Follow-up protocols for women with cervical cancer after primary treatment

  • Review
  • Intervention

Authors


Abstract

Background

Cervical cancer is the second most common cancer among women up to 65 years of age and is the most frequent cause of death from gynaecological cancers worldwide. Although surveillance of women after completion of primary treatment for cervical cancer is purported to have an impact on their overall survival (OS), no strictly defined follow-up protocols are available for these women. Wide diversity in management has been noted in the follow-up of women who have completed primary treatment for cervical cancer. Traditionally, women treated for cervical cancer undergo routine long-term, even life-long, follow-up. The primary objective of this practice has been to detect and treat recurrence early. This review sets out to systematically evaluate available evidence for the role of different models of follow-up after cervical cancer and the optimal use of investigations.

Objectives

To evaluate the benefits, harms and costs of different follow-up protocols for women who have completed primary treatment for cervical cancer.

Search methods

We searched CENTRAL (The Cochrane Library 2013, Issue 1), the Cochrane Gynaecological Cancer Group (CGCG) Trials Register, MEDLINE and EMBASE up to January 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of clinical guidelines and review articles and contacted experts in the field.

Selection criteria

We searched for randomised controlled trials (RCTs) that compared different follow-up protocols after primary treatment in women with cervical cancer.

Data collection and analysis

Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found, and therefore no data were analysed.

Main results

The search strategy identified 1,377 unique references, of which all were excluded on the basis of title and abstract.

Authors' conclusions

We found no evidence to inform decisions about different follow-up protocols after primary treatment for women with cervical cancer. Ideally, a large RCT or, at the very least, well-designed non-randomised studies (NRSs) that use multi-variate analysis to adjust for baseline imbalances are needed to compare these follow-up protocols. Such studies could include prospective trials conducted to determine the benefits and harms of different follow-up protocols upon completion of primary treatment for cervical cancer, along with an RCT undertaken to compare predefined follow-up protocols versus participant-initiated follow-up versus no follow-up until a participant is referred to a gynaecological oncology service after signs or symptoms of recurrence have been identified in the primary care or community setting.

Résumé scientifique

Les protocoles de suivi chez les femmes atteintes de cancer du col de l’utérus après un traitement primaire

Contexte

Le cancer du col de l'utérus est le deuxième cancer le plus fréquent chez les femmes de moins de 65 ans et est la cause la plus fréquente dans le monde de décès par cancer gynécologique. Malgré la surveillance des femmes après l'achèvement du traitement primaire contre le cancer du col de l'utérus, qui est censée avoir un impact sur leur survie globale (SG), aucun suivi strictement défini dans les protocoles n’est disponible pour ces femmes. Une diversité variée de la prise en charge a été observée dans le suivi des femmes qui ont terminé le traitement principal contre le cancer du col de l'utérus. Traditionnellement, les femmes ayant été traitées suite à un cancer du col de l'utérus sont soumises à un suivi de routine à long terme, voir à vie. L'objectif principal de cette pratique a été de détecter et de traiter la récurrence au plus tôt. Cette revue évalue systématiquement les preuves disponibles sur le rôle des différentes formes de suivi suite à un cancer du col de l'utérus et l'utilisation optimale d'examens.

Objectifs

Évaluer les bénéfices, les effets délétères et les coûts des différents protocoles de suivi chez les femmes qui ont terminé le traitement principal contre le cancer du col de l'utérus.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans CENTRAL ( La Bibliothèque Cochrane 2013, numéro 1), le registre du groupe Cochrane sur les cancers gynécologiques (GCCG), MEDLINE et EMBASE jusqu' en janvier 2013. Nous avons également consulté les registres des essais cliniques, les résumés de réunions scientifiques et les références bibliographiques des directives cliniques et des articles de revue et contacté des experts dans le domaine.

Critères de sélection

Nous avons recherché des essais contrôlés randomisés (ECR) ayant comparé différents protocoles de suivi après traitement primaire chez les femmes atteintes de cancer du col de l’utérus.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment évalué si les études potentiellement pertinentes remplissaient les critères d'inclusion. Aucun essai n'a été identifié et donc aucune donnée n’a été analysée.

Résultats principaux

La stratégie de recherche documentaire a identifié 1 377 références uniques, qui ont toutes été exclues sur la base des titres et des résumés.

Conclusions des auteurs

Nous n'avons trouvé aucune preuve permettant d'orienter les décisions concernant les différents protocoles de suivi après le traitement primaire chez les femmes atteintes de cancer du col de l’utérus. Idéalement, un ECR à grande échelle ou, au moins, des études non randomisées bien planifiées (ENR) qui utilisent une analyse multi-variée pour ajuster les déséquilibres de base, sont nécessaires afin de comparer ces protocoles de suivi. De telles études ont pu inclure des essais prospectifs qui déterminaient les avantages et les inconvénients des différents protocoles de suivi une fois le traitement primaire contre le cancer du col de l'utérus achevé, ceci avec un ECR qui comparait les protocoles de suivi prédéfinis par rapport au suivi selon l’initiative du patient ou à l'absence de suivi jusqu' à ce que le patient soit dirigé auprès des services d'oncologie gynécologique lorsque des signes ou des symptômes de récidive ont été identifiés dans le contexte de soins primaires ou de proximité.

Plain language summary

This review searched for trials of women followed up after their first treatment for cervical cancer to find out the best approach to this care. 

Cervical cancer is the second most common cause of death in women worldwide. The development of new diagnostic, treatment and follow-up strategies for cervical cancer merits attention. After completing treatment for cervical cancer, women are followed-up at regular intervals by their doctor/healthcare professional to identify whether the cancer has come back or has continued to grow even before the woman experiences symptoms of this. Follow-up also helps doctors to monitor for side effects that have happened because of the treatment. Currently, women in the UK usually have follow-up appointments every three months for one year, every six months for the next two years and then yearly for five years after completion of treatment. The idea behind these follow-up appointments is that women will receive prompt treatment if the cancer has come back, and this will improve their survival from the cancer and their quality of life. Evidence from RCTs is needed to ascertain whether this is the case. If it is, we also need to know how often it is best for women to have follow-up appointments, which healthcare professional should conduct the follow-up and what should happen at follow-up appointments, for example, what investigations would be useful.

In this review, we searched for randomised controlled trials that compared different follow-up approaches after first treatment for cervical cancer. We aimed to compare follow-up that is medical or nurse-led and is set down in a written procedure versus follow-up that is medical or nurse-led but responsive to the needs of women rather than being written in a procedure and delivered at pre-set times. We also wished to compare these types of follow-up versus follow-up initiated by the patient.  

Although we checked 1,377 titles and abstracts, we found no relevant trials that met the inclusion criteria. Therefore, no evidence is available to suggest that any form of follow-up approach is better or worse in terms of prolonging survival, improving quality of life or guiding the management of problems that can arise because of the treatment and that in the case of radiotherapy treatment worsen with time. This review highlights the need for good quality studies to compare different follow-up approaches after first-line treatment for cervical cancer. This information will be needed in the future to help women and healthcare professionals plan effective follow-up care after treatment for cervical cancer has been completed.

Résumé simplifié

Cette revue a recherché les essais sur le suivi des femmes atteintes du cancer du col de l'utérus après leur premier traitement pour déterminer la meilleure approche pour ce type de soins. 

Le cancer du col de l'utérus est la deuxième cause la plus fréquente de décès chez les femmes, ceci dans le monde entier. De nouveaux diagnostiques, traitements et stratégies de suivi, méritent d’être étudier. Après la fin du traitement contre le cancer du col de l'utérus, les femmes sont suivies à intervalles réguliers par leur docteur / professionnel de la santé pour déterminer si le cancer est revenu ou à continuer de croître même avant que la femme ressente ces symptômes. Le suivi permet également aux médecins de surveiller les effets secondaires suite au traitement. À ce jour, les femmes vivant au Royaume-Uni sont généralement suivies tous les trois mois durant la première année, tous les six mois durant les deux années suivantes, puis chaque année pendant cinq ans après l'achèvement du traitement. L’objectif de ces suivis est de fournir un traitement au plus tôt si le cancer réapparait et permettre ainsi d’améliorer la survie et la qualité de vie des femmes atteintes de cancer. Des preuves issues d'ECR sont nécessaires pour établir si cela est véridique. Si c’est le cas, nous devons également déterminer les périodes de suivi les plus adéquates, quels professionnels de la santé sont plus à même d’effectuer le suivi et en quoi consiste les rendez-vous de suivi, par exemple, quelles investigations seraient utiles.

Dans cette revue, nous avons recherché des essais contrôlés randomisés qui comparaient différentes approches de suivi après le premier traitement contre le cancer du col de l'utérus. Nous avions pour objectif de comparer le suivi médical, ou dispensé par le personnel infirmier, qui est appliqué selon une procédure écrite, par rapport au suivi médical, ou dispensé par le personnel infirmier, mais qui répond aux besoins des femmes plutôt que de suivre une procédure et effectuer le suivi à des moments prédéterminés. Nous avons également cherché à comparer ces types de suivi par rapport au suivi initié par le patient.

Bien que nous ayons vérifié 1 377 titres et résumés, nous n'avons trouvé aucun essai pertinent répondant aux critères d'inclusion. Par conséquent, nous ne disposons d'aucune preuve permettant de suggérer une forme de suivi plus qu’une autre en termes de prolongation de la survie, d’amélioration de la qualité de vie ou de guidance au niveau de la prise en charge des problèmes qui peuvent survenir en raison du traitement et qui peuvent s’aggraver avec le temps lors du traitement par radiothérapie. Cette revue souligne le besoin d'études de bonne qualité pour comparer différentes approches de suivi après le traitement de première ligne contre le cancer du col de l'utérus. À l’avenir, ces informations seront nécessaires pour aider les femmes et les professionnels de santé à planifier efficacement le suivi une fois le traitement contre le cancer du col de l'utérus achevé.

Notes de traduction

Traduit par: French Cochrane Centre 27th March, 2014
Traduction financée par: Minist�re Fran�ais des Affaires sociales et de la Sant�, Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Description of the condition

Cervical cancer is the second most common cancer among women up to 65 years of age and is the most frequent cause of death from gynaecological cancers. Worldwide, 530,232 new cases were diagnosed in 2008, with 275,008 deaths reported that year. Around 85% of cases worldwide occur in developing countries (GLOBOCAN 2008). The disproportionate burden of cervical cancer in developing countries and elsewhere in medically underserved populations is mainly due to lack of screening to identify precursor lesions or cases at an early stage. Cervical cancer incidence rates are lowest in Western Asia and highest in Eastern Africa, with a seven-fold variation in age-specific incidence rates among the regions of the world. A woman's risk of developing cervical cancer by 65 years of age ranges from 0.69% in developed countries to 1.38% in developing countries (GLOBOCAN 2008). The lifetime risk of developing cervical cancer in the UK is estimated to be 1 in 134 (Cancer Research UK 2012).

Cervical cancer is the 11th most common cancer among women in the UK, accounting for around 2% of all new cases of cancer in women. In 2009, 3,378 new cases of cervical cancer were diagnosed in the UK. The crude incidence rate shows that around 11 new cervical cancer cases are reported for every 100,000 women in the UK (Cancer Research UK 2012).

Cervical cancer incidence is related to age, but cervical cancer is unusual, as it does not follow the pattern of increasing incidence with increasing age that is seen for most cancers. Two peaks in age-specific incidence rates have been noted: the first in women 30 to 34 years of age (at 21.2 per 100,000 women) and the second in women 80 to 84 years of age (at 14 per 100,000 women). The earlier peak is related to the fact that many women becoming sexually active in their late teens or early 20s, giving rise to an increase in human papillomavirus prevalence. The second peak is due to increasing cancer incidence with age. In the UK between 2007 and 2009, an average of 21% of new cervical cancer cases were identified in women 65 years of age and older and it has been reported that there is a fall-off in screening in women over 50 years of age (NHS Information Centre 2012).

More than three-quarters (76%) of cervical cancer cases occur in 25- to 64-year-olds. Women between these ages in England and in Northern Ireland are currently offered cervical cancer screening at three- to five-year intervals. For women in Wales between 25 and 64 years of age, screening is offered every three years. In Scotland, women between 20 and 60 years of age are offered screening every three years.

Cervical cancer incidence rates have decreased dramatically since the introduction in 1988 of the UK National Health Service (NHS) cervical screening programmes. Rates reached a plateau in the early 2000s and decreased by 49% in the UK from their peak in 1985 to 1987 (at 16.3 per 100,000 women) to their lowest rates in 2002 to 2004 (at 8.4 per 100,000 women). This sharp drop was attributed to the fact that cervical screening detects and treats precursor lesions.

In the UK, the five-year cervical cancer survival rate is 66.6%, and the rate of disease-free survival is 58% (Vale 2010).

Description of the intervention

Although surveillance of women after completion of primary treatment for cervical cancer is purported to have an impact on their overall survival (OS), no strictly defined follow-up protocols are available for women after cervical cancer treatment (Nobbenhuis 2012; Zola 2007). Wide diversity in follow-up arrangements has been seen for women after they complete primary treatment for cervical cancer. Typically women who are disease free at the end of their primary treatment are followed up at three- to four-month intervals for the first year, six-monthly for the next two years and then annually until year five (Leeson 2013). Usually a physical examination is performed at each visit (Kesic 2006). Other routine surveillance tests include chest x-ray, ultrasound, computerised tomography (CT) scans, magnetic resonance imaging (MRI) and tumour markers.

How the intervention might work

Traditionally, women treated for cervical cancer have undergone routine long-term, even life-long, follow-up (Barnhill 1992; Kerr-Wilson 1995; Kew 2006). The primary objective of this approach has been to detect and treat recurrence early. The rationale is that if cervical cancer recurrence is picked up early (i.e. before the onset of symptoms), it is more likely to be amenable to treatment, and survival will be improved (Kunkler 1991). Increased risk of secondary cancers after treatment for cervical cancer has been reported (Chaturvedi 2007). These cancers generally occur late (i.e. more than five years after primary treatment) and are unlikely to be picked up on routine follow-up. When follow-up is continued for 10 years or longer, secondary tumours may be picked up, but this is not part of the rationale for follow-up in the UK. Routine follow-up may be important for women, as it is purported to provide the patient with appropriate psychological support and reassurance, opportunities for management of disease- or treatment-related symptoms and timely access to supportive and palliative care. Routine patient review may also be important for practitioners, as it allows for the collection of outcome data and offers clinicians time with cancer survivors, to balance the relentless and often distressing process of caring for women who are dying from their disease (Kerr-Wilson 1995).

Qualitative research in women treated for early-stage gynaecological cancer, including those who have been treated for cervical cancer, has shown that the overriding reason that women want to continue routine follow-up is fear of recurrence. Some women find routine visits to the hospital reassuring, especially if they are experiencing unexpected symptoms. For others, feelings of anxiety and apprehension may actually deter them from attending and may compromise the value of the consultation if they do attend (Bradley 2000). Detection of recurrence may be delayed because some women do not present with symptoms until their next routine appointment (Olaitan 2001). The use of alternative follow-up strategies has been tested in other cancers. For example, nurse-led follow-up in lung cancer (Moore 2002) and primary care follow-up for women with breast cancer (Grunfeld 1996) have been shown to be equally effective as conventional secondary care models. However, the impact of novel approaches on quality of life (QoL) generally has not been assessed (Herzog 2007). It is difficult to extrapolate these study results to cervical cancer because it has a different natural history.  

Why it is important to do this review

The idea that routine follow-up may not be effective in achieving its objectives has gained in popularity over the past decade. Indeed this notion is central to the Department of Health’s current ‘National Cancer Survivorship Initiative’, which seeks to change the clinical culture to achieve more effective follow-up (NCSI 2013). Increasing cancer incidence and improving survival rates are contributing to the growing number of cancer survivors. Survivors may encounter a range of potential effects as a result of the cancer itself or as a consequence of cancer treatments. Traditional follow-up care is primarily about the detection of cancer recurrence, yet the efficacy of follow-up is questionable. As Sartori points out, evidence of the value of follow-up procedures in cervical cancer is relatively poor; studies are retrospective and results are conflicting (Sartori 2007). To date, cost-benefit analyses have not indicated that follow-up strategies increase survival or improve quality of life (Forni 2007). The decision process for adopting new follow-up protocols needs to be informed by clinical trial results and cost-benefit analyses of the results. If gains are seen with one protocol over another, consideration of whether these gains are worth the burden to the healthcare system is needed. It is also uncertain whether the traditional form of follow-up identifies or adequately addresses survivors’ concerns. Aftercare must be planned differently to improve outcomes for survivors while using scarce healthcare resources efficiently (Jefford 2013). This provides a compelling argument for this review. The National Cancer Survivorship Initiative (NCSI 2013)) has developed principles for improved care of those living with and beyond cancer. These include risk-stratified pathways of follow-up care, the use of treatment summaries and care plans, information and education to enable choice and the confidence to self manage and rapid re-access to specialist care. As a priority, we need to establish an evidence-based framework of effective surveillance strategies, which can be embedded in new survivorship models of care that in turn are based on best available evidence.

Two recently published reviews have examined follow-up for women after treatment for cervical cancer. One aimed to determine the optimal recommended programme for the follow-up of women who are disease free after completing primary therapy for cervical cancer (Elit 2009a). Another reviewed the literature to find out whether a surveillance programme for women treated for cervical cancer impacts the clinical outcomes of those women who experience recurrence (Zanagnolo 2009). Although these authors acknowledged promise in the role of different investigations, notably positron emission tomography (PET) or integrated PET and CT, MRI andassessment of tumour markers, such as squamous cell carcinoma antigen (SCCAg) levels, to predict early recurrence, studies available to them for review had not linked the early detection of recurrence to survival outcomes. Also, no studies had looked at outcomes following treatment of asymptomatic recurrence detected early.

This review set out to systematically evaluate available evidence for the role of different models of follow-up after cervical cancer and the optimal and cost-effective use of investigations, including evaluation of the role of imaging technologies and tumour marker investigations, in the detection of recurrence. It will update work by Elit 2009a and Zanagnolo 2009.

Objectives

To evaluate the benefits, harms and costs of different follow-up protocols for women who have completed primary treatment for cervical cancer.

Methods

Criteria for considering studies for this review

Types of studies

  • Randomised controlled trials (RCTs)

Types of participants

Women 18 years of age or older diagnosed with primary cervical cancer of any histological subtype (i.e. squamous cell carcinoma and adenocarcinoma, as well as the less common types: adenosquamous carcinoma, clear-cell and small-cell carcinomas) and cancer of any FIGO (International Federation of Gynecology and Obstetrics) stage (FIGO 2009; Appendix 1).

Participants should have completed primary treatment for cervical cancer, which may have involved:

  • surgery alone;

  • a combination of surgery and radiotherapy;

  • radiotherapy alone;

  • radiotherapy combined with chemotherapy; or

  • rarely, a combination of chemotherapy and surgery when chemotherapy is used to shrink the tumour before surgery is performed. 

Types of interventions

We intended to compare the following three follow-up models.

Intensive

Predefined (i.e. protocol-driven) follow-up that is medical or nurse-led and is characterised by the use of:

  • clinical history taking; and

  • clinical examination that involves undertaking an abdominal examination; a pelvic bimanual examination; and rectovaginal and speculum examinations.

Additional routine surveillance tests may be included.

  • PAP cervical smear (for microinvasive disease treated by trachelectomy).

  • Serum tumour markers (e.g. SCCAg levels).

  • Radiological investigations: abdominal or pelvic ultrasound, CT, MRI, PET, integrated PET/CT, chest x-ray and intravenous pyelography.

Non-intensive

Responsive follow-up (i.e. driven by clinical need) that is medical or nurse-led rather than following a predefined protocol but is routinely characterised by the use of:

  • clinical history taking; and

  • clinical examination that involves undertaking an abdominal examination, a pelvic bimanual examination and rectovaginal and speculum examinations.

If clinical concern arises, other surveillance tests may include:

  • PAP cervical smear;

  • serum tumour markers (e.g. SCCAg  levels); or

  • radiological investigations: abdominal or pelvic ultrasound, CT, MRI, PET, integrated PET/CT, chest x-ray and intravenous pyelography. 

Patient-led

Follow-up that is initiated by the patient and in which further intervention and investigation are provided as a response to the patient’s initial report. This model is reliant on clinical history taking only.

Types of outcome measures

Primary outcomes
  • Overall survival (OS): survival until death from all causes (survival from the time when women were randomly assigned).

  • Recurrence-free survival (RFS): defined by inclusion of recurrence or relapse of cervical cancer (recurrence from the time when women were randomly assigned).

Secondary outcomes
  • Health-related quality of life (HRQoL), measured using scales that have been shown to be valid and reliable (e.g. European Organisation for the Research and Treatment of Cancer (EORTC), Quality of Life Questionnaire (QLQ), C-30 and the site specific Cervix (CX) 24 questionnaire.

  • Psychological effects, measured using scales that have been shown to be valid and reliable (e.g. Hospital Anxiety and Depression Scale (HADS)).

  • Cost-effectiveness, measured from the perspective of the hospital using investigation costs and OS exclusively.

  • Adverse events applicable to this review: increased anxiety; reduced QoL; possibility of false-positive findings at follow-up, resulting in further investigations and the attendant risks of those.

Search methods for identification of studies

Papers in all languages were sought, and translations would have been carried out if necessary.

Electronic searches

The following electronic databases were searched:

  • Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, Issue 1, 2013).

  • The Cochrane Gynaecological Cancer Collaborative Review Group (CGCG) Trial Register.

  • MEDLINE (1948 to January week 5, 2013).

  • EMBASE (1980 to week 05, 2013).

The CENTRAL, MEDLINE and EMBASE search strategies based on terms related to the review topic are presented in Appendix 2, Appendix 3 and Appendix 4, respectively.

All relevant articles found were identified on PubMed, and by using the 'Related articles' feature, a further search was carried out for newly published articles.

Searching other resources

Unpublished and grey literature

We searched metaRegister (http://www.controlled-trials.com/rct), Physicians Data Query (http://www.nci.nih.gov), http://www.clinicaltrials.gov and http://www.cancer.gov/clinicaltrials for ongoing trials. 

We searched conference proceedings and abstracts through Zetoc (http://zetoc.mimas.ac.uk) and WorldCat Dissertations.  

Handsearching

We handsearched reports of conferences through the following sources.

  • Gynecologic Oncology (Annual Meeting of the American Society of Gynecologic Oncologists).

  • International Journal of Gynecological Cancer (Annual Meeting of the International Gynecologic Cancer Society).

  • British Journal of Cancer.

  • British Cancer Research Meeting.

  • British Gynaecological Cancer Society Meeting (BGCS).

  • Annual Meeting of the European Society of Medical Oncology (ESMO).

  • Annual Meeting of the American Society of Clinical Oncology (ASCO). 

Reference lists and correspondence

We contacted the following experts in the field to try to identify any reports of trials.

  • Professor Henry Kitchener, Chair of Gynaecological Oncology at the University of Manchester and Chair of the NCRI Cervix/Vulva subgroup.

  • Dr Andy Nordin, Consultant Gynaecological Oncologist, Gynaecological NCIN NSSG Lead and Chair of the Gynaecology SSCRG, NCIN.

They did not know of any new or current studies or reports.

Data collection and analysis

Selection of studies

We downloaded all 2,350 titles and abstracts retrieved by electronic searching to the reference management database Endnote, duplicates were removed and the remaining references were examined by two review authors (AL and AB) independently. A number of case reports and retrospective studies were found in this areal however, none were of sufficient quality or met the inclusion criteria, so we did not alter our inclusion criteria to accommodate non-randomised studies (NRSs; see agreements and disagreements with other studies or reviews for details of these studies). All were excluded at this stage, as they clearly did not meet the inclusion criteria. We did not identify any ongoing RCTs that met our inclusion criteria from our searches of the grey literature. In future updates of the review, if studies are identified for inclusion, we will employ the following methods found under Differences between protocol and review.

Results

Description of studies

Results of the search

The search strategy identified 2,350 references: CGCG Specialised Register 282; CENTRAL 525, MEDLINE 642; EMBASE 901. When the search results were merged into Endnote and duplicates were removed, 1,377 unique references were identified. Two review authors (AL and AB) independently read the abstracts, and all references were excluded.

Two review authors (AL and AB) independently searched the grey literature; these searches identified no relevant studies.

Risk of bias in included studies

No trials were found; therefore the risk of bias tool was not applied.

Effects of interventions

No data were available for analysis.

Discussion

Summary of main results

No trials were identified that evaluated the benefits and harms of different follow-up protocols for women who have completed primary treatment for cervical cancer. Therefore the question of whether different protocols are associated with a survival benefit in terms of overall and recurrence-free survival cannot be answered by this review.

Overall survival and recurrence-free survival were specified as the primary outcomes of interest, but QoL should perhaps be the main focus if future trials are conducted, as cervical cancer is associated with recurrence and mortality rates, and any follow-up protocol needs to take into account both benefits and harms. The prognosis for women with cervical cancer is often poor, and in countries with worst survival, women probably will not receive any follow-up (American Cancer Society 2011).

Quality of the evidence

No studies met the inclusion criteria for this review, resulting in no evidence to assess.

Potential biases in the review process

A comprehensive search was performed, including a thorough search of the grey literature, and all references were sifted and data extracted by two review authors independently. We were restrictive in our inclusion criteria with regards to types of studies, as we planned to include only RCTs because we suspected that some of the NRS designs were of dubious quality and would have been prone to selection bias. No relevant NRSs appeared to use appropriate statistical adjustment or were of adequate quality. Therefore, we attempted to ensure (1) that we did not overlook any relevant evidence by searching a wide range of sources, and (2) that the review was not based on poor quality evidence by excluding case reports and poor quality retrospective studies. We believed it was better to highlight the need for RCTs or at the very least good quality NRSs, rather than report the results of low-quality studies, which are very likely to be misleading.

The greatest threat to the validity of the review is likely to be publication bias (i.e. studies that found follow-up regimens not effective and that may not have been published). We were unable to assess this possibility, as we did not find any studies that met the inclusion criteria.

Agreements and disagreements with other studies or reviews

We found no trials directly comparing different follow-up protocols after primary treatment for cervical cancer. As far as we are aware, no RCTs in this area are planned. The need for such studies to be designed and conducted is clear, as evidence derived from NRSs is inconsistent and unreliable.

Retrospective studies have been conducted to evaluate the effectiveness of routine follow-up in detecting recurrent disease (Bodurka Bevers 2000; Samlal 1998); to assess survival benefit in relation to early detection of recurrence (Duyn 2002; Kerbs 1982); and to establish which are the most sensitive follow-up surveillance methods for detection of recurrence (Soisson 1990).

The retrospective analysis of Bodurka Bevers 2000, which examines the efficacy of clinical surveillance for 993 women previously treated for stage IB and IIA cervical cancer, demonstrates that detection of asymptomatic recurrences is associated with prolonged OS and survival from time of initial detection of recurrence. In contrast, the retrospective analysis of Ansink 1996, which examines 674 sets of clinical records of women with stage IB cervical carcinoma treated by radical hysterectomy and lymph node dissection, concluded that routine follow-up is ineffective in detecting recurrent cervical cancer. Further conflict in results is evident between the findings of Bodurka Bevers 2000 and those of Morice 2004, which showed no survival benefit from detection of recurrence at an asymptomatic stage in women who had been treated for stage I and II carcinoma of the cervix. The results of Morice 2004 are supported by those of earlier studies by Duyn 2002.

Larson 1988 examined the records of 249 women with stage IB cervical cancer treated with radical hysterectomy to determine optimum surveillance strategies for detection of recurrence and concluded that combined clinical history and physical examination findings should serve as the mainstay of post-treatment surveillance. A decade later, Soisson 1990 focused on women who had undergone radical hysterectomy for FIGO stages IB and IIA cervical cancer for their evaluation of follow-up procedures. These results support the findings of Larson 1988. Of the 203 women in their study, 15% developed a recurrence, and 90% of these had had an abnormal physical examination or the presence of suspicious symptoms. A subsequent retrospective study by Sartori 2007 concluded that asymptomatic recurrence (i.e. 35% of recurrences in their study) can be diagnosed by pelvic examination, CT scan or both in 85% of cases. The limited evidence in cervical (as well as endometrial and vulval) cancer has, however, called into question the benefit of detecting recurrence at an asymptomatic stage because this did not appear to confer any survival benefit (Kew 2005). An additional problem in weighing the significance of studies is that it is difficult to compare results between them because the symptom status of the women successfully treated at the time of detection of recurrence is unclear.

Two recently published reviews of follow-up for women after treatment for cervical cancer have been identified. Elit 2009a aimed to determine the optimal recommended programme for the follow-up of women who are disease free after completing primary therapy for cervical cancer. Their review included 17 retrospective trials of follow-up in cervical cancer involving women at different stages and after completion of a range of different treatments. Recurrence was detected by a variety of surveillance tests, including physical examination, imaging or vaginal vault cytology. The authors reported a recurrence rate of 10% to 18%, with most cases detected within two years of treatment. Crucially, 26% of women were asymptomatic at the time of recurrence. With a significantly higher median survival for recurrent cervical cancer seen in asymptomatic versus symptomatic women with recurrent disease (Bodurka Bevers 2000; Zola 2007), available evidence suggests that women would benefit from having an earlier diagnosis of recurrent disease. Elit 2009a recommended that follow-up consultations should involve full physical examinations, although they presented little hard evidence to support their recommendation. They also noted that vaginal vault smears added little to the detection of early disease recurrence. Zanagnolo 2009 examined surveillance programmes for women who experience recurrence. They considered a range of surveillance procedures, including non-invasive surveillance by physical examination, cervical cytology, tumour markers and various imaging techniques of chest radiography, CT and MRI scans, PET and fluoro-2-deoxy-glucose PET (FDG-PET). Most of the 42 studies that they reviewed were retrospective analyses of follow-up data with one prospective cost analysis (Hricak 1996), a healthcare professional survey (Kew 2005), a prospective feasibility study (Kew 2006) and a handful of prospective studies examining the complementary roles of imaging techniques (Amit 2006; Chung 2007). Despite shortcomings of studies available for review by both Zanagnolo 2009 and Elit 2009a, recommendations were made for the use of MRI above CT scan in the follow-up of cervical cancer because of its increased specificity in the detection of recurrent disease. Brookes 2009 subsequently evaluated surveillance with PET or CT scans and found significantly higher survival in the asymptomatic recurrences of cervical cancer. These results call for prompt evaluation of the role of routine radiological surveillance post treatment—a conclusion also reached by authors of a survey report of UK gynaecological oncologists’ surgical management and follow-up of women with cervical cancer (Nobbenhuis 2012).

Three sets of national or international guidelines were identified:

This guideline, formed at a consensus meeting, acknowledged that the most appropriate follow-up strategy in cervical cancer has not been clearly stated. However, the guideline recommends that clinical follow-up with gynaecological examination with PAP smear should be performed every three months for the first two years, every six months for the next three years and yearly thereafter.

Recommendations state that squamous cell carcinoma antigen in squamous cell carcinoma may be useful in women’s follow-up if initially increased. They also acknowledge that PET or CT might have a role in early local recurrence and detection of metastasis.

  • Cancer Care Ontario: programme in evidence-based care (Elit 2009b).

This guideline acknowledges that no systematic reviews have examined clinical outcomes of randomised controlled trials or individual randomised controlled trials comparing one follow-up strategy versus another or comparing different time intervals of follow-up. Based on the Gynecology Cancer Disease Site Group expert consensus opinion informed by evidence from retrospective studies, the following recommendations have been made.

    • Women need to be informed about symptoms of recurrence because most women have signs or symptoms of recurrence that occur outside of scheduled follow-up visits.

    • Follow-up care after primary treatment should be conducted and coordinated by a physician experienced in the surveillance of women with gynaecological malignancy.

    • Continuity of care and dialogue between the healthcare professional and the patient may well enhance and facilitate early detection of cancer recurrence and may help avoid duplication of surveillance testing and effort.

    • A reasonable follow-up strategy involves follow-up visits every three to four months within the first two years and every six to 12 months from years three to five.

    • After five years of recurrence-free follow-up, the patient should return to annual assessment with a history, a general physical and pelvic examination with cervical/vaginal cytology performed by the primary care physician.

    • At a minimum, follow-up visits should include a patient history and a complete physical examination.

    • Symptoms elicited during the patient history should include general performance status, lower back pain, especially if it radiates down one leg, vaginal bleeding or unexplained weight loss.

    • A physical examination should attempt to identify abnormal findings related to general health and/or those that suggest vaginal, pelvic sidewall or distant recurrence. As central pelvic recurrences are potentially curable, the physical examination should include a speculum examination with bimanual and pelvic/rectal examination.

    • The routine use of other investigations in asymptomatic women is not advocated, as their role has yet to be evaluated in a definitive manner.

    • Little evidence suggests that vaginal vault cytology adds significantly to the clinical examination in detecting early disease recurrence. If cytology is performed as part of routine follow-up after surgery for cervical cancer, its role would be to detect new precancerous conditions of the vagina, and it should be done no more frequently than once a year. An abnormal cytology result that suggests the possibility of neoplasia warrants colposcopic evaluation and directed biopsy for histological confirmation.

    • The role of abdominal or pelvic computed tomography, magnetic resonance imaging scans, positron emission tomography or ultrasound as part of routine follow-up has not been fully evaluated in prospective studies.

    • Use of serum markers such as squamous cell carcinoma antigen or cancer antigen 125 has shown promise in predicting surgical findings or in monitoring the post-radiotherapy course when disease is present; however, their role in following women post-treatment has yet to be determined.

  • NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Cervical Cancer V.3. 2013 (NCCN 2013).

    • History and physical examination should be performed every three to six months for two years; every six to 12 months for another three to five years, then annually.

    • High-risk women should be assessed more frequently (e.g. every three months for first two years) than low-risk women (e.g. every six months).

    • Annual cytology/vaginal cytology tests can be considered as indicated to detect lower genital tract dysplasia; however, the detection rate of recurrent cervical cancer is low using cervical and vaginal cytology alone.

    • Patient education regarding symptoms suggestive of recurrence should be provided.

    • Imaging is not routinely recommended but may be indicated in women with symptoms or examination findings suspicious for recurrence.

In women at high risk for loco-regional (central or para-aortic) failure, a combined PET-CT scan (e.g. three to six months after treatment) or other radiological imaging may be useful in detecting asymptomatic disease that is potentially curable.

  • Laboratory assessment (e.g. complete blood count (CBC), blood urea nitrogen (BUN), creatinine) remains optional based on clinical indications.

  • Women with persistent or recurrent disease need to be evaluated through the use of additional imaging studies as clinically indicated and surgical exploration in selected cases.

  • Vaginal dilator use is recommended after radiotherapy. Women treated with radiotherapy are prone to vaginal stenosis.

Adapted with permission from Koh W-J, et. al., NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Cervical Cancer V.3.2013. © 2013 National Comprehensive Cancer Network, Inc.  Available at NCCN.org (accessed 23 September 2013).

Authors' conclusions

Implications for practice

Wide diversity in clinical practice characterises the management of follow-up of women treated for cervical cancer. We found no current research evidence to inform different models of follow-up care, and surveillance practices to detect recurrence are not consistently evidence based.

It is important that evidence-based national guidelines are established for the follow-up of primary and recurrent cervical cancer.

Implications for research

Prospective trials are needed to determine the benefits and harms of different follow-up protocols for women who have completed primary treatment for cervical cancer. A randomised controlled trial is required that will compare predefined follow-up protocols and participant-initiated follow-up versus no follow-up until a participant is referred back into a gynaecological oncology service as a result of suspicious symptoms or signs of recurrence identified in primary care or by community services. This trial could also consider the most effective healthcare professional to undertake follow-up and highlight the changes in practice required for success. This RCT should be a multi-centre trial that attempts to recruit as many women as possible to increase the power of the trial.

Acknowledgements

We thank Jane Hayes for designing the search strategy and Gail Quinn and Clare Jess for assisting with aspects of the editorial process. We also thank our multi-disciplinary team of advisors: Eleanor Armstrong, Jean Brown, Sarah Burton, Maggie Barrett, Lesley Smith and Pamela Morton, who contributed to the conception and design of the protocol, for example, by finalising the types of interventions to be examined. The team also alerted us to new grey literature.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the NIHR, the NHS or the Department of Health.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. FIGO staging for cervical cancer

Stage 1

The cancer cells are only within the cervix.

  • Stage 1A—microinvasive, seen only with colposcope.

  • Stage 1A1—microinvasive cancer is 3 mm or less deep and 7 mm or less wide.

  • Stage 1A2—microinvasive cancer is between 3 and 5 mm deep and is 7 mm or less wide.

  • Stage 1B—clinical cancer is confined to the cervix.

  • Stage 1B1—cancer is not larger than 4 cm.

  • Stage 1B2—cancer is larger than 4 cm.

Stage 2

The cancer has spread into surrounding structures such as the upper part of the vagina or the paracervical/parametrial tissues.

  • Stage 2A—cancer has spread into the upper part of the vagina.

  • Stage 2A1—tumour size is not larger than 4 cm.

  • Stage 2A2—tumour size is larger than 4 cm.

  • Stage 2B—cancer has spread into the paracervical/parametrial tissues.

Stage 3

The cancer has spread to areas such as the lower part of the vagina or tissues of the pelvic side wall.

  • Stage 3A—cancer has spread into the lower part of the vagina.

  • Stage 3B—cancer has spread through to the tissues of the pelvic side wall and may press on one of the ureters. If the tumour is causing pressure on a ureter, hydronephrosis may be noted.

Stage 4

The cancer has spread to the bladder or bowel or beyond the pelvic area.

  • Stage 4A—cancer has spread to nearby organs such as bladder and bowel.

  • Stage 4B—cancer has spread to more distant organs such as lungs, liver or bone.

Appendix 2. CENTRAL search strategy

  1. MeSH descriptor Uterine Cervical Neoplasms explode all trees

  2. cervi* near/5 (cancer* or neoplasm* or malignan* or tumor* or tumour* or carcinoma* or adenocarcinom*)

  3. (#1 OR #2)

  4. MeSH descriptor Follow-Up Studies explode all trees

  5. follow up or follow-up or followup

  6. surveillance

  7. MeSH descriptor Aftercare explode all trees

  8. aftercare or after care

  9. (#4 OR #5 OR #6 OR #7 OR #8)

  10. (#3 AND #9)

Appendix 3. MEDLINE search strategy

1 exp Uterine Cervical Neoplasms/
2 (cervi* adj5 (cancer* or neoplasm* or malignan* or tumor* or tumour* or carcinom* or adenocarcinom*)).mp.
3 1 or 2
4 Follow-Up Studies/
5 (follow up or follow-up or followup).mp.
6 surveillance.mp.
7 Aftercare/
8 (aftercare or after care).mp.
9 4 or 5 or 6 or 7 or 8
10 3 and 9
11 randomized controlled trial.pt.
12 controlled clinical trial.pt.
13 randomized.ab.
14 placebo.ab.
15 clinical trials as topic.sh.
16 randomly.ab.
17 trial.ti.
18 11 or 12 or 13 or 14 or 15 or 16 or 17
19 10 and 18
20 exp animals/ not humans.sh.
21 19 not 20

key:
mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier
pt=publication type
sh=subject heading
ab=abstract

Appendix 4. EMBASE search strategy

  1. exp uterine cervix tumor/

  2. ((cervical or cervix) adj3 (cancer* or neoplasm* or malignan* or tumor* or tumour* or carcinoma* or adenocarcinoma*)).mp.

  3. 1 or 2

  4. exp aftercare/

  5. follow up.ti,ab.

  6. follow-up.ti,ab.

  7. followup.ti,ab.

  8. aftercare.ti,ab.

  9. after care.ti,ab.

  10. surveillance.ti,ab.

  11. 4 or 5 or 6 or 7 or 8 or 9 or 10

  12. 3 and 11

  13. crossover procedure/

  14. randomized controlled trial/

  15. single blind procedure/

  16. random*.mp.

  17. factorial*.mp.

  18. (crossover* or cross over* or cross-over).mp.

  19. placebo*.mp.

  20. (doubl* adj blind*).mp.

  21. (singl* adj blind*).mp.

  22. assign*.mp.

  23. allocat*.mp.

  24. volunteer*.mp.

  25. 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24

  26. 12 and 25

key:
mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword
ti, ab title, abstract

What's new

DateEventDescription
27 March 2014AmendedContact details updated.

History

Protocol first published: Issue 10, 2010
Review first published: Issue 11, 2013

DateEventDescription
20 November 2013AmendedAuthor order corrected

Contributions of authors

Andrew Bryant and Anne Lanceley prepared the final version of the review, and Anne Lanceley gave final approval of the version to be published. The team of review authors have reviewed this version, and comments have been incorporated.

Declarations of interest

No conflicts of interest have been reported.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • Department of Health, UK.

    NHS Cochrane Collaboration Programme Grant Scheme CPG-10/4001/12

Differences between protocol and review

We identified no trials that met the inclusion criteria. In future updates of the review, we will employ the following methods.

Selection of studies

We will obtain copies of the full text of relevant references. Two review authors (AL and AB) will assess the eligibility of retrieved papers independently. We will resolve disagreements by discussion between the two review authors. We will document reasons for exclusion.

Data extraction and management  

For included trials, we will abstract data as recommended in Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Data will be extracted by two independent authors and will include the following.

  • Author, year of publication and journal citation (including language).

  • Country.

  • Setting.

  • Inclusion and exclusion criteria.

  • Study design, methodology.

  • Study population (participant characteristics, age, stage, comorbidities and previous treatment, and whether residual disease at the start of follow-up).

  • Number of participants in each arm of the trial.

  • Total number of intervention groups.

  • Cervical cancer details (FIGO stage, histology, tumour grade).

  • Interventions: exact description of the follow-up protocols received by experimental and control groups (including whether clinician or participant initiated, care setting and frequency, use of investigations, timing of follow-up events and decision to provide further treatment).

  • Length of follow-up.

  • Withdrawals from treatment protocol.

  • Number of participants who experienced delays in treatment or received all, part or none of the proposed treatment.

  • Risk of bias in study (see below).

  • Outcomes: OS, RFS, QoL, psychological effects, cost data and adverse events:

    • for each outcome: outcome definition;

    • for unit of measurement (if relevant);

    • for scales: upper and lower limits, and whether high or low score is good;

    • for results: number of participants allocated to each intervention group; and

    • for each outcome of interest: sample size, missing participants.

We will extract data on outcomes as explained below.

  • For time to event (e.g. overall survival) data, we will extract from trial reports the log of the hazard ratio [log(HR)] and its standard error; if these are not reported, we will attempt to estimate them from other reported statistics using the methods of Parmar 1998.

  • For dichotomous outcomes (e.g. adverse events or deaths if it was not possible to use a hazard ratio (HR)), we will extract the number of women in each treatment arm who experienced the outcome of interest and the number of women assessed at endpoint, to estimate a risk ratio (RR).

  • For continuous outcomes (e.g. QoL measures), we will extract the final value and the standard deviation of the outcome of interest and the number of women assessed at endpoint in each treatment arm at the end of follow-up, to estimate the mean difference (if trials measured outcomes on the same scale) or standardised mean differences (if trials measured outcomes on different scales) between treatment arms and their standard error.

We will extract both unadjusted and adjusted statistics, if reported.

When possible, all data extracted will be those relevant to an intention-to-treat analysis, in which participants are analysed in the groups to which they were assigned.

We will note the time points at which outcomes were collected and reported.

Data will be abstracted independently by two review authors (AL and MMcC) onto a data abstraction form specially designed for the review. We will resolve differences between review authors by discussion.

Assessment of risk of bias in included studies  

We will assess risk of bias in included RCTs using The Cochrane Collaboration's tool and the criteria specified in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions, 2008 (Higgins 2011). This will include an assessment of:

  • sequence generation;

  • allocation concealment;

  • blinding (of outcome assessors);

  • incomplete outcome data: We will code a satisfactory level of loss to follow-up for each outcome as follows.

    • Yes, if fewer than 20% of women are lost to follow-up and reasons for loss to follow-up were similar in both treatment arms.

    • No, if more than 20% of women are lost to follow-up or reasons for loss to follow-up differed between treatment arms.

    • Unclear if loss to follow-up is not reported.

  • selective reporting of outcomes; and

  • other possible sources of bias.

Two review authors will apply the risk of bias tool independently, and differences will be resolved by discussion or by appeal to a third review author.  We will summarise results in both a risk of bias graph and a risk of bias summary. Results of meta-analyses will be interpreted in the light of findings with respect to risk of bias.

Measures of treatment effect  

We will use the following measures of the effects of treatment.

  • For time to event data, we will use the HR, if possible.

  • For dichotomous outcomes, we will use the RR.

  • For continuous outcomes, we will use the mean difference between treatment arms.

Unit of analysis issues  

In the studies under review, results may be presented for several periods of follow-up, for example, at six months, one year and two years. To avoid unit of analysis error, we will compute an effect measure for each individual participant that incorporates all time points, such as total number of events, overall mean or a trend over time.

Dealing with missing data  

We will not impute missing outcome data for the primary outcome. If data are missing or only imputed data are reported, we will contact trial authors to request data on the outcomes only among participants who were assessed. 

Assessment of heterogeneity  

We will assess heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage of heterogeneity between trials that cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001) and, if possible, by subgroup analyses (see Subgroup analysis and investigation of heterogeneity). If evidence of substantial heterogeneity is found, we will investigate and report the possible reasons for this.

Assessment of reporting biases  

We will examine funnel plots corresponding to meta-analysis of the primary outcome to assess the potential for small study effects such as publication bias.

Data synthesis  

If sufficient clinically similar studies are available, we will pool their results in meta-analyses. We will use adjusted summary statistics if available; otherwise we will use unadjusted results.

  • For time-to-event data, we will pool HRs using the generic inverse variance facility of RevMan 5.

  • For any dichotomous outcomes, we will calculate the risk ratio for each study, and these values will then be pooled. 

  • For continuous outcomes, we will pool the mean differences between treatment arms at the end of follow-up if all trials measured the outcome on the same scale; otherwise we will pool standardised mean differences. 

If any trials include multiple treatment groups, we will divide the ‘shared’ comparison group into the number of treatment groups, and comparisons between treatment groups and the split comparison group will be treated as independent comparisons.

We will use random-effects models with inverse variance weighting for all meta-analyses (Der Simonian 1986).

Subgroup analysis and investigation of heterogeneity  

We will perform subgroup analyses to explore:

  • effects of disease status - residual versus no residual disease at commencement of follow-up;

  • whether the intervention is modified by the caregiver - doctor versus nurse; and

  • effects of care setting: acute care versus primary care.

We will consider factors such as age, stage, type of intervention, length of follow-up and adjusted/unadjusted analysis in interpretation of any heterogeneity.

Sensitivity analysis  

We will perform sensitivity analyses to exclude studies at high risk of bias.

Ancillary