Comparative Effectiveness of Sentinel Lymph Node Biopsy for Ductal Carcinoma In Situ
Condition: Ductal Carcinoma In Situ
MeSH terms: Carcinoma; Carcinoma in Situ; Carcinoma, Ductal; Carcinoma, Intraductal, Noninfiltrating
Study type: Observational

Summary: 
      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.
    

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.
    

Intervention name(s): Sentinel lymph node biopsy (SLNB)
Intervention type(s): Procedure
Intervention description(s): 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).
Observational model: Cohort
Time perspective: Retrospective
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.
      
Keywords: ductal carcinoma in situ (DCIS); sentinel lymph node biopsy (SLNB)