Indan Journal of Medical Research Indan Journal of Medical Research Indan Journal of Medical Research Indan Journal of Medical Research
  Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login  
  Home Print this page Email this page Small font sizeDefault font sizeIncrease font size Users Online: 3418       

   Table of Contents      
REVIEW ARTICLE
Year : 2013  |  Volume : 137  |  Issue : 6  |  Page : 1043-1051

Current concepts in the management of small cell lung cancer


1 Section of Hematology-Oncology, Department of Medicine, VA Nebraska Western Iowa Health Care System; Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
2 Department of Pathology-Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
3 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA

Date of Submission12-Feb-2013
Date of Web Publication4-Jul-2013

Correspondence Address:
Apar Kishor Ganti
Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center Omaha, NE 68198-7680
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


PMID: 23852285

Rights and PermissionsRights and Permissions
   Abstract 

Small cell lung cancer (SCLC) has a clinical course that is distinct from its more common counterpart non-small cell lung cancer. SCLC continues to be a major clinical problem, with an aggressive clinical course and short disease-free duration after initial therapy. Current optimal treatment consists of chemotherapy with platinum-etoposide, given concurrently with thoracic irradiation in patients with limited stage disease and chemotherapy alone in those with extensive stage. Prophylactic cranial irradiation (PCI) is recommended for patients who have responded to initial therapy, as it not only decreases the risk of brain metastases and but also improves overall survival. Newer targeted agents are currently being evaluated for this disease.

Keywords: Cisplatin - etoposide - small cell lung cancer - prophylactic cranial irradiation - thoracic radiation


How to cite this article:
Ganti AK, West WW, Zhen W. Current concepts in the management of small cell lung cancer. Indian J Med Res 2013;137:1043-51

How to cite this URL:
Ganti AK, West WW, Zhen W. Current concepts in the management of small cell lung cancer. Indian J Med Res [serial online] 2013 [cited 2019 Nov 22];137:1043-51. Available from: http://www.ijmr.org.in/text.asp?2013/137/6/1043/114393


   Introduction Top


Soon after its first description in 1959 [1] , small cell lung cancer (SCLC) was recognized to have a clinical course that was significantly different from its more common counterpart non-small cell lung cancer (NSCLC) [2] . While the incidence of SCLC is decreasing in the United States from about 25 per cent of all lung cancers in 1993 to about 13 per cent more recently [3] , it is unclear if the same holds true worldwide. The reasons for this decline in incidence are likely related to the changes in smoking patterns and habits in North America and Europe [4] . Despite this, SCLC is a significant clinical problem. Approximately two thirds of patients with SCLC are diagnosed with advanced disease, which tends to have an aggressive clinical course, often with paraneoplastic syndromes. This review focuses on the current approaches for the management of SCLC.


   Pathology Top


SCLC was originally thought to be a form of lymphoid neoplasm or unusual sarcoma. In 1926, Barnard first characterized this tumour as an unusual carcinoma and coined the term "oat cell carcinoma" [5] . The 2004 WHO definition, which is in use currently, classifies SCLC as a "malignant epithelial tumour consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli. The cells are round, oval or spindle-shaped. Nuclear molding is prominent. Necrosis is typically extensive and the mitotic count is high" [6] . This classification includes a variant: combined small cell carcinoma, which has a component of small cell carcinoma admixed with a >10 per cent non-small cell carcinoma component (any histologic subtype).

Despite the name, size alone does not reliably separate SCLC from other pulmonary neoplasms. Hence, in addition to size (2-3 times the diameter of a normal lymphocyte), the neoplastic epithelial cells should have the proper array of characteristic nuclear features, often with nuclear molding, and a high mitotic rate [7],[8] to make the diagnosis. Frequently, the tissue available to the pathologist is a small biopsy and/or cytology specimen and the limitations associated with using these small specimens should be acknowledged. The tumour sample often has significant necrosis and "crush" artifact that may further limit the amount of intact tumour that is available for assessment. While "crush" artifact is frequent in SCLC, it is non-specific [7] . If the tumour does not qualify as SCLC by initial morphologic assessment, additional studies often fail to clarify the diagnosis [9] .

SCLC is a high grade neuroendocrine carcinoma with a high mitotic activity (>10 mitoses/2 mm 2 ), averaging 60-80 mitoses/2 mm 2 , and widespread necrosis [6] . Of the immunoperoxidase antibody panels used to diagnose SCLC, CD45/LCA (leucocyte common antigen) and a keratin cocktail are probably the most useful. In a high grade tumour with the proper morphologic features on initial microscopic evaluation, a positive keratin stain and negative CD45/LCA stain support the diagnosis of SCLC and exclude the possibility of lymphoid tumours [10] . SCLC show positive keratin stains in virtually all cases and thyroid transcription factor-1 (TTF-1) positivity in the majority (70-90%) [7],[9] . Neuroendocrine markers such as chromogranin, synaptophysin and CD56/NCAM (neural cell adhesion molecule) are positive in 50-60 per cent of cases, but may be negative in a substantial proportion (10-30%) [9] . SCLC Ki-67 proliferation rates are high (70-100%) compared to other better differentiated NE tumours (typical carcinoid <5%, atypical carcinoid 5-20%). The p63 staining is generally negative in SCLC, which may be useful to differentiate SCLC from small cell variant of squamous cell carcinoma (positive for p63 in 90% of cases). A reliable diagnosis of SCLC can often be made on routine stains if high quality standard hematoxylin-eosin microscopic sections and well preserved tumour cells are available, often negating the need for additional studies.


   Staging system Top


Since systemic chemotherapy is the main treatment for all patients with SCLC, the main clinical purpose of the staging is to determine whether thoracic radiation should be incorporated in conjunction with chemotherapy for localized disease. Two systems are commonly used to stage SCLC: (i) The tumour-node-metastases (TNM) classification [11] , which is identical to that used for non-small cell lung cancer, and (ii) The VA Lung Study Group (VALSG) limited disease- extensive stage (LD-ED) system. Limited stage disease (LD) is confined to the ipsilateral hemithorax and all known disease can be encompassed within a single radiation port, while extensive stage disease (ED) includes disease in the contralateral hemithorax and distant metastases. The International Association for the Study of Lung Cancer (IASLC) defines limited stage as absence of distant metastatic disease [12] .

Although the IASLC system has a higher discriminatory power [13] , the VALSG system continues to be widely utilized, probably because of its simplicity [14] . In an analysis of 8088 SCLC patients, survival was found to be directly correlated with both T and N stages [15] and hence the TNM system should become the staging system of choice [16] .

The staging of patients with ipsilateral pleural effusion, supraclavicular nodes and contralateral mediastinal lymph node involvement is debated. Most trials for LD tend to exclude patients with isolated pleural effusions [17],[18],[19] , but survival of patients with isolated pleural effusions is similar to other patients with LD-SCLC [20],[21] . Supraclavicular lymph node involvement on the other hand, may predict for a slightly inferior survival [22],[23] . In a retrospective analysis of 264 patients with LD-SCLC, patients without clinically positive mediastinal lymph nodes had better outcomes compared to those with positive mediastinal or supraclavicular nodes, pleural effusion, or bronchial obstruction [24] .


   Management Top


Cytotoxic chemotherapy : SCLC is extremely chemosensitive [25] and multiple agents have shown activity in this disease, including platinum compounds (cisplatin, carboplatin), camptothecins (topotecan, irinotecan), podophyllotoxins (etoposide, teniposide), anthracyclines (doxorubicin, epirubicin), alkylating agents (cyclophosphamide, ifosfamide), taxanes (paclitaxel, docetaxel) and vincristine.

Trials conducted in the 1970s found that cyclophosphamide, doxorubicin/epirubicin and vincristine [CA(E)V] was effective for SCLC [26],[27],[28] . After the introduction of etoposide, randomized trials comparing etoposide-cisplatin (EP) with CA(E)V suggested that EP had superior response rates, and better disease free and overall survival in patients with limited stage disease. Even though response rates were higher with EP in patients with ED, this did not translate into a survival benefit [29],[30],[31],[32] . However, since EP is better tolerated it is currently the regimen of choice for initial treatment of SCLC. While trials using alternating CAV and EP showed slightly better outcomes than either combination alone, this did not represent a major improvement [30],[31],[32] .

When carboplatin was used instead of cisplatin in combination with etoposide [33] , there were no differences in response rates, but carboplatin was associated with significantly less toxicity. A second study evaluated the long-term survival following carboplatin-based chemotherapy with radiotherapy in patients with LD [34] . Patients had a median survival of 17.4 months, with a 5-yr overall survival of 20 per cent, findings comparable with cisplatin-based regimens.

The Japanese JCOG 9511 trial found higher response rates (84 vs. 68%) and median survival (12.8 vs. 9.4 months) with cisplatin-irinotecan compared to EP in patients with ED-SCLC [35] . As expected, irinotecan had lower haematologic side effects, but increased diarrhoea compared to etoposide. However, multiple trials outside Japan found similar outcomes with the two regimens [36],[37],[38],[39] . The discordant results may be due to pharmacogenomic differences between the Japanese and Western populations in irinotecan metabolism.

The low percentage of patients with LD-SCLC who experience long-term survival has led to studies examining the role of multi-drug therapy in an effort to increase the proportion of long-term survivors. The role of platinum-based triplet therapy has been investigated following the introduction of additional active agents, but a definite survival advantage has not been demonstrated at this time and cannot be recommended outside of a clinical trial.

Duration of therapy: Two randomized trials have been conducted to evaluate the role of additional cycles of therapy following four cycles of platinum-etoposide in patients with ED-SCLC [40],[41] . Both studies showed that although extended therapy improved progression-free survival, overall survival was similar.

A meta-analysis (14 trials; 2550 patients) suggested that maintenance/consolidation chemotherapy was associated with a 33 per cent increased survival at 1 and 2 years [42] . However, only one trial used what we would consider modern chemotherapy regimens in both induction and consolidation phases. Hence maintenance therapy for SCLC cannot be recommended outside of a clinical trial.


   Thoracic radiation Top


The majority of patients with LD-SCLC treated with chemotherapy alone relapse locally. In contrast, thoracic radiation therapy (TRT) can provide local control, but does not have a major impact on overall disease control [43] . Multiple randomized trials combined the two modalities to achieve better overall disease control. Two meta-analyses concluded that a combination of TRT and chemotherapy produced a small, but definite improvement in survival [44],[45] . This was however, at the expense of a small, but significant increase in the risk of treatment related death. Hence, the addition of thoracic radiation to combination chemotherapy is currently considered the standard of care in patients with LD-SCLC. A Canadian population-based retrospective study found that combined modality therapy improved median, 2- and 5-yr survival as compared to chemotherapy alone (15.1 months, 32 and 12% vs. 14.3 months, 26.9 and 9.9%, respectively) [46] . However, multiple issues are unresolved, including the total radiation dose, fractionation schedule and timing of radiation vis-à-vis chemotherapy.

The National Cancer Institute of Canada found that patients receiving a 37.5 Gy (Gray) had a better local control than those receiving 25 Gy [47] . However, this did not translate into better overall survival. A retrospective analysis of patients enrolled in three consecutive chemoradiation trials, treated with 45, 55 and 65 Gy found similar local control and overall survival with the three doses analyzed, suggesting that a dose of at least 45 Gy would be needed to obtain adequate local control [48] .

Currently, the most commonly utilized fractionation schedules involve single daily treatments of 1.8 to 2.0 Gy, five times per week, over 5 to 6 wk. Hyperfractionated radiotherapy (twice daily radiation with lower individual fractions) improves local control and possibly survival by applying higher doses of radiation given in a shorter time. A randomized phase III trial that randomized patients with LD-SCLC to either 1.8 Gy once-daily over 5 wk (25 treatment days) or accelerated 1.5 Gy twice-daily for 3 wk (15 treatment days) in conjunction with four cycles of EP [49] , showed that patients receiving the accelerated twice-daily schedule had better median survival (23 vs. 19 months), and 5-year overall survival (26 vs. 16%). Patients randomized to the twice-daily arm had an increased incidence of grade 3 oesophagitis requiring narcotic analgesics or feeding tube placement (27 vs. 11%). A criticism of this study has been that the two radiation doses used were not biologically equivalent and 45 Gy given on an accelerated twice-daily schedule should ideally be compared to 70 Gy given on a once-daily schedule [50] to answer this controversy. In addition, twice-daily radiation is not very practical, and, therefore, has never been widely utilized.

Various trials have compared early versus late TRT in combination with chemotherapy [Table 1] [18],[51],[52],[53],[54],[55],[56] . Unfortunately the results of these studies were conflicting, with two trials showing a benefit for early radiation [53],[54] , while the rest showed that both approaches provided similar results. A meta-analysis [57] suggested that while there was no difference between early or late TRT on overall survival, when only trials using platinum-based chemotherapy were considered, there was a significantly improved 5-year overall survival with early TRT.
Table 1: Timing of thoracic radiation therapy

Click here to view



   Surgery Top


Since SCLC is considered a systemic disease, there has not been a role for surgery in the management of these patients [58],[59],[60] . However, recent studies have shown promising results for surgical resection of early stage disease. Approximately 4-12 per cent of lung cancers in patients who present with a solitary lung nodule are SCLC [61] . Five-year survival rates following surgical resection of SCLC presenting as a solitary pulmonary nodule, ranged from 40-53 per cent [61] . Other studies have demonstrated 5-year survival rates of 27-42 per cent following resection of stage I or stage II (TNM system) disease [62],[63] . It is unclear if the biologic behaviour of SCLC in these patients who present with a solitary nodule is different compared to other forms of LD-SCLC. In these patients, systemic therapy is recommended following resection. Consideration to thoracic radiation must be given in patients who are found to have lymph node involvement in the resection specimen [64] . These results support continued research on the role of surgical resection in early stage SCLC.

In contrast, there is currently no role for resection in the multimodality treatment of locally advanced SCLC. A trial that randomized 328 patients with LD-SCLC who had achieved at least a partial response following chemotherapy with cyclophosphamide, doxorubicin, and vincristine, to either surgery or observation did not find a survival benefit with surgery [65] .


   Prophylactic cranial irradiation Top


The central nervous system (CNS) is a common site of metastasis in patients with SCLC. Almost 25 per cent of patients will have brain metastases at presentation [66] . Furthermore, of the patients who obtain a complete response with initial therapy, approximately 45 per cent will present with brain metastases as the only site of relapse at 2 years [67],[68] . CNS relapse is associated with greater deterioration in performance status, and an increased need for hospitalization [69] . Hence prevention of CNS relapse would be a good option in order to decrease the suffering caused by CNS metastases.

Multiple trials have been conducted to evaluate the role of prophylactic cranial irradiation (PCI) in SCLC [70] . Unfortunately, these were small and heterogenous and not surprisingly there was a wide variation in their findings. Despite this, all these studies showed a significant decrease in the incidence of brain metastases with PCI. The effects on overall survival however, varied among the trials. Two separate meta-analyses concluded that PCI decreased the incidence of brain metastases by 52-54 per cent and improved survival in patients who had achieved a complete response to therapy, by 16-18 per cent [71],[72] . A more recent study randomized patients with ED-SCLC who had not progressed following initial therapy, to either PCI or observation. Here, PCI decreased both the cumulative incidence of brain metastases (14.6 vs. 40.4%), and improved median survival (5.4 vs. 6.7 months) [73] . The 1-year survival rate was 27.1 per cent in the PCI group and 13.3 per cent in the control group. The similar findings in both meta-analyses in LD-SCLC and the randomized trial in ED-SCLC, have led to an increased use of PCI in patients with SCLC.

The optimal dose and fraction size for PCI are unclear. A randomized trial compared a standard dose of 25 Gy in 10 fractions PCI to high dose (36 Gy in 18 fractions once-daily or 36 Gy in 24 fractions using 1.5 Gy twice-daily PCI) in 720 patients with LD-SCLC who achieved complete response after chemotherapy and thoracic RT, showed no significant reduction of brain metastasis with higher dose PCI, but significant increase in mortality. Therefore, at present time, PCI at 25 Gy in 10 fractions should remain standard of care [74] .

One of the major concerns with the use of PCI is long-term neurotoxicity. However, the frequency and severity of the long-term toxicities associated with PCI are unclear. Given the survival advantage of PCI, patients who receive PCI tend to live longer and thus are at a greater risk of developing chronic neurotoxicity. In a retrospective analysis of 98 patients, those who received PCI had a significant improvement in the mean Q-TWiST (quality time without symptoms and toxicity) survival [75] . In another similar analysis that evaluated quality-adjusted life expectancy (QALE), PCI offered a benefit over no PCI (QALE = 4.31 and 3.70 for mild toxicity and 4.09 and 3.70 for substantial toxicity, respectively) [76] . The results of these analyses would suggest a benefit to utilization of PCI without undue toxicity; however, well designed clinical trials with this specific objective in mind are needed to answer this question conclusively.


   Relapsed/refractory SCLC Top


Although SCLC is very chemosensitive, most patients will relapse at varying intervals following initial treatment. Treatment of these patients is often challenging in the absence of good data to guide therapy in this setting.

In patients with chemosensitive disease, repeating the original regimen may be worthwhile [77],[78],[79] , especially if the patient had a sustained response initially (>6 months). Topotecan, a water-soluble, semi-synthetic derivative of camptothecin has demonstrated antitumour activity in relapsed/refractory SCLC. In a randomized phase III study of 210 patients with sensitive relapse, topotecan showed similar response rates, time to progression and median survival with cyclophosphamide, anthracycline and vincristine (CAV) [80] . More significantly, topotecan had greater symptom control and decreased interference with daily activities. The oral formulation of topotecan has similar response rates (18 vs. 22%), median survival (33 vs. 35 wk) and 1-year survival rates (33 vs. 29%) in patients with a chemosensitive relapse compared to intravenous topotecan [81] .

Amrubicin, a synthetic 9-amino anthracycline with minimal cardiotoxicity, has shown promising activity in SCLC [82] . A phase III trial comparing amrubicin to topotecan in 637 patients [83] found that although survival was similar in the two groups, amrubicin had a better median survival (6.2 vs. 5.7 months, P=0.047) in patients with refractory disease. Patients treated with amrubicin had significant improvement in their symptoms.

Multiple other agents, including paclitaxel, docetaxel, irinotecan, oral etoposide, vinorelbine and gemcitabine have been studied with modest activity in relapsed/refractory SCLC.


   Future directions Top


Despite various strategies, the overall survival in patients with SCLC has not improved significantly over the past decade. An increasing knowledge regarding the molecular biology of SCLC has led to the development of targeted agents that could potentially be useful in SCLC. Targets currently being investigated are listed in [Table 2].
Table 2: Pathways being targeted in SCLC

Click here to view



   Conclusions Top


Current treatment of SCLC involves chemotherapy with the addition of concurrent thoracic radiation for patients with limited disease. The most common chemotherapy regimen includes four cycles of etoposide and platinum. Addition of a third agent or intensifying therapy further has not demonstrated a survival benefit. Prophylactic cranial irradiation decreases the incidence of brain metastases and improves overall survival. Newer targeted agents, based on our understanding of the molecular carcinogenesis of SCLC are currently in clinical trials.

 
   References Top

1.Azzopardi JG. Oat-cell carcinoma of the bronchus. J Pathol Bacteriol 1959; 78 : 513-9.  Back to cited text no. 1
    
2.Cohen MH, Matthews MJ. Small cell bronchogenic carcinoma: a distinct clinicopathologic entity. Semin Oncol 1978; 5 : 234-43.  Back to cited text no. 2
    
3.Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006; 24 : 4539-44.  Back to cited text no. 3
    
4.Ettinger DS, Aisner J. Changing face of small-cell lung cancer: real and artifact. J Clin Oncol 2006; 24 : 4526-7.  Back to cited text no. 4
    
5.Barnard WG. The nature of the "oat-celled sarcoma" of the mediastinum. J Pathol Bacteriol 1926; 29 : 241-4.  Back to cited text no. 5
    
6.Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, editors. World Health Organization Classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004. p. 31-4.  Back to cited text no. 6
    
7.Travis WD. Lung tumours with neuroendocrine differentiation. Eur J Cancer 2009; 45 (Suppl 1): 251-66.  Back to cited text no. 7
    
8.Corrin B. Carcinoma of the lung. In: Pathology of the lungs., London: England Churchill Livingstone: 2000. p. 475-8.  Back to cited text no. 8
    
9.Nicholson SA, Beasley MB, Brambilla E, Hasleton PS, Colby TV, Sheppard MN, et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 2002; 26 : 1184-97.  Back to cited text no. 9
    
10.Wick MR, Leslie KO, Ritter JH, Mills SE. Neuroendocrine neoplasms of the lung. In: Leslie KO, Wick MR, editors. Practical pulmonary pathology. London England: Churchill Livingstone; 2005. p. 423-63.  Back to cited text no. 10
    
11.Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111 : 1710-7.  Back to cited text no. 11
    
12.Mountain CF. A new international staging system for lung cancer. Chest 1986; 89 (Suppl 4): 225S-33S.  Back to cited text no. 12
    
13.Micke P, Faldum A, Metz T, Beeh KM, Bittinger F, Hengstler JG, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer - what limits limited disease? Lung Cancer 2002; 37 : 271-6.  Back to cited text no. 13
    
14.Argiris A, Murren JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J 2001; 7 : 437-47.  Back to cited text no. 14
    
15.Shepherd FA, Crowley J, Van Houtte P, Postmus PE, Carney D, Chansky K, et al. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2007; 2 : 1067-77.  Back to cited text no. 15
    
16.Vallieres E, Shepherd FA, Crowley J, Van Houtte P, Postmus PE, Carney D, et al. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2009; 4 : 1049-59.  Back to cited text no. 16
    
17.Perry MC, Eaton WL, Propert KJ, Ware JH, Zimmer B, Chahinian AP, et al. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 1987; 316 : 912-8.  Back to cited text no. 17
    
18.Work E, Nielsen OS, Bentzen SM, Fode K, Palshof T. Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group. J Clin Oncol 1997; 15 : 3030-7.  Back to cited text no. 18
    
19.Bunn PA, Jr., Lichter AS, Makuch RW, Cohen MH, Veach SR, Matthews MJ, et al. Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. A prospective, randomized trial. Ann Intern Med 1987; 106 : 655-62.  Back to cited text no. 19
    
20.Dearing MP, Steinberg SM, Phelps R, Anderson MJ, Mulshine JL, Ihde DC, et al. Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years. J Clin Oncol 1990; 8 : 1042-9.  Back to cited text no. 20
    
21.Livingston RB, McCracken JD, Trauth CJ, Chen T. Isolated pleural effusion in small cell lung carcinoma: favorable prognosis. A review of the Southwest Oncology Group experience. Chest 1982; 81 : 208-11.  Back to cited text no. 21
    
22.Spiegelman D, Maurer LH, Ware JH, Perry MC, Chahinian AP, Comis R, et al. Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients. J Clin Oncol 1989; 7 : 344-54.  Back to cited text no. 22
    
23.Urban T, Chastang C, Vaylet F, Mathieu M, Leclerc P, Paillotin D, et al. Prognostic significance of supraclavicular lymph nodes in small cell lung cancer: a study from four consecutive clinical trials, including 1,370 patients. "Petites Cellules" Group. Chest 1998; 114 : 1538-41.  Back to cited text no. 23
    
24.Shepherd FA, Ginsberg RJ, Haddad R, Feld R, Sagman U, Evans WK, et al. Importance of clinical staging in limited small-cell lung cancer: a valuable system to separate prognostic subgroups. The University of Toronto Lung Oncology Group. J Clin Oncol 1993; 11 : 1592-7.  Back to cited text no. 24
    
25.Morstyn G, Ihde DC, Lichter AS, Bunn PA, Carney DN, Glatstein E, et al. Small cell lung cancer 1973-1983: early progress and recent obstacles. Int J Radiat Oncol Biol Phys 1984; 10 : 515-39.  Back to cited text no. 25
    
26.Livingston RB, Moore TN, Heilbrun L, Bottomley R, Lehane D, Rivkin SE, et al. Small-cell carcinoma of the lung: combined chemotherapy and radiation: a Southwest Oncology Group study. Ann Intern Med 1978; 88 : 194-9.  Back to cited text no. 26
    
27.Feld R, Evans WK, DeBoer G, Quirt IC, Shepherd FA, Yeoh JL, et al. Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung. J Clin Oncol 1984; 2 : 294-304.  Back to cited text no. 27
    
28.Feld R, Pringle JF, Evans WK, Keen CW, Quirt IC, Curtis JE, et al. Combined modality treatment of small cell carcinoma of the lung. Arch Intern Med 1981; 141 : 469-73.  Back to cited text no. 28
    
29.Sundstrom S, Bremnes RM, Kaasa S, Aasebo U, Hatlevoll R, Dahle R, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol 2002; 20 : 4665-72.  Back to cited text no. 29
    
30.Feld R, Evans WK, Coy P, Hodson I, MacDonald AS, Osoba D, et al. Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small-cell carcinoma of the lung. J Clin Oncol 1987; 5 : 1401-9.  Back to cited text no. 30
    
31.Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, 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 1991; 83 : 855-61.  Back to cited text no. 31
    
32.Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, 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 1992; 10 : 282-91.  Back to cited text no. 32
    
33.Skarlos DV, Samantas E, Kosmidis P, Fountzilas G, Angelidou M, Palamidas 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 1994; 5 : 601-7.  Back to cited text no. 33
    
34.Spigel DR, Hainsworth JD, Burris HA, Dannaher C, Hon J, Morrissey LH, et al. Long-term follow-up of limited stage small cell lung cancer patients treated with carboplatin-based chemotherapy and radiotherapy by the Minnie Pearl Cancer Research Network (MPCRN) ASCO Annnual Meeting Abstracts. J Clin Oncol 2004; 22 (Suppl 14): 7222.  Back to cited text no. 34
    
35.Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 346 : 85-91.  Back to cited text no. 35
    
36.Hanna N, Bunn PA, Jr., Langer C, Einhorn L, Guthrie T Jr, Beck T, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 2006; 24 : 2038-43.  Back to cited text no. 36
    
37.Lara PN, Jr., Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 2009; 27 : 2530-5.  Back to cited text no. 37
    
38.Zatloukal P, Cardenal F, Szczesna A, Gorbunova V, Moiseyenko V, Zhang X, et al. A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 2010; 21 : 1810-6.  Back to cited text no. 38
    
39.Schmittel A, Sebastian M, Fischer von Weikersthal L, Martus P, Gauler TC, Kaufmann C, et al; Arbeitsgemeinschaft Internistische Onkologie Thoracic Oncology Study Group. A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol 2011; 22 : 1798-804.  Back to cited text no. 39
    
40.Schiller JH, Adak S, Cella D, DeVore RF, 3 rd , Johnson DH. 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 2001; 19 : 2114-22.  Back to cited text no. 40
    
41.Hanna NH, Sandier AB, Loehrer PJ, Sr., Ansari R, Jung SH, Lane K, et al. Maintenance daily oral etoposide versus no further therapy following induction chemotherapy with etoposide plus ifosfamide plus cisplatin in extensive small-cell lung cancer: a Hoosier Oncology Group randomized study. Ann Oncol 2002; 13 : 95-102.  Back to cited text no. 41
    
42.Bozcuk H, Artac M, Ozdogan M, Savas B. Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A metaanalysis of the published controlled trials. Cancer 2005; 104 : 2650-7.  Back to cited text no. 42
    
43.Rosti G, Bevilacqua G, Bidoli P, Portalone L, Santo A, Genestreti G. Small cell lung cancer. Ann Oncol 2006; 17 (Suppl 2): ii5-10.  Back to cited text no. 43
    
44.Pignon JP, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RL, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992; 327 : 1618-24.  Back to cited text no. 44
    
45.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 1992; 10 : 890-5.  Back to cited text no. 45
    
46.Laskin JJ, Erridge SC, Coldman AJ, D'Yachkova Y, Speers C, Westeel V, et al. Population-based outcomes for small cell lung cancer: impact of standard management policies in British Columbia. Lung Cancer 2004; 43 : 7-16.  Back to cited text no. 46
    
47.Coy P, Hodson I, Payne DG, Evans WK, Feld R, MacDonald AS, et al. The effect of dose of thoracic irradiation on recurrence in patients with limited stage small cell lung cancer. Initial results of a Canadian Multicenter Randomized Trial. Int J Radiat Oncol Biol Phys 1988; 14 : 219-26.  Back to cited text no. 47
    
48.Arriagada R, le Chevalier T, Ruffie P, Baldeyrou P, De Cremoux H, Martin M, et al. Alternating radiotherapy and chemotherapy in 173 consecutive patients with limited small cell lung carcinoma. GROP and the French Cancer Center's Lung Group. Int J Radiat Oncol Biol Phys 1990; 19 : 1135-8.  Back to cited text no. 48
    
49.Turrisi AT, 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki 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 1999; 340 : 265-71.  Back to cited text no. 49
    
50.Choi NC, Herndon J, Rosenman J, Carey R, Chung CT, Bogart J, et al. Long term survival data from CALGB 8837: radiation dose escalation and concurrent chemotherapy (CT) in limited stage small cell lung cancer (LD-SCLC). Possible radiation dose-survival relationship. Proc Am Soc Clin Oncol 2002; 21 : A-1190 (Abstract).  Back to cited text no. 50
    
51.Perry MC, Herndon JE, 3 rd , Eaton WL, Green MR. Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083. J Clin Oncol 1998; 16 : 2466-7.  Back to cited text no. 51
    
52.Skarlos DV, Samantas E, Briassoulis E, Panoussaki E, Pavlidis N, Kalofonos HP, et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol 2001; 12 : 1231-8.  Back to cited text no. 52
    
53.Murray N, Coy P, Pater JL, Hodson I, Arnold A, Zee BC, 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 1993; 11 : 336-44.  Back to cited text no. 53
    
54.Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol 1997; 15 : 893-900.  Back to cited text no. 54
    
55.Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002; 20 : 3054-60.   Back to cited text no. 55
    
56.Spiro SG, James LE, Rudd RM, Trask CW, Tobias JS, Snee M, et al. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol 2006; 24 : 3823-30.  Back to cited text no. 56
    
57.De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, Kester A, Rutten I, Lambin P. Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol 2006; 17 : 543-52.  Back to cited text no. 57
    
58.Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet 1973; 2 : 63-5.  Back to cited text no. 58
    
59.Martini N, Wittes RE, Hilaris BS, Hajdu SI, Beattie EJ, Jr., Golbey RB. Oat cell carcinoma of the lung. Clin Bull 1975; 5 : 144-8.  Back to cited text no. 59
    
60.Mountain CF. Clinical biology of small cell carcinoma: relationship to surgical therapy. Semin Oncol 1978; 5 : 272-9.  Back to cited text no. 60
    
61.Kreisman H, Wolkove N, Quoix E. Small cell lung cancer presenting as a solitary pulmonary nodule. Chest 1992; 101 : 225-31.  Back to cited text no. 61
    
62.Inoue M, Miyoshi S, Yasumitsu T, Mori T, Iuchi K, Maeda H, et al. Surgical results for small cell lung cancer based on the new TNM staging system. Thoracic Surgery Study Group of Osaka University, Osaka, Japan. Ann Thorac Surg 2000; 70 : 1615-9.  Back to cited text no. 62
    
63.de Antonio DG, Alfageme F, Gamez P, Cordoba M, Varela A; Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracici Surgery (GCCB-S). Results of surgery in small cell carcinoma of the lung. Lung Cancer 2006; 52 : 299-304.  Back to cited text no. 63
    
64.Kalemkerian GP, Akerley W, Bogner P, Borghaei H, Chow LQ, Downey RJ, et al. Small cell lung cancer. J Natl Compr Canc Netw 2013; 11 : 78-98.  Back to cited text no. 64
    
65.Lad T, Piantadosi S, Thomas P, Payne D, Ruckdeschel J, Giaccone G. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 1994; 106 (Suppl 6): 320S-3S.  Back to cited text no. 65
    
66.Hochstenbag MM, Twijnstra A, Wilmink JT, Wouters EF, ten Velde GP. Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MR-imaging is useful at initial diagnosis. J Neurooncol 2000; 48 : 243-8.  Back to cited text no. 66
    
67.Arriagada R, Le Chevalier T, Borie F, Riviere A, Chomy P, Monnet I, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 1995; 87 : 183-90.  Back to cited text no. 67
    
68.Ball DL, Matthews JP. Prophylactic Cranial Irradiation: More Questions Than Answers. Semin Radiat Oncolo 1995; 5 : 61-8.  Back to cited text no. 68
    
69.Felletti R, Souhami RL, Spiro SG, Geddes DM, Tobias JS, Mantell BS, et al. Social consequences of brain or liver relapse in small cell carcinoma of the bronchus. Radiother Oncol 1985; 4 : 335-9.  Back to cited text no. 69
    
70.Le Pechoux C, Arriagada R. Prophylactic cranial irradiation in small cell lung cancer. Hematol Oncol Clin North Am 2004; 18 : 355-72.  Back to cited text no. 70
    
71.Meert AP, Paesmans M, Berghmans T, Martin B, Mascaux C, Vallot F, et al. Prophylactic cranial irradiation in small cell lung cancer: a systematic review of the literature with meta-analysis. BMC Cancer 2001; 1 : 5.  Back to cited text no. 71
    
72.Auperin A, Arriagada R, Pignon JP, Le Pechoux C, Gregor A, Stephens RJ, 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 1999; 341 : 476-84.  Back to cited text no. 72
    
73.Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, et al; EORTC Radiation Oncology Group and Lulng Cancer Group. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007; 357 : 664-72.  Back to cited text no. 73
    
74.Le Pechoux C, Dunant A, Senan S, Wolfson A, Quoix E, Faivre-Finn C, et al; Prophylactic Cranial irradiation (PCI) Collaborative Group. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 2009; 10 : 467-74.  Back to cited text no. 74
    
75.Tai TH, Yu E, Dickof P, Beck G, Tonita J, Ago T, et al. Prophylactic cranial irradiation revisited: cost-effectiveness and quality of life in small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002; 52 : 68-74.  Back to cited text no. 75
    
76.Lee JJ, Bekele BN, Zhou X, Cantor SB, Komaki R, Lee JS. Decision analysis for prophylactic cranial irradiation for patients with small-cell lung cancer. J Clin Oncol 2006; 24 : 3597-603.  Back to cited text no. 76
    
77.Batist G, Ihde DC, Zabell A, Lichter AS, Veach SR, Cohen MH, et al. Small-cell carcinoma of lung: reinduction therapy after late relapse. Ann Intern Med 1983; 98 : 472-4.  Back to cited text no. 77
    
78.Giaccone G, Ferrati P, Donadio M, Testore F, Calciati A. Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol 1987; 23 : 1697-9.  Back to cited text no. 78
    
79.Collard P, Weynants P, Francis C, Rodenstein DO. Treatment of relapse of small cell lung cancer in selected patients with the initial combination chemotherapy carboplatin, etoposide, and epirubicin. Thorax 1992; 47 : 369-71.  Back to cited text no. 79
    
80.von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17 : 658-67.  Back to cited text no. 80
    
81.Eckardt JR, von Pawel J, Pujol JL, Papai Z, Quoix E, Ardizzoni A, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 2007; 25 : 2086-92.  Back to cited text no. 81
    
82.Inoue A, Sugawara S, Yamazaki K, Maemondo M, Suzuki T, Gomi K, et al. Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402. J Clin Oncol 2008; 26 : 5401-6.  Back to cited text no. 82
    
83.Jotte R, Von Pawel J, Spigel DR, Socinski MA, O'Brien M, Paschold EH, et al. Randomized phase III trial of amrubicin versus topotecan (Topo) as second-line treatment for small cell lung cancer (SCLC). ASCO Annual Meeting Abstracts. J Clin Oncol 2011; 29 (Suppl 15): Abstract No.7000.  Back to cited text no. 83
    



 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
   Pathology
   Staging system
   Management
   Thoracic radiation
   Surgery
    Prophylactic cra...
    Relapsed/refract...
   Future directions
   Conclusions
    References
    Article Tables

 Article Access Statistics
    Viewed1248    
    Printed36    
    Emailed0    
    PDF Downloaded613    
    Comments [Add]    

Recommend this journal