Small-Cell Lung Cancer: Treatment Progress and Prospects
Small-Cell Lung Cancer: Treatment Progress and Prospects
ABSTRACT: Although small-cell lung cancer (SCLC) represents only 20% of all lung cancer cases in the United States, it is the most lethal subtype. Combination chemotherapy unequivocally offers the best chance for improved survival in SCLC. Either PE (platinum plus etoposide) or CAV (cyclophosphamide, Adriamycin, and vincristine) is a reasonable first-line therapy. Alternating PE with CAV does not appear to be significantly superior to PE or CAV alone. Increasing dose intensity, although sometimes associated with higher response rates, does not appear to significantly improve survival and should not be used outside of a clinical study. Several new agents with novel mechanisms of action show promise in treating SCLC. These include: gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), topotecan (Hycamtin), and irinotecan (Camptosar). Given the poor survival and response rates in relapsed patients and the chemoresponsiveness of SCLC, patients with newly diagnosed extensive disease should be encouraged to enroll in phase I or II trials. Thoracic radiotherapy confers a small survival advantage in limited-stage SCLC patients. Although prophylactic cranial irradiation does not significantly improve survival, it does reduce central nervous system (CNS) recurrences with minimal long-term sequelae. Surgery should be considered only for: (1) resection of a solitary pulmonary nodule, which must be followed by adjuvant chemotherapy; and (2) resection of an unresponsive chest tumor, which may harbor a non-small-cell lung cancer component.[ONCOLOGY 12(5): 647-662, 1998]
Lung cancer is the most common lethal malignancy. In 1997, there were 178,000 new cases of lung cancer in the United States and 160,400 deaths attributable to this cancer. Lung cancer is the third most commonly diagnosed malignancy in American adults but is the number one cause of cancer-related death in both men and women. Fortunately, both incidence and mortality have plateaued overall and are decreasing in American men. Unfortunately, no such trend has been observed in American women.
Although incidence and mortality of lung cancer are higher in African-American men than in white American men, mortality in the former group appears to be declining, as is occurring in the American male population as a whole. Lung cancer incidence and mortality are similar in white American and African American females and are increasing. This presumably reflects the American woman’s relatively late initiation to cigarette smoking and her greater reluctance to discontinue this deadly habit.
Lung cancer is separated histologically into small-cell and non-small-cell variants. Non-small-cell lung cancer (NSCLC) is responsible for 80% of all lung cancers diagnosed in the United States, while small-cell lung cancer (SCLC) accounts for only 20%. In a recent analysis of lung cancer incidence trends for 1974 to 1991, Travis and associates found that rates for both SCLC and NSCLC peaked around 1984 and subsequently declined for white American and African-American men. However, lung cancer rates among women continued to increase for all histologic subtypes, independent of race. Moreover, these authors noted a slightly increased rate of SCLC in white women and an increased rate of squamous cell lung cancer in African-American women.
This article will review SCLC, with a particular emphasis on recent developments in treatment.
In a worldwide overview of the epidemiology of SCLC, Parkin and Sankaranarayanan noted a decline in overall lung cancer incidence in males that was associated with an increase in the incidence of adenocarcinoma. They observed not only an increasing rate of lung cancer in women but also a rapid rise in SCLC incidence. Cultural trends in tobacco consumption best explain these data.[4,5] Clearly, tobacco exposure is the primary risk factor for SCLC. In fact, it is associated with small-cell cancer more than with any other form of lung cancer. Other risk factors include exposure to asbestos, second-hand smoke, radon-222, and bischloromethyl ether.
The exact role of such exposures in the development of SCLC is presently an area of active research. However, it is known that tobacco smoke contains procarcinogens and carcinogens, such as acetaldehyde, formaldehyde, benzene, and polycyclic aromatic hydrocarbons, which can induce a variety of genetic mutations that may ultimately lead to neoplasia.
For example, nearly all cases of SCLC show a deletion of the short arm of chromosome 3. It is believed that currently unidentified tumor-suppressor genes reside in the deleted region. Essentially all cases of SCLC have abnormalities of the retinoblastoma gene. The absence of its functional protein results in uncontrolled cellular proliferation. Also, somatic mutations of the p53 gene are found in 80% of SCLC cases. Finally, overexpression of the myc family of oncogenes is a common event in SCLC and connotes a poor prognosis.
In addition to environmental insults, host factors play a still poorly defined role in the development of SCLC. It is noteworthy that: (1) fewer than 10% to 15% of smokers develop lung cancer; (2) African-American men are more prone to the development of lung cancer than are white American men; and (3) some evidence shows that women are more likely to develop lung cancer than are men, after adjusting for the number of pack-years of cigarettes smoked.
These observations lend credibility to the notion of “differential susceptibility” to lung cancer. One source of differential susceptibility may be related to host metabolism of carcinogens. For example, Bouchard and colleagues recently found that high levels of activity of the cytochrome P-450 CYP2D6 were associated with a significantly increased risk of lung cancer, but only in heavy smokers.
More recently, Wiencke and associates demonstrated ethnic variations in the expression of the gene coding for nicotinamide adenine dinucleotide phosphate oxidoreductase, a cytosolic reducing enzyme thought to be important in the metabolism of certain lung carcinogens. These researchers found that polymorphisms of this gene were two times more common in Hispanic Americans, who develop lung cancer at significantly lower rates than white Americans and African-Americans; this finding still held even after the researchers corrected for variations in tobacco consumption. Moreover, differences in the frequencies of isozyme expression of glutathione transferase-mu, which metabolizes aromatic hydrocarbons, have been correlated with lung cancer susceptibility.
There are two well-known classification systems for SCLC. The 1981 World Health Organization (WHO) classification recognizes three subtypes: (1) the classic “oat cell” type, characterized by small oval or round cells with hyperchromatic nuclei, indistinct nucleoli, and scant cytoplasm; (2) the intermediate type, characterized by larger cells, pleomorphic nuclei, and more abundant cytoplasm; and (3) the combined type, characterized by the presence of features of squamous cell carcinoma or adenocarcinoma.
Because of similarities in the clinical behavior and biochemical and growth characteristics of the subtypes, researchers for the International Association for the Study of Lung Cancer (IASLC) proposed a new classification system in 1988 (Table 1). In this system, small-cell carcinoma denotes those cancers without a non-small-cell component. This entity comprises more than 90% of SCLC cases. The IASLC system also acknowledges two other subtypes of SCLC: (1) small-cell/large-cell cancer, characterized by a population of larger cells with an open chromatin pattern and prominent nucleoli; and (2) combined small-cell carcinoma, characterized by the presence of neoplastic squamous or glandular elements.
Although the interval from the development of symptoms to diagnosis is shorter for SCLC than for NSCLC patients, the presentation of the two histologic types is generally similar (Table 2). Symptoms and signs stem primarily from tumor location and bulk. In a retrospective review of lung cancer presentation and cell type, Chute and colleagues found that the most common symptoms in patients with limited-stage disease were cough (41%), weight loss (35%), dyspnea (33%), and chest pain (33%). Only patients with stage I squ}µ$s cell lung cancer reported weight loss with such a high frequency (36%). Due to the great frequency of mediastinal nodal disease in patients with SCLC, hoarseness, dysphagia, and superior vena cava syndrome also occur frequently.
Paraneoplastic syndromes, although a relatively uncommon occurrence in SCLC, are usually endocrinologic or neurologic in nature. [14,15] The most common endocrinologic syndrome is inappropriate secretion of antidiuretic hormone (SIADH), which is clinically apparent in 11% to 46% of SCLC patients.[14,15] This syndrome usually improves with successful treatment of the underlying malignancy and does not appear to adversely affect survival. Atrial natriuretic peptide (ANP), which promotes natriuresis and hypotension, may also contribute to hyponatremia in approximately 15% of SCLC patients. Its effects are ameliorated by cancer treatment. Ectopic adrenocorticotrophic hormone (ACTH) production, seen in < 5% of SCLC patients, presents with peripheral edema, proximal myopathy, hypertension, glucose intolerance, and metabolic alkalosis. Cushingoid stigmata are frequently absent, perhaps due to the rapidity with which the syndrome occurs.[14,15] Tumors with ectopic ACTH production are associated with a dismal prognosis, perhaps because of their poor response to therapy.
The neurologic paraneoplastic syndromes of SCLC include Lambert-Eaton myasthenic syndrome, cerebellar degeneration, encephalomyelitis, sensory neuropathy, and cancer-associated retinopathy. Seen in £ 5% of SCLC patients, Lambert-Eaton myasthenic syndrome develops because of the production of autoantibodies that interfere with voltage-gated calcium channels important to the release of acetylcholine from presynaptic neurons. Patients present with proximal myopathy, “waddling gait,” hyporeflexia, and autonomic dysfunction. Ocular and bulbar symptoms are much less common than in myasthenia gravis.
Like other paraneoplastic syndromes, treatment of Lambert-Eaton myasthenic syndrome is directed at the underlying cancer. However, guanidine hydrochloride, aminopyridine, plasma exchange, and immunosuppression have all been given with occasional success. It is noteworthy that the use of aminoglycosides, beta-blockers, calcium-channel blockers, and class Ia antiarrhythmics (such as quinidine, procainamide, and disopyramide) should be avoided in these patients to avoid acute myasthenic crisis.
Paraneoplastic cerebellar degeneration appears to be related to autoantibodies directed at Purkinje cells, although other antineuronal antibodies have been described as well. Cerebellar degeneration responds poorly to cancer therapy; this is due presumably to the rapid and permanent destruction of cerebellar cells. Like cerebellar degeneration, encephalomyelitis, sensory neuropathy, and cancer-associated retinopathy are suspected to represent autoimmune phenomena. These syndromes are minimally ameliorated by cancer treatment.