Background
Small cell lung cancer (SCLC) is considered distinct from other lung cancers, which are called non–small cell lung cancers (NSCLCs) because of their clinical and biologic characteristics. Small cell lung cancer exhibits aggressive behavior, with rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy and radiation, and frequent association with distinct paraneoplastic syndromes.[1, 2, 3] Surgery usually plays no role in its management except in rare situations.[4]
Pathophysiology
Small cell carcinomas, or oat cell carcinomas, arise in peribronchial locations and infiltrate the bronchial submucosa. Widespread metastases occur early in the course of the disease, with common spread to the mediastinal lymph nodes, liver, bones, adrenal glands, and brain. In addition, production of various peptide hormones leads to a wide range of paraneoplastic syndromes; the most common of these is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and the syndrome of ectopic adrenocorticotropic hormone (ACTH) production. In addition, autoimmune phenomena may lead to various neurologic syndromes, such as Lambert-Eaton syndrome.
Molecular pathogenesis
Recent studies have identified activation of oncogenes and inactivation of tumor suppressor genes in small cell lung cancer. The extent to which these changes are causative in the development of small cell lung cancer is not clearly known and remains an area of active research.
Oncogenes
Amplification of the myc family of oncogenes is the most common molecular abnormality identified in small cell lung cancer cell lines, xenografts in nude mice, and fresh tumor specimens.[5, 6] This change, however, is not identified in all small cell lung cancer tumors; therefore, myc expression is unlikely to be an initial event in the pathogenesis of small cell lung cancer.
C-myc, a member of the myc family, is found more commonly in relapsed tumors than in untreated tumors, and its expression in small cell lung cancer may carry a worse prognosis.[5, 6] Other members of the myc oncogene family include N-myc and L-myc, which have been found to be amplified in small cell lung cancer. N-myc amplification in small cell lung cancer has also been associated with resistance to therapy and a poorer prognosis.[5]
Overall, the exact role of amplification of the myc family of oncogenes in the pathogenesis of small cell lung cancer is not clearly understood at present and requires further study.
Other oncogenes that have been found to be amplified in small cell lung cancer include c-raf, c-erb -b2,[7] and c-fms, but their association with pathogenesis and prognosis is even less clear.
Tumor suppressor genes
The retinoblastoma (RB) tumor suppressor gene is on chromosome 13 (13q14), and a high percentage of small cell lung cancers (as many as 60%) do not express RB messenger ribonucleic acid (mRNA).[8] This high frequency of inactivation of a tumor suppressor gene suggests that this may be an important step in the molecular pathogenesis of small cell lung cancer.
The most common molecular abnormality, however, is deletion of part of chromosome 3 (3p14).[9] Mutations of the TP53 tumor suppressor gene are commonly found in both small cell lung cancer and non-small-cell lung cancer,[10, 11] but their precise role in pathogenesis is not clear. Tobacco smoking and radon exposure are associated with TP53 gene mutations.
Etiology
Tobacco use, uranium mining, and radon exposure are known to be associated with a risk of small cell lung cancer.
Smoking
The predominant cause of small cell lung cancer (and non-small-cell lung cancer), is tobacco smoking. Of all histologic types of lung cancer, small cell lung cancer and squamous cell carcinoma have the strongest correlation to tobacco.[12] Some 98% of patients with small cell lung cancer have a smoking history. Patients with diagnosed small cell lung cancer should be encouraged or required to stop smoking; this may contribute to improved survival.[13]
Uranium mining
All types of lung cancers occur with increased frequency in uranium miners, but small cell lung cancer is most common. The incidence is increased further in persons who smoke tobacco.
Radon exposure
Exposure to radon, an inert gas that develops from uranium decay, has also been reported to cause small cell lung cancer.
Epidemiology
Lung cancer is the second most common malignancy in both sexes, second only to prostate cancer in men and breast cancer in women.[14, 15, 16, 17, 18, 19, 20] More women die of lung cancer each year than breast cancer.
The epidemiology of small cell lung cancer (SCLC) has not changed over the last few years.[15, 19, 20] The incidence of small cell lung cancer was about 20-25% of all newly diagnosed lung cancers in the past. It currently stands at approximately 15%.
Globally, lung cancer is the most frequent malignancy in males, although it is the fifth most common cancer in females. According to World Health Organization (WHO) statistics, slightly more than 1 million cases of lung cancer are diagnosed annually around the world. This is less than expected, and the disparity most likely results from lack of diagnosis and/or underreporting in the developing countries.
The following table shows the estimated 2008-2010 numbers of newly diagnosed lung cancer cases and lung cancer deaths in the United States, which reflect historical differences in cigarette smoking between men and women and the decrease in smoking rates over the past 40 years.[15, 19, 20]
Table 1. 2008-2010 Estimates of New Cases of Lung Cancer and Estimates of Lung Cancer Deaths (Open Table in a new window)
| Newly Diagnosed Cases of Diagnosed Lung Cancer | Lung Cancer Deaths | |
| 2008 Estimates | ||
| Total (% of all cancers) | 215,020 (15%) | 161,840 (29%) |
| Men | 114, 690 | 90,810 |
| Women | 100,330 | 71,030 |
| 2009 Estimates | ||
| Total (% of all cancers) | 219,440 (15%) | 159,390 (28%) |
| Men | 116,090 | 88,900 |
| Women | 103,350 | 70,490 |
| 2010 Estimates | ||
| Total (% of all cancers) | 222,520 (15%) | 157,300 (28%) |
| Men | 116,750 | 86,220 |
| Women | 105,770 | 71,080 |
| Sources: American Cancer Society. Cancer facts & figures 2008,[15] 2009,[19] 2010.[20] | ||
Separate data for small cell carcinoma are not available. The incidence of lung cancer started to decline among males in the early 1980s and has continued to do so over past 20 years. By contrast, the incidence in women started to increase in the late 1970s and has only recently reached a plateau.[14, 19, 20]
According to information from the American Cancer Society, the probabilities of developing lung cancer for men and women among different age groups are as follows[20] :
- Birth to 39 years: men, 0.03%; women, 0.03%
- 40-59 years: men, 0.95%; women, 0.79%
- 60-69 years: men, 2.35%; women, 1.75%
- 70 years and older: men, 6.71%; women, 4.83%
- Birth to death: men, 7.73%; women, 6.31%
As with other histopathologic cases of lung cancer, most cases of small cell lung cancer occur in individuals aged 35-75 years; the incidence peaks in persons aged 55-65 years.
Among men, the age-adjusted incidence of lung cancer (per 100,000) ranges from 14 in Native Americans, 42-53 for Hispanic and Chinese Americans, 71-89 for Vietnamese and white persons, to 117 among black persons. Among women, the age-adjusted incidence of lung cancer ranges from 15 among Japanese persons, 16-25 among Hispanic and Chinese persons, 31-44 among Vietnamese, white, and black persons to 51 among Alaskan natives. In each ethnic group, the incidence is at least twice as high in males as in females. Age-adjusted mortality rates among different ethnic groups follow a similar pattern.
Prognosis
Approximately 65-70% of patients with small cell lung cancer have disseminated or extensive disease at presentation. Extensive-stage small cell lung cancers are incurable, and patients with extensive disease have a median survival duration of 6 weeks. Patients presenting with localized disease (ie, limited stage) have a median survival duration of about 12 weeks. These survival figures are for untreated patients.
The median survival of patients with small cell lung cancer who are treated with multiple-agent chemotherapy and multimodality therapy are as follows:
- For limited disease, 20 months, with a 2-year survival rate of 45%[21] and a 5-year survival rate of 20%
- For extensive disease, 12 months (In 1973, the 2-year survival rate was 1.5%; in 2000, the 2-year survival rate was 4.6%.)
Indicators of poor prognosis include relapsed disease, weight loss, and performance status. Patients who ambulate less than 50% of their waking hours and those with weight loss of more than 10% in 6 months have a worse prognosis.
Patient Education
Because tobacco smoking is the predominant cause of lung cancer, the only means of decreasing the incidence of this disease is decreasing the prevalence of smoking. The evidence is clear that the incidence of lung cancer is decreasing in men in the United States, which has coincided with a decrease in smoking among males.
Concerted efforts are required from government, public health agencies, and healthcare providers to increase public awareness of the hazards of smoking, devise tougher laws to restrict teen smoking, and restrict smoking in public places.
For patient education information, see the Cancer and Tumors Center, as well as Lung Cancer and Bronchoscopy.
Boffetta P, Trichopoulos D. Cancer of the lung, larynx, and pleura. In: Adami H, Hunter D, Trichopoulos D, eds. Textbook of Cancer Epidemiology. 2nd ed. New York, NY: Oxford University Press; 2008:349-67.
Krug LM, Kris MG, Rosenzweig K, Travis WD. Cancer of the lung. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 8th ed. Philadelphia, Pa: Lippincott Williams Wilkins; 2008:947-66.
Tsao A, Glisson B. Small cell lung cancer. In: Kantarjian H, Wolff R, Koller C, eds. MD Anderson Manual of Medical Oncology. New York, NY: McGraw-Hill; 2006:233-56.
Schreiber D, Rineer J, Vongtama D, et al. Surgery for limited-stage small cell lung cancer, should the paradigm shift? A SEER-based analysis. J Clin Oncol (Suppl). 2008;26:403s.
Johnson BE, Ihde DC, Makuch RW, Gazdar AF, Carney DN, Oie H, et al. myc family oncogene amplification in tumor cell lines established from small cell lung cancer patients and its relationship to clinical status and course. J Clin Invest. Jun 1987;79(6):1629-34. [Medline]. [Full Text].
Little CD, Nau MM, Carney DN, Gazdar AF, Minna JD. Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature. Nov 10-16 1983;306(5939):194-6. [Medline].
Schneider PM, Hung MC, Chiocca SM, Manning J, Zhao XY, Fang K, et al. Differential expression of the c-erbB-2 gene in human small cell and non-small cell lung cancer. Cancer Res. Sep 15 1989;49(18):4968-71. [Medline].
Hensel CH, Hsieh CL, Gazdar AF, Johnson BE, Sakaguchi AY, Naylor SL, et al. Altered structure and expression of the human retinoblastoma susceptibility gene in small cell lung cancer. Cancer Res. May 15 1990;50(10):3067-72. [Medline].
Naylor SL, Johnson BE, Minna JD, Sakaguchi AY. Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Nature. Oct 1-7 1987;329(6138):451-4. [Medline].
D'Amico D, Carbone D, Mitsudomi T, Nau M, Fedorko J, Russell E, et al. High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors. Oncogene. Feb 1992;7(2):339-46. [Medline].
Mitsudomi T, Lam S, Shirakusa T, Gazdar AF. Detection and sequencing of p53 gene mutations in bronchial biopsy samples in patients with lung cancer. Chest. Aug 1993;104(2):362-5. [Medline].
WYNDER EL, GRAHAM EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma; a study of 684 proved cases. J Am Med Assoc. May 27 1950;143(4):329-36. [Medline].
Parsons A, Daley A, Begh R, Aveyard P. Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. BMJ. Jan 21 2010;340:b5569. [Medline]. [Full Text].
Ahmedin Jemal, DVM, PhD, Rebecca Siegel, MPH, Elizabeth Ward, et al. Cancer Statistics, 2008. CA Cancer J Clin. 2008;58:71-96. [Full Text].
American Cancer Society. Cancer facts & figures 2008. Accessed December 21, 2010. Available at http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2008.
Frank AL. Epidemiology of lung cancer. In: Roth JA, Ruckdeschel J, Weisenburger T, eds. Thoracic Oncology. Philadelphia, Pa: WB Saunders Co; 1989:6-15.
Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. Oct 1 2006;24(28):4539-44. [Medline].
zz.
American Cancer Society. Cancer facts & figures 2009. Accessed December 21, 2010. Available at http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2009.
American Cancer Society. Cancer facts & figures 2010. Accessed December 21, 2010. Available at http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-and-figures-2010.
Arriagada R, Le Chevalier T, Pignon JP, Rivière A, Monnet I, Chomy P, et al. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med. Dec 16 1993;329(25):1848-52. [Medline].
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer [serial online]. 2011;v.2. Available with free registration at www.nccn.org:Accessed May 21 2011. Available at http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.
[Guideline] Simon GR, Turrisi A. Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. Sep 2007;132(3 Suppl):324S-339S. [Medline]. [Full Text].
Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. N Engl J Med. Jun 29 2011;[Medline].
Zakowski MF. Pathology of small cell carcinoma of the lung. Semin Oncol. Feb 2003;30(1):3-8. [Medline].
Hirsch FR, Matthews MJ, Aisner S, Campobasso O, Elema JD, Gazdar AF, et al. Histopathologic classification of small cell lung cancer. Changing concepts and terminology. Cancer. Sep 1 1988;62(5):973-7. [Medline].
[Best Evidence] Amarasena IU, Walters JA, Wood-Baker R, Fong K. Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev. Oct 8 2008;CD006849. [Medline].
Hanna NH, Einhorn LH. Small-cell lung cancer: state of the art. Clin Lung Cancer. Sep 2002;4(2):87-94. [Medline].
Lally BE, Urbanic JJ, Blackstock AW, Miller AA, Perry MC. Small cell lung cancer: have we made any progress over the last 25 years?. Oncologist. Sep 2007;12(9):1096-104. [Medline].
Schmittel A, Sebastian M, Fischer von Weikersthal L, et al. A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol. Aug 2011;22(8):1798-804. [Medline].
Demetri G, Elias A, Gershenson D, Fossella F, Grecula J, Mittal B, et al. NCCN Small-Cell Lung Cancer Practice Guidelines. The National Comprehensive Cancer Network. Oncology (Williston Park). Nov 1996;10(11 Suppl):179-94. [Medline].
Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. Jun 1 2011;29(16):2215-22. [Medline].
Klasa RJ, Murray N, Coldman AJ. Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol. Mar 1991;9(3):499-508. [Medline].
Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. Jul 15 2002;20(14):3054-60. [Medline].
Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki 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. Jan 28 1999;340(4):265-71. [Medline].
[Best Evidence] Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. Aug 16 2007;357(7):664-72. [Medline].
Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. Jan 10 2002;346(2):85-91. [Medline].
Hanna N, Bunn PA Jr, Langer C, Einhorn L, Guthrie T Jr, Beck T, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. May 1 2006;24(13):2038-43. [Medline].
Natale R, Lara P, Chansky K, et al. A randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated extensive stage small cell lung cancer (E-SCLC). J Clin Oncol. 2008;26 (suppl):400s.
Heigener D, Freitag L, Eschbach C et al. Topotecan/cisplatin (TP) compared to cisplatin/etoposide (PE) for patients with extensive disease-small cell lung cancer (ED-SCLC): final results of a randomised phase III trial. J Clin Oncol. 2008;26 (suppl):400s.
Jotte R, Conkling P, Reynolds C, Galsky MD, Klein L, Fitzgibbons JF, et al. Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy. J Clin Oncol. Jan 20 2011;29(3):287-93. [Medline].
Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Linnoila RI, Gazdar AF, et al. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol. Oct 1994;12(10):2022-34. [Medline].
Johnson BE, Bridges JD, Sobczeck M, Gray J, Linnoila RI, Gazdar AF, et al. Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol. Mar 1996;14(3):806-13. [Medline].
Johnson BE, Grayson J, Makuch RW, Linnoila RI, Anderson MJ, Cohen MH, et al. Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol. Mar 1990;8(3):396-401. [Medline].
Lassen U, Osterlind K, Hansen M, Dombernowsky P, Bergman B, Hansen HH. Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients. J Clin Oncol. May 1995;13(5):1215-20. [Medline].
| Newly Diagnosed Cases of Diagnosed Lung Cancer | Lung Cancer Deaths | |
| 2008 Estimates | ||
| Total (% of all cancers) | 215,020 (15%) | 161,840 (29%) |
| Men | 114, 690 | 90,810 |
| Women | 100,330 | 71,030 |
| 2009 Estimates | ||
| Total (% of all cancers) | 219,440 (15%) | 159,390 (28%) |
| Men | 116,090 | 88,900 |
| Women | 103,350 | 70,490 |
| 2010 Estimates | ||
| Total (% of all cancers) | 222,520 (15%) | 157,300 (28%) |
| Men | 116,750 | 86,220 |
| Women | 105,770 | 71,080 |
| Sources: American Cancer Society. Cancer facts & figures 2008,[15] 2009,[19] 2010.[20] | ||
| Organ System | Syndrome | Mechanism | Frequency |
| Endocrine | SIADH | Antidiuretic hormone | 5-10% |
| Ectopic secretion of ACTH | Adrenocorticotropic hormone | 5% | |
| Atrial natriuretic factor | |||
| Neurologic | Eaton-Lambert reverse myasthenic syndrome | 5-6% | |
| Subacute cerebellar degeneration | |||
| Subacute sensory neuropathy | |||
| Limbic encephalopathy | Anti-Hu, Anti-Yo antibodies | ||
| ACTH = adrenocorticotropic hormone; SIADH = syndrome of inappropriate antidiuretic hormone. | |||
| Regimen | Dose |
| “CAV” Regimen | |
| Cyclophosphamide | 1000 mg/m2 IV day 1 |
| Doxorubicin (Adriamycin) | 50 mg/m2 IV day 1 |
| Vincristine | 2 mg IV |
| “PE” Regimen | |
| Cisplatin | 25 mg/m2 IV days 1-3 |
| Etoposide | 100 mg/m2 IV days 1-3 |
| “CAVE” Regimen | |
| Cyclophosphamide | 1000 mg/m2 IV day 1 |
| Doxorubicin (Adriamycin) | 50 mg/m2 IV day 1 |
| Vincristine | 1.4 mg/m2 IV day 1 (maximum 2 mg) |
| Etoposide | 100 mg/m2 IV day 1 |
| “PEC” Regimen | |
| Paclitaxel | 200 mg/m2 IV day 1 |
| Etoposide | 50 mg/d PO alternating with 100 mg/d PO from days 1-10 |
| Carboplatin | AUC 6 IV day 1 |
| Single-Agent Regimens | |
| Topotecan | 1.5 mg/m2 IV day 1-5 |
| Etoposide | 50 mg PO bid days 1-14 |
| AUC = area under the concentration curve; bid = twice daily; IV = administered intravenously; PO = administered orally. | |

