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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.

Objective: The objective of this study was to examine patterns of care and outcomes of female cancer patients treated for sexual and menopausal symptoms following pelvic radiotherapy (PRT) at our institution's multidisciplinary Sexuality, Intimacy, and Menopause (SIMS) Program., Materials and Methods: We performed a retrospective review of 69 female patients who received PRT for gynecologic or gastrointestinal malignancies and were referred for SIMS Program intervention. Indications for referral and treatment patterns were summarized. Preintervention and postintervention, patients were screened at follow-up visits, and symptoms were recorded. Statistics were performed using Stata 13.1., Results: Cancer types included cervical (53.6%), endometrial (31.9%), anorectal (5.8%), and vulvar/vaginal (8.7%). The median age was 48 years (interquartile range: 38 to 58 y). Patients were educated on vaginal lubricants, moisturizers, and dilator therapy both before and after PRT. Reasons for SIMS referral included persistent menopausal symptoms (50.7%), dyspareunia (40.6%), vaginal dryness (37.7%), decreased libido (17.4%), intimacy concerns (17.4%), and/or physical examination alterations (27.5%). SIMS interventions included vaginal estrogen (77.3%), nonhormonal climacteric interventions (53%), systemic hormone therapy (31.8%), dehydroepiandrosterone (4.6%), testosterone cream (4.6%), and/or psychological pharmacotherapy or counseling (13.6%). With a median follow-up of 36 months (interquartile range: 18 to 58 mo), sexual symptoms improved or were stable in 83.6%, while menopausal symptoms improved or were stable in 80.5%., Conclusions: This study highlights the importance of multidisciplinary care in improving the sexual and menopausal symptoms of women after PRT. Future work examining the impact of intervention timing with respect to PRT and measures of patient satisfaction is warranted., Competing Interests: M.J.M. consults for TherapeuticsMD, Pfizer, AMAG, and Duchesnay. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Stress urinary incontinence (SUI) is a common benign disease causing a markedly negative impact on quality of life. Vaginal laser is a minimally invasive treatment and no major complications of this technique have been published to date. The purpose of the article is to present the first major adverse event related to this treatment., Materials and Methods: We present the case of a 48-year-old woman with an important complication after vaginal laser for SUI., Results: The patient presented a transverse vaginal septum and shortening of vaginal length after two sessions of vaginal erbium:yttrium aluminum garnet laser treatment. She required two surgical interventions, local injections, and pelvic floor physiotherapy, although currently the patient has not experienced complete resolution of symptoms., Discussion and Conclusions: Vaginal laser use can lead to serious adverse events. Selection of patients and treatment must be carried out with caution.

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.)

Objectives: Sexual dysfunction and radiation cystitis are common adverse events following radiotherapy for gynecological cancer (GC). This study aims to assess the efficacy of intravaginal CO 2 laser on GC survivors with dyspareunia following pelvic radiation and/or brachytherapy. Methods: This is the study protocol of a randomized double-blind placebo-controlled trial. All participants will receive five therapies (active or placebo) at monthly intervals. Outcomes will include a 10-cm visual analog scale measuring dyspareunia, vaginal dryness, and other symptom intensity, 3-day voiding diary, Day-to Day Impact of Vaginal Aging questionnaire, Female Sexual Function Index, European Organization for Research and Treatment of Cancer Quality of Life questionnaire cervical cancer module, Urogenital Distress Inventory short form, King's Health Questionnaire, International Consultation on Incontinence Questionnaire short form/female lower urinary tract symptoms, patient perception of improvement, sexual satisfaction of male partners, vaginal maturation value, and Vaginal Health Index. Differences between groups will be assessed at baseline and 1, 3, 6, 9, and 12 months following the five laser therapies. Results: As this is a study protocol, the study is ongoing with an expected end of recruitment and analysis date of 2021. Conclusion: Pelvic radiotherapy for GC increases the 5-year survival rate but with a negative impact on women's quality of life due to sexual dysfunction and radiation cystitis onset. With this study, CO 2 laser therapy will be evaluated for the first time in GC survivors treated with radiotherapy. ClinicalTrials.gov registration number: NCT03714581.

Background: The incidence of anal cancer is rising in the last decades and more women are affected than men. The prognosis after chemoradiation is very good with complete remission rates of 80-90%. Thus, reducing therapy-related toxicities and improving quality of life are of high importance. With the development of new radiotherapy techniques like IMRT (Intensity-modulated radiotherapy), the incidence of acute and chronic gastrointestinal toxicities has already been reduced. However, especially in female anal cancer patients genital toxicities like vaginal fibrosis and stenosis are of great relevance, too. Up to now, there are no prospective data reporting incidence rates, techniques of prevention or impact on quality of life. The aim of the DILANA trial is to evaluate the incidence and grade of vaginal fibrosis, to optimize radiotherapy by reducing dose to the vaginal wall to minimize genital toxicities and improve quality of life of anal cancer patients., Methods: The study is designed as a prospective, randomized, two-armed, open, single-center phase-II-trial. Sixty patients will be randomized into one of two arms, which differ only in the diameter of a tampon used during treatment. All patients will receive standard (chemo) radiation with a total dose of 45-50.4 Gy to the pelvic and inguinal nodes with a boost to the anal canal up to 54-60 Gy. The primary objective is the assessment of the incidence and grade of vaginal fibrosis 12 months after (chemo) radiation depending on the extent of vaginal dilation. Secondary endpoints are toxicities according to the CTC AE version 5.0 criteria, assessment of clinical feasibility of daily use of a tampon, assessment of compliance for the use of a vaginal dilator and quality of life., Discussion: Prospective studies are needed evaluating the incidence and grade of vaginal fibrosis after (chemo) radiation in female anal cancer patients. Furthermore, the assessment of techniques to reduce the incidence of vaginal fibrosis like intrafractional vaginal dilation as well as other radiotherapy-independent methods like using a vaginal dilator are essential. Additionally, implementation of a systematic assessment of vaginal stenosis is necessary to grant reproducibility and comparability of future data., Trial Registration: The trial is registered with clinicaltrials.gov (NCT04094454, 19.09.2019).

Background: Despite a lack of evidence and low compliance, current guidelines recommend the use of a vaginal dilator (VD) after pelvic radiotherapy (RT). We analyzed the effect of VD on vaginal stenosis (VS) and its influence on sexual quality of life (QoL) in women treated with adjuvant RT for endometrial cancer (EC)., Methods: Between 2014 and 2015, 56 consecutive patients were instructed to use a VD after completion of treatment. The maximum diameter of the comfortably introducible VD was measured before and at 1 year after treatment. The degree of VS was evaluated clinically, and sexual QoL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) sexual functioning items before RT, during RT, at 6 weeks, and at 1 year after RT., Results: One year after RT, mean VD diameter had decreased by 2.7 ± 3.2 mm (p < 0.001) and 36 patients (64.3%) had clinical VS (grade I-III). A larger decrease in VD diameter correlated with a higher degree of clinical VS (p < 0.001). VD use (p = 0.81), RT modality (p = 0.68), and adjuvant ChT (p = 0.87) had no influence on VD diameter. Sexual activity decreased during RT and increased beyond pre-RT values 1 year after RT (p < 0.001). Sexual enjoyment decreased continuously during and after completion of RT (p = 0.013) and was influenced negatively by a higher degree of clinical VS (p = 0.01)., Conclusion: Almost two thirds of patients developed clinical VS 1 year after adjuvant RT for EC, and sexual enjoyment was substantially reduced by VS. The use of a VD after RT may not serve to prevent sexual impairments and VS.

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.

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.

Background: UK guidelines recommend routine vaginal dilation during and after pelvic radiotherapy to prevent stenosis., Objective: To examine critically the evidence behind this guideline., Search Strategy: Cochrane-style systematic review of the data and literature relevant to vaginal dilation and stenosis attributable to radiotherapy., Selection Criteria: Any and every measure of vaginal or sexual function after radiotherapy., Data Collection and Analysis: Numerous papers gave recommendations on dilation during or immediately after radiotherapy, but only seven contained relevant data. Case reports describe vaginal fistulas or psychological morbidity. Two trials showed that encouraging dilation increased compliance, but the first trial found no difference in sexual function scores. One comparative unmatched trial showed no advantage from inserting mitomycin C. A report of five women implied that stenosis can be treated by dilation many years after radiotherapy. One uncontrolled observational report involving 89 women showed that the median vaginal length 6-10 weeks after therapy was measured at 6 cm, but women tolerated a 9-cm measurer after 4 months of dilation experience. One retrospective report implied that dilation lowered stenosis rates, but the control group is not comparable., Main Results: Dilation during or immediately after radiotherapy can cause damage, and there is no evidence that it prevents stenosis. Dilation might stretch the vagina if commenced after the inflammatory phase., Author's Conclusions: Dilation might help treat the late effects of radiotherapy, but it must not be assumed that this applies to the acute toxicity phase. Routine dilation during treatment is not supported by good evidence.

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.

Aims: We report the results of hyperbaric oxygen therapy (HBOT) used in the treatment of radiation-induced persistent side-effects after the irradiation of pelvic tumours., Materials and Methods: Between January 2001 and December 2005, 13 women (median age 60.3 years) with radiation combined proctitis/cystitis (n=6), longstanding vaginal ulcers and fistulas (n=5) and longstanding skin injuries (n=2) underwent HBOT in a multiplace chamber for a median of 27 sessions (range 16-40). The treatment schedule was HBOT 100% oxygen, at 2 absolute atmospheres, for 90 min, once a day. For radiation-induced toxicity grading we used the National Cancer Institute Common Toxicity Criteria (CTC) grading system, before and after HBOT., Results: Thirteen patients underwent an adequate number of HBOT sessions. The mean CTC grading score before HBOT was 3.3+/-0.75, whereas the mean CTC grading score after HBOT was 0.3+/-0.63. The scores showed a significant improvement after HBOT (P=0.001; exact Wilcoxon signed-rank test). Rectal bleeding ceased in five of six patients with proctitis and dysuria resolved in six of seven cystitis patients. Macroscopic haematuria stopped in seven of seven patients. Scar complications resolved in two of two patients. None reported HBOT-associated side-effects., Conclusion: HBOT is apparently safe and effective in managing radiation-induced late side-effects, such as soft tissue necrosis (skin and vagina), cystitis, proctitis and fistulas.

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.

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.

Purpose: To compare retrospectively two treatment protocols for postoperative intravaginal brachytherapy as to frequency of late radiation reactions and vaginal recurrence of disease., Methods and Materials: Two hundred seventeen patients with Stage I-II endometrial carcinoma underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by high-dose-rate (HDR) intracavitary irradiation, 5.5 Gy x 4 (22 Gy), to the upper 5 cm of the vagina. From 1988 to August 1991, the reference isodose was at 5 mm from the mucosal surface (standard treatment, 96 pts). From September 1991 to June 1996, the reference isodoses were chosen at 3 mm, 4 mm, or 5 mm depth depending on a clinical estimation of the mucosal thickness (individualized treatment, 121 pts). Maximum bladder and rectum doses were calculated from orthogonal X-ray films., Results: The patients were followed for 3 to 10 years. The rate of late vaginal reactions Grade 1 and 2 were 26% and 8%, respectively, after standard treatment, vs. 17% and 1% after individualized treatment (p = 0.005). Bladder reaction rates were 9% Grade 1 and 1% Grade 2 after standard treatment vs. 1% Grade 1 after individualized treatment (p = 0.005). Rectum reactions Grade 1 were seen in 5% and 1%, respectively. No Grade 3 reactions were observed. The reactions appeared after a median time interval of 9 months and 11 months, respectively. The rate of vaginal reactions was strongly correlated to the dose on the surface of the vaginal applicator, and the bladder reaction rate correlated with the calculated maximum bladder dose. Local vaginal recurrences were seen in 1 patient (1.0%) in the standard treatment group and in 3 patients (2.5%) in the individualized treatment group (p = 0.78)., Conclusions: By individualizing the depth of the reference dose in the vaginal mucosa according to its thickness and avoiding applicators with small diameters, the rate of reactions can be reduced without any significant increase in vaginal recurrences.

Background: Acute and late injuries of vulva and vagina are frequent and potentially serious complications in radiotherapy of gynecologic tumors. They still are reported poorly in literature., Methods: Based on a literature search a survey will be given of the modalities, which are used or recommended for prophylaxis or treatment of these radiation injuries. The principles of the different measures will be discussed with available study results., Results: Hygiene measures and the topical application of antimicrobial or granulation stimulating substances, which is mostly based on long standing clinical experience, are the principles of the treatment of acute reactions of vulva and vagina. The topical use of estrogen, which promotes proliferation of epithelium, is generally described in connection with treatment and prophylaxis of late radiation injuries. As a prophylaxis for the late reaction of vaginal stenosis, vaginal dilatation is recommended in literature., Conclusions: With the exception of a few reports on estrogen, there are no data about the effectiveness of the currently used medical substances. The local application of estrogen as prophylaxis of the acute reactions will therefore be examined in a prospective study.

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 define the incidence and severity of perioperative morbidity and its subsequent management with standard tandem and ovoid insertions and to evaluate pretreatment and treatment factors associated with an increased risk of perioperative morbidity., Methods and Materials: Ninety-five tandem and ovoid insertions were performed at the Fox Chase Cancer Center between 1985 and 1992 for cervical (n = 91) and endometrial (n = 4) cancer. Patients were placed on antibiotics in 19%, usually for a positive routine preoperative urine culture, but no patient was given prophylactic antibiotic therapy. Deep-vein thrombosis prophylaxis was practiced for 70% of implants and included subcutaneous heparin (40%), graduated compression elastic stockings (16%), and external pneumatic calf compression (14%). All patients were placed on prophylactic diphenoxylate hydrochloride, with doses ranging from three to eight tablets/day., Results: Intraoperative complications were seen in 3% of implants and included two perforations and a vaginal laceration in two patients. Twenty-four percent of implants (16 patients) developed temperatures of > 100.5 (range 100.6 to 103), although only one patient required implant removal because of fever. Management of fever included antibiotics in 35% and acetaminophen only in 65%. Five implants (5%) were removed emergently secondary to presumed sepsis (n = 1), exacerbation of chronic obstructive pulmonary disease, hypotension, change in mental status (n = 3), and myocardial infarction/congestive heart failure (n = 1). No patient developed a deep-vein thrombosis, pulmonary embolism, gastrointestinal obstruction, or died of a postoperative complication. Univariate analysis of pretreatment and treatment factors revealed older age (p < 0.005) and spinal/epidural anesthesia (p < 0.02) to be associated with increased perioperative morbidity, and older age (p < 0.05) and higher ASA classification (p < 0.02) to be associated with severe complications requiring removal of implant. Multivariate analysis revealed only older age (p < 0.01) to be significantly related to perioperative morbidity., Conclusions: Fever of > 100.5 was seen in 24% of implants and can be managed successfully without removal of the implant in 96% of cases. Use of antibiotics preoperatively and intraoperatively did not reduce the risk of perioperative temperature elevation. Use of routine diphenoxylate hydrochloride prophylaxis was tolerated without ileus or gastrointestinal obstruction clinically. Although routine deep-vein thrombosis prophylaxis is reasonable, our data would support a low risk of deep-vein thrombosis for untreated patients. Severe perioperative morbidity necessitated premature implant removal in only 5% of cases and was related to older age in multivariate analysis.

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.

As various chemotherapeutic agents are added to treatment routines, the possibility of adverse effects is appreciably increased, particularly in those organs for which the agents have specific toxicity. Symptoms most commonly associated with radiation sickness, such as malaise, anorexia, nausea, vomiting, diarrhea, dysphagia, dermatitis, and depleted hemopoietic elements, are usually seen late in the course of radiation therapy or shortly thereafter. Consequently, they are managed by the physician in charge of radiation or the patient's referring physician. The general physician may be concerned with symptoms arising from delayed organ pathology. These symptoms may arise in many tissues that are still considered somewhat radioresistant, but secondary to sequelae arising because of connective tissue changes from obliterative narrowing of the finer vasculature. Radiation may be only one of several possible causes, and the symptoms of sequelae may appear only after a long latent period, so that the previous radiation may not be considered in the differential diagnosis unless a detailed history is taken. The medical management of these sequelae is, in general, similar to that used for the pathology produced in these organs by other agents.

Vaginal reconstruction was performed in 14 patients who had developed vaginal stenosis secondary to extensive pelvic fibrosis after pelvic radiation therapy (12 patients) or prior vaginal reconstruction (2 patients). Sixteen procedures were performed using a split-thickness skin graft. All patients had satisfactory vaginal restoration, and 12 patients reported good vaginal function. No fistula developed as a result of the operative procedure, but one patient later developed a rectovaginal fistula resulting from tumor recurrence. Successful vaginal reconstruction can be achieved even years after initial therapy in patients who develop an obliterated vagina from previous radiation or surgery.