Purpose of This PDQ Summary
General Information About Small Cell Lung Cancer

Related Summaries Statistics Limited-Stage Disease Extensive-Stage Disease Prognostic Factors

Cellular Classification of Small Cell Lung Cancer
Stage Information for Small Cell Lung Cancer

Limited-Stage Disease Extensive-Stage Disease Other Staging and Prognostic Factors

Treatment Option Overview
Limited-Stage Small Cell Lung Cancer

Current Clinical Trials

Extensive-Stage Small Cell Lung Cancer

Current Clinical Trials

Recurrent Small Cell Lung Cancer

Current Clinical Trials

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Changes to This Summary (02/13/2009)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of small cell lung cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

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General Information About Small Cell Lung Cancer

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Other PDQ summaries containing information related to lung cancer include:

• Non-Small Cell Lung Cancer Treatment.
• Lung Cancer Prevention.
• Lung Cancer Screening.

Estimated new cases and deaths from lung cancer (small cell lung cancer and non-small cell lung cancer combined) in the United States in 2008:[1]

• New cases: 215,020.
• Deaths: 161,840.

Small cell lung cancer (SCLC) accounts for approximately 15% of bronchogenic carcinomas. The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[2] Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. Compared with other cell types of lung cancer, SCLC is more responsive to chemotherapy and radiation therapy; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis. It is the cancer most commonly associated with paraneoplastic syndromes, including the syndrome of inappropriate antidiuretic hormone secretion, paraneoplastic cerebellar degeneration, and Lambert-Eaton myasthenic syndrome.[2]

At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease (LD), and most 2-year disease-free survivors come from this group. For patients with LD, median survival of 16 to 24 months and 5-year survivals of 14% with current forms of treatment have been reported.[3-6] Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise cure rates.[7]

Improved long-term survival has been shown with combined modality therapy.[6,8][Level of evidence: 1iiA] Although long-term survivors have been reported among patients who received either surgery or chemotherapy alone, chemotherapy combined with thoracic radiation therapy (TRT) is considered the standard of care.[9] Adding TRT increases absolute survival by approximately 5% over chemotherapy alone.[8,10] The optimal timing of TRT relative to chemotherapy has been evaluated in multiple trials and meta-analyses with the weight of evidence suggesting a small benefit to early TRT.[4,11,12][Level of evidence: 1iiA] Prophylactic cranial radiation prevents central nervous system (CNS) recurrence and can improve survival in patients who have had a complete response to chemoradiation.[13,14][Level of evidence: 1iiA]

Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED) and have a worse prognosis than patients with LD. Median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare.

The pretreatment prognostic factors that consistently predict for prolonged survival include good performance status, female gender, and LD.[15-19] Patients with involvement of the CNS or liver at the time of diagnosis have a significantly worse outcome.[15-18] A number of biochemical factors including serum sodium, alkaline phosphatase, and lactate dehydrogenase have also been found to independently correlate with outcome.[16,20]

Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy made during the past 25 years. All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI Web site.

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed October 1, 2008. 
   
   
2. Govindan R, Page N, Morgensztern D, 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 24 (28): 4539-44, 2006.  [PUBMED Abstract]
   
   
3. Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996.  [PUBMED Abstract]
   
   
4. Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993.  [PUBMED Abstract]
   
   
5. 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 340 (4): 265-71, 1999.  [PUBMED Abstract]
   
   
6. Jänne PA, Freidlin B, Saxman S, et al.: Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 95 (7): 1528-38, 2002.  [PUBMED Abstract]
   
   
7. Videtic GM, Stitt LW, Dar AR, et al.: Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 21 (8): 1544-9, 2003.  [PUBMED Abstract]
   
   
8. Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992.  [PUBMED Abstract]
   
   
9. Chandra V, Allen MS, Nichols FC 3rd, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006.  [PUBMED Abstract]
   
   
10. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992.  [PUBMED Abstract]
    
    
11. Perry MC, Eaton WL, Propert KJ, et al.: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316 (15): 912-8, 1987.  [PUBMED Abstract]
    
    
12. 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 Oncol 20 (14): 3054-60, 2002.  [PUBMED Abstract]
    
    
13. Aupérin 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 341 (7): 476-84, 1999.  [PUBMED Abstract]
    
    
14. Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007.  [PUBMED Abstract]
    
    
15. Wolf M, Holle R, Hans K, et al.: Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): the role of sex as a predictor for survival. Br J Cancer 63 (6): 986-92, 1991.  [PUBMED Abstract]
    
    
16. Rawson NS, Peto J: An overview of prognostic factors in small cell lung cancer. A report from the Subcommittee for the Management of Lung Cancer of the United Kingdom Coordinating Committee on Cancer Research. Br J Cancer 61 (4): 597-604, 1990.  [PUBMED Abstract]
    
    
17. Paesmans M, Sculier JP, Lecomte J, et al.: Prognostic factors for patients with small cell lung carcinoma: analysis of a series of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer 89 (3): 523-33, 2000.  [PUBMED Abstract]
    
    
18. Albain KS, Crowley JJ, LeBlanc M, et al.: Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 9 (9): 1618-26, 1991.  [PUBMED Abstract]
    
    
19. Singh S, Parulekar W, Murray N, et al.: Influence of sex on toxicity and treatment outcome in small-cell lung cancer. J Clin Oncol 23 (4): 850-6, 2005.  [PUBMED Abstract]
    
    
20. Cerny T, Blair V, Anderson H, et al.: Pretreatment prognostic factors and scoring system in 407 small-cell lung cancer patients. Int J Cancer 39 (2): 146-9, 1987.  [PUBMED Abstract]
    
    

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Cellular Classification of Small Cell Lung Cancer

Review of pathologic material by an experienced lung cancer pathologist is important prior to initiating treatment of any patient with small cell lung cancer (SCLC).

The current classification of subtypes of SCLC is:[1]

• Small cell carcinoma.
• Combined small cell carcinoma (i.e., SCLC combined with neoplastic squamous and/or glandular components).

SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung. Neuroendocrine tumors include low-grade typical carcinoid, intermediate-grade atypical carcinoid, and high-grade neuroendocrine tumors including large-cell neuroendocrine carcinoma and SCLC. Because of differences in clinical behavior, therapy, and epidemiology, these tumors are classified separately in the World Health Organization (WHO) revised classification. The variant form of SCLC called mixed small cell/large cell carcinoma was not retained in the revised WHO classification. Instead, SCLC is now described with only one variant, SCLC combined, when at least 10% of the tumor bulk is made of an associated non-small cell component.

SCLC presents a proliferation of small cells with the following morphological features: [2]

• Scant cytoplasm.
• Ill-defined borders.
• Finely granular "salt and pepper" chromatin.
• Absent or inconspicuous nucleoli.
• Frequent nuclear molding.
• A high mitotic count.

Combined small cell carcinoma includes a mixture of small cell and large cell or any other non-small cell component. Any cases showing at least 10% of SCLC are diagnosed as combined SCLC, and SCLC is reserved to tumors with pure SCLC histology. SCLC associated with large-cell neuroendocrine carcinoma (LCNEC) is diagnosed as SCLC combined with LCNEC.

Although the diagnosis can usually be made based on cell morphology using light microscopy, additional pathological evaluation may be of value if the diagnosis is uncertain. Electron microscopy shows dense-core neurosecretory granules 100 nm in diameter.[3] Nearly all SCLC are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC.[3]

Although preinvasive and in situ malignant changes are frequently found in patients with NSCLC, these findings are rare in patients with SCLC.[4]

References

1. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. 
   
   
2. Brambilla E, Travis WD, Colby TV, et al.: The new World Health Organization classification of lung tumours. Eur Respir J 18 (6): 1059-68, 2001.  [PUBMED Abstract]
   
   
3. Guinee DG Jr, Fishback NF, Koss MN, et al.: The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 102 (4): 406-14, 1994.  [PUBMED Abstract]
   
   
4. Kumar V, Abbas A, Fausto N, eds.: Robins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, Pa: Elsevier Inc, 2005. 
   
   

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Stage Information for Small Cell Lung Cancer

Staging procedures for small cell lung cancer (SCLC) are important in distinguishing patients with disease limited to their thorax from those with distant metastases. Determining the stage of cancer allows an assessment of prognosis and a determination of treatment, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with limited-stage disease (LD). If extensive-stage disease (ED) is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include:

• A thorough physical examination.
• Routine blood counts and serum chemistries.
• Chest and upper abdominal computed tomography (CT) scanning.
• A radionuclide bone scan.
• A brain magnetic resonance imaging (MRI) scan or CT scan.
• Bone marrow aspirate or biopsy in selected patients where treatment would change based on the results.

LD SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port. No universally accepted definition of this term is available, and patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups. Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED).

ED SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1) are always considered to have ED.[1-3]

The role of positron emission tomography (PET) is still in evolution. SCLC is fluorodeoxyglucose avid at the primary site and at metastatic sites. The largest experience to date evaluated 120 patients with LD SCLC or ED SCLC.[4] Eight percent of patients were upstaged, and 2.3% of patients were downstaged. PET was more sensitive and specific than CT scans for non-brain distant metastases. In a small series of 24 patients with LD by conventional staging, 8.3% of patients were upstaged to ED.[5] Unsuspected nodal metastases were documented in 25% of patients, which altered the radiation plan in these patients. At this time, sensitivity, specificity, and positive- or negative-predictive value of PET scanning and its enhancement staging accuracy is uncertain.

At the time of initial diagnosis, approximately two-thirds of patients with SCLC have clinical evidence of metastases; most of the remaining patients have clinical evidence of extensive nodal involvement in the hilar, mediastinal, and sometimes supraclavicular regions. Although tumor, node, metastasis (TNM) staging has been applied in small series of patients with SCLC treated either with surgery alone or with combined modality therapy including surgery, a simpler staging system based on the anatomical extent of the disease as proposed originally by the Veterans Administration Lung Study Group (VALG) is commonly used to determine if patients have LD or ED.[5] In the VALG staging system, LD is defined as disease confined to one hemithorax, which can be safely encompassed within a tolerable radiation field. Patients with LD are treated with chemotherapy and thoracic radiation, whereas, for the most part, patients with ED (distant hematogenous metastases) receive only chemotherapy.

The International Association for the Study of Lung Cancer (IASLC) revised the VALG classification [5] in accordance with the TNM system.[6] In the IASLC system, the LD definition is consistent with TNM stages I to IIIB, and ED is limited to patients with distant metastases. According to the 1989 IASLC staging system for SCLC, ipsilateral and contralateral supraclavicular nodes and hilar or mediastinal nodes are included in LD. However, in the era of conformal techniques and increasing radiation dose for SCLC, it is likely no longer appropriate to treat all patients with LD in the same way, and radiation fields may be determined using more precise nodal categories. The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of TNM staging system for lung cancer.[3] Survivals for patients with clinical stages I and II are significantly different from those of stage III with N2 or N3 involvement.[2] Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED). The analysis suggests that, in the context of clinical trials in LD, accurate TNM staging may be critical and stratification based on TNM stage may be important.[2]

References

1. Ihde D, Souhami B, Comis R, et al.: Small cell lung cancer. Lung Cancer 17 (Suppl 1): S19-21, 1997.  [PUBMED Abstract]
   
   
2. Shepherd FA, Crowley J, Van Houtte P, et al.: The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2 (12): 1067-77, 2007.  [PUBMED Abstract]
   
   
3. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997.  [PUBMED Abstract]
   
   
4. Brink I, Schumacher T, Mix M, et al.: Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 31 (12): 1614-20, 2004.  [PUBMED Abstract]
   
   
5. Bradley JD, Dehdashti F, Mintun MA, et al.: Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 22 (16): 3248-54, 2004.  [PUBMED Abstract]
   
   
6. Stahel R, Ginsberg R, Havemann K, et al.: Staging and prognostic factors in small cell lung cancer: a consensus report. Lung Cancer 5 (4-6): 119-26, 1989. 
   
   

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Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Chemotherapy improves the survival of patients with limited-stage (LD) or extensive-stage (ED) small cell lung cancer (SCLC), but it is curative in only a minority of patients.[1,2] Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[3] With incorporation of current chemotherapy regimens into the treatment program, however, survival is prolonged, with at least a 4- to 5-fold improvement in median survival compared with patients who are given no therapy. The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen.[4-6][Level of evidence: 1iiA] No consistent survival benefit has resulted from increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy.[7-11][Level of evidence: 1iiA]

SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors.[12-14][Level of evidence: 1iiA] Prophylactic cranial radiation prevents central nervous system recurrence and may improve the long-term survival of patients who have responded to chemoradiation therapy [15-17][Level of evidence: 1iiA] and offers palliation of symptomatic metastatic disease. About 10% of the total population of patients remains free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. Even these patients, however, are at risk of dying from lung cancer (both small and non-small cell types).[4] The overall survival at 5 years is 5% to 10%.[4-6,14]

Despite treatment advances, the majority of patients with small cell lung cancer (SCLC) die of their tumor even with the best available therapy. Most of the improvements in the survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable.

Information about ongoing clinical trials is available from the NCI Web site.

References

1. Comis RL, Friedland DM, Good BC: Small-cell lung cancer: a perspective on the past and a preview of the future. Oncology (Huntingt) 12 (1 Suppl 2): 44-50, 1998.  [PUBMED Abstract]
   
   
2. Agra Y, Pelayo M, Sacristan M, et al.: Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Database Syst Rev (4): CD001990, 2003.  [PUBMED Abstract]
   
   
3. Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989.  [PUBMED Abstract]
   
   
4. Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990.  [PUBMED Abstract]
   
   
5. Lassen U, Osterlind K, Hansen M, et al.: 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 13 (5): 1215-20, 1995.  [PUBMED Abstract]
   
   
6. Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996.  [PUBMED Abstract]
   
   
7. Ihde DC, Mulshine JL, Kramer BS, 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 12 (10): 2022-34, 1994.  [PUBMED Abstract]
   
   
8. Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993.  [PUBMED Abstract]
   
   
9. Klasa RJ, Murray N, Coldman AJ: Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 9 (3): 499-508, 1991.  [PUBMED Abstract]
   
   
10. Elias AD, Ayash L, Frei E 3rd, et al.: Intensive combined modality therapy for limited-stage small-cell lung cancer. J Natl Cancer Inst 85 (7): 559-66, 1993.  [PUBMED Abstract]
    
    
11. Murray N, Livingston RB, Shepherd FA, et al.: Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 17 (8): 2300-8, 1999.  [PUBMED Abstract]
    
    
12. Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992.  [PUBMED Abstract]
    
    
13. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992.  [PUBMED Abstract]
    
    
14. Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993.  [PUBMED Abstract]
    
    
15. Turrisi AT 3rd, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19 (6): 1473-9, 1990.  [PUBMED Abstract]
    
    
16. Aupérin 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 341 (7): 476-84, 1999.  [PUBMED Abstract]
    
    
17. Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007.  [PUBMED Abstract]
    
    

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Limited-Stage Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Combined modality treatment with chemotherapy and thoracic radiation therapy (TRT) is the standard treatment for patients with limited-stage disease (LD) small cell lung cancer (SCLC). Mature results of prospective randomized trials suggest that combined modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[1-4][Level of evidence: 1iiA] The combination of platinum and etoposide with TRT is the most widely used treatment regimen.

Clinical trials have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival rates with less than a 3% treatment-related mortality.[3-7][Level of evidence: 1iiA] As noted above, no consistent survival benefit has resulted from increased dose intensity or dose density, administration of additional drugs, altered modes of administration of various chemotherapeutic agents, or maintenance chemotherapy.[8-15][Level of evidence: 1iiA] The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.

The optimal dose and timing of TRT remain controversial, and multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[3-6,8-10,16-19][Level of evidence: 1iiA] The amount of time from start to completion of TRT in LD SCLC may also impact on overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk = 0.62; 95% CI, 0.49–0.80; P = .0003).[19][Level of evidence: 1iiA]

Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin. One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years, P = .04).[16][Level of evidence: 1iiA] Esophagitis was increased with twice-daily treatment. Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to higher doses of greater than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[20][Level of evidence: 3iiiA] The current standard treatment of patients with LD SCLC should be a combination containing etoposide and cisplatin with chest radiation.

The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with a decreased performance status and increased comorbidity.[21] Elderly patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and prophylactic cranial irradiation (PCI). Elderly patients were also less likely to respond to therapy and had poorer survival outcomes. Whether this was a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.

No specific phase III trial in elderly patients with LD SCLC has been reported; however, three secondary analyses of cooperative group trials have been published evaluating outcomes in patients 70 years or older.[22-24] The survival outcomes for the elderly patients were identical to their younger counterparts in both trials. The elderly patients experienced more toxic effects, particularly hematologic, compared with younger patients. There was a significant increase in treatment-related mortality in the INT-0096 trial comparing etoposide and cisplatin with either once-daily or twice-daily radiation (1% for patients <70 years vs. 10% for patients ≥70 years; P = .01).[23] Because the elderly patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of elderly patients.

Patients presenting with superior vena cava syndrome are treated with combination chemotherapy with (for patients with LD SCLC) or without radiation therapy.[25,26] (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

A small minority of LD patients with adequate pulmonary function and with tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes may possibly benefit from surgical resection with or without adjuvant chemotherapy.[27-31][Level of evidence: 3iiiDii] However, patients who have undergone surgery generally have had very limited disease; no randomized trials have been conducted evaluating the addition of surgery to chemoradiation therapy.

The only randomized study evaluating the role of surgery in addition to chemoradiation therapy enrolled 328 patients with LD SCLC and found no OS benefit with the addition of pulmonary resection.[32][Level of evidence: 1iiA]

Patients who have achieved a complete remission can be considered for administration of PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment.[31,33,34] The majority of these patients relapse only in their brain, and nearly all of those who relapse in their CNS die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% by the administration of PCI.[33] A meta-analysis of seven randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and OS with the addition of PCI. The 3-year OS was improved from 15% to 21% with PCI.[33][Level of evidence: 1iiA]

Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[31,34-37] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated.[37] In addition, the majority of patients with SCLC have neuropsychological abnormalities present before the start of PCI and have no detectable decline in their neurological status for as long as 2 years after the start of their PCI.[37] Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment.[35-37] Additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.

Standard treatment options:

1. Combination chemotherapy and chest radiation (with or without PCI given to patients with complete responses).



2. Combination chemotherapy (with or without PCI in patients with complete responses) for patients with impaired pulmonary function or poor performance status.



3. Surgical resection followed by chemotherapy or chemotherapy plus chest radiation therapy (with PCI in patients with complete responses) for patients with stage I disease.[30]

Treatment options under clinical evaluation:

Areas of active clinical evaluation for patients with LD SCLC include new drug regimens, variation of drug doses in current regimens, surgical resection of the primary tumor, new radiation therapy schedules and techniques (e.g., three-dimensional treatment planning), and timing of thoracic radiation.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with limited stage small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992.  [PUBMED Abstract]
   
   
2. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992.  [PUBMED Abstract]
   
   
3. Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993.  [PUBMED Abstract]
   
   
4. Turrisi AT 3rd, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19 (6): 1473-9, 1990.  [PUBMED Abstract]
   
   
5. McCracken JD, Janaki LM, Crowley JJ, et al.: Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group Study. J Clin Oncol 8 (5): 892-8, 1990.  [PUBMED Abstract]
   
   
6. 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 Oncol 20 (14): 3054-60, 2002.  [PUBMED Abstract]
   
   
7. Johnson BE, Bridges JD, Sobczeck M, 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 14 (3): 806-13, 1996.  [PUBMED Abstract]
   
   
8. Fried DB, Morris DE, Poole C, et al.: Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 22 (23): 4837-45, 2004.  [PUBMED Abstract]
   
   
9. Spiro SG, James LE, Rudd RM, et al.: Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol 24 (24): 3823-30, 2006.  [PUBMED Abstract]
   
   
10. De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, et al.: Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol 17 (4): 543-52, 2006.  [PUBMED Abstract]
    
    
11. Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993.  [PUBMED Abstract]
    
    
12. Goodman GE, Crowley JJ, Blasko JC, et al.: Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study. J Clin Oncol 8 (1): 39-47, 1990.  [PUBMED Abstract]
    
    
13. Fukuoka M, Furuse K, Saijo N, et al.: Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 83 (12): 855-61, 1991.  [PUBMED Abstract]
    
    
14. Bleehen NM, Girling DJ, Machin D, et al.: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68 (6): 1150-6, 1993.  [PUBMED Abstract]
    
    
15. Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996.  [PUBMED Abstract]
    
    
16. 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 340 (4): 265-71, 1999.  [PUBMED Abstract]
    
    
17. Huncharek M, McGarry R: A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited-stage small cell lung cancer. Oncologist 9 (6): 665-72, 2004.  [PUBMED Abstract]
    
    
18. Pijls-Johannesma MC, De Ruysscher D, Lambin P, et al.: Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev (1): CD004700, 2005.  [PUBMED Abstract]
    
    
19. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al.: Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 24 (7): 1057-63, 2006.  [PUBMED Abstract]
    
    
20. Bogart JA, Herndon JE 2nd, Lyss AP, et al.: 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys 59 (2): 460-8, 2004.  [PUBMED Abstract]
    
    
21. Ludbrook JJ, Truong PT, MacNeil MV, et al.: Do age and comorbidity impact treatment allocation and outcomes in limited stage small-cell lung cancer? a community-based population analysis. Int J Radiat Oncol Biol Phys 55 (5): 1321-30, 2003.  [PUBMED Abstract]
    
    
22. Schild SE, Stella PJ, Geyer SM, et al.: The outcome of combined-modality therapy for stage III non-small-cell lung cancer in the elderly. J Clin Oncol 21 (17): 3201-6, 2003.  [PUBMED Abstract]
    
    
23. Yuen AR, Zou G, Turrisi AT, et al.: Similar outcome of elderly patients in intergroup trial 0096: Cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma. Cancer 89 (9): 1953-60, 2000.  [PUBMED Abstract]
    
    
24. Siu LL, Shepherd FA, Murray N, et al.: Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 14 (3): 821-8, 1996.  [PUBMED Abstract]
    
    
25. Urban T, Lebeau B, Chastang C, et al.: Superior vena cava syndrome in small-cell lung cancer. Arch Intern Med 153 (3): 384-7, 1993.  [PUBMED Abstract]
    
    
26. Würschmidt F, Bünemann H, Heilmann HP: Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases. Int J Radiat Oncol Biol Phys 33 (1): 77-82, 1995.  [PUBMED Abstract]
    
    
27. Osterlind K, Hansen M, Hansen HH, et al.: Treatment policy of surgery in small cell carcinoma of the lung: retrospective analysis of a series of 874 consecutive patients. Thorax 40 (4): 272-7, 1985.  [PUBMED Abstract]
    
    
28. Shepherd FA, Ginsberg RJ, Patterson GA, et al.: A prospective study of adjuvant surgical resection after chemotherapy for limited small cell lung cancer. A University of Toronto Lung Oncology Group study. J Thorac Cardiovasc Surg 97 (2): 177-86, 1989.  [PUBMED Abstract]
    
    
29. Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989.  [PUBMED Abstract]
    
    
30. Smit EF, Groen HJ, Timens W, et al.: Surgical resection for small cell carcinoma of the lung: a retrospective study. Thorax 49 (1): 20-2, 1994.  [PUBMED Abstract]
    
    
31. Chandra V, Allen MS, Nichols FC 3rd, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006.  [PUBMED Abstract]
    
    
32. Lad T, Piantadosi S, Thomas P, et al.: A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 106 (6 Suppl): 320S-323S, 1994.  [PUBMED Abstract]
    
    
33. Nugent JL, Bunn PA Jr, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 44 (5): 1885-93, 1979.  [PUBMED Abstract]
    
    
34. Aupérin 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 341 (7): 476-84, 1999.  [PUBMED Abstract]
    
    
35. Johnson BE, Patronas N, Hayes W, et al.: Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors. J Clin Oncol 8 (1): 48-56, 1990.  [PUBMED Abstract]
    
    
36. Laukkanen E, Klonoff H, Allan B, et al.: The role of prophylactic brain irradiation in limited stage small cell lung cancer: clinical, neuropsychologic, and CT sequelae. Int J Radiat Oncol Biol Phys 14 (6): 1109-17, 1988.  [PUBMED Abstract]
    
    
37. Cull A, Gregor A, Hopwood P, et al.: Neurological and cognitive impairment in long-term survivors of small cell lung cancer. Eur J Cancer 30A (8): 1067-74, 1994.  [PUBMED Abstract]
    
    

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Extensive-Stage Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

As in limited-stage (LD) small cell lung cancer (SCLC), chemotherapy should be given as a two-drug combination of platinum and etoposide in doses associated with at least moderate toxic effects to produce the best results in patients with extensive-stage disease (ED). Doses and schedules used in current programs yield overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with ED.[1,2][Level of evidence: 1iiA] A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those not receiving a platinum agent.[2][Level of evidence: 1iiA]

Cisplatin is associated with significant toxic effects and requires fluid hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is active in SCLC, is dosed according to renal function, and is associated with less nonhematological toxic effects. The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide.[3] The median survival was 11.8 months in the cisplatin arm and 12.5 months in carboplatin-treated patients.[3][Level of evidence: 1iiA] Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED. The combination of cisplatin and etoposide remains the gold standard for treatment, although carboplatin plus etoposide is an acceptable alternative for patients unable to tolerate cisplatin.[4]

The substitution of irinotecan for etoposide has yielded conflicting results. A phase III study conducted in Japan compared a standard two-drug regimen of cisplatin and etoposide with a combination of cisplatin and irinotecan.[5][Level of evidence: 1iiA] The planned enrollment was 230 patients younger than 70 years, however, the trial was stopped early with a total of 154 patients when an interim analysis found a significant difference favoring the irinotecan arm. The median survival in the cisplatin and irinotecan group was 12.8 months (95% confidence interval [CI], 11.7–15.2 months) while it was 9.4 months in the cisplatin and etoposide arm (95% CI, 8.1–10.8 months). The 2-year survival was 19.5% versus 5.2%. Hematologic toxic effects were more severe in the etoposide- and cisplatin-treated patients, while gastrointestinal toxic effects were worse in the irinotecan-treated and cisplatin-treated patients. However, no difference in response rate, median time-to-progression, or overall survival (OS) was reported from a second study that involved 331 patients with ED and compared cisplatin and etoposide with a modified weekly regimen of cisplatin and irinotecan.[6] The modified weekly irinotecan/cisplatin regimen resulted in less myelosuppression but more diarrhea and vomiting.[6][Level of evidence: 1iiA] Another study (SWOG-S0124) compared irinotecan versus etoposide with cisplatin using doses and schedules similar to the original Japanese study.

In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not found to be superior to etoposide and cisplatin.[7] The 1-year survival rate was 31% (95% CI, 27%–36%) and was deemed to be noninferior as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.[7][Level of evidence: 1iiA]

No consistent survival benefit has resulted from the addition of a third drug, such as paclitaxel, to etoposide and cisplatin.[8,9] The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.[3,10,11] No clear evidence is available from reported data that maintenance chemotherapy will improve survival duration.[12-14][Level of evidence: 1iiA] However, a meta-analysis of 14 published randomized trials reported odds ratios for 1- and 2-year OS of 0.67 (95% CI, 0.56–0.79, P < .001 and 0.53–0.86, P < .001, respectively). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.[15][Level of evidence: 1iiA]

The role of dose intensification in patients with SCLC remains unclear.[16-20] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[16,17] More recently, a number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[18-26] These studies have yielded conflicting results. Four studies have shown that a modest increase in dose intensity (25%–34%) was associated with a significant improvement in survival with no compromise in quality of life (QOL).[18-21][Level of evidence: 1iiA] Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles (23–25) showed no advantage.[22,23][Level of evidence: 1iiA]

The European Organization for Research and Treatment of Cancer reported a randomized comparison (EORTC-08923) of standard dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (GCSF) support.[24] The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival. A randomized phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks with twice weekly ICE with GCSF and autologous blood support.[25] Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment.[25][Level of evidence: 1iiA]. Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection. A randomized phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05).[26] However, given the small study size (only 70 patients), these results should be viewed with caution.

Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of prophylactic cranial irradiation (PCI). A randomized trial of 286 patients with response following 4 to 6 cycles of chemotherapy compared PCI versus no further therapy with symptomatic brain metastases.[27] The cumulative risk of brain metastases within 1 year was 14.6% in the radiation group (95% CI, 8.3–20.9) and 40.4% in the control group (95% CI, 32.1– 48.6).[27][Level of evidence: 1iiD] Radiation was associated with an increase in median disease-free survival (DFS) from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization. The 1-year survival rate was 27.1% (95% CI, 19.4–35.5) in the radiation group and 13.3% (95% CI, 8.1–19.9) in the control group. Radiation had side effects but did not have a clinically significant effect on global health status.[24]

Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with ED SCLC. Radiation therapy, however, plays an important role in palliation of symptoms of the primary tumor and of metastatic disease, particularly brain, epidural, and bone metastases.

Chest radiation therapy is sometimes given for superior vena cava syndrome, but chemotherapy alone, with radiation reserved for nonresponding patients, is appropriate initial treatment. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.) Brain metastases are treated with whole-brain radiation therapy. Intracranial metastases from small cell carcinoma, however, may respond to chemotherapy as readily as metastases in other organs.[28,29]

More patients with ED SCLC have greatly impaired performance status at the time of diagnosis when compared with patients with LD. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients.[22,30-36] Prospective randomized studies, however, have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent low-dose regimens or abbreviated courses of therapy. A study comparing chemotherapy every 3 weeks with treatment given as required for symptom control showed an improvement in QOL in those patients receiving regular treatment.[33][Level of evidence: 1iiDii] Other studies have tested intensive one-drug or two-drug regimens. A study conducted by the Medical Research Council demonstrated similar efficacy for an etoposide plus vincristine regimen and a four-drug regimen.[34] The latter regimen was associated with a greater risk of toxic effects and early death but was superior with respect to palliation of symptoms and psychological distress.[34][Level of evidence: 1iiC] Studies comparing a convenient oral treatment with single-agent oral etoposide versus combination therapy showed that the overall response rate and OS were significantly worse in the oral etoposide arm.[30,35][Level of evidence: 1iiA][25-27]

Subgroup analyses of phase II and phase III trials of SCLC patients by age showed that myelosuppression and doxorubicin-induced cardiac toxic effects were more severe in elderly patients than in younger patients and that the incidence of treatment-related death tended to be higher.[36] About 80% of elderly patients, however, received optimal treatment, and their survival was comparable to that of younger patients. The standard chemotherapy regimens for the general population could be applied to elderly patients in good general condition (i.e., performance status of 0–1, normal organ function, and no comorbidity). There is no evidence of a difference in response rate, DFS, or OS in elderly patients compared with younger patients.[28]

Standard treatment options:

1. Combination chemotherapy with or without PCI given to patients with complete responses:
   • EP or EC: etoposide plus cisplatin or carboplatin.

   Other regimens that appear to produce similar survival outcomes but have been studied less extensively or are in less common use include:

   • CAE/CDE: cyclophosphamide plus doxorubicin plus etoposide.
   • ICE: ifosfamide plus cisplatin plus etoposide.
   • Cisplatin plus irinotecan.
   • Cyclophosphamide plus doxorubicin plus etoposide plus vincristine.
   • CEV: cyclophosphamide plus etoposide plus vincristine.



2. Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases.

Treatment options under clinical evaluation:

Areas of active clinical evaluation in ED SCLC include evaluation of new drug regimens, dose intensity, alternative drug schedules, and high-dose chemotherapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with extensive stage small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Roth BJ, Johnson DH, Einhorn LH, et al.: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10 (2): 282-91, 1992.  [PUBMED Abstract]
   
   
2. Pujol JL, Carestia L, Daurès JP: Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 83 (1): 8-15, 2000.  [PUBMED Abstract]
   
   
3. Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer 59 (4): 584-90, 1989.  [PUBMED Abstract]
   
   
4. Okamoto H, Watanabe K, Kunikane H, et al.: Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer 97 (2): 162-9, 2007.  [PUBMED Abstract]
   
   
5. Noda K, Nishiwaki Y, Kawahara M, et al.: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346 (2): 85-91, 2002.  [PUBMED Abstract]
   
   
6. Hanna N, Bunn PA Jr, Langer C, 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 24 (13): 2038-43, 2006.  [PUBMED Abstract]
   
   
7. Eckardt JR, von Pawel J, Papai Z, et al.: Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol 24 (13): 2044-51, 2006.  [PUBMED Abstract]
   
   
8. Mavroudis D, Papadakis E, Veslemes M, et al.: A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol 12 (4): 463-70, 2001.  [PUBMED Abstract]
   
   
9. Niell HB, Herndon JE 2nd, Miller AA, et al.: Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 23 (16): 3752-9, 2005.  [PUBMED Abstract]
   
   
10. Spiro SG, Souhami RL, Geddes DM, et al.: Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 59 (4): 578-83, 1989.  [PUBMED Abstract]
    
    
11. Bleehen NM, Girling DJ, Machin D, et al.: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68 (6): 1150-6, 1993.  [PUBMED Abstract]
    
    
12. Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993.  [PUBMED Abstract]
    
    
13. Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996.  [PUBMED Abstract]
    
    
14. Schiller JH, Adak S, Cella D, et al.: 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 Oncol 19 (8): 2114-22, 2001.  [PUBMED Abstract]
    
    
15. Bozcuk H, Artac M, Ozdogan M, et al.: Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A metaanalysis of the published controlled trials. Cancer 104 (12): 2650-7, 2005.  [PUBMED Abstract]
    
    
16. Cohen MH, Creaven PJ, Fossieck BE Jr, et al.: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 61 (3): 349-54, 1977 May-Jun.  [PUBMED Abstract]
    
    
17. Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993.  [PUBMED Abstract]
    
    
18. Fukuoka M, Masuda N, Negoro S, et al.: CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer 75 (2): 306-9, 1997.  [PUBMED Abstract]
    
    
19. Woll PJ, Hodgetts J, Lomax L, et al.: Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer. J Clin Oncol 13 (3): 652-9, 1995.  [PUBMED Abstract]
    
    
20. Steward WP, von Pawel J, Gatzemeier U, et al.: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 16 (2): 642-50, 1998.  [PUBMED Abstract]
    
    
21. Thatcher N, Girling DJ, Hopwood P, et al.: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British Medical Research Council Multicenter Randomized Trial. Medical Research Council Lung Cancer Working Party. J Clin Oncol 18 (2): 395-404, 2000.  [PUBMED Abstract]
    
    
22. James LE, Gower NH, Rudd RM, et al.: A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign trial. Br J Cancer 73 (12): 1563-8, 1996.  [PUBMED Abstract]
    
    
23. Pujol JL, Douillard JY, Rivière A, et al.: Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 15 (5): 2082-9, 1997.  [PUBMED Abstract]
    
    
24. Ardizzoni A, Tjan-Heijnen VC, Postmus PE, et al.: Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923. J Clin Oncol 20 (19): 3947-55, 2002.  [PUBMED Abstract]
    
    
25. Lorigan P, Woll PJ, O'Brien ME, et al.: Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 97 (9): 666-74, 2005.  [PUBMED Abstract]
    
    
26. Buchholz E, Manegold C, Pilz L, et al.: Standard versus dose-intensified chemotherapy with sequential reinfusion of hematopoietic progenitor cells in small cell lung cancer patients with favorable prognosis. J Thorac Oncol 2 (1): 51-8, 2007.  [PUBMED Abstract]
    
    
27. Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007.  [PUBMED Abstract]
    
    
28. Twelves CJ, Souhami RL, Harper PG, et al.: The response of cerebral metastases in small cell lung cancer to systemic chemotherapy. Br J Cancer 61 (1): 147-50, 1990.  [PUBMED Abstract]
    
    
29. Nugent JL, Bunn PA Jr, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 44 (5): 1885-93, 1979.  [PUBMED Abstract]
    
    
30. Girling DJ: Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet 348 (9027): 563-6, 1996.  [PUBMED Abstract]
    
    
31. Murray N, Grafton C, Shah A, et al.: Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 16 (10): 3323-8, 1998.  [PUBMED Abstract]
    
    
32. Westeel V, Murray N, Gelmon K, et al.: New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 16 (5): 1940-7, 1998.  [PUBMED Abstract]
    
    
33. Earl HM, Rudd RM, Spiro SG, et al.: A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 64 (3): 566-72, 1991.  [PUBMED Abstract]
    
    
34. Randomised trial of four-drug vs less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Medical Research Council Lung Cancer Working Party. Br J Cancer 73 (3): 406-13, 1996.  [PUBMED Abstract]
    
    
35. Souhami RL, Spiro SG, Rudd RM, et al.: Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 89 (8): 577-80, 1997.  [PUBMED Abstract]
    
    
36. Sekine I, Yamamoto N, Kunitoh H, et al.: Treatment of small cell lung cancer in the elderly based on a critical literature review of clinical trials. Cancer Treat Rev 30 (4): 359-68, 2004.  [PUBMED Abstract]
    
    

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Recurrent Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

At the time of recurrence, many small cell lung cancer (SCLC) patients are potential candidates for further therapy. Although second-line chemotherapy has been shown to produce tumor regression, responses are usually short lived; the median survival is rarely more than 12 months and usually less than 6 months after second-line therapy.[1] Response to first-line chemotherapy predicts for subsequent response to second-line therapy.

In analogy to other chemosensitive tumors (e.g., Hodgkin lymphoma and ovarian epithelial cancer), two main categories of patients receiving second-line chemotherapy have been described: sensitive and resistant. Sensitive patients have a first-line response that lasted more than 90 days after treatment was completed. These patients have the greatest benefit from second-line chemotherapy. Resistant patients either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days of completion of their primary therapy.[2] Patients with sensitive disease respond to the same initial regimen in approximately 50% of cases; however, cumulative toxic effects may ensue.[3] Results from phase II studies of drugs such as topotecan, irinotecan, and gemcitabine indicate that response rates to agents vary depending on whether patients have sensitive, resistant, or refractory disease.[4-8][Level of evidence: 3iiiDii]

A randomized comparison of second-line treatment with either cyclophosphamide, doxorubicin, and vincristine (CAV) or topotecan in patients with sensitive disease reported no significant difference in response rates or survival, but palliation of common lung cancer symptoms was better with topotecan.[7][Level of evidence: 1iiC] A phase III trial comparing chemotherapy with best supportive care (BSC) in relapsed SCLC patients demonstrated that the addition of oral topotecan to BSC significantly increased overall survival and resulted in better symptom control compared with BSC alone.[9] The study enrolled 141 patients with chemosensitive or chemoresistant relapsed SCLC who were unsuitable for further standard intravenous chemotherapy. The median survival times for patients receiving topotecan plus BSC were 25.9 weeks versus 13.9 weeks for BSC alone (P = .01).[10][Level of evidence: 1iiA]

A randomized phase III trial (CWRU-SKF-1598) of 304 patients assessed the use of oral topotecan (2.3 mg/m²/day for 5 days every 21 days) or intravenous topotecan (1.5 mg/m²/day for 5 days every 21 days). Confirmed response rates were 18.3% and 21.9%, respectively.[11][Level of evidence: 1iiDii] Secondary endpoints of median survival and 1-year survival rates were also similar (33 weeks vs. 35 weeks and 33% vs. 29%, respectively). Patients receiving oral topotecan experienced less grade 4 neutropenia (47% vs. 64.2%) but more diarrhea of all grades (35.9% vs. 19.9%) compared with intravenous topotecan. Quality-of-life (QOL) analysis (using a nonvalidated QOL questionnaire) demonstrated no significant difference between the two arms.[11]

Patients with sensitive disease may achieve response to a number of agents including topotecan, irinotecan, taxanes, vinorelbine, paclitaxel, or gemcitabine.[4-8,11-13][Level of evidence: 3iiiDii] Response rates to combination agents are generally higher than those reported for single agents;[14,15] however, many studies do not report the patients with sensitive, resistant, or refractory disease.

Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression caused by the tumor have achieved successful palliation with endobronchial laser therapy (for endobronchial lesions only) and/or brachytherapy.[16] Expandable metal stents can be safely inserted under local anesthesia via the bronchoscope, which results in improved symptoms and pulmonary function in patients with malignant airways obstruction.[17] Patients with progressive intrathoracic tumor after failing initial chemotherapy can achieve significant tumor responses, palliation of symptoms, and short-term local control with external-beam radiation therapy. Only the rare patient, however, will experience long-term survival following salvage radiation therapy.[18]

Patients with central nervous system (CNS) recurrences can often obtain palliation of symptoms with radiation therapy and/or additional chemotherapy. The majority of patients treated with radiation therapy obtain objective responses and improvement following radiation therapy.[19] A retrospective review showed that 43% of patients treated with additional chemotherapy at the time of CNS relapse respond to second-line chemotherapy.[20]

Standard treatment options:

1. Topotecan.



2. Other chemotherapeutic agents.



3. Palliative radiation therapy.



4. Local palliation with endobronchial laser therapy, endobronchial stents, and/or brachytherapy.



5. Clinical trials of phase I or phase II drugs.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Davies AM, Evans WK, Mackay JA, et al.: Treatment of recurrent small cell lung cancer. Hematol Oncol Clin North Am 18 (2): 387-416, 2004.  [PUBMED Abstract]
   
   
2. Giaccone G, Donadio M, Bonardi G, et al.: Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy. J Clin Oncol 6 (8): 1264-70, 1988.  [PUBMED Abstract]
   
   
3. Postmus PE, Berendsen HH, van Zandwijk N, et al.: Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol 23 (9): 1409-11, 1987.  [PUBMED Abstract]
   
   
4. Sandler AB: Irinotecan in small-cell lung cancer: the US experience. Oncology (Williston Park) 15 (1 Suppl 1): 11-2, 2001.  [PUBMED Abstract]
   
   
5. van der Lee I, Smit EF, van Putten JW, et al.: Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol 12 (4): 557-61, 2001.  [PUBMED Abstract]
   
   
6. Masuda N, Fukuoka M, Kusunoki Y, et al.: CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10 (8): 1225-9, 1992.  [PUBMED Abstract]
   
   
7. Perez-Soler R, Glisson BS, Lee JS, et al.: Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 14 (10): 2785-90, 1996.  [PUBMED Abstract]
   
   
8. Masters GA, Declerck L, Blanke C, et al.: Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 21 (8): 1550-5, 2003.  [PUBMED Abstract]
   
   
9. von Pawel J, Schiller JH, Shepherd FA, et al.: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17 (2): 658-67, 1999.  [PUBMED Abstract]
   
   
10. O'Brien ME, Ciuleanu TE, Tsekov H, et al.: Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 24 (34): 5441-7, 2006.  [PUBMED Abstract]
    
    
11. Eckardt JR, von Pawel J, Pujol JL, et al.: Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 25 (15): 2086-92, 2007.  [PUBMED Abstract]
    
    
12. Ardizzoni A, Hansen H, Dombernowsky P, et al.: Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 15 (5): 2090-6, 1997.  [PUBMED Abstract]
    
    
13. Furuse K, Kubota K, Kawahara M, et al.: Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Japan Lung Cancer Vinorelbine Study Group. Oncology 53 (2): 169-72, 1996 Mar-Apr.  [PUBMED Abstract]
    
    
14. Smit EF, Fokkema E, Biesma B, et al.: A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 77 (2): 347-51, 1998.  [PUBMED Abstract]
    
    
15. Rocha-Lima CM, Herndon JE 2nd, Lee ME, et al.: Phase II trial of irinotecan/gemcitabine as second-line therapy for relapsed and refractory small-cell lung cancer: Cancer and Leukemia Group B Study 39902. Ann Oncol 18 (2): 331-7, 2007.  [PUBMED Abstract]
    
    
16. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.  [PUBMED Abstract]
    
    
17. Wilson GE, Walshaw MJ, Hind CR: Treatment of large airway obstruction in lung cancer using expandable metal stents inserted under direct vision via the fibreoptic bronchoscope. Thorax 51 (3): 248-52, 1996.  [PUBMED Abstract]
    
    
18. Ochs JJ, Tester WJ, Cohen MH, et al.: "Salvage" radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy. Cancer Treat Rep 67 (12): 1123-6, 1983.  [PUBMED Abstract]
    
    
19. Carmichael J, Crane JM, Bunn PA, et al.: Results of therapeutic cranial irradiation in small cell lung cancer. Int J Radiat Oncol Biol Phys 14 (3): 455-9, 1988.  [PUBMED Abstract]
    
    
20. Kristensen CA, Kristjansen PE, Hansen HH: Systemic chemotherapy of brain metastases from small-cell lung cancer: a review. J Clin Oncol 10 (9): 1498-502, 1992.  [PUBMED Abstract]
    
    

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