Cancer Treatment Information

Small Cell Lung Cancer
(PDQ®): Treatment

Date Last Modified: 09/29/2003

Table of Contents

General Information
Cellular Classification
Stage Information
Treatment Option Overview
Limited Stage Small Cell Lung Cancer
Extensive Stage Small Cell Lung Cancer
Recurrent Small Cell Lung Cancer
More Information

General Information

Note: Separate PDQ summaries on Prevention of Lung Cancer and Screening for Lung Cancer are also available.

Without treatment, small cell carcinoma of the lung has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. Compared with other cell types of lung cancer, small cell carcinoma has a greater tendency to be widely disseminated by the time of diagnosis, but is much more responsive to chemotherapy and irradiation.

Because patients with small cell lung cancer tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[1] However, with incorporation of current chemotherapy regimens into the treatment program, survival is unequivocally prolonged, with at least a 4- to 5-fold improvement in median survival compared with patients who are given no therapy. Furthermore, about 10% of the total population of patients remain free of disease over 2 years from the start of therapy, the time period during which most relapses occur. However, even these patients are at risk of dying from lung cancer (both small and non-small cell types).[2] The overall survival at 5 years is 5% to 10%.[2-4]

Limited stage disease

At the time of diagnosis, approximately 30% of patients with small cell carcinoma will have tumor confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited stage disease, and most 2-year disease-free survivors come from this group. In limited stage disease, median survival of 16 to 24 months with current forms of treatment can reasonably be expected.[5-7] A small proportion of patients with limited stage disease may benefit from surgery with or without adjuvant chemotherapy; these patients have an even better prognosis.

Extensive stage disease

Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive stage disease and have a worse prognosis than patients with limited stage disease. Median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare.

Prognostic factors

The pretreatment prognostic factors which consistently predict for prolonged survival include good performance status, female gender, and limited stage disease.[3,8,9] Patients with involvement of the central nervous system or liver at the time of diagnosis have a significantly worse outcome.[3,8-10] In general, patients who are confined to bed tolerate aggressive forms of treatment poorly, have increased morbidity, and rarely attain 2-year disease-free survival. However, patients with poor performance status can often derive significant palliative benefit and prolongation of survival from treatment.

Regardless of stage, the current prognosis for patients with small cell lung cancer is unsatisfactory even though considerable improvements in diagnosis and therapy have been made over the past 10 to 15 years. Therefore, all patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.

References

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]

Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract]

Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract]

Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract]

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]

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]

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]

Wolf M, Holle R, Hans K, et al.: Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): the role of sex as a predictor for survival. Br J Cancer 63 (6): 986-92, 1991. [PUBMED Abstract]

Rawson NS, Peto J: An overview of prognostic factors in small cell lung cancer. A report from the Subcommittee for the Management of Lung Cancer of the United Kingdom Coordinating Committee on Cancer Research. Br J Cancer 61 (4): 597-604, 1990. [PUBMED Abstract]

Chute JP, Venzon DJ, Hankins L, et al.: Outcome of patients with small-cell lung cancer during 20 years of clinical research at the US National Cancer Institute. Mayo Clin Proc 72 (10): 901-12, 1997. [PUBMED Abstract]

Cellular Classification

Review of pathologic material by an experienced lung cancer pathologist is important prior to initiating treatment of any patient with small cell lung cancer. The intermediate subtype of small cell carcinoma and the more readily recognized lymphocyte-like or "oat cell" subtype are equally responsive to treatment.

The current classification of subtypes of small cell lung cancer are:[1]

Small cell carcinoma.

Mixed small cell/large cell carcinoma.

Combined small cell carcinoma (small cell lung cancer combined with neoplastic squamous and/or glandular components).

Neuroendocrine carcinomas of the lung represent a spectrum of disease. At one extreme is small cell lung cancer, which has a poor prognosis. At the other extreme are bronchial carcinoids, with an excellent prognosis after surgical excision.[2] Between these extremes is an unusual entity called well-differentiated neuroendocrine carcinoma of the lung.[3] It has been referred to as malignant carcinoid, metastasizing bronchial adenoma, pleomorphic carcinoid, nonbenign carcinoid tumor, and atypical carcinoid. Like small cell lung cancer, it occurs primarily in cigarette smokers, but it metastasizes less frequently. The 5-year survival rate is greater than 50% in some series, and surgical cure appears possible in most stage I patients. Careful diagnosis is important, however, since the differential pathologic diagnosis from small cell lung cancer may be difficult.

References

Hirsch FR, Matthews MJ, Aisner S, et al.: Histopathologic classification of small cell lung cancer. Changing concepts and terminology. Cancer 62 (5): 973-7, 1988. [PUBMED Abstract]

Harpole DH Jr, Feldman JM, Buchanan S, et al.: Bronchial carcinoid tumors: a retrospective analysis of 126 patients. Ann Thorac Surg 54 (1): 50-4; discussion 54-5, 1992. [PUBMED Abstract]

Lequaglie C, Patriarca C, Cataldo I, et al.: Prognosis of resected well-differentiated neuroendocrine carcinoma of the lung. Chest 100 (4): 1053-6, 1991. [PUBMED Abstract]

Stage Information

Staging procedures are important in distinguishing patients who have disease limited to their thorax from those who have distant metastases. Determining the stage of cancer by nonsurgical means allows a better assessment of prognosis and identifies sites of tumor that can be evaluated for response. Also, the choice of treatment is usually influenced by stage, particularly when chest irradiation or surgical excision is added to chemotherapy for patients with limited stage disease. Staging procedures commonly used to document distant metastases include bone marrow examination, computed tomographic or magnetic resonance imaging scans of the brain, computerized tomographic scans of the chest and the abdomen, and radionuclide bone scans.

Because occult or overt metastatic disease is present at diagnosis in most patients, survival is usually not affected by small differences in the amount of locoregional tumor involvement. Therefore, the detailed TNM staging system developed for lung cancer by the American Joint Committee on Cancer (AJCC) is not commonly employed in patients with small cell carcinoma. (Refer to the PDQ summary on Non-Small Cell Lung Cancer Treatment for more information on this staging system.) A simple 2-stage system developed by the Veterans Administration Lung Cancer Study Group is more commonly used for staging small cell lung cancer patients.

Limited stage disease

Limited stage small cell lung cancer means tumor confined to the hemithorax of origin, the mediastinum, and the supraclavicular nodes, which can be encompassed within a "tolerable" radiation therapy port. There is no universally accepted definition of this term, and patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from limited stage by various groups.

Extensive stage disease

Extensive stage small cell lung cancer means tumor that is too widespread to be included within the definition of limited stage disease above. Patients with distant metastases (M1) are always considered to have extensive stage disease.[1,2]

References

Ihde D, Souhami B, Comis R, et al.: Small cell lung cancer. Lung Cancer 17 (Suppl 1): S19-21, 1997. [PUBMED Abstract]

Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997. [PUBMED Abstract]

Treatment Option Overview

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.)

The majority of patients with small cell lung cancer die of their tumor despite the best available treatment. Most of the improvements in the survival of patients with small cell lung cancer are attributable to clinical trials which have attempted to improve on the best available, accepted therapy. Patient entry into such studies is highly desirable.

Treatments under clinical evaluation in small cell lung cancer include studies of the timing of thoracic radiation therapy (for patients with limited stage disease) and studies evaluating the role of surgery for stage I patients in conjunction with varying drug doses in current regimens, using different schedules of chemotherapeutic agents, and using new drug regimens composed of standard and new agents.[1] Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.

Prospective randomized trials have not demonstrated a consistent survival advantage for patients treated with higher doses of chemotherapy.[2,3] One retrospective review of chemotherapy trials did not show consistent evidence for improved response rates or survival with more dose-intense chemotherapy regimens.[4][Level of evidence: 1iiA] Even chemotherapy of the intensity used in autologous bone marrow transplant regimens has not clearly been shown to improve survival in patients with small cell lung cancer.[5] A study that compared the combination of dose-intensive cisplatin, vincristine, doxorubicin, and etoposide with standard doses of cyclophosphamide, doxorubicin, vincristine/etoposide, and cisplatin (CAV/EP) found that the more dose intensive regimen produced a higher response rate, but at the cost of increased treatment-related mortality, and did not result in improved progression-free or overall survival.[6][Level of evidence: 1iiA]

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References

Comis RL, Friedland DM, Good BC: Small-cell lung cancer: a perspective on the past and a preview of the future. Oncology (Huntingt) 12 (1 Suppl 2): 44-50, 1998. [PUBMED Abstract]

Ihde DC, Mulshine JL, Kramer BS, et al.: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 12 (10): 2022-34, 1994. [PUBMED Abstract]

Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract]

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]

Elias AD, Ayash L, Frei E 3rd, et al.: Intensive combined modality therapy for limited-stage small-cell lung cancer. J Natl Cancer Inst 85 (7): 559-66, 1993. [PUBMED Abstract]

Murray N, Livingston RB, Shepherd FA, et al.: Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 17 (8): 2300-8, 1999. [PUBMED Abstract]

Limited Stage Small Cell Lung Cancer

In patients with limited stage 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 for patients with limited stage small cell lung cancer. Combinations containing 2 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=.04). However, esophagitis 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] (Refer to the PDQ summary on Superior Vena Cava Syndrome Treatment 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.[16-19]

Patients 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 significantly worse 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.

Standard treatment options:

Combination chemotherapy with chest irradiation (with or without PCI given to patients with complete responses):

EC: etoposide + cisplatin + 4500 cGy chest radiation therapy.[3,7]
Combination chemotherapy (with or without PCI in patients with complete responses), especially in patients with impaired pulmonary function or poor performance status.
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.[16-19]
Treatment options under clinical evaluation:

Areas of active clinical evaluation for patients with 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.[27,28] Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.

References

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]

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]

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]

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]

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). [Abstract] Proceedings of the American Society of Clinical Oncology 15:A-1103, 372, 1996.

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Arriagada R, Auperin A, et al.: Prophylactic cranial irradiation overview (PCIO) in patients with small cell lung cancer (SCLC) in complete remission (CR). [Abstract] Proceedings of the American Society of Clinical Oncology 17: A1758, 457a, 1998.

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]

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]

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]

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]

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]

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]

Extensive Stage Small Cell Lung Cancer

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 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 small cell lung cancer. Combinations containing 2 or more drugs are needed for maximal benefit.

The relative effectiveness of most 2- to 4-drug combination programs appears similar, and there are a large number of potential combinations. Some studies have administered 2 of these or other regimens in alternating sequences, but there is no proof that this strategy yields substantial survival improvement.[1-4] A phase III study conducted in Japan compared a standard 2- drug regimen of cisplatin and etoposide to a combination of cisplatin and irinotecan.[5][Level of evidence: 1iiA] The planned enrollment was 230 patients less than 70 years of age, however, the trial was stopped early with a total of l54 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 to 15.2 months) while it was 9.4 months in the cisplatin and etoposide arm (95% CI, 8.1 to 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 and cisplatin arm. Confirmatory trials are underway in Europe and the United States.

The 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.[6,7] There is no clear evidence from reported data that maintenance chemotherapy will improve survival duration.[8-11]

Combination chemotherapy plus chest irradiation does not appear to improve survival compared with chemotherapy alone in patients with 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. (Refer to the PDQ summary on Superior Vena Cava Syndrome for more information.) 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.[11,12]

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.[13,14] 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.[14-16] 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.[14] 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.[17-19] However, prospective studies have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated.[14] 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.[20] Patients treated for small cell lung cancer continue to have declining neuropsychologic function after 2 years from the start of treatment.[17-19] 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,[21-24] 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.[23-25]

Standard treatment options:

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.[26,27]
CAE: cyclophosphamide + doxorubicin + etoposide.[28]
EP or EC: etoposide + cisplatin or carboplatin.[29,30]
ICE: ifosfamide + carboplatin + etoposide.[31]
Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use, including:

Cyclophosphamide + doxorubicin + etoposide + vincristine.[32]
CEV: cyclophosphamide + etoposide + vincristine.[33]
Single-agent etoposide.[21]
PET: cisplatin + etoposide + paclitaxel.[34]
Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases.

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.[35] 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.[36-38] 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.[39] Active single agents undergoing further evaluation include paclitaxel and topotecan.[40,41]

Treatment options 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.[42][Level of evidence: 1iiA] Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.

References

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]

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]

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]

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]

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]

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]

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]

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]

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]

Arriagada R, Le Chevalier T, Borie F, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 87 (3): 183-90, 1995. [PUBMED Abstract]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Thatcher N: Ifosfamide/carboplatin/etoposide (ICE) regimen in small cell lung cancer. Lung Cancer 9(Suppl 1): s51-s67, 1993.

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Recurrent Small Cell Lung Cancer

The prognosis for patients with small cell lung carcinoma that has progressed despite chemotherapy is exceedingly poor regardless of stage. Expected median survival is 2 to 3 months. These patients should be considered for palliative therapy or clinical trials. Patients who are primarily resistant to chemotherapy and those who have received multiple chemotherapy regimens rarely respond to additional treatment. However, patients who have initially responded and relapsed more than 6 months following initial treatment are more likely to respond to additional chemotherapy. While no single chemotherapy regimen should be considered standard, those that have shown activity as second line treatment include oral etoposide, etoposide/cisplatin, cyclophosphamide/doxorubicin/vincristine (CAV), lomustine/methotrexate, paclitaxel, and topotecan.[1-8];[9][Level of evidence: 3iiiDiii] A randomized comparison of second line treatment with either CAV or topotecan reported no significant difference in response rates or survival, but palliation of common lung cancer symptoms was better with topotecan.[8][Level of evidence: 1iiC]

Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression due to tumor have achieved successful palliation with endobronchial laser therapy (for endobronchial lesions only) and/or brachytherapy.[10] Expandable metal stents can be safely inserted under local anesthesia via the bronchoscope, resulting in improved symptoms and pulmonary function in patients with malignant airways obstruction.[11] Patients with progressive intrathoracic tumor after failing initial chemotherapy can achieve significant tumor responses, palliation of symptoms, and short-term local control with external-beam radiation therapy. However, only the rare patient will experience long-term survival following "salvage" radiation therapy.[12]

Patients with central nervous system recurrences can often obtain palliation of symptoms with radiation therapy and/or additional chemotherapy. The majority of patients treated with radiation therapy obtain objective responses and improvement following radiation therapy.[13] A retrospective review showed that 43% of patients treated with additional chemotherapy at the time of CNS relapse respond to second-line chemotherapy.[14]

Standard treatment options:

1. Palliative radiation therapy.[12]

2. Salvage chemotherapy can provide some palliative benefit for patients previously sensitive to standard chemotherapy.[2,4-9]

3. Local palliation with endobronchial laser therapy, endobronchial stents, and/or brachytherapy.[10,11]

4. Clinical trials of phase I or phase II drugs. Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.

References

Greco FA: Treatment options for patients with relapsed small cell lung cancer. Lung Cancer 9(Suppl 1): s85-s89, 1993.

Johnson DH, Greco FA, Strupp J, et al.: Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol 8 (10): 1613-7, 1990. [PUBMED Abstract]

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]

Evans WK, Osoba D, Feld R, et al.: Etoposide (VP-16) and cisplatin: an effective treatment for relapse in small-cell lung cancer. J Clin Oncol 3 (1): 65-71, 1985. [PUBMED Abstract]

Sekine I, Nishiwaki Y, Kakinuma R, et al.: Late recurrence of small-cell lung cancer: treatment and outcome. Oncology 53 (4): 318-21, 1996 Jul-Aug. [PUBMED Abstract]

Chute JP, Kelley MJ, Venzon D, et al.: Retreatment of patients surviving cancer-free 2 or more years after initial treatment of small cell lung cancer. Chest 110 (1): 165-71, 1996. [PUBMED Abstract]

Ardizzoni A, Hansen H, Dombernowsky P, et al.: Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 15 (5): 2090-6, 1997. [PUBMED Abstract]

von Pawel J, Schiller JH, Shepherd FA, et al.: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17 (2): 658-67, 1999. [PUBMED Abstract]

Smit EF, Fokkema E, Biesma B, et al.: A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 77 (2): 347-51, 1998. [PUBMED Abstract]

Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990. [PUBMED Abstract]

Wilson GE, Walshaw MJ, Hind CR: Treatment of large airway obstruction in lung cancer using expandable metal stents inserted under direct vision via the fibreoptic bronchoscope. Thorax 51 (3): 248-52, 1996. [PUBMED Abstract]

Ochs JJ, Tester WJ, Cohen MH, et al.: "Salvage" radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy. Cancer Treat Rep 67 (12): 1123-6, 1983. [PUBMED Abstract]

Carmichael J, Crane JM, Bunn PA, et al.: Results of therapeutic cranial irradiation in small cell lung cancer. Int J Radiat Oncol Biol Phys 14 (3): 455-9, 1988. [PUBMED Abstract]

Kristensen CA, Kristjansen PE, Hansen HH: Systemic chemotherapy of brain metastases from small-cell lung cancer: a review. J Clin Oncol 10 (9): 1498-502, 1992. [PUBMED Abstract]

Changes to This Summary (09/29/2003)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

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Treatment options for childhood cancers.
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Information on complementary and alternative forms of cancer treatment.

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