Adjuvant (supplementary treatment after initial treatment) platinum-based anti-cancer drugs for early stage cervical cancer

Background
Cervical cancer is the second most common cancer among women. Most women with early stage cervical cancer (stages I to IIA) are cured with surgery or, radiotherapy, or both. Radiotherapy uses high energy x-rays to damage tumour cells. Chemotherapy (anti-cancer) drugs use different ways to stop tumour cells dividing so they stop growing or they die.

Review question
We undertook this review because it was unclear whether chemotherapy with a drug called cisplatin offered additional benefits or risks to women with early stage cancer with risk factors for recurrence, when given after surgery, after radiotherapy, or both. (Risks for recurrence include tumour spread to the lymph nodes, spread into the lymph and blood vessels, tumour depth of more than 10 mm, microscopic invasion of the connective tissues next to the womb, non-squamous type of cancer, and when it is unlikely that surgery has removed all the tumour cells).

Main Findings
In this review, we analysed data from four small trials of unclear quality. It was not possible to separate data of bulky early stage disease (stage IB2 and IIA lesions greater than 4 cm) from the overall results. We found limited evidence to suggest that the addition of cisplatin chemotherapy to radiotherapy prolongs survival (time to death) and delays progression of the cancer when given after surgery to women with cervical cancer stage IA2 to IIA with risk factors for recurrence. The combined therapy was associated with more severe side effects than radiotherapy alone.

Quality of the Evidence
This evidence is limited by the small numbers and moderate quality methodological quality of included studies.

What are the conclusions?
We conclude that it seems appropriate to offer these women chemotherapy plus radiotherapy after surgery, however, more evidence regarding the relative benefits and risks is needed; this will hopefully be provided by the results of three ongoing trials.

Authors' conclusions: 

The addition of platinum-based chemotherapy to adjuvant radiotherapy (chemoradiation) may improve survival in women with early stage cervical cancer (IA2-IIA) and risk factors for recurrence. Adjuvant chemoradiation is associated with an increased risk of severe acute toxicity, although it is not clear whether this toxicity is significant in the long term due to a lack of long-term data. This evidence is limited by the small numbers and low to moderate methodological quality of the included studies. We await the results of three ongoing trials, which are likely to have an important impact on our confidence in this evidence.

Read the full abstract...
Background: 

This is the second updated version of the original Cochrane review published in the Cochrane Library 2009, Issue 3.

Most women with early cervical cancer (stages I to IIA) are cured with surgery or radiotherapy, or both. We performed this review originally because it was unclear whether cisplatin-based chemotherapy after surgery, radiotherapy or both, in women with early stage disease with risk factors for recurrence, was associated with additional survival benefits or risks.

Objectives: 

To evaluate the effectiveness and safety of adjuvant platinum-based chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer.

Search strategy: 

For the original 2009 review, we searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2009, Issue 1), MEDLINE, Embase, LILACS, BIOLOGICAL ABSTRACTS and CancerLit, the National Research Register and Clinical Trials register, with no language restriction. We handsearched abstracts of scientific meetings and other relevant publications. We extended the database searches to November 2011 for the first update and to September 2016 for the second update.

Selection criteria: 

Randomised controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy (after radical surgery, radiotherapy or both) with no adjuvant chemotherapy, in women with early stage cervical cancer (stage IA2-IIA) with at least one risk factor for recurrence.

Data collection and analysis: 

Two review authors extracted data independently. Meta-analysis was performed using a random-effects model, with death and disease progression as outcomes.

Main results: 

For this second updated version we identified only one small trial reporting grade 4 toxicity results, without disease-free or overall survival data with a median follow-up of 16 months.

From the first updated version, we identified three trials that were ongoing, and remain so in 2016.

Four trials including 401 women with evaluable results with early cervical cancer were included in the meta-analyses. The median follow-up period in these trials ranged from 29 to 42 months. All women had undergone surgery first. Three trials compared chemotherapy combined with radiotherapy versus radiotherapy alone; and one trial compared chemotherapy followed by radiotherapy versus radiotherapy alone. It was not possible to perform subgroup analyses by stage or tumour size.

Compared with adjuvant radiotherapy, chemotherapy combined with radiotherapy significantly reduced the risk of death (two trials, 297 women; hazard ratio (HR) = 0.56, 95% confidence interval (CI): 0.36 to 0.87) and disease progression (two trials, 297 women; HR = 0.47, 95% CI 0.30 to 0.74), with no heterogeneity between trials (I² = 0% for both meta-analyses). Acute grade 4 toxicity occurred significantly more frequently in the chemotherapy plus radiotherapy group than in the radiotherapy group (three trials, 321 women; risk ratio (RR) 6.26, 95% CI 2.50 to 15.67). We considered the evidence for all three outcomes to be of a moderate quality, using the GRADE approach due to small numbers and limited follow-up in the included studies. In addition, it was not possible to separate data for bulky early stage disease.

In the one small trial that compared adjuvant chemotherapy followed by radiotherapy with adjuvant radiotherapy alone there was no difference in disease recurrence between the groups (one trial, 71 women; HR = 1.34; 95% CI 0.24 to 7.66) and overall survival was not reported. We considered this evidence to be of a low quality.

No trials compared adjuvant platinum-based chemotherapy with no adjuvant chemotherapy after surgery for early cervical cancer with risk factors for recurrence.

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