Small Cell Lung Cancer Treatment Professional Information

Extensive 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.

As in limited stage small cell carcinoma, chemotherapy should be given as multiple agents in doses associated with at least moderate toxic effects in order to produce the best results in 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 extensive stage disease. Since overt disseminated disease is present, combination chemotherapy is the cornerstone of treatment of this stage of small cell lung cancer. Combinations containing two or more drugs are needed for maximal benefit.

The relative effectiveness of many 2- to 4-drug combination programs appears similar, and there are a large number of potential combinations. Therefore, a representative selection of regimens that have been found to be effective by at least two independent groups has been provided. Some physicians have administered two of these or other regimens in alternating sequences, but there is no proof that this strategy yields substantial survival improvement.^1-3 Optimal duration of chemotherapy is not clearly defined, but there is no obvious improvement in survival when the duration of drug administration exceeds 6 months.^4,5 There is no clear evidence from reported data that maintenance chemotherapy will improve survival duration.^6-9

Combination chemotherapy plus chest irradiation does not appear to improve survival compared with chemotherapy alone in extensive stage small cell lung cancer. However, radiation therapy plays an extremely important role in palliation of symptoms of the primary tumor and of metastatic disease, particularly brain, epidural, and bone metastases.

Chest irradiation is sometimes given for superior vena cava syndrome, but chemotherapy alone (with irradiation reserved for nonresponding patients) is appropriate initial treatment. Brain metastases are appropriately treated with whole-brain radiation therapy. However, intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.^9,10

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.^11,12 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.^12-14 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.¹² 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.^15-17 However, prospective studies have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated.¹² 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.¹⁸ Patients treated for small cell lung cancer continue to have declining neuropsychologic function after 2 years from the start of treatment.^15-17 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.

Many more patients with extensive stage small cell carcinoma have greatly impaired performance status at the time of diagnosis when compared to 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,^19-22 However, prospective randomized studies 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.^21-23

Treatment options:

Standard:

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 + doxorubicin + vincristine ^24,25
   CAE: cyclophosphamide + doxorubicin + etoposide ²⁶
   EP or EC: etoposide + cisplatin or carboplatin ^27,28
   ICE: ifosfamide + carboplatin + etoposide ²⁹

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

   cyclophosphamide + methotrexate + lomustine ³⁰
   cyclophosphamide + methotrexate + lomustine + vincristine ³¹
   cyclophosphamide + doxorubicin + etoposide + vincristine ³²
   CEV: cyclophosphamide + etoposide + vincristine ³³
   single-agent etoposide ¹⁹

   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.³⁴ 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.^35-37 A variety of other strategies have been proposed, depending on the activity of the new agent in other tumors, in preclinical small cell lung cancer models, or the activity of drug analogs.³⁸ Active single agents undergoing further evaluation include paclitaxel and topotecan.^39,40

Under clinical evaluation:

Areas of active clinical evaluation in extensive stage small cell lung cancer 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.⁴¹[Level of evidence: 1iiA]

References:

1. Evans WK, Feld R, Murray N, et al.: Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer. Annals of Internal Medicine 107(4): 451-458, 1987.
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. Journal of Clinical Oncology 9(4): 614-624, 1991.
3. Roth BJ, Johnson DH, Schacter LP, 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. Journal of Clinical Oncology 10(2): 282-291, 1992.
4. Spiro SG, Souhami RL, Geddes DM, et al.: Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. British Journal of Cancer 59(4): 578-583, 1989.
5. 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.
6. 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.
7. Bleehen NM, Fayers PM, Girling DJ, et al.: 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. British Journal of Cancer 59(4): 584-590, 1989.
8. 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.
9. Twelves CJ, Souhami RL, Harper PG, et al.: The response of cerebral metastases in small cell lung cancer to systemic chemotherapy. British Journal of Cancer 61(1): 147-150, 1990.
10. Lee JS, Murphy WK, Glisson BS, et al.: Primary chemotherapy of brain metastasis in small-cell lung cancer. Journal of Clinical Oncology 7(7): 916-922, 1989.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. Carney DN, Grogan L, Smit EF, et al.: Single-agent oral etoposide for elderly small cell lung cancer patients. Seminars in Oncology 17(1, Suppl 2): 49-53, 1990.
20. Evans WK, Radwi A, Tomiak E, et al.: Oral etoposide and carboplatin: effective therapy for elderly patients with small cell lung cancer. American Journal of Clinical Oncology 18(2): 149-155, 1995.

     

21. Medical Research Council Lung Cancer Working Party: Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Lancet 348(9027): 563-566, 1996.

     

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. British Journal of Cancer 73(12): 1563-1568, 1996.

     

23. Souhami RL, Spiro SG, Rudd RM, et al.: Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. Journal of the National Cancer Institute 89(8): 577-580, 1997.

     

24. Feld R, Evans WK, DeBoer G, et al.: Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung. Journal of Clinical Oncology 2(4): 294-304, 1984.

     

25. Greco FA, Richardson RL, Snell JD, et al.: Small cell lung cancer: complete remission and improved survival. American Journal of Medicine 66(4): 625-630, 1979.

     

26. 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 Treatment Reports 66(2): 221-230, 1982.

     

27. Evans WK, Shepherd FA, Feld R, et al.: VP-16 and cisplatin as first-line therapy for small-cell lung cancer. Journal of Clinical Oncology 3(11): 1471-1477, 1985.
28. 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. Annals of Oncology 5(7): 601-607, 1994.
29. Thatcher N: Ifosfamide/carboplatin/etoposide (ICE) regimen in small cell lung cancer. Lung Cancer 9(Suppl 1): s51-s67, 1993.
30. Cohen MH, Creaven PJ, Fossieck BE, et al.: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treatment Reports 61(3): 349-354, 1977.
31. Hansen HH, Dombernowsky P, Hansen M, et al.: Chemotherapy of advanced small-cell anaplastic carcinoma: superiority of a four-drug combination to a three-drug combination. Annals of Internal Medicine 89(2): 177-181, 1978.
32. Jackson DV, Case LD, Zekan PJ, et al.: Improvement of long-term survival in extensive small-cell lung cancer. Journal of Clinical Oncology 6(7): 1161-1169, 1988.
33. 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. Journal of Clinical Oncology 7(4): 450-456, 1989.
34. Ettinger DS: Evaluation of new drugs in untreated patients with small-cell lung cancer: its time has come. Journal of Clinical Oncology 8(3): 374-377, 1990.
35. 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. Journal of Clinical Oncology 8(3): 385-389, 1990.
36. 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. Journal of Clinical Oncology 8(3): 390-395, 1990.
37. 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. Journal of the National Cancer Institute 84(14): 1077-1084, 1992.
38. Moore TD, Korn EL: Phase II trial design considerations for small-cell lung cancer. Journal of the National Cancer Institute 84(3): 150-154, 1992.
39. 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. Journal of Clinical Oncology 13(6): 1430-1435, 1995.
40. 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. Journal of Clinical Oncology 14(8): 2345-2352, 1996.
41. Klasa RJ, Murray N, Coldman AJ: Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. Journal of Clinical Oncology 9(3): 499-508, 1991.

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