Cirugía para el cáncer de pulmón de células pequeñas en estadio limitado
Resumen
Antecedentes
Las guías de tratamiento actual para el cáncer de pulmón de células pequeñas (CPCP) en estadio limitado recomiendan quimiorradioterapia concomitante con platino más irradiación craneal profiláctica, según la premisa de que el CPCP se disemina de forma precoz y es quimiosensible. Sin embargo, aunque en general hay una respuesta inicial favorable, la recidiva es frecuente y la tasa de curación del CPCP en estadio limitado todavía es relativamente deficiente. Algunas guías de práctica clínica recientes han recomendado la cirugía para el CPCP en estadio 1 (limitado) seguida de quimioterapia coadyuvante, pero esta recomendación se basa en gran parte en los resultados de estudios observacionales.
Objetivos
Determinar si, en los pacientes con CPCP en estadio limitado, la resección quirúrgica del cáncer mejora la supervivencia general y las muertes relacionadas con el tratamiento en comparación con la radioterapia o la quimioterapia, o una combinación de radioterapia y quimioterapia, o la mejor atención de apoyo.
Métodos de búsqueda
Se hicieron búsquedas en CENTRAL, MEDLINE, Embase, CINAHL y en Web of Science hasta el 11 enero 2017. Se hicieron búsquedas manuales de artículos de revisión, registros de ensayos clínicos y listas de referencias de artículos recuperados.
Criterios de selección
Se incluyeron los ensayos controlados aleatorios (ECA) con pacientes adultos diagnosticados con CPCP en estadio limitado, confirmado por citología o histología, y evaluación radiológica, considerado médicamente apropiado para resección y radioterapia radical, que asignaron al azar a los participantes a cirugía versus otra intervención.
Obtención y análisis de los datos
Los estudios identificados mediante la búsqueda se importaron a una base de datos de control de referencias. Se recuperó la versión de texto completo de los estudios relevantes, y dos autores de la revisión extrajeron los datos de forma independiente. Las medidas de resultado primarias fueron la supervivencia general y las muertes relacionadas con el tratamiento; y las medidas de resultado secundarias incluyeron la progresión locorregional, la calidad de vida y los eventos adversos.
Resultados principales
Se incluyeron tres ensayos con 330 participantes. La calidad de la evidencia se consideró muy baja para todos los resultados. La calidad de los datos estuvo limitada por la falta de informe completo de los resultados, el riesgo de sesgo incierto en los métodos de realización de los estudios y la antigüedad de los estudios (> 20 años). Los métodos de estadiaje del cáncer y los tipos de procedimientos quirúrgicos, que no reflejan la práctica actual, redujeron la confianza en la estimación del efecto.
Dos estudios compararon cirugía con radioterapia y en un estudio se administró quimioterapia a ambos brazos. Un estudio administró quimioterapia inicial, luego los pacientes que respondieron al tratamiento se asignaron al azar a cirugía versus control; después, a ambos grupos se les administró irradiación torácica y cerebral total.
Debido a la heterogeneidad clínica de los ensayos no fue posible agrupar los resultados para el metanálisis.
Los tres estudios informaron la supervivencia general. Un estudio informó una supervivencia general media de 199 días en el brazo quirúrgico, en comparación con 300 días en el brazo de radioterapia (P = 0,04). Un estudio informó una supervivencia general del 4% en el brazo quirúrgico, en comparación con el 10% en el brazo de radioterapia a los dos años. Por el contrario, un estudio informó una supervivencia general a los dos años del 52% en el brazo quirúrgico, en comparación con el 18% en el brazo de radioterapia. Sin embargo, esta diferencia no fue estadísticamente significativa (P = 0,12).
Un estudio informó una mortalidad posoperatoria temprana del 7% en el brazo quirúrgico, en comparación con una mortalidad del 0% en el brazo de radioterapia. Un estudio informó la diferencia en el grado medio de disnea como ‐1,2 al comparar la cirugía con la radioterapia, lo que indica que es probable que los participantes sometidos a radioterapia presenten más disnea. Este resultado se midió mediante una escala no validada.
Conclusiones de los autores
La evidencia a partir de los ECA actualmente disponibles no apoya una función de la resección quirúrgica en el tratamiento del cáncer de pulmón de células pequeñas en estadio limitado; sin embargo, las conclusiones están limitadas por la calidad de la evidencia disponible y la falta de datos contemporáneos. Los resultados de los ensayos incluidos en esta revisión no se pueden generalizar a los pacientes con cáncer de pulmón de células pequeñas en estadio clínico 1 estadiado de forma cuidadosa mediante métodos de estadiaje contemporáneos. Aunque algunas guías actualmente recomiendan la resección quirúrgica en el cáncer de pulmón de células pequeñas en estadio clínico 1, se necesitan ensayos controlados aleatorios prospectivos para determinar si hay efectos beneficiosos con respecto a la mortalidad a corto y a largo plazo y la calidad de vida en comparación con la quimiorradioterapia sola.
PICO
Resumen en términos sencillos
Cirugía para el cáncer de pulmón de células pequeñas en estadio limitado
Antecedentes
Hay diferentes tipos de cáncer de pulmón. A uno de los tipos se le llama cáncer de pulmón de células pequeñas. El cáncer de pulmón de células pequeñas se considera en estadio limitado si todavía está dentro del tórax o en estadio extensivo si se ha extendido fuera el tórax. Actualmente se recomiendan la quimioterapia y la radioterapia para el tratamiento del cáncer de pulmón de células pequeñas en estadio limitado si está localizado y no se ha extendido fuera de un lado del tórax.
Pregunta de la revisión
Se deseaba determinar si los pacientes con cáncer de pulmón de células pequeñas que no se ha diseminado fuera del tórax viven más tiempo con una operación para retirar el tumor, ya sea acompañada de quimioterapia, radioterapia, o ambas o ninguna, en comparación con quimioterapia, con o sin radioterapia.
Características de los estudios
Se buscaron los ensayos clínicos hasta el 11 de enero de 2017 y se incluyeron tres estudios con 330 pacientes a los que se les había diagnosticado cáncer de pulmón de células pequeñas que no se había diseminado fuera del tórax. A algunos pacientes se les proporcionó solamente cirugía y a otros no. Además, a algunos se les administró quimioterapia y radioterapia junto con la cirugía y a algunos se les administró quimioterapia y radioterapia sin cirugía. Se analizó si hubo diferencias en el tiempo de vida de los pacientes y si el tratamiento causó algún efecto secundario.
Hallazgos clave
Todos los datos fueron de muy baja calidad. Los tres estudios fueron muy diferentes, por lo que no fue posible combinarlos. Un estudio informó que los pacientes vivieron más tiempo sin cirugía (pero con radioterapia) que con cirugía. Un estudio informó que el 4% de los pacientes sobrevivía a los dos años con la cirugía en comparación con el 10% de los pacientes que sobrevivía con la radioterapia. Un estudio informó que el 52% de los pacientes sobrevivía con la cirugía en comparación con el 18% de los pacientes que sobrevivía con la radioterapia. La evidencia no apoya el uso de la cirugía en los pacientes con cáncer de pulmón de células pequeñas, pero la calidad de los datos es baja y tienen más de 20 años de antigüedad. Se necesitan mejores ensayos para comparar adecuadamente la cirugía con ninguna cirugía en los pacientes con cáncer de pulmón de células pequeñas.
Calidad de la evidencia
Se evaluó la calidad de la evidencia mediante uno de los siguientes grados: muy baja, baja, moderada o alta. La evidencia de muy baja calidad significa que existe incertidumbre acerca de los resultados. La evidencia de alta calidad significa que existe mucha seguridad acerca de los resultados. En esta revisión Cochrane se encontró que la evidencia fue de muy baja calidad para todos los resultados de los estudios. No fue posible combinar los ensayos ya que todos fueron muy diferentes y muy antiguos. Algunos ensayos no dieron suficiente información sobre su calidad.
Authors' conclusions
Summary of findings
| Surgery compared with no surgery for limited‐stage small‐cell lung cancer | |||
| Patient or population: People with limited‐stage small‐cell lung cancer Settings: ambulatory care Intervention: surgery Comparison: no surgery | |||
| Outcomes | Impact | No of Participants | Quality of the evidence |
| Survival | Survival is difficult to interpret in these studiesa | 3 studies (330 participants)b | ⊕⊖⊖⊖ very lowc |
| Treatment related mortality | Treatment‐related mortality is difficult to interpret in these studiesd | 2 studies (290 participants)e | ⊕⊖⊖⊖ very lowc |
| Loco‐regional progression | Loco‐regional progression is difficult to interpret in these studiesf | 2 studies (186 participants)g | ⊕⊖⊖⊖ very lowc |
| Quality of life | Quality of life is difficult to interpret in these studiesh | 1 study (144 participants)i | ⊕⊖⊖⊖ very lowj |
| GRADE Working Group grades of evidence aTreatment across trials were heterogenous: Fox 1973 compared surgery to radiotherapy. Lad 1994a administered induction chemotherapy to all participants, and then compared surgery to no surgery; following, all participants had chest and brain irradiation. Liao 1995 administered induction chemotherapy to all participants and then compared surgery to radiotherapy. The effect is difficult to interpret as the types of surgical procedures used in these studies do not reflect current clinical practice. bThis includes Fox 1973: surgery ‐ 71 participants; and radiotherapy ‐ 73 participants. Lad 1994a: surgery ‐ 70 participants; and no surgery ‐ 76 participants. Liao 1995: surgery ‐ 20 participants; and radiotherapy ‐ 20 participants. cStudies contributing to this outcome were at an unclear risk of bias which reduced our confidence in the estimation of effect. Downgraded once. Staging and surgical techniques don't necessarily reflect best current practice. Downgraded twice. dThe effect is difficult to interpret as the type of surgical procedures used in these studies do not reflect current clinical practice. eThis includes Fox 1973: surgery ‐ 71 participants; and radiotherapy ‐ 73 participants. Lad 1994a: surgery ‐ 70 participants; and no surgery ‐ 76 participants. fTreatments across trials were heterogenous: Fox 1973 compared surgery to radiotherapy. Lad 1994a administered induction chemotherapy to all participants, and then compared surgery to no surgery; following, all participants had chest and brain irradiation. Liao 1995 administered induction chemotherapy to all participants and then compared surgery to radiotherapy. gThis includes Lad 1994a: surgery ‐ 70 participants; and no surgery ‐ 76 participants; Liao 1995: surgery ‐ 20 participants; and radiotherapy ‐ 20 participants. hFox 1973 reported quality of life and dyspnoea using non‐validated scales. iThis includes Fox 1973: surgery ‐ 71 participants; and radiotherapy ‐ 73 participants. jStudies contributing to this outcome were at an unclear risk of bias which reduced our confidence in the estimation of effect. Downgraded once. Staging and surgical techniques don't necessarily reflect best current practice. Downgraded twice. The scales utilised were not validated. | |||
Background
Description of the condition
Lung cancer is a significant health burden around the world. It is the fifth most common malignancy and accounts for approximately 20% of all cancer‐related deaths and 5% of overall deaths. Overall survival of lung cancer is poor. The five‐year survival rate is 15% in Australia and the USA (AIHW & AACR 2012; NHMRC 2004).
Lung cancer is classified according to its histopathological subtype (Travis 2011; Travis 2013). Two major classes are non‐small‐cell lung cancer (NSCLC) (including adenocarcinoma, squamous cell carcinoma, and NSCLC not otherwise specified), accounting for 85% of lung cancers; and small‐cell lung cancer (SCLC). Histopathological characteristics guide further diagnosis and management. The treatment of NSCLC has been examined in other reviews (Manser 2005).
Small‐cell lung cancer is a specific clinical and histological entity. It comprises approximately 15% of all newly diagnosed lung cancers worldwide or 180,000 cases per year. It is particularly associated with tobacco use: 90% of those with SCLC are or were heavy smokers. Clinically SCLC tends to present in current or ex‐smokers over 70 years of age with a rapid onset of symptoms, generally consists of central and bulky tumours on chest imaging, and tends to spread early (van Meerbeeck 2011; Watson 1962). SCLC may cause paraneoplastic syndromes including, but not limited to, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Cushing syndrome, and Lambert–Eaton syndrome (van Meerbeeck 2011).
Staging for SCLC differs from NSCLC and other cancers. Because of its tendency for early dissemination, staging for SCLC was initially defined by the Veterans' Administration Lung Study Group (VALSG) in the 1950s as "limited" (within one radiation portal, defined as a single hemithorax and its corresponding ipsilateral, supraclavicular lymph nodes) or "extensive" (beyond one portal, and including distant metastases, and malignant pleural effusions) (Zelen 1973). Treatment is generally guided by this staging system. In 1989, the International Association for the Study of Lung Cancer (IASLC) recommended the expansion of the definition of "limited" to include all tumours limited to one hemithorax with regional lymph node metastases, including hilar, ipsilateral and contralateral mediastinal and ipsilateral and contralateral supraclavicular lymph nodes. The IASLC also recommended any patients with an ipsilateral pleural effusion, malignant or not, be included in the "limited stage" if no other metastases were present (Stahel 1989). Differentiating between these stages may mean the difference between offering chemotherapy plus radiotherapy, or chemotherapy alone; and given the advancement of radiation therapy since the 1950s, more accurate staging of nodal involvement may be of particular relevance for radiation treatment (Shepherd 2007). More recently clinicians recommend using the TNM staging system for SCLC (Appendix 1), to assist prognostication and guide future management. A large, retrospective analysis of the IASLC database demonstrated a significant difference in survival between T1 and other T categories, and between N0/N1 and N2/N3 categories, and between N1 and N2 categories (Shepherd 2007).
Description of the intervention
Current treatment guidelines recommend platinum‐based chemotherapy plus thoracic radiotherapy for the treatment of limited‐stage SCLC; and chemotherapy alone for extensive disease, with prophylactic cranial irradiation. These recommendations are based on the premise that SCLC disseminates early, and that it is very chemosensitive (Jett 2013; NCCN 2015; NHMRC 2015; NICE 2011). Consideration of surgery is currently recommended for those who have a solitary nodule, no hilar or mediastinal involvement based on adequate mediastinal staging, no distant metastases, and no contraindications to surgery (Jett 2013; NCCN 2015).
Although there is usually an initial good response to chemotherapy, the overall prognosis is poor. Median survival for patients with limited disease is 15 to 20 months, with 20% surviving to two years; and for those with extensive stage disease, median survival is 8 to 13 months with a two‐year survival at 5% (van Meerbeeck 2011).
Initially surgery was the treatment of choice for all types of lung cancer. However in 1969 a randomised controlled trial compared radiotherapy to surgery in patients with limited SCLC (Fox 1973). Although median survival rates were less than one year, it demonstrated a small but significant difference in survival favouring radiotherapy. After this trial, surgery was mostly abandoned in favour of radiotherapy. Shortly after, the first chemotherapeutic agents demonstrated benefit over radiotherapy and so chemo‐radiotherapy became the acceptable form of treatment (Anraku 2006). The dichotomous taxonomy of SCLC and NSCLC came about in the 1960s and 1970s following a trial showing the very poor outcomes of surgery for small‐cell or ‘oat cell’ cancer (Fox 1973). Criticisms of this trial are that it did not include many participants who would now be considered to have T1‐2 N0 disease; and that new diagnostic and surgical tools have been developed since this time (Brock 2005).
The principle of surgery in limited‐stage SCLC is an attempt to remove all viable tumour with curative intent. Surgical resection of presumed early SCLC may also be beneficial so as not to miss a mistakenly diagnosed SCLC which may indeed be a NSCLC or mixed neuroendocrine tumour, and may offer better local control than chemoradiation therapy (Anraku 2006).
Recently some large retrospective cohort studies have demonstrated a potential benefit from resection of limited‐stage SCLC. The International Association for the Study of Lung Cancer (IASLC) Lung Cancer Staging Project, involving 349 cases of early resection, demonstrated five‐year survival rates with pathologic stage I, II and III SCLC of 48%, 39% and 15% respectively (Vallieres 2009). Similar results were seen in the Surveillance, Epidemiology and End Results (SEER) retrospective study of 247 participants with stage I SCLC who underwent resection. This is compared to evidence from multiple clinical trials using non‐surgical chemo‐radiotherapy protocols with a five‐year survival rate of 10% to 15% (Yu 2010).
Numerous other retrospective cohort studies and case series have demonstrated a survival benefit for those undergoing surgery, including studies by Karrer 1995 which demonstrated a survival of 63% in the surgical arm compared to 37% with conventional therapy, Rostad 2004 which demonstrated a five‐year survival of 44.9% in the surgical arm compared to 11% with conventional therapy and Badzio 2004 which demonstrated a median survival of 22 months in the surgery arm compared to 11 months with conventional therapy.
These results conflict with some randomised controlled trials which demonstrate no significant benefit of surgery compared to conventional treatment (Lad 1994a), but these non‐randomised observational studies may be flawed by selection bias.
Why it is important to do this review
Given the poor prognosis of this condition and the current conflicting literature about the role of surgery in SCLC, this review sought to identify and appraise all randomised controlled trials available to determine if surgical resection of limited‐stage SCLC improves clinically important outcomes including survival.
Objectives
To determine whether, in patients with limited‐stage SCLC, surgical resection of cancer improves overall survival and treatment‐related deaths compared with radiotherapy or chemotherapy, or a combination of radiotherapy and chemotherapy, or best supportive care.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised, parallel‐group controlled trials. Randomised trials were defined as studies which are described by the author as ‘randomised’ anywhere in the manuscript. We included trials where randomisation is implied by the description of how participants were assigned to treatment and control groups. There were no language restrictions. All identified trials, published and unpublished, were potentially eligible for inclusion.
Types of participants
We included participants with a cytological or histopathological diagnosis of small‐cell lung carcinoma and limited‐stage disease, as defined by the authors in each paper. Methods used to qualify staging were recorded.
Types of interventions
We included surgical resection of lung cancer alone or in combination with any other therapy, compared to non‐surgical treatment or no treatment, and we excluded trials comparing surgery alone with surgery plus chemotherapy or radiotherapy.
Types of outcome measures
Primary outcomes
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Overall survival, defined as the time of randomisation to the time of death.
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Treatment‐related deaths.
Secondary outcomes
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Progression‐free survival, defined as the time of randomisation to the time of progression of disease or death.
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Loco‐regional progression.
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Quality of life.
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Adverse events, graded according the National Cancer Institute Common Toxicity Criteria (NCI CTCAE 2010).
Search methods for identification of studies
Electronic searches
We searched the following electronic databases (using the search strategies listed in Appendix 2).
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Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4) in the Cochrane Library.
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MEDLINE Ovid (1946 to 11 January 2017).
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Embase Ovid (1974 to 11 January 2017).
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CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1982 to 11 January 2015).
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Web of Science (to 11 January 2017).
We included publications from any year, language, and type or article.
Searching other resources
We handsearched reference lists of included studies, relevant chapters and review articles. We also searched clinical trial registries including the World Health Organization's International Clinical Trials Registry (apps.who.int/trialsearch/); and the US National Institutes of Health's ClinicalTrials.gov. We translated any relevant article into English for potential inclusion. Where data were missing, we attempted to contact authors.
Data collection and analysis
Selection of studies
Two independent review authors (KS and HB) independently screened all abstracts to determine whether they met the inclusion criteria. Full‐text publications were sought for those which possibly or definitely met the inclusion criteria. Then two independent authors (KS and HB) reviewed full‐text articles to determine eligibility. They resolved disagreement through discussion or reached consensus by consulting a third author (RM) where necessary.
Data extraction and management
Two review authors (KS and HB) independently extracted data from the included studies. We used a data collection form for study characteristics and outcome data, which we piloted on one study included in the review.
We extracted the following data.
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Methods: study design, duration of the study, study setting, and date of study.
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Participants: number, mean age and age range, gender, inclusion and exclusion criteria.
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Intervention: intervention, dose, mode of administration, concomitant treatments, and exclusions.
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Outcomes: primary and secondary outcomes as specified, type of scale used, and time points collected.
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Notes: funding for trial and any conflicts of interest for trial authors.
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'Risk of bias' summary.
We aimed to present results for time‐to‐event outcomes (such as OS and PFS) as hazard ratios (HRs) with 95% confidence intervals (CIs); and to present the treatment effects of dichotomous outcomes (such as OR and serious adverse events) as risk ratios (RRs) with 95% CIs (Higgins 2011).
Assessment of risk of bias in included studies
Two independent authors (HB and KS) assessed the included studies for risk of bias using the Cochrane's 'Risk of bias' assessment tool (Higgins 2011). We assessed the following.
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Allocation (random sequence generation and allocation concealment).
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Blinding of participants and personnel (checking for possible performance bias).
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Blinding of outcome assessors (checking for possible performance bias).
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Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations).
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Selective reporting bias (checking for whether the prespecified outcomes were met).
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Other bias (bias due to problems not covered elsewhere in the table).
We scored each of these domains separately as either low risk of bias, unclear risk of bias (insufficient information to make a judgement), or high risk of bias as outlined below.
Generation of allocation sequence
For each included study we described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We assessed the method used to generate the allocation sequence as either: low risk of bias (any truly random process such as random number table or computer random number generator); or unclear risk of bias (method used to generate sequence not clearly stated).
Allocation concealment
For each included study we described the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocation could have been foreseen in advance of (or during) recruitment, or changed after assignment. We assessed the methods as either: low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); or unclear risk of bias (method not clearly stated). We excluded studies that did not conceal allocation (e.g. open list).
Blinding or masking
For this type of intervention, it was likely that the participant was aware of what group they were assigned to. For each included study we described the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed the methods as either: low risk of bias (study stated that it was blinded and described the method used to achieve blinding); or unclear risk of bias.
Incomplete outcome data
We assessed the methods used to deal with incomplete data as either: low risk of bias (information from all participants were included in the main results, any dropouts are reported, any systematic differences between the two treatment arms are reported); unclear risk of bias (used 'last observation carried forward' analysis); or high risk of bias (used 'completer' analysis).
Selective reporting bias
We assessed the methods as either low risk of bias (when the study fully reported all prespecified outcomes); unclear risk of bias (when it appeared not all prespecified outcomes were fully reported); or high risk of bias (not all prespecified outcomes were reported).
Other bias
For each included study we described any important concerns we had about other possible sources of bias (e.g. baseline imbalance, bias of the presentation data, representation of gender, age of studies, and whether any other treatments were administered outside of the protocol).
We resolved any disagreement which arose whilst conducting the above procedures by discussion and consensus.
Measures of treatment effect
We planned to measure treatment effect using HRs for time‐to‐event variables. We planned to pool dichotomous data such as adverse events and present these using RRs and 95% CIs. We planned to pool continuous data such as quality of life scores, mean difference (MD) or the standardised mean difference (SMD) into Review Manager 2014. When data aggregation was not feasible, results were presented in a descriptive analysis.
Unit of analysis issues
Our unit of analysis is the participant. We did not identify any cluster randomised controlled trials.
Dealing with missing data
We attempted to contact the authors to obtain missing data, but at the time of the publication of the review there has been no response. We distinguished between intention‐to‐treat (ITT) and per protocol (PP) analyses when judging quality.
Assessment of heterogeneity
To assess statistical heterogeneity of pooled analyses we planned to use the I² statistic, which describes the percentage of the total variation across trials due to heterogeneity rather than sampling error. We considered significant statistical heterogeneity to be present if the I² was greater than 50% (Higgins 2011). Where significant heterogeneity was identified, we expected to further assess using pre‐determined subgroups.
Assessment of reporting biases
We planned to assess publication bias using funnel plot analysis, but given the small number of studies included this was not possible.
Data synthesis
We planned to pool measures of effect using a fixed‐effect model, unless there was significant heterogeneity (I² > 50%). In that case, we planned to analyse data using a random‐effects model. Based on the heterogeneity of the trials, we decided it was not possible to pool measures of effect. We reported trials as descriptive analyses.
We assessed the overall quality of the evidence using the GRADE system (GradePro 2015), according to the following parameters where applicable.
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Limitations in the design and implementation.
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Indirectness of evidence.
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Unexplained heterogeneity or inconsistency of results.
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Imprecision of results.
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High probability of publication bias.
The GRADE system uses the following criteria for assigning the grade of evidence based on RCTs.
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High: further research is very unlikely to change our confidence in the estimate of effect.
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Moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
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Low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
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Very low: any estimate of effect is very uncertain.
We decreased the grade of evidence if the following occurred.
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Serious (−1) or very serious (−2) limitation to study quality.
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Important inconsistency (−1).
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Some (−1) or major (−2) uncertainty about directness.
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Imprecise or sparse data (−1).
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High probability of reporting bias (−1).
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses to determine if the impact of the intervention varied across these groups, and if these groups identified a source of heterogeneity. However due to the small number and variability of trials we were unable to combine data and perform subgroup analyses.
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By TNM stage (to determine if more contemporary staging had a different effect on outcomes).
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Induction treatment (chemotherapy/radiotherapy/chemo‐radiotherapy) (to determine if different induction treatments had a different effect on outcomes).
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Adjuvant treatment (chemotherapy/radiotherapy/chemo‐radiotherapy) (to determine if different adjuvant treatments had different effects on outcomes).
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By publication date (to determine if this had an effect on heterogeneity).
Sensitivity analysis
Where applicable, we planned to perform sensitivity analyses by quality of studies as assessed by the risk of bias criteria; however, the small number of trials and variability between trials ruled this out.
Results
Description of studies
Results of the search
We identified 2954 citations using our search strategy, and selected 76 articles for full‐text review after screening the abstracts of the initial search results. Many trials were in languages other than English, and we sought Cochrane translators to assist in the screening of these studies. We found five papers eligible for inclusion. Fox 1973, Miller 1969 and Scadding 1966 described the same cohort of participants with different time points of outcome measurement and so we reported these as part of one trial. We included three trials with 330 participants. See Figure 1 for more details.
Study flow diagram.
Included studies
See the 'Characteristics of included studies' table.
We included three trials with 330 participants (Fox 1973; Lad 1994a; Liao 1995).
Study characteristics
All studies were described as randomised, parallel controlled trials. The three included studies were reported between 1973 and 1995, and their follow‐up ranged from 1 to 3 years (Liao 1995) to up to 10 years (Fox 1973).
Participants
Each study included participants diagnosed with histologically or cytologically confirmed SCLC, and were considered to have limited disease following radiological assessment. Bone marrow biopsy was performed in two trials (Lad 1994a; Liao 1995). Participants were only included if they were considered medically suitable for surgical resection and radical radiotherapy, except in Lad 1994a where participants were only included for randomisation after an initial response to chemotherapy.
Intervention
Surgical arm
Participants allocated to the surgical arm underwent thoracotomy with the intention of complete resection. Lad 1994a described complete resection in 77% of surgical participants, with 6% resulting in incomplete resection (positive margins), and 17% considered unresectable at time of thoracotomy. Fox 1973 described complete resection with pneumonectomy in 48%, a palliative pneumonectomy in 1%, thoracotomy only in 34%, and no resection in 18% of surgical participants. Liao 1995 did not describe any details of the methods or extent of the surgical resection, or the exact number of participants who ultimately underwent resection.
One trial performed nodal sampling from at least pretracheal, subcarinal, and intrapulmonary nodal stations during mediastinal nodal dissection, with the mean number of 3.6 N1 lymph nodes and mean 6.4 N2 nodes removed (Lad 1994a). Two trials did not provide details about nodal dissection/sampling (Fox 1973; Liao 1995).
Control arm
Lad 1994a compared surgery to no intervention. All participants underwent induction chemotherapy (cyclophosphamide, 1 g/m²; doxorubicin, 50 mg/m²; and vincristine 1.4 mg/m² every 3 weeks for five cycles), then objective responders (defined as “objective shrinking”, but specific criteria for this were not provided) were subsequently randomised to surgery with intent of complete resection followed by chest and whole brain irradiation, compared to chest and whole brain irradiation alone. Radiotherapy doses were 50 Gy in 25 fractions to the chest, and 30 Gy in 30 fractions in whole brain prophylaxis, delivered concurrently, in all participants.
Liao 1995 compared surgery to radiotherapy. All participants underwent two cycles of induction chemotherapy (IAO: Ifosfamide 1.2 g/m² intravenous (IV) for days 1 to 5, MESNA 400 mg IV TDS for days 1 to 5, Adriamycin 50 mg/m² IV for day 1, Vincristine 1 mg/m² for day 1). Subsequently, participants were randomised to surgical resection or radiotherapy (60 Gy). This was followed by an average of 2.8 cycles of chemotherapy in the surgical group and an average of 1.9 cycles of chemotherapy in the radiotherapy group.
Fox 1973 initially randomised participants to surgery or radiotherapy. Radical radiotherapy (3000 rads over 20 to 40 days), was applied in 85%, palliative radiotherapy in 11%, and no radiotherapy in 4% of control participants (due to refusal or deterioration).
Co‐interventions
Only one trial reported treatment outside the specified protocol (Fox 1973). In 55% of participants in the surgical arm, treatment other than surgery was given at some time during the two‐year period: chest radiotherapy was given to 34% in the first three months; radiotherapy for distant metastases was given in 11%; and chemotherapy was given to 18%. Twenty‐nine per cent of radiotherapy arm participants received further treatment over the two‐year period: 21% received radiotherapy for distant metastases; and chemotherapy was administered to 12% of participants (13/71 in the surgical arm and 9/73 in the radiotherapy arm).
Outcomes
For the primary outcome of survival, Lad 1994a reported median survival; Fox 1973 reported overall survival at 1, 2, 5, 6 and 10 years and mean survival; Liao 1995 reported overall survival at 1, 2 and 3 years.
Fox 1973 reported treatment‐related deaths and treatment‐related complications, and dyspnoea (but did not describe the scale on which this was measured).
Two studies reported loco‐regional progression (Lad 1994a; Liao 1995).
Excluded studies
See the 'Characteristics of excluded studies' table.
Risk of bias in included studies
We assessed the risk of bias in the included studies using the Cochrane 'Risk of bias' assessment tool (Higgins 2011), and included the domains of allocation, blinding, incomplete outcome data, and other bias.
Please see Figure 2 and Figure 3 for the risk of bias findings.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
We assessed random sequence generation as 'low risk' in one study (Fox 1973); and 'unclear risk' in two studies (Lad 1994a; Liao 1995).
We assessed allocation concealment as 'low risk' in one study (Fox 1973); and 'unclear risk' in two studies (Lad 1994a; Liao 1995), as methods of allocation concealment were not reported.
Blinding
We assessed blinding of participants and personnel and outcome assessors as 'unclear risk' in all three studies. It is likely that participants were aware of the intervention they were assigned to and it is likely the treating physicians were aware of the intervention received, and this may have affected the choice of co‐interventions. Lack of blinding is unlikely to have affected the results in the main outcome of survival but may have had an effect on the measurement of other outcomes.
Incomplete outcome data
Incomplete outcome data bias was assessed as low for one study (Lad 1994a), as reasons for participants not receiving allocated treatment were detailed, and all participants were accounted for at the time of follow‐up. We judged incomplete outcome data bias as high in one study (Liao 1995), as some participants were lost to follow‐up and further details were not provided. We judged incomplete outcome data bias as unclear in one study as although the reason for withdrawal was made clear, there were more withdrawals in the surgical group than the radiotherapy group (Fox 1973).
Only one study clearly used intention‐to‐treat analysis (Fox 1973).
Selective reporting
We judged selective reporting bias as low for two studies (Fox 1973; Lad 1994a), as all prespecified outcomes were detailed. We reported one study to be at high risk as prespecified outcomes (progression‐free survival and adverse events) were not reported and the reasons for this were unclear (Liao 1995).
Other potential sources of bias
We judged one study as 'high risk' as participants were eligible to receive further treatment following randomised intervention (Fox 1973). Intention‐to‐treat analysis was performed. We judged two studies as 'unclear risk' as it was not reported whether other participants received treatment outside the protocol (Lad 1994a; Liao 1995). Liao 1995 noted that the mean age of participants undergoing surgical intervention was lower (mean 50 years, range 33 to 74 years) compared to radiotherapy (mean age 54 years, range 31 to 66 years); however it is unclear how this may have affected the results.
All studies were published more than 20 years ago. Since this time, the requirements and reporting standards for conducting randomised controlled trials have become more rigorous. It is possible these trials did not adhere to current standards, leading to the introduction of bias.
Effects of interventions
See: Summary of findings for the main comparison
Primary outcomes
Survival
We intended to report overall survival using hazard ratios and 95% confidence intervals, but there were not enough appropriate extractable data to do this and so a descriptive analysis based on available evidence has been used.
Lad 1994a reported median survival as 15.4 months for the surgical arm and 18.6 months for the non‐surgical arm (146 participants, log‐rank P = 0.78).
Fox 1973 reported mean survival as 199 days in the surgical arm, and 300 days in the radiotherapy arm (P = 0.04; 144 participants). The number of participants alive in the surgical and radiotherapy arms was 21% and 22% respectively at 1 year, 4% and 10% respectively at 2 years, 1% and 4% respectively at 5 years, and 0% and 4% respectively at 10 years.
Liao 1995 reported overall survival at 1, 2 and 3 years. One‐year overall survival was: surgery group, 79%; radiotherapy group, 63%. Two‐year overall survival was: surgery group, 52%; radiotherapy group, 18%. Three‐year overall survival was: surgery group, 24%; radiotherapy group, 18% (P = 0.12, Chi² = 2.42).
Treatment‐related deaths
Fox 1973 reported treatment‐related deaths. Five deaths were directly attributable to surgical intervention (of 58 participants submitted to surgery), with an early postoperative mortality of 7%. Reasons included empyema, pulmonary embolus, myocardial infarction, chronic pleural space infection, and unknown cause. No radical radiotherapy participants died as a direct cause of treatment. Lad 1994a reported two deaths (3%) relating to surgery. No radiotherapy deaths were reported. Liao 1995 did not report treatment‐related deaths.
Secondary outcomes
Loco‐regional progression
Lad 1994a reported local progression in 25% and an additional 13% with distal relapse. They reported that patterns of treatment failure did not differ between the two groups; however individual group data were not available. Liao 1995 reported three out of 20 participants developed local recurrence in the surgical group compared to two out of 20 participants in the radiotherapy group. Distal metastases occurred in seven of 20 surgical participants, compared to ten out of 20 radiotherapy participants. Data was presented on the proportion of loco‐regional progression in each group at the end of the study but time‐to‐event data such as progression‐free survival were not reported.
Quality of life
Fox 1973 reported "well‐being" and "dyspnoea", using non‐validated scales (see Characteristics of included studies).
Well‐being was reported as "good" or "fair" in the majority of survivors in both arms. However at 3 months, 31% of surgical participants and 20% of radiotherapy participants were described as in "poor" condition; at 6 months, 43% of surgical participants and 29% of radiotherapy participants were similarly described; and at 12 months, 36% of surgical participants and 46% of radiotherapy participants were again described as in "poor" condition.
Mean degree of dyspnoea was recorded at 3, 6 and 12 months (adjusted for baseline assessment) (see Characteristics of included studies). Comparing surgery to radiotherapy, there was a difference of 0.1 at 3 months, −0.3 at 6 months, and −1.2 at 12 months, indicating participants in the radiotherapy group experienced more dyspnoea compared to the surgical group.
Discussion
Summary of main results
Conclusions about the role of surgery in the management of limited‐stage small‐cell lung cancer are constrained by the quality of the available evidence and the lack of contemporary randomised trial data. We identified three trials, all conducted more than 20 years ago.
The trial of Fox 1973 considerably changed the way SCLC was treated. It found survival was better in the non‐surgical compared to the surgical treatment group. Following this trial, surgery was largely abandoned in favour of radiotherapy. Chemotherapy was not included as part of the standard treatment protocol for this study; however subsequent studies supported the role of chemotherapy in addition to radiation in small‐cell carcinoma (Anraku 2006). The results of this study are not generalisable to current practice as most participants enrolled in this study had advanced disease, and staging was not comparable to current standards as chest imaging with computed tomography (CT) and positron emission tomography (PET) was not available at that time. Diagnosis was also made via rigid bronchoscopy, so peripheral nodules were not included. Treatment also did not include adjuvant chemotherapy at that time. In the surgical arm, only 34/71 participants underwent surgical resection; and during the 10‐year follow‐up other treatments were available — analysis was made as intention‐to‐treat, and subsequent interventions were not always completely recorded. There was also a considerably high rate of pneumonectomy, peri‐operative mortality, and R2 resections. Pneumonectomy is now rarely performed, and would not be advocated (Powell 2009). The high rate of mortality in the surgical arm may be due in part to the ongoing survival‐limiting effect of functioning with only one lung rather than being from a beneficial effect of radiotherapy on survival.
Lad 1994a included standard chemotherapy and radiotherapy for both arms, which is more comparable to current practice; and following this treatment, randomised participants to surgery or no surgery. They found no significant difference in survival between groups. Ten per cent of participants randomised to the surgical arm did not undergo resection; many participants had bulky nodal disease; and as tumours were diagnosed bronchoscopically, peripheral nodules were excluded. Liao 1995 treated all participants with chemotherapy, then randomised to surgery or radiotherapy. They found a higher survival rate in the surgical group compared to the radiotherapy group, but this was not statistically significant and because of the small number of participants and the risk of bias in this study it is difficult to interpret the significance of these findings.
Overall completeness and applicability of evidence
This review is limited by the paucity of good‐quality randomised controlled trials, and it is hard to compare participant characteristics and methods used 20 to 40 years ago to the diagnostic and therapeutic methods of our current practice. There were variations between the trials included in the review, particularly in the types of treatments delivered, and due to this clinical heterogeneity and the lack of appropriate quantitative data provided in trial reports it was not possible to draw firm conclusions or perform meta‐analyses. The review included trials which had examined the role of surgery in limited‐stage disease but none of the studies provided TNM staging for those included and it is likely the majority of the participants included in these studies had central and/or nodal disease. Therefore the findings of the review may not be generalisable to stage 1 small‐cell lung cancer, particularly stage 1A disease.
Quality of the evidence
Selection bias was judged as 'high' as the methods of randomisation and concealment allocation were often poorly described. Not all participants received their allocated treatments, and this was not always clearly reported; and some participants received other treatments during follow‐up which were incompletely reported and may have affected the overall outcome. There was also limited information provided regarding the extent of surgery, and the experience of the surgeons or the centre in which the treatment was conducted.
We judged the quality of evidence as 'very low' for all of the outcomes, according to the GRADE approach (GradePro 2015). There was an unclear risk of bias in the ways the studies were conducted, which reduced our confidence in the estimation of the effect. The way in which cancer was staged and methods of surgery which do not reflect current clinical practice led to concerns regarding indirectness of evidence. We were unable to combine studies as they were too heterogeneous.
Potential biases in the review process
We conducted this review in accordance with established Cochrane standards. Two review authors independently screened search results and resolved discrepancies by discussion and consensus. We did not restrict the literature search by language and we translated many studies into English to determine suitability for inclusion and for data extraction. We also contacted the study authors where it was unclear if a study met the inclusion criteria and to obtain further data, though none of the study authors responded.
Publication bias is possible, whereby a failure to identify unpublished trials could have led to an overestimation or underestimation of the effect of surgery on the treatment of SCLC.
Agreements and disagreements with other studies or reviews
To our knowledge this is the only systematic review available which examines the available evidence from randomised controlled trials for the use of surgery for limited‐stage small‐cell lung cancer. Our search only yielded a small number of older studies eligible for inclusion in the review, which demonstrated very little evidence for the role of surgery in SCLC. However there have been a number of recent, retrospective analyses performed that offer different findings.
The largest is a recent retrospective analysis of the Surveillance, Epidemiology and End Results (SEER) database which identified 3556 patients with stage I and II SCLC. Of these, 895 underwent resection. Median survival was 34.0 months (95% CI 29.0 to 39.0), compared to 16.0 months (95% CI 15.3 to 16.70, P < 0.001) in the non‐surgical patients. Median survival was significantly greater following lobectomy compared to wedge resection, which was still significantly better than no surgery. However the surgical cohort was younger, and likely a healthier cohort. These findings are similar to other retrospective studies, including the International Association for the Study of Lung Cancer (IASLC) Lung Cancer Staging Project which identified 349 cases of early stage resection which demonstrated five‐year survival rates with pathologic stage I, II and III SCLC of 48%, 39% and 15% respectively (Vallieres 2009), another retrospective study by Karrer 1995 which demonstrated a survival of 63% in the surgical arm compared to 37% with conventional therapy, Rostad 2004 which demonstrated a five‐year survival of 44.9% in the surgical arm compared to 11% with conventional therapy and Badzio 2004 which demonstrated a median survival of 22 months in the surgery arm compared to 11 months with conventional therapy. A more recent retrospective review from Lim 2008 analysed 59 patients who underwent surgical resection for known SCLC and demonstrated an excellent overall survival of 76% at one year (95% CI 65 to 88) and an overall five‐year survival of 52% (95% CI 40 to 68).
The findings of such observational studies have lent support to current clinical practice guidelines which recommend surgery for carefully staged stage 1 small‐cell lung cancer in those without contraindications for surgery; however these studies are likely affected by selection bias (Jett 2013; NCCN 2015). Whilst the results of this review may not be generalisable to stage 1 small‐cell lung cancers carefully staged in the modern era, the trend to increased treatment‐related deaths in the surgical arms of two of the studies included in this review emphasises the need for well‐conducted randomised controlled trials comparing surgery for stage 1 small‐cell cancer with non‐surgical treatment.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
| Surgery compared with no surgery for limited‐stage small‐cell lung cancer | |||
| Patient or population: People with limited‐stage small‐cell lung cancer Settings: ambulatory care Intervention: surgery Comparison: no surgery | |||
| Outcomes | Impact | No of Participants | Quality of the evidence |
| Survival | Survival is difficult to interpret in these studiesa | 3 studies (330 participants)b | ⊕⊖⊖⊖ very lowc |
| Treatment related mortality | Treatment‐related mortality is difficult to interpret in these studiesd | 2 studies (290 participants)e | ⊕⊖⊖⊖ very lowc |
| Loco‐regional progression | Loco‐regional progression is difficult to interpret in these studiesf | 2 studies (186 participants)g | ⊕⊖⊖⊖ very lowc |
| Quality of life | Quality of life is difficult to interpret in these studiesh | 1 study (144 participants)i | ⊕⊖⊖⊖ very lowj |
| GRADE Working Group grades of evidence aTreatment across trials were heterogenous: Fox 1973 compared surgery to radiotherapy. Lad 1994a administered induction chemotherapy to all participants, and then compared surgery to no surgery; following, all participants had chest and brain irradiation. Liao 1995 administered induction chemotherapy to all participants and then compared surgery to radiotherapy. The effect is difficult to interpret as the types of surgical procedures used in these studies do not reflect current clinical practice. bThis includes Fox 1973: surgery ‐ 71 participants; and radiotherapy ‐ 73 participants. Lad 1994a: surgery ‐ 70 participants; and no surgery ‐ 76 participants. Liao 1995: surgery ‐ 20 participants; and radiotherapy ‐ 20 participants. cStudies contributing to this outcome were at an unclear risk of bias which reduced our confidence in the estimation of effect. Downgraded once. Staging and surgical techniques don't necessarily reflect best current practice. Downgraded twice. dThe effect is difficult to interpret as the type of surgical procedures used in these studies do not reflect current clinical practice. eThis includes Fox 1973: surgery ‐ 71 participants; and radiotherapy ‐ 73 participants. Lad 1994a: surgery ‐ 70 participants; and no surgery ‐ 76 participants. fTreatments across trials were heterogenous: Fox 1973 compared surgery to radiotherapy. Lad 1994a administered induction chemotherapy to all participants, and then compared surgery to no surgery; following, all participants had chest and brain irradiation. Liao 1995 administered induction chemotherapy to all participants and then compared surgery to radiotherapy. gThis includes Lad 1994a: surgery ‐ 70 participants; and no surgery ‐ 76 participants; Liao 1995: surgery ‐ 20 participants; and radiotherapy ‐ 20 participants. hFox 1973 reported quality of life and dyspnoea using non‐validated scales. iThis includes Fox 1973: surgery ‐ 71 participants; and radiotherapy ‐ 73 participants. jStudies contributing to this outcome were at an unclear risk of bias which reduced our confidence in the estimation of effect. Downgraded once. Staging and surgical techniques don't necessarily reflect best current practice. Downgraded twice. The scales utilised were not validated. | |||
