Search

Objectives: To assess the predictive value of magnetic resonance imaging for vesicovaginal fistula development in cervical cancer patients with bladder invasion treated with definitive chemoradiotherapy., Methods: A retrospective review was conducted of the medical records of 43 cervical cancer patients with bladder invasion between 1999 and 2015. Bladder invasion was confirmed through magnetic resonance imaging (scores ≥3) or cystoscopic findings, with or without biopsy. Treatment included weekly cisplatin plus pelvic external beam radiotherapy, with extended-field radiotherapy. After external beam radiotherapy, patients received intracavitary brachytherapy or an external beam boost. Vesicovaginal fistula was diagnosed based on reported symptoms and relevant imaging tests during follow-up., Results: The median follow-up period was 67.4 months. The 5-year disease-free and overall survival rates were 66.4 %, and 71.8 %, respectively. Vesicovaginal fistula developed in five patients (12.8 %), with three cases occurring within 1 year post-treatment and two others at 16.7 and 64.5 months, respectively. In multivariate analysis, the height of bladder wall involvement on magnetic resonance imaging was the only significant predictor of vesicovaginal fistula (p = 0.041). Specifically, Vesicovaginal fistula occurred in 25 % of cases when bladder wall involvement was ≥20.3 mm, in 50 % of cases at ≥31.1 mm, and in 75 % of cases at ≥41 mm., Conclusions: The height of bladder wall involvement on magnetic resonance imaging is a significant predictor of vesicovaginal fistula formation in cervical cancer patients with bladder invasion. This finding can aid clinicians in better predicting this complication, improving patient counseling and management strategies., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Purpose: The 2020 World Health Organization classification divided endocervical adenocarcinoma (ADC) into human papillomavirus-associated (HPVA) and human papillomavirus-independent (HPVI) ADCs. This multi-institutional study aimed to investigate the clinical features and prognosis of patients with endocervical ADC based on the updated World Health Organization classification., Methods and Materials: We retrospectively reviewed the 365 patients with endocervical ADC who underwent radical hysterectomy from 7 institutions. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs., Results: Two hundred seventy-five (75.3%) and 90 (24.7%) patients had HPVA and HPVI ADC diagnoses, respectively. In all cases, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 58.2% and 71.3%, respectively. HPVI ADC showed higher rates of local recurrence (25.6% vs 10.9%) and distant metastasis (33.3% vs 17.5%) than HPVA ADC. Multivariate survival analysis revealed that HPVI ADC showed significantly worse DFS (hazard ratio [HR], 1.919; 95% confidence interval [CI], 1.324-2.781; P < .001), distant metastasis-free survival (HR, 2.100; 95% CI, 1.397-3.156; P < .001), and OS (HR, 2.481; 95% CI, 1.586-3.881; P < .001) than HPVA ADC. Patients with gastric- and serous-type HPVI ADC had significantly worse OS than those with other HPVI ADCs (P = .020). Similarly, invasive stratified mucin-producing-type HPVA ADC showed significantly worse OS than other HPVA ADCs (P < .001)., Conclusions: We demonstrated that HPVI ADC exhibited inferior DFS and OS and higher rates of local and distant recurrence compared with HPVA ADC. Gastric- and serous-type HPVI ADCs and invasive stratified mucin-producing-type HPVA ADC showed worse OS than other types of HPVI and HPVA ADCs, respectively. Our observation of significant differences in prognoses according to the histologic types needs to be validated in larger cohorts of patients with endocervical ADC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We conducted a prospective phase II study on whether extended-field irradiation (EFI) confers survival benefits depending on hypoxic markers in locally advanced uterine cervical cancer (LAUCC). RNA-seq was performed to identify immune and hypoxic gene signatures. A total of 288 patients were randomized to either EFI or pelvic radiotherapy (PRT). All patients completed chemoradiotherapy. Overall, significantly higher 5-year para-aortic recurrence free survival (PARFS) rate occurred in EFI (97.6%) than in PRT group (87.2%), with marginal tendency to improve disease-free survival (DFS; 78% vs 70%, P = .066). Subgroup analyses were performed based on carbonic anhydrase 9 (CA9)-only positive, CA9/hypoxia-inducible factor (HIF) double positive and CA9 negative. In the CA9-only positive, EFI successfully increased 5-year PARFS (100% vs 76.4%, P = .010), resulting in significantly improved long-term DFS (85.7% vs 54.7%, P = .023) compared to the PRT, while there was no such benefit of EFI in the CA9/HIFs double positive. RNA-seq analysis identified distinct immune high subgroup with negative correlation with hypoxia gene signatures (R = -.37, P < .01), which showed a higher 5-year DFS than the immune low (P = .032). Hypoxia-related genes were upregulated in the CA9/HIFs double positive compared to CA9 negative (P < .05). Only 17.4% of patients in CA9-negative group showed immune low signatures, while 40.0% of patients in the double-positive group exhibited immune low signatures. In conclusion, EFI improved PARFS significantly in all patients, but therapeutic efficacy of EFI in terms of improved DFS was solely observed in CA9-only positive LAUCC, and not in CA9/HIFs double-positive subgroup. RNA-seq analysis suggested that hypoxia-induced immunosuppression may be related to treatment resistance in LAUCC., (© 2022 UICC.)

Objective: In 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system of uterine cervix cancer, size criteria of primary tumor has been revised. This study aimed to evaluate the validity of this new size criteria (<2, 2-4, and ≧4 cm) in patients who underwent radical hysterectomy and adjuvant radiation therapy (RT) for early cervical cancer., Materials and Methods: We retrospectively examined 312 patients who underwent radical hysterectomy and adjuvant RT for early cervical cancer (IB-IIA) from 2001 to 2014. The effects of clinical and pathological factors on disease-free survival (DFS) and overall survival (OS) were evaluated in univariate and multivariate analyses., Results: After a median follow-up of 71.5 months, the 5-year DFS and OS rates were 89.5% and 94.7%, respectively. The primary tumor size was not a significant factor for DFS (p = 0.382) or OS (p = 0.725) in all patients., Conclusion: Primary tumor size was not a significant factor for survival in patients who received hysterectomy and adjuvant RT for early cervical cancer. Adequacy of new tumor size criteria (<2, 2-4, and ≧4 cm) in new 2018 FIGO stage needs to be validated in further studies., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022. Published by Elsevier B.V.)

Objective: This multi-institutional study aimed to identify the optimal treatment strategy for small cell carcinoma of the cervix., Study Design: We retrospectively collected the medical records of 166 patients diagnosed with small cell carcinoma of the uterine cervix from January 2000 to December 2015 from 13 institutions of the Korean Radiation Oncology Group. After excluding 18 (10.8 %) patients who initially had distant metastasis, the treatment outcomes of 148 patients were analyzed., Results: After a median 46.4 (1.4-231.9) months of follow-up, the 5-year progression-free survival (PFS) and overall survival (OS) rates of all patients were 45.9 % and 63.5 %, respectively. Distant metastasis was the dominant pattern of failure occurring in 67 patients (45.3 %). We stratified the patients according to the primary local treatment: primary surgery (n = 119), primary radiotherapy (RT) (n = 26), and no local treatment group (n = 3). Although the primary RT group had advanced disease (FIGO stage ≧ IIB) more frequently than the primary surgery group (80.8 % vs. 47.9 %), the PFS and OS did not differ between the groups in multivariate analysis., Conclusion: Definitive RT is a reasonable local treatment option for small cell cervical cancer, particularly for advanced cases. Given the high rates of distant relapse, an effective systemic therapy protocol is warranted for small cell cervical cancer patients., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To perform a systematic review and meta-analysis of the impact of brachytherapy (BT) technique (two-dimensional [2D] or three-dimensional image-guided [3D]) on outcomes of cervical cancer patients., Methods: PubMed and EMBASE databases were searched up to April 16, 2019, for studies which evaluated the effect of 3D-BT compared to 2D-BT in cervical cancer. Endpoints included cumulative incidence of severe toxicity, locoregional recurrence-free survival (LRRFS), progression-free survival (PFS), and overall survival (OS). Hazard ratios (HRs) were pooled in the meta-analysis using the random-effects model., Results: Six studies of eight cohorts were included in the quantitative synthesis. The pooled HR regarding toxicity was evaluated in five cohorts in three studies, and the HR of 3D-BT compared to 2D-BT was 0.54 (95% confidence interval [CI] 0.37-0.77). All six studies were included for the synthesis for LRRFS, and the pooled HR favors 3D-BT (0.61 [95% CI 0.40-0.93]). For PFS, three studies were included for analysis and 3D-BT was superior to 2D-BT (HR = 0.75 [95% CI 0.59-0.96]). Five studies were included for the pooled HR regarding OS, and pooled HR of 3D-BT compared to 2D-BT was 0.65 (95% CI 0.40-1.06)., Conclusion: 3D-BT might reduce severe toxicity and improve LRRFS and PFS in patients with cervical cancer. 3D-BT should be considered for standard management of cervical cancer, and efforts for adopting this procedure in Korea should be pursued.

Objective: This study investigated the effect of para-aortic lymph node sampling or dissection in recently revised International Federation of Gynecology and Obstetrics IIIC1p cervical cancer treated with primary surgery and adjuvant radiation therapy with concurrent chemotherapy., Methods: We retrospectively reviewed the records of 343 patients with early-stage cervical cancer and pathologically proven pelvic lymph node metastasis following curative surgery from 2001 to 2014. No patient had imaging evidence of para-aortic lymph node involvement, and all patients received adjuvant concurrent chemotherapy with or without concurrent chemotherapy. We investigated the significance of para-aortic lymph node sampling or dissection on disease-free survival and overall survival., Results: After median follow-up of 58.3 months, 5-year disease-free survival and overall survival in all patients were 69.9 and 80.2%, respectively. Disease-free survival and overall survival did not differ between the para-aortic lymph node dissection group and the No para-aortic lymph node dissection group (P = 0.700 and P = 0.605). However, patients with para-aortic lymph node-positive disease had poorer disease-free survival and overall survival compared with those with para-aortic lymph node-negative disease (P < 0.001 and P < 0.001)., Conclusions: This study found no survival benefit of para-aortic lymph node evaluation among patients with International Federation of Gynecology and Obstetrics IIIC1p cervical cancer who were clinically para-aortic lymph node-negative. Although para-aortic lymph node metastasis is a poor prognosticator, the benefit of para-aortic lymph node dissection in terms of survival needs further investigation., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: The purpose of this study was to evaluate the impact of high-risk factors on the survival of patients with cervical cancer treated with surgery followed by adjuvant chemoradiotherapy., Methods: From 2000 to 2014, medical records of 897 patients with International Federation of Gynecology and Obstetrics stage IB-IIA disease treated with surgery were retrospectively reviewed. Among them, 483 patients with high-risk factors, including pelvic lymph node metastasis, parametrial invasion, or resection margin involvement, were analyzed., Results: The median follow-up time was 57 months (range, 6-205 months). For patients with single and multiple high-risk factors, the 5-year DFS rates were 80.4% and 65.7%, respectively (p < 0.001), and 5-year OS rates were 87.3% and 75.1%, respectively (p = 0.001). Distant metastasis was the most common pattern of recurrence (86.1%). Furthermore, distant metastasis-free survival significantly differed with the number of high-risk factors present (single 82.7% vs. multiple 68.8%, p < 0.001). In the multivariate analysis, while parametrial invasion and resection margin involvement showed no association, the adenocarcinoma histology, pelvic lymph node metastasis, higher metastatic lymph node ratio, and multiple high-risk factors were independent prognosticators associated with poor DFS and OS., Conclusions: Patients with early-stage cervical cancer having multiple high-risk factors, adenocarcinoma histologic type, and pelvic lymph node metastasis accompanied by a higher lymph node ratio after surgery are more likely to have occult distant metastasis. Further, consolidation with systemic chemotherapy after adjuvant therapy might be considered to improve the survival outcome in this patient population., Competing Interests: Declaration of competing interest No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: There is no consensus on whether giving adjuvant concurrent chemoradiotherapy (CCRT) is more effective than adjuvant radiotherapy (RT) alone in patients with early stage cervical cancer and intermediate-risk factor(s). The purpose of this study was to evaluate survival difference according to adjuvant treatment in the intermediate-risk group., Methods: From 2000 to 2014, the medical records of patients with stage IB-IIA cervical cancer and a history of radical hysterectomy with pelvic lymph node dissection, followed by pelvic RT at a dose ≥40 Gy were retrospectively reviewed. Among these, 316 patients with one or more intermediate-risk factor(s) and no high-risk factors were included. The criteria defined the intermediate-risk group as those patients with any of the following intermediate-risk factors: lymphovascular space involvement, over one-half stromal invasion, or tumor size ≥4 cm., Results: The median follow-up duration was 70 months (range: 3-203 months). According to adjuvant treatment (adjuvant RT alone vs. adjuvant CCRT), the 5-year recurrence-free survival rates (90.8% vs. 88.9%, p=0.631) and 5-year overall survival rates (95.9% vs. 91.0%, p=0.287) did not show a significant difference in patients with any of the intermediate-risk factors. In multivariate analysis, a distinct survival difference according to adjuvant treatment was not found regardless of the number of risk factors., Conclusion: The present study showed that giving RT together with chemotherapy is not more effective than RT alone for stage IB-IIA cervical cancer patients with intermediate-risk factor(s)., Trial Registration: ClinicalTrials.gov Identifier: NCT01101451., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Objectives: To perform a systematic review and meta-analysis of the prognostic value of post-treatment ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) in uterine cervical cancer patients treated with radiotherapy (RT) with or without chemotherapy., Methods: PubMed and Embase databases were searched up to July 22, 2018, for studies which evaluated the response outcomes of ¹⁸F-FDG PET following RT, and their prognostic significance in uterine cervical cancer was assessed with overall survival (OS) or progression-free survival (PFS) as endpoints. Hazard ratios (HRs) were meta-analytically pooled using the random-effects model., Results: Eleven studies with 12 patient cohorts including 1,104 patients were included. For a quantitative synthesis of OS, 7 cohorts were included. Two cohorts which reported disease-specific survival instead of OS were also included with flexibility. Pooled HR of complete metabolic response (CMR) compared to partial metabolic response (PMR) was 0.19 (95% confidence interval [CI]=0.11-0.31). Pooled HR of CMR compared to progressive metabolic disease (PMD) was more evident at 0.07 (95% CI=0.04-0.12), and that of CMR compared to both PMR and PMD was 0.20 (95% CI=0.12-0.34). Quantitative synthesis for PFS was performed with a total of 8 cohorts. Pooled HR of CMR was 0.17 (95% CI=0.10-0.29) compared to PMR, 0.02 (95% CI=0.01-0.06) compared to PMD and 0.12 (95% CI=0.07-0.19) compared to both PMR and PMD., Conclusion: Response results of post-RT ¹⁸F-FDG PET were significant prognostic factors in patients with uterine cervical cancer, and ¹⁸F-FDG PET could be a reasonable follow-up imaging modality., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Purpose: We aimed to assess prognostic value of metastatic pelvic lymph node (mPLN) in early-stage cervical cancer treated with radical surgery followed by postoperative chemoradiotherapy. Also, we sought to define a high-risk group using prognosticators for recurrence., Materials and Methods: A multicenter retrospective study was conducted using the data from 13 Korean institutions from 2000 to 2010. A total of 249 IB-IIA patients with high-risk factors were included. We evaluated distant metastasis-free survival (DMFS) and disease-free survival (DFS) in relation to clinicopathologic factors including pNstage, number of mPLN, lymph node (LN)ratio (number of positive LN/number of harvested LN), and log odds of mPLNs (log(number of positive LN+0.5/number of negative LN+0.5))., Results: In univariate analysis, histology (squamous cell carcinoma [SqCC] vs. others), lymphovascular invasion (LVI), number of mPLNs (≤ 3 vs. &gt; 3), LN ratio (≤ 17% vs. &gt; 17%), and log odds of mPLNs (≤ ‒0.58 vs. &gt; ‒0.58) were significant prognosticators for DMFS and DFS. Resection margin involvement only affected DFS. No significant survival difference was observed between pN0 patients and patients with 1-3 mPLNs. Multivariate analysis revealed that mPLN &gt; 3, LVI, and non-SqCC were unfavorable index for both DMFS (p &lt; 0.001, p=0.020, and p=0.031, respectively) and DFS (p &lt; 0.001, p=0.017, and p=0.001, respectively). A scoring system using these three factors predicts risk of recurrence with relatively high concordance index (DMFS, 0.69; DFS, 0.71)., Conclusion: mPLN &gt; 3 in early-stage cervical cancer affects DMFS and DFS. A scoring system using mPLNs &gt; 3, LVI, and non-SqCC could stratify risk groups of recurrence in surgically resected early-stage cervix cancer with high-risk factors.

To determine whether the pelvic lymph node ratio (LNR) has significant prognostic value for survival and disease recurrence in node-positive, early stage cervical cancer patients.The medical records of 872 consecutive women who received postoperative adjuvant chemoradiotherapy were reviewed. Of these, 397 women with pathologically proven lymph nodal metastasis were included in this analysis and categorized into 3 groups according to their LNR: low (<0.1, n = 251), intermediate (0.1-0.4, n = 121), and high (>0.4, n = 25). The association between LNR and oncological outcome was evaluated using the Kaplan-Meier method and multivariate analysis.A total of 13,491 LNs were retrieved from 397 women, with a median harvest of 32 nodes per patient. There was a strong positive correlation between the number of metastatic LNs and LNR (r = 0.83, P < .01). With a median follow-up duration of 48 months, the 5-year overall survival (OS) and disease-free survival (DFS) rates were 73% and 67%, respectively. The OS and DFS curves among the pelvic LNR groups significantly differed: the 5-year OS rates of the low, intermediate, and high pelvic LNR groups were 83%, 66%, and 17% (P < .01), and the 5-year DFS rates were 77%, 56%, and 20% (P < .01), respectively.LNR is an important prognostic factor for survival outcomes in patients with uterine cervical cancer who underwent radical hysterectomy followed by adjuvant chemoradiotherapy.

Purpose: To investigate disease-free survival (DFS) and prognostic factors following the administration of postoperative (chemo)radiotherapy in patients with early-stage cervical cancers., Methods: The medical records of 1,069 patients from 10 participating institutions were reviewed. Statistically and clinically established factors were considered as candidates for constructing the prediction model. This model was validated, using bootstrapping to correct for optimistic bias., Results: The 5-year DFS rate was 81.1%, with a median follow-up period of 59.6 months. The statistically significant prognostic factors were as follows: pelvic lymph node metastasis, histologic type, parametrial invasion, lymphovascular space invasion, and tumor size. The nomogram for DFS was constructed, and it demonstrated a good discrimination performance, with an internally validated concordance index of 0.72., Conclusions: Our predictive model exhibited accurate predictions and may be useful in designing clinical trials to study if further chemotherapy can reduce the recurrence of disease in high-risk patients.

Purpose: We conducted this study to evaluate the outcomes of external-beam radiotherapy tumor boost (EBRT-B) in cervical cancer patients who could not receive intracavitary brachytherapy., Methods: A total of 11 hospitals provided the data of patients who received EBRT-B during the period from January 2005 through October 2012., Results: A total of 75 patients were included. The median radiotherapy dose was 46 Gy (range, 40-54 Gy) for whole pelvis and 24 Gy (range, 9-35 Gy) for EBRT-B. Initial tumor responses assessed at 2 to 6 months after radiotherapy were as follows: 46 with complete response, 22 with partial response, 2 with stable disease, and 3 with progressive disease. After a median follow-up time of 33 months, 30 patients (40.0%) showed disease progression including 21 (28.0%) with local progression. The 5-year local failure-free survival rate was 70.0%. Achieving complete response at the first follow-up visit and an overall treatment time of 53 days or less were significantly related to favorable local failure-free survival. The rate of grade 3 or higher toxicity was 2.6%., Conclusions: Approximately 70% of patients had local tumor control after curative radiotherapy using EBRT-B. Early tumor response and overall treatment time of 53 days or less were closely associated with favorable local control.

Purpose: To determine inter-observer variability in target volume definition of cervical cancer in radical and adjuvant radiotherapy (RT) settings., Methods: Eight physicians contoured CTVs of 2 patients underwent definitive and postoperative RT. Each volume was analyzed using the individual/median volume ratio and generalized conformity index (CIgen). And center of mass (COM) of each contour was calculated. Expert agreement was quantified using an expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE)., Results: For definitive RT, the individual/median volume ratio ranged from 0.51 to 1.41, and CIgen was 0.531. Mean 3-dimensional distances of average to each COM were 7.8 mm. For postoperative RT setting, corresponding values were 0.65-1.38, 0.563, and 5.3 mm. Kappa value of expert agreement was 0.65 and 0.67, respectively. STAPLE estimates of the sensitivity, specificity, and kappa measures of inter-physician agreement were 0.73, 0.98, and 0.65 for the definitive and 0.75, 0.98, and 0.67 for the adjuvant radiotherapy setting. The largest difference was observed in the superior-inferior direction, particularly in the upper vagina and the common iliac area., Conclusion: As there was still some variability in target delineation, more detailed guidelines for target volume delineation and continuing education would help to reduce this uncertainty.

Objective: To investigate the disease course and identify prognostic factors for survival in patients with residual disease according to post-treatment magnetic resonance imaging (MRI) following definitive concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer., Methods: We reviewed clinical data from the medical records of 545 consecutive women with biopsy-proven, International Federation of Gynecology and Obstetrics stage IB2-IVA uterine cervical cancer treated with CCRT. Post-treatment MRI was checked in all patients 3months after CCRT completion. Out of the 545 patients, 53 with residual cervical cancer based on MRI following definitive CCRT were included in this analysis., Results: Thirty-two patients were disease-free at the last follow-up. Of them, 31 had a residual tumor size of ≤2cm. Of these 32 women, 30 showed spontaneous regression of residual tumor during follow-up without salvage treatments, whereas the remaining two were alive with no evidence of disease after salvage surgery and chemotherapy. Disease progression was observed in 21 patients, including 7 local, 8 distant and 6 local and distant failures. Of these 21 women, 13 died of disease, 6 were alive with disease, and 2 remained disease-free after salvage treatments. Initial and residual tumor sizes were significant prognostic factors for overall survival; only residual tumor size was significant for local progression-free survival., Conclusions: About 60% of patients with residual disease detected on post-treatment MRI remained disease-free without further disease progression. Careful observation without immediate salvage treatments might be feasible in selected patients with a residual tumor size ≤2cm., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Purpose: The efficacy of prophylactic extended-field irradiation (EFI) plus concomitant cisplatin in patients with locally advanced uterine cervical cancer (LAUCC) is unknown, nor is it known whether tumor carbonic anhydrase IX (CA9) expression level, a hypoxia marker, influences survival outcome., Material and Methods: We recruited patients with UCC, FIGO stage IB1 with pelvic lymph node (LN) metastases to IVA with negative para-aortic LN on PET/CT. CA9 expression was examined and patients were randomized to either EFI or pelvic only radiotherapy (PRT) in each CA9 group. The primary outcomes were para-aortic recurrence-free survival (PARFS) and disease-free survival (DFS)., Results: Between 2006 and 2011, 79 patients with CA9-positive and 37 with CA9-negative tumors were enrolled, respectively. The median follow-up period was 69.2months (range 6.8-102.1). For CA9-positive patients, 5-year PARFS was 100% and 81.7% for those receiving EFI and PRT (p=0.007), respectively. DFS was 78.6% for EFI and 71.3% for PRT patients (p=0.353). For CA9-negative patients, 5y PARFS was 100% and 94.1% for EFI and PRT (p=0.317), respectively. DFS was 100% for EFI and 70.7% for PRT (p=0.018)., Conclusion: EFI significantly reduced recurrences in PAN in patients with CA9-positive tumors, but survival outcome was not improved, due to high local recurrence and high distant metastases rates. This study indicates the necessity for new therapeutic strategies for LAUCC patients whose tumors show high CA9 expression., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The functional inactivation of TP53 and Rb tumor suppressor proteins by the HPV-derived E6 and E7 oncoproteins is likely an important step in cervical carcinogenesis. We have previously shown siRNA technology to selectively silence both E6/E7 oncogenes and demonstrated that the synthetic siRNAs could specifically block its expression in HPV-positive cervical cancer cells. Herein, we investigated the potentiality of E6/E7 siRNA candidates as radiosensitizers of radiotherapy for the human cervical carcinomas. HeLa and SiHa cells were transfected with HPV E6/E7 siRNA; the combined cytotoxic effect of E6/E7 siRNA and radiation was assessed by using the cell viability assay, flow cytometric analysis and the senescence-associated β-galactosidase (SA-β-Gal) assay. In addition, we also investigated the effect of combined therapy with irradiation and E6/E7 siRNA intravenous injection in an in vivo xenograft model. Combination therapy with siRNA and irradiation efficiently retarded tumor growth in established tumors of human cervical cancer cell xenografted mice. In addition, the chemically-modified HPV16 and 18 E6/E7 pooled siRNA in combination with irradiation strongly inhibited the growth of cervical cancer cells. Our results indicated that simultaneous inhibition of HPV E6/E7 oncogene expression with radiotherapy can promote potent antitumor activity and radiosensitizing activity in human cervical carcinomas.

Aim: To evaluate the efficacy and toxicity of definitive extended-field intensity-modulated radiotherapy (EF-IMRT) with chemotherapy in cervical cancer with para-aortic lymph node (PAN) metastasis., Patients and Methods: The present retrospective cohort study involved 45 consecutive patients. EF-IMRT consisted of 46 Gy to pelvic and para-aortic regions, 14 Gy-boost to gross nodes, and 30 Gy in six fractions of intracavitary brachytherapy. Platinum-based chemotherapy occurred simultaneously., Results: Two-year overall and disease-free survival rates (median follow-up=30 months) were 85.4% and 61.7%, respectively. In 78%, 89%, and 89%, the primary cervical mass, pelvic metastasis, and PAN metastasis exhibited a complete response, respectively. Ten, four, and other four patients exhibited locoregional (including post-treatment residual disease), distant, and combined failure, respectively. The most common severe acute toxicity was hematological (n=36). One and two patients had severe late gastrointestinal and other toxicities, respectively., Conclusion: EF-IMRT (to 60 Gy) plus chemotherapy resulted in good locoregional control, survival rates, and acceptable toxicity., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: To develop a nomogram predicting the risks of distant metastasis following postoperative adjuvant radiation therapy for early stage cervical cancer., Materials and Methods: We reviewed the medical records of 1069 patients from ten participating institutions. Patients were divided into two cohorts: a training set (n=748) and a validation set (n=321). The demographic, clinical, and pathological variables were included in the univariate Cox proportional hazards analysis. Clinically established and statistically significant prognostic variables were utilized to develop a nomogram., Results: The model was constructed using four variables: histologic type, pelvic lymph node involvement, depth of stromal invasion, and parametrial invasion. This model demonstrated good calibration and discrimination, with an internally validated concordance index of 0.71 and an externally validated c-index of 0.65. Compared to FIGO staging, which showed a broad range in terms of distant metastasis, the developed nomogram can accurately predict individualized risks based on individual risk factors., Conclusions: The devised model offers a significantly accurate level of prediction and discrimination. In clinical practice it could be useful for counseling patients and selecting the patient group who could benefit from more intensive/further chemotherapy, once validated in a prospective patient cohort., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the prognostic influence of adenocarcinoma (AC) and adenosquamous carcinoma (ASC) in patients with FIGO stage IB-IIA cervical cancer who received radical hysterectomy followed by adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT)., Methods: We analyzed 1323 patients who satisfied the following criteria: histologically proven squamous cell carcinoma (SCC), AC, or ASC of the uterine cervix; FIGO stage IB-IIA disease; no history of neoadjuvant chemotherapy; and a history of radical hysterectomy with pelvic lymph node (PLN) dissection, followed by postoperative pelvic RT at a dose ≥ 45 Gy. The median age was 50 years. Median RT dose delivered to the whole pelvis was 50.4 Gy, and 219 (16.6%) patients received brachytherapy at a median dose of 24 Gy. Concurrent chemotherapy was delivered to 492 (37.2%) patients., Results: Pathologic risk factors were not different according to pathologic subtype. The median follow-up duration was 75.7 months. Locoregional recurrence-free survival, relapse-free survival (RFS), and overall survival were significantly affected by histology, tumor size, PLN metastasis, parametrial invasion, lymphovascular invasion, and deep stromal invasion. The 5-year RFS rates were 83.7%, 66.5%, and 79.6% in patients with SCC, AC, and ASC histology, respectively (P<0.0001). By multivariate analysis, AC histology was the only significant prognostic factor affecting all survival outcomes., Conclusions: AC histology was associated with poor survival outcomes in patients with FIGO stage IB-IIA cervical cancer who received adjuvant RT or CCRT. Prognosis of ASC histology was closer to that of SCC histology than that of AC histology., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: A nomogram is a predictive statistical model that generates the continuous probability of a clinical event such as death or recurrence. The aim of the study was to construct a nomogram to predict 5-year overall survival after postoperative radiation therapy for stage IB to IIA cervical cancer., Methods and Materials: The clinical data from 1702 patients with early-stage cervical cancer, treated at 10 participating hospitals from 1990 to 2011, were reviewed to develop a prediction nomogram based on the Cox proportional hazards model. Demographic, clinical, and pathologic variables were included and analyzed to formulate the nomogram. The discrimination and calibration power of the model was measured using a concordance index (c-index) and calibration curve., Results: The median follow-up period for surviving patients was 75.6 months, and the 5-year overall survival probability was 87.1%. The final model was constructed using the following variables: age, number of positive pelvic lymph nodes, parametrial invasion, lymphovascular invasion, and the use of concurrent chemotherapy. The nomogram predicted the 5-year overall survival with a c-index of 0.69, which was superior to the predictive power of the International Federation of Gynecology and Obstetrics (FIGO) staging system (c-index of 0.54)., Conclusions: A survival-predicting nomogram that offers an accurate level of prediction and discrimination was developed based on a large multi-center study. The model may be more useful than the FIGO staging system for counseling individual patients regarding prognosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Although tumor size is a prognostic factor in cervical cancer patients, its role in the diagnosis of lymph node metastasis is unclear. We therefore evaluated the diagnostic value of tumor and lymph node size compared with lymph node size alone in the detection of metastatic lymph nodes in patients with early-stage cervical cancer.We retrospectively evaluated 699 patients with International Federation of Obstetrics and Gynecology stage IB1-IIA cervical carcinoma who underwent magnetic resonance imaging before lymphadenectomy involving all visible lymph nodes in the surgical fields. Seven nodal groups were evaluated: para-aortic, both common iliac, both external iliac, and both internal/obturator areas. Pathologic evaluation was the diagnostic standard. The largest short-axis diameter of lymph nodes in each region and the largest tumor diameters were measured in magnetic resonance images. The value of additional information from magnetic resonance images was evaluated by receiver operating characteristic curve analysis.Of the 699 patients, 108 (15.8%) had lymph node metastases. The areas under the curve for measurements of lymph node size, tumor size, and both were (A) 0.635, (B) 0.706, and (C) 0.742, respectively (A vs B, P = 0.006; A vs C P < 0.001; B vs C, P = 0.002).This study illustrates that magnetic resonance imaging measurements of tumor size and tumor size plus lymph node size showed a higher diagnostic performance than lymph node size alone in predicting lymph node metastasis in patients with early-stage cervical cancer.

Objective: To develop a nomogram for predicting the probability of 5year survival after definitive concurrent chemoradiotherapy (CCRT) in locally advanced cervical cancer (LACC)., Methods: Between 1998 and 2008, 209 patients with LACC were treated with definitive CCRT. Multivariate analysis using Cox proportional hazards regression model was performed. A nomogram based on this Cox model was developed and internally validated by bootstrapping. Its performance was assessed by using the concordance index and a calibration curve., Results: The median age was 55years (range, 26-78). Of the patients, 9, 16, 129, 3, 42 and 10 had FIGO stage IB2, IIA, IIB, IIIA, IIIB, and IVA disease, respectively. Histology revealed that 190, 13, 4, and 2 patients had squamous, adenocarcinoma, adenosquamous, and small cell cervical cancer, respectively. In 91 patients, PET/CT was performed before CCRT. The median follow-up period was 51months (range, 6-151) and there were 50 (23.9%) disease-related deaths. Multivariate regression analysis revealed that histology, tumor size, and paraaortic lymph node metastasis (defined by MRI), but not PET/CT before CCRT, were independent predictors of overall survival. A nomogram for predicting the 5year survival incorporating these three significant variables was constructed. The concordance index was 0.69. The predictive ability of the nomogram proved to be superior to that of the FIGO staging system (p<0.05)., Conclusions: The nomogram was a better predictive model for overall survival than the FIGO staging system. If externally validated, it could be used to counsel patients with LACC who must choose additional treatment modalities after definitive CCRT., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with curative intent in patients with stage IVB cervical cancer initially presenting with paraortic and left supraclavicular lymph node metastases., Methods and Materials: The medical records of 25 patients with both paraortic and left supraclavicular lymph nodal metastases (group I) were reviewed and compared with those of 101 women with paraortic lymph node metastases alone (group II). Group I received a mean 59.4 Gy to the paraortic and left supraclavicular areas and 50.4 Gy to the pelvis, followed by 30 Gy of high-dose-rate brachytherapy in 6 fractions. Group II received the same dose to the paraortic area and pelvis followed by intracavitary brachytherapy. All patients received platinum-based chemotherapy simultaneously., Results: Of the 25 patients in group I, 16 (64%) experienced acute grade 3-4 hematologic toxicities, and 1 had a late grade 3 genitourinary toxicity. Complete responses, including the primary mass and pelvic, paraortic, and left supraclavicular lymph nodes, were observed in 13 patients (52%). At a median follow-up of 32 months for surviving patients, 3 experienced in-field failure, 6 showed distant failure, and 9 showed both. The 3-year overall and disease-free survival rates were 49% and 33%, respectively. In comparison, of the 101 patients in group II, 16 showed in-field failure, 14 experienced distant failure, and 11 showed both. The 3-year overall and disease-free survival rates were 69% and 57%, respectively., Conclusions: Curative CCRT is feasible in patients with stage IVB cervical cancer presenting with paraortic and left supraclavicular lymph nodal metastases, with acceptable late toxicity and high response rates, despite high rates of acute hematologic toxicity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim and Background: We reviewed the long-term clinical outcomes of patients treated with cisplatin-based concurrent chemoradiotherapy (CCRT) incorporating high-dose-rate (HDR) intracavitary brachytherapy (ICBT) in terms of toxicity, local control and survival rates. In addition, we identified prognostic factors for overall and disease-free survival., Methods and Study Design: . Two hundred and nine patients with stage IB2-IVA cervical cancer underwent curative cisplatin-based CCRT plus HDR ICBT. Women with stage IB2-IIB disease were given 41.4 Gy of external radiotherapy followed by 35 Gy (in 7 fractions) of ICBT. Women with stage IIIA-IVA were given 50.4 Gy followed by 30 Gy (in 6 fractions) of ICBT. Patients with parametrial disease or pelvic lymphadenopathy were given parametrial boosts via external beam radiation at a dose of up to 65 Gy to thickened and 60 Gy to unthickened parametrial regions., Results: One hundred and thirty (62%) patients experienced acute grade 3-4 hematological toxicities and 11 (5%) patients had late grade 3 gastrointestinal or genitourinary complications. Complete responses occurred in 168 (80%) women as determined by clinical and imaging studies. The median follow-up period was 52 months for surviving patients and the 5-year overall and disease-free survival rates were 74% and 67%, respectively. Multivariate analysis indicated that tumor size and paraaortic lymph node involvement were prognostically significant in terms of overall survival, and that tumor diameter was a significant prognostic factor and pelvic lymph node status a marginally significant prognostic factor for disease-free survival., Conclusions: Patients treated with our current HDR ICBT protocol have acceptably low late complication rates and local control and survival rates comparable to those reported in other studies. Tumor diameter was an important prognostic factor in terms of both overall and disease-free survival, emphasizing the need for modern ICBT methodologies.

Aims and Background: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy or radiotherapy alone in elderly patients with locally advanced cervical carcinoma (stage IB2-IVA)., Methods and Study Design: We retrospectively reviewed the medical records of 105 women aged 265 years who received radiotherapy (group I, n=61) or concurrent chemoradiotherapy (group II, n=44). Patients received a median dose of 76.4 Gy to point A, including 30-35 Gy of high-dose intracavity brachytherapy. The concurrent chemoradiotherapy group received platinum-based chemotherapy., Results: The median follow-up was 65 months for surviving patients. There was no significant difference in compliance to radiotherapy between the two groups. Most acute toxicities were hematologic; acute hematologic and gastrointestinal toxicity were significantly more common in group II. Five-year overall survival and cancer-specific survival rates were, respectively, 53.5% and 66.6% in group I and 61.8% and 68.8% in group II. Performance status, comorbidity index, tumor size, and stage were independent prognostic factors for overall survival, whereas stage was the only prognostic factor for cancer-specific survival., Conclusions: The analysis showed no benefit of concurrent chemoradiotherapy with respect to overall survival and cancer-specific survival in elderly women. A prospective study is needed to determine the role of concurrent chemoradiotherapy in this population.

Aims and Background: The prognosis for recurrent cervical carcinoma following initial surgery is dismal even when aggressive radiotherapy or salvage surgery is used. We retrospectively reviewed hospital records to evaluate the efficacy and feasibility of concurrent chemoradiotherapy as a salvage treatment., Methods: From 1999 to 2007, 47 patients received salvage chemoradiotherapy. Involved-field irradiation was delivered at a median dose of 64.8 Gy (range, 36-100.2), including brachytherapy boost in 10 patients. Pelvic re-irradiation was performed in 4 of the 12 women who had a previous history of pelvic radiotherapy. All but one patient received cisplatin-based concomitant chemotherapy during radiotherapy., Results: The median overall follow-up period was 27 months and for surviving patients was 57 months. The interval between initial surgery and recurrence was 22 months (range, 4-203), and the median recurrent mass size was 4 cm (range, 0.5-11). In 34 patients, recurrent tumors were confined to the pelvis (21 central and 13 peripheral). Grade 3-4 acute hematologic toxicity was the most frequent toxicity and was observed in 29 (62%) women. Five-year actuarial cumulative incidence of severe gastrointestinal and genitourinary toxicity was 13% and 7%, respectively. Thirty-three patients (70%) showed a complete response and 9 (19%) a partial response following salvage chemoradiation. Five-year overall and disease-free survival rates were 44% and 41%, respectively., Conclusions: Salvage chemoradiotherapy appears to be a feasible treatment option for women with recurrent cervical carcinoma following surgery. The treatment had a high salvage rate and acceptable late complication rate, despite being associated with substantial acute toxicity.

Purpose: To determine the efficacy and toxicity of extended-field radiotherapy (RT) with concurrent platinum-based chemotherapy in patients with uterine cervical carcinoma and positive para-aortic nodes., Methods and Materials: We retrospectively reviewed the results for 33 women with Stage IB-IVB cervical cancer. Each patient had received 59.4 Gy, including a three-dimensional conformal boost to the para-aortic lymph nodes and 41.4-50.4 Gy of external beam radiotherapy to the pelvis. Each patient also underwent six or seven applications of high-dose-rate brachytherapy (median, 5 Gy to point A at each session)., Results: The median follow-up period of surviving patients was 39 months. The most common acute toxicity was hematologic, observed in 23 women. Severe acute and late gastrointestinal toxicity was observed in 3 and 4 patients, respectively. More than three-quarters of patients showed a complete response, encompassing the primary mass, metastatic pelvic, and para-aortic lymph nodes. Of the 33 women, 15 had no evidence of disease, 6 had persistent disease, 4 developed in-field failures, and 6 developed distant failures. The 5-year overall and disease-free survival rate was 47% and 42%, respectively., Conclusion: Concurrent chemoradiotherapy with extended-field radiotherapy is feasible in women with uterine cervical carcinoma and positive para-aortic lymph nodes, with acceptable late morbidity and a high survival rate, although it was accompanied by substantial acute toxicity.

Objective: To compare monthly fluorouracil (FU) plus cisplatin and weekly cisplatin concurrent with radiotherapy for locally advanced cervical cancer., Methods: A total of 158 patients (stages IIB through IVA) without para-aortic lymph nodes were randomized to receive 3 monthly cycles of FU (1000 mg/m2/day i.v.) plus cisplatin (20 mg/m2/day i.v.) for 5 days (group I, n=79) or 6 cycles of weekly cisplatin (30 mg/m2 i.v.) (group II, n=79), concurrent with definitive radiotherapy. Radiotherapy consisted of external irradiation to the whole pelvis of 41.4-50.4 Gy in 23-28 fractions plus high-dose rate (HDR) intracavitary brachytherapy (30-35 Gy in 6-7 fractions) to point A, together with a parametrial boost. Compliance with treatment, toxicity, response, and survival was analyzed and compared., Results: Of the 158 women, 155 women were eligible for analysis; the median follow-up of surviving patients was 39 months. Full planned chemoradiotherapy was delivered to 47 (60%) and 55 (71%) patients in groups I and II, respectively. The incidence of acute grade 3/4 hematologic toxicity was 43% and 26% (p=0.037). The complete response rate of each group was 91%. Four-year overall and progression-free survival rates were 70% and 67%, respectively, in group I and 67% and 66%, respectively, in group II., Conclusions: The regimen of chemoradiation using weekly cisplatin significantly improves compliance with treatment and reduces acute hematologic toxicity, while not affecting response and survival rates.