> Table of Contents > Lung, Primary Malignancies
Lung, Primary Malignancies
Maryann R. Cooper, PharmD, BCOP
Gerald Gehr, MD
image BASICS
DESCRIPTION
  • Lung cancers (primary) are the leading cause of cancer-related death in the United States (estimated 159,260 deaths in 2015, 27% of all cancer-related deaths).
  • Divided into two broad categories
    • Non-small cell lung cancer (NSCLC) (>85% of all lung cancers)
      • Adenocarcinoma (˜40% of NSCLC): Most common type in the United States, most common type in nonsmokers, metastasizes earlier than squamous cell, poor prognosis; bronchoalveolar, a subtype of adenocarcinoma has better prognosis.
      • Squamous cell carcinoma (<25% of NSCLC): dose-related effect with smoking; slower growing than adenocarcinoma
      • Large cell (˜10% of NSCLC): prognosis similar to adenocarcinoma
    • Small cell lung cancer (SCLC) (16% of all lung cancers): centrally located, early metastases, aggressive
  • Other: mesothelioma, carcinoid tumor, and sarcoma
  • Staging
    • NSCLC: staged from 0 to IV based on: primary tumor (T), lymph node status (N), and presence of metastasis (M)
    • SCLC: staged based on disease location: limited to ipsilateral hemithorax (stages I-IIIB); extensive if metastatic beyond hemithorax (stages IIIB and IV)
  • Tumor locations: upper: 60%; lower: 30%; middle: 5%; overlapping and main stem: 5%
  • May spread by local extension to involve chest wall, diaphragm, pulmonary vessels, vena cava, phrenic nerve, esophagus, or pericardium
  • Most commonly metastasize to lymph nodes (pulmonary, mediastinal), then liver, adrenal, bone (osteolytic), kidney, brain
EPIDEMIOLOGY
Incidence
  • Estimated 224,210 new cases in the United States in 2015
  • Predominant age: >40 years; peak at 70 years
  • Predominant sex: male > female
Prevalence
  • Most common cancer worldwide
  • Lifetime probability: men: 1 in 13; women: 1 in 16
ETIOLOGY AND PATHOPHYSIOLOGY
Multifactorial; see “Risk Factors.”
Genetics
NSCLC
  • Oncogenes: Ras family (H-ras, K-ras, N-ras)
  • Tumor suppressor genes: retinoblastoma, p53
RISK FACTORS
  • Smoking (relative risk [RR] 10 to 30)
  • Secondhand smoke exposure
  • Radon
  • Environmental and occupational exposures
    • Asbestos exposure (synergistic increase in risk for smokers)
    • Air pollution
    • Ionizing radiation
    • Mutagenic gases (halogen ethers, mustard gas, aromatic hydrocarbons)
    • Metals (inorganic arsenic, chromium, nickel)
  • Lung scarring from tuberculosis
  • Radiation therapy to the breast or chest
GENERAL PREVENTION
  • Smoking cessation and prevention programs
  • Screening recommended by USPSTF but remains controversial; the risks of screening (e.g., radiation, biopsy) may offset the benefit (1)[A].
  • Annual screening with low-dose computed tomography in adults ages 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years
  • Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.
  • Prevention via aggressive smoking cessation counseling and therapy; a 20-30% risk reduction occurs within 5 years of cessation.
  • Avoid supplemental &bgr;-carotene and vitamin E in smokers.
  • Avoid hormone replacement therapy in postmenopausal smokers or former smokers (increased risk of death from NSCLC).
COMMONLY ASSOCIATED CONDITIONS
  • Paraneoplastic syndromes: hypertrophic pulmonary osteoarthropathy, Lambert-Eaton syndrome, Cushing syndrome, hypercalcemia from ectopic parathyroid-releasing hormone, syndrome of inappropriate antidiuretic hormone (SIADH)
  • Hypercoagulable state
  • Pancoast syndrome
  • Superior vena cava syndrome
  • Pleural effusion
  • Chronic obstructive pulmonary disease (COPD), other sequelae of cigarette smoking
image DIAGNOSIS
PHYSICAL EXAM
  • General: pain, performance status, weight loss
  • Head, eye, ear, nose, throat (HEENT): Horner syndrome, dysphonia, stridor, scleral icterus
  • Neck: supraclavicular/cervical lymph nodes, mass
  • Lungs: effusion, wheezing, airway obstruction, pleural effusion
  • Abdomen/groin: hepatomegaly or lymphadenopathy
  • Extremities: signs of hypertrophic pulmonary osteoarthropathy, deep venous thrombosis (DVT)
  • Neurologic: Rule out cognitive and focal motor defects.
DIFFERENTIAL DIAGNOSIS
  • COPD (may coexist)
  • Granulomatous (tuberculosis, sarcoidosis)
  • Cardiomyopathy
  • Congestive heart failure (CHF)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • CBC
  • BUN, serum creatinine
  • Liver function tests (LFTs), lactate dehydrogenase (LDH)
  • Electrolytes
    • Hypercalcemia (Paraneoplastic syndrome)
    • Hyponatremia (SIADH)
  • Sputum cytology
  • Chest x-ray (CXR) (compare with old films)
    • Nodule or mass, especially if calcified
    • Persistent infiltrate
    • Atelectasis
    • Mediastinal widening
    • Hilar enlargement
    • Pleural effusion
  • CT scan of chest (with IV contrast material)
    • Nodule or mass (central or peripheral)
    • Lymphadenopathy
  • Evaluation for metastatic disease
    • Brain MRI: Lesions may be necrotic, bleeding.
    • CT abdomen: hepatic, adrenal, renal masses
  • Positron emission tomography (PET) scan: to evaluate metastasis
  • Bone scan: advanced disease or bone pain
Follow-Up Tests & Special Considerations
CBC, BUN, serum creatinine, LFTs prior to each cycle of chemotherapy
Diagnostic Procedures/Other
  • Biopsy with pathology review
  • In patients with advanced NSCLC, determination of epidermal growth factor receptor (EGFR)-activating mutations, KRAS/NRAS mutations, and ALK gene rearrangements in patients with nonsquamous or mixed squamous histology
  • Pulmonary function tests
  • Enlarged mediastinal lymph nodes necessitate staging by mediastinoscopy, video-assisted thoracoscopy, or fine needle aspiration.
  • Transbronchial biopsy (Wang needle)
  • Bronchoscopy for surgical planning
  • Bone marrow aspirate (small cell)
  • Cervical mediastinoscopy (the upper, middle peritracheal, and subcarinal lymph nodes)
  • Anterior mediastinotomy (the posterior mediastinum and peritracheal, subazygous, hilar, and aortopulmonary window nodal regions)
  • Video-assisted thoracoscopy (associated pleural disease and suspected mediastinal nodal spread)
P.617

Test Interpretation
Pathologic changes from smoking are progressive: basal cell proliferation, development of atypical nuclei, stratification, metaplasia of squamous cells, carcinoma in situ, and then invasive disease.
image TREATMENT
GENERAL MEASURES
  • NSCLC
    • Stage I, stage II, and selected stage III tumors are surgically resectable. Neoadjuvant or adjuvant therapy is recommended for many patients with high risk IB, II, and III NSCLC. Patients with resectable disease who are not surgical candidates may receive curative radiation therapy.
    • Patients with unresectable or N2, N3 disease are treated with concurrent chemoradiation. Selected patients with T3 or N2 disease can be treated effectively with surgical resection and either preor postoperative chemotherapy or chemoradiation therapy.
    • Patients with distant metastases (M1) can be treated with radiation therapy or chemotherapy for palliation or best supportive care alone.
  • SCLC
    • Limited stage: concurrent chemoradiation
    • Extensive stage: combination chemotherapy
    • Consider prophylactic cranial irradiation (PCI) in patients achieving a complete or partial response (2)[A].
  • Quality-of-life assessments: Karnofsky performance scale (KPS), Eastern Cooperative Oncology Group (ECOG)
  • Discussions with patient and family about end-of-life care
MEDICATION
  • Chemotherapy is the mainstay of treatment.
  • Adjuvant chemotherapy following surgery improves survival in patients with fully resected stage II-III NSCLC.
  • Palliative measures: analgesics
  • Dyspnea: oxygen, morphine
First Line
  • NSCLC
    • Stages II-III: neoadjuvant or adjuvant chemotherapy (3,4)[A]
      • Cisplatin-based doublets (combination with paclitaxel, etoposide, vinorelbine, docetaxel, gemcitabine)
      • Carboplatin alternative for patients unlikely to tolerate cisplatin
      • Cisplatin plus pemetrexed (nonsquamous cell)
    • Unresectable stage IIA, IIIB
      • Concurrent chemoradiation
        • Cisplatin plus etoposide, vinblastine, or pemetrexed (nonsquamous cell) plus concurrent radiation
        • Carboplatin plus pemetrexed (nonsquamous cell) plus concurrent radiation
  • Stage IV
    • No chemotherapy regimen can be recommended for routine use.
    • Cisplatin or carboplatin-based doublets (5)[A]
    • +/− bevacizumab (nonsquamous cell)
    • Erlotinib or afatinib for patients with EGFR mutations
    • Crizotinib for patients with EML4-ALK translocations
      • Ceritinib for patients that fail or are intolerant to crizotinib
    • Maintenance therapy after 4 to 6 cycles in patients achieving a response or stable disease
      • Continuation of bevacizumab, pemetrexed (nonsquamous cell), gemcitabine, erlotinib, or crizotinib or switch to pemetrexed (nonsquamous cell), erlotinib (EGFR mutations), docetaxel or observation
  • SCLC
    • Cisplatin or carboplatin plus etoposide
Second Line
  • NSCLC
    • Cisplatin-based doublets +/− bevacizumab (nonsquamous cell) if not previously used
    • Docetaxel, pemetrexed (nonsquamous cell), erlotinib, gemcitabine, ramucirumab plus docetaxel, or nivolimab (squamous cell)
  • SCLC
    • Topotecan or CAV (cyclophosphamide, doxorubicin, vincristine), gemcitabine, docetaxel, paclitaxel
ADDITIONAL THERAPIES
  • Smoking cessation counseling
  • Consider IV bisphosphonates or denosumab in patients with bone metastases to reduce skeletalrelated events.
SURGERY/OTHER PROCEDURES
  • Resection for NSCLC, for stages I, II, and IIIa, if medically fit to undergo surgery
  • Resection of isolated, distant metastases has been achieved and may improve survival.
  • Resection involves lobectomy in 71%, wedge in 16%, and complete pneumonectomy in 18%.
  • Resection should be accompanied by lymph node dissection for pathologic staging.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Depends on clinical history; in general, postoperative visits every 3 to 6 months in the year after surgery with physical exam and CXR
  • Follow-up CT scans, as indicated
PATIENT EDUCATION
  • http://www.cancer.gov/about-cancer
  • http://smokefree.gov/
PROGNOSIS
  • For combined, all types and stages, 5-year survival rate is 16% (NSCLC: 17%; SCLC 6%).
  • NSCLC
    • Localized disease (stages I and II): 49%
    • Regional disease: 16%
    • Distant metastatic disease: 2%
  • SCLC
    • Without treatment: median survival from diagnosis of only 2 to 4 months
    • Limited-stage disease: median survival of 16 to 24 months; 5-year survival rate: 14%
    • Extensive-stage disease: median survival of 6 to 12 months; long-term disease-free survival is rare.
REFERENCES
1. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409.
2. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive smallcell lung cancer. N Engl J Med. 2007;357(7): 664-672.
3. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559.
4. Gilligan D, Nicolson M, Smith I, et al. Preoperative chemotherapy in patients with resectable nonsmall cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet. 2007;369(9577):1929-1937.
5. Delbaldo C, Michiels S, Rolland E, et al. Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease. Cochrane Database Syst Rev. 2007;(4):CD004569.
Additional Reading
&NA;
  • Collins LG, Haines C, Perkel R, et al. Lung cancer: diagnosis and management. Am Fam Physician. 2007;75(1):56-63.
  • Detterbeck FC, Lewis SZ, Diekemper R, et al. Executive summary: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(Suppl 5):7S-37S.
  • National Cancer Institute. General information about non-small cell lung cancer (NSCLC). http://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq#section/_4
  • National Cancer Institute. Small cell lung cancer treatment—for health professional (PDQ). http://www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq#section/_1CODES
Codes
&NA;
ICD10
  • C34.90 Malignant neoplasm of unsp part of unsp bronchus or lung
  • C34.10 Malignant neoplasm of upper lobe, unsp bronchus or lung
  • C34.30 Malignant neoplasm of lower lobe, unsp bronchus or lung
Clinical Pearls
&NA;
  • Prognosis and treatment of lung cancer differs greatly between small cell- and non-small cell histologies.
  • Adjuvant cisplatin-based chemotherapy improves survival in patients with completely resected stage II-III NSCLC.
  • Chemotherapy, with or without radiation, can be offered to patients with advanced NSCLC or SCLC.
  • There is little role for surgery in the treatment of SCLC.