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Abstract: This study investigated the efficacy of a vaginal dilator (VD) for the treatment of radiation-induced vaginal stenosis (VS) and the effect of a VD on sexual quality of life.Fifty three patients with endometrial or cervical cancers participated in this prospective observational study. All participants were treated with radical or adjuvant external beam radiotherapy and/or brachytherapy. They were routinely examined 4 times after radiotherapy (RT) and were also asked to complete a validated sexual function-vaginal changes questionnaire. SPSS version 20 and Minitab version 16 were used for the statistical analysis. The statistical significance was set at P < .05.The VS grading score decreased and the comfortably insertable VD size gradually increased throughout a year of VD use; all patients with initial grade 3 showed a VS of grade 2 after 12 months of VD use and 65.8% of the patients with initial grade 2 demonstrated a final VS of grade 1, while 77.8% of the participants who started with the first size of VD reached the third size after 12 months. Starting VD therapy ≤3 months after the end of RT was associated with a significant decrease in VS. A total of 60.9% of participants reported that they did not feel their vaginas were too small during intercourse after 12 months of dilation, whereas only 11.5% gave the same answer before starting dilation. Furthermore, 47.17% rated their satisfaction with their sexual life 5 out of 7 and only 3.77% gave a score of 3 after 12 months of dilation.Endometrial and cervical cancer survivors are encouraged to use VD to treat VS and for sexual rehabilitation after RT. This study recommends starting vaginal dilation no more than 3 months after treatment at least 2 to 3 times a week for 10 to 15 minutes over 12 months. However, larger, well-designed randomized clinical trials should be conducted to develop specific guidelines for VD use and efficacy in VS and sexual sexual quality of life after RT., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: We aimed to evaluate the effects of different therapeutic options to prevent the evolution of vaginal stenosis after pelvic radiotherapy in women with cervical cancer., Methods: open-label randomized clinical trial of 195 women, stage I-IIIB, aged 18-75 years, using topical estrogen (66), topical testosterone (34), water-based intimate lubricant gel (66), and vaginal dilators (29) to assess the incidence and severity of vaginal stenosis after radiotherapy at UNICAMP-Brazil, from January/2013 to May/2018. The main outcome measure was vaginal stenosis assessed using the Common Terminology Criteria for Adverse Events (CTCAE) scale and percental changes in vaginal volume. The women were evaluated at four different times: shortly after the end of radiotherapy, and four, eight, and 12 months after the beginning of the intervention. Statistical analysis was carried out using Symmetry test, Kruskal-Wallis test and multiple regression., Results: the mean age of women was 46.78 (±13.01) years, 61,03% were premenopausal and 73,84% had stage IIB-IIIB tumors. The mean reduction in vaginal volume in the total group was 25.47%, with similar worsening in the four treatment groups with no statistical difference throughout the intervention period. There was worsening of vaginal stenosis evaluated by CTCAE scale after 1 year in all groups (p < 0.01), except for the users of vaginal dilator (p = 0.37)., Conclusions: there was a reduction in vaginal volume in all treatment groups analyzed, with no significant difference between them. However, women who used vaginal dilators had a lower frequency and severity of vaginal stenosis assessed by the CTCAE scale after one year of treatment., Trial Registration: Brazilian Registry of Clinical Trials, RBR-23w5fv . Registered 10 January 2017 - Retrospectively registered.

Aim: To find diffusion-weighted (DW) magnetic resonance imaging (MRI) parameters predictive for radiation-induced vaginal stenosis (VS) in locally advanced cervical cancer (LACC) treated with neoadjuvant chemoradiation therapy (CRT)., Materials and Methods: Retrospective analysis of 43 patients with LACC who underwent 1.5 T DW-MRI before (baseline), after 2 weeks (early), and at the end of CRT (final). At MRI, vaginal length, thickness, width, and cervical tumour volume (TV) were measured. Vaginal signal intensity at DW-MRI was analysed at final MRI. CRT-induced VS was graded using Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Correlations between DW-MRI and clinical data were made using Wilcoxon's test, Mann-Whitney test, Fisher's exact test, or chi-squared test as appropriate. Receiver operating characteristic (ROC) curves were generated for variables to evaluate diagnostic ability to predict CRT-induced VS using a logistic regression model., Results: Asymptomatic vaginal toxicity (CTCAE Grade 1) was observed in 14 patients and symptomatic CRT-induced VS (CTCAE Grade ≥2) was detected in 29 patients. Baseline TV was higher in Grade 1 than in Grade ≥2 (p=0.013). Median vaginal length, thickness, and width decreased between baseline and final MRI in all patients (p<0.0001) without significant variances between CTCAE grades. Significant differences were observed in DW-MRI patterns (p<0.0001). In Grade ≥2, DWI showed signal loss of vaginal mucosa in 17 patients (63%) and diffuse restricted diffusion of vaginal wall in eight patients (30%). AUC was 0.938 (coefficient=4.72; p<0.001) for DWI and 0.712 (coefficient=-2.623×10 -5 ; p=0.004) for TV., Conclusions: This is the first study using DW-MRI for predicting CRT-induced VS. DWI is useful tool in patients with LACC after CRT for early prevention and management strategies for VS., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Sex steroid hormones and their receptors are important in female sexual function. The aim of this study was to investigate the expression and distribution of estrogen receptor (ER)α, ERβ, G-protein-coupled ER-1 (GPER), androgen receptor (AR), progesterone receptor (PR)A, PRB and connective tissue growth factor (CTGF) in the vaginal wall among women who had been treated for cervical cancer with radiotherapy. Material and methods: We included cervical cancer survivors treated with radiotherapy and premenopausal control women of the same age scheduled for benign gynecological surgery. We analyzed the expression and distribution of sex steroid hormone receptors and CTGF in biopsies from the vaginal wall, by real-time PCR and immunohistochemistry (IHC). Serum samples were analyzed for hormone levels and radiation dose at biopsy site were calculated and correlated to levels of the sex steroid hormone receptors. Results: In the cervical cancer survivors ( n  = 34), we found a lower expression of ERα at both mRNA and protein levels, compared to the control women ( n  = 37). In the survivors with high radiation dose at biopsy site, the immunostaining of ERα and AR was lower in the epithelium and the stroma, compared to survivors with minimal radiation dose. The later group showed expression of ERα comparable to the control women. The cancer survivors were sufficiently substituted with systemic estradiol with no difference in the serum estradiol levels compared to control women. Conclusions: We found that external radiation reduces the ERα and AR protein expression in the vaginal mucosa, indicating that the vaginal changes in irradiated cervical cancer survivors and the lack of response to hormonal treatment could be due to the decreases in sex steroid hormone receptor expression.

Background: Radiotherapy treatment for cervical cancer (CC) often induces side effects, including inflammation, dryness, dyspareunia. Considering its key role in the healing process, hyaluronic acid (HA) could be useful for the completion of radiotherapy., Objectives: The aim of this work was to evaluate the ability of HA to reduce the onset of side effects due to radiotherapy., Materials and Methods: In total, 180 women undergoing radiotherapy were randomized into two arms: controls and those treated with vaginal suppositories containing low-molecular-weight HA from day 1 of radiotherapy. The study lasted 5 weeks and was characterized by three visits: at baseline (T0), 15 days later (T1), and at the end of the radiotherapy cycle (T2). The onset of side effects, pain, safety, efficacy, acceptability of treatment, and compliance to the therapy were evaluated., Results: Patients in the control arm reported the onset and worsening of all symptoms with a moderate or severe grade at T2, whereas in the treatment arm almost 90% of patients reported the absence of symptoms or a mild grade. All patients in the treatment arm referred a lower intensity of pain on a visual analog scale compared with the control arm at T2 (6.85 ± 0.94 vs. 1.88 ± 1.02)., Conclusions: HA was able to help vaginal mucosa healing during radiotherapy in patients with CC., (© 2019 S. Karger AG, Basel.)

There are approximately 3,000 new UK diagnoses of cervical cancer annually, with many women presenting symptomatically. We aimed to identify and quantify features of cervical cancer in primary care in a case-control study in the UK. Putative features of cervical cancer were identified, and odd ratios and positive predictive values (PPVs) were calculated. About 1,006 women aged ≥40 years diagnosed with cervical cancer and 4,992 age-, sex- and practice-matched controls were selected from the Clinical Practice Research Datalink. Median age at diagnosis was 61 years (interquartile range 51-75). Seven symptoms and two abnormal investigations were associated with cervical cancer: post-menopausal bleeding, odds ratio 43 (95% confidence interval 25, 75); vaginal discharge or vaginitis 8.8 (5.2, 15), intermenstrual bleeding 4.7 (1.6, 14); haematuria 4.6 (2.1, 10); irregular menstruation 3.8 (1.6, 9.0); urinary tract infection 1.9 (1.3, 2.8); abdominal pain 1.8 (1.4, 2.5); high white cell count 5.1 (2.9, 8.8) and low haemoglobin 2.6 (1.8, 3.8): all p < .005. The PPV of cervical cancer in women aged ≥55 with post-menopausal bleeding was 4.6% (2.5, 8.3). Other than for post-menopausal bleeding no symptom is high risk. Some symptoms, particularly haematuria, may be helpful. The primary care clinician must consider the unlikely diagnosis when the likely diagnosis does not settle with treatment., (© 2017 John Wiley & Sons Ltd.)

Background: Cervical cancer survivors treated with radiotherapy report vaginal inelasticity and decreased lubrication that may affect their sexual health, but it is unknown which normal tissue reactions mediate these symptoms. The aim of this study was to investigate the morphology of the connective tissue of the vaginal wall in cervical cancer survivors treated with radiotherapy., Material and Methods: We recruited 34 cervical cancer survivors treated with radiotherapy and 37 age-matched controls. Via clinical examination the degree of vaginal atrophy and pelvic fibrosis were estimated. We collected vaginal biopsies, which underwent morphometric analysis focused on elastin and collagen. Additionally, radiation dose at biopsy site were calculated and correlated to the clinical and morphological findings., Results: The survivors had marked morphological vaginal changes, most prominent in the survivors that had received the highest radiation dose at the biopsy site. Mucosal atrophy was observed in 91% and pelvic fibrosis in 97%. A shorter vagina was measured; 7.0 cm versus 10.3 cm in controls (p < 0.001). The area fraction of elastin was greater in survivors; 10.0% (range 5.8-12.9), compared with controls; 3.4% (range 1.8-5.8), p < 0.001. The survivors had signs of elastosis with thick aggregated elastin fibers irregularly scattered throughout the connective tissue, while the controls had elastin fibers in a thin sub-epithelial layer. The area fraction of high density collagen in the connective tissue was larger among the survivors (p < 0.001). The collagen with the highest density (fibrosis) was more common in the group of cancer survivors that had received external radiation., Conclusions: We found drastic differences in the vaginal wall between the irradiated cervical cancer survivors and the controls, indicating that radiotherapy-induced vaginal symptoms are mediated by connective tissue fibrosis and elastosis. Our results also support that patients treated with external radiation have the highest risk of developing vaginal fibrosis with impairment of their sexual health.

Purpose: Vaginal stenosis is a major problem following radiotherapy in cervical cancer. We investigated a new dose planning strategy for vaginal dose de-escalation (VDD)., Materials and Methods: Fifty consecutive locally advanced cervical cancer patients without lower or middle vaginal involvement at diagnosis from 3 institutions were analysed. External beam radiotherapy was combined with MRI-guided brachytherapy. VDD was obtained by decreasing dwell times in ovoid/ring and increasing dwell times in tandem/needles. The aim was to maintain the target dose (D90 of HR-CTV⩾85Gy EQD2) while reducing the dose to the surface of the vagina to <140% of the physical fractional brachytherapy dose corresponding to a total EQD2 of 85Gy., Results: The mean vaginal loading (ovoid/ring) was reduced from 51% to 33% of the total loading with VDD, which significantly reduced the dose to the vaginal dose points (p<0.001) without compromising the target dose. The dose to the ICRU recto-vaginal point was reduced by a mean of 4±4Gy EQD2 (p<0.001), while doses to bladder and rectum (D 2cm 3 ) were reduced by 2±2Gy and 3±2Gy, respectively (p<0.001)., Conclusions: VDD significantly reduces dose to the upper vagina which is expected to result in reduction of vaginal stenosis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aim: During the last decades, therapies targeting cervical cancer have been considerably improved. Surgery and radiotherapy (RT) represent the main common therapeutic approach in cervical cancer. In order to minimize the side effects of radiotherapy approach, several protocols have been developed such as brachytherapy (BRT). Among the side effects associated with RT, the vaginal atrophy is the most important and common one. Vaginal atrophy, in turn, leads to additional alterations like inflammation, associated to relevant symptoms such as itching, burning and dyspareunia. All these alterations heavily affect the quality of women's life. The aim of our study was to evaluate the toxicity induced by RT on vaginal mucosa, and the adjuvant action of a product containing LMWHA, vitamin A, and Vitamin E (Santes®, Lo.Li. Pharma, Rome, Italy). The introduction of adjuvant therapies may have likely had a relevant place in providing that result., Methods: A prospective randomized study was designed. From October 2006 to October 2008, 45 women with a mean age 38 ± 6 years were enrolled. After surgery, all patients were treated with 4 weeks of RT and 4 weeks of BRT, concomitantly with chemiotherapy. They were randomly assigned in two groups: 23 women were treated with two suppositories (Santes®) per day for 4 months. For the first two months the preventive treatment was simultaneous to RT and BRT. Instead the control groups for composed by 22 patients and they did not undergo any treatment during RT. To evaluate the efficacy of Santes® treatment three biopsies were performed., Results: At the second biopsy, after the BRT therapy, the treated group showed a statistically significant improvement (P<0.05 vs. control) on inflammation, cell atypia, fibrosis, mucositis and bleeding. At the third biopsy, two months after BRT, further statistically improvement were observed for all RT/BRT associated side effects. The treatment showed an efficacy also in terms of pain severity., Conclusion: Our data suggest that low molecular weight HA shows good performances in treating RT-damaged tissue and plays a key role in all steps of the healing process. Indeed the results shows that women exposed to RT treatments and simultaneously treated with Santes®, had an optimal resolution of vaginal atrophy and related symptoms.

Objective: To assess actual rates of late vaginal stenosis and identify predisposing factors for complications among patients with previously untreated cervical cancer following high-dose-rate brachytherapy., Methods: We performed longitudinal analyses of 57 patients using the modified Dische score at 6, 12, 18, 24, 36, and 60 months after treatment, which consisted of 15 interstitial brachytherapys and 42 conventional intracavitary brachytherapys, with a median follow-up time of 36 months (range, 6 to 144 months)., Results: More than half of the patients developed grade 1 (mild) vaginal stenosis within the first year of follow-up, and grade 2 (97.5%, moderate) to grade 3 (severe) stenosis gradually increased with time. Actual stenosis rates for grade 1, 2, and 3 were 97.5% (95% confidence interval [CI], 92.7 to 97.5), 60.7% (95% CI, 42.2 to 79.3), and 7.4% (95% CI, 0 to 18.4) at 3 years after treatment. Pallor reaction grade 2-3 at 6 months was only a statistically significant predisposing factor for grade 2-3 late vaginal stenosis 3 years or later with a hazard ratio of 3.48 (95% CI, 1.32 to 9.19; p=0.018) by a multivariate Cox proportional hazard model. Patients with grade 0-1 pallor reaction at 6 months showed a grade ≥2 vaginal stenosis rate of 53%, whereas the grade 2-3 pallor reaction group achieved a grade ≥2 vaginal stenosis rate at 3 years at 100% (p=0.001)., Conclusion: High-dose-rate brachytherapy was associated with high incidence of late vaginal stenosis. Pallor reaction grade 2-3 at 6 months was predictive of late grade 2-3 vaginal stenosis at 3 years after treatment. These findings should prove helpful for patient counseling and preventive intervention.

Background and Purpose: Brachytherapy in the treatment of locally advanced cervical cancer has changed substantially because of the introduction of combined intracavitary/interstitial applicators and an adaptive target concept, which is the focus of the prospective, multi-institutional EMBRACE study (www.embracestudy.dk) on image-guided adaptive brachytherapy (IGABT). So far, little has been reported about the development of early to late vaginal morbidity in the frame of IGABT. Therefore, the aim of the present EMBRACE analysis was to evaluate the manifestation pattern of vaginal morbidity during the first 2 years of follow-up., Methods and Materials: In total, 588 patients with a median follow-up time of 15 months and information on vaginal morbidity were included. Morbidity was prospectively assessed at baseline, every 3 months during the first year, and every 6 months in the second year according to the Common Terminology Criteria for Adverse Events, version 3, regarding vaginal stenosis, dryness, mucositis, bleeding, fistula, and other symptoms. Crude incidence rates, actuarial probabilities, and prevalence rates were analyzed., Results: At 2 years, the actuarial probability of severe vaginal morbidity (grade ≥3) was 3.6%. However, mild and moderate vaginal symptoms were still pronounced (grade ≥1, 89%; grade ≥2, 29%), of which the majority developed within 6 months. Stenosis was most frequently observed, followed by vaginal dryness. Vaginal bleeding and mucositis were mainly mild and infrequently reported., Conclusion: Severe vaginal morbidity within the first 2 years after definitive radiation (chemo)therapy including IGABT with intracavitary/interstitial techniques for locally advanced cervical cancer is limited and is significantly less than has been reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild to moderate vaginal morbidity is still pronounced with currently applied IGABT, and it needs further attention., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The aim of the study was to evaluate the vaginal dose and toxicity in patients of cervical cancer treated with image guided brachytherapy at our institute., Materials and Methods: Thirty-five patients treated with image based brachytherapy for cervical cancer were included. Vaginal contouring was done on MRI at brachytherapy and with CT scans of subsequent brachytherapy fractions. Dose volume parameters (DVH) were reported in accordance with the GEC-ESTRO guidelines. These were correlated with vaginal toxicity (assessed by CTCAE version 3) and quality of sexual life assessed at one year of completion of treatment., Results: Vaginal shortness was observed in 22 out of 30 (62.8%) patients, Nine (25.7%) had vaginal dryness and in 10 (28.5%) patients, there was contact bleeding. No association could be demonstrated between the dose volume parameters and vaginal toxicity in the present study., Conclusions: The lack of association between dose volume parameters of vagina with vaginal morbidity may be due to uncertainties involved in the delineation of vaginal wall and dosimetry. Future research is required to accurately define vaginal dose distribution to study its correlation with vaginal morbidity. Vaginal morbidity needs to be documented in order to improve the sexual outcome in these patients.

Introduction: Data in literature about the use of adjuvant treatment to reduce acute adverse effects of radiotherapy on the pelvis are scant, with the exception of a few reports on the topical use of estrogen, which promotes proliferation of epithelium., Materials and Methods: In this prospective trial, α-tocopherol acetate was topically administered to patients affected by endometrial and cervical cancer and undergoing radiation treatment to avoid acute vaginal complications., Results: Vaginal application of α-tocopherol reduced vaginal toxicity and pain, although vaginal secretion was not significantly different in the 2 groups studied. The histological scoring system showed a significant reduction of inflammation, no difference in fibrosis, and an increase of acanthosis., Conclusions: The use of α-tocopherol as adjuvant treatment to reduce the acute adverse effects of radiotherapy on the vagina should be considered.

Introduction: There is paucity of information regarding a late toxic reaction after chemoradiation for locally advanced cervical cancer. We discuss this problem with special consideration to total vaginal necrosis (TVN), an underreported severe late complication of chemoradiation., Methods: The records of 98 cervical cancer patients who received chemoradiation at the Department of Oncology of the University College London Hospital between January 2004 and May 2008 were reviewed., Results: Eight women (8.2%) developed a severe late toxic reaction. From these, 3 patients (3.1% of the entire cohort and 37.5% of the patients with a severe late toxic reaction), who were 44 to 60 years old, developed a TVN 6 to 18 months after completion of chemoradiation. In all the TVN cases, surgical debridement was necessary to alleviate the symptoms. This was followed by an extensive period (up to 24 months) of consolidation. Heavy smoking (P = 0.022) was found to be a significant contributing factor for TVN., Conclusions: Total vaginal necrosis is an underreported but serious late complication after chemoradiation and leads to considerable chronic morbidity. Radiologic examinations and biopsies are required to exclude recurrent disease. Microvascular damage from radiation combined with heavy cigarette smoking is likely to be pivotal etiologic factors in the development of TVN. For radiotherapy-induced late toxic effects to step out of the gray area of oncologic literature, the clinical pictures should be reported in a more detailed manner. It might be a promising approach to work out a toxicity scale that combines the existing objectifiable grading systems with subjective quality-of-life assessments.

No research has investigated patients' representations of the vaginal symptoms commonly experienced after cervical cancer treatment. Leventhal's Self-regulation or Common Sense Model was used to explore these representations and their relationships with quality of life after cervical cancer. Women posttreatment for cervical cancer (n = 26) from a Midwest cancer center provided information on symptom representations for their 3 most bothersome symptoms and also completed a quality-of-life scale. Women perceived vaginal symptoms as mild to moderate overall but rated approximately one-third of 11 different symptoms as severe. Symptoms identified most frequently as the most bothersome were painful intercourse (23%), decrease in sexual desire (15%), and vaginal dryness (12%). On average, symptoms were mildly distressing and acute, had a minimal effect on life, and were associated with an indeterminate degree of perceived control. Cause was attributed equally to treatment and to the cancer. Quality of life was below normed data, to a degree consistent with a minimally important difference for total well-being scores and physical, emotional, and functional well-being. Emotional and consequence representations were significantly related to quality of life. Understanding and altering symptom representations may improve quality of life for women treated for cervical cancer.

Aims: To evaluate the incidence of, and factors affecting, late toxicities of women with carcinoma of the cervix treated with radical radiotherapy., Materials and Methods: Between 1996 and 2001, 1069 women with carcinoma of the cervix (stage I-IVA) were treated at our centre with external-beam radiotherapy (EBRT) and intra-cavitary radiotherapy (ICRT) (n = 871) or EBRT alone (n = 198). Median follow-up was 34 months. Median dose to point A was 81 Gy., Results: Five-year actuarial incidence of overall (all grades) and severe (grade 3/4) late toxicities in the rectum, bladder, small intestine and subcutaneous tissue were 12.3% and 1.1%, 11.2% and 1.2%, 9.2% and 0.2%, and 23.1% and 1.2%, respectively. Vaginal adhesions were seen in 29.6% of cases and stenosis in 33.9% of cases. On multivariate analysis, factors adversely affecting overall incidence of proctitis were anterior-posterior (AP) separation of patient more than 18 cm and presence of comorbid diseases. Presence of comorbid diseases was the only factor affecting the incidence of severe proctitis (grade 3/4). AP separation more than 18 cm adversely affected the incidence of cystitis, both overall and severe. Late toxicities (all grades) in small bowel were increased in subsets, like women younger than 50 years and women with comorbid diseases, but no factor emerged as significant for incidence of severe toxicities. Subcutaneous fibrosis was significantly higher in patients with AP separation over 18 cm, those treated by cobalt machines and those who received EBRT only. Severe subcutaneous fibrosis was influenced by the use of EBRT alone. Overall incidence of vaginal toxicity was higher in women whose overall treatment time (OTT) was shorter and in women who received ICRT. Vaginal stenosis was higher in elderly women and in women who received ICRT by low dose rate., Conclusions: Even with telecobalt machines, impressive results with acceptable late toxicity can be achieved in the treatment of cancer of the cervix using an ideal combination of EBRT with ICRT.

Purpose: To determine the usefulness of local mitomycin C application in the prophylaxis of vaginal narrowing after irradiation., Material and Methods: 31 patients with advanced cervical cancer qualified for the study. They underwent brachytherapy with iridium-192 isotope and external beam therapy with linear accelerators. In a blind probe method 16 patients were chosen to have an aqueous solution of mitomycin C applied to the vagina., Results: Radiotherapy caused a shortening of vaginal length in both groups (study and control). In the "mitomycin C group" complete vaginal occlusion was visibly less frequent as were solid fibrotic vault changes., Conclusions: This mode of morbidity prevention can potentially diminish the occurrence of local vaginal fibrosis and thus may improve patients' quality of life. Further investigations are needed to confirm these results.

The aim of our study was to determine the incidence, timing, and severity of vaginal stenosis in patients with carcinoma of the cervix who had received pelvic and/or vaginal radiotherapy as part of their treatment. We also sought to determine if there were any predisposing factors for the development of stenosis. A retrospective chart review was undertaken for all the patients diagnosed with carcinoma of the cervix between January 1, 1990, and December 31, 2000 and treated with pelvic and/or vaginal radiation at Westmead Hospital. Since January 1, 1990, data regarding vaginal stenosis has been prospectively recorded on all the patients. Data collected included patient demographics, stage of disease, treatments administered, and incidence, timing, and severity of vaginal stenosis. One hundred and eighty-eight patients were treated. Mean age was 58.6 years. Thirteen percent of patients had stage IB disease, 45% had stage II disease, 39.5% had stage III disease, and 1.5% had stage IV disease. One hundred and seventy-nine patients returned for follow-up, and data regarding vaginal toxicity were available in 98%. Twenty-seven percent had grade 1 toxicity (partial stenosis or shortening but not complete occlusion), and 11% had grade 2 (complete occlusion). Stenosis of any grade was noted at a mean of 9.6 months and median of 7.5 months (range, 26 days-5.6 years) from completion of treatment. The only prognostic factor associated with increased risk of stenosis was age greater than 50 years (odds ratio 2.26). Vaginal stenosis is a common complication of pelvic and vaginal radiotherapy, occurring in 38% of patients. Stenosis occurs most often in the first year after treatment. Patients over the age of 50 are most at risk.

Background: Involvement of the female genital tract by Darier's disease, an unusual genodermatosis, is uncommon, and the manifestation of the disease in a cervicovaginal smear is exceptionally rare., Case: A 39-year-old woman had an abnormal Pap smear caused by involvement of the female genital tract by Darier's disease. Cytologic examination showed features consistent with a low grade squamous intraepithelial lesion, but during a biopsy it was found to be vaginal involvement by Darier's disease., Conclusion: The correct interpretation of cytologic findings is not possible when the diagnosis of Darier's disease is not known since a low grade squamous intraepithelial lesion cannot be ruled out. This case underlines the importance of knowing the patient's medical histoiy in any moment of medical attention.

Purpose: The purpose of this investigation was to determine the irradiation tolerance level and complication rates of the proximal vagina to combined external irradiation and low dose rate (LDR) brachytherapy. Also, the mucosal tolerance for fractionated high dose rate (HDR) brachytherapy is further projected based on the biological equivalent dose (BED) of LDR for an acceptable complication rate., Materials and Methods: Two hundred seventy-four patients with stages I-IV cervical carcinoma treated with irradiation therapy alone from 1987 to 1997 were retrospectively reviewed for radiation-associated late sequelae of the proximal vagina. All patients received LDR brachytherapy and 95% also received external pelvic irradiation. Follow-up ranged from 15 to 126 months (median, 43 months). The proximal vagina mucosa dose from a single ovoid (single source) or from both ovoids plus the tandem (all sources), together with the external irradiation dose, were used to derive the probability of a complication using the maximum likelihood logistic regression technique. The BED based on the linear-quadratic model was used to compute the corresponding tolerance levels for LDR or HDR brachytherapy., Results: Grades 1 and 2 complications occurred in 10.6% of patients and Grade 3 complications occurred in 3.6%. There were no Grade 4 complications. Complications occurred from 3 to 71 months (median, 7 months) after completion of irradiation, with over 60% occurring in the first year. By logistic regression analysis, both the mucosal dose from a single ovoid or that from all sources, combined with the external irradiation dose, demonstrate a statistically significant fit to the dose response complication curves (both with P=0.016). The single source dose was highly correlated with the all source dose with a cross-correlation coefficient 0.93. The all source dose was approximately 1.4 times the single source dose. Over the LDR brachytherapy dose rate range, the complication rate was relatively stable to small variations of the underlying tumor biological characteristics and the dose rate. The complication rates change approximately an absolute 1% over the range of the alpha-beta ratio (alpha/beta) from 2 to 4 Gy and repair constant (mu) of 0.46/h to 0.60/h. The complication rates increased an absolute 2% over the mucosa dose rate from 1.75 to 3.50 Gy/h. They markedly increased as the dose rate increased above 3.00 Gy/h as in HDR brachytherapy. The projected HDR Grade 3 tolerance varied from 25 Gy for one fraction to 57 Gy for six fractions in addition to 20 Gy external irradiation for nominal 3-5% complication rates. The traditional LDR tolerance dose of 150 Gy was shown to yield nominal 11% and 4% Grades 1 and 2 and Grade 3 sequelae, respectively., Conclusions: The traditional 150 Gy LDR tolerance dose (single source plus external irradiation) can be relaxed to 175 Gy or equivalently a full mucosal dose of 238 Gy (all sources plus external irradiation) for a nominal 5% Grade 3 complication rate. Higher fractionation is necessary with four to six fractions in HDR therapy for similar rates of sequelae. The mucosal surface dose from a single ovoid, which can be readily computed, remains a convenient tolerance check for treatment planning purposes.

Historically, early stage vaginal cancer has been treated with low-dose-rate (LDR) brachytherapy with or without external beam radiation therapy (EBRT). Complication rates have been low and treatment efficacious. Although high-dose-rate (HDR) brachytherapy has been used for cervical cancer in many countries for over a decade, only more recently has it been integrated into treatment plans for vaginal cancer. This paper describes three patients treated with HDR brachytherapy who experienced significant late effects. Given the very limited amount of literature regarding the use of HDR brachytherapy in vaginal cancer, this analysis potentially contributes to an understanding of treatment-related risk factors for complications among patients treated with this modality.A focused review of hospital and departmental treatment records was done on three patients treated with HDR brachytherapy. Abstracted information included clinical data, treatment parameters (technique, doses, volume, combinations with other treatments) and outcomes (local control, survival, early and late effects). A review of the available literature was also undertaken. All patients had significant complications. Although statistical correlations between treatment parameters and complications are impossible given the limited number of patients, this descriptive analysis suggests that vaginal length treated with HDR brachytherapy is a risk factor for early and late effects, that the distal vagina has a lower radiation tolerance than the upper vagina with HDR as in LDR, and that combining HDR with LDR as done in our experience carries a high risk of late toxicity. Integration of HDR brachytherapy techniques into treatment plans for early stage vaginal cancers must be done cautiously. The etiology of the significant side effects seen here is likely to be multifactorial. For users of HDR brachytherapy in vaginal cancer, there is a need to further refine and standardize treatment concepts and treatment delivery. Ideally this will be based on continued careful observation and reporting of both favorable and unfavorable outcomes and experiences.

Background: In women with cervical cancer, treatment causes changes in vaginal anatomy and function. The effect of these changes on sexual function and the extent, if any, to which they distress women are not known., Methods: In 1996 and 1997, we attempted to contact 332 women with a history of early-stage cervical cancer (age range, 26 to 80 years) who had been treated in 1991 and 1992 at the seven departments of gynecological oncology in Sweden and 489 women without a history of cancer (controls) to ask them to answer an anonymous questionnaire about vaginal changes and sexual function., Results: We received completed questionnaires from 256 of the women with a history of cervical cancer and 350 of the controls. A total of 167 of 247 women with a history of cancer (68 percent) and 236 of 330 controls (72 percent) reported that they had regular vaginal intercourse. Twenty-six percent of the women who had cancer and 11 percent of the controls reported insufficient vaginal lubrication for sexual intercourse, 26 percent of the women who had cancer and 3 percent of the controls reported a short vagina, and 23 percent of the women who had cancer and 4 percent of the controls reported an insufficiently elastic vagina. Twenty-six percent of the women who had cancer reported moderate or much distress due to vaginal changes, as compared with 8 percent of the women in the control group. Dyspareunia was also more common among the women who had cervical cancer. The frequency of orgasms and orgasmic pleasure was similar in the two groups. Among the women who had cervical cancer, the type of treatment received had little if any effect on the prevalence of specific vaginal changes., Conclusions: Women who have been treated for cervical cancer have persistent vaginal changes that compromise sexual activity and result in considerable distress.

Purpose: Several reports document a negative impact of prolongation of overall treatment time in a course of irradiation on tumor control and survival. A correlation has been documented of incidence of significant treatment sequelae with increasing doses of irradiation, volume of the specific organ, and dose per fraction. However, no data were found on the potential correlation of overall irradiation treatment time with significant sequelae., Methods and Materials: Records were reviewed of 1,269 patients with carcinoma of the cervix (Stage IB to HI) treated with definitive irradiation (combination of external beam and two intracavitary insertions). Follow-up was obtained in 97% of patients (median, 12 years; minimum, 3 years; maximum, 28 years). The relationships between overall treatment time and time of brachytherapy and incidence of treatment sequelae were analyzed for each stage., Results: Overall incidence of Grades 2 (moderate) sequelae was 7% and of Grade 3 (severe) sequelae, 11%. There was no significant correlation of various incidences of Grade 2 and 3 sequelae with overall treatment times (8% in patients treated in less than 7 weeks, 9% in 7.1 to 9 weeks, and 12% when treatment time was longer than 9 weeks) (p = 0.08). In patients with Stage IB and IIA tumors, incidence of rectal toxicity (mostly proctitis) was comparable in patients treated in less than 7 or 7.1 to 9 weeks (4.1 and 6%, respectively) and slightly higher in those treated in longer periods (11.5%) (p = 0.24). In patients with Stage IIB and III, the incidence of Grade 2 and 3 small bowel morbidity was 2% in those treated in less than 7 weeks, 6% for 7.1 to 9 weeks, and 4.9% for longer times (p < or = 0.01). This increased morbidity was also correlated with total dose of irradiation to the lateral pelvic wall: 5 of 257 (2%) for less than 60 Gy and 21 of 438 (4.8%) for higher doses (p < or = 0.01). There was no significant correlation between the timing of brachytherapy (usually two low dose rate intracavitary insertions performed within 4.5 to 6.5 weeks of initiation of external beam therapy) and significant treatment sequelae., Conclusions: We observed a varied average incidence of Grade 2 and 3 morbidity in the bladder, rectum, and small intestine with different overall treatment times, without a definite pattern to suggest an impact of prolongation of treatment time on morbidity. Likewise, there was no significant correlation with the timing of intracavitary insertions and morbidity of therapy. Because prolongation of the overall treatment time has a well-documented detrimental effect on pelvic tumor control and survival in carcinoma of the cervix with no significant impact on morbidity, it is imperative to deliver radiation therapy in the shortest possible time and without schedule interruptions.

Purpose: to evaluate the early and late radiotherapeutic morbidity after combined external and intracavitary radiotherapy to the uterine cervix., Methods and Materials: The morbidity in 442 consecutive cervical cancer patients FIGO Stage IIB (139), IIIA (10), IIIB (221) and IVA (72) treated from 1974 to 1984 were recorded retrospectively according to our own previously described system (18). This system is based on the assumption that radiotherapeutic morbidity progresses in severity with time wherefore successive morbidity scoring rather than recording the maximal damage alone is required to estimate the burden of complications for a group of patients. The early and late morbidity (within or beyond 3 months after the end of radiotherapy) was graded into mild, moderate, severe, and causing death depending on the symptoms and signs, and the requirement and type of therapy. The late morbidity was characterized by both the frequency and the actuarially corrected estimate. Also, the combined morbidity in two, three, four and five organs and the probability of surviving without tumor recurrence and/or significant late morbidity were evaluated., Results: Early morbidity was most frequently seen in the rectosigmoideum (61%) and urinary bladder (27%). Medication for early morbidity was required in 68% and hospitalization in 10% of the patients. The frequencies of each late morbidity grade did not differ in relation to FIGO Stage while the actuarial estimates increased significantly with increasing stage. This reflects the poor prognosis in the more advanced stages, where few patients survived to develop late morbidity, and also points to the importance of latency in reporting late radiotherapeutic morbidity. In Stage IVA patients, the ratios between the actuarial estimate and the frequency of late severe rectosigmoid and urinary bladder morbidity were as high as 2.5 and 3, respectively. The highest 5-year risks (+/- 1 SE of the estimate) of late severe morbidity were found for the rectosigmoideum (28% +/- 3), small intestine (13% +/- 2) and urinary bladder (10% +/- 2). Rectosigmoid and urinary bladder complications constituted the most important part of the combined organ morbidity. Almost half of the patients developing late moderate rectosigmoid and one-third of those developing late moderate bladder complications, did so within one year after radiotherapy. Almost all complications were developed within 3 to 4 years after radiotherapy. The probability of surviving without recurrence and/or severe combined rectosigmoid and urinary bladder morbidity was low (23% +/- 2)., Conclusion: Actuarial estimates rather than frequencies should be reported to avoid underestimation of the risk of late radiotherapeutic morbidity in long-term survivors.

Purpose: This study was designed to document the incidence and degree of vaginal stenosis, sexual activity, and satisfaction in women treated with intracavitary radiation therapy for cervical or endometrial carcinoma., Methods and Materials: The incidence of vaginal stenosis in 90 patients treated for either cervical carcinoma (n = 42) or endometrial carcinoma (n = 48) with standard doses of intracavitary radiation from 1989 to 1992 with at least 6 months follow-up was recorded. Vaginal length was measured using a modified vaginal dilator calibrated in centimeters. Semistructured patient interviews documented pretreatment and posttreatment sexual activity and sexual satisfaction., Results: Vaginal length was found to be dependent on diagnosis (cervical vs. endometrial), stage (I vs. II/III), and follow-up interval (6-12 months, 12-24 months, and > 24 months). Slightly more women reported sexual activity post vs. pretreatment (31% active pretreatment vs. 43% active posttreatment). However, 22% of women reported a decrease in sexual frequency and 37% reported a decrease in sexual satisfaction. Reports for all parameters were worse for women treated for cervical carcinoma vs. women treated for endometrial carcinoma with the exception of dyspareunia., Conclusion: High-dose radiation for either cervical or endometrial carcinoma at standard doses with or without hysterectomy can cause a decrease in vaginal length as compared to the normal vaginal length of 8 to 9 cm documented by Masters and Johnson. Women treated with intracavitary implants remained as sexually active postimplant as preimplant, however, coital frequency and sexual satisfaction decreased while dyspareunia increased. The decrease in vaginal length may explain in part the decrease in sexual satisfaction but cause and effect have not been established.

1800 intrauterine contraceptive device users, during a period of more than thirteen years, and 1800 control non-users were examined clinically, cytologically and histopathologically for cervical pathological lesions. There was an increase, but not statistically significant, in the incidence of metaplasia, dyskariosis or mild dysplasia. There was no difference in neoplastic lesions.

Radiotherapy for uterine cervix carcinoma is an accepted treatment for all stages of invasive malignancy. The radiation modality is usually a combination of brachytherapy and external beam therapy for all except the most extensive tumours (stage IV--FIGO). Satisfactory results have been obtained in the Singapore General Hospital using low dose-rate radium applications in combination with cobalt teletherapy. Five year actuarial survival rates of 86.7% were obtained for FIGO stage I, 65.0% for stage II, 41.4% for stage III, 4.9% for stage IV with an overall rate of 54.0% for all stages. Corresponding 10-year rates were: 79.6%, 60.2%, 35.2%, 0% and 48.2%. Preliminary results of primary radiotherapy in 36 patients with cervical carcinoma treated by high dose-rate brachytherapy (microSelectron HDR) combined with 6MVP photons from a Siemens linear accelerator are presented. The patients were registered at the Mount Elizabeth Oncology Centre from November 1989 to December 1990 inclusive. The morbidity from high dose-rate therapy appears lower (9.1% for vaginal stenosis, 6.1% for non-severe proctitis) than for the radium series (4.1% and 20.8%) although the major complication rate appears similar (3% vs 2.8% respectively). The total failure rate is also lower at 19.4% for the HDR patients compared to 33.5% for the radium group. However, these rates are not strictly comparable as the HDR series consists of a small number of patients with limited follow-up. In the light of the data indicating acceptable morbidity with significant rate of early failure, the HDR brachytherapy doses have been increased whilst keeping within the limits set by other centres.

The Christie Hospital installed a Selectron afterloading machine in 1979. By early 1982 it became apparent that patients treated for carcinoma of the cervix using the Selectron had developed a high incidence of morbidity compared with patients treated by the standard Manchester radium technique. Initially, the majority opinion was that the patients had been overdosed, because little or no allowance had been made for the higher dose rate of 137Cs. The results of investigation suggest, however, that the main factor responsible for the morbidity was a change in technique, previously unrecognised, in that the rigid 137Cs applicators facilitate the use of a much higher proportion of long intrauterine tubes and larger vaginal components than used to be the case with radium. The evidence for this and the probable mechanism of the resulting damage are discussed.

172 cases of invasive carcinoma of the cervix treated at the Johns Hopkins Hospital are reviewed. Failure rates are examined by stage, demonstrating a high percentage of local recurrences in patients with late stage disease treated by a traditional regime of radiotherapy. Reasons for these failures are explored and a proposal for a more individualized approach to therapy is made.

The effects of irradiation therapy on the surrounding pelvic structures are well known. Most women develop some degree of vaginal stenosis following irradiation for cervical cancer. Although complete vaginal occlusion is less common, it seriously affects the patient's self-image. The author treated five patients who had complete vaginal occlusion following irradiation for stage II uterine cervical carcinoma. By means of a regimen of digital pressure and an estrogenic cream, for an average of six weeks, the function of the vagina was restored.

Current literature has demonstrated excellent results using postoperative megavoltage irradiation in patients who had simple hysterectomy in the presence of invasive cervical carcinoma. It has recently been suggested that total abdominal hysterectomy followed by postoperative irradiation should be used as a planned treatment for early-stage cervical carcinoma. Thirty-six cases of patients with cervical carcinoma treated with whole-pelvis irradiation following simple hysterectomy at the University of Louisville are reviewed.