Comparative Effectiveness of Sentinel Lymph Node Biopsy for Ductal Carcinoma In Situ

May 1, 2019 updated by: Yale University

Comparative Effectiveness of Sentinel Lymph Node Biopsy (SLNB) for Ductal Carcinoma In Situ (DCIS)

Patients with ductal carcinoma in situ (DCIS) treated with available therapies have experienced excellent outcomes and very low mortality rates due to the disease's non-invasive nature. However, considerable debate exists as to how the DCIS lesion should be treated. As a result, determining strategies to manage DCIS has been identified as a research priority. The role of sentinel lymph node biopsy (SLNB) for DCIS management is controversial in general and needs further scrutiny. Our study addresses this evidence gap as the investigators propose a retrospective cohort study to investigate the outcome of SLNB among DCIS patients. Specifically, the investigators will compare the outcomes, including survival outcomes and treatment side effects, among women older than 67 years of age with DCIS receiving SLNB vs. not receiving SLNB within 6 months of DCIS diagnosis. The investigators have two primary aims in this study: Aim 1: the investigators select our study sample using SEER-Medicare database. The investigators will determine associations between SLNB and acute/subacute side effects, including lymphedema, pain, and limitation of movement of upper extremity from the first breast conserving surgery to 9 months post-diagnosis. Aim 2: the investigators will determine associations between SLNB and long-term outcomes, including breast cancer specific mortality, ipsilateral invasive breast cancer diagnosis, subsequent mastectomy as treated recurrence, and lasting side effects, from >9 months post-diagnosis to death or the end of this study period.

Given the nature of our observational study design, the investigators will apply standard multivariate analyses and propensity score methodology to reduce the influence from confounders. The investigators will control for patient demographics, comorbidities, functional status, tumor characteristics, and prior healthcare utilization. Using distance to the nearest provider that uses SLNB for DCIS or surgeon's tendency in using SLNB for stage I/II breast cancer, the investigators also plan to conduct instrument variable analyses if necessary. Stratifying patients by key DCIS characteristics (including grade, comedonecrosis, and tumor size) and their predicted life expectancy (given their age and comorbidities), the investigators also hope to identify patient subgroups who may safely forgo SLNB. The study would provide evidence on the efficacy and safety outcome of SLNB for DCIS management.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Because of the non-invasive nature of ductal carcinoma in situ (DCIS), patients treated with available therapies have excellent outcomes and very low rates of breast cancer mortality. Considerable debate exists as to how the DCIS lesion should be treated, although there is a movement toward less intensive intervention by the identification of patient subsets with favorable prognoses. Some prospective studies have found that the rate of ipsilateral invasive cancer occurrence is still high after receiving breast conserving surgery (BCS) alone, even among patients with favorable pathologic characteristics. Such findings argue against active surveillance for DCIS treatment. However, evidence exists that older DCIS patients have a lower rate of ipsilateral recurrence because DCIS among older patients tends to be indolent. Identifying suitable subgroups among this lower risk group who may be safe to receive a less aggressive treatment could change the current practice pattern of aggressive treatment.

Even when DCIS patients opt to receive a less intensive treatment such as BCS without radiation therapy, they and their providers need to decide whether to undergo sentinel lymph node biopsy (SLNB). A systematic review has shown that evidence gaps exist regarding the benefits of SLNB for DCIS. Given that the likelihood of axillary recurrence is low among DCIS patients who received radiation therapy, routine SLNB is not recommended for DCIS patients. Of note, radiation therapy can control axillary disease if present. If the investigators plan to empower DCIS patients to choose less intensive management options, such as BCS forgoing radiation therapy (RT), it will be crucial for patients and providers to understand the role of SLNB.

The overarching goals of this study are to compare side effects and outcomes between receiving SLNB vs. not receiving SLNB among older DCIS patients who received BCS. With this data, the investigators also aim to identify sub-populations for whom less intensive treatments may be appropriate. Using the Surveillance, Epidemiology, and End Result (SEER)-Medicare linked data, our project's overarching aims are:

Among older women with DCIS who have received BCS as their first surgery, to compare the outcomes of receiving sentinel lymph node biopsy (SLNB) vs. not receiving SLNB within 6 months of DCIS diagnosis:

Aim 1: The investigators will determine associations between SLNB and acute/subacute side effects, including lymphedema, pain, and limitation of movement of upper extremity from the first BCS to 9 months post-diagnosis Aim 2: The investigators will determine associations between SLNB and long-term outcomes, including breast cancer specific mortality, ipsilateral invasive breast cancer diagnosis, subsequent mastectomy as treated recurrence, and lasting side effects, from > 9 months' post-diagnosis to death or the end of the study period.

Our study is a retrospective cohort study with the study population being DCIS patients older than 67 years (hereafter referred to as older women) who were enrolled in a fee-for-service Medicare program and resided in the SEER areas from 1998 to 2011 (2001 to 2013 for Aim 2) and who were followed up to 2012 (2015 for Aim 2). The investigators selected age 67 years as a cut-off value because the investigators plan to use two years of claims data to identify patient comorbidities and control for them in our statistical models, and data is first available at age 65. Given the nature of our observational study design, the investigators will apply standard multivariate analyses and propensity score methodology to reduce the influence from confounders. The investigators will control for patient demographics, comorbidities, functional status, tumor characteristics, and prior healthcare utilization. Using distance to the nearest provider that uses SLNB for DCIS or surgeon's tendency in using SLNB for stage I/II breast cancer, the investigators also plan to conduct instrument variable analyses if necessary. Stratifying patients by key DCIS characteristics (including grade, comedonecrosis, and tumor size) and their predicted life expectancy (given their age and comorbidities), the investigators also hope to identify patient subgroups who may safely forgo SLNB.

In comparisons of baseline characteristics between intervention and control groups, the investigators will conduct standard descriptive statistics using chi-square tests for categorical variables and t-tests for continuous variables. The investigators will tabulate the frequencies of outcomes of interests by the intervention vs. control group. For multivariable analyses, the investigators will apply proportional hazards models to test whether the intervention is associated with better outcomes.

the investigators plan to control for this issue using propensity score matching methodology. Prior literature has suggested inclusion of either all measured variables or those variables that are associated with treatment selection (SLNB status) when conducting an analysis using the propensity score method. Specifically, our approach to matching will be based on the Mahalanobis distance calculated using age, race, residence in a metropolitan county, comorbidity, prior influenza vaccination or prior visit to a primary care physician (both as proxies for access to care), income, preoperative MRI use, and tumor characteristics. Tumor characteristics include size, grade, comedonecrosis, and estrogen receptor status. By incorporating these factors in matching, the investigators expect to substantially decrease bias and balance the risk for outcomes of interest between the SLNB and non-SLNB groups. The difference in outcomes between the control and intervention groups will be estimated in a Kaplan-Meier curve. The investigators will estimate the relative risk in the propensity score matched sample using the standard method for matched-pair data. The investigators will use the Cox proportional hazards models to investigate the association between various factors (grade, tumor size, and estrogen receptor status) and outcomes.

Study Type

Observational

Enrollment (Actual)

28291

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • SEER-Medicare Dataset

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

67 years to 94 years (Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Sampling Method

Non-Probability Sample

Study Population

Our study populations were generated within the SEER-Medicare linked database. The populations consist of female DCIS patients ages 67-94 years who were enrolled in a fee-for-service Medicare program and resided in the SEER areas.

Description

Inclusion Criteria:

  • Female DCIS patients older than 67 years and younger than 94 years who were enrolled in a fee-for-service Medicare program and resided in the SEER areas.
  • Aim 1: DCIS patients who received breast conserving surgery (BCS) as their first surgery
  • Aim 1: DCIS patients who were diagnosed DCIS between January 1998 and December 2011
  • Aim 2: DCIS patients who were diagnosed DCIS between January 2001 and December 2013

Exclusion Criteria:

  • Aim 1: DCIS patients who received mastectomy as their first surgery
  • Aim 2: DCIS patients who received BCS at the beginning yet received mastectomy in the end

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

  • Observational Models: Cohort
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Aim 1 Cohort

The Aim 1 Cohort is constructed to perform analysis to address study objective Aim 1. This cohort includes patients diagnosed at ages 67-94 years with DCIS between January 1998 and December 2011, and received BCS as their first surgery. Patients in this cohort include those who received sentinel lymph node biopsy (SLNB) and who didn't receive SLNB.

The Aim 1 Cohort and the Aim 2 Cohort can overlap.
Procedure: Sentinel lymph node biopsy (SLNB)
Intervention is defined as that the DCIS patient has undergone SLNB. Patients in each cohort (group) include those who underwent SLNB (intervention) and those who did not (control).
Aim 2 Cohort

The Aim 2 Cohort is constructed to perform analysis to address study objective Aim 2. This cohort includes patients diagnosed at ages 67-94 years with DCIS between January 2001 and December 2013, and received BCS as their first surgery. Patients in this cohort include those who received sentinel lymph node biopsy (SLNB) and who didn't receive SLNB.

The Aim 1 Cohort and the Aim 2 Cohort can overlap.
Procedure: Sentinel lymph node biopsy (SLNB)
Intervention is defined as that the DCIS patient has undergone SLNB. Patients in each cohort (group) include those who underwent SLNB (intervention) and those who did not (control).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Side Effects (Claim-based Measure), Including Lymphedema, Seroma, Wound Infection, or Pain
Time Frame: From the first BCS to 9 months post-diagnosis.
Primary outcomes for Aim 1: Acute and subacute side effects include any complication, lymphedema, seroma, wound infection, and pain.
From the first BCS to 9 months post-diagnosis.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Receipt of Mastectomy
Time Frame: 6 months within DCIS diagnosis
Secondary outcomes for Aim 1: receipt of mastectomy with and without SLNB after initial BCS through 6 months after DCIS diagnosis.
6 months within DCIS diagnosis
Receipt of Radiation Therapy
Time Frame: 9 months within DCIS diagnosis
Secondary outcomes for Aim 1: Receipt of radiation therapy within 9 months of DCIS diagnosis.
9 months within DCIS diagnosis
Overall Survival
Time Frame: From 9 months post-diagnosis to death/end of study period (up to 1.5 years)
Secondary outcomes for Aim 2.
From 9 months post-diagnosis to death/end of study period (up to 1.5 years)
Lasting Side Effects (Claim-based Measure), Including Lymphedema, Seroma, Wound Infection, or Pain
Time Frame: From 9 months post-diagnosis to death/end of study period (up to 1.5 years)
Secondary outcomes for Aim 2: unadjusted side effects (any side effects, lymphedema, any infection, seroma, pain) in the matched sample by use of sentinel lymph node biopsy (SLNB). Any side effects refer to the occurrence of one or more of the following complications since diagnosis of DCIS: lymphedema related complications, any infection, seroma, and any pain.
From 9 months post-diagnosis to death/end of study period (up to 1.5 years)
Breast Cancer Specific Mortality
Time Frame: From 9 months post-diagnosis to death/end of study period (up to 1.5 years)
Primary outcomes for Aim 2: Breast cancer specific mortality from 9 months post-diagnosis to death or the end of the study period (December, 2014).
From 9 months post-diagnosis to death/end of study period (up to 1.5 years)
Ipsilateral Invasive Breast Cancer Occurrence
Time Frame: From 9 months post-diagnosis to death/end of study period (up to 1.5 years)
Primary outcomes for Aim 2: Ipsilateral invasive breast cancer occurrence after 9 months of a DCIS diagnosis, per SEER reports.
From 9 months post-diagnosis to death/end of study period (up to 1.5 years)
Treated Recurrence
Time Frame: From 9 months post-diagnosis to death/end of study period (up to 1.5 years)
Primary outcomes for Aim 2: Treated recurrence was defined by the receipt of mastectomy after 9 months of a DCIS diagnosis in the Aim 2 matched cohort.
From 9 months post-diagnosis to death/end of study period (up to 1.5 years)

Collaborators and Investigators

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

Sponsor

Yale University

Collaborators

Patient-Centered Outcomes Research Institute

Investigators

  • Principal Investigator: Shi-Yi Wang, MD, PhD, Yale University

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

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 (Actual)

January 25, 2017

Primary Completion (Actual)

June 1, 2018

Study Completion (Actual)

June 29, 2018

Study Registration Dates

First Submitted

August 30, 2016

First Submitted That Met QC Criteria

September 15, 2016

First Posted (Estimate)

September 20, 2016

Study Record Updates

Last Update Posted (Actual)

May 15, 2019

Last Update Submitted That Met QC Criteria

May 1, 2019

Last Verified

May 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PCORI-SW-1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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.

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