Agentes antiinflamatorios no esteroideos para inducir la regresión y prevenir la progresión de la neoplasia intraepitelial cervical
Resumen
Antecedentes
Ésta es una versión actualizada de la revisión Cochrane original publicada en el número 4, 2014. La neoplasia intraepitelial cervical (NIC) precede el desarrollo del carcinoma invasivo del cuello uterino. El tratamiento actual de la NIC es muy eficaz pero hay morbilidades para la paciente relacionadas con dolor, hemorragia, infección, estenosis cervical y parto prematuro en un embarazo posterior. El tratamiento eficaz con fármacos en lugar de cirugía sería beneficioso.
Objetivos
Evaluar la efectividad y la seguridad de los agentes antiinflamatorios no esteroides (AINE), que incluyen los inhibidores de ciclooxigenasa 2 (COX‐2), para inducir la regresión y prevenir la progresión de la neoplasia intraepitelial cervical (NIC).
Métodos de búsqueda
Anteriormente, se realizaron búsquedas en el Registro Especializado de Ensayos Controlados del Grupo Cochrane de Cáncer Ginecológico (Cochrane Gynaecological Cancer Group), el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (2013, número 11), MEDLINE (noviembre de 2013) y Embase (semana 48 de noviembre de 2013). Se realizó una búsqueda actualizada en agosto de 2017 para CENTRAL (2017, número 8), MEDLINE (julio, semana 3, 2017) y Embase (julio, semana 31, 2017). También se realizaron búsquedas en los registros de ensayos y en las revistas como parte de la actualización.
Criterios de selección
Ensayos controlados aleatorizados (ECA) o ensayos controlados de AINE para el tratamiento de la NIC.
Obtención y análisis de los datos
Tres revisores extrajeron los datos de forma independiente y evaluaron los riesgos de sesgo de acuerdo con la metodología Cochrane. Los datos de resultado se agruparon mediante metanálisis de efectos fijos.
Resultados principales
En tres ECAs, 171 mujeres mayores de 18 años fueron asignadas al azar para recibir celecoxib 400 mg diarios durante 14 a 18 semanas versus placebo (un estudio, 130 participantes), celecoxib 200 mg dos veces al día por vía oral durante seis meses versus placebo (un estudio, 25 participantes), o rofecoxib 25 mg una vez al día por vía oral durante tres meses versus placebo (un estudio, 16 participantes). El estudio con rofecoxib se interrumpió cuando el medicamento fue retirado del mercado en 2004. Los ensayos se realizaron de junio de 2005 a abril de 2012, de junio de 2002 a octubre de 2003 y de mayo a octubre de 2004, respectivamente. Se decidió incluir los datos del estudio de rofecoxib ya que los resultados pueden ser similares cuando se utilizan otros AINE de este tipo.
La regresión parcial o completa de la NIC 2 o NIC 3 se produjo en 31 de 70 (44%) en los brazos de tratamiento y en 19 de 62 (31%) en los brazos de placebo (riesgo relativo [RR] 1,45; intervalo de confianza [IC] del 95%: 0,93 a 2,27; valor de p 0,10), tres estudios, 132 participantes; evidencia de calidad moderada). La regresión completa de la NIC 2 o NIC 3 se produjo en 15 de 62 (24%) de los que recibieron celecoxib versus 10 de 54 (19%) de los que recibieron placebo (RR 1,31; IC del 95%: 0,65 a 2,67; valor de P 0,45; dos estudios, 116 participantes; evidencia de calidad moderada). La regresión completa de la NIC 2 o NIC 3 se produjo en 14 de 62 (23%) de los que recibieron celecoxib versus 8 de 54 (15%) de los que recibieron placebo (RR 1,56; IC del 95%: 0,72 a 3,4; valor de P 0,26; dos estudios, 116 participantes; evidencia de calidad moderada).
La progresión a un grado más alto de NIC, pero no a un cáncer invasivo, ocurrió en uno de 12 (8%) de los que recibieron celecoxib y dos de 13 (15%) que recibieron placebo (RR 0,54; IC del 95%: 0,05 a 5,24; valor de P 0,60; un estudio, 25 participantes; evidencia de calidad muy baja). Dos estudios no informaron ningún caso de progresión a cáncer invasivo dentro del marco de tiempo del estudio. No se informó toxicidad en los dos artículos originales. El ensayo agregado en esta actualización tuvo un efecto adverso gastrointestinal de grado 3 en el brazo de tratamiento, pero por lo demás tuvo efectos secundarios similares de grado 1 a 2 entre los grupos de tratamiento y de placebo. Aunque los estudios estuvieron bien realizados y la asignación fue aleatorizada, en ambos estudios se detectó algún riesgo de sesgo. Además, la duración de los estudios fue corta, lo que puede enmascarar la identificación de la progresión al cáncer.
El agregado del ensayo en esta actualización cuadruplicó el número de pacientes en la revisión original y fue un ensayo multicéntrico bien diseñado, lo que aumentó la calidad general de la evidencia de muy baja a moderada para esta revisión.
Conclusiones de los autores
Actualmente no existen datos convincentes que apoyen un beneficio para los AINE en el tratamiento de la NIC. Con la adición de este nuevo ensayo aleatorio más grande, se calificaría como evidencia general de calidad moderada según los criterios de GRADE.
PICO
Resumen en términos sencillos
Tratamiento del precáncer cervical (NIC) con agentes antiinflamatorios para inducir la regresión y prevenir la progresión al cáncer cervicouterino
Antecedentes
Esta revisión es una actualización de una revisión publicada anteriormente en la Base de Datos Cochrane de Revisiones Sistemáticas (Cochrane Database of Systematic Reviews) 2014, Número 4 sobre agentes antiinflamatorios no esteroides (AINE) para inducir la regresión y prevenir la progresión de la neoplasia intraepitelial cervical (NIC). La neoplasia intraepitelial cervical (NIC) es una afección precancerosa frecuente del cuello uterino asociada con el VPH (el virus del papiloma humano), que puede ocurrir en cualquier persona, pero que se encuentra comúnmente en mujeres jóvenes que desean mantener su fertilidad y cuyo tratamiento a menudo implica una escisión quirúrgica. La NIC puede progresar al cáncer invasivo del cuello uterino. La NIC se identifica mediante cribado y se puede tratar con cirugía del cuello uterino, ya sea mediante la extirpación con escisión quirúrgica o la destrucción de las células que cubren el cuello uterino, como la terapia con láser, el calentamiento o la congelación. Aunque lo anterior es eficaz en la mayoría de los casos, la cirugía puede causar efectos no deseados inmediatos como hemorragia e infección, o complicaciones posteriores que incluyen dificultades con las menstruaciones debido a la cicatrización del cuello uterino y trabajo de parto prematuro.
Se ha encontrado que los AINE previenen el desarrollo del cáncer del intestino grueso y otros órganos, pero con algunos efectos secundarios no deseados, especialmente en el corazón y los vasos sanguíneos. Aunque el rofecoxib, utilizado en uno de estos estudios, se retiró del mercado en 2004, puede arrojar luz sobre la factibilidad del tratamiento con otros AINE.
El objetivo de la revisión fue descubrir si la administración de los AINE a las pacientes con NIC podría promover la regresión o prevenir la progresión al cáncer cervicouterino sin riesgos excesivos o efectos secundarios.
Objetivo de la revisión
Identificar la utilidad de tratar la NIC con fármacos antiinflamatorios no esteroides (AINE) como el celecoxib para causar la regresión de los resultados anormales y evitar los procedimientos quirúrgicos.
Características de los estudios
Se identificaron tres estudios aleatorizados hasta agosto de 2017, que incluían 171 mujeres mayores de 18 años, con NIC moderada o grave. Los ensayos se realizaron de junio de 2005 a abril de 2012, de junio de 2002 a octubre de 2003 y de mayo a octubre de 2004. Uno de ellos se interrumpió antes de que se completara. A las pacientes se les dio celecoxib o rofecoxib versus placebo (comprimido de azúcar) diariamente por vía oral durante un período de tres a seis meses.
Resultados clave
Con el agregado del tercer ensayo a esta revisión, ahora hay un número suficiente de pacientes en la revisión para concluir que los AINE tienen un efecto mínimo sobre el placebo para causar la regresión de la NIC. Ninguna paciente progresó a cáncer cervical invasivo y, en general, el fármaco fue bien tolerado en comparación con el placebo.
Calidad de la evidencia
Los estudios parecen haber sido bien realizados. Existen algunas preguntas relacionadas con la calidad de la evidencia en relación con la ocultación y el abandono del estudio por parte de las mujeres antes de completar los fármacos asignados. Por lo tanto, se concluyó que la certeza (calidad) de la evidencia era moderada. No hubo información suficiente para evaluar la exactitud de la presentación de la información. Es posible que existan otros estudios incompletos y no informados que no se hayan identificado.
Conclusión
La literatura disponible en este momento sugiere que no hay datos convincentes que sugieran que los AINE sean un tratamiento para la NIC.
Authors' conclusions
Summary of findings
| Non‐steroidal anti‐inflammatory agents (NSAIDs) compared with placebo for CIN 2 or CIN 3 | ||||||
| Patient or population: women with CIN 2 or CIN 3 Settings: outpatient Intervention: celecoxib 400 mg by mouth daily for 14‐18 weeks, celecoxib 200 mg by mouth twice daily for six months or rofecoxib 40 mg by mouth daily for three months Comparison: placebo tablet by mouth, daily for three to six months | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of Participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Progression of CIN to a higher grade of CIN | 77 per 10001 | 42 per 1000 | RR 0.54 (0.06 to 5.24) | 25 (one study) | ⊕⊝⊝⊝3 | |
| Partial or complete regression of CIN 2 or CIN 3 | 308 per 10002 | 447 per 1000 | RR 1.45 (0.93 to 2.27) | 132 (three studies) | ⊕⊕⊕⊝3 | |
| Complete regression of CIN 2 or CIN 3 | 174 per 10001 | 228 per 1000 | RR 1.31 (0.65 to 2.67) | 116 (two studies) | ⊕⊕⊕⊝3 | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1The basis for the assumed risk is from the spontaneous complete regression rate in the placebo arm of Farley 2006 and Rader 2017 2 The basis for the assumed risk is from the combined spontaneous partial or complete regression rates in the placebo arms of Farley 2006; Hefler 2006; Rader 2017 3Given the increased sample size with the addition of Rader 2017, we have upgraded the certainty to high other than the Progression analysis as it is based on one small study and thus remained very low certainty. | ||||||
Background
Description of the condition
This review is an update of a previously published review in The Cochrane Database of Systematic Reviews 2014, Issue 4 on 'Non‐steroidal anti‐inflammatory agents (NSAIDs) to induce regression and prevent the progression of cervical intraepithelial neoplasia' (Grabosch 2014).
Invasive carcinoma of the cervix is the most common cancer in women in developing countries with more than 500,000 cases diagnosed worldwide each year (Ferlay 2010). It is preceded by cervical intraepithelial neoplasia (CIN), which can be detected on cervical cytology screens (Papanicolaou test or Pap smear). Treatment of CIN is effective at reducing, but not eliminating, the risk of subsequent invasive carcinoma (Soutter 1997). However, the cost of treatment of CIN and follow‐up is high, and the surgery involved can have short‐ and long‐term adverse effects (Arbyn 2008; Martin‐Hirsch 2010).
Description of the intervention
The family of agents called non‐steroidal anti‐inflammatory agents (NSAIDs), including aspirin, ibuprofen, indomethacin, naproxen, piroxicam, and sulindac (Fischer 2011), are able to block both cyclooxygenase (COX) ‐1 and ‐2 enzymes. Selective COX‐2 inhibitors such as celecoxib, rofecoxib and valdecoxib specifically interfere with COX‐2. These agents can be taken orally.
How the intervention might work
COX enzymes catalyse the rate‐limiting step in the conversion of arachidonic acid to prostaglandins and other eicosanoids (DeWitt 1991). COX‐1 is involved in homeostatic functions such as gastrointestinal cytoprotection and is constitutively expressed in most tissues, whereas COX‐2 is rapidly induced after stimulation of quiescent cells by growth factors and also by oncogenes, carcinogens and tumour‐promoters (Hia 1992; Hershmann 1996).
Over‐expression of COX‐2 is thought to be a key factor in malignant transformation in many tissues (Mohammed 1999; Lim 2000; Shamma 2000; Shariat 2003; Shirahama 2000; Surh 2005; Tan 2005). Increased levels of COX‐2 protein expression have been reported in malignancies arising in various sites such as the stomach (Lim 2000), breast (Hwang 1998), oesophagus (Shamma 2000), ovary Munkarah 2005, cervix (Ferrandina 2000; Ferrandina 2002; Kulkarni 2001; Ryu 2000), and colon (Eberhart 1994; Soslow 2000).
COX‐2 may play a role in malignant transformation in the cervix. Increased COX‐2 expression is found with higher grades of CIN (Farley 2004; Mitchell 2007). There is an increased risk of persistent or recurrent disease when resection margins (following excisional procedures) are positive for the enzyme (Farley 2004). COX‐2 is present in invasive carcinoma (Dursun 2007; Farley 2004; Kim 2005; Kulkarni 2001; Mitchell 2007). Similar to other cancers (Cao 2002; Sobolewski 2010), high levels of expression are associated with poorer prognostic features such as shorter time to first recurrence, decreased survival (Farley 2004; Ferrandina 2000; Ferrandina 2002; Gaffney 2001), increased lymph node metastasis or parametrial invasion (Gaffney 2003; Kim 2003; Ryu 2000), and chemotherapy or radiation resistance (Ferrandina 2000; Kim 2002).
The mechanism of the effect on the development of tumours is still being investigated, but it has already been shown that increased expression of COX‐2 will inhibit apoptosis (Tsujii 1995), promote angiogenesis (Tsujii 1998), and enhance the invasiveness of malignant cells (Tsujii 1997). It has been hypothesised that over‐expression of COX‐2 could impair host immune responses (Huang 1998; Pockaj 2004), partly because COX‐2 inhibitors reverse tumour‐associated immunosuppression (Huang 1998; Stolina 2000).
The inhibition of the prostaglandin biosynthetic cascade by NSAIDs has been demonstrated to modulate carcinogenesis in both human and animal epithelial tissues (Kelloff 1996). Selective COX‐2 inhibitors suppress tumorigenesis in experimental models of colon, bladder, breast, prostate, stomach, skin, and lung cancers (Elmets 2010; Fischer 1999; Fischer 2011; Harris 2000; Kawamori 1998; Liu 2000; Narisawa 1981; Okajima 1998; Reddy 2000.
One of the proposed benefits of selective COX‐2 inhibitors was a reduction of significant gastrointestinal toxicity related to blocking of COX‐1 from non‐selective NSAIDs (Psaty 2006). While this is true, COX‐2 inhibition is unfortunately associated with other adverse effects, principally related to inhibition of the production of prostacyclin in the arterial endothelial and smooth muscle cells (Grosser 2006). In two large randomised controlled trials (RCTs) investigating celecoxib for the prevention of colorectal adenomas, cardiovascular events (myocardial infarction, stroke, congestive heart failure, and death) were increased 12.7% in patients taking celecoxib, and reduced by 4.4% in those taking aspirin (Arber 2006; Bertagnolli 2006; Psaty 2006). These patients had a median age of 59 to 61, were treated for relatively long periods of time (one to three years) and many had pre‐existing cardiovascular disease. While these patients represent a different population than most who would be treated for CIN, cardiovascular events remain a concern with the use of COX‐2 inhibitors. Rofecoxib, a COX‐2 inhibitor, which was used by one of the studies in this review, was withdrawn from the market in 2004 for such concerns.
It should be noted that many women may experience regression of CIN without treatment: CIN 2 regression is estimated in around 50% of women within six months (Bleecker 2014) and CIN 3 regression in approximately 30% of women within six months. In a RCT investigating medical treatment for CIN 2/CIN 3, 31% in the placebo arm had complete histologic regression in six months (Follen 2001), whilst in another similar study 32% of CIN 2/CIN 3 lesions regressed to a lower level of CIN in three months without treatment (Alvarez 2003). Differences in regression may be related to the subtype of high risk human papillomavirus (HPV) as HPV‐16 and HPV‐33 are less likely to be spontaneously cleared and more likely to progress to higher CIN (Jaisamrarn 2013).
Why it is important to do this review
The potential use of NSAIDs, including COX‐2 inhibitors, to induce regression or prevent the progression of CIN to invasive carcinoma is an exciting prospect. To our knowledge, no recent systematic review has been published that specifically addresses this subject.
Objectives
To evaluate the effectiveness and safety of non‐steroidal anti‐inflammatory agents (NSAIDs), including cyclooxygenases inhibitors, to induce regression and prevent the progression of cervical intraepithelial neoplasia (CIN).
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) or non‐RCTs.
Studies were considered only if they included details of how the grading of CIN was determined. The gold standard for follow‐up of CIN includes cervical cytology, colposcopy and biopsy, where indicated. However, studies were accepted for review with cytologic assessment only. Progression was defined as elevation of the grade of dysplasia by at least one grade (CIN 1 to CIN 2, CIN 2 to CIN 3 and CIN 3 to invasive disease). Regression was defined as reduction in the grade of dysplasia by at least one grade (CIN 3 to CIN 2, CIN 2 to CIN 1, and CIN 1 to no dysplasia).
Types of participants
Women 18 years of age and over with an initial diagnosis of CIN.
Types of interventions
Treatment with non‐steroidal anti‐inflammatory agents (NSAIDs), including cyclooxygenase‐2 (COX‐2) inhibitors alone, by any route in an outpatient setting.
Types of outcome measures
Primary outcomes
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Progression of CIN to higher grades of CIN
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Progression of CIN to invasive carcinoma
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Regression of CIN
Secondary outcomes
Adverse events related to treatment.
Search methods for identification of studies
We searched for papers in all languages and planned to have them translated as necessary.
Electronic searches
For the original query, we searched the Specialised Register of the Cochrane Gynaecological Cancer Review Group (CGCRG), the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2013, Issue 11) (see Appendix 1); MEDLINE (1946 up to Novemeber, 2013) (see Appendix 2); and Embase (1980 up to 2013, week 48) (see Appendix 3). An updated literature search was performed in August 2017 through CENTRAL (2017, Issue 8), MEDLINE (July week 3, 2017) and Embase (July week 31, 2017).
Searching other resources
We carried out an electronic search of abstracts presented to the annual or biennial meetings of the following organisations: Society of Gynecologic Oncologists, International Gynecological Cancer Society, European Society of Gynecologic Cancer, American Society of Colposcopy and Cervical Pathology, and the American Society of Clinical Oncology by reviewing their respective online journals of Gynecologic Oncology, The International Journal of Gynecological Cancer, Journal of Lower Genital Tract Diseases and Journal of Clinical Oncology.
We searched the following databases for ongoing trials.
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Metaregister (http://www.controlled‐trials.com/rct).
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Physicians Data Query (http://www.nci.nih.gov).
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http://www.clinicaltrials.gov.
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http://www.cancer.gov/clinicaltrials.
Handsearching
We checked the references from published studies to identify additional trials.
Data collection and analysis
The methodology of the review was based on the guidelines stated in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Higgins 2011).
We downloaded all titles and abstracts retrieved by electronic searching and removed duplicates. Three review authors (originally OMS and CWH, and recently SMG and CWH) examined the remaining references independently. We excluded those studies which clearly did not meet the inclusion criteria and obtained copies of the full text of potentially relevant references. Three review authors (originally OMS and CWH, and recently SMG and CWH) independently assessed the eligibility of retrieved papers. The review authors resolved disagreements by discussion. There was no disagreement that required resolution from a third review author. We documented reasons for exclusion.
Selection of studies
Three review authors (originally OMS and CWH, and recently SMG and CWH) searched the titles and abstracts from the initial computerised searches for potential trials to include. The review authors then independently assessed the full text of these provisionally included studies to determine whether a study met the inclusion criteria. We resolved disagreement by consensus.
Data extraction and management
We analysed the included studies for the following data.
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Author, year of publication and journal citation (including language)
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Country
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Setting
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Inclusion and exclusion criteria
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Study design, methodology
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Study population
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Total number enrolled
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Patient characteristics
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Age
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Co‐morbidities
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Other baseline characteristics
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Intervention details
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Patients receiving NSAIDs of any type or route for the purposes of CIN treatment were considered in the intervention group
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Comparison
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Patients used as the controls in the selected studies (not receiving NSAIDs) were used as the comparison
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Risk of bias
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Duration of accrual
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Compliance
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Duration of follow‐up
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Outcomes: For each outcome we extracted the outcome definition
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Results: We extracted the number of participants allocated to each intervention group, the total number analysed for each outcome, and the missing participants
If reported, we extracted both unadjusted and adjusted statistics.
Where possible, all data extracted were relevant to an intention‐to‐treat analysis, in which participants are analysed in the groups to which they were assigned.
Three review authors (initially OMS and CWH and later SMG and CWH) independently extracted data onto a data abstraction form specially designed for the review. Differences between review authors were resolved by discussion.
Assessment of risk of bias in included studies
We assessed the risk of bias in included RCTs using Cochrane's 'Risk of bias' tool and the criteria specified in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This included assessment of the following domains.
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Selection bias: Random sequence generation and allocation concealment
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Performance bias: Blinding of participants and personnel (patients and treatment providers)
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Detection bias: Blinding of outcome assessment
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Attrition bias: Incomplete outcome data. We recorded the proportion of participants whose outcomes were not reported at the end of the study and considered greater than 20% attrition to be at a high risk of bias
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Reporting bias: Selective reporting of outcomes
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Other possible sources of bias
Three review authors (initially OMS and CWH and later SMG and CWH) applied the 'Risk of bias' tool (Appendix 4) independently and differences were resolved by discussion. We have presented results in a 'Risk of bias' graph and 'Risk of bias' summary and interpreted the results of the meta‐analyses in light of the findings with respect to risk of bias.
Measures of treatment effect
We used the following measures of the effect of treatment.
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For time to event data, we planned to use the hazard ratio (HR), if possible.
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For dichotomous outcomes, we used the risk ratio (RR).
Dealing with missing data
We did not impute missing outcome data for the primary outcome.
Assessment of reporting biases
Given the description of outcomes reported in the studies, we did not examine funnel plots corresponding to meta‐analysis of the primary outcome to assess the potential for small‐study effects such as publication bias.
Data synthesis
Statistical analysis was performed using Review Manager 5.3 software (RevMan 2014). Where appropriate, we pooled results of comparable trials using a fixed‐effect model. We reported results as RRs with their corresponding 95% confidence intervals (CIs). We performed the meta‐analysis using Review Manager 5.3 (RevMan 2014).
Results
Description of studies
Results of the search
For the previous version of this review (Grabosch 2014), the search strategy identified references that we screened by title and abstract in order to identify studies as potentially eligible for the review. From 232 unique references, we identified six articles as potentially eligible for the review. Following the full‐text screening of these six articles, we excluded four for the reasons described in the table 'Characteristics of excluded studies'. The remaining two RCTs met the inclusion criteria and are described in the table 'Characteristics of included studies'. We did not identify any additional relevant studies fro the ancillary searches.
With the updated search, we identified 35 new references with one article meeting the criteria for inclusion (Figure 1).
Study flow diagram.
Included studies
The initial two included RCTs randomised a total of 41 women; one study included 25 women (Farley 2006), and the other study 16 women (Hefler 2006). The new study included in this version of the review (Rader 2017) involved 130 women resulting in a total of 171 women included in this review. All three studies used cyclooxygenase‐2 (COX‐2) inhibitors.
The studies were performed as a multi‐institution United States trial (Rader 2017), and two single‐institution trials at Tripler United States Army Medical Center in Hawaii, USA (Farley 2006), and Medical University of Vienna, Austria (Hefler 2006), respectively. The Austrian study was closed early when rofecoxib was withdrawn from the market, due to potential toxicity (Hefler 2006). The mean age of the treatment and placebo groups was 23 years ± 4 years and 22.5 years ± 3 years (overall range 19 to 27 years) (Farley 2006), and 27.1 years ± 3.3 years and 31.2 years ± 5.5 years (overall range 24 to 36 years) (Hefler 2006). The multi‐institution trial did not include a median age for the groups; however, overall age range was 18 to 49 years (Rader 2017). Thirty‐one patients had CIN 2, 25 patients had CIN 2‐3, and 76 had CIN 3. The treatment groups received celecoxib 400 mg once daily by mouth for 14 to 18 weeks (Rader 2017), celecoxib 200 mg twice daily by mouth for six months (Farley 2006), and rofecoxib 25 mg by mouth daily (Hefler 2006). In all studies the comparison arm received placebo tablets (Characteristics of included studies).
Excluded studies
We excluded four studies because they were reviews of chemoprevention (Mitchell 2007; Vlastos 2003), a clinical study of celecoxib together with chemoradiation for the treatment of cervical cancer (Herrera 2007), and a laboratory investigation of celecoxib in cervical cancer cell lines (Ferrandina 2003) (Characteristics of excluded studies).
Risk of bias in included studies
We assessed the risk of bias as being lower in the completed study (Farley 2006), as the randomisation code in the other study (Hefler 2006) was broken when rofecoxib could no longer be given to patients (Characteristics of included studies), (Figure 2; Figure 3).
'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.
Overall, the multi‐institution trial (Rader 2017) had a low risk of bias, but it should be noted that 91 of 130 (70%) enrolled completed the study with evaluable tissue thus contributing to possible attrition bias.
Allocation
Sequence generation
Adequacy of randomisation was confirmed in all three studies (Farley 2006; Hefler 2006; Rader 2017).
Allocation
Concealment of allocation was low risk in Farley 2006, and Rader 2017, but was unclear for Hefler 2006. (Characteristics of included studies)
Blinding
Performance bias was assessed as being at low risk of bias in Farley 2006 and Rader 2017 where both patients and the examining physicians were blinded to the treatment arm to which the patients were randomised, and unclear in Hefler 2006, since the statistician and pathologist were blinded at all times, but the randomisation code was broken (Characteristics of included studies).
Detection bias was assessed as low risk of bias with physicians, patients and pathologist blinded at all times in Farley 2006 and Rader 2017, but unclear in Hefler 2006 because of the broken code (Characteristics of included studies).
Incomplete outcome data
Attrition bias was assessed as high risk in Farley 2006 because "five patients (20%) discontinued the study early but were included in the final statistical analysis" and unclear in Hefler 2006 (Characteristics of included studies). For Rader 2017, we have assessed this as low risk given that the higher number of patients included in the study decreases the potential for bias even with a high loss of eligible/evaluable patients and that the analysis was performed on both the patients completing the trial and as an intent‐to‐treat analysis.
Selective reporting
There was insufficient information to assess in the studies.
Other potential sources of bias
One study closed early (Farley 2006), but otherwise, there are insufficient data to identify whether other sources of bias exist.
Effects of interventions
See: Summary of findings for the main comparison
Efficacy
Primary outcomes
1. Progression of CIN to higher grades of cervical intraepithelial neoplasia (CIN)
Progression to a higher grade of CIN occurred in one out of 12 (8%) of those receiving celecoxib and two out of 13 (15%) receiving placebo (risk ratio (RR) 0.54, 95% confidence interval (CI) 0.06 to 5.24; P value 0.60) (Analysis 1.1, one study, 25 participants; very low‐certainty evidence).
The Heffler study did not comment on progression (Hefler 2006). There was no progression of disease in Rader 2017.
2. Progression of CIN to invasive carcinoma
Neither single‐institution study reported on progression to invasive cancer (Farley 2006; Hefler 2006). There was no progression of disease in Rader 2017.
3. Regression of CIN
Partial or complete regression of CIN 2 or CIN 3 occurred in 31 out of 70 (44%) in the treatment arms and 19 of 62 (31%) in the placebo arms (RR 1.45, 95% CI 0.93 to 2.27; P value 0.10) (Analysis 2.1: three studies, 132 participants; moderate‐certainty evidence).
Complete regression of CIN 2 or CIN 3 occurred in 15 of 62 (24%) of those receiving celecoxib versus 10 of 54 (19%) of those receiving placebo (RR 1.31, 95% CI 0.65 to 2.67; P value 0.45 (Analysis 2.2; two studies, 116 participants; moderate‐certainty evidence).
Partial regression of CIN 2 or CIN 3 occurred in 14 of 62 (23%) of those receiving celecoxib versus 8 of 54 (15%) of those receiving placebo (RR 1.56, 95% CI 0.72 to 3.40; P value 0.26) (Analysis 2.3, two studies, 116 participants; moderate certainty evidence).
Secondary outcome
Adverse events related to treatment were not reported in either single‐institution study (Farley 2006; Hefler 2006). Other than one Grade 3 adverse event in the treatment group of Rader 2017, the grade 1 and 2 toxicities were similar between the treatment and placebo arms.
Discussion
The pursuit of non‐invasive methods to prevent the progression of cervical intraepithelial neoplasia (CIN) remains important in order to allow women to avoid the potentially serious morbidities of invasive treatments, including pain, bleeding, infection, cervical stenosis and premature birth in a subsequent pregnancy, and to reduce the healthcare costs involved in the prevention of invasive carcinoma of the cervix. Although there are sound theoretical reasons why non‐steroidal anti‐inflammatory agents (NSAIDs) might have an effect on prevention of progression of CIN (as detailed in the Background), the findings of this review are not surprising in view of the small size and quality of the published data that were identified. The questions can only be resolved through the performance of appropriately designed clinical trials; such trials are difficult to perform in this setting.
It is important to note that any therapeutic benefit demonstrated as a result of further clinical trials will need to be weighed against the possible adverse effects of both NSAIDs and cyclooxygenase‐2 (COX‐2) inhibitors that have been identified in large chemoprevention studies for colorectal adenomas.
In light of the causal association of high‐risk human papilloma virus (HPV) infection with the development and progression of CIN (Munoz 2006), and the high negative predictive value of clearance of high‐risk HPV infection following treatment, such testing might be an important factor to incorporate in future studies (Paraskevaidis 2004). However, HPV‐16 status did not seem to contribute to celecoxib response with 36.2% and 38.5% responding with and without the virus in the newly reviewed trial (Rader 2017).
Summary of main results
We found no convincing evidence to support the use of NSAIDS in CIN 2/3 to induce complete or partial regression, or to prevent progression to higher grades.
Overall completeness and applicability of evidence
This update includes recently published data which adds to the body of literature that unfortunately, while well‐tolerated, NSAIDs do not prove effective in the treatment of CIN significantly more than the disease is naturally cleared while on placebo. With the addition of this larger trial, the authors feel that this topic has been adequately explored.
Quality of the evidence
The trials in our original review appear to have been well‐conducted although they were of small size and one was closed early due to withdrawal of the study agent. With the addition of the multi‐institution randomised trial in this update (Rader 2017), we have upgraded the evidence to moderate certainty according to GRADE criteria given that the addition of the new trial quadrupled the number of patients in our original review and was a well‐designed multi‐centre trial (summary of findings Table for the main comparison). Given that the natural history of CIN lends to some regression without intervention and no convincing evidence that NSAIDs have a significant impact over placebo, we do not feel that further research would alter the conclusions.
Potential biases in the review process
We undertook a comprehensive search to identify eligible studies. Three review authors extracted data independently. It is possible that there are other incomplete and unreported studies that have not been identified. We chose to retain data from the use of rofecoxib (removed from the market in 2004) in the review as findings may be similar to other COX‐2 inhibitors.
Agreements and disagreements with other studies or reviews
We did not identify any relevant studies or reviews.
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.
Comparison 1 Progression of CIN, Outcome 1 Progression of CIN to higher grade of CIN.
Comparison 2 Regression of CIN 2 and 3, Outcome 1 Partial or complete regression of CIN 2 or CIN 3.
Comparison 2 Regression of CIN 2 and 3, Outcome 2 Complete regression of CIN 2 or CIN 3.
Comparison 2 Regression of CIN 2 and 3, Outcome 3 Partial regression of CIN 2 or CIN 3.
| Non‐steroidal anti‐inflammatory agents (NSAIDs) compared with placebo for CIN 2 or CIN 3 | ||||||
| Patient or population: women with CIN 2 or CIN 3 Settings: outpatient Intervention: celecoxib 400 mg by mouth daily for 14‐18 weeks, celecoxib 200 mg by mouth twice daily for six months or rofecoxib 40 mg by mouth daily for three months Comparison: placebo tablet by mouth, daily for three to six months | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of Participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Progression of CIN to a higher grade of CIN | 77 per 10001 | 42 per 1000 | RR 0.54 (0.06 to 5.24) | 25 (one study) | ⊕⊝⊝⊝3 | |
| Partial or complete regression of CIN 2 or CIN 3 | 308 per 10002 | 447 per 1000 | RR 1.45 (0.93 to 2.27) | 132 (three studies) | ⊕⊕⊕⊝3 | |
| Complete regression of CIN 2 or CIN 3 | 174 per 10001 | 228 per 1000 | RR 1.31 (0.65 to 2.67) | 116 (two studies) | ⊕⊕⊕⊝3 | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1The basis for the assumed risk is from the spontaneous complete regression rate in the placebo arm of Farley 2006 and Rader 2017 2 The basis for the assumed risk is from the combined spontaneous partial or complete regression rates in the placebo arms of Farley 2006; Hefler 2006; Rader 2017 3Given the increased sample size with the addition of Rader 2017, we have upgraded the certainty to high other than the Progression analysis as it is based on one small study and thus remained very low certainty. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Progression of CIN to higher grade of CIN Show forest plot | 1 | 25 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.54 [0.06, 5.24] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Partial or complete regression of CIN 2 or CIN 3 Show forest plot | 3 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.93, 2.27] |
| 2 Complete regression of CIN 2 or CIN 3 Show forest plot | 2 | 116 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.65, 2.67] |
| 3 Partial regression of CIN 2 or CIN 3 Show forest plot | 2 | 116 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.56 [0.72, 3.40] |
