Posttreatment squamous cell carcinoma antigen predicts treatment failure in patients with cervical squamous cell carcinoma treated with concurrent chemoradiotherapy.

OBJECTIVE: To analyze the association between posttreatment squamous cell carcinoma antigen (SCC Ag) and treatment failure in patients with cervical SCC treated with concurrent chemoradiotherapy (CCRT). METHODS: We reviewed patients with cervical SCC who were treated with definitive radiotherapy or CCRT between June 2012 and May 2015 at our institute. A receiver operating characteristic (ROC) curve was used to analyze the cutoff value of posttreatment SCC Ag in predicting treatment failure. Log-rank tests and Cox proportional hazards models were used to identify whether posttreatment SCC Ag was significant in predicting disease-free survival (DFS). RESULTS: A total of 559 patients were included in this study. With the ROC curve, the optimal cutoff posttreatment SCC Ag level was 1.8 ng/mL (sensitivity 27.1%, specificity 96.6%). A posttreatment SCC Ag level ≥ 1.8 ng/mL was observed in 47 patients. The multivariate analysis showed that posttreatment SCC Ag (hazard ratio 5.10; 95% confidence interval, 3.31-7.88; p < 0.001) was an independent prognostic factor of DFS. The 3-year overall survival (OS), DFS, local control, and distant control rates of patients with posttreatment SCC Ag < 1.8 ng/mL and ≥1.8 ng/mL were 90.7% and 46.4% (p < 0.001), 84.8% and 31.9% (p < 0.001), 81.4% and 69.5% (p < 0.001), and 90.4% and 54.1% (p < 0.001), respectively. CONCLUSION: Patients with posttreatment SCC Ag ≥ 1.8 ng/mL suffer due to a high rate of treatment failure and poor survival.

Outcome and toxicity of radical radiotherapy or concurrent Chemoradiotherapy for elderly cervical cancer women.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for local advanced cervical cancer. However, for elderly patients, studies are limited and the outcomes are controversial. We retrospectively analyzed the efficacy and tolerance of radical radiotherapy (RT) or CCRT in elderly cervical cancer patients and performed comparisons between them. METHODS: We retrospectively analyzed the elderly cervical cancer patients (≥70 years old) treated with radical RT or CCRT between January 2006 and December 2014. For external beam radiotherapy, 50Gy in 25 fractions or 50.4Gy in 28 fractions were delivered via 3-dimensional conformal radiation therapy or intensity modulated radiation therapy. High-dose-rate intracavitary brachytherapy was performed with a dose of 30-36Gy in 5-7 fractions to point A. Concurrent chemotherapy regimens included weekly cisplatin and paclitaxel. RESULTS: Seventy-three patients were eligible for this study. Twenty-one(28.8%) and 52(71.2%) patients suffered with FIGO stage IB-IIA and IIB-IVA disease, respectively. Twenty-four (32.9%) patients received CCRT. The median duration of follow-up was 32.4 months (4.8-118.8 months). The 3-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) were 64.9%, 67.8% and 66.5%, respectively. By multivariate analysis, CCRT was a significant predictive factor of OS(p = 0.023, 95% confidence interval [CI]: 1.172-8.860), CSS(p = 0.031, 95% CI: 1.131-13.908)and DFS(p = 0.045, 95% CI: 1.023 ~ 6.430). The 3-year OS of patients received RT and CCRT were 54.3% and 83.1%, CSS were 56.8% and 87.1%, DFS were 57.6% and 83.3%. There was no treatment related death. Grade 3-4 acute hematological, gastrointestinal and urinary toxicity incidences were 31.5%, 19.1% and 12.3%, respectively. For grade 3-4 chronic gastrointestinal and genitourinary toxicities, the incidences were 4.1% and 2.7%, respectively. Compared with RT, CCRT was related with high grade 3-4 hematological toxicity (16.3% and 62.5% respectively, p < 0.001), respectively. However, acute nonhematological toxicity and chronic toxicity were not significantly different. CONCLUSION: Elderly cervical cancer patients could tolerate radical RT and CCRT very well and get a favored survival. Compared with RT, CCRT could improve the survival of elder cervical cancer patients with similar nonhematological toxicity. CCRT should be considered in elderly cervical cancer patients.

Homology modeling and docking studies of ENPP4: a BCG activated tumoricidal macrophage protein.

BACKGROUND: The 3D structure and functions of ENPP4, a protein expressed on the surface of Bacillus Calmette-Guerin (BCG)-activated macrophages, are unknown. In this study, we analyzed the 3D structure of ENPP4 and determined its tumoricidal effects on MCA207 cells. RESULTS: Homology modeling showed that Arg305, Tyr341, Asn291, and Asn295 are important residues in substrate, adenosine triphosphate (ATP), binding. A molecular dynamics study was also carried out to study the stability of ENPP4 (including zinc atoms) as well as its ligand-enzyme complex. BCG increased ENPP4 expression in macrophages, and specific blocking of ENPP4 in BCG-activated macrophages (BAMs) significantly reduced their cytotoxicity against MCA207 cells. CONCLUSIONS: These results indicate that zinc remains inside the ENPP4 protein, a BCG activated tumoricidal macrophage protein, throughout the simulation. Important information for the design of new inhibitors was obtained.

Nomograms Predicting Survival of Cervical Cancer Patients Treated With Concurrent Chemoradiotherapy Based on the 2018 FIGO Staging System.

Background: In 2018, a revised staging system was released for cervical cancer, which defined pelvic and paraaortic lymph node metastasis as stages IIIC1 and IIIC2, respectively. In this study, we constructed and validated nomograms to predict the 3- and 5-year survival of patients with cervical cancer based on the revised International Federation of Gynecology and Obstetrics (FIGO) staging system. Methods: We retrospectively examined patients with 2009 FIGO stage IB-IVA cervical cancer who were treated at our institute between 2011 and 2015. Patients were randomized into the model development and validation cohorts (2:1). Univariate and multivariate analyses were conducted for the model development cohort to identify prognostic factors. In the multivariate analysis, nomograms were built to predict overall survival (OS) and disease-free survival (DFS) using significant variables. The nomograms were assessed based on the discrimination and calibration in both cohorts. Discrimination was assessed using the concordance index. Calibration was performed by comparing the mean nomogram estimated survival and the mean observed survival. Results: We included 1,192 patients, with 795 and 397 patients in the model development and validation cohorts, respectively. In the model development cohort, the median follow-up period was 49.2 months. After multivariate analysis, age, histology, 2018 FIGO stage, and pelvic lymph node number were independent factors for OS. Histology, 2018 FIGO stage, squamous cell carcinoma antigen, and pelvic lymph node number were significant predictors of DFS. The nomograms constructed to predict OS and DFS were based on these factors. In both model cohorts, the concordance index for the nomogram-predicted OS and DFS was 0.78 and 0.75 and 0.74 and 0.67, respectively. The calibration curve revealed good agreement between the nomogram predictions and actual values. Conclusion: We constructed robust nomograms to predict the OS and DFS of patients with cervical cancer undergoing treatment with concurrent chemoradiotherapy based on the 2018 FIGO staging system.

Recurrence Features and Factors influencing Post-relapse Survival in Early-stage Endometrial Cancer after Adjuvant Radiotherapy.

Purpose: To evaluate the recurrent patterns and effect of clinicopathological factors on survival after recurrence (R-OS) in early stage endometrial cancer (EC). Methods: Patients with FIGO stage I-II EC, who underwent post-surgery radiotherapy (RT) at our institution between 2000 and 2017, were enrolled. First recurrent patterns, overall survival (OS), and R-OS were evaluated. Univariate and multivariate analyses (MVA) were used to evaluate factors associated with R-OS. Results: 756 patients were analyzed including 510 patients who received vaginal brachytherapy (VBT) and 246 patients who received external beam radiotherapy (EBRT) ± VBT, of whom 66 patients experienced recurrence, including 21 locoregional relapses and 45 distant metastases. Outside RT field recurrence predominated intra-RT field recurrence (106 versus 10 lesions). The 5-year OS rates for patients with and without recurrence were 62.2% and 98.2%, respectively (p<0.001). Among patients who underwent previous VBT, the 5-year OS rates were 61.1%, 92.3%, and 99.1% for distant metastasis, locoregional relapse, and non-recurrence, respectively (p<0.001); among patients who received EBRT ± VBT, the 5-year OS rates were 51.4%, 50.0%, and 98.3%, respectively (p<0.001).On Cox MVA of R-OS for locoregional recurrence patients, para-aortic lymph node metastasis was associated with poorer R-OS (hazard ratio [HR] 10.047, p=0.039), and salvage RT was superior to other therapies (HR 0.06, p=0.026). On Cox MVA of R-OS for distant metastasis, patients with brain metastasis (p=0.041) had the worst R-OS and patients benefited most from combined therapy (HR 0.02, p=0.001). Conclusion: Recurrent patterns were dominated by outside RT field and distant metastasis for early-stage ECs after adjuvant RT. The modality of prior RT had an impact on the choice of salvage therapy. RT could still be an effective salvage treatment for patients who develop locoregional recurrence. Patients with distant metastasis may benefit from combined therapies.

A modified delineation method of para-aortic nodal clinical target volume in patients with locally advanced cervical cancer.

PURPOSE: To validate the nodal center coverage (NCC) of the three mainstream delineation methods of para-aortic nodal clinical target volume (CTV) and propose a modified delineation method of para-aortic nodal CTV in prophylactic extended-field irradiation (EFI) of cervical cancer. METHODS: A total of 106 patients with para-aortic lymph nodes (PALNs) identified on PET/CT were included at Peking Union Medical College Hospital between 2011 and 2020. PALNs were classified as left lateral para-aortic (LLPA), aorto-caval (AC), and right para-caval (RPC). Distances from the nodal center to the aorta and inferior vena cava (IVC) were measured. The NCC of the three mainstream delineation methods of para-aortic nodal CTV (CTV-K, CTV-S, and CTV-D) and a modified CTV (CTV-M) was calculated. Radiotherapy plans were created based on 4 CTVs for 10 selected patients who received prophylactic EFI. The chi-squared test and the Student's t-test were performed. RESULTS: We identified 344 PALNs (216 LLPA, 101 AC, and 27 RPC) in 106 patients. Mean distance from the nodal center to the aorta was 9.6 mm in the LLPA and 7 mm in the AC and from the nodal center to the IVC was 5.6 mm in the AC and 5.6 mm in the RPC. CTV-D improved the NCC of 98% compared with 92% for CTV-K (p = 0.002) and 95% for CTV-S (p = 0.046). CTV-M provided the same satisfactory NCC as CTV-D (97% vs. 98%, p = 0.485). The V50Gy to the duodenum, the Dmean to the bilateral kidneys, and the V45Gy to the small bowel were significantly lower on the CTV-M-based plan than on the CTV-D-based plan (p = 0.001, 0.011, and 0.001, respectively). CONCLUSION: CTV-D provided more satisfactory NCC than CTV-K and CTV-S. CTV-M provided the same satisfactory NCC as CTV-D and reduced the dose to the critical structures.

The 100 Most Cited Papers in Radiotherapy or Chemoradiotherapy for Cervical Cancer: 1990-2020.

OBJECTIVE: This work aims to analyze the 100 most cited papers in radiotherapy or chemoradiotherapy for cervical cancer. METHODS: The 100 most cited papers in radiotherapy or chemoradiotherapy between 1990 and 2020 were identified with Thompson Reuters Web of Science citation indexing on August 24, 2020. The publication years, source titles, countries/regions, total citations, and average citations per year were extracted from the Web of Science. The research type and research domain were classified by the authors. RESULTS: These 100 papers were cited a total of 28,714 times, and the median number of citations was 169.5 (ranging from 116 to 1,700 times). The most cited paper was "Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer" by Rose et al., with a total citation of 1,700 times. The International Journal of Radiation Oncology Biology Physics (40 papers), Radiotherapy and Oncology (14 papers), and the Journal of Clinical Oncology (12 papers) published the largest number of papers. USA (47 papers), Austria (18 papers), Canada (13 papers), and England (13 papers) contributed the largest number of papers. Image-guided adaptive brachytherapy (IGABT) had the largest number of papers (25 papers). Concurrent chemotherapy was the most cited research domain, with 10,663 total citations and 592.4 citations per paper. CONCLUSION: In the present study, we conducted a bibliometric analysis of the 100 most cited papers in radiotherapy or concurrent chemoradiotherapy for cervical cancer in the past 30 years. IGABT and concurrent chemotherapy were the most cited research domains.

Higher Dose to Organs at Risk: The Unintended Consequences of Intravenous Contrast Use in Computed Tomography Simulation for Cervical Cancer.

PURPOSE: To compare the volumes of interest and doses to the organs at risk on contrast and noncontrast scans in patients with cervical cancer who underwent prophylactic extended-field radiation therapy (EFRT). METHODS AND MATERIALS: We reviewed twenty cervical cancer patients treated with prophylactic EFRT at Peking Union Medical College Hospital between March 2021 and April 2021. Each patient underwent noncontrast and contrast scans during simulation. All structures were contoured, and radiation therapy plans were created based on both scans. Student t test and Pearson correlation coefficient test were performed. RESULTS: Compared with the noncontrast scan, on the contrast scan, the mean volume of the inferior vena cava expanded by 44% (P ≤ .001), and the mean volume of the para-aortic nodal clinical target volume increased by 17% (P ≤ .001). For the second portion of the duodenum, the V30 (38.2% vs 43.8%, P = .038), V35 (27.6% vs 35.1%, P = .002), V40 (18.3% vs 26.3%, P = .014), V45 (11.2% vs 18.5%, P = .008), and V50 (4.2% vs 9.1%, P = .005) were significantly lower on the noncontrast scan than on the contrast scan. For the third portion of the duodenum, the V45 (78.4% vs 81.6%, P = .03) and V50 (59.7% vs 67%, P ≤ .001) were significantly lower on the noncontrast scan than on the contrast scan. For the right kidney, the V5, V10, V15, V20, and V25 on the contrast and noncontrast scans were 85.4% versus 79.8% (P = .013), 52.5% versus 45.6% (P = .021), 25.6% versus 20.1% (P = .003), 11.1% versus 7.5% (P = .001), and 3.8% versus 2.3% (P = .027), respectively. CONCLUSIONS: Compared with the noncontrast scan, expansion of the inferior vena cava on the contrast scan can lead to excessive contouring and an overdose to the duodenum and right kidney in cervical cancer patients treated with prophylactic EFRT.

The Role of the Metabolic Parameters of 18F-FDG PET/CT in Patients With Locally Advanced Cervical Cancer.

PURPOSE: To evaluate the role of the pre-treatment cervical and lymph node (LN) metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) for locally advanced cervical cancer (LACC) patients receiving concurrent chemoradiotherapy or radiotherapy. METHODS: we reviewed 125 consecutive patients with LACC who underwent pre-treatment 18F-FDG PET/CT examination and concurrent chemoradiotherapy or radiotherapy from February 2010 to December 2015 at our institute. The mean standardized uptake value (SUVmean), maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of cervical lesion and lymph node (LN) were recorded. Receiver operator characteristic curve, C-index, Kaplan-Meier method, and Cox proportional hazards models were performed. RESULTS: The median follow-up was 62 months (range, 4-114 months). For 125 included patients with cervical cancer, the 5-year overall survival (OS), disease-free survival (DFS), local control (LC) and distant metastasis-free survival (DMFS) rates were 83.6%, 75.1%, 92.3% and 79.9%, respectively. Cervical MTV (c-index 0.59-0.61) and cervical TLG (c-index 0.60-0.62) values calculated with a threshold of 40% SUVmax presented stronger prediction capability than cervical SUVmean (c-index 0.51-0.58) and cervical SUVmax (c-index 0.53-0.57) for OS, DFS, LC, and DMFS. In univariate analysis, cervical TLG ≥ 113.4 had worse DFS and DMFS. Cervical MTV ≥ 18.3 cm3 had worse OS and DMFS. In multivariate analysis, cervical TLG ≥ 113.4 implied worse OS, DFS, and DMFS. In either univariate or multivariate analyses, cervical SUVmean and cervical SUVmax had no statistically significant correlation with OS, DFS, LC and DMFS. For 55 cervical cancer patients with positive LN, LN SUVmax presented strongest prediction capability for OS (c-index = 0.79), DFS (c-index = 0.72), LC (c-index = 0.62), and DMFS (c-index = 0.79). In multivariate analysis, LN SUVmax remained significant biomarker linked to OS, DFS, and DMFS. CONCLUSION: Pre-treatment cervical and LN metabolic parameters were associated with survival outcomes in patients with LACC. In our study, we found that pre-treatment cervical TLG and LN SUVmax may be important prognostic biomarkers for OS, DFS, and DMFS. However, further prospective studies with a large number of patients are required to evaluate the value of the metabolic parameters in survival outcomes prediction.

Prophylactic Extended-Field Irradiation in Patients With Cervical Cancer: A Literature Review.

Currently, the standard radiation field for locally advanced cervical cancer patients without evidence of para-aortic lymph node (PALN) metastasis is the pelvis. Due to the low accuracy of imaging in the diagnosis of PALN metastasis and the high incidence of PALN failure after pelvic radiotherapy, prophylactic pelvic and para-aortic irradiation, also called extended-field irradiation (EFI), is performed for patients with cervical cancer. In the era of concurrent chemoradiotherapy, randomized controlled trials are limited, and whether patients with cervical cancer can benefit from prophylactic EFI is still controversial. With conformal or intensity-modulated radiation therapy, patients tolerate prophylactic EFI very well. The severe toxicities of prophylactic EFI are not significantly higher than those of pelvic radiotherapy. We recommend delivering prophylactic EFI to cervical cancer patients with common iliac lymph nodes metastasis. Clinical trials are needed to investigate whether patients with ≥3 positive pelvic lymph nodes and FIGO stage IIIB disease can benefit from prophylactic EFI. According to the distribution of PALNs, it is reasonable to use the renal vein as the upper border of the radiation therapy field for patients treated with prophylactic EFI. The clinical target volume expansion of the node from the vessel should be smaller in the right para-caval region than in the left lateral para-aortic region. The right para-caval region above L2 or L3 may be omitted from the PALN target volume to reduce the dose to the duodenum. More clinical trials on prophylactic EFI in cervical cancer are needed.

Risk factors associated with Para-Aortic Lymph Node Failure after pelvic irradiation in patients with Cervical Cancer.

Objective: Previous studies have shown that prophylactic extended-field irradiation can reduce para-aortic lymph node failure (PALNF) rates in patients with cervical cancer. As such, this type of irradiation may particularly benefit patients with a high risk of PALNF. In the present study, we analyzed the risk factors for PALNF in patients with cervical cancer treated with pelvic irradiation in order to identify potential indications of prophylactic extended-field irradiation. Methods: We evaluated patients with 2018 FIGO stage IB3-IIIC1 cervical cancer who were treated with definitive pelvic radiotherapy or concurrent chemoradiotherapy at our institution between 2011 and 2014. Univariate and multivariate analyses were performed to identify risk factors for PALNF. Results: We included 572 patients in the study. The median follow-up period was 37.9 months. Eighteen patients (3.1%) first site of tumor relapse was the para-aortic lymph nodes, and thus showed PALNF. Using multivariate Cox regression analysis, we identified two significant risk factors for PALNF: tumor extension to the pelvic wall (hazard ratio, HR 3.60, p=0.026) and ≥ 2 pelvic MLNs (HR 5.30, p=0.005). For patients with and without risk factors, the 3-year overall survival, disease-free survival, and PALNF rates were 77.3% and 90.1% (p<0.001), 56.4% and 83.1% (p<0.001), and 12.0% and 2.3% (p<0.001), respectively. Conclusion: Tumor extension to the pelvic wall and ≥ 2 pelvic MLNs are positively associated with PALNF after pelvic irradiation in patients with cervical cancer. Further trials will be required to validate whether patients with these two risk factors may benefit from prophylactic extended-field irradiation.

Validation of the 2018 FIGO Staging System of Cervical Cancer for Stage III Patients with a Cohort from China.

PURPOSE: To validate the 2018 revised FIGO cervical cancer staging system for stage III patients with a cohort from China. PATIENTS AND METHODS: Patients with stage III cervical cancer (FIGO 2018) treated with definitive radiotherapy at our institute were reviewed. Each patient was evaluated with both the 2014 and 2018 staging systems. Disease-free survival (DFS) was calculated with the Kaplan-Meier method. Receiver operative characteristic (ROC) curves for the predictive accuracy of DFS in patients with cervical cancer according to different FIGO staging systems were created. RESULTS: Between January 2008 and December 2014, a total of 586 patients with FIGO stage IIIC cervical cancer (2018) were treated with definitive radiotherapy at our institute. The 3-year DFS for patients according to FIGO stage (2014) were as follows: IB2 73.2%, IIA 63.7%, IIB 66.7%, IIIA 64.7%, and IIIB 59.6% (P=0.580). The 3-year DFS according to FIGO stage (2018) were IIIA 79.9%, IIIB 70.4%, IIIC1 66.3% and IIIC2 29.8% (P<0.001). The AUC values for DFS were 0.552 (95% CI: 0.503-0.600, P=0.037) and 0.623 (95% CI: 0.575-0.671, P<0.001) for the 2014 and 2018 FIGO staging systems, respectively. CONCLUSION: The 2018 FIGO staging system of cervical cancer showed more distinction within stages and better predictive accuracy for DFS than the preceding staging system in patients with stage III disease from China.

Efficacy and toxicity of image-guided intensity-modulated radiation therapy combined with dose-escalated brachytherapy for stage IIB cervical cancer.

Considering internal organ motion and tumor regression, it is controversial to use intensity-modulated radiation therapy (IMRT) in definitive radiotherapy for cervical cancer. In this study, we evaluated the efficacy and toxicity of IMRT combined with dose-escalated intracavitary brachytherapy (ICBT) for cervical cancer. In total, 373 consecutive FIGO-stage-IIB cervical cancer patients treated with IMRT combined with ICBT and concurrent chemotherapy were included in this study. A dose of 50.4 Gy in 28 fractions was delivered to the pelvis for IMRT. Weekly cone-beam computed tomography or daily megavoltage computed tomography was used for image guiding. For ICBT, 30-36 Gy in five to seven fractions were prescribed to point A. All patients received concurrent chemotherapy. The median follow-up duration was 32.5 months (range, 3.1-119.8 months). The three-year overall survival, disease-free survival and local control rates were 87.5%, 82.2% and 92.5%, respectively. Sixty patients (16.1%) experienced treatment failure, including 23 patients (6.2%) with pelvic relapse. The incidences of ≥grade 3 chronic gastrointestinal and genitourinary toxicity were 2.7% and 2.4%, respectively. These findings indicate that image-guided IMRT combined with dose-escalated ICBT results in good survival with acceptable toxicity in stage IIB cervical cancer patients.