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Radiotherapy Versus Low-Dose Tamoxifen Following Breast Conserving Surgery for Low-Risk Breast Ductal Carcinoma in Situ

Primary Purpose

Breast Ductal Carcinoma in Situ

Status
Recruiting
Phase
Phase 3
Locations
Taiwan
Study Type
Interventional
Intervention
Low-dose tamoxifen
Whole breast radiotherapy
Sponsored by
National Taiwan University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Ductal Carcinoma in Situ

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Women
  2. New histologically diagnosed breast ductal carcinoma in situ (DCIS).
  3. Age ≥ 40 years
  4. Low risks of BRCA (breast cancer)1 and BRCA2: Manchester Score < 10
  5. The DCIS must be detected by mammogram and must be unicentric, and no-mass lesion.
  6. Status post breast conserving surgery
  7. Pathological characteristics (all characteristics) 7.1 Lesions ≤ 2.5 cm in greatest dimension on pathologic specimen (use the largest measured size from the pathology report to obtain the required measurement of ≤ 2.5 cm).

    7.2 Must be classified as low or intermediate nuclear grade DCIS but without comedo necrosis according to Pathologic Guidelines (section 9.2.2) 7.3 Margins as assessed by the ink method will be 3 mm or greater. 7.4 Must be estrogen receptor (ER)-positive DCIS, ER percentage must be ≥10%

  8. Clinically node negative.

Exclusion Criteria:

  1. Known BRCA1 or BRCA2 mutation
  2. Age < 40 years
  3. Women whose DCIS is palpable at the time of diagnosis, or multi-centric (mammography), or mass (mammography), or who have bloody nipple discharge.
  4. Pathological characteristics 4.1 Lesions measuring greater than 2.5 cm in greatest dimension on pathologic specimen.

    4.2.High-grade lesions or low to intermediate grade with comedo necrosis as classified by the Guidelines.

    4.3. Margins as assessed by the ink method will be less than 3 mm. 4.4. ER-negative DCIS or ER-positive percentage < 10% in tumor cells

  5. Post-mastectomy patients
  6. Prior diagnosis of neoplasm within 5 years, except cervical intraepithelial neoplasia type 1 (CIN1) or localized non-melanomatous skin cancer.
  7. Evidence of clinically significant cardiac disease, as defined by cardiac disease (New York Cardiac disease grade II), history of myocardial infarction, cerebral stroke, unstable arrhythmia, and unstable angina pectoris within 12 months before study entry.
  8. Pregnant or lactating status.

Sites / Locations

  • National Taiwan University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Radiotherapy arm

Tamoxifen arm

Arm Description

Radiotherapy for ipsilateral whole breast with 50 Gy/25 fractions or 40.05 Gy/15 fractions

Tamoxifen 5 mg QD for 10 years

Outcomes

Primary Outcome Measures

Breast tumor recurrence
Ispilateral, regional recurrence, contralateral recurrence, and distant recurrence [DCIS or invasive cancer event]

Secondary Outcome Measures

The overall survival
Overall survival
Adverse effects
Adverse effects of radiotherapy and tamoxifen

Full Information

First Posted
July 7, 2019
Last Updated
August 4, 2019
Sponsor
National Taiwan University Hospital
Collaborators
Tri-Service General Hospital, Koo Foundation Sun Yat-Sen Cancer Center, Kaohsiung Medical University, Kyoto University, Mackay Memorial Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04046159
Brief Title
Radiotherapy Versus Low-Dose Tamoxifen Following Breast Conserving Surgery for Low-Risk Breast Ductal Carcinoma in Situ
Official Title
Radiotherapy Versus Low-Dose Tamoxifen Following Breast Conserving Surgery for Low-Risk and Estrogen Receptor-Positive Ductal Carcinoma in Situ of Breast: an International Open-label Randomized Non-inferiority Trial
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Recruiting
Study Start Date
April 30, 2019 (Actual)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Taiwan University Hospital
Collaborators
Tri-Service General Hospital, Koo Foundation Sun Yat-Sen Cancer Center, Kaohsiung Medical University, Kyoto University, Mackay Memorial Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Although the results obtained from ECOG E5194 cohort 1 (criteria: mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins ≥ 3 mm) and RTOG 9804 trial (the same enrolled clinicopathological features to cohort 1 of ECOG E5194 trial) demonstrated that the 7-year ipsilateral breast tumor recurrence (IBTR) ranged from 5.6% to 10.5% for low-risk ductal carcinoma in situ (DCIS) patients, the aforementioned two studies included a proportional patients who had young age and negative estrogen receptor (ER) status tumor. Previous studies and our studies revealed that age < 40 years and ER-negative status in tumor were independent prognostic factor for recurrence of breast DCIS irrespective of tumor characteristics. The UK/ANZ randomized trial, enrolling high-risk and low-risk clinicopathologic features of DCIS, demonstrated that a benefit of tamoxifen in terms of reducing the IBTR is observed in the BCS alone group but not found in the BCS plus RT group. A recent published randomized trial showed that tamoxifen at the dose of 5 mg/day for 3 years. Based on the aforementioned results, we hypothesized that the administration of tamoxifen is not inferior than the prescription of RT in terms of reducing the IBTR for DCIS patients who had age more than 40 years, the pathological features meeting the ECOG E5194 cohort 1 criteria, and positive ER status in tumors. To approve the hypothesis, we will design a randomized non-inferiority trial to assess whether the effect of administration of tamoxfien (5 mg per day) for 10 years following BCS is not inferior in terms of reducing IBTR when comparing RT following BCS for patients who had low-risk clinicopathologic features (age more than 40 years and ECOG E5194 cohort 1 criteria) and positive-ER status of breast DCIS.
Detailed Description
[Background] Radiotherapy (RT) following breast conserving surgery (BCS) is commonly used in ductal carcinoma in situ (DCIS) of breast to decrease local recurrence. Previous retrospective studies suggested that a substantial proportional of low-risk DCIS patients who underwent BCS alone will not develop a subsequent invasive breast cancer over time. To further identify a population of patients with low-risk DCIS in whom adjuvant RT could be safely omitted, two prospective trials and one randomized trial have been published the ipsilateral breast tumor recurrence (IBTR) rate in patients with low-risk breast DCIS, including smaller size, larger margin width, and lower grade. The 5-year IBTR rate in Dana Farber/Harvard Cancer Institute (low to intermediate grade disease and a margin width of 10 mm) was 12% for breast DCIS patients who underwent BCS alone. The Eastern Cooperative Oncology Group (ECOG) E5194 reported a 12-year IBTR rate of 14.4% (7-year IBTR rate, 10.5%) for patients with low-risk DCIS (cohort 1 criteria: mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins ≥ 3 mm) who underwent BCS alone. The risk for DCIS and invasive cancer increased steadily over time, without any plateau. Another randomized trial, Radiation Therapy Oncology Group (RTOG) 9804, showed the IBTR rates from that at 5 years (3.5%) to that at 7 years (6.7%) in post-BCS patients with low-risk breast DCIS (similar criteria of ECOG E5194 trial, cohort 1) who did not receive RT. In contrast, the 7-year IBTR rate was low (0.9%) for patients who underwent BCS and received RT in RTOG 9804 trial. Our retrospective study showed that the 7-year IBTR rate was 5.6% in breast DCIS patients who had criteria of cohort 1 of ECOG E5194 trial and underwent BCS alone. Taken together, two prospective clinical trials and our retrospective study disclosed that the 7-year IBTR for BCS alone group (no RT) ranged from 5.6% to 10.5%, even if patients whose clinicopathologic features met the criteria of ECOG E5194 cohort 1. These results suggest that RT following BCS is indicated for these patients who have low-risk breast DCIS. Another randomized trial, UK/ANZ [UK, Australia, and New Zealand] DCIS trial], including high-risk and low-risk breast DCIS patients, demonstrated a significant benefit of tamoxifen (20 mg every day for 5 years) in terms of reducing the ipsilateral (Hazard ratio [HR], 0·77; 95% confidence interval [CI], 0·59-0·98; P = 0·04) and contralateral breast events (HR, 0·27; 95% CI, 0·12-0·59; P = 0·001) in the BCS alone group, and this benefit of tamoxifen was not observed in the BCS plus RT group for ipsilateral events (HR, 0·93; 95%, 0·50-1·75; P = 0·8). These findings suggest that even if patients with low-risk clinicopatholgical features of DCIS (relatively low-risk of IBTR), the addition of tamoxifen in patients who had received RT may not reduce IBTR than those receiving RT alone. However, the estrogen receptor (ER) status among the patients with DCIS enrolled in the aforementioned three prospective randomized trials (ECOG E5194 trial, RT9804 trial, and UK/ANZ trial) was initially unknown. In a retrospective analysis of the relationship between ER status and response to tamoxifen in 732 patients (41%) who comprised the original NSABP B-24 population (76% positive for ER), the significant effect of tamoxifen in reducing ipsilateral and contralateral breast events was demonstrated in ER-positive DCIS but not in ER-negative tumors. Our retrospective study also showed that age < 40 years and negative ER status in tumors were closely associated with the higher IBTR rate. Among our patients with cohort 1 criteria of ECOG E519 study, the 7-year IBTR rate for ER-positive group and ER-negative group was 5.0% and 8.0%, respectively. [Rationale] Although the results obtained from ECOG E5194 (cohort 1) and RTOG 9804 trial (the same enrolled clinicopathological features to cohort 1 of ECOG E5194 trial) demonstrated that the 7-year IBTR ranged from 5.6% to 10.5% for low-risk DCIS patients, the aforementioned two studies included a proportional patients who had young age and negative ER status tumor. Previous studies and our studies revealed that age < 40 years and ER-negative status in tumor were independent prognostic factor for recurrence of breast DCIS irrespective of tumor characteristics. The UK/ANZ randomized trial, enrolling high-risk and low-risk clinicopathologic features of DCIS, demonstrated that a benefit of tamoxifen in terms of reducing the IBTR is observed in the BCS alone group but not found in the BCS plus RT group. In a recent published data of a randomized trial of comparing low-dose tamoxifen (5 mg QD) for 3 years with placebo in prevention of recurrence of women with hormone-positive DCIS or lobular carcinoma in situ, low-dose tamoxifen was demonstrated to significantly decrease local recurrence when compared with placebo arm. These findings indicate that tamoxifen at the dose of 5 mg/day can decrease the incidence of recurrence in women with operated hormone sensitive DCIS with a limited toxicity. However, the effect of the administration of low-dose tamoxifen is similar to the RT effect in terms of reducing IBTR for patients who had the criteria of ECOG E5194 cohort 1 and positive ER status remains unclear. [Hypotheses] Based on the aforementioned results, we hypothesized that the administration of tamoxifen is not inferior than the prescription of RT in terms of reducing the IBTR for DCIS patients who had age more than 40 years, the pathological features meeting the ECOG E5194 cohort 1 criteria, and positive ER status in tumors. To approve the hypothesis, we will design a randomized non-inferiority trial to assess whether the effect of administration of tamoxfien (5 mg per day) for 10 years following BCS is not inferior in terms of reducing IBTR when comparing RT following BCS for patients who had low-risk clinicopathologic features and positive-ER status of breast DCIS. [Study Design] We will design a randomized non-inferiority trial to assess whether the effect of administration of tamoxfien (5 mg) for 10 years following BCS is not inferior in terms of reducing IBTR when comparing RT (in terms of 50 Gy in 25 fractions or 40.05 Gy in 15 fractions) following BCS for patients who had age more than and equal 40 years, low-risk clinicopathological features (ECOG E5194 cohort 1 criteria), and positive-ER status of breast DCIS.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Ductal Carcinoma in Situ

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Non-inferiority trial
Masking
None (Open Label)
Allocation
Randomized
Enrollment
810 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Radiotherapy arm
Arm Type
Active Comparator
Arm Description
Radiotherapy for ipsilateral whole breast with 50 Gy/25 fractions or 40.05 Gy/15 fractions
Arm Title
Tamoxifen arm
Arm Type
Experimental
Arm Description
Tamoxifen 5 mg QD for 10 years
Intervention Type
Drug
Intervention Name(s)
Low-dose tamoxifen
Other Intervention Name(s)
LDT
Intervention Description
Low-dose tamoxifen is not inferior than radiotherapy in decreasing ipsilateral breast tumor recurrence and side effect
Intervention Type
Radiation
Intervention Name(s)
Whole breast radiotherapy
Other Intervention Name(s)
WBRT
Intervention Description
Ipsilateral breast tumor recurrence and side effect
Primary Outcome Measure Information:
Title
Breast tumor recurrence
Description
Ispilateral, regional recurrence, contralateral recurrence, and distant recurrence [DCIS or invasive cancer event]
Time Frame
through study completion, an average of 1 year
Secondary Outcome Measure Information:
Title
The overall survival
Description
Overall survival
Time Frame
through study completion, an average of 1 year
Title
Adverse effects
Description
Adverse effects of radiotherapy and tamoxifen
Time Frame
through study completion, an average of 1 year

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Women New histologically diagnosed breast ductal carcinoma in situ (DCIS). Age ≥ 40 years Low risks of BRCA (breast cancer)1 and BRCA2: Manchester Score < 10 The DCIS must be detected by mammogram and must be unicentric, and no-mass lesion. Status post breast conserving surgery Pathological characteristics (all characteristics) 7.1 Lesions ≤ 2.5 cm in greatest dimension on pathologic specimen (use the largest measured size from the pathology report to obtain the required measurement of ≤ 2.5 cm). 7.2 Must be classified as low or intermediate nuclear grade DCIS but without comedo necrosis according to Pathologic Guidelines (section 9.2.2) 7.3 Margins as assessed by the ink method will be 3 mm or greater. 7.4 Must be estrogen receptor (ER)-positive DCIS, ER percentage must be ≥10% Clinically node negative. Exclusion Criteria: Known BRCA1 or BRCA2 mutation Age < 40 years Women whose DCIS is palpable at the time of diagnosis, or multi-centric (mammography), or mass (mammography), or who have bloody nipple discharge. Pathological characteristics 4.1 Lesions measuring greater than 2.5 cm in greatest dimension on pathologic specimen. 4.2.High-grade lesions or low to intermediate grade with comedo necrosis as classified by the Guidelines. 4.3. Margins as assessed by the ink method will be less than 3 mm. 4.4. ER-negative DCIS or ER-positive percentage < 10% in tumor cells Post-mastectomy patients Prior diagnosis of neoplasm within 5 years, except cervical intraepithelial neoplasia type 1 (CIN1) or localized non-melanomatous skin cancer. Evidence of clinically significant cardiac disease, as defined by cardiac disease (New York Cardiac disease grade II), history of myocardial infarction, cerebral stroke, unstable arrhythmia, and unstable angina pectoris within 12 months before study entry. Pregnant or lactating status.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chiun-Sheng Huang, MD, PhD, MPH
Phone
+(886)-2-87339036
Email
huangcs@ntu.edu.tw
First Name & Middle Initial & Last Name or Official Title & Degree
Sung-Hsin Kuo, M.D.,Ph.D
Phone
+886-223123456
Ext
67144
Email
shkuo101@ntu.edu.tw
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chiun-Sheng Huang, MD, PhD, MPH
Organizational Affiliation
Department of Surgery, National Taiwan University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Taiwan University Hospital
City
Taipei
ZIP/Postal Code
100
Country
Taiwan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sung-Hsin Kuo, M.D.,Ph.D.
Phone
+(886)-223123456
Ext
67144
Email
shkuo101@ntu.edu.tw
First Name & Middle Initial & Last Name & Degree
Chiun-Sheng Huang, MD, PhD, MPH

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Share participant data
IPD Sharing Time Frame
5 years after completion of study
IPD Sharing Access Criteria
Will be available after contacting with Principle investigators

Learn more about this trial

Radiotherapy Versus Low-Dose Tamoxifen Following Breast Conserving Surgery for Low-Risk Breast Ductal Carcinoma in Situ

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