Bethesda Handbook of Clinical Oncology, 2nd Edition

Thorax

3

Small Cell Lung Cancer

Neelima Denduluri

Martin E. Gutierrez

Medical Oncology Clinical Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Small cell lung cancer (SCLC) constitutes approximately 15% to 25% of all lung cancers. SCLC has an aggressive natural history with a rapid doubling time, and a much greater propensity for regional and distant metastases than the other major types of lung cancers. In addition, SCLC differs from non–small cell lung cancer (NSCLC) in being highly sensitive to initial chemotherapy and radiation therapy. Therefore, the principles of management for this class of tumors differ significantly from those pertaining to NSCLC.

EPIDEMIOLOGY AND ETIOLOGY

Approximately 35,000 to 40,000 new cases of SCLC are diagnosed in the United States every year, comprising 18% of all lung cancers as assessed by the National Cancer Institute's Surveillance, Epidemiology, and End Results data. Epidemiologic data suggest that SCLC is increasing in incidence, particularly in women.

Risk factors implicated in the development of SCLC include cigarette smoking and exposure to uranium and radon gas.

MOLECULAR ABNORMALITIES

  • SCLC is distinguished from all other human cancers by its high incidence of tumor-suppressor gene inactivation. More than 90% of patients with SCLC exhibit loss of the short arm on chromosome 3. Approximately 80% of SCLC inactivates p53 function (which is an important sensor of DNA damage and regulates progression through cell-cycle checkpoints) and more than 90% of SCLC inactivates Rb function, a major determinant of the G1/S cell-cycle checkpoint.
  • Other important molecular abnormalities seen in SCLC include c-mycamplification found in 44% of the cell lines after progression from cytotoxic chemotherapy and BCL-2 gene overexpression in approximately 72% of SCLC cases.
  • There are also abnormalities in the receptor tyrosine kinase/ligand; insulin-like growth factor-1 (IGF-1), and associated receptor in more than 95% of SCLC. The IGF-1/IGF-1R (insulin-like growth factor-1 receptor) autocrine loop plays a prominent role in the growth of SCLC. Phosphatidyl inositol 3-kinase (PI3K)-Akt signaling initiated by IGF-1 protects cells from apoptosis.
  • c-Kit is co-expressed in 70% of SCLC, and the HGF/c-Met pathway has been involved in angiogenesis, cell motility, growth, invasion, and differentiation.
  • Telomerase, which is believed to block senescence by preventing telomeric shortening, is overexpressed in SCLC.

P.54

PATHOLOGY

An accurate pathologic diagnosis is essential for treatment planning. This is aided by obtaining tissue blocks wherever possible because crush artifacts in needle aspirations or bronchoscopy can lead to mistaken diagnoses of SCLC. The older term, “oat-cell,” is believed to reflect the morphology of crush artifact.

The cell from which SCLC originates is undefined, but it is believed to be the peptide hormone–secreting basal neuroendocrine or Kulchitsky cell. These cells often stain with silver and have demonstrable neurosecretory granules.

The current pathologic classification of SCLC recognizes three classes:

  • Small cell carcinoma (comprising more than 90% of all SCLCs).
  • Mixed small and large cell variant.
  • Combined small and non–small cell carcinoma.

No consistent clinical or prognostic differences have been identified among these groups. Atypical neuroendocrine carcinoid tumors and NSCLCs with neuroendocrine differentiation exhibit a genetic pattern and a clinical course distinct from those of SCLC.

CLINICAL FEATURES

Most SCLCs have an identifiable pulmonary lesion. Most frequently, SCLCs begin in a central, endobronchial location; local symptoms may include cough, dyspnea, wheezing, hemoptysis, chest pain, postobstructive pneumonia, superior vena cava (SVC) syndrome, hoarseness, and dysphagia. Approximately 4% of SCLCs may only be in extrapulmonary sites (i.e., cervix, head and neck, esophagus, colon, prostate, and others). Approximately two-thirds of patients have distant metastases at diagnosis. Common sites of extranodal metastases include bone, liver, central nervous system (CNS), and bone marrow. A significant number of metastases to endocrine organs are also seen.

Symptoms related to distant metastases include headaches, seizures, visual disturbances, jaundice, transaminitis, bone marrow involvement with resultant pancytopenia, bone pain, neurologic weakness secondary to cord compression, and anorexia. Because of the neuroendocrine nature of SCLC, several paraneoplastic syndromes are associated with SCLC. These include hyponatremia [syndrome of inappropriate secretion of antidiuretic hormone (SIADH), secretion of excess atrial natriuretic peptide], Cushing syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) production, Eaton-Lambert syndrome, cerebellar ataxia, and subacute sensory neuropathy.

STAGING

The intensity of treatment regimens that are currently recommended (treatment-related mortality of up to 5%) dictates the need for accurate staging. The main goal of staging is to identify those patients who may benefit from combined-modality treatment (combining chemotherapy with concurrent thoracic radiation) (see Table 3.1).

TABLE 3.1. Veterans Affairs Lung Cancer Study Group Staging of Small Cell Lung Cancer and Prognosis

Stage

%

Survival

Untreated

Combination chemotherapy

Contralateral hilar, mediastinal, or supraclavicular nodes usually included in limited-stage disease.
Ipsilateral malignant pleural effusion is considered extensive disease.

Limited-stage disease

30–40

12 wk

12–20 mo

   Tumor confined to one hemithorax and regional lymph nodes that can be encompassed within a radiotherapy pora

Extensive-stage disease

60–70

5 wk

7–11 mo

Disease extending beyond the limits described for limited-stage diseaseb

The most frequently used staging system is the Veterans Administration Lung Group (Table 3.1). The TNM classification suggested by the American Joint Commission for Cancer (AJCC) is rarely used; it is applied primarily to select the exceedingly small population of patients (stage I) who may benefit from surgical resection in addition to combination chemotherapy.

Necessary components of an adequate staging evaluation include a complete history and physical examination, chest x-ray (CXR), computerized tomography (CT) scan, bronchoscopy if chest CT scan/CXR are nonrevealing, complete blood count (CBC), comprehensive metabolic panel including lactate dehydrogenase (LDH) and alkaline phosphatase levels, CT scan of the liver and adrenal glands, and a bone scan. Magnetic resonance imaging (MRI) of the

P.55


head, if possible, is indicated; if there is a contraindication to MRI, a CT scan of the head with contrast is recommended at miniminum, and a positron emission tomography (PET) scan is also indicated. One must consider a bone marrow biopsy if pancytopenia may be an issue to dictate treatment.

TREATMENT

Although several single agents show activity against SCLC, significantly superior response rates and survival with use of multiagent therapy have made combination chemotherapy the standard approach in initial treatment. Optimal regimens yield 80% to 90% response rates, 50% to 60% complete response rates, and 2-year survival rates of 15% to 40%. Five-year survival is 15% to 25% (see Table 3.2).

TABLE 3.2. Stage-dependent Treatment of SCLC

Stage

Treatment

Limited-stage disease

·   Combination chemotherapy

·   Hyperfractionated thoracic radiation

·   Prophylactic cranial irradiation may be considered in complete responders

Extensive-stage disease

·   Combination chemotherapy

·   Referrals to clinical trials or single-agent chemotherapy are acceptable alternatives in selected patients

The most important factors that predict a favorable outcome are extent of disease, good performance status, biology of the small cell tumor, and smoking cessation. Several combinations have been used successfully (see Table 3.3). The most commonly used regimen currently is etoposide and cisplatin (EP) because of its favorable toxicity profile. Schiller et al. (1) considered adding topotecan after four cycles of etoposide/cisplatin to ascertain whether this therapy would improve survival in patients with platinum-sensitive disease (not recurring within 60 days or progressing within 60 days after receiving cisplatin-based therapy). Adding topotecan versus observation only did not translate to increased survival.

TABLE 3.3. Summary of Commonly Used Chemotherapeutic Regimens

Regimen

Dose

Duration

AUC, area under the curve; EP, etoposide/cisplatin; CI, cisplatin/irinotecan; CAV, cyclophosphamide/doxorubicin/vincristine; CAE, cyclophosphamide/doxoruicin/etoposide; CDVE, cyclophosphamide/doxorubicin/vincristine/etoposide.

EP

   Etoposide

120 mg/m2 i.v. d 1–3

   Cisplatin

60 mg/m2 i.v. d 1

Cycles repeated every 4 wk, for four cycles

 

   Etoposide

100 mg/m2 i.v. d 1–3

 

 

   Carboplatin

AUC 6 i.v. d 1

 

 

   Etoposide

100 mg/m2 i.v. d 1–3

 

 

   Cisplatin

25 mg/m2 i.v. d 1–3

 

 

   Etoposide

80 mg/m2 i.v. d 1–3

Cycles repeated every 3 wk, for four cycles

 

   Cisplatin

80 mg/m2 i.v. d 1

 

 

CI

 

   Cisplatin

60 mg/m2 i.v. on d 1

Every 4 wk, for four cycles

 

   Irinotecan

60 mg/m2 i.v. on d 1, 8, and 15

 

 

CAV

 

   Cyclophosphamide

1,000 mg/m2 i.v. d 1

Cycles repeated every 3 wk, continued for four to six cycles

 

   Doxorubicin

45 mg/m2 i.v. d 1

 

 

   Vincristine

1 mg/m2 i.v. d 1

 

 

CAE

 

   Cyclophosphamide

1,000 mg/m2 i.v. d 1

Cycles repeated every 3 wk, continued for four to six cycles

 

   Doxorubicin

45 mg/m2 i.v. d 1

 

 

   Etoposide

50 mg/m2 i.v. d 1–3

 

 

CAVE

 

   Cyclophosphamide

1,000 mg/m2 IV d 1

Cycles repeated every 3 wk, continued for four to six cycles

 

   Doxorubicin

50 mg/m2 i.v. d 1

 

 

   Vincristine

1.5 mg/m2 i.v. d 1

 

 

   Etoposide

60 mg/m2 i.v. d 1–5

 

 

P.56

 

The optimal duration of chemotherapy is four to six cycles (or two cycles beyond best response). Longer duration of treatment has not been shown to be of any benefit. High-dose chemotherapy with autologous stem-cell reinfusion has not been demonstrated to be superior to conventional therapy in phase III trials and is currently used only in clinical trials.

Thoracic radiation provides a marginal survival advantage and reduced local recurrence rates when added to chemotherapy in limited-stage disease. Most regimens incorporating radiation therapy use a total dose of 45 to 50 Gy. The optimal timing of radiotherapy is concurrent with chemotherapy. Takada et al. (2) demonstrated an increase in response rate (35% versus 54%) and in 5-year survival rate with concurrent radiation therapy and chemotherapy. In a study of 231 patients, the median survival was 19.7 months in the sequential arm and 27.2 months in the concurrent arm. Turrisi et al. (3) demonstrated that chemotherapy (cisplatin and etoposide) and concurrent twice-daily radiation therapy are better than daily radiation alone, with a median survival of 19 months versus 23 months.

Use of prophylactic cranial irradiation (PCI) has received considerable attention because the risk of developing CNS metastases in 2-year survivors otherwise approaches 50% to 60%.

P.57


Auperin et al. (4) conducted a meta-analysis of 987 patients; the relative risk of death was 0.84 in the patients who received PCI. PCI improved both overall survival rate at 3 years (by 5.4%) and disease-free survival rate among patients with SCLC in complete remission. Therefore, PCI is recommended in patients with complete remission. PCI has not been shown to result in clinically significant neuropsychological sequelae.

Extensive-stage Disease

Combination chemotherapy without thoracic irradiation is the cornerstone of therapy. Combination chemotherapies identical to those used in limited-stage disease are used with overall response rates of 60% to 80%, complete response rates of 15% to 20%, and median survival of 7 to 11 months. Five-year survival is less than 5%. Radiation therapy is used in local control of distant disease (CNS and other isolated metastatic sites not responding to systemic chemotherapy).

In this setting, cisplatin and carboplatin are thought to be equivalent in efficacy. The most efficacious regimens seem to be irinotecan/cisplatin or cisplatin/etoposideg–based regimens. Noda et al. (5) reported increases in survival rate with irinotecan/cisplatin compared with etoposide/cisplatin (12.8 versus 9.4 months 5-year survival and 19.5% versus 5.2% 2–year), survival with greater diarrhea toxicity but better hematologic toxicity. Currently there are two randomized clinical trials in the United States comparing irinotecan/cisplatin combination versus the standard-of-care regimen of cisplatin/etoposide.

Recurrent Disease or Disease Progressing with Initial Therapy

Recurrent disease or disease progressing with initial therapy has an extremely poor prognosis, with a median survival of 2 to 3 months. Treatment options in this group are limited. Thoracic irradiation should be considered in those patients whose recurrence is confined to the thorax and who have not previously received irradiation but need symptomatic relief. Patients who have not received a platinum-containing regimen or who have not relapsed for 6 months after receiving cisplatin or carboplatin may benefit from combinations containing cisplatin.

Platinum-refractory SCLC is defined as progression during first-line therapy or progression in a period less than or equal to 3 months after completing first-line therapy. In this setting, response rates are poor. However, multiple single-agent regimens have been shown to have some activity in patients who have recurrence of disease after 3 months, including taxol with a 34% response rate, docetaxel with a 26% response rate, and topotecan/irinotecan with a 40% to 60% response rate. Three-drug combinations have been studied with no improvement in disease response or survival. Patients may be referred to clinical trials that are testing new pharmacologic agents currently under development that target oncogenes and signaling pathways.

Long-time Survivors of SCLC are at High Risk for Developing Second Primary Tumors of NSCLC in Addition to Recurrent SCLC

Patients who are able to quit smoking seem to do better than patients who continue to smoke. These patients should be considered for chemoprevention strategies.

REFERENCES

  1. Schiller JH, Adak S, Cella D. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593—a phase III trial of the eastern cooperative oncology group. J Clin Oncol2001;19(8):2114–2122.
  2. Takada M, Fukuoka M, Kawahara M, 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 Oncol2002;20(14):3054–3060.

P.58

 

  1. Turrisi AT III, 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 Med1999;340(4):265–271.
  2. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic Cranial Irradiation Overview Collaborative Group. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med1999;341(7):476–484.
  3. Noda K, Nishiwaki Y, Kawahara M. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer.N Engl J Med2002;346(2):85–91.

Selected Readings

Adjei AA, Marks RS, Bonner JA. Current guidelines for the management of small cell lung cancer. Mayo Clin Proc 1999;74:809–816.

Demetri G, Elias A, Gershenson D, et al. NCCN small-cell lung cancer practice guidelines. Oncology 1996;10(Suppl. 11):179–194.

Ihde DC, Pass HI, Glatstein E. Small cell lung cancer. In: De Vita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 5th ed. Philadelphia, PA: Lippincott-Raven Publishers, 1997:911–949.

Kelly K, Mikhaeel-Kamel N. Medical treatment of lung cancer. J Thorac Imaging 1999;14:257–265.

Sandler AB. Current management of small cell lung cancer. Semin Oncol 1997;244:463–476.

Teng M, Choy H, Ettinger D. Combined chemoradiation therapy for limited-stage small-cell lung cancer. Oncology 1999;13(10 Suppl. 5):107–115.