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doi:10.1378/chest.07-1384
(Chest. 2007; 132:314S-323)
© 2007 American College of Chest Physicians
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Evidence for Management of Small Cell Lung Cancer*

ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)

David J. Samson, MS; Jerome Seidenfeld, PhD; George R. Simon, MD, FCCP; Andrew T. Turrisi, III, MD; Claudia Bonnell, RN, MLS; Kathleen M. Ziegler, PharmD and Naomi Aronson, PhD

* From the Technology Evaluation Center (Mr. Samson, Dr. Seidenfeld, Ms. Bonnell, and Dr. Ziegler), Blue Cross Blue Shield Association, Washington, DC; H. Lee Moffitt Cancer Center (Dr. Simon), Tampa, FL; and Wayne State University (Dr. Turris), Detroit, MI.

Correspondence to: David J. Samson, MS, Technology Evaluation Center, Blue Cross Blue Shield Association, 1310 G St, NW, Washington, DC 20005; e-mail: david.samson{at}bcbsa.com


   Abstract
TOP
 Abstract
Introduction
 Key Questions
 Materials and Methods
 Results
 Discussion and Future Research
 Conclusions
 References
 
Purpose: This systematic review addressed the following key questions on managing small cell lung cancer (SCLC): the sequence, timing, and dosing characteristics of primary thoracic radiotherapy (TRTx) for limited-stage disease; primary TRTx for extensive-stage disease; effect of prophylactic cranial irradiation (PCI); positron emission tomography (PET) for staging; treatment of mixed histology tumors; surgery; and second-line and subsequent-line treatment for relapsed/progressive disease.

Methods: The review methods were defined prospectively in a written protocol. We primarily sought randomized controlled trials that compared the interventions of interest.

Results: Robust evidence was lacking for all questions except PCI, for which a patient-level metaanalysis showed that PCI improves survival of SCLC patients who achieved complete response after primary therapy from 15.3 to 20.7% (p = 0.01). The case for concurrent over sequential radiation delivery rests largely on a single multicenter trial. Support for early concurrent therapy comes from one multicenter trial, but two other multicenter trials found no advantage. Metaanalysis did not find significant reductions in 2-year and 3-year mortality rates for early TRTx. Favorable results from a single-center trial on TRTx for extensive stage disease need replication in a multicenter setting. Relevant comparative studies were nonexistent for management of mixed histology disease and surgery for early limited SCLC. PET may be more sensitive in detecting extracranial disease than conventional staging modalities, but studies were of poor quality.

Conclusions: PCI improves survival among those with a complete remission to primary therapy. A research agenda is needed to optimize the effectiveness of TRTx and its components.

Key Words: carboplatin • chemotherapy • cisplatin • etoposide • irinotecan • meta-analysis • paclitaxel • prophylactic cranial irradiation • radiation therapy • small cell lung cancer • systematic review


   Introduction
TOP
 Abstract
 Introduction
Key Questions
 Materials and Methods
 Results
 Discussion and Future Research
 Conclusions
 References
 
Small cell lung cancer (SCLC) accounts for 13 to 20% of the 172,570 new cases and 163,510 deaths from lung cancer expected in the United States in 2005.12345678 Untreated SCLC is aggressive, with a median survival of 2 to 4 months after diagnosis.4 Most clinicians use a simplified dichotomous staging scheme developed by the Veterans Administration Lung Cancer Study Group.348 Limited-stage SCLC (approximately 30% of patients at diagnosis) includes those with tumor confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes.348 In extensive-stage SCLC, tumor has spread outside these limits.48

Diagnostic procedures commonly used to establish the presence of distant metastases include bone marrow aspiration, brain scans using CT or MRI, chest and abdomen scans using CT, and radionuclide bone scans.248 Whether positron emission tomography (PET) metabolic scanning using 18-fluorodeoxyglucose provides any additional information to current staging techniques is uncertain.23

Chemotherapy is used for most patients, either as adjuvant therapy for the few patients eligible for surgery, or as primary therapy for patients with inoperable tumors. Current guidelines389 recommend platinum-etoposide combinations in patients with limited-stage disease and platinum-based regimens in patients with extensive-stage disease. According to the 2003 American College of Chest Physicians (ACCP) guidelines, there is no evidence on the benefit of maintenance chemotherapy in any patient achieving a partial or complete remission (CR), and maintenance therapy is not recommended outside of a clinical trial.3 The 2007 guideline from the National Comprehensive Cancer Network essentially agrees with this position, noting that maintenance yields a minor prolongation of response duration without improving survival, yet increases the risk of toxicity.8

Surgery is usually limited to patients with smaller tumors (T1 or T2) and no evidence of nodal involvement or spread outside the hemithorax of origin.48 Whether surgery added to chemotherapy for patients with limited-stage disease improves survival is currently uncertain.

Metaanalyses published in the 1990s demonstrated the benefit of adding thoracic radiotherapy (TRTx) to chemotherapy in patients with limited-stage disease.1011 Uncertainties remain with respect to optimal timing, sequencing, and radiation regimens (ie, dosages and fractionation schemes).912 Metaanalyses using different study inclusion criteria have addressed the timing of TRTx administered with chemotherapy for limited-stage SCLC.13141516 These metaanalyses included varying numbers of studies and did not consistently demonstrate a significant advantage of early TRTx over late TRTx.

The role of radiation therapy in extensive disease is less established than in patients with limited-stage disease.2 Several large studies21718 reported in the 1980s by the Southwest Oncology Group and that did not randomize patients to TRTx vs no TRTx suggested that, although thoracic radiation reduced initial relapse at the primary tumor site, there was no effect on overall survival.

Clinicians often add prophylactic cranial irradiation (PCI), particularly for patients achieving a CR after primary therapy. Without PCI, patients who achieve an extracranial CR have a 50 to 80% actuarial risk for CNS metastases within 2 to 3 years.319 In addition, among patients who achieve a CR with chemotherapy, approximately 15% have brain metastases as the initial or only manifestation of recurrence.19

Most patients respond to primary therapy but relapse after remissions of varying duration.2 Second-line therapy is offered to most patients if the first remission has lasted 3 to 6 months; relapse after ≥3 months is also known as sensitive relapse.2 Evidence of benefit is lacking from second-line therapy for refractory SCLC (ie, no remission after primary therapy). Response to second-line therapy appears to be related to the chemotherapy agents administered in both the induction and second-line regimens.2 It is also unknown whether third-line or subsequent lines of therapy for relapsed or progressive SCLC improve outcomes compared with best supportive care.

The ACCP nominated SCLC as a topic for an evidence report to support updating of its 2003 guideline. Consultation with technical experts, some nominated by ACCP, identified nine key issues in need of systematic review.


   Key Questions
TOP
 Abstract
 Introduction
 Key Questions
Materials and Methods
 Results
 Discussion and Future Research
 Conclusions
 References
 
1. For limited-stage SCLC, what are the relative benefits and harms (survival, toxicity, and quality of life) of TRTx combined with chemotherapy in alternating fashion, concurrently, or sequentially?

2. For limited-stage SCLC, do outcomes (survival, toxicity, or quality of life) differ if concurrent TRTx is administered in early vs late chemotherapy cycles?

3. For limited-stage SCLC, do outcomes (survival, toxicity, quality of life) of primary therapy differ if one varies dose rate, treatment interval, or fractionation scheme for delivering TRTx? Comparisons of interest include:

a. Accelerated regimens (>10 Gy/wk completed over a short interval) vs standard duration regimens (<10 Gy/wk) vs split courses delivered over the standard interval; and

b. Single daily fractions vs hyperfractionated (two or more daily fractions or concomitant boost).

4. What are the relative benefits and harms (survival, toxicity, and quality of life) of adding TRTx to chemotherapy for primary treatment of extensive-stage SCLC?

5. What are the benefits and harms (survival, toxicity and quality of life) of PCI?

6. Does the addition of PET scanning improve the accuracy of staging for patients with SCLC over the use of other techniques, including CT and MRI, without PET?

7. What are the outcomes (survival, toxicity, and quality of life) of treatments used to manage patients with mixed SCLC/non-small cell lung cancers?

8. What is the role of surgery, and what is its impact on survival in patients with early stage SCLC? How do available studies define early stage SCLC?

9. What are the outcomes of second-line or subsequent-line therapy in patients with relapsed or progressive SCLC? Where available data permit, patients with limited-stage and extensive-stage disease will be addressed separately, as will those with refractory disease (relapse or progression within 3 months of primary treatment).


   Materials and Methods
TOP
 Abstract
 Introduction
 Key Questions
 Materials and Methods
Results
 Discussion and Future Research
 Conclusions
 References
 
The review methods were defined prospectively in a written protocol. A technical expert group provided consultation. The draft report was also reviewed by other experts and stakeholders.

Primary outcomes include duration of survival, disease-free or progression-free survival, quality of life, brain metastasis, and adverse events. Secondary outcomes include response rates, response duration, and recurrence. For key question 6 (PET staging), additional outcomes are diagnostic accuracy and changes in patient management.

Electronic database searches of MEDLINE (through December 21, 2004), EMBASE (through March 4, 2005), and the Cochrane Controlled Trials Register (through March 11, 2005) were conducted. The search was not limited to the English language, but foreign-language references without abstracts were excluded. Relevant conference proceedings were searched electronically.

We sought randomized, controlled trials (RCTs) that compared the interventions of interest. Where randomized trials were limited or nonexistent, we sought additional studies. For question 8 (surgery), we also sought nonrandomized comparative trials, prospective or retrospective. For question 9 (second-line or subsequent-line therapy), we also sought phase II multicenter studies reporting on at least 25 patients. For question 6 (PET staging), we sought single-arm trials that permitted computation of specificity and sensitivity in relation to an appropriate reference standard.

A single reviewer screened titles and abstracts for full-text retrieval; a second reviewer reviewed citations marked as uncertain. Review of full-text articles was conducted in the same fashion to determine inclusion in the systematic review. One reviewer performed primary data abstraction and a second reviewer reviewed the evidence tables for accuracy. All disagreements were resolved by consensus.

The general approach to assessing quality of evidence from studies of therapeutic interventions developed by the US Preventive Services Task Force20 was applied. For diagnostic studies, we used the Quality Assessment of Diagnostic Accuracy Studies tool.21

We performed a metaanalysis that combined studies included in key questions 1 and 2. The metrics used were 2-year and 3-year mortality relative risks (RRs). Publication bias and heterogeneity of treatment effects were assessed. Pooled RR estimates were made with the inverse variance weighted method. Influence analysis, subgroup/sensitivity analyses, and random effects metaregression were performed. Additional details on the methods and findings of this systematic review can be obtained from the full Agency for Healthcare Research and Quality Evidence Report.22


   Results
TOP
 Abstract
 Introduction
 Key Questions
 Materials and Methods
 Results
Discussion and Future Research
 Conclusions
 References
 
Key Question 1: For limited-stage SCLC, what are the relative benefits and harms (survival, toxicity, and quality of life) of TRTx combined with chemotherapy in alternating fashion, concurrently, or sequentially?

Table 1 summarizes RCTs concerning this key question. One multicenter trial23 and one single-center trial24 (n = 307) compared concurrent and sequential TRTx. Results are not conclusive but suggest better outcomes for concurrent TRTx. Overall survival adjusted for confounders significantly favored concurrent TRTx in the trial by Takada et al23 (n = 228), although unadjusted results were not significant. Additionally, the trial by Park et al24 found significantly longer response duration for concurrent TRTx. Of 11 types of adverse events reported, only leukopenia occurred significantly more frequently in the concurrent TRTx group in both studies.


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  		Table 1.. Summary of Trials Comparing Alternating, Concurrent, and Sequential TRTx*

 
No conclusions could be drawn on alternating TRTx. No significant differences in overall or progression- free survival were found in any of five trials: two comparisons to sequential TRTx (n = 458),2526 two comparisons with concurrent TRTx (n = 266),2728 and one comparison of early and late alternating TRTx (n = 199).2930

Key Question 2: For limited-stage SCLC, do outcomes differ if concurrent TRTx is administered in early vs late chemotherapy cycles?

The evidence is equivocal, finding no difference or small advantage for early concurrent TRTx.31323334353637383940 Among studies summarized in Table 2 , one large multicenter trial of good quality significantly favored concurrent therapy given in an early cycle,313233 as did two smaller trials. Of the two large multicenter trials that found no significant difference in survival, one did not use platinum chemotherapy343536 and the other is published only in abstract.40 Leukopenia/neutropenia appeared to be more common with early TRTx.


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  		Table 2.. Summary of Trials Comparing Times to Give Concurrent TRTx*

 
A metaanalysis was performed in an attempt to obtain clearer results. All but one study selected for key questions 1 and 2 were viewed as comparing early and late TRTx, and were pooled to give a more robust analysis. We did not find statistically significant reductions in 2-year and 3-year mortality rates for early TRTx over late TRTx. At 2 years, the pooled random effects RR for death is 0.936 and the 95% confidence interval is 0.860 to 1.019 (Fig 1 ). At 3 years, the fixed effects RR is 0.995 (95% confidence interval, 0.958 to 1.032; Fig 2 ).


Figure 1
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  		Figure 1.. Two-year mortality random effects forest plot.

 

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  		Figure 2.. Three-year mortality fixed effects forest plot.

 
Key Question 3: For limited-stage SCLC, do outcomes (survival, toxicity, quality of life) of primary therapy differ if one varies dose rate, treatment interval, or fractionation scheme for delivering TRTx?

Evidence to compare dose rates, treatment intervals, or fractionation schemes is limited (Table 3 ). Two RCTs compared one vs two fractions per day for previously untreated SCLC. One compared an accelerated regimen vs the standard duration, whereas the other compared a split-course regimen vs the standard duration.


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  		Table 3.. Summary of Trials Comparing One vs Two Fractions of TRTx per Day*

 
Compared to a single daily fraction, two daily fractions delivered concurrently with platinum chemotherapy improved overall survival (23 months vs 19 months; log rank p = 0.04) in a large multicenter trial4142 of good quality. The second trial434445 is difficult to interpret because multiple variables were studied simultaneously (n = 161), but there was no difference in survival with one vs two fractions per day. Esophagitis was more frequent with two fractions daily.

Key Question 4: What are the relative benefits and harms (survival, toxicity, and quality of life) of adding thoracic radiation therapy to chemotherapy for primary treatment of extensive-stage SCLC?

Among five RCTs,4647484950 one RCT (n = 99)46 shown in Table 4 suggests that adding concurrent TRTx improves survival of patients with extensive-stage disease that responds to an initial three cycles of platinum/etoposide chemotherapy with a CR outside the thorax and at least a partial response in the thorax. Uncontrolled data from the same trial suggest little to no benefit for other patients. Grades 3/4 esophagitis were more common with TRTx.


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  		Table 4.. Selected Characteristics of Trials Comparing Chemotherapy With vs Without TRTx*

 
Key Question 5: What are the benefits and harms (survival, toxicity and quality of life) of PCI?

An individual patient data metaanalysis on seven RCTs (n = 987) conducted by the Cochrane PCI Overview Collaborative Group51 shows that PCI improves survival of SCLC patients in CR after primary therapy. Table 5 shows that PCI increases the 3-year survival rate from 15.3 to 20.7% (p = 0.01), an absolute increase of 5.4%. PCI also significantly decreases the risk for brain metastasis and increases the likelihood of disease-free survival. The sole trial52 reported after the metaanalysis generally agrees with these findings.


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  		Table 5.. The Presence or Absence of PCI*

 
Subgroup analyses showed that PCI significantly decreases brain metastases for SCLC patients in CR regardless of age, disease stage, or performance status at diagnosis, and whether TRTx is part of the induction regimen. Survival benefit does not appear to differ among subgroups.

Additional subgroup analyses suggested that increasing the PCI dose from 8 to 40 Gy and starting PCI within the first 6 months after achieving complete response may reduce the likelihood of brain metastases. However, these hypotheses, derived from subgroup analyses, require formal testing in RCTs.

Although data are scant, acute toxicities of PCI seem tolerable at the doses used in these trials (8 to 40 Gy in 1.8 to 3-Gy fractions) and neurocognitive deficits no greater than existed before PCI.

Key Question 6: Does the addition of PET scanning improve the accuracy of staging for patients with SCLC over the use of other techniques, including CT and MRI, without PET?

The evidence is limited and of poor quality, and thus no conclusions can be drawn. Six studies535455565758 (n = 277) suggest that, except for brain metastases, PET added to conventional staging is more sensitive in detecting disease. However, there is so much uncertainty about the execution and interpretation of the reference standard in all of these studies that confidence is quite low in estimates of diagnostic and staging accuracy. The frequency of incorrect changes in stage attributable to PET is unknown because of incomplete reporting.

Key Question 7: What are the outcomes (survival, toxicity, and quality of life) of treatments used to manage patients with mixed SCLC/non-SCLCs?

There are few studies of any design that included patients with mixed histology. No conclusions can be drawn from the available evidence.

Key Question 8: What is the role of surgery and what is its impact on survival in patients with early stage SCLC? How do available studies define early stage SCLC?

We sought studies that compared surgery to no surgery in patients with very early limited SCLC, defined as no preoperative evidence of involved nodes (clinically N0). Two randomized controlled trials5960 and eight nonrandomized comparative studies61626364656667686970 were reviewed. None studied a homogeneous group of patients with respect to nodal status, nor were separate outcomes reported for a subgroup of patients without evidence of nodal involvement. Thus, no conclusion can be drawn.

Key Question 9: What are the outcomes of second-line or subsequent-line therapy in patients with relapsed or progressive SCLC?

Nine RCTs address second-line or subsequent-line treatment of SCLC, each of which compared different sets of chemotherapy regimens.717273747576777879 Two randomized trials7678 directly compared chemotherapy with best supportive care for recurrent SCLC. Spiro et al76 studied second-line methotrexate plus doxorubicin and found an overall response rate of 23% for the chemotherapy arm. O’Brien et al78 reported that oral topotecan resulted in a statistically significant increase in survival (26 weeks vs 14 weeks) and slower decline in quality of life. High-grade neutropenia occurred in one third of patients. Another trial71 compared oral vs IV topotecan; leukopenia and neutropenia were more frequent with the IV route, but survival and response were no greater. Other RCTs found higher rates of adverse events for one treatment over another but no associated survival advantage that would offset increased high-grade toxicity.

Five multicenter phase II trials8081828384 of note published since 2000 have reported overall response rates ≥20%. Only one study,80 using topotecan plus cisplatin, enrolled >50 patients. Approximately one fourth of both sensitive and refractory patients responded. Three fourths or more of both patient groups had high-grade leukopenia and neutropenia. A small study81 of irinotecan plus cisplatin found very high rates of partial response and low hematologic toxicity. The combination of paclitaxel, ifosfamide, and cisplatin82 achieved a high overall response rate and high-grade leukopenia in nearly all patients. One fourth of those receiving paclitaxel plus carboplatin had a response, and approximately one half had high-grade neutropenia.8384 In a study84 of doxorubicin plus carboplatin, nearly half of patients responded; however, four of five patients had grade 3 or 4 granulocytopenia.


   Discussion and Future Research
TOP
 Abstract
 Introduction
 Key Questions
 Materials and Methods
 Results
 Discussion and Future Research
Conclusions
 References
 
The purpose of this systematic review is to characterize the scientific literature available to address nine key questions concerning SCLC. Recommendations regarding management of SCLC are contained in a separate article.85 The strongest evidence available for this report is a patient-level metaanalysis showing that PCI improves survival of SCLC patients who achieved CR after primary therapy. No other question yielded evidence so robust. Our conclusions typically relied on a single trial showing treatment effects that were modest at best, and sometimes equivocal. This was apparent in our review of evidence for the sequence, timing, dosing, and fractionation of TRTx. For example, the case for concurrent over sequential delivery rests largely on a single multicenter trial.23 Support for early concurrent therapy comes from the multicenter trial by Murray et al,31 Coy et al,32 and Feld et al313233; however, two other multicenter trials by Perry-Ahles et al343536 and James et al40 found no advantage. However, the metaanalysis of 11 studies did not find significant reductions in 2- and 3-year mortality for early TRTx. For some questions (ie, management of mixed histology disease; surgery for early limited SCLC), comparative trials were nonexistent. Results reported by Jeremic et al46 on TRTx for extensive-stage disease need replication in a multicenter setting.

PET may be more sensitive in detecting disease outside the brain than conventional staging modalities. Future studies should fully report the frequency of correct and incorrect staging changes when PET is added to conventional tests and should link diagnostic performance to outcomes such as improvement in survival or reduced morbidity. Studies should be conducted according to standards described by the Quality Assessment of Diagnostic Accuracy Studies21 and reported according to the Standards for Reporting of Diagnostic Accuracy statement.8687

Complicating the evaluation of SCLC treatment are overall poor outcomes and small effect sizes, necessitating large numbers of patients in trials. Furthermore, interventions are multimodal with a multiplicity of variables that might contribute to the effectiveness.

Trials that are poorly designed, conducted, or reported waste limited resources. To advance clinical knowledge and practice, the field should adhere to standards of research quality and set an agenda for research priorities. Given modest gains in survival, quality of life assessment should be integral to clinical trials and should adhere to recommended research methods, including handling of missing data.


   Conclusions
TOP
 Abstract
 Introduction
 Key Questions
 Materials and Methods
 Results
 Discussion and Future Research
 Conclusions
References
 
PCI improves survival among those with a complete response to primary therapy. A research agenda is needed to optimize the effectiveness of TRTx and its components. PET for staging may be useful, but its role awaits clarification by rigorous studies. No relevant evidence was available to address management of mixed histology disease or surgery for early limited SCLC.


   Acknowledgements
 
The research team acknowledges the efforts of Maxine A. Gere, MS, for general editorial assistance and program support; Carol Gold-Boyd for administrative support; Mark D. Grant, MD, MPH, and Thomas A. Ratko, PhD, for fact checking; Tracey Perez, RN, JD, for program support; and William F. Lawrence, MD, MS, of the Agency for Healthcare Research and Quality for advice as our Task Order Officer.


   Footnotes
 
Abbreviations: ACCP = American College of Chest Physicians; CR = complete remission; PCI = prophylactic cranial irradiation; PET = positron emission tomography; RCT = randomized, controlled trial; RR = relative risk; SCLC = small cell lung cancer; TRTx = thoracic radiotherapy

This project was funded under Contract No. 290-02-0026 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication May 30, 2007. Accepted for publication June 5, 2007.


   References
TOP
 Abstract
 Introduction
 Key Questions
 Materials and Methods
 Results
 Discussion and Future Research
 Conclusions
 References
 

  1. American Cancer Society. Cancer facts and figures 2005. Atlanta, GA: American Cancer Society, 2005. Available at: http://www.cancer.org/downloads/STT/CAFF2005f4PWSecured.pdf. Accessed June 15, 2005
  2. Murren, JR, Turrisi, AT, Pass, HI Small cell lung cancer. DeVita, VT, Jr Hellman, S Rosenberg, SA eds. Cancer: principles and practice of oncology. 7th ed. 2005,810-843 Lippincott, Williams & Wilkins. Philadelphia, PA:
  3. Simon, GR, Wagner, H, for the American College of Chest Physicians. Small cell lung cancer. Chest 2003;123(suppl),259S-271S[CrossRef][Medline]
  4. National Cancer Institute, National Institutes of Health. Physicians data query (PDQ): small cell lung cancer treatment (health professional version); last modified May 17, 2005. Available at: http://cancernet.nci.nih.gov/cancertopics/pdq/treatment/small-cell-lung/healthprofessional. Accessed June 15, 2005
  5. Chua, YJ, Steer, C, Yip, D Recent advances in management of small-cell lung cancer. Cancer Treat Rev 2004;30,521-543[CrossRef][ISI][Medline]
  6. Ettinger, DS Overview and state of the art in the management of lung cancer. Oncology (Huntingt) 2004;18(suppl 4),3-9
  7. Stupp, R, Monnerat, C, Turrisi, AT, III, et al Small cell lung cancer: state of the art and future perspectives. Lung Cancer 2004;45,105-117[CrossRef][ISI][Medline]
  8. National Comprehensive Cancer Network. National Comprehensive Cancer Network practice guidelines in oncology v. 1.2007: small cell lung cancer. Available at: http://www.nccn.org/professionals/physician_gls/PDF/sclc.pdf. Accessed January 9, 2007
  9. Osterlind, K Chemotherapy in small cell lung cancer. Eur Respir J 2001;18,1026-1043[Abstract/Free Full Text]
  10. 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;10,890-895[Abstract]
  11. Pignon, JP, Arriagada, R, Ihde, DC, et al A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327,1618-1624[Abstract]
  12. Turrisi, AT, III Platinum combined with radiation therapy in small cell lung cancer: focusing like a laser beam on crucial issues. Semin Oncol 1994;21(suppl),36-42[Medline]
  13. Cancer Care Ontario. The role of thoracic radiotherapy as an adjunct to standard chemotherapy in limited-stage small cell lung cancer: update; January 2003. Available at: //www.cancercare.on.ca/pdf/full7_13_3.pdf. Accessed December 20, 2005
  14. Huncharek, M, McGarry, R A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited-stage small cell lung cancer. Oncologist 2004;9,665-672[Abstract/Free Full Text]
  15. Pijls-Johannesma MCG, De Ruysscher D, Lambin P, et al. Early vs late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev (database online). Issue 4, 2004
  16. Fried, DB, Morris, DE, Poole, C, et al Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 2004;22,4837-4845[Abstract/Free Full Text]
  17. Livingston, RB, Mira, JG, Chen, TT, et al Combined modality treatment of extensive small cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 1984;2,585-590[Abstract]
  18. Livingston, RB, Schulman, S, Mira, JG, et al Combined alkylators and multiple-site irradiation for extensive small cell lung cancer: a Southwest Oncology Group Study. Cancer Treat Rep 1986;70,1395-1401[ISI][Medline]
  19. Carney, DN Prophylactic cranial irradiation and small-cell lung cancer. N Engl J Med 1999;341,524-526[Free Full Text]
  20. Harris, RP, Helfand, M, Woolf, SH, et al Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20(suppl),21-35[ISI][Medline]
  21. Whiting, P, Rutjes, AWS, Dinnes, J, et al Development and validation of methods for assessing the quality of diagnostic accuracy studies. Health Technol Assess 2004;8,1-248[Medline]
  22. Seidenfeld, J, Samson, DJ, Bonnell, CJ, et al Management of small cell lung cancer: evidence report/technology assessment No. 143; prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-Based Practice Center under contract 290-02-0026. 2006 Agency for Healthcare Research and Quality. Rockville, MD: AHRQ publication 06-E016
  23. Takada, M, Fukuoka, M, Kawahara, M, et al Phase III study of concurrent vs 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;20,3054-3060[Abstract/Free Full Text]
  24. Park, SK, Kim, GH, Jeong, SS, et al The effects according to the timing of thoracic radiotherapy in limited stage small cell lung cancer. Tuberc Respir Dis 1996;43,903-915
  25. Sun, Y, Zhang, XR, Yin, WB, et al Prospective multimodality treatment of SCLC: experience during the past 18 years. Gan To Kagaku Ryoho 1995;22(suppl),222-225[Medline]
  26. Gregor, A, Drings, P, Burghouts, J, et al Randomized trial of alternating vs sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study. J Clin Oncol 1997;15,2840-2849[Abstract]
  27. Lebeau, B, Chastang, C, Brechot, JM, et al A randomized trial of delayed thoracic radiotherapy in complete responder patients with small-cell lung cancer: petites Cellules Group. Chest 1993;104,726-733[Medline]
  28. Blackstock, AW, Bogart, JA, Matthews, C, et al Split-course vs continuous thoracic radiation therapy for limited-stage small-cell lung cancer: final report of a randomized phase III trial. Clin Lung Cancer 2005;6,287-292[Medline]
  29. Work, E, Nielsen, OS, Bentzen, SM, et al Randomized study of initial vs late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer: Aarhus Lung Cancer Group. J Clin Oncol 1997;15,3030-3037[Abstract]
  30. Work, E, Bentzen, SM, Nielsen, OS, et al Prophylactic cranial irradiation in limited stage small cell lung cancer: survival benefit in patients with favourable characteristics. Eur J Cancer 1996;32A,772-778
  31. Murray, N, Coy, P, Pater, JL, et al Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer: the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1993;11,336-344[Abstract/Free Full Text]
  32. Coy, P, Hodson, DI, Murray, N, et al Patterns of failure following loco-regional radiotherapy in the treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys 1994;28,355-362[Medline]
  33. Feld, R, Payne, D, Hodson, I, et al Complications of treatment of small cell carcinoma of the lung: experience from a recent Canadian trial. Antibiot Chemother 1988;41,204-209[Medline]
  34. Perry, MC, Eaton, WL, Propert, KJ, et al Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 1987;316,912-918[Abstract]
  35. Ahles, TA, Silberfarb, PM, Rundle, AC, et al Quality of life in patients with limited small-cell carcinoma of the lung receiving chemotherapy with or without radiation therapy, for cancer and leukemia group B. Psychother Psychosom 1994;62,193-199[CrossRef][ISI][Medline]
  36. Perry, MC, Herndon, JE, III, Eaton, WL, et al 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;16,2466-2467[Abstract]
  37. Jeremic, B, Shibamoto, Y, Acimovic, L, et al Initial vs delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol 1997;15,893-900[Abstract/Free Full Text]
  38. Qiao, TK, Zhou, DA, Xin, L, et al Concurrent radiotherapy combined with carboplatin and etoposide in limited stage small cell lung cancer. Zhonghua Jie He He Hu Xi Za Zhi 2004;27,237-239[Medline]
  39. Skarlos, DV, Samantas, E, Briassoulis, E, et al Randomized comparison of early vs 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;12,1231-1238[Abstract/Free Full Text]
  40. James, LE, Spiro, S, O’Donnell, KM, et al A randomised study of timing of thoracic irradiation in small cell lung cancer (SCLC): study 8. Lung Cancer 2003;41(Suppl 2),S23
  41. 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. N Engl J Med 1999;340,265-271[Abstract/Free Full Text]
  42. Yuen, AR, Zou, G, Turrisi, AT, et al Similar outcome of elderly patients in intergroup trial 0096: cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma. Cancer 2000;89,1953-1960[CrossRef][ISI][Medline]
  43. Schild, SE, Bonner, JA, Shanahan, TG, et al Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;59,943-951[CrossRef][Medline]
  44. Sloan, JA, Bonner, JA, Hillman, SL, et al A quality-adjusted reanalysis of a phase III trial comparing once-daily thoracic radiation vs. twice-daily thoracic radiation in patients with limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002;52,371-381[CrossRef][Medline]
  45. Bonner, JA, Sloan, JA, Shanahan, TG, et al Phase III comparison of twice-daily split-course irradiation vs once-daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol 1999;17,2681-2691[Abstract/Free Full Text]
  46. Jeremic, B, Shibamoto, Y, Nikolic, N, et al Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 1999;17,2092-2099[Abstract/Free Full Text]
  47. Nou, E, Brodin, O, Bergh, J A randomized study of radiation treatment in small cell bronchial carcinoma treated with two types of four-drug chemotherapy regimens. Cancer 1988;62,1079-1090[CrossRef][Medline]
  48. Lebeau, B, Chastang, C, Brechot, JM, et al A randomized trial of delayed thoracic radiotherapy in complete responder patients with small-cell lung cancer: petites Cellules Group. Chest 1993;104,726-733[Medline]
  49. Rosenthal, MA, Tattersall, MHN, Fox, RM, et al Adjuvant thoracic radiotherapy in small cell lung cancer: ten-year follow-up of a randomized study. Lung Cancer 1991;7,235-241
  50. Brincker, H, Hindberg, J, Hansen, PV Cyclic alternating polychemotherapy with or without upper and lower half-body irradiation in small cell anaplastic lung cancer: a randomized study. Eur J Cancer Clin Oncol 1987;23,205-211[Medline]
  51. Prophylactic Cranial Irradiation Overview Collaborative Group.. Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission. Cochrane Database Syst Rev 2000;4,CD002805[Medline]
  52. Cao, K, Huang, H, Tu, M Clinical study of prophylactic cranial irradiation for small-cell lung cancer. Zhonghua Zhong Liu Za Zhi 2000;22,336-338[Medline]
  53. Bradley, JD, Dehdashti, F, Mintun, MA, et al Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 2004;22,3248-3254[Abstract/Free Full Text]
  54. Brink, I, Schumacher, T, Mix, M, et al Impact of (18F)FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 2004;31,1614-1620[CrossRef][ISI][Medline]
  55. Kamel, EM, Zwahlen, D, Wyss, MT, et al Whole-body (18)F-FDG PET improves the management of patients with small cell lung cancer. J Nucl Med 2003;44,1911-1917[Abstract/Free Full Text]
  56. Shen, YY, Shiau, YC, Wang, JJ, et al Whole-body 18F-2-deoxyglucose positron emission tomography in primary staging small cell lung cancer. Anticancer Res 2002;22,1257-1264[ISI][Medline]
  57. Blum, R, MacManus, MP, Rischin, D, et al Impact of positron emission tomography on the management of patients with small-cell lung cancer: preliminary experience. Am J Clin Oncol 2004;27,164-171[CrossRef][ISI][Medline]
  58. Schumacher, T, Brink, I, Mix, M, et al FDG-PET imaging for the staging and follow-up of small cell lung cancer. Eur J Nucl Med 2001;28,483-488[CrossRef][ISI][Medline]
  59. Lad, T, Piantadosi, S, Thomas, P, et al 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(6 suppl),320S-323S
  60. Liao, M, Zhao, J, Zhou, Y Multimodality therapy of late stage lung cancer. Zhonghua Zhong Liu Za Zhi 1995;17,384-386[Medline]
  61. Badzio, A, Kurowski, K, Karnicka-Mlodkowska, H, et al A retrospective comparative study of surgery followed by chemotherapy vs. non-surgical management in limited-disease small cell lung cancer. Eur J Cardiothorac Surg 2004;26,183-188[Abstract/Free Full Text]
  62. Badzio, A, Jassem, J, Kurowski, K, et al The impact of primary pulmonary resection on local control and survival in limited disease (LD) small cell lung cancer (SCLC) patients (pts): a retrospective comparative study. Lung Cancer 2005;49 (suppl 2),S316
  63. Shepherd, FA, Ginsberg, RJ, Patterson, GA, et al A prospective study of adjuvant surgical resection after chemotherapy for limited small cell lung cancer. a University of Toronto Lung Oncology Group study. J Thorac Cardiovasc Surg 1989;97,177-186[Abstract]
  64. Namikawa, S, Den, T, Kimura, M, et al The role of surgical resection and the effects of neo-adjuvant therapy in the management of small cell lung cancer. Surg Today 1994;24,342-346[CrossRef][Medline]
  65. Hara, N, Ichinose, Y, Kuda, T, et al Long-term survivors in resected and nonresected small cell lung cancer. Oncology 1991;48,441-447[Medline]
  66. Hara, N, Ohta, M, Ichinose, Y, et al Influence of surgical resection before and after chemotherapy on survival in small cell lung cancer. J Surg Oncol 1991;47,53-61[Medline]
  67. Friess, GG, McCracken, JD, Troxell, ML, et al Effect of initial resection of small-cell carcinoma of the lung: a review of Southwest Oncology Group Study 7628. J Clin Oncol 1985;3,964-968[Abstract/Free Full Text]
  68. 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 1985;40,272-277[Abstract/Free Full Text]
  69. Rostad, H, Naalsund, A, Jacobsen, R, et al Small cell lung cancer in Norway: should more patients have been offered surgical therapy? Eur J Cardiothorac Surg 2004;26,782-786[Abstract/Free Full Text]
  70. George, TK, Fitzgerald, D, Brown, BS, et al Long-term survival in limited-stage small cell lung carcinoma: experience in Rochester, New York from 1975 to 1981. Cancer 1986;58,1193-1198[Medline]
  71. von Pawel, J, Gatzemeier, U, Pujol, JL, et al Phase ii comparator study of oral vs intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol 2001;19,1743-1749[Abstract/Free Full Text]
  72. von Pawel, J, Schiller, JH, Shepherd, FA, et al Topotecan vs cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17,658-667[Abstract/Free Full Text]
  73. Postmus, PE, Smit, EF, Kirkpatrick, A, et al Testing the possible non-cross resistance of two equipotent combination chemotherapy regimens against small-cell lung cancer: a phase II study of the EORTC Lung Cancer Cooperative Group. Eur J Cancer 1993;29A,204-207
  74. Trillet-Lenoir, V, Lasset, C, Arpin, D, et al Comparison of 2 cisplatin and etoposide dosages in relapsing small cell lung cancer [in French]. Bull Cancer 1992;79,1173-1181[ISI][Medline]
  75. O’Bryan, RM, Crowley, JJ, Kim, PN, et al Comparison of etoposide and cisplatin with bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide for salvage treatment in small cell lung cancer: a Southwest Oncology Group Study. Cancer 1990;65,856-860[CrossRef][ISI][Medline]
  76. Spiro, SG, Souhami, RL, Geddes, DM, et al Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 1989;59,578-583[ISI][Medline]
  77. Sculier, JP, Lafitte, JJ, Lecomte, J, et al A phase II randomised trial comparing the cisplatin-etoposide combination chemotherapy with or without carboplatin as second-line therapy for small-cell lung cancer. Ann Oncol 2002;13,1454-459[Abstract/Free Full Text]
  78. O’Brien, M, Ciuleanu, T, Tsekov, H, et al Survival benefit of oral topotecan plus supportive care vs supportive care alone in relapsed, resistant SCLC. Lung Cancer 2005;49(Suppl 2),S54
  79. Wolff, SN, Birch, R, Sarma, P, et al Randomized dose-response evaluation of etoposide in small cell carcinoma of the lung: a Southeastern Cancer Study Group Trial. Cancer Treat Rep 1986;70,583-587[Medline]
  80. Ardizzoni, A, Hansen, H, Dombernowsky, P, et al Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease: the European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 1997;15,2090-2096[Abstract/Free Full Text]
  81. Ando, M, Kobayashi, K, Yoshimura, A, et al Weekly administration of irinotecan (CPT-11) plus cisplatin for refractory or relapsed small cell lung cancer. Lung Cancer 2004;44,121-127[Medline]
  82. Kosmas, C, Tsavaris, NB, Malamos, NA, et al Phase II study of paclitaxel, ifosfamide, and cisplatin as second-line treatment in relapsed small-cell lung cancer. J Clin Oncol 2001;19,119-126[Abstract/Free Full Text]
  83. Kakolyris, S, Mavroudis, D, Tsavaris, N, et al Paclitaxel in combination with carboplatin as salvage treatment in refractory small-cell lung cancer (SCLC): a multicenter phase II study. Ann Oncol 2001;12,193-197[Abstract/Free Full Text]
  84. Sonpavde, G, Ansari, R, Walker, P, et al Phase II study of doxorubicin and paclitaxel as second-line chemotherapy of small-cell lung cancer: a Hoosier Oncology Group Trial. Am J Clin Oncol 2000;23,68-70[Medline]
  85. Simon, GR, Turrisi, A Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition) Chest 2007;132,314-329
  86. Bossuyt, PM, Reitsma, JB, Bruns, DE, et al Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Clin Chem 2003;49,1-6[Abstract/Free Full Text]
  87. Bossuyt, PM, Reitsma, JB, Bruns, DE, et al The STARD statement for reporting of studies of diagnostic accuracy: explanation and elaboration. Clin Chem 2003;49,7-18[Abstract/Free Full Text]




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