This trial is being conducted to confirm the superiority, in terms of overall survival, of primary tumour resection plus systemic therapy to systemic therapy alone in patients with Stage IV breast cancer who are not refractory to primary systemic therapy. The inclusion criteria for the study are as follows: untreated patients with histologically confirmed invasive breast cancer with one or more measurable metastatic lesions diagnosed by radiological examination. All patients receive primary systemic therapy according to the estrogen receptor and human epidermal growth factor receptor type-2 status of the primary breast cancer after the first registration. After 3 months, the patients without disease progression are randomized to the primary tumour resection plus systemic therapy arm or the systemic therapy alone arm. The primary endpoint is the overall survival, and the secondary endpoints are proportion of patients without tumour progression at the metastatic sites, yearly local recurrence-free survival, proportion of local ulcer/local bleeding, yearly primary tumour resection-free survival, adverse events of chemotherapy, operative morbidity and serious adverse events. The patient recruitment was commenced in May 2011. Enrolment of 410 patients for randomization is planned over a 5 year recruitment period. We hereby report the details of the study.
The incidence of metastatic breast cancer (Stage IV), defined as a primary breast tumour with distant metastasis, is increasing, accounting for ∼3% of all newly diagnosed patients with breast cancer in Japan, not significantly different from the 6% reported from the USA according to the Surveillance, Epidemiology and End Results data. The treatment of Stage IV breast cancer has traditionally been palliative care with chemotherapy, hormonal therapy and/or radiation therapy (1,2). According to the Hortobagyi algorithm (3), hormonal therapy is chosen as the first therapy for hormone receptor-positive Stage IV breast cancer without life-threatening metastases. If the tumour is hormone receptor-negative or resistant to hormone therapy, chemotherapy is used, although it might severely impair the quality of the patient's life. Current anti-tumour drugs, such as anthracyclines and taxanes, are quite effective, as are molecular-target drugs, such as trastuzumab. Resection of the primary tumour is not considered a curative treatment; it is used solely as local therapy to prevent uncontrolled chest wall disease. Therefore, the local surgery is performed relatively late in the treatment course, and only if the primary tumour and metastases have been reduced and controlled with the systemic therapy.
The possibility of surgical procedures improving the survival of these patients has been reported by several retrospective studies (4–8); however, these studies essentially suffer from biases such as arbitrary patient selection, diverse timing of surgery or various regimens of systemic therapy. Therefore, this subject still remains a hotly debated topic at major breast conferences. Improvements in primary systemic therapies have increased the numbers of Stage IV patients with resectable small primary tumours and metastatic lesions controllable by treatment. With all of these new developments, we need definitive guidelines for the treatment of these patients. It will be necessary to perform prospective studies for evaluation of the efficacy of primary tumour resection for Stage IV breast cancer. This trial is being conducted to investigate the efficacy of primary tumour resection plus systemic therapy and that of systemic therapy alone for patients with Stage IV breast cancer. Breast cancers with resistance to primary systemic therapy (PST) increase during the primary resection and need to take next regimen immediately. So we randomize only Stage IV breast cancer which is still sensitive to systemic therapy in this study.
This study is being conducted to confirm the superiority, in terms of overall survival, of primary tumour resection plus systemic therapy to systemic therapy alone in untreated breast cancer patients with metastatic lesions (Stage IV) who are not refractory to conventional PST according to the estrogen receptor (ER) and human epidermal growth factor receptor type-2 (HER2) status of the primary lesions (Fig. 1).
This study is a multi-institutional prospective randomized controlled trial being conducted with the participation of 30 hospitals belonging to the JCOG Breast Cancer Study Group.
The primary endpoint is overall survival (OS), which is defined as the number of days from randomization (second registration) to death from any cause, and it is censored at the last follow-up date when the patient is alive. The secondary endpoints are the proportion of patients without tumour progression at the metastatic sites, yearly local recurrence-free survival, proportion of local ulcer/local bleeding, yearly primary tumour resection-free survival, adverse events of chemotherapy, operative morbidity and serious adverse events.
Histologically confirmed invasive breast cancer in biopsy specimens obtained from the tumour.
The presence/absence of overexpression of ER and HER2 in the tumour examined.
Neither bilateral breast cancer nor invasion to the contralateral breast.
At least one measurable metastatic lesion other than the breast tumour and axillary lymph nodes detected by computed tomography or magnetic resonance imaging before primary registration.
No brain metastasis.
Women aged 20–80 years old.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. PS 2 caused by the symptoms of bone metastasis is also eligible.
No surgery, chemotherapy or radiotherapy for any other malignancies within the previous 5 years.
No history of invasive breast cancer. Non-invasive breast cancer resected completely by partial mastectomy is also eligible.
Neither prior chemotherapy for breast cancer nor prior radiotherapy for the ipsilateral breast (radiotherapy for bone metastasis within 30 Gy and up to 10 times before the registration is allowed).
Adequate organ functions.
Availability of written informed consent.
Second registration (after primary therapy)
Primary therapy was administered after the first registration and the protocol treatment has not been discontinued.
Objective response to primary chemotherapy was not progressive disease or not evaluable (NE).
Within 28 days from the date of response evaluation.
Adequate organ functions.
Complete resection expected to be possible by total or partial mastectomy without resection of adjacent organs and/or wide skin transplantation.
No active bleeding from the breast tumour necessitating blood transfusion within 28 days prior to the second registration.
Exclusion criteria (no exclusion criteria at the second registration)
Simultaneous or metachronous (within 5 years) double cancers.
Infectious disease requiring treatment.
Body temperature of 38°C or higher.
Pregnant or breast-feeding women.
Systemic and continuous steroid treatment.
Comorbid unstable angina pectoris or history of myocardial infarction within the previous 6 months.
Uncontrolled diabetes mellitus or the disease being treated by continuous insulin administration.
Primary Systemic Therapy
All enrolled patients for the first registration receive the PST. PST is decided according to the ER and HER2 status and the disease situation and continued for three cycles.
ER-positive patients with no life-threatening diseases receive the following hormonal therapy.
Pre-menopausal patients: oral tamoxifen 20 mg/body daily plus goserelin 3.6 mg/body every 4 weeks.
Post-menopausal patients: oral letrozole 2.5 mg/body daily for 4 weeks.
ER-negative and/or life-threatening diseases receive the following chemotherapy.
HER2-positive: paclitaxel (PTX) 80 mg/m2 (Days 1, 8, 15) plus weekly trastuzumab 2 mg/kg (Days 1, 8, 15, 22) every 4 weeks.
HER2-negative: PTX 80 mg/m2 (Days 1, 8, 15) every 4 weeks.
After three cycles of PST, the JCOG Data Center confirms the patient eligibility, and randomizes the patients either to the primary tumour resection plus systemic therapy arm or to the systemic therapy alone arm. The randomization is conducted by the minimization method with balancing the arms according to ER status (positive/negative), HER2 status (positive/negative), metastatic site(s) (presence/absence of visceral metastasis) and institution.
Primary tumour resection plus systemic therapy arm
The patients undergo the complete resection of the primary lesions after the second registration. Prophylactic axillary lymph node dissection and/or resection of adjacent organs are not allowed. As long as the tumour is resected completely, it does not matter whether the surgical procedure is partial mastectomy or total mastectomy. After the operation, the patients restart to receive the same systemic therapy as before for as long as possible as additional therapy.
Systemic therapy alone arm
After the second registration, the patients continue to receive the same systemic therapy as additional therapy for as long as possible.
All randomized patients are followed for 6 years. Physical, blood and radiological examinations of distant metastases are conducted every 6 months.
Primary analysis and statistical hypothesis
If the overall survival of the patients treated by primary tumour resection plus systemic therapy is significantly longer than that of the patients administered systemic therapy alone, the primary tumour resection will be judged to be the new standard treatment. The estimated median overall survival of patients with Stage IV breast cancer is commonly 24 months (9,10). The duration between the first and the second registration is 4 months. In this study, we shall assume that the median OS in the systemic therapy alone arm after the second registration will be 20 months, and it will be considered a clinically relevant prolongation if the median OS of primary tumour resection plus systemic therapy is longer by 6.0 months (hazard ratio: 0.77).
Sample size and follow-up period
The primary endpoint will require 359 events in total to be assessed, in order to obtain a statistical power of 80% with a one-sided significance level of 0.05. Thus, the planned sample size is 410 patients for the second registration and 500 patients for the first registration (assuming that 20% of the patients may not proceed to the second registration.) for comparing the two survival curves, assuming an accrual time of 5 years and a follow-up time of 4 years according to the calculation by the method of Schoenfeld and Richeter (11).
Interim analysis and monitoring
An interim analysis is planned to be performed twice, taking into account multiplicity using the Lan and DeMets alpha spending function. The Data and Safety Monitoring Committee (DSMC) of the JCOG independently reviews the interim analysis report, and an early termination of the trial may be considered at that stage. In-house interim monitoring is performed by the Data Center to ensure data submission, patient eligibility, protocol compliance, safety and on-schedule study progress. The monitoring reports are submitted to and reviewed by the DSMC every 6 months.
Registration of the protocol
The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID UMIN000005586), on 11 May 2011. The details are available at the following web address: http://www.umin.ac.jp/ctr/
Participating Institutions (From North to South)
Hokkaido Cancer Center, Tochigi Cancer Center, Jichi Medical University, Gunma Prefectural Cancer Center, Saitama Cancer Center, National Cancer Center Hospital East, Chiba Cancer Center, National Cancer Center Hospital, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo Medical Center, Keio University Hospital, St. Luke's International Hospital, Tokai University School of Medicine, Kanagawa Cancer Center, Kitasato University School of Medicine, Yokohama Rosai Hospital, Niigata Cancer Center Hospital, Shizuoka General Hospital, Aichi Cancer Center Hospital, Nagoya Medical Center, Kinki University School of Medicine, Osaka National Hospital, Okayama University Hospital, Kure Medical Center Chugoku Cancer Center, Fukuyama Medical Center, Hiroshima City Asa Hospital, Shikoku Cancer Center, National Kyushu Cancer Center, Kitakyushu Municipal Medical Center and Nagasaki Medical Center.
This study was supported by a National Cancer Center Research and Development Fund (23-A-16 and 23-A-17), a Grants-in-Aid for Cancer Research (20S-1 and 20S-6) from the Ministry of Health, Labour and Welfare of Japan.
Conflict of interests statement
Hiroji Iwata receives honoraria for speaking events from Chugai Pharmaceutical Co., Ltd.
The authors are grateful to Dr Hiroshi Katayama and Ms Kazumi Kubota for their support in the preparation of the manuscript.