Trial name or title

Primary Operation in SYnchronous meTastasized InVasivE Breast Cancer (POSYTIVE)

Methods

• Randomised clinical trial

• Austrian Breast & Colorectal Cancer Study Group

• 254 patients

• May 2010 to May 2019

Participants

Inclusion criteria:

• Patients aged ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2

• Untreated synchronous metastasised invasive carcinoma of the breast with the primary tumour in situ (bilateral synchronous metastasised breast cancer patients are eligible)

• The primary tumour must be identified and may be any size; however, primary resection with resection‐free margins must be possible.

• Invasive adenocarcinoma of the breast on histological examination

• The metastatic site must be identified by radiological assessment (CT of the chest and the abdomen OR ultrasound and chest X‐ray for visceral metastases; bone scan and/or CT and/or MRI for bone metastases). A biopsy is not necessary.

• Written informed consent must be obtained and documented prior to beginning any protocol‐specific procedures and according to local regulatory requirements.

• Able to comply with the protocol requirements during the treatment and follow‐up period

Exclusion criteria:

• Patients in whom an R0 resection (microscopic free margins) is clinically questionable

• Inflammatory cancer

• Patients with a brain metastasis

• Patients who are not eligible for general anaesthesia and operations

• Patients without metastatic breast cancer (patients with a tumour marker value (CEA, CA15‐3) above normal levels without radiological‐proven evidence of metastases are not eligible for the study).

• Patients with a second untreated malignancy

• Any previous malignancy treated with curative intent, and the patient has not been disease‐free for 5 years; exceptions are:

  • carcinoma in situ of the cervix;

  • squamous carcinoma of the skin;

  • basal cell carcinoma of the skin.

• Patients with any recurrent cancer disease

• Pregnant or lactating women

• Patients are not allowed to be part of another local therapy trial.

Interventions

Local therapy consists of lumpectomy or mastectomy with or without radiotherapy (according to centre tumour board decision) with a resection‐free margin of at least 1 mm or more demonstrated on paraffin embedded histological sections. Intraoperative frozen sections are allowed but not definitive for margin assessment. Sentinel node biopsy may be performed and must always be followed by axillary dissection of level I and II (axillary surgery level I and II is mandatory).

Outcomes

Primary outcome measure:

• to evaluate the median survival of patients with synchronous metastasised breast cancer and the primary tumour in place comparing arm A with local therapy to the primary tumour versus arm B without local therapy [ Time Frame: time point at which 50% of all randomised participants died ] [ Designated as safety issue: No ]

Secondary outcome measures:

• time to distant progression [ Time Frame: time to treatment change due to systemic progression ] [ Designated as safety issue: No ]

• time to local progression [ Time Frame: increase in size > 25% of the primary tumour in arm B (no local therapy). Local recurrence in arm A (local therapy). ] [ Designated as safety issue: No ]

Starting date

May 2010

Contact information

[email protected], [email protected]

Notes

Trial name or title

Early surgery or standard palliative therapy in treating patients with stage IV breast cancer

Methods

• Randomised clinical trial

• Eastern Cooperative Oncology Group ‐ USA

• 880 patients

• February 2011 to June 2025

Participants

Disease characteristics:

• Diagnosis of intact primary (not recurrent) invasive carcinoma of the breast stage IV disease. Confirmation of the primary tumour should be by needle biopsy (preferred). Incisional surgical biopsy allowed as long as there is residual palpable or tumour image in the breast.

• Must be judged to be candidate for complete resection with free margins followed by radiation therapy (if radiation therapy is indicated)

• For women not undergoing axillary dissection, sentinel node biopsy should document an axillary nodal burden of 1 to 2 involved lymph nodes (i.e. ACOSOG Z‐11 criteria may be applied).

• Prior non‐invasive (DCIS) cancer allowed provided there has been no recurrence.

• Prior ipsilateral invasive cancer allowed if more than 5 years previous.

• No synchronous contralateral breast cancer

• Patients should have at least 1 organ system involved with distant metastatic disease. If patient has only 1 metastatic lesion/focus, this must be proven by biopsy, and the pathology report confirming the diagnosis of primary breast cancer, as well as the metastatic site, must be available.

• Must have available radiologic reports documenting disease status within the past 6 weeks prior to initiating systemic therapy

• Central nervous system metastases allowed provided projected survival > 6 months.

• Patients must have completed at least 16 weeks of optimal systemic therapy (appropriate to the tumour biological profile and the patient's age and menopausal status). If systemic therapy is discontinued for toxicity, but there is no distant progression and at least 12 weeks of therapy have been delivered, then the patient remains eligible. Radiation therapy (if indicated) must begin within 12 weeks of final therapeutic surgical procedure (including re‐excision for free margins and completion of axillary dissection).

• Patients may register at any time from the time of diagnosis of stage IV breast cancer (if eligibility criteria met) to the time when a maximum of 30 weeks of induction systemic therapy has been completed. Patients must be randomised within 16 to 32 weeks after the start of systemic therapy.

• Patients must not have experienced disease progression since the start of systemic therapy, as evidenced by radiographic documentation of disease status before treatment and within 4 weeks +/‐ 2 weeks prior to randomisation, including: no new sites of disease; no enlargement of existing sites by 20% or more in longest diameter; no symptomatic deterioration.

• Patients who require radiotherapy to bone metastases during induction systemic therapy are eligible. Local disease at the primary site must be asymptomatic. Hormone receptor status known.

Patient characteristics:

• Menopausal status not specified.

• Patients must have adequate organ function to undergo local therapy 4 weeks +/‐ 2 weeks prior to randomisation per investigator discretion and institutional guidelines.

• More than 5 years since other primary cancers that were curatively treated

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use an accepted and effective contraception method.

Interventions

Patients undergo surgery comprising BCT or total mastectomy according to patient and treating physician preference. Surgery is to occur no later than 10 weeks after completion of 32 weeks of systemic therapy. Free surgical margins must be achieved with re‐excision or mastectomy for patients undergoing BCT. After completion of BCT, patients undergo radiotherapy once a day, 5 days per week. Patients who had mastectomy undergo radiotherapy at the discretion of treating physician.

Outcomes

Primary outcome:

1. overall survival

Secondary outcomes:

1. health‐related quality of life

2. uncontrolled chest wall disease

3. circulating tumour cells

Starting date

February 2011

Contact information

Seema Khan ‐ [email protected]

Notes

NCT01242800

Trial name or title

The effect of primary surgery in patients with stage IV breast cancer with bone metastasis only

Methods

• Randomised clinical trial

• Federation of Breast Diseases Societies ‐ Turkey

• 288 women

• April 2014 to April 2017

Participants

Inclusion criteria:

• Female between 18 and 80 years of age

• Primary breast tumour amenable for complete surgical resection

• Women in good physical condition for receiving protocol‐driven locoregional and systemic treatment

• Women eligible for sentinel lymph node biopsy and receiving radiotherapy

Exclusion criteria:

• Primary tumour not amenable for complete resection (such as tumour extending to neighbouring tissues; T4a,c or inflammatory breast cancer; T4d)

• Primary tumour with extended infection, bleeding, or necrosis

• Women with poor physical condition that prevents the patient from receiving protocol‐driven locoregional and systemic treatment

• Synchronous primary cancer at the contralateral breast

• Previous diagnosis of other cancers (excluding basal cell skin cancer, squamous cell skin cancer, cervical intraepithelial neoplasia)

• Clinically involved contralateral axillary nodes

• Women not suitable for adequate follow‐up

• Failure to give informed consent

Interventions

Surgery to primary tumour: mastectomy, lumpectomy

Outcomes

• Primary: overall survival

• Secondary: progression‐free survival

Starting date

April 2014

Contact information

[email protected]

Notes

NCT02125630

Trial name or title

A randomized controlled trial comparing primary tumour resection plus systemic therapy with systemic therapy alone in metastatic breast cancer (PRIM‐BC): Japan Clinical Oncology Group Study JCOG1017

Methods

• Randomised clinical trial

• Japan Clinical Oncology Group (JCOG)

• 600 women

Participants

Inclusion criteria:

• Females between 20 and 80 years of age

First registration

• Histologically proven breast cancer confirmed by biopsy from the tumour

• Presense/absence of overexpression of oestrogen receptor and HER2 was examined by IHC or FISH analyses.

• Neither bilateral breast cancer nor invasion to contralateral breast

• At least 1 measurable lesion other than the breast tumour and ipsilateral axillary lymph nodes was detected by CT or MRI before primary registration.

• No brain metastasis

• Women aged 20 to 80 years old

• ECOG performance status of 0 or 1. Performance status of 2 caused by the symptom from bone metastasis is also eligible.

• No prior surgery, chemotherapy, or radiotherapy for any other malignancies within 5 years

• No history of invasive breast cancer. Non‐invasive breast cancer resected completely by partial mastectomy is eligible.

• Neither prior chemotherapy for breast cancer nor prior radiotherapy for ipsilateral breast (radiotherapy for bone metastasis within 30 Gy and 10 times before registration is allowed)

• Sufficient organ functions

• Written informed consent

Second registration (after primary chemotherapy)

• Primary chemotherapy was performed after the first registration and protocol treatment is not discontinued.

• Objective response of primary chemotherapy was neither progressive disease nor not evaluable.

• Within 28 days from the date of response evaluation

• Sufficient organ functions

• Complete resection is expected to be possible by total or partial mastectomy without resection of adjacent organs or wide skin transplant, or both.

• No active bleeding from breast tumour that necessitates blood transfusion within 28 days before second registration

Exclusion criteria:

First registration (no exclusion criteria at second registration)

• Simultaneous or metachronous (within 5 years) double cancers

• Infectious disease to be treated

• Body temperature of 38 °C or higher

• Pregnant or lactating women

• Psychiatric diseases

• Systemic and continuous steroids medication

• Comorbid unstable angina pectoris or history of myocardial infarction within 6 months

• Uncontrollable hypertension

• Diabetes mellitus uncontrollable or treated by continuous insulin administration

Interventions

Primary tumour resection plus systemic therapy

Outcomes

Primary outcomes:

1. overall survival

Secondary outcomes:

1. proportion of women without progression in metastatic sites

2. yearly local recurrence‐free survival

3. incidence of local ulcer/local bleeding

4. yearly primary tumour resection‐free survival

5. adverse events of chemotherapy

6. operative morbidity

7. serious adverse events

Starting date

November 2011

Contact information

hiwata@aichi‐cc.jp

Notes

doi: 10.1093/jjco/hys120; protocol ID UMIN000005586