1 Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC), 75654 Paris Cedex 13; 2 Institut Gustave Roussy, 94805 Villejuif Cedex; 3 Centre Léon Bérard, 69373 Lyon Cedex 08; 4 Centre Paul Papin, 49033 Angers Cedex 01, France
* Correspondence to: Dr B. Fervers, SOR-FNCLCC, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cedex 08, France. Tel: +33-4-78-78-28-01; Fax: +33-4-78-78-28-83; Email: fervers{at}lyon.fnclcc.fr
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Abstract |
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Materials and methods:: The SORs are developed using a methodology based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery.
Results:: In 1999, the initial SORs for the management of women with cervical cancer were published. At that time the use of chemoradiotherapy was considered as an option. Since this original publication, five randomised trials comparing chemoradiotherapy with radiotherapy have been published, as well as a systematic review and two other clinical practice guidelines. In the light of this additional evidence, it was decided to update the guidelines on chemoradiotherapy in women with cervical cancer.
Conclusion:: After selection, critical analysis and integration of new evidence, chemoradiotherapy has become a standard for women with cervical cancer.
Key words: clinical practice guideline, concomitant chemoradiotherapy, uterine cervical cancer
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Introduction |
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Given the importance of this disease, there is much on-going research to identify the most effective treatments, and methods for diagnosis and surveillance. However, it is not always possible for physicians and other health care professions to keep abreast of these results, and in the event that the results are discordant, they are not always able to integrate them into their practice. Clinical practice guidelines are systematically developed statements that aim to aid practitioners and patients to make decisions about appropriate health care in specific clinical situations. This is achieved by providing a summary of the best currently available evidence for a particular treatment in a particular clinical situation. Since 1993, the French National Federation of Cancer Centres (Fédération Nationale des Centres de Lutte Contre le Cancer; FNCLCC) have been producing clinical practice guidelines in the setting of a collaborative project: the SOR (Standards, Options and Recommendations) project. The project, which involves a collaboration between the French regional cancer centres, the public and private hospitals and clinics, as well as the private practice sector, has produced over 50 clinical practice guidelines covering the initial management of patients with cancer, from diagnosis to surveillance. The methodology used is based on a combination of evidence-based summaries and expert consensus regarding the application of the evidence in the French setting. The details of this methodology have been published [2] and are also available on the FNCLCC web site (http://www.fnclcc.fr).
A multidisciplinary working-group was set up by the FNCLCC to review the best available evidence for the management of patients with all stages of carcinoma of the cervix. In 1999, this group produced clinical practice guidelines (SORs) for the management of these patients [3].
A literature search was performed, using a defined search strategy, to identify the available publications. Following the selection and critical appraisal of the articles, the working group produced a document with the proposed SORs based on scientific evidence or expert agreement. The document was then peer-reviewed by independent experts, and their comments were integrated in the final version.
When all the members of the working group agreed, based on the best available evidence, that a procedure or intervention was beneficial, inappropriate or harmful, it was classified as a Standard, and when the majority agreed, it was classified as an Option (Table 1). In the SORs there can be several Options for a given clinical situation. Recommendations provide additional information that enables the available options to be ranked using explicit criteria (e.g. survival, toxicity) with an indication of the level of evidence. These recommendations therefore help clinicians to select an appropriate option. Clinicians can, thereby, make choices for the management of patients using this information and taking into consideration local circumstances, skills, equipment, resources and patient preferences. The adaptation of the SOR to the local situation is allowable if the reason for the choice is sufficiently transparent. This possibility to adapt the guidelines is crucial for their successful implementation. Inclusion of patients in clinical trials is an appropriate form of patient management in oncology and is recommended frequently within the SORs, particularly in situations where only weak evidence exists to support a procedure or an intervention.
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In 1999, after the publication of the SOR, five randomised trials assessing concomitant radiotherapy and chemotherapy were reported [48
]. To determine if these results would modify the SORs for the management of patients with cervical cancer, the FNCLCC convened a multidisciplinary working group to review and critically analyse all the available data for concomitant chemotherapy and radiotherapy for stage IBIVB cervical cancers. The results of this process and the updated SOR have been published in French [9
]. The new evidence changed chemoradiotherapy from an option to a standard (level of evidence A) for women with poor prognosis stage IB, IIA and proximal IIB cancers (i.e. tumour 4 cm or bigger, positive pelvic lymph nodes and/or microscopic invasion of the parametrium), and distal IIB, III and IVA cancers. Since then four other randomised clinical trials, a systematic review and two guidelines have been published. These data have been analysed and included in the present publication.
This article is not intended to be a full guideline on management of patients with uterine cervical cancers. Here we present the updated information concerning the chemotherapy component in chemoradiotherapy. Other aspects of the management of these patients in the full guideline will be updated as new data become available.
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Materials and methods |
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Analysis of data
The results from the RCTs are discordant, thus in this report we performed a meta-analysis, using the Easy-MA software [10] for three outcomes (overall survival, disease-free survival and progression-free survival). The data were analysed as survival data (not mortality data) using the relative risk statistic. The heterogeneity was tested using the Q Cochran test. Data for adverse events were also collected and a descriptive analysis was performed.
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Results |
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In the National Comprehensive Cancer Network guidelines [12], it was stated, on the basis of five trials, that: although the determination of the optimum chemotherapy to be used with concurrent radiation will require further investigation, it appears that cisplatin-containing regimens or cisplatin alone should now be considered as part of the standard treatment regimen in patients with locally advanced cervical cancer.
The Cancer Care Ontario Practice Guidelines Initiative (CCOPGI) guideline, originally published in 2002 and updated in 2003 [13] recommends that women, for whom treatment with radiotherapy is being considered, should be offered concurrent cisplatin. Also, although recognising that there are no direct comparisons of different cisplatin regimens, on the basis of the toxicity data reviewed, this guideline recommends that a weekly dose of 40 mg/m2 should be used. They acknowledged that other schedules and doses have been used, and that there is no conclusive evidence that one dose and schedule is better than another. They also concluded that there was insufficient evidence available to recommend the addition of 5-fluorouracil (FU) to cisplatin during radiotherapy.
Update of the SOR clinical practice guideline
To update the SOR clinical practice guideline, a total of 12 randomised clinical trials in which combination radio- and chemotherapy for the treatment of various stages of cervical cancer of the cervix were evaluated. One other trial was not taken into consideration [14] because the trial is still ongoing. The 12 trials, which included 3407 patients, were identified in the literature and they provided data for outcomes of interest (Table 3). All the trials except one [15
] provided results for overall survival. Data for disease-free survival were available in all except four trials [7
, 8
, 16
, 17
] and data for progression-free survival were available in three trials [8
, 15
, 16
]. Three of the trials were included in the first SOR [14
, 18
, 19
]. For the update, five full reports of trials were identified [4
, 5
, 7
, 8
, 20
] and one abstract [6
]. Updated results for one of these trials [5
] have been recently published [21
]. The efficacy results from the updated paper have been analysed here. The trial published as an abstract [6
] has been published as a full report [16
] and three other trials have also been published [17
, 22
, 23
] and are included here. In addition, the update includes a Cochrane systematic review [11
] and two clinical practice guidelines that have been published recently in the United States [12
] and in Canada [13
].
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Four of the trials tested chemoradiotherapy with cisplatin alone [4, 7
, 17
, 18
]. One of these trials had three groups [7
]; one group received cisplatin alone, the control group received hydroxyurea and the third group received both cisplatin and hydroxyurea. Three of the trials tested a combination of cisplatin and 5-FU [8
, 16
, 21
], one trial tested chemotherapy with 5-FU only [15
], and another tested a combination of vincristine, cisplatin and bleomycin [19
]. One trial tested mitomycin C chemotherapy [22
] and one tested combined mitomycin C and 5-FU [23
]. The remaining trial tested epirubicin chemotherapy [20
]. Patients in the control groups received radiotherapy exclusively, except for those in one trial testing cisplatin and 5-FU where hydroxyurea was given to patients in the control group but not to those in the treatment group [8
]. In one trial all the patients underwent hysterectomy 36 weeks after radiotherapy or chemoradiotherapy [4
].
Efficacy analysis: meta-analysis
The results for each trial for the three outcomes analysed are summarised in Table 4. The meta-analysis for overall survival (Figure 1) showed a statistically significant difference in favour of chemoradiotherapy [relative risk (RR)=1.20; 95% confidence interval (CI) 1.141.26, P < 0.001; P hetero=0.21]. Disease-free survival (Figure 2) was also statistically significantly higher in favour of chemoradiotherapy (RR=1.26; 95% CI 1.171.35; P < 0.001; P hetero=0.16). Data for progression-free survival (Figure 3) was available in only three trials and the meta-analysis showed a statistically significant difference in favour of chemoradiotherapy (RR=1.31; 95% CI 1.181.45; P < 0.001; P hetero=0.64).
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Discussion |
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These results were obtained with chemotherapy based on various molecules, including cisplatin, either alone or with other cytotoxic drugs, such as 5-FU. For a similar level of benefit, the combination of cisplatin, 5-FU and hydroxyurea was more toxic than cisplatin alone in one trial in which the two protocols were compared.
The total dose of external irradiation should not be modified with the addition of chemotherapy, and should remain in the range of 4045 Gy with 1.8 Gy per session with a classical schedule of five sessions per week [24]. In particular, a decrease in the total dose should be avoided. The total treatment duration should remain less than 55 days as the impact on local control has been clearly demonstrated [25
27
]. Future randomised trials should aim to establish optimal chemotherapy regimens for combination with external-beam radiotherapy. The efficacy of concomitant chemobrachytherapy should also be evaluated in randomised controlled trials.
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Conclusions |
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Acknowledgements |
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Received for publication July 12, 2004. Revision received February 17, 2005. Accepted for publication February 17, 2005.
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References |
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