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Adjuvant external beam radiotherapy (EBRT) was shown to decrease pelvic relapses in patients with an early stage cervical cancer and intermediate-risk histopathological prognostic factors, at the cost of increased bowel morbidity. We examined the feasibility and results of adjuvant brachytherapy alone as an alternative to EBRT in this situation. Medical records of consecutive patients receiving adjuvant brachytherapy between 1991 and 2018 for an early stage cervical cancer were examined. Patients were included if they presented a pT1a2N0 or pT1b1N0 disease following radical colpohysterectomy. Adjuvant vaginal wall brachytherapy (without EBRT) was indicated because of a tumor size ≥ 2 cm and/or presence of lymphovascular space invasion (LVSI). Patients received 60 Gy to 5 mm of the vaginal wall, through low-dose or pulse-dose rate technique. Patients' outcome was examined for disease control, toxicities and prognostic factors. A total of 40 patients were included. Eight patients (20%) had LVSI, 26 patients (65%) had a tumor size ≥ 2 cm. With median follow-up time of 42.0 months, 90% of patients were in complete remission and four patients (10%) experienced tumor relapse, all in the peritoneal cavity, and associated with synchronous pelvic lymph node failure in 2/4 patients. No vaginal or isolated pelvic nodal failure was reported. At 5 year, overall survival was 83.6% (CI95%: 67.8–100%) and disease-free survival was 85.1% (CI95%: 72.6–99.9%). In univariate analysis, probability of relapse correlated with tumor size ≥ 3 cm (P = 0.004). No acute or late toxicity grade more than 2 was reported. Brachytherapy alone was a well-tolerated adjuvant treatment for selected patients with intermediate risk factors. The risk of relapse in patients with tumor size ≥ 3 cm was however high, suggesting that EBRT is more appropriate in this situation. [ABSTRACT FROM AUTHOR]

Abstract Genetic variations among HR-HPV types lead to altered biological functions with possible clinical significance in different geographical locations. To explore intratype genetic variations of HPV51 E6, E7, L1 and L2 genes originating from Southwest China, a total of 5204 cervical scraped cell samples were collected for DNA extraction and HPV typing. And then the E6, E7, L1 and L2 genes of HPV51 (n = 79) were sequenced and compared to the reference sequence (M62877). The ConSurf server was used for identification of conserved structural and functional amino acids of the E6 and E7 oncogenes, and the changes of the secondary structure were analyzed by PSIPred software. Phylogenetic trees were constructed by the maximum likelihood method implemented in IQ-TREE. The selection pressure acting on the E6, E7, L1 and L2 genes was estimated by Datamonkey web server. 13 nucleotide polymorphism sites were observed in E6-E7 gene and the most common mutation sites were C395T (S100L), C756T (S66L), C796T, A832G. 36 nucleotide polymorphism sites were identified in full length L1 gene and the non-synonymous mutations T6311G, A6312T (V264G), G6313A (G265S) A5674C (I52L), A6335C (N272T), A6586C (T354P) and synonymous mutations A5649T, C6147T, A6435G, G6570A, A6651G, T6774C, A6784C, A6882G, C6918A, and G6984A were the most common mutations. 53 nucleotide variation sites were identified in full-length L2 gene including four insertion sites (4418A, 4670G, 4693A, 4694C) and one deletion site (A4430). Besides, the non-synonymous mutations G4227A (V32I), A4407G (I92V), G4945A (D271N), C4985A (T284K), T5260G (L376V), A5335C (T401P) and the synonymous mutations A4166G, G4229A, G4283A, T4453C, C4566A, T4596C, C4695T, C4830T, G4839A, A5160C, and T5286G were the most common mutations. Specially, a triallelic mutation site (G4461C/A) in L2 was identified, with 26% G4461C (E109D) being non-synonymous mutation. Selective pressure analysis showed that only codon site 66 in E7 and 52 in L1 were the positively selected sites and codon sites 72, 107, 342, 412, 427 were negatively selected sites in L2 gene. Our investigation also suggests that A2 and A4 were the most frequent HPV51 lineage in Southwest China. Highlights • It is the first study to identify the genetic variability of HPV51 E6, E7, L1 and L2 genes in Southwest China. • The majorly prevailing isolates and the major mutations of HPV51 E6, E7, L1 and L2 in Southwest China were identified. • The major nonsynonymous mutations identified in L1 were all located in immunodominant loop structures. • Several major mutations in L2 were discovered at conserved cross-reacting epitopes regions and other vital functional regions. • Some variations identified are predicted to result in functional protein changes, which could have clinical implications. [ABSTRACT FROM AUTHOR]

Abstract Introduction Although FDA approved for over 10 years, uptake of the human papillomavirus (HPV) vaccination has been slow, particularly among states in the Deep South with high cervical cancer incidence and mortality. The purpose of this study was to explore variables associated with cervical cancer among survivors who were age-eligible for the HPV vaccine and to assess HPV vaccination history, barriers, perceptions, and other associated behaviors within this cohort. Methods A mixed methods strategy was used for the study, first identifying eligible cervical cancer survivors from our institution and abstracting demographic and clinicopathologic medical record data. Twenty-three participants from this cohort then completed semi-structured qualitative telephone interviews regarding HPV vaccination participation, knowledge, and attitudes. Interviews were audio-recorded, transcribed, and analyzed using thematic content analysis. Results Of the 464 cervical cancer patients treated at our institution from 2011 to 2016, 137 (30%) were under age 40 at diagnosis. Seventy-seven women with invasive disease were identified (median age = 33 years), and 56% had been seen by a gynecologist within 5 years of diagnosis. Forty-six of these women met eligibility criteria for inclusion in the qualitative interview, of which 23 successfully completed (response rate = 50%). Of those interviewed, the majority (84%) reported current access to regular medical care. While 90.9% did not receive any doses of HPV vaccination, 78.3% stated they likely would have been vaccinated if it had it been recommended. Four major themes were identified within the interviews: HPV knowledge, vaccine acceptability, healthcare engagement, and provider communication. Conclusions Qualitative interviews revealed significant missed opportunities for prevention since most participants stated they would have been vaccinated if given the option. Substantial gaps in knowledge and mixed understanding HPV's association with cervical cancer were observed, demonstrating potential missed opportunities for education and communication between providers of multiple specialties and their patients. [ABSTRACT FROM AUTHOR]

Abstract Aim To our knowledge there are no studies exploring Saudi women's understanding of the importance of the human papillomavirus (HPV) vaccine. In the present study, we examined the awareness of HPV and women's attitudes toward the HPV vaccine. Method Nine focus groups were formed in Riyadh City, Saudi Arabia, including 77 women between the ages of 18 and 45 years old. Face-to-face interviews were conducted in 58 female healthcare providers to examine women's awareness of cervical cancer, HPV, barriers, acceptance, beliefs, and attitudes towards the HPV vaccine. Results Focus group discussions revealed a lack of knowledge and awareness of cervical cancer, HPV, and the HPV vaccine. Cultural concerns regarding screening and vaccinating for a conventionally known sexually transmitted infection were an emerging theme in addition to not perceiving cervical cancer screening as necessary because women with no signs and symptoms considered themselves not at risk for developing cervical cancer. Approximately 30% of healthcare providers other than physicians were unaware of prevention methods, and 63.3% did not practice any screening methods for cervical cancer and attributed the lack of screening to "no specific reasons at all". Conclusion Because of the unfavorable knowledge and attitude of HPV infection and the associated vaccine from the women in the present study, emphasis should be directed to educate and promote awareness of women to the risk factors of cervical cancer and to the need for screening programs and the administration of the vaccine. [ABSTRACT FROM AUTHOR]

Purpose: The poor outcome of locally advanced cervical cancer has been associated with extensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor. In the present study, measures of tumor hypoxia and IFP were provided using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) and related to the treatment outcomes.Methods and Materials: The data from 54 cervical cancer patients treated with concurrent cisplatin-based chemoradiotherapy were studied. A low-enhancing tumor volume (LETV) and peritumoral fluid flow velocity (v0) were used as measures of tumor hypoxia and IFP, respectively.Results: Poor disease-free survival and overall survival were associated with large LETV and high v0. The multivariate analysis results suggested that the prognostic power of v0 and LETV is independent of established clinical prognostic factors and that the prognostic power of v0 is strong compared with that of LETV. The outcomes was especially poor for patients with a high v0 combined with a large LETV and especially good for those with a low v0 combined with a small LETV, with 5-year disease-free survival and overall survival of 13% versus 100%, respectively.Conclusions: The outcome of locally advanced cervical carcinoma seems to be influenced strongly by the tumor IFP and to a lesser extent by tumor hypoxia. DCE-MRI might have the power to provide important biomarkers for the outcome of cervical cancer. [ABSTRACT FROM AUTHOR]

Purpose: To assess cervical tumor hypoxia using the hypoxia tracer 18F-fluoroazomycin arabinoside (18F-FAZA) and compare different reference tissues and thresholds for quantifying tumor hypoxia.Methods and Materials: Twenty-seven patients with cervical cancer were studied prospectively by positron emission tomography (PET) imaging with 18F-FAZA before starting standard chemoradiation. The hypoxic volume was defined as all voxels within a tumor (T) with standardized uptake values (SUVs) greater than 3 standard deviations from the mean gluteus maximus muscle SUV value (M) or SUVs greater than 1 to 1.4 times the mean SUV value of the left ventricle, a blood (B) surrogate. The hypoxic fraction was defined as the ratio of the number of hypoxic voxels to the total number of tumor voxels.Results: A 18F-FAZA-PET hypoxic volume could be identified in the majority of cervical tumors (89% when using T/M or T/B > 1.2 as threshold) on the 2-hour static scan. The hypoxic fraction ranged from 0% to 99% (median 31%) when defined using the T/M threshold and from 0% to 78% (median 32%) with the T/B > 1.2 threshold. Hypoxic volumes derived from the different thresholds were highly correlated (Spearman's correlation coefficient ρ between T/M and T/B > 1-1.4 were 0.82-0.91), as were hypoxic fractions (0.75-0.85). Compartmental analysis of the dynamic scans showed k3, the FAZA accumulation constant, to be strongly correlated with hypoxic fraction defined using the T/M (Spearman's ρ=0.72) and T/B > 1.2 thresholds (0.76).Conclusions: Hypoxia was detected in the majority of cervical tumors on 18F-FAZA-PET imaging. The extent of hypoxia varied markedly between tumors but not significantly with different reference tissues/thresholds. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the correlation between positron emission tomography/computed tomography (PET/CT) response and outcome in the era of magnetic resonance imaging (MRI)-based planning and to assess whether the addition of diffusion-weighted MRI (DW-MRI) could more accurately classify treatment response and prognosis.Methods and Materials: A retrospective chart review identified 244 consecutive patients with International Federation of Gynecology and Obstetrics stage IB1-IVA cervical cancer treated with concurrent chemoradiation, including high-dose-rate image-based brachytherapy, between 2007 and 2016. Image-based brachytherapy was delivered with 5 intracavitary/interstitial fractions, each 5 to 6 Gy per fraction.Results: An complete response on posttreatment PET/CT (PET-CR) was discovered in 50 of 244 patients (20%) at a median interval of 3.3 months (range, 2.1-7.7 months) after treatment. After a median follow-up of 27 months, 2-year overall survival was 83% in all patients. Metabolic response significantly impacted 2-year overall survival (94% complete response on posttreatment PET/ CT vs 62.4% PET-IR, P < .001). Of those with a PET-IR, 16 of 50 patients (32%) suffered a local recurrence. A total of 27 of 50 patients with a PET-IR underwent DW-MRI; 11 of 27 posttreatment DW-MRI scans (40%) were interpreted as positive by central review (median apparent diffusion coefficient of 0.973 × 10-3 mm2/s). Of the DW-MRI-positive patients, 9 of 11 (81.8%) suffered a histologically confirmed local recurrence, and 2 of 11 patients are without evidence of disease. Additionally, 16 of 27 DW-MRI studies were interpreted as negative, and 2 of 16 (12.5%) of these patients suffered a local recurrence. Diffusion-weighted MRI findings significantly impacted 2-year overall survival (83% negative DW-MRI vs 36% positive DW-MRI, P = .049).Conclusion: Incomplete PET/CT response was documented in 20% of patients after image-based brachytherapy for locally advanced cervical cancer. Integration of DW-MRI helped accurately identify patients at risk for persistent disease and worse long-term outcome. The value of DW-MRI requires further validation in a large prospective dataset as this modality may allow earlier evaluation and salvage treatment in those with PET-IR. [ABSTRACT FROM AUTHOR]

Abstract Specific genetic mutations in human papillomavirus type 16 (HPV16) DNA are considered important in cervical lesion progression. This study analyzes to what extent radiotherapy treatment contributes to viral DNA mutation in cervical cell carcinomas, and the biological significance of these mutations. Serial tumor tissue, including 44 cervical cancer samples, collected before and after radiotherapy, and 52 biopsies with benign cervices, were tested and analyzed for the presence of HPV16, and for the integrity of the E2 gene. Analysis was performed with polymerase chain reaction (PCR), and a bidirectional sequencing assay was performed to find HPV16 E2 gene variants. HPV16 E2 accounted for 81.8% and 37.5% among tumor and benign cervices respectively (p = 0.02). The incremental number of DNA mutations was associated with radiotherapy treatment. Most E2 gene mutations involved regions encoding the amino-terminal and carboxy-terminal regions of E2 in the tumor irradiated samples. Amino acid changes T135 K, A143T, N203D and P208A in the amino-terminal region were the most common mutations across the irradiated samples. Rather, the mutations in the carboxy-terminal region (T3694A and T3805G) were synonymous changes. Specific nucleotide deletions were detected in the hinge domain, at positions 3455A > −, 3466 T > −, and 3501A > −. The mutation degree is influenced by the irradiation modalities, interestingly E2 sequence mutation being found widely after radiotherapy treatment with a total fractioned dose of 50 Gy (p = 0.004). E2 mutation has predictive and biological significance in cervical cancer patients receiving curative radiation therapy. Possibly, E2 mutation could influence viral genome intactness and could serve as an intrinsic marker for cervical cancer. [ABSTRACT FROM AUTHOR]

Highlights • Cervical cancer rates are higher in Māori vs other women in New Zealand. • Both HPV vaccination and HPV screening are predicted to reduce this disparity. • Increased vaccine and screening coverage could further reduce but may not close gap. • Multiple approaches will be required, including beyond vaccination and screening. • These potentially include access to cervical cancer treatment, and tobacco control. Abstract Background Cervical cancer rates are over twice as high, and screening coverage is lower, in Māori women compared to other women in New Zealand, whereas uptake of HPV vaccine is higher in Maori females. We aimed to assess the impact of HPV vaccination and the proposed transition to 5-yearly primary HPV screening in Māori and other women in New Zealand, at current participation levels; and additionally to investigate which improvements to participation in Māori females (in vaccination, screening, or surveillance for screening-defined higher-risk women) would have the greatest impact on cervical cancer incidence/mortality. Methods An established model of HPV vaccination and cervical screening in New Zealand was adapted to fit observed ethnicity-specific data. Ethnicity-specific models were used to estimate the long-term impact of vaccination and screening (vaccination coverage 63% vs 47%; five-year screening coverage 68% vs 81% in Maori vs European/Other women, respectively). Results Shifting from cytology to HPV-based screening is predicted to reduce cervical cancer incidence by 17% (14%) in Maori (European/Other) women, respectively. The corresponding reductions due to vaccination and HPV-based screening combined were 58% (44%), but at current participation levels long-term incidence would remain almost twice as high in Māori women (6.1/100,000 compared to 3.1/100,00 in European/Other women). Among strategies we examined, the greatest impact came from high vaccine coverage and achieving higher attendance by Māori women under surveillance for screen-detected abnormalities. Conclusion Relative reductions in cervical cancer due to vaccination and HPV-based screening are predicted to be greater in Maori than in European/Other women. While these interventions have the potential to substantially reduce between-group differences, cervical cancer incidence would remain higher in Maori women. These findings highlight the importance of multiple approaches and the potential influence of factors beyond HPV prevention. [ABSTRACT FROM AUTHOR]

Purpose: To study the prognostic value of gross tumor volume (GTV) shrinkage and its dosimetric implication in a large cohort of patients with cervical cancer receiving definitive chemoradiotherapy plus image guided adaptive brachytherapy.Methods and Materials: Clinical records of consecutive patients treated in our institution between February 2004 and November 2015 by concurrent chemoradiotherapy (45 Gy in 25 fractions ± lymph node boosts) followed by a magnetic resonance imaging-guided adaptive pulse-dose rate brachytherapy were included. The prognostic value of GTV and its evolution after chemoradiotherapy were examined first on initial staging magnetic resonance imaging and then at time of brachytherapy. All measures and measurement cutoffs were selected using time-dependent area under the curve for 3-year progression-free survival (PFS).Results: GTV evolution between diagnosis and the time of brachytherapy was assessed in 247 patients. After chemoradiotherapy, complete response was observed in 75 patients (28%). Optimal cutoffs were GTV = 55 cm3 at diagnosis, GTV = 7.5 cm3 at brachytherapy, and GTV reduction ≥90%. All patients with volume above or reduction below these cutoffs had significant reduced overall survival, PFS, local control, and distant metastasis control (P < .001). Patients with anemia at diagnosis had a lower tumor volume response rate (P < .001). In multivariate analysis, incorporating the International Federation of Gynecology and Obstetrics stage, N+ stage, anemia, and dosimetric parameters for image guided adaptive brachytherapy, GTV optimal volume reduction after chemoradiotherapy was independently associated with improved overall survival, PFS, local control, and distant metastasis control (P < .001).Conclusions: These results could provide a rationale for dose de-escalation studies in brachytherapy for patients displaying optimal GTV volumetric reduction after chemoradiotherapy and may reinforce the need for dose escalation in poorly responding patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Head and neck squamous cell carcinoma (HNSCC) may present with cervical metastases without an apparent primary tumor. Detecting the primary tumor results in more targeted treatment. Acquisition of DWI is improving with less artifacts and image distortion. We assessed the diagnostic value of DWI and 18F-FDG-PET/CT for detecting primary tumors in patients presenting with nodal metastasis of an unknown primary HNSCC.Materials and Methods: For this retrospective study we included 31 patients (male/female ratio = 23/8, median age = 66 years, age range = 40-80 years) who presented with a pathologically proven cervical nodal metastasis from HNSCC without overt primary tumor location between January 2013 and November 2016 and underwent both DWI and 18F-FDG-PET/CT. Both modalities were assessed qualitatively and quantitatively. With ROC analysis we determined the optimal cut-off for imaging parameters in separating occult malignancy from benign tissue.Results: Qualitative analysis of MRI including DWI resulted in a sensitivity of 81.3% (95%CI) = 53.7-95.0) and specificity of 73.3% (95%CI = 44.8-91.1). With qualitative scoring of 18F-FDG-PET/CT a sensitivity and specificity of 93.8% (95%CI = 67.8-99.7) and 73.3% (95%CI = 44.8-91.1) were found. With quantitative analysis sensitivity and specificity of SUVmax were 81.3% (95%CI = 53.6-95.0) and 93.3% (95%CI = 66.0-99.7), respectively. Combining DWI and 18F-FDG-PET/CT resulted in a sensitivity of 93.8% (95%CI = 67.7-99.7%) and specificity of 60.0% (95%CI = 32.9-82.5%).Conclusion: In this study on HNSCC patients presenting with clinically UP lesions the diagnostic accuracy of qualitative analysis with DWI and 18F-FDG-PET/CT and quantitative analysis of 18F-FDG-PET/CT using SUVmax were high. Adding DWI did not improve the accuracy of 18F-FDG-PET/CT. [ABSTRACT FROM AUTHOR]

Objective An improved nerve-sparing radical hysterectomy (NSRH), which is based on the paravesico-vaginal space, has been recently introduced in a phase II, prospective clinical trial by our team. This study aims to report the surgical and oncological outcomes of this improved NSRH. Methods One hundred seventy-seven consecutive patients were enrolled in our study and underwent the improved NSRH. The proportion of successful catheter removal and postvoid residual urine volume (PVR) of 50 mL or less at postoperative day 7 or day 4 was used to assess surgical outcomes. The local control rate (LCR), disease free survival (DFS), and overall survival (OS) were used to assess oncological outcomes. Results Postoperative 30-day complications occurred in 27/177 (15.3%) patients. The rate of successful catheter removal and PVR of 50 mL or less were 85.2% (23/27) and 66.7% (18/27) at postoperative day 7, and 73.3% (110/150) and 35.3% (53/150) at postoperative day 4. A total of 13 (7.9%) patients showed recurrence after a median follow-up time of 39.2 months (range 3.2-68.1 months). The estimated 2-year and 5-year DFS rates were 92.2% and 91.1%, respectively. Seven (4.2%) patients presented local recurrence, and five (3.0%) patients were dead at the end of the follow-up period. The estimated 5-year LCR and OS were 95.1% and 96.2%, respectively. In univariate analysis, International Federation of Gynecology and Obstetrics (FIGO) stage, lymphovascular space invasion (LVSI), and lymph node metastasis were found to be the prognostic risk factors of DFS. Patients with LVSI were associated with a worse DFS according to the multivariate analysis. Conclusions The improved NSRH in our study may provide better surgical outcomes without compromising the survival in patients with early cervical cancer. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of different hospital patient loads on the standard of care and treatment outcomes of patients with cervical cancer treated primarily with radiation therapy and to identify factors that may contribute to survival differences among hospitals.Methods and Materials: We used the Taiwan Cancer Registry database to extract data on a total of 2582 International Federation of Gynecology and Obstetrics stage IB to IVA patients with uterine cervical cancer diagnosed from 2007 to 2013 who underwent primarily curative radiation therapy (with or without chemotherapy). We explored associations among hospital patient loads, clinical parameters, the type of care given, and survival.Results: Patients who received treatment at hospitals with small and medium patient loads (≤5 cases annually) were older and had more advanced-stage disease than other patients. Positive associations were evident between the use of chemotherapy and brachytherapy and hospital patient load. Patients treated at hospitals with large patient loads (>5 cases annually) experienced better overall survival than those treated at hospitals with small or medium patient loads (P < .001). Stepwise addition of variables to multivariable analyses indicated that greater use of chemotherapy and brachytherapy were major contributors to the better survival of patients treated at hospitals with large patient loads. However, larger hospital patient load per se (>5 vs ≤5 cases annually) was also independently prognostic for better survival of patients with bulky tumors or advanced-stage disease.Conclusions: We found that the inferior survival rate of patients with cervical cancer treated at hospitals with smaller patient loads was attributable not only to a lower standard of care in such hospitals but also to the smaller patient load. Our findings indicate how treatment should be improved in hospitals with small and medium patient loads. [ABSTRACT FROM AUTHOR]

Objective: With the population aging, development of safe and effective treatments for elderly patients with cancer is needed. Although old age is considered a poor prognostic factor, this is not only because of the patient's disease condition or response to treatment, but also because of treatment strategy and intensity. The purpose of this study was to clarify the influence of age on treatment and prognosis in patients with cervical cancer.Methods: Women with stage Ib-IV cervical cancer treated at our institution between 1997 and 2014 were retrospectively analyzed. Patients were stratified by age into groups for analysis, <65 years and ≥65 years. Categorical variables were compared using chi-squared and Fisher's exact tests. Survival analyses were performed using the Kaplan-Meier method, and comparisons were made using the log-rank test. Subsequently, Cox proportional hazards models were developed to find independent prognostic factors.Results: Of 959 patients included in our study, 247 were ≥65 and 712 were <65 years of age. Elderly patients tended to be at a more advanced stage than younger patients (p < 0.001). Elderly patients more commonly had comorbidities. More received standard treatment in the younger patient group at any disease stage than in the elderly patient group (p < 0.001). Similar rates of adverse effects caused by surgery or radiotherapy were seen in patients from both groups. Although overall survival was statistically shorter in elderly patients (74.7 vs. 57.1%, p < 0.001), there was no significant difference in disease-specific survival for patients treated only with standard treatment. In multivariate analyses, clinical stage, histological type, treatment intensity, and primary surgery remained independent prognostic factors. Age was not an independent prognostic factor.Conclusions: The influence of age on prognosis in patients with cervical cancer was less than we expected. Elderly patients might have better outcomes depending on the type of standard treatment they receive. The appropriate modality and intensity of treatment should be based on the patient's general condition and background. [ABSTRACT FROM AUTHOR]

Objectives: Protein 16 (p16CDKN2A) and transforming growth factor-beta 1 (TGF- β1) are important tumor suppressor molecules. The aim of this study was to evaluate the frequency and simultaneous expression of p16CDKN2A and TGF- β1 in cervical intraepithelial neoplasia (CIN) and cervical cancer and their relationship whit the neoplasia progression.Study Design: To evaluate the expressions of p16CDKN2A and TGF- β1 an immunohistochemical study of both proteins in 75 cervical tissues (24 CIN I, 17 CIN II, 15 CIN III and 19 squamous cell cancer) was performed.Results: Increased expression of epithelial and stromal p16CDKN2A in all grades of CIN and cancer was observed. Healthy controls were negative. The frequency of p16CDKN2A expression in the patients was as follow: 75% in CIN I and 100% in CIN II, CIN III and cancer. TGF- β1 expression was found increased in all patients with CIN I and CIN II and decreased in CIN III and cancer; 60% of patients with CIN III and 16% with cancer showed reactivity for TGF- β1. High intensity of p16CDKN2A reactivity and low intensity of TGF- β1 reactivity were observed.Conclusions: The linear frequency of p16CDKN2A expression accompanied by decreased frequency of TGF- β1 in CIN III and cancer could be involved in the neoplasia progression. [ABSTRACT FROM AUTHOR]

Despite different treatment strategies, locally advanced cervical cancer (CC) persists as one of the most incurable cancers among women worldwide. In fact, this setting of patients are at high risk of persistent and recurrent disease. In recent years, researches have investigated immune check-point inhibitors in hopes of determining improved response to therapy with prolongation of survival. We reviewed the published literature and conference proceedings and presented pivotal trials supporting immune check-point inhibitors use in the treatment of CC. [ABSTRACT FROM AUTHOR]

Purpose Hispanic women experience a disproportionate burden of cervical cancer morbidity and mortality compared to non-Hispanic women. Increasing HPV vaccination among Hispanic adolescents can help alleviate disparities. This study aimed to identify parental psychosocial predictors associated with HPV vaccine initiation and correlates of parental intentions to obtain the vaccine for their Hispanic adolescent daughters aged 11–17 years. Methods This study is part of a larger three-arm randomized controlled trial testing the effectiveness of interventions to increase HPV vaccination. Parents of adolescent females were recruited in community clinics where we conducted baseline surveys. We obtained electronic medical records six months after baseline to assess vaccination status. Multilevel logistic regression was used to identify correlates of parental intentions to vaccinate and predictors of HPV vaccine initiation. Analyses with initiation as the outcome also controlled for intervention study arm. The Integrated Behavioral Model guided selection of psychosocial and outcome variables. Results Our sample (n = 765) consisted mostly of mothers with less than a high school education born outside of the U.S. Forty-one percent had a household income less than $15,000. Most daughters had public or private insurance. Twenty-one percent initiated the HPV vaccine series. Correlates of intention to vaccinate intention included subjective norms related to daughter’s doctor (AOR = 1.04; 95% CI 1.01–1.07), belief that the vaccine is safe (AOR = 1.38; 95% CI 1.06–1.78), self-efficacy to obtain the vaccine for their daughter (AOR = 2.39; 95% CI 1.52–3.77), and parental concern about vaccine side effects (AOR = 0.73; 95% CI 0.60–0.89). Intentions predicted initiation (AOR = 2.01; 95% CI 1.10–5.26); concern about sexual disinhibition decreased the odds of having a vaccinated daughter at follow-up (AOR = 0.66; 95% CI 0.47–0.92). Discussion Parental intention and concerns about sexual disinhibition predict vaccine initiation. Further research is needed to explore the role of intention as a potential mediator between psychosocial variables and vaccination status. [ABSTRACT FROM AUTHOR]

Background Human papillomavirus (HPV) vaccination is a major strategy for preventing cervical and other ano-genital cancers. Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to ‘no vaccination’. Methods In a multi-centre cluster randomized trial of two vs three doses of quadrivalent HPV vaccination (Gardasil™) in India, suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10–18 year old girls leading to four study groups, two by design and two by default. They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity for the vaccine-targeted HPV types and HPV infections. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov , number NCT00923702. Findings Of the 17,729 vaccinated girls, 4348 (25%) received three doses on days 1, 60, 180 or later, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses on days 1 and 60, and 4950 (28%) received one dose. One dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18, albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period. The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients. The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women. Conclusion Our results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules, although the study suffer from some limitations. Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented. Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current standard of care for cervical cancer prevention is ‘no intervention’. [ABSTRACT FROM AUTHOR]

During the last 12 years, over 80 countries have introduced national HPV vaccination programs. The majority of these countries are high or upper-middle income countries. The barriers to HPV vaccine introduction remain greatest in those countries with the highest burden of cervical cancer and the most need for vaccination. Innovation and global leadership is required to increase and sustain introductions in low income and lower-middle income countries. [ABSTRACT FROM AUTHOR]

Although human papillomavirus (HPV) vaccines were initially licensed based on efficacy after three-dose regimens in women aged 15–26 years, it was recognized early in clinical development that comparable immunogenicity could be obtained after just two doses when administered to younger girls. In both Canada and Mexico, public health authorities made the decision to administer two doses 6 months apart with a planned additional dose at 60 months, while simultaneously doing further study to determine if the third dose would confer meaningful additional benefit. This delayed third dose approach permitted a more cost-effective program with opportunities for improved compliance while minimizing injections and leaving open the opportunity to provide a full three-dose vaccination series. It required close cooperation across many governmental and civil society leadership bodies and real-time access to emerging data on HPV vaccine effectiveness. Although still limited, there is increasing evidence that even one-dose vaccination is sufficient to provide prolonged protection against HPV infection and associated diseases. Ongoing clinical trials and ecological studies are expected to consolidate existing data regarding one dose schedule use. However, to accelerate the preventive effect of HPV vaccination some jurisdictions, in particular those with limited resources may already consider the initiation of a one dose vaccination with the possibility of giving the second dose later in life if judged necessary. Such an approach would facilitate vaccination implementation and might permit larger catch-up vaccination programs in older girls (or as appropriate, girls and boys), thereby accelerating the impact on cervical cancer and other HPV-associated diseases. [ABSTRACT FROM AUTHOR]

Background Although guidelines for prophylactic human papillomavirus (HPV) vaccination recommend two doses for girls ages 9–14 years, several studies have demonstrated similar protection with one dose. Our objective was to evaluate the long-term health and economic impacts of routine one-dose HPV vaccination compared to (1) no vaccination and (2) two-dose HPV vaccination in a low-income country. Methods We used a three-tiered hybrid modeling approach that captured HPV transmission, cervical carcinogenesis, and population demographics to project long-term health and economic outcomes associated with one-dose HPV vaccination (assuming 80% efficacy against HPV-16/18 infections under three waning scenarios) and two-dose HPV vaccination (assuming 100% efficacy over the lifetime) in Uganda. Costs included the vaccine program (dosage and delivery) costs over a 10-year period and cervical cancer costs over the lifetimes of the current population of Ugandan women. Health outcomes included number of cervical cancer cases and disability-adjusted life years (DALYs). Incremental cost-effectiveness ratios (i.e., cost per DALY averted) were calculated and compared against the Ugandan per-capita gross domestic product. Results Routine one-dose HPV vaccination of 9-year-old girls required substantial upfront investment but was cost-saving compared to no vaccination when accounting for the cost-offsets from future cancers averted. Forty years after initiating routine vaccination and depending on assumptions of vaccine waning, one-dose HPV vaccination with equivalent coverage (70%) averted 15–16% of cervical cancer cases versus 21% with two-dose vaccination but required only half the upfront economic investment. Vaccination with two doses had an attractive cost-effectiveness profile except if one-dose vaccination enabled higher coverage (90% vs. 70%) and did not wane. Conclusions One-dose HPV vaccination resulted in cost-savings compared to no vaccination and could be cost-effective compared to two-dose vaccination if protection is longstanding and higher coverage can be achieved. [ABSTRACT FROM AUTHOR]

Background Women in sub-Saharan Africa have high dual burden of HPV and HIV infections, which can interact to increase cervical cancer (CC) risk. The 9-valent HPV (9vHPV) vaccine has high demonstrated effectiveness against HPV types causing 90% of CC. Additionally, one dose of the 9vHPV vaccine has the potential to achieve greater coverage at lower costs than a two-dose schedule. However, the potential impact of single-dose 9vHPV vaccine accounting for HPV-HIV interactions has not been estimated. Methods We adapted a dynamic HIV transmission model to include HPV acquisition and CC pathogenesis and projected the impact of a single dose 9vHPV preadolescent vaccination in KwaZulu-Natal, South Africa. We report health impacts of HPV vaccination separately for HIV-positive women stratified by HIV treatment and CD4 count and HIV-negative women. Results At 90% coverage of females age 9 years with 80% lifelong vaccine efficacy, single dose HPV vaccination was projected to reduce CC incidence by 74% and mortality by 71% in the general female population at 70 years after the start of the vaccination program. Age-standardized CC incidence and mortality reductions were comparable among HIV-negative women, HIV-positive women, and HIV-positive women on ART. Health benefits were reduced when assuming waning protection at 10, 15 and 20 years after vaccination. Discussion Single dose 9vHPV vaccination is projected to avert substantial CC burden in South Africa and similar high HIV prevalence settings. Health benefits were comparable across all female subpopulations stratified by HIV status, CD4 count, and ART status. [ABSTRACT FROM AUTHOR]

The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose. [ABSTRACT FROM AUTHOR]

As a seriously global health problem, cervical cancer is a great risk to women which threatens their lives. Approximately 30% patients who received definitive treatment may fail to recover from this disease. Accordingly, there is an imperatively need to explore alternative therapeutic approaches for this disease. Several studies have revealed that miR-9 was a critical regulator during cervical cancer growth. Here, we reported that the miR-9 was overexpressed in cervical tumor tissue and exerted a promoting effect on human cervical cancer cell (SiHa) growth. Both in vitro and in vivo experiments confirmed that miR-9 could stimulate the proliferation and migration of SiHa cells. In contrast, inhibition of miR-9 induced apoptosis in SiHa cells. In addition, dual luciferase reporter system assay verified that there was a strong target relationship between miR-9 and FOXO3. Result of western blot assay showed that the inhibition of miR-9 increased the expression of FOXO3. Moreover, miR-9 regulated FOXO3 downstream proteins Bax, Bcl-2 and p-Akt expressions, which suggesting that miR-9 was involved in the SiHa cells apoptosis. In conclusion, our results suggest that the inhibition of miR-9 could induce apoptosis in cervical cancer by targeting FOXO3 and presented a potential molecular target for the treatment of cervical cancer patients. [ABSTRACT FROM AUTHOR]

Introduction Previous studies have investigated the anatomical distribution of para-aortic lymph nodes (PAN) in patients with cervical cancer. However, an atlas for accurate clinical target volume (CTV) delineation has yet to be defined. The purpose of this study was to design and verify a computerized tomography (CT) atlas to provide guidance for contouring the PAN CTV in patients with cervical cancer. Materials and methods This prospective study included 21 cervical cancer patients (design cohort) with 39 pathological PAN identified on (18)F-FDG PET-CT. PAN [left lateral para-aortic (LLPA), aorto-caval (AC), right para-caval (RPC) nodes] were delineated on CT simulation scans. Measurements were taken from the volumetric centre of the nodes to the edge of aorta and inferior vena-cava (IVC). Initially the aorta and IVC were expanded by the mean distance to the lymph node centre to create a CTV. Expansion margins were then increased asymmetrically until the CTV resulted in a clinically acceptable number of PAN included. The CTV was validated on a further 10 patients (validation cohort) with 29 PAN. A detailed contouring guide and accompanying visual atlas for elective PAN CTV delineation was created based on the validated margins. Results For the design cohort ( n  = 21 patients, 39 PAN), the mean distance from the centre of the node to the aorta was 8 mm (range 4–17) for both LLPA (range 4–17) and AC (range 4–15) regions. Mean distance from the IVC to the centre of the nodes was 5 mm (range 4–6) in the RPC region and 6 mm (range 3–15) in the AC region. No PAN was superior to the T12-L1 interspace or the left renal vein or inferior to the L5-S1 interspace. For validation cohort ( n  = 10 patients, 29 PAN), mean distance from centre of the node to the aorta was 9 mm (range 5–15) in the LLPA region, 7 mm (range 6.5–14) in the AC region. Mean distance from the ICV to the centre of the nodes was 3 mm (range 2.5–4) in the RPC region and 5 mm (range 3–10) in the AC region. A CTV expansion from the aorta of 10 mm circumferentially and 15 mm laterally, and from the IVC of 8 mm anteromedially and 6 mm posterolaterally resulted in coverage of 97% (38/39) of PAN in the design cohort. On prospective validation, the described CTV included 97% (28/29) of PAN in the validation cohort. Conclusion We propose the following PAN CTV; expansion from aorta of 10 mm circumferentially except 15 mm laterally, expansion from the IVC of 8 mm anteromedial and 6 mm posterolaterally. The suggested CTV includes 97% (28/29) PAN in a validated patient cohort. A detailed guide and accompanying visual atlas is provided to aid delineation of the PAN CTV in patients with cervical cancer. [ABSTRACT FROM AUTHOR]

Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix ® or Gardasil ®, prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomédicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution. [ABSTRACT FROM AUTHOR]

Purpose To monitor early response for locally advanced cervical cancers undergoing concurrent chemo-radiotherapy (CCRT) by ultrasonic histogram. Methods B-mode ultrasound examinations were performed at 4 time points in thirty-four patients during CCRT. Six ultrasonic histogram parameters were used to assess the echogenicity, homogeneity and heterogeneity of tumors. Results I peak increased rapidly since the first week after therapy initiation, whereas W low , W high and A high changed significantly at the second week. The average ultrasonic histogram progressively moved toward the right and converted into more symmetrical shape. Conclusion Ultrasonic histogram could be served as a potential marker to monitor early response during CCRT. [ABSTRACT FROM AUTHOR]

Objectives To gain insight into the most suitable foreign value set among Malaysian, Singaporean, Thai, and UK value sets for calculating the EuroQol five-dimensional questionnaire index score (utility) among patients with cervical cancer in Indonesia. Methods Data from 87 patients with cervical cancer recruited from a referral hospital in Yogyakarta province, Indonesia, from an earlier study of health-related quality of life were used in this study. The differences among the utility scores derived from the four value sets were determined using the Friedman test. Performance of the psychometric properties of the four value sets versus visual analogue scale (VAS) was assessed. Intraclass correlation coefficients and Bland-Altman plots were used to test the agreement among the utility scores. Spearman ρ correlation coefficients were used to assess convergent validity between utility scores and patients’ sociodemographic and clinical characteristics. With respect to known-group validity, the Kruskal-Wallis test was used to examine the differences in utility according to the stages of cancer. Results There was significant difference among utility scores derived from the four value sets, among which the Malaysian value set yielded higher utility than the other three value sets. Utility obtained from the Malaysian value set had more agreements with VAS than the other value sets versus VAS (intraclass correlation coefficients and Bland-Altman plot tests results). As for the validity, the four value sets showed equivalent psychometric properties as those that resulted from convergent and known-group validity tests. Conclusions In the absence of an Indonesian value set, the Malaysian value set was more preferable to be used compared with the other value sets. Further studies on the development of an Indonesian value set need to be conducted. [ABSTRACT FROM AUTHOR]

Purpose: Most women with cervical cancer in Sub-Saharan Africa present with locally advanced disease. These women require external beam radiation therapy and brachytherapy for curative treatment, but data on their outcomes remain sparse. We report data on treatment characteristics, follow-up, toxicity, and cancer outcomes in a large population of patients from the National Centre for Radiotherapy in Accra, Ghana.Methods and Materials: The charts of patients treated from 2006 to 2011 were reviewed. Patients treated without brachytherapy or with palliative intent were excluded. Staging computed tomography scans were not routinely performed. Cobalt 60 external beam radiation therapy was followed by 2 low-dose-rate brachytherapy insertions. Concurrent weekly cisplatin was recommended. Because many patients experienced delays from diagnosis to treatment, we calculated overall survival and locoregional recurrence from the date of first radiation therapy to the event date-or last follow-up when no event recurred-using the Kaplan-Meier (product-limit) method.Results: We included 250 patients with a median age at diagnosis of 55 years. The International Federation of Gynecology and Obstetrics stage was IIB or lower in 63% of patients. The median dose to point A was 83 Gy (range, 60-97.5 Gy). The median doses to the bladder and rectal points were 71 Gy and 65 Gy, respectively. Of the patients, 69% received ≥4 cycles of concurrent cisplatin. The median overall treatment time was 73 days. The median follow-up period was 2.4 years, with 3-year overall survival and locoregional recurrence rates of 86% and 19%, respectively. The most commonly reported late side effect was vaginal stenosis and shortening, occurring in 32% of patients. We also identified nearly 300 patients who were offered curative treatment but never returned to start treatment.Conclusions: We report promising outcomes in a population of women with cervical cancer treated with concurrent chemoradiation therapy and brachytherapy in Ghana. To our knowledge, this is the largest series of its kind, and it demonstrates what can be achieved with a well-established cancer program in Sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the long-term disease control and toxicity to the organs at risk after dose-escalated image-based adaptive brachytherapy (BT) in cervical cancer. Methods and Materials Sixty patients of cervical cancer were treated with external radiotherapy 46 Gy in 23 fractions with weekly cisplatin and MRI-guided BT 7 Gy × 4 fractions with a minimum dose of 85.7 Gy (EQD2) to the high-risk clinical target volume (HRCTV). The BT dose was initially prescribed to point A and plans were optimized to ensure coverage of both point A and HRCTV while maintaining doses to the organs at risk within the recommended constraints. Patients were followed up clinically every three months for the first two years and six months thereafter. Toxicity scoring for urinary and bowel symptoms was done using CTCAE version 3.0. Results The mean doses to the point A and D90 HRCTV were 85.5 (±2.75) Gy and 98.4 (±9.6) Gy EQD2 respectively. The mean 2 cc EQD2, the bladder, rectum, and sigmoid were 90.6 Gy, 70.2 Gy, and 74.2 Gy respectively. The overall survival at a median followup of 49.8 months was 91.66%. Six (10%) patients developed grade 3 gastrointestinal toxicity. One patient developed grade 3 bladder toxicity. The incidence of bladder, rectal, and sigmoid toxicity increased significantly with doses >85 Gy, 66 Gy, and >71 Gy EQD2 respectively. Conclusions While the incidence of grade 3-4 toxicity was low (8.3% for gastrointestinal toxicity and 1.6% for bladder), the threshold for development of grade 1-2 bladder and rectal toxicity was lower than the doses recommended by the GEC-ESTRO group. By adhering to volume-based prescriptions, there is scope of further reduction in toxicity to organs at risk. [ABSTRACT FROM AUTHOR]

Purpose To study the dosimetric impact of deformable image registration–based contour propagation on MRI-based cervical cancer brachytherapy planning. Methods and Materials High-risk clinical target volume (HRCTV) and organ-at-risk (OAR) contours were delineated on MR images of 10 patients who underwent ring and tandem brachytherapy. A second set of contours were propagated using a commercially available deformable registration algorithm. “Manual-contour” and “propagated-contour” plans were optimized to achieve a maximum dose to the most minimally exposed 90% of the volume ( D 90 ) (%) of 6 Gy/fraction, respecting minimum dose to the most exposed 2cc of the volume ( D 2cc ) OAR constraints of 5.25 Gy and 4.2 Gy/fraction for bladder and rectum/sigmoid (86.5 and 73.4 Gy equivalent dose in 2 Gy fractions [EQD 2 ] for external beam radiotherapy [EBRT] + brachytherapy, respectively). Plans were compared using geometric and dosimetric (total dose [EQD 2 ] EBRT + brachytherapy) parameters. Results The differences between the manual- and propagated-contour plans with respect to the HRCTV D 90 and bladder, rectum, and sigmoid D 2cc were not statistically significant (per-fraction basis). For the EBRT + brachytherapy course, the D 2cc delivered to the manually contoured OARs by the propagated-contour plans ranging 98–107%, 95–105%, and 92–108% of the dose delivered by the manual-contour plans (max 90.4, 70.3, and 75.4 Gy for the bladder, rectum, and sigmoid, respectively). The HRCTV dose in the propagated-contour plans was 97–103% of the dose in the manual-contour plans (maximum difference 2.92 Gy). Increased bladder filling resulted in increased bladder dose in manual- and propagated-contour plans. Conclusions When deformable image registration–propagated contours are used for cervical brachytherapy planning, the HRCTV dose is similar to the dose delivered by manual-contour plans and the doses delivered to the OARs are clinically acceptable, suggesting that our algorithm can replace manual contouring for appropriately selected cases that lack major interfractional anatomical changes. [ABSTRACT FROM AUTHOR]

Purpose Given the limited data using an interstitial approach with 3D-based planning for definitive cervical cancer utilizing the GEC-ESTRO defined high-risk clinical target volume (HR-CTV), we reviewed our institutional experience of cervical cancer patients with HR-CTVs ≥ 30 cc to determine whether our clinical and toxicity outcomes are acceptable. Methods A retrospective review of 37 cervical cancer patients with high-risk clinical target volumes (HR-CTVs) ≥30 cc treated with interstitial image-guided brachytherapy (IS IGBT) was performed. All patients received external beam radiotherapy to a median dose of 45 Gy, followed by IS IGBT delivered in a single implant to a median dose of 6 Gy × 5 fractions. Median HR-CTV was 59 cc. A median HR-CTV D 90 of 87.44 Gy was achieved. Kaplan–Meier method was used to evaluate local control (LC), distant control, and overall survival (OS), with stratification by overall treatment time (OTT) ≤ 7 or >7 weeks. Results Median followup was 17 months. The estimated 2-year LC, distant control, and OS were 77.6% (confidence interval [CI]: 63.8–94.5%), 56.8% (CI: 41.3–78.1%), and 54.4% (CI: 39.4–75%), respectively. The 2-year LC for OTT ≤7 weeks and >7 weeks were 100% and 58.3%, respectively ( p = 0.026). The 2-year OS for OTT ≤7 weeks and >7 weeks were 77.8% and 38%, respectively ( p = 0.021). Discussions IS IGBT can achieve a high D 90 to the HR-CTV even in the setting of large-volume disease and results in a favorable LC and toxicity profile. OTT > 7 weeks is associated with significant decrease in LC and OS. Conclusions Efforts should be made to complete whole treatment within 7 weeks as this is associated with improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Background and purpose To analyse the clinical use of needles and examine the feasibility to meet the planning criteria in three fractions of cervical cancer brachytherapy. Furthermore, to investigate whether the needles with the largest discrepancy between application and loading are essential to treatment planning. Materials and methods For 22 patients we analysed the applied and loaded needle patterns, and examined the dosimetric results for small (<30 cm 3 ) and large (≥30 cm 3 ) CTV HR . We removed from the clinical plans (CP) the needles applied most, but with the lowest loading frequency and intensity and re-optimized these plans (RP). Results On average 5.8 needles were applied and 4.8 loaded per fraction, with average intensity 22% (17% for small, 29% for large CTV HR ). Mid-lateral needles were applied and loaded most frequently and intensely. The average CTV HR D 90% prescribed dose was 88.8 Gy (SD 4.2) EQD2 10 , the average OAR D 2 cm 3 limit was respected. Omitting the mid-ventral needles, minimal statistically significant differences were found in dose distributions between RP and CP. Conclusions Applying on average 5.8 needles per fraction it was possible to meet the planning criteria for targets and OARs in three BT fractions for both small and large CTV HR . The mid-ventral needles were not essential in treatment planning, unless situated in the vicinity of the GTV res . [ABSTRACT FROM AUTHOR]

Objectives: Implicit associations influence behaviour, but their impact on cancer screening intentions is unknown.Methods: We assessed implicit associations with cervical cancer screening using an evaluative priming task. Participants were shown primes ('Pap test', neutral or non-word) followed by positive or negative target words. The test is based on the assumption that response times are shorter if primes and targets are strongly associated in the participant's mind. The Dutch screening program targets women aged 30-60, 226 of them completed online assessments twice. Prior to the second assessment participants were randomized to reading versus not reading the leaflet about the cervical screening program.Results: After controlling for knowledge and screen history, response times for 'Pap test' no longer differed between positive and negative targets. Implicit associations were not correlated with explicit attitudes or screening intentions. Reading the screening leaflet resulted in improved knowledge levels (p<0.001), but implicit associations, explicit attitudes, and screening intentions remained similar.Conclusion: Cervical cancer screening intentions were related to explicit attitudes, but not to implicit associations. The screening leaflet did not affect screening intentions.Practice Implications: We recommend achieving a deepened interest in the screening program among risk groups, e.g. by adapting the information leaflet. [ABSTRACT FROM AUTHOR]

Introduction Persistent high-risk HPV (HR-HPV) infection is associated with a greater risk of cervical cancer. Patients and methods Statistical data on the prevalence of HR-HPV infections in the Algerian population is lacking. We conducted a prospective study of 300 women aged between 25 and 50 years, screened for cervical cancer from 2012 to 2015 in Sidi Bel Abbès, a western region of Algeria. We aimed to assess the reliability of the repeated use of the HC II test (three longitudinal HPV tests 9 months apart from each other) in diagnosing the persistence of HR-HPV infection. Results The prevalence of HR-HPV infection was 7.33% and infected women were aged 37.9 ± 3 years. For 90.9% of HR-HPV-positive patients, the infection persisted for a mean of 18.5 months [95% CI: 16.9–22.1 months]. Among these patients, 55.55% developed CIN1 and 11.11% developed CIN2. The sensitivity of the HC II test was 81.74% [95% CI: 71.3–89.6] and its positive predictive value associated with abnormal cervical biopsy was 27.49% [95% CI: 16.0–33.33]. Conclusion Repeating the HC II test is a good predictor for identifying women at high risk of cervical cancer. [ABSTRACT FROM AUTHOR]

Purpose To investigate the dosimetric effects due to interfractional changes in catheter position and variation in patient's anatomy during the course of interstitial high-dose-rate (HDR) brachytherapy. Methods and Materials A total of 15 patients with either cervical or vaginal cancer underwent interstitial HDR brachytherapy. Interstitial catheters and fiducials were placed under fluoroscopy and intraoperative 3T MRI to confirm the desired catheter placement for adequate target volume coverage. Single plan was generated from first-fraction CT fused with the MRI and used for all fractions of treatment. CT image was acquired before each treatment and registered to the first-fraction CT. Displacement of fiducials and catheters was calculated for each fraction and its effects on dosimetric parameters such as dose covering 90% for high-risk clinical target volume and intermediate-risk clinical target volume and dose to the 2 cm 3 of the volume for bladder, rectum, sigmoid, and bowel were studied. Results Average movements of fiducials and catheters were 1.6 mm (range: 0.1–7.1 mm) and 1.7 mm (range: 0.1–4.5 mm), respectively. Overall, deviation of the delivered dose to the target in each fraction was insignificant for all patients ( p -value: 0.66 for high-risk clinical target volume and 0.87 for intermediate-risk clinical target volume). The mean dose to organs at risk showed maximum difference up to 0.9, 2.7, 1.6, and 2.1 Gy for bladder, rectum, sigmoid, and bowel, respectively ( p -value: 0.88, 0.34, 0.68, and 0.85 for bladder, rectum, sigmoid, and bowel, respectively). Conclusions The interfractional dosimetric variation for both target and organs at risk was within clinically acceptable limit throughout the entire course of interstitial HDR-Syed brachytherapy. Only 6% of cases performed replanning, which could be readily identified using CT imaging. [ABSTRACT FROM AUTHOR]

Background Increased platelet has been identified as an independent and unfavorable prognostic indicator in various cancers including cervical cancer. In our study, the prognostic value of preoperative platelet count combining with FIGO (International Federation of Gynecology and Obstetrics) stage in patients with operable cervical cancer was investigated. Methods A large cohort study including 800 operable cervical cancer patients was conducted from May 2005 to December 2012. Cancer-related biomarkers such as platelet count, hematocrit, hemoglobin, RDW was evaluated together with FIGO staging system in stage IA1–IIA2 cervical cancer patients. The prediction validity of platelet together with FIGO stage was then evaluated by receiver operating characteristic (ROC) curve, and the areas under the curve (AUCs) were compared by Z test. Results Univariate cox proportional hazard analysis demonstrated that hematocrit, platelet count, hemoglobin, FIGO stage, tumor differentiation, PLN (pelvic lymph node metastasis), LVSI (vascular lymph node invasion) were associated with overall survival (OS) and disease free survival (DFS), instead of RDW (red cell distribution width), age and histological subtype. Multivariate analysis demonstrated that preoperative platelet and FIGO stage were independent predictors for OS and DFS in cervical cancer. Furthermore, significant improvements were found after the combination of platelet count and FIGO stage in predicting OS and DFS for cervical cancer patients ( P = 0.0128 and P = 0.0385, respectively). Conclusions Combination of platelet count and FIGO stage improved the prediction performance of FIGO staging and provide additional risk stratification for operable cervical cancer patients. [ABSTRACT FROM AUTHOR]

Significant heterogeneity in the tumor microenvironment of human cervical cancer patients is known to challenge treatment outcomes in this population. The current standard of care for cervical cancer patients is radiation therapy and concurrent cisplatin (CDDP) chemotherapy. Yet this treatment strategy fails to control loco-regional disease in 10–30% of patients. In order to improve the loco-regional control rate, a thermosensitive liposome formulation of CDDP (HTLC) was developed to increase local concentrations of drug in response to mild hyperthermia (HT). The HTLC formulation in combination with local HT demonstrated a significant therapeutic advantage in comparison to free drug and Lipoplatin™ in ME-180 and SiHa xenograft models of human cervical cancer, as well as in four distinct cervical patient-derived xenograft models. Differential response to HTLC + HT treatment was observed between the ME-180 and SiHa tumor models. Tumor doubling time, in vitro cell sensitivity, and tumor drug accumulation were found to be non-predictive of treatment efficacy. Rather, tumor microenvironment parameters, in particular elevated levels of both tumor hypoxia and associated stromal content, were found to serve as the overriding factors that limit drug efficacy. The prognostic value of these markers may enable stratification of cervical cancer patients for implementation of personalized medicine in the clinical setting. [ABSTRACT FROM AUTHOR]

Purpose To examine the feasibility of using diffusion-weighted images (DWIs) coregistered with T2-weighted (T2w) sequence in treatment planning system to improve target delineation for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer patients. Methods and Materials We retrospectively examined the records of consecutive patients who were referred to our institution for pulse-dose-rate IGABT between May and December 2015 after concurrent chemoradiation. An MRI with T2w and DWI sequences with a maximum diffusion factor of 1000 s/mm 2 on a 1.5 or 3.0-T MR scanner was performed after placement of the vaginal mold applicator. T2w defined gross tumor volume (GTV T2 ) and diffusion volume on DWI sequences (CTV DWI ) were retrospectively delineated, if achievable, by radiologist and radiation oncologist. Concordances between CTV DWI and GTV T2 , high-risk and intermediate-risk clinical target volumes (CTV HR and CTV IR ) were evaluated. Results Forty-four patients were identified: 23 patients (52%) had a GTV T2 delineated, CTV DWI was delineated in 42 patients (95%). Intraobserver and interobserver conformity indexes were <0.75 in 11 patients (26%) and 23 patients (54%), respectively. There was a positive correlation between GTV T2 and CTV DWI volumes ( p = 0.038, r = 0.58). Median CTV HR and CTV DWI D 90 were 37.3 Gy (17.1–48.9 Gy) and 33 Gy (22–97 Gy), respectively ( p = 0.659). CTV DWI could have pointed CTV HR delineation modifications in a total of 32 of 44 (73%) patients with CTV DWI /CTV HR conformity < 1. CTV DWI volume was totally encompassed by CTV IR in all patients. Conclusions These results suggest that DWI images as anatomical sequence without apparent diffusion coefficient mapping might have led to CTV HR modifications. Still, interobserver and intraobserver variations in delineation are substantial, and artifacts make it difficult to implement. [ABSTRACT FROM AUTHOR]

The present work proposed a simple, one pot, and green approach for the deoxygenation of graphene oxide (GO) using pyrogallol as reducing and stabilizing agent. This synthetic strategy prevents the utilization of toxic reducing reagents during synthesis. The characterization results of Ultra violet visible (UV–Vis), X-ray diffraction (XRD), X-ray photo electron spectroscopy (XPS), Transmission electron microscopy (TEM) for the synthesized GO and reduced graphene oxide (RGO) indicated the strong removal of oxygen groups after reduction which followed by stabilization with oxidized form of pyrogallol. TEM analysis showed the thin transparent silk like sheets of graphene. FTIR analysis confirmed the stabilization of graphene sheets with oxidized pyrogallol molecules. XRD and XPS analysis represented the deoxygenation of GO to RGO. The in-vitro cytotoxicity of RGO towards HeLa cells is dose dependant. The prepared RGO also exhibited the percent cell viability of about 80% even at higher concentrations indicating the less toxic nature of the RGO stabilized with pyrogallol. These results have represented that this synthetic approach is effective for the preparation of bulk scale RGO in a simple, less expensive and eco-friendly method. Since this method avoids the use of chemical reagents that are toxic in nature, the produced graphene are likely to offer several potential biomedical applications. [ABSTRACT FROM AUTHOR]

Purpose: The clinical characteristics and outcomes of patients with metastatic recurrent cervical cancer remain poorly understood. The goals of the present study were to investigate the survival outcomes according to the recurrence site in a large cohort of cervical cancer patients.Methods and Materials: Of 1322 patients with primary cervical cancer from 2000 to 2013, 205 with recurrence after primary or adjuvant postoperative radiation were enrolled retrospectively. Aggressive salvage therapy (AST), which was defined as salvage therapy that aimed not only to relieve symptoms but also to ablate recurrent tumors by the single or combined application of surgical resection of local recurrence, metastasectomy, or metastasis-directed irradiation, followed by chemotherapy, was performed according to our institutional guidelines. The patterns of recurrence, application rate and mode of AST, and survival outcomes were evaluated retrospectively under approval from the institutional review board.Results: Regarding the pattern of recurrence, distant-only (DO) recurrence was most common (59.5%), followed by combined (21.5%), central (cervix or vaginal stump; 10.7%), and pelvic (pelvic lymph nodes or pelvic side wall; 8.3%) recurrence. Two subgroups (distant lymph nodes and lung parenchyma) of the DO group demonstrated remarkably good prognosis and were categorized as type A DO; the other subgroups were labeled type B DO. Patients with type A DO recurrence constituted 36% of all recurrences and 83.8% of them received AST. The 5-year overall survival rates were significantly greater in the type A DO group than in the other groups (44.8% in the type A DO group, 12.6% in the pelvic group, and 6.8% in the type B DO group).Conclusions: We identified a patient subgroup with favorable outcomes after salvage therapy, type A DO, defined as recurrence in the distant lymph nodes only or in the lung parenchyma only. A future prospective trial is needed to investigate whether AST improves survival in this group. [ABSTRACT FROM AUTHOR]

Purpose: Worse treatment outcomes can be expected with prolongation of the overall treatment time (OTT) during definitive chemoradiation therapy (CRT) for cervical cancer. In the adjuvant setting, data on the relative importance of the OTT and the importance of RT and chemotherapy synchronization are scarce. Using the National Cancer Database, we evaluated the effect of these treatment variables on overall survival in the adjuvant CRT setting.Methods and Materials: The present analysis included nonmetastatic cervical cancer patients undergoing hysterectomy followed by adjuvant CRT. The proportional hazard model was used to estimate the effect of prognostic factors (age, comorbidity, race, tumor size, tumor grade, tumor histologic type, number of high-risk pathologic factors) and time-related variables (surgery to RT start interval [SR], OTT [RT start to end dates], package time [from diagnosis date to CRT end date] and optimum CRT synchronization [whether chemotherapy and RT start dates coincided]) on survival.Results: Of 3051 patients, 60% finished RT within 7 weeks and 85% received optimum CRT. Among other factors, univariate analysis identified longer OTT (hazards ratio [HR] 1.33; P<.001), longer SR (HR 1.17; P=.05), and nonoptimum CRT timing (HR 1.21; P=.04) as poor prognosticators. Of these factors, SR (HR 1.20; P=.04) and OTT (HR 1.21; P=.002) retained significance on multivariate analysis. An OTT >7 weeks remained a significant factor even after propensity score matching (P=.04).Conclusions: The results of our analysis suggest that prolongation of the adjuvant CRT duration >7 weeks is associated with poor survival and SR of <8 weeks should be attempted whenever clinically feasible. [ABSTRACT FROM AUTHOR]

Objective: In Reunion Island, the standardized mortality rate for cervical cancer is 4.8/100,000 women, twice higher than in Metropolitan France. For locally advanced disease, the standard of care includes a treatment by brachytherapy. Nevertheless, brachytherapy was not available on the Island before 2016. The objective of this study was to assess the impact of the management of patients with invasive cervical cancer on mortality in Reunion.Methods: We have identified all the women hospitalized in one of the health care centers of the Island diagnosed with invasive cervical cancer between 01/01/2010 and 31/12/2015. The guidelines of the French Society of Gynecological Oncology (FSGO) were considered as the reference to evaluate professional practices. The characteristics that had an influence on global survival after log-rank test were included in a multivariate analysis according to the Cox Model.Results: Retrospective analysis identified 303 women meeting inclusion criteria. The assessment of professional practices showed that the decisions on 11.6% of the patients discussed during multidisciplinary meetings, were not applied, consequentially leading to a decrease in survival (p=0.001). A total of 156 patients (51.5%) were administered a treatment in accordance with the guidelines of the FSGO and had a better survival, even after multivariate analysis (HR 2.53 [CI 95% 1.55-4.14], p<10-3). Nonconformity was associated with the lack of access to brachytherapy on the Island. Women on the Island presented low rates of screening tests (cover rates 53.2%).Conclusion: The absence of treatment in accordance with the guidelines and decisions taken during multidisciplinary meetings and the absence of brachytherapy were associated to a higher mortality among patients with invasive cervical cancer in Reunion Island. We hope that the implementation of brachytherapy in Reunion will address these deficiencies. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to evaluate temporal trends in the volume of cervical cancer brachytherapy cases available to trainees as a potential contributing factor to national trends toward decreased utilization of brachytherapy for locally advanced cervical cancer. Methods and Materials The National Cancer Database was queried to identify a cohort of women diagnosed with locally advanced cervical cancer during 2004–2013 who received primary radiation therapy. We identified academic facilities that reported radiation therapy and brachytherapy delivery the study period, categorized facilities based on annual number of cases, and evaluated temporal trends. Results A total of 6290 patients treated at 220 facilities were evaluated. During the study period, the proportion of facilities with higher brachytherapy volume remained stable. The trend of each grouping was not significant ( p > 0.05) with the exception of centers treating one case per year, which demonstrated a decrease over time ( p = 0.022). Conclusions Our analysis suggests that cervical cancer case volume at academic institutions, available for resident training, was stable throughout the study period. These findings suggest that targeting resident educational programs should not be the highest priority for interventions to improve rates of appropriate brachytherapy utilization for cervical cancer. [ABSTRACT FROM AUTHOR]

Purpose In image-guided adaptive brachytherapy (IGABT), dose distributions are optimized for each fraction. Optimum fractional dose can be constant or adapted to previous fractions and a conjecture about the future ones. We evaluate the efficacy of different fraction size schemes, derived from total IGABT dose constraints, against constant per-fraction constraints. Methods and Materials This retrospective planning study included 20 IGABT patients where four different fractionation schedules were compared based on modern planning recommendations. A total high-risk–clinical target volume D 90 (minimum dose in 90% of the volume) dose aim of 90.0 Gy with constant per-fraction organs at risk (OARs) dose constraint planning (CONST) was compared with conservative and aggressive fractionation compensation (COMP) techniques. COMP allows variations in the per-fraction dose constraints. Dose accumulation was performed through dose summation at a given volume and equivalent uniform dose (EUD) worst-case dose estimates. Results No significant differences were identifiable between dose metrics of CONST and COMP in the total patient population. However, a subgroup of patients with alternating dose-limiting OARs had significant benefit from COMP. Median high-risk–clinical target volume dose escalation ranged from 5% to 12%, whereas OAR dose increases were lower and ranged from 3% to 8%. EUD-based planning delivered similar tumor doses, although slightly lower OAR doses. By distributing the treatment aim over an increased number of treatment fractions, median tumor dose could be increased by a further 8% per additional treatment fraction at the same OAR dose levels for both CONST and COMP. Conclusions COMP is effective in patients with alternating dose-limiting OARs and is enhanced using more treatment fractions and EUD constraints. [ABSTRACT FROM AUTHOR]

Background To test the hypothesis that atlas-based active bone marrow (ABM)-sparing intensity modulated radiation therapy (IMRT) yields similar dosimetric results compared to custom ABM-sparing IMRT for cervical cancer patients. Methods We sampled 62 cervical cancer patients with pre-treatment FDG-PET/CT in training ( n = 32) or test ( n = 30) sets. ABM was defined as the subvolume of the pelvic bone marrow (PBM) with standardized uptake value (SUV) above the mean on the average FDG-PET image (ABM Atlas ) vs. the individual’s PET (ABM Custom ). Both were deformed to the planning CT. Overlap between the two subvolumes was measured using the Dice coefficient. Three IMRT plans designed to spare PBM, ABM Atlas , or ABM Custom were compared for 30 test patients. Dosimetric parameters were used to evaluate plan quality. Results ABM Atlas and ABM Custom volumes were not significantly different ( p = 0.90), with a mean Dice coefficient of 0.75, indicating good agreement. Compared to IMRT plans designed to spare PBM and ABM Custom , ABM Atlas -sparing IMRT plans achieved excellent target coverage and normal tissue sparing, without reducing dose to ABM Custom (mean ABM Custom dose 29.4 Gy vs. 27.1 Gy vs. 26.9 Gy, respectively; p = 0.10); however, PTV coverage and bowel sparing were slightly reduced. Conclusions Atlas-based ABM sparing IMRT is clinically feasible and may obviate the need for customized ABM-sparing as a strategy to reduce hematologic toxicity. [ABSTRACT FROM AUTHOR]

18 F-fluorodeoxyglucose PET/CT ( 18 F-FDG-PET/CT) is widely applied in oncology for disease staging, assessment of therapy response, relapse diagnosis, follow-up and target volume delineation. In particular, it can detect early response during chemoradiotherapy (interim) because functional modifications usually precede morphological ones. This ability is crucial to the radiation oncologist for the management of patients, to avoid persisting with ineffective therapy − often leading toxicity − and to shift to potentially more effective alternatives. Interim 18 F FDG-PET imaging in rectal and cervical cancer, the main malignancies of the pelvic district, has been applied and a broad literature is available, although some results are discordant. This systematic review summarizes the application of 18 F FDG-PET/CT during the chemoradiotherapy of locally advanced pelvic malignancies in order to clarify its capability to predict response and prognosis and its potential role to tailor therapy, which seems to be validated in rectal cancer, whilst less conclusive in cervical cancer. [ABSTRACT FROM AUTHOR]

Purpose For patients with cervical cancer the delivery of chemotherapy with radiotherapy improves survival compared with radiotherapy alone. However, high rates of acute hematologic toxicity occur when combining both therapies due to the damage of the red bone marrow (RBM). This study aimed to reduce the radiation damage to the RBM. A tool has been developed for semi-automatic delineation of the red bone marrow based on MR-only. This delineation can be included into the treatment planning process to reduce the volume of RBM irradiated in patients receiving pelvic radiation therapy. Methods 13 patients with cervical cancer were enrolled. All the patients underwent MR, CT and FDG-PET imaging. A tool for RBM determination from water and fat MR images was developed. Our MR-based RBM tool was optimized and validated with the FDG-PET scans of the patients. Results Our tool identified RBM regions in the pelvic area. The mean total volume of these regions was 34% of the pelvic bone marrow. The corresponding SUV values based on the FDG-PET scans were above the reported threshold of active/red bone marrow. Conclusion This study shows that delineations of the RBM for the radiotherapy with RBM sparing can be generated semi-automatically using MR scans only. [ABSTRACT FROM AUTHOR]

Purpose To implement coverage probability (CovP) for dose planning of simultaneous integrated boost (SIB) of pathologic lymph nodes in locally advanced cervical cancer (LACC). Material and methods CovP constraints for SIB of the pathological nodal target (PTV-N) with a central dose peak and a relaxed coverage at the perimeter were generated for use with the treatment planning system Eclipse: PTV-N D98 >90%, CTV-N D98 >100% and CTV-N D50 >101.5% of prescribed dose. Dose of EBRT was 45 Gy/25 fx with a SIB of 55–57.5 Gy depending on expected dose from brachytherapy (BT). Twenty-five previously treated patients with 47 boosted nodes were analysed. Nodes were contoured on cone beam CT (CBCT) and the accumulated dose in GTV-N CBCT and volume of body, pelvic bones and bowel receiving >50 Gy (V50) were determined. Results Nearly all nodes (89%) were visible on CBCT and showed considerable concentric regression during EBRT. Total EBRT and BT D98 was >57 Gy EQD2 in 98% of the visible nodes. Compared to treatment plans aiming for full PTV-N coverage, CovP significantly reduced V50 of body, bones and bowel ( p < 0.001) Conclusion CovP is clinically feasible for SIB of pathological nodes and significantly decreases collateral SIB dose to nearby OAR. [ABSTRACT FROM AUTHOR]

Purpose: To quantify longitudinal changes in active bone marrow (ABM) distributions within unirradiated (extrapelvic) and irradiated (pelvic) bone marrow (BM) in cervical cancer patients treated with concurrent chemoradiation therapy (CRT).Methods and Materials: We sampled 39 cervical cancer patients treated with CRT, of whom 25 were treated with concurrent cisplatin (40 mg/m2) and 14 were treated with cisplatin (40 mg/m2) plus gemcitabine (50-125 mg/m2) (C/G). Patients underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and 1.5 to 6.0 months after treatment. ABM was defined as the subvolume of bone with standardized uptake value (SUV) above the mean SUV of the total bone. The primary aim was to measure the compensatory response, defined as the change in the log of the ratio of extrapelvic versus pelvic ABM percentage from baseline to after treatment. We also quantified the change in the proportion of ABM and mean SUV in pelvic and extrapelvic BM using a 2-sided paired t test.Results: We observed a significant increase in the overall extrapelvic compensatory response after CRT (0.381; 95% confidence interval [CI]: 0.312, 0.449) and separately in patients treated with cisplatin (0.429; 95% CI: 0.340, 0.517) and C/G (0.294; 95% CI: 0.186, 0.402). We observed a trend toward higher compensatory response in patients treated with cisplatin compared with C/G (P=.057). Pelvic ABM percentage was reduced after CRT both in patients receiving cisplatin (P<.001) and in those receiving C/G (P<.001), whereas extrapelvic ABM percentage was increased in patients receiving cisplatin (P<.001) and C/G (P<.001). The mean SUV in pelvic structures was lower after CRT with both cisplatin (P<.001) and C/G (P<.001). The mean SUV appeared lower in extrapelvic structures after CRT in patients treated with C/G (P=.076) but not with cisplatin (P=.942). We also observed that older age and more intense chemotherapy regimens were correlated with a decreased compensatory response on multivariable analysis. In patients treated with C/G, mean pelvic bone marrow dose was found to be negatively correlated with the compensatory response.Conclusion: Patients have differing subacute compensatory responses after CRT, owing to variable recovery in unirradiated marrow. Intensive chemotherapy regimens appear to decrease the extrapelvic compensatory response, which may lead to increased hematologic toxicity. [ABSTRACT FROM AUTHOR]