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Information from PDQ -- for Health Professionals
Small cell lung cancer
208/00040
** 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] With incorporation of
current chemotherapy regimens into the treatment program, however, 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]
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.
Patients with tumor that has spread beyond the supraclavicular areas are said
to have extensive stage disease and have a worse prognosis than patients with
limited stage. Median survival of 6 to 12 months is reported with currently
available therapy, but long-term disease-free survival is rare.
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.
References:
1. 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.
2. 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. Journal of Clinical Oncology 8(3): 396-401,
1990.
3. 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. Journal of
Clinical Oncology 13(5): 1215-1220, 1995.
4. Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on
lung cancer. Cancer 77(9): 1947-1955, 1996.
5. 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.
6. 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.
7. 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.
8. 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. British Journal of Cancer 63(6): 986-992, 1991.
9. 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.
British Journal of Cancer 61(4): 597-604, 1990.
10. 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 Clinic Proceedings 72(10): 901-912,
1997.
** 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:
1. Hirsch FR, Matthews MJ, Aisner S, et al.: Histopathologic classification
of small cell lung cancer: changing concepts and terminology. Cancer
62(5): 973-977, 1988.
2. Harpole DH, Feldman JM, Buchanan S, et al.: Bronchial carcinoid tumors: a
retrospective analysis of 126 patients. Annals of Thoracic Surgery
54(1): 50-55, 1992.
3. Lequaglie C, Patriarca C, Cataldo I, et al.: Prognosis of resected
well-differentiated neuroendocrine carcinoma of the lung. Chest 100(4):
1053-1056, 1991.
** 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 --
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 --
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:
1. Ihde D, Souhami B, Comis R, et al.: Small cell lung cancer. Lung Cancer
17(suppl 1): S19-S21, 1997.
2. Mountain CF: Revisions in the International System for Staging Lung
Cancer. Chest 111(6): 1710-1717, 1997.
** 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 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 (http://cancer.gov/clinical_trials).
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:
1. Comis RL, Friedland DM, Good BC: Small-cell lung cancer: a perspective on
the past and a preview of the future. Oncology (Huntington NY) 12(1
suppl 2): 44-50, 1998.
2. 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.
Journal of Clinical Oncology 12(10): 2022-2034, 1994.
3. Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic
doses and survival in patients with limited small-cell lung cancer. New
England Journal of Medicine 329(25): 1848-1852, 1993.
4. 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.
5. Elias AD, Ayash L, Frei E, et al.: Intensive combined modality therapy
for limited-stage small-cell lung cancer. Journal of the National
Cancer Institute 85(7): 559-566, 1993.
6. 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. Journal of Clinical
Oncology 17(8): 2300-2308, 1999.
** LIMITED STAGE SMALL CELL LUNG CANCER **
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.)
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 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=0.04). 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] 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:
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
therapy[5]
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 with stage I disease.[16-19]
Treatment options 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.[27,28]
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: 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. 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. Auperin 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. New England Journal of Medicine 341(7): 476-484, 1999.
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: A1758, 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. Ettinger DS: Concurrent paclitaxel-containing regimens and thoracic
radiation therapy for limited-disease small cell lung cancer. Seminars
in Radiation Oncology 9(2 suppl 1): 148-150, 1999.
** EXTENSIVE STAGE SMALL CELL LUNG CANCER **
Note: Some citations in the text of this section are followed by a level of
evidence. The PDQ editorial boards use a formal ranking system to help the
reader judge the strength of evidence linked to the reported results of a
therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more
information.)
As in limited stage small cell 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 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.
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 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.[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:
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 [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]
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.[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]
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. 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.
Journal of Clinical Oncology 19(8): 2114-2122, 2001.
5. Noda K, Nishiwaki Y, Kawahara M, et al.: Irinotecan plus cisplatin
compared with etoposide plus cisplatin for extensive small-cell lung
cancer. New England Journal of Medicine 346(2): 85-91, 2002.
6. 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.
7. Bleehan 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. British Journal of Cancer 68(6): 1150-1156, 1993.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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): 563-566, 1996.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. Thatcher N: Ifosfamide/carboplatin/etoposide (ICE) regimen in small cell
lung cancer. Lung Cancer 9(Suppl 1): s51-s67, 1993.
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. Glisson BS, Kurie JM, Perez-Soler R, et al.: Cisplatin, etoposide, and
paclitaxel in the treatment of patients with extensive small-cell lung
carcinoma. Journal of Clinical Oncology 17(8): 2309-2315, 1999.
35. 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.
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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.
** RECURRENT SMALL CELL LUNG CANCER **
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 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 (http://cancer.gov/clinical_trials).
References:
1. Greco FA: Treatment options for patients with relapsed small cell lung
cancer. Lung Cancer 9(Suppl 1): s85-s89, 1993.
2. 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. Journal of Clinical Oncology 8(10):
1613-1617, 1990.
3. 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.
4. Evans WK, Osoba D, Feld R, et al.: Etoposide (VP-16) and cisplatin: an
effective treatment for relapse in small-cell lung cancer. Journal of
Clinical Oncology 3(1): 65-71, 1985.
5. Sekine I, Nishiwaki Y, Kakinuma R, et al.: Late recurrence of small-cell
lung cancer: treatment and outcome. Oncology 53(4): 318-321, 1996.
6. 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): 165-171, 1996.
7. 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. Journal of
Clinical Oncology 15(5): 2090-2096, 1997.
8. von Pawel J, Schiller JH, Shepherd FA, et al.: Topotecan versus
cyclophosphamide, doxorubicin, and vincristine for the treatment of
recurrent small-cell lung cancer. Journal of Clinical Oncology 17(2):
658-667, 1999.
9. Smit EF, Fokkema E, Biesma B, et al.: A phase II study of paclitaxel in
heavily pretreated patients with small-cell lung cancer. British
Journal of Cancer 77(2): 347-351, 1998.
10. Miller JI, Phillips TW: Neodymium:YAG laser and brachytherapy in the
management of inoperable bronchogenic carcinoma. Annals of Thoracic
Surgery 50(2): 190-196, 1990.
11. 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): 248-252, 1996.
12. Ochs JJ, Tester WJ, Cohen MH, et al.: "Salvage" radiation therapy for
intrathoracic small cell carcinoma of the lung progressing on
combination chemotherapy. Cancer Treatment Reports 67(12): 1123-1126,
1983.
13. Carmichael J, Crane JM, Bunn PA, et al.: Results of therapeutic cranial
irradiation in small cell lung cancer. International Journal of
Radiation Oncology, Biology, Physics 14(3): 455-459, 1988.
14. Kristensen CA, Kristjansen PE, Hansen HH: Systemic chemotherapy of brain
metastases from small-cell lung cancer: a review. Journal of Clinical
Oncology 10(9): 1498-1502, 1992.
Date Last Modified: 06/2002
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