Large volume was associated with increased risk of acute non-hematologic adverse events in the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer: preliminary results of prospective phase I/II clinical trial.

OBJECTIVE: This is the preliminary results of a multi-center prospective clinical trial evaluating the feasibility of the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer. METHODS: Patients with FIGO stage IB2, IIA2, IIB, IIIA, IIIB and IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by MRI were eligible. Protocol therapy consisted of 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of hybrid of intracavitary and interstitial and pelvic radiotherapy with central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase I part was that the rate of grade ≥ 3 acute non-hematologic adverse events related to hybrid of intracavitary and interstitial would be <10%. RESULTS: Between October 2015 and October 2019, 74 patients underwent primary registration, with 52 patients eventually proceeding to the secondary registration. The median pretreatment tumor width was 5.7 cm, and FIGO Stages were IB2 10, IIA2 2, IIB 20 and IIIB 20, respectively. The median high-risk clinical target volume D90 was 72.0 Gy (54.8-86.6 Gy, EQD2), rectum D2cc was 53.7 Gy (29.3-80.3 Gy) and bladder D2cc was 69.8 Gy (38.9-84.8 Gy). The rate of grade ≥ 3 non-hematologic adverse events related to hybrid of intracavitary and interstitial was 1.9% (1/52), and 17.3% (9/52) of patients experienced non-hematologic adverse events related to hybrid of intracavitary and interstitial of any grade. In multivariate analysis, high-risk clinical target volume ≥ 35 ml was associated with an increased risk of any grade of acute non-hematologic adverse events related to hybrid of intracavitary and interstitial (P = 0.036). CONCLUSION: The feasibility and reproducibility of hybrid of intracavitary and interstitial were demonstrated from a multi-center prospective clinical trial.

Manual vacuum aspiration (women's MVA) for endometrial biopsy for patients with suspected endometrial malignancies.

AIM: Endometrial biopsy is generally performed with a metal uterine curette sonde; however, recently, many types of vacuum aspirators are available, including the manual vacuum aspiration (MVA) system. We used the women's MVA system for endometrial sampling and evaluated its effectiveness in determining the presence of endometrial malignancy. METHODS: Forty-seven samples were examined using the following procedures after measuring endometrial thickness by transvaginal ultrasonography: fractional curettage biopsy (Bx; 20 samples), total curettage under general anesthesia (T/C; 13 samples), and MVA (14 samples). The quality of the endometrial samples was classified into four types: 1-4, where 1 denoted poor and 4, good quality. RESULTS: The mean score of the MVA group was significantly higher than that of the partial curettage biopsy group (p = 0.0065). No differences were observed between the MVA and total curettage groups (p = 1.00). When patients were divided into two groups according to endometrial thickness (<10 mm or ≥10 mm) and analyzed, both the MVA and T/C groups did not show a significant difference in their scores compared to the Bx group when the endometrial thickness was <10 mm. However, when the endometrial thickness was ≥10 mm, the MVA and T/C groups had significantly better scores than the Bx group (p = 0.0225 and p = 0.0244, respectively). Vagal reflex, as an adverse event, was observed only in two patients in the Bx group (2/20, 10%). CONCLUSION: Considering its quality and safety, Karman-type MVA for endometrial sampling could be an alternative to fractional curettage using a metallic uterine curette sonde.

Stage III disease of ovarian, tubal and peritoneal cancers can be accurately diagnosed with pre-operative CT. Japan Clinical Oncology Group Study JCOG0602.

PURPOSE: Computed tomography of the abdomen and pelvis is a useful imaging modality for identifying origin and extent of ovarian cancer before primary debulking surgery. However, the International Federation of Gynecology and Obstetrics staging for ovarian cancer is determined based on surgico-pathological findings. The purpose of this study is to determine whether computed tomography staging can be the surrogate for surgico-pathological International Federation of Gynecology and Obstetrics staging in advanced ovarian cancer undergoing neoadjuvant chemotherapy. METHODS: Computed tomography staging was compared with surgico-pathological International Federation of Gynecology and Obstetrics staging in primary debulking surgery arm patients in a randomized controlled trial comparing primary debulking surgery and neoadjuvant chemotherapy (JCOG0602). The cancer of primary debulking surgery arm was identically diagnosed regarding the origin and extent with the cancer of neoadjuvant chemotherapy arm before accrual, using imaging studies (computed tomography and/or magnetic resonance imaging), cytological examination (ascites, pleural effusion or tumor contents fluid) and tumor marker (CA125 > 200 U/mL and CEA < 20 ng/mL). Institutional computed tomography staging was also compared with computed tomography staging by central review. RESULTS: Among 149 primary debulking surgery arm patients, 147 patients who underwent primary debulking surgery immediately were analyzed. Positive predictive values and sensitivity of computed tomography staging for surgical stage III disease (extra-pelvic peritoneal disease and/or retroperitoneal lymph node metastasis) were 99%. Meanwhile, positive predictive values for the presence of small (≤2 cm) extra-pelvic peritoneal disease were low; <20% in omentum. Accuracy of institutional computed tomography staging was comparable with computed tomography staging by central review. CONCLUSIONS: Preoperative computed tomography staging in each institution can be the surrogate for surgico-pathological diagnosis in stage III disease of ovarian cancer patients undergoing neoadjuvant chemotherapy without diagnostic surgery, but reliability of diagnosis of stage IIIB disease is inadequate.Clinical trial registration: UMIN000000523(UMIN-CTR).

Propensity score-matched analysis of systemic chemotherapy versus salvage hysterectomy for persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy.

BACKGROUND: The aim of the current study was to evaluate oncologic outcomes of patients who were treated with salvage hysterectomy (HT), compared to systemic chemotherapy (CT) for persistent cervical cancer after definitive radiotherapy (RT)/ concurrent chemoradiotherapy (CCRT). METHODS: Patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions from 2005 to 2014 were reviewed retrospectively (n = 317). Those who underwent a HT for persistent cervical cancer after definitive RT/CCRT were matched with propensity scores for patients who underwent systemic CT. Oncologic outcomes between the two groups using a propensity score matched-cohort analysis were compared. RESULTS: A total of 142 patients with persistent cervical cancer after definitive RT/CCRT were included after matching (HT: 71, systemic CT: 71). All background factors between HT and CT groups were well balanced. Median overall survival was 3.8 and 1.5 years in the HT and CT groups, respectively (p = 0.00193, hazards ratio [HR] 0.41, 95% confidence interval [CI] 0.23-0.73), Increasing residual tumor size was significantly associated with a high incomplete resection rate (p = 0.016, Odds Ratio 1.11, 95%CI 1.02-1.22). Severe late adverse events occurred in 7 patients (9.9%) in the HT cohort. CONCLUSION: The current study demonstrated that, when compared to systemic CT, the adoption of salvage HT for patients with persistent cervical cancer after definitive RT/CCRT reduced mortality rate by about 60%. This indicates that salvage HT could be curative treatment for those patients. Further prospective clinical trials with regard to salvage HT after RT/CCRT are warranted.

A multi-center retrospective study of neuroendocrine tumors of the uterine cervix: Prognosis according to the new 2018 staging system, comparing outcomes for different chemotherapeutic regimens and histopathological subtypes.

OBJECTIVE: To analyze the clinical behavior of neuroendocrine tumors (NETs) of the uterine cervix, we conducted a multicenter, retrospective study of 193 patients. METHODS: We evaluated the prognosis of NETs according to the new International Federation of Gynecology and Obstetrics (FIGO) staging system, compared the clinical response to different chemotherapy regimens, and compared different histological subtypes of NETS. RESULTS: Diagnoses of the subjects were atypical carcinoid tumor (ACT, n = 37), small cell neuroendocrine carcinoma (SCNEC, n = 126), large cell neuroendocrine carcinoma (LCNEC, n = 22), and NET, not elsewhere classified (n = 8), according to central pathological review. According to FIGO 2018, 69, 17, 74, and 33 patients were at stage I, II, III, or IV, respectively. Five-year survival was 64.5%, 50.1%, 30.2%, and 3.4% for patients at stage I, II, III and IV. About 40% of patients with stage IIIC1 survived >5 years. On multivariate analyses, locally-advanced disease, para-aortic node metastasis, distant metastasis, and <4 cycles of chemotherapy were associated with poor survival. Histological subtype and pelvic node metastasis had no prognostic significance. Response rates to etoposide-platinum (EP) or irinotecan-platinum (CPT-P) regimens were 43.8% (28/64), but only 12.9% to a taxane-platinum (TC) regimen (4/31). The response rate for ACT was 8.7% (2/23), significantly less than the 36.6% for high-grade neuroendocrine carcinomas (HGNEC: both SCNEC and LCNEC, 41/111). CONCLUSIONS: Locally-advanced, extra-pelvic disease and insufficient chemotherapy were independent prognostic factors for cervical NET. HGNEC showed good responses to EP or CPT-P but not TC. Chemotherapy was less effective for ACT, which had a prognosis identical to HGNEC.

Analysis of gastric-type mucinous carcinoma of the uterine cervix - An aggressive tumor with a poor prognosis: A multi-institutional study.

OBJECTIVE: Gastric-type mucinous carcinoma (GAS) is a novel variant of mucinous carcinoma of the uterine cervix. As shown in the original Japanese group description, in recent studies, GAS represents a more aggressive disease than the usual-type endocervical adenocarcinoma (UEA). Detailed clinicopathological features of this variant remain to be elucidated in a larger series of patients. METHODS: Patients were enrolled by the Gynecologic Cancer Study Group of the Japan Clinical Oncology Group after receiving the approval of each Institutional Review Board. The study population comprised of women with stage I to II endocervical adenocarcinomas who underwent surgery between 2000 and 2009. Representative slides were evaluated by central pathological review (CPR), categorized into either GAS or UEA, and correlated with clinicopathological features and outcome. RESULTS: Among the 393 enrolled patients with endocervical adenocarcinoma, 328 patients met the criteria for CPR and the study eligibility criteria and were included in further analysis. A total of 95 of the 328 tumors were classified as GAS. Compared with UEA, GAS was more significantly associated with bulky mass, deep stromal invasion, lymphovascular space invasion, parametrial invasion, ovarian metastasis, positive ascitic fluid cytology, pelvic lymph node metastasis, and pathological (p) T stage but was not related to the degree of histological differentiation. Disease-free survival (P < 0.0001) and overall survival (P < 0.0001) were poorer in patients with GAS than in those with UEA. CONCLUSIONS: GAS showed aggressive behavior with ominous histopathological predictors as well as decreased survival. GAS is therefore considered a distinct entity that should be distinguished from UEA. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry: UMIN000007987.

Single-arm confirmatory trial of postoperative concurrent chemoradiotherapy using intensity modulated radiation therapy for patients with high-risk uterine cervical cancer: Japan Clinical Oncology Group study (JCOG1402).

A single-arm multi-center confirmatory trial was started in Japan to confirm the efficacy and safety of post-radical hysterectomy concurrent chemoradiotherapy using intensity-modulated radiation therapy (IMRT-CCRT) for patients with high-risk uterine cervical cancer, for which the current standard treatment is CCRT using three-dimensional conformal radiation therapy (3DCRT-CCRT). This study began in April 2017 and a total of 220 patients will be accrued from 44 institutions within 3.5 years. The primary endpoint is 3-year relapse-free survival. The secondary endpoints are overall survival, loco-regional relapse-free survival, proportion of late lower gastrointestinal adverse events greater than or equal to grade 3, proportion of lower edema limbs, adverse events, and serious adverse events. This trial was registered at the Japan Registry of Clinical Trials as jRCTs031180194 (https://jrct.niph.go.jp/).

A multi-institutional observational study on the effects of three-dimensional radiotherapy and weekly 40-mg/m2 cisplatin on postoperative uterine cervical cancer patients with high-risk prognostic factors.

BACKGROUND: The aim of this study was to evaluate the effects of treatment with both three-dimensional radiotherapy (3DRT) and weekly 40-mg/m2 cisplatin on postoperative uterine cervical cancer patients with high-risk prognostic factors. METHODS: We conducted a retrospective multi-institutional chart review of postoperative uterine cervical cancer patients with high-risk prognostic factors who had been treated with both 3DRT and weekly 40-mg/m2 cisplatin from 2007 to 2012. Each participating hospital provided detailed information regarding patient characteristics, treatment outcomes, and treatment complications. RESULTS: The eligible 96 patients were analyzed. The median follow-up period was 61 months. The 3-year relapse-free survival, overall survival (OS), and locoregional relapse-free survival (LRFS) rates were 76%, 90%, and 88%, respectively. In multivariate analysis, the histological finding of either adenocarcinoma or adenosquamous carcinoma was a significant risk factor for both OS and LRFS. The percentage of patients with grade ≥ 3 acute hematologic toxicity, acute lower gastrointestinal toxicity (GIT), and late lower GIT were 45%, 19%, and 17%, respectively. CONCLUSIONS: The outcomes of concurrent chemoradiotherapy (CCRT) using weekly 40-mg/m2 cisplatin are similar to those in the previous studies that used several chemotherapy regimens. However, postoperative CCRT using 3DRT had a high level of late GIT.

Identifying selection criteria for non-radical hysterectomy in FIGO stage IB cervical cancer.

AIM: This retrospective study sought to identify the selection criteria required for a non-radical hysterectomy with minimal parametrectomy in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB invasive cervical cancer. METHODS: Overall, 461 patients with FIGO stage IB cervical cancer who underwent a radical hysterectomy were reviewed clinicopathologically according to pathological tumor size (≤2 cm, >2 - ≤4 cm, and > 4 cm). RESULTS: The pathological parametrial involvement rate in the less than equal to 2 cm group (2%) was significantly lower than in greater than 2-less than equal to 4 cm (13%) or greater than 4 cm (29%) groups (both P < 0.001). The 5-year overall survival rate was significantly higher in the less than equal to 2 cm group (97%, 95% confidence interval [CI] 94-99%) compared with greater than 2-less than equal to 4 cm (90%, 95% CI 94-86%) and greater than 4 cm (70%, 95% CI 79-60%) groups (both P < 0.001). Cox model analysis identified tumor size to be an independent prognostic factor for survival (95% CI 1.33-5.78) and recurrence (95% CI 1.31-5.66) compared to other pathological factors. However, a significant difference between the three groups was not found in rates of Grade 3 or 4 adverse events following radical hysterectomy (P = 0.19). CONCLUSIONS: Tumor size is an independent prognostic factor for survival in patients with FIGO stage IB invasive cervical cancer. This retrospective study suggests that FIGO stage IB patients with a less than equal to 2 cm tumor size are optimal candidates for non-radical hysterectomy with minimal parametrectomy, and without resulting bladder dysfunction.

Prognostic factors and optimal therapy for stages I-II neuroendocrine carcinomas of the uterine cervix: A multi-center retrospective study.

PURPOSE: We aimed to determine appropriate treatment guidelines for patients with stages I-II high-grade neuroendocrine carcinomas (HGNEC) of the uterine cervix in a multicenter retrospective study. PATIENTS AND METHODS: We reviewed the clinicopathological features and prognoses of 93 patients with HGNEC of International Federation of Gynecology and Obstetrics (FIGO) stages I and II. All patients were diagnosed with HGNEC by central pathological review. RESULTS: The median overall survival (OS) and disease-free survival (DFS) were 111.3months and 47.4months, respectively. Eighty-eight patients underwent radical surgery, and five had definitive radiotherapy. The hazard ratio (HR) for death after definitive radiotherapy to death after radical surgery was 4.74 (95% confidence interval [CI], 1.01-15.90). Of the surgery group, 18 received neoadjuvant chemotherapy. Pathological prognostic factors and optimal adjuvant therapies were evaluated for the 70 patients. Forty-one patients received adjuvant chemotherapy with etoposide-platinum (EP) or irinotecan-platinum (CPT-P). Multivariate analyses identified the invasion of lymphovascular spaces as a significant prognostic factor for both OS and DFS. Pelvic lymph node metastasis was also a prognostic factor for DFS. Adjuvant chemotherapy with an EP or CPT-P regimen appeared to improve DFS (HR=0.27, 95% CI, 0.10-0.69). A trend toward improved OS was also observed, but was not statistically significant (HR=0.39, 95% CI, 0.15-1.01). CONCLUSION: Radical surgery followed by adjuvant chemotherapy with an EP or CPT-P regimen was optimal treatment for stages I and II HGNEC of the uterine cervix.

Clinical tumor diameter and prognosis of patients with FIGO stage IB1 cervical cancer (JCOG0806-A).

OBJECTIVE: In order to determine indications for less radical surgery such as modified radical hysterectomy, the risk of pathological parametrial involvement and prognosis of FIGO stage IB1 cervical cancer patients undergoing standard radical hysterectomy with pre-operatively assessed tumor diameter≤2 cm were investigated. METHODS: We conducted a retrospective multi-institutional chart review of patients with FIGO stage IB1 cervical cancer who underwent primary surgical treatment between 1998 and 2002. The eligibility criteria for the analyses were (i) histologically-proven squamous cell carcinoma, adenocarcinoma or, adenosquamous cell carcinoma, (ii) radical hysterectomy performed, (iii) clinical tumor diameter data available by MR imaging or specimens by cone biopsy, and (iv) age between 20 and 70. Based on the clinical tumor diameter, patients were stratified into those with the following tumors: i) 2 cm or less (cT≤2 cm) and ii) greater than 2 cm (cT>2 cm). We expected 5-year OS of ≥95% and parametrial involvement<2-3% for patients with cT≤2 cm who underwent radical hysterectomy. RESULTS: Of the 1269 patients enrolled, 604 were eligible for the planned analyses. Among these, 571 underwent radical hysterectomy (323 with cT≤2 cm and 248 with cT>2 cm). Parametrial involvement was present in 1.9% (6/323) with cT≤2 cm and 12.9% (32/248) with cT>2 cm. Five-year overall survivals were 95.8% (95% CI 92.9-97.6%) in cT≤2 cm and 91.9% (95% CI 87.6-94.8%) in cT>2 cm patients. CONCLUSION: Patients with cT≤2 cm had lower risk of parametrial involvement and more favorable 5-year overall survival. They could therefore be good candidates for receiving less radical surgery.

Non-randomized confirmatory trial of modified radical hysterectomy for patients with tumor diameter 2 cm or less FIGO Stage IB1 uterine cervical cancer: Japan Clinical Oncology Group Study (JCOG1101).

A non-randomized confirmatory trial was started in Japan to evaluate the efficacy of modified radical hysterectomy in patients with tumor diameter 2 cm or less FIGO Stage IB1 uterine cervical cancer, for which the current standard is radical hysterectomy. This study began in January 2013 and a total of 240 patients will be accrued from 37 institutions within 3 years. The primary endpoint is 5-year survival. The secondary endpoints are overall survival, relapse-free survival, local relapse-free survival, percent completion of modified radical hysterectomy, percent local relapse, percent pathological parametrial involvement, days until self-urination and residual urine disappearance, blood loss, operation time, percent post-operative radiation therapy, adverse events and severe adverse events. This trial was registered at the UMIN Clinical Trials Registry as UMIN 000009726 (http://www.umin.ac.jp/ctr/).

Minimization of curative surgery for treatment of early cervical cancer: a review.

Surgery is effective and useful for curative treatment of patients with early invasive cervical cancer, yet minimization of surgical procedures provides many additional advantages for patients. Because the mean age of patients diagnosed with cervical precancer and invasive cancer has been decreasing, the need for minimization of surgery to reduce disruption of fertility is increasing. Trachelectomy is an innovative procedure for young patients with invasive cancer. Minimally invasive procedures are increasingly implemented in the treatment of patients with early cervical cancer, such as laparoscopic/robotic surgery and sentinel lymph node navigation. The use of modified radical hysterectomy may not only be curative but also minimally invasive for Stage IA2-IB1 patients with a tumor size <2 cm in diameter. Here, we have summarized and discussed the minimally invasive procedures for the treatment of patients with early cervical cancer.

CT based three dimensional dose-volume evaluations for high-dose rate intracavitary brachytherapy for cervical cancer.

BACKGROUND: In this study, high risk clinical target volumes (HR-CTVs) according to GEC-ESTRO guideline were contoured retrospectively based on CT images taken at the time of high-dose rate intracavitary brachytherapy (HDR-ICBT) and correlation between clinical outcome and dose of HR-CTV were analyzed. METHODS: Our study population consists of 51 patients with cervical cancer (Stages IB-IVA) treated with 50 Gy external beam radiotherapy (EBRT) using central shield combined with 2-5 times of 6 Gy HDR-ICBT with or without weekly cisplatin. Dose calculation was based on Manchester system and prescribed dose of 6 Gy were delivered for point A. CT images taken at the time of each HDR-ICBT were reviewed and HR-CTVs were contoured. Doses were converted to the equivalent dose in 2 Gy (EQD2) by applying the linear quadratic model (α/ß = 10 Gy). RESULTS: Three-year overall survival, Progression-free survival, and local control rate was 82.4%, 85.3% and 91.7%, respectively. Median cumulative dose of HR-CTV D90 was 65.0 Gy (52.7-101.7 Gy). Median length from tandem to the most lateral edge of HR-CTV at the first ICBT was 29.2 mm (range, 18.0-51.9 mm). On univariate analysis, both LCR and PFS was significantly favorable in those patients D90 for HR-CTV was 60 Gy or greater (p = 0.001 and 0.03, respectively). PFS was significantly favorable in those patients maximum length from tandem to edge of HR-CTV at first ICBT was shorter than 3.5 cm (p = 0.042). CONCLUSION: Volume-dose showed a relationship to the clinical outcome in CT based brachytherapy for cervical carcinoma.

Nuclear Y-box-binding protein-1 is a poor prognostic marker and related to epidermal growth factor receptor in uterine cervical cancer.

OBJECTIVE: Y-box binding protein-1 (YB-1) is a member of the cold shock protein family and functions in transcription and translation. Many studies indicate that YB-1 is strongly expressed in tumor cells and is considered a marker of tumor aggressiveness and clinical prognosis. Overexpression of epidermal growth factor receptor (EGFR) has been associated with poor outcomes in cervical cancer. Clinical trials of EGFR family-base therapy are currently being initiated in cervical cancer. Nuclear YB-1 expression correlates with EGFR expression in various types of cancer. However, the clinical significance of nuclear YB-1 expression in different settings, the correlation with EGFR, and the prognostic implications of YB-1 expression in cervical cancer remain elusive. PATIENTS AND METHODS: Nuclear YB-1 expression was immunohistochemically analyzed in tissue specimens obtained from 204 patients with cervical cancer who underwent surgery. Associations of nuclear YB-1 expression with clinicopathological factors such as survival, EGFR expression, and human epidermal growth factor receptor 2 (HER2) expression were investigated. RESULTS: Nuclear YB-1 expression was found in 41 (20.2%) of 204 cases of cervical cancer and correlated with disease stage, tumor diameter, stromal invasion, and lymph-node metastasis. Nuclear YB-1 expression also correlated with EGFR expression (P=0.0114) as well as HER2 expression (P=0.0053). Kaplan-Meier survival analysis showed that nuclear YB-1 expression was significantly associated with poor progression-free survival (P=0.0033) and overall survival (P=0.0003), respectively. CONCLUSION: Nuclear YB-1 expression is a prognostic marker and correlates with EGFR expression in cervical cancer.

Status of treatment for the overall population of patients with stage IVb endometrial cancer, and evaluation of the role of preoperative chemotherapy: a retrospective multi-institutional study of 426 patients in Japan.

OBJECTIVE: We previously reported on the role of cytoreduction in 248 patients with surgical stage IVb endometrial cancer (EMCA). This study aimed to evaluate the clinical characteristics, prognosis according to initial treatment, and impact of preoperative chemotherapy in the overall population of patients with clinical and surgical stage IVb EMCA. METHODS: A multi-institutional retrospective analysis was performed in 426 patients diagnosed with clinical and surgical stage IVb EMCA from 1996 to 2005. Factors associated with overall survival (OS) were identified using univariate and multivariate analyses. RESULTS: The median OS for all 426 patients was 14 months. Patients were divided into three groups according to their initial treatment: primary surgery group (n=279), primary chemotherapy group (n=125), and palliative care group (n=22). The median OS times for these groups were 21, 12, and 1 month, respectively (p<0.0001). Patients in the primary surgery group had better performance status (PS) and lower numbers of extra-abdominal metastases than those in the primary chemotherapy group. Multivariate analysis identified good PS, endometrioid histology, absence of clinical intra-abdominal stage IVb metastasis, hysterectomy, and chemotherapy as independent predictors of OS. In the primary chemotherapy group, 59 patients subsequently underwent surgery, and these patients had similar OS to those in the primary surgery group. CONCLUSIONS: Hysterectomy and chemotherapy may prolong OS in selected patients with stage IVb EMCA. Our data suggest that primary chemotherapy followed by surgery may be a useful treatment choice in patients not suitable for primary surgery.

[Smoking and obstetric and gynecological disorders].

Smoking causes various health problems in women in relation to their life cycle. About the effects of smoking on obstetric and gynecological disorders, it is clarified that smoking has adverse effects on menopausal disorders, miscarriage, premature birth, low birth weight infant, breast cancer, uterine cancer and ovarian cancer. The high rate of smoking among women of reproductive age is of particular concern for the next generation because smoking affects not only the women themselves, but also the fetus. It is necessary to promote smoking prevention education to prevent women from developing a smoking habit and to provide smoking cessation education and support for smokers.

Plan quality association between dummy run and individual case review in a prospective multi-institutional clinical trial of postoperative cervical cancer patients treated with intensity-modulated radiotherapy: Japan clinical Oncology Group study (JCOG1402).

BACKGROUND AND PURPOSE: The Japan Clinical Oncology Group (JCOG) 1402 conducted a multicenter clinical trial of postoperative intensity-modulated radiotherapy (IMRT) for high-risk uterine cervical cancer patients. We assess effectiveness of the quality assurance (QA) program in central review through dummy runs (DRs) performed before patient enrollment and post-treatment individual case review (ICR), and clarify the pitfalls in treatment planning. MATERIAL AND METHODS: The ICRs were conducted using the same QA program as the DR for 214 plans. The deviations were compared with those demonstrated in the DRs, and the pitfalls were clarified. Fifteen face-to-face meetings were held with physicians at participating institutions to provide feedback. RESULTS: Two-hundred and eighty-eight deviations and nine violations were detected in the 214 plans. The patterns of the deviations observed in the ICRs were similar to that in the DR. Frequent deviations were observed in clinical target volume (CTV) delineations, 50% in the DRs and 37% in the ICRs, respectively. In the ICRs, approximately 1.4 deviations/violations were observed per plan, which was lower than DR. Nine violations included inaccurate CTV delineation and improper PTV (planning target volume) margin, which had risks in loco-regional failures by inadequate dose coverage. CONCLUSIONS: Our developed QA program commonly used in DR and ICR clarified the pitfalls in treatment plans. Although the frequent deviations in CTV delineations were observed in the ICR, the deviations decreased compared to that in the DR. More specified face-to-face meetings with participating institutions will be necessary to maintain the quality of IMRT in the clinical protocol.

Phase I/II prospective clinical trial for the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer.

OBJECTIVE: The purposes of this trial were to demonstrate the feasibility and effectiveness of the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients in the phase I/II prospective clinical trial. METHODS: Patients with FIGO stage IB2-IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by magnetic resonance imaging were eligible for this clinical trial. The protocol therapy included 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of HBT and pelvic radiotherapy with a central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase II part was 2-year pelvic progression-free survival (PPFS) rate higher than historical control of 64%. RESULTS: Between October 2015 and October 2019, 73 patients were enrolled in the initial registration and 52 patients proceeded to the secondary registration. With the median follow-up period of 37.3 months (range, 13.9-52.9 months), the 2- PPFS was 80.7% (90% confidence interval [CI]=69.7%-88%). Because the lower range of 90% CI of 2-year PPFS was 69.7%, which was higher than the historical control ICBT data of 64%, therefore, the primary endpoint of this study was met. CONCLUSION: The effectiveness of HBT were demonstrated by a prospective clinical study. Because the dose goal determined in the protocol was lower than 85 Gy, there is room in improvement for local control. A higher dose might have been needed for tumors with poor responses.

Clinicopathological and prognostic impact of human epidermal growth factor receptor type 2 (HER2) and hormone receptor expression in uterine papillary serous carcinoma.

Uterine papillary serous carcinoma (UPSC) is a rare and aggressive variant of endometrial carcinoma. Little is known about the pathological and biological features of this tumor. Human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression have an important role in tumor behavior and clinical outcome, but their relevance in UPSC is not clear. In the present study, the immunohistochemical expression of HER2 and HR was assessed in 27 patients with Stage I disease, 13 with Stage II disease, 25 with Stage III disease, and 6 with Stage IV disease. Correlations between HER2 and HR expression and the clinicopathological parameters of UPSC were evaluated using Cox's univariate and multivariate analyses. For all patients, the 5-year recurrence-free survival (RFS) and overall survival (OS) rates were 51% and 66%, respectively; in patients with Stage I, II, III and IV disease, the RFS and OS were 67%/81%, 59%/77%, 43%/54% and 0%/0%, respectively. Of all 71 patients, 14% (10/71) were positive for HER2 and 52% (37/71) were positive for HR. Overexpression of HER2 was correlated with lower OS (P = 0.01), whereas HR overexpression was correlated with higher OS (P = 0.008). In multivariate models, HER2, HR, and histologic subtype were identified as independent prognostic indicators for RFS (P = 0.022, P = 0.018, and P = 0.01, respectively), but HR was the only independent factor associated with OS (P = 0.044). Thus, HER2 and HR are prognostic variables in UPSC, with HR an independent prognostic factor for OS.