Strahlenther Onkol (2021) 197:520–527

https://doi.org/10.1007/s00066-021-01782-5

ORIGINAL ARTICLE

Conventional 3D conformal radiotherapy and volumetric modulated

arc therapy for cervical cancer: Comparison of clinical results with
special consideration of the influence of patient- and treatment-related
parameters
Leif Hendrik Dröge1 · Franziska-Felicitas von Sivers1 · Markus Anton Schirmer1 · Hendrik Andreas Wolff2,3,4

Received: 9 November 2020 / Accepted: 30 March 2021 / Published online: 3 May 2021
© The Author(s) 2021

Abstract
Purpose Intensity-modulated radiotherapy (IMRT) for cervical cancer yields favorable results in terms of oncological
outcomes, acute toxicity, and late toxicity. Limited data are available on clinical results with volumetric modulated arc
therapy (VMAT). This study’s purpose is to compare outcome and toxicity with VMAT to conventional 3D conformal
radiotherapy (3DCRT), giving special consideration to the influence of patient- and treatment-related parameters on side
effects.
Materials and methods Patients with cervical cancer stage I–IVA underwent radiotherapy alone or chemoradiotherapy
using 3DCRT (n = 75) or VMAT (n = 30). Survival endpoints were overall survival, progression-free survival, and locore-
gional control. The National Cancer Institute Common Terminology Criteria for Adverse Events and the Late Effects of
Normal Tissues criteria were used for toxicity assessment. Toxicity and patient- and treatment-related parameters were
included in a multivariable model.
Results There were no differences in survival rates between treatment groups. VMAT significantly reduced late small
bowel toxicity (OR = 0.10, p = 0.03). Additionally, VMAT was associated with an increased risk of acute urinary toxicity
(OR = 2.94, p = 0.01). A low body mass index (BMI; OR = 2.46, p = 0.03) and overall acute toxicity ≥grade 2 (OR = 4.17,
p < 0.01) were associated with increased overall late toxicity.
Conclusion We demonstrated significant reduction of late small bowel toxicity with VMAT treatment, an improvement
in long-term morbidity is conceivable. VMAT-treated patients experienced acute urinary toxicity more frequently. Further
analysis of patient- and treatment-related parameters indicates that the close monitoring of patients with low BMI and of
patients who experienced relevant acute toxicity during follow-up care could improve late toxicity profiles.

Keywords Gynecologic cancer · Radiochemotherapy · Intensity-modulated radiotherapy · Urinary toxicity · Small bowel
toxicity · Body mass index

This work is part of the doctoral thesis of Franziska-Felicitas von

Sivers.

Availability of data and material The datasets generated and/or

analyzed in the current study are available from the corresponding
author by reasonable request.
2
University Medical Center Göttingen, Göttingen, Germany
 Dr. Leif Hendrik Dröge, MD
3
[email protected] Department of Radiology, Nuclear Medicine and
Radiotherapy, Radiologie München, 80333 Munich, Germany
1 4
Department of Radiotherapy and Radiation Department of Radiotherapy and Radiation Oncology,
Oncology, University Medical Center Göttingen, University Medical Center Regensburg, Regensburg,
Robert-Koch-Straße 40, 37075 Göttingen, Germany Germany

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Strahlenther Onkol (2021) 197:520–527 521

Introduction tients received abdominal ultrasound and chest radiograph

or a CT scan of the chest and abdomen. A pelvic MRI
Radiotherapy and chemoradiotherapy (RT/CRT) reduce lo- scan was performed for local tumor staging. A rectoscopy
cal and distant recurrence and improve survival in cervical or cystoscopy was performed in patients with clinical or
cancer [1, 2], not seldom at the expense of side effects radiological suspicion of invasion into rectum or bladder.
[3–6]. Recently, intensity-modulated radiotherapy (IMRT) According to local practice, surgical staging was not rou-
and volumetric modulated arc therapy (VMAT) were in- tinely performed. The treatment strategies (e.g., definitive
troduced into radiation oncology practice [7, 8]. IMRT RT/CRT vs. primary surgery) were discussed and deter-
was demonstrated to achieve favorable results in terms of mined on an individual basis in the multidisciplinary tu-
oncological outcomes and toxicity [9–12]. VMAT, at the mor board. Owing to the changes in treatment strategies
planning level, achieved excellent dose distributions [13, over the study period of approximately two decades and to
14]. On a clinical level, a few studies have reported favor- the retrospective study design, it is difficult to further con-
able toxicity profiles or promising outcomes with VMAT, cretize and generalize the indications. Overall, patients with
whereby these studies focused on adjuvant treatment [15], FIGO stages IIIA-IVA were preferably treated with defini-
neoadjuvant treatment [16], or treatment in elderly patients tive RT/CRT. The options in patients with FIGO stage IIB
[17]. However, comparisons of VMAT with other external were, depending on further clinical factors, primary surgery,
beam radiotherapy (EBRT) techniques are still rare [18]. definitive RT/CRT, and neoadjuvant RT/CRT. Patients with
We introduced VMAT to our clinic in 2009. The purpose FIGO stages I–IIA preferably underwent primary surgery.
of the current study was to compare clinical results of 3D The indication for adjuvant RT/CRT was determined de-
conformal radiotherapy (3DCRT) and VMAT when treating pending on histopathological adverse features. A neoadju-
cervical cancer. The endpoints were outcome and toxicity. vant RT/CRT for cervical cancer is not routinely used out-
We included patient- and treatment-related parameters with side of clinical trials. Here, according to local practice at
a possible influence on side effects in multivariable analysis. our gynecological cancer center, the indication could be set
after particularly intense discussion in the tumor board. Pa-
tients were informed in detail about the individual treatment
Patients and methods character before informed consent was given.

Patients Radiation therapy and chemotherapy

We included patients who were treated with RT/CRT for EBRT was applied with 6-MeV or 20-MeV linear accelera-
cervical cancer of Fédération Internationale de Gynécolo- tor photons. The target volumes were defined according to
gie et d‘Obstétrique (FIGO) stages I–IVA. Patients with the respective guidelines [21, 22]. The planning target vol-
distant metastases or paraaortic lymph node spread were ume was defined by adding a 10-mm margin to the clinical
excluded. The staging procedures were performed accord- target volume. The International Commission on Radiation
ing to the respective guidelines [19, 20] at our gynecological Units and Measurements (ICRU) reports provided the basis
cancer center or at a hospital selected by the patient. Pa- for plan calculation [23, 24]. In 3DCRT, a four-field box

Fig. 1 a, b Intraindividual comparison (transverse views) of dose distributions with a 3D conformal radiotherapy (3DCRT) plan (a) and a volumet-
ric modulated arc therapy (VMAT/RapidArc® , Varian Medical Systems, Palo Alto, USA) plan (b). The color wash ranges from 95% to 30% of the
prescribed dose of 50.4 Gy, the thick red line indicates the planning target volume

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technique (anteroposterior/right and left lateral) was used. son of patient characteristics and toxicity (cut-off p < 0.05).
In definitive RT/CRT, a two-field technique (anteroposte- A multivariable model (ordinal logistic regression [28], cut-
rior/posteroanterior) with central shielding was used for off p < 0.05) was established in cases of differences in tox-
boost therapy [25]. VMAT was performed using RapidArc® icity endpoints in the univariable analysis. First, the vari-
(Varian Medical Systems, Palo Alto, USA). The treatment ables were dichotomized (see Supplementary Table S1).
plans were calculated with the progressive resolution al- Secondly, parameters with a tendency towards an influ-
gorithm in Eclipse. These dose constraints were used for ence on toxicity (p < 0.2) were included in the multivari-
both 3DCRT and VMAT: small bowel ≥50 Gy in ≤10 cm3 able model. The survival times (overall survival, OS; pro-
volume and ≥40 Gy in ≤100 cm3 volume; rectum ≥65 Gy in gression-free survival, PFS; and locoregional control, LC)
≤17% volume and ≥40 Gy in ≤50% volume; bladder ≥65 Gy were calculated from the day of RT/CRT initiation. The log-
in ≤25% volume and ≥40 Gy in ≤50% volume. Fig. 1a, b rank test was performed to compare treatment groups (cut-
and Supplementary Figs. 1a, b and 2 illustrate a compari- off p < 0.05). We used SPSS v12.0 (IBM) for Kendall’s tau
son of dose distributions and dose–volume histograms with test, Mann–Whitney U test, and ordinal logistic regression.
3DCRT and VMAT. The chi-square test and the log-rank test were performed
Where indicated, high-dose-rate brachytherapy was ad- using STATISTICA v.10.0.1011.0 (StatSoft Inc.).
ministered. In definitive RT/CRT, in patients with stages
IB2–IVA, MRI was performed after EBRT. The treating ra-
diation oncologist chose between an intracavitary or a com- Results
bined intracavitary/interstitial approach, depending on tu-
mor shrinkage and patient anatomy. The brachytherapy was Patients
delivered to a total dose of 24 Gy (weekly sessions of 6 Gy).
In postoperative RT/CRT, in patients with close or positive In total, 105 consecutive patients (treatment between
vaginal margins, intracavitary brachytherapy was applied 11/1995 and 06/2014) met the inclusion criteria. Among
(10 Gy, two sessions of 5 Gy in 1 week). these, 75 (71%) were treated with 3DCRT and 30 (29%)
Where indicated, chemotherapy was given concurrently with VMAT. During the time period, 8 patients were irradi-
with RT. Standardly, weekly cisplatin (40 mg/m2 total body ated with IMRT. Since this study focused on patients treated
surface area, total 240 mg/m2, six cycles) was administered. with VMAT, these patients were not considered in further
In cases of decreased renal function, a different regimen analysis. Additionally, during the period, in 9 patients,
was selected or chemotherapy was omitted. the paraaortic region was included in treatment volumes.
Due to the relevant bias for outcomes and toxicities, these
Assessment of toxicity and follow-up patients were excluded from further analysis, too. In the
study cohort, the median follow-up was 56.1 months (range
The Common Terminology Criteria for Adverse Events 5.0–287.2) for the 3DCRT cohort and 29.3 months (range
(CTCAE) criteria (version 5.0) [26] were used to assess 5.2–65.3) for the VMAT cohort. Treatment groups were
acute toxicities. Patients were monitored at least weekly, in- balanced in baseline clinical characteristics (Table 1).
cluding physical examination and the acquisition of blood
samples. After RT/CRT, patients were monitored at least Radiation therapy and chemotherapy
every second week until symptoms were satisfactorily con-
trolled. The highest score of skin toxicity, proctitis, enteritis, Definitive RT/CRT was performed in 53 patients (50%),
and urinary toxicity was used to classify the grade of overall adjuvant RT/CRT was performed in 31 patients (30%), and
acute toxicity. The “Late Effects of Normal Tissues-subjec- neoadjuvant RT/CRT was applied in 21 patients (20%; Ta-
tive, objective, management, and analytic” (LENT-SOMA) ble 2). The reasons for omission of brachytherapy were pa-
criteria [27] were used to assess late toxicities. Patients were tient refusal (n = 4), technical infeasibility (n = 6), and dete-
monitored at least annually for 5 years. The highest score rioration of patient condition (n = 1). In total, in 36/53 (68%)
of skin toxicity, proctitis, small bowel toxicity, urinary tox- patients with definitive RT/RCT, in 23/31 patients (74%)
icity and vaginal toxicity was used to classify the grade of with adjuvant RT/RCT, and in 21/21 patients (100%) with
overall late toxicity. neoadjuvant RT/RCT, concomitant chemotherapy was ap-
plied. Patients who were not suitable for cisplatin received
Statistics mitomycin C (n = 4), 5-fluorouracil/mitomycin C (n = 1), or
carboplatin (n = 1).
The chi-square test (dichotomous variables), the Kendall’s
tau test (ordinal variables), and the Mann–Whitney U test
(continuous variables) were used for univariable compari-

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Table 1 Patient characteristics Table 2 Treatment characteristics

Parameter Study group p-value Parameter Study group
3D conformal Volumetric modu- 3D conformal Volumetric modulated
radiotherapy lated arc therapy radiotherapy arc therapy
Age, yearsb 55.2 (25–88) 56.3 (32–87) 0.9 Treatment regimen
Body mass 25.8 (15.7–45.9) 26.7 (19.8–40.5) 0.5 Definitivea 39 (52.0) 14 (46.7)
indexb Brachytherapya 32 (82.1) 10 (71.4)
FIGO stagea 0.1 Radiotherapy, total 70.1 (59.4–84.4) 69.7 (59.0–78.4)
I 22 (29.4) 7 (23.3) dose [Gy]b
II 25 (33.3) 12 (40.0) Received planned 39 (100.0) 14 (100.0)
III 25 (33.3) 5 (16.7) dose
IV 3 (4.0) 6 (20.0) Postoperativea 25 (33.3) 6 (20.0)
Histological subtypea 0.8 Brachytherapy 4 (16.0) 0 (0.0)
Squamous 62 (82.7) 26 (86.7) Radiotherapy, total 51.1 (48.6–60.4) 50.4 (all patients)
cell dose [Gy]b
Non-squa- 13 (17.3) 4 (13.3) Received planned 24 (96.0) 6 (100.0)
mous cell dose
Adenocarcinoma 11 (14.7) 3 (10.0) Preoperativea 11 (14.7) 10 (33.3)
Adenosquamous 1 (1.3) 1 (3.3) Radiotherapy, total 46.0 (45.0–50.4) 45.5 (45.0–50.4)
dose [Gy]b
Undifferentiated 1 (1.3) 0 (0.0)
Received planned 11 (100.0) 10 (100.0)
Histologic gradinga, c 0.7
dose
G1 2 (2.7) 1 (3.9)
Chemotherapya
G2 56 (75.7) 18 (69.2)
Yes 56 (74.7) 24 (80.0)
G3 16 (21.6) 7 (26.9)
Received full dose 45 (80.4) 23 (95.8)
FIGO Fédération Internationale de Gynécologie et d‘Obstétrique Received cisplatin 55 (98.2) 19 (79.2)
a
Data give the number of patients; the numbers in parentheses denote
aData give the number of patients; the numbers in parentheses denote
the percentage
b
Data give the mean, the numbers in parentheses give the range the percentage
c bData give the mean, the numbers in parentheses give the range
The information on histologic grading is missing in five patients

Outcome nary toxicity occurred in only a very small number of pa-

tients (n = 1 for 3DCRT and VMAT, Table 3 [acute organ
There were no significant differences in outcome between toxicity] and Supplementary Table S2 [hematologic toxic-
3DCRT-treated and VMAT-treated patients. ity]). The late toxicity data were available for 64 3DCRT-
In patients who underwent definitive RT/CRT, the 2-year treated patients (85.3%) and for 26 VMAT-treated patients
OS was 61% for both 3DCRT and VMAT (p = 0.9). The (86.7%). Late small bowel toxicity and overall late toxi-
2-year PFS was 80% for 3DCRT and 74% for VMAT city were significantly less frequent in the VMAT group
(p = 0.5). The 2-year LC was 85% for 3DCRT and 74% (Table 4).
for VMAT (p = 0.6). In multivariable analysis, the VMAT treatment was inde-
In patients who received adjuvant RT/CRT, 2-year OS pendently associated with an increased risk of acute urinary
was 96% for 3DCRT and 100% for VMAT (p = 0.6). The toxicity (p = 0.01, Table 5 and Supplementary Table S1). In
2-year PFS was 88% for 3DCRT and 100% for VMAT VMAT-treated patients, the risk for late small bowel tox-
(p = 0.5). The 2-year LC was 96% for 3DCRT and 100% icity was significantly reduced (p = 0.03). The overall oc-
for VMAT (p = 0.6). currence of late toxicity was significantly more frequent in
In patients who underwent neoadjuvant RT/CRT, the patients with low BMI (p = 0.03) and in patients with overall
2-year OS was 82% for 3DCRT and 90% for VMAT acute toxicity ≥grade 2 (p < 0.01).
(p = 0.7). The 2-year PFS was 100% for 3DCRT and 86%
for VMAT (p = 0.4). The 2-year LC was 100% for both
3DCRT and VMAT (p = 0.3). Discussion

Toxicity Within a prospective randomized trial, when comparing

IMRT with 3DCRT, Gandhi et al. reported a comparable
Overall acute urinary toxicity occurred more frequently dur- clinical outcome and a significant reduction of acute and
ing VMAT treatment, whereas high-grade (≥grade 3) uri- chronic toxicity with IMRT [10]. Thus, high-quality evi-

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Table 3 Acute toxicity Table 4 Late toxicity

Toxicity Study group p-value Toxicity Study group p-value
grade 3D conformal Volumetric modu- grade 3D conformal ra- Volumetric modulated
radiotherapy lated arc therapy diotherapy arc therapy
b
Skin a 0.6 Skina 0.9b
0 15 (20.0) 4 (13.4) 0 55 (85.9) 22 (84.6)
1 42 (56.0) 19 (63.3) 1 8 (12.5) 4 (15.4)
2 17 (22.7) 6 (20.0) 2 1 (1.6) 0 (0.0)
3 1 (1.3) 1 (3.3) Proctitisa 0.5b
b
Proctitisa 0.08 0 42 (65.6) 20 (77.0)
0 22 (29.4) 3 (10.0) 1 6 (9.4) 1 (3.8)
1 25 (33.3) 13 (43.3) 2 8 (12.5) 1 (3.8)
2 27 (36.0) 13 (43.3) 3 7 (10.9) 1 (3.8)
3 1 (1.3) 1 (3.4) 4 1 (1.6) 3 (11.6)
Enteritisa 0.6b Small bowel toxicitya <0.001b*
0 30 (40.0) 12 (40.0) 0 45 (70.2) 25 (96.2)
1 19 (25.4) 5 (16.7) 1 4 (6.3) 0 (0.0)
2 25 (33.3) 12 (40.0) 2 7 (10.9) 0 (0.0)
3 1 (1.3) 1 (3.3) 3 4 (6.3) 1 (3.8)
Urinary toxicitya 0.03b* 4 4 (6.3) 0 (0.0)
0 45 (60.0) 11 (36.7) Urinary toxicitya 0.1b
1 24 (32.0) 14 (46.7) 0 30 (46.9) 18 (69.2)
2 5 (6.7) 4 (13.3) 1 17 (26.6) 3 (11.5)
3 1 (1.3) 1 (3.3) 2 8 (12.5) 3 (11.5)
Overall acute toxicitya 0.18b 3 7 (10.9) 0 (0.0)
0 1 (1.3) 0 (0.0) 4 2 (3.1) 2 (7.8)
1 27 (36.0) 8 (26.7) Overall late toxicitya 0.04b*
2 44 (58.7) 19 (63.3) 0 19 (29.7) 15 (57.7)
3 3 (4.0) 3 (10.0) 1 15 (23.4) 4 (15.5)
*Statistically significant p-value 2 12 (18.8) 3 (11.5)
a
Data give the number of patients; the numbers in parentheses denote 3 12 (18.8) 1 (3.8)
the percentage 4 6 (9.3) 3 (11.5)
b
Univariate comparison, Kendall’s tau test
*Statistically significant p-value
a
Data give the number of patients; the numbers in parentheses denote
dence supports the wide use of IMRT in cervical cancer. the percentage
b
Univariate comparison, Kendall’s tau test
Further studies compared planning results with VMAT to
results with IMRT [13, 14, 29]. There appears a certain
amount of heterogeneity in the results: Cozzi et al. and In our study, VMAT significantly reduced late small
Sharfo et al. found similar target volume coverage, while bowel toxicity. Late small bowel toxicity is known to be
Renard-Oldrini et al. found an improvement with VMAT correlated with the bowel volume receiving higher radiation
[13, 14, 29]. While Cozzi et al. found improved organs at doses (≥50 Gy) [31]. Cozzi et al. demonstrated a great re-
risk sparing, Sharfo et al. do not support this finding [13, duction of the bowel volume receiving ≥40 Gy with VMAT
14]. However, in cervical cancer treatment, VMAT is used in cervical cancer. This reflects the technique’s potential
only in 26% of the radiation oncology facilities in Germany to achieve a minimization of the high-dose volumes [13].
[30]. Due to the rareness of the disease, only a limited num- Our study indicates that these dosimetric advantages trans-
ber of patients are treated per facility [30]. These aspects late into clinical benefits. In the VMAT group, small bowel
might explain that to date, only a few, mostly small studies toxicity only occurred in 1 patient (3.8%). Due to the re-
have reported clinical results with VMAT [15–18]. A sys- duction of small bowel toxicity, an improvement in long-
tematic comparison of VMAT with other EBRT techniques term morbidity is absolutely conceivable.
has only been occasionally reported [18]. We herein com- Additionally, it has to be considered that lesser side
pared clinical results with VMAT to clinical results with effects could result in a reduction of treatment breaks,
conventional 3DCRT. and, consequently, in more effective local and systemic
treatment. In our study, there were no differences in sur-

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Table 5 Influence of radiotherapy technique and patient- and treatment-related parameters on toxicity
Parameter Acute toxicity Late toxicity
Urinary toxicity Small bowel toxicity Overall late toxicity
OR (CI) p-value OR (CI)a p-value OR (CI) p-value
Radiotherapy techniquea 0.01 0.03 0.1
3DCRT (75) 1.00 – 1.00 – 1.00 –
VMAT (30) 2.94 (1.27–6.67) – 0.10 (0.01–0.78) – 0.46 (0.18–1.16) –
Radiotherapy, total dosea 0.4
>50.4 Gy (65) 1.00 – – – – –
≤50.4 Gy (50) 0.58 (0.17–1.93) – – – – –
Brachytherapya 0.5
Yes (46) 1.00 – – – – –
No (59) 0.67 (0.20–2.25) – – – – –
Hysterectomy prior to treatmenta 0.2
Yes (31) – – 1.00 – – –
No (74) – – 0.52 (0.18–1.51) – – –
Acute toxicity, enteritisa 0.1
<grade 2 (66) – – 1.00 – – –
≥grade 2 (39) – – 2.56 (0.89–7.69) – – –
Body mass indexa,b 0.03*
Median: 25.4
≥median (49) – – – – 1.00 –
<median (49) – – – – 2.46 (1.09–5.55) –
Overall acute toxicitya <0.01*
<grade 2 (36) – – – – 1.00 –
≥grade 2 (69) – – – – 4.17 (1.69–10.04) –
OR odds ratio, CI confidence interval, 3DCRT 3D conformal radiotherapy, VMAT volumetric modulated arc therapy
*Statistically significant p-value
a
Parameters were preselected in univariate analysis for multivariate model, see Supplementary Table S1
b
The information on body mass index is missing in seven patients

vival rates at 2 years. Similarly, previous studies have [10, 16]. Gandhi et al. found no differences in rates of geni-
reported comparable survival rates with IMRT and con- tourinary toxicity rates when comparing IMRT and conven-
ventional EBRT techniques [9, 11]. In a study by Roszak tional 3DCRT [10]. The authors discuss that in their study’s
et al., gastrointestinal toxicity was the main reason for 3DCRT-treated patients, the lack of blocks used could have
interruptions of RT/CRT [32], whereas the overall rates led to higher genitourinary toxicity rates (here, ≥grade 3
of severe gastrointestinal toxicity (≥grade 3) are lower toxicity in 13.6% of the patients) as compared to previ-
than 10% for conventional and novel EBRT techniques ous studies [10]. In our study, blocks were used for boost
[11, 16]. Similarly, we found ≥grade 3 overall acute toxic- therapy in 3DCRT [25]. Thus, possibly due to the increase
ity in ≤10% of patients. However, of course, novel EBRT in the total volume of the bladder wall being exposed to
techniques should aim at reducing both severe and less pro- irradiation with VMAT, higher toxicity rates might be ex-
nounced side effects. Eventually, the already low rates of plained. However, the increase was seen primarily in the
severe treatment-related toxicity with conventional EBRT <grade 3 toxicities. In line with other studies, severe acute
techniques might leave limited space to attain improved urinary toxicity occurred in less than 5% of all patients [16,
outcome through a possible reduction of treatment breaks. 17]. Thus, the significance for the whole patient population
Interestingly, we found that the VMAT treatment was remains limited and increased attention should be paid to
associated with an increased risk of acute urinary toxi- long-term side effects and quality of life, which are espe-
city. During RT/CRT, genitourinary toxicity is less com- cially important from a patient perspective [5]. Finally, due
mon than gastrointestinal toxicity, with relevant toxicities to the relatively small sample size, the heterogeneity of the
in only 1.5% of patients [4]. These low rates are compara- cohort, and the rare occurrence of genitourinary toxicity, an
ble to ≥grade 3 urinary toxicity with VMAT in our study overinterpretation of the findings should be avoided.
(3.3%), with VMAT in the study by Vandecaastele et al. In our study, a low BMI and acute toxicity ≥grade 2
(0%), and with IMRT in the study by Gandhi et al. (0%) were associated with increased overall late toxicity. Previ-

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ous studies have demonstrated an influence of patient- or itoring of patients with a low BMI and of patients who
treatment-related parameters on side effects in RT/CRT of experienced acute toxicity ≥grade 2 could improve late
pelvic malignancies [32–37]. Furthermore, there is evidence toxicity profiles. Finally, modern irradiation techniques
that the severity of acute toxicity is correlated with the oc- with lower rates of toxicity could pave the way for more
currence of late toxicity [36, 38]. First, we found that a low effective systemic treatment options. This could result in
BMI was associated with a twofold-increased risk of over- a relevant improvement of outcomes and quality of life.
all late toxicity. In patients treated with CRT, the influence Supplementary Information The online version of this article (https://
of bodily constitution on chemotherapy pharmacokinetics doi.org/10.1007/s00066-021-01782-5) contains supplementary mate-
might explain the differences in damage to normal tissues rial, which is available to authorized users.
[35]. Furthermore, the links between adipose tissue, chronic
Funding The authors received no specific financial support for the
inflammation, and the immune system may provide a pos- research, authorship, and/or publication of this article.
sible explanation [34]. Secondly, in our study, overall acute
toxicity ≥grade 2 was associated with a fourfold-increased Author Contribution LHD, FFS, MAS, and HAW initiated the study.
risk of overall late toxicity. This finding is in line with previ- MAS and HAW contributed to its design and coordination. LHD and
FFS collected the clinical data. LHD, FFS, MAS, and HAW performed
ous studies which found an association of acute toxicity and the statistical analysis and interpreted the results. LHD and HAW took
late toxicity in treatment of gynecologic malignancies [36, the lead in writing the manuscript. All authors read and approved the
38]. The predictive value of the BMI and of the occurrence final manuscript.
of acute toxicity ≥grade 2 bear important implications for
Funding Open Access funding enabled and organized by Projekt
clinical practice. In both patient groups, close monitoring DEAL.
during follow-up is reasonable.
A retrospective single-center study may suffer from bi-
ases which could have distorted the results. Furthermore, Declarations
we included patients with different treatment schedules,
different radiation doses, different chemotherapy regimens Conflict of interest L.H. Dröge, F.-F. von Sivers, M.A. Schirmer, and
H.A. Wolff declare that they have no competing interests.
or no concomitant chemotherapy administered, and differ-
ent staging procedures (e.g., a relevant proportion of pa- Ethical standards This investigation was approved by the local ethics
committee of the University of Göttingen Medical Center (application
tients without surgical lymph node staging). Additionally,
number 8/5/14An). The study has been conducted in accordance with
we did not include an analysis of dose–volume histograms the Declaration of Helsinki principles.
in our study, which could further clarify the relationships
Open Access This article is licensed under a Creative Commons At-
between RT technique and side effects. The multivariable tribution 4.0 International License, which permits use, sharing, adapta-
analysis, including patient- and treatment-related parame- tion, distribution and reproduction in any medium or format, as long as
ters, addressed these issues in part. Additionally, the long you give appropriate credit to the original author(s) and the source, pro-
period of the study might have led to changes in local treat- vide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
ment practice. Since physician-dependent differences in the included in the article’s Creative Commons licence, unless indicated
delineation of target volumes significantly contribute to het- otherwise in a credit line to the material. If material is not included
erogeneity in RT/CRT of cervical cancer [39], as previously in the article’s Creative Commons licence and your intended use is not
reported, we developed strategies to improve treatment ho- permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view
mogeneity [39]. The incidence of cervical cancer is low, a copy of this licence, visit http://creativecommons.org/licenses/by/4.
and studies on VMAT treatment are rare. Thus, our study 0/.
significantly contributes to the understanding of the role
of VMAT and patient- and treatment-related parameters in
RT/CRT of cervical cancer. References
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Reducing uncertainties about the effects of chemoradiotherapy for
Conclusion cervical cancer: a systematic review and meta-analysis of individual
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