Denton Et Al-2003-Cochrane Database of Systematic Reviews

Cochrane Database of Systematic Reviews
Interventions for the physical aspects of sexual dysfunction in

women following pelvic radiotherapy (Review)
Denton AS, Maher J
Denton AS, Maher J.

Interventions for the physical aspects of sexual dysfunction in women following pelvic radiotherapy.
Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD003750.
DOI: 10.1002/14651858.CD003750.
www.cochranelibrary.com
Interventions for the physical aspects of sexual dysfunction in women following pelvic radiotherapy (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Analysis 1.1. Comparison 1 Resolution of acute vaginal mucositis, Outcome 1 Resolution of acute vaginal mucositis using
BDZ and placebo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Analysis 2.1. Comparison 2 Prevention of vaginal stenosis, Outcome 1 Prevention of VS using intercourse or a vaginal
stent. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Analysis 3.1. Comparison 3 Reduction of vaginal radiation symptoms that prevent intercourse, Outcome 1 Reduction of
vaginal bleeding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Analysis 3.2. Comparison 3 Reduction of vaginal radiation symptoms that prevent intercourse, Outcome 2 Improvement
in dyspareunia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Analysis 3.3. Comparison 3 Reduction of vaginal radiation symptoms that prevent intercourse, Outcome 3 Improved
vaginal mucosa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Interventions for the physical aspects of sexual dysfunction in women following pelvic radiotherapy (Review) i
[Intervention Review]
Interventions for the physical aspects of sexual dysfunction in

women following pelvic radiotherapy
Arshi S Denton1 , Jane Maher2

1 Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, UK. 2 Department of Radiotherapy and Oncology, Mount Vernon
Hospital, Northwood, UK
Contact address: Arshi S Denton, Centre for Cancer Treatment, Mount Vernon Hospital, Rickmansworth Rd, Northwood, Middlesex,
HA6 2RN, UK. arshi.denton@nhs.net, arshidenton@blueyonder.co.uk.
Editorial group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group.

Publication status and date: Stable (no update expected for reasons given in ’What’s new’), published in Issue 2, 2015.
Citation: Denton AS, Maher J. Interventions for the physical aspects of sexual dysfunction in women following pelvic radiotherapy.
Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD003750. DOI: 10.1002/14651858.CD003750.
ABSTRACT
Background
Following pelvic radiotherapy (RT), a proportion of women experience problems related to sexual function, which are multifactorial
in origin. The physical components relate to distortion of the perineum and vagina, which may occur as a result of surgery and/or
radiotherapy and compromise sexual activity resulting in considerable distress.
Objectives
The aim of this review was to evaluate the evidence for treatment options addressing the physical components of sexual dysfunction
arising from pelvic radiotherapy as prevention or treatment of acute or late complications.
Search methods
The concepts used included synonyms for radiation therapy and brachytherapy and synonyms for the spectrum of physical aspects
of sexual dysfunction in women. randomized. We searched the Cochrane Controlled Trials Register (CENTRAL), Issue 1, 2002,
MEDLINE 1966 to 2002, EMBASE 1980 to 2002, CANCERCD 1980 to 2002, Science Citation Index 1991 to 2002, CINAHL
1982 to 2002, as well as sources of grey literature. We also hand searched relevant textbooks and contacted experts in the field.
Selection criteria
Any study describing the therapeutic trial of a treatment to relieve the physical aspects of female sexual dysfunction which had developed
following pelvic radiotherapy was considered. The quality of each study was then assessed by two reviewers independently to determine
its suitability for inclusion in statistical analysis.
Data collection and analysis
Thirty-two references met the inclusion criteria for the search but of these only four were suitable to be included for statistical analysis.
Main results
The strongest evidence for benefit is the grade IC data in the topical oestrogens and benzydamine sections which describes the treatment
of acute radiation vaginal changes. The use of vaginal dilators to prevent the development of vaginal stenosis is supported by grade IIC
evidence. The value of hyperbaric oxygen therapy and surgical reconstruction is supported by the much weaker grade IIIC evidence in
the form of case series.
Interventions for the physical aspects of sexual dysfunction in women following pelvic radiotherapy (Review) 1
Authors’ conclusions
These findings reflect the quality of published data regarding interventions for this aspect of the management of radiation induced
complications. Although there is grade IC evidence, these studies are not recent, the allocation concealment is unclear in the text, and
overall there is a variable level of assessment of the response, emphasising the need for more studies to be conducted with improved
designs to clarify the investigative process and support the final result.
PLAIN LANGUAGE SUMMARY
Vaginal dilators and intercourse are useful for alleviating post-radiotherapy vaginal problems, but more evidence is required to
assess oestrogens and benzydamine
The physical side effects of radiotherapy to the female pelvis may lead to difficulty and/or pain during intercourse. Studies of treatments
(vaginal oestrogens, benzydamine douches, dilators, and intercourse) were neither recent nor good quality. This review endorses the
current recommendation of using dilators and/or intercourse to prevent vaginal narrowing, however although some studies recommend
the use of vaginal oestrogen or benzydamine douches, they are not statistically significant and large randomized trials are required to
assess their effectiveness.
BACKGROUND • postcoital bleeding (bleeding after sexual intercourse)

Following pelvic radiotherapy, a proportion of women experience
problems related to sexual function, which are multifactorial in The acute radiation reaction may produce any of the listed spec-
origin. The physical components of this relate to distortion of the trum of symptoms but is dominated by vaginal and vulval mu-
perineum and vagina, which may occur as a result of surgery and/ cositis (inflammation of the mucosa), pain and ulceration. The
or radiotherapy and compromises sexual activity resulting in con- presentation of late side effects is dominated by fibrosis, loss of
siderable distress (Bergmark 1999). The rapid cell turnover of the elasticity and sensation producing vaginal shortening and stenosis,
vaginal and vulval epithelium allows for natural exfoliation of the telangiectasia (fragile superficial blood vessels), postcoital bleeding
outer most layers of non-dividing cells and makes the epithelium and pain on intercourse. Increased susceptibility to trauma and
very sensitive to the effects of radiation. There are two phases of infection are not uncommon although poorly reported so that the
radiation toxicity, the acute reaction occurs during the course of true prevalence is not known (Grigsby 1995). These manifesta-
radiotherapy and for a few months afterwards. In contrast, the late tions are often compounded further by the effects of radiation in-
reaction may follow on from the acute reaction for a minimum duced ovarian failure which results in decreased vaginal lubrica-
period of three months or develop after a symptom free interval tion and thinning of the vaginal epithelium. Although there are
of not less than three months from completion of radiotherapy. few statistics on the frequency of this type of toxicity, the acute
The following symptoms and presentations contributing to sex- reaction is reported relatively frequently as it is associated with dis-
ual dysfunction evolve over months to years after completion of comfort, easily recognised and by definition self-limiting. How-
treatment: ever the development of late complications may be more insidious
or difficult to diagnose and therefore often poorly documented.
• vaginal dryness Certain risk factors predispose to susceptibility for late toxicity and
include diabetes, arterial disease and tumour bulk.
• atrophic vaginitis
While concentrating on tumour response, discussion of sexual is-
• vaginal/vulval ulceration or necrosis
sues may be cursory, or be considered awkward or embarrassing to
• vaginal stenosis (narrowing of the vagina) address because of age, religious or marital status. Vaginal stenosis
for example, should be documented regularly as part of tumour
• shortened vaginal canal
surveillance, however this is frequently poorly recorded and in-
• dyspareunia i.e. pain related to sexual intercourse consistently graded. Therefore, the other physical components of
sexual dysfunction arising from pelvic radiotherapy, are probably METHODS
also under-reported.
The principles of treatment vary according to the different phases
of the development of toxicity: Criteria for considering studies for this review
Attempts to prevent or limit the acute reaction Types of studies

• maintenance of hygiene The systematic review has included studies that met the following
• treatment of infection criteria:
• regular dilatation of the vaginal canal Randomized controlled trials. Randomized studies, which are
described by the author(s) as randomized anywhere in the
manuscript. Quasi-randomized trials in which participants are al-
Treatment of the acute reaction located by methods which are not truly random. Cohort studies
where the comparability of cohorts has been established or existing
• active treatment of ulceration confounding factors adjusted. Well designed case control retro-
• hormone replacement therapy (HRT) when indicated spective studies where evidence has shown that selection bias and
(Fraunholz 1998) confounding variables have been addressed or considered. Lon-
• compensation for mucosal dryness with lubricants gitudinal surveys or case histories. All identified trials, published
and unpublished were eligible.
Conclusions from the non-randomized, non-controlled data have
Prevention of late side effects only been drawn if there is insufficient evidence from randomized
controlled trials, and the quality and the validity of the study has
• vaginal dilators
been established.
• lubricants
As this review concentrated on the ’best evidence’, the quality of
• HRT
all the studies identified was graded using the criteria described by
the NHS Executive in their Reviews on Commissioning Cancer
services.
Treatment of established late side effects Grading Criteria used by the NHS Executive
• Hyperbaric oxygen therapy
• Surgical reconstruction Grade I (Strong evidence)
Randomized controlled trial or review of randomized controlled
Both patients and partners should be made aware of the poten- trials
tial consequences of treatment during initial consultations prior IA: Calculation of sample size and accurate and standard definition
to therapy with reinforcement thereafter. Baseline sexual func- of outcome variables
tion should be documented for comparisons to be made subse- IB: Accurate and standard definition of outcome variables
quently. There is considerable current emphasis on education and IC: None of the above
prevention of potential sexual dysfunction, but both prophylaxis Grade II (Fairly strong evidence)
and management of established problems need to be standardised. Prospective study with a comparison group (non-randomized con-
Measuring outcome is difficult and brings us back to the nature of trolled trial or good observation study)
the presenting problem and the impact that sexual problems have IIA: Calculation of sample size and accurate and standard defini-
on quality of life (QOL), regardless of age or marital status (Cull tion of outcome variables
1993). IIB: One of the above
IIC: None of the above
Grade III (Weak evidence)
Retrospective study
IIIA: Comparison group, calculation of sample size and accurate
OBJECTIVES
and standard definition of outcome variables
Our aim was to review the evidence for treatment options address- IIIB: Two of the above criteria
ing the physical components of sexual dysfunction arising from IIIC: None of the above
pelvic radiotherapy either as prevention or treatment of acute or Grade IV (Weak evidence)
late complications. Cross sectional study
Using the concept of hierarchy of evidence, whereby some research radiation is immediate and persists for three to six months. Al-
methodologies are accepted as more robust than others, conclu- though re-epithelisation occurs, normal structure and appearance
sions have been drawn, with more weight given to well-conducted, may never return. One study suggests that up to 80% of women
controlled studies. have some degree of vaginal stenosis following therapeutic irradi-
ation (Abitol 1974) and that stricture of the upper third of the
vagina is more commonly seen. In most cases the maximum steno-
Types of participants sis occurs within a three to six month period. Complete vaginal
1. Women confirmed to have a pelvic malignancy. occlusion occurs infrequently. The stenosis occurs as a result of the
2. Patients must all have received pelvic radiotherapy as part of formation of adhesions, together with the circumferential fibro-
their treatment schedule (primary radiotherapy, postoperative ra- sis of upper vaginal tissue. This leads to contraction of the vagi-
diotherapy, with or without chemotherapy or palliative). nal vault and a shortened vagina. Subsequently difficulties may
arise for the clinician at follow up with limited access for tumour
surveillance because of the narrowed aperture of the vagina. More
Types of interventions importantly stenosis may cause physical problems with sexual in-
Preliminary review of the literature suggested the following treat- tercourse producing dyspareunia (painful intercourse) and post-
ments have been used for vaginal or perineal toxicity; coital bleeding. As a means of preventing this and treating estab-
lished stenosis clinicians may recommend the use of dilators or
sexual intercourse with lubrication.
Prevention of acute complications
• Antiseptic douches
• Vaginal dilators Oestrogens
• Sexual intercourse As a direct and immediate response to radiation to the vagina, there
is loss of virtually all epithelium in the areas receiving the maximal
Treatment of acute complications surface radiation and this loss persists through the first three to
six months after radiation. Following this period there is early
• Antiseptic douches
epithelial replacement consisting of a thin and incomplete layer
• Treatment of infection and ulceration
of basal cells. The epithelial covering becomes progressively more
• Vaginal dilators
complete and by two years the epithelium assumes a nearly normal
• Topical oestrogen creams
structure. Inflammatory changes gradually diminish in a manner
reciprocal to the epithelial changes. The use of topical oestrogen
Prevention of late complications following completion of radiation therapy is thought to have a
significant effect upon the promotion of epithelial regeneration,
• Vaginal dilators
and may be even more pronounced when topical oestrogen is given
• Lubricants
to patients who are three months or longer post radiation.
• Oestrogen creams/HRT
Treatment of late complications Benzydamine
• Vaginal dilators This compound belongs to the group of anti-inflammatories

• Lubricants which act directly on inflammation by stabilising cells and lysoso-
• Oestrogen creams and HRT mal membranes and by inhibiting the synthesis of prostaglandins.
• Hyperbaric oxygen and agents for treating the ischaemic Benzydamine is used topically and is well absorbed through the
and fibrotic component skin reaching higher concentrations in the underlying inflamed
• Reconstruction of the vagina or perineum tissue than after oral administration. In addition it has analgesic,
local anaesthetic and antimicrobial effects. The anti-inflammatory
properties of this agent have already been documented in other
Vaginal dilators areas predominantly as an oral antiseptic mouthwash for head and
As part of the treatment for endometrial and cervical cancer, pa- neck radiation reactions.
tients are likely to receive external beam radiation and/or intra-
cavitary irradiation either as the primary treatment or in conjunc-
tion with surgery. The assessment of patients following intracav- Hyperbaric oxygen therapy (HBO)
itary treatment may reveal vaginal stenosis although this is gen- The repair of radionecrotic areas is limited by the reduced blood
erally poorly recorded. The response of the vaginal epithelium to supply and conservative therapy is often all that is recommended.
The limited vascularity is the precise reason why conservative ther- Secondary outcomes
apy frequently fails to result in complete healing. HBO acts to Secondary outcome measures have been assessed by the effect of
stimulate collagen formation at the wound edges through eleva- the various interventions listed above on mortality, morbidity and
tion of local tissue oxygen tensions. New microvasculature depen- quality of life scores. Where the outcome measures were not in-
dent on a collagen matrix for physical support is greatly enhanced cluded in the study under consideration, contact was made with
in this setting and allows re-epithelisation to occur. A course of the individual author(s) to establish whether there was data on
HBO provides a rich capillary bed in surrounding radiation dam- these outcomes and if it could be supplied.
aged tissue that although hypoperfused and hypoxic are still viable.
This angiogenic effect fails to occur when oxygen is administered
under normal pressures. Search methods for identification of studies
Vaginal reconstruction Electronic searches

Sexual response is a complex issue, and many variables interact. Concepts
As anatomical restoration of the vagina is a prerequisite for inter- A. Synonyms for radiation therapy and brachytherapy
course, severe distortion or obliteration of the vagina following B. Synonyms for the spectrum of physical aspects of sexual dys-
therapy for pelvic malignancy not only limits the access to regular function in women
tumour surveillance but can be psychologically devastating and C. Combine concepts A and B with the Boolean operator ’AND’
repair or surgical correction may be the only option available. Of A filter was not used because of the wide range of interventions
note is the fact that surgery in the irradiated field is often compli- searched for and also because initially, any type of study was con-
cated by poor and delayed wound healing, but in those women sidered without restriction to randomized controlled trials.
who are keen to resume sexual activity, the benefits of reconstruc- This basic strategy was expanded for text and MeSH terms before
tion may be outweighed by the potential risks. being applied to a sequence of databases.
Reconstructive surgery after severe radiation damage or necrosis For specific databases the strategy was altered accordingly.
may serve two functions, firstly to repair a perineal defect and limit The hits were handsearched to identify relevant references.
further tissue damage and secondly to reconstruct a vagina that The inclusion criteria were then applied to determine which stud-
may have been completely obliterated. Significant stenosis and ies were included in the systematic review. The search strategy
even complete obliteration of a normal vagina can occur follow- for MEDLINE Appendix 1 was modified as appropriate for the
ing pelvic radiotherapy. Stenosis can also occur following vaginal relevant databases. In order to be as comprehensive as possible
repairs. While it is relatively straightforward to create an adequate the above search strategies were employed to identify all relevant
cavity between the rectum and the bladder for vaginal agenesis, studies irrespective of language. Studies predating 1966 were not
restoration of the vaginal form and function in the irradiated field systematically searched.
can be very different. The following electronic databases were searched using the search
strategies developed in close collaboration with a qualified librarian
from the Systematic Review Training Unit.
Comparisons of interventions Initial searches in MEDLINE using combinations of MeSH head-
Studies using the randomization of a therapy versus a placebo/ ings and free text words provided many thousands of references,
nothing or therapies versus each other are included in a compar- the majority of which were irrelevant. Difficulties arose in devising
isons table of the response, with the presenting features of the ra- a search strategy that was both sensitive and specific.
diation toxicity in the perineum or vagina and the specific inter- A randomised controlled study filter was not used in any of the
vention used. databases due to the requirement that any trial using a non-surgical
intervention was considered.
1. MEDLINE - on OVID. Searched from 1966 to 2002. This was
Types of outcome measures performed using the stated search strategy with combination of the
concepts using the Boolean operator AND. The search combined
MeSH terms and an extensive free text search.
2. EMBASE - on OVID. Searched from 1980 to 2002. The con-
Primary outcomes cepts in the search were combined as for MEDLINE and were
Primary outcome measures have been determined by response of developed as for MEDLINE.
the presenting symptoms (including time to resolution and the 3. CANCER CD - on Silver Platter. Searched from 1980 to 2002.
duration of response) to the various interventions listed above for The concepts of the search strategy were combined and developed
the physical aspects of sexual dysfunction. as for MEDLINE but using only free text terms.
4. SCIENCE CITATION INDEX on BIDS ISI from 1991 to This group of studies was assessed independently by both review-
2002. ers to determine if they complied with the preceding inclusion
The concepts of the search strategy were combined and developed criteria to judge, which articles were to be included in the review.
as for MEDLINE but using only free text terms. Where differences existed they were resolved by consensus and
5. CINAHL - on OVID. Searched from 1982 to 2002. The con- when necessary in consultation with a third reviewer. Justification
cepts in the search were combined as for MEDLINE and were for excluding studies was documented at that stage.
developed as for MEDLINE.
6. Database of Controlled trials Register (CENTRAL / CCTR
Cochrane Library 2002, Issue 2). The concepts in the search were Data extraction and management
combined as for MEDLINE and were developed as for MEDLINE A data extraction form was specifically designed for the review.
but with appropriate modifications. The following data items were extracted independently, masked
with respect to journal publication, authorship and place where
research was carried out. The object of this is to critically assess:
Searching other resources 1. Trial quality characteristics
2. Participants: number of subjects at baseline, gender, mean age,
type of malignancy and grade of radiation toxicity.
Hand searching 3. Interventions: which category of agent was used, method of
1. Review of reference lists of identified studies administration and dose
2. Reference lists from relevant textbooks were searched: 4. Outcome data
• Treatment of Cancer, Price and Sikora, Third edition; 5. Potential confounding factors: any assessment of previous treat-
• Cancer Principles and Practice of Oncology, De Vita et al ment
5th edition; The evaluation of methodological quality of the trials included
• Oxford Textbook of Oncology, Peckham M, Pinedo H and was as described in the Cochrane Handbook. Each trial was rated
Veronesi U, Oxford University Press 1995. according to the quality of allocation and concealment categories.
Category A: adequate concealment
Category B: uncertain, indication of adequacy
Personal Contact Category C: inadequate concealment
Category D: not used
1. Personal contact with individual authors of the relevant studies.
Differences in data extraction were resolved by referring back to the
A letter with the list of included studies was sent to the first author
original article and discussion between the two reviewers. Where
asking for information on published and unpublished studies not
necessary, information was sought from the authors of the primary
included in the list.
study for clarification of the missing information.
2. A letter to every member of the UK Link-Gynaecological On-
Dichotomous data i.e. where present was expressed as the odds
cology Group requesting unpublished data.
ratio (OR) and a common odds ratio calculated. Uncertainty in
3. Contact by letter to every member of the EORTC Gynaecolog-
each treatment was expressed using confidence intervals (CIs).
ical Oncology group requesting unpublished data.
Continuous data i.e. symptom scores were converted to the
4. Letters published in ’Clinical Oncology’ and ’Palliative
weighted mean differences (WMDs) and an overall weighted mean
Medicine’ explaining the review and requesting unpublished data.
difference calculated with standard errors (SEs).
5. Contact with the Gynaecological Cancer Cochrane Review
Data from different studies were only pooled when the outcome
group.
measures were the same. The Cochrane Review Manager software
RevMan was used for estimation of overall treatment effects/meta-
analysis of results. Both fixed and random effects models were used
Data collection and analysis to calculate a weighted average of the treatment effects across the
studies under review.
Selection of studies
All records from each of the databases above were imported into
the bibliographic package Reference Manager and merged into RESULTS
one core database where all titles, keywords and abstracts could
be inspected for relevance. Full text was obtained of all relevant
articles for further evaluation. A final list of all potential relevant Description of studies
articles was therefore created in Reference Manager.
The results of the electronic search strategies are listed in Table 1 thirty-five were treated after this period when a new vaginal stent
and the overall search results have been listed in Table 2. had been introduced and patients were fitted with the appropriate
size of stent after completion of radiotherapy, and instructed on
its use, daily for one year even if they were sexually active. All
Specific types of interventions cases were assessed at six weeks for tumour response and then
three monthly thereafter and at one year to determine clinically
whether the vaginal dimensions were the same as at the time of
Vaginal Dilators intracavitary treatment. Any reduction was deemed to be evidence
of stenosis. The baseline characteristics were comparable in both
Using the search strategy stated, there were only two references that
groups. Of those who had not used a stent, 20 out of 35 (54%) had
addressed the use of vaginal dilators. Poma 1980 is a retrospective
evidence of stenosis at follow up. Of those that had used a stent,
case series, level IIIC evidence. Decruze 1999 is a retrospective
four out of 35 (11%) had evidence of stenosis. The four who were
study with historical controls, level IIC evidence.
found to have vaginal stenosis were noted to be using the stent
Poma 1980, level IIIC
incorrectly and on rectification were noted to have improvement
Post irradiation vaginal occlusion: nonoperative management.
of their stenosis. Although most of the cases had used the stent
This is a retrospective series of five cases with established complete
to prevent the development of vaginal stenosis, the four in whom
vaginal stenosis. All patients received radiotherapy for carcinoma
it was not prevented, had a therapeutic effect in the established
of the cervix a minimum of three years earlier and subsequently
stenosed vagina. Side effects were not reported. Statistical analysis
presented with complete vaginal occlusion. The common feature
was not performed on this data in the reference and there was no
in the sexual background of these five cases was that they had re-
QOL assessment.
duced sexual activity before their cancer was diagnosed and be-
Both studies demonstrated a significant benefit maintained for the
lieved that menopause and their disease was associated with a nat-
follow up period of one year, although the retrospective case series
ural cessation of sexual relations.
suffers from selection bias, and is weaker evidence than the effect
The intervention used was applied digital pressure to the introitus
shown by Decruze 1999. Side effects were not noted in either of
twice a day with the application of Premarin vaginal cream 2g
the studies, nor was there any mention of mortality, or a formal
dose, for a period of six to eight weeks. They were instructed to
quality of life assessment.
stop pressure or dilatation when and if pain and bleeding ensued.
Even though Decruze 1999 is not a randomized study, it has been
The response to treatment was assessed by vaginal measurements
included in the review and the statistical analysis is presented in
at the start, and then at four and six to eight weeks after treatment.
the results section.
All cases had a marked progressive improvement at both four and
six to eight weeks and a minimum dimension of ten cm (length) by
three cm (width). Sexual intercourse started in all cases by the sixth
Oestrogens
week. Cytological smears improved in three of the cases during the
oestrogenic treatment but this vanished after the cream ceased. All Using the search strategy stated four references were identified that
cases were monitored for one year and the functional capacity was addressed the issue of vaginal oestrogens following pelvic radio-
maintained. therapy. All were in English and were of differing levels of evi-
No side effects were reported. Statistical analysis was not per- dence.
formed. Although quality of life impact has not been assessed, Pitkin 1965, is a prospective series with an active treatment group
there is a statement about the diminished self-image all had before and concurrent placebo group, level IIA. Here the intervention
treatment and the definite improvement in their self-esteem and was used in the treatment of acute and late toxicity.
self-confidence following treatment. Pitkin 1971, is a controlled double-blinded study, level IC, assess-
Decruze 1999, level IIB ing the effect of topical oestrogens in acute toxicity.
Prevention of vaginal stenosis in patients following vaginal Hintz 1981, is a prospective observational study with a non-ran-
brachytherapy. domized control group, level IIC, used in the treatment of late
This is a retrospective series with a concurrent historical control side effects.
group for comparison to assess whether sexual intercourse or the Poma 1980, is a retrospective case series, level IIIC, used in the
use of a vaginal stent could prevent the development of vaginal treatment of late toxicity.
stenosis. The authors examined the records of seventy women Pitkin 1965, level IIA
who received intracavitary brachytherapy, either with or without The effect of topical oestrogen on the irradiated vaginal epithe-
external beam radiotherapy for the treatment of cervical or uterine lium.
cancer. Thirty-five were treated during the period of 1991 to 1994 This is a prospective series with an active treatment group and
when the advice after completion of radiotherapy was to resume a placebo group although there are no details about randomiza-
regular sexual intercourse to maintain vaginal patency. The other tion or concealment allocation. Forty-nine cases had been treated
with radiation for carcinoma of the cervix three months ago. The Although we have tried to contact the authors for more informa-
subjects selected include only those who were under 50, had in- tion we have not had a response which we assume is because this
tercourse at least monthly and had no evidence of residual dis- was published in 1965.
ease. The baseline assessment included a vaginal smear and punch Pitkin 1971, level IC
biopsy. The gross appearance of the cervix and upper vagina was Post irradiation vaginitis. An evaluation of prophylaxis with topical
noted and cases were questioned about their vaginal bleeding, dis- oestrogen.
charge and dyspareunia. This is a controlled double-blinded study although the method
Each case was given a supply of 0.01% dienestrol or identical of randomization is not stated. Ninety-three women received pri-
cream base containing no oestrogenic substance and instructed to mary radiotherapy for carcinoma of the cervix. Exclusion criteria
insert one applicator full intravaginally three times weekly for one removed patients with obvious residual tumour, and those who
month. The method of randomisation is not stated and whether had received systemic oestrogen. Each subject was interviewed on
the clinician was blinded is not clear. Three months later smears completion of radiotherapy and received a supply of vaginal cream
and biopsies were repeated and the same information recorded. which either did or did not contain 0.01% dienestrol, one ap-
In order to facilitate comparison a classification for smears and plicator full to be inserted into the vagina at night, three times a
biopsies was developed, based on the maturation of the vaginal week till the cream was exhausted (mean six to nine months). Both
epithelium of the 49 cases over a period of three months to three active and placebo agents were supplied by the manufacturer in
years following radiotherapy (RT). identical packaging, identified by a code number which was kept
Thirty-one cases (from different time periods after radiation) by the manufacturer till the study was complete. The response was
treated with oestrogen had an average histological grade of 3.33 assessed by the degree of bleeding, intercourse with dyspareunia,
after treatment (versus 1.57 from smears and biopsies at the same vaginal calibre and vaginal epithelium in both groups. At the end
time interval who were untreated). This effect was greater in those of the treatment the code was broken and 44 used the oestrogen
who had received oestrogen cream more than three months after cream while 49 received the placebo. The baseline characteristics
RT. of both groups were comparable.
Sixteen out of 31 complained of discharge or bleeding prior to Results table
oestrogen therapy and 13 reported improvement or disappearance Bleeding Oestrogen Placebo
of the symptoms. Twelve out of 31 complained of dyspareunia Total 44 49
and 10 out of 31 reported various degrees of relief following the No PV bleed 35 32
use of topical oestrogen. Contact bleed 9 13
Seven cases were treated with placebo-the average histological Spontaneous bleeding 0 4
grade was essentially the same as those taken at the same time in- The differences in the incidence and severity of bleeding was not
terval post radiation prior to any treatment. significant (p>0.05) using the Chi squared test. The odds ratio of
The author’s conclusion was that the application of a topical oe- bleeding occurring, regardless of intensity in the treatment group
strogen was found to accelerate the regeneration of the epithelium was 0.48 (95% CI 0.19 to 1.24).
and that this was more pronounced in the cases who had intervals Dyspareunia Oestrogen Placebo
of greater than three months after RT. The duration of follow up Total 44 49
was three months and no side effects were reported. There was no Intercourse 26 30
statistical analysis of data and no quality of life assessment. No dyspareunia 20 14
As this was a controlled study, although the issue of randomiza- Mild dyspareunia 6 10
tion was unclear, our intention was to include the results in the Severe dyspareunia 0 6
MetaView program. However for the following reasons the data The difference in incidence and severity of dyspareunia was sig-
is not in a suitable format to be used: nificantly less in the oestrogen treated group (p>0.05) using the
1. The mean change in score of the epithelium before and after Chi squared test The odds ratio of dyspareunia occurring in the
the treatment means that one cannot dichotomise the results and treatment group was 0.26 (95% CI 0.08 to 0.84).
similarly for the placebo group where there was no mean change Vagina (V) Oestrogen Placebo
quoted. Neither can this information be used as continuous data Total 44 49
as there is no standard error or deviation available. V calibre normal 19 10
2. Thirteen out of 16 reported improvement from discharge or % V Calibre normal 43.2 20.4
bleeding as a result of topical oestrogens but were not matched by V epithelium normal 19 5
a comparative value in the placebo group. % V epithelium normal 43.2 10.2
3. Ten out of 12 reported improvement from dyspareunia as a The vaginal calibre was normal twice as often in the oestrogen
result of topical oestrogens but were not matched by a comparative treated group (p>0.01) using the Chi squared test. The vaginal
value in the placebo group. epithelium was normal four times as often in the oestrogen treated
group (p>0.05) using the Chi squared test. sessed and the data provided as a change in the mean score and
The patients having intercourse were significantly younger and similarly so for the placebo group so that the results could not be
had generally less marked degrees of vaginal constriction than non- dichotomised and used. This could not be used as continuous data
coital patients but the incidence of bleeding and epithelium did either as there was no documentation of the standard error or the
not differ significantly between the two groups. standard deviation of the samples. Although there were reductions
Side effects were not reported. There was no quality of life assess- in the numbers of cases with dyspareunia and bleeding after the
ment. In summary the oestrogen treated patients in comparison use of oestrogens there was no comparable data for the control
with the controls had significantly less dyspareunia, alterations in group. The impression is that the effect of oestrogens is beneficial
the vaginal epithelium and vaginal narrowing. Coitus indepen- but there is no follow up period for duration.
dently was also associated with a normal vaginal calibre. Level IC, Pitkin 1971, was used in the treatment of acute toxicity.
Hintz 1981, level IIC The method of allocation concealment was not clearly stated. The
Systemic absorption of conjugated oestrogenic cream by the irra- odds ratio for the effects of oestrogens on bleeding was not signif-
diated vagina. icant. The odds ratio of dyspareunia occurring in the treatment
This is a prospective observational study with a non random- group was 0.26 (95% CI 0.08 to 0.84) or 3.81 (95% CI 1.19
ized control group. The treatment group consisted of six post- to 12.16) in the placebo group. The vaginal calibre was normal
menopausal women treated with radiotherapy for carcinoma of twice as often in the oestrogen treated group (p<0.01) using the
the cervix a minimum of one year ago. The control group con- Chi squared test. The vaginal epithelium was normal four times
sisted of three women who were also postmenopausal and had re- as often in the oestrogen treated group (p<0.05) using the Chi
ceived radiotherapy to non pelvic areas. Neither study nor control squared test. The details for abnormal calibre and epithelium are
patients had used oestrogen in any form for at least three months not stated and cannot be assumed. Here there was good evidence
prior to the study. All cases received Premarin vaginal cream con- for the benefit of oestrogens but no duration of response.
taining 1.25 mg of conjugated oestrogens per 2g of cream to be Level IIC, Hintz 1981 again showed a benefit for the use of top-
used nightly for two weeks. ical oestrogens in late toxicity, both in the irradiated and post-
Baseline assessment was with a subjective assessment of vaginal menopausal mucosa but the period of follow up and response was
dryness and follicle stimulating hormone (FSH), leutenising hor- short at three weeks.
mone (LH) and oestrodiol levels. These were repeated four hours Level IIIC, Poma 1980, showed no significant difference in the
after the first application of vaginal cream. The vaginal mucosa improvement in all cases in the treatment of late toxicity and the
was then reassessed three weeks later with an evaluation of the duration of response was one year.
clinical status and side effects to determine the response. At follow All these studies showed outcome improvements with the use of
up the appearance of the vaginal mucosa after two weeks of nightly vaginal oestrogen applications in both acute and late toxicity but
Premarin was subjectively scored as improved in four out of six without the duration of response. Pitkin 1971is the only study in
treatment and two out of three control patients. this section where the data is suitable for inclusion in the systematic
An independent OR was conducted which demonstrated a value review for statistical analysis.
of one (95% CI 0.05 to 18.92) for the effect of topical oestrogen
on the irradiated and non-irradiated postmenopausal vaginal mu-
cosa. For both groups the FSH was unchanged from the baseline
whereas at four hours the LH decreased significantly (p<0.01) us- Benzydamine
ing the Student’s t test. This indicates the in vivo biological effect of
The search strategy described identified four studies that were
the plasma oestrogens. The oestrodiol levels increased significantly
potentially relevant. Two were in English and two were in Russian
from the baseline values (p<0.01). For the control group exactly
text requiring translation.
the same differences were seen and there were no significant differ-
Bentivoglio 1981 contains two separate relevant studies, one which
ences when comparing the mean differences between groups. Side
is a double blind controlled trial level IC, (details of allocation
effects were not noted and there was no QOL assessment. Hence
concealment not clearly stated) and the other is an uncontrolled
it appears that the irradiated cervix absorbs oestrogenic vaginal
prospective series, level IIC.
cream comparably to non-irradiated controls, however if systemic
Volteranni 1987 is also a double blind randomized controlled trial
oestrogen is contraindicated this route does not provide safety.
(details of allocation concealment not clearly stated) level IC.
Poma 1980, level IIIC.
Kanaev 1998 is a retrospective case series as is Chulkova 1997 ,
Post irradiation vaginal occlusion: non-operative management. See
both level IIIC.
previous section.
All these studies used benzydamine as an intervention in the treat-
Summary of research evidence
ment of acute radiation vaginal mucositis.
Level IIA, Pitkin 1965, topical oestrogens were used in acute and
Bentivoglio 1981, level IC and level IIIC
late toxicity. The epithelial response to topical oestrogens was as-
Use of topical benzydamine in gynaecology
This reference contains two studies, one a controlled clinical trial Benzydamine and the dosage was halved due to irritation. There
and the other a case series. was no quality of life assessment.
Volteranni 1987, level IC
Topical Benzydamine in the treatment of vaginal radiomucositis
A. Controlled clinical trial This is a double blind randomized clinical trial although there
A double blind randomized clinical trial was conducted on 30 pa- are no details of the methods of the allocation concealment or
tients, who had recently completed brachytherapy with or without blinding but reference to the assessors being blinded. Although
external beam radiotherapy for carcinoma of the cervix or uterus not stated the implication is that both patients and clinicians were
and developed acute vaginitis. The method of randomization was blinded. Thirty-two patients were treated, 16 with benzydamine
not stated and nor was the blinding of the patients or clinicians. All and 16 with placebo. All were women who were had recently re-
the cases had developed acute vaginal symptoms during the course ceived brachytherapy for the treatment of gynaecological malig-
of their radiation therapy. The symptoms and signs of pain, pru- nancy and had already developed acute vaginal mucositis as a result
ritis, tension, burning sensation, vaginal tenderness and oedema of the preceding external beam radiotherapy and/or brachyther-
were rated on a three point scale (0=absent and 2=severe) pre and apy. The treatment was with preparations of either benzydamine
post treatment as was the clinical impression which was graded or placebo prepared by the pharmacy and coded with instruc-
as excellent, good, fair, slight and nil. There were three equally tions to use twice daily for 14 days as a vaginal douche. The base-
divided groups of 10, treated with 0.1% benzydamine vaginal line symptoms were assessed by a mean score of the subjective as-
douche, 0.1% benzydamine alone (i.e. no preservative) and with sessment of the presenting symptoms and also the mean score of
placebo. Douching with the products under study was carried out the objective assessment from the colposcopic appearance pre and
twice daily for 15 days beginning 24 hours after completion of post intervention. Baseline characteristics and scores were higher
radiotherapy. The response was scored at days five and fifteen. Af- in the benzydamine group as twice as many cases were receiving
ter 15 days of treatment a significant reduction in the total score brachytherapy after external beam radiotherapy. The response was
occurred in all three groups. But the mean decrease in the total assessed on the changes in the subjective and objective scores in
score with the placebo (38.8%) was lower than with either benzy- both groups.
damine plus preservative (87%) or benzydamine alone (90.7%). The benzydamine group had a statistically significant fall in the
The covariance analysis showed that there was no statistically sig- total score by 25.5% (p<0.05) and the placebo group had a sta-
nificant difference between the two preparations of benzydamine tistically significant rise in the score by 72% (p<0.001) (both Stu-
but both were significantly superior to placebo. At the end of the dent’s t test). The clinical opinion was good or excellent in nine
15th day of treatment, excellent or good overall improvement oc- out of 16 of the treatment group, and 15 out of 16 of the placebo
curred in 17 out of 20 of the treatment group and in four out of group did not derive any therapeutic benefit. This was determined
10 in the placebo group. Side effects were noted in three of the on colposcopic appearance by submission to three independent
cases treated with benzydamine and the dosage was halved due to assessors who were blinded to the treatment. Side effects were not
local irritation. There was no quality of life assessment. noted and there was no quality of life assessment.
Kanaev 1998, level IIIC
The use of Tantum Rosa in the prevention of the treatment of
B. Prospective case series for post radiotherapy acute vaginitis radiation-induced vaginitis and proctitis
This was a retrospective study. Twenty patients with acute radia-
An uncontrolled trial was carried out on 30 cases following
tion induced vaginitis (RT for carcinoma of the vagina in six cases
brachytherapy for carcinoma of the cervix or uterine body. Vagi-
and carcinoma of the uterus in fourteen cases) were characterised
nal douches of 0.1% benzydamine, were used twice daily for 15
by hyperaemia of the mucous membrane, monolayer and necrotic
days beginning 24 hours after completion of radiation therapy.
epithelium. Eighteen sustained their injuries within the first six
The severity of the symptoms was assessed at the start and at days
months of receiving radiotherapy and two after this period. The
five and fifteen of treatment using the score previously described.
intervention was Tantum Rosa powder 9.4g diluted in 500 ml
The clinical overall impression was also judged at the end of treat-
of water. A tampon was soaked in this solution and applied for
ment. Benzydamine vaginal douches produced a highly significant
15 to 30 minutes twice daily for two weeks. Treatment response
(p<0.001) average overall improvement i.e. reduction of score and
was assessed on the degree of resolution of objective change in
improvement in all symptoms and signs after both five and fifteen
the mucosa after treatment. In 15 out of 20 cases the radiation
days of treatment. After 15 days the mean total score had decreased
induced injury in the vagina disappeared a week after initiation of
by 84.8% for symptoms and signs. There was without exception
the treatment . A check one to two months after completion of
an improvement in each symptom and sign after both five and
treatment with Tantum Rosa showed that in all the cases that had
fifteen days of treatment. Overall improvement occurred in all 30
been observed to improve and the mucous membrane had a nor-
patients treated with the trial period-26 good or excellent and four
mal appearance. In cases where this preparation was not used, per-
were slight. Side effects were noted in four of the cases treated with
sistent mucositis was noted with progressive stenosis of the vagina. one developed a rectovaginal fistula after five treatments requiring
It is not clear from the results whether the responders were in the a colostomy and HBO was not then reinstated. The duration of
acute or late group. follow up is not stated so the duration of the response is not clear.
There is no statistical analysis, no quality of life assessment and The only side effect noted was of one case of a tympanic membrane
although side effects were looked for there were none. Although rupture which healed without problems. There was no statistical
there were two cases of late radiation vaginal mucositis this report analysis and no quality of life data.
essentially refers to treatment effects on acute symptoms. Roberts 1991, level IIIC, USA
Chulkova 1997, level IIIC Management of radionecrosis of the vulva and distal vagina.
Clinical experience with the use of Tantum Rosa in cancer patients This is a retrospective series of 12 cases although only one case
This is a retrospective series. Thirty cases received radiotherapy received hyperbaric oxygen therapy. All 12 had received radical
for gynaecological malignancy and subsequently presented with radiotherapy for gynaecological malignancies (seven were vulva,
radiation vaginal mucositis during the course of RT or shortly af- three were vaginal and two were endometrial), a mean period of
ter completing treatment. Baseline assessment was made by de- 16.2 months previously (range three to 69 months). Seven had
termination of bacterial species, pH in the vagina, measurement chronic medical conditions that may have compromised the blood
of the fraction of leucocytes in the vaginal mucosa, and this was supply in the irradiated area. Seven presented with areas of necrosis
assessed post treatment to determine the response. The interven- in the vulva and five in the vagina. All had failed to respond to
tion was Tantum Rosa vaginal douche twice daily for 10 to 14 conservative measures with surgical debridement, antibiotics and
days. Twenty-four of the 30 cases responded to treatment with a intensive local applications and only one with a particularly large
substantial drop in the leucocyte fraction of the vaginal mucosa. necrotic ulcer was treated with HBO.
Side effects were not reported. There was no statistical analysis and The details of HBO are not given. This therapy failed to produce
no quality of life data. a response and did not produce even partial healing. There are
no reports of side effects or quality of life in the case treated with
HBO and surgery was eventually performed.
Hyperbaric oxygen therapy (HBO) Williams 1992, level IIC, USA
The treatment of pelvic soft tissue radiation necrosis with hyper-
Using the search strategy stated there were four relevant studies
baric oxygen.
relating to the use of hyperbaric oxygen therapy for perineal and
This is a prospective observational study of 14 cases with ra-
vaginal radiation injuries. All were in English and all were un-
dionecrosis of the vagina treated with hyperbaric oxygen therapy.
controlled case series, with one prospective observational study
All were female and had received radiotherapy for cervical can-
(Williams 1992) and the remainder being retrospective. All these
cer in nine cases, endometrial cancer in one case, vaginal cancer
references address the use of HBO therapy for late radiation in-
in three cases and colonic cancer in one case. The interval from
juries.
radiotherapy is not stated. The inclusion criteria allowed women
Glassburn 1997, level IIIC
who were free of active malignancy and had failure of healing for
Treatment of necrotic wounds with hyperbaric oxygen
a minimum period of three months despite conservative therapy
This is a retrospective series of 12 cases with established ra-
with antiseptic irrigation, debridement and topical agents.
dionecrotic (tissue death caused by radiation) wounds of the per-
Eleven had soft tissue necrosis of the vaginal vault and two had
ineum. All 12 were female and had received pelvic radiotherapy a
vaginal necrosis with an associated rectovaginal fistula. The final
minimum of one year previously, for carcinoma of the cervix in 10
case had massive necrosis of the abdominal wall, sacrum and vagina
cases, urethral cancer and Hodgkin’s Disease in the final case. The
with rectovaginal and vesicovaginal fistulae.
radiation injuries were in the vaginal vault in eight cases, in the
The intervention used was a monoplace hyperbaric chamber com-
perineum in two cases and vesicovaginal fistula in the remaining
pressed to two atmospheres of pressure for 90 to 120 minute ses-
two. In all cases, malignant disease had been excluded by investi-
sions once or twice a day with 44 treatments on average (range 18
gations and biopsy and all had failed to respond to conservative
to 143). The response to treatment was assessed on the degree of
measures such as debridement, cleansing and antibiotics.
resolution of the radionecrotic area. All of the 11 with just vault
The treatment used was HBO in a monoplace chamber at two and
necrosis had shown marked improvement or resolution within
a half to three atmospheres of pressure of 100% oxygen for 40 to
eight weeks of completing therapy (one of the 11 developed re-
60 minutes a day, four to five times a week. The average number
current tumour which healed well after exenteration and has re-
of treatments was 23 (range five to 53). The response to treatment
mained well at nine months). Both the cases with fistulae under-
was assessed by the resolution of the wounds after treatment with
went defunctioning colostomies followed by hyperbaric oxygen
HBO.
therapy with resolution of necrosis-without relapse at three years.
Of the 12 with vault or perineal necrosis, eight showed marked
Treatment failure occurred in the case with massive necrosis who
or complete healing of their wounds. Three developed recurrent
progressed and died in spite of active therapy.
tumour having been clear of recurrence at the start of HBO and
A ruptured tympanum occurred in one case healing spontaneously. Vaginal reconstruction
No statistical analysis quality of life data was available.
Using the search strategy stated 10 reports were identified which
Feldmeier 1996, level IIIC
were potentially relevant. All were retrospective case series and
Hyperbaric oxygen an adjunctive treatment for delayed radiation
uncontrolled, but addressed the issue of surgical reconstruction of
injuries of the abdomen and pelvis
the perineum or vagina following established radiation damage.
This is a retrospective series of 12 women who had sustained ra-
These studies are summarised in Table 3.
dionecrotic injuries to the perineum (seven) and vagina (five). The
median time of interval of referral for hyperbaric oxygen therapy
Berek 1983, level IIIC
after completion of radiation therapy was 18 months. All had re-
Delayed vaginal reconstruction in the fibrotic pelvis following ra-
ceived pelvic radiotherapy for the following malignancies: carci-
diation or previous reconstruction
noma of the vulva in two cases, cervix in five, anus in two, rec-
This is a retrospective series of 12 cases. All developed a fibrotic
tosigmoid junction in one and bladder in one. The dimensions
pelvis with distortion of the vagina as a result of pelvic radiotherapy
of the ulcer or baseline appearance were available in all cases. All
a minimum of four years earlier. The primary tumours irradiated
had failed to respond to conservative therapies. All the cases in this
were cervical cancer in seven cases, vaginal cancer in four cases and
series were graded according to the RTOG grading system and all
endometrial cancer in one case. Nine of the 12 had undergone
were grade IV.
primary surgery before radiotherapy. The indication for surgery
The intervention used was hyperbaric oxygen therapy 90 minute
in all cases was vaginal stenosis.
treatments, six days/week, at 2.4 atmospheres of pressure in a mul-
Split thickness skin grafts were used in all cases during the process
tiplace hyperbaric chamber with a minimum course of 20 treat-
of vaginal reconstruction, placed over a stent and inserted into
ments and a median number of 46 in those that healed. The re-
the newly created vaginal pocket after excision of the scar tissue.
sponse to treatment was assessed on the degree of resolution of
The response to treatment was assessed on the subjective degree
the radionecrotic area. In the perineal sites three healed (one with
of intercourse after treatment. The response was classed as: Good,
surgery and the other two without surgery) and four failed. Of
if intercourse was with suitable penetration and was pain-free; sat-
these four, one died of a CVA and the other three failed to heal be-
isfactory if the patient reported that she could have intercourse
cause of residual tumour). All five of the vaginal lesions responded
without pain but the calibre of the vagina was smaller than previ-
well with resolution of the ulcerated areas. Therefore the response
ously; and poor if it was not at all satisfactory. All of the procedures
rate was eight out of 12. The duration of the response is not stated.
succeeded and all achieved at least a satisfactory result with a min-
There was no statistical analysis and no quality of life data. Side
imum graft take of 80%. Vaginal function was good in 11 cases
effects were not noted.
and satisfactory in one case and this response was maintained for
The four case series all address the issue of hyperbaric oxygen
a minimum of one year. One of the good responders developed
therapy for established late toxicity that had failed to respond to
a tumour recurrence with fistulation within the next six months
all other conservative measures. Although benefit is suggested all
and remained sexually active dying within a year. Three others re-
these reports suffer from a lack of a control group and selection
lapsed and died within one to nine years of treatment. There was
and publication bias. There are occasional reports of side effects
no statistical analysis, no report of side effects and no quality of
related to this intervention and in the total 39 cases there were two
life assessment.
reports of aural barotrauma which were self-limiting and healed
Roberts 1991, level IIIC
spontaneously. Although deaths occurred in these series none were
Management of radionecrosis of the vulva and distal vagina
treatment related but rather a consequence of the progressive dis-
This is a retrospective series of twelve cases. All the women had
ease process.
received radical radiotherapy for the following gynaecological ma-
Hyperbaric oxygen therapy in the treatment of radiation related
lignancies: seven were vulva, three were vaginal and two were en-
necrosis in the pelvis has a sound theoretical basis and the pre-
dometrial, a mean period of 16.2 months ago (range three to 69
liminary results in these reports are largely convincing. However
months). Seven had chronic medical conditions that may have
these results are essentially based on weak evidence from small
compromised the blood supply in the irradiated area. Seven pre-
retrospective series hampered by selection and publication bias.
sented with areas of necrosis in the vulva and five in the vagina.
It is unlikely that randomized studies will ever be conducted in
All had failed to respond to conservative measures with surgical
this setting because of the rarity of the condition and the few fa-
debridement, antibiotics and intensive local applications and only
cilities offering this intervention. However what is feasible is that
one with a particularly large necrotic ulcer was treated with HBO.
those cases that are treated in this setting are entered into a central
Conservative therapy failed to respond and did not produce even
database with formal pre and post treatment standardised assess-
partial healing in any of the cases.
ments that can be analysed against matched concurrent controls
Ten were treated with radical excision of the radionecrotic site
to assess the true benefit of this potentially valuable therapy.
and two were not fit for surgery. Six out of 10 underwent radical
excision of the radionecrotic site without removal of the pelvic
viscera (one requiring a colostomy because of the proximity of the split thickness skin grafts and one received an amnion graft.
ulcer to the anus and the anal sphincter-this was later closed). Four Surgery involved the following steps:
out of 10 required pelvic exenteration. Tissue coverage was with i. Resection of the scarred vagina and creation of an adequate space
flaps in seven cases and primary closure in three. Three out of the between the bladder and rectum.
10 had recurrent tumour in their specimens although this was not ii. Harvesting of a split thickness skin graft from the inner thigh
clinically expected. or buttocks, or collection of an amnion graft.
Eight out of the 10 patients healed but of these two developed iii. Fashioning the graft into a hollow cylinder over a mould
flap necrosis with introital necrosis (one was surgically corrected). iv. Placement of the graft and mould into the newly created pelvic
Three out of eight were sexually active. space with the cut surface facing outwards.
Seven out of 10 treated surgically are alive without disease, two died Postoperatively the mould was removed on day five and the patient
of disease progression and one died without evidence of disease. was issued with a perspex oburator of adequate size and instructed
Of the two not fit enough for surgery one died from a recurrence to lubricate it with dienoestrol cream and insert it into the neo-
within the ulcer and the other patient is alive but the radiation vagina three times per day for 10 to 15 minutes continuing for six
ulcer is unchanged. months.
The mean time from radionecrosis to surgery was eight and a half The response to treatment was assessed in terms of both vaginal
months (range two to 20) due to the wait for conservative therapy calibre, length and the ability to have satisfactory intercourse. The
to have an effect. Recurrent problems have not occurred in any mean follow up period was four years and four out of the six
patient who healed after surgery. There are no reports of side effects achieved 90 % graft take normal patency with good sexual func-
or quality of life data tion. The remaining two had unsuccessful grafts and restenosed
Morley 1991, level IIIC with failure to resume sexual activity. At completion of follow up
Full thickness graft vaginoplasty for the treatment of the stenotic four were alive and two were dead, (one with disease and the other
or fore-shortened vagina. without), both at four years after reconstruction. No side effects
This is a retrospective series, in which is included an isolated case were noted, there was no quality of life assessment and no statis-
of radiation induced vaginal stenosis that underwent surgical cor- tical analysis.
rection. The case in question underwent radiotherapy for Ewing’s Woods 1992, level IIIC
sarcoma although the interval from completion of radiotherapy is Experience with vaginal reconstruction utilizing the modified Sin-
not stated. gapore flap.
The baseline assessment of vaginal stenosis and apical foreshorten- This is a retrospective series of seven women who had undergone
ing was evaluated at surgery and then this area was incised to create pelvic radiotherapy and surgery leaving them with perineal defects
an adequate space for the full thickness skin graft taken from the requiring vaginal reconstruction. All seven had received preopera-
flank overlying the iliac crest. The graft was then sutured in place tive and intraoperative RT and at the time of pelvic exenteration a
and packed so that the graft was firmly applied to the recipient posterior perineal defect was left which was repaired with vaginal
site. The packing was then removed on the sixth postoperative day reconstruction synchronously.
and replaced by an obturator used continuously initially and then The technique used was with a modified Singapore flap which
12 hours a day for the next three to four months. Patients could are raised fasciocutaneous flaps, bilaterally in the groin crease just
participate in intercourse by the sixth week. lateral to the labia and include the deep fascia. The base of the
The response was assessed by the take of the graft, restoration of flaps are undermined at the subcutaneous level and tunneled under
vaginal capacity and the resumption of sexual function. The case in the labia. To avoid any possible compromise of the flaps the labia
question had at least 80% take, normal vaginal depth and calibre are divided posteriorly and the flaps inset with the apex of the
and full functional satisfaction. No intraoperative or postoperative neovagina sutured to the sacrum or the adjacent structures to avoid
complications were reported and the response was maintained for prolapse.
the median follow up of 25 months. While there were numerous complications postoperatively none
No statistics or quality of life data was available. were related to flap failure. Despite urine leakage, fistulae, abscess
Hyde 1999, level IIIC formation and dehiscence there was no flap necrosis at any time.
Vaginal reconstruction in the fibrotic pelvis All surgical complications were related to the extent of the surgery
This is a retrospective series of six women who developed pelvic compounded by poor healing in an irradiated field. Only two of
fibrosis as a result of radiotherapy with additional surgery and this series have resumed intercourse as the rest were undergoing
who subsequently underwent vaginal reconstruction over a 10 year adjuvant therapy or were generally unwell postoperatively. Me-
period. All had severe vaginal stenosis and none were able to have chanical problems were not the disabling factor. There was no
vaginal intercourse. In all six, the proximal half of the vagina was quality of life assessment or statistical data.
completely obliterated and the length of the vagina ranged for two Skene 1990, level IIIC
to four cm with a calibre of one to two cm. Five of the cases had Perineal, vulval and vaginoperineal reconstruction using the rectus
abdominis myocutaneous flap. was the desire for continuing sexual intercourse post exenteration.
This is a retrospective case series of five people who had all devel- The technique used was the pudendal thigh fasciocutaneous flap.
oped perineal radionecrosis following radiotherapy for carcinoma The flaps were raised in the thigh creases just lateral to the hair
of the anus. One of these had also developed a recurrence in the bearing area of the labia majora and included skin, subcutaneous
anus and rectovaginal septum. In all five cases the rectus abdomi- tissues, deep fascia of the thigh and adductor muscles. Bilateral
nus myocutaneous flap was used to reconstruct the vagina and per- flaps were used in all cases. The flaps were technically easy to per-
ineum. All had previously undergone a defunctioning colostomy form in all cases. The response was assessed by patient interview
for persistent sphincter damage after radiation. All underwent to- and clinical assessment 19 months after surgery.
tal pelvic exenteration with urinary diversion and vaginal recon- Partial apical flap necrosis occurred in four patients. One patient
struction. A loop of colon or ileum (pedicled) was used for the developed necrosis of both flaps followed by a enterovaginal fistula.
vagina and the flap was used to recreate vulva and perineum. The One case who did not have flap necrosis developed a rectovaginal
donor site for the flap closed with primary closure in all cases as fistula at the site of rectal anastamosis. The functional results were
did the perineal wounds. All cases with urinary diversions were disappointing. No patient has had successful coitus. Other long
continent and practised self intermittent catheterisation success- term sequelae involve vulvar pain in two cases, chronic vaginal
fully. One patient had a perineal recurrence which was successfully discharge two, hair growth in four cases and protrusion of the flap
excised at 16 months with good healing maintained at six months. in two cases.
Sexual function was not assessed and there was no quality of life Achauer 1983, level IIIC
or statistical data. No side effects were reported. Gluteal thigh flap in the reconstruction of complex wounds
Germann 1998, level IIIC This is a retrospective case series of reconstructive surgery in nine
The partial gluteus maximus musculocutaneous turnover flap. An cases, three of whom had sustained radiation perineal wounds.
alternative concept for simultaneous reconstruction of combined The three were all females who had sustained radiation ulcers of
defects of the posterior perineum/sacrum and the posterior vaginal the perineum following radiotherapy to the vagina and vulva a
wall. minimum of six months earlier. Two had developed non-healing
This is a retrospective series including an isolated case report of perineal ulcerations and the third had extensive radiation necrosis
reconstruction following surgery and radiotherapy. The case was of the vulvar region with a large perineal wound. Conservative
a female who had undergone AP resection for a rectal carcinoma therapy had failed in all cases.
with pre and postoperative radiation followed by postoperative The intervention used was a gluteal thigh flap transferred as an is-
chemotherapy. Wound infections complicated the postoperative land although the most severe case required bilateral flaps. The re-
course resulting in a 10x10cm sacral perineal defect. The first flap sponse to treatment was assessed by the degree of healing, postop-
failed and then the same procedure was attempted with a myocu- erative complications and whether the vagina was functioning. In
taneous turnover flap as a modification of the gluteus maximus one of the three cases the postoperative period was uncomplicated
flap to address the particular reconstructive problems. The flaps with primary healing and a functioning vagina (the most severe
neurovascular innervation was left in tact with the inferior gluteal perineal wound). In one of the cases the wound margin separated
artery and the posterior cutaneous femoral nerve. The skin islands requiring revision and then healed. The third case required evacu-
were there to fill the perineal defect or for vaginal reconstruction. ation of a haematoma postoperatively so that healing was delayed
This flap enabled the successful reconstruction of the posterior by three weeks. Flap necrosis was not stated in any of the cases.
vaginal wall and appropriate soft tissue coverage and the donor site There is no long term follow up details in this series and although
healed with primary closure. Postoperative healing was unevent- the two with postoperative complications healed the state of the
ful. The neovagina showed no shortening or healing and sexual vagina is not stated. There was no quality of life or statistical data
intercourse was resumed by the patient. There was no quality of and no side effects were reported.
life or statistical data and no side effects were reported. Jurado 2000, level IIIC
Gleeson 1994, level IIIC Primary vaginal and pelvic floor reconstruction at the time of pelvic
Pudendal thigh fasciocutaneous flaps for vaginal reconstruction in exenteration. A study of morbidity.
gynecologic oncology. This was a retrospective series of 45 cases of pelvic exenteration
This is a retrospective series of vaginal reconstructive surgery in for gynaecologic malignancy. Sixteen of these cases had previously
seven cases who had all undergone radiotherapy for pelvic ma- received external beam radiotherapy and subsequently underwent
lignancy and then required pelvic exenteration. The reconstruc- vaginal reconstruction at the time of pelvic exenteration using the
tion was performed at the time of exenteration. The malignancies placement of a myocutaneous flap with left rectus abdominis in
treated were as follows: three cervix, two endometria, one vagina 11 cases, the gracilis muscle in three cases and the Singapore fas-
and one bladder cancer. The duration from radiotherapy or the ciocutaneous flap in two cases. Although 29 had no reconstruc-
outcome of treatment and the reason for subsequent surgery are tive surgery 15 of them received intraoperative radiotherapy but
not stated. The indication for vaginal reconstruction in all cases details of this group are not stated in this type of classification and
have been excluded. degree of bleeding, intercourse with dyspareunia, vaginal calibre
The graft attached successfully in 14 out of 16 cases with a partial and vaginal epithelium in both groups which were comparable.
dehiscence in two cases. Three had secondary infections and partial 3.Bentivoglio 1981 reports a double-blinded randomized clini-
necrosis and five were noted to have a partial stenosis although cal trial of patients who had recently completed radiotherapy for
this was significantly associated with the use of the gracilis flap carcinoma of the cervix or uterus and who had developed acute
(p=0.015). Among our 16 cases only four responded affirmatively vaginitis. The method of randomization is not stated and nor was
about having normal intercourse. the blinding of the patients or clinicians. The effect of topical ben-
With this small series and particularly with so few cases in the zydamine and a placebo was compared.
Singapore and gracilis groups it is impossible to draw any con- 4. Volteranni 1987 reports a double-blinded randomized clinical
clusions about which flap has the best risk-to-benefit ratio. The trial although there are no details of the methods of the alloca-
fasciocutaneous Singapore flap may be a good choice when the tion concealment or blinding but reference to the assessors being
rectus abdominis flap would be too large or when there is insuf- blinded. Although not stated the implication is that both patients
ficient space for passage through the levator hiatus or under the and clinicians were blinded. The study compares the effect of top-
pubic arch, however this provides much less bulk for filling the ical benzydamine with a placebo in two comparable groups with
pelvis. The rectus abdominis myocutaneous flap seems to be the established acute vaginitis.
preferable option because of its advantages over the gracilis muscle:
reliability, size accessibility, less likelihood of prolapse, requiring
only a single flap and closure of the donor site as a continuation Effects of interventions
of the laparotomy incision.
Decruze 1999
The first eight studies demonstrate differing degrees of response
Although this data is not randomized the odds ratio (OR) of de-
in terms of functional capacity, from the effect of surgical recon-
veloping vaginal stenosis following use of the stent was 0.1 (95%
struction but the duration of this response or follow up is not
CI 0.03 to 0.033) and relying on sexual intercourse alone the odds
consistently reported. Selection and publication bias are factors
ratio of developing vaginal stenosis was 10.33 (95% CI 3.00 to
which will affect the interpretation of these results. Flap necrosis,
35.63). The response was maintained for the follow up period of
reported in seven out of 58 cases is a noted side effect although
one year.
there were no reports of surgical mortality. Of note is the fact that
the quality of life assessment was not conducted in any of these se-
Pitkin 1971
ries which, given the nature of the outcome would have been very
The useable data are represented in the MetaView program. It
useful in a full evaluation of the clinical result. The 10 retrospective
is not feasible to assume the reciprocal numbers for abnormal
reports are essentially small series providing anecdotal evidence of
calibre and abnormal epithelium as these would have been stated.
the outcomes with split thickness skin grafts post radiation. In
Although we have written to the authors we have not had a reply
the absence of further controlled series no further comment can
presumably related to the fact this trial was published in 1971. The
be made from these results except that subsequent reconstructive
OR for the improvement in dyspareunia using topical oestrogens
techniques should be assessed with objective comparisons using
compared to the placebo is 3.81 (95% CI 1.19 to 12.16) favouring
matched controls and parallel quality of life assessments which
the use of vaginal oestrogen cream.
would be critical in this situation. Therefore none of these studies
Volteranni 1987
were included in the statistical analysis of the systematic review.
This data is represented in the MetaView program in the compar-
isons section and the odds ratio for the resolution of acute radia-
tion vaginal mucositis with the use of benzydamine therapy versus
placebo is 19.29 (95% CI 2.03 to 183.42) favouring the use of
Risk of bias in included studies benzydamine.
Of the previously listed reports four studies were suitable to be Bentivoglio 1981
included for statistical analysis : Decruze 1999; Pitkin 1971; The data for the RCT component of this article is represented in
Bentivoglio 1981 and Volteranni 1987. the MetaView program in the dichotomised form for the response
1. Decruze 1999 is a retrospective series with a concurrent histor- of scores for the clinical symptoms and signs, although individual
ical control group, although there was no actual randomization scores were not given. The OR for the resolution of acute radia-
the two groups were comparable. It examines the prevention of tion vaginal mucositis after the use of benzydamine therapy versus
vaginal stenosis using either a stent or sexual intercourse placebo is 8.5 (95% CI 1.46 to 49.54).
2. Pitkin 1971 reports a controlled double-blinded study although The two level IC studies Bentivoglio 1981 and Volteranni 1987
the method of randomization is not stated. The study compares both compared the resolution of acute vaginal mucositis following
the effect of a vaginal oestrogen based cream with a placebo on the treatment with benzydamine with the effect of a placebo. The
effect of established acute toxicity. The response was assessed by the primary outcome measures were the same in both studies and so
the results were combined with an OR of 12.31 (95% CI 3.13 to clarify the investigative process and support the final result. These
48.48) favouring the effects of benzydamine therapy. findings are a reflection of the quality of the data that is published
Overall baseline assessments were conducted on all cases other regarding interventions for this aspect of the management of ra-
than those included in the reports treated with vaginal reconstruc- diation-induced complications.
tion and hyperbaric oxygen therapy. Similarly in these two sec-
PPreventionof vaginal stenosis, using either graduated vaginal dila-
tions none of the cases had their responses objectively assessed al-
tors, stents or by advocating regular sexual intercourse, is standard
though this was performed using various scoring systems, grades
practice although uptake and implementation of these measures is
or histological parameters in the majority of reports in the other
variable. This recommendation is made regardless of sexual activ-
sections. The dilator section has one retrospective series with a
ity and principally to facilitate clinical assessment with a vaginal
concurrent control group examining the prevention of the devel-
examination. Therefore, having demonstrated in Decruze’s non-
opment of vaginal stenosis. Both the topical oestrogens section
randomized study, the clear benefits of using a vaginal stent, a
and the benzydamine have two quasi-randomized controlled stud-
RCT would be difficult to justify on ethical grounds. Hence the
ies in each section, addressing the treatment of acute vaginal mu-
evidence is sufficient to endorse the widespread recommendation
cositis. The odds ratios in each of these sections are demonstrated
for the use of vaginal dilators.
in the comparisons and data sections where the data can be used.
All demonstrate a benefit for the treatment being investigated al- The evidence for the use of topical oestrogen or benzydamine in
though different interventions cannot be directly compared. The this situation is less clear due to date, quality and size of studies.
two remaining sections on hyperbaric oxygen therapy and surgical In order to support their implementation these trials should be
reconstruction have only case series. repeated with larger numbers to confirm the benefit.
The strongest evidence is the level IC data in the topical oestro-
gens (Pitkin 1971) and benzydamine sections (Bentivoglio 1981; In a climate where the acute and late toxicity of radical treatments
Volteranni 1987) for the treatment of acute radiation vaginal is gaining more profile we should be in a position to offer both
changes. The use of vaginal dilators to prevent the development preventative and active treatments on the strength of high quality
of vaginal stenosis is supported by level IIC evidence. The value evidence. This will only occur if patients are rigorously entered
of hyperbaric oxygen therapy and surgical reconstruction is sup- into randomized controlled trials for the various treatment options
ported by the much weaker level IIIC evidence in the form of already discussed. This could be facilitated by the development
case series. Quality of life issues to determine the overall benefit of a central database of patients with toxicities used as a source
of these interventions were not reported in any of the studies. for recruitment into multicentre trials with standardised baseline
and outcome assessments so that results can be pooled and as-
similated for more effective clinical impact. Such a database, may
be particularly useful in the rarer interventions which are limited
by resources and facilities such as hyperbaric oxygen therapy and
DISCUSSION
reconstructive surgery. In these situations the effect of treatment
Although we have focused on interventions for the physical aspects should be assessed objectively and subjectively and compared with
of sexual dysfunction produced by pelvic radiotherapy they cannot matched controls with full outcome evaluations including quality
be considered in isolation but in the context of their psychological of life assessments.
impact and associated changes in endocrine function.
Acute toxicity from pelvic radiotherapy is a relatively common
manifestation whereas late toxicity is less frequently reported. The AUTHORS’ CONCLUSIONS
treatment options are limited and are often administered outside
the context of a trial with neither formal baseline grading of toxicity Implications for practice
of treatment nor appropriate assessment of response. In addition
The success of vaginal stents in the prevention of vaginal stenosis
the available studies have not included either the impact of the
following pelvic radiotherapy endorses the recommendations cur-
radiation related toxicity nor the effect that the treatments for this
rently being made by oncology departments, to maintain vaginal
complication have on the patient’s subjective assessment in the
patency by some form of vaginal dilatation and supports their re-
form of quality of life scores which is paramount to the complete
inforcement. Other reported interventions, in particular the use of
interpretation of the data.
benzydamine douches and vaginal oestrogens, may look promis-
Although there is level IC evidence (oestrogens and benzydamine) ing and appear to be effective in the prevention and treatment of
as stated previously, these studies are not recent, the allocation radiation complications affecting the vagina and vulva. However
concealment is unclear in the text, and overall there is a variable one or two small studies (even if well conducted) are statistically
level of assessment of the response, emphasising the need for more underpowered and provide insufficient evidence. The variable na-
contemporary studies to be conducted with improved designs to ture of this spectrum of acute and late radiation complications
requires large placebo controlled studies to establish whether par- patients should be referred to regional centres with an interest in
ticular treatments are effective before they can be recommended radiation-induced toxicity. In this way baseline assessments may
for general use in this setting. be standardised, perhaps using validated check-lists or question-
naires, therapeutic interventions may be randomized and outcome
data could be pooled to assess the response to treatment objec-
Implications for research tively. This approach would provide an evidence base of results
of different treatments to develop a standardised integrated care
Radiation complications in the pelvis affecting the physical aspects pathway for this difficult condition.
of sexual function in women are infrequently reported by patients
to the clinicians who deliver the pelvic radiotherapy, and a num-
ber of fundamental issues remain to be clarified. First, the true
incidence of these complications is not clear. Therefore, physi-
ACKNOWLEDGEMENTS
cians caring for patients who have undergone pelvic radiotherapy
need to be more aware that these patients may develop problem- Cullimore Fellowship
atic symptoms which may need detailed questioning to elicit and
Mrs Dimitrinka Nikolova for her assistance in translating papers
which may require specialist assessment to characterize in detail.
Secondly, there is an urgent need to define clearly the diagnostic Systematic Review Training Unit
criteria and a unified grading system by which these problems may
Institute of Child Health
be categorised. Without such a system, it is unlikely that mean-
ingful randomized studies can be designed for application in a Millman Street
multi-centre setting. To aid physicians and patients and to pro-
London WC1N 3EJ
mote research, we propose that cases should be enrolled into re-
gional or centralised registers of radiation toxicity or that all such UK
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Bentivoglio G, Diani F. Use of topical benzydamine in
gynaecology. Clinical and Experimental Obstetrics & Berek 1983 {published data only}
Gynecology 1981;8(3):103–10. Berek JS, Hacker NF, Lagasse LD, Smith ML. Delayed
vaginal reconstruction in the fibrotic pelvis following
Decruze 1999 {published data only} radiation or previous reconstruction. Obstetrics and
Decruze SB, Guthrie D, Mangani R. Prevention of vaginal gynecology 1983;61(6):743–8.
stenosis in patients following vaginal brachytherapy. Clinical
Oncology 1999;11:46–8. Borotsova 1996 {published data only}
Borovtsova TM, Krylov SV, Udovichenko VI. Makmiror
Pitkin 1971 {published data only} complex in the treatment of post radiation infectious
Pitkin RM, VanVoorhis LW. Post irradiation vaginitis. An vulvovaginitis in cancer patients. Voprosy onkologii 1996;42
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1971;99(2):417–21.
Cart.-Alcarese 1995 {published data only}
Volteranni 1987 {published data only} Cartwright-Alcarese F. Addressing sexual dysfunction
Volterrani F, Tana S, Trenti N. Topical Benzydamine in the following radiation therapy for a gynaecological malignancy.
treatment of vaginal radiomucositis. International Journal of Oncology nursing forum 1995;22(8):1227–32.
Tissue Reaction 1987;9(2):169–71. Chulkova 1997 {published data only}
Chulkova OV. Clinical experience with the use of Tantum
References to studies excluded from this review Rosa in cancer patients. Voprosy onkologii 1997;43(3):
339–40.
Achauer 1983 {published data only} Feldmeier 1996 {published data only}
Achauer BM, Turpin IM. Gluteal thigh flap in the Feldmeier JJ, Heimbach RD, Davolt DA, Court WS,
reconstruction of complex wounds. Archives of Surgery Stegmann BJ, Sheffield PJ. Hyperbaric oxygen as an
1983;118(1):18–22. adjunctive treatment for delayed radiation injuries of the
abdomen and pelvis. Undersea and Hyperbaric medicine Poma 1980 {published data only}
1996;23(4):205–13. Poma PA. Post irradiation vaginal occlusion: nonoperative
Germann 1998 {published data only} management. International Journal of Gynaecoloy and
Germann G, Cedidi C, Petracic A, Kallinowski F, Herrfarth Obstetrics 1980;18(2):90–2.
C. The partial gluteus maximus musculocutaneous turnover Rhomberg 1988 {published data only}
flap. An alternative concept for simultaneous reconstruction Rhomberg W, Eiter H. Radiation induced vaginal necrosis.
of combined defects of the posterior perineum/sacrum and Strahlentherapie und Onkologie 1988;164(9):527–30.
the posterior vaginal wall. British Journal of Plastic Surgery
Roberts 1991 {published data only}
1998;51(8):620–3.
Roberts WS, Hoffman MS, La Polla JP, Ruas E, Fiorica JV,
Glassburn 1997 {published data only} Cavanagh D. Management of radionecrosis of the vulva and
Glassburn JR, Brady LW. Treatment of necrotic wounds with distal vagina. American Journal of Obstetrics and Gynecology
hyperbaric oxygen. Proceedings of the 6th international 1991;164:1235–8.
congress of Hyperbaric medicine, Aberdeen University
Robinson 1999 {published data only}
Press. 1977:279–85.
Robinson JW, Faris PD, Scott CB. Psychoeducational group
Gleeson 1994 {published data only} increases vaginal dilation for younger women and reduces
Gleeson NC, Baile W, Roberts WS, Hoffman MS, Fiorica sexual fears for women of all ages with gynaecological
JV, Finan MA, Cavanagh D. Pudendal thigh fasciocutaneous carcinoma treated with radiotherapy. International journal
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Gynecologic Oncology 1994;54(3):269–74.
Schover 1987 {published data only}
Hendren 1994 {published data only} Schover LR, Evans RB, von Eschenbach AC. Sexual
Hendren WH, Atala A. Use of bowel for vaginal rehabilitation in a cancer centre: diagnosis and outcome in
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752–7. 445–61.
Hintz 1981 {published data only} Skene 1990 {published data only}
Hintz BL, Kagan AR, Gilbert HA, Rao AR, Chan Skene AI, Gault DT, Woodhouse CR, Breach NM, Thomas
P, Nussbaum H. Systemic absorption of conjugated JM. Perineal, vulval and vaginoperineal reconstruction using
oestrogenic cream by the irradiated vagina. Gynecologic the rectus abdominis myocutaneous flap. British Journal of
Oncology 1981;12(1):75–82. Surgery 1990;77:635–7.
Hyde 1999 {published data only} Williams 1992 {published data only}
Hyde SE, Hacker NF. Vaginal reconstruction in the fibrotic Williams JA, Clarke D, Dennis WA, Dennis EJ, Smith
pelvis. The Australian & New Zealand Journal of Obstetrics ST. The treatment of pelvic soft tissue radiation necrosis
& Gynaecology 1999;39(4):448–53. with hyperbaric oxygen. American Journal of Obstetrics and
Jurado 2000 {published data only} Gynecology 1992;167:412–6.
Jurado M, Bazan A, Elejabeitia J, Paloma V, Matrinez- Woods 1992 {published data only}
Monge R, Alcazar JL. Primary vaginal and pelvic floor Woods JE, Alter G, Meland B, Podratz K. Experience with
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Abitol 1974
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Abitol MM, Davenport JH. Sexual dysfunction after
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Moldovan VI. Effect of ethonium on the healing of Obstetrics and Gynaecology 1974;119(2):181–9.
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Bergmark 1999
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Bergmark K, Avall-Lundqvist E, Dickman PW,
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Morley GW, DeLancey JO. Full thickness graft vaginoplasty in women with a history of cervical cancer. The New
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Obstetrics and gynecology 1991;77(3):485–9.
Cull 1993
Pitkin 1965 {published data only} Cull A, Cowie VJ, Farquharson DIM, Livingstone
Pitkin RM, Bradbury JM. The effect of topical oestrogen JRB, Smart GE, Elton RA. Early stage cervical cancer:
on the irradiated vaginal epithelium. American Journal of psychosocial and sexual outcomes of treatment. British
Obstetrics and gynecology 1965:175–82. Journal of Cancer 1993;68:1216–20.
Fraunholz 1998
Fraunholz IB, Schopohl B, Bottcher HD. Management of
radiation injuries of the vagina and vulva. Strahlentherapie
and Onkologie 1998;174(Suppl III):90–2.
Grigsby 1995
Grigsby PW, Russell A, Bruner D, Eifel P, Koh WJ, Spanos
W, Stetz J, Stitt JA, Sullivan J. Late injury of cancer therapy
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1281–99.
∗
Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Bentivoglio 1981
Methods Double blind randomized controlled trial
Participants Thirty women having completed external beam RT and brachytherapy for carcinoma of
the uterus with established acute vaginitis
Interventions Comparison of three groups of 10 treated with:

0.1% benzydamine douche; 0.1% benzydamine alone (i.e. no preservative); or placebo.
All of the douches were administered twice daily for 15 days beginning 24 hours after the
last treatment of RT
Outcomes Improvement in the symptoms of acute vaginitis using a baseline and post-treatment as-
sessment with a three point score
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Decruze 1999
Methods Retrospective series with historical control group
Participants Seventy women receiving brachytherapy and external beam RT for gynaecological tumours
between 1991 and 1997
Interventions Comparison of sexual intercourse and the use of a vaginal stent to maintain vaginal patency
after completion of treatment
Outcomes The development of vaginal stenosis
Notes
Risk of bias
Allocation concealment (selection bias) Unclear risk D - Not used
Pitkin 1971
Participants Ninety-three cases all receiving RT for carcinoma of the cervix
Interventions Comparison of 0.01% dienestrol or placebo vaginal cream administered three times a week
with identical packaging.
(44 oestrogen cream and 49 placebo)
Outcomes The development of vaginal bleeding, dyspareunia, stenosis and assessment of vaginal
epithelium
Notes
Risk of bias
Volteranni 1987
Participants Thirty-two women with gynaecological cancers all having recently completed RT with the
development of acute vaginitis
Interventions Equal groups treated with benzydamine and placebo douches.
Outcomes The subjective improvement of vaginal symptoms using baseline and post-treatment scores
and objective assessment with colposcopy for both groups
Notes
Risk of bias
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Achauer 1983 Retrospective series of three cases with non-healing perineal wounds which had failed other treatments and
treated with a surgical flap
Adrien 1983 Description of the technique for the management of vaginal fistulae for patients with radiation damage but
no patient data
Berek 1983 Retrospective series of 12 cases with late radiation fibrosis of the pelvis and vagina treated with reconstructive
surgery
Borotsova 1996 Retrospective series describing the treatment of infective vulvovaginitis but not related to previous radiation
Cart.-Alcarese 1995 Review addressing sexual dysfunction following radiation therapy for gynaecological malignancy. No patient
data
Chulkova 1997 Retrospective series of 30 cases with acute vaginal symptoms following pelvic RT for gynaecological malignancy,
treated with benzydamine douche
Feldmeier 1996 Retrospective series of 12 cases with late radiation injuries to the perineum and vagina treated with hyperbaric
oxygen
Germann 1998 Case report of surgical reconstruction following late radiation necrosis in the perineum as a complication of
treatment for rectal cancer
Glassburn 1997 Retrospective series of 12 cases with radionecrotic wounds in the pelvis treated with hyperbaric oxygen
Gleeson 1994 Retrospective series of seven cases requiring reconstructive surgery following complications following pelvic
exenteration and postoperative radiotherapy
Hendren 1994 Retrospective series using bowel for vaginal reconstruction for congenital malformations and not related to
post radiation
Hintz 1981 Retrospective series of six cases treated with postoperative RT for carcinoma of the cervix, with postmenopausal
symptoms receiving a trial of oestrogen vaginal cream
Hyde 1999 Retrospective series of six cases who have developed severe vaginal stenosis following pelvic RT for gynaeco-
logical malignancy and were treated with surgical reconstruction of the vagina
Jurado 2000 Retrospective series of sixteen cases all treated with pelvic RT for gynaecological malignancy and pelvic exen-
teration for relapse. All subsequently underwent surgical reconstruction with a flap
Kanaev 1998 Retrospective series of 20 cases with late radiation vaginitis following pelvic RT for gynaecological malignancy.
All were treated with benzydamine/Tantum Rosa douches
Moldovan 1974 Retrospective series describing the effect of ethonium on the healing of radiation injuries to the skin and
mucous membrane but does not relate to vaginal or pelvic injuries
(Continued)
Morley 1991 Case report of radiation induced late vaginal stenosis treated with surgical reconstruction
Pitkin 1965 Prospective series with an active treatment group and placebo group comparing the effect of topical oestrogen
on the irradiated vaginal epithelium. Incomplete results reported so that the available data cannot be submitted
to further analysis
Poma 1980 Retrospective series of five cases with complete vaginal stenosis related to late radiation changes. All were treated
with a combination of vaginal oestrogen cream and digital pressure to the introitus
Rhomberg 1988 Retrospective series of three cases with late radiation vaginal necrosis, that describes the natural history without
intervention
Roberts 1991 Case report of one case of a large radionecrotic ulcer in the vulvovaginal region treated with hyperbaric oxygen
Robinson 1999 Review of the use of psycho educational groups to reduce sexual fears of women of all ages treated with RT
for gynaecological cancer. This mentions the use of dilators but there is no patient data
Schover 1987 Sexual rehabilitation in a cancer centre which mentions the use of dilators as a therapeutic option in counselling
sessions with self-help advice but no results
Skene 1990 Retrospective series of five cases with perineal radionecrosis following treatment for carcinoma of the anus
treated with surgical reconstruction
Williams 1992 Prospective observational study of 14 cases with radiation necrosis of the vault treated with hyperbaric oxygen
Woods 1992 Retrospective series of seven cases with pelvic defects following a combination of surgery and pelvic RT, treated
with vaginal reconstruction
DATA AND ANALYSES
Comparison 1. Resolution of acute vaginal mucositis
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Resolution of acute vaginal 2 62 Odds Ratio (M-H, Fixed, 95% CI) 12.31 [3.13, 48.48]
mucositis using BDZ and
placebo
Comparison 2. Prevention of vaginal stenosis
No. of No. of
1 Prevention of VS using 1 70 Odds Ratio (M-H, Fixed, 95% CI) 10.33 [3.00, 35.63]
intercourse or a vaginal stent
Comparison 3. Reduction of vaginal radiation symptoms that prevent intercourse
No. of No. of
1 Reduction of vaginal bleeding 1 93 Odds Ratio (M-H, Fixed, 95% CI) 4.77 [1.89, 12.02]
2 Improvement in dyspareunia 1 56 Odds Ratio (M-H, Fixed, 95% CI) 3.81 [1.19, 12.16]
3 Improved vaginal mucosa 1 9 Odds Ratio (M-H, Fixed, 95% CI) 1.0 [0.05, 18.91]
Analysis 1.1. Comparison 1 Resolution of acute vaginal mucositis, Outcome 1 Resolution of acute vaginal
mucositis using BDZ and placebo.
Review: Interventions for the physical aspects of sexual dysfunction in women following pelvic radiotherapy
Comparison: 1 Resolution of acute vaginal mucositis
Outcome: 1 Resolution of acute vaginal mucositis using BDZ and placebo
Study or subgroup Benzydamine Placebo Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bentivoglio 1981 17/20 4/10 64.6 % 8.50 [ 1.46, 49.54 ]
Volteranni 1987 9/16 1/16 35.4 % 19.29 [ 2.03, 183.41 ]
Total (95% CI) 36 26 100.0 % 12.31 [ 3.13, 48.48 ]

Total events: 26 (Benzydamine), 5 (Placebo)
Heterogeneity: Chi2 = 0.32, df = 1 (P = 0.57); I2 =0.0%
Test for overall effect: Z = 3.59 (P = 0.00033)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10

Favours placebo Favours BDZ
Analysis 2.1. Comparison 2 Prevention of vaginal stenosis, Outcome 1 Prevention of VS using intercourse
or a vaginal stent.
Comparison: 2 Prevention of vaginal stenosis
Outcome: 1 Prevention of VS using intercourse or a vaginal stent
Study or subgroup Stent Intercourse Odds Ratio Weight Odds Ratio

Decruze 1999 20/35 4/35 100.0 % 10.33 [ 3.00, 35.63 ]
Total (95% CI) 35 35 100.0 % 10.33 [ 3.00, 35.63 ]

Total events: 20 (Stent), 4 (Intercourse)
Heterogeneity: not applicable
0.1 0.2 0.5 1 2 5 10

Favours intercourse Favours stent
Analysis 3.1. Comparison 3 Reduction of vaginal radiation symptoms that prevent intercourse, Outcome 1
Reduction of vaginal bleeding.
Comparison: 3 Reduction of vaginal radiation symptoms that prevent intercourse
Outcome: 1 Reduction of vaginal bleeding
Study or subgroup Oestrogen Placebo Odds Ratio Weight Odds Ratio

Pitkin 1971 35/44 22/49 100.0 % 4.77 [ 1.89, 12.02 ]
Total (95% CI) 44 49 100.0 % 4.77 [ 1.89, 12.02 ]

Total events: 35 (Oestrogen), 22 (Placebo)
0.1 0.2 0.5 1 2 5 10

Favours placebo Favours oestrogen
Improvement in dyspareunia.
Outcome: 2 Improvement in dyspareunia

Pitkin 1971 20/26 14/30 100.0 % 3.81 [ 1.19, 12.16 ]
Total (95% CI) 26 30 100.0 % 3.81 [ 1.19, 12.16 ]

0.1 0.2 0.5 1 2 5 10

Improved vaginal mucosa.
Outcome: 3 Improved vaginal mucosa

Pitkin 1971 4/6 2/3 100.0 % 1.00 [ 0.05, 18.91 ]
Total (95% CI) 6 3 100.0 % 1.00 [ 0.05, 18.91 ]

0.1 0.2 0.5 1 2 5 10

ADDITIONAL TABLES
Table 1. Results of the electronic search strategies
Database source No. of records No. of new records No. eligible
MEDLINE 2057 2057 32
EMBASE 1132 0 0
Cancer CD 329 0 0
Central CCTR 24 0 0
SCI 218 0 0
CINAHL 415 0 0
Dissertation Abstracts 2 2 0
SIGLE 0 0 0
ISTP 0 0 0
Boston Spa 0 0 0
Table 1. Results of the electronic search strategies (Continued)
Inside Conferences 0 0 0
NRR 0 0 0
Table 2. Results of all searches
Type of searching Source No. eligible records
Electronic searches Major Databases 32
Grey Literature 0
Hand Searching Reference searching 0
Bibliographic databases 0
Personal contact 0
World wide web 0
Table 3. Summary of the potentially relevant studies in the vaginal reconstruction sectio
Authors Number in Technique Response rate function duration of response Side effects
study
Achauer 1982 3 Gluteal thigh 3/3 1 coitus not specified (NS) 2 postoperative com-
flap plications
Berek 1983 12 Split thickness 12/12 12 coitus 1 year none

skin graft
Roberts 1991 10 Exenteration and 8/10 3 coitus NS none

flap
Morley 1991 1 Full thickness 1/1 1 coitus 25 months none

skin graft
Hyde 1999 6 Split thickness 4/6 4 coitus 4 years none

skin graft
Skene 1990 5 Rectus ab- 5/5 NS 6 months

dominis myocu-
taneous flap
Table 3. Summary of the potentially relevant studies in the vaginal reconstruction sectio (Continued)
Germann 1998 1 Gluteus 1/1 1 coitus NS none

maximus flap
Woods 1992 7 Bilat fasciocuta- 2/7 2 coitus NS none

neous graft
Gleason 1991 7 Fasciocutaneous 0/7 0 coitus NS 4 flap necroses, 2 fis-

flap tula
Jurado 2000 11 Rectus abdo my- 10/11 2 coitus NS 3 partial necrosis

ocutaneous flap
3 Fasciocutaneous 2/3 1 coitus NS 3 partial stenosis

flap
2 Gracilis muscle 2/2 1 coitus NS none
APPENDICES
Appendix 1. MEDLINE search strategy

The Search strategy developed for searching MEDLINE, which was adapted for the other databases is as follows:
#1 exp Radiotherapy/
#2 Radiotherapy/ or radiotherapy.mp.
#3 “RADIAT$”.mp.
#4 exp Radiation injuries
#5 “rt”.fs
#6 “VAGINAL STENOSIS”.mp
#7 exp Vulvovaginitis
#8 “VULVOVAGINITIS”.mp
#9 exp Vaginal discharge
#10 “VAGINAL DISCHARGE”.mp
#11 exp Ulcer
#12 Vaginal ulcer$.mp. [mp=title, abstract, heading word, trade name, manufacturer name]
#13 Vulval itching.mp. [mp=title, abstract, heading word, trade name, manufacturer name]
#14 exp Vulvitis
#15 “VULVITIS”.mp
#16 “POSTCOITAL BLEEDING”.mp
#17 exp Dyspareunia
#18 “DYSPAREUNIA”.mp
#19 “ATROPHIC VAGINITIS”.mp.
#20 “VAGINAL BLEEDING”.mp
#21 vulv$.mp. [mp=title, abstract, heading word, trade name, manufacturer name]
#22 vagin$.mp. [mp=title, abstract, heading word, trade name, manufacturer name]
#23 #1 or #2 or #3 or #4 or #5
#24 #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22
#25 #23 and #24
WHAT’S NEW
Date Event Description
11 February 2015 Amended Contact details updated.
11 July 2012 Review declared as stable This review is no longer being updated. Substantial crossover with ’Vaginal dilator
therapy for women receiving pelvic radiotherapy’. Cochrane Database of Systematic
Reviews 2010, Issue 9. Art. No.: CD007291. DOI: 10.1002/14651858.CD007291.
pub2
HISTORY
Date Event Description
20 October 2008 Amended Converted to new review format.
7 September 2002 New citation required and conclusions have changed Substantive amendment
CONTRIBUTIONS OF AUTHORS
Arshi Denton carried out the review
Dr Maher was directly involved in the review, data extraction and analysis of the studies in this project.
DECLARATIONS OF INTEREST
None known
SOURCES OF SUPPORT
Internal sources
• Cullimore Fellowship, UK.
External sources
• No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)

Brachytherapy [adverse effects]; Dyspareunia [etiology; therapy]; Pelvic Neoplasms [∗ radiotherapy]; Radiation Injuries [∗ complications];
Randomized Controlled Trials as Topic; Sexual Dysfunction, Physiological [etiology; ∗ therapy]
MeSH check words

Female; Humans

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Cochrane Database of Systematic Reviews

Interventions for the physical aspects of sexual dysfunction in

Denton AS, Maher J

Denton AS, Maher J.

Interventions for the physical aspects of sexual dysfunction in

Arshi S Denton1 , Jane Maher2

Editorial group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group.

PLAIN LANGUAGE SUMMARY

BACKGROUND • postcoital bleeding (bleeding after sexual intercourse)

Attempts to prevent or limit the acute reaction Types of studies

Treatment of late complications Benzydamine

• Vaginal dilators This compound belongs to the group of anti-inflammatories

Vaginal reconstruction Electronic searches

Characteristics of included studies [ordered by study ID]

Methods Double blind randomized controlled trial

Interventions Comparison of three groups of 10 treated with:

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Methods Retrospective series with historical control group

Outcomes The development of vaginal stenosis

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Methods Double blind randomized controlled trial

Participants Ninety-three cases all receiving RT for carcinoma of the cervix

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Methods Double blind randomized controlled trial

Interventions Equal groups treated with benzydamine and placebo douches.

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Study Reason for exclusion

Comparison 1. Resolution of acute vaginal mucositis

Comparison 2. Prevention of vaginal stenosis

Comparison 3. Reduction of vaginal radiation symptoms that prevent intercourse

Comparison: 1 Resolution of acute vaginal mucositis

Outcome: 1 Resolution of acute vaginal mucositis using BDZ and placebo

Study or subgroup Benzydamine Placebo Odds Ratio Weight Odds Ratio

Volteranni 1987 9/16 1/16 35.4 % 19.29 [ 2.03, 183.41 ]

Total (95% CI) 36 26 100.0 % 12.31 [ 3.13, 48.48 ]

0.1 0.2 0.5 1 2 5 10

Comparison: 2 Prevention of vaginal stenosis

Outcome: 1 Prevention of VS using intercourse or a vaginal stent

Study or subgroup Stent Intercourse Odds Ratio Weight Odds Ratio

Total (95% CI) 35 35 100.0 % 10.33 [ 3.00, 35.63 ]

0.1 0.2 0.5 1 2 5 10

Comparison: 3 Reduction of vaginal radiation symptoms that prevent intercourse

Outcome: 1 Reduction of vaginal bleeding

Study or subgroup Oestrogen Placebo Odds Ratio Weight Odds Ratio

Total (95% CI) 44 49 100.0 % 4.77 [ 1.89, 12.02 ]

0.1 0.2 0.5 1 2 5 10

Comparison: 3 Reduction of vaginal radiation symptoms that prevent intercourse

Outcome: 2 Improvement in dyspareunia

Study or subgroup Oestrogen Placebo Odds Ratio Weight Odds Ratio

Total (95% CI) 26 30 100.0 % 3.81 [ 1.19, 12.16 ]

0.1 0.2 0.5 1 2 5 10

Comparison: 3 Reduction of vaginal radiation symptoms that prevent intercourse

Outcome: 3 Improved vaginal mucosa

Study or subgroup Oestrogen Placebo Odds Ratio Weight Odds Ratio

Total (95% CI) 6 3 100.0 % 1.00 [ 0.05, 18.91 ]

0.1 0.2 0.5 1 2 5 10

Database source No. of records No. of new records No. eligible

MEDLINE 2057 2057 32

Table 2. Results of all searches

Type of searching Source No. eligible records