Hysterectomy with medical management for cervical cancer that has spread to nearby tissues only

The issue
Cancer of the neck of the womb (cervical cancer) is the commonest cancer among women up to 65 years of age. A high proportion of women in developing countries are diagnosed with locally advanced disease (spread to nearby tissues, but no obvious distant spread). They are usually treated with radiotherapy, with or without chemotherapy (medical treatment). Hysterectomy (surgery to remove the womb and the cervix) with medical treatment is also used, especially in developing countries where access to radiotherapy is limited.

The aim of the review
Is hysterectomy with medical treatment more beneficial compared to medical treatment alone in locally advanced cervical cancer?

How was the review conducted?
A literature search from 1966 to February 2014 identified seven trials at moderate to high risk of bias. These included 1217 women and compared: hysterectomy with radiotherapy versus radiotherapy alone; hysterectomy with chemoradiotherapy versus chemoradiotherapy alone; hysterectomy with chemoradiotherapy versus internal radiotherapy (brachytherapy) with chemoradiotherapy; and hysterectomy with upfront (neoadjuvant) chemotherapy versus radiotherapy alone.

What are the main findings?
Two studies, including 374 women, compared preoperative radiotherapy and hysterectomy versus radiotherapy alone, but only one trial reported overall survival, with no difference between the groups. These studies found no difference in the risk of disease progression (or death) or five-year tumour-free survival.

One study, including 61 women, reported no difference in overall and recurrence-free survival between chemotherapy and hysterectomy versus chemoradiotherapy alone.

Another study comparing internal radiotherapy (brachytherapy) versus hysterectomy in 211 women who received chemoradiotherapy found no difference in the risk of death or disease progression.

By combining results from three of the independent studies that assessed 571 women, we found that fewer women who received neoadjuvant chemotherapy plus hysterectomy died than those who received radiotherapy alone. However, many women in the first group also had radiotherapy. There was no difference in the number of women who were disease-free after treatment.

Adverse events were incompletely reported. Results of single trials showed no differences in severe adverse events between the two groups in any comparison. Limited data suggested that the interventions appeared to be reasonably well tolerated, although more evidence is needed.

Quality of life measures were not reported.

What are the conclusions?
We found insufficient evidence that hysterectomy added to radiation and chemoradiation improved survival, quality of life or adverse events in locally advanced cervical cancer compared with medical treatment alone. Overall, the quality of the evidence was variable and was universally downgraded due to concerns about risk of bias. The quality of the evidence for neoadjuvant chemotherapy and radical hysterectomy versus radiotherapy alone for survival outcomes was moderate, with evidence from other comparisons being of low quality. Further data from carefully planned trials assessing medical management with and without hysterectomy are likely to impact on how confident we are about these findings.

Authors' conclusions: 

From the available RCTs, we found insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with locally advanced cervical cancer who are treated with radiotherapy or chemoradiotherapy alone. The overall quality of the evidence was variable across the different outcomes and was universally downgraded due to concerns about risk of bias. The quality of the evidence for neoadjuvant chemotherapy and radical hysterectomy versus radiotherapy alone for survival outcomes was moderate, with evidence from other comparisons of low quality. This was mainly based on poor reporting and sparseness of data where results were based on single trials. More trials that assess medical management with and without hysterectomy may test the robustness of the findings of this review as further research is likely to have an important impact on our confidence in the estimate of effect.

Read the full abstract...
Background: 

Cervical cancer is the second commonest cancer among women up to 65 years of age and is the most frequent cause of death from gynaecological cancers worldwide. Sources suggest that a very high proportion of new cervical cancer cases in developing countries are at an advanced stage (IB2 or more) and more than a half of these may be stage III or IV. Cervical cancer staging is based on findings from clinical examination (FIGO) staging). Standard care in Europe and US for stage IB2 to III is non-surgical treatment (chemoradiation). However in developing countries, where there is limited access to radiotherapy, locally advanced cervical cancer may be treated with a combination of chemotherapy and hysterectomy (surgery to remove the womb and the neck of the womb, with or without the surrounding tissues). It is not certain if this improves survival. Therefore, it is important to systematically assess the value of hysterectomy in addition to radiotherapy or chemotherapy, or both, as an alternative intervention in the treatment of locally advanced cervical cancer (stage IB2 to III).

Objectives: 

To determine whether hysterectomy, in addition to standard treatment with radiation or chemotherapy, or both, in women with locally advanced cervical cancer (stage IB2 to III) is safe and effective compared with standard treatment alone.

Search strategy: 

We searched the Cochrane Gynaecological Cancer Group Trials Register, CENTRAL, MEDLINE, EMBASE and LILACS up to February 2014. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies.

Selection criteria: 

We searched for randomised controlled trials (RCTs) that compared treatment protocols involving hysterectomy versus radiotherapy or chemotherapy, or both, in women with advanced stage (IB2 to III) cervical cancer presenting for the first time.

Data collection and analysis: 

We assessed study eligibility independently, extracted data and assessed risk of bias. Where possible, overall and progression or disease-free survival outcomes were synthesised in a meta-analysis using the random-effects model. Adverse events were incompletely reported so results of single trials were described in narrative form.

Main results: 

We included seven RCTs (1217 women) of varying methodological quality in the review; most trials were at moderate or high risk of bias.

Three were multi-centre trials, two were single-centre trials, and in two trials it was unclear if they were single or multi-centre. These trials compared the following interventions for women with locally advanced cervical cancer (stages IB2 to III):

hysterectomy (simple or radical) with radiotherapy (N = 194) versus radiotherapy alone (N = 180); hysterectomy (simple or radical) with chemoradiotherapy (N = 31) versus chemoradiotherapy alone (N = 30); hysterectomy (radical) with chemoradiotherapy (N = 111) versus internal radiotherapy with chemoradiotherapy (N = 100); hysterectomy (simple or radical) with upfront (neoadjuvant) chemotherapy (N = 298) versus radiotherapy alone (N = 273).

One trial (N = 256) found no difference in the risk of death or disease progression between women who received attenuated radiotherapy followed by hysterectomy and those who received radiotherapy (external and internal) alone (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.61 to 1.29). This trial also reported no difference between the two groups in terms of adverse effects (18/129 grade 3 or 4 adverse effects in the hysterectomy and radiation group and 19 cases in 18/121 women in the radiotherapy alone group). There was no difference in 5-year tumour-free actuarial survival (representation of the probable years of survivorship of a defined population of participants) or severe complications (grade 3) in another trial (N = 118) which reported the same comparison (6/62 versus 6/56 in the radiation with surgery group versus the radiotherapy alone group, respectively). The quality of the evidence was low for all these outcomes.

One trial (N = 61) reported no difference (P value > 0.10) in overall and recurrence-free survival at 3 years between chemoradiotherapy and hysterectomy versus chemoradiotherapy alone (low quality evidence). Adverse events and morbidity data were not reported.

Similarly, another trial (N = 211) found no difference in the risk of death (HR 0.65, 95% CI 0.35 to 1.21, P value = 0.19, low quality evidence), disease progression (HR 0.70, 95% CI 0.31 to 1.34, P value = 0.24, low quality evidence) or severe late complications (P value = 0.53, low quality evidence) between women who received internal radiotherapy versus hysterectomy after both groups had received external-beam chemoradiotherapy.

Meta analysis of three trials of neoadjuvant chemotherapy and hysterectomy versus radiotherapy alone, assessing 571 participants, found that women who received neoadjuvant chemotherapy plus hysterectomy had less risk of death than those who received radiotherapy alone (HR 0.71, 95% CI 0.55 to 0.93, I2 = 0%, moderate quality evidence). However, a significant number of the participants that received neoadjuvant chemotherapy plus hysterectomy had radiotherapy as well. There was no difference in the proportion of women with disease progression or recurrence between the two groups (RR 0.75, 95% CI 0.53 to 1.05, I2 = 20%, moderate quality evidence).

Results of single trials reported no apparent (P value > 0.05) difference in long-term severe complications, grade 3 acute toxicity and severe late toxicity between the two groups (low quality evidence).

Quality of life outcomes were not reported in any of the trials.

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