1. Patient recruitment and evaluation

Between January 2005 and December 2015, patients with metachronous distant metastatic uterine cervical cancer who underwent definitive therapy at seven institutions in Korea were evaluated. The patients in our study were selected based on the 2009 FIGO staging. Patients 1) with histologically or clinically proven metachronous metastatic uterine cervical cancer, 2) who completed curative treatment and maintained a disease-free status for more than 3 months (radical treatment is defined as R0 or R1 surgical resection or radiation therapy with a radiation dose of >50 Gy delivered to the cervix), and 3) with an Eastern Cooperative Oncology Group performance score of 0–2 at the time of metachronous metastases were included in the study. By contrast, those 1) with lymph node (LN) metastases that exceeded the regional LNs at the time of initial diagnosis based on the American Joint Committee on Cancer Staging, 7th edition; 2) with metastases in distant organs at the time of initial diagnosis; 3) who underwent elective radiotherapy to the para-aortic LNs as a curative treatment (if the upper boundary of the pelvic irradiation is between T12 and L3, it is considered as para-aortic LN radiotherapy); 4) who experienced pelvic recurrence 1 month prior to the occurrence of distant recurrences; and 5) with previous history of other malignancies were excluded. Various treatments were performed in patients who had metachronous recurrence. Based on the first treatment performed after the cancer recurrence occurred, surgery or radiation therapy (including CCRT) was defined as local treatment, whereas chemotherapy was defined as systemic treatment. This study was approved by the Institutional Review Board of each participating institution (principal institution IRB number: 2018AS0110) and the Korean Radiation Oncology Group (KROG 18-10). We retrospectively reviewed the patients’ medical records after approval.

Oncologic outcomes, including overall survival (OS) and progression-free survival (PFS), were evaluated. The OS and PFS were estimated from the date of the first metachronous metastases to the date of death, the last follow-up examination, or tumor progression. The OS from the initial diagnosis (OSi) was also described in this study. A low metastatic burden was defined as a limited number of metastatic sites (5 or fewer). If more than 5 metastases were found, it was defined as a high metastatic burden. In this study, recurrence was categorized into LN metastasis and organ metastasis. LN metastasis was subdivided into para-aortic metastasis, mediastinal metastasis, supraclavicular metastasis, cervical metastasis, inguinal metastasis, and metastasis in other LNs. Distant organ metastases were subdivided into lung metastasis, liver metastasis, brain metastasis, bone metastasis, peritoneum metastasis, and metastasis in other areas. In each area, the number of recurrences within the area was not considered.

Local treatment was defined as initial therapy after recurrence, followed by surgery and radiation therapy (including CCRT). Each institution followed their standard guidelines in conducting a follow-up, and follow-up schedules were carried out according to the following protocol. All patients had follow-ups at 3- or 6-month intervals after treatment. At each follow-up, a detailed questionnaire was administered to assess the patients’ clinical status and to conduct a physical examination; magnetic resonance imaging, computed tomography (CT), and/or positron emission tomography/CT (PET/CT) were also performed.

The primary goal of this study was to evaluate the OS and PFS of patients with metachronous distant metastases that occurred after curative treatment of uterine cervical cancer according to the clinical information. We analyzed the prognostic factors such as age, squamous cell carcinoma antigen (SCC Ag) level, recurrence sites (LNs or organs), number of metastases, disease-free interval (DFI), and treatment method. We intend to classify a favorable prognostic group that will show an improvement in survival after undergoing curative salvage treatment for uterine cervical cancer. In addition, as a secondary goal, the patterns of distant metastases and the type of treatment were analyzed.