Debulking hysterectomy followed by chemoradiotherapy versus chemoradiotherapy for FIGO stage (2019) IB3/II cervical cancer
Abstract
Background
With an estimated 570,000 new cases reported globally in 2018, and increasing numbers of new cases in countries without established human papillomavirus (HPV) vaccination programmes, cervical cancer is the third most common cancer in women worldwide. The majority of global disease burden (around 85%) is in low‐and middle‐income countries (LMICs), with estimates of cervical cancer being the second most common cancer in women in such regions. As it commonly affects younger women, cervical cancer has the greatest impact on years of life lost (YLL) and adverse socioeconomic outcomes compared to all other cancers in women. Management of cervical cancer depends on tumour stage.
Radical hysterectomy with lymphadenectomy is the standard primary treatment modality for International Federation of Gynecology and Obstetrics (FIGO) stage (2019) 1B1 to 1B3 disease. However, for larger primary tumours, radical hysterectomy is less commonly recommended. This is mainly due to a high incidence of unfavourable histopathological parameters, which require adjuvant concurrent chemoradiotherapy (CCRT) (chemotherapy given with radiotherapy treatment). CCRT is the standard of care and is widely used as first‐line treatment for cervical cancer considered to be not curable with surgery alone (i.e.those with locally advanced disease). However, a sizable cohort of women managed with primary CCRT will have residual disease within the cervix following treatment.
Debulking' hysterectomy to remove (debulk) the primary tumour in locally advanced disease, prior to CCRT, may be an alternative management strategy, avoiding the potential need for surgery for residual cervical disease following CCRT, which may be more extensive, or have increased morbidity due to CCRT. However, this strategy may subject more women to unnecessary surgery and its inherent risks.
Objectives
To assess the efficacy and harms of debulking hysterectomy (simple or radical) followed by chemoradiotherapy (CCRT) versus CCRT alone for FIGO (2019) stage IB3/II cervical cancer.
Search methods
We systematically searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 4), MEDLINE via Ovid (1946 to 12 April 2021) and Embase via Ovid (1980 to 12 April 2021). We also searched other registers of clinical trials, abstracts of scientific meetings and reference lists up to 12 April 2021.
Selection criteria
We searched for randomised controlled trials (RCTs), quasi‐RCTs or non‐randomised studies (NRSs) comparing debulking hysterectomy followed by CCRT versus CCRT alone for locally advanced FIGO (2019) stage IB3/II cervical malignancy.
Data collection and analysis
We applied Cochrane methodology, with two review authors independently assessing whether potentially relevant studies met the inclusion criteria. We planned to apply standard Cochrane methodological procedures to analyse data and risk of bias.
Main results
We did not find any evidence for or against debulking hysterectomy followed by CCRT versus CCRT alone for FIGO (2019) stage IB3/II cervical cancer. We did not identify any studies assessing the validity of debulking hysterectomy for these women.
Authors' conclusions
There was no evidence for or against debulking hysterectomy followed by CCRT versus CCRT alone for FIGO (2019) stage IB3/II cervical cancer.
PICOs
Plain language summary
Debulking hysterectomy followed by chemoradiotherapy versus chemoradiotherapy for FIGO (2019) stage IB3/II cervical cancer
What is the issue?
Cervical cancer arises from the neck of the womb (cervix). Worldwide, cervical cancer is the third most common cancer in women, with an estimated 570,000 new cases in 2018. The majority of the burden of the disease is in low‐ and middle‐income countries (LMICs). As it mostly occurs in younger women (mostly 25 to 30 year‐olds in the UK), the disease has significant adverse effects on women and the global socioeconomic situation as a whole.
Cervical cancer management is based on the spread of the cancer (stage of the disease) at the time of diagnosis. International Federation of Gynecology and Obstetrics (FIGO) staging classification describes disease as per spread, with stage IA1 disease as microscopic disease and stage IVB cancers as having spread to distant sites throughout the body. In stage IB3/II disease, the cancer is either quite large within the cervix or has already spread to immediately neighbouring tissues, without obviously involving more distant tissues or organs. Stage IB3/II disease is often termed as locally advanced cervical cancer.
In early stage disease, where a small tumour is confined to the cervix, surgical treatment (removal of uterus (womb) and pelvic lymph nodes) will cure the vast majority of women. However, when cervical cancer spreads to adjacent tissues or organs, surgery is unlikely to be curative and so, instead of surgery, radiotherapy is offered in combination with weekly chemotherapy (chemoradiotherapy). Although chemoradiotherapy is able to cure the majority of women with locally advanced cervical cancer, nearly a quarter will have residual cancer within their cervix.
If there is residual (remaining) disease in the cervix after chemoradiotherapy, options include a 'simple' hysterectomy (surgery to remove the womb and cervix), a radical hysterectomy (hysterectomy including removal of a cuff of vagina and parametrial tissue (tissues surrounding the cervix)), or exenterative surgery (which involves removal of the womb, cervix, vagina and parametrial tissue together with removal of the bladder and/or bowel and formation of stomas to divert urine or bowel contents). Surgery following radiotherapy is more complex and has a higher risk of complications due to scarring and loss of tissue perfusion.
This group of women might benefit from hysterectomy prior to chemoradiotherapy to reduce the volume of their disease and improve their chance of cure. However, studies comparing outcomes of radical hysterectomy and pelvic lymph node dissection and/or pelvic chemoradiotherapy in early stage disease show that combination treatment does not improve survival and those who had both radical surgery and radiotherapy/chemoradiotherapy had worse side effects. A more limited hysterectomy might debulk the cancer prior to chemoradiotherapy and improve survival rates without having a significant impact on quality of life. However, surgery prior to chemoradiotherapy would subject the three‐quarters of women, who would not benefit from surgery, to the additional risks of major surgery. Surgery first would also delay the onset of chemoradiotherapy, which might reduce the chance of success of otherwise curative treatment, and thereby, lower survival rates.
We wanted to evaluate the evidence for the role of planned debulking hysterectomy followed by chemoradiotherapy compared to chemoradiotherapy alone in women with locally advanced cervical cancer.
What did we do?
e searched the scientific literature over 75 years (from 1946 to 12 April 2021) for randomised controlled trials (RCTs) and non‐randomised studies (NRSs) that compared debulking hysterectomy prior to chemoradiotherapy compared to chemoradiotherapy alone in women with locally advanced cancer of the cervix.
What did we find?
We found no studies for or against the effectiveness of debulking hysterectomy followed by chemoradiotherapy compared to chemoradiotherapy alone in women with locally advanced cancer of the cervix.
Our conclusions
There is no evidence for the role of debulking hysterectomy followed by chemoradiotherapy compared to chemoradiotherapy alone in women with locally advanced cancer of the cervix.
Authors' conclusions
Background
See Appendix 1 for glossary of terms.
Description of the condition
Worldwide, cervical cancer is the third most common cancer in women, with an estimated 569,800 new cases and 311,000 deaths in 2018 (Ferlay 2019). The number of reported new cases in 2018 increased compared to 2012 and this trend is expected to continue. Most cervical cancer cases (85%, or 448,000 cases) and deaths (87%, or 231,000 cases) occurred in low‐income countries in 2012 (Ferlay 2015; WHO 2019). In addition to a higher incidence of cervical cancer in low‐resourced regions, patients in these areas are more likely to present with advanced stage disease. Stage IIB to IVA of the International Federation of Gynecology and Obstetrics (FIGO) staging classification describes increasingly advanced pelvic disease, whilst stage IVB cancers have spread to distant sites throughout the body (Bhatla 2019; Moore 2010) (see Table 1 and Table 2 for details of FIGO staging). Cervical cancer results in exceptional socioeconomic burden, as it affects young women with child‐rearing and economic responsibilities. Its peak age of incidence is 25 to 29 years in the UK (Cancer Research UK). In 2010, there were 4 million age‐weighted years of life lost (YLL) to cervical cancer. Going beyond simple mortality statistics, YLL assesses the wider burden of the disease on society and the impact of the age at which deaths occur. Cervical cancer is fourth on the overall list of devastating cancers, after lung, stomach and liver cancer, but it is the cancer with the greatest YLL impact on women (Goldstein 2010).
| Stage | Description |
|---|---|
| I | The carcinoma is strictly confined to the cervix (extension to the corpus should be disregarded) |
| IA | Invasive carcinoma that can be diagnosed only by microscopy with maximum depth of invasion ≤ 5 mma |
| IA1 | Measured stromal invasion ≤ 3 mm in depth |
| IA2 | Measured stromal invasion > 3 mm and ≤ 5 mm in depth |
| IB | Invasive carcinoma with measured deepest invasion > 5 mm (greater than stage IA); lesion limited to the cervix uteri with size measured by maximum tumour diameterb |
| IB1 | Invasive carcinoma > 5 mm depth of stromal invasion and ≤ 2 cm in greatest dimension |
| IB2 | Invasive carcinoma > 2 cm and ≤ 4 cm in greatest dimension |
| IB3 | Invasive carcinoma > 4 cm in greatest dimension |
| II | The cervical carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall |
| IIA | Involvement limited to the upper two‐thirds of the vagina without parametrial invasion |
| IIA1 | Invasive carcinoma ≤ 4 cm in greatest dimension |
| IIA2 | Invasive carcinoma > 4 cm in greatest dimension |
| IIB | With parametrial invasion but not up to the pelvic wall |
| III | The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or non‐functioning kidney and/or involves pelvic and/or para‐aortic lymph nodes |
| IIIA | Carcinoma involves lower third of the vagina, with no extension to the pelvic wall |
| IIIB | Extension to the pelvic wall and/or hydronephrosis or non‐functioning kidney (unless known to be due to another cause) |
| IIIC | Involvement of pelvic and/or paraaortic lymph nodes (including micrometastases)c, irrespective of tumour size and extent (with r and p notations)d |
| IIIC1 | Pelvic lymph node metastasis only |
| IIIC2 | Para‐aortic lymph node metastasis |
| IV | The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to stage IV |
| IVA | Spread of the growth to adjacent organs |
| IVB | Spread to distant organs |
aImaging and pathology can be used, when available, to supplement clinical findings with respect to tumour size and extent; in all stages pathological findings supercede imaging and clinical findings.
bThe involvement of vascular/lymphatic spaces should not change the staging. The lateral extent of the lesion is no longer considered.
cIsolated tumour cells do not change the stage but their presence should be recorded.
dAdding notation of r (imaging) and p (pathology), to indicate the findings that are used to allocate the case to stage IIIC. For example, if imaging indicates pelvic lymph node metastasis, the stage allocation would be stage IIIC1r; if confirmed by pathological findings, it would be stage IIIC1p. The type of imaging modality or pathology technique used should always be documented. When in doubt, the lower staging should be assigned.
Corrigendum to 'Revised FIGO staging for carcinoma of the cervix uteri' (Bhatla 2019 (Corrigendum)).
'Revised FIGO staging for carcinoma of the cervix uteri' (Bhatla 2019).
| Stage | Description |
|---|---|
| I | The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded) |
| IA | Invasive carcinoma, which can be diagnosed only by microscopy with deepest invasion ≤ 5 mm and largest extension ≥ 7 mm |
| IA1 | Measured stromal invasion of ≤ 3.0 mm in depth and extension of ≤ 7.0 mm |
| IA2 | Measured stromal invasion of > 3 mm and not > 5 mm with an extension of not > 7 mm |
| IB | Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IA |
| IB1 | Clinically visible lesion ≤ 4.0 cm in greatest dimension |
| IB2 | Clinically visible lesion > 4.0 cm in greatest dimension |
| II | Cervical carcinoma invades beyond the uterus but not to the pelvic wall or to the lower third of the vagina |
| IIA | Without parametrial invasion |
| IIA1 | Clinically visible lesion ≤ 4.0 cm in greatest dimension |
| IIA2 | Clinically visible lesion > 4.0 cm in greatest dimension |
| IIB | With obvious parametrial invasion |
| III | The tumour extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney |
| IIIA | Tumour involves lower third of the vagina with no extension to the pelvic wall |
| IIIB | Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney |
| IV | The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to stage IV. |
| IVA | Spread of the growth to adjacent organs |
| IVB | Spread to distant organs |
'Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium' (Pecorelli 2009).
Whilst working on this review a new staging classification was presented as oral abstract in October 2018 (Bhatla 2018). As the published version was an abstract only, it did not have a detailed staging chart. The work on this review was therefore suspended, in anticipation of full published data. Once that was published in January 2019 ( Bhatla 2019), all interim examined studies were revisited by authors to reflect any changes to the ongoing review. In October 2019, a major corrigendum was published to the staging system (Bhatla 2019 (Corrigendum) This corrigendum reflected multiple changes in tumour size measurement cut‐off points and inclusion of 'micrometastasis' in stage IIIC. The authors took a note of this and completely overhauled the review again, carefully re‐examining all studies. This was performed to capture historic data, as previous studies were based on the pre 2018/19 FIGO staging systems, and to better future‐proof the review, as new studies and research will be based on FIGO 2018 staging, with the 2019 corrections. We refer to the staging used as FIGO 2019 throughout the review for clarity and brevity.
Stagewise incidence data vary as per geographical locations and there is expected heterogeneity in sub‐stage granular data following the refreshed 2019 staging system. Overall, the incidence of cervical cancer ranges from 4.9 to 21.3% for stage I and 17.8 to 56.0% for stage II, in various publications. Because of limitations of worldwide cancer registry data capture, this figure may not be fully representative, but signifies the burden of disease that falls within the stage spectrum of cervical cancer addressed in this review (Mahantshetty 2021).
Description of the intervention
Hysterectomy is a surgical procedure to remove the uterus (womb) and cervix (neck of the womb). 'Simple hysterectomy' is the term historically used to denote this procedure. In contrast, a radical hysterectomy is a more extensive procedure, which also involves the removal of adjacent tissues (the parametria, supporting ligaments and a cuff of the upper vagina). Radical hysterectomy is associated with higher risks of surgical complications and morbidity than simple hysterectomy. The most common complication is long‐term bladder dysfunction, which occurs in up to 44% of cases, and can have a detrimental impact on quality of life (Covens 1993). Other significant complications of radical hysterectomy include early bladder atony (1 in 27), sexual dysfunction (1 in 45), and urinary fistula (1 in 83) (Hacker 2015). Both types of hysterectomy can be performed with curative intent for cervical cancer, but simple hysterectomy is only recommended for very small volume, early‐stage tumours (Schmeler 2011). The role of simple hysterectomy versus radical hysterectomy is currently being examined for cervical cancer < 2 cm in an RCT (NCT01658930).
'Debulking' surgery is a term taken from ovarian cancer surgery, which indicates surgery to remove the majority of the tumour volume, but it is not curative on its own; it is used as an adjunct to other treatment modalities (e.g. chemotherapy, radiotherapy or concurrent chemoradiotherapy (CCRT)). In cervical cancer management, debulking hysterectomy refers to a hysterectomy to remove the main bulk of the cancer, without achieving a wide surgical tumour clearance margin, performed as part of a planned treatment programme prior to combined chemotherapy and radiotherapy(CCRT).
How the intervention might work
The management of cervical cancer depends on tumour stage, with surgical resection applicable to early‐stage disease and CCRT recommended as primary treatment for locally advanced disease. Radical hysterectomy with lymphadenectomy is the more commonly recommended primary treatment for FIGO (2019) stage 1B1 to 1B3 disease, (Table 1) (previously categorised as FIGO (2009) stage IB1 and IB2 disease (Table 2)). Adjuvant CCRT can be avoided, if the primary tumour is resected with good surgical margins, and lymph nodes are clear of disease. However, for larger primary tumours, radical hysterectomy is less commonly performed under modern management pathways of care, due to a high incidence of unfavourable histopathological parameters, such as inadequate surgical resection of margins or positive lymph nodes, requiring adjuvant CCRT.
Current management recommendations are based on the results of a RCT in FIGO (2009) stage IB‐IIA disease, which demonstrated equivalent rates of survival for those treated with radical hysterectomy compared to radiotherapy (5‐year overall survival = 83%, and disease‐free survival = 74%, for both groups (Green 2001; Landoni 1997)). However, severe morbidity was more common in the surgical group (28% for surgery versus 12% for radiotherapy); those who required radiotherapy after radical surgery had much greater morbidity. The Landoni 1997 study confirmed an earlier study that demonstrated that radiotherapy following hysterectomy compounds the risk of treatment‐related morbidity, particularly if a radical hysterectomy has been performed (Parkin 1989). These studies predate the use of CCRT, which has been shown to be superior to radiotherapy alone for locally advanced cervical cancer, with a 6% improvement in five‐year survival (hazard ratio (HR) 0.81, P < 0.001) (MAG MRC‐CTU 2008).
For intermediate‐stage disease confined to the pelvis, recent and ongoing research assesses the value of neoadjuvant chemotherapy to improve outcomes from radical hysterectomy, and compares neoadjuvant chemotherapy and radical hysterectomy with chemoradiotherapy (NACCCMA 2003).
However, a cohort of women managed with primary CCRT will have residual disease within the cervix following treatment. Persistent central disease, proven on post‐CCRT biopsy, can be as high as 24% (Boers 2014). Providing there is no evidence of distant metastatic disease, these women may have potentially curable disease, but treatment requires complex 'salvage' surgery. For some people, clearance of disease will be feasible in the form of post‐radiation hysterectomy, but often very radical surgery, called exenteration, is necessary, involving resection of the uterus, cervix, bladder and/or rectum. This can be very morbid surgery, especially in a pre‐irradiated field, with high complication rates. In addition, many women will require a diversion (stoma) of the urinary and/or bowel drainage after this surgery.
'Debulking' hysterectomy to remove (debulk) the primary tumour in intermediate‐stage disease prior to CCRT is an alternative strategy to avoid the potential need for hysterectomy for residual cervical disease following CCRT. However, surgery prior to CCRT would subject the three‐quarters of women, who do not benefit from surgery, to the additional risks of major surgery. Surgery first would also delay the onset of chemoradiotherapy, which might reduce the chance of success of otherwise curative treatment, and, thereby, lower survival rates.
Why it is important to do this review
It is important to systemically evaluate the evidence for debulking hysterectomy prior to CCRT compared to CCRT alone for locally advanced cervical cancer. The majority of the global population has no access to coordinated national screening programmes for cervical cancer prevention, and cervical cancers are commonly diagnosed following the onset of symptoms. Therefore, worldwide the majority of women with cervical cancer present with locally advanced disease. It is anticipated that the results of this review would have a greater impact on care of women in low‐income countries.
Radical hysterectomy and chemoradiotherapy subject women to the risk of significant compounded morbidity associated with both treatment modalities. Generally, therefore, a combination of surgery and radiotherapy is avoided (Landoni 1997). As a result, CCRT alone has become the standard treatment modality for moderately locally advanced pelvic disease without distant metastasis (FIGO stage (2019) IB3/bulky IIA/early IIB). Notwithstanding, some women require salvage hysterectomy following CCRT because of persistent central disease. Recently it has been reported that 17% of patients could be offered salvage hysterectomy after completion of primary CCRT treatment because of biopsy‐proven persistence of central disease (Boers 2014).
A Cochrane Review ‘Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer’ (Kokka 2015) looked at the role of hysterectomy (with or without pelvic lymphadenectomy) in cases of locally advanced cervical cancer. The seven included studies examined the role of interval or adjuvant hysterectomies (i.e. following non‐surgical oncology treatments (chemotherapy and radiotherapy)) in various settings for locally advanced cervical cancer. This review of ‘Debulking hysterectomy followed by chemoradiotherapy versus chemoradiotherapy for FIGO (2019) stage IB3/II cervical cancer’, will complement our knowledge base, by evaluating the role of primary debulking hysterectomy prior to CCRT for locally advanced cervical cancer.
Objectives
To assess the efficacy and harms of debulking hysterectomy (simple or radical) followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone for FIGO (2019) stage IB3/II cervical cancer.
Methods
Criteria for considering studies for this review
Types of studies
We planned to include randomised controlled trials (RCTs). We intended to primarily include individually randomised trials (in which individuals were randomised to either the intervention or the control arm of the experiment, or randomised to receive different interventions). If none or inadequate individually randomised trials were found, we planned to include cluster‐RCTs (trials that have as the unit of randomisation, a group or treatment centre, or where groups of professionals are implementing interventions). Whenever a cluster‐RCT would be included, it would be specifically highlighted. Though not primarily intended, if we identified no RCTs, we planned to include non‐randomised studies (NRS) with a concurrent comparison where results for intervention effects were adjusted for baseline characteristics. As no studies met our inclusion criteria, we were not able to apply the following methods for data extraction and analysis, although these will be used in future updates of the review, if any studies meet the inclusion criteria.
Types of participants
Adult women (18 years and older) presenting for the first time, diagnosed to have cervical cancer (ICD 10, WHO 2010) with locally advanced cervical cancer, staged as FIGO (2019) stage IB3, IIA and IIB.
Types of interventions
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Primary debulking hysterectomy (simple or radical) followed by concurrent chemoradiotherapy (CCRT) compared to CCRT alone.
(In order to distinguish CCRT as a single pathway after initial tumour reduction hysterectomy as opposed to CCRT for disease recurrence after initial management of hysterectomy only, we adhered to an intention‐to‐treat time frame for commencing CCRT of three months).
Types of outcome measures
We planned to analyse studies that fulfilled the above criterion and report any or all or any combination of following outcomes.
Primary outcomes
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Overall survival (OS): survival until mortality from all causes. We planned to assess survival from the time when women were randomised into the studies
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Surgery‐related adverse events: surgery‐related complications measured as the proportion of women who develop one or more of the items below (according to the study definition) within 12 weeks
We planned to classify complications into intraoperative and postoperative complications.
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Intraoperative complications
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Haemorrhage
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Bladder injury
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Gastrointestinal tract injury ‐ small or large bowel
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Vascular injury
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Ureteric injury
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Nerve injury
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Cardiac or respiratory complications
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Anaphylaxis
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We planned to classify postoperative complications as either early (before discharge from hospital or within seven days of surgery), late (from seven days to follow‐up: within 12 weeks of surgery), or total (early and late):
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Wound breakdown
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Infection
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Lymphocyst/lymphoedema
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Abscess
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Bowel obstruction/ileus
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Bowel perforation
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Primary haemorrhage
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Secondary haemorrhage
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Ureteric obstruction
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Fistula (urinary or bowel)
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Anastomotic leak
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Hernia
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Cardiac or respiratory complications
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Pulmonary embolism
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Deep vein thrombosis
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Neurological
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Psychiatric/psychosexual problems
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CCRT‐related adverse events: CCRT‐related complications, measured as the proportion of women who develop one or more of the items below (according to the study definition) within two years:
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Haematological or blood (leukopenia, anaemia, thrombocytopenia, neutropenia, haemorrhage)
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Gastrointestinal or bowel (nausea, vomiting, anorexia, diarrhoea, proctitis, bowel obstruction)
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Genitourinary (sexual dysfunction, urinary frequency, haematuria, incontinence, renal failure)
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Skin (stomatitis, mucositis, desquamation, alopecia, allergy)
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Lymphoedema (swelling of the legs due to lymphatic obstruction)
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Infection
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Neurological or nervous system (peripheral and central)
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Pulmonary or lung (dyspnoea)
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General (weakness, fatigue, lethargy, malaise)
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Secondary outcomes
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Disease‐free survival (DFS): apparent recurrence‐free length of time after treatment
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Progression‐free survival (PFS): the length of time from entry into the trial until progression of the disease or death
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Local control: the length of time the growth of the cancer remains arrested after treatment
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Quality of life, measured by a validated scale, will be discussed if included in the studies, including respective measuring parameters
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Cost implications (any measurable, to patient, society or country) will be reviewed if included in the studies, including respective measuring parameters
Where possible, we planned to group the complications as per Common Terminology Criteria for Adverse Events (CTCAE 2017).
Search methods for identification of studies
Searches were made without any language restrictions. Where needed, valid translation was planned.
Electronic searches
The following electronic databases were searched on 12 April 2021:
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the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 4), in the Cochrane Library;
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MEDLINE via Ovid (1946 to April 12 2021);
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Embase via Ovid (1980 to 2021 week 14).
Search strategies are listed in Appendix 2; Appendix 3: Appendix 4. Search strategies for other databases were adapted accordingly.
Searching other resources
We searched the metaRegister of Controlled Trials (mRCT) of ISRCTN registry (http://www.isrctn.com/page/mrct : redirected to www.nihr.ac.uk). Physicians Data Query (http://www.nci.nih.gov redirected to www.cancer.gov), http://www.clinicaltrials.gov, and http:/ /www.cancer.gov/clinicaltrials, International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en/). WorldCat Dissertations and ZETOC (http://zetoc.mimas.ac.uk) were searched for abstracts and conference proceedings. Reports of conferences were hand searched from the following (as available).
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Gynecologic Oncology (Annual Meeting of the American Society of Gynecologic Oncologist)
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American Society of Gynaecologic Oncology
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International Journal of Gynecological Cancer (Annual Meeting of the International Gynecologic Cancer Society)
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British Journal of Cancer
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British Cancer Research Meeting
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Annual Meeting of the European Society of Medical Oncology (ESMO)
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Annual Meeting of the American Society of Clinical Oncology (ASCO)
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Annual Meeting of the British Gynaecological Cancer Society (BGCS)
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Meetings of European Society of Gynaecological Oncology (ESGO)
We searched Cochrane Database of Systematic Reviews and the System for Information on Grey Literature in Europe (SIGLE). We also searched Physicians Data Query (www.cancer.gov/publications/pdq), ClinicalTrials.gov (www.clinicaltrials.gov), International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en/) and NIH NCI trials database (www.cancer.gov/clinicaltrials), conference proceedings and abstracts through ZETOC (zetoc.mimas.ac.uk), and WorldCat Dissertations (www.worldcat.org) for any ongoing unpublished trials. We planned to approach the principal investigator of those studies for possible release of data.
Data collection and analysis
Selection of studies
We downloaded and saved all relevant titles and abstracts retrieved by electronic searching. We used database software e.g. Zotero. We transferred all titles and abstracts retrieved by electronic searching to (Covidence 2022). After the duplicates were removed, two review authors (MC, JK) independently examined the remaining references. Studies not meeting the inclusion criteria were excluded. Following Cochrane methodology, the eligibility of retrieved papers were independently analysed by two review authors (MC, JK). Any disagreements were resolved by discussion between the two review authors as well as external expert consultation (AN), as required. Reasons for exclusion were documented for future reference.
Data extraction and management
We did not identify any included studies. In future updates of this review two review authors (MC, JK) will independently extract the outcome data from the included studies using Covidence 2022 as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We plan to resolve any disagreements by consensus or by involving a third review author (AN).
This will include data on the following.
Trial information
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Study information
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Author, year of publication, journal citation and language of the study
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Country
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Setting
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Inclusion and exclusion criteria
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Study design, methodology
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Study population
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Total number enrolled
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Patient’s information
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Age
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Comorbidities
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Type of primary treatment (surgery or chemoradiation with dose and duration), and combination
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Performance status
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Cervical cancer details at diagnosis: stage, grade, histology
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Intervention (hysterectomy) details
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Type of hysterectomy (simple or radical with debulking intent))
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Timing of hysterectomy
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Means of prophylaxis (antibiotics, low molecular weight heparin or any other measures)
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Grade or prior training of surgeon
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Medical treatment details: type: radiotherapy (local/extended) or chemotherapy or chemoradiation
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Timing of medical treatment (intention‐to‐treat time frame of three months)
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Risk of bias in study ('Assessment of risk of bias in included studies'): where possible we will provide quotations from study reports
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Duration of follow‐up
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Outcomes ‐ OS and PFS, quality of life, and severe adverse events
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For each outcome:
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outcome definition (with diagnostic criteria if relevant)
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unit of measurement (if relevant)
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for scales: upper and lower limits, and whether high or low score is good
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Results
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Number of participants allocated to each intervention group
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For each outcome of interest: sample size; missing participants
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Assessment of risk of bias in included studies
As no studies met our inclusion criteria, these methods could not be applied. Two review authors (MC, JK) planned to assess the risk of bias using the Cochrane Collaboration’s tool for assessment of risk of bias and as per the criteria specified in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021), where applicable.
In future updates of this review differences will be resolved by external expert consultation (AN), if required. We planned to provide quotations from study reports as justification for the decisions made by the review authors. The assessment of risk of bias would have included the assessment of selection bias (comparability of groups and confounding/adjustment), performance bias, detection bias, attrition bias, reporting bias and incomplete outcome data bias. We will independently analyse each item as being at high, low or unclear risk of bias.
If we cannot identify suitable RCTs, we will include good‐quality NRS. We will assess the risk of bias in NRS according to the Cochrane ROBINS‐I tool, and we plan to record results in the template (Sterne 2016). We intend to classify NRS at high risk of bias if they are at 'serious’ risk according to the Cochrane ROBINS‐I tool. We will aim to assess the included studies for their risk of bias based on the seven domains, as described in the ROBINS‐I tool (Sterne 2016).
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Bias due to confounding bias in the selection of participants into the study bias in the classification of interventions.
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Bias due to deviations from the intended intervention. Bias due to missing data.
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Bias in measurement of outcomes.
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Bias in the selection of the reported result.
We will record the appropriate quote from the published paper, as justification for the judgement for each item in the risk of bias table. While interpreting treatment effects and meta‐analyses, we plan to take into account the risk of bias for the analysed studies that contributed to that outcome. Where information on the risk of bias stems from unpublished data, we will communicate with the corresponding trial author, and comment will be noted in the review.
Measures of treatment effect
We planned to structure the following measures to measure the effect of treatment.
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For time to event data: hazard ratio (HR) with 95% confidence intervals (CIs)
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For dichotomous outcomes: risk ratio (RR) with 95% CIs
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For continuous outcomes: mean difference (MD) between treatment arms with 95% CIs
For trials having multiple treatment groups, we planned to divide the ‘shared’ comparison group into the number of treatment groups and comparisons between each treatment group and treat the split comparison group as independent comparisons. We aimed to use the random‐effects models with inverse variance weighting for all meta‐analyses (DerSimonian 1986).
Based on the available data in individual studies, the review authors planned to perform subgroup analyses on the different types of hysterectomies that were performed and the histological types of cervical malignancies.
Unit of analysis issues
As no relevant studies were identified this issue is not applicable to the present version of the review.
Dealing with missing data
As no studies met our inclusion criteria, review authors did not impute any missing outcome data for any of outcomes and we did not have to request missing data from authors. In future updates of this review for each included study, we will check for missing data and we will report the percentage of observations with missing data. If missing data are not published, we will contact the corresponding original investigator to request the same. If our communication with the investigators is not successful, or we are unable to obtain the missing data, we will interpret only the available data and not impute missing outcome data for any of the analysis outcomes.
Assessment of heterogeneity
We had planned to assess the heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials that could not be ascribed to sampling variation (Higgins 2003) or by a formal statistical test of the significance of the heterogeneity (Deeks 2001) but we did not assess heterogeneity in view of lack of qualifying studies.
Assessment of reporting biases
We planned to assess funnel plots of the primary outcome to assess the potential for biases, including small‐study effects such as publication bias, if there were a sufficient number of studies in meta‐analysis, but we did not assess reporting bias in view of the lack of qualifying studies. In future updates we will visually assess funnel plot asymmetry. If we identify the asymmetry of funnel plots, we will perform exploratory analyses to investigate the possible impact on outcome (Sterne 2016).
Data synthesis
We planned to pool results in meta‐analyses using the Cochrane Review Manager software (RevMan) (Review Manager 2020) if sufficient numbers of clinically similar studies are available.For future updates of this review;
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For time‐to‐event data, we will pool hazard ratios using the generic inverse variance facility of Review Manager 2020.
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For any dichotomous outcomes, we will calculate the risk ratio for each study and then pool them.
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For continuous outcomes, we will pool the mean differences between the treatment arms at the end of follow‐up if all trials measure the outcome on the same scale; otherwise we will pool standardised mean differences.
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 treat the split comparison group as independent comparisons.
We will use the random‐effects models with inverse variance weighting for all meta‐analyses (DerSimonian 1986).
Subgroup analysis and investigation of heterogeneity
Based on the available data in individual studies, the review authors wil aim to perform subgroup analysis on the different types of hysterectomies that were performed and the histological types of cervical malignancies.
Sensitivity analysis
We will aim to perform sensitivity analyses excluding studies at high risk of bias.
Summary of findings and assessment of the certainty of the evidence
In future updates of this review, if we identify studies for inclusion we will present a summary of findings table which includes the studies that qualify as per inclusion criterion as per methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2021). We plan to present the results of the meta‐analysis for the outcomes as outlined in the 'Types of outcome measures' section.
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Overall survival (OS)
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Surgery‐related adverse events
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Intraoperative complications
The certainty of our body of evidence will be assessed according to the five GRADE principles (risk of bias, consistency of effect, imprecision, indirectness and publication bias), as recommended in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021; Meader 2014). Based on the aforementioned principles, the data will be subcategorised into four levels of certainty (high, moderate, low, or very low certainty). Decisions to downgrade evidence will be justified with footnotes to assist with the reader's comprehension of the review.
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: 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‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Results
Description of studies
Results of the search
We identified a total of 616 unique studies after excluding duplicates until 12 April 2021. Two review authors (MC, JK) read the abstracts independently and those that did not meet the inclusion criteria were excluded at this stage. After initial evaluation at the end of June 2016, we could not find any randomised controlled trials (RCTs) or good‐quality non‐randomised studies (NRSs) comparing debulking hysterectomy followed by CCRT with CCRT for FIGO (2019) stage IB3/II cervical cancer (Table 1) (equivalent to FIGO (2009) stage IB2/II cervical cancer (Table 2)). After reviewing 616 abstracts, we did not identify any RCTs or good‐quality NRSs which met the inclusion criteria Figure 1.
PRISMA Diagram
Included studies
No studies met our inclusion criteria.
Excluded studies
Lack of relevant RCTs was the most important reason for exclusion. Although review authors expanded the scope to include available high‐quality NRSs, none were identified.
We identified studies where sequencing of primary and adjuvant therapies did not match the inclusion criterion. In some studies, radical surgery or simple hysterectomy was used as adjuvant therapy instead of a primary therapy. In some other articles, the staging of included patients did not match inclusion staging criterion (Darus 2008; Keys 2003; Liu 2020; Perez 1987; Shim 2017; Varela 2020; Wen 2011; Yang 2020; Zhang 2020).
Another group of studies compared curative intent radical hysterectomy followed by variable adjuvant therapies versus CCRT alone (in cases where radical hysterectomy could not achieve cure). However, this Cochrane Review aimed to investigate the role of debulking hysterectomy. These two surgical approaches and intents are quite different. Classical radical hysterectomy has curative intent, while debulking hysterectomy (simple/radical) is hypothesised to be more of a facilitatory intent (and not primarily curative) for a better adjuvant treatment response. Additionally, after hysterectomy (used with curative intent), participants were offered varied and tailored chemotherapy and/or radiotherapy adjuvant regimens, whereas our review was focused on standard chemoradiotherapy regimens for adjuvant need (Park 2012; Takekuma 2016; Yamashita 2010; Zhao 2016).
We found several other studies where individual inclusion treatment arms were analysed for toxicities and feasibility instead of head‐to‐head comparison of efficacy. Naturally, these needed to be excluded from this review (Lee 2013; Yessaian 2004).
Several other studies were noted where, despite keyword‐based search result similarities, the arms of research did not match the inclusion criteria of this review (Li 2016; Mahmoud 2016; Micha 2006; Rogers 2009; Takekuma 2018; Xie 2016).
Risk of bias in included studies
None identified
Allocation
Not applicable
Blinding
Not applicable
Incomplete outcome data
Not applicable
Selective reporting
Not applicable
Other potential sources of bias
Not applicable
Effects of interventions
Not applicable
Discussion
Summary of main results
We did not find any evidence on the relative benefits and risks of debulking hysterectomy followed by CCRT versus CCRT alone for FIGO (2019) stage IB3/II cervical cancer. As we could not find RCTs for inclusion in our analysis, we gradually broadened the search to include non‐randomised studies or lower‐certainty evidence, such as case series. However, we could not identify any studies that addressed the management pathway under investigation.
Overall completeness and applicability of evidence
We found no evidence on debulking hysterectomy followed by CCRT versus CCRT alone for FIGO (2019) stage IB3/II cervical cancer.
Quality of the evidence
To interpret the findings and to rate the certainty of evidence, we intended to use the GRADE approach (Schunemann 2020) with stepwise analysis of the overall certainty of evidence for each outcome individually, stratifying the evidence from “high certainty” to “moderate”, “low” or “very low” depending on the risk of bias, indirectness of evidence, inconsistency, imprecision of effect estimates or potential publication bias. We had provision to use the GRADE profiler software to produce a summary of findings table with the results of this analysis (GRADEpro).
Potential biases in the review process
To our knowledge, there were no biases in the review process. To preempt any selection bias of this review, authors and the Cochrane support team endeavoured in an inclusive way to identify and include any qualifying study. When we could not identify any qualifying studies in 2016, we made further incremental attempts over the next five years to recognise and include any eligible studies.
Agreements and disagreements with other studies or reviews
None. Multiple international guidelines advise a treatment strategy to avoid combination 'radical hysterectomy' (primary curative surgery) and adjuvant CCRT, where feasible (British Gynaecological Cancer Society, Cervical Cancer Guidelines 2021 (Reed 2021), The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer (Cibula 2018)). However, the role of debulking hysterectomy specifically remains unexamined.
| Stage | Description |
|---|---|
| I | The carcinoma is strictly confined to the cervix (extension to the corpus should be disregarded) |
| IA | Invasive carcinoma that can be diagnosed only by microscopy with maximum depth of invasion ≤ 5 mma |
| IA1 | Measured stromal invasion ≤ 3 mm in depth |
| IA2 | Measured stromal invasion > 3 mm and ≤ 5 mm in depth |
| IB | Invasive carcinoma with measured deepest invasion > 5 mm (greater than stage IA); lesion limited to the cervix uteri with size measured by maximum tumour diameterb |
| IB1 | Invasive carcinoma > 5 mm depth of stromal invasion and ≤ 2 cm in greatest dimension |
| IB2 | Invasive carcinoma > 2 cm and ≤ 4 cm in greatest dimension |
| IB3 | Invasive carcinoma > 4 cm in greatest dimension |
| II | The cervical carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall |
| IIA | Involvement limited to the upper two‐thirds of the vagina without parametrial invasion |
| IIA1 | Invasive carcinoma ≤ 4 cm in greatest dimension |
| IIA2 | Invasive carcinoma > 4 cm in greatest dimension |
| IIB | With parametrial invasion but not up to the pelvic wall |
| III | The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or non‐functioning kidney and/or involves pelvic and/or para‐aortic lymph nodes |
| IIIA | Carcinoma involves lower third of the vagina, with no extension to the pelvic wall |
| IIIB | Extension to the pelvic wall and/or hydronephrosis or non‐functioning kidney (unless known to be due to another cause) |
| IIIC | Involvement of pelvic and/or paraaortic lymph nodes (including micrometastases)c, irrespective of tumour size and extent (with r and p notations)d |
| IIIC1 | Pelvic lymph node metastasis only |
| IIIC2 | Para‐aortic lymph node metastasis |
| IV | The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to stage IV |
| IVA | Spread of the growth to adjacent organs |
| IVB | Spread to distant organs |
| aImaging and pathology can be used, when available, to supplement clinical findings with respect to tumour size and extent; in all stages pathological findings supercede imaging and clinical findings. Corrigendum to 'Revised FIGO staging for carcinoma of the cervix uteri' (Bhatla 2019 (Corrigendum)). 'Revised FIGO staging for carcinoma of the cervix uteri' (Bhatla 2019). | |
| Stage | Description |
|---|---|
| I | The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded) |
| IA | Invasive carcinoma, which can be diagnosed only by microscopy with deepest invasion ≤ 5 mm and largest extension ≥ 7 mm |
| IA1 | Measured stromal invasion of ≤ 3.0 mm in depth and extension of ≤ 7.0 mm |
| IA2 | Measured stromal invasion of > 3 mm and not > 5 mm with an extension of not > 7 mm |
| IB | Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IA |
| IB1 | Clinically visible lesion ≤ 4.0 cm in greatest dimension |
| IB2 | Clinically visible lesion > 4.0 cm in greatest dimension |
| II | Cervical carcinoma invades beyond the uterus but not to the pelvic wall or to the lower third of the vagina |
| IIA | Without parametrial invasion |
| IIA1 | Clinically visible lesion ≤ 4.0 cm in greatest dimension |
| IIA2 | Clinically visible lesion > 4.0 cm in greatest dimension |
| IIB | With obvious parametrial invasion |
| III | The tumour extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney |
| IIIA | Tumour involves lower third of the vagina with no extension to the pelvic wall |
| IIIB | Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney |
| IV | The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to stage IV. |
| IVA | Spread of the growth to adjacent organs |
| IVB | Spread to distant organs |
| 'Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium' (Pecorelli 2009). | |
