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Pelvic radiotherapy remains an important part of the treatment or constitutes the primary treatment of many cancers e. There is a continuous development of new radiation methods to save normal tissue without compromising cure rate and survival 1 - 4. Earlier studies have revealed that patients undergoing radiotherapy for their pelvic cancer suffer from a considerable amount of late effects influencing negatively on their quality of life QOL and sexual functioning 5 - 8.

In female cancer patients vaginal morbidity seems to be critical for the resumption and maintenance of a healthy sexual life. The introduction of modern radiotherapy modalities has generated a hope that late effects following treatment of pelvic cancers may decrease in the future. Lately, technical progress has been made to determine the dose intensity pattern that will best conform to the tumor shape; e. The main purpose is to allow a higher radiation dose to be focused within the tumour while minimizing the dose to surrounding normal critical structures.

The 4D target concept for image-guided adaptive brachytherapy IGAB purposes to take into that following external radiotherapy the residual tumor volume at the time of brachytherapy is smaller than the primary tumor. Therefore the volume of the residual tumor can be considered as the high risk target while the primary tumor volume can be considered as an intermediate risk target and may not need as high a radiation dose 3.

Hence normal tissue may be spared. The addition of brachytherapy allows a high localized target doses with tissue sparing low non-target doses. For cervical cancer, brachytherapy is delivered using an applicator inserted close to or in the tumor target. To optimize the dose lateral in the pelvis, applicators have been developed that allows insertion of angled needles into the pelvis in which the radiation source can travel and dwell in different positions according to the target calculations. The limiting factor for the total dose delivery of radiation is normal tissue tolerance.

Hence, in managing pelvic cancer with radiotherapy, a delicate balance between cure and tissue tolerance have to be dealt with. In general, the occurrence of complications is dose and fractionation dependent and there may be a long latency periods for many adverse late effects to emerge, probably due to scattered irradiation remaining in the organs around the tumour. The accumulated radiation dose to the pelvic organs is important for acute bowel, bladder, and genital toxicity. Radiation effects are progressive and may become symptomatic after a latent period but there may be a continuous progression from the acute oedema, mucosal and sub-mucosal inflammation and persistent ulceration and necrosis to fibrosis 9 - The rapid cell-turnover of the vaginal and vulva epithelium make them very sensitive to the effects of radiation.

Following pelvic radiation, acute radiation effects include vaginal erythema, moist desquamation, and a confluent mucositis. The mucosa may demonstrate severe congestion and submucosal hemorrhage hyperemia. These effects usually resolve within 2 to 3 months after radiotherapy.

In some patients, however, there is a progressive vascular compromise and tissue hypoxia may result in epithelial sloughing, ulcer formation and necrosis. On the longer term, vaginal wall thinning, adhesions, atrophia and fibrosis may occur often followed by decreased vaginal elasticity, narrowing, shortening and ultimately total vaginal stenosis 812 - With a median period of 1 to 2 years late effects may arise when the sub-mucosa undergoes varying degrees of fibrotic change, organ capacity reduces and teleangectasia may develop.

Further, ischaemia from radiation-induced endarteritis obliterans may give rise to a fragile neovasculature that tends to bleed. The end result may include vaginal and vaginal entrance stenosis and fragility. Similar effects are observed in the bladder and rectum resulting in late effects as urgency, hemorrhagic cystitis, tenesmi and fecal incontinence 591117 A healthy sexual response is described having four phases; desire, excitement, orgasm and resolution whereas female sexual dysfunction FSD includes desire, arousal, orgasmic and sexual pain disorders Current knowledge of the complexities related to female hypoactive sexual desire, arousal and pain sexual disorders has prompted recommendation of a classification system based on physical as well as psychological pathophysiology, and a personal distress criterion for most diagnostic 19 This includes a re-definition of sexual desire to include the concept of receptivity.

Sexual arousal disorders are separated into genital and subjective subtypes while the definition of dyspareunia reflects the possibility of having pain that precludes sexual intercourse.

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The anticipation and fear of pain characteristic of vaginismus is noted while the assumed muscular spasm is omitted given the lack of evidence 19 Late effects of radiotherapy and QOL aspects are most validly measured by the patient and patient reported outcomes PROs are today widely accepted as outcome measures. Further, ificant vaginal, vulval, and perineal changes may arise after radiotherapy and cause considerable pain during all phases of sexual interaction in the first months following radiotherapy.

Later, chronic changes may arise which may render sexual intercourse impossible. These radiation induced changes are usually not included in questionnaires assessing FSD; e. However, questionnaires and late effects scales have emerged that explicitly address mucosal changes and their impact on sexuality following radiotherapy; e. The goal of the present review was to summarize the latest knowledge on pelvic radiotherapy and sexual function in women focusing on studies I from the period to ; II that used PROs as outcome measure; III that were randomized controlled trials RCTs where FSD at least constituted a secondary outcome; and IV that reported from modern radiotherapy modalities.

A further aspect primarily related to vaginal or perineal brachytherapy was evaluated. A similar search has been done before 7 and the present search was therefore focused on the past 5 years and with a special interest in identifying RCTs that evaluated PROs related to FSD. Two randomized controlled studies were identified that reported PROs dealing with issues on sexuality following radiotherapy for rectal or endometrial cancer 128 Both studies will be described in details below in the respective disease-specific sections.

Studies included in the present narrative review are summarized in Table 1. These studies represent a selected part of studies retrieved as described above. These two studies are summarized due to their longitudinal de and the existing sparse knowledge on sexual function after radiotherapy for bladder and vulva cancer, respectively. Most studies were retrospective cross-sectional in de while a few older studies were prospective longitudinal 81632 Summarizing the general findings in observational studies published beforeit can be concluded that pelvic radiotherapy is associated with multiple organic changes and psychological issues that have the potential to negatively impact on female sexuality 121334 - Women reported a feeling of lack of femininity, sexual attractiveness and confidence besides being distressed by vaginal bleeding, vaginal pain, vaginal dryness, vaginal shortening, and decreased elasticity resulting in fear of having sex and less sexual enjoyment 81214 - 1636 During the past 5 years several studies have emerged that focuse on a pd less toxic effect of IGAB and IMRT but few studies included PROs and the literature published after did not reveal any new knowledge or evidence of less toxicity related to pelvic radiotherapy.

from both periods before and after will be addressed in each disease-specific section below with a special focus on from the few RCTs and from studies evaluating modern radiotherapy methods. The past 15 years of research within the field of using PROs to assess late effects in this patient group has assessed more general aspect of QOL, gastrointestinal, and urological late effects 3948 - 50 and only a few older studies 51 have included data on sexual functioning. However, a few newer studies assessed sexual functioning in more details 14752 although sexual functioning was not the primary outcome in any of these studies.

The earlier studies used non-validated questionnaires or items 4751 while the randomized controlled study of Nout et al. Nunns et al. The overall incidence of vaginal stenosis was Only 20 out of 75 women were sexually active prior to treatment. The primary end-point was vaginal vault recurrence while QOL aspects were secondary outcomes.

The sample size was large enough to show ificant differences in both recurrence and QOL-related endpoints. QOL was evaluated prior to radiotherapy and 2 and 4 weeks and 6, 12, 18, 24, 36, 48, and 60 months after radiotherapy by self-assessment of questionnaires or single items developed and internationally validated by the European Organization of Research and Treatment of Cancer EORTC group.

No difference was observed in overall survival between the two radiation groups. Sexual interest and activity increased during the first six months post-radiation and no difference was observed between the two radiation groups in sexual interest, activity, enjoyment, or vaginal dryness. However, compared to an age-matched control group of women from the general population ificant impairment was observed both regarding sexual interest, activity, enjoyment and vaginal dryness in both groups Some smaller, recently published, cross-sectional studies did not find any difference in sexual functioning between women undergoing hysterectomy and postoperative VBT compared to women who had hysterectomy only 5455 or compared to healthy postmenopausal women All three studies used validated questionnaires but conclusions may very well have been biased by a very small of patients actually receiving VBT 54 In the study of Damast et al.

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It is concluded that applying postoperative VBT to women with endometrial cancer carries a comparatively high risk of vaginal changes and sexual impairment at the same level as that found after EBRT. Advanced cervical cancer is treated with EBRT, brachytherapy and concomitant chemotherapy. Patients, identified with histologically high risk factors for recurrence after surgery for early stage disease, e.

A couple of longitudinal studies have been published assessing sexual functioning following primary or postoperative radiotherapy for cervical cancer 81632 and found persistent sexual dysfunction with limited or no indication of improvement over time. In the longitudinal study of Jensen et al. Throughout the study period of two years, ificant severe sexual dysfunction and vaginal morbidity were reported by the patients compared to controls: e.

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Several cross-sectional studies have confirmed these in comparatively large samples 1213404657 - Hence, from the literature before including both longitudinal and cross-sectional studies in patients receiving either adjuvant or primary radiotherapy showed that the effects of radiotherapy is progressive and persistent over time especially related to the vaginal mucosal morbidity with no or little improvement to be expected. Further, ificant psychological impairment; e. Up to the period beforestudies on QOL issues after radiotherapy reported on late effects after traditional EBRT and brachytherapy.

However, most studies still reported on traditional radiotherapy 61 or did not provide sufficient information on radiotherapy modality applied to assess potential improvement related to modern radiotherapy modalities 62 - The literature after still revealed ificant sexual impairment following pelvic radiotherapy for advanced cervical cancer, especially related to vaginal changes; tightness, shortness, dryness, dyspareunia, vaginal bleeding 6264 - Several authors have explored more psychological aspects of sexual functioning in cervical cancer patients. Abbott-Anderson et al.

Similar worries were found in the study of Mantegna et al. Despite a ificant improvement in sexual activity during the first three months following treatment, patients treated with chemo-radiation reported ificantly lower levels of sexual activity compared to patients treated with surgery only for early stage disease Juraskova et al. In the study of Lindegaard et al. Hence, no PROs were included but overall, an improvement in survival was observed besides ificant less urological, gastrointestinal, and vaginal morbidity as assessed by the doctor at gynaecological examination 3.

The same author participated in a multicenter study prospectively evaluating the effects of definite chemo-radiation and IGAB which had the main purpose of comprehensively assess early and late vaginal morbidity The CTCAE, version 3 26 was used to grade vaginal morbidity and by nature, as mentioned by the authors, potentially biased by subjective interpretation by the doctor assessing the morbidity and knowing what treatment modality that was given 60 Further, as the author claims, this grading system does not work for e.

It is concluded that the prevalence of severe or life-threatening vaginal morbidity is limited after definite radiation chemotherapy including IGAB. PROs were included in a recent in press study by the same author in a mono-institutional prospective study of 50 patients receiving IGAB for advanced cervical cancer and assessed before, during, 1 week and 3 months after radiotherapy 4.

These are awaited in a later paper personal correspondence. It is concluded that patients with advanced cervical cancer still represent a group at high risk of experiencing persistent sexual dysfunction both related to vaginal morbidity and to more psychologically related elements of femininity and body-image. Radiation therapy can be used in different settings for the management of patients with vulvar cancer.

Studies evaluating sexual function after vulvar cancer are scarce and based on small sample sizes and further characterized by heterogeneity on disease stage, treatment modality, and used methodology to assess sexual function. Most studies relied on a retrospective or cross-sectional de, control groups were seldom included, and most often dealt with extensive surgical procedures that were used decades ago

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Pelvic radiotherapy and sexual function in women