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: To provide risk estimations for vaginal morbidity with regard to vaginal dilation (summarizing the use of dilators and/or sexual activity) in locally advanced cervical cancer patients (LACC) treated with definitive radiochemotherapy and image-guided adaptive brachytherapy (IGABT) within the prospective, multi-institutional EMBRACE-I study. MATERIAL/METHODS: Physician-assessed vaginal morbidity (CTCAEv3.0), use of vaginal dilators and patient-reported sexual activity (EORTC-CX24) were prospectively assessed at baseline and during regular follow-up. Frequency analysis for vaginal dilation was performed in a sub-cohort of patients with ≥3 follow-ups. Regular dilation was defined if reported in ≥50% of follow-ups, no/infrequent dilation if reported in <50%. Actuarial estimates were calculated with Kaplan-Meier method; comparisons evaluated with the log-rank test. Univariate and multivariable Cox proportional hazard regression 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 to no/infrequent dilation (23% vs. 37%, p≤0.001). This univariate finding was confirmed by multivariable analysis, after adjusting for other risk factors (HR=0.630, p=0.001). Regular vaginal dilation was also associated with a significantly higher risk for vaginal dryness G≥1 (72% vs. 67%, p=0.028) and bleeding G≥1 (61% vs. 34%, p≤0.001). CONCLUSION: Vaginal stenosis represents irreversible fibrotic changes that can cause pain during gynecological examination and dyspareunia in LACC 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 both can be clinically managed.

Early clinical outcomes of hybrid brachytherapy for locally advanced cervical cancer: making adverse situations in a favorable scenario.

Purpose: To investigate the feasibility and early clinical outcomes of combined intra-cavitary (IC) and interstitial (IS) image-guided adaptive brachytherapy (IGABT) as curative and definitive treatment of patients treated with chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). Material and methods: Data from medical records of all consecutive patients with histologically proven cervical cancer (FIGO 2018 stage IB-IV), treated by brachytherapy after CCRT at our institution between 2017 and 2020 were reviewed. Results: One hundred and forty-two patients with LACC FIGO 2018 stages (IB: 20.4%, II: 31.7%, III: 45.8%, IV: 2.1%) underwent brachytherapy at our institution, out of which 53.5% underwent combined brachytherapy technique (IC/IS). Median number of implanted catheters was 3 (range, 1-6 catheters). None of the 142 patients required invasive hemorrhage management. With a median follow-up of 21.6 (95% CI [confidence interval]: 19.1-23.5%) months, local relapse was observed in nine patients (6.3%), with four showing persistent and progressive disease. The estimated 2-year local and pelvic relapse-free survival were 92% (95% CI: 84-96%) and 90% (95% CI: 83-94%), respectively. The estimated 2-year disease-free survival for the entire population was 80% (95% CI: 71-87%). The 2-year overall survival (OS) rate for the entire population was 92% (95% CI: 84-96%). Acute toxicity G3 was reported in two (1.4%) patients. High-grade late toxicity (grade 3) was reported in 9 (6.3%) patients. Conclusions: Combined IC/IS brachytherapy for LACC allows for recommended doses to achieve local control even in large tumors after CCRT improving target volume coverage, with low rates of acute morbidity. Hybrid brachytherapy technique (IC/IS) is essential to have a favorable scenario at the time of brachytherapy to correctly treat locally advanced cervical cancer patients.

Dose-effect relationship between vaginal dose points and vaginal stenosis in cervical cancer: An EMBRACE-I sub-study.

BACKGROUND AND PURPOSE: To evaluate dose-effect relationships between vaginal dose points and vaginal stenosis in patients treated for locally advanced cervical cancer with radio(chemo)therapy and image-guided adaptive brachytherapy. MATERIAL AND METHODS: Patients from six centres participating in the EMBRACE-I study were included. Information on doses to different vaginal dose points, including the Posterior-Inferior Border of Symphysis (PIBS) points and recto-vaginal reference (RV-RP) point, were retrieved from the treatment planning system. In addition, the vaginal reference length (VRL) was evaluated. Vaginal stenosis was prospectively assessed according to the CTCAEv3.0 system at baseline and follow-up. Primary endpoint was grade 2 or higher (G ≥ 2) vaginal stenosis. Impact of dose to the vaginal dose points, and impact of VRL, age, vaginal involvement and applicator on vaginal stenosis G ≥ 2 was evaluated with a Cox proportional-hazard regression model. RESULTS: 301 patients were included. Median follow-up was 49 months. During follow-up, the incidence of G0, G1, G2, and G3 vaginal stenosis was 25% (76), 52% (158), 20% (59) and 3% (8), respectively. Median total doses to PIBS+2 cm, PIBS, PIBS-2 cm and the RV-RP were 52.9 (IQR 49.3-64.7), 41.0 (IQR 15.4-49.0), 4.1 (IQR 2.9-7.0) and 64.6 (IQR 60.0-70.6) Gy EQD23, respectively. Higher doses to the PIBS, PIBS + 2 cm and RV-RP points were significantly associated with increased risk for vaginal stenosis G ≥ 2. Other risk factors for vaginal stenosis were: vaginal involvement at diagnosis, higher age, shorter VRL and use of a tandem-ovoid applicator. CONCLUSION: Higher doses to the PIBS+2 cm, PIBS and RV-RP dose points are associated with vaginal stenosis G ≥ 2.

Dose-volume correlation of cumulative vaginal doses and late toxicity after adjuvant external radiation and brachytherapy for cervical cancer.

PURPOSE: To investigate dose-response relationship between vaginal doses and long-term morbidity. METHODS AND MATERIALS: Patients receiving adjuvant pelvic (chemo) radiation and brachytherapy for cervical cancer from January 2011 to December 2014 were included. Baseline vaginal length was determined clinically and from imaging at BT planning. Dose points were defined along mucosa and at 5 mm depth at 12, 3, 6, and 9 'o' clock positions at every 2 cm from apex to introitus. Cumulative equivalent doses in 2 Gy were calculated. Vaginal stenosis was reported in reference to baseline length according to CTCAE version 3.0. Receiver operator characteristics curve was used to identify dose thresholds for univariate and multivariate analysis. RESULTS: Overall, 78 women with median age of 49 (32-71) years were included. The median dose at vaginal apex mucosa and 5 mm depth was 118 Gy3 (78-198) and 81 Gy3 (70-149) respectively. At median follow-up of 36 (18-60) months, vaginal stenosis ≥25%, and grade ≥ II telangiectasia was observed in 33.3% and 45.7%, respectively. On receiver operator characteristics analysis, apical mucosal dose >142 Gy3 and recto-vaginal point dose >86 Gy3 predicted for stenosis on univariate (p = 0.02, p = 0.06) and multivariate analysis (p = 0.04). The probability of stenosis increased from 32% at 70 Gy3, 38% at 80 Gy3, and 45% at 90 Gy3 rectovaginal point dose. No correlation was observed between vaginal doses and telangiectasia and vaginal stenosis and sexual quality of life. CONCLUSION: Vaginal apex mucosal dose >142 Gy3 independently predicts for vaginal stenosis.

Dose-effect relationship and risk factors for vaginal stenosis after definitive radio(chemo)therapy with image-guided brachytherapy for locally advanced cervical cancer in the EMBRACE study.

BACKGROUND/PURPOSE: To identify risk factors for vaginal stenosis and to establish a dose-effect relationship for image-guided brachytherapy in locally advanced cervical cancer. MATERIALS/METHODS: Patients from the ongoing EMBRACE study with prospectively assessed morbidity (CTCAEv3.0) at baseline and at least one follow-up were selected. Patient-, disease- and treatment characteristics were tested as risk factors for vaginal stenosis G ⩾ 2 in univariate and multivariable analyses (Cox proportional hazards model) and a dose-effect curve was deduced from the estimates. The ICRU rectum point was used to derive the recto-vaginal reference point dose. RESULTS: In 630 patients included (median follow-up 24months), 2-year actuarial estimate for vaginal stenosis G ⩾ 2 was 21%. Recto-vaginal reference point dose (HR=1.025, p=0.029), external beam radiotherapy (EBRT) dose >45 Gy/25 fractions (HR=1.770, p=0.056) and tumor extension in the vagina (HR=2.259, p ⩽ 0.001) were risk factors for vaginal stenosis, adjusted for center reporting effects. Based on the model curve, the risk was 20% at 65 Gy, 27% at 75 Gy and 34% at 85 Gy (recto-vaginal reference point dose). CONCLUSION: Keeping the EBRT dose at 45 Gy/25 fractions and decreasing the dose contribution of brachytherapy to the vagina decrease the risk of stenosis. A planning aim of ⩽65 Gy EQD2 (EBRT+brachytherapy dose) to the recto-vaginal reference point is therefore proposed.

Pelvic radiotherapy and sexual function in women.

BACKGROUND: During the past decade there has been considerable progress in developing new radiation methods for cancer treatment. Pelvic radiotherapy constitutes the primary or (neo) adjuvant treatment of many pelvic cancers e.g., locally advanced cervical and rectal cancer. There is an increasing focus on late effects and an increasing awareness that patient reported outcomes (PROs) i.e., patient assessment of physical, social, psychological, and sexual functioning provides the most valid information on the effects of cancer treatment. Following cure of cancer allow survivors focus on quality of life (QOL) issues; sexual functioning has proved to be one of the most important aspects of concern in long-term survivors. METHODS: An updated literature search in PubMed was performed on pelvic radiotherapy and female sexual functioning/dysfunction. Studies on gynaecological, urological and gastrointestinal cancers were included. The focus was on the period from 2010 to 2014, on studies using PROs, on potential randomized controlled trials (RCTs) where female sexual dysfunction (FSD) at least constituted a secondary outcome, and on studies reporting from modern radiotherapy modalities. RESULTS: The literature search revealed a few RCTs with FSD evaluated as a PRO and being a secondary outcome measure in endometrial and in rectal cancer patients. Very limited information could be extracted regarding FSD in bladder, vulva, and anal cancer patients. The literature before and after 2010 confirms that pelvic radiotherapy, independent on modality, increases the risk significantly for FSD both compared to data from age-matched healthy control women and compared to data on patients treated by surgery only. There was only very limited data available on modern radiotherapy modalities. These are awaited during the next five years. Several newer studies confirm that health care professionals are still reluctant to discuss treatment induced sexual dysfunction with patients. CONCLUSIONS: Pelvic radiotherapy has a persistent deteriorating effect on the vaginal mucosa impacting negatively on the sexual functioning in female cancer patients. Hopefully, modern radiotherapy modalities will cause less vaginal morbidity but results are awaited to confirm this assumption. Health care professionals are encouraged to address potential sexual dysfunction both before and after radiotherapy and to focus more on quality than on quantity.