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Background: Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, well-planned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests., Methods: The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m²), 4-6 times administered intravenously. The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs., Trial Registration: ClinicalTrials.gov Identifier: NCT05421650; Clinical Research Information Service Identifier: KCT0007137., Competing Interests: Yong Bae Kim received research funding from the National R&D Program for Cancer Control through the National Cancer Center (NCC) funded by the Ministry of Health & Welfare, Republic of Korea (HA22C0021) and 2023 Bio Industry Technology Development Project funded by Ministry of Trade, Industry and Energy (20024089). Asima Mukhopadhyay received honoraria from the National R&D Program for Cancer Control through the National Cancer Center (NCC) funded by the Ministry of Health & Welfare, Republic of Korea (HA22C0083) for her lecture presented at the 2022 Asian Society of Gynecologic Oncology (ASGO) webinar. Nirmala Chandralega Kampan received support for attending the meeting from Roche., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

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.)

This study is an international multi-institutional retrospective study comparing the clinical outcomes between intracavitary brachytherapy (ICBT) and the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients treated with definitive radiation therapy. Locally advanced cervical cancer, the initial size of which is larger than 4 cm and treated by concurrent chemoradiotherapy and image-guided adaptive brachytherapy, were eligible for this retrospective study. Patients who received HBT at least once were included in the HBT group, and patients who received only ICBT were included in the ICBT group. Anonymized data from 469 patients from 13 institutions in Japan, one from Korea and one from Thailand, were analyzed. Two hundred eighty and 189 patients were included in the ICBT group and the HBT group, respectively. Patients in the HBT group had more advanced stage, non-Scc histopathology, a higher rate of uterine body involvement, larger tumor at diagnosis, larger tumor before brachytherapy and a lower tumor reduction ratio. With a median follow-up of 51.3 months (2.1-139.9 months), 4-y local control (LC), progression-free survival (PFS) and overall survival (OS) for the entire patient population were 88.2%, 64.2% and 83%, respectively. The HBT group received a higher HR-CTV D90 than that of the ICBT group (68.8 Gy vs 65.6 Gy, P = 0.001). In multivariate analysis, the non-Scc histological subtype, HR-CTV D95 ≤ 60 Gy, reduction ratio ≤ 29% and total treatment time (TTT) ≥ 9 weeks were identified as the independent adverse prognostic factors for LC. Regarding LC, no difference was found between ICBT and HBT (4-y LC 89.3% vs 86.8%, P = 0.314). After adjustment for confounding factors by propensity score matching, no advantage of applying HBT was demonstrated regarding LC, PFS, or OS. Despite the fact that HBT patients had more adverse clinical factors than ICBT patients, HBT delivered a higher dose to HR-CTV and resulted in comparable LC., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: This study aimed to evaluate the oncologic outcomes according to disease burden in uterine cervical cancer patients with metachronous distant metastases., Methods: Between 2005 and 2015, 163 patients with metachronous distant metastases from uterine cervical cancer after receiving a definitive therapy were evaluated at seven institutions in Korea. Low metastatic burden was defined as less than 5 metastatic sites, whereas high metastatic burden was others. Each metastasis site was divided based on the lymph node (LN) and organs affected. The overall survival (OS) and progression-free survival (PFS) were assessed. Cox proportional hazards models, including other clinical variables, were used to evaluate the survival outcomes., Results: The median follow-up duration was 22.2 months (range: 0.3-174.8 months). Para-aortic LNs (56.4%), lungs (26.4%), supraclavicular LNs (18.4%), and peritoneum (13.5%) were found to be the common metastasis sites. Among 37 patients with a single metastasis, 17 (45.9%) had LN metastases and 20 (54.1%) had organ metastases. The 1- and 2-year OS rates were 73.9% and 55.0%, respectively, whereas the PFS rates were 67.2% and 42.9%, respectively. SCC Ag after recurrence and high metastatic burden were significant factors affecting the OS (p=0.004 and p<0.001, respectively). Distant organ recurrence, short disease-free interval (≤2 years), and high metastatic burden were unfavorable factors for PFS (p=0.003, p=0.011, and p=0.002, respectively)., Conclusion: A favorable oncologic outcome can be expected by performing salvage treatments in selected patients with a long disease-free interval, low metastatic burden, and/or lymphatic-only metastasis., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2022. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: To propose and evaluate an active method for sparing the small bowel in the treatment field of cervical cancer brachytherapy by prone position procedure., Methods: The prone position procedure consists of five steps: making bladder empty, prone-positioning a patient on belly board, making the small bowel move to abdomen, filling the bladder with Foley catheter and finally turning the patient into the supine position. The proposed method was applied for the treatment of seven cervical cancer patients. Its effectiveness was evaluated and a correlation between the patient characteristics and the volumetric dose reduction of small bowel was also investigated. Brachytherapy treatment plans were built before and after the proposed method, and their dose-volume histograms were compared for targets and organs-at-risk. In this comparison, all plans were normalized to satisfy the same D90% for high-risk clinical target volume., Results: For the enrolled patients, the average dose of small bowel was significantly reduced from 75.2 ± 4.9 Gy before to 60.2 ± 4.0 Gy after the prone position procedure, while minor dosimetric changes were observed in rectum, sigmoid and bladder. The linear correlation to body mass index, thickness and width of abdominopelvic cavity and bladder volume were 76.2, 69.7, 28.8 and -36.3%, respectively., Conclusions: The application of prone position procedure could effectively lower the volumetric dose of the small bowel. The dose reduction in the small bowel had a strong correlation with the patient's obesity and abdominal thickness. This means the patients for whom the proposed method would be beneficial can be judiciously selected for safe brachytherapy., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study aimed to validate the performance of the Korean Gynecologic Oncologic Group (KGOG)-1024 risk model in predicting the risk of distant failure after chemoradiation in patients with locally advanced cervical cancer (LACC)., Methods: In a retrospective cohort of 297 patients who received concurrent chemoradiation for advanced cervical cancer, individual risk was calculated using the KGOG-1024 risk model. The cohort was categorized into three risk groups (low-, intermediate-, and high-risk groups) according to the calculated risk. The means of the calculated and observed risks were compared within each group., Results: The study population was classified into low-, intermediate-, and high-risk groups according to the KGOG-1024 risk model (27.2%, 49.3%, and 23.5% of patients, respectively). The calculated and observed 5-year cumulative incidence rates were 12.4% vs. 16.4% in the low-risk group, 23.2% vs. 25.9% in the intermediate-risk group, and 50.7% vs. 36.3% in the high-risk group. Overall, the calculated and observed risk was 26.7% vs. 25.6%., Conclusions: The KGOG-1024 risk assessment model accurately predicted distant recurrence after chemoradiation in patients with LACC, especially in the low- and intermediate-risk groups. The model may be helpful for identifying patients for future trials assessing the possible benefit of adjuvant systemic treatment after chemoradiation., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The majority of uterine cervical cancer is known to be related to human papillomavirus (HPV), and HPV-related tumors are known to be radio-sensitive. In the management of HPV-related oropharyngeal cancer, de-intensification of treatment has been attempted; however, no such attempt is performed in the management of cervical cancer. The aim of this study was to identify a group of patients who can safely be treated by de-escalated treatment intensity., Methods: From the Asian international multi-institutional retrospective study involving 13 Japanese, one Thailand, and one Korean institutions based on 469 patients, squamous cell carcinoma (Scc), tumor reduction ratio ≥29%, tumor size before brachytherapy ≤4 cm, and total treatment time (TTT) <9 weeks were identified as factors having an influence on local control. Based on these findings, low-risk patients having these four factors were extracted, and treatment outcomes categorized in 10 Gy increment of CTV HR D 90 were compared., Results: Among 469 patients, 162 patients (34.5%) met the criteria of low-risk group, and 63, 41, 43, and 15 patients were categorized in CTV HR D 90 50-60 Gy, 60-70 Gy, 70-80 Gy, and >80 Gy, respectively. While 4-y progression-free survival ranged from 66 to 80%, 4-y local control was consistently over 90% in every dose group. Rectum and bladder D 2cc and incidence of late adverse events decreased as CTV HR D 90 decreased., Conclusions: The low-risk patients achieved favorable local control with CTV HR D 90 <80 Gy. A personalized treatment strategy based on tumor response could also be adopted for cervical cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to compare the clinical outcomes of chemoradiotherapy with or without bevacizumab in patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer., Methods: 41 patients with stage IVB cervical cancer who underwent chemoradiotherapy between August 2015 and December 2017 were retrospectively analyzed. This study included 11 patients who received bevacizumab before or after radiotherapy (group A) and 30 patients who received conventional chemoradiotherapy without bevacizumab (group B). We excluded the following patients: those with dual primary cancers; those whose pathologic diagnosis was neither squamous cell carcinoma nor adenocarcinoma; those who did not undergo radiotherapy; or those from whom follow-up data could not be collected. We analyzed the treatment responses, toxicities, progression-free survival, and overall survival rates., Results: A total of 41 patients were included in the analysis. The median follow-up was 19 months (range 3-108). The response rates at 3 months after treatment were 90.9% in group A and 83.3% in group B (p=0.54). After completing all treatments, the complete response rates were 81.8% in group A and 47% in group B (p=0.04). Grade ≥3 gastrointestinal toxicities, including bleeding, fistula, perforation, and obstruction, were more frequent in group A (54.5%) than in group B (6.7%) (p=0.003). The 12 month progression-free survival and overall survival rates were similar in both arms (12 month progression-free survival: 45.5% vs 46.7%, respectively, p=0.22; 12 month overall survival: 81.8% vs 72.9%, respectively, p=0.57). Patients with node-only metastasis had better 12 month progression-free survival in group B than in group A (59.1% vs 42.9%, respectively, p=0.04). However, the responses to both treatments did not differ in patients with organ metastasis., Conclusions: Bevacizumab for stage IVB cervical cancer is associated with higher complete response rates. However, patients treated with bevacizumab experienced more bowel toxicities. Bevacizumab did not improve progression-free survival among patients with node-only metastasis., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: High rate of false-positive tests is a major obstacle to use human papillomavirus (HPV) detection as a diagnostic tool for high-grade squamous intraepithelial lesions or cervical cancer (HSIL+). We investigated whether type-specific viral load or physical state of HPV 16, 18, and 58 are useful biomarkers for HSIL+., Materials and Methods: Type-specific viral loads of E6 and E2 genes in cervical cells from 240, 83, and 79 HPV 16-, 18-, and 58-infected women, respectively, were determined using real-time polymerase chain reaction. Viral loads were normalized to cellular DNA (copy/cell). Total and integrated viral loads and physical state were compared between HSIL+ and controls, and diagnostic value was determined using receiver operating characteristic analysis., Results: Viral loads of HPV 16, 18, and 58 were significantly different in lesions in the same pathologic grade. High type-specific total viral loads were significantly associated with HSIL+ (odds ratio [OR], 14.065, 39.472, and 7.103 for HPV 16, 18, and 58, respectively). High integrated viral load was related to HSIL+ in women with HPV 16 (OR, 8.242), and integrated state was associated with HSIL+ in women with HPV 18 (OR, 9.443). Type-specific total viral load was significantly associated with HSIL+ (area under curve, 0.914, 0.937, and 0.971 for HPV 16, 18, and 58, respectively), indicating an excellent performance in detecting HSIL+., Conclusion: Type-specific total viral load may be a powerful diagnostic marker for HSIL+ in HPV 16-, 18-, and 58-infected HSIL+ lesions. If demonstrated in all other high-risk HPV types, this method can lead to a paradigm shift in the strategy of equivocal cytologic abnormalities.

The present study investigated the association between single nucleotide polymorphisms (SNPs) in immune- or DNA repair-related genes and the integration pattern of human papillomavirus (HPV), a promising prognostic marker in cervical cancer. The HPV integration patterns of cervical cancer patients were determined by polymerase chain reaction and in situ hybridization, and categorized as episomal (group A), single-copy or multi-copy tandem repetition integrated (group B), and undetectable HPV types (group C). After sample and SNP quality control, 166,505 SNPs in 161 samples (38, 111, and 12 patients in groups A, B, and C, respectively) were examined. None of the SNPs reached genome-wide significance, and several candidate SNPs for future study were selected, including rs10999435 on chromosome 10q22, rs1322054 on chromosome 9q32-33, and rs10902171 on chromosome 11p15. Luciferase assay identified rs1322054 as the primary functional variant to regulate gene expression in immune cell. Further studies are needed to determine the genetic background of different integration patterns of HPV in cervical cancer patients.

Human leukocyte antigen (HLA) class II alleles have been previously associated with cervical cancer. However, these associations vary widely across racial and ethnic groups. Therefore, we evaluated the effect of HLA class II alleles on cervical cancer in a Korean population. HLA-DRB1, HLA-DQB1, and HLA-DQA1 alleles were analyzed in 457 cervical cancer patients and compared to those of 926 control subjects. The odds ratio (OR) of each allele between the patients and controls was calculated using the logistic regression model. Patients, had significantly lower frequencies of HLA-DRB1 and HLA-DQB1 alleles than control subjects: HLA-DRB1*13:02:01 (4.4% vs 8.8%; OR 0.48, 95% confidence interval (CI) 0.27-0.84; p = 0.001), HLA-DRB1*04:06 (2.1% vs 4.7%; OR 0.44, 95% CI 0.20-0.97; p = 0.033), and HLA-DQB1*06:04:01 (2.3% vs 5.0%; OR 0.46, 95% CI 0.22-0.94; p = 0.021). No significant association was observed for HLA-DQA1. Protective associations between HLA-DRB1*13:02, HLA-DRB1*04:06, and HLA-DQB1*06:04 alleles and cervical cancer were found in the Korean population., (Copyright © 2018. Published by Elsevier Inc.)

Background: The aim of the present study was to verify the dosimetric accuracy of two-dimensional (2D) in vivo rectal dosimetry using an endorectal balloon (ERB) with unfoldable EBT3 films for high-dose-rate (HDR) brachytherapy for cervical cancer. The clinical applicability of the technique was discussed., Material and Methods: ERB inflation makes the EBT3 films unrolled, whereas its deflation makes them rolled. Patient-specific quality assurance (pQA) tests were performed in 20 patient plans using an Ir-192 remote afterloading system and a water-filled cervical phantom with the ERB. The dose distributions measured in ERBs were compared with those of the treatment plans., Results: The absolute dose profiles measured by the ERBs were in good agreement with those of treatment plans. The global gamma passing rates were 96-100% and 91-100% over 20 pQAs under the criteria of 3%/3 mm and 3%/2 mm, respectively, with a 30% low-dose threshold. Dose-volume histograms of the rectal wall were obtained from the measured dose distributions and showed small volume differences less than 2% on average from the patients' plans over the entire dose interval. The positioning error of the applicator set was detectable with high sensitivity of 12% dose area variation per mm. Additionally, the clinical applicability of the ERB was evaluated in volunteers, and none of them felt any pain when the ERB was inserted or removed., Conclusions: The 2D in vivo rectal dosimetry using the ERB with EBT3 films was effective and might be clinically applicable for HDR brachytherapy for cervical and prostate cancers to monitor treatment accuracy and consistency as well as to predict rectal toxicity.

Zinc finger with KRAB and SCAN domain 3 (ZKSCAN3) upregulates genes encoding proteins involved in cell differentiation, proliferation and apoptosis. ZKSCAN3 has been reported to be overexpressed in several human cancers such as colorectal cancer and prostate cancer and is proposed as a candidate oncoprotein. However, the molecular mechanism by which ZKSCAN3 participates in carcinogenesis is largely unknown. Here, we evaluated ZKSCAN3 expression in uterine cervical cancers (CC) by immunohistochemistry using formalin-fixed, paraffin-embedded tissues from 126 biopsy samples from 126 patients. The clinicopathological findings were analyzed and compared with ZKSCAN3 expression levels. ZKSCAN3 was strongly overexpressed in CCs compared to adjacent non-neoplastic cervical mucosa tissues. Moreover, a gene copy number assay showed amplified ZKSCAN3 in CC samples. ZKSCAN3 overexpression was also significantly associated with poor overall survival of the patients. Overall, our findings indicate that ZKSCAN3 overexpression is a frequent event in uterine CC and is correlated with a poor clinical outcome. ZKSCAN3 could be developed as a molecular marker for prognostic prediction and early detection.

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: The standard chemoradiation therapy currently used for locally advanced cervical cancer (LACC) patients does not reflect the biological heterogeneity of this disease, and there is an increasing need for the development of biomarkers that can help guide the individualized treatment regimens. The purpose of this study was to investigate the prognostic value of the integration pattern of human papillomavirus (HPV) in LACC patients., Methods and Materials: The HPV integration pattern was determined by in situ hybridization and polymerase chain reaction, and the tumors were classified as the episomal pattern (group A), as the single-copy integrated or multicopy tandem repetition-integrated pattern (group B), or as undetectable HPV (group C). Ninety-eight LACC patients were included in a development dataset and 106 independent patients in a validation dataset. The multivariate Cox model was used to examine the effect of the HPV integration pattern on disease-free survival (DFS). The model was validated internally by the leave-one-out cross-validation method and externally by an independent dataset., Results: After adjustment for significant prognostic factors (stage, histologic grade, histologic type, and tumor size), the HPV integration pattern was significantly associated with DFS in the development (P=.032) and validation (P=.023) datasets. Survival was worst in group C and best in group A. The multivariate model with HPV integration pattern as an explanatory variable showed good discrimination ability and could separate patients with different risk profiles., Conclusions: This study identified the HPV integration pattern, as determined by in situ hybridization and polymerase chain reaction, as a strong prognostic biomarker for DFS in LACC patients treated by chemoradiation therapy. This finding may open the possibility of personalized treatment of these patients., (Copyright © 2017. Published by Elsevier Inc.)

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.

Purpose: To analyze the toxicities and dose-volume histogram parameters of external-beam and magnetic resonance imaging-based intracavitary brachytherapy in cervical cancer patients., Methods and Materials: Acute and late toxicities were assessed in 135 patients divided into four groups: group 1, grade 0; group 2, grades 1-4; group 3, grades 0-1; and group 4, grades 2-4. The doses at the International Commission on Radiation Units and Measurements (D ICRU ) and minimum doses to the most exposed 0.1, 1, 2, and 5 cc (D 0.1cc , D 1cc , D 2cc , and D 5cc ) of normal organs were calculated as equivalent doses in 2 Gy (α/β = 3)., Results: The median follow-up was 35.2 months. For rectum, D ICRU , D 0.1cc , D 1cc , and D 2cc were significantly different between groups 1 and 2 and D ICRU , D 0.1cc , and D 1cc between groups 3 and 4. For bladder, D 0.1cc , D 1cc , and D 2cc were significantly different between groups 1 and 2 and D ICRU , D 1cc , D 2cc , and D 5cc between groups 3 and 4. Grade 2-4 bladder toxicity occurred in fewer patients with D 2cc  ≤ 95 Gy than those with D 2cc  > 95 Gy (7% vs. 22%, p = 0.014)., Conclusions: D ICRU , D 0.1cc , D 1cc , and D 2cc are relevant for predicting late rectal toxicities. The patients with bladder D 2cc  > 95 Gy are required to be in close observation for severe late toxicities., (Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this work was to identify prognostic factors for survival after magnetic resonance image (MRI)-guided brachytherapy combined with external beam radiotherapy for cervical cancer., Material and Methods: External beam radiotherapy of 45-50.4 Gy was delivered by either three-dimensional conformal radiotherapy or helical tomotherapy. Patients also received high-dose-rate MRI-guided brachytherapy of 5 Gy in 6 fractions., Results: We analyzed 128 patients with International Federation of Gynecology and Obstetrics stage IB-IVB cervical cancer who underwent MRI-guided brachytherapy. Most patients (96 %) received concurrent chemotherapy. Pelvic lymph node metastases and para-aortic lymphadenopathies were found in 62 % and 14 % of patients, respectively. The median follow-up time was 44 months. Complete remission was achieved in 119 of 128 patients (93 %). The 5‑year local recurrence-free, cancer-specific, and overall survival rates were 94, 89, and 85 %, respectively. Negative pelvic lymphadenopathy, gross tumor volume (GTV) dose covering 90 % of the target (GTV D90) of >110 Gy, and treatment duration ≤56 days were associated with better overall survival in univariate analyses. Multivariable analysis showed that GTV D90 of >110 Gy and treatment duration ≤56 days were possibly associated with overall survival with near-significant P-values of 0.062 and 0.073, respectively., Conclusions: The outcome of MRI-guided brachytherapy combined with external beam radiotherapy in patients with cervical cancer was excellent. GTV D90 of >110 Gy and treatment duration ≤56 days were potentially associated with overall survival.

Background: Anyplex II HPV HR (Anyplex&#95;HR; Seegene, Seoul, Korea) is a new multiplex real-time polymerase chain reaction assay for screening cervical cancer, and it is designed to detect 14 high-risk human papillomaviruses along with all the genotype information in a single tube. The aim of this study was to evaluate the performance of the Anyplex&#95;HR in comparison to that of the Cobas 4800 HPV (Cobas&#95;4800; Roche Molecular Diagnostics, Pleasanton, CA, USA) and the Hybrid capture 2 (HC2; Qiagen GmbH, Hilden, Germany)., Methods: The performance of the Anyplex&#95;HR for high-risk human papillomavirus genotype detection was prospectively evaluated against that of the HC2 and the Cobas&#95;4800 at the National Cancer Center using 400 cervical samples. All discrepant samples were confirmed by polymerase chain reaction with type-specific primers followed by sequencing., Results: The overall agreement and kappa value of the Anyplex&#95;HR with the Cobas&#95;4800 were 98.0% and 0.96, respectively. The level of agreement between the two assays and the corresponding kappa values for human papillomavirus16, human papillomavirus18 and other high-risk human papillomaviruses were 99.5%, 99.8% and 98.8%, and 0.98, 0.96 and 0.97, respectively. The agreement and kappa value of the HC2 with the Cobas&#95;4800 were 95.3% and 0.91. The human papillomavirus positivity of the Anyplex&#95;HR and the Cobas&#95;4800 in low-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion samples demonstrated 100% concordance. Both the Anyplex&#95;HR and the Cobas&#95;4800 showed excellent results in the precision test., Conclusions: The Anyplex&#95;HR is comparable with the Cobas&#95;4800 and the HC2 for human papillomavirus DNA testing, and it may prove more useful for follow-up testing and patient management by providing genotyping information additional to human papillomavirus16 and human papillomavirus18., (© The Author(s) 2016.)

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.)

Purpose: We identified the predictive factors for locoregional failure after definitive chemoradiation in patients with locally advanced cervical cancer., Methods: Altogether, 397 patients with locally advanced cervical cancer (stage IB2-IVA) were treated with definitive chemoradiation between June 2001 and February 2010. Platinum-based concurrent chemotherapy was given to all patients with median radiation dose of external beam radiotherapy 50.4 Gy in 28 fractions and intracavitary radiotherapy 30 Gy in 6 fractions. Competing risk regression analysis was used to reveal the predictive factors for locoregional failure., Results: During the median follow-up of 7.2 years, locoregional failure occurred in 51 (12.9%) patients. The estimated 3-year rate of locoregional control was 89%, whereas the overall survival rate was 82%. After univariate and multivariate analyses, large tumor size (>5 cm), young age (≤40 years), nonsquamous histology, positive lymph node on magnetic resonance imaging, and advanced stage (III-IV) were identified as risk factors for locoregional failure (P = 0.003, P = 0.075, P = 0.005, P = 0.055, and P < 0.001, respectively). After risk grouping according to the coefficients from the multivariate model, we identified a high-risk group for locoregional failure after treatment with definitive chemoradiation as follows: (1) tumor size larger than 5 cm, and at least 1 other risk factor or (2) tumor size 5 cm or less, and at least 3 other risk factors. The cumulated estimated 3-year rate of locoregional failure of the high-risk group was 26%, which was significantly higher than that of the low-risk group (7%, P < 0.001). The 3-year overall survival rates of the 2 groups were also significantly different (57% vs 86%, P < 0.001)., Conclusions: Large tumor size (>5 cm), young age (≤40 years), nonsquamous histology, positive lymph node on magnetic resonance imaging, and advanced stage are all risk factors for locoregional failure after definitive platinum-based chemoradiation in patients with locally advanced cervical cancer. In the high-risk group, further clinical trials are warranted to improve the locoregional control rate.

Purpose: Defects in the DNA damage repair process can cause genomic instability and play an important role in cervical carcinogenesis. The purpose of this study was to analyze the association of 29 candidate single nucleotide polymorphisms (SNPs) in genes in the DNA repair pathway, TP53, and TP53BP1 with the risk of cervical cancer., Materials and Methods: Twenty-nine SNPs in four genes in the DNA repair pathway (ERCC2, ERCC5, NBS1, and XRCC1), TP53, and TP53BP1 were genotyped for 478 cervical cancer patients and 922 healthy control subjects, and their effects on cervical carcinogenesis were analyzed., Results: The most significant association was found for rs17655 in ERCC5, with an age-adjusted p-value < 0.0001, for which a strong additive effect of the risk allele C was observed (odds ratio, 2.01 for CC to GG). On the other hand, another significant polymorphism rs454421 in ERCC2 showed a dominant effect (odds ratio, 1.68 for GA+AA to GG) with an age-adjusted p-value of 0.0009. The association of these polymorphisms remained significant regardless of the age of onset. The significant result for rs17655 was also consistent for subgroups of patients defined by histology and human papillomavirus (HPV) types. However, for rs454421, the association was observed only in patients with squamous cell carcinoma and non-HPV 18 type., Conclusion: The results of this study show a novel association of cervical cancer and the genes involved in the nucleotide excision pathway in the Korean population.

Purpose: This study was conducted to investigate the incidence and survival outcomes of second primary cancers after the diagnosis of cervical cancer., Materials and Methods: Data from the Korea Central Cancer Registry between 1993 and 2010 were reviewed and analyzed. Standardized incidence ratios (SIRs) of second primary cancers among women with cervical cancer were analyzed. Kaplan-Meier survival curves were constructed for cervical cancer patients with or without a second primary cancer., Results: Among 72,805 women with cervical cancer, 2,678 (3.68%) developed a second primary cancer within a mean follow-up period of 7.34 years. The overall SIR for a second cancer was 1.08 (95% confidence interval, 1.04 to 1.12). The most frequent sites of second primary cancers were the vagina, bone and joints, vulva, anus, bladder, lung and bronchus, corpus uteri, and esophagus. However, the incidence rates of four second primary cancers (breast, rectum, liver, and brain) were decreased. The 5-year and 10-year overall survival rates were 78.3% and 72.7% in all women with cervical cancer, and for women with a second primary cancer, these rates were 83.2% and 65.5% from the onset of cervical cancer and 54.9% and 46.7% from the onset of the second primary cancer, respectively., Conclusion: The incidence rates of second primary cancers were increased in women with cervical cancer compared to the general population, with the exception of four decreasing cancers. The 10-year overall survival rates were decreased in cervical cancer patients with a second primary cancer.

Background: This study investigated the clinical manifestations of lower extremity edema (LEE) in locally advanced cervical cancer patients treated with two different strategies., Methods: In total, 79 cervical cancer survivors with International Federation of Gynecology and Obstetrics stage IB2-IIB were included. Six survivors with stage IB1 and who had been suspicious for lymph node metastasis on pretreatment image also were included. Forty-two patients received radiotherapy after pretreatment laparoscopic surgical staging (Group 1), and 43 patients received primary radiotherapy (Group 2). The patients' medical records and survey results of the Korean version of the Gynecologic Cancer Lymphedema Questionnaire (GCLQ-K) were analyzed., Results: The incidence of LEE was higher in Group 1 than in Group 2 (69.0 vs. 11.6 %; P < 0.001). The duration of LEE was longer in Group 1 (mean 77.3 vs. 9.4 months). At the time of survey, 47.6 % of the patients in Group 1 were clinically diagnosed with lymphedema compared with no patients in Group 2. In GCLQ-K, the mean symptom cluster scores for general swelling (0.74 vs. 0.09; P < 0.001), limb swelling (0.22 vs. 0.00; P = 0.006), and heaviness (0.45 vs. 0.23; P = 0.033) were significantly higher in Group 1. One patient in Group 1 developed lymphedema-related angiosarcoma that was diagnosed at 7.8 years after surgery., Conclusions: Patients with cervical cancer who underwent radiotherapy after laparoscopic surgical staging more commonly experienced LEE and related symptoms than patients who underwent primary radiotherapy. As LEE decreases patients' quality of life, it should be considered during patient consultation and surveillance.

Aim: to compare surgical outcomes and health-related quality of life (HRQOL) between total laparoscopic (TLRH) and total robotic radical hysterectomy (TRRH) for cervical cancer., Patients and Methods: Surgical outcomes and HRQOL were compared between the two groups. Pre- and postoperative HRQOL data from 36-item Short Form (SF-36) and European Organization Research and Treatment of Cancer Quality of Life-C30(EORTC QOL-C30) questionnaires were recorded., Results: In the TRRH group, there were more cases of para-aortic lymphadenectomy (p<0.01), longer operative time (p<0.01), less estimated blood loss (p<0.01), and more harvested pelvic lymph nodes (p=0.04). There were no significant differences in the SF-36 and the EORTC QOL-C30 between the two groups., Conclusion: TRRH surgical outcomes were associated with less blood loss and more harvested pelvic lymph nodes but longer operative times with statistical significance. The short-term postoperative HRQOL outcomes did not show any significant inter-group differences., (Copyright© 2015 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.)

Objectives: Lymph node involvement in cervical cancer is an indication of poor prognosis and the risk tends to increase according to the level of lymph node involvement. However, the specific prognostic significance of retrocrural lymph node involvement has not been well characterized because of its small size and deep location. The aim of this study was to assess its prognostic value., Patients and Methods: A total of 217 patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IA2-IVA cervical cancer were retrospectively enrolled. All the patients had undergone pretreatment (18)F-fluorodeoxy-D-glucose ((18)F-FDG) PET/CT. Of these patients 145 were treated with concurrent chemoradiotherapy, and in this group we assessed the relationship of retrocrural lymph node involvement with the risk of disease progression., Results: Retrocrural lymph node involvement was seen in 7.4% of patients (16/217). All of them had para-aortic lymph node involvement and 56% of the 16 patients (9/16) had concomitant supraclavicular lymph node involvement. In the patients treated with concurrent chemoradiotherapy it was found that the higher the level of (18)F-FDG-positive lymph nodes detected in them, the worse the progression-free survival experienced by them (none vs. pelvic, pelvic vs. para-aortic, para-aortic vs. retrocrural; P<0.05); however, there was no difference in progression outcome between retrocrural and supraclavicular areas (P=NS). On multivariate Cox proportional hazard analysis, the highest level of (18)F-FDG PET/CT-positive lymph nodes in the para-aortic [hazard ratio (HR) 6.05, 95% confidence interval (CI) 2.18-16.81], retrocrural (HR 17.05, 95% CI 5.34-54.44), and supraclavicular areas (HR 19.56, 95% CI 7.15-53.54) was a significant prognostic factor., Conclusion: The highest level of lymph node involvement in para-aortic, retrocrural, supraclavicular areas was a significant prognostic factor for progression in uterine cervical cancer patients who were treated with concurrent chemoradiotherapy. Retrocrural lymph node involvement shows a similar outcome with supraclavicular involvement, but leads to a worse outcome in terms of progression compared with para-aortic lymph node involvement.

Integration of human papillomavirus (HPV) DNA into the host genome is a critical aetiological event in the progression from normal cervix to intraepithelial neoplasm, and finally to invasive cervical cancer. However, there has been little work on how HPV integration status relates to treatment outcome for cervical carcinomas. In the current study, HPV E2 and E6 gene copy numbers were measured in 111 cervical cancer tissues using real-time QPCR. Integration patterns were divided into four groups: single copy-integrated with episomal components (group 1), single copy-integrated without episomal components (group 2), multicopy tandem repetition-integrated (group 3), and low HPV (group 4) groups. A relapse-predicting model was constructed using multivariable Cox proportional hazards model to classify patients into different risk groups for disease-free survival (DFS). The model was internally validated using bootstrap resampling. Oligonucleotide microarray analysis was performed to evaluate gene expression patterns in relation to the different integration groups. DFS rate was inferior in the order of the patients in group 4, group 2/3, and group 1. Multivariate analysis showed that histologic grade, clinical stage group, and integration pattern were significant prognostic factors for poor DFS. The current prognostic model accurately predicted the risk of relapse, with an area under the receiver operating characteristic curve (AUC) of 0.74 (bootstrap corrected, 0.71). In conclusion, these data suggest that HPV integration pattern is a potent prognostic factor for tailored treatment of cervical cancer.

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.)

Background and Purpose: Lymph node (LN) metastasis is a well-known prognostic factor of the cervical cancer. In the current study, the size of metastatic LN was evaluated for its significance in the patients treated with definitive radiotherapy., Materials and Methods: LN metastasis was evaluated for the 268 consecutive patients. The short-axis diameters of the largest LN were measured on magnetic resonance images for the 155 patients with LN metastasis. All the patients were classified into three groups: the negative lymphadenopathy (group N), the small (<15mm) lymphadenopathy (group SP), and the large (≥15mm) lymphadenopathy (group LP)., Results: Patients in the group LP showed significantly lower survival rates than the groups N and SP (5-year overall survival rates of 89%, 82%, and 58%, for groups N, SP, and LP, respectively, P<0.001; 5-year disease-free survival rates of 80%, 67%, and 50%, respectively, P<0.001). Regarding the pattern of failure, patients in the group LP showed inferior regional control rates and higher distant metastasis., Conclusion: The current study shows that the patients with large metastatic LNs are at increased risk of dying from early distant metastasis with substantial number of combined regional failures. Adoption of more effective systemic treatment as well as high radiotherapy dose for LNs may improve cure rates for these patients., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Purpose: We assessed the value of dose-volumetric parameters predicting rectosigmoid mucosal changes (RMC) and late rectosigmoid complications (LRC)., Methods: Between January 2004 and February 2006, 77 patients with stage IB-IIIB cervical cancer underwent external beam radiotherapy and computed tomography (CT)-based intracavitary irradiation. Total dose to the rectal point and several dose-volumetric parameters for rectosigmoid colon (D20cc, D15cc, D10cc, D5cc, D2cc, D1cc, and D0.1cc , defined as the minimal doses received by the highest irradiated volumes of 20, 15, 10, 5, 2, 1, and 0.1 cc, respectively), were calculated using the equivalent dose in 2 Gy fractions (α/β = 3, Gy3). The RMC and LRC were graded by rectosigmoidoscopy and Radiation Therapy Oncology Group criteria every 6 months, respectively., Results: Of 77 patients, 27 (35.1%) patients developed RMC ≥ score 3 and 22 (28.6 %) patients developed LRC ≥ grade 2. There was a positive correlation between RMC score and LRC grade (r = 0.728, p < 0.001). In multivariate analyses, D5cc, among the dose-volumetric parameters, was significant parameter for the risks of RMC ≥ score 3 and LRC ≥ grade 2 (p < 0.05)., Conclusions: D5cc may be a more reliable estimate than other dose-volumetric parameters for predicting the risk of RMC ≥ score 3 and LRC ≥ grade 2 in CT-based brachytherapy.

Aim: The purpose of this study was to describe the features of patients with brain metastasis from cervical cancer., Material and Methods: The medical records of patients with cervical cancer between February 2001 and June 2011 were reviewed retrospectively. Clinical characteristics, symptoms, treatment and survival in patients with brain metastasis were analyzed., Results:   Eleven patients with brain metastasis from cervical cancer were identified, representing an incidence of brain metastasis in the study population of 0.45%. Median patient age at initial diagnosis of cervical cancer was 50 years (range 33-75 years). Non-squamous cell carcinoma was diagnosed in six (54.5%) of the 11 patients, with small cell carcinoma diagnosed in two patients. Ten of the 11 patients had lung-related metastasis at presentation; eight patients had lung metastasis, one had mediastinal lymph node metastasis, and one had pleural metastasis. The median interval from diagnosis of cervical cancer to identification of brain metastasis was 15.4 months (range 3.4-83.3 months). Nine patients presented with neurologic symptoms, such as headache, nausea, vomiting, seizure and extremity weakness. Initially, six patients received whole brain radiotherapy: three patients received chemotherapy; one underwent surgery; and one patient refused treatment. The median survival time after diagnosis of the brain metastases was 5.9 months (range 0.7-19 months)., Conclusion: The prognosis after diagnosis of the brain metastasis in patients with uterine cervical cancer is poor. The small cell type and lung metastasis seem to be related with brain metastasis and may be regarded as risk factors., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

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.)

Objective: The prognosis of stage IVB cervical cancer is generally poor. In the current study, treatment outcomes were evaluated in patients with International Federation of Gynecologic Oncology stage IVB cervical cancer treated with radiotherapy and chemotherapy for progression-free survival (PFS) and treated-related toxicities., Study Design: The medical records of the patients with stage IVB cervical cancer who were treated at the National Cancer Center, South Korea were reviewed retrospectively. From February 2002 to February 2010, 45 patients were diagnosed with FIGO stage IVB cervical cancer. Survival and toxicities were compared between the 13 patients with concomitant chemoradiotherapy (CCRT) with weekly cisplatin versus 20 patients with CCRT with 5-fluorouracil/cisplatin., Results: Initial treatment included weekly cisplatin-CCRT, 5-fluorouracil/cisplatin-CCRT, neoadjuvant chemotherapy, and radiotherapy with subsequent combination chemotherapy in 13, 20, 4, and 5 patients, respectively. Overall survival (OS) and PFS were 26.2 and 6.7 months, respectively. There was no statistical difference in OS (p = 0.47) and PFS (p = 0.64) between the weekly cisplatin-CCRT and 5-fluorouracil/cisplatin-CCRT groups; however, the incidence of anemia >grade 3 as an acute toxicity was higher in the 5-fluorouracil/cisplatin-CCRT chemotherapy regimen group than the weekly cisplatin-CCRT group (p = 0.03). Acute toxicity >grade 2 showed a tendency to be higher in the 5-fluorouracil/cisplatin-CCRT group. Based on multivariate analysis, poor performance status was the only independent prognostic factor of OS (p = 0.03, 9.77; 95% CI 1.3-73.3) and PFS (p = 0.04, 9.58; 95% CI 1.14-81.26)., Conclusions: CCRT using combination chemotherapeutic agents may not have survival advantage over single agent cisplatin-based CCRT. Further improvement in treatment is needed to increase survival outcomes and to decrease treatment-related toxicities in patients with stage IVB cervical cancer.

Objective: To evaluate the effectiveness of ovarian transposition procedures in preserving ovarian function in relation to the location of the transposed ovaries in patients who underwent surgery with or without pelvic radiotherapy., Design: Retrospective., Setting: Uterine cancer center., Patient(s): A total of 53 patients with cervical cancer who underwent ovarian transposition between November 2002 and November 2010., Intervention(s): Ovarian transposition to the paracolic gutters with or without radical hysterectomy and lymph node dissection., Main Outcome Measure(s): Preservation of ovarian function, which was assessed by patient's symptoms and serum FSH level., Result(s): Lateral ovarian transposition was performed in 53 patients. Based on receiver operator characteristic curve analysis, optimum cutoff value of location more than 1.5 cm above the iliac crest was significantly associated with preservation of ovarian function after treatment (area under receiver operator characteristic curve: 0.757, 95% confidence interval [CI]: 0.572-0.943). In univariate analysis, higher location of transposed ovary more than 1.5 cm from the iliac crest was the only independent factor for intact ovarian function (odds ratio 9.91, 95% CI: 1.75-56.3). Multivariate analysis confirmed that the location of transposed ovary (odds ratio 11.72, 95% CI 1.64-83.39) was the most important factor for intact ovarian function., Conclusion(s): Location of transposed ovary higher than 1.5 cm above the iliac crest is recommended to avoid ovarian failure after lateral ovarian transposition after primary or adjuvant pelvic radiotherapy in cervical cancer., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Human papillomavirus (HPV) DNA is considered as a hallmark of cervical cancer. We investigated whether persistent HPV DNA at the cervix is associated with local recurrence after radiotherapy in patients with locally advanced cervical cancer. A total of 156 patients with HPV-positive cervical cancer (International Federation of Gynecology and Obstetrics stage IB-IVB) treated with radiotherapy between July 2003 and December 2006 were analyzed. HPV DNA was measured prior to radiotherapy and after completion of radiotherapy. The results of HPV DNA test at postradiotherapy 1, 3, 6 and 12 months were analyzed individually for association with local recurrence-free survival (LRFS). In addition, the result of any last follow-up HPV test within 24 months postradiotherapy was defined as the overall status of HPV at 24 months and was also analyzed for association with LRFS. HPV DNA was cleared in 127 patients (81.4%) and persistent in 29 patients (18.6%) by 24 months. In 18 patients with local recurrences, 14 patients (78%) showed positive HPV tests at 1-3 months. Among the various time points analyzed, a positive HPV test at 3 months was the most accurate predictor of local recurrence. Multivariate analysis indicated that overall status of HPV at 24 months, low HPV viral load and histologic grade as being significantly related to poor LRFS. In HPV-positive cervical carcinoma treated primarily with radiotherapy, persistent HPV DNA within 24 months after treatment indicates a high risk of local recurrence. Diagnostic accuracy of HPV test was highest at 3 months., (Copyright © 2010 UICC.)

Purpose: To develop a prediction model to identify a low-risk group for distant recurrence in patients with locally advanced cervical cancer treated by concurrent chemoradiation., Methods and Materials: Prospectively, 62 patients with locally advanced cervical cancer were recruited as a training cohort. Clinical variables and parameters obtained from positron emission tomography (PET) and magnetic resonance imaging were analyzed by logistic regression. For the test set, 54 patients were recruited independently. To identify the low-risk group, negative likelihood ratio (LR) less than 0.2 was set to be a cutoff., Results: Among the training cohort, multivariate logistic analysis revealed that advanced International Federation of Gynecology and Obstetrics (FIGO) stage and a high serum squamous cancer cell (SCC) antigen level were significant risk factors (p=0.015 and 0.025, respectively). Using the two parameters, criteria to determine a low-risk subset for distant recurrence were postulated: (1) FIGO Stage IIB or less and (2) pretreatment SCC<2.4 (Model A). Positive pelvic node on PET completely predicted all cases with distant recurrence and thus was considered as another prediction model (Model B). In the test cohort, although Model A did not showed diagnostic performance, Model B completely predicted all cases with distant recurrence and showed a sensitivity of 100% with negative LR of 0. Across the training and test cohort (n=116), the false negative rate was 0 (95% confidence interval 0%-7.6%)., Conclusions: Positive pelvic node on PET is a useful marker in prediction of distant recurrence in patients with locally advanced cervical cancer who are treated with concurrent chemoradiation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Purpose: To identify the impact of 3D CT-based high-dose-rate intracavitary radiotherapy (ICR) on late rectal bleeding (LRB) and local control (LC) in patients with cervical cancer., Material and Methods: The outcomes of 97 consecutive patients treated with 3D CT-based ICR (3D-ICR) were compared with those of 133 consecutive historical patients with conventional 2D brachytherapy planning (2D-ICR). The median follow-up periods were 41 and 56 months for the 3D and 2D groups, respectively., Results: The overall rectal bleeding rate was similar between the groups (42% for 3D-ICR vs. 44% for 2D-ICR); however, the incidence of severe LRB was higher in the 2D-ICR group than in the 3D-ICR group (13% vs. 2%, respectively; p=0.02). In multivariate analysis, the factors associated with severe LRB were tumor >4 cm (12% vs. 3%) and 2D-ICR (10% vs. 2%). The LC rates were 97% and 91% for 3D-ICR and 2D-ICR, respectively (p=0.14); the progression-free survival rate was 80% for both groups. A significant difference in the LC rates between the two groups was observed in patients with larger tumor sizes with the tumor diameter of over 4 cm (98% vs. 81% by 3D-ICR vs. 2D-ICR, respectively; p=0.02)., Conclusions: The implementation of 3D-ICR in radiotherapy for cervical cancer can reduce the incidence of severe LRB and may improve the LC rate., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: To investigate whether expression of carbonic anhydrase XII (CA12) is associated with histologic grade of the tumors and radiotherapy outcomes of the patients with invasive cervical cancer., Methods: CA12 expression was examined by immunohistochemical stains in cervical cancer tissues from 183 radiotherapy patients. Histological grading was classified as well (WD), moderately (MD) or poorly differentiated (PD). Oligonucleotide microarray experiment was performed using seven cervical cancer samples to examine differentially expressed genes between WD and PD cervical cancers. The association between CA12 and histological grade was analyzed by chi-square test. CA12 and histological grades were analyzed individually and as combined CA12 and histologic grade categories for effects on survival outcome., Results: Immunohistochemical expression of CA12 was highly associated with the histologic grade of cervical cancer. Lack of CA12 expression was associated with PD histology, with an odds ratio of 3.9 (P = 0.01). Microarray analysis showed a fourfold reduction in CA12 gene expression in PD tumors. CA12 expression was marginally associated with superior disease-free survival. Application of the new combined categories resulted in further discrimination of the prognosis of patients with moderate and poorly differentiated tumor grade., Conclusions: Our study indicates that CA12 may be used as a novel prognostic marker in combination with histologic grade of the tumors.

Background: To investigate the significance of monitoring the levels of the serum squamous cell carcinoma antigen (SCC-Ag) for the detection of recurrent disease in patients with cervical cancer treated by concurrent chemoradiotherapy., Methods: The records of 112 patients with cervical cancer were reviewed. Serum SCC-Ag levels were measured at regular follow-up visits. A SCC-Ag level of 2 ng/mL was considered the upper limit of normal. Biochemical failure was defined as two consecutively increasing SCC-Ag values above normal. Recurrent disease was confirmed by histologic and radiographic studies., Results: Eighteen patients (16%) developed recurrent disease. Sixteen patients had initially elevated SCC-Ag, post-treatment normalization of SCC-Ag, and tumor recurrence. The SCC-Ag difference (ΔSCC-Ag), defined as the difference between the last value after two consecutively increases above normal and the value immediately before the elevation, had good clinical performance in predicting cancer recurrence. The cutoff value of ΔSCC-Ag was 0.95 ng/mL., Conclusions: SCC-Ag is a relatively good method for the detection of disease recurrence in patients with cervical cancer who were treated by concurrent chemoradiotherapy.

Purpose: To examine the effect of the human papillomavirus (HPV) type 16-E6 (HPV 'early' gene) oncoprotein on in vitro radiosensitivity of HPV-negative/p53 mutant C33a cervical cancer cells., Methods and Materials: The human cervical cancer cell line C33a was stably transfected with either the HPV16 E6 cDNA cloned into the vector pcDNA3.0 (C33aE6) or the empty-vector control (C33aV). Radiosensitivity, DNA damage, and cell cycle measurements were made using standard clonogenic assays, immunofluorescent assessment of nuclear histone H2AX phosphorylated on serine-139 (gamma-H2AX) foci, and flow cytometry. Western immunoblotting and fluorescence confocal microscopy were used to analyse the changes in cellular proteins. Real-time polymerase chain reaction (PCR) was used to compare levels of aurora A mRNA., Results: Compared to C33aV cells, C33aE6 cells showed enhanced radiation cell killing. This was associated with a large amount of polyploidy which was followed by late cell death in C33aE6 cells. Aurora A was highly expressed in C33aE6 cells at pre- and post-irradiation times compared to C33aV cells. Silencing aurora A resulted in a reduced amount of residual gamma-H2AX foci in C33aE6 cells, and diminished the difference in radiosensitivity between the C33aE6 and C33aV cells., Conclusion: Our in vitro results indicate that genetic instability could be augmented in the HPV-infected cancer cells by up-regulation of aurora A, especially against a background of dysfunctional p53. Further studies are needed to examine whether aurora A could be a viable therapeutic target in HPV-related tumours.

Unlabelled: We assessed the diagnostic performance of (18)F-FDG PET in detecting paraaortic lymph node (PALN) metastasis in patients with cervical cancer., Methods: Through a search of MEDLINE and EMBASE (1980 to March 2009), we performed a random-effects meta analysis. A summary receiver-operating-characteristic curve was constructed using hierarchical regression models. To identify other sources of heterogeneity, regression meta analysis was performed., Results: Patients (n = 385) from 10 studies were analyzed. Although specificity of (18)F-FDG PET was consistent (97%; 95% confidence interval [CI], 93%-99%), sensitivity was low and heterogeneous among the studies (34%; 95% CI, 10%-72%). Although regression meta analysis did not identify any source to which heterogeneity could be attributed, it revealed a trend of increasing sensitivity according to an increase in the prevalence of PALN metastasis (P = 0.001). In the 5 studies with prevalence greater than 15%, estimated sensitivity and specificity were 73% (95% CI, 53%-87%) and 93% (95% CI, 86%-97%), respectively. With the diagnostic performance, assuming the prevalence of 15%, the calculated false-positive and -negative rates were 35% and 5%, respectively., Conclusion: In detecting PALN metastasis, PET performs acceptably only in populations with a relatively high probability of PALN metastasis. Otherwise, we found no evidence to justify the evaluation of PALN based solely on PET in cervical cancer.

Objectives: The purpose of this study was to clarify the role of resection for suspicious thoracic metastasis in cervical cancer patients with thoracotomy or video-assisted thoracic surgery (VATS)., Methods: A retrospective study was performed involving patients with primary and recurrent cervical cancer who underwent surgical resections for suspicious thoracic metastatic lesions at a single academic institution between January 2003 and February 2009., Results: Twenty-three pulmonary resections were performed on 21 patients via thoracotomies (n=10), VATS (n=11), and thoracotomies following VATS (n=2). All suspicious pulmonary lesions were completely resected in all 3 surgical groups. A total of 49 surgical procedures were performed, as follows: 25 wedge resections, 9 lobectomies, 12 mediastinal lymph node dissections, 1 segmentectomy, 1 diaphragmatic resection, and 1 pleurectomy. The pathologic evaluation revealed metastasis from cervical cancer, primary lung cancer, no pathologic abnormality, and tuberculosis in 14, 7, 2, and 1 of the surgical specimens, respectively; 1 patient had primary lung cancer and mediastinal lymph node metastasis from cervical cancer. Different pathologic diagnoses were rendered in 6 patients compared to the image-based diagnoses. After pulmonary metastasectomy, 2 patients died from the disease, 3 patients were alive with disease, and 16 patients were alive without disease, with a median follow-up of 16 months (range, 2-67 months)., Conclusions: Resection of suspicious thoracic metastasis with thoracotomy or VATS permits accurate pathologic diagnosis and favorable curative resection in selected patients with cervical cancer.

Background and Purpose: The possibility of using gammaH2AX foci as a marker of DNA damage and as a potential predictor of tumour response to treatment was examined using biopsies from 3 sets of patients with advanced carcinoma of the cervix. The relation between endogenous gammaH2AX expression and hypoxia was also examined., Materials and Methods: Set 1 consisted of 26 biopsies that included pre-treatment and 24h post-radiation treatment samples. Pre-treatment biopsies from 12 patients in Set 2 were used to develop image analysis software while pre-treatment biopsies from 33 patients in Set 3 were examined for the relation between staining for the hypoxia marker pimonidazole and endogenous gammaH2AX expression. Formalin-fixed paraffin-embedded sections were analyzed after antigen retrieval and fluorescence antibody labeling for the hypoxia markers CAIX or pimonidazole in combination with gammaH2AX staining., Results: Before treatment, 24+/-19% of cells contained gammaH2AX foci, with most positive cells containing fewer than 5 foci per nucleus. Twenty-four hours after exposure to the first fraction of 1.8-2.5Gy, 38+/-19% contained foci. CAIX positive cells were 1.4 times more likely to exhibit endogenous gammaH2AX foci, and pimonidazole-positive cells were 2.8 times more likely to contain gammaH2AX foci. For 18 patients for whom both pre-treatment and 24h post-irradiation biopsies were available, local control was unrelated to the fraction of cells that retained gammaH2AX foci. However, 24h after irradiation, tumours that had received 2.5Gy showed a significantly higher fraction of cells with residual gammaH2AX foci than tumours given 1.8Gy., Conclusions: Endogenous gammaH2AX foci are enriched in hypoxic tumour regions. Small differences in delivered dose can produce quantifiable differences in residual DNA damage that can overshadow inter-tumour differences in response., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To evaluate whether human papillomavirus (HPV) viral load measured in cervical smear and HPV type 18 are associated with radiotherapy outcomes in uterine cervical cancer. PATIENTS AND METHODS HPV DNA: was semiquantitatively measured in the cervical smears of 169 radiotherapy patients. HPV viral load was classified as low or high according to median HPV DNA titer and examined for its prognostic value. The multivariable Cox proportional hazards model was used to adjust for covariates. A relapse-predicting model was constructed to classify three risk groups for disease-free survival (DFS), which were used for internal validation., Results: Patients with lower HPV viral load showed worse DFS in univariate analysis. HPV type 18, younger patient age, stage group, nodal status, histologic grade, and histologic type were other prognostic factors for poor DFS. Among these factors, all except stage group were associated with HPV viral load. Multivariate analysis showed the strong influence of HPV viral load for poor DFS. The prognostic model developed using our outcome data performed well in predicting the risk of relapse., Conclusion: Our data suggest that HPV viral load is a strong independent prognostic factor for DFS. HPV type 18 showed a significant relationship with poor radiotherapy outcome in univariate analysis, but not in multivariate analysis.

The formation of a pH gradient, which is characterized by intracellular alkalinization and extracellular acidification, plays a key role in the growth and metastasis of tumor cells. However, the underlying mechanisms of alkalinization-induced cell growth are not known. In this study, we investigated the roles of eukaryotic translation elongation factor 1 alpha (eEF1A) in alkalinization-induced cell growth. In all cell lines tested (NIH3T3, HEK293, and HeLa), cell growth was affected by the modulation of intracellular pH. In general, weak intracellular alkalinization produced increased cell growth, whereas intracellular acidification resulted in decreased cell growth. It is interesting to note that portions of actin-bound eEF1A proteins were gradually reduced from acidic to alkaline conditions, suggesting an increase in levels of functionally active, free-form eEF1A. Over-expression of eEF1A caused increased cell growth in HeLa cells. It should be noted that dissociation of eEF1A from actin by transfection with the actin-binding domain deleted eEF1A construct further increased cell growth under acidic conditions, whereas most of the intact eEF1A was bound to actin. Conversely, knockdown of eEF1A by treatment with eEF1A1 and eEF1A2 siRNAs nullified the effects of alkalinization-induced cell growth. The above findings suggest that an increase in free-form eEF1A under alkaline conditions plays a critical role in alkalinization-induced cell growth.

Objective: To determine the requirement and benefit of laparoscopy-assisted surgical procedures for optimal placement of intracavitary radiotherapy (ICR) tandem in patients with cervical cancer patients., Methods: We reviewed a database of 231 cervical cancer patients who underwent radiotherapy and computed tomography-based 3-dimensional ICR planning at our institute between July 2003 and December 2007., Results: Misplacement of ICR tandem was identified in 12 patients. Optimal placement of ICR tandem was possible in 6 patients under sonographic guidance at the second attempt. Laparoscopy-assisted placement of an ICR tandem was required in 6 patients (2.6%) because of failures of ICR tandem insertion. As a result of this procedure, tandem insertions were corrected in all patients, with the exception of 1 patient who initially presented with fixed pelvic wall disease with an acute angle between the uterine body and the cervical axis. Laparoscopic procedures were tolerable with a median operative time of 68 minutes and an estimated blood loss of less than 20 mL. There were no complications related to the laparoscopic procedures. All the patients remain free of local disease at the time of this writing. There was 1 patient with grade 4 late radiation toxicity of the bowel who developed a rectovaginal fistula 3 months after completion of ICR., Conclusions: Laparoscopy-assisted placement of an ICR tandem was required in 2.6% of the patients with primary advanced cervical cancer. Laparoscopy-assisted placement of an ICR tandem allows optimal implementation of ICR in difficult cases without causing significant morbidity and without delaying the planned ICR.

Purpose: To analyze the effect of allogeneic blood transfusion on clinical outcome in 119 patients with stage IIB cervical cancer who were treated with radiotherapy +/- chemotherapy., Patients and Methods: Medical records were examined for hemoglobin levels before and during radiotherapy, history of allogeneic blood transfusions and the time point when transfusions were given. These factors were retrospectively analyzed along with other clinical risk factors for influences on the patients' clinical outcomes., Results: Thirty-two patients (26.9%) received packed red blood cell transfusion (mean, 3.4 units; range, 1-12 units) before or during radiotherapy. Median follow-up period was 39.3 months (range, 7.6-58.4 months). Patients with history of transfusion showed poorer metastasis-free survival and a trend toward poorer overall survival than non-transfused patients. When patients who received transfusions were sub-divided by the time of transfusion, those who received transfusions before radiotherapy had significantly poorer clinical outcome than those who received transfusions during radiotherapy. In a multivariable analysis, patients with pretreatment transfusion showed a higher risk of distant metastasis (HR = 3.75, 95% CI: 1.28-12.15, p = 0.017) and decreased overall survival rates (HR = 4.62, 95% CI: 1.15-18.54, p = 0.031) compared with those of other patients., Conclusion: Our results suggest that allogeneic blood transfusions given before radiotherapy may be associated with higher incidence of distant metastases and decreased survival in patients with stage IIB cervical cancer.