Vaginal changes, sexual functioning and distress of women with locally advanced cervical cancer treated in the EMBRACE vaginal morbidity substudy.

OBJECTIVE: The EMBRACE-vaginal morbidity substudy prospectively evaluated physician-assessed vaginal changes and patient-reported-outcomes (PRO) on vaginal and sexual functioning problems and distress in the first 2-years after image-guided radio(chemo)therapy and brachytherapy for locally advanced cervical cancer. METHODS: Eligible patients had stage IB1-IIIB cervical cancer with ≤5 mm vaginal involvement. Assessment of vaginal changes was graded using CTCAE. PRO were assessed using validated Quality-of-Life and sexual questionnaires. Statistical analysis included Generalized-Linear-Mixed-Models and Spearman's rho-correlation coefficients. RESULTS: 113 eligible patients were included. Mostly mild (grade 1) vaginal changes were reported over time in about 20% (range 11-37%). At 2-years, 47% was not sexually active. Approximately 50% of the sexually active women reported any vaginal and sexual functioning problems and distress over time; more substantial vaginal and sexual problems and distress were reported by up to 14%, 20% and 8%, respectively. Physician-assessed vaginal changes and PRO sexual satisfaction differed significantly (p ≤ .05) between baseline and first follow-up, without further significant changes over time. No or only small associations between physician-assessed vaginal changes and PRO vaginal functioning problems and sexual distress were found. CONCLUSIONS: Mild vaginal changes were reported after image-guided radio(chemo)therapy and brachytherapy, potentially due to the combination of tumors with limited vaginal involvement, EMBRACE-specific treatment optimization and rehabilitation recommendations. Although vaginal and sexual functioning problems and sexual distress were frequently reported, the rate of substantial problems and distress was low. The lack of association between vaginal changes, vaginal functioning problems and sexual distress shows that sexual functioning is more complex than vaginal morbidity alone.

Lichen Sclerosis is Associated With a High Rate of Local Failure After Radio(chemo)therapy for Vulvar Cancer.

AIMS: Radio(chemo)therapy plays an important role in the treatment of vulvar cancer, either as postoperative treatment or as definitive treatment in patients who present with inoperable disease. Only limited data are available regarding outcome after modern state of the art radio(chemo)therapy and more information regarding prognostic factors are warranted. The aim of this study was to evaluate disease outcomes after radio(chemo)therapy in patients with vulvar cancer with special emphasis on the impact of lichen sclerosis on local control. MATERIALS AND METHODS: All consecutive patients (n = 109) from the western half of Denmark who were treated with definitive (n = 52) or postoperative (n = 57) radio(chemo)therapy between January 2013 and January 2020 were included. Local control, cause-specific survival and overall survival, as well as morbidity, were analysed using Kaplan-Meier statistics. Prognostic factors for local control were analysed in univariate and multivariate analysis. RESULTS: At a median follow-up of 35 (4-95) months, 46 (42.0%) patients were diagnosed with recurrence. Eighty per cent of the recurrences were located to the vulva region, leading to a 5-year local control of 58.9% (confidence interval 47.9-69.9). Cause-specific survival was 62.9% (confidence interval 53.1-72.7), whereas overall survival was 58.0% (confidence interval 47.6-68.5). Grade 3-4 morbidity was diagnosed in 10 (9%) patients. Lichen sclerosis (hazard ratio 3.89; confidence interval 1.93-7.79) was an independent risk factors for local recurrence. Patients without lichen sclerosis had a 5-year local control rate of 83.6% (confidence interval 67.2-99.0) and 62.6% (confidence interval 43.2-82.0) after postoperative and definitive radio(chemo)therapy, respectively. In patients with lichen sclerosis, the local control rate was 44.0% (confidence interval 19.3-69.0) and 17.6% (confidence interval 0-30.0) after postoperative and definitive radio(chemo)therapy, respectively. CONCLUSION: Radio(chemo)therapy plays an important role in the treatment of vulvar cancer. However, despite dose escalation, a substantial proportion of patients experienced local relapse. Pre-existing lichen sclerosis seems to have a significant impact on the risk of recurrence. This should influence surveillance programmes for these patients.

Clinical and imaging findings in cervical cancer and their impact on FIGO and TNM staging - An analysis from the EMBRACE study.

OBJECTIVE: To investigate differences in local tumour staging between clinical examination and MRI and differences between FIGO 2009, FIGO 2018 and TNM in patients with primary cervical cancer undergoing definitive radio-chemotherapy. METHODS: Patients from the prospective observational multi-centre study "EMBRACE" were considered for analysis. All patients had gynaecological examination and pelvic MRI before treatment. Nodal status was assessed by MRI, CT, PET-CT or lymphadenectomy. For this analysis, patients were restaged according to the FIGO 2009, FIGO 2018 and TNM staging system. The local tumour stage was evaluated for MRI and clinical examination separately. Descriptive statistics were used to compare local tumour stages and different staging systems. RESULTS: Data was available from 1338 patients. For local tumour staging, differences between MRI and clinical examination were found in 364 patients (27.2%). Affected lymph nodes were detected in 52%. The two most frequent stages with FIGO 2009 are IIB (54%) and IIIB (16%), with FIGO 2018 IIIC1 (43%) and IIB (27%) and with TNM T2b N0 M0 (27%) and T2b N1 M0 (23%) in this cohort. CONCLUSIONS: MRI and clinical examination resulted in a different local tumour staging in approximately one quarter of patients. Comprehensive knowledge of the differential value of clinical examination and MRI is necessary to define one final local stage, especially when a decision about treatment options is to be taken. The use of FIGO 2009, FIGO 2018 and TNM staging system leads to differences in stage distributions complicating comparability of treatment results. TNM provides the most differentiated stage allocation.

Assessment of dose to functional sub-structures in the lower urinary tract in locally advanced cervical cancer radiotherapy.

PURPOSE: To provide an analysis of dose distribution in sub-structures that could be responsible for urinary toxicity after Image-Guided Adaptive BrachyTherapy (IGABT) in Locally Advanced Cervical Cancer (LACC). METHODS: 105 LACC patients treated with radiochemotherapy and IGABT were selected. Sub-structures (bladder wall, trigone, bladder neck, urethra) were contoured on IGABT-planning MRIs. D2cm3 and D0.1cm3, ICRU Bladder-Point (ICRU BP) and Posterior-Inferior Border of Symphysis points (PIBS, PIBS + 2 cm, PIBS - 2 cm) doses were extracted. Internal-Urethral-Ostium (IUO) and PIBS-Urethra (PIBS-U) points were defined as urethral dose surrogates. Finally, the Vaginal Reference Length (VRL) was extracted. Values were converted into total EBRT + BT equivalent dose in 2 Gy fractions using α/ß = 3 and T1/2 = 1.5 h. RESULTS: Median D2cm3 for bladder and trigone were 71.7[interquartile-range:66.5;74.1]Gy and 57.8[53.3;63.6]Gy, respectively, while median D0.1cm3 were 82.2[77.6;89.1]Gy and 70.7[62.0;76.7]Gy, respectively. Median ICRU BP dose was 63.7[56.5;70.5]Gy and correlated with trigone D2cm3 and D0.1cm3, while bladder and trigone D2cm3 had poor correlation (R2 = 0.492), as well as D0.1cm3 (R2 = 0.356). Bladder neck D0.1cm3 was always lower than trigone D0.1cm3 and higher than IUO. Correlation between PIBS + 2 cm and IUO was poor (R2 = 0.273), while PIBS and PIBS-U were almost equal (R2 = 0.990). VRL correlated with dose to bladder base. CONCLUSIONS: The study confirmed that ICRU BP and trigone doses correlate. Bladder D2cm3 is not representative of trigone dose because hotspots are often placed in the bladder dome. VRL is a good indicator for bladder base sparing. In addition to D2cm3 and D0.1cm3 for whole bladder, ICRU BP, trigone D2cm3 and D0.1cm3, IUO and PIBS are useful for lower urinary tract reporting.

Urinary and sexual dysfunction in women after resection with and without preoperative radiotherapy for rectal cancer: a population-based cross-sectional study.

AIM: Knowledge of urinary and sexual dysfunction in women after rectal cancer treatment is limited. This study addresses this in relation to the use of preoperative radiotherapy, type of surgery and the presence of bowel dysfunction. METHOD: All living female patients who underwent abdominoperineal excision (APE) or low anterior resection (LAR) for rectal cancer in Denmark between 2001 and 2007 were identified. Validated questionnaires (the ICIQ-FLUTS and the SVQ) on urinary and sexual function were completed by 516 (75%) and 482 (72%) recurrence-free patients in 2009. RESULTS: Urgency and incontinence were reported by 77 and 63% of respondents, respectively. Vaginal dryness, dyspareunia and reduced vaginal dimensions occurred in 72, 53 and 29%, respectively, and 69% reported that they had little/no sexual desire. Preoperative radiotherapy was associated with voiding difficulties (OR = 1.63, 95% CI 1.09-2.44), reduced vaginal dimensions (OR = 4.77, 95% CI 1.97-11.55), dyspareunia (OR = 2.76, 95% CI 1.12-6.79), lack of desire (OR = 2.22, 95% CI 1.09-4.53) and reduced sexual activity (OR = 0.55, 95% CI 0.30-0.98). Patients undergoing APE had a higher risk of dyspareunia (OR = 2.61, 95% CI 1.00-6.85). Bowel dysfunction after LAR was associated with bladder storage difficulties (OR = 1.64, 95% CI 1.01-2.65), symptoms of incontinence (OR = 2.17, 95% CI 1.35-3.50), lack of sexual desire (OR = 2.69, 95% CI 1.21-5.98), sexual inactivity (OR = 0.48, 95% CI 0.24-0.96) and sexual dissatisfaction (OR = 0.40, 95% CI 0.20-0.82). CONCLUSION: Urinary and sexual problems are common in women after treatment for rectal cancer. Preoperative radiotherapy interferes with several aspects of urinary and sexual functioning. Bowel dysfunction after LAR is associated with urinary dysfunction and a reduction in sexual desire, activity and satisfaction.

A 10-year experience of total pelvic exenteration for primary advanced and locally recurrent rectal cancer based on a prospective database.

AIM: The study was conducted in a dedicated centre treating the majority of Danish patients with intended curative total pelvic exenteration for primary advanced (PARC) or locally recurrent (LRRC) rectal cancer. We compared PARC and LRRC and analysed postoperative morbidity and mortality, and long-term outcome. METHOD: There were 90 consecutive patients (PARC/LRRC 50/40) treated between January 2001 and October 2010, recorded on a prospectively maintained database. RESULTS: The median age was 63 (32-75) years with a gender ratio of 7 women to 83 men. All patients were American Society of Anesthesiologists level I or II. Sacral resection was performed in five patients with PARC and 15 with LRRC (P=0.002). R0 resection was achieved in 33 (66%) patients with PARC and in 15 (38%) with LRRC, R1 resection in 17 (34%) with PARC and 20 (50%) with LRRC and R2 resection in five (13%) with LRRC. R0 resection was more frequent in PARC (P=0.007). Forty-four (49%) patients had no postoperative complications. Fifty-five major complications were registered. Two (2.2%) patients died within 30 days, and the total in-hospital mortality was 5.6%. The median follow-up was 12 (0.4-91) months. The 5-year survival was 46% for PARC and 17% for LRRC (P=0.16). CONCLUSION: Pelvic exenteration is associated with considerable morbidity but low mortality in an experienced centre. Pelvic exenteration can improve long-term survival, especially for patients with PARC. However, pelvic exenteration is also justified for patients with LRRC.

A national cohort study of long-course preoperative radiotherapy in primary fixed rectal cancer in Denmark.

OBJECTIVE: Preoperative radiotherapy has been shown to enable a fixed rectal cancer to become resectable which in turn may result in long-time survival. In this study, we analysed the outcome of long-course preoperative radiotherapy in fixed rectal cancer in a national cohort including all Danish patients registered with primary inoperable rectal cancer and treated in the period May 2001 to December 2005. METHOD: The study was based on surgical and demographic data from a continuously updated and validated national database. In addition, retrospective data were retrieved from all departments of radiotherapy concerning technique of radiotherapy, dose and fractionation and use of concomitant chemotherapy. Outcome was determined by actuarial analysis of local control, disease-free survival and overall survival. RESULTS: A total of 258 patients with fixed rectal cancer received long-course radiotherapy (> 45 Gy). The median age at diagnosis was 66 years (range: 32-85) and 185 (72%) patients were male. The resectability rate was 80%, and a R0 resection was obtained in 148 patients (57% of all patients and 61% of those operated). The 5-year local recurrence rate for all patients was 5% (95% CI: 3-7%), and the actuarial distant recurrence rate was 41% (95% CI: 35-47%). The cumulative 5-year disease-free survival was 27% (95% CI: 22-32%) and overall 5-year survival was 34% (95% CI: 29-39%). CONCLUSIONS: This study is the first population-based report on outcome of preoperative long-course radiotherapy in a large unselected patient group with clinically fixed rectal cancer. Most patients could be resected with the intention of cure and one in three was alive after 5 years.

Clinical outcome in 520 consecutive Danish rectal cancer patients treated with short course preoperative radiotherapy.

AIM: The purpose of this study was to analyse the results of preoperative short course radiotherapy in a consecutive, national cohort of patients with rectal cancer. METHODS: Through a validated, prospective national database we identified 520 Danish patients who presented with high-risk mobile tumours in the lower two thirds of the rectum and were referred for preoperative radiotherapy with 5 x 5 Gy. The inclusion period was 56 months. Radiotherapy data was retrospectively collected. RESULTS: Of the 520 patients, 514 completed radiotherapy and 506 had surgery. Surgery was considered curative in 439 patients. The 3-year local recurrence rate was 4.0% (95% CI 2.5-6.5%) and the distant recurrence rate at 3 years was 18.7% (95% CI 15.4-22.5%). The 5-year disease free survival rate was 40.2% (95% CI 27.0-53.1%) and overall survival 50.4% (95% CI 36.1-63.1%). Most tumours (61%) were classified as T3 or T4 and 41% of the local recurrences occurred in patients with a fixed tumour at surgery. CONCLUSION: This study confirms data from randomised studies that the short course 5 x 5 Gy regime is a feasible treatment for locally advanced rectal cancer even when applied in a population outside clinical trials.

Perineal healing and survival after anal cancer salvage surgery: 10-year experience with primary perineal reconstruction using the vertical rectus abdominis myocutaneous (VRAM) flap.

Salvage surgery of recurrent or persistent anal cancer following radiotherapy is often followed by perineal wound complications. We examined survival and perineal wound complications in anal cancer salvage surgery during a 10-year period with primary perineal reconstruction predominantly performed using vertical rectus abdominis myocutaneous (VRAM) flap. Between 1997 and 2006, 49 patients underwent anal cancer salvage surgery. Of these, 48 had primary reconstruction with VRAM. Overall survival was computed by the Kaplan-Meier method and mortality rate ratios (MRRs) by Cox regression. One patient (2%) died within 30 days postoperatively. Postoperative complications necessitated reoperation in eight (16%) patients. We found no major perineal wound infections. Major perineal wound breakdown occurred in the only patient in whom VRAM was not used. Five-year survival was 61% [95% confidence interval (CI) 43-75%]. Free resection margins (R0) were obtained in 78% of patients, with 5-year survival of 75% (95% CI 53-87%). Involved margins, microscopically only (R1) or macroscopically (R2), strongly predicted an adverse outcome [age-adjusted 2-year MRRs (95% CI) R1 vs. R0 = 4.1 (0.7-23.6), R2 vs. R0 = 10.9 (2.2-54.2)]. We conclude that anal cancer salvage surgery can yield long-time survival but obtaining free margins is critical. A low rate of perineal complications is achievable by primary perineal reconstruction using VRAM flap.

Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma.

PURPOSE: This study was designed to compare tumor hypoxia assessed by invasive O2 sensitive electrodes and pimonidazole labeling in primary human cervix carcinomas. METHODS AND MATERIALS: Twenty-eight patients with primary cervix carcinomas (FIGO Stage Ib-IVa) were investigated. Both invasive pO2 measurements and pimonidazole labeling were obtained in all patients. Before treatment, patients were given pimonidazole as a single injection (0.5 g/m2 i.v.). Ten to 24 h later, oxygenation measurements were done by Eppendorf histography, and after this procedure biopsies were taken for pimonidazole-binding analysis. Tumor oxygen partial pressure (pO2) was evaluated as the median tumor pO2 and the fraction of pO2 values < or = 10 mmHg (HF10). Biopsies were formalin fixed and paraffin embedded, and hypoxia was detected by immunohistochemistry using monoclonal antibodies directed against reductively activated pimonidazole. Pimonidazole binding was evaluated by a semiquantitative scoring system. RESULTS: Both Eppendorf measurements and pimonidazole binding showed large intra-and intertumor variability. A comparison between pimonidazole binding expressed as the fraction of fields at the highest score and HF10 showed a trend for the most well-oxygenated tumors having a low fraction of fields; however, the correlation did not reach statistical significance (p = 0.43, r = 0.165; Spearman's rank correlation test). CONCLUSION: Hypoxia measured in human uterine cervix carcinomas is heterogeneously expressed both within and between tumors when assessed by either invasive pO2 measurements or pimonidazole binding. Despite a trend that tumors with high pO2 values expressed less pimonidazole binding, no correlation was seen between the two assays in this preliminary report.