|Management of small cell lung cancer
|Seidenfeld J, Samson D J, Bonnell C, Ziegler K M, Aronson N
This evaluation of methods for the management of small-cell lung cancer was unable to draw conclusions for the questions addressed because of the limited, often poor-quality, and equivocal evidence. Given this lack of available evidence, the cautious approach to the conclusions and suggestions for further research seem appropriate.
To evaluate methods for the management of small-cell lung cancer (SCLC). Several research questions, relating to benefits, harms, diagnosis, different treatment regimens and outcomes, were addressed.
MEDLINE (to December 2004), EMBASE (to March 2005) and the Cochrane Controlled Trials Register (to March 2005) were searched. Relevant conference proceedings were also searched electronically. The technical expert panel and peer reviewers were asked to provide information on additional studies. To be included, studies had to have the minimum of an English abstract.
Study designs of evaluations included in the review
Randomised controlled trials (RCTs) were eligible for inclusion; where RCT data were unavailable, non-randomised comparative studies were also sought. For the assessment of the diagnostic accuracy of FDG PET, diagnostic cohort studies were eligible for inclusion.
Specific interventions included in the review
Studies evaluating chemotherapy with concurrent, sequential, alternating, standard-interval, accelerated, split-course, single daily fractions, or hyperfractionated thoracic radiotherapy (TRTx) were eligible for inclusion, depending on the specific research question being addressed. For diagnosis, studies of fluorodeoxyglucose positron emission tomography (FDG PET) added to other staging modalities (computed tomography and magnetic resonance imaging) were eligible for inclusion.
Reference standard test against which the new test was compared
The authors stated that FDG PET should be compared with other imaging modalities and an appropriate reference standard, but did not provide specific details.
Participants included in the review
Studies of patients with a histopathologically confirmed diagnosis of SCLC were eligible for inclusion. Studies of mixed populations were excluded if less than 80% were of the population of interest and data for SCLC patients were not reported separately.
Outcomes assessed in the review
The primary outcomes of interest were survival (duration, disease-free, progression-free, brain metastasis-free), quality of life, palliation of symptoms, and treatment-related and peri-operative adverse events. The secondary outcomes included response rates, durations, and resection and recurrence rates for treatment interventions, as well as diagnostic accuracy, staging accuracy, change in stage and impact on management decisions for PET.
How were decisions on the relevance of primary studies made?
A single reviewer selected studies for inclusion. A second reviewer reviewed studies where the first was uncertain; any disagreements were resolved by referral to a third reviewer.
Assessment of study quality
One reviewer assessed study quality and a second reviewer checked the assessment; any disagreements were resolved by referral to a third reviewer. RCTs were assessed in relation to comparability of groups, methods of randomisation, allocation concealment, loss to follow-up, blinding, definitions of interventions, outcomes considered, adjustment for confounders in the analysis and the use of an intention-to-treat analysis. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool, which evaluates the following biases: spectrum, selection, clinical review, disease progression, differential verification, partial verification, test review and diagnostic review bias. The studies were graded as good, fair or poor.
The data were extracted into pre-specified evidence tables. One reviewer performed the initial data extraction and a second reviewer checked this for accuracy. Any disagreements were resolved by discussion or consultation with a third reviewer.
Methods of synthesis
How were the studies combined?
Where an adequate number of studies that did not show excessive heterogeneity were available, the results were combined; a random-effects model was used due to the presence of statistically significant heterogeneity. Publication bias was assessed using funnel plots and the Egger regression test.
How were differences between studies investigated?
Heterogeneity was assessed statistically using the Cochran Q test, and sources of heterogeneity were explored using random-effects meta-regression and subgroup analyses. The same set of dichotomous variables (relating to intervention characteristics and study quality) were used for both the subgroup and regression analyses. Study details and results were tabulated, and differences between the studies were discussed in the text.
Results of the review
Fifty-nine studies met the inclusion criteria.
TRTx combined with alternating, concurrent or sequential chemotherapy (6 RCTs, n=1,120): the evidence suggested that outcomes were better for concurrent TRTx compared with sequential TRTx, but not significantly so (2 RCTs). There was no evidence to suggest any difference between alternating and sequential TRTx (2 RCTs), between alternating and concurrent TRTx (1 RCT), or between early and late alternating TRTx (1 RCT).
Concurrent TRTx given early or late in the chemotherapy cycle (6 RCTs, n=1,177): the evidence showed either no difference (3 RCTs) or a small advantage (3 RCTs) for early TRTx; however, leukopenia or neutropenia was more common, significantly so in 2 RCTs. A meta-analysis, including all trials that could be viewed as comparing early and late TRTx (11 RCTs), showed no significant difference in 2- or 3-year mortality.
Variations in the dose rate, treatment interval, or fractionation scheme for delivering TRTx (2 RCTs, n=678): one study reported increased survival with two daily fractions compared with one; the other reported no difference. Oesophagitis was reported more frequently with two daily fractions in both trials.
Addition of TRTx to chemotherapy for the primary treatment of extensive-stage SCLC (5 RCTs, n=238): the included trials were of a poor quality and probably underpowered. One reported that adding TRTx to chemotherapy improved survival of some extensive-stage disease patients, but resulted in an increase in oesophagitis; none of the other trials reported such differences.
Addition of FDG PET to the diagnostic regimen (6 studies; n=277): except for the detection of brain metastases, PET added to conventional staging had greater sensitivity than conventional staging alone. Three studies reported a high frequency of management changes resulting from FDG PET, but did not report whether these changes were of benefit or harm. However, the quality of the included studies was poor and the findings may not be reliable.
Treatments for mixed SCLC and non-SCLC: no studies that evaluated the treatments used to manage patients with mixed small-cell and non-small-cell cancers met the inclusion criteria.
Role of surgery and its impact on survival (2 RCTs; 1 case-control; 1 prospective non-randomised study; 4 retrospective analyses and 2 registry analyses; n=1,125 in total): owing to the lack of evidence for the appropriate population, no conclusions were drawn regarding the role of surgery.
Second- or subsequent-line therapy in patients with relapsed or progressive SCLC (9 RCTs, n=1,389; 5 phase II trials, n=252): of 8 RCTs reporting overall survival, seven reported no significant difference between the groups. No study reported a significant difference in time to progression (2 RCTs) or tumour response (7 RCTs). Of the 2 studies reporting quality-of-life outcomes, one reported a significantly higher proportion of patients with improved symptoms for intravenous topotecan compared with CAV (cyclophosphamide, doxorubicin, vincristine). Intravenous topotecan was associated with a higher incidence of anaemia and thrombocytopenia than CAV (1 RCT), and high-dose platinum/etoposide chemotherapy with a higher incidence of leukopenia than low dose (1 RCT).
Whilst prophylactic cranial irradiation improved survival amongst those with a complete response to primary therapy, more research is needed to determine the optimal treatment regimens. FDG PET may be a useful tool for staging, but further good-quality research is needed to clarify its role. The management of mixed histology disease and the role of surgery in early SCLC could not be addressed due to a lack of evidence.
The review questions were clear, with well-defined inclusion criteria, and relevant sources were searched. However, the search had some limitations; publication bias was shown to be present for some outcomes, and language bias may also be an issue. A single reviewers selected the studies, and only those decisions where uncertainty arose were assessed by a second reviewer; this may lead to the introduction of bias or studies being missed in error. A second reviewer checked the data extraction, thereby reducing the potential for errors. Quality was assessed using appropriate criteria. The analysis seemed appropriate, but was limited by the paucity and poor quality of the available data. Given the evidence available, the cautious approach to conclusions and the suggestions for further research seem appropriate.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors recommended the use of well-conducted RCTs in which quality of life is an integral assessment and consensus definitions for patient enrolment criteria, subgroup characteristics and trial end points are used. The authors suggested that future diagnostic studies should be conducted according to the Standards for the Reporting of Diagnostic Accuracy Studies (STARD) guidelines and the QUADAS tool.
Agency for Healthcare Research and Quality, contract number 290-02-0026.
Seidenfeld J, Samson D J, Bonnell C, Ziegler K M, Aronson N. Management of small cell lung cancer. Rockville, MD, USA: Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment; 143. 2006
Other publications of related interest
Samson DJ, Seidenfeld J, Simon GR, Turrisi III AT, Bonnell C, Ziegler KM, et al. Evidence for management of small cell lung cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd edition). Chest 2007;132:314S-23S.
Subject indexing assigned by CRD
Antineoplastic Agents /therapeutic use; Antineoplastic Combined Chemotherapy Protocols /therapeutic use; Antineoplastic Protocols; Biological Response Modifiers /therapeutic use; Brain Neoplasms /prevention & Carcinoma, Small Cell /drug therapy /prevention & Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Cranial Irradiation; Drug Therapy; Lung Neoplasms /drug therapy /radiotherapy /surgery; Neoplasm Metastasis; Neoplasm Recurrence, Local /therapy; Neoplasm Staging; Pneumonectomy; Positron-Emission Tomography; Radiotherapy Dosage; Radiotherapy, Adjuvant; Treatment Outcome; control /radiotherapy /secondary /surgery; control /secondary
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.