Small Cell Lung Cancer Treatment Professional Information

Limited Stage 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 levels of evidence summary for more information.

In patients with small cell lung cancer, 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 of limited stage small cell lung cancer. 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 to those receiving chemotherapy alone.^1,2 Most of the benefit occurred in patients less than 65 years of age. 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 showing a positive effect for combined modality therapy employed thoracic irradiation early in the course of treatment, concurrently with chemotherapy.^3-6

Studies strongly suggest that minimal tumor doses in the range of 4,000 to 4,500 cGy 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 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 over 3 weeks, compared to once-daily radiation therapy given over 5 weeks (26% versus 16% at 5 years, p=0.04). However, esopohagitis was increased with twice-daily treatment.⁸[Level of evidence: 1iiA] The current standard treatment of patients with limited stage small cell lung cancer 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 2- to 5-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.^3,6,7,9-11 The optimal duration of chemotherapy for patients with limited stage small cell lung cancer is not clearly defined but there is no improvement in survival after the duration of drug administration exceeds 3 to 6 months.^3,7,12 There is no evidence from randomized trials that maintenance chemotherapy prolongs survival for patients with limited stage small cell lung cancer.^9,13

Patients presenting with superior vena cava syndrome are treated with combination chemotherapy with or without radiation therapy.^14,15 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.^16-19

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.^20,21 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.^3,7,21 The risk of developing central nervous system metastases can be reduced by more than 50% by the administration of PCI in doses of 2400 cGy.²¹ A meta-analysis of 7 randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and overall survival with the addition of PCI. The 3-year overall survival was improved from 15% to 21% with PCI.²²[Level of evidence: 1iiA]

Retrospective studies have shown that long-term survivors of small cell lung cancer (>2 years from the start of treatment) have a high incidence of central nervous system impairment.^23-25 However, prospective studies have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated.²¹ 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 up to 2 years after the start of their cranial irradiation.²⁶ Patients treated for small cell lung cancer continue to have declining neuropsychologic function after 2 years from the start of treatment.^23-25 Therefore, 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.

Treatment options:

Standard:

1. Combination chemotherapy with one of the following regimens and chest irradiation (with or without PCI given to patients with complete responses):

   The following regimens produce similar survival outcomes:

   EC: etoposide + cisplatin + 4000-4500 cGy chest radiation therapy^3,7
   ECV: etoposide + cisplatin + vincristine + 4500 cGy chest radiation therapy⁵

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 in highly selected cases.^16-19
   

Under clinical evaluation:

Areas of active clinical evaluation in limited stage small cell lung cancer
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., 3-dimensional treatment planning), and timing of thoracic radiation.^27-29

References:

1. Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. New England Journal of Medicine 327(23): 1618-1624, 1992.
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. Journal of Clinical Oncology 10(6): 890-895, 1992.
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. Journal of Clinical Oncology 11(2): 336-344, 1993.
4. Turrisi AT, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. International Journal of Radiation Oncology, Biology, Physics 19(6): 1473-1479, 1990.
5. McCracken JD, Janaki LM, Crowley JJ, et al.: Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group study. Journal of Clinical Oncology 8(5): 892-898, 1990.
6. Takada M, Fukuoka M, Furuse K, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy (TRT) in combination with cisplatin (C) and etoposide (E) for limited-stage (LS) small cell lung cancer (SCLC): preliminary results of the Japan Clinical Oncology Group (JCOG). Proceedings of the American Society of Clinical Oncology 15:A-1103, 372, 1996.
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. Journal of Clinical Oncology 14(3): 806-813, 1996.
8. Turrisi AT III, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. New England Journal of Medicine 340(4): 265-271, 1999.

    

9. Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. Journal of Clinical Oncology 11(7): 1230-1240, 1993.
10. 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. Journal of Clinical Oncology 8(1): 39-47, 1990.
11. 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. Journal of the National Cancer Institute 83(12): 855-861, 1991.
12. Bleehan NM, Girling DJ, Machin D, et al, for the Medical Research Council Lung Cancer Working Party: 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. British Journal of Cancer 68(6): 1150-1156, 1993.
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. Journal of Clinical Oncology 14(8): 2337-2344, 1996.
14. Urban T, Lebeau B, Chastang C, et al.: Superior vena cava syndrome in small-cell lung cancer. Archives of Internal Medicine 153(3): 384-387, 1993.
15. Wurschmidt F, Bunemann H, Heilmann HP: Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases. International Journal of Radiation Oncology, Biology, Physics 33(1): 77-82, 1995.
16. 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): 272-277, 1985.
17. 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. Journal of Thoracic and Cardiovascular Surgery 97(2): 177-186, 1989.
18. Prasad US, Naylor AR, Walker WS, et al.: Long-term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44(10): 784-787, 1989.
19. Smit EF, Groen HJ, Timens W, et al.: Surgical resection for small cell carcinoma of the lung: a retrospective study. Thorax 49(1): 20-22, 1994.
20. Nugent JL, Bunn PA, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 44(5): 1885-1893, 1979.
21. Arriagada R, Le Chevalier T, Borie F, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Journal of the National Cancer Institute 87(3): 183-190, 1995.
22. Arriagada R, Auperin A, et al., on behalf of the PCIO Collaborative group: Prophylactic cranial irradiation overview (PCIO) in patients with small cell lung cancer (SCLC) in complete remission (CR). Proceedings of the American Society of Clinical Oncology 17: A-1758, 457a, 1998.
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. Journal of Clinical Oncology 8(1): 48-56, 1990.
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. International Journal of Radiation Oncology, Biology, Physics 14(6): 1109-1117, 1988.
25. Cull A, Gregor A, Hopwood P, et al.: Neurological and cognitive impairment in long-term survivors of small cell lung cancer. European Journal of Cancer 30A(8): 1067-1074, 1994.
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. International Journal of Radiation Oncology, Biology, Physics 33(1): 179-182, 1995.
27. Turrisi AT: Incorporation of radiotherapy fractionation in the combined-modality treatment of limited small-cell lung cancer. Chest 103(4, Suppl): 418s-422s, 1993.
28. Ihde DC, Grayson J, Woods E, et al.: Twice daily chest irradiation as an adjuvant to etoposide/cisplatin therapy of limited stage small cell lung cancer. In: Salmon SE, Ed.: Adjuvant Therapy of Cancer VI. Philadelphia: W.B. Saunders Company, 1990, pp 162-165.
29. Armstrong JG, Rosenstein MM, Kris MG, et al.: Twice daily thoracic irradiation for limited small cell lung cancer. International Journal of Radiation Oncology, Biology, Physics 21(5): 1269-1274, 1991.

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