Primary surgery versus primary radiation therapy with or without chemotherapy for early adenocarcinoma of the uterine cervix
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objectives of this review are to compare the effectiveness and safety of primary surgery for early stage AC of the uterine cervix with primary radiotherapy or chemoradiotherapy.
Background
Cervical cancer is the second most common cancer among women worldwide. The prognosis of patients with cervical cancer depends on FIGO (International Federation of Gynecologists and Obstetricians) stage at time of diagnosis, presence of lymph node metastases, tumour size and histological type. The three major histologic types of invasive cervical cancer are squamous cell carcinomas (SCC), adenocarcinomas (AC) and or adenosquamous carcinoma (ASC). SCC comprise 80% of cases, and AC and ASC comprise approximately 15% (ACOG 2002). Over the past 40 years the relative proportion and absolute incidence of AC compared to SCC has increased, especially in women younger than 35 years (Alfsen 2000; Chan 2003; Krane 2001; Liu 2001; Schoolland 2002; Vizcaino 1998).
Screening methods screen for SCC, effectively reduce both incidence and mortality of invasive squamous cancer (Smith 2000), by early detection and treatment of preinvasive lesions. Although screening reduces mortality from cervical AC, the incidence remains unaltered (Nieminen 1995). It remains controversial whether or not patients with AC have a worse prognosis. The literature is inconsistent. Some studies report a similar prognosis for AC of the uterine cervix and SCC (Grisaru 2001; Ishikawa 1999; Kilgore 1988) whereas others report a poorer prognosis for AC (Bulk 2003; Eifel 1995; Hopkins 1991). Questions remain about what factors account for this apparent poorer prognosis. Cervical AC may metastasise earlier (Lea 2002) or may be detected later (Drescher 1989; Hurt 1977). It may respond less well to radiotherapy (Hong 2000; Hurt 1977), have a higher incidence of relapse and less successful treatment of recurrent disease (Kasamatsu 2002; Lai 1999) or possibly the inclusion of special subtypes such as clear cell carcinoma (Look 1996) could account for this difference in prognosis.
Treatment protocols used for SCC and AC are similar. Microinvasive disease is managed by cone biopsy or simple hysterectomy for FIGO stage IA disease. Radical hysterectomy (removal of the uterus with adjacent tissue and draining pelvic lymph nodes) has become standard management for the majority of early cervical cancers, but external beam irradiation along with a vaginal application of a radioactive source to the cervix has been increasingly employed for bulky stage I and II disease (tumour diameter more than four centimetres). In 1999, after the publication of four randomised controlled trials (RCTs) on this issue (Keys 1999; Morris 1999; Rose 1999; Whitney 1999) the National Cancer Institute (USA) issued an alert that combined chemoradiation should be considered for all patients with cervical cancer who previously would be treated with radiotherapy. In 2002 a Cochrane review showed concomitant chemotherapy and radiotherapy improve overall survival (OS) and progression‐free survival (PFS) in locally advanced cervival cancer (Green 2001).
After primary surgery it may be useful to add radiotherapy (in up to 50% of operated patients depending on the selection criteria of the series). In primary radiotherapy in selected cases adjuvant surgery (salvage hysterectomy) may br performed if the tumour recurres locally (Weiner 1975). The use of surgery and radiotherapy leads to more severe morbidity (Barter 1989, Landoni 1997) than either used alone. Complications of radical hysterectomy are chronic bladder dysfunction (3 to 13%), ureterovaginal or vesicovaginal fistula(1 to 2%), pulmonary embolism (1to 2%), small bowel obstruction (1%), lymphocoele formation (5 to 8%), hydroureter nephrosis (3%), abdominal hernia. Complications of radiotherapy arise later but are often permanent: proctitis (7.6%), radiation colitis, early menopause, sexual dysfunction, shortening and fibrosis of the vagina, oedema of the legs (0.6%), hydroureter nephrosis (5%), vesicovaginal fistula (1.4%). The combination of radical surgery followed by radiotherapy carries the worst morbidity: hydroureter nephrosis (10%), severe oedema of the legs (9%), lymphocoele formation (15%), ureterovaginal or vesicovaginal fistula (7.4%), vesical complications and bowel morbidity (Boronow 1971; Landoni 1997; Kucera 1998; Waggoner 2003).
For early SCC, the outcome is similar after either primary surgery or primary radiotherapy (Landoni 1997). There are reports that this is not the case for early AC of the uterine cervix: some studies have reported that the outcome is better after primary surgery (Chen 1999; Kucera 1998). There are no systematic reviews about surgery versus (chemo)radiotherapy in the treatment of cervical cancer.
Objectives
The objectives of this review are to compare the effectiveness and safety of primary surgery for early stage AC of the uterine cervix with primary radiotherapy or chemoradiotherapy.
Methods
Criteria for considering studies for this review
Types of studies
Only studies on the effectiveness of treatment for cervical cancer will be incorporated. It is anticipated that only a very small number of RCTs will have been conducted on cervical cancer treatment. Therefore, observational studies, case‐control studies, non‐randomised studies with concurrent controls and studies with historical controls will also be considered for incorporation in this review. There will be no language restrictions.
Types of participants
Patients with histologically proven AC or ACS of the uterine cervix will be included. For the purpose of this review early stage AC is defined as cancer in which the primary tumour is confined to the cervix and upper two thirds of the vagina or the parametrium (FIGO stage I‐A to II‐B).
FIGO Stage I
Carcinoma is strictly confined to the cervix (extension to the corpus should be disregarded). Invasive carcinoma which can be diagnosed only by microscopy. All macroscopically visible lesions, even with superficial invasion, are allotted to Stage I‐B carcinomas. The involvement of vascular spaces, venous or lymphatic, should not change the stage allotment.
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I‐A1 Measured stromal invasion of not more than 3.0 mm in depth and width of not more than 7.0 mm.
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I‐A2 Measured stromal invasion of more than 3.0 mm and not more than 5.0 mm with a width of not more than 7.0 mm.
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I‐B1 Clinically visible lesions not more than 4.0 cm, or preclinical lesions greater than I‐A2.
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I‐B2 Clinically visible lesions more than 4.0 cm.
FIGO Stage II
Cervical carcinoma invades beyond the uterus, but not to the pelvic sidewall or to the lower third of the vagina.
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II‐A No obvious parametrial involvement
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II‐B Obvious parametrial involvement (Benedet 2001)
Types of interventions
The following surgical interventions will be studied:
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Extrafascial hysterectomy or Rutledge class I hysterectomy, which is defined as removal of all cervical tissue by incision of the pubocervical ligament allowing reflection and retraction of the ureters laterally without actual dissection from the ureteral bed.
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Rutledge class II extended hysterectomy, which is defined as the removal of the medial half of the cardinal and uterosacral ligaments and upper third of the vagina. It is usually combined with a pelvic lymphadenectomy.
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Radical hysterectomy or Rutledge class III extended hysterectomy, which can be defined as the removal of the entire cardinal and uterosacral ligaments and removal of the upper third of the vagina and a pelvic lymphadenectomy (Piver 1974).
The following radiation therapy interventions will be studied:
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Whole pelvis radiotherapy, defined as external beam radiation in which the clinical target volume (CTV) encompasses the cervix, the uterus, the upper 2/3 of the vagina, the parametria and the draining lymph nodes at risk, up to the level of L5‐S1
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Vaginal application of a radioactive source to the cervix (brachytherapy). There are different brachytherapy techniques that apply the radioactive source for short periods of time or for several days.
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Chemoradiation, which is defined as concomitant radiotherapy and cytotoxic chemotherapy.
Types of outcome measures
Primary outcomes
The primary outcomes are OS and disease free survival (DFS).
Secondary outcomes
Secondary outcomes of interest are adverse effects of treatment as intestinal, urogenital and menopausal complications and quality of life (QOL).
Search methods for identification of studies
Electronic searches
There is evidence that trials with statistically significant results are more likely to be published than those with inconclusive or negative results (Dickersin 1990;Dickersin 1992;Easterbrook 1991). The literature search will be carried out according to the criteria set by the Cochrane Gynaecological Cancer Review Group. Searches of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE will be done.
The search strategy will use the following Mesh Headings
#1 genital neoplasms, female [MeSH] AND cervix neoplasms [MeSH]
#2 AC [MeSH] AND cervix neoplasms [MeSH]
#3 adenosquamous carcinoma [MeSH] AND cervix neoplasms [MeSH]
#4 cervix neoplasms [MeSH] AND gynaecologic surgical procedures [MeSH]
#5 cervix neoplasms [MeSH] AND radiotherapy [MeSH] OR brachytherapy [MeSH]
#6 #2 AND #4
#7 #2 AND #5
#8 #3 AND #4
#9 #3 AND #5
#10 #7 AND #9
The Web of Science and the register of ongoing controlled trials will be checked (http://www.controlled‐trials.com). The reference lists of the selected publications will be searched. All relevant articles found will be identified on PubMed, and using the 'related articles' feature, a further search will be carried out for newly published articles.
Searching other resources
A hand search of publications on the treatment of cervical cancer in the following journals will be carried out: CME Journal of Gynecologic Oncology (from 1995), International Journal of Gynecologic Cancer (from 1993). Abstracts from conferences on gynaecological cancer (IGCS, SGO) and the British Library's Inside Conferences will be checked.
Data collection and analysis
Data extraction and management
For included studies, data on characteristics of patients and interventions (surgery, radiotherapy, chemotherapy), study quality and endpoints will be abstracted independently by two reviewers onto data abstraction forms (Table 1; Table 2; Table 3; Table 4) specially developed for the review. Differences between reviewers will be resolved by discussion or by appeal to a third reviewer if necessary. No effort will be made to blind the reviewers for names of investigators, institutions, journals etc. The data abstraction forms are designed a priori and will be filled out independently.
| intervention A | intervention B |
| Study identification: Form filled in by: |
| yes ‐ no |
| Did study population meet our criteria? |
| yes ‐ no |
| Did study population meet our criteria? |
| yes ‐ no |
| Did study population meet our criteria? |
Methodological quality of included RCTs will be assessed using the following criteria:
Blinding
We will code separately the blinding of patients, treatment providers and outcome assessors as:
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yes
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no
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unclear.
Randomisation
We will code the randomisation of participants to intervention groups as:
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adequate e.g. a computer‐generated random sequence or a table of random numbers
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inadequate e.g. date of birth, clinic ID‐number or surname
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unclear e.g. not reported
Allocation concealment
We will code the concealment of allocation sequence from treatment providers and participants as:
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adequate e.g. where the allocation sequence could not be foretold (A)
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unclear e.g. not reported (B)
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inadequate e.g. the computer‐generated random sequence was displayed so treatment providers could see which arm of the trial the next participant was assigned to, or kept in a sealed opaque envelope (C)
Loss to follow‐up
We will record the number of participants in each intervention arm whose outcomes were not reported at the end of the study; we will note if loss to follow‐up was not reported.
Methodological quality of non‐randomised studies will be assessed as above with the exception of randomisation and additionally assessed on the basis of:
Comparability of treatment groups at baseline
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yes
-
no
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unclear
Adjustment for potential confounders
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yes
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no
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unclear
Participants
For each trial, data on the number of patients assigned to each treatment, analysed and excluded from the investigators' analyses will be extracted independently. The distribution of patients by age, stage, histology, grade and performance status will be abstracted where available.
Interventions
Data on the type of surgery will be collected. Details of dose and fractionation of external beam radiotherapy and details of the brachytherapy dose, insertions and dose rate will be collected. Details of any chemotherapy given concomitantly with radiotherapy will be recorded. Details on duration or follow up and ascertainment of long‐term toxicity will also be recorded.
Outcomes
OS and DFS will be the primary outcomes, while complications of treatment such as radiation toxicity, menopause, intestinal and urogenital complications and QOL will be secondary outcomes.
Assessment of risk of bias in included studies
Quality assessment
All titles and abstracts retrieved by electronic searching will be downloaded to a reference management database (e.g. Reference Manager or Endnote), duplicates will be removed and the remaining references will be examined by two reviewers (AB, YV) independently. Those studies which clearly do not meet the inclusion criteria will be excluded and copies of the full text of potentially relevant references will be obtained. The eligibility of retrieved papers will be assessed independently by two reviewers (AB, YV). Reasons for exclusion will be documented. The number of references excluded will be reported in a QUOROM flow chart (Table 5).
| RCT's included | RCTs excluded |
| potentially relevant RCTs identified and screened for retrievel (n=...) | |
| RCTs excluded with reason (n=...) | |
| RCTs retreaved for more detailed evaluation (n=...) | |
| RCTs excluded, with reasons (n=...) | |
| Potentially appropriate RCTs to be included in the meta analysis (n=...) | |
| RCTs excluded from meta‐analysis, with reason (n=...) | |
| RCTs included in meta‐analysis (n=...) | |
| RCTs withdrawn, by outcome, with reasons (n=...) | |
| RCTs with usable information, by outcome (n=...) |
Assessment of heterogeneity
Heterogeneity between studies will be assessed by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003) , and by a chi‐square test of the significance of the heterogeneity (Deeks 2001), irrespective of whether HRs or ORs were calculated. If there is evidence of substantial heterogeneity, the possible reasons for this will be investigated and reported.
Data synthesis
For meta‐analysis of the time‐to‐event outcomes (OS and PFS), the most appropriate statistic is the hazard ratio (HR). If provided in a trial report, the HR and associated variance will be used directly in the meta‐analysis. Alternatively, using the methods described in Parmar 1998, they will be estimated indirectly from other summary statitics (95% confidence intervals (CI), P‐values, total number of events) or from data extracted from published Kaplan‐Meier curves (Parmar 1998). Where feasible, a number of methods will be used to indirectly estimate the trial HR, to check its reliability. The estimated HRs will then be combined across all trials using the generic inverse variance facility in Revman to give a pooled HR. This represents the overall risk of an event with surgery versus radiotherapy. In some papers only overall rates of local and distant recurrence may be presented rather than a time‐to‐event analysis of these events. Therefore, only an odds ratio (OR) of the rates of recurrence can be calculated, with no account being taken of the time to recurrence or any censoring. Figures for recurrence will be extracted from the text and the OR calculated from the total number of patients and the observed number of recurrences on each arm. The ORs for individual trials will be combined across all trials. These ORs indicate the odds of a local or distant recurrence in the surgery arm versus the radiotherapy arm.
Chi‐square tests will also be used to assess the consistency of effect across different subsets of trials and are referred to as chi‐square test for interaction. Pooling of data will only take place if there is no clinical heterogeneity and if there are outcomes that can be combined. In the absence of statistical heterogeneity, a fixed effects model will be used, if there is statistical heterogeneity a random effects model will be used. Where pooling is not appropriate the results of eligible trials will be discussed in a narrative form. Ideally analysis will be on an intention‐to‐treat basis, but information required for this may be lacking from the original papers.
In all tests of significance a two‐sided p‐value will be given.
Sensitivity analysis
If there is major variation in the quality of studies, this will be examined in a sensitivity analysis.
| intervention A | intervention B |
| Study identification: Form filled in by: |
| yes ‐ no |
| Did study population meet our criteria? |
| yes ‐ no |
| Did study population meet our criteria? |
| yes ‐ no |
| Did study population meet our criteria? |
| RCT's included | RCTs excluded |
| potentially relevant RCTs identified and screened for retrievel (n=...) | |
| RCTs excluded with reason (n=...) | |
| RCTs retreaved for more detailed evaluation (n=...) | |
| RCTs excluded, with reasons (n=...) | |
| Potentially appropriate RCTs to be included in the meta analysis (n=...) | |
| RCTs excluded from meta‐analysis, with reason (n=...) | |
| RCTs included in meta‐analysis (n=...) | |
| RCTs withdrawn, by outcome, with reasons (n=...) | |
| RCTs with usable information, by outcome (n=...) |
