Current Clinical Trials

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.)

In patients with limited-stage small cell lung cancer (SCLC), combination chemotherapy produces results that are clearly superior to single-agent treatment, and moderately intensive doses of drugs are superior to doses that produce only minimal or mild hematologic toxic effects. Current programs yield overall objective response rates of 65% to 90% and complete response rates of 45% to 75%. Because of the frequent presence of occult metastatic disease, chemotherapy is the cornerstone of treatment for patients with limited-stage SCLC. Combinations containing two or more drugs are needed for maximal effect.

Mature results of prospective randomized trials suggest that combined modality therapy produces a modest but significant improvement in survival compared with chemotherapy alone. Two meta-analyses showed an improvement in 3-year survival rates of about 5% for those receiving chemotherapy and radiation therapy compared with those receiving chemotherapy alone.[1,2] Most of the benefit occurred in patients younger than 65 years. Combined modality treatment is associated with increased morbidity and, in some trials, increased treatment-related mortality from pulmonary and hematologic toxic effects; proper administration requires close collaboration between medical and radiation oncologists.[3] In general, those studies including the SWOG-S0124 trial, for example showing a positive effect for combined modality therapy employed thoracic radiation therapy early in the course of treatment and concurrently with chemotherapy.[3-6]

Studies strongly suggest that minimal tumor doses in the range of 40 Gy to 45 Gy or more (standard fractionation) are necessary to effectively control tumors in the thorax.

The combination of etoposide and cisplatin chemotherapy with concurrent chest radiation therapy has now been used in multiple single institutional studies and in cooperative group studies. These studies have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival with less than a 3% treatment-related mortality.[3-7] 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 given for 5 weeks (26% vs. 16% at 5 years, P = .04). Although single daily fractions to higher doses are feasible, their clinical benefits are yet to be defined.[8][Level of evidence: 3iiiA] Esophagitis was increased with twice-daily treatment.[9][Level of evidence: 1iiA] The current standard treatment of patients with limited-stage SCLC should be a combination containing etoposide and cisplatin plus chest radiation therapy administered during the first or second cycle of chemotherapy administration.

The relative effectiveness of two- to five-drug regimens and different schedules of chest radiation therapy appear to be similar. A representative selection of regimens incorporating chemotherapy plus chest radiation therapy are listed below. The use of alternating chemotherapy regimens has not proven more effective than the consistent administration of a single regimen.[3,6,7,10-12] The optimal duration of chemotherapy for patients with limited-stage SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months.[3,7,13] No evidence is available from randomized trials EORTC-LCCG and European Lung Cancer Working Party that maintenance chemotherapy prolongs survival for patients with limited-stage SCLC.[10,14]

Patients presenting with superior vena cava syndrome are treated with combination chemotherapy with or without radiation therapy.[15,16] (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.) A small minority of limited-stage patients with adequate pulmonary function and with tumor 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.[17-20]

Patients treated with chemotherapy with or without chest radiation therapy who have achieved a complete remission can be considered for administration of prophylactic cranial irradiation (PCI). Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system metastases within 2 to 3 years after starting treatment.[21,22] The majority of these patients relapse only in their brain, and nearly all of those who relapse in their central nervous system die of their cranial metastases.[3,7,22] The risk of developing central nervous system metastases can be reduced by more than 50% by the administration of PCI in doses of 24 Gy.[22] 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 overall survival (OS) with the addition of PCI. The 3-year OS was improved from 15% to 21% with PCI.[22][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 central nervous system impairment.[23-25] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated.[22] In addition, the majority of patients with small cell lung cancer have neuropsychological abnormalities present before the start of cranial irradiation and have no detectable decline in their neurological status for as long as 2 years after the start of their cranial irradiation.[26] Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment.[23-25] 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 with chest irradiation (with or without PCI given to patients with complete responses):
   • EC: etoposide plus cisplatin plus 45 Gy chest radiation therapy.[3,7]



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



3. Surgical resection followed by chemotherapy or chemotherapy plus chest radiation therapy (with or without PCI in patients with complete responses) for patients with stage I disease.[17-20]

Treatment options under clinical evaluation:

Areas of active clinical evaluation for patients with limited-stage 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.[27,28]

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. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. 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]
    
    
22. 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]
    
    
23. 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]
    
    
24. 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]
    
    
25. 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]
    
    
26. Komaki R, Meyers CA, Shin DM, et al.: Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys 33 (1): 179-82, 1995.  [PUBMED Abstract]
    
    
27. Turrisi AT 3rd: Incorporation of radiotherapy fractionation in the combined-modality treatment of limited small-cell lung cancer. Chest 103 (4 Suppl): 418S-422S, 1993.  [PUBMED Abstract]
    
    
28. Ettinger DS: Concurrent paclitaxel-containing regimens and thoracic radiation therapy for limited-disease small cell lung cancer. Semin Radiat Oncol 9 (2 Suppl 1): 148-50, 1999.  [PUBMED Abstract]
    
    

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