Yong Bae Kim

Radiotherapy patterns of care for recurrent ovarian cancer by gynecologic and radiation oncologists: a Korean Gynecologic Oncology Group study (KGOG-3064S1)

Risk factors for lower extremity lymphedema after surgery in cervical and endometrial cancer

Lower extremity lymphedema (LEL) is a well-known adverse effect related to cervical and endometrial cancer (CEC); however, very few studies have elucidated the clinicopathologic risk factors related to LEL. We investigated the incidence and risk factors in patients who received primary surgery and/or adjuvant radiotherapy (RT) or chemotherapy for CEC. We retrospectively reviewed 2,565 patients who underwent primary surgery following CEC diagnosis between January 2007 and December 2020. LEL diagnosis was based on objective and subjective assessments by experts. We identified important predictors of LEL to construct a nomogram predicting individual risks of LEL. For internal validation of the nomogram, the original data were separated using the split-sample method in a 7:3 ratio of training data and test data. Overall, 858 patients (33.5%) received RT, 586 received external beam RT (EBRT), and 630 received intracavitary RT. During follow-up period, LEL developed in 331 patients, with an overall cumulative 5-year incidence of 13.3%. In multivariate analysis, age at primary treatment, use of docetaxel-based chemotherapy, type of hysterectomy, type of surgical pelvic lymph node (LN) assessment, number of dissected pelvic and para-aortic LNs, and EBRT field were the independent predictors of LEL. We subsequently developed the nomogram showing excellent predictive power for LEL. LEL is associated with various treatment modalities, and their interactions may increase the possibility of occurrences. De-escalation strategies for treatment modalities should be considered to reduce LEL in patients with CEC.

Radiotherapy in recurrent ovarian cancer: updated results of involved-field radiation therapy

This study aimed to update the possible clinical benefits of radiation therapy in recurrent ovarian cancer. The medical records of 495 patients with recurrent ovarian cancer after initially undergoing maximal cytoreductive surgery and adjuvant platinum-based chemotherapy based on the pathologic stage between January 2010 and December 2020 were analyzed: 309 and 186 patients were treated without and with involved-field radiation therapy, respectively. Involved-field radiation therapy is defined as radiation therapy only to the areas of the body involved by tumor. The prescribed doses were ≥45 Gy (equivalent dose in 2 Gy/fraction). Overall survival was compared between patients treated with and without involved-field radiation therapy. The favorable group was defined as patients who satisfied at least four of the following factors: good performance, no ascites, normal CA-125, platinum-sensitive tumor, and nodal recurrence. The median age of the patients was 56 years (range 49-63) and median time to recurrence was 11.1 months (range 6.1-15.5). 217 patients (43.8%) were treated at a single site. Radiation therapy, performance status, CA-125, platinum sensitivity, residual disease, and ascites were all significant prognostic factors. The 3-year overall survival of all patients, patients treated without radiation therapy, and patients treated with radiation therapy was 54.0%, 44.8%, and 69.3%, respectively. Radiation therapy was associated with higher overall survival rates in the unfavorable and favorable patient groups. Patient characteristics showed higher rates of normal CA-125, lymph node metastasis only, lower platinum sensitivity, and higher rates of ascites in the radiation therapy group. After propensity score matching, the radiation therapy group showed superior overall survival to the non-radiation therapy group. Normal CA-125, good performance status, and platinum sensitivity were associated with a good prognosis in patients treated with radiation therapy. Our study showed that higher overall survival was observed in patients treated with radiation therapy in recurrent ovarian cancer.

Kallikrein 5 overexpression is associated with poor prognosis in uterine cervical cancer

Kallikrein 5 (KLK5), which is frequently observed in normal cervico-vaginal fluid, is known to be related to prognosis in several solid tumors. We investigated the prognostic significance of KLK5 in uterine cervical cancer using tumor tissue microarray and immunohistochemistry staining. We analyzed samples of 165 patients with uterine cervical cancer who received definitive radiation therapy between 2004 and 2012. We divided patients into two groups stratified by their KLK5 activity by immunohistochemistry staining: negative/weak (0-1+) (n=120 patients) and moderate/strong (2-3+) group (n=45 patients). Patient and tumor characteristics, patterns of failure, and survival outcomes were compared. Univariable and multivariable analyses were performed to identify prognostic factors. Patients with KLK5 2-3+ were younger (median: 52 vs. 60 years) and had frequent paraaortic lymph node involvement (40.0% vs. 18.3%) than those with KLK5 0-1+. With a median follow-up of 60.8 (interquartile range, 47.5-77.9) months, patients with KLK5 2-3+ had inferior 5-year locoregional recurrence-free survival and distant metastasis-free survival of 61.7% (vs. 77.5% in KLK5 0-1+ group) and 59.4% (vs. 72.8% in the KLK5 0-1+ group), respectively (all p<0.05). KLK5 2-3+ expression retained its significance after adjusting for other well-known prognostic factors of tumor size and stage in multivariable analysis. KLK5 overexpression is associated with the aggressiveness of cervical cancer and may underlie the diminished response to conventional treatments. Therefore, KLK5 could be a reliable prognostic factor in cervical cancer.

A novel gene signature associated with poor response to chemoradiotherapy in patients with locally advanced cervical cancer

We aimed to investigate the distinct transcriptional landscape in poor responders to concurrent chemoradiotherapy (CCRT) and to gain mechanistic insights into treatment resistance in cervical cancer. RNA sequencing was performed in patients with locally advanced cervical cancer treated with platinum-based CCRT. Transcriptome data of no durable benefit (NDB; progression-free period 5 years) patients were compared. The NDB score was estimated for each patient using differentially expressed genes between NDB and DCB patients. The potential response to programmed death-1 blockade was estimated using the tumor immune dysfunction and exclusion (TIDE) score and T-cell-inflamed gene expression profile (GEP). NDB patients exhibited a distinct transcriptional profile compared to DCB patients, such as higher signatures of extracellular matrix organization and epithelial-to-mesenchymal transition. The fraction of cancer-associated fibroblasts (CAFs) within the tumor was significantly higher in NDB patients than in DCB patients. High NDB scores were significantly associated with poor survival in the Cancer Genome Atlas cervical cancer cohort (n=274; p=0.015) but only in patients who received curative aim radiotherapy (p=0.002). Patients with high NDB scores displayed significantly higher TIDE prediction scores and lower T-cell-inflamed GEP scores than those with low NDB scores. Patients with cervical cancer having poor CCRT or RT outcomes exhibited a distinct gene signature that could predict treatment outcomes. For poor responders, immune checkpoint inhibitors may be less effective whereas CAF-targeting treatments may be a promising approach.

Prognostic factors of dose-response relationship for nodal control in metastatic lymph nodes of cervical cancer patients undergoing definitive radiotherapy with concurrent chemotherapy

Regional control is occasionally unsatisfactory in cervical cancer, with the optimal radiation dose for nodal metastases in definitive radiotherapy (RT) with concurrent chemotherapy (CRT) remaining controversial. We investigated dose-response relationship for nodal local control in cervical cancer. We identified 115 patients with 417 metastatic nodes who received definitive CRT for cervical cancer with nodal metastases. External beam radiation therapy and brachytherapy plans were summated to determine total dose received by each node. Prognostic factors of nodal control and dose-response relationship were investigated using Cox-regression and restricted cubic spline function. The 2-year progression-free survival rate was 69.4%. Among 43 patients with failures, 17 patients (37.5%) had regional failure included in first failure sites of which all except one were in-field only regional failures. Total 30 nodes showed recurrence at initial metastatic site after treatment. Neutrophil-to-lymphocyte ratio (NLR) ≥3.1, total radiation dose (minimum dose received by 98% of the target volume in equivalent dose in 2 Gy per fractions), and initial nodal volume ≥5.29 mL were poor prognostic factors (all p<0.050) of nodal local control. Restricted cubic spline functions revealed strongest dose-response relationship in high NLR (NLR ≥3.1) and initial nodal volume ≥5.29 mL subgroup. Initial nodal volume, radiation dose

Therapeutic effects of surgical debulking of metastatic lymph nodes in cervical cancer IIICr: a trial protocol for a phase III, multicenter, randomized controlled study (KGOG1047/DEBULK trial)

Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, well-planned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m²), 4-6 times administered intravenously. The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs. ClinicalTrials.gov Identifier: NCT05421650; Clinical Research Information Service Identifier: KCT0007137.

Therapeutic Effect of Surgical Debulking of Metastatic Lymph Nodes in Cervical Cancer Stage IIICr

This study is a prospective, multicenter and randomized clinical trial (DEBULK trial) to determine the therapeutic effect of surgical debulking of bulky or multiple lymph nodes before concurrent chemoradiation therapy (CCRT) in cervical cancer stage IIICr.