Concurrent definitive chemoradiation incorporating intensity-modulated radiotherapy followed by adjuvant chemotherapy in high risk locally advanced cervical squamous cancer: a phase II study.

BACKGROUND: Although the prognosis of locally advanced cervical cancer has improved dramatically, survival for those with stage IIIB-IVA disease or lymph nodes metastasis remains poor. It is believed that the incorporation of intensity-modulated radiotherapy into the treatment of cervical cancer might yield an improved loco-regional control, whereas more cycles of more potent chemotherapy after the completion of concurrent chemotherapy was associated with a diminished distant metastasis. We therefore initiated a non-randomized prospective phaseII study to evaluate the feasibility of incorporating both these two treatment modality into the treatment of high risk locally advanced cervical cancer. OBJECTIVES: To determine whether the incorporation of intensity-modulated radiotherapy and the addition of adjuvant paclitaxel plus cisplatin regimen into the treatment policy for patients with high risk locally advanced cervical cancer might improve their oncologic outcomes. STUDY DESIGN: Patients were enrolled if they had biopsy proven stage IIIA-IVA squamous cervical cancer or stage IIB disease with metastatic regional nodes. Intensity-modulated radiotherapy was delivered with dynamic multi-leaf collimators using 6MV photon beams. Prescription for PTV ranged from 45.0 ~ 50.0 Gy at 1.8 Gy ~ 2.0 Gy/fraction in 25 fractions. Enlarged nodes were contoured separately and PTV-nodes were boosted simultaneously to a total dose of 50.0-65 Gy at 2.0- 2.6 Gy/fraction in 25 fractions. A total dose of 28 ~ 35 Gy high-dose- rate brachytherapy was prescribed to point A in 4 ~ 5 weekly fractions using an iridium- 192 source. Concurrent weekly intravenous cisplatin at 30 mg/m2 was initiated on the first day of radiotherapy for over 1-h during external-beam radiotherapy. Adjuvant chemotherapy was scheduled within 4 weeks after the completion of concurrent chemo-radiotherapy and repeated 3 weeks later. Paclitaxel 150 mg/m2 was given as a 3-h infusion on day1, followed by cisplatin 35 mg/m2 with 1-h infusion on day1-2 (70 mg/m2 in total). RESULTS: Fifty patients achieved complete response 4 weeks after the completion of the treatment protocol, whereas 2 patients had persistent disease. After a median follow-up period of 66 months, loco-regional (including 2 persistent disease), distant, and synchronous treatment failure occurred in 4,5, and 1, respectively. The 5-year disease-free survival, loco-regional recurrence-free survival, distant-metastasis recurrence-free survival was 80.5%, 90.3%, and 88.0%, respectively. Four of the patients died of the disease, and the 5-year overall survival was 92.1%. Most of the toxicities reported during concurrent chemo-radiotherapy were mild and transient. The occurrence of hematological toxicities elevated mildly during adjuvant chemotherapy, as 32% (16/50) and 4% (2/50) patients experienced grade 3-4 leukopenia and thrombocytopenia, respectively. Grade 3-4 late toxicities were reported in 3 patients. CONCLUSIONS: The incorporation of intensity-modulated radiotherapy and adjuvant paclitaxel plus cisplatin chemotherapy were highly effective and well-tolerated in the treatment of high-risk locally advanced cervical cancer. The former yields an improved loco-regional control, whereas distant metastases could be effectively eradicated with mild toxicities when adjuvant regimen was prescribed.

The Fgl2 interaction with Tyrobp promotes the proliferation of cutaneous squamous cell carcinoma by regulating ERK-dependent autophagy.

Human fibroleukin 2 (Fgl2), a member of the fibrinogen superfamily, can cleave prothrombin to generate thrombin or is secreted in a soluble form as a new type of effector of Tregs with immunomodulatory functions. However, there is little research on the role of Fgl2 in cutaneous squamous cell carcinoma (CSCC) growth. We examined the expression of Fgl2 in samples from CSCC patients and CSCC cell lines. Then, the effect of Fgl2 on CSCC was evaluated in vitro and in animals. Regulation of autophagy by Fgl2 was explored in CSCC. Coimmunoprecipitation (Co-IP) and immunofluorescence colocalization experiments were conducted to identify the regulatory effect of Fgl2 on the downstream protein Tyrobp. Then, gain- or loss-of-function analyses and evaluation of Tyrobp expression were performed to validate its role in autophagy and proliferation promoted by Fgl2. Here, our study demonstrated that Fgl2 promoted the proliferation of CSCC cells in vitro and in vivo. Knocking down Fgl2 reduced CSCC cell proliferation and inhibited autophagy in CSCC. Mechanistically, Fgl2 interacted with Tyrobp and promoted ERK-dependent autophagy, resulting in the proliferation of CSCC cells. Our study suggested that Fgl2 could be a promising prognostic biomarker and useful therapeutic target for CSCC.

A feasibility study of a modified treatment strategy combined external beam radiation therapy and brachytherapy for cervical cancer.

PURPOSE: To evaluate the feasibility of a modified treatment strategy combined external beam radiation therapy (EBRT) and brachytherapy (BT) for cervical cancer through a dosimetry analysis. MATERIAL AND METHODS: This study retrospectively selected 12 cervical cancer patients treated with the conventional treatment strategy, which consisted of 45─50 Gy/25 fractions of EBRT using volumetric-modulated arc therapy (VMAT) and image-guided BT with a fraction dose of 5─7 Gy. The modified treatment strategy decreased the central EBRT dose while increasing the number of BT fractions. New target volumes were additionally contoured, and new VMAT EBRT plans were generated for the modified treatment strategy. The dosimetric parameters for evaluation included the doses to the most irradiated 2 cc (D2cc) of the organs at risk (OARs) and doses to at least 90% (D90) of the gross tumor volume (GTV) and high-risk clinical target volume (HR-CTV). The total doses to OARs and targets obtained by adding the equivalent doses in 2 Gy fraction (EQD2) from the EBRT and BT plans were used for quantitative comparison between the modified and conventional treatment strategies. RESULTS: Comparison to the conventional treatment strategy, the modified treatment strategy resulted in a higher bladder D2cc, a slightly lower rectal D2cc and a similar HR-CTV D90, all with no significant differences (p > 0.05). The GTV D90 of the modified treatment strategy was significantly higher than that of the conventional treatment strategy (p < 0.01). CONCLUSION: The modified treatment strategy can significantly increase the BT dose while remaining the total doses to the bladder and rectum basically unchanged, demonstrating its feasibility and promising prospect in clinical use.

Comparison of two inverse planning algorithms for cervical cancer brachytherapy.

PURPOSE: To compare two inverse planning algorithms, the hybrid inverse planning optimization (HIPO) algorithm and the inverse planning simulated annealing (IPSA) algorithm, for cervical cancer brachytherapy and provide suggestions for their usage. MATERIAL AND METHODS: This study consisted of 24 cervical cancer patients treated with CT image-based high-dose-rate brachytherapy using various combinations of tandem/ovoid applicator and interstitial needles. For fixed catheter configurations, plans were retrospectively optimized with two methods: IPSA and HIPO. The dosimetric parameters with respect to target coverage, localization of high dose volume (LHDV), conformal index (COIN), and sparing of organs at risk (OARs) were evaluated. A plan assessment method which combines a graphical analysis and a scoring index was used to compare the quality of two plans for each case. The characteristics of dwell time distributions of the two plans were also analyzed in detail. RESULTS: Both IPSA and HIPO can produce clinically acceptable treatment plans. The rectum D2cc was slightly lower for HIPO as compared to IPSA (P = 0.002). All other dosimetric parameters for targets and OARs were not significantly different between the two algorithms. The generated radar plots and scores intuitively presented the plan properties and enabled to reflect the clinical priorities for the treatment plans. Significant different characteristics were observed between the dwell time distributions generated by IPSA and HIPO. CONCLUSIONS: Both algorithms could generate high-quality treatment plans, but their performances were slightly different in terms of each specific patient. The clinical decision on the optimal plan for each patient can be made quickly and consistently with the help of the plan assessment method. Besides, the characteristics of dwell time distribution were suggested to be taken into account during plan selection. Compared to IPSA, the dwell time distributions generated by HIPO may be closer to clinical preference.

Nomograms based on HPV load for predicting survival in cervical squamous cell carcinoma: An observational study with a long-term follow-up.

OBJECTIVE: To investigate the prognostic value of pretreatment human papillomavirus (HPV) viral load for cervical cancer, and to develop nomograms based on HPV load and other clinicopathological factors for long-term survival. METHODS: We conducted a prospective study on cervical squamous cell carcinoma (SCC) patients diagnosed between January 2003 and December 2008. Cervical samples were tested for HPV viral load by the Hybrid Capture II (HCII) assay before treatment and 6 months after treatment. Clinical characteristics and follow-up information were also collected. A multivariable Cox proportional hazards model was used to adjust covariates in both the radical hysterectomy (RH) treatment group and concurrent chemoradiotherapy (CCRT) treatment group to identify relevant covariates, and then nomograms were constructed and used for internal validation. RESULTS: A total of 520 SCC patients enrolled in this study with a median follow-up of 127 months, 360 patients received RH, whereas 160 patients received CCRT. The median HPV viral load in RH and CCRT groups was 356.10 and 294.29, respectively. Tumor size was positively correlated with high pretreatment HPV load in both groups. In CCRT group, the advanced International Federation of Gynecology and Obstetrics (FIGO) stage and enlarged retroperitoneal lymph node status determined by computed tomography (LNSCT) were correlated with low HPV load group. Initial HPV viral load, FIGO stage and lymph node metastasis were prognostic factors for RH group, whereas HPV viral load, squamous cell carcinoma antigen (SCC-Ag) level and LNSCT were identified as prognostic factors for CCRT group. Nomograms incorporating these predictors for 10-year progression-free survival (PFS) were constructed [concordance index (C-index): 0.756, 0.749]. CONCLUSIONS: A low pretreatment HPV viral load is an independent prognostic factor for poor prognosis of cervical SCC and is related to other clinicopathological factors. The survival nomogram based on HPV viral load could predict the long-term prognosis.

MicroRNA-492 overexpression involves in cell proliferation, migration, and radiotherapy response of cervical squamous cell carcinomas.

MicroRNAs (miRNAs) are small non-coding RNA that target protein-coding mRNAs at the post-transcriptional level. The aim of this study was to define the role of miR-492 in cervical squamous cell carcinomas. After microRNA profiling and comparison, we firstly detected miR-492 expression in 104 tumor tissues biopsies derived from advanced staged (FIGO IIB-IIIB) cervical squamous cell carcinoma patients before receiving concomitant chemoradiotherapy and found miR-492 expression was significantly higher in the specimens that were sensitive to concomitant chemoradiotherapy, as compared with insensitive cancer specimens (P < 0.05). Moreover, higher expression of miR-492 was associated with pelvic lymph node metastasis (LNM) (P < 0.05). Further studies illustrated ectopic miR-492 overexpression in SiHa cells promoted cell proliferation, migration, and enhanced the sensitivity of cervical cancer cells to irradiation by promoting apoptosis. In addition, we identified TIMP2 as a direct miR-492 target, which has been shown to be critical in modulating cancer cell migration and invasion. We also confirmed that miR-492 expression levels in positive pelvic LNM were much higher than negative LNM and miR-492 played a vital role in pelvic lymph node metastasis via regulating miR-492/TIMP2/MMP10 axis. In particular, miR-492 was correlated with prognosis in the subgroup of patients with negative pelvic LNM (P < 0.05) and had a promising value in predicting treatment response in the subgroup of patients with positive pelvic LNM (an AUC of 85%, 75.00% specificity, and 95.24% sensitivity). Taken together, the results suggested that miR-492 may serve as a potential biomarker for cervical cancer treatment and prognosis.

A phase 2 study of nanoparticle albumin-bound paclitaxel plus nedaplatin for patients with advanced, recurrent, or metastatic cervical carcinoma.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and nedaplatin (NDP) are used for the treatment of patients with cervical cancer. However, to the authors' knowledge, the use of this combination regimen among patients with advanced, recurrent, or metastatic cervical cancer has rarely been reported. METHODS: Patients with pathologically confirmed, stage IVB (FIGO staging 2009), recurrent or metastatic cervical cancer were eligible. Nab-paclitaxel at a dose of 175 mg/m2 plus NDP at a dose of 80 mg/m2 was administered intravenously every 3 weeks. The primary endpoint of the current study was the objective response rate (ORR). The secondary endpoints were progression-free survival, overall survival, and safety. RESULTS: A total of 27 patients were included (5 with late-stage and 22 with recurrent or metastatic disease). The mean age of the patients was 48.26 ± 9.21 years. Of these 27 patients, 25 had squamous cell carcinoma (92.6%). A total of 26 patients completed 92 cycles of chemotherapy, with an average of 3.4 cycles per patient. The ORR was 50.0% (13 of 26 patients). The overall survival was 16.6 months (95% confidence interval, 12.6-20.6 months) and the progression-free survival was 9.1 months (95% confidence interval, 2.4-15.8 months).The ORR of patients with an interval of >12 months from receipt of prior chemotherapy was significantly higher than that of those with a shorter interval (71.4% vs 25.0%; P = .034). The most common adverse effects reported were myelosuppression, gastrointestinal reactions, fatigue, and peripheral neuropathy. The incidence of grade 3 neutropenia was 33.3% (adverse effects were graded on a scale from 0 to 4 according to the National Cancer Institute's Common Terminology Criteria for Adverse Events [version 3.0]). The incidence of grade 3 thrombocytopenia and anemia was 7.4% and 18.5%, respectively. The incidence of grade 1 to 2 peripheral neuropathy was reported to be as high as 51.9%. No case of hypersensitivity was observed. CONCLUSIONS: The combination of nab-paclitaxel plus NDP for the treatment of patients with late-stage, recurrent, or metastatic cervical cancer appears to be active and tolerable. Cancer 2017;123:420-425. © 2016 American Cancer Society.

Distribution and attribution of high-risk human papillomavirus genotypes in cervical precancerous lesions in China.

While human papillomavirus vaccine was recently approved by China Food and Drug Administration, mapping of high-risk human papillomavirus distribution and attribution in cervical precancerous lesions in China becomes critical in development of a high-risk human papillomavirus-based cervical cancer screening and prevention strategy. In total, 1016 patients with cervical precancerous lesions diagnosed in the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences were analyzed retrospectively, including 111 patients with low-grade squamous intraepithelial lesions and 905 patients with high-grade squamous intraepithelial lesions. HPV16, 58, 52, 33, and 31 were the most common high-risk human papillomavirus genotypes in order of decreasing frequency among high-risk human papillomavirus-positive high-grade squamous intraepithelial lesions; this differed from the high-risk human papillomavirus distribution in low-grade squamous intraepithelial lesions (HPV16, 52, 39, 56, and 58). The distribution of high-risk human papillomavirus genotypes in single-type infections for high-grade squamous intraepithelial lesions (HPV16, 58, 33, and 52) was similar to that in multiple-type infections (HPV16, 58, 52, and 33). By contrast, a more diverse distribution spectrum of high-risk human papillomavirus genotypes for low-grade squamous intraepithelial lesions was observed between single-type (HPV16, 52, 39, and 56) and multiple-type infection (HPV52, 68, 58, 59, 39 and 56). A previously published method was adopted to calculate the fractional proportion of individual high-risk human papillomavirus genotypes in multiple infections. For this proportional attribution, HPV16 (48.9%), 58 (10.0%), 33 (5.5%), and 52 (5.5%) were the most frequent among all high-grade squamous intraepithelial lesions, whereas HPV16 (13.2%), 52 (11.6%), 39 (9.5%), and 56 (7.6%) were the most frequent among all low-grade squamous intraepithelial lesions. Differences in high-risk human papillomavirus distribution and proportional attribution in different cervical pathology statuses (high-grade squamous intraepithelial lesions and low-grade squamous intraepithelial lesions) demonstrated the critical role of persistent infection of certain high-risk human papillomavirus such as HPV16, 58, 33, and 52 in carcinogenesis of cervical cancer. Distinctively high prevalence of HPV58, 33 and 52 in Chinese cervical intraepithelial neoplasia population, especially in high-grade squamous intraepithelial lesions, should be taken into consideration in cervical cancer screening strategy and vaccine development.

[Clinical analysis of 32 cases with neuroendocrine carcinoma of the uterine cervix in early-stage disease].

OBJECTIVE: To investigate the survival and recurrence data after treatment in neuroendocrine carcinoma of the uterine cervix (NECUC) with stage Ib-IIa, and to analyse its prognostic factors. METHODS: Thirty-two cases of primary NECUC in early-stage disease treated from Jan. 2005 to Dec. 2013 at Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences were reviewed, and their data of clinicopathologic characteristics were collected and analysed. The median age was 37 years (range, 23-57 years). The distribution by International Federation of Gynecology and Obstetrics (FIGO) clinical stage: 19 cases stage Ib1, 10 cases stage Ib2, 1 case stage IIa1, 2 cases stage IIa2. Pathologic types: 22 cases of small cell carcinoma, 1 case of atypical carcinoid, 9 cases of mixed carcinoma. The diameter of cervical tumor: 12 cases ≥4 cm, 20 cases <4 cm. All patients underwent radical hysterectomy and pelvic ± para-aortic lymphadenectomy, and 15 cases of them were preserved unilateral or bilateral ovaries. Pathologic examination showed that 25 cases with cervical deep stromal invasion thickness ≥1/2, 21 cases with lymph-vascular space invasion (LVSI), and 18 cases with pelvic and (or) para-aortic lymph nodes involvement. Ten cases were performed neoadjuvant chemotherapy (range,1-3 cycles), all patients received postoperative chemotherapy (range,3-6 cycles), and 15 patients were treated with radiotherapy after surgery. The follow-up data were updated on Jul. 2014. The median follow-up time was 18 months (range, 7-71 months). A retrospective analysis was conducted to analyse the survival and recurrence data,and to explore the prognostic factors of NECUC. RESULTS: Thirteen patients died during the follow-up period. The cumulative progression-free survival (PFS) of 2 and 5 years were respectively 54.2% and 38.1%, and the estimated median PFS was 29 months. The cumulative overall survival (OS) of 2 and 5 years were respectively 56.1% and 44.9%, and the estimated median OS was 31 months. Fourteen cases had recurrence, and the median recurrence time was 9 months (range, 3-30 months). Recurrent or metastatic sites: 2 cases in pelvis, 4 cases in liver, 3 cases in lung, 3 cases in adrenal glands, 3 cases in bones, 2 cases in brain, 1 case in pancreas, 1 case in lymph nodes of para-aorta and neck, and 3 cases had metastasis in two or more organs. Thirteen cases with recurrence died of disease, and another one is alive with disease. The univariate analysis showed that lesion size of the cervix and FIGO stage were significant prognostic factors (P<0.01), while age, tumor components, deep invasion in cervical stromal, LVSI, pelvic and (or) para-aortic lymph nodes involvement, neoadjuvant chemotherapy, adjuvant radiotherapy and preserving ovaries were not significantly associated with prognosis (all P>0.05). CONCLUSION: The prognosis of NECUC in early-stage is poor and the lesion size of the cervix and FIGO stage are prognostic factors.

Cervical metastasis of breast cancer: A case report and literature review.

RATIONALE: Cervical metastasis of breast cancer is rare and its clinical manifestations are similar to those of primary cervical cancer. It is thus easy to misdiagnose, with diagnosis mainly depending on pathology and immunohistochemistry. There have been few studies on its treatment and there is thus no standard treatment plan. PATIENT CONCERNS: This is a 64-year-old female patient presented with a 2-month history of abnormal postmenopausal vaginal discharge, who had previous history of breast cancer. DIAGNOSES: Based on the gynecological examination, imaging results, pathology, and immunohistochemical results, a diagnosis of metastatic carcinoma of the cervix and breast cancer was confirmed. INTERVENTIONS: She received computed tomography-guided 3-dimensional high-dose-rate brachytherapy in combination with chemotherapy. OUTCOMES: She achieved complete response locally. This case provides a new local treatment option for patients with inoperable localized cervical metastases. LESSONS: We hope that this report and the accompanying review help to enrich the literature pertaining to the treatment of rare cervical metastases, providing a foundation for the improved survival of affected patients.

Improvement of accumulated dose distribution in combined cervical cancer radiotherapy with deep learning-based dose prediction.

Purpose: Difficulties remain in dose optimization and evaluation of cervical cancer radiotherapy that combines external beam radiotherapy (EBRT) and brachytherapy (BT). This study estimates and improves the accumulated dose distribution of EBRT and BT with deep learning-based dose prediction. Materials and methods: A total of 30 patients treated with combined cervical cancer radiotherapy were enrolled in this study. The dose distributions of EBRT and BT plans were accumulated using commercial deformable image registration. A ResNet-101-based deep learning model was trained to predict pixel-wise dose distributions. To test the role of the predicted accumulated dose in clinic, each EBRT plan was designed using conventional method and then redesigned referencing the predicted accumulated dose distribution. Bladder and rectum dosimetric parameters and normal tissue complication probability (NTCP) values were calculated and compared between the conventional and redesigned accumulated doses. Results: The redesigned accumulated doses showed a decrease in mean values of V50, V60, and D2cc for the bladder (-3.02%, -1.71%, and -1.19 Gy, respectively) and rectum (-4.82%, -1.97%, and -4.13 Gy, respectively). The mean NTCP values for the bladder and rectum were also decreased by 0.02‰ and 0.98%, respectively. All values had statistically significant differences (p < 0.01), except for the bladder D2cc (p = 0.112). Conclusion: This study realized accumulated dose prediction for combined cervical cancer radiotherapy without knowing the BT dose. The predicted dose served as a reference for EBRT treatment planning, leading to a superior accumulated dose distribution and lower NTCP values.

Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multicenter, Randomized, Open-label, Prospective Trial.

PURPOSE: The purpose of this study was to evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. METHODS AND MATERIALS: In this phase 3, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiation therapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiation therapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiation therapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea, ≥G1 and ≥G2 diarrhea lasting at least 3 days, and damage to the rectal mucosa due to radiation therapy measured by endoscopy. RESULTS: Two hundred and eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 142). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs 14.8 and 4.5 days, respectively; P < .001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs 55.7%, P < .001). Three patients felt intolerable or abdominal pain after rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P = .061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P < .001). CONCLUSIONS: The results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.

[Study of the radiotherapy modality for patients with stage IIb-IIIb cervical stump cancer].

OBJECTIVE: To investigate the radiotherapy modality progress of stageIIb-IIIb cervical stump cancer. METHODS: The clinical data of 13 patients with stageIIb-IIIb cervical stump cancer undergoing radiotherapy from January 2000 to April 2012 was reviewed. Before 2006, 8 patients received conventional external beam radiotherapy and brachytherapy.Since 2006, 5 patients received intensity-modulated radiotherapy (IMRT) and brachytherapy. RESULTS: The median survival was 12-139 months. The median overall survivals and disease free survivals in the conventional radiotherapy (CRT) group were 57 months and 50 months, 3 cases of them recurred during 8-19 months and died of tumor progression.While, the median overall survivals and disease free survival in the IMRT group both were 21 months and nobody recurred. In the CRT group, 7 patients suffered toxicities, including 5 patients grade I-II acute rectum reaction, 2 patients grade I bladder reaction; and 3 had grade I-III, late rectum reaction, 2 patients for grade II bladder late reaction.In the IMRT group, toxicities including 1 case grade I acute or late rectum reaction, and no bladder reaction. CONCLUSION: In our experience, the recommended IMRT and interstitial brachytherapy for the selected patients with advanced cervical stump carcinoma may be obtain better tumor dose distribution and more sparing of the organ at risk.

Applying Multi-Metric Deformable Image Registration for Dose Accumulation in Combined Cervical Cancer Radiotherapy.

(1) Purpose: Challenges remain in dose accumulation for cervical cancer radiotherapy combined with external beam radiotherapy (EBRT) and brachytherapy (BT) as there are many large and complex organ deformations between different treatments. This study aims to improve deformable image registration (DIR) accuracy with the introduction of multi-metric objectives for dose accumulation of EBRT and BT. (2) Materials and methods: Twenty cervical cancer patients treated with EBRT (45-50 Gy/25 fractions) and high-dose-rate BT (≥20 Gy in 4 fractions) were included for DIR. The multi-metric DIR algorithm included an intensity-based metric, three contour-based metrics, and a penalty term. Nonrigid B-spine transformation was used to transform the planning CT images from EBRT to the first BT, with a six-level resolution registration strategy. To evaluate its performance, the multi-metric DIR was compared with a hybrid DIR provided by commercial software. The DIR accuracy was measured by the Dice similarity coefficient (DSC) and Hausdorff distance (HD) between deformed and reference organ contours. The accumulated maximum dose of 2 cc (D2cc) of the bladder and rectum was calculated and compared to simply addition of D2cc from EBRT and BT (ΔD2cc). (3) Results: The mean DSC of all organ contours for the multi-metric DIR were significantly higher than those for the hybrid DIR (p ≤ 0.011). In total, 70% of patients had DSC > 0.8 using the multi-metric DIR, while 15% of patients had DSC > 0.8 using the commercial hybrid DIR. The mean ΔD2cc of the bladder and rectum for the multi-metric DIR were 3.25 ± 2.29 and 3.54 ± 2.02 GyEQD2, respectively, whereas those for the hybrid DIR were 2.68 ± 2.56 and 2.32 ± 3.25 GyEQD2, respectively. The multi-metric DIR resulted in a much lower proportion of unrealistic D2cc than the hybrid DIR (2.5% vs. 17.5%). (4) Conclusions: Compared with the commercial hybrid DIR, the introduced multi-metric DIR significantly improved the registration accuracy and resulted in a more reasonable accumulated dose distribution.

[Analysis of 25 cases of brain metastasis from gynecological cancers].

OBJECTIVE: To discuss the clinical characteristics, treatment and prognostic factors of brain metastasis from gynecological cancers. METHODS: Clinical records of 25 brain metastasis patients from gynecological cancers admitted from January 1999 to January 2009 were reviewed retrospectively. The curative effects of different treatments were compared. The prognostic factors were determined using the Cox regression model. RESULTS: There were 14 cases ovarian malignant tumor, 6 cases cervical carcinoma and 5 cases uterine malignant tumor. Seven cases (28%, 7/25) had solitary metastatic lesion in the brain. Extracranial metastases were detected in 18 cases (72%, 18/25). Five patients only received one kind of treatment, and the mean survival time was 4.0 months (0.5 to 9.5 months). Sixteen patients received combined treatment, 3 of them received combined treatment including surgery, and the mean survival time was 8.4 months (4.1 to 13.4 months); 13 of them received chemotherapy and radiotherapy, and the mean survival time was 14.2 months (4.3 to 58.1 months). Four patients received only palliative supportive care, and the survival time was only 0.1 to 1.0 month. The Cox regression model showed that Karnofsky performance status scale, with or without extracranial metastases and the treatment method were the independent prognostic factors of brain metastasis from gynecological cancers (P < 0.05). CONCLUSION: The incidence of brain metastasis from gynecological cancers is low and the prognosis is very poor. Combined treatments may get better effects.

[Comparative analysis of neoadjuvant therapies in stage Ib2 and IIa2 cervical carcinoma].

OBJECTIVE: To compare the clinical efficacy of neoadjuvant chemotherapy plus vaginal intracavitary irradiation, neoadjuvant chemotherapy alone and vaginal intracavitary irradiation alone followed by radical hysterectomy in patients with stage Ib2 and IIa2 bulkly cervical carcinoma. METHODS: Between January 2000 and December 2009, 224 patients with stage Ib2 and IIa2 bulkly cervical carcinoma (tumor diameter > 4 cm) received neoadjuvant therapy combined surgery in Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences were respectively analyzed, and they were divided into 3 groups according to the preoperative neoadjuvant therapy, the neoadjuvant chemotherapy combined vaginal intracavitary irradiation group (chemotherapy combined irradiation group, n = 86), the neoadjuvant chemotherapy alone group (chemotherapy group, n = 48), the vaginal intracavitary irradiation alone group (irradiation group, n = 90). The efficacy, postoperative risk factors, postoperative adjuvant therapy and survival were compared among the 3 groups. RESULTS: Among the chemotherapy combined irradiation group, chemotherapy group and irradiation group, the response rate (RR) were respectively 62% (53/86), 42% (20/48) and 37% (33/90), and there was significant difference (P = 0.003). The comparison of deep stromal invasion, lymph node metastases, lympho-vascular space involvement (LVSI) and other risk factors among the 3 groups, which showed that there were no statistically significant differences (P > 0.05). In chemotherapy combined irradiation group, the percentage of stromal invasion ≥ 1/2 was lower than that in chemotherapy group [53% (46/86) vs. 73% (35/48), P = 0.027], and the percentage of lymph node metastases was significantly lower than irradiation group [17% (15/86) vs. 29% (26/90), P = 0.046], and the risk factors-free rate was significantly higher than chemotherapy group [44% (38/86)vs. 25% (12/48), P = 0.028]. Among the chemotherapy combined irradiation group, chemotherapy group and irradiation group, the percentage of postoperative radiation therapy were respectively 47% (40/86), 67% (32/48) and 62% (56/90), and the differences were statistically significant (P = 0.035). The five-year disease free survival (DFS) was 79%, 75% and 78%, respectively. The five-year overall survival (OS) was respectively 81%, 78% and 81% among 3 groups, and there were no statistically significant differences (P > 0.05). Among 224 patients, the five-year DFS of the patients with 0, 1 and ≥ 2 risk factors after surgery were 90%, 75% and 57%, and OS were 95%, 82% and 65%, and there were no statistically significant differences (P < 0.01, respectively). Of patients without postoperative risk factors, the five-year OS in those without receiving postoperative radiation therapy was 96%, while 89% in received postoperative radiation therapy patients, there were no statistically significant differences (P = 0.263). CONCLUSION: There are no differences of DFS and OS among the neoadjuvant chemotherapy combined vaginal intracavitary irradiation group, the neoadjuvant chemotherapy alone group and the vaginal intracavitary irradiation alone group patients with stage Ib2 and IIa2. Patients without risk factors after neoadjuvant therapies have better prognosis.

Therapeutic strategy analysis of patients with advanced stage high-grade neuroendocrine cervical cancer: A real-world multicenter study.

OBJECTIVE: To explore the management of high-grade neuroendocrine cervical cancer (HGNECC) since there has been no standard treatment for it. METHODS: Data on the management of HGNECC were retrospectively analyzed. Patients with FIGO stage IIB to IVB HGNECC from six hospitals were enrolled. The Kaplan-Meier method was used for survival analysis. Prognostic factors were determined using a Cox proportional-hazards regression model. RESULTS: A total of 43 patients were included in the study. The multivariate analysis showed that chemotherapy was the preferred treatment as it improved progression-free survival (PFS; P = 0.008) and overall survival (OS; P = 0.005). Distance metastasis was a significant negative prognostic factor for OS (P = 0.002), while radical surgery was a significant positive prognostic factor for PFS (P = 0.05). Compared with those who had received cisplatin and etoposide (≥5 cycles), patients who had received paclitaxel plus platinum-based chemotherapy showed better PFS and OS. Five patients (two at stage IIB and three at stage IV) showed relatively long-term survival. Of these patients, four had undergone radical surgery including tumor-debulking, while three also received adjuvant chemotherapy. CONCLUSION: Paclitaxel plus cisplatin or paclitaxel plus carboplatin may be more effective than etoposide plus cisplatin. Radical surgery followed by chemotherapy may be a favorable alternative intervention for selected patients with advanced stage cancer.

Intensity-modulated radiotherapy combined with intracavitary brachytherapy for locally advanced cervical cancer with uterus didelphys.

The purpose of this study was to investigate the clinical application of intensity-modulated radiotherapy combined with intracavitary radiotherapy for locally advanced cervical cancer complicated with uterus didelphys. We retrospectively reviewed the medical records of six patients with locally advanced cervical cancer associated with uterine malformations treated at the National Cancer Center/Cancer Hospital (Beijing, China) between 2015 and 2018. Six cases, including cervical squamous cell carcinoma (n = 3), cervical adenocarcinoma (n = 2), and clear cell adenocarcinoma (n = 1) were identified by pathological diagnosis. Uterine malformation included uterus didelphys (n = 6), with vaginal subseptum (n = 2). Six cases were treated with pelvic intensity-modulated radiotherapy. Four patients received three- dimensional intracavitary brachytherapy based on computed tomography, and two patients received conventional two-dimensional intracavitary brachytherapy. The acute and delayed responses of gastrointestinal and genitourinary toxicities were ≤grade 2 in 5 patients. Five patients achieved clinical complete remission and four patients had no recurrence during the follow-up period. One patient with cervical adenocarcinoma expired due to progression of the disease. The clinical results suggest that advanced cervical cancer associated with uterus didelphys required individual radiotherapy. The use of intensity-modulated radiotherapy combined with three-dimensional intracavitary brachytherapy is recommended in concurrent chemoradiotherapy.

Prognostic Nomograms Predicting Survival in Patients With Locally Advanced Cervical Squamous Cell Carcinoma: The First Nomogram Compared With Revised FIGO 2018 Staging System.

OBJECTIVES: To develop nomograms to assess prognostic factors for 5-year overall survival (OS) and 5-year progression-free survival (PFS) in locally advanced cervical squamous cell carcinoma (LACSC). METHODS: Overall, 618 patients with LACSC were included in this retrospective analysis. Nomograms for 5-year OS and PFS were developed based on Cox proportional hazards regression models. Concordance index (C-index) and calibration curves were used to define the predictive and discriminatory capacity of the nomogram. A comparison between the nomogram and the International Federation of Gynecology and Obstetrics (FIGO) staging system was conducted using time-dependent receiver operating characteristic (tROC) and area under the curve (tAUC). RESULTS: Multivariate analysis identified several prognostic factors for OS including squamous cell carcinoma antigen (SCC-Ag), body mass index (BMI), tumor size, pelvic wall involvement, and para-aortic lymph node metastasis (PALNM). Prognostic factors for PFS included BMI, hemoglobin (HGB), tumor size, pelvic wall involvement, pelvic lymph node metastasis (PLNM) and PALNM. Following bootstrap correction, the C-index of OS and PFS was 0.713 and 0.686, respectively. These nomograms showed superior performance compared with the FIGO 2009 and 2018 staging schema. CONCLUSIONS: Nomograms were developed to identify prognostic factors for 5-year OS and PFS in patients with LACSC. These nomograms showed good prognostication and are more comprehensive in predicting survival outcomes than existing staging criteria.