Nerve‐sparing radical hysterectomy compared to standard radical hysterectomy for women with early stage cervical cancer (stage Ia2 to IIa)

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the efficacy and safety of nerve‐sparing radical hysterectomy in adult women with stage Ia2 to IIa cervical cancer.

Background

Description of the condition

Cervical cancer remains a major health burden, with an age‐standardised incidence rate (ASR) of 14.0 per 100,000 person‐years (Ferlay 2015). In 2012, there were an estimated 528,000 new cases worldwide (Ferlay 2015). Approximately 85% of the global burden and nine out of ten (87%) cervical cancer deaths occur in low‐ and/or middle‐income countries (Ferlay 2015). This high rate of cervical cancer‐related death in these countries is mainly due to deficiencies in surveillance systems (Parkin 2014). Treatment for cervical cancer depends on the clinical stage of the disease. Staging of cervical cancer (processes carried out to find out how far the cancer has spread) is based on clinical findings obtained from physical examination and diagnostic tests, which are used to assess the size of cervical mass, invasion into the tissues surrounding the cervix, and the spread to lymph nodes or distant organs (FIGO Committee 2014). The International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer is provided in Appendix 1 (FIGO Committee 2014).

A radical hysterectomy (also known as a Wertheim's hysterectomy) is performed to remove the uterus (womb), cervix, upper vagina and the parametria (tissues surrounding the cervix and upper vagina) (Verleye 2009; Marin 2014). Radical hysterectomy in conjunction with bilateral pelvic lymphadenectomy (the surgical removal of the lymph nodes found in the pelvis) is the standard surgical treatment for FIGO stage Ia2–IIa cervical cancer, when preservation of fertility is not required or advisable (Verleye 2009), although more limited treatment, such as cone biopsy (removal of a cone shaped piece of tissue from the cervix) or simple hysterectomy, with lymph node dissection, is increasingly considered for small volume disease. Concurrent chemoradiation (combination of drug and radiotherapy given at the same time) is also acknowledged as a standard treatment option for women with early stage cervical cancer (Vale 2010). Decision‐making is based on individual patient characteristics and preferences, as well as weighing up the surgical risks with the longer‐term risks of chemoradiation.

Radical hysterectomy can be performed via laparotomy (open surgery), laparoscopic or robotic techniques (types of less invasive surgery). At present, there are three standard classification systems for radical hysterectomy (Marin 2014; Verleye 2009), including the Piver‐Rutledge‐Smith classification (Piver 1974), Querleu and Morrow classification (Querleu 2008), and the Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer (GCG‐EORTC) classification (Mota 2008) (See Appendix 2).

Five‐year survival rates of women undergoing radical hysterectomy for stage Ia2 to IIa cervical cancer are over 80% (Hongladaromp 2014; Kim 2000; Mahawerawat 2013; Srisomboon 2011; Suprasert 2010). The procedure can, however, result in significant long‐term complications (Laterza 2015; Manchana 2009; Suprasert 2010). Bladder dysfunction, caused by the disruption of the pelvic autonomic nerves during resections of parametria and paracolpium (the tissues surrounding the vagina), can be a major, distressing complication and may occur in up to 70% of women following radical hysterectomy (Laterza 2015; Plotti 2011; Suprasert 2010). Early postoperative bladder dysfunction includes a significant reduction of maximal urethral closure pressure (MUCP), increased volume of postvoid residual urine, detrusor muscle underactivity and diminished bladder sensation, which, in some cases, may require prolonged urethral catheterisation. Late postoperative bladder dysfunction involves a persistent reduction of MUCP, voiding with abdominal straining, high volume of postvoid residual urine, detrusor muscle over‐activity, and stress urinary incontinence (loss of urine caused by physical stress, e.g. sneezing or jumping) with estimates ranging from 8% to 47% (Katepratoom 2014; Laterza 2015).

Description of the intervention

The uterus, upper vagina, bladder and rectum receive innervation from both the sympathetic and parasympathetic supplies of the autonomic nervous system. These nerves control smooth muscle function and pain sensation in viscera (internal organs). The sympathetic supply arises from T11‐L2 nerve roots, which form a branching network called the superior hypogastric plexus (also referred to as the presacral nerve). The superior hypogastric plexus enters the pelvis, dividing into right and left hypogastric nerves. The pelvic splanchnic nerve is formed from parasympathetic fibres from S2‐S4 nerve roots. The pelvic splanchnic nerve merges with the hypogastric nerve to form left and right inferior hypogastric plexuses, which travel via the uterosacral ligaments (tissues that connect between the posterior‐lower part of the uterus to the anterior aspect of the sacrum) where they branch to supply the uterus and bladder (Fujii 2007; Huber 2015).

In terms of urinary function, the sympathetic nervous system relaxes the bladder muscle (detrusor muscle) to increase bladder capacity and constricts the internal urethral sphincter to inhibit the micturition (bladder voiding) reflex. The parasympathetic nervous system stimulates a series of contractions of the bladder muscle and relaxes the internal urethral sphincter (muscle that acts as a valve to control the exit of urine from the bladder), resulting in voluntary urination (Laterza 2015).

Nerve‐sparing radical hysterectomy is a modified radical hysterectomy, developed to permit surgical removal (resection) of oncologically relevant tissues surrounding the cervical lesion, while preserving pelvic autonomic nerves (Charoenkwan 2010; Fujii 2008; Kato 2003). During nerve‐sparing radical hysterectomy, parametrial dissection is carried out under directed visualisation of the adjacent pelvic autonomic nerves. Fibres of the hypogastric nerve can be identified in the mesoureter (tissues surrounding the ureter), approximately 2 cm to 3 cm beneath the ureter (tubes that carry urine from kidneys to the bladder). To minimise the risk of accidental transection (severing), the hypogastric nerve is partly dissected away from the level of resection of the posterior parametrium. During resection of the lateral parametrium, the inferior hypogastric plexus is directly visualised, partly dissected and separated to avoid disruption during resection. The vesical branch of inferior hypogastric plexus can be identified by following the course of the inferior hypogastric plexus from the uterosacral ligaments and is separated from the blood vessels of the tissue surrounding the vagina during resection of the anterior parametrium (Charoenkwan 2006; Charoenkwan 2010; Fujii 2007; Fujii 2008).

Nerve‐sparing radical hysterectomy appears safe and feasible without compromising the extent of resection and the rate of cancer recurrence when compared to the standard techniques of radical hysterectomy (Charoenkwan 2006; Xue 2016). A factor predicting the likelihood of the success of nerve‐sparing radical hysterectomy is the FIGO stage of the disease. Women with stage Ib1 cervical cancer are more likely to have successful preservation of autonomic nerves during laparoscopic nerve‐sparing radical hysterectomy than those with a higher stage of disease (stage Ib2 to IIa) (Kim 2015).

How the intervention might work

The extent of potential injury to pelvic autonomic nerves is associated with the extent of the operation (Butler‐Manuel 2000; Ercoli 2003). The surgical steps of radical hysterectomy that potentially damage the pelvic autonomic nerves are the resection of parametrial tissues, particularly posterior and anterior parametria (Ercoli 2003). Previous quantitative immunocytochemistry studies (postoperative examination of tissue removed during surgery using antibodies to highlight nerve fibres when viewed under a microscope) indicated that the presence of nerve trunks (the main stem of a nerve), autonomic ganglia (nerve connection hubs), and free nerve fibres within the parametrial tissues, which were accidentally transected during conventional radical hysterectomy (Butler‐Manuel 2000; Ercoli 2003; Maas 2005; Mantzaris 2008). In addition, when a more careful approach is used during resection of the parametria, through identification and isolation of the adjacent pelvic autonomic nerves, significantly fewer autonomic nerves are disrupted iatrogenically (inadvertently) during nerve‐sparing radical hysterectomy than in conventional radical hysterectomy (Maas 2005; Mantzaris 2008). This results in a substantial reduction in nerve disruption and may lower the risk of developing bladder dysfunction after radical hysterectomy (Charoenkwan 2010; Fujii 2007; Tseng 2012).

Why it is important to do this review

Although the survival outcomes of women undergoing standard radical hysterectomy with pelvic lymphadenectomy for stage Ia2 to IIa cervical cancer are generally good, bladder dysfunction following standard radical hysterectomy can affect quality of life (QoL) significantly (Ceccaroni 2012; Wu 2010). Nerve sparing radical hysterectomy may offer improved QoL. However, there is the potential that a nerve‐sparing approach may compromise oncological outcomes and increase the risk of disease recurrence. We aim to assess the benefits and harms of this approach in order to inform women and their surgeons about whether a more refined surgical approach is warranted, or whether a more traditional radical resection is to be recommended.

Objectives

To evaluate the efficacy and safety of nerve‐sparing radical hysterectomy in adult women with stage Ia2 to IIa cervical cancer.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs).

Types of participants

Women aged 18 years or older undergoing radical hysterectomy (Piver class III, Querleu and Morrow type C, or GCG‐EORTC type III) for stage Ia2 to IIa cervical cancer. Appendix 1 and Appendix 2 display the details of the FIGO staging classification of cervical cancer, and the classifications of radical hysterectomy, respectively. If studies include other stages of cervical cancer, we will contact trial authors to retrieve data related to the women with stage Ia2 to IIa cervical cancer only. If this is not possible, we will only include studies where at least 80% of participants were diagnosed with stage Ia2 to IIa cervical cancer.

Types of interventions

RCTs comparing nerve‐sparing radical hysterectomy with pelvic lymphadenectomy versus standard radical hysterectomy with pelvic lymphadenectomy for cervical cancer stage Ia2 to IIa (See Description of the intervention for details of the differences between the two surgical interventions).

Types of outcome measures

Primary outcomes

• Overall survival: survival until death from all causes. Survival will be assessed from the time when women were enrolled in the study.

• Rate of intermittent self‐catheterisation (ISC) at one month after the operation.

• QoL: assessed using a scale that has been validated through reporting of norms in a peer‐reviewed publication, i.e. European Organization for Research and Treatment of Cancer (EORTC) QLQ‐CX24 cervical cancer‐specific QoL questionnaire (Greimel 2006).

Secondary outcomes

• Time to postvoid residual volume of urine ≤ 50 mL after operation (days) (amounts of urine measured by clean intermittent catheterisation after the patient feels as though bladder is empty).

• Postvoid residual volume of urine at 1 month, 3 months, 6 months, and 12 months after operation (mL).

• Adverse events (excluding bladder dysfunction): we will categorise the severity of the following adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE 2010): febrile morbidity; surgical site infections; genitourinary complications (e.g. fistula, hydronephrosis, vaginal stenosis); gastrointestinal complications (e.g. fistula, constipation); lymphovascular complications (e.g. lymphocyst, lymphoedema, thrombosis, embolism); direct surgical morbidity (e.g. injury to bladder, ureter, small bowel or colon); reoperation (an operation to correct a condition not corrected by a previous operation or to correct the complications of a previous operation); readmission (a hospitalisation that occurs within 30 days after discharge from hospital); blood component transfusion (the transfer of blood or blood components from one person (the donor) into the bloodstream of another person (the recipient).

• Subjective urinary symptoms: using a standard questionnaire, i.e. International Prostate Symptom Score (IPSS) (Barry 1992)

• Disease‐free survival (DFS): survival until the appearance of a new lesion of disease. Survival will be assessed from the time when women are enrolled in the study.

• Rate of cancer recurrence: we will classify recurrences as loco‐regional or distant.

• Rate of urinary tract infection during the month after operation diagnosed by cultivation of urine.

• Maximal urethral closure pressure (MUCP) from urodynamic measurements (cmH₂O).

• Maximum flow rate (mL per second) and number of women with low maximum flow rate (< 15 mL per second) obtained urodynamic measures.

• Detrusor pressure at maximum flow and number of women with low detrusor pressure at maximum flow (< 25 cmH₂O).

• Sexual dysfunction: using a validated scale, i.e. Sexual function‐Vaginal change Questionnaire (SVQ) (Jensen 2004).

• Cost‐effectiveness: using a validated scale, i.e. European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO‐MCBS) (Cherny 2015).

• Operative time (minutes).

• Estimated blood loss (mL).

• Subjective urinary symptoms: using a standard questionnaire, i.e. International Prostate Symptom Score (IPSS) (Barry 1992)

• Disease‐free survival (DFS): survival until the appearance of a new lesion of disease. Survival will be assessed from the time when women are enrolled in the study.

• Rate of cancer recurrence: we will classify as loco‐regional and distant recurrences.

• Rate of urinary tract infection during the month after operation diagnosed by cultivation of urine.

• Maximal urethral closure pressure (MUCP) from urodynamic measurements (cmH₂O).

• Maximum flow rate (mL per second) and number of women with low maximum flow rate (< 15 mL per second) obtained urodynamic measures.

• Detrusor pressure at maximum flow and number of women with low detrusor pressure at maximum flow (< 25 cmH₂O).

• Sexual dysfunction: using a validated scale, i.e. Sexual function‐Vaginal change Questionnaire (SVQ) (Jensen 2004).

• Cost‐effectiveness: using a validated scale, i.e. European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO‐MCBS) (Cherny 2015).

• Operative time (minutes).

• Estimated blood loss (mL).

We plan to present a 'Summary of findings' table to report the following outcomes listed in order of priority (see Appendix 3; Data synthesis):

• overall survival;

• rate of ISC one month after operation;

• time to postvoid residual volume of urine ≤ 50 mL after operation;

• postvoid residual volume of urine one month after operation;

• rate of adverse event excluding bladder dysfunction;

• disease‐free survival;

• QoL.

Search methods for identification of studies

We will include RCTs, irrespective of the language of publication, publication status or sample size.

Electronic searches

We will search the following databases:

• Cochrane Central Register of Controlled Trials (CENTRAL, latest issue);

• MEDLINE (1946 to present date);

• Embase (1980 to present date).

The Ovid MEDLINE search strategy is presented in Appendix 4. For databases other than MEDLINE, we will adapt the search strategy accordingly. All relevant articles will be identified on PubMed and we will make a further search for newly published articles using the 'related articles’ feature.

Searching other resources

Ongoing trials and grey literature

We will search the World Health Organization's International Clinical Trials Registry Platform (www.who.int/ictrp/en) and ClinicalTrials.gov to identify any ongoing trials. If we identify ongoing trials that have not been published, we plan to approach the principal investigators and major co‐operative groups active in this area, to ask for relevant data. We will search the following databases for grey literature: Open Grey (www.opengrey.eu) and Index to Theses (ProQuest Dissertations & Theses: UK & Ireland).

Handsearching

We will handsearch the citation lists of included studies, key textbooks and previous systematic reviews, and we plan to contact experts in the field to identify further reports of trials. We will also handsearch the reports of conferences from the following sources (from the year when electronic conference proceedings became available to current):

• Annual Meeting of the American Society of Gynecologic Oncology;

• Annual Meeting of the European Society of Medical Oncology;

• Annual Meeting of the American Society of Clinical Oncology;

• Annual Meeting of the British Gynaecological Cancer Society;

• Biennial Meeting of the Asian Society of Gynecologic Oncology;

• Biennial Meeting of the Asia and Oceania Federation of Obstetrics and Gynaecology;

• Biennial Meeting of the European Society of Gynaecological Oncology; and

• Biennial Meeting of the International Gynecologic Cancer Society.

Data collection and analysis

Selection of studies

We will download all titles and abstracts retrieved by electronic searching to a reference management database (EndNote). After duplicates are removed, we will transfer these data to Covidence (www.covidence.org). We plan to exclude those studies that clearly do not meet the inclusion criteria and we will obtain copies of the full text of potentially relevant references. Independently, two review authors (CK and AA) will assess the eligibility of the retrieved reports/publications. We will resolve any disagreement through discussion or, if required, we will consult a third person (KG or PL). We will identify and exclude duplicates and collate multiple reports of the same study. We will use the details regarding the selection process in Covidence to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table (Liberati 2009).

Data extraction and management

Two review authors (CK and AA) will independently extract study characteristics and outcome data from included studies. We plan to note when outcome data are not reported in a usable way in the 'Characteristics of included studies' table. We intend to resolve disagreements by consensus or by involving a third person (KG or PL).

For included studies, we will extract the following data.

• Author, year of publication and journal citation (including language)

• Country

• Setting

• Inclusion and exclusion criteria

• Study design and methodology

• Study population and disease characteristics

  • Total number enrolled

  • Participant characteristics

  • Age

  • Co‐morbidities

  • Other baseline characteristics

  • Surgical technique (laparotomy, laparoscopy or robotic‐assisted procedure)

  • Estimated blood loss (mL)

  • Stage of cervical cancer

  • Histopathological subtype of cervical cancer

  • Tumour size (largest tumour diameter)

  • Lymphadenectomy details including technique (sampling versus complete dissection) and status of lymph nodes (negative or positive for metastasis)

  • Radicality of the operation

  • Operative time (minutes)

  • Postoperative adjuvant treatment received and indication

• Intervention details

  • Nerve‐sparing radical hysterectomy

• Comparison

  • Conventional radical hysterectomy

• Risk of bias in study (see below)

• Duration of follow‐up

• Outcomes: for each outcome, we will extract the outcome definition and unit of measurement (if relevant). For adjusted estimates, we will record variables adjusted for in analyses.

• Results: we will extract the number of participants allocated to each intervention group, the total number analysed for each outcome and the missing participants.

• Notes: funding for trial and notable conflicts of interest of trial authors.

We will extract results as follows.

• For time‐to‐event data (survival outcomes and time to post void residual urine ≤ 50 mL after operation ), we will extract the log of the hazard ratio (log(HR)) and its standard error from trial reports. If these are not reported, we plan to estimate the log (HR) and its standard error using the methods of Parmar 1998.

• For dichotomous outcomes (e.g. adverse events and urinary tract infection), we will extract the number of women in each treatment arm who experienced the outcome of interest and the number of women assessed at endpoint, in order to estimate a risk ratio (RR).

• For continuous outcomes (e.g. time to postvoid residual urine ≤ 50 mL after operation, volume of postvoid residual urine and QoL measures), we will extract the final value and standard deviation of the outcome and the number of women assessed at endpoint in each treatment arm at the end of follow‐up, in order to estimate the mean difference between treatment arms (if trials measured outcomes on the same scale) or standardised mean difference (if trials measured outcomes on different scales) between treatment arms and its standard error.

Where possible, we intend to extract data according to an intention‐to‐treat analysis, in which participants will be analysed in the groups to which they were assigned.

Assessment of risk of bias in included studies

We will assess and report on the methodological quality and risk of bias of included studies in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), which recommends the explicit reporting of the following individual issues for RCTs.

• Selection bias: random sequence generation and allocation concealment

• Performance bias: blinding of participants and personnel (participants and outcome assessors)

• Detection bias: blinding of outcome assessment

• Attrition bias: incomplete outcome data (i.e. incomplete follow‐up outcomes and treatment‐related complications)

• Reporting bias: selective reporting of outcomes

• Other potential bias

Two review authors (CK and AA) will apply the 'Risk of bias' tool independently and resolve differences by discussion or by appeal to a third review author (KG or PL). We will judge each item as being at high, low or unclear risk of bias as set out in the criteria displayed in Appendix 5 (Higgins 2011). We will provide a quote from the study report or a statement (or both) as justification for the judgement for each item in the 'Risk of bias' table. We will summarize the results in both a 'Risk of bias' graph and a 'Risk of bias' summary. When interpreting treatment effects and meta‐analyses, we will take into account the risk of bias for the studies that contributed to that outcome. Where information on risk of bias relates to unpublished data, or correspondence with a trialist, we plan to note this in the table.

Measures of treatment effect

We plan to use the following measures of the effect of treatment.

• For time‐to‐event outcomes (survival outcomes and time to postvoid residual urine ≤ 50 mL after operation), we plan to use hazard ratios (HR) with 95% confidence intervals (CI).

• For dichotomous outcomes (e.g. adverse events and urinary tract infection) we plan to analyse data on the basis of the number of events and number of people assessed in the intervention and comparison groups. We will use these to calculate the RR and 95% CI.

• For continuous outcomes (e.g. volume of postvoid residual urine and QoL measures), we plan to analyse data based on the mean, standard deviation (SD) and number of people assessed for both the intervention and comparison groups to calculate the mean difference (MD) between treatment arms with a 95% CI. If the MD is reported without individual group data, we intend to use this to report the study results. If more than one study measures the same outcome using different tools, we plan to calculate the standardised mean difference (SMD) and 95% CI using the inverse variance method.

Unit of analysis issues

The units of analysis are the participants receiving interventions of interest. A study with multiple intervention groups is not applicable for this review, as we plan to compare the two interventions, namely nerve‐sparing radical hysterectomy versus standard radical hysterectomy.

Dealing with missing data

We will not impute missing outcome data for any of the outcomes. We plan to attempt to contact study authors to obtain missing data.

Assessment of heterogeneity

We will assess clinical heterogeneity by visual inspection of the forest plots. Also, we will assess statistical heterogeneity in each meta‐analysis using the I² statistic and Chi² test (Deeks 2001; Higgins 2011). We plan to perform subgroup analysis to investigate the potential heterogeneity of the included studies, if feasible. If there is evidence of substantial clinical and methodological heterogeneity across the included studies, we plan to apply a narrative review approach to data synthesis.

Assessment of reporting biases

We intend to examine funnel plots corresponding to meta‐analysis of the primary outcome to assess the potential for small study effects such as publication bias, if we identify more than 10 studies. We plan to assess funnel plot asymmetry visually (Sterne 2011).

Data synthesis

We will carry out statistical analysis using Cochrane Review Manager 5 software (Review Manager 2014). We will use the random‐effects model with inverse variance weighting for all meta‐analyses (DeSimonian 1986).

• For time‐to‐event data, we plan to pool hazard ratios using the generic inverse variance method.

• For any dichotomous outcomes, we plan to calculate the risk ratio (RR) for each study and then pool these.

• For continuous outcomes, we plan to pool the mean differences (MD) between the treatment arms, if all trials measure the outcome on the same scale; otherwise we plan to pool standardised mean differences (SMD).

Main outcomes of 'Summary of findings' table for assessing the quality of the evidence

Appendix 3 displays a 'Summary of findings' table, which we have prepared to summarize the results of the meta‐analysis based on the methods described in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011).

We will present the results of meta‐analysis and overall quality of the evidence for seven main outcomes as outlined in Types of outcome measures according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, which will take into account issues not only related to internal validity (risk of bias, inconsistency, imprecision, publication bias), but also to external validity such as directness of results (Langendam 2013). We will create a 'Summary of findings' table using GRADEpro GDT (www.gradepro.org). We will downgrade the evidence from high quality by one level for each serious limitation, or by two levels for any very serious limitation. The GRADE levels of evidence can be interpreted as shown below.

• High quality: the true effect lies close to that of the estimate of the effect.

• Moderate quality: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

• Low quality: the true effect may be substantially different from the estimate of the effect.

• Very low quality: the true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis and investigation of heterogeneity

We will carry out subgroup analysis for the following factors.

• Surgical approach technique (laparotomy versus minimally‐invasive approach i.e. laparoscopy, robotic‐assisted technique)

• Stage of the disease (Ia2‐Ib1 versus Ib2 or higher stages)

• Degree of lymph node dissection: pelvic versus pelvic and para‐aortic

We will assess subgroup differences by interaction tests available within Review Manager 5 (Review Manager 2014). We will report the results of subgroup analyses quoting the Chi² statistic and P value, the interaction test, and I² statistic values.

Sensitivity analysis

For all outcomes for which pooling are feasible, we will perform sensitivity analyses to determine the robustness of the findings by:

• repeating the analysis excluding any unpublished studies;

• repeating the analysis excluding RCTs judged to be at high or unclear risk of bias for allocation concealment.

• repeating the analysis excluding RCTs that contained women with cervical cancer other than stage Ia2 to IIa

Appendices

Appendix 1. The International Federation of Gynecology and Obstetrics (FIGO) staging for carcinoma of the cervix

FIGO Stage			Description
I			The carcinoma is confined to the cervix.
	IA		Invasive cancer identified only microscopically. (All gross lesions even with superficial invasion are Stage IB cancers.) Invasion is limited to measured stromal invasion with a maximum depth of 5 mm and no wider than 7 mm.
		IA1	Measured invasion of stroma ≤ 3 mm in depth and ≤ 7 mm width
		IA2	Measured invasion of stroma > 3 mm and < 5 mm in depth and ≤ 7 mm width
	IB		Clinical lesions confined to the cervix, or preclinical lesions greater than stage IA
		IB1	Clinical lesions no greater than 4 cm in size
		IB2	Clinical lesions > 4 cm in size
II			The carcinoma extends beyond the uterus, but has not extended onto the pelvic wall or to the lower third of vagina.
	IIA		Involvement of up to the upper two‐thirds of the vagina. No obvious parametrial involvement
		IIA1	Clinically visible lesion ≤ 4 cm
		IIA2	Clinically visible lesion > 4 cm
	IIB		Parametrial involvement, but not onto the pelvic sidewall
III			The carcinoma has extended onto the pelvic sidewall. On rectal examination, there is no cancer free space between the tumour and pelvic sidewall. The tumour involves the lower third of the vagina. All cases of hydronephrosis or non‐functioning kidney should be included unless they are known to be due to other causes.
	IIIA		Involvement of the lower vagina but no extension onto pelvic sidewall
	IIIB		Extension onto the pelvic sidewall, or hydronephrosis/non‐functioning kidney
IV			The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder and/or rectum.
	IVA		Spread to adjacent pelvic organs
	IVB		Spread to distant organs

Appendix 2. Classifications of radical hysterectomy

Piver‐Rutledge‐Smith ( Piver 1974)	Extent of surgery
Class I: extrafascial hysterectomy	Identification of ureters to avoid injury Uterine vessels are resected and ligated close to the uterine isthmus Uterosacral and cardinal ligaments are not removed No vaginal portion is excised
Class II: modified radical hysterectomy (Wertheim)	Ureters are dissected in the paracervical tissues but are not separated from the pubovesical ligament Uterine arteries are resected and ligated beside and medial the ureter Uterosacral and cardinal ligaments are excised up to the medial half portions Vagina is excised up to the upper third level Pelvic lymphadenectomy
Class III: classical radical hysterectomy (Meigs)	Complete dissection of ureters from the pubovesical ligament except for the small part where the umbilical bladder artery is located to the level of their penetration into the bladder Uterine arteries are cut off at the origin Uterosacral and cardinal ligaments are resected as close to sacral insertion and pelvic side wall, respectively Vagina is removed up to the upper half level
Class IV	Class IV differs from the Class III according to the following issues; Complete dissections of the ureters from the pubovesical ligament Umbilical artery is sacrificed Vagina is removed up to the three‐quarters level
Class V	Class V differs from Class IV with the addition of the excision of a portion of the ureter or bladder which is involved by the tumour
Querleu and Morrow ( Querleu 2008)	Extent of surgery
Type A: minimum resection of paracervix (extrafascial hysterectomy)	The position of ureters are determined by palpation or direct vision without freeing from their beds The paracervix is transected medial to the ureter but lateral to the cervix The uterosacral and vesicouterine ligaments are not transected at the distance from the uterus Vaginal resection is at a minimum, generally less than 10 mm without removal of the paracolpos
Type B: transection of paracervix at the ureter	B1	Ureters are unroofed and dissected laterally, permitting transection of the paracervix at the level of the ureteral tunnel The posterior and deep neural component of the paracevix caudal to the deep uterine vein is not resected At least 10 mm of the vagina from the cervix or tumour is excised
	B2	As described in B1 with additional removal of the lateral paracervical lymph nodes
Type C: transection of paracervix at junction with internal iliac vascular system	C1	Uterosacral ligament is transected at the sacral insertion Vesicouterine ligament is transected at the bladder Ureters are mobilised completely Vagina is excised at least 15‐20 mm from the tumour and the corresponding paracolpos is resected routinely WITH the preservation of the autonomic nerves
	C2	As described in C1 but WITHOUT the preservation of the autonomic nerves
Type D: Laterally extended resection	D1	Resection of the entire paracervix at the pelvic side wall along with the hypogastric vessels, exposing the roots of the sciatic nerve Total resection of the vessels of the lateral part of the paracervix
	D2	As described in D1 plus resection of the entire paracervix with the hypogastric vessels and adjacent fascia and muscles
GCG‐EORTC a (Mota 2008)	Extent of surgery
Type I	Simple hysterectomy
Type II: modified radical hysterectomy b	The uterus, paracervix and upper vagina (10‐20 mm) are removed after dissection of the ureters to the point of their entry to the bladder Uterine arteries are cut off and ligated Medial half of parametria and proximal uterosacral ligaments are transected
Type III: radical hysterectomy b	En bloc removal of the uterus with the upper third of the vagina along with the paracervical and paravaginal tissues Uterine arteries are cut off and ligated at their origin The entire width of the parametria is resected bilaterally The entire uterosacral ligament is resected
Type IV: extended radical hysterectomy b	Differs from Type 3, as three‐quarters of the vagina and paravaginal tissues are resected
Type V: partial exenterationb	Terminal ureters or segments of bladder or rectum are resected along with the uterus and parametria

^a Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer ^b in conjunction with a systematic bilateral pelvic lymphadenectomy

Appendix 3. 'Summary of findings' table

Title: Nerve‐sparing radical hysterectomy compared to standard radical hysterectomy for women with early stage cervical cancer (stage Ia2 to IIa)
Patient or population: women with stage Ia2 to IIa cervical cancer Settings: specialist hospital Intervention: nerve‐sparing radical hysterectomy with pelvic lymph node dissection Comparison: standard radical hysterectomy with pelvic lymph node dissection
Outcomes	Illustrative comparative risks*		Relative effect (95% CI)	Number of participants (studies)	Quality of evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
Overall survival
Rate of ISC at 1 month after operation
Time to postvoid residual volume of urine ≤ 50 mL after operation
Postvoid residual volume of urine at 1 month
Rate of adverse events (excluding bladder dysfunction)
Disease‐free survival
Quality of life
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; ISC: intermittent self‐catheterisation; MD: mean difference; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: there is uncertain about the estimate.

Appendix 4. MEDLINE Ovid search strategy

1. Uterine Cervical Neoplasms/ 2. (cervi* adj5 (cancer* or tumor* or tumour* or neoplas* or carcinoma* or adenocarcinoma* or malignan*)).mp. 3. 1 or 2 4. exp Hysterectomy/ 5. hysterectom*.mp. 6. ((uter* or womb) adj5 (remov* or excis*)).mp. 7. 4 or 5 or 6 8. Urinary Bladder/ 9. Urinary Catheterization/ 10. exp Urinary Bladder Diseases/ 11. exp Lower Urinary Tract Symptoms/ 12. exp Urination Disorders/ 13. exp Urinary Tract Infections/ 14. Urination/ 15. ((bladder* or urethra* or ureter* or urin* or urologic*) adj5 (dysfunction* or disorder* or disease* or infect* or incontinence* or urgenc* or injur* or damage*)).mp. 16. 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 17. 3 and 7 and 16

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

Appendix 5. 'Risk of bias' assessment

'Risk of bias' assessment based on Chapter 8 of Higgins 2011:

• Random sequence generation

  • Low risk of bias, e.g. participants assigned to treatments on the basis of a computer‐generated random sequence or a table of random numbers.

  • High risk of bias, e.g. participants assigned to treatments on the basis of date of birth, clinic ID number or surname, or no attempt to randomise participants.

  • Unclear risk of bias, e.g. not reported, information not available.

• Allocation concealment

  • Low risk of bias, e.g. where the allocation sequence could not be foretold.

  • High risk of bias, e.g. allocation sequence could be foretold by patients, investigators or treatment providers.

  • Unclear risk of bias, e.g. not reported.

• Blinding of participants and personnel

  • Low risk of bias if participants and personnel were adequately blinded.

  • High risk of bias if participants were not blinded to the intervention that the participant received.

  • Unclear risk of bias if this was not reported or unclear.

• Blinding of outcomes assessors

  • Low risk of bias if outcome assessors were adequately blinded.

  • High risk of bias if outcome assessors were not blinded to the intervention that the participant received.

  • Unclear risk of bias if this was not reported or is unclear.

• Incomplete outcome data: we will record the proportion of participants whose outcomes were not reported at the end of the study. We will code a satisfactory level of loss to follow‐up for each outcome as:

  • Low risk of bias, e.g. if fewer than 20% of participants were lost to follow‐up and reasons for loss to follow‐up were similar in both treatment arms

  • High risk of bias, e.g. if more than 20% of participants were lost to follow‐up or reasons for loss to follow‐up differed between treatment arms.

  • Unclear risk of bias, e.g. if loss to follow‐up was not reported.

• Selective reporting of outcomes

  • Low risk of bias, e.g. review reports all outcomes specified in the protocol.

  • High risk of bias, e.g. it is suspected that outcomes have been selectively reported in the study.

  • Unclear risk of bias, e.g. it is unclear whether outcomes have been selectively reported.

• Other bias

  • Low risk of bias, e.g. the review authors do not suspect any other source of bias and the trial appears to be methodologically sound.

  • High risk of bias, e.g. the review authors suspect that the trial was prone to an additional bias.

  • Unclear risk of bias, e.g. the review authors are uncertain whether an additional bias may have been present.

Contributions of authors

Chumnan Kietpeerakool (CK): conceived the review question, developed, co‐ordinated and completed the protocol Apiwat Aue‐aungkul (AA): conceived the review question, developed, and completed the protocol Khadra Galaal (KG): developed, and completed the protocol Chetta Ngamjarus (CN): performed part of the editing of the protocol and advised on part of the protocol Pisake Lumbiganon (PL): co‐ordinated the development of the protocol, edited the protocol and advised on the protocol

Sources of support

Internal sources

• Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen University, Thailand.

• Gynaecological Oncology, Princess Alexandra Wing, Royal Cornwall Hospital, Truro, UK.

• Department of Biostatistics and Demography, Faculty of Public Health, Khon Kaen University, Thailand.

• Cochrane Thailand, Thailand.

External sources

• Thailand Research Fund (Distinguished Professor Award), Thailand.

Declarations of interest

CK: nothing to declare AA: nothing to declare KG: nothing to declare CN: nothing to declare PL: nothing to declare

New