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Cochrane Database of Systematic Reviews

Intervenciones para el melanoma in situ, incluido el léntigo maligno

Information

DOI:
https://doi.org/10.1002/14651858.CD010308.pub2Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 19 December 2014see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Skin Group

Copyright:
  1. Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

  • Thrasivoulos Tzellos

    Correspondence to: Department of Dermatology, Faculty of Health Sciences, University Hospital of North Norway, Harstad, Norway

    [email protected]

    [email protected]

  • Athanassios Kyrgidis

    Division of Evidence Based Dermatology, Dessau Medical Center, Dessau, Germany

    Dermatology and Skin Cancer Unit, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Reggio Emilia, Italy

    1st Department of Otolaryngology, Head & Neck Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece

  • Simone Mocellin

    Dept. Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy

    Istituto Oncologico Veneto, IOV‐IRCCS, Padova, Italy

  • An‐Wen Chan

    Women's College Research Institute, University of Toronto, Toronto, Canada

  • Pierluigi Pilati

    Meta‐Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

  • Zoe Apalla

    State Clinic of Dermatology, Hospital of Skin and Venereal Diseases, Thessaloniki, Greece

Contributions of authors

TT was the contact person with the editorial base.
TT and AK co‐ordinated contributions from the co‐authors and wrote the final draft of the review.
TT and AK screened papers against eligibility criteria.
TT and AK obtained data on ongoing and unpublished studies.
TT and AK appraised the quality of papers.
TT and AK extracted data for the review and sought additional information about papers.
TT and AK entered data into RevMan.
TT and AK (with the help of all authors) analysed and interpreted data.
TT and AK worked on the methods sections.
ZA and TT drafted the clinical sections of the background and responded to the clinical comments of the referees.
TT and AK (with the help of all authors) responded to the methodology and statistics comments of the referees.
PP was the consumer co‐author and checked the review for readability and clarity, as well as ensuring outcomes are relevant to consumers.
TT is the guarantor of the update.

Disclaimer

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, UK.

Sources of support

Internal sources

  • Dessau Medical Center, Dessau, Germany.

    Provided internet facilities

  • Freie Universität Berlin, Germany.

    Provided online literature

  • Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

    Provided internet facilities and online literature

  • Hospital of Skin and Venereal Diseases, Thessaloniki, Greece.

    Provided internet facilities

  • Women's College Research Institute, University of Toronto, Toronto, Canada.

    Provided internet facilities and online literature

  • University Hospital of North Norway, Harstad, Troms, Norway.

    Provided internet facilities and online literature

External sources

  • The National Institute for Health Research (NIHR), UK.

    The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

Declarations of interest

Thrasivoulos Tzellos: Nothing to declare.
Athanassios Kyrgidis: Nothing to declare.
Simone Mocellin: Nothing to declare.
An‐Wen Chan: Nothing to declare.
Pierluigi Pilati: Nothing to declare.
Zoe Apalla: Nothing to declare.

Acknowledgements

We wish to thank Dr Mark Hyde, corresponding author of the included study (Hyde 2012), for replying to our requests and providing access to primary data of the study. We would also like to thank Shaheen Haque Hussain, co‐author of the protocol (Apalla 2013), who withdrew her name from the author list of the review.

The Cochrane Skin Group editorial base wishes to thank Sam Gibbs, who was the Cochrane Dermatology Editor for this review; Matthew Grainge and Thomas Chu, who were the Statistical Editors; Ching‐Chi Chi, who was Methods Editor; the clinical referees, Susan O'Connell and Eleni Linos; and the consumer referee, Colette O'Sullivan.

Version history

Published

Title

Stage

Authors

Version

2014 Dec 19

Interventions for melanoma in situ, including lentigo maligna

Review

Thrasivoulos Tzellos, Athanassios Kyrgidis, Simone Mocellin, An‐Wen Chan, Pierluigi Pilati, Zoe Apalla

https://doi.org/10.1002/14651858.CD010308.pub2

2013 Jan 31

Interventions for melanoma in situ, including lentigo maligna

Protocol

Zoe Apalla, Thrasivoulos Tzellos, Athanassios Kyrgidis, Simone Mocellin, An‐Wen Chan, Shaheen Haque Hussain, Pierluigi Pilati

https://doi.org/10.1002/14651858.CD010308

Differences between protocol and review

The order of authors in the byline has changed after agreement with all authors; we changed the contact author, and the new contact author is Thrasivoulos Tzellos.

In our protocol, we reported that a 'Summary of findings' table would include only primary outcomes. We decided to include both primary and secondary outcomes for reasons of better readability and presentation, since there was only one study included.

With regard to 'Types of outcome measures', we decided to swap our primary and secondary outcomes so 'Histological or clinical complete clearance rate' is now our first primary outcome, and 'Clinical or histological local recurrence rate' is our first secondary outcome. The reasons for this change, which was a unanimous decision, were 1) In order for recurrence rate to be measurable, a complete clearance rate is a prerequisite, 2) we identified no outcomes pertaining to 'Clinical or histological local recurrence rate' in this instance of the review.

After discussion with all authors, we rephrased 'Histological or clinical complete clearance rate' as 'Histological or clinical complete response rate', because this is a more common and universal way of expressing this outcome in oncology. The nature of the outcome did not change with this modification; however, we feel that readability has increased.

Taking into account the mechanism of action of the treatments used in the included studies, we added 'Inflammatory response' as a secondary outcome to Types of outcome measures.

Notes

A search of Medline and Embase in January 2016 did not identify any new relevant studies, confirming the authors' thoughts. Thus, an update has not been considered necessary at this time. Our Information Specialist will run a new search in January 2017 to re‐assess whether an update is needed.

Keywords

MeSH

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Study flow diagram
Figures and Tables -
Figure 1

Study flow diagram

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study
Figures and Tables -
Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 1 Primary outcome: Histological complete response (ITT).
Figures and Tables -
Analysis 1.1

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 1 Primary outcome: Histological complete response (ITT).

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 2 Primary outcome: Histological complete response (available‐case analysis).
Figures and Tables -
Analysis 1.2

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 2 Primary outcome: Histological complete response (available‐case analysis).

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 3 Secondary outcome: Discontinuation of treatment because of harms.
Figures and Tables -
Analysis 1.3

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 3 Secondary outcome: Discontinuation of treatment because of harms.

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 4 Secondary outcome: Inflammatory response (overall Inflammation score) for participants who finished study.
Figures and Tables -
Analysis 1.4

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 4 Secondary outcome: Inflammatory response (overall Inflammation score) for participants who finished study.

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 5 Secondary outcome: Inflammatory response (overall Inflammation score) for all participants.
Figures and Tables -
Analysis 1.5

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 5 Secondary outcome: Inflammatory response (overall Inflammation score) for all participants.

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 6 Secondary outcome: Inflammatory response (number of lesions with grade 2 or 3).
Figures and Tables -
Analysis 1.6

Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 6 Secondary outcome: Inflammatory response (number of lesions with grade 2 or 3).

Summary of findings for the main comparison. Imiquimod 5% cream with tazarotene 0.1% gel compared with Imiquimod 5% cream alone for melanoma in situ, including lentigo maligna

Imiquimod 5% cream with tazarotene 0.1% gel compared with Imiquimod 5% cream alone for melanoma in situ, including lentigo maligna

Patient or population: participants with melanoma in situ, including lentigo maligna
Settings: 1 academic centre in the US
Intervention: imiquimod 5% cream with tazarotene 0.1% gel
Comparison: imiquimod 5% cream alone

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Imiquimod 5% cream alone

Imiquimod 5% cream with tazarotene 0.1% gel

Primary outcome:

Histological complete response (intention‐to‐treat)
No residual LM in staged excision 2 months post‐treatment

587 per 1000

657 per 1000
(475 to 910)

RR 1.12
(0.81 to 1.55)

90
(1 study)

⊕⊕⊝⊝
low¹

Primary outcome:

Histological complete response ( available‐case analysis)
No residual LM in staged excision 2 months post‐treatment

659 per 1000

784 per 1000
(593 to 1000)

RR 1.19
(0.9 to 1.57)

78
(1 study)

⊕⊕⊝⊝
low¹

Secondary outcome:

Discontinuation of treatment because of harms
Discontinuation of treatment due to adverse effects

22 per 1000

136 per 1000
(17 to 1000)

RR 6.27
(0.79 to 50.02)

90
(1 study)

⊕⊕⊝⊝
low¹

Secondary outcome:

Inflammatory response (number of lesions with grade 2 or 3)
Grade 2 or 3 Inflammation²

591 per 1000

815 per 1000
(615 to 1000)

RR 1.38
(1.04 to 1.84)

88
(1 study)

⊕⊕⊝⊝
low¹

Secondary outcome:

Inflammatory response

(overall Inflammation score) for all participants
Mean grade of inflammation in each group²

The mean overall inflammation score (inflammatory response) for all participants in the intervention groups was 0.60 higher
(0.2 to 1 higher)

88
(1 study)

⊕⊕⊝⊝
low¹

*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

GRADE = Grading of Recommendations Assessment, Development and Evaluation.
LM = lentigo maligna.
¹Published evidence is limited to a single randomised trial.
²(0 indicates no inflammation; 1, pink; 2, red; and 3, the presence of erosions, oozing, or eschar).

Figures and Tables -
Summary of findings for the main comparison. Imiquimod 5% cream with tazarotene 0.1% gel compared with Imiquimod 5% cream alone for melanoma in situ, including lentigo maligna
Table 1. Glossary of medical terms

Medical term

Explanation

Intraepidermal

something confined within the epidermis

Preinvasive

a malignant tumour that remains constricted in the epithelium, while the dermo‐epidermal junction preserves its integrity

Eschar

a dry scab or slough formed on the skin as a result of a burn or by the action of a corrosive or caustic substance

Invasive

a malignant tumour that breaks the dermo‐epidermal junction and invades the dermis

Lentigo maligna

a subtype of preinvasive intraepidermal melanoma, associated specifically with chronic solar exposure

Vehicle

an excipient or a menstruum, a substance, usually without therapeutic action, used as a medium to give bulk for the administration of medicines

Apoptosis

a genetically directed process of cell self‐destruction that is marked by the fragmentation of nuclear DNA. It is activated either by the presence of a stimulus or removal of a suppressing agent or stimulus, and is a normal physiological process eliminating DNA‐damaged, superfluous, or unwanted cells. It is a synonym for programmed cell death

Actinic keratosis

rough, scaly macule or patch of skin that it is considered precancerous and is associated with chronic sun exposure

Lentigo senilis

a flat brownish, pigmented spot on the skin, due to increased deposition of melanin and an increased number of melanocytes

Seborrheic keratosis

a benign skin tumour that occurs singly or in clusters on the surface of the skin, is usually light to dark brown or black in colour, and typically has a warty texture often with a waxy appearance

Patch

a greater than 1 cm circumscribed area of discolouration on the skin

Cytokine

a small protein released by cells that has a specific effect on the interactions between cells, on communications between cells, or on the behavior of cells

Innate immunity

immunity that occurs naturally as a result of a person's genetic constitution or physiology and does not arise from a previous infection or vaccination

Blinding

the concealment of group assignment ‐ to either the treatment or control group ‐ from the knowledge of participants, investigators in a clinical trial, or both

Tumour islands

aggregates of tumour cells

Figures and Tables -
Table 1. Glossary of medical terms
Comparison 1. Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary outcome: Histological complete response (ITT) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 Primary outcome: Histological complete response (available‐case analysis) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3 Secondary outcome: Discontinuation of treatment because of harms Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4 Secondary outcome: Inflammatory response (overall Inflammation score) for participants who finished study Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

5 Secondary outcome: Inflammatory response (overall Inflammation score) for all participants Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

6 Secondary outcome: Inflammatory response (number of lesions with grade 2 or 3) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 1. Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna