Purpose. – To compare the efficacy of intensity-modulated radiotherapy, three-dimensional conformalradiotherapy, and conventional radiotherapy for cervical cancer treatment.Materials and methods. – Whole pelvis intensity-modulated radiotherapy, three-dimensional conformalradiotherapy, and conventional radiotherapy plans were designed for 16 patients with stage IIB cervicalcancer, each using the prescribed dose of 50.4 Gy/28 fractions. Dose–volume histograms of the targetvolume and organs at risk were evaluated.Results. – Compared to the 3D conformal and conventional radiotherapy plans, the intensity-modulatedradiotherapy plan demonstrated superior conformal treatment. The mean planning target volume doseof all three plans reached the target effective therapeutic dose. The planning target volume dose of theintensity-modulated radiotherapy plan was significantly higher than that of either the three-dimensionalconformal radiotherapy or conventional radiotherapy plan (P < 0.05). When more than 30 Gy was admin-istered in intensity-modulated radiotherapy, organs at risk including the small intestine, rectum, bladder,and bone marrow received a significantly reduced volume of radiation. In comparison of the average plan-ning target volume doses, significant volume reductions in irradiation of organs at risk were obtainedwith full bladders.Conclusions. – An intensity-modulated radiotherapy plan with appropriate margins encompassing theprimary tumour and potential microscopic pelvic disease reduces the dose to organs at risk withoutcompromising target coverage. Intensity-modulated radiotherapy is an appropriate definitive treatmentfor patients with cervical cancer.
ots clés :ancer du col utérinadiothérapie conformationnelle avecodulation d’intensité
emplissage vésical
Objectif de l’étude. – Comparer l’efficacité de la radiothérapie conformationnelle avec modulationd’intensité, de la radiothérapie conformationnelle tridimensionnelle et de la radiothérapie classique dansle cancer du col utérin.Matériels et méthodes. – Une radiothérapie pelvienne de 50,4 Gy en 28 fractions a été planifiée pour16 patientes atteintes d’un cancer du col utérin de stade IIB avec chacune des trois techniques. Les résultats
omparés avec les histogrammes dose–volume du volume cible et des organes
746 Y. Lv et al. / Cancer/Radiothérapie 18 (2014) 745–752
Résultats. – La radiothérapie conformationnelle avec modulation d’intensité a donné les meilleurs résul-tats, la dose délivrée dans le volume cible prévisionnel étant supérieure à celle atteinte avec les deuxautres techniques (p < 0,05). Dès que la dose dépassait 30 Gy, la dose délivrée par radiothérapie confor-mationnelle avec modulation d’intensité dans l’intestin grêle, le rectum, la vessie et la moelle osseuse étaitsignificativement réduite. Le remplissage vésical aboutissait aussi à une diminution de la dose délivréedans les organes à risque.Conclusion. – Une radiothérapie conformationnelle avec modulation d’intensité avec des margesadéquates de la tumeur primaire et des extensions potentielles microscopiques permet une diminutionde la dose délivrée dans les organes à risque sans compromettre la couverture de la cible et s’avère untraitement approprié du cancer du col utérin.
Cervical cancer is the third most commonly diagnosed cancernd was the fourth leading cause of cancer deaths among womenorldwide in 2008 [1]. The majority of patients diagnosed with
ervical cancer received radiation as a treatment component. Theathological and anatomic characteristics of cervical cancer make it
good target for radiotherapy. First, squamous cell carcinoma anddenocarcinoma are sensitive to radiotherapy. Second, tumours areenerally confined to the pelvis during development. Third, the tar-et dose for the tumour can be reached with limited irradiation tohe surrounding organs. Finally, the natural cavity of the vagina
akes it accessible for brachytherapy.Conventional radiotherapy for cervical cancer is composed
f brachytherapy and external beam radiotherapy. Althoughrachytherapy boosts the local dose to the tumour, external beamadiotherapy aims to reduce the size of the gross tumour andhe presence of microscopic disease in the pelvic area. Externaleam radiotherapy targets include primary tumours, subclinical
esions (parametrical uterine tissue, and vagina), and regionalymph nodes (common iliac, external and internal iliac, obtura-or, and presacral nodes) [2]. Because the cervix is localized inhe pelvic centre and surrounded by the bladder, rectum, smallntestine, and vagina, it is difficult to protect these organs atisk from irradiation using conventional radiotherapy. Grade 3/4cute radiation proctitis was observed in up to 16.7% of patientsnd grade 3/4 acute cystitis occurs in up to 18.3% of patientseceiving conventional radiotherapy [3]. Multicentre data suggesthat complications, including radiation proctitis and cystitis, occurn 5 to 30% of cervical cancer patients after radiotherapy [4].hree-dimensional conformal radiation therapy was subsequentlyeveloped to avoid organs at risk irradiation. Conventional 3D con-ormal radiotherapy is composed of a set of fixed radiation beams,hich are shaped using the projection of the target volume andormally have uniform intensity across the field. When appro-riate, conventional fields can be modified using simple devices,uch as compensating filters or wedges. With advances in newechnologies, including computed tomography (CT), magnetic res-nance imaging (MRI), and 3D planning software, radiotherapyechniques have significantly improved. More recently, intensity-
odulated radiation therapy has been proposed to treat cervicalancer. The intensity of each beam can be purposely alteredy the summation of hundreds of beamlets in order to satisfylinical target goals and normal tissue doses. In addition, theuence can be adjusted within individual beamlets, the sum ofhich represents the entire aperture’s contribution [5]. There-
ore, when individual contributions from each beam are summed,omplex 3D dose clouds can be generated with concave shapesnd steep dose gradients. This results in highly conformal treat-
ent, where the high dose regions of the plan are confined to
he target only, and doses to organs at risk can be minimized.ntensity-modulated radiotherapy has been shown to reduce
asson SAS pour la Société française de radiothérapie oncologique (SFRO).
normal tissue irradiation [6] and has been associated with reducedacute toxicity compared to conventional 3D conformal radiothe-rapy [6–11].
One complication in utilizing intensity-modulated radiothe-rapy for cervical cancers is the interfractional position change oforgans near the cervix. Utilizing intensity-modulated radiotherapyin mobile organs not only results in underdose to the target butalso presents a high risk of overdose to nearby organs because ofthe nature of the steep dose gradient. In general, motion of theorgans is attributable to variations in bladder filling and rectal fill-ing, and the majority of motion occurs in the anterior–posteriorand superior–inferior directions, with mean interfraction move-ments of 4–7 mm [12–14]. However, it is worth noting that theseare the average distances, and in some instances the distance hasbeen reported to be as large as 2.8 cm [14]. To avoid complicationsof intensity-modulated radiotherapy in cervical cancer patients,effective control of the clinical target volume position and bladderfilling status is critical [2,15].
With the aim of addressing the inconsistencies that have arisenbased on previous studies, we conducted a dosimetric study to com-pare conventional radiotherapy, 3D conformal radiotherapy, andintensity-modulated radiotherapy plans. We performed quantita-tive dosimetric analyses of irradiation on the tumour target andorgans at risk, including the bladder, rectum, small intestine, andpelvic bone marrow. In addition, we compared the dosimetric char-acteristics of targets and organs at risk during different bladderstates.
2. Materials and methods
2.1. Patient selection
Approval for this study was obtained from the local ethicsreview board and all patients provided informed consent for study.
Sixteen patients with stage IIB (FIGO staging) cervical carcinomathat presented to our department from July 2011 to March 2013were included in the study. All patients were diagnosed by biopsywith cervical squamous cell carcinoma and were untreated beforecommencing the study. The average age of patients was 52 years(range: 38–79 years). They received written and verbal advice onbladder filling prior to their planning appointment. Patients wereadvised to “void the bladder and then drink 500 ml of water withinthe next 15 minutes. After 30 minutes, proceed with the plannedradiotherapy. This process should be repeated daily prior to eachtreatment”.
2.2. Methods and protocols
2.2.1. Position
All patients were immobilized using MED-TEC vacuum body
bags (Klarity Medical, Guangzhou, China) while they were in asupine position with their hands clasped over their head and their
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egs closed naturally. Surface markers were determined using atereotactic frame.
.2.2. ImagingPrior to CT scan, a Foley catheter was inserted into the patient’s
ladder and connected to a drainage bag. The bladder was emp-ied and then approximately 200–250 ml saline was refilled to the
aximal extent tolerated. A swab soaked with 15% diatrizoate waslaced at the orificium vaginae to aid the delineation. The contrastgent iohexol (90 ml) was intravenously injected through a high-ressure syringe (brand), with an injection rate of 3.0 ml/s. Therst enhanced pelvic CT scan with a full bladder was performed
rom the top edge of the L3 vertebral body to the bottom edge ofhe ischial tuberosity, with a thickness of 5 mm. After scanning,he bladder was emptied and immediately, a second scan with anmpty bladder was acquired under the same conditions. The fullnd empty bladder scans were transmitted and registered in theopslane Venus treatment planning system (VENUS 5014 software,uoneng Co., Shanghai, China).
.2.3. Target and organs at risk delineationClinical target volume and organs at risk were contoured on
he full and empty bladder scans. The pelvic clinical target volumeontouring guidelines for radiation therapy issued by Radiationherapy Oncology Group (RTOG) in combination with 3D distribu-ion patterns of clinical metastatic pelvic lymph nodes were useds a guide for contouring [16–18]. Contouring of target and normalissues (bladder, rectum, and small bowel) was performed in eachatient on individual axial CT slices on Eclipse TPS, according to
nternational Commission on Radiation Units and MeasurementsICRU) report 50. The same contours were used for both treatmentechniques. The clinical target volume started from the commonliac artery bifurcation and was composed of the primary tumour,terus, adnexaes, part of vagina (the upper half of vagina when noumour involvement was observed in the vagina, or two thirds ofhe vagina when the upper half vagina was involved), and pelvicymph nodes (common iliac, external iliac, internal iliac, obtura-or, and presacral). The planning target volume was defined as thelinical target volume plus a 1.0-cm margin.
.2.4. Development of the treatment planUsing the three-dimensional radiation TPS, three radiation
reatment plans were designed for therapy with a full bladder: con-entional, 3D conformal, and intensity-modulated radiotherapylans. Intensity-modulated radiotherapy plans with same condi-ions were designed for therapy with an empty bladder.
.2.4.1. IMRT plans consisted of a seven-field technique. The pre-cription dose to the whole pelvis of planning target volume was0.4 Gy in 28 fractions of 1.8 Gy, with each fraction by 6MV-X-ray.he maximum allowable organs at risk doses were defined as fol-ows: rectal V40 < 50%, bladder V40 < 50%, bone marrow V30 < 50%,nd small intestine V45 < 10%. Because all objectives generally can-ot be met in the treatment volume, the objectives were prioritizeds planning target volume, small intestine, rectum, bladder, andone marrow.
.2.4.2. 3D conformal radiotherapy plans consisted of standard four-eld irradiation (anteroposterior, posteroanterior, and two lateralelds). A multileaf collimator was used in order to reduce the vol-me of normal tissue. Prescription doses of planning target volumeere 50.4 Gy in 28 fractions at 1.8 Gy each with 6MV-X line.
.2.4.3. Conventional radiotherapy plans consisted of two-field verti-al irradiation. Fields were based on classic bony landmarks. Theuperior border was L3/L4, the inferior border was the bottom of
pie 18 (2014) 745–752 747
the obturator, 1.5 cm lateral beyond the pelvic brim. The same pre-scription doses of 50.4 Gy in 28 fractions of 1.8 Gy each, with 6MV-Xline with SSD 100 were used to simulate the intensity-modulatedand 3D conformal radiotherapy plans.
2.2.5. Assessment of treatment plansIntensity-modulated radiotherapy treatment plans must meet
the following two criteria:
• at least 95% of the final planning target volume received 95% ofthe dose, and the planning target volume internal dose gradientwas no more than 10%;
• all cold spots were out of the radiation field and no hot spots wereshown in the bladder wall or rectal wall.
2.2.6. Content observationIsodose curves and dose–volume histograms at cross sections of
the three plans for the filling bladder were generated. The volumevalues were determined for planning target volume and organs atrisk dose distribution, and the maximum dose (Dmax), the minimumdose (Dmin), and average dose (Dmean) were calculated.
The plans were quantitatively evaluated using the dose–volumehistograms generated by the treatment planning system. Thehomogeneity index (HI) was defined as:
HI = D5%−D95%D50% , where D5, D95, and D50 are the doses received by
5, 95, and 50% volume of the planning target volume. Conformityof high dose around the target was evaluated by calculating theconformity index (CI) at a given isodose level (e.g., CI = VPTV95%
VPTv ×VPTV95%
Vt ). The monitor units (MU) for each plan and treatment timewere used to assess treatment efficiency.
The mean doses of planning target volume and organs at riskat the different levels of irradiated volumes (V10, V20, V30, V40, andV45) for three plans organs at risk were determined.
2.2.7. StatisticsAll statistical analyses were performed using SPSS 17.0 statistics
software (SPSS, Chicago, IL, USA). All variables were analysed usingpaired t-tests, and P < 0.05 was considered statistically significant.
3. Results
3.1. Comparison of planning target volume among the threeradiotherapy plans
At the same prescription dose of 50.4 Gy, the mean planningtarget volume dose of the intensity-modulated, 3D confor-mal, and conventional radiotherapy plans were 5077.01 ± 5.00,5015.51 ± 45.77, and 4790.64 ± 175.97 cGy, respectively (Table 1).The mean planning target volume dose of all three plans reachedthe effective target therapeutic dose. The planning target volumedose of the intensity-modulated radiotherapy plan was signifi-cantly higher than those of the 3D conformal and conventionalradiotherapy plans (P < 0.05).
As shown in Fig. 1 in the intensity-modulated radiotherapy plan,the concave shape of the 95% isodose curve is similar to that ofthe target. However, in the 3D conformal and conventional radio-therapy plans, the 95% isodose curves are a square shape, and themajority of the bladder, rectum, small intestine, and bone marrowwere covered.
The homogeneity index and conformity index for these patientsare shown in Table 1. The mean homogeneity indexes for intensity-
modulated, 3D conformal, and conventional radiotherapies were1.02, 1.14, and 1.26, respectively. The target dose conformity wasdetermined by comparing the volume of the planning target vol-ume with the volume encompassed by 95% isodose body. The mean
748 Y. Lv et al. / Cancer/Radiothérapie 18 (2014) 745–752
Table 1Distribution of planning target volumes according to the radiotherapy technique for cervix cancers.Volumes cibles prévisionnels selon la technique de radiothérapie du cancer du col utérin.
Intensity-modulated radiotherapy 3D conformal radiotherapy Conventional radiotherapy
= 16, � ± s; P < 0.05 for all paired comparisons in each variable group, except for co
onformity indexes 95% were 0.89, 0.54, and 0.36 for the intensity-odulated, 3D conformal, and conventional radiotherapy plans,
espectively. Compared to 3D conformal and conventional radio-herapy, intensity-modulated radiotherapy provided significantlyetter homogeneity and target dose conformity. The average num-ers of monitor units delivered by the three plans were 662.5, 255.5,nd 229.75, respectively (Table 1). Thus, intensity-modulatedadiotherapy increased the treatment time and reduced the effi-iency of machine.
.2. Organs at risk dose distribution of the three plans
The mean doses to organs at risk, including the bladder, rectum,mall intestine, and bone marrow, were compared among the threelans (Table 2). The intensity-modulated radiotherapy plan wasuperior to the 3D conformal and conventional radiotherapy plans,
ig. 1. Axial views of isodose distribution in radiotherapy for cervical cancer. A. Intensity-mIsodoses de radiothérapie du cancer du col utérin. A. Radiothérapie conformationnelle av
C. Radiothérapie
255.50 ± 9.25 229.75 ± 29.42
ison between two groups; *P = 0.251.
with statistically significant lower mean doses to the organs at risk.The dose–volume parameters among these plans were comparedin individual organs at risk.
3.3. Bladder
In comparisons of the volume of intensity-modulated radiothe-rapy to the 3D conformal and conventional radiotherapy plans forthe bladder, significant differences were observed from the 20 Gydose level (P < 0.05), and a significant volume reduction was shownfrom the 30 Gy level (Table 3). At the 30, 40, and 45 Gy levels,
volume reductions of 12.48, 28.59, and 34.70% were observed com-pared to 3D conformal radiotherapy, whereas reductions of 20.57,55.06, and 69.22% were observed compared to conventional radio-therapy.
odulated radiotherapy. B. 3D conformal radiotherapy. C. Conventional radiotherapy.ec modulation d’intensité. B. Radiothérapie conformationnelle tridimensionnelle.
classique.
Y. Lv et al. / Cancer/Radiothérapie 18 (2014) 745–752 749
Table 2Mean dose to organs at risk according to the technique for cervix cancer radiotherapy.Dose moyenne aux organes à risque pour la radiothérapie du cancer du col utérin selon la technique.
Organs at risk Intensity-modulated radiotherapy 3D conformal radiotherapy Conventional radiotherapy
oses are expressed in centigrays; n = 16, � ± s; P < 0.05 for all paired comparisons i
.4. Rectum
In the rectum, significant differences (P < 0.05) and volumeeduction was shown from 30 Gy (Table 3). At the 30, 40, and 45 Gyevels, reductions of 10.84, 24.82, and 25.92% were found comparedo 3D conformal radiotherapy, whereas reductions of 13.36, 58.40,nd 70.11% were observed compared to conventional radiotherapy.
.5. Small intestine
At low radiation levels (10 Gy), although a larger volume of smallntestine was irradiated in intensity-modulated radiotherapy thann the 3D conformal and conventional radiotherapy plans, no statis-ical significance was obtained (P > 0.05). However, the irradiatedolume of small intestine was lower in the intensity-modulatedadiotherapy plan when patients received more than 20 Gy andignificant differences were found from 30 Gy (P < 0.05; Table 3).
.6. Pelvic bone marrow
The volume of irradiation to both sides of the pelvic bone mar-ow is compared in Table 3. Intensity-modulated radiotherapy
able 3omparison of the dose–volume parameters of organs at risk according to the technique
aramètres dose–volume des organes à risque pour la radiothérapie du cancer du col utérin, s
Organs at risk Intensity-modulated radiotherapy
BladderV10* 100.00 ± 0.00V20 99.08 ± 0.43
V30 79.43 ± 3.11
V40 44.94 ± 1.94
V45 30.78 ± 3.87
RectumV10* 99.9 ± 0.20
V20* 99.65 ± 0.79
V30 86.64 ± 10.02
V40 41.60 ± 8.98
V45 29.89 ± 6.77
Small intestineV10* 91.24 ± 5.04
V20* 64.69 ± 9.32�
V30 32.40 ± 4.01
V40 10.87 ± 1.84
V45 5.80 ± 1.56
Bone marrow, leftV10 87.32 ± 3.92
V20 60.93 ± 4.99
V30 26.75 ± 3.83
V40 4.60 ± 2.63V45 1.20 ± 1.16
Bone marrow, rightV10 87.88 ± 3.39#
V20 61.45 ± 2.78�
V30 26.76 ± 5.10
V40 6.38 ± 2.02
V45 1.57 ± 0.99
xpressed in percent; n = 16, � ± s; *P > 0.05 for all paired comparisons in each variable groomparisons in other variable groups, except for comparison between therapies; #P > 0.0
variable group, except for comparison between two groups; *P = 0.198; #P = 0.372.
was superior to 3D conformal and conventional radiotherapies inreducing volume to the pelvic bone marrow. Although reducedirradiated volumes were observed in both sides when compar-ing intensity-modulated to 3D conformal radiotherapy at the 10 Gydose level, significantly higher volumes were obtained comparedto the conventional radiotherapy plan (P < 0.05). However, signifi-cantly reduced volumes were observed on both sides at doses from20 to 45 Gy (P < 0.05).
3.7. Planning target volume mean dose of theintensity-modulated radiotherapy plan in full and empty bladders
To elucidate the effect of bladder filling on intensity-modulatedradiotherapy, the planning target volume dose distribution anddose to organs at risk were compared in 16 patients with full andempty bladders.
With respect to the Dmax, Dmin, and Dmean, there were no sig-
nificance differences between full and empty bladders (P > 0.5)(Table 4). However, irradiation to bladder, rectum, and small intes-tine was reduced with full bladder (Table 5). When dose–volumehistograms for these organs were compared, inconsistent results
for cervix cancer radiotherapy.elon la technique.
3D conformal radiotherapy Conventional radiotherapy
up, except for comparison between two therapies (�P < 0.05). P < 0.05 for all paired5; *P = 0.246; �P = 0.055; �P = 0.305.
750 Y. Lv et al. / Cancer/Radiothéra
Table 4Comparison of planning target volume dose distribution between intensity-modulated radiotherapy of cervical cancer with a full bladder and an empty bladder.Radiothérapie avec modulation d’intensité du cancer du col utérin : comparaison desvolumes cible prévisionnels avec vessie pleine ou vide.
= 16, � ± s; represents paired-sample t-tests; P indicates P-value, and values lesshan 0.05 were considered statistically significant.
ere obtained. Irradiation volumes with full bladder were signifi-antly reduced at V40 and V45 in the bladder and at V20 and V30 in themall intestine. Notably, volumes at V40 and V45 of the small intes-ine were reduced with full bladder but no statistical significanceas observed. The mean dose to the pelvic bone marrow showed no
tatistical significance (P = 0.080) between full and empty bladderst various volume levels.
. Discussion
Based on the dosimetric analyses in this study, intensity-odulated radiotherapy demonstrated superior conformal treat-ent compared to 3D conformal and conventional radiotherapies.
ntensity-modulated radiotherapy provided significantly superiorlanning target volume coverage as well as significantly lower irra-iation doses to organs at risk including the small intestine, rectum,ladder, and bone marrow. When comparing the effect of blad-er filling, no differences were observed in the planning targetolume average dose between full and empty bladders. However,
he irradiated volume of bladder, rectum, and small intestine wereignificantly reduced with a full bladder.
The use of intensity-modulated radiotherapy for the treat-ent of gynaecologic malignancies has increased significantly in
able 5omparison of dose distribution to organs at risk between intensity-modulated radiotheradiothérapie avec modulation d’intensité du cancer du col utérin : comparaison des distribu
Organs at risk and bladder state V10 (%) V20 (%) V3
= 16, � ± s; t represents paired-sample t-tests; P indicates P-value, and values less than
pie 18 (2014) 745–752
recent years [5]. Many studies have reported dosimetric benefits ofintensity-modulated radiotherapy in cervical cancer, which bene-fits the small intestine, rectum, bladder, and bone marrow [19–22].However, conflicting reports have shown intensity-modulatedradiotherapy is inconsistent reducing the irradiated volume oforgans at risk [14,23–28]. A meta-analysis pooled from 13 arti-cles compared intensity-modulated to 3D conformal radiotherapytreatment plans and found that although there was significantvolume reduction in the small intestine and rectum when receiv-ing high dose radiation, no statistically significant decreases inbladder or bone marrow volume was obtained [29]. However,these studies are partly retrospective, with variations in rela-tive organs at risk planning prioritization. Thus, final comparisonsare difficult without uniform planning constraints, and, intensity-modulated radiotherapy treatment for gynaecologic malignanciesis not yet generally recommended by the National ComprehensiveCancer Network (NCCN) [29]. In this study, we compared plan-ning target volume coverage and irradiation volume to organs atrisk in 16 patients receiving intensity-modulated, 3D conformal,or conventional radiotherapy plans. Intensity-modulated radio-therapy demonstrated superior conformal treatment compared tothe two other techniques. The isodose curve formed a concave“U” shape tightly focal on the target, demonstrating a significantadvantage over conventional radiotherapy, which formed a squareshape covering the majority of the bladder, rectum, small intestine,and bone marrow. In addition, intensity-modulated radiotherapyprovided significantly better homogeneity and target dose confor-mity compared to the two other techniques. Moreover, dosimetricadvantages are observed when the irradiated volume to organsat risk is compared among the three plans. Organs at risk werepreferentially spared with the intensity-modulated radiotherapyplan because of the use of conformal avoidance (i.e., limiting
the radiation dose below the designated threshold limit). Signifi-cant differences were shown in these organs receiving more than30 Gy, and the reductions became more apparent in organs withhigher irradiation volume. Numerous studies have demonstrated
apies of cervical cancer with a full and an empty bladder.tions de doses aux organes à risque avec vessie pleine ou vide.
osimetric benefits of intensity-modulated radiotherapy in gynae-ologic cancers, manifested predominantly in benefits to the smallntestine, rectum, and bladder [19,20,22,23,30]. In a study compar-ng intensity-modulated radiotherapy with conventional four-field
hole pelvis radiotherapy, there was no difference in the averagearget volume, but intensity-modulated irradiation significantlyeduced the dose to organs at risk at the V50, V45, V40, and V30 lev-ls [31]. There was an apparent difference in V50 in most patients:4% (bladder), 58% (small intestine), 54% (sigmoid), and 84% (rec-um). In another study, van de Bunt et al. also concluded thatntensity-modulated radiotherapy is superior in sparing organs atisk (bladder, small intestine, and rectum) compared to conven-ional and conformal treatment, particularly when the volume isreater than 30 Gy [32].
Radiation-induced bone marrow damage is dependent on bothose and volume [33,34]. Bone marrow is extremely sensitive toadiotherapy with histopathologic changes evident in doses as lows 4 Gy and complete hypoplasia with doses higher than 50 Gy34]. In a phase 2 postoperative study, Klopp et al. reported thatimiting the volume of bone marrow in pelvic intensity-modulatedadiotherapy with cisplatin therapy reduced rates of hematologicoxicity and improved tolerance to chemotherapy in cervical can-er patients [35]. Their results suggested that the volume of bonearrow receiving 40 Gy and the median dose to bone marrow
orrelated with higher rates of grade 2 or above toxicity amongatients receiving weekly cisplatin. Reducing radiation to the bonearrow relieves hematologic toxicity and minimizes neutrope-
ia and anaemia, thus ensuring anti-tumour therapy progress. Inddition, it reduces the cost of treatment by obviating the needor blood transfusions and growth factors [35]. Application ofighly conformal intensity-modulated radiotherapy reduces bonearrow irradiation. With the goal of sparing bone marrow, sev-
ral studies have applied intensity-modulated radiotherapy planshat included the bone marrow as an additional treatment plan-ing constraint in patients with cervical and endometrial cancer21,36]. When comparing organs at risk sparing with the conven-ional or intensity-modulated radiotherapy, bone marrow-sparinglans significantly reduced irradiation to the bladder, small intes-ine, and rectum, but also further reduced pelvic bone marrowrradiation at low volumes. In one study, bone marrow-sparingntensity-modulated radiotherapy reduced the pelvic bone marrowolume receiving a dose superior to 16.4 Gy. Bone marrow-sparingntensity-modulated radiotherapy reduced the volume of ilium,ower pelvis bone marrow, and small intestine receiving dosesuperior to 27.7, 18.7, and 21.1 Gy, respectively. In addition,one marrow-sparing intensity-modulated radiotherapy reducedhe volume of lumbosacral spine bone marrow at all dose lev-ls in all patients [21]. In another study, bone marrow-sparingntensity-modulated radiotherapy treatment plans demonstrated
significant reduction in the volume of bone marrow receivingore than 40% (18 Gy) of the prescription dose (45 Gy) comparedith both conventional intensity-modulated radiotherapy and
our-field treatment. On average, bone marrow-sparing intensity-odulated radiotherapy resulted in only 60% of the bone marrow
olume irradiated to more than 50% of the dose compared with7.4% (P < 0.001) of the bone marrow volume in a four-field plan and5.7% (P < 0.003) of the volume in an intensity-modulated radio-herapy plan [36]. In our study, the maximum allowable dose forone marrow was defined as V30 < 50% in the intensity-modulatedadiotherapy plan. Although bone marrow volume was assigned
last objective priority, the bone marrow objective was reachednd intensity-modulated radiotherapy significantly reduced irra-
iated volume of both sides of bone marrow at doses from 20 to5 Gy (P < 0.05). Our results indicate that using a well-designedlan, intensity-modulated radiotherapy can reduce bone marrow-paring to low volumes.
pie 18 (2014) 745–752 751
Due to its special anatomical position, the cervix easily movesand is subject to the impact of surrounding organs, such as thefilling state of the bladder and rectum. Due to the repetition ofradiation treatments, variations in patient positions usually takeplace throughout the entire treatment process, and thus, the phys-ical status of the internal organs changes as well. In addition,cervical tumour regression during treatment should also be con-sidered. Mobile organs compromise the efficacy of therapy andincrease irradiation to the organs at risk. In order to deliver anadequate dose to achieve sufficient efficacy for treatment as wellas minimize organs at risk irradiation, several different methodsare used to compensate for the discrepancies occurring in eachfraction [37]. However, further studies are needed to evaluatethese methods. Bladder filling has been proposed to overcomethese issues during cervical cancer radiotherapy [15,23,32,38].However, a reproducible bladder filling protocol has not beendeveloped due to individual differences in patients, poor com-pliance with bladder filling instructions, and the inability to fillthe bladder within a specified time [14,32]. However, bladderfilling remains a feasible method. Although consistency in blad-der filling is not always achieved, patients can still benefit fromit, particularly regarding organs at risk sparing [23,39]. In ourstudy, three steps were applied to avoid position changes. First,we applied a catheter to refill the bladder during CT imaging fortreatment planning. Second, an immobilized body bag was usedto constrain the motion. Third, all patients were instructed tostrictly follow the bladder filling instructions. Although no dif-ferences were found in average planning target volume dosesbetween full and empty bladders, significant reductions in irradi-ation to the bladder, small intestine, and rectum were obtainedfor full bladder Our results suggest that bladder filling may limitthe volume amount of the bladder and intestine in the treat-ment area and help reduce the radiation dose to the organs atrisk.
It is worth noting that the strength of this study is that allpatients recruited were stage IIB patients with no operation afterradiotherapy. The homogeneous pathology background made ourresults more predominant in comparison of efficacy and toxicity ofintensity-modulated radiotherapy and avoided background incon-sistency resulting from other published series with mixed clinicalsituations and sometimes mixed diseases.
Intensity-modulated radiotherapy plans also have advantagesregarding toxicity, predominantly in terms of gastrointestinal,hematologic, and genitourinary toxicity [24,28]. Due to the poten-tial for complications during the long-term follow-up period, wewere not able to include clinical outcomes in this report. How-ever, a prospective study is now underway at our hospital tocompare the clinical outcomes of these patients. Another limita-tion of this study is we did not measure organ motion, which mayresult in treatment inconsistencies. Our results suggest that well-planned intensity-modulated radiotherapy benefits cervical cancerpatients in areas with limited resources. Moreover, cliniciansshould be aware that new image-guided radiotherapy techniqueswill improve the accuracy of radiation field placement and reduceexposure to healthy tissue during radiation treatments, which isbeneficial to patients.
In summary, we have demonstrated the dosimetric superi-ority of intensity-modulated radiotherapy over conformal andconventional radiotherapies in the treatment of cervical cancer.Intensity-modulated radiotherapy provided significantly superiorplanning target volume coverage as well as significantly lower irra-diation to organs at risk, including the small intestine, rectum,
bladder, and bone marrow. It is anticipated that this reductionin normal tissue irradiated volume will translate into overallreductions in acute as well as late treatment-related toxici-ties.
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isclosure of interest
The authors declare that they have no conflicts of interest con-erning this article.
eferences
[1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics.CA Cancer J Clin 2011;61:69–90.
[2] Gnep K, Mazeron R. Radiotherapy for cervix carcinomas: clinical target volumedelineation. Cancer Radiother 2013;17:486–92.
[3] Du XL, Tao J, Sheng XG, Lu CH, Yu H, Wang C, et al. Intensity-modulated radiationtherapy for advanced cervical cancer: a comparison of dosimetric and clinicaloutcomes with conventional radiotherapy. Gynecol Oncol 2012;125:151–7.
[4] Ogino I, Kitamura T, Okamoto N, Yamasita K, Aikawa Y, Okajima H, et al. Laterectal complication following high dose rate intracavitary brachytherapy incancer of the cervix. Int J Radiat Oncol Biol Phys 1995;31:725–34.
[5] Wagner A, Jhingran A, Gaffney D. Intensity-modulated radiotherapy in gyne-cologic cancers: hope, hype or hyperbole? Gynecol Oncol 2013;130:229–36.
[6] Mazeron R, Dumas I, El Khouri C, Levy A, Attar M, Haie-Meder C. Intensity-modulated radiotherapy in cervical cancer: towards a new standard? CancerRadiother 2014;18:154–60.
[7] Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Con-current cisplatin-based radiotherapy and chemotherapy for locally advancedcervical cancer. N Engl J Med 1999;340:1144–53.
[8] Eifel PJ, Winter K, Morris M, Levenback C, Grigsby PW, Cooper J, et al. Pelvicirradiation with concurrent chemotherapy versus pelvic and para-aortic irra-diation for high-risk cervical cancer: an update of radiation therapy oncologygroup trial (RTOG) 90-01. J Clin Oncol 2004;22:872–80.
[9] Mundt AJ, Lujan AE, Rotmensch J, Waggoner SE, Yamada SD, Fleming G, et al.Intensity-modulated whole pelvic radiotherapy in women with gynecologicmalignancies. Int J Radiat Oncol Biol Phys 2002;52:1330–7.
10] Hasselle MD, Rose BS, Kochanski JD, Nath SK, Bafana R, Yashar CM, et al. Clinicaloutcomes of intensity-modulated pelvic radiation therapy for carcinoma of thecervix. Int J Radiat Oncol Biol Phys 2011;80:1436–45.
11] Folkert MR, Shih KK, Abu-Rustum NR, Jewell E, Kollmeier MA, Makker V,et al. Postoperative pelvic intensity-modulated radiotherapy and concurrentchemotherapy in intermediate- and high-risk cervical cancer. Gynecol Oncol2013;128:288–93.
12] Harris EE, Latifi K, Rusthoven C, Javedan K, Forster K. Assessment of organmotion in postoperative endometrial and cervical cancer patients treatedwith intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys2011;81:e645–50.
13] Haripotepornkul NH, Nath SK, Scanderbeg D, Saenz C, Yashar CM. Evaluation ofintra- and inter-fraction movement of the cervix during intensity-modulatedradiation therapy. Radiother Oncol 2011;98:347–51.
14] Jhingran A, Salehpour M, Sam M, Levy L, Eifel PJ. Vaginal motion and bladderand rectal volumes during pelvic intensity-modulated radiation therapy afterhysterectomy. Int J Radiat Oncol Biol Phys 2012;82:256–62.
15] Han Y, Shin EH, Huh SJ, Lee JE, Park W. Interfractional dose variation duringintensity-modulated radiation therapy for cervical cancer assessed by weeklyCT evaluation. Int J Radiat Oncol Biol Phys 2006;65:617–23.
16] Lim K, Small W, Portelance L, Creutzberg C, Jürgenliemk-Schulz IM, MundtA, et al. Consensus guidelines for delineation of clinical target volume forintensity-modulated pelvic radiotherapy for the definitive treatment of cervixcancer. Int J Radiat Oncol Biol Phys 2011;79:348–55.
17] Taylor A, Rockall AG, Reznek RH, Powell ME. Mapping pelvic lymph nodes:guidelines for delineation in intensity-modulated radiotherapy. Int J RadiatOncol Biol Phys 2005;63:1604–12.
18] Japan Clinical Oncology GroupToita R, Ohno T, Kaneyasu Y, Uno T, Yoshimura R,et al. A consensus-based guideline defining the clinical target volume for pelviclymph nodes in external beam radiotherapy for uterine cervical cancer. Jpn JClin Oncol 2010;40:456–63.
19] Roeske JC, Lujan A, Rotmensch J, Waggoner SE, Yamada D, Mundt AJ. Intensity-modulated whole pelvic radiation therapy in patients with gynecologicmalignancies. Int J Radiat Oncol Biol Phys 2000;48:1613–21.
20] Heron DE, Gerszten K, Selvaraj RN, King GC, Sonnik D, Gallion H, et al. Conven-tional 3D conformal versus intensity-modulated radiotherapy for the adjuvant
[
pie 18 (2014) 745–752
treatment of gynecologic malignancies: a comparative dosimetric study ofdose-volume histograms small star, filled. Gynecol Oncol 2003;91:39–45.
21] Mell LK, Tiryaki H, Ahn KH, Mundt AJ, Roeske JC, Aydogan B. Dosimetriccomparison of bone marrow-sparing intensity-modulated radiotherapy ver-sus conventional techniques for treatment of cervical cancer. Int J Radiat OncolBiol Phys 2008;71:1504–10.
22] Igdem S, Ercan T, Alc o G, Zengin F, Ozgüles R, Geceer G, et al. Dosimetriccomparison of intensity-modulated pelvic radiotherapy with 3D conformalradiotherapy in patients with gynecologic malignancies. Eur J Gynaecol Oncol2009;30:547–51.
23] Georg P, Georg D, Hillbrand M, Kirisits C, Potter R. Factors influencing bowelsparing in intensity-modulated whole pelvic radiotherapy for gynaecologicalmalignancies. Radiother Oncol 2006;80:19–26.
24] Chen M-F, Tseng C-J, Tseng C-C, Kuo Y-C, Yu C-Y, Chen W-C. Clinical outcomein posthysterectomy cervical cancer patients treated with concurrent cisplatinand intensity-modulated pelvic radiotherapy: comparison with conventionalradiotherapy. Int J Radiat Oncol Biol Phys 2007;67:1438–44.
25] Shih KK, Milgrom SA, Abu-Rustum NR, Kollmeier MA, Gardner GJ, Tew WP, et al.Postoperative pelvic intensity-modulated radiotherapy in high risk endome-trial cancer. Gynecol Oncol 2013;128:535–9.
26] Chen CC, Lin JC, Jan JS, Ho SC, Wang L. Definitive intensity-modulated radia-tion therapy with concurrent chemotherapy for patients with locally advancedcervical cancer. Gynecol Oncol 2011;122:9–13.
27] Liang Y, Bydder M, Yashar CM, Rose BS, Cornell M, Hoh CK, et al. Prospectivestudy of functional bone marrow-sparing intensity-modulated radiation ther-apy with concurrent chemotherapy for pelvic malignancies. Int J Radiat OncolBiol Phys 2013;85:406–14.
28] Poorvu PD, Sadow CA, Townamchai K, Damato AL, Viswanathan AN. Duo-denal and other gastrointestinal toxicity in cervical and endometrial cancertreated with extended-field intensity-modulated radiation therapy to paraaor-tic lymph nodes. Int J Radiat Oncol Biol Phys 2013;85:1262–8.
29] Yang B, Zhu L, Cheng H, Li Q, Zhang Y, Zhao Y. Dosimetric comparison ofintensity-modulated radiotherapy and three-dimensional conformal radio-therapy in patients with gynecologic malignancies: a systematic review andmeta-analysis. Radiat Oncol 2012;7:197.
30] Portelance L, Chao KS, Grigsby PW, Bennet H, Low D. Intensity-modulated radia-tion therapy (IMRT) reduces small bowel, rectum, and bladder doses in patientswith cervical cancer receiving pelvic and para-aortic irradiation. Int J RadiatOncol Biol Phys 2001;51:261–6.
31] Forrest J, Presutti J, Davidson M, Hamilton P, Kiss A, Thomas G. A dosimetricplanning study comparing intensity-modulated radiotherapy with four-fieldconformal pelvic radiotherapy for the definitive treatment of cervical carci-noma. Clin Oncol (R Coll Radiol) 2012;24:63–70.
32] van de Bunt L, Jurgenliemk-Schulz IM, de Kort GA, Roesink JM, Tersteeg RJ,van der Heide UA. Motion and deformation of the target volumes during IMRTfor cervical cancer: what margins do we need? Radiother Oncol 2008;88:233–40.
33] Sacks EL, Goris ML, Glatstein E, Gilbert E, Kaplan HS. Bone marrow regenerationfollowing large field radiation: influence of volume, age, dose, and time. Cancer1978;42:1057–65.
34] Scarantino CW, Rubin P, Constine 3rd LS. The paradoxes in patterns and mech-anism of bone marrow regeneration after irradiation. 1. Different volumes anddoses. Radiother Oncol 1984;2:215–25.
35] Klopp AH, Moughan J, Portelance L, Miller BE, Salehpour MR, Hildebrandt E,et al. Hematologic toxicity in RTOG 0418: a phase 2 study of postoperativeIMRT for gynecologic cancer. Int J Radiat Oncol Biol Phys 2013;86:83–90.
36] Lujan AE, Mundt AJ, Yamada SD, Rotmensch J, Roeske JC. Intensity-modulatedradiotherapy as a means of reducing dose to bone marrow in gynecologicpatients receiving whole pelvic radiotherapy. Int J Radiat Oncol Biol Phys2003;57:516–21.
37] Yan D, Ziaja E, Jaffray D, Wong J, Brabbins D, Vicini F, et al. The use of adaptiveradiation therapy to reduce setup error: a prospective clinical study. Int J RadiatOncol Biol Phys 1998;41:715–20.
38] Kerkhof EM, van der Put RW, Raaymakers BW, van der Heide UA, Jurgenliemk-Schulz IM, Lagendijk JJ. Intrafraction motion in patients with cervical
cancer: the benefit of soft tissue registration using MRI. Radiother Oncol2009;93:115–21.
39] Pan H, Qiu J, Quan H, Sun S, Guan Q, Zhang F. Bladder anatomical changes anddose variation during the course of intensity-modulated radiation therapy ofcervical cancer. Chin J Radiat Oncol 2011;20:218–21.
