SOR guidelines for concomitant chemoradiotherapy for patients with uterine cervical cancers: evidence update bulletin 2004

C. Haie-Meder1,2, B. Fervers1,3,*, E. Fondrinier1,4, M. Haugh1,3, C. Lhomme1,2 and J. P. Guastalla1,3

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Background:: In 1993 the French National Federation of Cancer Centres (FNCLCC) initiated the Standards, Options and Recommendations (SOR) project. This is a collaboration between the FNCLCC, the 20 French cancer centres, and specialists from French public universities, general hospitals and private clinics, and some specialists learned societies. The main objective is to develop clinical practice guidelines to improve the quality of health care and the outcome of cancer patients.

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


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Cervical cancer is the seventh most common cancer worldwide, and is the second most common cancer among women, after breast cancer [1Go]. In 2000 the 5-year prevalence rate was 1 401 400, the incidence was 4 706 000, and the mortality rate was 2 334 000.

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 [2Go] 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 [3Go].

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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Table 1. Definition of Standards, Options and Recommendations

 
The type of evidence underlying any ‘Standard’, ‘Option’ or ‘Recommendation’, is indicated using a classification developed by the FNCLCC based on previously published methods. The level of evidence depends not only on the type and quality of the studies reviewed, but also on the concordance of the results (Table 2). When no clear scientific evidence exists, judgement is made according to the professional experience and consensus of the expert group (‘expert agreement’), and this is validated by the peer-review process.


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Table 2. Definition of level of evidence

 
In the original SORs, there was no standard for stage IB, IIA and proximal IIB tumours [3Go], and three options were proposed: radiotherapy only, surgery only or radiotherapy plus surgery. The original SOR defined the combination of external radiotherapy and brachytherapy as standard treatment for women with advanced-stage disease, with either lymph node involvement or local invasion into the vagina [3Go]. The SOR concluded that randomised trials had shown that hydroxyurea might have a radiosensitisation activity and confer long-term benefit (improved relapse-free and overall survival) when given in combination with radiotherapy (level of evidence C). However, it was recommended that this needed further confirmation in good-quality randomised clinical trials. The original SOR guideline recommended the evaluation of other drugs that might be more effective and less toxic [3Go].

In 1999, after the publication of the SOR, five randomised trials assessing concomitant radiotherapy and chemotherapy were reported [4Go–8Go]. 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 IB–IVB cervical cancers. The results of this process and the updated SOR have been published in French [9Go]. 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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Data sources
Four databases, MEDLINE®, CANCERLIT®, TOXLINE® and EMBASE®, were searched using combinations of the following key words: cervix neoplasms, radiotherapy, drug therapy, antineoplastic agents, combined modality therapy. The search strategy, which was reported in the two previous reports [3Go, 9Go], was extended to March 2004 in MEDLINE. This search was complemented with data from the National Cancer Institute in the USA (http://www.nci.nih.gov) and with references from the personal references of the members of the working group. The search enabled randomised controlled trials (RCTs) comparing concomitant chemoradiotherapy and radiotherapy alone or with a radiosensitiser to be identified.

Analysis of data
The results from the RCTs are discordant, thus in this report we performed a meta-analysis, using the Easy-MA software [10Go] 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.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Analysis of systematic reviews and clinical practice guidelines
A systematic review was published in 2002 [11Go] in which 19 randomised clinical trials were included. Two of these trials were unpublished, two were published in conference proceedings; one was published in Spanish and one in Chinese. The remaining trials correspond to those included in this evidence update bulletin. The authors of this review concluded that there is strong evidence to suggest that chemoradiotherapy improves overall survival and progression-free survival, with both platinum and non-platinum chemotherapy. Some evidence exists to suggest that the effect was more pronounced in trials including a higher proportion of stage I and II patients. Chemoradiotherapy showed a significant benefit for local and distance recurrence. Haematological and gastrointestinal toxicities were significantly more frequent in the chemoradiotherapy group, but acute side-effects were generally of short duration and resolved with medical management. Details of late toxicity were sparse and therefore it was not possible to say if there was a higher rate with combined therapy. The authors suggested that further research was needed to assess if there is more benefit for patients with early stage disease than for those with late stage disease, and also to evaluate the impact of the radiotherapy dose and duration, of including other cytotoxic drugs in addition to cisplatin, and the drug scheduling.

In the National Comprehensive Cancer Network guidelines [12Go], 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 [13Go] 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 [14Go] 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 [15Go] provided results for overall survival. Data for disease-free survival were available in all except four trials [7Go, 8Go, 16Go, 17Go] and data for progression-free survival were available in three trials [8Go, 15Go, 16Go]. Three of the trials were included in the first SOR [14Go, 18Go, 19Go]. For the update, five full reports of trials were identified [4Go, 5Go, 7Go, 8Go, 20Go] and one abstract [6Go]. Updated results for one of these trials [5Go] have been recently published [21Go]. The efficacy results from the updated paper have been analysed here. The trial published as an abstract [6Go] has been published as a full report [16Go] and three other trials have also been published [17Go, 22Go, 23Go] and are included here. In addition, the update includes a Cochrane systematic review [11Go] and two clinical practice guidelines that have been published recently in the United States [12Go] and in Canada [13Go].


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Table 3. Trial characteristics

 
The characteristics of the trials are summarised in Table 3. The inclusion criteria were not the same in all the trials, resulting in populations with varying distributions of disease stages. In addition, the treatment schemas for both radiotherapy and chemotherapy used in these trials were different.

Four of the trials tested chemoradiotherapy with cisplatin alone [4Go, 7Go, 17Go, 18Go]. One of these trials had three groups [7Go]; 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 [8Go, 16Go, 21Go], one trial tested chemotherapy with 5-FU only [15Go], and another tested a combination of vincristine, cisplatin and bleomycin [19Go]. One trial tested mitomycin C chemotherapy [22Go] and one tested combined mitomycin C and 5-FU [23Go]. The remaining trial tested epirubicin chemotherapy [20Go]. 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 [8Go]. In one trial all the patients underwent hysterectomy 3–6 weeks after radiotherapy or chemoradiotherapy [4Go].

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) 1.14–1.26, 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 1.17–1.35; 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 1.18–1.45; P < 0.001; P hetero=0.64).


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Table 4. Results from clinical trials included in analysis

 


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Figure 1. Results from meta-analysis using relative risk (RR) of overall survival data from 11 trials. A perpendicular bar (point estimate) and a horizontal bar [95% confidence interval (CI)] represent the results for the individual trials.

 


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Figure 2. Results from meta-analysis using relative risk (RR) of disease-free survival data from eight trials. A perpendicular bar (point estimate) and a horizontal bar [95% confidence interval (CI)] represent the results for the individual trials.

 


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Figure 3. Results from meta-analysis using relative risk (RR) of progression-free survival data from three trials. A perpendicular bar (point estimate) and a horizontal bar [95% confidence interval (CI)] represent the results for the individual trials.

 
Toxicity analysis
When data were reported, the rate of toxic side-effects was higher in patients receiving chemoradiotherapy than in those receiving radiotherapy. Wong et al. [18Go] reported that patients receiving radiotherapy experienced only grade 0/1 side-effects, whereas many of those receiving chemoradiotherapy experienced grade 2/3 side-effects. Tseng et al. [19Go] reported 22 (36%) grade 3/4 side-effects in the 60 patients receiving chemoradiotherapy, versus 11 (17.7%) in the 62 patients receiving radiotherapy. In addition 14 patients (23.3%) experienced treatment-related late toxicity in the chemoradiotherapy group, compared with eight (12.9%) in the radiotherapy group. Keys et al. [4Go] reported a higher rate of grade 3/4 side-effects in patients receiving chemoradiotherapy compared with those receiving radiotherapy (35% (64/186) versus 13% (25/183), respectively). In the group receiving chemoradiotherapy, 39 and 26 patients experienced transient haematological and gastrointestinal complications, respectively, compared with three and nine patients in the group receiving radiotherapy. Morris et al. [5Go] reported that 33% (65/195) and 22% (11/195) of patients receiving chemoradiotherapy experienced early (before 60 days) grade 3 and 4 toxic side-effects, respectively, compared with 3% (5/193) and 1% (1/193) of patients receiving radiotherapy. One patient in the chemoradiotherapy group experienced a grade 5 toxic side-effect. However, they reported that 10% (20/193) of patients receiving radiotherapy experienced late grade 4 toxic side-effects compared with 8% (16/193) of those receiving chemoradiotherapy. Rose et al. [7Go] reported a significantly higher rate of leukopenia and other haematological events in the patients receiving chemoradiotherapy with three drugs (71/173; 41%) compared with those receiving chemoradiotherapy with cisplatin (37/176; 21%) and those receiving radiotherapy only (35/177; 20%). Whitney et al. [8Go] reported that patients experienced predominantly haematological and gastrointestinal effects, with 8% (14/169) in the chemoradiotherapy group compared with 4% (8/188) in the radiotherapy group. The rate of late major complications (grade 3/4 at 3 years) was 16.2% and 16.5%, respectively. Wong et al. [20Go] reported that no patients experienced a grade 4 toxic complication. They also reported only one grade 3 complication in the radiotherapy group (haemoglobin), compared with 130 in the chemoradiotherapy group (n=110) (leukocyte count, 25; alopecia, 105). Peters et al. [16Go] observed that there were 27 episodes of grade 4 toxicity in 21 patients (mainly haematological) in the chemoradiotherapy group (n=122) compared with four episodes in the radiotherapy group (n=112). Roberts et al. [22Go] reported that 31/78 (40%) patients in the chemoradiotherapy group experienced moderate or severe leukopenia compared with 9/82 (11%) in the radiotherapy group. Three patients experienced moderate or severe thrombocytopenia, and one patient experienced a life-threatening episode. The rate of non-haematological toxic events was similar for both groups. Pearcey et al. [17Go] reported 31 (24%) grade 3 and nine (7%) grade 4 toxic events in the group receiving chemoradiotherapy (n=127), compared with four (3%) and zero, respectively, in the group receiving radiotherapy (n=126). Lorvidhaya et al. [23Go] reported that the patients in the chemoradiotherapy group experienced a higher rate of grade 2 bone marrow and haematological events (45/233) compared with those in the radiotherapy group (31/342). They also experienced a higher rate of grade 3/4 leukopenia/thrombocytopenia (14/233 versus 2/342).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Significant improvement in overall, disease-free and progression-free survival was observed with concomitant chemoradiotherapy containing cisplatin compared with radiotherapy alone. This was reported in women with stage IB, IIA and IIB disease with poor prognostic factors (diameter >4 cm and/or pelvic lymph node involvement and/or microscopic invasion of the parametrium) and stage III and IVA. None of the patients enrolled in these studies, irrespective of the tumour stage, had para-aortic node involvement. Therefore, concomitant chemoradiotherapy can be considered to be the standard treatment for these patients (Standard: level of evidence A). It is possible that patients with stage III or IVA disease may benefit less than those with lower stage disease, but this should be confirmed (Option: level of evidence B1). Haematological and gastrointestinal effects are the main side-effects seen with radio-chemotherapy and they occur more frequently than with radiotherapy alone (level of evidence: B2). The late effects rates have not been determined yet as follow-up was not long enough to be assessed.

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 40–45 Gy with 1.8 Gy per session with a classical schedule of five sessions per week [24Go]. 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 [25Go–27Go]. 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.


    Conclusions
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
The SOR guidelines are summarised in Table 5. On the basis of this critical analysis of studies of concomitant radio-chemotherapy in the treatment of cervical cancer, the working group has updated the Standards, Options and Recommendations for the treatment of cancers of the uterine cervix without para-aortic lymph node involvement, distinguishing between:

  1. IB1, IIA and proximal IIB stages, with a good prognosis (under 4 cm and without lymph node involvement (radiology or after surgery) and without microscopic invasion of the parametrium if operated),
  2. IB, IIA and proximal IIB stages, with a poor prognosis (4 cm or bigger and/or pelvic lymph node involvement),
  3. distal stage IIB and stages III and IVA.
Only the patients in the last two groups should be considered for treatment with concomitant radio-chemotherapy (Standard: level of evidence A).


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Table 5. Therapeutic indications for patients with stage IB, IIA and proximal IIB tumours with poor prognosis (4 cm or larger and/or pelvic lymph node involvement) without para-aortic lymph node involvement

 
The recommendations concerning patients with para-aortic lymph node involvement are unchanged [3Go], since the studies analysed in this update have not added new data on these cancers.


    Acknowledgements
 
We would like to thank the Ministry of Employment and Solidarity and the National League against Cancer for financial support. We would also like to thank Sylvie Guillo who performed the literature search.

Received for publication July 12, 2004. Revision received February 17, 2005. Accepted for publication February 17, 2005.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
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3. Resbeut M, Fondrinier E, Fervers B et al. Fédération Nationale des Centres de Lutte Contre le Cancer, Société Française d'Oncologie Gynécologique. Standards, Options et Recommandations. Cancers invasifs du col utérin (stades non métastatiques), vol 9. EUROTEXT. Paris, France: John Libbey 1999.

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22. Roberts KB, Urdaneta N, Vera R et al. Interim results of a randomized trial of mitomycin C as an adjunct to radical radiotherapy in the treatment of locally advanced squamous-cell carcinoma of the cervix. Int J Cancer 2000; 90: 206–223.[CrossRef][ISI][Medline]

23. Lorvidhaya V, Chitapanarux I, Sangruchi S et al. Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys 2003; 55: 1226–1232.[CrossRef][ISI][Medline]

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