically significant findings (non-lung cancer)	S	Modifier: may add on to category 0–4 coding	As appropriate to the specific finding	NA	10%

Diagnosis Confirmation

Patients with suspected lung cancer should be referred to a pulmonologist within a multidisciplinary thoracic oncology team to help guide workup.⁶ Confirmation of the diagnosis should be made by one or more of the following methods, with further testing if suspicion is high and findings are negative: sputum cytology, thoracentesis of pleural fluid, bronchoscopy (often with endobronchial ultrasonography and/or electromagnetic navigation with or without fine-needle aspiration), or mediastinoscopy depending on local availability and expertise.²¹

STAGING

Staging of lung cancer follows the eighth edition of the American Joint Committee on Cancer's staging manual.²² Staging revisions from the seventh edition were based on analysis of a database of 94,708 cases by the International Association for the Study of Lung Cancer Staging from 1999 to 2010.²³ The tumor, node, metastasis (TNM) classification describes the anatomic extent of the disease, is based on clinical and pathologic staging, and guides eventual treatment and prognosis²² (eTable B). Clinical TNM is based on history and physical examination findings, imaging, and staging procedures, and a pathologic TNM based on postsurgical histopathologic classification. The composite of these composes the TNM stage with associated prognostic stage groups I to IV²² (eTable C). TNM staging is recommended for NSCLC and SCLC for prognostic and tumor stratification purposes.²² For NSCLC, brain imaging should be performed in stage IIA patients with consideration for stage IB patients; patients with stages III to IV disease should have magnetic resonance imaging of the brain to assess for metastases even in the absence of clinical disease.^7,24 Patients with any stage of SCLC should have brain imaging performed, preferably using magnetic resonance imaging.⁸ In patients who may undergo curative treatment, positron emission tomography CT should be performed to assess intrathoracic lymph node involvement and guide subsequent sampling.^2,10

		Label
T (Primary)
T0	No primary tumor
Tis	Carcinoma in situ (squamous or adenocarcinoma)	Tis
T1	Tumor ≤ 3 cm
T1a(mi)	Minimally invasive adenocarcinoma	T1a (mi)
T1a	Superficial spreading tumor in central airways*	T1a SS
T1a	Tumor ≤ 1 cm	T1a ≤ 1
T1b	Tumor > 1 cm but ≤ 2 cm	T1b > 1–2
T1c	Tumor > 2 cm but ≤ 3 cm	T1c > 2–3
T2	Tumor > 3 cm but ≤ 5 cm or Tumor involving visceral pleura, main bronchus (not carina), or atelectasis to hilum†	T2 Visc Pl T2 Centr
T2a	Tumor > 3 cm but ≤ 4 cm	T2a > 3–4
T2b	Tumor > 4 cm but ≤ 5 cm	T2b > 4–5
T3	Tumor > 5 cm but ≤ 7 cm or Tumor invading chest wall, pericardium, phrenic nerve or Separate tumor nodule(s) in the same lobe	T3 > 5–7 T3 Inv T3 Satell
T4	Tumor > 7 cm or Tumor invading mediastinum, diaphragm, heart, great vessels, recurrent laryngeal nerve, carina, trachea, esophagus, spine or Tumor nodule(s) in a different ipsilateral lobe	T4 > 7 T4 Inv T4 Ipsi Nod
N (Regional lymph nodes)
N0	No regional node metastasis
N1	Metastasis in ipsilateral pulmonary or hilar nodes
N2	Metastasis in ipsilateral mediastinal/subcarinal nodes
N3	Metastasis in contralateral, mediastinal/hilar, or supraclavicular nodes
M (Distant metastasis)
M0	No distant metastasis	M1a Pl Dissem
M1a	Malignant pleural/pericardial effusion‡ or pleural/pericardial nodules or Separate tumor nodule(s) in a contralateral lobe	M1a Contr Nod
M1b	Single extrathoracic metastasis	M1b Single
M1c	Multiple extrathoracic metastases (1 or > 1 organ)	M1c Multi
TX, NX	T or N status not able to be assessed	NA

T/M	Label	N0	N1	N2	N3
T1	T1a ≤ 1	IA1	IIB	IIIA	IIIB
	T1b > 1–2	IA2	IIB	IIIA	IIIB
	T1c > 2–3	IA3	IIB	IIIA	IIIB
T2	T2 Centr, Visc Pl	IB	IIB	IIIA	IIIB
	T2a > 3–4	IB	IIB	IIIA	IIIB
	T2b > 4–5	IIA	IIB	IIIA	IIIB
T3	T3 > 5–7	IIB	IIIA	IIIB	IIIC
	T3 Inv	IIB	IIIA	IIIB	IIIC
	T3 Satell	IIB	IIIA	IIIB	IIIC
T4	T4 > 7	IIIA	IIIA	IIIB	IIIC
	T4 Inv	IIIA	IIIA	IIIB	IIIC
	T4 Ipsi Nod	IIIA	IIIA	IIIB	IIIC
M1	M1a Contr Nod	IVA	IVA	IVA	IVA
	M1a Pl Dissem	IVA	IVA	IVA	IVA
	M1b Single	IVA	IVA	IVA	IVA
	M1c Multi	IVB	IVB	IVB	IVB

Treatment

NON–SMALL CELL LUNG CANCER

The treatment of NSCLC varies based on staging, nonsquamous (usually adenocarcinoma) vs. squamous histology, and genetic and immunotherapy biomarker testing. Treatment options presented here provide an overview; however, specific regimens will vary based on the availability of treatment options and clinical experience of the multidisciplinary treatment team. Patients with advanced disease should be offered early palliative care.⁷

Patients with stages I to II NSCLC are usually offered a combination of three treatments: surgery, which can include complete resection of the tumor (usually stages I and II), and mediastinal lymph node dissection or lymph node sampling; radiotherapy; and adjuvant platinum-based chemotherapy.²⁵ Select patients who have stage III NSCLC but do not have disease progression after chemotherapy may benefit from immunotherapy.^7,26 Video-assisted thoracic surgery has lower mortality and hospital length of stay compared with open thoracotomy.²⁷ Nonsurgical candidates can be offered radiotherapy and platinum-based chemotherapy.²⁸ For patients with stage IV disease, palliative care and immunotherapy with or without platinum-based chemotherapy are recommended.⁷ In patients with fewer than three brain metastases, stereotactic radiotherapy or surgery with stereotactic radiotherapy is recommended.²⁹ With more than three brain metastases, whole brain radiation is recommended, although it may not improve neurocognitive symptoms or overall survival.^28,29 Radiotherapy and bisphosphonates are recommended for bone metastases to reduce pain and risk of skeletal fractures.^28,29

All patients who have NSCLC with nonsquamous NSCLC, mixed histology, or small-volume biopsies should be offered genetic and immunotherapy testing (e.g., broad-based, next-generation sequencing).⁷ Common driver mutations, preferred treatment options, and common adverse effects are listed in eTable D. Genetic testing can predict overall prognosis and responsiveness to targeted therapies; however, U.S. Food and Drug Administration–approved therapies depend on histologic subtype, disease progression, and timing with first-line systemic chemo-therapy.⁷ Standard first-line therapy for advanced NSCLC is immunotherapy with or without chemotherapy, based on PD-L1 (programmed death-ligand 1) status of expression on tumor cells.⁷

Genetic mutation	National Comprehensive Cancer Network preferred therapy	Common adverse effects (> 20%)
Anaplastic lymphoma kinase	Alectinib (Alecensa), brigatinib (Alunbrig), or lorlatinib (Lorbrena)	Anemia, arthralgia, constipation, cough, diarrhea, edema, fatigue, headache, mood effects, myalgia, nausea, weight gain
BRAF V600E	Dabrafenib (Tafinlar) plus trametinib (Mekinist)	Chills, cough, decreased appetite, diarrhea, dry skin, dyspnea, edema, fatigue, hemorrhage, nausea, pyrexia, rash, vomiting
Epidermal growth factor receptor	Osimertinib (Tagrisso)	Anemia, cough, diarrhea, dry skin, fatigue, leukopenia, lymphopenia, musculoskeletal pain, nail toxicity, neutropenia, rash, stomatitis, thrombocytopenia
MET ex 14 skipping	Capmatinib (Tabrecta) or tepotinib (Tepmetko)	Decreased appetite, diarrhea, dyspnea, fatigue, musculoskeletal pain, nausea, peripheral edema, vomiting
NTRK gene fusion	Larotrectinib (Vitrakvi) or entrectinib	Arthralgia, cognitive impairment, constipation, cough, diarrhea, dizziness, dysesthesia, dysgeusia, dyspnea, edema, fatigue, increased AST/ALT, myalgia, nausea, pyrexia, vision disorders, vomiting, weight gain
PD-L1/ PD-1	Pembrolizumab (Keytruda)	Abdominal pain, constipation, cough, decreased appetite, diarrhea, dyspnea, fatigue, musculoskeletal pain, nausea, pruritus, pyrexia, rash
	Atezolizumab (Tecentriq)	Cough, decreased appetite, dyspnea, fatigue/asthenia, nausea
	Durvalumab (Imfinzi)	Cough, dyspnea, fatigue, pneumonitis/radiation pneumonitis, rash, upper respiratory tract infections
RET	Selpercatinib (Retevmo) or pralsetinib (Gavreto)	Constipation, decreased albumin, decreased calcium, decreased leukocytes, decreased lymphocytes, decreased platelets, decreased sodium, diarrhea, dry mouth, edema, fatigue, hypertension, increased alkaline phosphatase, increased AST/ALT, increased creatinine, increased glucose, increased total cholesterol, musculoskeletal pain, rash
ROS1	Entrectinib (Rozlytrek) or crizotinib (Xalkori)	Arthralgia, cognitive impairment, constipation, cough, decreased appetite, diarrhea, dizziness, dysesthesia, dysgeusia, dyspnea, edema, fatigue, increased AST/ALT, myalgia, nausea, neuropathy, pyrexia, upper respiratory infection, vision disorders, vomiting, weight gain

PD-L1 expression (listed as a percentage between 0 and 100) of 50% or more can change the recommended immunotherapy regimen^7,29,30 (eTable E).

Non–small cell lung cancer first-line systemic therapy

Genetic mutation	Type	First-line therapy	Response or stable disease*
PD-L1 ≥ 50%	Nonsquamous cell	Pembrolizumab (Keytruda)	Pembrolizumab
		Carboplatin (Paraplatin) or cisplatin plus Pemetrexed (Alimta) plus Pembrolizumab	Pembrolizumab plus Pemetrexed
		Atezolizumab (Tecentriq)	Atezolizumab plus Bevacizumab (Avastin)
		Cemiplimab (Libtayo)	Atezolizumab
			Nivolumab (Opdivo) plus Ipilimumab (Yervoy)
			Cemiplimab
	Squamous cell	Pembrolizumab	Pembrolizumab
		Carboplatin plus Paclitaxel or albumin-bound paclitaxel (Abraxane) plus Pembrolizumab	Atezolizumab
		Atezolizumab	Nivolumab plus Ipilimumab
		Cemiplimab	Cemiplimab
PD-L1 ≥ 1% to < 50%	Nonsquamous cell	Carboplatin or cisplatin plus Pemetrexed plus Pembrolizumab	Pembrolizumab
			Pembrolizumab plus Pemetrexed
			Atezolizumab plus Bevacizumab
			Atezolizumab
			Nivolumab plus Ipilimumab
	Squamous cell	Carboplatin plus Paclitaxel or albumin-bound paclitaxel plus Pembrolizumab	Pembrolizumab
	Squamous cell		Nivolumab plus Ipilimumab
Small cell lung cancer first-line systemic therapy

Stage	First-line therapy (4 cycles)		Subsequent systemic therapy†

Limited stage	Cisplatin and etoposide (Etopophos)		Topotecan (Hycamtin) Lurbinectedin (Zepzelca) Enroll in clinical trial
Extensive stage	Carboplatin and etoposide and atezolizumab, followed by maintenance atezolizumab Carboplatin and etoposide and durvalumab (Imfinzi), followed by maintenance durvalumab Cisplatin and etoposide and durvalumab, followed by maintenance durvalumab	-	Topotecan Lurbinectedin Enroll in clinical trial

In 2017, five-year survival for localized NSCLC was 59%, with only 5.8% for five-year survival in patients with distant metastases; however, there have been reductions in mortality since 2013 likely due to a decrease in incidence and advancements in therapies, as described previously ³¹ (Table 5²²).

SMALL CELL LUNG CANCER

For patients with limited-stage SCLC, the standard of care is etoposide (Etopophos) plus cisplatin chemotherapy and concurrent thoracic radiotherapy, with surgical resection offered in select patients.^8,32 Patients with significant comorbidities, including chronic kidney disease, may be offered an alternative carboplatin (Paraplatin)–based chemotherapy regimen with similar effectiveness.³² For patients with extensive-stage SCLC, four to six cycles of one of several combination chemotherapy/immunotherapy regimens should be offered with maintenance immunotherapy.⁸ Consolidative thoracic radiation may be considered for select patients with residual intrathoracic disease who have responded to systemic chemotherapy.⁸ In patients with limited-stage SCLC, prophylactic cranial irradiation for brain metastases reduces mortality.³³ Localized palliative radiation for nonpulmonary sites, including whole brain radiotherapy for brain metastases, should be offered.²⁸ Patients with relapse after initial therapy have overall poor prognosis; however, several second-line systemic therapy options are available. ^8,34 Prognosis remains poor, with only 20% to 25% five-year survival for limited-stage SCLC and less than 10% two-year survival for extensive-stage SCLC³⁵ (Table 5²²).

Screening

As of 2021, the U.S. Preventive Services Task Force (USPSTF) has recommended annual low-dose CT screening in adults 50 to 80 years of age who have a 20 pack-year smoking history and currently smoke or have quit smoking within the past 15 years.³⁶ This replaces the 2013 recommendation of annual CT screenings for patients 55 to 80 years of age with at least a 30 pack-year history.³⁷ The criteria for discontinuing screening are unchanged, including patients who have quit smoking for more than 15 years, have limited life expectancies (less than 10 years), or are not willing to undergo curative lung surgery.³⁶

The updated recommendation is based on two major randomized controlled trials, the National Lung Screening Trial and the Dutch–Belgian lung-cancer screening trial (Nederlands–Leuvens Longkanker Screenings Onderzoek).^38,39 Both of these trials found reductions in lung cancer mortality, with a number needed to screen to prevent one lung cancer death of 323 over 6.5 years of follow-up and 130 over 10 years of follow-up, respectively.^38–40 Through systematic review of these trials and modeling studies from the Cancer Intervention and Surveillance Modeling Network, the USPSTF updated its criteria for screening.³⁶ Earlier screening recommendations are based on studies that suggest this may help address screening disparities for certain populations, including women and Black and Hispanic people.^41,42 Compared with the previous USPSTF 2013 guideline, Cancer Intervention and Surveillance Modeling Network data suggest that earlier screenings would be associated with an increase in the reduction of lung cancer mortality, from a 9.8% reduction to 12.1% to 14.4%, and life-years gained, from 4,882 life-years to 6,018 to 7,596 per 100,000.^37,43 The American Academy of Family Physicians supports the USPSTF's grade B recommendation of lung cancer screening in adults at increased risk; however, the harms of annual CT screenings are still not well documented, and further research is needed.⁴⁴ Research gaps include evaluating potential harms associated with increased radiation exposure, identifying better technology to differentiate benign and malignant lung nodules to avoid overdiagnosis, and addressing the cost and availability of increased screening in economically disadvantaged populations.⁴⁴

Smoking Cessation and Counseling

Smoking cessation reduces morbidity and mortality in patients with lung cancer; however, no randomized controlled trials have compared specific cessation interventions in this population.^29,45 Exercise training may improve exercise capacity and quality of life.⁴⁶ Nursing interventions can help patients with dyspnea, and a range of psychological interventions may improve coping skills and quality of life.⁴⁷

Although all actively smoking patients should be offered cessation support, lung cancer screening for eligible patients coupled with cessation support may be associated with higher quitting rates.⁴⁸ This combination is believed to serve as a teachable moment during a time when patients are the most receptive to quitting advice. Cessation assistance in combination with CT screening has been associated with a reduction in lung cancer–specific mortality and the potential to improve the cost-effectiveness ratio of screening.^49,50 Patients who quit smoking have been shown to reduce their risk of lung cancer by 39.1% after five years.⁵¹ Patients should also be counseled that quitting smoking will reduce their risk of all second cancers by 3.5 times.⁵²

This article updates previous articles on this topic by Latimer and Mott^¹² and Collins, et al.^⁵³

Data Sources: A PubMed search was completed in Clinical Queries using the key terms lung cancer, diagnosis, treatment, and screening. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. The Agency for Healthcare Research and Quality Effective Healthcare Reports, the U.S. Preventive Services Task Force, the Cochrane Database of Systematic Reviews, DynaMed, Essential Evidence Plus, the National Institute for Health and Care Excellence, and the National Comprehensive Cancer Network were also searched. Search dates: April and May 2021, and January 28, 2022.

The authors thank Hamid Mirshahidi, MD, associate professor of medicine, hematology and oncology, and Laren Tan, MD, associate professor of medicine, pulmonary and critical care, Loma Linda University School of Medicine, for thoughtful advice and review of the manuscript.

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