Phase II study of niraparib in recurrent or persistent rare fraction of gynecologic malignancies with homologous recombination deficiency (JGOG2052) / 부인종양

Background@#Poly (adenosine diphosphate)-ribose polymerase (PARP) inhibitors for tumors with homologous recombination deficiency (HRD), including pathogenic mutations in BRCA1/2, have been developed. Genomic analysis revealed that about 20% of uterine leiomyosarcoma (uLMS) have HRD, including 7.5%–10% of BRCA1/2 alterations and 4%–6% of carcinomas of the uterine corpus, and 2.5%–4% of the uterine cervix have alterations of BRCA1/2. Preclinical and clinical case reports suggest that PARP inhibitors may be effective against those targets. The Japanese Gynecologic Oncology Group (JGOG) is now planning to conduct a new investigator-initiated clinical trial, JGOG2052. @*Methods@#JGOG2052 is a single-arm, open-label, multi-center, phase 2 clinical trial to evaluate the efficacy and safety of niraparib monotherapy for a recurrent or persistent rare fraction of gynecologic malignancies with BRCA1/2 mutations except for ovarian cancers. We will independently consider the effect of niraparib for uLMS or other gynecologic malignancies with BRCA1/2 mutations (cohort A, C) and HRD positive uLMS without BRCA1/2 mutations (cohort B). Participants must have 1–3 lines of previous chemotherapy and at least one measurable lesion according to RECIST (v.1.1). Niraparib will be orally administered once a day until lesion exacerbation or unacceptable adverse events occur. Efficacy will be evaluated by imaging through an additional computed tomography scan every 8 weeks. Safety will be measured weekly in cycle 1 and every 4 weeks after cycle 2 by blood tests and physical examinations. The sample size is 16–20 in each of cohort A and B, and 31 in cohort C. Primary endpoint is the objective response rate.

Incidence of gastrointestinal perforation associated with bevacizumab in combination with neoadjuvant chemotherapy as first-line treatment of advanced ovarian, fallopian tube, or peritoneal cancer: analysis of a Japanese healthcare claims database / 부인종양

Objective@#To assess the incidence of bevacizumab-associated gastrointestinal (GI) perforation during first-line treatment of patients with ovarian, fallopian tube, or peritoneal cancer receiving neoadjuvant chemotherapy (NAC) in Japanese real-world clinical practice. @*Methods@#A retrospective study was conducted using a healthcare claims database owned by Medical Data Vision Co., Ltd. (study period, 2008–2020). Patients who initiated first-line treatment of ovarian, fallopian tube, or peritoneal cancer were identified and divided into NAC and primary debulking surgery (PDS) groups. The incidence of bevacizumab-associated GI perforation was compared within the NAC group and between the groups. @*Results@#Paclitaxel + carboplatin (TC) was most commonly used as first-line treatment (39.5% and 59.6% in the NAC and PDS groups, respectively). TC + bevacizumab was used in 9.3% and 11.6% of patients in the NAC and PDS groups, respectively. In the NAC group receiving TC, the proportion of patients with risk factors for GI perforation was lower among patients with versus without concomitant bevacizumab. The incidence of GI perforation in the NAC group was 0.38% (1/266 patients) in patients receiving TC + bevacizumab and 0.18% (2/1,131 patients) in patients receiving TC without bevacizumab (risk ratio=2.13; 95% confidence interval [CI]=0.19 to 23.36; risk difference=0.20; 95% CI=−0.58 to 0.97). None of the 319 patients in the PDS group receiving TC + bevacizumab had GI perforation. @*Conclusion@#No notable increase was observed in GI perforation associated with NAC containing bevacizumab. We conclude that bevacizumab is prescribed with sufficient care in Japan to avoid GI perforation.

Lymphadenectomy issues in endometrial cancer / 부인종양

Objectives@#This review aims to introduce preoperative scoring systems to predict lymph node metastasis (LNM) and ongoing clinical trials to investigate the therapeutic role of lymphadenectomy for endometrial cancer. @*Methods@#We summarized previous reports on the preoperative prediction models for LNM and evaluated their validity to omit lymphadenectomy in our recent cohorts. Next, we compared characteristics of two ongoing lymphadenectomy trials (JCOG1412, ECLAT) to examine the survival benefit of lymphadenectomy in endometrial cancer, and described the details of JCOG1412. @*Results@#Lymphadenectomy has been omitted for 64 endometrial cancer patients who met lowrisk criteria to omit lymphadenectomy using our scoring system (LNM score) and no lymphatic failure has been observed. Other two models also produced comparable results. Two randomized phase III trials to evaluate survival benefit of lymphadenectomy are ongoing for endometrial cancer. JCOG1412 compares pelvic lymphadenectomy alone with pelvic and para-aortic lymphadenectomy to evaluate the therapeutic role of para-aortic lymphadenectomy for patients at risk of LNM. For quality assurance of lymphadenectomy, we defined several regulations, including lower limit of the number of resected nodes, and submission of photos of dissected area to evaluate thoroughness of lymphadenectomy in the protocol. The latest monitoring report showed that the quality of lymphadenectomy has been well-controlled in JCOG1412. @*Conclusion@#Our strategy seems reasonable to omit lymphadenectomy and could be generalized in clinical practice. JCOG1412 is a high-quality lymphadenectomy trial in terms of the quality of surgical procedures, which would draw the bona-fide conclusions regarding the therapeutic role of lymphadenectomy for endometrial cancer.

Phase 2 single-arm study on the safety of maintenance niraparib in Japanese patients with platinum-sensitive relapsed ovarian cancer / 부인종양

Objective@#The primary objective of this study was to evaluate the safety of niraparib 300 mg/day in Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting. @*Methods@#Phase 2, multicenter, open-label, single-arm study enrolled Japanese patients with platinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens.The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30 days after initial niraparib administration) was justified by the incidences of a global pivotal phase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematological adverse event of niraparib. The overall safety analysis examined other treatment-emergent adverse events (TEAEs). @*Results@#Enrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8–79.1) kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib 300 mg/day but this decreased in subsequent cycles (mean±standard deviation dose intensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration.Other common TEAEs included nausea, and decreased platelet or neutrophil counts. No progression-free or overall survival events occurred; only 1 of 4 response-evaluable patients had a post-baseline tumor assessment (stable disease). @*Conclusion@#The incidence of grade 3 or 4 thrombocytopenia-related events in Japanese ovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall, the safety profile was acceptable and consistent with the known safety profile and previous experience with niraparib.

Nerve-sparing radical hysterectomy in the precision surgery for cervical cancer / 부인종양

Precision cancer surgery is a system that integrates the accurate evaluation of tumor extension and aggressiveness, precise surgical maneuvers, prognosis evaluation, and prevention of the deterioration of quality of life (QoL). In this regard, nerve-sparing radical hysterectomy has a pivotal role in the personalized treatment of cervical cancer. Various types of radical hysterectomy can be combined with the nerve-sparing procedure. The extent of parametrium and vagina/paracolpium excision and the nerve-sparing procedure are tailored to the tumor status. Advanced magnetic resonance imaging technology will improve the assessment of the local tumor extension. Validated risk factors for perineural invasion might guide selecting treatment for cervical cancer. Type IV Kobayashi (modified Okabayashi) radical hysterectomy combined with the systematic nerve-sparing procedure aims to both maximize the therapeutic effect and minimize the QoL impairment. Regarding the technical aspect, the preservation of vesical nerve fibers is essential. Selective transection of uterine nerve fibers conserves the vesical nerve fibers as an essential piece of the pelvic nervous system comprising the hypogastric nerve, pelvic splanchnic nerves, and inferior hypogastric plexus. This method is anatomically and surgically valid for adequate removal of the parametrial and vagina/paracolpium tissues while preserving the total pelvic nervous system. Local recurrence after nerve-sparing surgery might occur due to perineural invasion or inadequate separation of pelvic nerves cutting through the wrong tissue plane between the pelvic nerves and parametrium/paracolpium. Postoperative management for long-term maintenance of bladder function is as critical as preserving the pelvic nerves.

Asian Society of Gynecologic Oncology International Workshop 2018 / 부인종양

The Asian Society of Gynecologic Oncology International Workshop 2018 on gynecologic oncology was held in the Ajou University Hospital, Suwon, Korea on the 24th to 25th August 2018. The workshop was an opportunity for Asian doctors to discuss the latest findings of gynecologic cancer, including cervical, ovarian, and endometrial cancers, as well as the future of fertility-sparing treatments, minimally invasive/radical/debulking surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Clinical guidelines and position statement of Asian countries were presented by experts. Asian clinical trials for gynecologic cancers were reviewed and experts emphasized the point that original Asian study is beneficial for Asian patients. In Junior session, young gynecologic oncologists presented their latest research on gynecologic cancers.

Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02) / 부인종양

OBJECTIVE: Rikkunshito, an herbal medicine, is widely prescribed in Japan for the treatment of anorexia and functional dyspepsia, and has been reported to recover reductions in food intake caused by cisplatin. We investigated whether rikkunshito could improve chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients treated with cisplatin. METHODS: Patients with uterine cervical or corpus cancer who were to receive cisplatin (50 mg/m² day 1) and paclitaxel (135 mg/m² day 0) as first-line chemotherapy were randomly assigned to the rikkunshito group receiving oral administration on days 0–13 with standard antiemetics, or the control group receiving antiemetics only. The primary endpoint was the rate of complete control (CC: no emesis, no rescue medication, and no significant nausea) in the overall phase (0–120 hours). Two-tailed p<0.20 was considered significant in the planned analysis. RESULTS: The CC rate in the overall phase was significantly higher in the rikkunshito group than in the control group (57.9% vs. 35.3%, p=0.175), as were the secondary endpoints: the CC rate in the delayed phase (24–120 hours), and the complete response (CR) rates (no emesis and no rescue medication) in the overall and delayed phases (63.2% vs. 35.3%, p=0.095; 84.2% vs. 52.9%, p=0.042; 84.2% vs. 52.9%, p=0.042, respectively), and time to treatment failure (p=0.059). Appetite assessed by visual analogue scale (VAS) appeared to be superior in the rikkunshito group from day 2 through day 6. CONCLUSION: Rikkunshito provided additive effect for the prevention of CINV and anorexia.

Lymphadenectomy can be omitted for low-risk endometrial cancer based on preoperative assessments / 부인종양

OBJECTIVE: According to the International Federation of Gynecology and Obstetrics staging, some surgeons perform lymphadenectomy in all patients with early stage endometrial cancer to enable the accurate staging. However, there are some risks to lymphadenectomy such as lower limb lymphedema. The aim of this study was to investigate whether preoperative assessment is useful to select the patients in whom lymphadenectomy can be safely omitted. METHODS: We evaluated the risk of lymph node metastasis (LNM) using LNM score (histological grade, tumor volume measured in magnetic resonance imaging [MRI], and serum CA-125), myometrial invasion and extrautrerine spread assessed by MRI. Fifty-six patients of which LNM score was 0 and myometrial invasion was less than 50% were consecutively enrolled in the study in which a lymphadenectomy was initially intended not to perform. We analyzed several histological findings and investigated the recurrence rate and overall survival. RESULTS: Fifty-one patients underwent surgery without lymphadenectomy. Five (8.9%) who had obvious myometrial invasion intraoperatively underwent systematic lymphadenectomy. One (1.8%) with endometrial cancer which was considered to arise from adenomyosis had para-aortic LNM. Negative predictive value of deep myometrial invasion was 96.4% (54/56). During the mean follow-up period of 55 months, one patient with deep myometrial invasion who refused an adjuvant therapy had tumor recurrence. The overall survival rate was 100% during the study period. CONCLUSION: This preoperative assessment is useful to select the early stage endometrial cancer patients without risk of LNM and to safely omit lymphadenectomy.

Multivariate prognostic analysis of adenocarcinoma of the uterine cervix treated with radical hysterectomy and systematic lymphadenectomy / 부인종양

OBJECTIVE: The aim of this study was to investigate the prognostic factors and treatment outcome of patients with adenocarcinoma of the uterine cervix who underwent radical hysterectomy with systematic lymphadenectomy. METHODS: A total of 130 patients with stage IB to IIB cervical adenocarcinoma treated with hysterectomy and systematic lymphadenectomy from 1982 to 2005 were retrospectively analyzed. Clinicopathological data including age, stage, tumor size, the number of positive node sites, lymphovascular space invasion, parametrial invasion, deep stromal invasion (>2/3 thickness), corpus invasion, vaginal infiltration, and ovarian metastasis, adjuvant therapy, and survival were collected and Cox regression analysis was used to determine independent prognostic factors. RESULTS: An estimated five-year survival rate of stage IB1 was 96.6%, 75.0% in stage IB2, 100% in stage IIA, and 52.8% in stage IIB. Prognosis of patients with one positive-node site is similar to that of those with negative-node. Prognosis of patients with multiple positive-node sites was significantly poorer than that of negative and one positive-node site. Multivariate analysis revealed that lymph node metastasis, lymphovascular space invasion, and parametrial invasion were independent prognostic factors for cervical adenocarcinoma. Survival of patients with cervical adenocarcinoma was stratified into three groups by the combination of three independent prognostic factors. CONCLUSION: Lymph node metastasis, lymphovascular space invasion, and parametrial invasion were shown to be independent prognostic factors for cervical adenocarcinoma treated with hysterectomy and systematic lymphadenectomy.

Multivariate survival analysis of the patients with recurrent endometrial cancer / 부인종양

OBJECTIVE: Few studies on the prognosticators of the patients with recurrent endometrial cancer after relapse have been reported in the literature. The aim of this study was to determine the prognosticators after relapse in patients with recurrent endometrial cancer who underwent primary complete cytoreductive surgery and adjuvant chemotherapy. METHODS: Thirty-five patients with recurrent endometrial cancer were included in this retrospective analysis. The prognostic significance of several clinicopathological factors including histologic type, risk for recurrence, time to relapse after primary surgery, number of relapse sites, site of relapse, treatment modality, and complete resection of recurrent tumors were evaluated. Survival analyses were performed by Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. RESULTS: Among the clinicopathological factors analyzed, histologic type (p=0.04), time to relapse after primary surgery (p=0.03), and the number of relapse sites (p=0.03) were significantly related to survival after relapse. Multivariate analysis revealed that time to relapse after primary surgery (hazard ratio, 6.8; p=0.004) and the number of relapse sites (hazard ratio, 11.1; p=0.002) were independent prognostic factors for survival after relapse. Survival after relapse could be stratified into three groups by the combination of two independent prognostic factors. CONCLUSION: We conclude that time to relapse after primary surgery, and the number of relapse sites were independent prognostic factors for survival after relapse in patients with recurrent endometrial cancer.