Lung Cancer

Cigarette smoking continues to contribute to the risk of lung cancer long after a person has stopped smoking. The American Cancer Society evaluated this relationship in a 6-year prospective study involving more than 900,000 persons. This study included persons who had never smoked, current smokers, and former smokers. As expected, the risk of dying of lung cancer was lower in patients who had quit smoking early in life than in those who quit later on, and the risk was significantly lower in those who quit than in those who did not. In a person who smoked 26 cigarettes a day starting at 17 years of age and stopped smoking between the ages of 30 and 49, the risk of death from lung cancer is slightly greater than that of persons who never smoked. For a person who started smoking at 17 years of age and quit smoking between the ages of 50 and 64, the risk of death from lung cancer plateaus at the risk level at the time of quitting and remains level until about the age of 75, at which time the risk appears to increase further. In this model, the annual lung cancer mortality for current smokers at age 75 is 1% for men and 0.5% for women, which is approximately 20 times higher than that of nonsmokers.

A minority of lung cancer patients present with paraneoplastic manifestations; these features may be important clues to early diagnosis and may have a bearing on treatment options. The biology of some of these syndromes remains poorly characterized, but some of the syndromes may relate to cytokine-mediated responses to antigens from the intrathoracic lung tumor, rather than the result of distant spread of cancer. The most common paraneoplastic feature associated with lung cancer is clubbing of the fingers from periosteal swelling of the distal phalanges, which may occur in 5% to 15% of patients. In a small percentage of patients, clubbing may be part of a symptomatic hypertrophic osteoarthropathy. These patients often complain of a distal symmetrical arthritis that most commonly involves the ankles or knees but can also involve the wrists, elbows, and other joints. Misdiagnosis of this condition as a strictly rheumatologic phenomenon often results in delayed recognition of the underlying neoplasm. Although weight loss and fatigue are commonly an indication of distant metastasis, they can also represent a paraneoplastic phenomenon that occasionally occurs even with early-stage tumors. Especially in patients with SCLC, paraneoplastic manifestations can also take the form of specific neurologic syndromes, such as the Lambert-Eaton syndrome. These patients present with muscle weakness caused by antibodies to the postsynaptic acetylcholine receptor of the motor end plate. A variety of peripheral neuropathies and central nervous system involvement such as subacute cerebellar degeneration or limbic encephalitis occur less commonly. Another category of neoplastic syndromes relates to aberrant hormone or peptide production by lung cancer tumor cells. The most common of these is hyponatremia secondary to the production of antidiuretic hormone. Hypercalcemia can result from tumors that secrete parathyroid hormone; Cushing syndrome can be caused by tumors that secrete adrenocorticotropic hormone. In general, these hormonal syndromes are more common in SCLC than in NSCLC, because of the neuroendocrine nature of SCLC. However, hypercalcemia can have a range of causes including both remote effects and direct interactions between tumor and bone and is much more common in NSCLC than in SCLC.

Most patients with lung cancer present with advanced inoperable disease. Screening for lung cancer at an earlier stage is therefore an attractive idea, especially because persons at high risk for lung cancer can be readily identified by a smoking history. Early studies of screening produced disappointing results. Randomized trials of screening suggested that chest x-ray alone was not a satisfactory screening tool for the detection of early lung cancer tumors. Curable tumors are often too small or indistinct to be detected on a standard chest x-ray. Spiral CT scanning is a more sensitive technique for lung cancer screening. With this technique, radiologists obtain a low-resolution image of the entire thorax in a single breath-hold; this approach is associated with low radiation exposure and relatively rapid throughput, as compared with standard CT scans. A number of studies have demonstrated the feasibility of spiral CT scanning in screening for lung cancer. In the Early Lung Cancer Action Project (ELCAP), 1,000 asymptomatic persons older than 60 years who had a smoking history of 10 or more pack-years underwent both spiral CT and chest x-ray. CT detected malignant nodules in 2.7% of the patients, compared with 0.6% by chest x-ray. Benign nodules were detected at a rate of 20.6% by CT, compared with 6.1% by chest x-ray; consequently, careful follow-up is critical for avoiding unnecessary biopsy. A Mayo Clinic study of spiral CT also demonstrated enhanced detection of malignant nodules, most of which were early-stage lung cancer; however, the high yield of benign nodules (60%) detected on spiral CT emphasizes the potential drawback of this technique. At present, no data from randomized trials exist to allow an evidence-based recommendation either for or against lung cancer screening.

The treatment of NSCLC is based on the stage of disease, as determined by the TNM staging system. For stage I or stage II disease, surgical resection is the standard treatment. Inoperable stage III disease is treated with definitive radiation therapy and chemotherapy; in a subset of patients with stage IIIA disease, the addition of surgical resection is associated with improved outcome. Stage IV disease is treated with chemotherapy, palliative radiation, and supportive care. The International Adjuvant Lung Cancer Trial (IALT) randomized patients with NSCLC of stage I through stage IIIA to undergo either cisplatin-based chemotherapy or observation; the study found a 4% absolute improvement in survival in the group that received chemotherapy, which consisted largely of regimens of cisplatin and etoposide or cisplatin and vinorelbine.