JCOG2110: a randomized trial for OLIGo metastases breast cAncer with or without Metastasis-dIrected therapy

JRCT ID: jRCTs031230439

Registered date:08/11/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Advanced breast cancer with 3 or fewer oligo metastases
• Date of first enrollment: 08/11/2023
• Target sample size: 340
• Study type: Interventional

Intervention(s)

Systemic drug therapy
1) Luminal breast cancer
<Denovo stage IV>
Premenopausal: Aromatase inhibitor + CDK4/6 inhibitor +LHRH agonist, or Fulvestrant + CDK4/6 inhibitor +LHRH agonist.
Postmenopausal: Aromatase inhibitor + CDK4/6 inhibitor.
<Recurrence after completion of postoperative endocrine therapy>
Premenopausal: Aromatase inhibitor + CDK4/6 inhibitor +LHRH agonist, or Fulvestrant + CDK4/6 inhibitor +LHRH agonist.
Postmenopausal: Aromatase inhibitor + CDK4/6 inhibitor, or Fulvestrant + CDK4/6 inhibitor
<Recurrence during postoperative endocrine therapy>
Premenopausal: Fulvestrant + CDK4/6 inhibitor +LHRH agonist, or Aromatase inhibitor + CDK4/6 inhibitor +LHRH agonist.
Postmenopausal: Fulvestrant + CDK4/6 inhibitor.

2) HER2-positive breast cancer
Pertuzumab + Trastuzumab + Taxane (docetaxel or paclitaxel).

3) Triple negative breast cancer
<PD-L1 negative>following a) or b)
a) Taxane (naive for taxane)
b) S-1 or Capecitabine or Eriblin (previously treated with taxane)
<PD-L1 positive>following a) or b)
a) Pembrolizumab + Gemcitabine + Carboplatin
b) Atezolizumab + Nab-paclitaxel
<BRCA-mutation positive>
Olaparib

Arm A
Continuation of systemic drug therapy.
Arm B
Metastasis-directed therapy (radiation or surgery for oligometastasis)
+ systemic drug therapy.

<Radiation>
Brain metastases: 18-24 Gy/1 fr. or 27 Gy/3 fr. or 30 Gy/5 fr.
Lung metastasis: peripheral 42 Gy/4 fr., central 50 Gy/8 fr., ultra central 45 Gy/10 fr. or 60 Gy/25 fr.
Liver/adrenal metastasis: 40 Gy/5 fr.
Bone metastasis: 35 Gy/5 fr.
Distant lymph nodes metastasis: 45 Gy/10 fr. or 60 Gy/25 fr.
Other distant metastases: 35 Gy/5 fr.
Regional lymph nodes: 60 Gy/25 fr.

<Surgery>
Lung metastases: wedge resection or segmentectomy
Liver metastases: partial resection or segmentectomy
Other lymph node/visceral metastases: partial resection or lumpectomy
Breast: mastectomy or breast-conserving surgery, axillary dissection in case of axillary lymph node metastasis

Outcome(s)

• Primary Outcome: Overall survival after second registration
• Secondary Outcome: Overall survival after primary registration, Progression-free survival, Progression site (oligometastasis, lesion other than oligometastasis), Oligometastatic progression-free survival for each definitive local therapy (group B only), Adverse event rate, Serious adverse event rate, HR-QOL non-worsening rate.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: <= 80age old
• Gender: Both

Include criteria

Primary Registration Eligibility Criteria
(1) Histologically diagnosed as invasive breast cancer. Biopsy from oligometastasis is desirable but not required.
(2) Histologically proven positive/negative for ER, PgR, and HER2, and classified as luminal, HER2-positive, or TN breast cancer.
(3) One of the following <1> to <4>;
<1>In case of no history of breast cancer in the past, either (i) or (ii) below.
(i) Unilateral noninvasive breast cancer at registration, diagnosed as invasive breast cancer by biopsy from oligometastasis
(ii) Unilateral invasive breast cancer at registration
<2>In case of having a history of mastectomy or breast-conserving
surgery for unilateral noninvasive breast cancer, either (i) or (ii) below.
(i) Absence of breast/chest wall tumor at registration and diagnosed as invasive breast cancer by biopsy from oligometastasis
(ii) Unilateral invasive breast cancer at registration (whether ipsilateral or contralateral to previous breast cancer)
<3>In case of having a history of mastectomy or breast-conserving
surgery for unilateral invasive breast cancer, either (i) or (ii) below.
(i) Absence of breast/chest wall tumor at registration
(ii) Ipsilateral invasive/noninvasive breast cancerto previous breast cancer at registration and diagnosed as recurrence
<4>In case of having a history of mastectomy or breast-conserving
surgery for unilateral noninvasive breast cancer and contralateral invasive breast cancer, no breast/chest wall tumor at registration.
(4) Diagnosed with advanced breast cancer with oligometastasis by neck to pelvis enhanced CT, FDG-PET (PET/CT), and brain enhanced MRI.
(5) oligometastasis defined as:
(i) Maximum diameter of each tumor is 3 cm or less
(ii) Total number of 3 or less.
(iii) In case of brain metastasis, maximum diameter is 2 cm or less and asymptomatic.
(6) No distant metastasis other than oligometastasis.
(7) Metastasis-deirected therapy (radiation or surgery) is considered feasible for all oligometastases.
(8) In case of bone metastasis, none of the following:
(i) Metastasis of three consecutive vertebral bodies
(ii) Spinal metastasis entending into the spinal canal (Bilsky grade is 1b or higher)
(iii) Long bone metastasis extending to the femoral head, neck, and trochanter
(iv) Long bone metastasis with more than 1/3 of bone cortical defects
(v) Severe pain uncontrolled with drugs.
(9) Aged 18-80 years.
(10) ECOG performance status of 0 or 1.
(11) A measurable lesion is not required.
(12) No history of surgery, drug therapy, or radiotherapy for distant metastasis. Bisphosphanate preparations and RANKL inhibitors before registration, and surgery for the purpose of diagnosing metastasis are permitted.
(13) No radical surgery of the primary tumor or regional lymph nodes between diagnosis of oligometastasis to registration.
(14) In the case of recurrent breast cancer, disease-free interval of 12 months or more from surgery, perioperative chemotherapy, or molecular targeted therapy for initial treatment of breast cancer.
(15) No prior treatment of endocrine therapy, chemotherapy, molecular targeted therapy, and immunotherapy against any other malignancies within 5 years.
(16) Adequate organ function within 14 days prior to the first registration.
(i) ANC >= 1500 cells/mm3
(ii) Hemoglobin >= 9.0 g/dL
(iii) Platelet count >= 100,000/ mm3
(iv) Serum bilirubin <= 1.5 mg/dL
(v) AST <= 100 U/L
(vi) ALT <= 100 U/L
(vii) Creatinine <= 1.5 mg/dL (<= 2.3 mg/dL for luminal breast cancer)
(17) Ejection fraction of cardiac function is defined over 50%.
(18) Written informed consent.

Secondary Registration Eligibility Criteria
(1) Primary registration in this study, and the planned number of courses of systemic drug therapy by subtype has been performed.
(2) No progression or new distant metastasis by response evaluation.
(3) Secondary registration is within 28 days from response evaluation.
(4) Within 84-126 days from the primary registration.
(5) At least one oligometastasis remains on imaging and considered feasible to definitive local therapy.
(6) No metastasis-direceted therapy for breast cancer after primary registration.
(7) ECOG performance status of 0 or 1.
(8) Adequate organ function within 14 days prior to the second registration.
(i) ANC >= 1500 cells/mm3
(ii) Hemoglobin >= 9.0 g/dL
(iii) Platelet count >= 100,000/ mm3
(iv) Serum bilirubin <= 1.5 mg/dL
(v) AST <= 100 U/L
(vi) ALT <= 100 U/L
(vii) Creatinine <= 1.5 mg/dL (<= 2.3 mg/dL for luminal breast cancer)

Exclude criteria

(1) Active malignancies curatively treated with no evidence of disease for >= 5 years prior to randomization.
(2) Infection with care.
(3) Fever up 38 degrees Celcius.
(4) Childbearing potential, delivery after 28 days, breastfeeding
(5) Mental disorders.
(6) Continuously take steroids or immunosuppressive drugs.
(7) Unstable angina or history of cardiac infarction within 6months.
(8) Uncontrolled Hypertension.
(9) Uncontrolled Diabetes mellitus.
(10) Congestive heart failure deserved class II of New York Heart Association (NYHA), uncontrolled Dilated or Hypertrophic cardiomyopathy.
(11) Severe arrhythmia need to cure (except Atrial fibrillation, Paroxysmal supraventricular tachycardia)
(12) Interstitial pneumonia, pulmonary fibrosis, severe emphysema diagnosed chest CT scan.
(13) HBs Ag+

Related Information

• Primary Sponsor: Shien Tadahiko
• Source(s) of Monetary Support: National Cancer Center Japan