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Surgery for cervical intraepithelial neoplasia

  1. Pierre PL Martin-Hirsch1,*,
  2. Evangelos Paraskevaidis2,
  3. Andrew Bryant3,
  4. Heather O Dickinson3

Editorial Group: Cochrane Gynaecological Cancer Group

Published Online: 4 DEC 2013

Assessed as up-to-date: 23 NOV 2012

DOI: 10.1002/14651858.CD001318.pub3


How to Cite

Martin-Hirsch PPL, Paraskevaidis E, Bryant A, Dickinson HO. Surgery for cervical intraepithelial neoplasia. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD001318. DOI: 10.1002/14651858.CD001318.pub3.

Author Information

  1. 1

    Royal Preston Hospital, Lancashire Teaching Hospital NHS Trust, Gynaecological Oncology Unit, Preston, Lancashire, UK

  2. 2

    Ioannina University Hospital, Department of Obstetrics and Gynaecology, Ioannina, Greece

  3. 3

    Newcastle University, Institute of Health & Society, Newcastle upon Tyne, UK

*Pierre PL Martin-Hirsch, Gynaecological Oncology Unit, Royal Preston Hospital, Lancashire Teaching Hospital NHS Trust, Sharoe Green Lane, Fullwood, Preston, Lancashire, PR2 9HT, UK. martin.hirsch@me.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 4 DEC 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of the condition

Cervical cancer is the second most common cancer among women (GLOBOCAN 2009). A woman's risk of developing cervical cancer by age 65 years ranges from 0.8% in developed countries to 1.5% in developing countries (IARC 2002). In Europe, about 60% of women with cervical cancer are alive five years after diagnosis (EUROCARE 2003). Cervical screening aims to identify women with asymptomatic disease and to treat the disease with a low morbidity procedure thus lowering the risk of developing invasive disease. In countries with effective screening programmes, dramatic reductions have occurred in the incidence of disease and the stage of cancer if disease is diagnosed (Peto 2004). Cervical intraepithelial neoplasia (CIN) is the most common pre-malignant lesion, with atypical squamous changes in the transformation zone of the cervix. Mild, moderate or severe changes are described by their depth (CIN 1, 2 or 3). If CIN progresses it develops into squamous cancer. In contrast, the much rarer glandular pre-cancerous abnormalities (cervical glandular intraepithelial neoplasia or CGIN) becomes cervical adenocarcinoma.

Human papillomavirus (HPV) is the cause of pre-cancerous abnormalities of the cervix. HPV has over 100 subtypes and is present in over 95% of pre-invasive and invasive squamous carcinomas of the cervix. Serotypes associated with cervical squamous lesions may be designated as having a high or low risk for progression to malignancy. HPV infection in young women is commonly a transient infection and the body's own immune response clears the disease from the cervical tissues. If pre-invasive disease has been present and the immunological response clears HPV infection then the pre-invasive disease will resolve. Sexually active young women under 30 years of age have a very high rate of HPV infection whilst women over 30 years of age have a much lower HPV infection rate (Sargent 2008). This is a reflection of the natural history of disease, with a 50% regression rate and only a 10% progression rate of low grade CIN in young women (Ostor 1993).

The frequency of abnormal Papanicolaou smear test results and subsequent CIN varies with the population tested, the test used and the reported accuracy. It is estimated to range between 1.5% to 6% (Cirisano 1999).

When CIN is identified, colposcopists generally treat CIN 2 or high grade disease and either observe or immediately treat CIN 1 depending on personal preference. The aim of this review was to compare different treatment modalities to assess their effectiveness for treating disease.

 

Description of the intervention

Current treatment for cervical intraepithelial neoplasia (CIN) is by local ablative therapy or by excisional methods, depending on the nature and extent of disease. Traditionally, prior to colposcopy, all lesions were treated by knife excisional cone biopsy or by ablative radical point diathermy. Knife cone biopsy and radical point diathermy are usually performed under general anaesthesia and are no longer the preferred treatment as various more conservative local ablative and excisional therapies can be performed in an out-patient setting.

Patients are suitable for ablative therapy provided that:
(1) the entire transformation zone can be visualised (satisfactory colposcopy);
(2) there is no suggestion of micro-invasive or invasive disease;
(3) there is no suspicion of glandular disease;
(4) the cytology and histology correspond.

Excisional treatment is mandatory for a patient with an unsatisfactory colposcopy, suspicion of invasion or glandular abnormality. There is now a trend to utilise low morbidity excisional methods, either laser conisation or large loop excision of the transformation zone (LLETZ), in place of destructive ablative methods. Excisional methods offer advantages over destructive methods in that they can define the exact nature of disease and the completeness of excision or destruction of the transformation zone. Incomplete excision or destruction of the transformation zone is an important indicator of patients at risk of treatment failure or recurrence of disease.

The treatment modalities included in this review are described below.

 

Knife cone biopsy

Traditionally, broad deep cones were performed for most cases of CIN. Excision of a wide and deep cone of the cervix is associated with significant short and long term morbidity (peri-operative, primary and secondary haemorrhage, local and pelvic infection, cervical stenosis and mid-trimester pregnancy loss) (Jordan 1984; Leiman 1980; Luesley 1985). A less radical approach is now generally adopted, tailoring the width and depth of the cone according to colposcopic findings. The procedure is invariably performed under general anaesthesia. Peri-operative haemostasis can be difficult to achieve and various surgical techniques have been developed to reduce bleeding. Routine ligation of the cervical vessels is commonly performed. This technique also allows manipulation of the cervix during surgery. Sturmdorf sutures have been advocated by some surgeons to promote haemostasis; others recommend circumferential locking sutures, electrocauterisation or cold coagulation, or vaginal compression packing.
The treatment success (that is no residual disease on follow up) of knife cone biopsy is reported as 90% to 94% (Bostofte 1986; Larson 1983; Tabor 1990) in non-randomised studies.

 

Laser conisation

This procedure can be performed under general or local analgesia. A highly focused laser spot is used to make an ectocervical circumferential incision to a depth of 1 cm. Small hooks or retractors are then used to manipulate the cone to allow deeper incision and complete the endocervical incision. Haemostasis, if required, is generally achieved through laser coagulation by defocusing the beam. A disadvantage of laser conisation is that the cone biopsy specimen might suffer from thermal damage, making histological evaluation of margins impossible.
The treatment success of laser cone biopsy is reported as 93% to 96% (Bostofte 1986; Tabor 1990) in non-randomised studies. The major advantages are accurate tailoring of the size of the cone, low blood loss in most cases, and less cervical trauma than with knife cut cones.

 

Loop excision of the transformation zone

Large loop excision of the transformation zone is often abbreviated to LLETZ in the UK or LEEP (loop electrosurgical excisional procedure) in the USA. A wire loop electrode on the end of an insulated handle is powered by an electrosurgical unit. The current is designed to achieve a cutting and coagulation effect simultaneously. Power should be sufficient to excise tissue without causing a thermal artefact. The procedure can be performed under local analgesia.
Treatment success of LLETZ is reported as 98% (Prendeville 1989), 96% (Bigrigg 1990), 96% (Luesley 1990), 95% (Whiteley 1990), 91% (Murdoch 1992) and 94% (Wright TC 1992) in non-randomised studies.

 

Laser ablation

A laser beam is used to destroy the tissue of the transformation zone. Laser destruction of tissue can be controlled by the length of exposure. Defocusing the beam permits photocoagulation of bleeding vessels in the cervical wound.
Treatment success of laser ablation is reported as 95% to 96% (Jordan 1985).

 

Cryotherapy

A circular metal probe is placed against the transformation zone. Hypothermia is produced by the evaporation of compressed refrigerant gas passing through the base of the probe. The cryonecrosis is achieved by crystallization of intracellular water. The effect tends to be patchy as sublethal tissue damage tends to occur at the periphery of the probe.
In non-controlled studies the success of treatment of CIN3 varied, between 77% and 93%, 87% (Benedet 1981), 77% (Hatch 1981), 82% (Kaufman 1978), 84% (Ostergard 1980), and 93% (Popkin et al 1978).
Utilising a double freeze-thaw-freeze technique improved the reliability in the observational study by Creasman 1984. Rapid ice-ball formation indicates that the depth of necrosis will extend to the periphery of the probe. The procedure can be associated with unpleasant vasomotor symptoms.

 

Why it is important to do this review

This systematic review examines the efficacy and morbidity of local ablative and excisional therapies for eradicating disease. The effectiveness and morbidity of the various forms of treatment have generally been evaluated in uncontrolled observational studies. Hence direct comparison of treatment effects of alternative treatments is unreliable because of variable patient selection, treatment outcomes and follow-up criteria. We have, therefore, only included trials which appear to be randomised in order to reduce selection bias and potentially provide results with greater certainty.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

To assess the effectiveness and safety of alternative surgical treatments for CIN

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials (RCTs). Quasi-randomised controlled trials were included in the first version of the review but excluded from the second version as they did not contribute to any meta-analyses.

 

Types of participants

Women with CIN confirmed by biopsy and undergoing surgical treatment. We have not included treatments for glandular intraepithelial neoplasia in our review.

 

Types of interventions

We considered direct comparisons between any of the following interventions.

  1. Laser ablation.
  2. Laser conisation.
  3. Large loop excision of the transformation zone (LLETZ).
  4. Knife conisation.
  5. Cryotherapy.

Other types of surgical interventions for CIN were considered if relevant trials were found. We also compared variations in technique within a single intervention (for example blend versus cut setting for LLETZ, single versus double freeze cryotherapy).

 

Types of outcome measures

 

Primary outcomes

  1. Residual disease detected on follow-up examination.

 

Secondary outcomes

  1. Adverse events, classified according to CTCAE 2006:
    1. peri-operative severe pain;
    2. peri-operative severe bleeding, primary and secondary haemorrhage;
    3. depth and presence of thermal artifact;
    4. inadequate colposcopy at follow up;
    5. cervical stenosis at follow up;
    6. vaginal discharge.
  2. Duration of treatment.

 

Search methods for identification of studies

There were no language restrictions.

 

Electronic searches

See: the Cochrane Gynaecological Cancer Group methods used in reviews.
The following electronic databases were searched:

  • The Cochrane Gynaecological Cancer Review Group Trial Register;
  • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library);
  • MEDLINE;
  • EMBASE.

The MEDLINE, EMBASE and CENTRAL search strategies are presented in Appendix 1, Appendix 2 and Appendix 3 respectively.

Databases were searched from 1966 until 2000 in the original review and updated in April 2009 and November 2012. All relevant articles found were identified on PubMed and, using the 'related articles' feature, a further search was carried out for newly published articles.

 

Searching other resources

 

Unpublished and grey literature

Metaregister, Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov and www.cancer.gov/clinicaltrials were searched for ongoing trials.

 

Handsearching

 
First version of the review

The citation lists of included studies were checked through handsearching and experts in the field were contacted to identify further reports of trials. Sixteen journals that were thought to be the most likely to contain relevant publications were handsearched (Acta Cytologica, Acta Obstetrica Gynecologica Scandanavia, Acta Oncologica, American Journal of Obstetrics and Gynaecology, British Journal of Obstetrics and Gynaecology, Cancer, Cytopathology, Diagnostic Cytopathology, Gynecologic Oncology, International Journal of Cancer, International Journal of Gynaecological Cancer, Journal of Family Practice, Obstetrics and Gynaecology).

 
Second version of the review

This update is based on RCTs identified by electronic literature databases. All 16 previously handsearched publications are indexed in MEDLINE. As the accuracy of indexing RCTs is now very robust, further handsearching was not performed.

 

Data collection and analysis

 

Selection of studies

 
First version of the review

In the original review, all the possible publications identified by manual and electronic searches were collated onto an Excel spreadsheet. Two authors (P M-H and EP) independently scrutinised the studies to see if they met the inclusion or exclusion criteria. Diasagreements were resolved after discussion.

 
Second version of the review

All titles and abstracts retrieved by electronic searching were downloaded to the reference management database Endnote, duplicates were then removed and the remaining references examined by four review authors (AB, HD, PM-H, SK) working independently. Those studies which clearly did not meet the inclusion criteria were excluded and copies of the full text of potentially relevant references were obtained. The eligibility of retrieved papers were assessed independently by two review authors (PM-H, SK). Disagreements were resolved by discussion between the two authors. Reasons for exclusion were documented.

 

Data extraction and management

For included studies, data were extracted on the following.

  • Author, year of publication and journal citation (including language).
  • Country.
  • Setting.
  • Inclusion and exclusion criteria.
  • Study design, methodology.
  • Study population:
    • total number enrolled,
    • patient characteristics,
    • age.
  • CIN details.
  • Intervention details:
    • variations in technique.
  • Risk of bias in study (see below).
  • Duration of follow up.
  • Outcomes – see below.

Data on outcomes were extracted as below for:

  • dichotomous outcomes (e.g. residual disease, pain, haemorrhage, inadequate colposcopy, cervical stenosis, vaginal discharge), where we extracted the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at the end point in order to estimate a risk ratio;
  • continuous outcomes (e.g. depth of thermal artifact, duration of procedure), where we extracted the final value and standard deviation of the outcome of interest and the number of patients assessed at the end point in each treatment arm at the end of follow up in order to estimate the mean difference between treatment arms and its standard error.

Where possible, all data extracted were those relevant to an intention-to-treat analysis, in which participants were analysed in groups to which they were assigned.

The time points at which outcomes were collected and reported were noted.

Data were abstracted independently by two review authors (AB, SK) 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

The risk of bias in included RCTs was assessed using the following questions and criteria.

 
Sequence generation

Was the allocation sequence adequately generated?

  • Yes, e.g. a computer-generated random sequence or a table of random numbers
  • No, e.g. date of birth, clinic identity number or surname
  • Unclear, e.g. if not reported

 
Allocation concealment

Was allocation adequately concealed?

  • Yes, e.g. where the allocation sequence could not be foretold
  • No, e.g. allocation sequence could be foretold by patients, investigators or treatment providers
  • Unclear, e.g. if not reported

 
Blinding

Assessment of blinding was restricted to blinding of outcome assessors since it is generally not possible to blind participants and treatment providers to surgical interventions.

Was knowledge of the allocated interventions adequately prevented during the study?

  • Yes
  • No
  • Unclear

 
Incomplete reporting of outcome data

We recorded the proportion of participants whose outcomes were not reported at the end of the study; we noted whether or not loss to follow up was reported.

Were incomplete outcome data adequately addressed?

  • Yes, if fewer than 20% of patients were lost to follow up and reasons for loss to follow up were similar in both treatment arms
  • No, if more than 20% of patients were lost to follow up or reasons for loss to follow up differed between treatment arms
  • Unclear, if loss to follow up was not reported

 
Selective reporting of outcomes

Are reports of the study free of suggestion of selective outcome reporting?

  • Yes, e.g. if the report included all outcomes specified in the protocol
  • No, if otherwise
  • Unclear, if insufficient information available

 
Other potential threats to validity

Was the study apparently free of other problems that could put it at a high risk of bias?

  • Yes
  • No
  • Unclear

The risk of bias tool was applied independently by two review authors (AB, SK) and differences were resolved by discussion. Results were presented in both a risk of bias graph and a risk of bias summary. Results of the meta-analyses were interpreted in light of findings with the risk of bias assessment.

 

Measures of treatment effect

We used the following measures of the effect of treatment.

  • For dichotomous outcomes, we used the risk ratio.
  • For continuous outcomes, we used the mean difference between treatment arms.

 

Dealing with missing data

We did not impute missing outcome data for any outcome.

 

Assessment of heterogeneity

Heterogeneity between studies was assessed by visual inspection of forest plots, estimation of the percentage of the heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), a formal statistical test of the significance of the heterogeneity (Deeks 2001) and, where possible, by subgroup analyses (see below). If there was evidence of substantial heterogeneity, the possible reasons for this were investigated and reported.

 

Data synthesis

The results of clinically similar studies were pooled in meta-analyses.

  • For any dichotomous outcomes, the risk ratio was calculated for each study and these were then pooled.
  • For continuous outcomes, the mean difference between the treatment arms at the end of follow up was pooled, if all trials measured the outcome on the same scale; otherwise standardised mean differences were pooled.   

A random-effects model with inverse variance weighting was used for all meta-analyses (DerSimonian 1986).

 

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were performed where possible, grouping the trials by:

  • CIN stage (CIN1, CIN2, CIN3).

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

 

Results of the search

The original search strategy identified references which were then screened by title and abstract in order to identify 29 studies as potentially eligible for the review. The updated search strategy identified 1225 unique references in April 2009. The title and abstract screening of these references identified 10 studies as potentially eligible for the review. Overall, the full text screening of these 39 studies excluded 10 for the reasons described in the table Characteristics of excluded studies. The remaining 29 RCTs met our inclusion criteria and are described in the table Characteristics of included studies. No new studies were identified for inclusion in November 2012.

Searches of the grey literature did not identify any additional relevant studies.

 

Included studies

The 29 included trials randomised a total of 5441 women, of whom 4509 were analysed at the end of the trials. The largest of these studies recruited 498 participants (Mitchell 1998) and the smallest recruited 40 women (Cherchi 2002; Paraskevaidis 1994).

The majority of studies were performed in single centres in a university setting, with multi-centre designs being used by the minority (Alvarez 1994; Berget 1987; Dey 2002; Vejerslev 1999). These trials were mainly from Europe and North America with the exceptions being Peru (Santos 1996) and Zimbabwe (Chirenje 2001).

A total of 865 women participating in the trials had a diagnosis of CIN 1,1185 had CIN2, 1843 had CIN3, 25 had micro-invasion or carcinoma and 52 were negative at final histology, with the remainder having unknown histology or their status was not given. The average age of the participants within the trials was 31.8 years.

Eighteen studies included laser techniques as part of their methodology. These trials compared the use of laser surgery to cryotherapy (Berget 1987; Jobson 1984; Kirwan 1985; Kwikkel 1985; Mitchell 1998; Townsend 1983), knife conisations (Bostofte 1986; Kristensen 1990; Larsson 1982; Mathevet 1994), LLETZ using either conisation techniques (Crompton 1994; Mathevet 1994; Oyesanya 1993; Paraskevaidis 1994; Santos 1996; Vejerslev 1999) or laser ablation (Alvarez 1994; Dey 2002; Mitchell 1998) and the different laser techniques (ablation versus conisation (Partington 1989).

Nine studies included knife conisation as part of their methodology, including comparisons with loop excision (Duggan 1999; Giacalone 1999; Mathevet 1994; Takac 1999), laser surgery (Bostofte 1986; Kristensen 1990; Larsson 1982; Mathevet 1994) or NETZ (Sadek 2000) with or without the insertion of haemostatic sutures (Gilbert 1989; Kristensen 1990).

Eighteen trials investigated diathermy excision of the transformation zone using LLETZ (or LEEP) or similar techniques such as needle excision of the transformation zone (NETZ). These included comparisons of LLETZ with knife conisation (Duggan 1999; Giacalone 1999 Mathevet 1994; Takac 1999), cryotherapy (Chirenje 2001), laser conisation techniques (Crompton 1994; Mathevet 1994; Oyesanya 1993; Paraskevaidis 1994; Santos 1996; Vejerslev 1999) or laser ablative techniques (Alvarez 1994; Dey 2002; Mitchell 1998). Further trials compared LLETZ with radical diathermy (Healey 1996), NETZ (Sadek 2000; Panoskaltsis 2004a) or using different techniques (bipolar electrocautery scissors versus monopolar energy scalpel (Cherchi 2002) or pure cut versus blend settings (Nagar 2004)).

Eight trials included the use of cold coagulation as a technique, comparing this to LLETZ (Chirenje 2001) or laser surgical techniques (Berget 1987; Jobson 1984; Kirwan 1985; Kwikkel 1985; Mitchell 1998; Townsend 1983). A further trial compared differing types of cryotherapy, single versus double freeze techniques (Schantz 1984).

 

Excluded studies

Eleven references were excluded from this review as they were found to be non-randomised studies (Bar-AM 2000; Lisowski 1999), quasi-RCTs (Ferenczy 1985; Girardi 1994; Gunasekera 1990; O'Shea 1986; Singh 1988), a review or commentary of earlier trials (Gentile 2001; Panoskaltsis 2004b) or an RCT which did not report any of the outcomes specified in this review (Boardman 2004).

 

Risk of bias in included studies

Most trials were at moderate or high risk of bias: 22 trials satisfied less than three of the criteria that we used to assess risk of bias, six satisfied three of the criteria, and only one trial was at low risk of bias (Healey 1996) as it satisfied four of the criteria (see Figure 1; Figure 2).

 FigureFigure 1. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
 FigureFigure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

 

Sequence generation

Adequacy of randomisation was confirmed in 14 trials (Alvarez 1994; Cherchi 2002; Chirenje 2001; Crompton 1994; Dey 2002; Duggan 1999; Giacalone 1999; Healey 1996; Mathevet 1994; Mitchell 1998; Panoskaltsis 2004a; Santos 1996; Schantz 1984; Vejerslev 1999), where an appropriate method of sequence generation was used to assign women to treatment groups. The method of randomisation was not reported in the other 15 trials.

 

Allocation

Concealment of allocation was satisfactory in 11 trials (Alvarez 1994; Cherchi 2002; Chirenje 2001; Crompton 1994; Dey 2002; Giacalone 1999; Gilbert 1989; Healey 1996; Oyesanya 1993; Panoskaltsis 2004a; Partington 1989) but was not reported in any of the other 18 trials.

 

Blinding

None of the trials reported whether or not the outcome assessor was blinded, except for the trial of Healey 1996 where the investigators collecting and analysing the data were blinded to the treatment mode.

 

Incomplete outcome data

Loss to follow up was low in 25 of the trials, with at least 80% of women being assessed at the end of the trial. It was unsatisfactory in the other four trials (Alvarez 1994; Duggan 1999; Jobson 1984; Mitchell 1998) as, in at least one of the outcomes, less than 80% of women were assessed at the end point.

 

Selective reporting

In all 29 trials it was unclear whether outcomes had been selectively reported as there was insufficient information to permit judgement.

 

Other potential sources of bias

In all 29 trials there was insufficient information to assess whether any important additional risk of bias existed.

 

Effects of interventions

 

Single freeze cryotherapy compared with double freeze cryotherapy

In the trial of Schantz 1984, the single freeze technique was associated with a statistically non-significant increase in the risk of residual disease within 12 months compared with the double freeze technique (RR 2.66, 95% CI 0.96 to 7.37). (See  Analysis 1.1).

 

Laser ablation compared with cryotherapy

 

Residual disease

Meta-analysis of six RCTs (Berget 1987; Jobson 1984; Kirwan 1985; Kwikkel 1985; Mitchell 1998; Townsend 1983), assessing 935 participants, found no significant difference between the two treatments (RR 1.13, 95% CI 0.73 to 1.76). The percentage of the variability in effect estimates that was due to heterogeneity rather than sampling error (chance) may represent moderate heterogeneity (I2 = 35%).

Since only six studies were included in meta-analysis, funnel plots were not examined.

The conclusions above were robust to subgroup analyses examining CIN1, CIN2 and CIN3 separately. Meta-analysis of four trials assessing 73 women with CIN1, 289 women with CIN2 and 205 women with CIN3 showed no statistically significant differences between laser ablation and cryotherapy in the risk of residual disease in each of the subgroups (RR 2.75, 95% CI 0.68 to 11.11, I2 = 0%; RR 1.37, 95% CI 0.65 to 2.88, I2 = 0%; and RR 1.38, 95% CI 0.62 to 3.09, I2 = 0%; respectively). (See  Analysis 2.1;  Analysis 2.2).

 

Peri-operative severe pain

Meta-analysis of three RCTs (Berget 1987; Kwikkel 1985; Townsend 1983), assessing 493 participants, showed no statistically significant difference in the risk of peri-operative severe pain in women who received either laser ablation or cryotherapy (RR 2.00, 95% CI 0.64 to 6.27). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance did not appear to be important (I2 = 9%). (See  Analysis 2.3).

 

Peri-operative severe bleeding

Meta-analysis of two RCTs (Berget 1987; Kwikkel 1985), assessing 305 participants, showed no statistically significant difference in the risk of peri-operative severe bleeding in women who received either laser ablation or cryotherapy (RR 5.83, 95% CI 0.71 to 47.96). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 2.4).

 

Vasomotor symptoms

In the trial of Townsend 1983, laser ablations were associated with a statistically large and significant decrease in the risk of vasomotor symptoms compared with cryotherapy (RR 0.02, 95% CI 0.00 to 0.40). (See  Analysis 2.5).

 

Malodorous discharge

Meta-analysis of two trials (Berget 1987; Townsend 1983), assessing 400 participants, found that laser ablations were associated with a statistically significant decrease in the risk of malodorous discharge compared with cryotherapy (RR 0.30, 95% CI 0.12 to 0.77). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent considerable heterogeneity (I2 = 81%). (See  Analysis 2.6).

 

Inadequate colposcopy

Meta-analysis of two trials (Berget 1987; Jobson 1984), assessing 272 participants, found that laser ablations were associated with a statistically significant decrease in the risk of an inadequate colposcopy when compared with cryotherapy (RR 0.38, 95% CI 0.26 to 0.56). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 2.7).

 

Cervical stenosis

Meta-analysis of two trials (Berget 1987; Mitchell 1998), assessing 464 participants, showed no statistically significant difference in the risk of cervical stenosis in women who received either laser ablation or cryotherapy (RR 1.45, 95% CI 0.45 to 4.73). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 2.8).

 

Laser conisation compared with knife conisation

 

Residual disease (all grades)

Meta-analysis of two trials (Bostofte 1986; Mathevet 1994), assessing 194 participants, found no evidence that residual disease differed between laser conisation and knife conisation (RR 0.64, 95% CI 0.22 to 1.90). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 3.1).

 

Primary haemorrhage

Meta-analysis of two trials (Bostofte 1986; Kristensen 1990), assessing 316 participants, found no statistically significant difference between laser conisation and knife conisation in the risk of primary haemorrhage (RR 0.53, 95% CI 0.18 to 1.54). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent moderate heterogeneity (I2 = 40%). (See  Analysis 3.2).

 

Secondary haemorrhage

Meta-analysis of three trials (Kristensen 1990; Larsson 1982; Mathevet 1994), assessing 359 participants, showed little difference in the risk of secondary haemorrhage in women who received either laser conisation or knife conisation (RR 0.91, 95% CI 0.34 to 2.40). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance did not appear to be important (I2 = 17%). (See  Analysis 3.3).

 

Inadequate colposcopy at follow up

Meta-analysis of two trials (Bostofte 1986; Mathevet 1994), assessing 160 participants, found that laser conisation was associated with a statistically significant decrease in the risk of inadequate colposcopy compared with knife conisation (RR 0.57, 95% CI 0.39 to 0.81). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 3.4).

 

Cervical stenosis at follow up

Meta-analysis of four trials (Bostofte 1986; Kristensen 1990; Larsson 1982; Mathevet 1994), assessing 1009 participants, found that laser conisation was associated with a statistically significant decrease in the risk of cervical stenosis compared with knife conisation (RR 0.38, 95% CI 0.19 to 0.76). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent moderate heterogeneity (I2 = 45%). (See  Analysis 3.5).

 

Ectocervical and endocervical margins with disease

In the trial of Mathevet 1994, laser conisation was associated with a large and statistically significant increase in the risk of thermal artifact compared with knife conisation (RR 29.00, 95% CI 1.79 to 468.90). (See  Analysis 3.6).

 

Laser conisation compared with laser ablation

Only the trial of Partington 1989 reported data on laser conisation versus laser ablation.

 

Residual disease (all grades)

There was no statistically significant difference in the risk of residual disease in women who received either laser conisation or laser ablation (RR 0.75, 95% CI 0.21 to 2.62). (See  Analysis 4.1).

 

Significant peri-operative bleeding

There was no statistically significant difference in the risk of significant peri-operative bleeding in women who received either laser conisation or laser ablation (RR 1.50, 95% CI 0.45 to 4.99). (See  Analysis 4.2).

 

Secondary haemorrhage

There was no statistically significant difference in the risk of secondary haemorrhage in women who received either laser conisation or laser ablation (RR 2.00, 95% CI 0.74 to 5.43). (See  Analysis 4.3).

 

Inadequate colposcopy at follow up

There was no statistically significant difference in the risk of inadequate colposcopy in women who received either laser conisation or laser ablation (RR 5.00, 95% CI 0.61 to 41.28). (See  Analysis 4.4).

 

Laser conisation compared to loop excision

 

Residual disease

Meta-analysis of four trials (Mathevet 1994; Oyesanya 1993; Santos 1996; Vejerslev 1999), assessing 889 participants, showed little difference in the risk of residual disease in women who received laser conisation or loop excision (RR 1.24, 95% CI 0.77 to 1.99). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 5.1).

 

Duration of procedure

Meta-analysis of three trials (Crompton 1994; Oyesanya 1993; Paraskevaidis 1994), assessing 419 participants, found that laser conisation was associated with a statistically significant increased operating time compared with loop excision (mean difference (MD) 11.66, 95% CI 1.37 to 21.95). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance represented highly variable findings across trials (I2 = 99%), although it appears sensible to pool the results as findings were consistent in that all trials favoured loop excision. (See  Analysis 5.2).

 

Peri-operative severe bleeding

In the trial of Vejerslev 1999, laser conisation was associated with a statistically large and significant increase in the risk of peri-operative severe bleeding compared with loop excision (RR 8.75, 95% CI 01.11 to 68.83). (See  Analysis 5.3).

 

Peri-operative severe pain

Meta-analysis of two trials (Oyesanya 1993; Santos 1996), assessing 594 participants, showed no statistically significant difference in the risk of peri-operative severe pain in women who received either laser conisation or loop excision (RR 4.34, 95% CI 0.25 to 75.67). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent moderate heterogeneity (I2 = 52%). (See  Analysis 5.4).

 

Secondary haemorrhage

Meta-analysis of four trials (Mathevet 1994; Oyesanya 1993; Santos 1996; Vejerslev 1999), assessing 889 participants, showed no statistically significant difference in the risk of secondary haemorrhage in women who received laser conisation or loop excision (RR 1.41, 95% CI 0.72 to 2.76). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 5.5).

 

Significant thermal artefact

Meta-analysis of two trials (Mathevet 1994; Oyesanya 1993), assessing 373 participants, showed no statistically significant difference in the risk of significant thermal artefact in women who received laser conisation or loop excision (RR 2.38, 95% CI 0.61 to 9.34). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent considerable heterogeneity (I2 = 83%). (See  Analysis 5.6).

 

Depth of thermal artefact

In the trial of Paraskevaidis 1994, there was statistically significantly more depth of thermal artefact for laser conisation compared with loop excision (MD 0.27, 95% CI 0.19 to 0.35). (See  Analysis 5.7).

 

Inadequate colposcopy at follow up

Meta-analysis of two trials (Mathevet 1994; Santos 1996), assessing 339 participants, showed no statistically significant difference in the risk of inadequate colposcopy in women who received laser conisation or loop excision (RR 1.38, 95% CI 0.48 to 3.97). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent substantial heterogeneity (I2 = 76%). (See  Analysis 5.8).

 

Cervical stenosis at follow up

Meta-analysis of three trials (Mathevet 1994; Santos 1996; Vejerslev 1999), assessing 560 participants, found that there was no statistically significant difference in the risk of cervical stenosis between laser conisation and loop excision (RR 1.21, 95% CI 0.57 to 2.57). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance did not appear to be important (I2 = 13%). (See  Analysis 5.9).

 

Vaginal discharge

In the trial of Vejerslev 1999 there was no statistically significant difference between laser conisation and loop excision in the amount of vaginal discharge after the operation (RR 1.01, 95% CI 0.68 to 1.48). (See  Analysis 5.10).

 

Laser ablation compared to loop excision

 

Residual disease

Meta-analysis of three trials (Alvarez 1994; Dey 2002; Mitchell 1998), assessing 911 participants, showed little difference in the risk of residual disease in women who received either laser ablation or loop excision (RR 1.15, 95% CI 0.59 to 2.25). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent moderate heterogeneity (I2 = 54%). (See  Analysis 6.1).

 

Severe peri-operative pain

The trial of Alvarez 1994, which assessed 185 participants, showed no statistically significant difference in the risk of severe peri-operative pain in women who received laser ablation compared with loop excision (RR 0.38, 95% CI 0.02 to 7.91). (See  Analysis 6.2).

 

Primary haemorrhage

Meta-analysis of two trials (Alvarez 1994; Mitchell 1998), assessing 560 participants, showed no statistically significant difference in the risk of primary haemorrhage in women who received laser ablation or loop excision (RR 0.35, 95% CI 0.04 to 3.14). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 6.3).

 

Secondary haemorrhage

Analysis of two trials (Alvarez 1994; Mitchell 1998) assessed only the 231 participants from the Mitchell 1998 trial since a relative risk was not estimable for the trial of Alvarez 1994. The trial of Mitchell 1998 showed no statistically significant difference in the risk of secondary haemorrhage in women who received either laser ablation or loop excision (RR 0.54, 95% CI 0.14 to 2.10). (See  Analysis 6.4).

 

Knife cone biopsy compared to loop excision

 

Residual disease

Meta-analysis of three trials (Duggan 1999; Giacalone 1999; Mathevet 1994), 279 participants, found no statistically significant between knife conisation and loop excision in the risk of residual disease (RR 0.47, 95% CI 0.20 to 1.08). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 7.1).

 

Primary haemorrhage

Meta-analysis of two trials (Giacalone 1999; Takac 1999), assessing 306 participants, showed little difference in the risk of primary haemorrhage in women who received knife conisation or loop excision (RR 1.04, 95% CI 0.45 to 2.37). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 7.2).

 

Inadequate colposcopy at follow up

Meta-analysis of three trials (Duggan 1999; Giacalone 1999; Mathevet 1994), assessing 291 participants, showed no statistically significant difference in the risk of inadequate colposcopy in women who received knife conisation or loop excision (RR 1.63, 95% CI 0.85 to 3.15). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent moderate heterogeneity (I2 = 57%). (See  Analysis 7.3).

 

Cervical stenosis

Meta-analysis of three trials (Duggan 1999; Giacalone 1999; Mathevet 1994), assessing 249 participants, showed little difference in the risk of cervical stenosis in women who received knife conisation or loop excision (RR 1.12, 95% CI 0.44 to 2.84). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance did not appear to be important (I2 = 4%). (See  Analysis 7.4).

 

Radical diathermy compared to loop excision

Only the trial of Healey 1996 reported data on radical diathermy versus loop excision.

 

Duration of blood loss

There was little difference between the duration of blood loss in women who received either radical diathermy or loop excision (MD -1.20, 95% CI -5.20 to 2.80). (See  Analysis 8.1).

 

Blood stained or watery discharge

There was little difference between the amount of blood stained or watery discharge in women who received radical diathermy or loop excision (MD 0.80, 95% CI -3.84 to 5.44). (See  Analysis 8.2).

 

Yellow discharge

There was little difference between the amount of yellow discharge in women who received either radical diathermy or loop excision (MD -1.10, 95% CI -6.43 to 4.23). (See  Analysis 8.3).

 

White discharge

There was little difference between the amount of white discharge in women who received radical diathermy or loop excision (MD -1.60, 95% CI -6.74 to 3.54). (See  Analysis 8.4).

 

Upper abdominal pain

There was little difference in upper abdominal pain in women who received radical diathermy or loop excision (MD -0.30, 95% CI -1.86 to 1.26). (See  Analysis 8.5).

 

Lower abdominal pain

There was little difference in lower abdominal pain in women who received either radical diathermy or loop excision (MD 0.50, 95% CI -5.84 to 6.84). (See  Analysis 8.6).

 

Deep pelvic pain

There was no evidence of a difference in deep pelvic pain in women who received radical diathermy or loop excision (MD 1.00, 95% CI -2.49 to 4.49). (See  Analysis 8.7).

 

Vaginal pain

Radical diathermy was associated with statistically significant increased vaginal pain compared with LLETZ (MD 10.50, 95% CI 5.37 to 15.63). (See  Analysis 8.8).

 

Knife cone biopsy with or without haemostatic sutures

 

Primary haemorrhage

Meta-analysis of two trials (Gilbert 1989; Kristensen 1990), assessing 522 participants, showed no statistically significant difference in the risk of primary haemorrhage in women who received knife conisation with or without haemostatic sutures (RR 0.42, 95% CI 0.06 to 3.23). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent substantial heterogeneity (I2 = 69%). (See  Analysis 9.1).

 

Secondary haemorrhage

Meta-analysis of two trials (Gilbert 1989; Kristensen 1990), assessing 515 participants, found that knife cone biopsy with haemostatic sutures was associated with a statistically significant increase in the risk of secondary haemorrhage compared with using no sutures (RR 2.68, 95% CI 1.27 to 5.66). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 9.2).

 

Cervical stenosis at follow up

Meta-analysis of two trials (Gilbert 1989; Kristensen 1990), assessing 307 participants, showed no statistically significant difference in the risk of cervical stenosis in women who received knife conisation with or without haemostatic sutures (RR 1.75, 95% CI 0.65 to 4.72). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance may represent considerable heterogeneity (I2 = 91%). (See  Analysis 9.3).

 

Inadequate colposcopy at follow up

In the trial of Gilbert 1989, knife cone biopsy with haemostatic sutures was associated with a statistically significant increase in the risk of inadequate colposcopy compared with using no sutures (RR 2.32, 95% CI 1.59 to 3.39). (See  Analysis 9.4).

 

Dysmenorrhoea

Meta-analysis of two trials (Gilbert 1989; Kristensen 1990), assessing 277 participants, found that knife cone biopsy with haemostatic sutures was associated with a statistically significant increase in the risk of dysmenorrhoea compared with using no sutures (RR 2.50, 95% CI 1.41 to 4.45). The percentage of the variability in effect estimates that was due to heterogeneity rather than by chance was not important (I2 = 0%). (See  Analysis 9.5).

 

Bipolar electrocautery scissors versus monopolar energy scalpel

Only the trial of Cherchi 2002 reported data on bipolar electrocautery scissors versus a monopolar energy scalpel.

 

Peri-operative bleeding

Women who underwent surgery for LLETZ had statistically significant less peri-operative blood loss when the surgeon used bipolar electrocautery scissors compared to when the surgeon used a monopolar energy scalpel (MD -6.90, 95% CI -8.57 to -5.23). (See  Analysis 10.1).

 

Duration of procedure

Bipolar electrocautery scissors were associated with statistically significant reduced operative time for LLETZ than for the monopolar energy scalpel (MD -11.90, 95% CI -16.84 to -6.96). (See  Analysis 10.2).

 

Primary haemorrhage

There was no statistically significant difference between bipolar scissors and monopolar scalpel for LLETZ in the risk of primary haemorrhage (RR 0.11, 95% CI 0.01 to 1.94). (See  Analysis 10.3).

 

LEEP (loop electrosurgical excisional procedure) versus cryotherapy

Only the trial of Chirenje 2001 reported data on LEEP versus cryotherapy.

 

Residual disease at six months

There was no statistically significant difference in the risk of residual disease at six months in women who received either LEEP or cryotherapy (RR 0.55, 95% CI 0.22 to 1.37). (See  Analysis 11.1).

 

Residual disease at 12 months

There was a statistically significant decrease in the risk of residual disease at 12 months in women who received LEEP compared to those who received cryotherapy (RR 0.32, 95% CI 0.13 to 0.78). (See  Analysis 11.2).

 

Primary haemorrhage

There was no statistically significant difference in the risk of primary haemorrhage in women who received LEEP or cryotherapy (RR 4.00, 95% CI 0.45 to 35.47). (See  Analysis 11.3).

 

Secondary haemorrhage

There was a statistically significant increase in the risk of secondary haemorrhage in women who received LEEP compared to those who received cryotherapy (RR 1.98, 95% CI 1.62 to 2.41). (See  Analysis 11.4).

 

Offensive discharge

There was a statistically significant increase in the risk of offensive discharge in women who received LEEP compared to those who received cryotherapy (RR 1.16, 95% CI 1.02 to 1.31). (See  Analysis 11.5).

 

Watery discharge

There was a statistically significant decrease in the risk of watery discharge in women who received LEEP compared to those who received cryotherapy (RR 0.86, 95% CI 0.79 to 0.93). (See  Analysis 11.6).

 

Peri-operative severe pain

There was no statistically significant difference in the risk of peri-operative severe pain in women who received LEEP or cryotherapy (RR 1.00, 95% CI 0.14 to 7.03). (See  Analysis 11.7).

 

Pure cut setting versus blend setting when performing LLETZ (large loop excision of the transformation zone)

Only the trial of Nagar 2004 reported data on pure cut setting versus blend setting for LLETZ.

 

Residual disease at six months

There was no statistically significant difference in the risk of residual disease at six months in women whose surgeon used either pure cut or blend setting when they performed LLETZ (RR 1.70, 95% CI 0.31 to 9.27). (See  Analysis 12.1).

 

Depth of thermal artefact at deep stromal margin

There was a statistically significant shorter depth of thermal artefact at the deep stromal margin in women whose surgeon used pure cut for LLETZ than for women whose surgeon used the blend setting when they performed LLETZ (MD -0.06, 95% CI -0.10 to -0.02). (See  Analysis 12.2).

 

LLETZ (large loop excision of the transformation zone) versus NETZ (needle excision of the transformation zone)

 

Residual disease at 36 months

In the trial of Sadek 2000, there was a statistically significant increase in the risk of residual disease at 36 months in women who received LLETZ compared to those who received NETZ (RR 10.00, 95% CI 1.35 to 74.00). (See  Analysis 13.1).

 

Peri-operative pain

In the trial of Panoskaltsis 2004a, there was no statistically significant difference in the risk of perioperative pain between women who received LLETZ and those who received NETZ (RR 0.85, 95% CI 0.50 to 1.44). (See  Analysis 13.2).

 

Peri-operative blood loss interfering with treatment

In the trial of Panoskaltsis 2004a, there was a statistically significant decrease in the risk of peri-operative blood loss in women who received LLETZ compared to those who received NETZ (RR 0.32, 95% CI 0.14 to 0.73). (See  Analysis 13.3).

 

Bleeding requiring vaginal pack

In the trial of Panoskaltsis 2004a, there was no statistically significant difference in the risk of bleeding requiring a vaginal pack between women who received LLETZ and those who received NETZ (RR 0.14, 95% CI 0.01 to 2.75). (See  Analysis 13.4).

 

Cervical stenosis at follow up

In the trial of Panoskaltsis 2004a, there was no statistically significant difference in the risk of cervical stenosis between women who received LLETZ and those who received NETZ (RR 0.58, 95% CI 0.31 to 1.11). (See  Analysis 13.5).

 

Knife conisation versus NETZ (needle excision of the transformation zone)

 

Residual disease at 36 months

In the trial of Sadek 2000, there was no statistically significant difference in the risk of residual disease at 36 months between women who received knife conisation and those who received NETZ (RR 5.00, 95% CI 0.62 to 40.64). (See  Analysis 14.1).

 

LLETZ (large loop excision of the transformation zone) versus knife conisation

In the trial of Sadek 2000, there was no statistically significant difference in the risk of residual disease at 36 months between women who received LLETZ and those who received knife conisation (RR 2.00, 95% CI 0.76 to 5.25).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Summary of main results

(1) For double versus single freeze technique cryotherapy, the evidence suggests that cryotherapy should be used with a double freeze technique rather than single freeze in order to reduce the risk of residual disease within 12 months, although statistical significance was not reached. The single freeze technique had higher treatment failure rates.

(2) Laser ablation demonstrated no overall difference in residual disease after treatment for CIN compared with cryotherapy. Cryosurgery appears to have a lower success rate but the majority of authors used a single freeze thaw technique. Creasman (Creasman 1984) demonstrated that using a double freeze-thaw-freeze technique improves results towards those achieved by destructive and excisional methods. However, analysis of results demonstrated that there was no significant difference for the treatment of CIN1 and 2; laser ablation appeared to be better, but not significantly so, for treating CIN3. The clinician's choice of treatment of low grade disease must therefore be influenced by the side effects related to the treatments.
Laser ablation was associated with significantly fewer vasomotor symptoms and less malodorous discharge or inadequate colposcopy at follow up compared with cryotherapy. No other statistical differences were observed in any other side effects, although there may be more peri-operative pain and bleeding for laser ablation. Since the number of events was low, this needs to be explored further.

(3) Four trials compared laser conisation and knife conisation (Bostofte 1986; Kristensen 1990; Larsson 1982; Mathevet 1994). For the two trials that evaluated residual disease after laser conisation or knife conisation, no significant difference was observed between the two groups. There was also no evidence of a difference between the two interventions for primary and secondary haemorrhage. Significant thermal artefact prevented interpretation of resection margins in 38% of laser cones compared to none in the knife cones, which was statistically significant. Laser conisation produced significantly fewer inadequate colposcopes (transformation zone seen in its entirety) at follow up and cervical stenosis was significantly less common after this treatment.

(4) Only the trial of Partington 1989 compared laser conisation with laser ablation for ectocervical lesions. There was no significant difference with respect to residual disease at follow up, peri-operative severe bleeding, secondary haemorrhage or inadequate colposcopy at follow up.

(5) Six trials compared laser conisation with large loop excision of the transformation zone (LLETZ) (Crompton 1994; Mathevet 1994; Oyesanya 1993; Paraskevaidis 1994; Santos 1996; Vejerslev 1999). There was no significant difference with respect to residual disease at follow up, peri-operative severe pain, secondary haemorrhage, significant thermal artefact, inadequate colposcopy or cervical stenosis. However, laser conisation takes significantly longer to perform, has a significantly higher rate of perioperative bleeding and produces a greater depth of thermal artefact.

(6) Laser ablation compared to LLETZ was evaluated by four trials. Alvarez 1994 was included in the comparison but its methodology differed from the trials of Dey 2002, Gunasekera 1990 and Mitchell 1998. The Alvarez 1994 trial performed LLETZ on all the patients randomised to that group whereas laser ablation was only performed if colposcopic directed biopsies were performed. There was no difference in residual disease rates between the two treatments. There was no significant difference in the risk of primary or secondary haemorrhage or peri-operative severe pain.

(7) For knife cone biopsy compared to loop excision, (a) six randomised trials evaluated knife cone biopsy and loop excision (Duggan 1999, Giacalone 1999, Girardi 1994, Mathevet 1994, Sadek 2000, Takac 1999). The trials found that there was no evidence of a difference between the two interventions on residual disease rate.
(b) Measuring primary haemorrhage, the trials of Giacalone 1999, Duggan 1999, Mathevet 1994 found that there was no statistical difference in inadequate colposcopy rates between knife conisation and loop excision. There was also no clear evidence that there was any difference in primary haemorrhage or cervical stenosis rates.

(8) For radical diathermy versus LLETZ, there was no significant difference between these two modalities with regards to the side effects reported, with exception of significantly increased vaginal pain in those undergoing radical diathermy. Residual disease rates were not an outcome measure in the single trial identified.

(9) For haemostatic sutures, there was no evidence that haemostatic sutures were significantly different for the risk of primary haemorrhage or cervical stenosis compared to using no routine sutures or vaginal packing in the two included trials (Gilbert 1989; Kristensen 1990). Use of haemostatic sutures did however increase the risk of secondary haemorrhage, dysmenorrhoea and inadequate follow-up colposcopy.

(10) One trial compared the use of bipolar electrocautery scissors with a monopolar energy scalpel during LLETZ (Cherchi 2002). Bipolar electrocautery scissors were associated with a significant reduction in perioperative bleeding and duration of the procedure but no change in the rate of primary haemorrhage.

(11) One trial compared the use of LEEP versus cryotherapy (Chirenje 2001). This trial found that women who received the loop electrosurgical excisional procedure (LEEP) had significantly lower rates of watery discharge and residual disease at 12-month follow up but an increased risk of secondary haemorrhage and offensive discharge. There was no significant difference in the rates of primary haemorrhage, residual disease at six months or peri-operative severe pain.

(12) One trial compared pure cut settings versus blend settings for LLETZ (Nagar 2004) and found no significant difference in the rates of residual disease between the settings but a reduced depth of thermal artefact at the deep stromal margin in women whose surgeon used a pure cut setting for LLETZ.

(13) Two trials compared LLETZ and needle excision of the transformation zone (NETZ) (Panoskaltsis 2004a; Sadek 2000) but reported on different outcomes. There was no significant difference between the techniques in terms of perioperative pain, bleeding requiring vaginal packing or cervical stenosis at follow up. LLETZ was associated with a reduction in peri-operative blood loss but an increase in residual disease rates at 36-month follow up. There was no difference in residual disease rates for NETZ compared to knife conisation.

 

Overall completeness and applicability of evidence

The incidence of treatment failures following surgical treatment of CIN has been demonstrated by case series reports, as illustrated in the Background section, to be low. The reports from randomised and non-randomised studies suggest that most surgical treatments have around 90% success rate. In these circumstances, several thousand women would have to be treated to demonstrate a significant difference between two techniques. The vast majority of RCTs evaluating the differences in treatment success are grossly underpowered to demonstrate a significant difference between treatment techniques and no real conclusions can be drawn on differences of treatment effect. The largest of these studies recruited 498 participants (Mitchell 1998) and the smallest recruited 40 women (Cherchi 2002; Paraskevaidis 1994). It might be the case that if a well-conducted mega-trial was conducted no difference in treatment effect would be demonstrated. The RCTs and meta-analyses have demonstrated some clear differences in morbidity and these should be considered as significant outcomes when deciding upon optimum management.

The trials compare different interventions and report different outcomes, which limits the analyses and means that many outcome measures include only one trial per treatment pairing.

 

Quality of the evidence

In total, 29 trials were included in this review. A total of 5441 women participated of whom 4509 were analysed. We have used a pragmatic approach to the RCTs included in the comparisons. Slight variations of surgical technique occur in some of the comparisons, which reflects the differences in clinical practice. If we considered that these differences did not seriously alter the intervention compared with the other interventions in the comparison, then the trial was considered in the same analysis. For example, when we compared laser ablation to cryotherapy, we included trials using single and double freeze techniques.

Many analyses included only one or two randomised trials due to the different outcome measures chosen and reported in the trials. This limits the conclusions which may be drawn from some of the analyses. Furthermore, the method of randomisation in many of the trials was not optimised so that the results might be prone to bias due to inherent methodological flaws in these trials.

 

Potential biases in the review process

A comprehensive search was performed, including a thorough search of the grey literature, and all studies were sifted and data extracted by at least two review authors working independently. We restricted the included studies to RCTs as they provide the strongest level of evidence available. Hence, we have attempted to reduce bias in the review process.

The greatest threat to the validity of the review is likely to be the possibility of publication bias. That is, studies that did not find the treatment to be effective may not have been published. We were unable to assess this possibility as the analyses were restricted to meta-analyses of a small number of trials or single trials.

 

Agreements and disagreements with other studies or reviews

The conclusions reflect the previous findings from the original Cochrane review by the authors. Furthermore, a Canadian group published an independent systematic review on the same subject and the findings were the same as the original review (Nuovo 2000). The review by Nuovo 2000 used similar methodologies as the original Cochrane review and used quasi-randomised trials as well as gold standard RCTs within their meta-analyses.

The single RCT by Dey 2002 almost demonstrated a significant reduction in treatment failures with LLETZ compared to laser ablation, in contrast to other studies. This trial included HPV testing as well as cytology for screening for treatment failures, which enhances the detection of disease.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice

The evidence from the 29 RCTs identified suggests that there is no overwhelmingly superior surgical technique for eradicating CIN. Cryotherapy appears to be an effective treatment of low grade disease but not of high grade disease.
Choice of treatment of ectocervical situated lesions must therefore be based on cost, morbidity and whether excisional treatments provide more reliable biopsy specimens for assessment of disease compared to colposcopic directed specimens taken before ablative therapy. Colposcopic directed biopsies have been shown to under diagnose micro-invasive disease compared with excisional biopsies performed by knife or loop excision, particularly if high grade disease is present (Anderson 1986; Chappatte 1991). However, the accuracy of colposcopic directed biopsies compared to excisional biopsies is not the objective of this review.

Cryotherapy is easy to use, cheap and, as demonstrated, associated with low morbidity. It should be considered a viable alternative for the treatment of low grade disease, particularly where resources are limited.

Laser ablation appears to cause more peri-operative severe pain and perhaps more primary and secondary haemorrhage compared to loop excision. The trials with adequate randomisation methods suggest that there is no difference in residual disease between the two treatments. It could be suggested that LLETZ is superior as equipment is cheaper and it also permits confirmation of disease status by providing an excision biopsy.

Laser conisation takes longer to perform, requires greater operative training and more expensive investment in equipment, produces more peri-operative pain, greater depth and severe thermal artefact than loop excision. Therefore, the use of LLETZ may be preferred rather than laser excision unless the lesion is endocervical. In this situation, a narrow and deep cone biopsy can be performed, reducing tissue trauma and providing a clear resection margin.

Knife cone biopsy still has a place if invasion or glandular disease is suspected. In both diseases adequate resection margins that are free of disease are important for prognosis and management. In such cases, LLETZ or laser conisation can induce thermal artefact so that accurate interpretation of margins is not possible.

 
Implications for research

We would advocate a large multi-centre trial of sufficient power to evaluate whether ablation is as effective as LLETZ in terms of treatment failures. A systematic review (Kyrgiou 2004) of pre-term delivery rates after treatment suggests that there is a higher rate after excisional treatment compared to ablation. The single RCT by Dey 2002 suggests that ablation is associated with higher failure rates after treatment. A definitive RCT of ablation compared with LLETZ, to see if the two modalities have similar outcomes, is needed. If one modality has genuinely poorer treatment outcomes, this might influence decision making based on pregnancy outcomes.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

The authors would like to thank Sarah Keep for her contribution on previous versions of this review.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
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Comparison 1. Single freeze cryotherapy versus double freeze cryotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual Disease within 12 months1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 2. Laser ablation versus cryotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual Disease (All Grades of CIN)6935Risk Ratio (IV, Random, 95% CI)1.13 [0.73, 1.76]

 2 Residual Disease (CIN1, CIN2, CIN3)4567Risk Ratio (IV, Random, 95% CI)1.51 [0.91, 2.51]

    2.1 CIN1
473Risk Ratio (IV, Random, 95% CI)2.75 [0.68, 11.11]

    2.2 CIN2
4289Risk Ratio (IV, Random, 95% CI)1.37 [0.65, 2.88]

    2.3 CIN3
4205Risk Ratio (IV, Random, 95% CI)1.38 [0.62, 3.09]

 3 Peri-operative Severe Pain3493Risk Ratio (IV, Random, 95% CI)2.00 [0.64, 6.27]

 4 Peri-operative Severe Bleeding2305Risk Ratio (IV, Random, 95% CI)5.83 [0.71, 47.96]

 5 Vaso-motor Symptoms1Risk Ratio (IV, Random, 95% CI)Subtotals only

 6 Malodorous Discharge2400Risk Ratio (IV, Random, 95% CI)0.30 [0.12, 0.77]

 7 Inadequate Colposcopy at Follow-up2272Risk Ratio (IV, Random, 95% CI)0.38 [0.26, 0.56]

 8 Cervical Stenosis at Follow-up2464Risk Ratio (IV, Random, 95% CI)1.45 [0.45, 4.73]

 
Comparison 3. Laser conisation versus knife conisation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual Disease (All Grades of CIN)2194Risk Ratio (IV, Random, 95% CI)0.64 [0.22, 1.90]

 2 Primary Haemorrhage2306Risk Ratio (IV, Random, 95% CI)0.53 [0.18, 1.54]

 3 Secondary Haemorrhage3359Risk Ratio (IV, Random, 95% CI)0.91 [0.34, 2.40]

 4 Inadequate Colposcopy at Follow-up2160Risk Ratio (IV, Random, 95% CI)0.57 [0.39, 0.81]

 5 Cervical Stenosis at Follow-up41007Risk Ratio (IV, Random, 95% CI)0.38 [0.19, 0.76]

 6 Significant Thermal Artifact Prohibiting Interpretation of Resection Margin1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 4. Laser conisation versus laser ablation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual Disease (All Grades of Disease)1Risk Ratio (IV, Random, 95% CI)Subtotals only

 2 Peri-operative Severe Bleeding1Risk Ratio (IV, Random, 95% CI)Subtotals only

 3 Secondary Haemorrhage1Risk Ratio (IV, Random, 95% CI)Subtotals only

 4 Inadequate Colposcopy at Follow-up1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 5. Laser conisation versus loop excision

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual Disease4889Risk Ratio (IV, Random, 95% CI)1.24 [0.77, 1.99]

 2 Duration of Procedure3419Mean Difference (IV, Random, 95% CI)11.66 [1.37, 21.95]

 3 peri-operative severe bleeding1Risk Ratio (IV, Random, 95% CI)Subtotals only

 4 Peri-operative Severe Pain2594Risk Ratio (IV, Random, 95% CI)4.34 [0.25, 75.67]

 5 Secondary Haemorrhage4889Risk Ratio (IV, Random, 95% CI)1.41 [0.72, 2.76]

 6 Significant Thermal Artefact on Biopsy2373Risk Ratio (IV, Random, 95% CI)2.38 [0.61, 9.34]

 7 Depth of Thermal Artifact1Mean Difference (IV, Random, 95% CI)Subtotals only

 8 Inadequate Colposcopy2339Risk Ratio (IV, Random, 95% CI)1.38 [0.48, 3.97]

 9 Cervical Stenosis3560Risk Ratio (IV, Random, 95% CI)1.21 [0.57, 2.57]

 10 Vaginal discharge1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 6. Laser ablation versus loop excision

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual Disease3911Risk Ratio (IV, Random, 95% CI)1.15 [0.59, 2.25]

 2 Peri-operative Severe Pain1281Risk Ratio (IV, Random, 95% CI)0.38 [0.02, 7.91]

 3 Primary Haemorrhage2560Risk Ratio (IV, Random, 95% CI)0.35 [0.04, 3.14]

 4 Secondary Haemorrhage2560Risk Ratio (IV, Random, 95% CI)0.54 [0.14, 2.10]

 
Comparison 7. Knife conisation versus loop excision

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual Disease3279Risk Ratio (IV, Random, 95% CI)0.47 [0.20, 1.08]

 2 Primary Haemorrhage2306Risk Ratio (IV, Random, 95% CI)1.04 [0.45, 2.37]

 3 Inadequate Colposcopy at Follow-up3291Risk Ratio (IV, Random, 95% CI)1.63 [0.85, 3.15]

 4 Cervical Stenosis3251Risk Ratio (IV, Random, 95% CI)1.12 [0.44, 2.84]

 
Comparison 8. Radical diathermy versus LLETZ

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of blood loss1Mean Difference (IV, Random, 95% CI)Subtotals only

 2 Blood stained / watery discharge1Mean Difference (IV, Random, 95% CI)Subtotals only

 3 Yellow discharge1Mean Difference (IV, Random, 95% CI)Subtotals only

 4 White discharge1Mean Difference (IV, Random, 95% CI)Subtotals only

 5 Upper Abdominal Pain1Mean Difference (IV, Random, 95% CI)Subtotals only

 6 Lower Abdominal Pain1Mean Difference (IV, Random, 95% CI)Subtotals only

 7 Deep Pelvic Pain1Mean Difference (IV, Random, 95% CI)Subtotals only

 8 Vaginal Pain1Mean Difference (IV, Random, 95% CI)Subtotals only

 
Comparison 9. Knife cone biopsy: haemostatic sutures versus none

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Primary Haemorrhage2522Risk Ratio (IV, Random, 95% CI)0.42 [0.06, 3.23]

 2 Secondary Haemorrhage2515Risk Ratio (IV, Random, 95% CI)2.68 [1.27, 5.66]

 3 Cervical Stenosis2307Risk Ratio (IV, Random, 95% CI)1.75 [0.65, 4.72]

 4 Inadequate Colposcopy at Follow-up1Risk Ratio (IV, Random, 95% CI)Subtotals only

 5 Dysmenorrhoea2277Risk Ratio (IV, Random, 95% CI)2.50 [1.41, 4.45]

 
Comparison 10. Bipolar electrocautery scissors versus monopolar energy scalpel

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Peri-operative bleeding1Mean Difference (IV, Random, 95% CI)Subtotals only

 2 Duration of procedure1Mean Difference (IV, Random, 95% CI)Subtotals only

 3 Primary haemorrhage1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 11. LEEP versus cryotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual disease at 6 months1Risk Ratio (IV, Random, 95% CI)Subtotals only

 2 Residual disease at 12 months1Risk Ratio (IV, Random, 95% CI)Subtotals only

 3 Primary haemorrhage1Risk Ratio (IV, Random, 95% CI)Subtotals only

 4 Secondary haemorrhage1Risk Ratio (IV, Random, 95% CI)Subtotals only

 5 Offensive discharge1Risk Ratio (IV, Random, 95% CI)Subtotals only

 6 Watery discharge1Risk Ratio (IV, Random, 95% CI)Subtotals only

 7 Peri-operative severe pain1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 12. Pure cut setting versus blend setting when performing LLETZ

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual disease at 6 months1Risk Ratio (IV, Random, 95% CI)Subtotals only

 2 Depth of thermal artefact at deep stromal margin1Mean Difference (IV, Random, 95% CI)Subtotals only

 
Comparison 13. LLETZ versus NETZ

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual disease at 36 months1Risk Ratio (IV, Random, 95% CI)Subtotals only

 2 Peri-operative pain1Risk Ratio (IV, Random, 95% CI)Subtotals only

 3 Peri-operative blood loss interfering with treatment1Risk Ratio (IV, Random, 95% CI)Subtotals only

 4 Bleeding requiring vaginal pack1Risk Ratio (IV, Random, 95% CI)Subtotals only

 5 Cervical stenosis at follow-up1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 14. Knife conisation versus NETZ

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual disease at 36 months1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 15. LLETZ versus Knife conisation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Residual disease at 36 months1Risk Ratio (IV, Random, 95% CI)Subtotals only

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. MEDLINE search strategy

Medline Ovid

1   exp Cervical Intraepithelial Neoplasia/
2   CIN.mp.
3   (cervi* and (intraepithel* or epithel*)).mp.
4   (cervi* and dysplasia).mp.
5   (cervi* and carcinoma in situ).mp.
6   (cervi* and cancer in situ).mp.
7   (cervi* and (precancer* or pre-cancer*)).mp.
8   1 or 2 or 3 or 4 or 5 or 6 or 7
9   randomized controlled trial.pt.
10 controlled clinical trial.pt.
11 randomized.ab.
12 placebo.ab.
13 clinical trials as topic.sh.
14 randomly.ab.
15 trial.ti.
16 9 or 10 or 11 or 12 or 13 or 14 or 15
17 (animals not (humans and animals)).sh.
18 16 not 17
19 8 and 18

 key: mp=title, original title, abstract, name of substance word, subject heading word
      pt=publication type
      sh=Medical Subject Heading (Mesh)

 

Appendix 2. Embase search strategy

EMBASE Ovid 1

  1. exp Uterine Cervix Carcinoma in Situ/
  2. CIN.mp.
  3. (cervi* and (intraepithel* or epithel*)).mp.
  4. (cervi* and dysplasia).mp.
  5. (cervi* and carcinoma in situ).mp.
  6. (cervi* and cancer in situ).mp.
  7. (cervi* and (precancer* or pre-cancer*)).mp.
  8. 1 or 2 or 3 or 4 or 5 or 6 or 7
  9. Randomized Controlled Trial/
  10. Crossover Procedure/
  11. Double Blind Procedure/
  12. Single Blind Procedure/
  13. random*.mp.
  14. factorial*.mp.
  15. (crossover* or cross over* or cross-over*).mp.
  16. placebo*.mp.
  17. (doubl* adj blind*).mp.
  18. (singl* adj blind*).mp.
  19. assign*.mp.
  20. allocat*.mp.
  21. volunteer*.mp.
  22. or/9-21
  23. 8 and 22
  24. limit 23 to yr="1997 - 2009"

key:  mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name

 

Appendix 3. Central search strategy

CENTRAL Issue 2, 2009

  1. MeSH descriptor Cervical Intraepithelial Neoplasia explode all trees
  2. CIN
  3. cervi* and (intraepithel* or epithel*)
  4. cervi* and dysplasia
  5. cervi* and carcinoma in situ
  6. cervi* and cancer in situ
  7. cervi* and (precancer* or pre-cancer*)
  8. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
  9. (#8), from 1997 to 2009

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 23 November 2012.


DateEventDescription

26 February 2014AmendedContact details updated.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Review first published: Issue 4, 1998


DateEventDescription

2 December 2013AmendedAuthor citation amended.

18 November 2013New citation required but conclusions have not changedNo new studies identified for inclusion.

23 November 2012New search has been performedLiterature searches re-run.

11 May 2010New citation required but conclusions have not changedReview updated to reflect new Cochrane methodology and authorship.

19 May 1999New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Pierre Martin-Hirsch contributed to the original review and sifting, preparation and discussions of the updates. Andrew Bryant and Heather Dickinson updated the review in 2010.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Department of Health, UK.
    NHS Cochrane Collaboration programme Grant Scheme CPG-506

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Restriction to RCTs

We restricted the review to RCTs in the update so quasi-randomised trials included in the original review were excluded.

Other types of surgical interventions for CIN, other than those specified in the protocol were also considered as relevant trials were found. We also compared variations in technique within a single intervention (for example blend versus cut setting for LLETZ, single versus double freeze cryotherapy).

There was an insufficient number of trials in each of the meta analyses to assess reporting biases and carry out sensitivity analysis so the following sections were removed:

 

Assessment of reporting biases  

Funnel plots corresponding to meta-analysis of the primary outcome will be examined to assess the potential for small study effects such as publication bias. If these plots suggest that treatment effects may not be sampled from a symmetric distribution, as assumed by the random effects model, further meta-analyses will be performed using a fixed-effect model.

 

Sensitivity analysis  

Sensitivity analyses will be performed excluding trials which did not report adequate concealment of allocation.

None of the trials imputed missing data. Although some of the outcomes that we specified were not reported in included trials, we did not contact trial authors as all trials reported over five years ago and most significantly longer. We removed the following text from the 'dealing with missing data' section:

 

Dealing with missing data

If data were missing or only imputed data were reported we contacted trial authors to request data on the outcomes only among participants who were assessed.

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
Alvarez 1994 {published data only}
  • Alvarez R, Helm W, Edwards P, Naumann W, Partridge E, Shingleton H, et al. Prospective randomised trial of LLETZ versus laser ablation in patients with cervical intra-epithelial neoplasia. Gynecologic Oncology 1994;52:175-9.
Berget 1987 {published data only}
Bostofte 1986 {published data only}
  • Bostofte E, Berget A, Falck Larsen J, Pedersen H, Rank F. Conisation by carbon dioxide or cold knife in the treatment of cervical intra-epithelial neoplasia. Acta Obstetricia et Gynecologica Scandinavica 1986;65:199-202.
Cherchi 2002 {published data only}
  • Cherchi P L, Capobianco G, Ambrosini G, Fadda GM, Piga MD, Canetto AM, et al. Utility of bipolar electrocautery scissors for cervical conization. European Journal of Gynaecological Oncology 2002; Vol. 23, issue 2:154-6.
Chirenje 2001 {published data only}
  • Chirenje ZM, Rusakaniko S, Akino V, Mlingo M. A randomised clinical trial of loop electrosurgical excision procedure (LEEP) versus cryotherapy in the treatment of cervical intraepithelial neoplasia. Journal of Obstetrics and Gynaecology 2001; Vol. 21, issue 6:617-21.
Crompton 1994 {published data only}
Dey 2002 {published data only}
Duggan 1999 {published data only}
  • Duggan B, Felix J, Muderspach L, Gebhardt J, Groshen S, Morrow P, et al. Cold-Knife conization versus conization by loop electrosurgical excision procedure: a randomized, prospective study. American Journal of Obstetrics and Gynecology 1999;180:276-82.
Giacalone 1999 {published data only}
  • Giacalone PL, Laffargue F, Aligier N, Roger P, Combecal J, Daures JP. Randomized study comparing two techniques of conization: cold knife versus loop excision. Gynecologic Oncology 1999;75(3):356-60.
Gilbert 1989 {published data only}
  • Gilbert L, Sunders N, Stringer R, Sharp F. Hemostasis and cold knife cone biopsy: a prospective randomized trial comparing a suture versus non-suturing technique. Obstetrics and Gynecology 1989;74:640-3.
Healey 1996 {published data only}
  • Healey M, Warton B, Taylor N. Postoperative symptoms following LLETZ of radical cervical diathermy with fulguration: A randomised double-blind study. The Australian & New Zealand Journal of Obstetrics & Gynaecology 1996;36:179-81.
Jobson 1984 {published data only}
  • Jobson V, Homesley H. Comparison of cryosurgery and carbon dioxide laser ablation for the treatment of CIN. Colposcopy and Gynecologic Laser Surgery 1984;1:173-80.
Kirwan 1985 {published data only}
Kristensen 1990 {published data only}
  • Kristensen G, Jensen L, Holund B. A randomised trial comparing two methods of cold knife conisation with laser conisation. Obstetrics and Gynecology 1990;76:1009-13.
Kwikkel 1985 {published data only}
  • Kwikkel H, Helmerhorst T, Bezemer P, Quaak M, Stolk J. Laser or cryotherapy for cervical intra-epithelial neoplasia: a randomised study to compare efficacy and side effects. Gynecologic Oncology 1985;22:23-31.
Larsson 1982 {published data only}
Mathevet 1994 {published data only}
  • Mathevet P, Chemali E, Roy M, Dargent D. Long-term outcome of a randomized study comparing three techniques of conization: cold knife, laser, and LEEP. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2003; Vol. 106, issue 2:214-8.
  • Mathevet P, Dargent D, Roy M, Beau G. A randomised prospective study comparing three techniques of conisation: cold knife, laser, and LEEP. Gynecologic Oncology 1994;54:175-9.
Mitchell 1998 {published data only}
  • Mitchell M, Tortolero-Luna G, Cook E, Whittaker L, Rhodes-Morris H, Silva E. A randomized clinical trial of cryotherapy, laser vaporization and loop electrosurgical excision for the treatment of squamous intra-epithelial lesions of the cervix. Obstetrics and Gynaecology 1998;92:737-44.
Nagar 2004 {published data only}
  • Nagar HA, Dobbs SP, McClelland HR, Price JH, McClean G, McCluggage WG. The large loop excision of the transformation zone cut or blend thermal artefact study: a randomized controlled trial. International Journal of Gynecological Cancer 2004; Vol. 14, issue 6:1108-11.
Oyesanya 1993 {published data only}
  • Oyesanya O, Amersinghe C, Manning E. Out patient excisional management of cervical Intra-epithelial neoplasia: A prospective randomized comparison between loop diathermy excision and laser excisional conisation. American Journal of Obstetrics and Gynecology 1993;168:485-8.
Panoskaltsis 2004a {published data only}
  • Panoskaltsis T, Ind TE, Perryman K, Dina R, Abrahams Y, Soutter WP. Needle versus loop diathermy excision of the transformation zone for the treatment of cervical intraepithelial neoplasia: a randomised controlled trial. BJOG 2004; Vol. 111, issue 7:748-53.
Paraskevaidis 1994 {published data only}
  • Paraskevaidis E, Kichener H, Malamou-Mitsi V, Agnanti N, Lois D. Thermal tissue damage following laser and large loop conisation of the cervix. Obstetrics and Gynecology 1994;84:752-4.
Partington 1989 {published data only}
  • Partington C, Turner M, Soutter W, Griffiths, Krausz T. Laser vaporization versus laser excision conisation in the treatment of cervical intraepithelial neoplasia. Obstetrics and Gynecology 1989;73:775-9.
Sadek 2000 {published data only}
  • Sadek A L, Istre O Trolle G B. A randomized prospective study of cold knife, large loop excision and needle excision of the transformation zone for treatment of cervical intraepithelial neoplasia. 26th FIGO World Congress of Obstetrics and Gynecology; Sept 3-8 2000; Washington DC 2000; Vol. Book 3:60, Abstract FC3.23.06.
Santos 1996 {published data only}
  • Santos C, Galdos R, Alvarez M, Velarde C, Barriga O, Dyer R, et al. One-session management of cervical intraepithelial neoplasia: A solution for developing countries. Gynecologic Oncology 1996;61:11-5.
Schantz 1984 {published data only}
  • Schantz A, Thormann L. Cryosurgery for Dysplasia of the uterine ectocervix. Acta Obstetricia et Gynecologica Scandinavica 1984;63:417-20.
Takac 1999 {published data only}
Townsend 1983 {published data only}
Vejerslev 1999 {published data only}
  • Vejerslev LO, Schouenborg L, Sørensen F, Nielsen D, Sørensen SS, Juhl BR, et al. Loop diathermy or laser excisional conization for cervical intraepithelial neoplasia. Acta Obstetricia et Gynecologica Scandinavica 1999; Vol. 78, issue 10:900-5.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
Bar-AM 2000 {published data only}
  • Bar-Am A, Daniel Y, Ron IG, Niv J, Kupferminc MJ, Bornstein J, Lessing JB. Combined colposcopy, loop conization, and laser vaporization reduces recurrent abnormal cytology and residual disease in cervical dysplasia. Gynecologic Oncology 2000;78(1):47-51.
Boardman 2004 {published data only}
  • Boardman LA, Steinhoff MM, Shackelton R, Weitzen S, Crowthers L. A randomized trial of the Fischer cone biopsy excisor and loop electrosurgical excision procedure. Obstetrics and Gynecology 2004;104(4):745-50.
Ferenczy 1985 {published data only}
Gentile 2001 {published data only}
  • Gentile G, Tallarini A. Ablative techniques in the treatment of cervical lesions. Tumori 2001;87 Suppl(5):12.
Girardi 1994 {published data only}
  • Girardi F, Heydarfadai M, Koroschetz F, Pickel H, Winter R. Cold-knife conisation versus loop excision: histolopathologic and clinical results of a randomised trial. Gynecologic Oncology 1994;55:368-70.
Gunasekera 1990 {published data only}
  • Gunasekera C, Phipps J, Lewis B. Large loop excision of the transformation zone (LLETZ) compared to carbon dioxide treatment of CIN: a superior mode of treatment. British Journal of Obstetrics and Gynaecology 1990;97:995-8.
Lisowski 1999 {published data only}
  • Lisowski-P, Knapp-P, Zbroch-T, Kobylec-M, Knapp-P. The effectiveness of conservative treatment of cervical lesions using the LLETZ and CO2 laser. Przeglad Lekarski 1999;56:72-5.
O'Shea 1986 {published data only}
  • O'Shea R, Need J, Pomeroy G. Cryotherapy versus electrocoagulation diathermy for cervical intraepithelial neoplasia- a prospective randomised trial. Colposcopy and Gynecologic Laser Surgery 1986;2(3):159-61.
Panoskaltsis 2004b {published data only}
Singh 1988 {published data only}
  • Singh P, Loke K, Hii J, Sabaratnam A, Lim-Tan S, Kitchener H, et al. Cold coagulation versus cryotherapy for treatment of cervical intraepithelial neoplasia: results of a prospective randomized trial. Colposcopy and Gynecologic Laser Surgery 1988;4(4):211-21.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
Anderson 1986
  • Anderson M. Are we vaporizing microinvasive lesions?. RCOG Perinatology Press 1986;1:127-31.
Benedet 1981
  • Benedet J, Nickerson K, White G. Laser therapy for cervical intraepithelial neoplasia. Obstetrics and Gynecology 1981;57:188.
Bigrigg 1990
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