Clinical Trials /

ExclUsive endocRine Therapy Or Partial Breast Irradiation for Women Aged ≥70 Years With Luminal-A Early Stage Breast Cancer (EUROPA)

NCT04134598

Description:

Rationale and relevance for patients and the scientific community. In low risk early stage patients ≥70 years, exclusive Partial Breast Irradiation (PBI) as radiation therapy (RT) approach might be superior in terms of Health-Related Quality of Life (HRQoL), when compared to exclusive endocrine therapy (ET) following breast-conserving surgery (BCS). Assuming an equal rate of disease control, unnecessary long-term toxicity of ET may be avoided. Current standard therapy. BCS plus ± RT ± ET (depending on the molecular characterization of tumors in terms of hormonal expression status and national guidelines).

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: ExclUsive endocRine Therapy Or Partial Breast Irradiation for Women Aged ≥70 Years With Luminal-A Early Stage Breast Cancer (EUROPA)
  • Official Title: ExclUsive endocRine Therapy Or Partial Breast Irradiation for Women Aged ≥70 Years With Luminal-A Early Stage Breast Cancer (EUROPA): A Randomized Phase II-III Randomized Controlled Trial Comparing Health Related Quality of Life by Patient Reported Outcome Measures

Clinical Trial IDs

  • ORG STUDY ID: EUROPA
  • NCT ID: NCT04134598

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
Endocrine Therapy (ET): letrozole, anastrozole, exemestane, tamoxifenHormonal therapyEndocrine Therapy (ET)

Purpose

Rationale and relevance for patients and the scientific community. In low risk early stage patients ≥70 years, exclusive Partial Breast Irradiation (PBI) as radiation therapy (RT) approach might be superior in terms of Health-Related Quality of Life (HRQoL), when compared to exclusive endocrine therapy (ET) following breast-conserving surgery (BCS). Assuming an equal rate of disease control, unnecessary long-term toxicity of ET may be avoided. Current standard therapy. BCS plus ± RT ± ET (depending on the molecular characterization of tumors in terms of hormonal expression status and national guidelines).

Detailed Description

      Study Background. BCS has been established as the preferred treatment option for early stage
      breast cancer (BC) or for initially inoperable tumors that respond sufficiently to
      preoperative therapy. BCS plus RT obtains at least the same results in terms of survival,
      without the huge impact on the patient's body image and HRQoL as that seen after mastectomy.
      For decades, standard whole breast irradiation (WBI) consisted of 45-50 Gy delivered at
      1.8-2.0 Gy/fraction over 4.5-5 weeks with or without a boost dose to the surgical bed. Large
      phase 3 trials evaluating different hypofractionation schedules proved that overall treatment
      time could be reduced without compromising local control and safety profile.

      PBI has been introduced as an alternative treatment method for selected patients with early
      stage BC. Potential advantages of accelerated PBI include shorter treatment time, equivalent
      disease control, improved safety profile, and cost reduction as compared to standard WBI. The
      role of PBI has been investigated in large-scale prospective phase 3 clinical trials (i.e.,
      NSABP-B29/RTOG 0413, IRMA, RAPID, IMPORT-LOW, GEC-ESTRO trials).

      5-year results of the IMPORT-LOW trial showed non-inferiority of PBI when compared to WBI in
      women with low risk early BC, with a 5-year local recurrence (LR) rate of 0.5%. Ongoing
      research explores other modalities of RT that will minimize toxicities without reducing
      effectiveness. Intensity-modulated radiotherapy (IMRT) has the theoretical advantage of a
      further increase in dose conformity compared with three-dimensional techniques, with
      increased normal tissue sparing. To date, only the Florence IMRT-APBI phase 3 trial reported
      the outcomes of exclusive IMRT accelerated PBI compared to WBI, demonstrating no significant
      difference between the two groups in terms of ipsilateral breast tumor recurrences (IBTR).
      The PBI group presented significantly better results considering acute (p=0.0001), late
      (p=0.004), and cosmetic outcome (p=0.045). The subgroup analysis evaluating patients aged 70
      years or older, showed a 5-year IBTR rate of 1.9% for both groups, and significantly better
      results in terms of acute skin toxicity, in favor of the PBI arm. Therefore, a significant
      impact on patients' compliance to RT could translate into a consistent improvement of overall
      HRQoL.

      Heart exposure to ionizing radiation during RT for BC increases subsequent rates of ischemic
      heart disease (IHD). The increase is proportional to the mean dose to the heart. Women with
      pre-existing cardiac risk factors have greater absolute increases in risk from RT. An age >70
      years seems to be one of the most significant factor for IHD occurrence. PBI represents one
      of several effective strategies to reduce cardiac radiation dose when compared to WBI.

      Postoperative RT in the elderly is a matter of constant debate. RT was shown to benefit these
      patients with regards to local control; however, the absolute benefit is small (for low risk
      subtypes). Moreover, considering the poor compliance of elderly patients to conventional RT
      treatment time (3-6 weeks), conventional RT is often omitted in cases of low-risk BC, at the
      expense of reducing the local control rate by less than 4%.

      In an unplanned subgroup analysis of the PRIME-II trial by estrogen receptor (ER) score, LR
      at 5 years for women in the rich ER subgroup was lower than in the whole population; for
      patients assigned no RT, 3% had a LR compared with 1% of women allocated WBI (5-year IBTR was
      3.3%, and 1.2%, respectively).

      The British Association of Surgical Oncology (BASO)-II trial confirmed that patients treated
      with either exclusive adjuvant RT or ET with tamoxifen had an equivalent LR rate per year of
      0.8%. These data suggested that RT or ET alone resulted in excellent disease control in older
      women with early BC, and that the combination of treatments may have less benefit than
      expected. A direct comparison between PBI or ET omission as adjuvant treatment is lacking in
      the existing literature.

      Conversely, the toxicity profile of ET is well known, and could significantly impact long
      term HRQoL of these potentially frail patients. Elderly patients with early BC are a unique
      population with regards to good prognosis and potential comorbidities, thus minimizing
      treatment to maintain HRQoL without compromising survival is extremely important. In the
      decision-making process for adjuvant therapy, estimates of the patient's risk of benefit
      and/or harm with treatment should be performed together with an assessment of baseline
      comorbidities, life expectancy and care preferences. Many large phase III studies reported on
      the detrimental effects of postmenopausal ET on bone density and fractures incidence,
      thromboembolic complications, sexual, and cognitive functionality. Moreover, patient's
      compliance and oral treatment adherence may be a concern, and some patients would like to
      avoid the toxicities associated with ET.

      Considering that the potential benefit of PBI alone could be better than that of the RT-only
      effect reported in the above WBI-using trials, it may be possible to avoid the long term
      toxicity of ET and favorably impact HRQoL in selected patients, such as elderly patients with
      a good prognosis.

      Importantly, all previously published de-escalation studies were designed and performed in
      order to evaluate RT omission, regardless of efficacy and compliance of ET. When expecting a
      comparable efficacy among tested treatment modalities, HRQoL might be the factor with the
      most influence on the treatment decision-making process and should therefore be the primary
      endpoint.
    

Trial Arms

NameTypeDescriptionInterventions
Partial Breast Irradiation (PBI)ExperimentalPartial Breast Irradiation (PBI)
    Endocrine Therapy (ET)Active ComparatorEndocrine Therapy (ET)
    • Endocrine Therapy (ET): letrozole, anastrozole, exemestane, tamoxifen

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Women aged ≥70 years;
    
              -  histologically proven invasive adenocarcinoma of the breast;
    
              -  pathological T1 (pT1) stage (clinical T1-2 [cT1-2] stage is allowed);
    
              -  clinical and pathological N0 (cN0 and pN0) stage (isolated tumor cells [i+] allowed);
    
              -  any tumor grade (if pT ≤10 mm), G1-2 tumor grade (if pT between 11 and 19 mm);
    
              -  Luminal-A by immunohistochemistry (IHC)-based on local assessment (consistent with
                 14th St. Gallen consensus definition):
    
                   -  ER+ (defined as ≥50% by IHC staining),
    
                   -  PgR+ (in any case PgR should be at least >20% by IHC staining),
    
                   -  Human epidermal growth factor receptor 2 (HER2)- (0 or 1+ following IHC staining
                      and proven negative by in-situ hybridization [ISH] in case of 2+), and
    
                   -  Ki67 ≤20% by IHC staining;
    
              -  surgically treated with BCS with or without sentinel node biopsy (SNB);
    
              -  no clinical evidence of distant metastases. Imaging work up is not mandatory to enter
                 the trial. If there are signs/symptoms suggesting the presence of local relapse or
                 distant metastasis, an appropriate work up should be performed according to the
                 treating physician standard practice. A patient with confirmed local relapse or
                 distant metastasis will no longer be eligible for the trial;
    
              -  postoperative final surgical margins ≥2 mm;
    
              -  baseline HRQoL questionnaires completion;
    
              -  adjuvant bisphosphonates and denosumab are allowed;
    
              -  before patient registration/randomization, written informed consent must be given.
    
            Exclusion Criteria:
    
              -  Preoperative systemic treatments (i. e., chemotherapy, endocrine therapy);
    
              -  current treatment with any hormonal agents such as tamoxifen, raloxifene or other
                 selective estrogen receptor modulators (SERMs), either for osteoporosis or BC
                 prevention (patients are eligible if these medications are discontinued prior to
                 randomization);
    
              -  prior breast or thoracic RT;
    
              -  known disorders associated with a higher risk for complications following RT such as
                 collagen vascular disease, dermatomyositis, systemic lupus erythematosis or
                 scleroderma;
    
              -  prior diagnosis, detection, or treatment of any other invasive cancer (except basal or
                 squamous cell carcinoma of the skin that has been definitely treated);
    
              -  any psychological, familial, sociological or geographical condition potentially
                 hampering compliance with the study protocol and follow-up schedule; these conditions
                 should be discussed with the patient before registration;
    
              -  patients must not be considered a poor medical risk due to serious, uncontrolled
                 medical disorder, non-malignant systemic disease, or active uncontrolled infection.
                 Examples include but are not limited to uncontrolled ventricular arrhythmia, recent
                 (within 3 months) myocardial infarction or uncontrolled major seizure disorder.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:70 Months
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Patient reported outcome measures (PROM) HRQoL as assessed by EORTC Quality of Life Questionnaire (QLQ) C30
    Time Frame:Change from baseline at 24 months
    Safety Issue:
    Description:EORTC Quality of Life Questionnaire (QLQ) C30.The QLQ-C30 is a cancer HRQoL questionnaire using PROMs for individual patient management. It includes five function domains (physical, emotional, social, role, cognitive), eight symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond on a four-point scale from "not at all" to "very much" for most items. Raw scores are linearly converted to a 0-100 scale with higher scores reflecting higher levels of function and higher levels of symptom burden.

    Secondary Outcome Measures

    Measure:Patient reported outcome measures (PROM) HRQoL as assessed by EORTC Quality of Life Questionnaire (QLQ) BR23 module
    Time Frame:Change from baseline at 24 months
    Safety Issue:
    Description:EORTC QLQ BR23 module. The EORTC QLQ BR23 is a breast-specific module that comprises of 23 questions to assess body image, sexual functioning, sexual enjoyment, future perspective, systemic therapy side effects, breast symptoms, arm symptoms and upset by hair loss. All scores are linearly transformed to a 0 to 100 scale. A high or healthy level of functioning is represented by a high functional score. A high QoL is represented by a high score for global health status or QoL. More severe symptoms or problems are represented by high symptom scores or items.
    Measure:Patient reported outcome measures (PROM) HRQoL as assessed by EORTC Quality of Life Questionnaire (QLQ) ELD14
    Time Frame:Change from baseline at 24 months
    Safety Issue:
    Description:EORTC QLQ ELD14 questionnaire. The QLQ ELD14 is a validated HRQoL questionnaire for cancer patients aged ⩾70 years.
    Measure:Time to ipsilateral breast tumor recurrence (IBTR)
    Time Frame:24 months
    Safety Issue:
    Description:Time to ipsilateral breast tumor recurrence (IBTR)
    Measure:Time to locoregional recurrence (LRR)
    Time Frame:24 months
    Safety Issue:
    Description:Time to locoregional recurrence (LRR)
    Measure:Time to contralateral breast cancer (CBC)
    Time Frame:24 months
    Safety Issue:
    Description:Time to contralateral breast cancer (CBC)
    Measure:Time to distant metastases (DM)
    Time Frame:24 months
    Safety Issue:
    Description:Time to distant metastases (DM)
    Measure:Breast cancer specific survival (BCSS)
    Time Frame:24 months
    Safety Issue:
    Description:Breast cancer specific survival (BCSS)
    Measure:Overall survival (OS)
    Time Frame:24 months
    Safety Issue:
    Description:Overall survival (OS)
    Measure:Adverse events
    Time Frame:24 months
    Safety Issue:
    Description:Adverse events
    Measure:Cosmesis evaluation
    Time Frame:24 months
    Safety Issue:
    Description:Harvard Breast Cosmesis Scale. A 4-point breast cosmesis grading scale.

    Details

    Phase:Phase 2/Phase 3
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Azienda Ospedaliero-Universitaria Careggi

    Trial Keywords

    • Partial Breast Irradiation
    • Radiation Therapy
    • Endocrine Therapy
    • Breast Conserving Surgery
    • Elderly
    • Health Related Quality of Life
    • Patients Reported Outcome Measures
    • Breast Cancer

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