Interventions for the treatment of Paget's disease of the vulva

  • Review
  • Intervention

Authors


Abstract

Background

Extra-mammary Paget's disease is a rare form of superficial skin cancer. The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. There is a range of interventions from surgical to non-invasive techniques or treatments. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery. There is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations, and destruction of anatomy. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and it is important to evaluate the available evidence. It is essential to assess whether newer cell-specific treatments, such as photodynamic therapy and imiquimod, can reduce the need for radical surgery.

Objectives

To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva.

Search methods

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

Selection criteria

We searched for randomised controlled trials (RCTs) and well-designed non-randomised studies that compared different interventions in women with Paget's disease of the vulva,

Data collection and analysis

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

Main results

The search strategy identified 635 unique references. We found 31 references (which reported on 30 studies) in full text after inspection of titles and abstracts, but we excluded them all as they did not meet the inclusion criteria. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease. Surgery continues to be the mainstay of treatment in the current literature, with other treatments limited to case reports or treatment of inoperable or recurrent disease.

Authors' conclusions

We found no reliable evidence to inform decisions about different interventions for women with Paget's disease of the vulva. Ideally, a multicentre RCT of reasonable size is needed. In particular, evidence regarding the increasing use of imiquimod would be helpful to women and clinicians alike. Well-designed non-randomised studies, that use multivariate analysis to adjust for baseline imbalances, as well as other key methodological strengths, are also lacking.

Résumé scientifique

Interventions pour le traitement de la maladie Paget de la vulve

Contexte

La maladie de Paget extra-mammaire est une forme rare de cancer de la peau superficielle. La localisation la plus fréquente est la vulve. Elle se retrouve principalement chez les femmes blanches ménopausées. La maladie de Paget de la vulve se propage souvent dans une façon occulte aux marges et au-delà des bords apparents. Il existe un éventail d'interventions qui vont des techniques chirurgicales à des traitements non invasifs. Les défis des interventions est d'éliminer ou traiter la maladie qui pourrait ne pas être visible, sans traiter de trop et minimiser la morbidité associée à la chirurgie radicale. Il y a peu de consensus concernant le traitement. La chirurgie, méthode par défaut, est le traitement le plus courant, mais l'exérerèse chirurgicale adéquate de la maladie est difficile et la récidive est courante, conduisant à des nouvelles opérations, et une destruction de l'anatomie. Des traitements alternatifs comme la thérapie photodynamique, la thérapie au laser, la radiothérapie, les traitements topiques ou même la chimiothérapie ont été proposés et il est important d'évaluer les preuves de leur efficacité disponibles. Il est primordial de déterminer si les nouveaux traitements cellulaires spécifiques, tels que la thérapie photodynamique et l' imiquimod, peuvent réduire la nécessité d'une chirurgie radicale.

Objectifs

Évaluer les bénéfices et inconvénients des différentes modalités de traitement pour la prise en charge de la maladie de Paget de la vulve.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais du groupe Cochrane sur les cancers gynécologiques, le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE et EMBASE jusqu' à septembre 2013. Nous avons également consulté les registres des essais cliniques, les résumés de réunions scientifiques et les références bibliographiques des articles de revue et contacté des experts dans le domaine.

Critères de sélection

Nous avons recherché des essais contrôlés randomisés (ECR) et des études non randomisées bien planifiées qui comparaient différentes interventions chez les femmes atteintes de la maladie de Paget de la vulve,

Recueil et analyse des données

Deux auteurs de la revue ont ,indépendamment évalué si les études potentiellement pertinentes remplissaient les critères d'inclusion. Nous n'avons pas trouvé d'essais et, par conséquent, aucune donnée n'a été analysée.

Résultats principaux

La stratégie de recherche documentaire a identifié 635 références bibliographiques uniques. Nous avons trouvé 31 références (qui avaient rendu compte de 30 études) dans le texte complet après un examen des titres et résumés, mais nous les avons exclues car elles ne répondaient pas aux critères d'inclusion. Cependant, nous avons inclus un nombre exhaustif d'études dans lesquelles nous avons identifié une analyse de plus de 10 femmes, car c'était le seul moyen de preuve factuelle dans cette maladie rare. Une intervention chirurgicale constitue le pilier du traitement dans la littérature actuelle, avec d'autres traitements limités à des rapports de cas ou lors de d’inopérabilité ou de récidive de la maladie.

Conclusions des auteurs

Nous n'avons trouvé aucune preuve fiable pour orienter les décisions sur différentes interventions pour les femmes atteintes de maladie de Paget de la vulve . Dans les meilleurs des cas, un ECR multicentrique de taille raisonnable est nécessaire. Des preuves concernant l'utilisation croissante de l'imiquimod seraient particulièrement utiles pour les femmes et les cliniciens. Des études non randomisées bien planifiées, qui utilisent une analyse multifactorielle pour corriger les déséquilibres de départ, ainsi que d'autres renforts méthodologiques clés, sont également manquantes.

Plain language summary

No evidence was available for the comparison of different interventions for women with Paget's disease of the vulva

Background

Extramammary Paget’s disease of the vulva is a rare type of superficial skin cancer. It is most common in postmenopausal white women. It is an intraepithelial (layer of cells that forms the surface or lining of an organ) condition that can present as white and red scaly areas on the vulva that may be itchy and painful. The diagnosis is made by examination and tissue sampling. Abnormal cells often extend outside the clinically abnormal area, so some studies suggest frozen section at time of surgery, where a pathologist can give a rapid report of small biopsies to say whether the skin is involved with Paget's or not. Other treatments include: topical medication, such as imiquimod (patient-applied cream); radiotherapy; chemotherapy; photodynamic therapy (form of phototherapy using light-sensitive compounds that are exposed selectively to light, whereupon they become toxic to targeted cancerous and other diseased cells); and laser therapy; or a combination of these approaches. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment. Avoiding the long-term complications of radical surgery, such as pain and scarring, a feeling of mutilation and loss of femininity, is very important to women. Surgery is still the most common treatment, but it is challenging to remove the disease completely, and recurrence is common, leading to repeated operations, and mutilation of the vulva. The aim of this review was to evaluate the benefits and harms of different treatments for Paget's disease of the vulva.

Study characteristics

We searched for randomised controlled trials (trials where treatment is allocate to women in a random manner) and well-designed non-randomised studies that compared different treatments in women aged 18 years or older with biopsy-confirmed Paget's disease of the vulva.

Key results and quality of evidence

We searched scientific databases and contacted experts and identified and checked the titles and abstracts of 635 possibly relevant articles and retrieved 31 of these references in full text. However, we found no studies that met our inclusion criteria. We identified a number of non-randomised studies and drafted a detailed narrative of their results, but these studies were of poor quality and were at high risk of bias. Therefore, there is currently no evidence to determine whether any form of treatment is better or worse in terms of prolonging survival, delaying progression or recurrence, improving quality of life or minimising toxicity. The review highlights the need for good-quality studies comparing different interventions for the management of Paget's disease of the vulva. Women and clinicians would value more evidence for guiding surgical and non-surgical management of this disease. In particular, non-invasive medical management would spare women from the adverse effects and consequences of surgery.

Résumé simplifié

Aucune preuve n'était disponible pour la comparaison de différentes interventions pour les femmes atteintes de maladie de Paget de la vulve

Contexte

La maladie Paget extra-mmamaire vulvaire est un type rare de cancer superficiel de de la peau. Elle est plus fréquente chez les femmes blanches ménopausées. Il s' agit d'une affection intra-épithéliale (couche de cellules qui fait la surface ou muqueuse d'un organe) qui peut se manifester comme des zones squameuses blanches et rouges sur la vulve qui peuvent être prurigineuses et douloureuses. Le diagnostic est établi par un examen médical et le prélèvement des tissus. Les cellules anormales souvent s'étendent en dehors de la zone anormale du point de vue clinique, de sorte que certaines études suggèrent de faire des coupes congélées au moment de l'intervention chirurgicale, alors un examen pathologique des biopsies de petite taille peut être fait rapidement pour déterminer si la peau est atteinte par le Paget ou non. D'autres traitements sont : des médicaments topiques, tels que l'imiquimod (crème appliqueée par les patientes), la radiothérapie, la chimiothérapie, la thérapie photodynamique (forme de photothérapie à l'aide de composés photosensibles qui exposent sélectivement la lumière au point de devenir toxique pour des cibles cancéreuse et d'autres cellules malades) et le traitement au laser; ou une combinaison de ces approches. Eviter des problèmes liés à la chirurgie radicale comme la douleur et la cicatrisation est un aspect important à prendre en considération car le sentiment de mutilation et de perte de la féminité sont des aspects importants pour les femmes. La chirurgie est toujours le traitement le plus courant, mais c'est difficile d'éliminer la maladie complètement. La récidive est courante, conduisant à des opérations répétées et à la mutilation de la vulve. L'objectif de cette revue était d'évaluer les bénéfices et préjudices de différents traitements de la maladie Paget de la vulve.

Caractéristiques de l'étude

Nous avons recherché des essais contrôlés randomisés (essais où le traitement est assigné aux femmes d'une manière aléatoire) et des études non randomisées bien planifiées qui comparaient différents traitements chez les femmes âgées de 18 ans ou plus avec la maladie de Paget de la vulve confirmée avec une biopsie.

Principaux résultats et qualité des preuves

Nous avons effectué des recherches dans les bases de données scientifiques, contacté des experts et identifié et vérifié les titres et résumés de 635 articles potentiellement pertinents et 31 extraits des références bibliographiques d'articles dans leur intégralité. Cependant, nous n'avons trouvé aucune étude répondant à nos critères d'inclusion. Nous avons identifié un certain nombre d'études non randomisées et rédigé un rapport détaillé de leurs résultats, mais ces études étaient de mauvaise qualité et présentaient un risque élevé de biais. Par conséquent, il n'existe actuellement aucune preuve permettant de déterminer si une forme de traitement est meilleure ou pire en termes de prolongation de la survie, retarder la progression ou la récidive, améliorer la qualité de vie ou la minimiser la toxicité. Cette revue souligne le besoin de disposer d'études de bonne qualité qui comparent les différentes interventions pour la prise en charge de la maladie Paget de la vulve. Les femmes et les cliniciens devraient avoir davantage de preuves pour guider la prise en charge chirurgicale ou non-chirurgicale de cette maladie. En particulier, la prise en charge médicale non invasive qui pourrait épargner aux femmes les effets indésirables et les conséquences de l'opération.

Notes de traduction

Traduit par: French Cochrane Centre 27th March, 2014
Traduction financée par: Financeurs pour le Canada : 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; pour la France : Minist�re en charge de la Sant�

Background

Description of the condition

Extra-mammary Paget's disease is a rare form of intraepithelial skin cancer (adenocarcinoma). The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. It is characterised by infiltration of the squamous mucosa or adenexa by vacuolated Paget cells. It is an intraepithelial adenocarcinoma that presents as slowly expanding, asymmetrical white and red scaly plaques on the vulva, which may be itchy and painful. The diagnosis is made by finding the characteristic changes on skin biopsy. Immunohistochemistry is required to exclude the differential diagnoses of melanoma and vulval intraepithelial neoplasia. Paget's disease may be primary, arising as an intraepithelial adenocarcinoma, or secondary due to Pagetoid spread of an adjacent or contiguous in situ or invasive tumour. There have been reports of an association with distant tumours, particularly breast cancer, although the strength of this association is unknown. Any screening for distant tumours may involve lengthy and invasive investigations, and also delay the appropriate treatment of the Paget's disease itself (Heymann 1993; Kanitakis 2007). Immunohistochemical stains can guide further investigations. Tissue staining negative for cytokeratin 20 favours a cutaneous origin for Paget's (primary or secondary due to an underlying adnexal adenocarcinoma) and positive staining favours an endodermal origin, where a visceral malignancy should be more keenly sought. The presence of Paget’s disease around the perianal area or around the urethra should prompt a search for urothelial or rectal tumours. One clinicopathological study in 1977 reported 13 cases of Paget's disease of the vulva (Lee 1977): four (31%) of the women had underlying invasive carcinoma of the adnexal structures and three (23%) had adnexal carcinoma in situ. In four women (31%), a second malignancy was found (Lee 1977). A more recent case series reviewed 10 women with vulval Paget's disease (Fanning 1999). About 34% of patients recurred, at a median time interval of three years, with 12% having invasive Paget's disease of the vulva and 4% had a vulval adenocarcinoma. The association between Paget's disease and other malignancies is variable across the literature, with one literature review showing the association to be between 0% and 50%, and with no significant difference between women with Paget's disease and the rate of cancer in that demographic group (Preti 2003).

Wilkinson and Brown subclassified Paget's disease of the vulva into primary or secondary disease (Wilkinson 2002). Primary Paget's disease is of vulval cutaneous origin, and secondary vulval Paget's disease is due to a non-cutaneous neoplasm, often of adjacent sites.

Description of the intervention

Surgery can involve local excision, radical excision or vulvectomy. Margins often extend outside the clinically abnormal area, so some studies suggest frozen section or preoperative mapping biopsies to delineate the margins of excision. Other interventions include topical imiquimod (an immune response modifier), radiotherapy, chemotherapy, photodynamic therapy (topical and systemic) and laser therapy, or a combination of these approaches. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery.

How the intervention might work

Surgery removes the abnormal area. Disease tends to be multifocal, and complete eradication is not guaranteed. Surgical excision can also cause significant vulval mutilation, with consequent psychological morbidity (Tsutsumida 2003). Photodynamic therapy works by the exposure of sensitised cells to a specific wavelength of light, which activates a cascade of photochemical and photobiological events, causing irreversible damage to tumour tissue (Shieh 2002). Radiotherapy destroys tissues by damaging deoxyribonucleic acid (DNA), affecting normal as well as abnormal tissues. Chemotherapy has been used alone or in conjunction with radiotherapy. Topical imiquimod, usually a 5% cream, is an immune response modifier that induces high levels of interferon, although the complete mechanism of action is complex and not fully understood. It causes inflammation, which in some cases can be poorly tolerated (Woodmansee 2006). Carbon dioxide (CO2) laser has been used in other vulval conditions, such as vulval intraepithelial neoplasia (Maclean 1995), since the 1970s and was initially used for treatment of disease of the cervix. The depth of destruction can be controlled and planned, but needs to be deep enough to decrease the likelihood of recurrence.

Why it is important to do this review

Paget's disease is a rare condition, and there is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations and mutilation of the vulva. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and we considered that it was important to evaluate the available evidence. Paget's disease most commonly occurs in elderly women, and having evidence-based alternative treatments to surgery would be of benefit to these women.

Objectives

To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva.

Methods

Criteria for considering studies for this review

Types of studies

We wanted to include randomised controlled trials (RCTs). However, since RCTs were unlikely, we also searched for non-randomised studies with concurrent comparison groups:

  • quasi-randomised trials;

  • non-randomised trials;

  • prospective and retrospective cohort studies;

  • case series of 10 or more women.

We excluded case-controlled studies, uncontrolled observational studies and case series of fewer than 10 women.

In order to minimise selection bias if no RCTs were identified, we only included studies that used statistical adjustment for baseline case mix using multivariable analyses (e.g. disease severity, age, co-morbidity, previous treatment).

Types of participants

Adult women (aged 18 years or older) with biopsy-confirmed Paget's disease. We applied no exclusion criteria.

Types of interventions

We searched for all interventions used in Paget's disease. The mainstay of treatment is surgery, which is either conservative or radical.

Other interventions that are used include: radiotherapy; topical treatments, including steroids; photodynamic therapy; imiquimod; systemic treatments, including chemotherapeutic agents and any treatment combinations. We considered comparisons of any two treatment modalities.

Types of outcome measures

We did not use outcome measures as part of the inclusion criteria.

Primary outcomes
  • Overall survival. Survival was assessed from the time when women were enrolled in the study.

  • Disease-free survival. Defined as the documented time between treatment and confirmed recurrence.

Secondary outcomes
  • Quality of life (QoL), measured using a validated scale.

  • Adverse events classified according to CTCAE 2006:

    • direct surgical morbidity;

    • surgically related systemic morbidity;

    • delayed (hospital) discharge and recovery;

    • toxicity of photodynamic therapy;

    • radiotherapy toxicity;

    • chemotherapy toxicity.

  • Toxicity was grouped as:

    • haematological;

    • gastrointestinal;

    • genitourinary;

    • skin;

    • neurological;

    • pulmonary.

Search methods for identification of studies

Electronic searches

We searched the following electronic databases:

  • the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register to September 2013;

  • the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 7, 2013;

  • MEDLINE (from 1948 to September 2013);

  • EMBASE (from 1980 to September 2013).

The CENTRAL, MEDLINE and EMBASE search strategies are presented in Appendix 1, Appendix 2 ad Appendix 3, respectively.

We identified all relevant articles on PubMed and, using the 'related articles' feature, we carried out a further search for newly published articles.

Searching other resources

We searched:

Handsearching

We handsearched and checked the citation lists of included studies, key textbooks and previous systematic reviews. We handsearched reports of the following conferences:

  • Annual Meeting of the American Society of Gynaecologic Oncologist;

  • Annual Meeting of the International Gynaecologic Cancer Society;

  • British Cancer Research Meeting;

  • Annual Meeting of European Society of Medical Oncology;

  • Annual Meeting if the American Society of Clinical Oncology;

  • British Society for the study of Vulval Disease;

  • International Society for the Study of Vulvo-Vaginal Disease;

  • European College for the Study of Vulval Disease.

Data collection and analysis

Selection of studies

We downloaded all titles and abstracts retrieved by electronic searching to the reference management database Endnote. We removed duplicates and two review authors (KE, JM) independently examined the remaining references. We excluded studies that clearly did not meet the inclusion criteria and obtained copies of the full text of potentially relevant references. Two review authors (KE, EA) independently assessed the eligibility of the retrieved papers and resolved any disagreements by discussion. When necessary, a third review author (SC or AB) participated in discussions. We documented reasons for exclusions. We excluded all articles that we retrieved, as they did not meet the inclusion criteria. We did not identify any studies that met our inclusion criteria from our searches of the grey literature. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease (See Effects of interventions for studies, which included at least 10 women and Agreements and disagreements with other studies or reviews for a general discussion of a wider range of studies and reviews).

In future updates of the review, we will use the above methodology and the methods described in Differences between protocol and review.

Results

Description of studies

Results of the search

The search strategy identified 635 separate references by title and abstracts. Two review authors (KE, JM) sifted through these and excluded abstracts that did not include at least 10 women with Paget's disease of the vulva and then applied the other inclusion criteria. Where the contents of the paper were not clear from the abstract, we obtained the full-text papers in order to be rigorous in the searching. We identified 31 references that reported on 30 studies that potentially met the inclusion criteria. We excluded all studies after inspection of the full papers.

Two review authors (KE, JM) independently searched the grey literature and did not identify any relevant studies. All studies were at a high risk of bias and retrospective in nature.

Included studies

None of the studies met our inclusion criteria and we excluded them all from the review. However, 20 studies were included in a narrative discussion in Effects of interventions. All the studies were retrospective data analyses, the earliest women included was diagnosed in 1939. Across the studies, the age range was 35 to 100 years, but there were minimal other demographic data available due to the retrospective nature of the data collection. There were 581 women included with some data for analysis. The most common surgery was a wide local excision (n = 202; 35%) and radical vulvectomy (n = 157; 27%). In total, 135 women had a simple vulvectomy, 48 women had a hemivulvectomy and one woman had a skinning vulvectomy. Ultracision was used to treat one woman, primary chemotherapy was used in seven cases, primary radiotherapy in 14 cases and laser therapy was in 23 cases. Two women undergoing surgery had been treated with neoadjuvant radiotherapy. Treatment regimens for radiotherapy and chemotherapy were not clearly documented in any of the papers, and, therefore, further discussion will focus on the surgical management.

Although some women received treatments in addition to surgery, all 20 studies discussed contained women having a variety of surgical interventions, ranging from wide excisions to radical vulvectomies. Case series ranged from 10 to 100 women. Data were variable between the papers; some contained limited clinical data because the main focus was discussion of pathology. Forty of the 306 women across all the studies had a cancer at another site, although 10 of these were definitely metachronus, and for many it was unclear. They are described in greater detail in Table 1.

Table 1. Details of excluded studies
  1. 5-FU: fluorouracil; CVA: cerebrovascular accident; DoD: dead of disease; FS: frozen section; MEP: mitomycin + etoposide + cisplatin; RV: radical vulvectomy; SV: simple vulvectomy; WLE: wide local excision.

StudyMethodsParticipantsInterventionOutcomesNotes
Bakalianou 2008

Retrospective review of records

1996-2005

11 women with Paget's disease of the vulva' from 1 centre in Athens. Median age 64 years (range 53 to 75)Ultracision, SV, RV with groin node dissectionAll had topical steroid use before diagnosis. 1/11 had ultracision, 7/11 had SV, 3/11 had radical surgery. All had FSs (10/11 margins negative at FS, 9/11 negative at final pathology). 3/11 had a recurrence, 1/1 who had ultracision, 1/7 with SV, 1/3 with RV. 2/2 with positive margins1 had concurrent breast cancer
Black 2007Retrospective review from pathology database28 women with Paget's disease of the vulva', median age 68 years, range 48 to 86.RV, SV, WLE3/28 had RV, 18/28 had SV, 7/28 had WLE. 14/20 with positive margins recurred, 3/8 with negative margins recurred. 14/17 further surgery, 1/17 treated with Retin-A11 women had a secondary malignancy
Crawford 1999Retrospective data collection, time period not defined21 women with diagnosis of Paget's disease of the vulva'WLE, hemivulvectomy, RVWLE 13, hemivulvectomy 2, RV 5. 1 woman had biopsies only. Margins not documented by type of surgery. 13/20 had positive margins, 1/7 recurrence with negative margins, 7/13 recurrence with positive margins2 women died of other malignancies, 1 died from CVA after hip surgery, 1 died of metastatic Paget's
Curtin 1990

Retrospective data

1939-1987

31 women, age range 49-84 years with a histological diagnosis of Paget's disease of the vulva'WLE, vulvectomy or skinning vulvectomy, RV4 had WLE, 22 had vulvectomy and 3 had a RV. 1 woman had a skinning vulvectomy. Out of 28 women, 14 had negative margins, 8 had positive margins, 6 were not documented. 3/14 with positive margins recurred, 2/8 with negative margins recurredNo mortality. 5 adenocarcinomas excluded
Fanning 1999

Retrospective data

1962-1996 Multiple institutions

100 women with Paget's disease of the vulva'. Age range 35-100 yearsRV with or without node dissection, radical hemivulvectomy, WLE58 radical vulvectomies, 10 radical hemivulvectomies, 32 WLE. Recurrence 18/58 radical, 2/10 hemivulvectomy, 14/32 WLE. Median time to recurrence 3 years. Not able to assess margins in this study as retrospective. 4 women had an adenoca at resection1 woman DoD
Feuer 1990Retrospective review 1969-198719 women with Paget's disease of the vulva' mean age 65.2 years, range 44-81WLE, SV, hemivulvectomy, RV4/19 WLE, 9/19 SV, 2/19 hemivulvectomy, 4/19 RV. 9/19 recurred, 1 DoD. 8/9 recurrences treated surgically 1 treated with laser and 5 5-FU. 2/4 WLE recurred, 5/9 SV recurred, 1/2 hemivulvectomy recurred, 1/4 RV recurred5 had an associated malignancy. No comment on margin status
Fishman 1995

Retrospective review and re-review of all histology

1982 to 1993

14 women from 1 centre with known Paget's disease of the vulva'. Mean age 70.5 years, range 57-83WLE, SV, modified RV8/14 WLE, 3/14 SV, 3/14 modified RV. 2/5 with positive margins recurred, 3/9 with negative margins recurred. After clinical judgement of negative margins, 6/17 were positive at final pathology. After FS, 3/8 that were negative at FS were positive at final pathology. No difference between FS and inspection (P value = 1). 2/8 having a WLE recurred, 1/3 having a SV recurred, 2/3 having a modified RV recurred7 women had a metachronus cancer
Goldblum 1997Retrospective review from 1 centre19 women with Paget's disease of the vulva', median age 65 years, range 56-86SV, RV, RV + groin node dissection13/19 SV, 4/19 RV, 2/19 RV + groin node dissection. 4/13 recurrences in SV group, 1/4 recurrences in RV. Minimal invasion had no effect on recurrence or prognosis; 2/7 minimally invasive recurred compared with 3/7 intraepithelial (5 were initially invasive)No comment on margin status
Lee 1977

Retrospective data

1940-1976

13 women with confirmed Paget's disease of the vulva. Median age 65 years, range 38-86SV, RV, radiotherapy8/13 SV, 4/13 RV. 2 had pre-surgical radiotherapy. 1/8 recurrence after SV, 1/4 re-excision for positive margins after RV, 2/4 recurrences with RV but all free of disease after re-excision4 had other cancers, 3 deaths of other causes
Lee 2010

Retrospective data

1990-2009

14 women with diagnosis of Paget's disease of the vulva'. Mean age 54.3 years, range 29-72Hemivulvectomy, WLE, RV2/14 hemivulvectomy, 5/14 WLE, 7/14 RV. Positive margins in 8/14. 3/8 recurrences with positive margins, 2/6 recurrences with negative marginsRecurrences treated with radiotherapy
Louis-Sylvestre 2001Retrospective review of patient records52 women with biopsy-confirmed Paget's disease of the vulva. Mean age 67 years, range 39-94Surgery, surgery + laser therapy, laser therapy alone31 had surgery alone, 7 recurrences at 1 year (23%); 15 had surgery + laser therapy with 5 recurring within 1 year (33%); 6 had laser therapy alone with 4 recurrences at 1 year (67%)Treatment was chosen by size of lesion so the largest lesions had laser therapy, so the survival rate may be related to disease rather than treatment
Molinie 1993

Retrospective data

1976-1990

36 women age range 45-91 years with a histological diagnosis of Paget's disease of the vulvaLocal excision, partial vulvectomy or RV29 women followed-up. 11 vulvectomies; 4 involved margins, 2/4 recurred. 4 clear margins, 3/4 recurred.14 partial vulvectomies; 12 involved margins, 3/12 recurred. 1 clear margin, 1/1 recurred. 4 local excisions, all clear margins 2/4 recurred. Others margins not known. Altogether 11/29 recurrences, 5/16 with positive margins, 5/9 with negative margins3 died of associated malignancy
Niikura 2006

Retrospective data

1986-2005

22 women with Paget's disease of the vulva. Mean age 71.5 years, range 51-85SV, RV + groin node dissection, chemotherapy (cisplatin and 5-FU)18 SV, 3 RV, 1 primary chemotherapy (stage 4 disease) dead of disease after 12/12. 3/18 SV had positive margins; 2 treated with etoposide, 1 with radiotherapy. 2/3 RV positive margins; 1 treated with radiotherapy, 1 with MEP. Only 1 recurrence in whole series (RV + MEP)2 associated malignancies
Parker 2000

Retrospective data

1944-1997

76 women with a diagnosis of Paget's disease of the vulva, mean age 67.5 years6 women had chemotherapy, 12 had radiotherapy. 20 had WLE, 26 had SV, 20 had RV, 2 had no treatment53% having surgery had positive margins, 23% negative, 26% unknown. Recurrence was 31% in those with positive margins, 33% in those with negative margins16% DoD. Exact chemotherapy used not documented
Petkovic 2006

Retrospective review

1995-2000

10 women in 1 institution with Paget's disease of the vulva, mean age 58 years, range 46-84WLE, RV and bilateral groin node dissection8/10 WLE, 2/10 RV; 2/8 recurrences with WLE, 1/2 recurrences with radical surgery. No comment on margins2 women previously treated before treatment in the centre
Pierie 2003Retrospective data review of all particitants with extramammary Paget's disease25/33 participants had Paget's disease of the vulva'. Median age 70 yearsLocal excision, hemivulvectomy, radiotherapy5/25 local excision, 18/25 hemivulvectomy, 2/25 radiotherapy. 10/25 recurred; 2/5 local excisions, 8/18 hemivulvectomy, 0/2 radiotherapy. Margin status not broken down for tumour type. No radical surgeryNo perioperative mortality or disease-related mortality
Roh 2010

Retrospective review

1996-2008

11 women with histologically verified Paget's disease of the vulva, mean age 66.6 years, range 52-77WLE, RV, SV7/11 WLE, 2/11 SV, 2/11 RV. 6/11 recurred; 4/8 with positive margins, 2/3 with negative margins. 4/7 with WLE, 0/2 with SV, 2/2 with RV. 4/6 recurrences had further excisions with no further disease, 1 had photodynamic therapy and was alive with disease, 1 declined treatment and died of diseaseNo surgical mortality/morbidity. 1 DoD. 3 had previous cancers 3-15 years before diagnosis of Paget's
Shaco-Levy 2010Retrospective56 women with known diagnosis of Paget's of the vulva. Mean age 69 years, range 42-89WLE, SV, partial vulvectomy, RV, laser ablationSurgical extent did not affect recurrence rate. 11/37 recurrences in those with conservative surgery, 5/16 recurrences with radical surgery, 2/2 recurrences with laser ablation. 6 women received adjuvant radiotherapy; 1 died of disease, 5 had no further recurrences. 32% recurrence rate. 20/30 with positive margins recurred, 3/17 with negative margins recurredCurrently 43% no evidence of disease
Stacy 1986

Retrospective data

1975-1984

13 women with biopsy- confirmed Paget's disease of the vulva or anus. Women with anal disease excluded for this review; data from 10 women' analysed. Age range 45-81 yearsSV, RV9 simple vulvectomies, 1 RV. FS showed positive margins in 4/8. 2 had positive margins on final specimens with no FS, 1 had re-excision, 1 no re-excision and no recurrence. All free of disease in follow-up-
Tebes 2002

Retrospective data

1988-2000

23 women with Paget's disease of the vulva, age range 46-84 years'WLE, and if adenoca present proceed to RV and node dissection17 WLE, 6 radical resections. 13 women with negative FS margins, 6 of these had positive margins in final resection. 2/17 with negative margins recurred, 6/16 with positive margins recurred. Mean time to recurrence 30 months. 2/6 with radical resections recurred, 6/17 with conservative surgery recurred. All those with invasive disease had a radical resection5 women (22%) had other primary cancers all treated previously

All studies were from large hospitals in Europe and Northern America, reporting from retrospective reviews of patient and histopathological records. Few information were available in the studies regarding patient demographics although all reported age.

Excluded studies

We excluded 30 references after obtaining the full text paper for the following reasons.

For further details of all the excluded studies, see Table 1 and the Characteristics of excluded studies table.

Risk of bias in included studies

No studies met our inclusion criteria and we excluded them all from the review. We did, however, report some results in a narrative discussion in the Effects of interventions section. These studies were retrospective case series and were at a high risk of bias, although we did not objectively and subjectively assess this since they did not meet the inclusion criteria.

Effects of interventions

None of the studies used any statistical adjustment for baseline case mix using multivariable analyses. The number of included women in most of the studies was low, which may account for the lack of statistical adjustment. We have presented the main results of the studies but have not made any inferences due to the problem of selection bias and fact that all studies were at a high risk of bias.

The 20 studies discussed here met all the inclusion criteria, except having any statistical adjustment to decrease the risk of bias. Any meta-analysis, therefore, would be invalid, but their results warrant discussion.

Data on survival were available from eight studies (Crawford 1999; Curtin 1990; Fanning 1999; Lee 1977; Molinie 1993; Parker 2000; Pierie 2003; Roh 2010). These included information on 306 women and reported 23 deaths. There were 14 deaths related to disease, five deaths from other malignancies and four deaths related to other causes. Since nearly all treatment in the studies was surgical, we cannot comment on mortality to treatment modality. Two series used chemotherapy as a first-line treatment (Niikura 2006; Parker 2000). One woman in the Niikura 2006 study was given chemotherapy for stage IV disease, and they died of disease. The chemotherapy used was cisplatin plus fluorouracil. Six women out of 76 (8%) in the Parker 2000 study had chemotherapy as the primary treatment. However, in this study there was no documentation regarding what chemotherapy regimens were used, or how women were selected for chemotherapy. In this series of women, chemotherapy was associated with poor prognosis with regards to survival, compared with other treatment, but this is likely to be due to selection bias, and this difference cannot be expanded any further due to the small series and lack of detailed information. In this same study (Parker 2000), 12 women were also treated with primary radiotherapy (16%), although again there was no documentation of treatment regimens, and whether doses used were of palliative or radical levels. Survival was again shown to be worse after radiotherapy, but the same caveats apply as to their comments on chemotherapy.

The largest series of laser therapy included six women having laser alone and 15 women having a combination of laser and surgery (Louis-Sylvestre 2001). The recurrence rates for the small number of women having laser alone were very high (67% at one year), but laser alone was only used in women with large, likely inoperable lesions, so it is not possible to draw conclusions regarding the efficacy of the treatment.

Radiotherapy was used as a first-line treatment in only four women across all the other papers. With these small numbers, it is not possible to form any conclusions as to its effectiveness as a treatment. With the data available in the studies, it is also not possible to draw any conclusions with regards to disease-free survival, as, due to the nature of retrospective series, there is not adequate information with which to categorise recurrences.

The studies contained variable length of follow-up, varying from nine months up to 38 years. Accurate survival data were not possible given the number of women followed up for fewer than five years. Of the 40 women across all the studies who had a confirmed malignancy at another site (13%), at least 10 of these were metachronus and treated before the presentation of Paget's of the vulva. It is not possible from the data in the studies to define clearly the number of secondary Paget's included.

Margin status

Margin status of the initial specimens after surgery were known and clearly documented in 13 out of the 19 studies. Due to the small numbers in each series, most papers favoured the margin status making no difference to chance of recurrence. However, with the small numbers involved, inferences should not be made as to the risk of recurrence based on margin status in these women. Out of the 529 women in the 19 studies, margin status and recurrence data were known in 307, although follow-up length was variable, from months to more than 20 years. This highlights the difficulties of extracting meaningful information from data collected retrospectively, when in these studies, margin status was only known in 57% of women.

Radical versus conservative surgery

The exact surgery performed is described in different ways in different studies. Wide local excision, hemi-vulvectomy, simple vulvectomy and radical vulvectomy sometimes with groin node dissection are the most common. It could be assumed that the more radical the surgery, the larger the lesion, but these data are not possible to extract from the papers. None of the study authors described in detail the surgery undertaken for women in their study. Tebes 2002 states that all those with invasive disease had radical surgery, but this does not apply to other studies. In all of the studies, almost twice as many women had conservative surgery than radical. It seems reasonable that surgery should be tailored to the size of the lesion, and radical surgery to be used only when necessary to obtain clear margins.

Discussion

Summary of main results

We did not identify any studies that met our inclusion criteria. Consequently, there is no evidence from this review as to which treatment modality is most effective and safe in the Paget's disease of the vulva. We were able to review the results of 20 studies in detail that reported on at least 10 women with biopsy-confirmed Paget's disease of the vulva. We were unable to make any comparisons between treatment modalities, due to minimal numbers of women having non-surgical treatment. Due the variation in the radicality of the surgery itself, we cannot make any inferences about disease recurrence.

Overall completeness and applicability of evidence

At the outset of this review, we were aware, due to the rare nature of Paget's disease of the vulva, that accumulation of helpful outcome data would be difficult. We set a cut-off of series with at least 10 women, in order to try to include as much of the published data as possible, while excluding case reports and very small case series. The accumulation of meaningful data on rare diseases remains challenging, but is a vital part of extending our knowledge base on rare conditions.

It was noticeable that the majority of published data is now relatively old (10 out of 20 studies were pre-2000) and there was no published prospective data collection. This meant that it was not possible to gain any evidence regarding morbidity from these papers, as morbidity data need to be collected prospectively. Other flaws in retrospective data collection include a lack of clarity in decision making regarding choices of surgery and whether any other treatment options had been offered or discussed.

We have specifically reviewed only women with Paget's disease of the vulva. There is evidence that may be available for perianal disease or scrotal disease in men that may be appropriate to guide treatment.

Quality of the evidence

There is no available evidence of adequate quality; selected retrospective studies formed the only available evidence base and are the best that is available currently in the literature, but these study designs are significantly flawed. While taking into account the inherent problems with these data, the way forward is to collect prospective data on all treatments for Paget's disease of the vulva, ideally as a national database, in order that clear outcome and morbidity data, as well as patient satisfaction data can be collected.

Potential biases in the review process

Due to the retrospective nature of all the studies, there are no morbidity data available, or patient satisfaction analysis, and, therefore, no comment can be made on QoL between treatments. This is significant when considering radical surgery, and re-excision after previous surgery. Selection bias is challenging when dealing with retrospective studies, when radicality of treatment would be dependent on surgeon choice. Most of the women in the studies had treatment before the advent of the multidisciplinary team, and, therefore, alternative treatments to surgery may not have been available, or not considered. It was not possible to extract this information from the studies.

Agreements and disagreements with other studies or reviews

There are no other systematic reviews of Paget's disease of the vulva. Our initial search strategy included several case reports of successful treatment with 5% imiquimod in, eight women (Bertozzi 2009; Hatch 2008; Sendagorta 2010; Tonguc 2011; Wang 2003). Other treatments that have been used and published as case reports include laser ablation (Valentine 1992), primary curative intent radiotherapy (Luk NM 2003; Moreno-Arias 2003), and photodynamic therapy (Raspagliesi 2006, which was a pilot study of six women, but with no control group). Nardelli carried out a review into photodynamic therapy for mammary and extramammary Paget's disease (Nardelli 2011). It contained 23 studies, but nine were single case reports only. The largest study included only two women with Paget's disease of the vulva (Li 2010). These data were collected prospectively, but neither woman had a complete response. Across all Paget's disease, this non-systematic review concluded that evidence was limited, and most women across all studies and Paget's sites had follow-up of one year or less.

The published literature regarding treatment of Paget's disease of the vulva is dominated by surgical treatment. This is likely to be due to the nature of the published studies, which are retrospective series of women who have undergone surgery, rather than a proper cohort. However, there is also no evidence for surgery as a treatment of Paget's disease of the vulva, and currently any treatment is not based on evidence, but on empirical reasoning.

Authors' conclusions

Implications for practice

There is no evidence to support the use of surgery over any other treatment modality, yet the published research implies that surgery is the mainstay of treatment of Paget's disease of the vulva, although there is a wide variation in the radicality of surgery carried out. In addition, there is no evidence in the current literature to advise regarding other treatment modalities. No recommendations regarding treatment modality can, therefore, be made from the current available literature and women need to be made aware that any treatment including surgery does not have a clear evidence base. Women should be able to discuss different treatment modalities with their clinician and be referred to other centres for alternatives to surgery, if appropriate. Ideally, treatment should be offered as part of a trial.

Implications for research

In rare diseases, it is accepted that prospective randomised controlled trials are difficult but not impossible, so in order to provide further evidence regarding management every attempt should be made to set one up. Practically, the way forwards would be to design a large international multicentre trial, as well as carefully planned prospective data collection with consideration to bias. The collection of cases centrally with a key dataset would enable data to be extracted retrospectively, which will aid development of a more robust literature. The flaws in the excluded studies examined in this review were that data were collected retrospectively over a long time period, and important information was not available including morbidity data, reasons for treatment selection and robust survival data. Publication of any significant case series of treatments other than surgery would enhance the available literature regarding the management of Paget's disease of the vulva.

Acknowledgements

We thank Jo Morrison for clinical expertise. We thank Jane Hayes for designing the search strategy and Gail Quinn and Clare Jess for their contribution to the editorial process. We are also very grateful for the helpful and detailed feedback given by the peer-referees. We are also very grateful to George Smith for his many useful comments throughout the editorial process.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group.

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. CENTRAL search strategy

  1. MeSH descriptor Paget Disease, Extramammary, this term only

  2. paget*

  3. (#1 OR #2)

  4. MeSH descriptor Vulva explode all trees

  5. vulva*

  6. (#4 OR #5)

  7. (#3 AND #6)

Appendix 2. MEDLINE search strategy

  1. Paget Disease Extramammary/

  2. paget*.mp.

  3. 1 or 2

  4. exp Vulva/

  5. vulva*.mp.

  6. 4 or 5

  7. 3 and 6

key: mp=title, original title, abstract, name of substance word, subject heading word, unique identifier

Appendix 3. EMBASE search strategy

  1. Paget skin disease/

  2. paget*.mp.

  3. 1 or 2

  4. vulva/

  5. vulva*.mp.

  6. 4 or 5

  7. 3 and 6

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

What's new

Last assessed as up-to-date: 2 September 2013.

DateEventDescription
11 February 2015AmendedContact details updated.

History

Protocol first published: Issue 7, 2011
Review first published: Issue 10, 2013

DateEventDescription
27 March 2014AmendedContact details updated.

Contributions of authors

Katharine Edey: writing of protocol and review. Assessment of literature for inclusion, analysis of papers. John Murdoch: assessment of literature for inclusion. Ernest Allen: paper analysis. Susan Cooper: review of protocol and review. Andrew Bryant: statistical support and assistance in writing of the review.

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Department of Health, UK.

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

Differences between protocol and review

Results of retrospective studies and case reports are discussed in the Effects of interventions and Agreements and disagreements with other studies or reviews sections.

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 (KE, EA) will independently assess the eligibility of retrieved papers. We will resolve any disagreements by discussion between the two review authors. We will document reasons for exclusion.

Data extraction and management  

We will use a specifically designed data extraction form to document data on characteristics of participants (inclusion criteria, age, co-morbidity, previous treatment, number enrolled) and interventions (surgery, radiotherapy, photodynamic therapy, chemotherapy), risk of bias, duration of follow-up and outcomes. Two review authors (KE, EA) will extract and document author, year of publication, journal, language and data.

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

  • For dichotomous outcomes (e.g. adverse events or deaths if it is not possible to use an 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, in order to estimate a risk ratio.

  • For continuous outcomes (e.g. QoL) we will extract the final value and 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, in order to estimate the mean difference between treatment arms and its standard error.

For non-randomised studies (if applicable), we will extract adjusted statistics.

All data extracted will be by an intention-to-treat analysis, where possible and we will note the time points at which outcomes were collected and reported.

We will resolve differences between review authors by discussion or by appeal to a third review author (SC) if necessary.

Assessment of risk of bias in included studies  

The risk of bias in included studies will be assessed using The Cochrane Collaboration's tool and the criteria specified in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a): This will include assessment of:

  • sequence generation;

  • allocation concealment;

  • blinding (of participants, healthcare providers and outcome assessors). Surgical assessment is unlikely to be blinded.

    • We will record the proportion of participants whose outcomes were not reported at the end of the study. We will code the satisfactory level of loss to follow-up for each outcome as:

      • low risk of bias, if less than 20% of women were lost to follow-up and reasons for loss to follow-up were similar in both treatment arms;

      • high risk of bias, if more than 20% of women were lost to follow-up or reasons for loss to follow-up differed between treatment arms;

      • unclear risk of bias, if loss to follow-up was not reported;

  • selective reporting of outcomes;

  • other possible sources of bias.

Potential biases are likely to be greater for non-randomised studies compared with randomised trials. The risk of bias in non-randomised controlled trials will be assessed in accordance with four additional questions and criteria.

Cohort selection

  1. Were relevant details of criteria for assignment of women to treatments provided?

    1. Yes (low risk of bias).

    2. No (high risk of bias).

    3. Unclear.

  2. Was the group of women who received the intervention (surgery, radiotherapy, photodynamic therapy, chemotherapy) representative?

    1. Low risk of bias, if they were representative of women with Paget's disease of the vulva.

    2. High risk of bias, if group of women was selected.

    3. Unclear risk of bias, if selection of group was not described.

  3. Was the group of women who received the comparison intervention (surgery, radiotherapy, photodynamic therapy, chemotherapy) representative?

    1. Low risk of bias, if drawn from the same population as the intervention group.

    2. High risk of bias, if drawn from a different source.

    3. Unclear risk of bias, if selection of group not described.

Comparability of treatment groups

  1. Were there no differences between the two groups or differences controlled for, in particular with reference to age, histological grade, performance status, grade of operating surgeon (if direct comparison of surgical interventions)?

    1. Yes, if at least two of these characteristics were reported and any reported differences were controlled for.

    2. No, if the two groups differed and differences were not controlled for.

    3. Unclear, if fewer than two of these characteristics were reported even if there were no other differences between the groups, and other characteristics had been controlled for.

Two review authors (KE, JM) will independently apply the 'Risk of bias' tool and resolve differences by discussion or by appeal to a third review author (SC or EA). We will present results in both a 'Risk of bias' graph and a 'Risk of bias' summary. Results of meta-analyses will be interpreted in light of the findings with respect to risk of bias.

Measures of treatment effect  

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

  • For time to event data, such as disease-free survival, we will use the HR, if possible.

  • For dichotomous outcomes, we will use the risk ratio.

  • For continuous outcomes, such as QoL scores, we will use the mean difference between treatment arms if all trials measured the outcome on the same scale, otherwise standardised mean differences will be used.

If adjusted results are available in RCTs, they will be preferred; otherwise, we will use unadjusted results. If we identify no RCTs, adjusted results will be used or the study will be excluded (see above).

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 heterogeneity between trials that cannot be ascribed to sampling variation (Higgins 2003), and by a formal statistical test of the significance of the heterogeneity (Deeks 2001). If there is evidence of substantial heterogeneity, the possible reasons for this will be investigated and reported.

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. If these plots suggest that treatment effects may not be sampled from a symmetric distribution, as assumed by the random-effects model, we will perform further meta-analyses using fixed-effect models.

Data synthesis  

If sufficient, clinically similar studies are available, we will pool their results in meta-analyses.

  • For time-to-event data, we will pool HRs using the generic inverse variance facility of Review Manager (RevMan 2012).

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

  • For continuous outcomes, we will pool the mean differences between the 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 have multiple treatment groups, we will divide the 'shared' comparison group into the number of treatment groups and treat the comparisons between each treatment group and the split comparison group as independent comparisons.

Random-effects models with inverse variance weighting will be used for all meta-analyses (DerSimonian 1986). If possible, we will synthesise studies making different comparisons using the methods of Bucher 1997.

Subgroup analysis and investigation of heterogeneity  

In interpretation of any heterogeneity, we will consider factors such as age, cancer stage, type of intervention, length of follow-up and adjusted/unadjusted analysis. We do not plan to carry out any subgroup analyses a priori.

Sensitivity analysis  

We will perform sensitivity analyses

excluding studies at high risk of bias.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bakalianou 2008No statistical adjustment to reduce the threat of selection bias
Black 2007No statistical adjustment to reduce the threat of selection bias
Crawford 1999No statistical adjustment to reduce the threat of selection bias
Curtin 1990No statistical adjustment to reduce the threat of selection bias
Fanning 1999No statistical adjustment to reduce the threat of selection bias
Feuer 1990No statistical adjustment to reduce the threat of selection bias
Fishman 1995No statistical adjustment to reduce the threat of selection bias
Goldblum 1997No statistical adjustment to reduce the threat of selection bias
Koss 1968A report of 10 cases, but on review of the paper, 2 participants had melanoma, therefore only 8 participants had Paget's disease
Lee 1977No statistical adjustment to reduce the threat of selection bias
Lee 2010No statistical adjustment to reduce the threat of selection bias
Louis-Sylvestre 2001No statistical adjustment to reduce the threat of selection bias
Martorell-Calatayud 2009 Was only a case report
Molinie 1993No statistical adjustment to reduce the threat of selection bias
Niikura 2006No statistical adjustment to reduce the threat of selection bias
Parker 2000No statistical adjustment to reduce the threat of selection bias
Parmley 1975Only comments on 7 participants with invasive Paget's, no data on the 10 non-invasive so cohort too small
Petkovic 2006No statistical adjustment to reduce the threat of selection bias
Pierie 2003No statistical adjustment to reduce the threat of selection bias
Roh 2010No statistical adjustment to reduce the threat of selection bias
Shaco-Levy 2010No statistical adjustment to reduce the threat of selection bias
Shingleton 1970Contained only 1 participant with biopsy-confirmed Paget's disease
Stacy 1986No statistical adjustment to reduce the threat of selection bias
Strempel 1958Contained only 3 participants with biopsy-confirmed Paget's disease
Tanaka 2009Contained only 7 participants with biopsy-confirmed Paget's disease
Tebes 2002No statistical adjustment to reduce the threat of selection bias
Wang 2003Case report only of use of imiquimod 5%
Zawislak 2004Case report only of photodynamic therapy

Characteristics of studies awaiting assessment [ordered by study ID]

Fontanelli 2013

Methods 
Participants 
Interventions 
Outcomes 
NotesPaper not available from any UK source

Lu 1999

Methods 
Participants 
Interventions 
Outcomes 
NotesPaper not available from any UK source

Shrestha 2010

Methods 
Participants 
Interventions 
Outcomes 
NotesPaper not available from any UK source

Ancillary