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 (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]
   
   
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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]
    
    
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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]
    
    
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