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.)

As in limited-stage small cell cancer (SCLC), chemotherapy should be given as multiple agents in doses associated with at least moderate toxic effects to produce the best results in patients with extensive-stage disease. Doses and schedules used in current programs yield overall response rates of 70% to 85% and complete response rates of 20% to 30% in patients with extensive-stage disease. Since overt disseminated disease is present, combination chemotherapy is the cornerstone of treatment of this stage of SCLC. Combinations containing two or more drugs are needed for maximal benefit.

The relative effectiveness of most two- to four-drug combination programs appears similar, and a large number of potential combinations are available. Some studies such as the ECOG-7593 trial, for example, have administered two of these or other regimens in alternating sequences, but no proof exists that this strategy yields substantial survival improvement.[1-4] 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 extensive disease and compared cisplatin and etoposide with a modified weekly regimen of cisplatin and irinotecan.[6][Level of evidence: 1iiA] The modified weekly irinotecan/cisplatin regimen resulted in less myelosuppression but more diarrhea and vomiting.[6][Level of evidence: 1iiA] A third study (SWOG-S0124) comparing irinotecan versus etoposide with cisplatin using doses and schedules similar to the original Japanese study is under way. 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.

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.[8,9] No clear evidence is available from reported data that maintenance chemotherapy will improve survival duration.[10-13]

Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with extensive-stage SCLC. Radiation therapy, however, plays an extremely 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 irradiation reserved for nonresponding patients, is appropriate initial treatment. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.) Brain metastases are appropriately treated with whole-brain radiation therapy. Intracranial metastases from small cell carcinoma, however, may respond to chemotherapy as readily as metastases in other organs.[13,14]

Patients with small cell lung cancer treated with chemotherapy with or without chest irradiation, 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.[15,16] 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.[16-18] 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.[16] 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.[16][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.[19-21] Prospective studies, however, have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated.[16] In addition, the majority of patients with SCLC 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.[22] Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment.[19-21] 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.

Many more patients with extensive-stage SCLC have greatly impaired performance status at the time of diagnosis when compared with patients with limited-stage disease. 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.[23-26] 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 or low-dose regimens.[25-27]

Standard treatment options:

1. Combination chemotherapy with one of the following regimens with or without PCI given to patients with complete responses: The following regimens produce similar survival outcomes:
   • CAV: cyclophosphamide plus doxorubicin plus vincristine.[28,29]
   • CAE: cyclophosphamide plus doxorubicin plus etoposide.[30]
   • EP or EC: etoposide plus cisplatin or carboplatin.[31,32]
   • ICE: ifosfamide plus carboplatin plus etoposide.[33]
   • Cisplatin plus irinotecan.[5]

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

   • Cyclophosphamide plus doxorubicin plus etoposide plus vincristine.[34]
   • CEV: cyclophosphamide plus etoposide plus vincristine.[35]
   • Single-agent etoposide.[23]
   • PET: cisplatin plus etoposide plus paclitaxel.[36]



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



3. Identification of effective new agents is difficult in patients who have previously been treated with standard chemotherapy because response rates to agents, even of known efficacy, are known to be lower than in previously untreated patients. This situation led to the suggestion that patients with extensive disease who are medically stable be treated with new agents under evaluation, with provisions for early change to standard combination therapy if there is no response.[37] Such a strategy has been shown to be feasible, with survival comparable to survival with initial standard therapy, as long as the patients with extensive disease are carefully chosen.[38-40] A variety of other strategies have been proposed, depending on the activity of the new agent in other tumors, in preclinical SCLC models, or the activity of drug analogs.[41] Active single agents undergoing further evaluation include paclitaxel and topotecan.[42,43]

Treatment options under clinical evaluation:

Areas of active clinical evaluation in extensive-stage SCLC include evaluation of new drug regimens, dose intensity, alternative drug schedules, and high-dose chemotherapy. A meta-analysis of long-term outcomes in extensive-stage disease did not show consistent evidence for improved response rates or survival for more intense chemotherapy regimens.[44][Level of evidence: 1iiA]

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. Evans WK, Feld R, Murray N, et al.: Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer. A multicenter, randomized clinical trial by the National Cancer Institute of Canada. Ann Intern Med 107 (4): 451-8, 1987.  [PUBMED Abstract]
   
   
2. Wolf M, Pritsch M, Drings P, et al.: Cyclic-alternating versus response-oriented chemotherapy in small-cell lung cancer: a German multicenter randomized trial of 321 patients. J Clin Oncol 9 (4): 614-24, 1991.  [PUBMED Abstract]
   
   
3. 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]
   
   
4. 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]
   
   
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. 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]
   
   
9. 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]
   
   
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. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. Lee JS, Murphy WK, Glisson BS, et al.: Primary chemotherapy of brain metastasis in small-cell lung cancer. J Clin Oncol 7 (7): 916-22, 1989.  [PUBMED Abstract]
    
    
15. 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]
    
    
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. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. 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]
    
    
22. 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]
    
    
23. Carney DN, Grogan L, Smit EF, et al.: Single-agent oral etoposide for elderly small cell lung cancer patients. Semin Oncol 17 (1 Suppl 2): 49-53, 1990.  [PUBMED Abstract]
    
    
24. Evans WK, Radwi A, Tomiak E, et al.: Oral etoposide and carboplatin. Effective therapy for elderly patients with small cell lung cancer. Am J Clin Oncol 18 (2): 149-55, 1995.  [PUBMED Abstract]
    
    
25. 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]
    
    
26. 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]
    
    
27. 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]
    
    
28. Feld R, Evans WK, DeBoer G, et al.: Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung. J Clin Oncol 2 (4): 294-304, 1984.  [PUBMED Abstract]
    
    
29. Greco FA, Richardson RL, Snell JD, et al.: Small cell lung cancer. Complete remission and improved survival. Am J Med 66 (4): 625-30, 1979.  [PUBMED Abstract]
    
    
30. Aisner J, Whitacre M, Van Echo DA, et al.: Combination chemotherapy for small cell carcinoma of the lung: continuous versus alternating non-cross-resistant combinations. Cancer Treat Rep 66 (2): 221-30, 1982.  [PUBMED Abstract]
    
    
31. Evans WK, Shepherd FA, Feld R, et al.: VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 3 (11): 1471-7, 1985.  [PUBMED Abstract]
    
    
32. Skarlos DV, Samantas E, Kosmidis P, et al.: Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 5 (7): 601-7, 1994.  [PUBMED Abstract]
    
    
33. Thatcher N: Ifosfamide/carboplatin/etoposide (ICE) regimen in small cell lung cancer. Lung Cancer 9(Suppl 1): s51-s67, 1993. 
    
    
34. Jackson DV Jr, Case LD, Zekan PJ, et al.: Improvement of long-term survival in extensive small-cell lung cancer. J Clin Oncol 6 (7): 1161-9, 1988.  [PUBMED Abstract]
    
    
35. Hong WK, Nicaise C, Lawson R, et al.: Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: a randomized trial of the Bristol Lung Cancer Study Group. J Clin Oncol 7 (4): 450-6, 1989.  [PUBMED Abstract]
    
    
36. Glisson BS, Kurie JM, Perez-Soler R, et al.: Cisplatin, etoposide, and paclitaxel in the treatment of patients with extensive small-cell lung carcinoma. J Clin Oncol 17 (8): 2309-15, 1999.  [PUBMED Abstract]
    
    
37. Ettinger DS: Evaluation of new drugs in untreated patients with small-cell lung cancer: its time has come. J Clin Oncol 8 (3): 374-7, 1990.  [PUBMED Abstract]
    
    
38. Blackstein M, Eisenhauer EA, Wierzbicki R, et al.: Epirubicin in extensive small-cell lung cancer: a phase II study in previously untreated patients: a National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol 8 (3): 385-9, 1990.  [PUBMED Abstract]
    
    
39. Evans WK, Eisenhauer EA, Cormier Y, et al.: Phase II study of amonafide: results of treatment and lessons learned from the study of an investigational agent in previously untreated patients with extensive small-cell lung cancer. J Clin Oncol 8 (3): 390-5, 1990.  [PUBMED Abstract]
    
    
40. Ettinger DS, Finkelstein DM, Abeloff MD, et al.: Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: an Eastern Cooperative Oncology Group randomized study. J Natl Cancer Inst 84 (14): 1077-84, 1992.  [PUBMED Abstract]
    
    
41. Moore TD, Korn EL: Phase II trial design considerations for small-cell lung cancer. J Natl Cancer Inst 84 (3): 150-4, 1992.  [PUBMED Abstract]
    
    
42. Ettinger DS, Finkelstein DM, Sarma RP, et al.: Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 13 (6): 1430-5, 1995.  [PUBMED Abstract]
    
    
43. Schiller JH, Kim K, Hutson P, et al.: Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial. J Clin Oncol 14 (8): 2345-52, 1996.  [PUBMED Abstract]
    
    
44. 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]
    
    

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