Neha Vapiwala, MD and Charles B. Simone, II, MSIV
Abramson Cancer Center of the University of Pennsylvania
Last Modified: March 29, 2006
Lung cancer is the second most common malignancy in males and females, surpassed in incidence only by prostate and breast cancer, respectively. Moreover, it is the most common cause of cancer death in both genders, in part because it is diagnosed at more advanced stages and in part because management is less successful than breast and prostate cancer. In the US, mortality from lung cancer represents about thirty percent of all cancer-related deaths.
Lung cancer is generally divided into two main types, non-small cell and small cell. This histological classification scheme has significant implications in terms of the origin, natural history and management of these tumors, as outlined below.
Epidemiology and Etiology
- Incidence of over 170,000 cases yearly, with a trend of decreasing incidence in men but increasing incidence in women secondary to changes in smoking behaviors. No known racial predilection exists. Mortality of greater than 160,000 deaths in the United States in 2005 .
- Etiology of most lung cancers is related to chronic cellular damage and DNA mutations from exposure to carcinogens such as cigarette smoke (the cause of 87% of cases), ionizing radiation, radon gas, asbestos, and industrial chemicals.
- Hereditary links or molecular genetic defects have not been established.
- Risk factors include: exposure to carcinogens, as mentioned above, especially tobacco smoke, which shows a direct link between dose and cancer risk and acts synergistically with other carcinogens to increase risk; history of interstitial lung disease; history of tuberculosis.
Screening in Asymptomatic, High-Risk Population
- There has never been a documented decrease in mortality from lung cancer due to screening, and no professional society has endorsed routine screening in high-risk patients.
- The yield of screening chest radiography (CXR) is low; sputum cytology has an even lower sensitivity compared to CXR.
- Spiral chest CT scan can improve sensitivity, but at this time it is not considered a cost-effective screening test and has not been shown to decrease mortality.
- History: About 90% of patients are symptomatic at diagnosis .
- Local effects: cough (45-75% of patients), hemoptysis, (25-55%), dyspnea (30-50%), sputum production (most often associated with bronchoalveolar cell carcinoma), chest pain (often dull and intermittent for early stage disease, severe and constant for locally advanced disease), shoulder and arm pain (Pancoast's tumors), Horner's syndrome, hoarseness (from compression of the recurrent laryngeal nerve), wheezing, dysphagia, superior vena cava (SVC) syndrome.
- Metastatic effects: weight loss, bone/back pain, fatigue, weakness, headaches, seizures, back pain, paraplegia.
- Paraneoplastic syndromes (10-20%): hypercalcemia, hyponatremia, anemia, weight loss, digital clubbing, Eaton-Lambert myasthenia syndrome, peripheral neuropathy, hypercortisol effects.
- Physical exam: Abnormal lung and/or cardiac auscultation is possible. Signs of SVC compression may be present and include facial or upper extremity swelling, dilated neck veins, plethora, and a prominent venous pattern on the chest. Signs of metastatic disease include neurological abnormalities, bone pain to percussion, weakness, cachexia.
- Most common sites of metastasis: brain, bone, liver, adrenals, skin.
- Lab studies: Variable CBC and chemistry panel; hyponatremia from paraneoplastic vasopressin-like factors or hypercalcemia from PTH-like substance; pulmonary function tests; no specific tumor markers routinely used.
- Radiologic studies: CXR; CT scan of the chest and upper abdomen, including the liver and adrenal glands, with a sensitivity and specificity of determining mediastinal lymph node involvement of 57% and 82%, respectively; PET scans have improved sensitivity and specificity over CT scans for identifying lymph node involvement and metastatic disease and upstage 15-20% of patients; bone scan +/- brain CT if symptoms or disease stage warrant; MRI not shown to improve accuracy of staging .
- Diagnostic studies: Sputum cytology; CT-guided needle aspiration; bronchoscopy; mediastinoscopy; video-assisted thoracoscopic surgery; thoracotomy.
Natural Course and Pathology
- Staging: Both a clinical and a pathologic assessment together are critical in the selection of therapy; distinction between clinical stage and pathologic stage should be considered when evaluating reports of survival outcome.
- Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy.
- NSCLC: The Revised International System for Staging Lung Cancer, which employs TNM staging, was adopted in 1997 by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer to provide greater specificity for patient groups and to clarify the classification of multiple tumor nodules (satellite tumor nodules, intrapulmonary ipsilateral metastasis).
- SCLC: As occult or overt metastatic disease is usually present at diagnosis, survival is generally not affected by small differences in the amount of locoregional tumor involvement. A simple 2-stage system of limited vs. extensive disease, developed by the Veterans Administration Lung Cancer Study Group, is commonly used.
- Non-Small Cell Lung Cancers (80% of all lung cancers)
- Squamous cell carcinoma
- 25-30% of total lung cancer cases
- Two-thirds have anatomically central origin, thus often diagnosed on sputum cytology
- Grow relatively slowly; often grow large before symptoms occur
- Exhibit cavitation due to central necrosis
- 30-40% of total lung cancer cases
- Most common lung cancer in women, nonsmokers and former smokers
- Two-thirds originate peripherally in pulmonary tree, thus more commonly found as an asymptomatic solitary peripheral nodule
- More commonly metastasize to brain and other distant sites compared to other non-small cell cancers
- Bronchioloalveolar subtype incidence is rising and is often diffuse/multicentric with prominent mucin production
- Large cell carcinoma
- 10-15% of total lung cancer cases
- Commonly large, peripheral lesions
- High propensity to metastasize to regional lymph nodes and distant sites
- Small Cell Lung Cancers (15-20% of all lung cancers)
- Occurs almost exclusively in smokers
- Commonly grow centrally in bronchi, submucosal locations
- Often very aggressive tumors with rapid growth, early metastasis
- Up to 70% are widely disseminated at diagnosis to bone, liver, brain, and/or lung
- Frequently associated with paraneoplastic syndromes (especially SIADH, hypercortisolism)
- Other Lung Cancers
- Carcinoid tumors, bronchial gland carcinomas, and metastatic disease from another primary site
- Early stage NSCLC
- Surgery lobectomy and lymph node dissection for all subtypes, with 50% 5-year survival rates in Stage I patients, and 30% 5-year survival rates in Stage II patients [4, 5, 6].
- Alternative procedures: pneumonectomy (higher perioperative mortality compared with lobectomy); wedge or segmental resection (3 to 5 times higher incidence of local recurrence, lower survival) [3, 7].
- Patients with medically inoperable Stage I or II disease may be treated with radiation therapy or radiofrequency ablation, performed percutaneously with CT guidance or intraoperatively.
- Radiation therapy may be used alone for nonresectable patients, preoperatively (neoadjuvant) to shrink a tumor, or postoperatively (adjuvant) to decrease local recurrence or target positive regional lymph nodes.
- Radiation therapy is most often used postoperatively for patients at high risk for locoregional relapse (hilar/mediastinal disease, multiple positive lymph nodes or bulky nodal disease, squamous histology, extracapsular extension, close/positive surgical margins).
- Radiation can improve local control in patients with Stage I and II disease and may increase survival in Stage III disease.
- Chemotherapy may be used as an adjuvant treatment since many patients treated with surgery alone subsequently develop regional or distant metastases . Additionally, neoadjuvant chemotherapy has been shown to improve disease-free survival when compared to patients treated with surgery alone .
- Chemotherapy agents commonly used to treat lung cancer include: etoposide or teniposide, cisplatin or carboplatin, ifosfamide, cyclophosphamide, vincristine, doxorubicin, paclitaxel, docetaxel, gemcitabine, and vinorelbine.
- Chemoradiation [9, 10, 11, 12, 13] has been shown to increase survival in patients with Stage III inoperaple disease who have a good performance status and minimal weight loss (= 5%).
- Chemoradiation therapy given sequentially can decrease the development of distant metastases, while chemoradiation given concurrently can improve locoregional control .
- Photodynamic therapy (PDT) combines a photosensitizing drug with a specific type of light to kill localized cancer cells. Although PDT has minimal side effects and can be repeated multiple times in the event of tumor recurrence or limited treatment response, PDT generally is only used to treat small, superficial lung lesions. It is also used to palliate obstructing endobronchial lesions.
- Late stage NSCLC
- Radiation therapy is standard treatment for Stage IIIB patients. When combined with adjuvant cytotoxic chemotherapy the overall 5-year survival rates are improved from the 5% achieved with radiation alone .
- Unresectable disease should be treated with concurrent chemoradiation, often followed by consolidation chemotherapy in patients with good performance status.
- New chemotherapy agents, including paclitaxel (Taxol), docetaxel (Taxotere), topotecan, irinotecan, vinorelbine, or gemcitabine ( Gemzar ® ), may be used in combination with cisplatin or carboplatin in the treatment of advanced NSCLC .
- Palliative radiation or chemotherapy for distant metastases, can improve patient quality of life, but survival rates remain very poor (5-year survival rates of < 5%) .
- Targeted Therapies/Biologic Therapies , new classes of medications that have been specifically designed to function at precise molecular pathways and receptors, are currently being investigated for their use in the treatment of late stage NSCLC. Such therapies, which are often given in conjunction with standard chemotherapeutic agents, include farnesyl transferase inhibitors, signal transduction inhibitors (including the tyrosine kinase inhibitor, erlotinib [Tarceva]), antiangiogenic agents, and monoclonal antibodies (including trastuzumab [Herceptin]).
- Early stage SCLC (Limited, M0)
- Chemotherapy and local radiation given concurrently can achieve a 14% reduction in the mortality rate when compared to chemotherapy alone .
- Chemotherapeutic regiments often include cisplatin or carboplatin and etoposide or teniposide.
- Radiation therapy given twice daily has been shown to significantly increase survival when compared to standard daily regiments .
- Prophylactic cranial irradiation remains controversial but can decrease the risk of brain metastasis and result in a 5.4% increase in the rate of survival at three years .
- Late stage SCLC (Extensive, M1)
- The combination of cisplatin or carboplatin with etoposide is the standard of care in the United States for the treatment of extensive SCLC disease.
- Alternative treatment strategies include the use of taxanes, topoisomerase I inhibitors (topotecan, irinotecan), gemcitabine or vinorelbine, and high-dose chemotherapy with autologous bone marrow transplantation.
- Palliative radiation or chemotherapy for local and distant symptoms are employed to improve patient quality of life .
- Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55(1):10-30.
- Midthun DE, Jett, JR. Clinical presentation of lung cancer. In: Pass, HI, et al (Eds), Lung Cancer: Principles and Practice, Lippincott-Raven, Philadelphia 1996. p.421.
- Movsas B, Khuri F, Kernstine K. Non-small-cell lung cancer. In Pazdur R, et al (Eds), Cancer Management: A Multidisciplinary Approach, Ninth Edition, 2005-6. CMP, Manhasset, NY 2004. p. 111-54.
- Ginsberg RJ, Hill LD, Eagan RT, et al. Modern thirty-day operative mortality for surgical resections in lung cancer. Journal of Thoracic and Cardiovascular Surgery. 1983;86(5):654-8.
- Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Annals of Thoracic Surgery. 1995;60(3):615-23.
- Warren WH, Faber LP. Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. Journal of Thoracic and Cardiovascular Surgery. 1994;107(4):1087-93.
- Martini N, Bains MS, Burt ME, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. Journal of Thoracic and Cardiovascular Surgery. 1995;109(1):120-9.
- Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol. 2002;20(1):247-53.
- Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. New England Journal of Medicine. 1990;323(14):940-5.
- LeChevalie r T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. Journal of the National Cancer Institute. 1991;83(6):417-23.
- Schaake-Koning C, Van dan Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. New England Journal of Medicine. 1992;326(8):524-30.
- Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. Journal of the National Cancer Institute. 1995;87(3):198-205.
- Komaki R, et al. Impact of adding concurrent chemotherapy to hyperfractionated radiotherapy for locally advanced non-small cell lung cancer (NSCLC): comparison of RTOG 83-11 and RTOG 91-06. Am J Clin Oncol. 1997;20(5):435-40.
- Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet. 1993;342(8862):19-21.
- Marino P, Pampallona S, Preatoni A, et al. Chemotherapy vs supportive care in advanced non-small-cell lung cancer: results of a meta-analysis of the literature. Chest. 1994;106(3):861-5.
- Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. New England Journal of Medicine. 1992;327(23):1618-24.
- Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340(4):265-71.
- Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341(7):476-84.
- Ochs JJ, Tester WJ, Cohen MH, et al. "Salvage" radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy. Cancer Treatment Reports. 1983;67(12):1123-6.