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Seidenfeld J, Bonnell C, Ziegler KM, et al. Management of Small Cell Lung Cancer. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Jul. (Evidence Reports/Technology Assessments, No. 143.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Management of Small Cell Lung Cancer.

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The objective of this Evidence Report is to systematically review and synthesize available evidence on managing patients diagnosed with small cell lung cancer (SCLC). The Key Questions addressed here were proposed by the American College of Chest Physicians, the partner organization for this evidence report and were refined after consultation with experts.

Peer Review

A technical expert group provided consultation for the systematic review. The draft report was reviewed by 10 external reviewers, including members of the technical expert group, the Task Order Officer, other invited technical experts, and stakeholders (Appendix E).* Revisions were made to the draft report based on reviewers' comments.

Study Selection Criteria

Types of Studies

All questions, except Question 6, addressed therapeutic interventions. We sought randomized, controlled trials that compared the interventions of interest. No minimum number of patients per study arm was required for randomized, controlled trials. Because there were few randomized, controlled trials available to address Questions 8 and 9, we sought additional studies. For Question 8 (surgery), we also sought nonrandomized comparative trials, both prospective and retrospective in design. For Question 9 (second- or subsequent-line therapy), we also sought phase II multicenter trials reporting on at least 25 patients.

Question 6 (PET for staging) addresses a diagnostic intervention. Although we sought randomized, controlled trials comparing the outcomes of SCLC patients staged with and without use of PET, no such studies were identified. We then sought prospective, single-arm trials that reported on at least 25 patients undergoing imaging to stage SCLC; correlated 18-fluorodeoxyyglucose (FDG) PET findings with findings from other imaging modalities and an appropriate reference standard; and permitted computation of sensitivity and specificity.

Our search and selection criteria included English-language studies, as well as foreign-language studies that had an English-language abstract.

Studies were excluded if no outcome of interest to this review was reported. Studies were also excluded if the patient population of interest was fewer than 80 percent of included patients, or, alternatively, results for the patient population of interest were not separately reported. When multiple reports were available for the same study, it was counted as a single trial and outcome data from the report with the longest follow-up were used.

Types of Participants

  • Key Questions 1–3 (First-line chemotherapy with thoracic radiotherapy [TRTx]) — patients with a histopathologically confirmed diagnosis of SCLC staged as limited disease.
  • Key Question 4 (thoracic radiation therapy) — Patients with a histopathologically confirmed diagnosis of SCLC staged as extensive disease undergoing first-line therapy.
  • Key Question 5 (prophylactic cranial irradiation) — Patients with a histopathologically confirmed diagnosis of SCLC that has completely responded to primary therapy (regardless of stage).
  • Key Question 6 (PET staging) — Patients with a histopathologically confirmed diagnosis of SCLC.
  • Key Question 7 (management mixed disease) — Patients with a histopathologically confirmed diagnosis of mixed small cell/non-small cell lung cancer.
  • Key Question 8 (surgery) — Patients with a histopathologically confirmed diagnosis of SCLC staged as limited disease with small tumors and no nodal involvement
  • Key Question 9 (second- or subsequent-line therapy) — Patients with a histopathologically confirmed diagnosis of SCLC that either relapsed or progressed after a response that lasted at least 3 months following primary therapy for: (a) limited-stage or (b) extensive-stage disease; or (c) patients with refractory disease (defined as no response or progression within 3 months of primary therapy).

Types of Interventions

  • Key Question 1 — Comparison of chemotherapy combined with sequential TRTx, chemotherapy combined with concurrent TRTx and chemotherapy combined with alternating TRTx.
  • Key Question 2 — Chemotherapy combined with concurrent TRTx initiated early cycles (i.e., 1 or 2) versus chemotherapy combined with concurrent TRTx initiated in late cycles (i.e., 3 or later).
  • Key Question 3 — Chemotherapy combined with standard-interval TRTx versus chemotherapy combined with accelerated TRTx: OR chemotherapy combined with split-course TRTx chemotherapy combined with standard-interval TRTx; OR chemotherapy combined with single daily fractions of TRTx; OR chemotherapy combined with hyperfractionated TRTx.
  • Key Question 4 — Chemotherapy combined with TRTx versus chemotherapy alone.
  • Key Question 5 — Prophylactic cranial irradiation (PCI) versus no prophylactic radiation after primary therapy is completed and response is assessed.
  • Key Question 6 — Positron-emission tomography (PET) vs. no PET, added to other staging modalities, including computed tomography (CT) and magnetic resonance imaging (MRI).
  • Key Question 7 — Chemotherapy with or without TRTx delivered in any sequence or schedule used for limited-stage SCLC
  • Key Question 8 — Surgical excision of SCLC tumors, preceded by neoadjuvant chemotherapy or followed by adjuvant chemotherapy, and either with or without TRTx and PCI, versus no surgical excision
  • Key Question 9 — Chemotherapy using drugs approved by the U.S. Food and Drug Administration for at least one indication to treat a malignant disease (various regimens).

Types of Outcomes

Primary (health) outcomes of interest include:

  • duration of survival, disease-free survival, and/or progression-free survival
  • quality of life
  • brain metastasis-free survival and subsequent treatment(s) for brain metastasis
  • palliation of measurable symptoms
  • treatment-related adverse events
  • perioperative adverse events

Secondary (intermediate) outcomes include:

  • objective response rates (complete and partial responses; separately and summed)
  • response durations
  • pathologically complete resection rates
  • recurrence rates

For key question 6 (PET staging) additional outcomes of interest are:

  • diagnostic accuracy
  • outcomes other than diagnostic accuracy, such as staging accuracy, change in stage and impact on management decisions

Search Strategy and Review

Search Strategy

Electronic databases. The following databases were searched for citations. The full search strategy is displayed in Appendix A. * The search was not limited to English-language references, but foreign-language references without abstracts were disregarded.

  • MEDLINE® (through 12/21/04)
  • EMBASE (through 03/04/05)
  • Cochrane Controlled Trials Register (through 03/11/05)

Additional Sources of Evidence. The Technical Expert Panel and individuals and organizations providing peer review were asked to inform the project team of any studies relevant to the key questions that were not included in the draft list of selected studies.

Search Screen

Search results were stored in a ProCite® database. Using the study selection criteria for screening titles and abstracts, a single reviewer marked each citation as either: (1) eligible for review as full-text articles; (2) ineligible for full-text review; or (3) uncertain. Citations marked as uncertain were reviewed by a second reviewer and resolved by consensus opinion, with a third reviewer to be consulted if necessary. Using the final study selection criteria, review of full-text articles was conducted in the same fashion to determine inclusion in the systematic review. A total of 630 references were retrieved at a full-text level; 89 were included in this review (Figure 1). Records of the reason for exclusion for each paper retrieved in full-text, but excluded from the review, were kept in the ProCite® database (see Appendix D, Excluded Studies).

Figure 1. QUOROM Flow Diagram.


Figure 1. QUOROM Flow Diagram.

Data Extraction and Analysis

Data Elements

The data elements below were abstracted, or recorded as not reported, from therapeutic intervention studies.

  • critical features of the study design (for example, patient inclusion/exclusion criteria, number of subjects, use of blinding);
  • potential patient characteristic confounders:
    • age
    • gender
    • race
    • extent of disease and stage
    • performance status
    • comorbidities
  • treatment protocols (for example, treatment intensity, frequency, duration, other prior and concurrent treatment factors);
  • patient monitoring procedures (for example, follow-up duration and frequency, outcome assessment methods); and
  • the specified key outcomes and data analysis method (when statistical test results were lacking for adverse events data, reviewers performed tests with the STATMAN statistical program).

The data elements below were abstracted, or recorded as not reported, from diagnostic accuracy studies of imaging modalities used in staging SCLC:

  • patient selection criteria
  • details about the reference standard (validity and degree of detail in description)
  • decision rules for determining which patients received the reference standard
  • whether the index test and reference standard were interpreted blind to each other
  • whether verification bias (index test results influenced decisions to perform reference standard) was avoided
  • details about the index test (degree of detail about performing of test, interpretation)
  • study design (prospective, retrospective)
  • reporting of diagnostic accuracy results (completeness, appropriate calculation of accuracy measures, use of confidence intervals)
  • outcomes other than diagnostic accuracy, such as staging accuracy, change in stage and impact on management decisions

Evidence Tables

Templates for evidence tables were created in Microsoft Excel® and Microsoft Word® Appendix B).* One reviewer performed primary data abstraction of all data elements into the evidence tables, and a second reviewer reviewed the evidence tables for accuracy. Disagreements were resolved by discussion, and if necessary, by consultation with a third reviewer. When small differences occurred in quantitative estimates of data from published figures, the values obtained by the two reviewers were averaged.

Assessment of Study Quality

Therapeutic Studies

The general approach to grading evidence developed by the U.S. Preventive Services Task Force (Harris et al. 2001) was applied. Quality of the abstracted studies was assessed by one reviewer and fact-checked by a second. Discordant quality assessments were resolved by discussion or by consultation with a third reviewer, if necessary. The quality criteria for randomized, controlled trials were as follows:

  • Initial assembly of comparable groups: adequate randomization, including concealment and whether potential confounders (e.g., baseline characteristics, other concomitant care) were distributed equally among groups
  • Maintenance of comparable groups (includes attrition, crossovers, adherence, contamination)
  • Important differential loss to follow-up or overall high loss to follow-up
  • Measurements: equal, reliable, and valid (includes masking of outcome assessment)
  • Clear definition of interventions
  • All important outcomes considered
  • Analysis: adjustment for potential confounders, intention-to-treat analysis

Diagnostic Studies

The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool underwent a rigorous development process by Whiting, Rutjes, Dinnes, et al. (2004) and includes the following items:

  • Was the spectrum of patients representative of the patients who will receive the test in practice?
  • Were selection criteria clearly described?
  • Is the reference standard likely to classify the target condition correctly?
  • Is the period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests?
  • Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis?
  • Did patients receive the same reference standard regardless of the index test result?
  • Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)?
  • Was the execution of the index test described in sufficient detail to permit replication of the test?
  • Was the execution of the reference standard described in sufficient detail to permit replication of the reference standard?
  • Were the index test results interpreted without knowledge of the results of the reference standard?
  • Were the reference standard results interpreted without knowledge of the results of the index test?
  • Were the same clinical data available when test results were interpreted as would be available when the test is used in practice?
  • Were uninterpretable/intermediate test results reported?
  • Were withdrawals from the study explained?

Definition of Ratings Based on Criteria

The rating of therapeutic intervention studies encompasses the 3 quality categories described below. No analogous quality categories have been incorporated into the QUADAS tool for assessing diagnostic accuracy studies. Rather, each of the 14 QUADAS items is considered individually.

Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study (follow-up at least 80 percent); reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; all important outcomes are considered; and appropriate attention to confounders in analysis. In addition, for randomized, controlled trials (RCTs), intention to treat analysis (i.e., all patients randomized were analyzed) is used.

Fair: Studies will be graded “fair” if any or all of the following problems occur, without the fatal flaws noted in the “poor” category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred with follow-up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are accounted for. Intention-to-treat analysis is done for RCTs.

Poor: Studies will be graded “poor” if any of the following fatal flaws exists: Groups assembled initially are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied at all equally among groups (including not masking outcome assessment); and key confounders are given little or no attention. For RCTs, intention-to-treat analysis is lacking.


Quantitative synthesis of evidence was carried out by combining studies meeting selection criteria for key questions 1 and 2. Eleven such randomized controlled trials (RCTs) could be viewed as comparing early and late thoracic radiotherapy (TRTx) for limited-stage small cell lung cancer (see “Results: Results of Meta-Analysis/Meta-Regression”). This Review defines early TRTx as given in cycles 1 or 2 and late as given in cycle 3 or later and at least 3 weeks after the start of early TRTx. Of the 11 RCTs, all provide 3-year overall survival data and 9 give 2-year data. The metrics used in the meta-analysis were 2-year and 3-year mortality relative risks (RRs). Estimates of survival were multiplied by sample sizes and rounded to the nearest whole number to derive the numbers alive and dead at 2 years and 3 years. While this method has been used in 4 previous meta-analyses on the timing of TRTx for limited SCLC, it does not take into account censoring and therefore may inflate subject counts. Even if a consensus method to incorporate censoring was available, it could not be applied to 6 of 11 studies due to insufficient detail in articles. Our method assures easy comparisons with previous meta-analyses and inclusion of more studies.

Meta-analysis was not worth pursuing for other questions in this Review. For key questions 3, 4, 7, 8, and 9, there was either an inadequate number of studies or excessive heterogeneity of treatments for pooled analysis. Question 5 was the subject of a recent patient-level meta-analysis (Auperin, Arriagada, Pignon, et al. 1999; Prophylactic Cranial Irradiation Overview Collaborative Group, 2000; Carney, 1999) and thus, a meta-analysis was not necessary for this Review. Uncertainty about the reference standard used in studies on question 6 was so great that a meta-analysis could give unwarranted weight to uniformly poor quality studies.

The first step in the meta-analysis was to assess whether publication bias was likely. This was first done visually with funnel plots, in which the trials are sorted along the vertical axis in ascending order of the standard error of the log odds ratio. A formal test for publication was performed using Egger's linear regression (Egger, Davey Smith, Schneider, et al., 1997). Trial standardized effect estimates were fit to precision values (the inverse of the standard error), using least squares and trial's inverse variance as weights. Asymmetry suggestive of publication bias would be indicated by a regression intercept value that significantly deviates from zero.

The next step in the meta-analysis is to determine whether significant heterogeneity of treatment effects exists. A standard test for heterogeneity is the Q statistic (Cochran, 1954). The null hypothesis of homogeneity is rejected below an alpha level of 0.10. If rejected, the combined RR point estimate should be computed with a random effects (RE) model (DerSimonian and Laird, 1986). Where necessary, the between-study variance component (tau squared) was calculated using the algebraic method described by Sutton, Abrams, Jones, et al. (2000). If the null hypothesis of homogeneity is not rejected, a fixed effects (FE) model would be used (Cochran, 1937).

Pooled estimates of treatment effects were derived using the inverse variance-weighted method (Cochran, 1937). Meta-analysis results are presented graphically in forest plots. Subgroup/sensitivity analyses were performed for these variables: whether early TRTx was given at the earliest opportunity; whether hyperfractionation was used; whether platinum was included in chemotherapy (CTx); whether early TRTx was given concurrent with CTx; and whether the trial was rated as being of good quality. Influence analysis was conducted by excluding each trial individually to reveal the impact on effect estimates. Results are presented graphically.

Random effects meta-regression, as described by Berkey, Hoaglin, Mosteller, et al. (1995), was conducted to explore sources of heterogeneity. All covariates are dichotomous variables, the same variables as those in subgroup/sensitivity analyses. Single variables were tested first. Multiple variables were included only as an exercise due to concerns of overfitting. Analyses were carried out using STATA 9.0 and Microsoft Excel 2002.



Appendixes cited in this report are provided electronically at http://www​​/pub/evidence​/pdf/lungcansmall/lungcan.pdf


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