Intervention Review

You have free access to this content

Surgical treatment of stage IA2 cervical cancer

  1. Fani Kokka1,*,
  2. Andrew Bryant2,
  3. Elly Brockbank3,
  4. Arjun Jeyarajah3

Editorial Group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

Published Online: 29 MAY 2014

Assessed as up-to-date: 30 SEP 2013

DOI: 10.1002/14651858.CD010870.pub2


How to Cite

Kokka F, Bryant A, Brockbank E, Jeyarajah A. Surgical treatment of stage IA2 cervical cancer. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD010870. DOI: 10.1002/14651858.CD010870.pub2.

Author Information

  1. 1

    Queen Elizabeth The Queen Mother Hospital, Women's Health, Birchington Ward, Kent, UK

  2. 2

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

  3. 3

    St. Bartholomew's Hospital, Department of Gynaecological Oncology, London, UK

*Fani Kokka, Women's Health, Birchington Ward, Queen Elizabeth The Queen Mother Hospital, St Peters Road, Kent, CT9 4AN, UK. fani.kokka@nhs.net. kokkaf@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 29 MAY 2014

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 up to 65 years of age and is the most frequent cause of death from gynaecological cancers worldwide (GLOBOCAN 2008). A woman's risk of developing cervical cancer by age 65 years ranges from 0.69% in developed countries to 1.38% in developing countries (GLOBOCAN 2008). The age-standardised rate of cervical cancer varies between countries from 4 to 30 cases per year in 100,000 women under 75 years of age. In Europe, about 60% of women with cervical cancer are alive 5 years after diagnosis (EUROCARE 2003).

Cervical cancer is staged according to the International Federation of Gynecology and Obstetrics (FIGO) system (Benedet 2003), which is based on findings from clinical examination (Appendix 1). Stage I cervical cancer is confined to the cervix. Stage I is divided into stage IA and IB. Stage IA is the earliest stage of cervical cancer where the cancer is so small it cannot be seen with the naked eye; however, visual inspection with a colposcope after application of acetic acid (vinegar) may demonstrate features suggestive of invasion (Shastri 2013). Stage IA is subdivided further to stages IA1 and IA2. Women with FIGO stage IA2 cervical cancer have measured stromal invasion (when the cancer breaks through the basement membrane of the epithelium) of greater than 3 mm and no greater than 5 mm in depth with a horizontal surface extension of no more than 7 mm.

It is well recognised that survival rates decrease with increasing stage at presentation. Women with lesions less than 4 cm in diameter and confined to the cervix (FIGO stage IB1) at presentation have a five-year survival rate of 92%, while women with cancer spread beyond the true pelvis to adjacent organs (FIGO stage IVA) have a five-year survival rate of only 17% (Jemal 2008).

Survival in cervical cancer is negatively associated with the incidence of pelvic and para-aortic lymph node metastasis. The incidence of pelvic and para-aortic lymph node metastasis in cervical cancer increases with stage (Eifel 1997), and this increase becomes more significant for stage IB2 and above (21% pelvic lymph node metastasis in tumours less than 3 cm versus 35% pelvic lymph nodes metastasis in tumours greater than 3 cm) (Piver 1975). In women with FIGO stage IA2 cervical cancer, the mean incidence of pelvic lymph node metastasis is 10% (Magrina 2001). However, evidence suggests that correctly staged IA2 cases have much lower incidence of lymph node metastases (Creasman 1998; Rogers 2009).

 

Description of the intervention

For stage IA2, radical hysterectomy with pelvic lymphadenectomy or radiotherapy have been the standard treatments depending on age, medical co-morbidities and other clinicopathological features (ESGO 2010; Hoskins 1976; Morley 1976; NCI 2014; Newton 1975; NICE 2010). Both treatments (surgical and radiotherapy) have similar efficacy (Eifel 1993). This review will focus on the surgical management of stage IA2 cervical cancer.

In the surgical treatment of stage IA2 cervical cancer, pelvic lymph nodes are removed by open or laparoscopic procedure because the cancer can spread to these lymph nodes first. Obturator nerve injury, lymphocyst formation and lymphoedema are side effects specifically associated with the removal of the lymph nodes. In order to avoid the morbidity of complete lymphadenectomy, sentinel lymph node (SLN) biopsy may be used to target lymph node metastases (Lecuru 2011). The SLN is the first node to receive lymphatic drainage from the primary tumour, so when nodal metastases occur, the SLN will theoretically be the first node involved. If the SLN does not contain metastatic malignant cells, then the remainder of the lymph nodes are presumed to be negative for metastatic disease. The SLN approach for cervical cancer is not routinely practised as yet and is largely limited to clinical studies/trials.

The primary site of the cervical cancer is removed with radical hysterectomy or radical trachelectomy, depending on whether the woman wants to preserve fertility.

Radical hysterectomy involves the removal of the cervix, uterus, the upper part of the vagina (removal of a vaginal cuff with the aim of a tumour-free margin of 2 cm) and the tissues around the cervix (parametrial tissue). Although this type of surgery has excellent treatment outcomes, it does carry potentially significant side effects including: vascular (blood vessel), ureteric, bladder injury, deep venous thrombosis, pulmonary embolism, fistula formation and urinary/bowel/sexual dysfunction (Achouri 2013; Bergmark 1999; Frumovitz 2005; Kadar 1983; Low 1981; Sood 2002).

An alternative surgical option for women with stage IA2 cervical cancer, who are interested in future fertility, is radical trachelectomy. Radical trachelectomy involves removing the cervix, upper part of the vagina (removal of a vaginal cuff with the aim of a tumour-free margin of 2 cm) and the parametrial tissue (Shepherd 1998). Radical trachelectomy is a well-established conservative approach and appears to be safe and effective in when performed by an experienced surgeon in allowing a high chance of future conception. Late miscarriage and prematurity are the most serious issues in pregnancies following trachelectomy. In addition, women who become pregnant after radical trachelectomy need to deliver by elective caesarean section, since a permanent suture is placed around the upper cervix to prevent the cervix opening prematurely in pregnancy. Although caesarean section is generally considered a safe operation, it is still a major abdominal surgery with all its associated risks. Other side effects of radical trachelectomy include ureteric and bladder injury, and fistula formation. These risks are higher when extensive cervical and parametrial tissue is removed (Burnett 2003; Dargent 2000; Nishio 2009; Plante 2004; Shepherd 2006; Ungár 2005). Of note, parametrial involvement with cancerous cells in clinical stage IA2 disease is uncommon (Schmeler 2011). In women who underwent radical surgery for clinical stage IA1 or IA2 and IB1 cervical cancer, the incidence of parametrial involvement in women with tumour size 2 cm or less, negative pelvic lymph nodes and depth of invasion 10 mm or less was 0.6% (Covens 2002). Other studies showed similar results and women at low risk for parametrial spread are considered those with negative pelvic lymph nodes, no lymphovascular space invasion (LVSI) and tumours less than 2 cm (Frumovitz 2009; Kinney 1995; Steed 2006; Stegeman 2007; Strnad 2008; Wright 2007).

The clearance of the central cervical cancer and the removal of the pelvic lymph glands can be performed by a combination of approaches (abdominal or vaginal, laparoscopic or robotic) (Persson 2012; Wright 2012).

 

Why it is important to do this review

In order to avoid complications of more radical surgical methods, while not negatively impacting on cancer recurrence or survival rates, less invasive options, such as simple hysterectomy, simple trachelectomy or conisation, with or without pelvic lymphadenectomy, may be feasible for stage IA2 disease, considering the relative low risk of local or distant metastatic disease. The evidence for less radical tumour excision and the therapeutic role of systematic lymphadenectomy in stage IA2 cervical cancer is not clear.

 

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 evaluate the effectiveness and safety of less radical surgery in stage IA2 cervical cancer.

 

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

 

Types of studies

  • Randomised controlled trials (RCTs).

 

Types of participants

Adult women (aged 18 years or older) with a confirmed histological diagnosis of stage IA2 cervical cancer.

 

Types of interventions

 

Intervention for central tumour clearance

Simple hysterectomy

  • abdominal: open or laparoscopic
  • vaginal: local excision of the cervix (knife cone biopsy, large loop excision of the transformation zone (LLETZ), needle excision of the transformation zone (NETZ), trachelectomy

versus

Radical hysterectomy

  • abdominal: open or laparoscopic
  • vaginal

or

Radical trachelectomy

  • abdominal (open or laparoscopic)
  • vaginal

 

Intervention for systematic pelvic lymph node dissection

  • systematic pelvic lymph node dissection (open or laparoscopic procedure)

versus

  • no systematic pelvic lymph node dissection

 

Types of outcome measures

 

Primary outcomes

  • Overall survival (OS): survival until death from all causes. Survival was assessed from the time when women were enrolled in the study.

 

Secondary outcomes

  • Progression-free survival (PFS) (or disease progression or recurrence).
  • Quality of life (QoL), measured using a scale that has been validated through reporting of norms in a peer-reviewed publication.

  • Adverse events, classified according to CTCAE 2006, for example: direct surgical morbidity (e.g. injury to bladder, ureter, vascular, nerve, small bowel or colon, presence and complications of adhesions, febrile morbidity, intestinal obstruction, haematoma, local infection); surgically related systemic morbidity (chest infection, thrombo-embolic events, cardiac events, cerebrovascular accident, length of stay, delayed discharge, unscheduled re-admission); radiotherapy toxicity; long-term surgical complications (bladder/bowel dysfunction, fistula/lymphocyst formation, lymphoedema, psychosexual complications); other side effects not categorised above.

  • Grades of toxicity extracted and grouped as: haematological (leukopenia, anaemia, thrombocytopenia, neutropenia, haemorrhage); gastrointestinal (nausea, vomiting, anorexia, diarrhoea, liver, proctitis) and genitourinary.

 

Search methods for identification of studies

We searched for papers in all languages and carried out translations, if necessary.

 

Electronic searches

See: Cochrane Gynaecological Cancer Group methods used in reviews.

We searched the following electronic databases: the Cochrane Gynaecological Cancer Review Group Specialised Register; Cochrane Register of Controlled Trials (CENTRAL); MEDLINE and EMBASE from 1966 to September 2013.

The CENTRAL, MEDLINE AND EMBASE search strategies are presented in Appendix 2; Appendix 3; and Appendix 4, respectively.

All relevant articles found were identified on PubMed and, using the 'related articles' feature, we carried out further searches for newly published articles.

 

Searching other resources

 

Unpublished and grey literature

We conducted a Google search for Internet-based resources and open-access publications. We searched metaRegister (www.controlled-trials.com/rct, Physicians Data Query (www.nci.nih.gov), www.clinicaltrials.gov and www.cancer.gov/clinicaltrials for ongoing trials. Two ongoing trials were identified through these searches; however, these studies are still actively recruiting and only one was a definitive Phase 3 comparative trial (NCT01658930).

We searched conference proceedings and abstracts through ZETOC (zetoc.mimas.ac.uk) and WorldCat Dissertations.

We also contacted an expert in the field: Mr David Oram.

 

Handsearching

We handsearched the citation lists of included studies, key textbooks and previous systematic reviews.

We handsearched reports of conferences in the following sources:

  • Society of Gynecologic Oncology (Annual Meeting of the American Society of Gynecologic Oncology);
  • International Journal of Gynecological Cancer (Biannual Meeting of the International Gynaecologic Cancer Society);
  • British Journal of Cancer (BJC);
  • British Society of Gynaecological Cancer (BGCS);
  • British Cancer Research Meeting;
  • Annual Meeting of European Society of Medical Oncology (ESMO);
  • Annual Meeting of the American Society of Clinical Oncology (ASCO).

 

Data collection and analysis

 

Selection of studies

We downloaded all titles and abstracts retrieved by electronic searching to the reference management database Endnote and removed duplicates. Two review authors (FK, AB) independently examined the remaining references. There were several case reports and retrospective studies in this area; however, none were of sufficient quality or met the inclusion criteria, so we did not alter our inclusion criteria to accommodate non-randomised studies (see Agreements and disagreements with other studies or reviews for details of these studies). We excluded all studies at this stage, as they clearly did not meet the inclusion criteria. We identified one ongoing RCT that met our inclusion criteria. In future updates of the review, we will include the results of this trial and we will employ the methods found in the Differences between protocol and review.

 

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 search strategy identified 367 references in MEDLINE, 762 in EMBASE and 236 in CENTRAL. When the search results were merged into Endnote and duplicates were removed, there were 982 unique references. Two review authors (FK, AB) independently read the abstracts and excluded all studies because they did not meet the inclusion criteria.

Two review authors (FK, EB) independently searched the grey literature; these searches also did not identify any relevant studies.

We identified two relevant ongoing trials (NCT01048853; NCT01658930), but one trial is an early Phase trial examining conservative surgery and does not have a comparison group (NCT01048853). The NCT01658930 trial is a definitive Phase 3 trial comparing simple hysterectomy versus radical hysterectomy in women with low-risk early-stage cervical cancer (see Characteristics of ongoing studies).

 

Risk of bias in included studies

We found no completed trials and, therefore, the 'Risk of bias' tool was not applied.

 

Effects of interventions

No data were available for analysis.

 

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

We identified no relevant and eligible completed RCTs examining different surgical techniques in women with stage IA2 cervical cancer, therefore the question of whether different types of surgery are associated with a survival benefit, in terms of OS and PFS, cannot be answered by this review.

The prognosis for women with stage IA2 cervical cancer treated with standard surgery is excellent with a five-year survival of 95% to 98% (Cancer Research UK). In order to change our practice to less radical or non-radical surgery, we must ensure that the oncological outcomes remain excellent. QoL may be of less importance in women with stage IA2 disease than in women with more advanced disease, where prognosis is not as good. However, its relevance as a secondary outcome remains high, especially as many women will be younger at the time of diagnosis and, therefore, potentially have years where adverse effects may have an impact. In current and future trials, primary survival outcomes, as well as a thorough examination of QoL and severe short- and long-term adverse events and toxicity of adjuvant treatment as secondary outcomes, should be reported. This would allow a full examination of the benefits and harms of different surgical techniques and aftercare to aid decision making for women and their clinicians.

 

Quality of the evidence

No completed studies met the inclusion criteria for this review, resulting in no evidence to assess.

 

Potential biases in the review process

We performed a comprehensive search, including a thorough search of the grey literature, and two review authors independently sifted all references. We were restrictive in our inclusion criteria with regards to types of studies, as we planned to include only RCTs due to high risk of selection bias in non-randomised studies. Our search strategies were designed with an RCT filter so it was not possible to ascertain whether relaxing our inclusion criteria would have identified relevant non-randomised studies that used appropriate statistical adjustment or were of adequate quality. We attempted to re-run the searches without the RCT filter, but there were a substantial number of references identified and we decided that highlighting a lack of evidence from RCTs was a significant finding in itself and thought it was better to highlight the need for RCTs rather than report the results of low-quality studies that may be misleading.

The greatest threat to the validity of the review is likely to be publication bias, that is, studies that found insignificant or unfavourable results may not have been published. We were unable to assess this possibility, as we did not find any studies that met the inclusion criteria, despite searching the grey literature.

 

Agreements and disagreements with other studies or reviews

Less radical or non-radical surgery in carefully selected women with stage IA2 cervical cancer may reduce the morbidity of radical surgical treatments, especially the long-term side effects of autonomic dysfunction. Based on previous reviews (Reade 2013; Schmeler 2011), and retrospective studies (Covens 2002; Frumovitz 2009; Kinney 1995; Steed 2006; Stegeman 2007; Strnad 2008; Wright 2007), which suggest there is a very small risk of parametria and pelvic lymph node metastasis in low-risk stage IA2 cervical cancer, less radical or non-radical surgery may be an option in these cases. However, this systematic review of the current literature found no RCTs and there is a lack of evidence that this is a safe and effective alternative treatment.

However, we identified two ongoing trials examining different surgical techniques in women with stage IA2 cervical cancer, although only one meets our inclusion criteria (see Characteristics of ongoing studies)

1. NCT01048853: conservative surgery for women with cervical cancer

  • US multicentre trial comparing standard surgery (radical hysterectomy or radical trachelectomy and pelvic lymph node with or without para-aortic lymph node dissection) in low-risk, early-stage cervical cancer versus conservative surgery (simple hysterectomy and pelvic lymph node dissection).
  • Women desiring future fertility undergo cervical conisation and pelvic lymph node dissection only.

The estimated primary completion date is August 2015.

2. NCT01658930: radical versus simple hysterectomy and pelvic node dissection in patients with early-stage cervical cancer

  • International, multicentre trial comparing standard surgery (radical hysterectomy and pelvic lymph node dissection) in low-risk, early-stage cervical cancer versus conservative surgery (simple hysterectomy and pelvic lymph node dissection).

The estimated primary completion date is September 2019.

However, these are ongoing trials (and only the NCT01658930 is a comparative Phase 3 trial), therefore the question of whether different types of surgery are associated with a survival benefit in terms of OS and PFS cannot be answered by this review.

 

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

We are unable to reach any conclusions as to the effectiveness and safety of different surgical techniques in the treatment of stage IA2 cervical cancer. Consequently, clinical practice is likely to remain unchanged and unchallenged. It is very unlikely that any clear recommendation about the type of surgery that should be offered can be made from non-randomised studies alone. Surgical trials often present a greater challenge than trials examining other treatment modalities, but this should not be cited as a reason for not conducting one. Trialists need to be pro-active in this area as there is currently a substantial gap in the evidence.

 
Implications for research

We found no evidence to inform decisions about different surgical techniques in women with stage IA2 cervical cancer. Hopefully, the one large current ongoing RCT identified (NCT01658930) and the possibility that the other ongoing trial (NCT01048853) will progress to a definitive Phase 3 trial, will allow an assessment of the role of less conservative surgery in stage IA2, low-risk cervical cancer in the future. These multicentre trials aim to recruit large numbers of participants and this will help to increase the power of the trials and the nature of the NCT01658930 trial should at the very least offer internal validity as it is multicentre in Canada. A sufficiently large trial could also consider factors such as histological type of tumour, presence or absence of lymphovascular space invasion, depth of stromal invasion, tumour size, age, adjuvant treatment in an attempt to assist in individualising treatment in clinical practice.

 

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

We thank Jo Morrison for clinical and editorial advice, Jane Hayes for designing the search strategy, and Gail Quinn and Clare Jess for their contribution to the editorial process. We also thank Mr David Oram for his expert opinion and the referees for many helpful suggestions and comments.

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, National Health Service (NHS) or the Department of Health.

 

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

This review has no analyses.

 

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. Cervical cancer staging


International Federation of Gynecology and Obstetrics (FIGO) classification for cervical cancer

STAGE CHARACTERISTICS

ICarcinoma is strictly confined to the cervix (extension to the corpus should be disregarded).

IAInvasive cancer identified only microscopically. All gross lesions, even with superficial invasion, are stage IB cancers. Invasion is limited to a measured stromal invasion with a maximal depth of 5 mm and a horizontal extension of not > 7 mm. Depth of invasion should not be > 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates. Vascular space involvement, either venous or lymphatic, should not alter the staging.

IA1 Measured stromal invasion of not > 3 mm in depth and extension of not > 7 mm.

IA2 Measured stromal invasion of > 3 mm and not > 5 mm in depth with an extension of not > 7 mm.

IB Clinical lesions confined to the cervix or preclinical lesions > IA. All gross lesions even with superficial invasion are stage IB cancers.

IB1 Clinical lesions not > 4 cm in size.

IB2 Clinical lesions > 4 cm in size.

IIThe carcinoma extends beyond the cervix, but has not extended onto the pelvic wall; the carcinoma involves the vagina, but not as far as the lower third.

IIANo obvious parametrial involvement. Involvement of up to the upper two-thirds of the vagina.

IIBObvious parametrial involvement, but not into the pelvic sidewall.

IIIThe carcinoma has extended onto the pelvic wall; on rectal examination there is no cancer-free space between the tumour and the pelvic wall; the tumour involves the lower third of the vagina; all cases with a hydronephrosis or non-functioning kidney should be included, unless they are known to be due to other causes.

IIIA No extension onto the pelvic wall, but involvement of the lower third of the vagina.

IIIB Extension onto the pelvic wall or hydronephrosis or non-functioning kidney.

IVThe carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum.

IVASpread of the growth to adjacent organs.

IVBSpread to distant organs.



 

Appendix 2. CENTRAL search strategy

  1. MeSH descriptor: [Uterine Cervical Neoplasms] explode all trees
  2. (cervi* near/5 (cancer* or neoplas* or tumor* or tumour* or malignan* or carcinoma* or adenocarcinoma*))
  3. #1 or #2
  4. MeSH descriptor: [Hysterectomy] explode all trees
  5. MeSH descriptor: [Conization] this term only
  6. MeSH descriptor: [Lymph Node Excision] explode all trees
  7. (hysterectom* or trachelectom* or cone biopsy or conization or conisation or lymphadenectom* or (lymph* near/5 (dissect* or excis* or surg*)))
  8. #4 or #5 or #6 or #7
  9. #3 and #8

 

Appendix 3. MEDLINE search strategy

MEDLINE Ovid

  1. Uterine Cervical Neoplasms/
  2. (cervi* adj5 (cancer* or neoplas* or tumor* or tumour* or malignan* or carcinoma* or adenocarcinoma*)).mp.
  3. 1 or 2
  4. exp Hysterectomy/
  5. Conization/
  6. exp Lymph Node Excision/
  7. (hysterectom* or trachelectom* or cone biopsy or conization or conisation or lymphadenectom* or (lymph* adj5 (dissect* or excis* or surg*))).mp.
  8. 4 or 5 or 6 or 7
  9. 3 and 8
  10. randomized controlled trial.pt.
  11. controlled clinical trial.pt.
  12. randomized.ab.
  13. placebo.ab.
  14. clinical trials as topic.sh.
  15. randomly.ab.
  16. trial.ti.
  17. 10 or 11 or 12 or 13 or 14 or 15 or 16
  18. 9 and 17

key:
mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier
pt=publication type
ab=abstract
ti=title
sh=subject heading

 

Appendix 4. EMBASE search strategy

EMBASE Ovid

  1. exp uterine cervix tumor/
  2. (cervi* adj5 (cancer* or neoplas* or tumor* or tumour* or malignan* or carcinoma* or adenocarcinoma*)).mp.
  3. 1 or 2
  4. exp hysterectomy/
  5. uterine cervix conization/
  6. uterine cervix biopsy/
  7. exp lymph node dissection/
  8. (hysterectom* or trachelectom* or cone biopsy or conization or conisation or lymphadenectom* or (lymph* adj5 (dissect* or excis* or surg*))).mp.
  9. 4 or 5 or 6 or 7 or 8
  10. 3 and 9
  11. crossover procedure/
  12. double-blind procedure/
  13. randomized controlled trial/
  14. single-blind procedure/
  15. random*.mp.
  16. factorial*.mp.
  17. (crossover* or cross over* or cross-over*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
  18. placebo*.mp.
  19. (double* adj blind*).mp.
  20. (singl* adj blind*).mp.
  21. assign*.mp.
  22. allocat*.mp.
  23. volunteer*.mp.
  24. 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23
  25. 10 and 24

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

 

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: 30 September 2013.


DateEventDescription

1 April 2015AmendedContact 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

Protocol first published: Issue 12, 2013
Review first published: Issue 5, 2014


DateEventDescription

11 February 2015AmendedContact details updated.

23 October 2014AmendedOn-going trail (NCT01658930) contact information updated.



 

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

Andrew Bryant and Fani Kokka prepared the final version of the review.

Eleanor Brockbank and Arjun Jeyarajah gave final approval of the version to be published.

The team of authors have reviewed this version and comments have been incorporated.

 

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

There are no conflicts of interest.

 

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-10/4001/12

 

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

We did not identify any trials that met the inclusion criteria. In future updates of the review, we will employ the following methods:

 

Selection of studies

We will obtain copies of the full text of relevant references. We will assess the eligibility of retrieved papers independently by two review authors (FK, AB). We will resolve disagreements by discussion between the two review authors. We will document reasons for exclusion.

 

Data extraction and management

For included studies, data will be abstracted as recommended in Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions 2012. This will include data 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
    • participant characteristics
    • age
    • co-morbidities
    • previous treatment

  • cervical cancer details at diagnosis
    • stage
    • grade
    • histology
  • intervention details
    • simple hysterectomy
      • abdominal (open or laparoscopic)
      • vaginal
    • local excision (knife cone biopsy, LLETZ, NETZ, trachelectomy)
    • extent of tumour excision (cervical, parametrial, vaginal tissue removed)
    • no systematic pelvic lymph node dissection

  • comparison details
    • radical hysterectomy
      • abdominal (open or laparoscopic)
      • vaginal
    • radical trachelectomy
      • abdominal (open or laparoscopic)
      • vaginal
    • systematic pelvic lymph node dissection
      • (open or laparoscopic procedure)
    • extent of lymphadenectomy (pelvic with or without para-aortic, number of lymph nodes removed)

  • risk of bias in study (see below)
  • duration of follow-up
  • outcomes - OS and PFS, QoL and severe adverse events
    • for each outcome: outcome definition (with diagnostic criteria if relevant)
    • unit of measurement (if relevant)
    • for scales: upper and lower limits, and whether high or low score is good
    • results: number of participants allocated to each intervention group
    • for each outcome of interest: sample size; missing participants

We will extract data on outcomes as below.

  • For time-to-event (OS and PFS) data, we will extract the log of the hazard ratio [log(HR)] and its standard error from trial reports; if these are not reported, we will attempt to estimate them from other reported statistics using the methods of Parmar 1998.
  • For dichotomous outcomes (e.g. adverse events), we will extract the number of women in each treatment arm who experience 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. QoL), we will extract the final value and standard deviation of the outcome of interest 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 (MD) (if trials measured outcomes on the same scale) or standardised mean differences (SMD) (if trials measured outcomes on different scales) between treatment arms and the standard error.

Where possible, all data extracted will be those relevant to an intention-to-treat analysis, in which women are analysed in the groups to which they were assigned.

We will note the time points at which outcomes were collected and reported.

Two review authors (FK, EB) will independently abstract the data onto a form specially designed for the review. We will resolve differences by discussion or by appeal to a third review author (AB).

 

Assessment of risk of bias in included studies

We will assess the risk of bias in included RCTs in accordance with guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using The Cochrane Collaboration's 'Risk of bias' tool and the criteria specified in Chapter 8. This will include assessment of:

  • sequence generation;
  • allocation concealment;
  • blinding (restricted to blinding of outcome assessors as not possible to blind participants and healthcare providers);
  • incomplete outcome data:
    • we will record the proportion of participants whose outcomes are not reported at the end of the study. We will code the satisfactory level of loss to follow-up for each outcome as:
      • low risk, if less than 20% of participants are lost to follow-up and reasons for loss to follow-up are similar in both treatment arms,
      • high risk, no, if more than 20% of participants are lost to follow-up or reasons for loss to follow-up are different between treatment arms,
      • unclear risk if loss to follow-up is not reported or reported in insufficient detail to make a judgement;
  • selective reporting of outcomes;
  • other possible sources of bias.

We will apply the 'Risk of bias' tool and resolve differences by discussion or by appeal to a third review author (AB). We will summarise results will be summarised in both a risk of bias graph and a risk of bias summary figure. We will interpret results of meta-analyses in light of the findings with respect to risks of bias.

 

Measures of treatment effect

We will use the following measures of the effect of treatment.

  • For time-to-event data, we will use the hazard ratio (HR), if possible.
  • For dichotomous outcomes, we will use the RR.
  • For continuous outcomes, we will use the MD between treatment arms.

 

Dealing with missing data

We will not impute missing outcome data for the primary outcome. If data are missing or only imputed data are reported, we will contact trial authors to request data on the outcomes only among participants who were assessed.

 

Assessment of heterogeneity

We will assess heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage heterogeneity (I2 statistic) between trials that cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001), and, if possible, by subgroup analyses (Subgroup analysis and investigation of heterogeneity). If there is evidence of substantial heterogeneity, we will investigate and report the possible reasons for this.

 

Assessment of reporting biases

We will generate and examine funnel plots corresponding to meta-analysis of the primary outcome to assess the potential for small-study effects such as publication bias.

 

Data synthesis

If sufficient, clinically similar studies are available, we will pool their results in meta-analyses.

  • For time-to-event data, we will pool HRs using the generic inverse variance facility of Review Manager 5 (RevMan 2012).
  • For any dichotomous outcomes, we will calculate the RR for each study and will then pool these.
  • For continuous outcomes, we will pool the MDs between the treatment arms at the end of follow-up if all trials measured the outcome on the same scale; otherwise, we will pool the SMD.

If any trials have multiple treatment groups, we will divide the 'shared' comparison group into the number of treatment groups and comparisons between each treatment group and will treat the split comparison group as independent comparisons.

We will use random-effects models with inverse variance weighting for all meta-analyses (DerSimonian 1986).

 

Subgroup analysis and investigation of heterogeneity

We will conduct subgroup analyses, grouping the trials by:

  • histological type of tumour;
  • presence or absence of LVSI;
  • depth of stromal invasion;
  • tumour size;
  • age of the participants;
  • type or procedure (open or laparoscopic, abdominal or vaginal);
  • adjuvant treatment.

 

Sensitivity analysis

We will perform sensitivity analyses excluding studies at high risk of bias.

References

References to ongoing studies

  1. Top of page
  2. AbstractRésumé scientifique
  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 ongoing studies
  20. Additional references
NCT01048853 {published data only}
  • NCT01048853. Conservative surgery for women with cervical cancer. clinicaltrials.gov/show/NCT01048853 (accessed 9 May 2014).
NCT01658930 {published data only}
  • NCT01658930. Radical versus simple hysterectomy and pelvic node dissection in patients with early stage cervical cancer. clinicaltrials.gov/show/NCT01658930 (accessed 9 May 2014).

Additional references

  1. Top of page
  2. AbstractRésumé scientifique
  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 ongoing studies
  20. Additional references
Achouri 2013
Benedet 2003
Bergmark 1999
Burnett 2003
  • Burnett AF, Roman LD, O'Meara AT, Morrow CP. Radical vaginal trachelectomy and pelvic lymphadenectomy for preservation of fertility in early cervical carcinoma. Gynecologic Oncology 2003;88(3):419-23.
Cancer Research UK
  • Cancer Research UK. Cervical cancer statistics and outlook: outcome overall and by stage. www.cancerresearchuk.org/cancer-help/type/cervical-cancer/treatment/cervical-cancer-statistics-and-outlook#stage (accessed 9 May 2014).
Covens 2002
  • Covens A, Rosen B, Murphy J, Laframboise S, DePetrillo AD, Lickrish G, et al. How important is removal of the parametrium at surgery for carcinoma of the cervix?. Gynecologic Oncology 2002;84(1):145-9.
Creasman 1998
  • Creasman WT, Zaino RJ, Major FJ, DiSaia PJ, Hatch KD, Homesley HD. Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis. A Gynecologic Oncology Group study. American Journal of Obstetrics and Gynecology 1998;178(1 Pt 1):62-5.
CTCAE 2006
  • CTCAE. Common terminology criteria for adverse events. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf (accessed 9 May 2014).
Dargent 2000
Deeks 2001
  • Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. Egger M, Davey Smith G, Altman DG (eds). Systematic Reviews in Health Care: Meta-Analysis in Context. 2nd Edition. London: BMJ Publication Group, 2001.
DerSimonian 1986
Eifel 1993
Eifel 1997
  • Eifel PJ, Berek J, Thigpen JT. Cancer of the cervix, vagina and vulva. In: deVita VTJ, Hellman S, Rosenberg SA editor(s). Cancer: Principles and Practice of Oncology. 5th Edition. Philadelphia, PA: J.B. Lippincott Co, 1997:1433-77.
ESGO 2010
  • European Society of Gynaecological Oncology. Algorithms for management of cervical cancer. www.esgo.org/Education/Documents/Algorithms%20english%20version.pdf (accessed 9 May 2014).
EUROCARE 2003
  • Sant M, Aareleid T, Berrino F, Bielska Lasota M, Carli PM, Faivre J, et al: EUROCARE Working Group. EUROCARE-3: survival of cancer patients diagnosed 1990-94 - results and commentary. Annals of Oncology 2003;14(Suppl 5):v61-118.
Frumovitz 2005
  • Frumovitz M, Sun CC, Schover LR, Munsell MF, Jhingran A, Wharton JT, et al. Quality of life and sexual functioning in cervical cancer survivors. Journal of Clinical Oncology 2005;23:7428-36.
Frumovitz 2009
  • Frumovitz M, Sun CC, Schmeler KM, Deavers MT, Dos Reis R, Levenback CF, et al. Parametrial involvement in radical hysterectomy specimens for women with early-stage cervical cancer. Obstetrics and Gynecology 2009;114(1):93-9.
GLOBOCAN 2008
  • Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Cancer incidence and mortality worldwide: IARC cancer. globocan.iarc.fr (accessed 9 May 2014).
Higgins 2003
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Hoskins 1976
  • Hoskins WJ, Ford JH, Jr Lutz MH, Averette HE. Radical hysterectomy and pelvic lymphadenectomy for the management of early invasive cancer of the cervix. Gynecologic Oncology 1976;4(3):278-90.
Jemal 2008
Kadar 1983
Kinney 1995
  • Kinney WK, Hodge DO, Egorshin EV, Ballard DJ, Podratz KC. Identification of a low-risk subset of patients with stage IB invasive squamous cancer of the cervix possibly suited to less radical surgical treatment. Gynecologic Oncology 1995;57(1):3-6.
Lecuru 2011
  • Lecuru F, Mathevet P, Querleu D, Leblanc E, Morice P, Daraï E, et al. Bilateral negative sentinel nodes accurately predict absence of lymph node metastasis in early cervical cancer: results of the SENTICOL study. Journal of Clinical Oncology 2011;29(13):1686-91.
Low 1981
  • Low JA, Mauger GM, Carmichael JA. The effect of Wertheim hysterectomy upon bladder and urethral function. American Journal of Obstetrics and Gynecology 1981;139:826-34.
Magrina 2001
  • Magrina JF. The prognostic significance of pelvic and aortic lymph node metastases. CME Journal of Gynecologic Oncology 2001;6:302-6.
Morley 1976
  • Morley GW, Seski JC. Radical pelvic surgery versus radiation therapy for stage I carcinoma of the cervix (exclusive of microinvasion). American Journal of Obstetrics and Gynecology 1976;126(7):785-98.
NCI 2014
  • National Cancer Institute (NCI). Cervical cancer treatment (PDQ®): stage IA cervical cancer. www.cancer.gov/cancertopics/pdq/treatment/cervical/HealthProfessional/page6 (accessed 9 May 2014).
Newton 1975
  • Newton M. Radical hysterectomy or radiotherapy for stage I cervical cancer. A prospective comparison with 5 and 10 years follow-up. American Journal of Obstetrics and Gynecology 1975;123(5):535-42.
NICE 2010
  • National Institute for Health and Care Excellence. Laparoscopic radical hysterectomy for early stage cervical cancer: guidance. www.nice.org.uk/guidance/IPG338/Guidance/pdf (accessed 9 May 2014).
Nishio 2009
  • Nishio H, Fujii T, Kameyama K, Susumu N, Nakamura M, Iwata T, et al. Abdominal radical trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer in a series of 61 women. Gynecologic Oncology 2009;115(1):51-5.
Parmar 1998
Persson 2012
  • Persson J, Imboden S, Reynisson P, Andersson B, Borgfeldt C, Bossmar T. Reproducibility and accuracy of robot-assisted laparoscopic fertility sparing radical trachelectomy. Gynecologic Oncology 2012;127(3):484-8.
Piver 1975
  • Piver MS, Chung WS. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma. Obstetrics and Gynecology 1975;46(5):507-10.
Plante 2004
  • Plante M, Renaud MC, François H, Roy M. Vaginal radical trachelectomy: an oncologically safe fertility-preserving surgery. An updated series of 72 cases and review of the literature. Gynecologic Oncology 2004;94(3):614-23.
Reade 2013
RevMan 2012
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.
Rogers 2009
Schmeler 2011
Shastri 2013
  • Shastri SS, Mittra I, Mishra G, Gupta S, Dikshit R, Badwe R. Vinegar screening could slash cervical cancer mortality by one-third in low-resource countries. http://am.asco.org/vinegar-screening-could-slash-cervical-cancer-mortality-one-third-low-resource-countries 2013.
Shepherd 1998
Shepherd 2006
Sood 2002
  • Sood AK, Nygaard I, Shahin MS, Sorosky JI, Lutgendorf SK, Rao SS. Anorectal dysfunction after surgical treatment for cervical cancer. Journal of the American College of Surgeons 2002;195:513-9.
Steed 2006
Stegeman 2007
  • Stegeman M, Louwen M, van der Velden J, ten Kate FJ, den Bakker MA, Burger CW, et al. The incidence of parametrial tumor involvement in select patients with early cervix cancer is too low to justify parametrectomy. Gynecologic Oncology 2007;105(2):475-80.
Strnad 2008
  • Strnad P, Robova H, Skapa P, Pluta M, Hrehorcak M, Halaska M, et al. A prospective study of sentinel lymph node status and parametrial involvement in patients with small tumour volume cervical cancer. Gynecologic Oncology 2008;109(2):280-4.
Ungár 2005
Wright 2007
Wright 2012
  • Wright JD, Herzog TJ, Neugut AI, Burke WM, Lu YS, Lewin SN, et al. Comparative effectiveness of minimally invasive and abdominal radical hysterectomy for cervical cancer. Gynecologic Oncology 2012;127(1):11-7.