Trial of Surgical Excision Margins in Thick Primary Melanoma - 2

August 16, 2018 updated by: Peter Gillgren

Long-term Follow-up of Survival in Surgical Resected Invasive Cutaneous Melanomas: Comparing 2-cm Versus 4 -cm Resection Margins - a Randomized, Multicenter Trial

Objectives: The purpose of this study was to assess the long-term follow-up of the overall and melanoma-specific survival in the randomised, open-lable multicenter trial (NTC NCT01183936) comparing excision margin of 2 cm versus 4 cm for patients with primary cutaneous malignant melanoma (CMM) thicker than 2 mm.

Study hypothesis: The hypothesis is that there is no difference between the two treatment arms measured as melanoma-specific survival and overall survival.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Historically, CMMs have been excised with wide resection margins of 5-cm or more with the radical removal of lymph nodes. This treatment emerged from a recommendation from Handley in 1907 based on a single pathological specimen. This "radical" surgical management resulted in bad cosmetic results, lymphedema, long hospital inpatient stay, frequent skin grafting and/or complicated skin flap reconstructions. Not until some 60-plus years later did questions arise in clinical practices whether the need for this extensive surgery was mandated and clinical practice was not substantially changed until the late 1980's. Retrospective studies published in the 1980s suggested that narrower excision margins may be appropriate for treatment of some CMMs, especially thinner lesions.

Nowadays, the recommendations for surgical treatment are based on the Breslow thickness of the CMM, since it is considered the most important prognostic indicator of localized disease and is therefore the information upon which today's surgical strategies are founded. However, recommendations vary over the world, especially for thicker tumors which is clearly presented by Ethun et al. (2016). For CMM of ≤ 1 mm thickness most centers use a 1 cm margin, but for tumors 1.01 - 4 mm the margins of resection are 1-3 cm depending on the country. Most patients with primary CMM > 4 mm are operated on with a margin of 2-cm today. The different national guidelines are thus, somewhat confusing and in a report from 2004 Thomas JM et al. showed that a 1-cm margin for CMM with a poor prognosis (≥2 mm) is associated with a greater risk of regional recurrence than in a 3-cm margin, but with a similar survival rate.

Today, according to Sladden et al. (2018), there have been published six randomized controlled trials (RCTs) assessing outcomes for surgical excision margins based upon Breslow thickness of invasive tumors. Three out of those six RCTs have included patients with CMMs 2-4 cm thick. Still, there are controversies and this report points out gaps of knowledge, e.g. lack of evidence about the optimal depth of excision and the optimal and minimal excision margins, since 1-cm versus 2-cm resection margins of invasive CMMs have not been directly compared yet.

Interestingly, out of one of the three RCTs analyzing melanomas with 2-4 mm thickness, long-term follow up data has recently been published by Hayes et al. 2016. They report an extended follow-up with a median follow-up of almost 9 years, concluding that 1-cm margin is not safe for high-risk CMMs compared to 3-cm margin.

From this point, based up on those interesting results, the investigators now present long-term follow-up of survival in patients included in the RCT published 2011 by Gillgren et al.

The original trial by Gillgren et al. 2011, is a randomized multicenter trial, launched from the Swedish Melanoma Study Group and the Danish Melanoma Group in 1992, included 936 patients from January 22 1992 to May 19 2004. Patients were recruited from Sweden (6 centers with 644 pat), Denmark (180 pat), Estonia (80 pat) and Norway (32 pat). Randomization routines were set up by the steering committee and eligible patients were randomized locally by telephone calls to national and international cancer centers (upon a histologically proven diagnoses and signed patient consent form). Only patients with a CMM >2 mm and with localized disease (who fulfilled the in- and exclusion criteria) were eligible for study inclusion. Patients with CMM on the hands, feet, head-neck and ano-genital region were excluded. Final surgery must had been planned within 8 weeks after date of diagnosis. All analyses were conducted according to the intention-to-treat principle.

Patients were followed clinically every 3 months for 2 years and thereafter every 6 months up to 5 years, with a median follow-up of 6.7 years. Follow-up data was thus collected from cancer registries, cause of death registries and medical records.

Statistical analyses were made by Kaplan Meier life-table curves. Prognostic factors were assessed with the use of a uni- and multivariate Cox regression analysis.

In the original study, the primary melanomas were removed either by an excisional biopsy (margin of 1-3 mm) or with a 2-cm margin before randomization. Patients were randomly assigned (1:1) to either a 2-cm surgical excision margin or a 4-cm surgical excision margin. The physician enrolled the patients after histological confirmation of melanomas >2 mm. Patients who had a diagnostic initial excision were randomized to the 2-cm group or to an additional wide local excision with a margin of up to either 2 cm or 4 cm. Patients who had a 2 cm initial excision were allocated to either no further surgery and randomized to the 2-cm group. Radical surgery was to be performed within 8 weeks after the date of diagnosis. The method of surgery was to extend to, or include, the deep fascia. Pathological excision margins were not registered. The sentinel node biopsy technique was introduced in the end of the enrolment period and was allocated to the same follow-up as the other patients. There were no protocol violations since the sentinel node biopsies were all in clinical stage IIA-C preoperatively. The patients were followed by standard clinical routines within participating centers at that time every 3 months for 2 years and then every 6 months until 5 years. Data on clinical relapse were obtained at the follow-up visits. Outcome data were also assessed from regional cancer registries, the national cause-of-death registries, and medical records.

In the long-term follow-up study, each country collected date of death, primary cause of death and underlying cause of death from central registries. The entire cohort was followed-up until Dec 31, 2016.

Study Type

Interventional

Enrollment (Actual)

936

Phase

  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 75 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Melanoma >2 mm
  • Age ≤ 75 yr
  • Patients operated on with ≤ 2-cm at diagnosis
  • Final surgery planned within 8 weeks after date of diagnosis
  • Patient fit for surgery
  • Signed patient consent form

Exclusion Criteria:

  • Melanoma on hand, foot, head-neck or ano-genital regions
  • The presence of in-transit- regional and/or distant spread of the disease
  • Illness making patient unfit for surgery
  • Previous malignancies except basal cell- and in-situ colli uteri cancer

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 2 cm margin of excision
Patients with CMM >2 mm treated with an excision of 2-cm.
Procedure: 2-cm margin
Patients with CMM treated with a surgical safety margin of 2-cm in the surrounding skin and down to the fascia.
Active Comparator: 4 cm margin of excision
Patients with CMM >2 mm treated with an excision of 4-cm.
Procedure: 4-cm margin
Patients with CMM treated with a surgical safety margin of 4-cm in the surrounding skin and down to the fascia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Melanoma-specific survival
Time Frame: 24.9 years
Cause of death: cutaneous malignant melanoma
24.9 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 24.9 years
Cause of death: all death causes
24.9 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Peter Gillgren

Investigators

  • Principal Investigator: Ulrik Ringborg, M.D., Ph.d., Karolinska inteitutet

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 1992

Primary Completion (Actual)

May 1, 2004

Study Completion (Actual)

December 1, 2006

Study Registration Dates

First Submitted

August 7, 2018

First Submitted That Met QC Criteria

August 16, 2018

First Posted (Actual)

August 20, 2018

Study Record Updates

Last Update Posted (Actual)

August 20, 2018

Last Update Submitted That Met QC Criteria

August 16, 2018

Last Verified

August 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Margins Melanoma -2
  • Country specific (OTHER: Swe; Nat Reg Nr, Dk; 5 dig ser nr (8XXXX), Ea; 5 dig ser nr (7XXXX), Ny; 4 dig ser nr (9XXX))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

IPD Plan Description

Data could be shared with other researchers in a worldwide meta analysis after the actual study is completed.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Melanoma

Clinical Trials on 2-cm margin

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Cambodia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe