International Journal of

Radiation Oncology
biology physics

www.redjournal.org

Clinical Investigation

Vaginal Dose Is Associated With Toxicity in

Image Guided Tandem Ring or Ovoid-Based
Brachytherapy
Matthew Susko, MS, Oana Craciunescu, PhD, Sheridan Meltsner, PhD,
Yun Yang, PhD, Beverly Steffey, MS, Jing Cai, PhD,
and Junzo Chino, MD
Department of Radiation Oncology, Duke Cancer Center, Durham, North Carolina

Received Sep 18, 2015, and in revised form Dec 11, 2015. Accepted for publication Dec 15, 2015.

Summary
This work demonstrates an
association between vaginal
dose and all grades of
vaginal toxicity in the treat-
ment of cervical and uterine
cancer using tandem ring or
ovoid brachytherapy. This
retrospective analysis is the
largest series to date to
demonstrate this effect in the
era of image-guided brachy-
therapy. These results merit
further confirmation; howev-
er, consideration of vaginal
dose in treatment planning
may be warranted.
Purpose: To calculate vaginal doses during image guided brachytherapy with volume-
based metrics and correlate with long-term vaginal toxicity.
Methods and Materials: In this institutional review boardeapproved study, institu-
tional databases were searched to identify women undergoing computed tomography
and/or magnetic resonanceeguided brachytherapy at the Duke Cancer Center from
2009 to 2015. All insertions were contoured to include the vagina as a 3-
dimensional structure. All contouring was performed on computed tomography or
magnetic resonance imaging and used a 0.4-cm fixed brush to outline the applicator
and/or packing, expanded to include any grossly visible vagina. The surface of the
cervix was specifically excluded from the contour. High-dose-rate (HDR) and low-
dose-rate (LDR) doses were converted to the equivalent dose in 2-Gy fractions using
an a/b of 3 for late effects. The parameters D0.1cc, D1cc, and D2cc were calculated
for all insertions and summed with prior external beam therapy. Late and subacute
toxicity to the vagina were determined by the Common Terminology Criteria for
Adverse Events version 4.0 and compared by the median and 4th quartile doses,
via the log-rank test. Univariate and multivariate hazard ratios were calculated via
Cox regression.
Results: A total of 258 insertions in 62 women who underwent definitive radiation
therapy including brachytherapy for cervical (nZ48) and uterine cancer (nZ14)
were identified. Twenty HDR tandem and ovoid, 32 HDR tandem and ring, and 10
LDR tandem and ovoid insertions were contoured. The median values (interquartile
ranges) for vaginal D0.1cc, D1cc, and D2cc were 157.9 (134.4-196.53) Gy, 112.6

Reprint requests to: Junzo Chino, MD, Department of Radiation Annual Meeting of the American Society for Radiation Oncology,
Oncology, Duke Cancer Center, DUMC 3085, Durham, NC 27710. Tel: September 22-25, 2013, Atlanta, GA.
(919) 668-7336; E-mail: junzo.chino@duke.edu Conflict of interest: none.
Portions previously presented at the American Brachytherapy Society
annual meeting, April 18-20, 2013, New Orleans, LA, and at the 55th

Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e7, 2016
0360-3016/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2015.12.360
2 Susko et al. International Journal of Radiation Oncology
Biology
Physics

(96.7-124.6) Gy, and 100.5 (86.8-108.4) Gy, respectively. At the 4th quartile cutoff
of 108 Gy for D2cc, the rate of late grade 1 toxicity at 2 years was 61.2% (95% con-
fidence interval [CI] 43.0%-79.4%) below 108 Gy and 83.9% (63.9%-100%) above
(PZ.018); grade 2 or greater toxicity was 36.2% (95% CI 15.8%-56.6%) below
108 Gy and 70.7% (95% CI 45.2%-96.2%) above (PZ.004); and grade 3 or worse
toxicity was 9.9% (95% CI 0.0%-23.6%) below 108 Gy and 30.0% (95% CI
4.7%-55.3%) above (PZ.025). This association was maintained on multivariate
analysis, independent of covariates such as applicator type, age, and dose rate.
Conclusions: Vaginal dose was associated with all grades of vaginal toxicity.
Confirmation at other sites using this methodology will be necessary to establish
reproducibility; however, the integration of routine calculation of vaginal dose
may be warranted. Ó 2016 Elsevier Inc. All rights reserved.

Introduction (T&R) implant brachytherapy. Both low-dose-rate (LDR)

The current standard of care for treatment of cervical and
inoperable uterine cancer involves definitive radiation ther-
apy with combination external beam and brachytherapy (1).
This treatment, however, is not without its inherent risks and
long-term sequelae (2, 3). For the vagina, these risks include
vaginal stenosis, dyspareunia, necrosis, and vesico/rec-
tovaginal fistula (4). These adverse effects have the potential
to negatively impact quality of life and can compromise the
ability of a physician to detect local recurrence (5).
The development of magnetic resonance (MR) and
computed tomography (CT) compatible applicators has
resulted in the ability to perform unprecedented volumetric
calculation of doses to target and normal tissues within the
female pelvis (6, 7). Historically, the vaginal apex dose has
been limited to a point dose of 120 to 160 Gy, or alternately
200% of the brachytherapy prescription dose (8, 9). How-
ever, with 3-dimensional planning, it remains uncertain
which point within the vagina would be the best to select
and how this would correlate with modern dosimetric
concepts such as D2cc. Moreover, there is a distinct pos-
sibility that, as plans are optimized beyond “point A” film-
based plans to meet high-risk clinical tumor volume
(HRCTV) goals and organ at risk constraints, doses to the
vaginal wall may change in an unpredictable fashion and
potentially result in unexpected toxicity (10).
The purpose of this project was to calculate vaginal
doses with modern volume-based metrics and compare
these doses with historically held constraints to understand
the factors that may influence long-term vaginal toxicity.
Methods and Materials
Patient characteristics
Between 2009 and 2015 women undergoing pelvic
brachytherapy for cervical and uterine cancer at a single
institution were identified. All women were initially treated
with whole-pelvic radiation therapy followed by intra-
cavitary tandem and ovoid (T&O) or tandem and ring
and high-dose-rate (HDR) techniques were allowed in the
analysis; use of primarily interstitial applicators such as
Syed-Neblett templates was an exclusion criterion for this
study. This study was performed with the approval of the
Duke University Health System Institutional Review Board.
Follow-up and data extraction
Records of women treated with CT and/or MR-guided
brachytherapy were identified for retrospective review. The
median follow-up period for the identified women was
12 months. Follow-up dates were considered to include
visits with the patient’s primary gynecologic oncologist,
radiation oncologist, or medical oncologists if applicable.
Dates of local progression and distant progression were
gathered from patient records and were considered indica-
tive if found on imaging, physical examination, or patho-
logic examination. The data for toxicity were gathered from
patient records and included self-reported symptoms and
changes on the bimanual or speculum examination. Tox-
icities were reported as the earliest date of onset of the
highest grade of vaginal, genitourinary, or gastrointestinal
symptoms or examination findings, beginning 1 month after
completion of brachytherapy, to capture subacute and late
toxicity. Data on sexual activity, vaginal dilator use, and
dyspareunia were extracted from records of either the gy-
necologic oncologist or the radiation oncologist. All tox-
icities were graded according to the Common Terminology
Criteria for Adverse Events, version 4 (11).
Brachytherapy techniques
All women received external beam radiation therapy with
or without concurrent chemotherapy before initiating
brachytherapy. During each brachytherapy fraction, CT and
or MR images were obtained after applicator placement,
and a customized plan was developed after prospective
contouring of the HRCTV, rectum, bladder, sigmoid, and
small bowel. All women were treated with T&O and T&R
applicators using the largest possible ovoids or ring cap. All
Volume -
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plans were initially developed with a point Aebased plan,
optimized as per recommendations of the American
Brachytherapy Society (12). Individual dwell positions
were then manually varied by the treating radiation
oncologist to maximize coverage of the HRCTV while
respecting normal tissue dose. Inverse planning was not
utilized. Graphic optimization was used sparingly, and
dwell times were always reviewed before plan approval.
There were no specific rules for limiting the variability of
each dwell position; however, efforts were made to smooth
the transition in dwell times between positions.
Contouring
Beginning in mid-2012 this institution began prospectively
contouring the vagina as a 3-dimensional organ using a 0.4-
cm fixed brush at the time of brachytherapy treatment,
expanded to include all vagina identifiable on CT or MR
imaging. The 0.4-cm brush was chosen because it was the
smallest available from the treatment planning system. If
both images were available, the MR image was used to
generate the contour. Regardless of the tumor site, the
surface of the cervix was specifically excluded from this
contour (Fig. 1). For women treated before mid-2012, this
contour was generated retrospectively and did not influence
treatment decisions. All contours were generated by the
treating radiation oncologist.
Dose conversion
High dose rate and LDR doses were converted to the
equivalent dose in 2-Gy fractions (EQD2) using an a/b of 3
Vagina
HRCTV
Vagina Vagina
Fig. 1. Example of vaginal contouring. A 0.4-cm fixed brush used to outline the applicators, packing, and additional vagina
seen on magnetic resonance imaging or computed tomography. Note that the mucosa overlying the cervix was specifically
excluded from this volume. Abbreviation: HRCTV Z high-risk clinical tumor volume.
Vaginal dose associated with toxicity in IGBT 3
for late effects, summed with prior external beam treat-
ment. The D.1cc, D1cc, D2cc, D5cc, and D10cc values for
the vagina and D2cc values for the rectum, sigmoid,
bladder, and small intestine were calculated for each patient
via the Eclipse treatment planning system (Varian Medical
Systems, Palo Alto). These values were defined as the
minimum dose received by the volume of tissue receiving
the maximum dose of radiation. After the initial experience
(mid-2012), D5cc and D10cc were not routinely calculated,
because the entire structure did not always attain these
volumes. The dose to the vagina was also considered after
this point in the development of each fractions plan; how-
ever, no strict constraints were applied.
Statistical analysis
Analysis was performed with SPSS version 21 (IBM, New
York, NY). Univariate and multivariate analyses were
performed via Cox regression to test for associations with
vaginal toxicity as defined above. Toxicity was also
compared at the median and 4th quartile vaginal doses as
arbitrary cut points via the Kaplan-Meier method and the
log-rank test. P values were calculated for 2-tailed com-
parisons, and a value <.05 was selected for significance.
Results
Sixty-two women met the criteria for inclusion within this
study, with characteristics shown in Table 1. The median
age was 55.5 years (interquartile range [IQR] 42.8-
68.7 years), with a range from 22.51 to 87.33 years. Forty-
eight women (77.4%) were treated for cervical cancer, and
HRCTV
Vagina
4 Susko et al. International Journal of Radiation Oncology
Biology
Physics

Table 1 Patient characteristics Table 2 Dosimetric characteristics: median dose (Gy) of

Characteristic n or median (IQR) organs at risk

Median age (y) 55.5 (42.8-68.7) Organ Median IQR

Median LDR (h) 60 (51.5-69) Bladder D2cc 76.79 68.1-80.9
Median follow-up (mo) 11.8 (4.7-31.7) Rectum D2cc 58.45 53.5-66.3
Median EBRT dose (Gy) 45 (45-45) Sigmoid D2cc 65.29 59.9-69.3
Disease Bowel D2cc 60.7 52.9-71.3
Uterine 14 Vagina D0.1cc 157.91 134.4-196.5
Cervical 48 Vagina D1cc 112.59 96.7-124.6
Chemotherapy Vagina D2cc 100.5 86.8-108.4
Yes 51 Vagina D5cc 81.68 74.3-91.1
No 11 Vagina D10cc 68.98 61.8-76.4
LDR/HDR Abbreviation as in Table 1.
LDR 10 D2cc values for common organs at risk within the pelvis. Vaginal
HDR 52 dose parameters shown from D0.1cc to D10cc.
Brachytherapy technique
T&O 39
T&R 23 women developed fistula, and 3 developed vaginal vault
Sexually active necrosis necessitating hospitalizations. The initial present-
Yes 22 ing stage of disease ranged from IB to IIIB, with none of
No 40
the women having stage IV disease. Of the women who
Abbreviations: EBRT Z external beam radiation therapy; HDR Z
developed vaginal vault necrosis, none were current
high dose rate; IQR Z interquartile range; LDR Z low dose rate;
T&O Z tandem and ovoid; T&R Z tandem and ring. smokers or cocaine users at the time of treatment. Addi-
tionally, all documented cases of fistula and vaginal vault
necrosis had no evidence of recurrence at the time of
14 (22.6%) were treated for uterine cancer. Concurrent evaluation. Overall 2-year rates of vaginal toxicity can be
chemotherapy was given to 51, with the most common found in Table 3. The 2-year rate of grade 1 toxicity or
regimen being single agent cisplatin (nZ48). Thirty greater was 58.1% (95% confidence interval [CI] 37.5%-
women were treated with T&O applicators, and 32 were 78.7%) below the median vaginal D2cc dose (100.5 Gy)
treated with T&R applicators. The median follow-up length and was 78.0% (95% CI 59.4%-96.6%) above (PZ.124);
for women in this study was 12 months, with an IQR of 4.7- the rates of grade 2 toxicity or greater above and below the
31.7 months. Ten were treated with LDR brachytherapy, median were 34.4% (95% CI 12.1%-56.7%) and 58.8%
whereas 52 were treated with HDR brachytherapy. The (95% CI 35.5%-82.1%), respectively (PZ.146); and the
LDR treatments were delivered in a single insertion at the rates of grade 3 or greater toxicity above and below the
completion of external beam; the median number of hours median were 4.5% (95% CI 00.0%-13.1%) and 27.6%
was 60, with a median dose of 39.8 Gy. The majority (95% CI 5.1%-50.4%), respectively (PZ.075). Using the
receiving HDR brachytherapy were prescribed 5.5 Gy per fourth quartile of the vaginal D2cc as a cutoff, the rate of
fraction after 45 Gy of external beam radiation therapy grade 1 toxicity was 61.2% (95% CI 43.0%-79.4%) in
(EBRT). Five women received 50.4 Gy EBRT, and 3 of the women with D2cc <108 Gy and 83.9% (95% CI 63.9%-
HDR cohort received a dose other than 5.5 Gy, with a 100%) for >108 Gy (PZ.018). Similarly, grade 2 or
concomitant change in the number of fractions to account greater toxicity rates were 36.2% (95% CI 15.8%-56.6%)
for the different dose. <108 Gy and 70.7% (95% CI 45.2%-96.2%) >108 Gy
The median tissue doses for bladder, rectum, sigmoid,
bowel, and vagina are listed in Table 2. The bladder,
rectum, sigmoid, and bowel dose values were measured at Table 3 2-year toxicity rates
D2cc, with the median doses (IQR) being 76.79 (68.1-80.9) Toxicity With toxicity (%) 95% CI (%) Log-rank P
Gy, 58.45 (53.5-66.3) Gy, 65.29 (59.9-69.3) Gy, and 60.70 Grade 1þ toxicity .018
(52.9-71.3) Gy, respectively. The median (IQR) vaginal <108 Gy 61.2 43.0-79.4
doses at D0.1cc, D1cc, D2cc, D5cc, and D10cc were >108 Gy 83.9 63.9-100
157.91 (134.4-196.5) Gy, 112.59 (96.7-124.6) Gy, 100.50 Grade 2þ toxicity .004
(86.8-108.4) Gy, 81.68 (74.3-91.1) Gy, and 68.98 (61.8- <108 Gy 36.2 15.8-56.6
76.4) Gy, respectively. All values are reported in terms >108 Gy 70.7 45.2-96.2
of EQD2, including both the brachytherapy and EBRT Grade 3þ toxicity .025
doses. <108 Gy 9.9 0-23.6
In total, 36 women were noted to have vaginal toxicity >108 Gy 30.0 4.7-55.3
during their follow-up. Of these, 15 (41.7%) were grade 1, Rates of 1þ, 2þ, and 3þ toxicity separated by the vaginal D2cc
threshold of 108 Gy. All doses are calculated to D2cc.
15 (41.7%) grade 2, and 6 (17.6%) grade 3 or higher. Three
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(PZ.004) (Fig. 2). The rates of grade 3 or worse toxicity 1.0

including fistula and necrosis were 9.9% (95% CI 0.0%-
Vaginal D2cc >108 Gy
23.6%) for D2cc >108 Gy and 30.0% (95% CI 4.7%- 0.9
Vaginal D2cc <108 Gy
55.3%) for >108 Gy (PZ.025) (Fig. 3). Additional 0.8
comparisons were made of grade 2 or greater toxicity using

Vaginal Grade 3+ Toxicity

the 4th quartile of vaginal D0.1cc and D1cc as cutoffs. The 0.7
lower 3 quartiles of vaginal D01.cc had a toxicity rate of 0.6
47.7% (95% CI 27.9%-67.5%), compared with 45.1% (95%
CI 14.5%-75.7%) (PZ.911). For vaginal D1cc the lower 3 0.5
quartiles had a toxicity rate of 36.0% (95% CI 17.2%- 0.4
54.8%), compared with 77.8% (95% CI 51.3%-100%) for
0.3
the upper quartile (PZ.003).
Univariate analysis for potential covariates was per- 0.2 P=.024
formed, including tandem and ovoid versus ring, use of
0.1
chemotherapy, uterine versus cervical cancer, LDR versus
HDR, bladder D2cc, rectal D2cc, and age. Vaginal D2cc is 0.0
.0 .5 1.0 1.5 2.0 2.5
demonstrated to be a significant factor associated with rates
Time (Years)
of grade 2 or greater vaginal toxicity, with a hazard ratio number at risk (n=62)
(HR) of 1.02 (95% CI 1.004-1.036, PZ.015). Other factors, < 108 Gy 46 32 20 18 13 12
> 108 Gy 16 11 7 5 4 4
including dose to the bladder and rectum, were not signifi-
cant. Multivariate analysis demonstrated that vaginal D2cc Fig. 3. Incidence of grade 3 and greater toxicity stratified
(HR 1.029, 95% CI 1.006-1.052, PZ.012) remained the only by vaginal D2cc of 108 Gy.
significant factor associated with grade 2 or higher vaginal
toxicity. Univariate analysis of D1cc of the vagina was also
significant for grade 2 or higher toxicity (HR 1.015 per Gy, the Groupe Européen de Curiethérapie and the European
95% CI 1.002-1.028, PZ.019). On multivariate analysis, Society for Radiotherapy & Oncology (GEC-ESTRO),
D1cc was the only factor that remained significant (HR provide practitioners an unprecedented ability to apply
1.018 per Gy, 95% CI 1.001-1.035, PZ.042), albeit with a dose-volume adaptation and escalation to target volumes
lesser effect size than the comparable analysis of D2cc. (7). Recent investigations have reported excellent locore-
gional control when HRCTV goals are met, with a reduc-
Discussion tion in long-term toxicity (13). However, although
constraints have been established for numerous organs at
risk, such as the rectum, sigmoid, and bladder, the criteria
Modern image guided brachytherapy (IGBT) concepts, for the vaginal mucosa have not been well established
such as the dose-volume histogram parameters endorsed by (10, 14). This study sought to elucidate the dose-volume
histogram parameters and associated factors involved with
1.0 vaginal toxicity during image-guided brachytherapy
Vaginal D2cc >108 Gy (IGBT) when compared with historically held constraints.
0.9
Vaginal D2cc <108 Gy Retrospective analysis of women receiving EBRT and
0.8 historical film-based LDR brachytherapy demonstrated a
Grade 2+ Vaginal Toxicity

0.7 vaginal dose tolerance of 150 Gy, above which rates of

toxicity rose from 4% to 11% in total (8). Further evidence
0.6 supporting this figure comes from a recent retrospective
P=.004
0.5 study by Murakami et al (15) of CT-based interstitial IGBT
with EBRT that found a D2cc threshold of 145 Gy in EQD2
0.4
to be predictive of high-grade vaginal toxicity (vaginal
0.3 ulcer). Both the present study and the Murakami et al study
0.2 demonstrate that a D2cc over a certain threshold can be
predictive of higher rates of high-grade vaginal toxicity.
0.1
These two studies share numerous similarities: both retro-
0.0 spectively examined a heterogeneous population, with
.0 .5 1.0 1.5 2.0 2.5
multiple types of primary cancer (cervical, uterine), as well
Time (Years)
number at risk (n=62) as different treatment procedures. The present study, which
< 108 Gy 46 30 19 15 11 10 examined a larger cohort, additionally found that the rates
> 108 Gy 16 8 5 3 3 3
of grade 2 or higher toxicity were associated with a lower
Fig. 2. Incidence of grade 2 and greater toxicity stratified vaginal D2cc than previously reported and suggest that a
by vaginal D2cc of 108 Gy. cutoff value of 108-110 Gy may also be considered.
6 Susko et al.
The difference in dose threshold in this series compared
with the Murakami et al series as well as historic controls
may be due to the contouring method. The present series
excludes the mucosa overlying the cervix, because cervical
necrosis is often expected with brachytherapy and is
seldom a source of persistent symptoms. The contour rather
emphasizes the lateral, anterior, and posterior walls of the
vagina, injury to which may lead to symptomatic toxicity.
This method results in a calculated dose, particularly to
larger volumes such as the 2ccs, that is much lower than
other methods may arrive at. Thus the doses in this series,
owing to the very specific manner of contouring, are not
directly comparable to series that do not use this method.
The 108-Gy value was arrived at by a preplanned
quartile-based analysis, with 108 Gy being the 4th quartile
of D2cc dose. As an exploratory analysis, a variety of cut
points at 10-Gy intervals were examined for the rates of
either grade 2 or greater toxicity or grade 3 or greater
toxicity (Fig. 4). There were few patients at risk below a
cutoff of 90 Gy and above 140 Gy. The rates for grade 2 or
greater continuously increase throughout the examined
range; however, the 110-Gy cut point attained the highest
significance (PZ.006)dthough this may have been a
function of the number of patients available for analysis in
each cohort. Similarly, the rates of grade 3 or greater also
increased throughout the range, though the largest increase
was noted between the 100-Gy cut point (4.8%) to the 110-
Gy cut point (11.7%).
The Vienna group has used a standardized protocol and
routine examination to assess for clinical outcome and late
rectal, bladder, and vaginal toxicities from IGBT (16). The
initial treatment and assessment of these patients were
prospective, in a highly standardized manner, and demon-
strated good clinical outcomes with acceptable rates of late
toxicity. The methods of treatment were uniform
throughout the patient population and used a standardized
dosimetric analysis (17). Within this series Fidarova et al
used colposcopy to retrospectively assess 34 patients for
vaginal mucosal changes after IGBT and did not find any
correlation between D2cc radiation dose in EQD2 and
toxicity (16, 18). One strength of the Fidarova et al study
was the use of a superior and standardized technique
0.5
0.4 Grade 2+ Toxicity
Toxicity Rate
0.3
0.2
Grade 3+ Toxicity
0.1
0 morbidity in carcinoma of the uterine cervix: Dosimetric and clinical
90 100 110 120 130 140
Vaginal D2cc Cut Off (Gy)
Fig. 4. Exploratory analysis of vaginal D2cc cut points
and rates of grade 2 or greater vaginal toxicity (open cir-
cles) and grade 3 or greater toxicity (filled circles). Rates
are given for toxicity below the given cut point.
International Journal of Radiation Oncology
Biology
Physics
(colposcopy) to measure side effects; however, the well-
established brachytherapy protocol used by the Vienna
group may not reflect all practices. Additionally, the high
median vaginal D2cc may have only captured the plateau of
the vaginal dose response and not the toxicity relationship
at lower doses. It is also worth remarking that the use of
interstitial needles, as is often used in the Vienna group,
will likely decrease the vaginal dose, particularly in cases
where the HRCTV extends laterally. Of note, however,
Fidarova et al did observe that adverse events occurred
predominantly in the upper vagina with a mean dose of
141 Gy, similar to the rates observed both in this study and
that of Murakami et al.
The limitations of this study include its retrospective
nature and the heterogeneous characteristics of the treat-
ment procedures and patient population. The single-
institution nature of this study may narrow the scope of
these results owing to varying institutional practices in
different settings, and the findings should be confirmed.
However, the present study represents the largest cohort to
examine the effect of vaginal D2cc on rates of vaginal
toxicity to date. Taken together with previous studies, this
evidence does support the idea of using D2cc of the vaginal
mucosa as a potential organ at risk constraint. Before this
study there was no evidence of a dose-effect relationship at
D2cc below the level of 140 Gy; however, the present study
finds a relationship as low as 108 Gy for all grades of
toxicity. Lack of prospective evidence on this topic leaves
this dose threshold as a potential constraint to be used
moving forward, though validation at other institutions will
be critical.
Conclusion
All grades of subacute and late vaginal toxicity were
associated with a vaginal dose. This association was
maintained after controlling for covariates. Additional
prospective evidence will be needed to fully establish the
dose-response relationship of vaginal toxicity and IGBT
doses; however, this study provides initial evidence in
support of vaginal dose constraints.
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