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Base de datos Cochrane de Revisiones Sistemáticas Protocolo - Intervención

Adjuvant chemotherapy and/or radiotherapy after surgery for uterine carcinosarcoma

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Versión publicada: 17 octubre 2007 Historial de versiones

https://doi.org/10.1002/14651858.CD006812

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the role of adjuvant radiotherapy and/or systemic chemotherapy in the management of uterine carcinosarcoma.

Specifically we would wish to address the following questions.

  • Is adjuvant radiotherapy and/or systemic chemotherapy more effective than surgery alone in improving survival?

  • Is adjuvant radiotherapy and/or systemic chemotherapy more effective than surgery alone in delaying recurrence?

  • Is adjuvant radiotherapy and/or systemic chemotherapy acceptable?

Background

Uterine carcinosarcomas are uncommon accounting for 4.3% of all cancers of the uterine corpus in Western Populations (Young 1981). The worldwide annual incidence is between 0.5 and 3.3 cases per 100,000 women (Harlow 1986). In the UK the incidence is quoted to be 1 per 100,000 women and of these 87% are carcinosarcomas (Olah 1992). Uterine carcinosarcomas, also called malignant mixed mesodermal tumours (MMT) or malignant mixed mullerian tumours (MMMT) are a rare subset of uterine sarcomas with both malignant epithelial and malignant mesenchymal components. Surveillance Epidemiology, and End Results (SEER) programme data also demonstrated that carcinosarcoma was the predominant uterine sarcoma (0.82/100,000) followed by leiomyosarcoma (0.64/100,000) and endometrial stromal sarcoma (0.19/100,000) (Harlow 1986).

Carcinosarcomas, which tend to be agressive, can be subdivided histologically into homologous and heterologous types and it is important to differentiate the tumours that are monoclonal that is those derived from a single stem cell from true mixed cell tumours (Zelmanowicz 1998). This histological distinction (McCluggage 2002) is significant as the natural history of true mixed carcinosarcomas appears the more aggressive.

Histological diagnosis and clinical staging (based on findings at surgery) usually follows primary treatment which is surgical cytoreduction. In a prospective multicentre Gynecologic Oncology Group (GOG) study of carcinosarcomas 61 of the 301 patients (20%) with clinical Stage I and II disease were reassigned to pathological Stages III and IV on the basis of lymphnode metatases. The study also revealed a recurrence rate of 53% for all carcinosarcomas, with 44% for homologous and 63% for heterologous tumours (Major 1993).

Following primary surgery subsequent management includes further surgery for resection of isolated metastases, radiation to sites of local recurrence and palliative hormonal or systemic chemotherapy for advanced disease, but no clear consensus on adjuvant treatments exists (Omura 1983). As the overall 5 year cancer related survival for carcinosarcomas was less than 30% (Nielsen 1989; Olah 1992) and the median survival for metastatic MMT was less than 12 months, adjuvant treatment is an important issue.

To date the role of adjuvant radiotherapy in the management of uterine MMT has not been tested in a randomized controlled trial (RCT). The literature is predominantly retrospective data and suggested that adjuvant pelvic irradiation in 44 patients with carcinosarcoma increased the rate of pelvic control without affecting survival. This is because nearly 50% recurred in sites beyond the pelvis (Salazar 1978).

GOG addressed the issue of distant spread in their investigation of adjuvant chemotherapy in stage I and II disease in a prospective RCT (Omura 1985). The trial failed to show a significant difference in recurrence rate, progression‐free interval, or survival. GOG reported a progression‐free survival (PFS) rate of 63% and an overall survival (OS) rate of 74% after a minimum follow up of two years with the use of ifosfamide and cisplatin in carcinosarcoma, but with grade 3 or 4 neutropenia as well as grade 3 or 4 thrombocytopenia in 63% and 26% of patients respectively (Sutton 1997).

Nielsen, in a retrospective review of 60 cases of carcinosarcoma treated between 1959 and 1982, demonstrated no significant survival advantage or pelvic recurrence free survival for surgery plus pelvic irradiation, or for surgery plus chemotherapy compared with surgery alone in cases of MMT after stratification according to stage (Nielsen 1989).

The costs in terms of toxicity, quality of life (QOL) and financial investment, are considerable with both chemotherapy and radiotherapy, therefore there is a need to assess effectiveness rigorously.

Objectives

To evaluate the role of adjuvant radiotherapy and/or systemic chemotherapy in the management of uterine carcinosarcoma.

Specifically we would wish to address the following questions.

  • Is adjuvant radiotherapy and/or systemic chemotherapy more effective than surgery alone in improving survival?

  • Is adjuvant radiotherapy and/or systemic chemotherapy more effective than surgery alone in delaying recurrence?

  • Is adjuvant radiotherapy and/or systemic chemotherapy acceptable?

Methods

Criteria for considering studies for this review

Types of studies

Prospective RCTs examining radiotherapy and/or systemic chemotherapy after surgery for uterine carcinosarcoma. If no RCTs exist retrospective studies might be considered.

Types of participants

Women of any age with a histological diagnosis of uterine carcinosarcoma of any International Federation of Gynecology and Obstetrics (FIGO) stage (Shepherd 1989).

Types of interventions

Surgery followed by radiotherapy and/or systemic chemotherapy.

Types of outcome measures

  • OS

  • Disease free survival (DFS)

  • QOL

Search methods for identification of studies

Electronic searches

See: Gynaecological Cancer Group search strategy

Electronic databases : An electronic search will be performed using the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE from 1966, EMBASE from 1980, CINAHL (1982 ‐ to date), Psych Lit (1986 ‐ to date) CancerLit (1986 ‐ to date) with the following search strategy (MEDLINE Ovid web) adapted for the other databases. No language restriction will be applied. The following trial registers will also be searched ‐ NHMRC Clinical Trials Register, UKCCCR Register of Cancer Trials, Meta‐Register and Physician Data Query Protocols .

1. carcinosarcoma
2. Carcinosarcoma.DE
3. mixed mullerian tumo
4. Mixed‐Tumor‐Mullerian.DE
5. mixed mesodermal tumo
6. 1 or 2 or 3 or 4 or 5
7. endometri*
8. corpus uteri
9. uter*
10. uterine neoplasms.DE
11. 7 or 8 or 9 or 10
12. 6 and 11
13. radiother*
14. radiation therapy
15. Radiotherapy.DE or Radiotherapy‐Adjuvant>DE
16. 13 or 14 or 15
17. chemother*
18. Drug‐therapy or Chemotherapy‐adjuvant.DE or Drug‐therapy‐combination.DE or Antineoplastic‐Combined‐Chemotherpay‐Protocols>DE
19. 17 or 18
20. 12 and 16
21. 12 and 19
22. 20 or 21

Searching other resources

Reference lists of articles and other reviews on the subject will be checked for the purpose of retrieving further information, either published or unpublished, and researchers involved in this area will be contacted.

Data collection and analysis

Selection of studies

Studies that meet the inclusion criteria will be identified according to the search strategy described. Two authors (KG, RA) will screen titles and abstracts of studies identified from the search and eliminate articles that are obviously not relevant to the search question. If there are any disagreements between authors based on the title, a review of the abstract will be conducted. The two authors (KG, RA) will independently assess each abstract according to a checklist of the selection criteria. If both authors determine that the study is not eligible for inclusion no further action will be taken. If one or both the authors determine that the article may be eligible for inclusion, full text article will be obtained. Each author will then independently determine if these studies are eligible for inclusion. Disagreements about inclusions will be resolved by discussion with a third author (KD). Further information will be sought from the authors where papers contain insufficient information to make a decision about eligibility.

A formal review will be conducted in accordance with the Cochrane Handbook guidelines.

Data extraction and management

Data will be extracted by two independent authors and will include:

  • participant characteristics (age, stage and postoperative residuum of disease)

  • number of participants in each arm of the trial

  • type of intervention (chemotherapy agents and radiotherapy, dosage and timing of administration relative to surgery)

  • methodological quality data as described above

  • length of follow up

  • QOL data from reliable and validated tools. Symptom improvement or deterioration will be recorded

  • withdrawals from treatment protocol

  • number of participants who experience delays in treatment or received all, part or none of the proposed treatment

Hazard Ratio (HR) and its variance summarising (i) risk of recurrence and (ii) survival. If survival methods have been used, but the HR have not been reported, they will estimated using Parmar's method (Parmar 1998). If this is not possible, odds ratios (OR) or relative risks (RR) will be extracted if they have been reported or can be calculated.

Assessment of risk of bias in included studies

Quality assessment

Assessment of the quality of a trial will be made in accordance with guidelines in the Cochrane Handbook (Higgins 2005).

Quality issues that will be addressed for RCTs and recorded as adequate, inadequate or unclear will be:

  • whether the method of allocation was truly random e.g. computer generated random numbers etc

  • whether there was proper concealment of allocation

  • whether intention to treat analysis was performed

  • whether loss to follow up was accounted for

A description of the quality of the trials will be included in the review and further analysis considered depending on numbers.

Data synthesis

If similar studies of good quality are present, these will be grouped together and analysed using the Review Manager statistical package. We will, where possible, meta‐analyse data from different scales using the standardised mean difference (SMD). For meta‐analysis of time to event outcomes, the most appropriate statistic is the HR, which will be used if it is provided or can be calculated from the trial report. Where this is not possible, the OR will be estimated and interpreted with caution. If it is possible to account for withdrawals from from trials this will be included in the calculations.

If appropriate, sensitivity and sub‐group analyses will be performed to analyse studies with different interventions. Differences between the results of included studies will be checked for heterogeneity using the I2 test. A fixed effects model will be used if there is no evidence of statistical heterogeneity (I2 < 25%). If there is substantial heterogeneity (I2>25%), the possible clinical and methodological reasons for this will be explored qualitatively and a random effects model will be used. A funnel plot will be used to assess whether the assumptions underlying the random effects model appear to be valid.If the funnel plot is asymmetric, indicating that the size of the study is related to the estimated size of the treatment effect, the results of both fixed and random effects models will be reported.

If we find inadequate numbers of RCTs to pool the data, we will write a description of their main findings.