Association Between the Regular Use of Vaginal Dilators and/or Sexual Activity and Vaginal Morbidity in Locally Advanced Cervical Cancer Survivors: An EMBRACE-I Study Report.

PURPOSE: The purpose of this study was to provide risk estimations for vaginal morbidity with regard to vaginal dilation (summarizing the use of dilators and/or sexual activity) in patients with locally advanced cervical cancer treated with definitive radiochemotherapy and image guided adaptive brachytherapy within the prospective, multi-institutional EMBRACE-I study. METHODS AND MATERIALS: Physician-assessed vaginal morbidity (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0), use of vaginal dilators, and patient-reported sexual activity (EORTC-CX24) were prospectively assessed at baseline and during regular follow-ups. Frequency analysis for vaginal dilation was performed in a subcohort of patients with ≥3 follow-ups. Regular dilation was defined if reported in ≥50% of follow-ups, and no/infrequent dilation if reported in <50%. Actuarial estimates were calculated with Kaplan-Meier method; comparisons were evaluated with the log-rank test. Univariate and multivariable Cox proportional hazard regressions were used to evaluate risk factors for vaginal stenosis G≥2. RESULTS: The EMBRACE-I study included a total of 1416 patients (2008-2015); 882 were evaluated in the present report with a median follow-up of 60 months. Of those, 565 (64%) reported regular dilation. This was associated with a significantly lower 5-year risk of vaginal stenosis G≥2 compared with no/infrequent dilation (23% vs 37%, P ≤ .001). This univariate finding was confirmed by multivariable analysis, after adjusting for other risk factors (hazard ratio, 0.630; P = .001). Regular vaginal dilation was also associated with a significantly higher risk for vaginal dryness G≥1 (72% vs 67%, P = .028) and bleeding G≥1 (61% vs 34%, P ≤ .001). CONCLUSIONS: Vaginal stenosis represents irreversible fibrotic changes that can cause pain during gynecologic examination and dyspareunia in locally advanced cervical cancer patients survivors. Regular vaginal dilation (defined as the use of dilators and/or sexual activity) is associated with a significantly lower risk for G≥2 vaginal stenosis, suggesting a potential improvement of vaginal patency. It is also associated with a significantly higher risk for mild G≥1 dryness and bleeding (no higher risk for G≥2), which can be clinically managed.

Poor Adherence to Self-Applied Topical Drug Treatment Is a Common Source of Low Lesion Clearance in Patients with Actinic Keratosis-A Cross-Sectional Study.

BACKGROUND: Many treatments for actinic keratosis (AK) have been proven efficient in clinical trials. However, patients with AK may still experience unsatisfactory therapeutic outcomes in clinical practice. OBJECTIVES: To investigate patient adherence to self-applied topical interventions for AK and to explore factors associated with adherence in a real-world setting. METHODS: A cross-sectional study was conducted. Patients presenting with AK were asked to complete a self-administered questionnaire about their last topical AK treatment. RESULTS: A total of 113 patients participated with a median age of 78.5 years (range 58-94). Fifty-four patients (47.8%) received topical diclofenac, ten (8.8%) imiquimod, nine (8%) 5-fluorouracil, nine (8%) 5-fluorouracil plus salicylic acid, and eight (7.1%) photodynamic therapy. The non-adherence rate was 46.9% (n = 53), and only 30.9% (n = 35) used the topical treatments according to the summary of product characteristics (SmPC). These subgroups were compared. Patients of the non-compliant group were significantly less informed about the application time of the specific topical intervention (p = 0.002) and adjusted the timeframe (p < 0.001) and application frequency of the therapy (p = 0.02) independently of their physician. Conversely, patients reporting a sufficient pre-treatment consultation (p = 0.019) generally complied with the SmPC compliance application. CONCLUSIONS: A thorough pre-treatment consultation can help to increase treatment adherence and ensure lesion clearance.

Overall Severe Morbidity After Chemo-Radiation Therapy and Magnetic Resonance Imaging-Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). METHODS AND MATERIALS: From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. RESULTS: In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. CONCLUSIONS: This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas.

Risk Factors for Local Failure Following Chemoradiation and Magnetic Resonance Image-Guided Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study. MATERIALS AND METHODS: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis. RESULTS: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTVHR), maximum tumor dimension, CTVHR > 45 cm3, overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTVHR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology. CONCLUSION: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer.

Image-guided adaptive brachytherapy for advanced cervical cancer spreading to the bladder and/or rectum: Clinical outcome and prognostic factors.

INTRODUCTION: Refinements of brachytherapy techniques have led to better local control of locally advanced cervical cancer (LACC), especially with the development of image-guided adaptive brachytherapy (IGABT). Data on the efficacy of brachytherapy in cervical cancer spreading to adjacent organs are scarce. We report the experience of our institution in the treatment of these advanced tumors with IGABT. MATERIALS AND METHODS: Medical records of patients treated for a LACC spreading to the bladder and/or rectum between 2006 and 2020 at Gustave Roussy Institute were analyzed. Dosimetric parameters were collected and converted into 2 Gy per fraction equivalent doses, including the minimal dose received by 90% of the high-risk target volume (D90 CTVHR) and intermediate-risk target volume (D90 CTVIR), as well as the dose received by the most exposed 2 cm3 of the organs at risk. A Cox regression model was used to study the potential associations between clinical and dosimetric factors with survival endpoints and fistula formation. RESULTS AND STATISTICAL ANALYSIS: A total of 81 patients were identified. All patients received pelvic+/- para-aortic radiotherapy, 45 Gy in 25 fractions +/- boost to gross lymph nodes. Concomitant platinum-based chemotherapy was administered in 93.8% of cases. The median D90 CTVHR dose was 75.5 GyEQD2 (SD: 10.39 GyEQD2) and median CTVHR volume was 47.6 cm3 (SD: 27.9 cm3). Median bladder and rectal D2cm3 dose were 75.04 GyEQD2 (SD: 8.72 GyEQD2) and 64.07 GyEQD2 (SD: 6.68 GyEQD2). After a median follow-up of 27.62 ± 25.10 months, recurrence was found in 34/81 patients (42%). Metastatic failure was the most common pattern of relapse (n = 25). Use of a combined interstitial/intracavitary technique and D90 CTVHR ≥ 75.1 GyEQD2 were prognostic factors for OS in univariate analysis (HR = 0.24, 95%IC: 0.057-1, p = 0.023; HR = 0.2, 95%IC: 0.059-0.68, p = 0.0025, respectively). In multivariate analysis, a D90 CTVHR ≥ 75.1 GyEQD2 was significant for OS (HR = 0.23; 95%IC: 0.07, 0.78, p = 0.018). The occurrence of vesicovaginal fistula (VVF) was the most frequent pattern of local recurrence (HR = 4.6, 95%CI: 1.5-14, p = 0.01). CONCLUSION: Advances in brachytherapy modalities improved local control and survival while reducing toxicities. Enhancing local control through dose escalation and combined intracavitary/interstitial brachytherapy techniques is a major factor in patients cure probability, together with systemic intensification to better control distant events.

Implementation of Image-Guided Brachytherapy for Pediatric Vaginal Cancers: Feasibility and Early Clinical Results.

Background: Brachytherapy (BT) has a major role in pediatric cancers of the lower genital tract, as part of a multimodal organ conservative strategy. Scarce data are available on the location of image-guided BT. Methods: Medical records of all consecutive girls treated in our center between 2005 and 2020 for a vaginal tumor with exclusive image-guided PDR-BT were retrospectively examined, with a focus on treatment parameters, patient compliance, and clinical outcome, including analysis of local control, survival and late toxicity rates. Results: Twenty-six patients were identified, with a median age of 25 months. Histological types were rhabdomyosarcoma, malignant germ cell tumor (MGCT) and clear cell adenocarcinoma in 18 (69%), 7 (27%) and 1 (4%) patients, respectively. Ten (33%) patients had prior surgery and 25 (96%) received chemotherapy prior to BT. The median prescribed dose was 60 Gy through pulses of 0.42 Gy. Global compliance was satisfactory, but three (12%) patients required replanning because of applicator displacement. After a median follow-up of 47.5 months, one patient with MGCT referred for salvage treatment of a local recurrence had a local and metastatic relapse. The local control rate probability was 96% at the last follow-up. Late toxicity rates ≥ grade 2 and ≥ grade 3 were reported in 23% and 11%, respectively, with gynecological toxicities being the most frequent side effect. Two patients required dilatation for vaginal stenosis. Conclusions: PDR-BT allowed similar local control compared to the historical low-dose rate technique. An indirect comparison suggests fewer treatment-related toxicities by integrating image guidance and optimization capabilities, but longer follow-up is necessary. Due to the rarity of the disease and the technical aspects of BT in these very young patients, referral to specialized high-volume centers is recommended.

Long-term urological complications after conservative local treatment (surgery and brachytherapy) in children with bladder-prostate rhabdomyosarcoma: A single-team experience.

BACKGROUND: Outcome of children with bladder-prostate rhabdomyosarcoma (RMS) has improved with multimodal therapies, including surgery and/or radiotherapy for local treatment. Our aim was to report long-term urological complications after a conservative approach combining conservative surgery and brachytherapy. PATIENTS AND METHODS: Eighty-six patients, free of disease, were retrospectively reviewed. Symptoms related to urinary tract obstruction, incontinence, infection, and lithiasis were reported and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) classification. Only symptomatic patients underwent urodynamic studies. Risk factors for complications were analyzed. RESULTS: There were 76 males and 10 females. The median follow-up was 6.3 years (18 months to 24 years). Complications occurred after a median follow-up of 5 years (0-21). Twenty-two patients (26%) had long-term urological complications. Urinary tract obstruction was found in 15 patients (17%) and urinary incontinence in 14 patients (16%). Recurrent urinary tract infection occurred in four patients and urinary lithiasis in four (5%). The underlying physiopathology included bladder dysfunction in 15 patients (17%), urethral stenosis in six (7%), and ureterovesical junction stenosis in five (6%). On univariate analysis, posterior bladder wall dissection (p = .001), bladder neck trigone dissection (p = .010), and partial prostatectomy (p = .023) were significantly associated with an increased risk of bladder dysfunction; on multivariate analysis, only age ≤2 years (p = .028) at operation and posterior bladder wall dissection (p = .006) were found to be significant. CONCLUSION: The conservative surgical approach combined with brachytherapy for bladder-prostate RMS leads to long-term urological complications in 26% of survivors. Optimizing brachytherapy doses for young children and establishing a clear and long-term follow-up protocol could help to reduce these complications.

Brachytherapy for Pediatric Patients at Gustave Roussy Cancer Campus: A Model of International Cooperation for Highly Specialized Treatments.

PURPOSE: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. METHODS AND MATERIALS: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. RESULTS: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. CONCLUSIONS: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

Prognostic Implications of Uterine Cervical Cancer Regression During Chemoradiation Evaluated by the T-Score in the Multicenter EMBRACE I Study.

PURPOSE: A simple scoring system (T-score, TS) for integrating findings from clinical examination and magnetic resonance imaging (MRI) of the primary tumor at diagnosis has shown strong prognostic capability for predicting local control and survival in locally advanced cervical cancer treated with chemoradiation and MRI-guided brachytherapy (BT). The aim was to validate the performance of TS using the multicenter EMBRACE I study and to evaluate the prognostic implications of TS regression obtained during initial chemoradiation. METHODS AND MATERIALS: EMBRACE I recruited 1416 patients, of whom 1318 were available for TS. Patients were treated with chemoradiation followed by MRI-guided BT. A ranked ordinal scale of 0 to 3 points was used to assess 8 anatomic locations typical for local invasion of cervical cancer. TS was calculated separately at diagnosis (TSD) and at BT (TSBT) by the sum of points obtained from the 8 locations at the 2 occasions. RESULTS: Median TSD and TSBT was 5 and 4, respectively. TS regression was observed in 71% and was an explanatory variable for BT technique (intracavitary vs intracavitary/interstitial) and major dose-volume histogram parameters for BT, such as high-risk clinical target (CTVHR), CTVHR D90 (minimal dose to 90% of the target volume), D2cm3 bladder (minimal dose to the most exposed 2 cm3 of the bladder), and D2cm3 rectum. TS regression (TSBT≤5) was associated with improved local control and survival and with less morbidity compared with patients with TSBT remaining high (>5) despite initial chemoradiation. TS regression was significant in multivariate analysis for both local control and survival when analyzed in consort with already established prognostic parameters related to the patient, disease, and treatment. CONCLUSIONS: TS was validated in a multicenter setting and proven to be a strong multidisciplinary platform for integration of clinical findings and imaging with the ability to quantitate local tumor regression and its prognostic implications regarding BT technique, dose-volume histogram parameters, local control, survival, and morbidity.

Brachytherapy for the Conservative Treatment of Female Peri-Urethral Carcinoma.

Introduction: Peri-urethral cancers (PUC) are rare tumors. Brachytherapy (BT), either monotherapy or combined with radiation therapy, is a preferred treatment option to spare the morbidity of surgery and achieve organ preservation. We report, to the best of our knowledge, the largest experience of brachytherapy among women with PUC. Patients and Methods: This is a retrospective review of the medical records of female patients with PUC who underwent low- or pulse-dose-rate BT with or without external beam radiotherapy at Gustave Roussy between 1990 and 2018. Patients were categorized according to the treatment intention into a primary and recurrent group. The Kaplan-Meier method was used for survival analysis, and the Cox proportional-hazard model was used for univariate analysis. Brachythewharapy-related adverse events were reported according to Common Terminology Criteria for Adverse Events version 4. Results: We identified 44 patients with PUC who underwent BT. Of the 44 patients, 22 had primary tumors and 22 had recurrent tumors. Histologies were mainly adenocarcinoma (n = 20) and squamous cell carcinoma (n = 14). The median prescribed dose was 60 Gy for the 24 patients treated with BT alone and 20 Gy (IQ range: 15-56.25 Gy) for the 20 patients treated with BT in combination with EBRT. With a median follow-up of 21.5 months (range 7.5-60.8), a total of six patients experienced local relapse (17.5%). The 2-year overall survival probability was 63% (95%CI: 49.2-81.4%). The most common toxicities were acute genito-urinary grade 1-2 toxicities. At the last follow-up, four patients experienced focal necrosis. Conclusions: In this cohort of women with PUC undergoing BT, we observed an 80% probability of local control with acceptable morbidity. Though survival was poor, with high metastatic relapse probability, BT was useful to focally escalate the dose and optimize local control in the context of an organ sparing strategy.

Inoperable scalp cutaneous angiosarcoma: Complete response after definitive external beam radiation therapy - brachytherapy association.

Effective treatments are scarce in non-operable scalp cutaneous angiosarcoma patients. Curative-intent definitive sequential IMRT and plesiobrachytherapy allowed complete response with limited side effect in two elder patients. This could represent a non-invasive therapeutic option for patients with locally advanced presentation.

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort.

OBJECTIVE: To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. RESULTS: In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). CONCLUSION: IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.

Impact of Vaginal Symptoms and Hormonal Replacement Therapy on Sexual Outcomes After Definitive Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer: Results from the EMBRACE-I Study.

PURPOSE: To evaluate patient-reported sexual outcomes after chemoradiation therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer in the observational, prospective, multicenter EMBRACE-I study. METHODS AND MATERIALS: Sexual outcomes were assessed prospectively with the European Organization for Research and Treatment of Cancer Qualify of Life Questionnaire (EORTC-QLQ-CX24) at baseline and follow-up. Crude incidence and prevalence rates of sexual activity, vaginal functioning problems (dryness, shortening, tightening, pain during intercourse), and sexual enjoyment were evaluated. Associations between pain during intercourse and vaginal functioning problems or sexual enjoyment were calculated, pooling observations over all follow-ups (Spearman correlation coefficient). In patients who were frequently sexually active (≥50% of follow-ups), the effects of regular hormonal replacement therapy (HRT) on vaginal functioning problems were evaluated (Pearson χ2). RESULTS: The analysis involved 1045 patients with a median follow-up of 50 months. Sexual activity was reported by 22% of patients at baseline and by 40% to 47% of patients during follow-up (prevalence rates). Vaginal functioning problems in follow-up were dryness (18%-21%), shortening (15%-22%), tightening (16%-22%), pain during intercourse (9%-21%), and compromised enjoyment (37%-47%). Pain during intercourse was significantly associated with vaginal tightening (r = 0.544), shortening (r = 0.532), and dryness (r = 0.408) and negatively correlated with sexual enjoyment (r = -0.407). Regular HRT was associated with significantly less vaginal dryness (P = .015), shortening (P = .024), pain during intercourse (P = .003), and borderline higher sexual enjoyment (P = .062). CONCLUSIONS: Vaginal functioning problems are associated with pain and compromised sexual enjoyment. Further effort is required for the primary prevention of vaginal morbidity with dose optimization and adaptation. Secondary prevention strategies, including HRT for vaginal and sexual health after radiation therapy in locally advanced cervical cancer, should be considered and sexual rehabilitation programs should be developed further.

Radiation Therapy Techniques and Treatment-Related Toxicity in the PORTEC-3 Trial: Comparison of 3-Dimensional Conformal Radiation Therapy Versus Intensity-Modulated Radiation Therapy.

PURPOSE: Radiation therapy techniques have developed from 3-dimensional conformal radiation therapy (3DCRT) to intensity modulated radiation therapy (IMRT), with better sparing of the surrounding normal tissues. The current analysis aimed to investigate whether IMRT, compared to 3DCRT, resulted in fewer adverse events (AEs) and patient-reported symptoms in the randomized PORTEC-3 trial for high-risk endometrial cancer. METHODS AND MATERIALS: Data on AEs and patient-reported quality of life (QoL) of the PORTEC-3 trial were available for analysis. Physician-reported AEs were graded using Common Terminology Criteria for Adverse Events v3.0. QoL was assessed by the European Organisation for Research and Treatment of Cancer QLQC30, CX24, and OV28 questionnaires. Data were compared between 3DCRT and IMRT. A P value of ≤ .01 was considered statistically significant due to the risk of multiple testing. For QoL, combined scores 1 to 2 ("not at all" and "a little") versus 3 to 4 ("quite a bit" and "very much") were compared between the techniques. RESULTS: Of 658 evaluable patients, 559 received 3DCRT and 99 IMRT. Median follow-up was 74.6 months. During treatment no significant differences were observed, with a trend for more grade ≥3 AEs, mostly hematologic and gastrointestinal, after 3DCRT (37.7% vs 26.3%, P = .03). During follow-up, 15.4% (vs 4%) had grade ≥2 diarrhea, and 26.1% (vs 13.1%) had grade ≥2 hematologic AEs after 3DCRT (vs IMRT) (both P < .01). Among 574 (87%) patients evaluable for QoL, 494 received 3DCRT and 80 IMRT. During treatment, 37.5% (vs 28.6%) reported diarrhea after 3DCRT (vs IMRT) (P = .125); 22.1% (versus 10.0%) bowel urgency (P = 0039), and 18.2% and 8.6% abdominal cramps (P = .058). Other QoL scores showed no differences. CONCLUSIONS: IMRT resulted in fewer grade ≥3 AEs during treatment and significantly lower rates of grade ≥2 diarrhea and hematologic AEs during follow-up. Trends toward fewer patient-reported bowel urgency and abdominal cramps were observed after IMRT compared to 3DCRT.

Risk factors for nodal failure after radiochemotherapy and image guided brachytherapy in locally advanced cervical cancer: An EMBRACE analysis.

OBJECTIVE: To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study. MATERIALS AND METHODS: Data for pelvic NF and para-aortic (PAO) NF (NFPAO) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1). RESULTS: 1338 patients with 152 NF and 104 NFPAO events were analysed with a median follow-up of 34.2 months (IQR 16.4-52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NFPAO (HR 0.53, 95%-CI 0.28-1.00, p = 0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NFPAO (HR 0.38, 95%-CI 0.17-0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF. CONCLUSION: In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NFPAO, particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis.

Pulse-dose-rate interstitial brachytherapy in anal squamous cell carcinoma: clinical outcomes and patients' health quality perception.

PURPOSE: To examine clinical outcomes and quality of life of patients with anal squamous cell carcinoma treated with interstitial pulsed-dose-rate brachytherapy (PDR-BT) with a boost to residual tumor after external radiotherapy. MATERIAL AND METHODS: Medical records of patients receiving a brachytherapy boost after radiotherapy for anal squamous cell carcinoma in our Institute between 2008 and 2019 were retrospectively reviewed. After receiving pelvic irradiation ± concurrent chemotherapy, patients received PDR-BT boost to residual tumor, in order to deliver a minimal total dose of 60 Gy. Patients' outcomes were analyzed, with primary focus on local control, sphincter preservation, morbidity, and quality of life. RESULTS: A total of 42 patients were identified, included 24, 13, and 5 patients with I, II, and III tumor stages, respectively. Median brachytherapy (BT) dose was 20 Gy (range, 10-30 Gy). Median dose per pulse was 42 cGy (range, 37.5-50 cGy). With median follow-up of 60.4 months (range, 5.4-127.4 months), estimated local control and colostomy-free survival rates at 5 years were both 88.7% (95% CI: 67.4-96.4%). The largest axis of residual lesion after external beam radiation therapy (EBRT) and poor tumor shrinkage were associated with more frequent relapses (p = 0.02 and p = 0.007, respectively). Out of 40 patients with more than 6 months follow-up, only one experienced severe delayed toxicity (fecal incontinence). Health quality perception was very good or good in 20 of 22 (91%) patients, according to their replies of quality-of-life surveys. A total dose ≥ 63 Gy was associated with higher number of anorectal grade 1+ toxicities (n = 1.5 vs. n = 0.61, p = 0.02). CONCLUSIONS: In this cohort of 42 patients with mainly I and II tumor stages, PDR-BT boost allowed for local control in 88.7% of patients, with only one grade 3 anorectal toxicity.

Nomogram Predicting Overall Survival in Patients With Locally Advanced Cervical Cancer Treated With Radiochemotherapy Including Image-Guided Brachytherapy: A Retro-EMBRACE Study.

PURPOSE: To present a nomogram for prediction of overall survival (OS) in patients with locally advanced cervical cancer (LACC) undergoing definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT). METHODS AND MATERIALS: Seven hundred twenty patients with LACC treated with radiochemotherapy including IGABT in 12 institutions (median follow-up 56 months) were analyzed; 248 deaths occurred. Thirteen candidate predictors for OS were a priori chosen on the basis of the literature and expert knowledge. Missing data (7.2%) were imputed using multiple imputation and predictive mean matching. Univariate analysis with a multivariable Cox regression model for OS stratified by center was performed. Stepwise selection of predictive factors with the Akaike Information Criterion was used to obtain a predictive model and construct a nomogram for OS predictions 60 months from diagnosis; this was internally validated by concordance probability as a measure of discrimination and a calibration plot. RESULTS: Thirteen potential predictive factors were evaluated; 10 factors reached statistical significance in univariate analysis (age, Hemoglobin, FIGO Stage2009, tumor width, corpus involvement, lymph node involvement, concurrent chemotherapy, dose to 90% of the high-risk clinical target volume, volume of CTV at the first brachytherapy [CTVHRVolumeBT], overall treatment time [OTT]). Four factors were confirmed significant within the multivariable Cox regression model (FIGO Stage2009, lymph node involvement, concurrent chemotherapy, CTVHRVolumeBT). The predictive model and corresponding nomogram were based on 7 Akaike Information Criterion-selected factors (age, corpus involvement, FIGO Stage2009, lymph node involvement, concurrent chemotherapy, CTVHRVolumeBT, OTT) and showed promising calibration and discrimination (cross-validated concordance probability c = 0.73). CONCLUSIONS: This is the first nomogram to predict OS in patients with LACC treated with IGABT. In addition to previously reported factors (age, FIGO2009 stage, corpus involvement, chemotherapy delivery, OTT, lymph node involvement), status of primary tumor at the time of brachytherapy seems to be an essential outcome predictor. These results can facilitate individualized tailoring of treatment and patient counseling during the treatment.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

BACKGROUND: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. METHODS: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. FINDINGS: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae. INTERPRETATION: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. FUNDING: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.

Pulsed Dose Rate Brachytherapy of Lip Carcinoma: Clinical Outcome and Quality of Life Analysis.

PURPOSE: Lip carcinoma represents one of the most common types of head and neck cancer. Brachytherapy is a highly effective therapeutic option for all stages of lip cancers. We report our experience of pulsed dose rate brachytherapy (PDR) as treatment of lip carcinoma. METHODS AND MATERIALS: this retrospective single center study included all consecutive patients treated for a lip PDR brachytherapy in our institution from 2010 to 2019. The toxicities and outcomes of the patients were reported, and a retrospective quality of life assessment was conducted by phone interviews (FACT H&N). RESULTS: From October 2010 to December 2019, 38 patients were treated in our institution for a lip carcinoma by PDR brachytherapy. The median age was 73, and the majority of patients presented T1-T2 tumors (79%). The median total dose was 70.14 Gy (range: 60-85 Gy). With a mean follow-up of 35.4 months, two patients (5.6%) presented local failure, and seven patients (19%) had lymph node progression. The Kaplan-Meier estimated probability of local failure was 7.2% (95% CI: 0.84-1) at two and four years. All patients encountered radiomucitis grade II or higher. The rate of late toxicities was low: three patients (8.3%) had grade II fibrosis, and one patient had grade II chronic pain. All patients would highly recommend the treatment. The median FACT H&N total score was 127 out of 148, and the median FACT H&N Trial Outcome Index was 84. CONCLUSIONS: This study confirms that an excellent local control rate is achieved with PDR brachytherapy as treatment of lip carcinoma, with very limited late side effects and satisfactory functional outcomes. A multimodal approach should help to improve regional control.