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Trial record 19 of 53 for:    "Breast Carcinoma in Situ" | "Hormones"

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

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ClinicalTrials.gov Identifier: NCT04046159
Recruitment Status : Recruiting
First Posted : August 6, 2019
Last Update Posted : August 6, 2019
Sponsor:
Collaborators:
Tri-Service General Hospital
Koo Foundation Sun Yat-Sen Cancer Center
Kaohsiung Medical University
Kyoto University
Mackay Memorial Hospital
Information provided by (Responsible Party):
National Taiwan University Hospital

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.


Condition or disease Intervention/treatment Phase
Breast Ductal Carcinoma in Situ Drug: Low-dose tamoxifen Radiation: Whole breast radiotherapy Phase 3

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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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 810 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Non-inferiority trial
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 30, 2019
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: Radiotherapy arm
Radiotherapy for ipsilateral whole breast with 50 Gy/25 fractions or 40.05 Gy/15 fractions
Radiation: Whole breast radiotherapy
Ipsilateral breast tumor recurrence and side effect
Other Name: WBRT

Experimental: Tamoxifen arm
Tamoxifen 5 mg QD for 10 years
Drug: Low-dose tamoxifen
Low-dose tamoxifen is not inferior than radiotherapy in decreasing ipsilateral breast tumor recurrence and side effect
Other Name: LDT




Primary Outcome Measures :
  1. Breast tumor recurrence [ Time Frame: through study completion, an average of 1 year ]
    Ispilateral, regional recurrence, contralateral recurrence, and distant recurrence [DCIS or invasive cancer event]


Secondary Outcome Measures :
  1. The overall survival [ Time Frame: through study completion, an average of 1 year ]
    Overall survival

  2. Adverse effects [ Time Frame: through study completion, an average of 1 year ]
    Adverse effects of radiotherapy and tamoxifen



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04046159


Contacts
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Contact: Chiun-Sheng Huang, MD, PhD, MPH +(886)-2-87339036 huangcs@ntu.edu.tw
Contact: Sung-Hsin Kuo, M.D.,Ph.D +886-223123456 ext 67144 shkuo101@ntu.edu.tw

Locations
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Taiwan
National Taiwan University Hospital Recruiting
Taipei, Taiwan, 100
Contact: Sung-Hsin Kuo, M.D.,Ph.D.    +(886)-223123456 ext 67144    shkuo101@ntu.edu.tw   
Principal Investigator: Chiun-Sheng Huang, MD, PhD, MPH         
Sponsors and Collaborators
National Taiwan University Hospital
Tri-Service General Hospital
Koo Foundation Sun Yat-Sen Cancer Center
Kaohsiung Medical University
Kyoto University
Mackay Memorial Hospital
Investigators
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Principal Investigator: Chiun-Sheng Huang, MD, PhD, MPH Department of Surgery, National Taiwan University Hospital

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Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT04046159     History of Changes
Other Study ID Numbers: 201902048MINC
First Posted: August 6, 2019    Key Record Dates
Last Update Posted: August 6, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Share participant data
Supporting Materials: Study Protocol
Clinical Study Report (CSR)
Time Frame: 5 years after completion of study
Access Criteria: Will be available after contacting with Principle investigators

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Carcinoma In Situ
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Carcinoma
Carcinoma in Situ
Carcinoma, Ductal
Carcinoma, Intraductal, Noninfiltrating
Carcinoma, Ductal, Breast
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Neoplasms, Ductal, Lobular, and Medullary
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Tamoxifen
Estrogen Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents