A substantive amendment to this systematic review was last made on 13 August 1998. Cochrane reviews are regularly checked and updated if necessary.Current treatment for cervical intra-epithelial neoplasia 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 now not the preferred treatment of choice as various more conservative local ablative and excisional therapies can be performed in an out-patient setting.Background and objectives: Cervical intra-epithelial neoplasia is treated by local ablation or lower morbidity excision techniques. Choice of treatment depends on the severity of the disease. The objective of this review was to assess the effects of alternative surgical treatments for cervical intra-epithelial neoplasia.
Search strategy: We searched the Cochrane Gynaecological Cancer Group trials register and Medline up to July 1997.
Selection criteria: Randomised and quasi-randomised trials of alternative surgical treatments in women with cervical intra-epithelial neoplasia.
Data collection and analysis: Trial quality was assessed and two reviewers abstracted data independently.
Main results: Twenty-two trials were included. Seven surgical techniques were tested in various comparisons. No significant difference in eradication of disease was shown, other than between laser ablation and loop excision. This was based on one trial where the quality of randomisation was doubtful. Large loop excision of the transformation zone appeared to provide the most reliable specimens for histology. Morbidity was lower than with laser conisation, although all five trials did not provide data for every outcome. There were not enough data to assess the effect on morbidity compared with laser ablation.
Reviewers conclusions: The evidence suggests that there is no obviously superior surgical technique for treating cervical intra-epithelial neoplasia.
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/destruction of the transformation zone. Incomplete excision/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 (Luesley 1985, Jordan 1984, Leiman G 1980). 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 this. 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.
Treatment success (i.e. no residual disease on follow-up) of knife cone biopsy is reported as 90-94% (Bostofte 1986, Tabor 1990, Larson 1983) 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 to complete the endocervical incision. Haemostasis if required is generally achieved by laser coagulation by defocussing the beam. A disadvantage of laser conisation is that the cone biopsy specimen might suffer from thermal damage making histological evaluation of margins impossible.
Treatment success of laser cone biopsy is reported as 93-96% (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 knife cut cones.
Loop Excision of The Transformation Zone:
Large Loop Excision of the Transformation Zone is often abbreviated to LLETZ in the U.K. or LEEP (Loop Electrosurgical Excisional Procedure) in the U.S.A.. 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 an coagulation effect simultaneously. Power should be sufficient to excise tissue without causing thermal artefact. The procedure can be performed under local analgesia.
Treatment success of LLETZ is reported as 97.4% Murdoch (1984), Prendeville 98% (1989), Bigrigg 95.9% (1990), Luesley 95.9% (1990), Whiteley 94.9% (1990), Murdoch 91%(1992) and Wright 94% (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% Wright (1984) and Jordan 96% (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 sub-lethal 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% Kauffman (1978), 84% Ostergard (1980), 93% Popkin (1978).
Utilising a DOUBLE freeze-thaw-freeze technique improves the reliability 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.
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 been generally evaluated by 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 thus reducing selection bias and providing more reliable results. Randomised trials are the only reliable and valid method of generating truly comparable comparison groups.
2..To assess the characteristics and morbidity associated with different therapies with regards to
a) duration of treatment
b) peri-operative pain
c) peri-operative bleeding, prmary and secondary haemorrhage
d) Depth and presence of thermal artifact
e) Adequate colposcopy at follow-up
f) Cervical Stenosis at follow-up
2..Charactersitics and Morbidity
a) duration of treatment
b) peri-operative severe pain
c) peri-operative severe bleeding, primary and secondary haemorrhage
d) Depth and presence of thermal artifact
e) Adequate colposcopy at follow-up
f) Cervical Stenosis at follow-up
See: Collaborative Review Group search strategy
A computerised Medline search was conducted to identify all registered randomised trials comparing surgical treatments for CIN before July 1997Sixteen journals thought to be most likely to contain relevant publications were hand searched, (Acta Cytologica, Acta Obstetrica Gynecologica Scandanavia, Acta Oncologica, American Journal of Obstetrics and Gynaecology, British Journal of Cancer, British Journal of Obstetrics and Gynaecology, British Medical Journal, Cancer, Cytopathology, Diagnostic Cytopathology, Gynaecologic Oncology, International Journal of Cancer, International Journal of Gynaecological Cancer, Journal of Family Practice, Lancet, Obstetrics and Gynaecology).
Randomised controlled trials were analysed for the method of randomisation, inclusion criteria, number of women included, treatment intervention (and variations in technique), duration of follow-up and out-comes residual disease and morbidity.1) Laser Ablation compared with Cryotherapy
a) Residual Disease
Six RCTs reported the incidence of residual disease. The study by Berget (1991) used the same group of patients as the study by Berget (1987) hence the former publication was used in the analysis as it contained longer and more consistent follow-up data. None of the trials produced results that reached statistical significance. Meta-analysis failed to demonstrate a significant difference between the two treatments OR 1.15 95% CI(0.74-1.78)
Stratification of disease revealed an apparent significant difference between the two treatment options when treating CIN1 OR 3.33 95%CI (1.1-10.1), and a non-significant difference for CIN2 OR 1.58 95% CI(0.69-3.2) and CIN3 OR 0.7 95% CI(0.34-1.47).
b) Peri-operative Severe Pain
Laser ablation was associated with a higher incidence of severe peri-operative severe pain OR 2.38 95% CI(0.9 -6.28).
c) Peri-operative Severe Bleeding
Laser ablation was associated with significantly more peri-operative severe bleeding OR 7.45 95% CI(1.68-33).
d) Vaso-motor Symptoms
One study by Townsend (1983) reported the incidence of vaso-motor symptoms (principally light headedness). Cryosurgery caused significantly more symptoms OR 0.11 95% CI(0.04-0.28).
e) Malodorous Discharge
Two trials (Berget 1987 and Townsend 1983) provided sufficient data to allow analysis of the incidence of malodorous vaginal discharge. Laser ablation caused significantly less symptoms OR 0.23 95%CI (0.15-0.35)
f) Adequate Colposcopy
Three studies (Berget 1987, Jobson 1984 and Ferenczy 1985) reported on adequate colposcopy at follow-up in the two treatment groups. Laser Ablation was associated with a significantly higher adequate colposcopy rate compared to cryosurgery OR 4.64 95% CI (2.98-7.27).
g) Cervical Stenosis
Berget (1987) reported on the incidence of cervical stenosis. Laser ablation was associated with higher rate of cervical stenosis but not significantly so when compared to cryotherapy OR 1.96 95% CI(0.52-7.44) .
2) Laser Conisation compared with Knife Conisation
a) Residual Disease (All Grades)
In the two trials (Bostofte 1986 and Methevet 1994), the direction of effect suggested that there was more residual disease in the knife cone group but no conclusions can be made as the confidence intervals are wide OR 0.63 95% CI(0.2-1.93).
b) Primary Haemorrhage
Two trials reported data on primary haemorrhage (Bostofte 1986 and Kristensen 1990). The incidence of secondary haemorrhage in cone biopsies performed with and without Sturmdorf sutures were combined. Laser conisation was associated with a lower incidence of primary haemorrhage OR 0.51 95% CI( 0.23-1.16).
c) Secondary Haemorrhage
Three trials (Kristensen 1990, Larsson 1982, Mathevet 1994) reported on secondary haemorrhage. They produced heterogenous results. There was no significant difference OR 0.81 95% CI (0.35-1.86).
d) Cervical Stenosis at Follow-up
Two trials ( Bostofte 1986, Malthevet 1994) reported on satisfactory colposcopy at follow-up examination. Laser conisation produced a significantly higher adequate colposcopy rate OR 2.73 95% CI(1.47-5.08).
e) Cervical Stenosis at Follow-up
Four Trials (Bostofte 1986, Kristensen 1990, Larsson 1982, Mathevet 1994) reported on cervical stenosis at follow-up. All trials demonstrated the same direction of effect. Laser conisation resulted in significantly less cervical stenosis at follow-up examination OR 0.39 95% CI (0.25-0.61).
f) Ectocervical and Endocervical Margins with Disease
One trial Mathevet (1994) reported on the presence of thermal artifact prohibiting interpretation of resection margins. As expected knife cone biopsy produced no such cases compared to 14 out of 37 laser cones OR 11.4 95% CI (3.54-36).
3) Laser Conisation compared with Laser Ablation
a) Residual Disease (All Grades)
Only one trial (Partington 1989) reported on this outcome. There was no significant difference demonstrated OR 0.73 95% CI(0.19-2.87)
b) Significant Peri-operative Bleeding
Only one trial (Partington 1989) reported on this outcome. There was no significant difference demonstrated OR 1.55 95% CI (0.42-5.7)
c) Secondary Haemorrhage
Only one trial (Partington 1989) reported on this outcome. There was no significant difference demonstrated OR 2.17 95%CI (0.73-6.48)
d) Adequate Colposcopy at Follow-up
Only one trial (Partington 1989) reported on this outcome. Laser ablation appeared to produce more adequate colposcopies at follow -up than laser conisation OR 0.25 95% CI (0.06-1.27).
4) Laser Conisation compared to LLETZ
a) Residual disease
Three trials reported on residual disease at follow-up (Mathevet 1994, Oyesanya 1993, Santos 1996). They produced heterogenous results. The largest trials by Oyesanya and Santos demonstrated more residual disease in the laser conisation group, but this just failed to achieve significance. The final meta-analysis was OR 1.22 95% (0.71-2.12)
b) Duration of Procedure
Three studies measured the duration of treatment (Crompton 1994, Oyesanya 1993, Paraskevaidis 1994). All demonstrated a significant increased difference in operating time WMD 11.76 95% CI (10.6-12.9).
c) Peri-operative Severe Pain
Oyesanya (1993) demonstrated that there were significantly more women complaining of severe pain during laser conisation. OR 7.81 95% (2.03-29.3). However the trial by Santos (1996) did not demonstrate any significant difference. There was insufficient data in the trial by Crompton (1994) to include in the analysis, their assessment of pain by linear analogue scales did not demonstrate any difference in pain scores. The final meta-analysis was OR 5.36 95%CI (1.02-17.2).
d) Secondary Haemorrhage
The trials did not demonstrate any significant difference OR 0.89 95% CI (0.34-2.34).
e) Significant Thermal Artifact
Methevet (1994) and Oyesanya (1993) demonstrated significantly more thermal artefact in laser cone biopsy specimens OR 2.82 95%CI (1.56-5.1).
f) Depth of Thermal Artifact
Paraskevaidis (1994) demonstrated a significant difference in depth of thermal artifact WMD 0.27 95%CI (0.19-0.35).
g) Adequate Colposcopy at Follow-up
Methevet (1994) demonstrated that loop excision produced more adequate colposcopies at follow-up OR 0.27 95% CI(0.08-0.89).
However, Santos (1996) did not a significant difference, the final meta-analysis being OR 0.94 95% CI(0.59-1.54)
h) Cervical Stenosis at Follow-up
Methevet (1994) and Santos (1996) did not demonstrate any significant difference OR 1.15 95% CI(0.57-2.33).
5) Laser Ablation compared to Loop excision
a) Residual disease
Three trials reported residual disease (Alvarez 1996, Gunaskera 1990 and Raju 1995). The trial by Raju (1995) was included as it appeared to be randomised but did not specifically state that it was. This trial demonstrated a significant higher residual disease in the laser ablation group, whilst the other two trials demonstrated a non-significant difference. It could be argued that the trial by Raju (1995) should be excluded from the comparison as there is no clear cut evidence that it was randomised.
b) Two trials reported on the incidence of severe peri-operative pain (Alvarez 1996, Gunaskera 1990). They produced heterogenous results, the final meta-analysis demonstrating a higher incidence of women complaining of severe pain during laser ablation OR 4.4 95% CI (1.86-10.4).
c) Primary Haemorrhage
The trials by Alvarez (1996) and Gunaskera (1990) did not demonstrate any significant difference OR 2.34 95% CI(0.46-11.93).
d) Secondary Haemorrhage
The trials by Alvarez (1996) and Gunaskera (1990) did not demonstrate any significant difference OR 7.32 95% CI(0.76-71.9)
6) Knife Cone Biopsy compared to Loop excision
There was no significant difference between knife cone biopsy and loop excision with respect to residual disease, primary haemorrhage or adequate colposcopy at follow-up in the one trial that compared these two treatment modalities, Giradi (1994).
7) Radical Diathermy compared to Loop Excision
Only one trial compared these two treatments Healey (1996). There was no significant difference with respect to duration of the following symptoms: blood loss , watery discharge, white or yellow discharge, upper or lower abdominal pain, deep pelvic pain. There was significantly more vaginal pain when using radical diathermy.
8) Knife Cone Biopsy with or without Haemostatic Sutures.
a) Primary Haemorrhage
Kristensen (1990) demonstrated that routine Sturmdorf sutures reduced the risk of primary haemorrhage OR 0.18 95% CI(0.05-0.71), however this effect was not demonstrated by Gilbert (1990) OR 1.0 95% CI(0.34-2.9).
b) Secondary Haemorrhage
Gilbert (1989) and Kristensen (1990) demonstrated that routine sutures significantly increase the risk of secondary haemorrhage OR 3.81 95%CI (1.11-13.15).
c) Cervical Stenosis at Follow-up
Gilbert (1989) and Kristensen (1990) demonstrated no difference in cervical stenosis OR 1.05 95% CI (0.48-2.3)
d) Adequate Colposcopy at Follow-up
Gilbert (1989) demonstrated that avoidance of routine suturing reduced inadequate colposcopy rates.
e) Dysmenorrhoea
Gilbert (1989) and Kristensen (1990) demonstrated that routine sutures increased the risk of dysmenorrhoea OR 2.42 95%CI (0.95-6.15).
We have used a pragmatic approach to 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 differ from other interventions in the comparison, then the trial was considered in the analysis. For example, when we compared laser ablation to cryotherapy, we included trials using single and double freeze technique.
1.
Laser ablation compared with cryotherapy demonstrated no overall difference in residual disease after treatment for CIN. Cryosurgery appears to have a lower success rate but the majority of authors used a single freeze thaw technique. Although 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 CIN 1 and 2 but laser ablation appeared to be better but not significantly so at treating CIN3. We therefore cannot recommend cryosurgery for the treatment of high grade disease. The clinicians 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 more per-operative and significant post operative bleeding and crosurgery was associated with significantly more vaso-motor symptoms. Laser ablation produced significantly more adequate colposcopies (transformation zone seen in its entirety) at follow-up and cervical stenosis appeared to be less common after this treatment.
2.
Only one trial (Mathevet 1994) evaluated residual disease after laser conisation or knife conisation. There was no significant difference between the two groups. Primary haemorhage appeared to be substantially less in the laser conisation but failed to reach significance, the direction of effect was similar with regards to secondary haemorrgage. Significant thermal artifact prevented interpretation of resection margins in 38% of laser cones compared to none in the knife cones. Laser conisation produced significantly more adequate colposcopies (transformation zone seen in its entirety) at follow-up and cervical stenosis was significantly less common after this treatment.
3.
Only one trial compared laser conisation with laser ablation for ectocervical lesions (Partington 1989). there was no significant difference with respect to residual disease at follow-up. Laser conisation appeared to increase peri-operative bleeding and secondary haemorrhage but neither outcome achieved significance. Laser conisation appeared to reduce adequate colposcopy at follow-up.
4.
Only four trials compared laser conisation with LLETZ (Crompton 1994, Mathevet 1994,Oyesanya 1993, Santos 1996). there was no significant difference with respect to residual disease at follow-up but the direction of effect suggested that LLETZ might have the advantage. Laser conisation takes significantly longer to perform, the depth of themal artifact and incidence of significant thermal damage are all significantly increased.
5.
Laser ablation compared to LLETZ was evaluated by three trials. Alvarez 1994 was included in the comparison but its methodology differed from the trials by Gunasekera 1990 and Raju 1995. Alvarez performed LLETZ on all the patients randomised to that group whereas laser ablation was only performed if colposcopic directed biopsies were performed.
In the other two trials treatment was performed in both arms after colposcopic biopsies had confirmed CIN. The trial by Raju 1995 demonstrated a marked difference in residual disease in the two treatment groups with 29 out of 320 having recurrence in the LLETZ group compared to 118 out of 318 women in the laser ablation group. Such marked differences in treatment success were not seen in any other randomised study included in the review. There was no obvious explanation for this atypical result when we examined the trial methodology other than the study does not adequately state the method of allocation of treatment. Meta-analysis including the trial by Raju 1995 demonstrated significantly more residual disease after laser ablation OR 3.13 95%CI (2.28-4.3). Meta-analysis excluding this trial demonstrated no difference in the two treatments OR 0.90 95% CI (0.49-1.68).
There was no significant difference in primary or secondary haemorrhage but there appeared to be an increased chance of haemorrhage after laser ablation.
6.
Knife conisation compared to LLETZ was evaluated by one trial Giradi 1994. There was no apparent difference in residual disease, adequate colposcopy or primary haemorrhage in the two treatments.
7.
Haemostatic sutures significantly reduced the risk of primary haemorrhage but increased the risk of secondary haemorrhage, dysmenorrhoea, cervical stenosis and inadequate follow-up colposcopy in the study compared with no routine haemostatic sutures and vaginal packing.
Cryotherapy is easy to use, cheap and as demonstrated is associated with low morbidity and 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 the superior as it is 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, more expensive investment in equipment, produces more peri-operative pain, greater depth and severe thermal artifact than loop excision. We would therefore recommend the use of LLETZ 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 is still has a place if invasion or glandular disease is suspected. In both diseases adequate resection margins free of disease are important for prognosis and management. In such cases, LLETZ or laser conisation can induce thermal artifact so that accurate interpretation of margins is not possible.
References to studies included in this review
Alvarez (published data only) Alvarez R, Helm W, Edwards P, Naumann W, Partridge E, Shingleton H, McGee J, Hall J, Higgins R, Malone J. Prospective randomised trial of LLETZ versus laser ablation in patients with cervical intra-epithelial neoplasia. Gynecol Oncol 1994 52; : 175-9. Berget (published data only) Berget A, Andreason B, Bock, Bostofte E, Hobjorn S, Isager-Sally L, Philipsen T, Schantz A, Weber T. Outpatient treatment of cervical intra-epithelial neoplasia: the CO2 laser versus cryotherapy: a randomised trial. Acta Obstet Gynecol Scand 1987 66; : 531-6. Berget A (published data only) Berget A, Andreason B, Bock J. Laser and cryosurgery for cervical intraepithelial neoplasia. Acta Obstet Gynecol 1991 70; : 231-5. Bostofte (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 Obstet Gynaecol Scand 1986 65; : 199-202. Crompton (published data only) Crompton A, Johnson N. Which is more painful? a randomised trial comparing loop with laser excision of the cervical transformation zone. Gynecol Oncol 1994 52; : 392-394. Ferenczy (published data only) Gilbert (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. Obstet Gynecol 74; : 640-3. Girardi (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. Gynecol Oncol 1994 55; : 368-70. Gunasekera (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. Br J Obstet Gynecol 1990 97; : 995-8. Healey (published data only) Healey M, Warton B, Taylor N. Postoperative Symptoms Following LLETZ ot Radical Cervical diathermy with fulguration: A randomised double-blind study. Aust NZ J Obstet Gynecol 1996; 36: 179-81. Jobson (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: 173-180. Kirwan (published data only) Kirwan P, Smith I, Naftalin N. A study of cryosurgery and CO2 laser in treatment of carcinoma in situ (CINIII) of the uterine cervix. Gynecol Oncol 1985 22; : 195-200. Kristensen (published data only) Kristensen G, Jensen L, Holund B. A randomised trial comparing two methods of cold knife conisation with laser conisation. Obstet Gynecol 1990 76; : 1009-13. Kwikkel (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 eficacy and side effects. Gynecol Oncol 1985 22; : 23-31. Larsson (published data only) Larsson G, Alm P, Grudsell H. Laser conisation versus cold knife conisation. Surgery,Gyneacology,Obstetrics 1982 154; : 59-64. Mathevet (published data only) Mathevet P, Dargent D, Roy M, Beau G. A randomised prospective study comparing three techniques of conisation: cold knife, laser, and LEEP. Gynaecol Oncol 1994 54; : 175-9. Oyesanya (published data only) Oyesanya O, Amersinghe C, Manning E. Out patient excisional management of cervical Intra-epithelial. neop; : A prospec-7. Paraskevaidis (published data only) Paraskevaidis E, Kichener H, Malamou-Mitsi V, Agnanti N, Lois D. Thermal tissue damage folowing laser and large loop conisation of the cervix. Obstet Gynecol 194 84 752; : -54. Partington (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. Obstet Gynecol 1989 73; : 775-9. Raju (published data only) Raju K, Henderson E, Trehan A. A study comparing LLETZ and CO2 laser treatment for cervical intra-epithelial neoplasia with and without Associated Human Papilloma Virus. Eur J Gynaecol Oncol 1995 16; : 92-6. Santos (published data only) Santos C, Galdos R, Alvarez M, Velarde C, Barriga O, Dyer R, Estrada H, Almonte M. One-session management of cervical intraepithelial neoplasia:.A solution for developing countries. Gynecol Oncol 1996 61; : 11-15. Townsend (published data only) Townsend D, Richart R. Cryotherapy and carbon dioxide laser management of CIN: A controlled comparison. Obstet and Gynecol 1983; 61: 75-78. * indicates the major publication for the study Additional references Anderson Anderson M. Are we vaporizing microinvasive lesions? RCOG Perinatology Press 1986 127; : -132. Benedet Benedet J, Nickerson K, White G. Laser therapy for cervical intraepithelial neoplasia. Obstet Gynecol 1981 57; : 188-. Bigrigg Bigrigg M, Coding B, Pearson et al. Colposcopic diagnosis and treatment of cervical dysplasia at a single visit. Lancet 1990 2:33; : 229-. Bostofte Bostofte E, Berget A, Larsen J, Pedersen P, Rank F. Conisation by carbon dioxide laser or cold knife in the treatment of cervical intraepithelial neoplasia. Acta Obstet Gynecol Scand 1986 65; : 199-202. Chappatte Chappatte O, Byrne D, Raju K, Nayagam M, Kenney A. Histological differences between colposcopic-dirscted biopsy and loop excision of the transformation zone: a cause for concern. Gynecol Oncol 1991 43; : 46-50. Creasman Creasman W, Hinshaw W, Clarke-Pearson D. Cyrosurgery in the management of cervical intraepithelial neoplasia. Obstet Gynecol 1984 63; : 145-. Hatch Hatch K, Shingleton H, Austin M. Cryosurgery of cervical intraepithelial neoplasia. Obstet Gynecol 1981 57; : 692-. Jordan Jordan J Jordan J, Woodman C, Mylotte M, Emens J, Williams D. The treatment of cervical intraepithelial neoplasia by laser vaporisation. Br J Obstet Gynecol 1985 92; : 394-5. Kaufman Kaufman R, Irwin J. The cryosurgical therapy of cervical intraepithelial neoplasia. Am J Obstet Gynecol 1978 131; : 831-. Larson Larson G. Conisation for preinvasive and invasive carcinoma. Acta Obstet Gynecol Scand Supp 1983 114; : 1-40. Leiman Leiman g, Harrison N, Rubin A. Pregnancy following conisation of the cervix: complications related to cone biopsy. Am J Obstet Gynecol 1980 136; : 14-8. Luesley Luesley D Luesley D, Cullimore J, Redman C. Loop excision of the cervical transformation zone in patients with abnormal cervical smears. BMJ 1990 300; : 1690-. Murdoch Murdoch J, Grimshaw R, Monaghan J. Loop diathermy excision of the abnormal cervical transformatioon zone. Int J Gynecol Path 1991 1; : 105-. Murdoch J Murdoch J, Grimshaw R, Morgan P, Monaghan J. The impact of loop diathermy on management of early invasive cervical cancer. Int J Gynecol Cancer 1992 2; : 129-. Ostergard Ostergard D. Cryosurgical treatment of cervical intraepithelial neoplasia. Obstet Gynecol 1980 56; : 233-. Popkin Popkin D, Scali V, Ahmed M. Cryosurgery for the treatment of cervical intrraepithelial neoplasia. Am J Obstet Gynecol 1978 130; : 551-. Prendeville Prendeville W, Cullimore J, Norman S. Large loop excision of the transformation zone (LLETZ): a new method of management for women with cervical intraepithelial neoplasia. Br J Obstet Gynecol 1989 96; : 1054-. Tabor Tabor A, Berget A. Cold knife and laser conisation for cervical intraepithelial neoplasia. Obstet Gynecol 1990 76; : 633-5. Whiteley Whiteley P, Olah K. Treatment of cervical intraepithelial neoplasia: experience with low voltage diathermy loop. Am J Obstet Gynecol 1990 162; : 1272-. Wright Wright V, Davies E, Riopelle M. Laser surgery for cervical intraepithelial neoplasia. Am J Obstet Gynecol 1983 145; : 181-. Extramural sources of support to the review Intramural sources of support to the review Fig 02 LASER CONISATION VERSUS KNIFE CONISATION Fig 03 LASER CONISATION VERSUS LASER ABLATION Fig 04 LASER CONISATION VERSUS LOOP EXCISION Fig 05 LASER ABLATION VERSUS LOOP EXCISION Fig 06 KNIFE CONISATION VERSUS LOOP EXCISION Fig 07 RADICAL DIATHERMY VERSUS LLETZ Fig 08 KNIFE CONE BIOPSY: HAEMOSTATIC SUTURES VERSUS NONE Ferencczy A,
Comparison of cryo- and carbon dioxide laser therapy for cervical intraepithelial neoplasia
Obstet Gynecol 1985: 66: 793-98Jordan J
Symposia on cervical neoplsaia, excisional methods
Colp Laser Surg 1984. 1: 271Luesley D, McCrum A, Terry P, Wade-Evans T
Complications of cone biopsy related to the dimensions of the cone and the influence of prior colposcopic assessment
Br J Obstet Gynecol. 1985. 92: 158Reviewer(s) Martin-Hirsch PL, Paraskevaidis E, Kitchener H Date of most recent amendment 23 February 1999 Date of most recent substantive amendment 13 August 1998 Contact address Dr Pierre Martin-Hirsch
Senior Registrar/Lecturer
University Department of Obstetrics and Gynaecology
St Mary s Hospital
Whitworth Park
Manchester
UK
M13 0JH
Telephone: + 44 161 276 6461
Facsimile: + 44 161 273 3958
E-mail:Cochrane Library number CD001318 Editorial group Cochrane Gynaecological Cancer Group Editorial group code HM-GYNAECA This review should be cited as :
Martin-Hirsch PL, Paraskevaidis E, Kitchener H. Surgery for cervical intraepithelial neoplasia (Cochrane Review). In: The Cochrane Library, Issue 2, 1999. Oxford: Update Software.Sources of support
Comment, Reply and Editorial notes
Two new trials which may be relevant to this review have recently been identified. Work is currently under way to include data from these studies, and the updated review will appear on the next version of the Cochrane Library. In the meantime, those wishing to make medical decisions based on this review are advised to contact the lead author of the review.Keywords
HUMAN; FEMALE; CERVIX-NEOPLASMS / surgery; CERVICAL-INTRAEPITHELIAL-NEOPLASMS / surgery; LASER-SURGERY / methods; CRYOSURGERY / methods; TREATMENT-OUTCOME;List of comparisons
Fig 01 LASER ABLATION VERSUS CRYOTHERAPY
Tables of other data
Tables of other data are not available for this review
| Study | Method | Participants | Interventions | Outcomes | Notes |
|---|---|---|---|---|---|
| Alvarez | True randomisation, allocation by computer generation (sealed envelopes) | 375 women with cervical smears suggesting CIN 2 or 3, or 2 smears equivalent to CIN1 Women with adequte colposcopy included with entire lesion visible, not pregnant Women with vaginitis, lesion extending to vagina, evidence of invasion excluded. | Primary LLETZ Colposcopic directed biopsy and endocervical curettage, Only if positive Laser Ablation of Transformation Zone | Histological status of LLETZ or colposcopic specimens Operators impression of significant peri-operative bleeding Women s subjective opinion of peri-operative pain Women s subjective opinion of post-operative severe discomfort, heavy discharge, severe bleeding Residual disease ( cytology) at 3 and 6 months | 195 randomised to LLETZ, 180 To Laser All women had paracervical 1% lidocaine with 1: 100,000 ephidrine LLETZ group: 6 treated by laser ablation due to technical problems, 4 failed to attend for treatment Laser group: 66 women did not require treatment, 114 required treatment 4 women were treated by LLETZ , 2 by cryosurgery due to technical problems |
| Berget | Method of randomisation not stated | 204 women with entire squamo-columnar junction visible CIN 1 on 2 biopsies 3-6 months apart, CIN 2 or 3 not extending 3 mm into crypts No extension onto vagina or lesion or 12.5 mm into canal | Cryotherapy Laser Ablation | Operators impression of significant peri-operative bleeding >25cc Women s subjective opinion of peri-operative pain ( mild, moderate severe, Severe being that the woman would not consider the treatment again) Women s subjective opinion of post-operative discomfort, heavy discharge, bleeding (None, Mild, Moderate, Severe) Post operative cervical stenosis Satisfactory folow-up colposcopy at 3 months Residual diseasse ( histological) at 3 months (all women) Residual disease (histological) at 9 and 15 months ( incomplete follow-up data) | 103 randomised to Laser, 101 randomised to Cryotherapy Laser performed ablated 2 mm lateral to transformation zone to a depth of 5-7mm Cryo coagulation (DOUBLE freeze thaw freze technique) or more if the iceball did not exceed the probe (25mm) by 4 mm. Local analgesia was not routinely administered |
| Berget A | Method of randomisation not stated | 204 women with entire squamo-columnar junction visible CIN 1 on 2 biopsies 3-6 months apart, CIN 2 or 3 not extending 3 mm into crypts No extension onto vagina or lesion or 12.5 mm into canal | Cryotherapy Laser Ablation | Residual diseasse ( histological) at 3, 9, 15, 21, 33, 45, 80 months | 103 randomised to laser, 101 to cryotherapy 6 laser and 2 cryotherapy women refused to be followed up Women were offered repeat treatment with the same method of treatment as part of protocol. 3 laser and 6 cryotherapy women refused repeat treatment. Laser performed ablated 2 mm lateral to transformation zone to a depth of 5-7mm Cryo coagulation (DOUBLE freeze thaw freeze technique) or more if the iceball did not exceed the probe (25mm) by 4 mm. Local analgesia was not routinely administered |
| Bostofte | Method of randomisation not stated | 123 women with CIN1,2,3 | Laser Conisation Knife Conisation | Duration Peri-operative bleeding (quanity mls) Post-operative bleeding (primary requiring treatment and Secondary) Post-operative pain (use of analgesics) Adequate colposcopy Cervical stenosis ( failure to pass cotton swab) Women complaining of dysmenorrhoea Residual disease (3-36 months) | All procedures performed under general anaesthesia Knife cone biopsy women had vaginal packing for 24 hours and 3 gms Tranexamic acid for 10 days. Sturmdorf sutures were not used, lateral cervical arteries used Laser conization women did not have vaginal packing or Tranexamic acid 59 women randomised to laser conisation, 64 to knife conisation |
| Crompton | True randomisation, allocation by computer generation (sealed envelopes) | 80 women recruited with CIN3 Women with a history of previous cervical surgery, peri- or post menopausal or whose lesion extends to vagina | Laser Excision of the Transformation Zone LLETZ | Subjective scoring of pain by attendant nurse Subjective scoring of pain by women by linear analogue scale Peri-operative bleeding (none, spotting, requiring coagulation) Operative time | All women had intra-cervical 4mls 2% lignocaine with 0.3 IU /mls Octapressin prior to treatment (1 spoiled data sheet) |
| Ferenczy | Quasi-randomisation, allocation by alternate assignment | 294 women with CIN 1,2,3 CIN present on ectocervix with or without marginal extension inrto caervical canal | Cryotherapy Laser Ablation | Significant Peri-operative bleeding Adequate Colposcopy at Follow-up Residual Disease | 147 randomised to laser, 147 to cryotherapy Women were offered repeat treatment with the same method of treatment as part of protocol. 3 laser and 6 cryotherapy women refused repeat treatment. Data included in comparison is for one treatment only Laser performed ablated 5 mm lateral to lesion to a depth of 5mm Cryo coagulation (SINGLE freeze thaw technique) iceball extending 5 mm lateral to lesion. Local analgesia was not routinely administered |
| Gilbert | True randomisation: sealed envelopes | 200 women undergoing knife cone biopsy | Lateral haemostatic sutures and interrupted sutures if indicated Vaginal pack with Monsels solution | Duration of surgical procedure Operative blood loss Primary haemorrhage Secondary haemorrhage | |
| Girardi | Quasi-randomisation, allocation by odd/even birth dates | 90 women with CIN 2 or 3 or persistant CIN1 | LLETZ Knife conisation | Incomplete resection margins (endocervical, ectocervical or both) Primary haemorrhage requiring treatment Residual disease at 3 months | 38 women randomised to loop excision, 52 to knife conisation All women had pre-operative intracervical local analgesia and vasopressin 2 women with incomplete resection of endocervical disease had vaginal hysterectomy |
| Gunasekera | Quasi-randomisation, allocation by unit number | 199 women with CIN 2 or 3 Women with a history of previous cervical surgery or squamo-columnar junction not completely visible, suspicion of invasion or glandular disease excluded | Laser ablation LLETZ | Duration of procedure (insuffient data for analysis) Peri-operative blood loss (subjective assessed by operator mild, moderate, severe) Primary haemorrhage Secondary haemorrhage Acceptability of procedure/ pain (subjectively scored by womenn : not unpleasant, moderate, very unpleasant) Residual disease at 6 months | 98 women randomised to LLETZ, 101 to laser ablation All women had paracervical 2% lignocaine with 1: 100,000 adrenaline |
| Healey | True randomisation, allocation by sealed envelopes | 55 women with CIN | Radical diathermy LLETZ | Duration of blood loss Duration of watery/ blood stained discharge Duration of yellow discharge Duration of upper abdominal pain Duration of lower abdominal pain Duration of deep pelvic pain Duration of vaginal pain | |
| Jobson | Method of randomisation not stated | 125 women with CIN 1,2,3 Women with satisfactory colposcopy, negative endocervical curettage, reproductive years | Laser ablation Cryotherapy | Vasovagal reaction Patient acceptance (would patient have repeat treatment) Satisfactory colposcopy at 4 months Residual disease at 4 and 12 months | 42 women were randomised to laser ablation, 39 to cryotherapy and completed protocol Laser performed ablated 2 mm lateral to transformation zone to a depth of 5-7mm. Women had pre-operative oral ibuprofen. Cryo coagulation (DOUBLE freeze thaw freeze technique) or more if the iceball did not exceed the probe (28mm) by 4-5mm. With or without analgesia |
| Kirwan | Method of randomisation not stated | 106 women with CIN 3 Adequate colposcopy and no extension to vagina | Laser ablation Cryotherapy | Residual disease at 4 and 10 months | 71 women were randomised to laser ablation, 35 to cryotherapy Laser performed ablated transformation zone to a depth of 7mm Cryo coagulation ( DOUBLE freeze thaw freeze technique) . |
| Kristensen | Method of randomisation not stated | 183 women with CIN2 or 3 | Knife cone with anterior+posterior Sturmdorf sutures Knife cone without haemostatic sutures but with vaginal packing for 6-8hours Laser cone | Resection margins free of disease Primary haemorrhage Secondary haemorrhage Cervical stenosis Dysmenorrhoea | 62 women randomised to knife cone with sutures, 60 women to knife cone with packing, 61 to laser cone All procedures performed under general anaesthesia All procedures performed with lateral sutures and intra-cervical vasopressin |
| Kwikkel | Method of randomisation not stated | 105 women with CIN1,2,3 Adquate colposcopy, no suspicion of invasion | Laser Ablation Cryotherapy | Peri-operative pain Peri-operative bleeding Residual disease at 3-18 months | Laser performed ablating the transformation zone to a depth of 6-7mm Cryo coagulation (DOUBLE freeze thaw freeze technique) using a probe (18mm) 2 women in cryotherapy group, 2 women in laser group lost to follow-up |
| Larsson | Method of randomisation not stated | 110 women with CIN3 | Laser conisation Knife conisation | Peri-operative blood loss (insufficient data for analysis) Primary haemorrhage (bleeding requiring intervention in first 4 days) Secondary haemorrhage (bleeding after 4th day) | 55 women were randomised to laser conisation, 55 to knife conisation All procedures performed under general anaesthesia Bood loss estimated by alkaline haematin extraction from swabs etc |
| Mathevet | True randomisation, allocation by sealed envelopes | 110 women with CIN 1,2,3 Squamo-columnar junction NOT completely visible | Knife cone Laser cone LLETZ | Ectocervical resection margin involved with disease Endocervical resection margin involved with disease Presence of thermal artifact not permitting evaluation of resection margins Peri-operative bleeding requiring haemostatic sutures (loop+laser only) Secondary haemorrhage Cervical stenosis Satisfactory colposcopy Residual disease at 6 months | 37 women were randomised to knife conisation, 37 to laser conisation, 36 to loop All 3 treatments performed as an out-patient procedure with 10-20 mls 1% xylocaine with ephidrine. At knife conisation haemostasis was achieved by Sturmdorf sutures, laser cone by laser coagulation and Monsels solution, loop excision by coagulation and Monsels solution |
| Oyesanya | True randomisation, allocation by sealed envelopes | 300 women with CIN 1,2,3 Women with adequate colposcopy, no evidence of invasion | Laser conisation LLETZ | Duration of treatment Patient subjective assesment of pain (none/minimal, moderate, severe) Peri-operative blood loss (difference in weight of blood stained / dry swabs) Secondary haemorrhage Presence of thermal artifact not permitting evaluation of resection margins Dysmenorrhoea Residual disease at 3-12 months | 150 women randomised to laser conisation, 150 to loop excision Intra-cervical 6mls Citanest (0.5% prilocaine with Octapressin) used pre-operatively |
| Paraskevaidis | Method of randomisation not stated | 40 women undergoing elective hysterectomy | Laser conisation LLETZ | Duration of procedure Depth of thermal injury | |
| Partington | True randomisation, allocation by sealed envelopes | 100 women with CIN 1,2,3 Women with adequate colposcopy , no evidence of invasion, lesion no more than 5mm into canal | Laser conisation Laser ablation | Duration of treatment Significant peri-operative bleeding Women s subjective opinion of peri-operative pain (mild, moderate, severe) Secondary haemorrhage (seen in out-patients) Secondary haemorrhage (required admission) Adequate colposcopy Cervical stenosis Dysmennorrhoea Residual disease at 6, 12 , 24 months | 50 women randomised to laser conisation, 50 women randomised to laser ablation Haemostasis achieved by pressure with a cotton swab or Monsel solution Laser Excision 2mm margin to lesion and to a depth of 2-3mm Laser ablation to a depth of 10mm Intra-cervical 3% prilocaine with Octapressin used pre-operatively |
| Raju | Method of randomisation not stated | 642 women with CIN 1,2,3 Adequate colposcopy, no extension to vagina | Laser ablation LLETZ | Residual disease at 6 months | 318 women treated by laser ablation, 324 by LLETZ Intra-cervical 2-6mls. 1% lignocaine with 1;200,000 adrenaline used pre-operatively |
| Santos | True randomisation, allocation by random tables | 447 women with CIN 1,2,3 Women with suspicion of invasion, extensive lesion, pregnant were excluded | LLETZ Laser conisation | Residual disease Significant peri-operative bleeding Secondary haemorrhage Cervical stenosis at follow-up Satisfactory colposcopy at follow-up | 145 women randomised to laser conisation, 147 to loop Intra-cervical 6mls 2% lidocaine with 1:80,000 ephidrine used preoperatively |
| Townsend | Method of randomisation not stated | 200 women with CIN 1,2,3 Adequate colposcopy, no evidence of invasion | Laser ablation Cryotherapy | Severe cramps Vasomotor symptoms Residual disease at 6 months. | 100 women randomised to laser ablation, 100 randomised to cryotherapy Cryo coagulation (SINGLE freeze thaw technique) using a probe (18mm) with iceball extending 5 mm beyond abnormal epithelium Laser ablation of all transformation zone |