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Acute chemoradiotherapy toxicity in cervical cancer patients

  • Marija Zivkovic Radojevic EMAIL logo , Aleksandar Tomasevic , Vesna Plesinac Karapandzic , Neda Milosavljevic , Slobodan Jankovic and Marko Folic
Published/Copyright: September 2, 2020
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Open Medicine
From the journal Open Medicine Volume 15 Issue 1

Abstract

During radiotherapy treatment for cervical cancer, up to 84% of patients exhibit some form of acute radiation toxicity (ART). The primary aim of this clinical study is to determine the impact of angiotensin-converting enzyme (ACE) inhibitors, β-blockers and other risk factors such as the patient’s anatomical characteristics on ART emergence in patients with locally advanced cervical cancer treated by chemoradiotherapy. This is a combination of two nested case–control studies within the cohort of patients with locally advanced cervical cancer based on the analysis of potential risk factors for the onset of ART in patients treated with 3D conformal radiotherapy (3D-CRT) and 2D conventional radiotherapy (2D-RT), prospectively followed up from January 2017 to September 2018 in a tertiary care hospital. The ACE inhibitors and bladder volume were identified as factors that significantly affect the occurrence of ART in patients treated with 3D-CRT. In patients treated with 2D-RT, the factors that significantly affect the occurrence of ART were ACE inhibitors, body mass index (BMI), brachytherapy rectal and bladder dose. This study has shown that BMI, radiation dose received by the bladder and rectum are of exceptional importance for the occurrence of the ART and also that therapy with ACE inhibitors was associated with the decreased chances of the ART.

Keywords: cervical cancer; radiotherapy; acute radiation toxicity; ACE inhibitors

1 Introduction

Cervical cancer is the fourth most common malignancy among women [1]. The gold-standard treatment for locally advanced cervical cancer (Federation Internationale de Gynecologie etd’ Obstetrique (FIGO) stage IIb to IVa) is concurrent chemoradiotherapy (CCRT), including chemotherapy with external beam radiotherapy (EBRT), followed by brachytherapy [2,3].

Radiotherapy treatment can cause acute radiation toxicity (ART) (within 90 days, from initiation of treatment) and/or chronic radiation toxicity (months and years after completion of radiotherapy). During radiotherapy treatment for cervical cancer, up to 84% of patients exhibit some form of ART [4,5,6]. The most common manifestations are hematological, gastrointestinal or genitourinary toxicity. The intensity and severity of these adverse radiotherapy effects depend on the radiation dose, the fractionation regime, the radiation technique applied and the duration of the treatment [6]. However, the interactions among the patient’s individual characteristics, the disease stage, genetic aspects, comorbidities and other applied therapeutic modalities are also known to be factors [7,8,9,10]. The emergence of serious ART is one of the most important causes of the development of chronic toxicity, which often requires extensive intervention and increasing costs of the long-term treatment. As a result, there is ample incentive to work on the timely and accurate identification and monitoring of patients at an increased risk of developing ART.

Also, it is unknown whether the individual therapy, prescribed for the treatment of other nononcological diseases, during radiation can contribute to the emergence and severity of ART. Given that antihypertensives are among the most prescribed drugs, and that their action is manifested through receptors expressed in various tissues and organs, their use might exert certain influence on the effects of the radiotherapy applied. Earlier experimental studies have shown that angiotensin-converting enzyme (ACE) inhibitors have some effect on reducing radiation toxicity, while the influence of one of the most commonly used drugs in light of ART during the radiotherapy remains controversial [11,12,13,14,15,16,17,18,19].

The primary aim of this clinical study is to determine the impact of ACE inhibitors, β-blockers and other potential risk factors such as the patient’s pelvic and anatomical characteristics on ART emergence in patients with locally advanced cervical cancer treated by chemoradiotherapy.

2 Subjects and methods

2.1 Study design

This study was designed as the combination of two nested case–control studies within the cohort of patients with locally advanced cervical cancer based on the analysis of potential risk factors important for the onset of ART in 54 patients treated with 3D conformal radiotherapy (3D-CRT) and 84 patients treated with 2D conventional radiotherapy (2D-RT), prospectively followed up from January 2017 to September 2018 in a tertiary care hospital. This study was reviewed and approved by the Ethics Committee.

2.2 Study sample

All patients who met the inclusion criteria for study participation were monitored during the CCRT, following the informed consent. Depending on the outcome of the occurrence of ART underway 2D-RT or 3D-CRT, they were classified into two groups. The group of cases consisted of patients with verified locally advanced cervical cancer, initially treated with CCRT, who developed ART grade 2 or higher according to the relevant Common Terminology Criteria for Adverse Events version 4.03 during radiotherapy treatment [20]. The number of case was equal to the number of control besides the fact that the gender of the patients is the same and age of patients was a matching criterion. For each case, all possible match controls were found from the cohort group. If there were multiple match controls for one case, only one was chosen by randomization using a random number generator from SPSS-18 statistical software.

All patients, without exception, were subjected to standard preventative measures for ART minimization according to the hospital protocol. These measures include the prevention of gastrointestinal toxicity (prescribing a hygienic diet regimen during radiotherapy), hematology (control of laboratory analyzes once a week) and genitourinary toxicities (maintaining hygiene, adequate fluid intake, urine culture, providing protocols to ensure constant bladder overload) as well as adherence to radiotherapy constrains for the organs at risk.

The inclusion criteria were as follows: 18–80 years of age, pathohistologically verified cervical cancer, FIGO stages from IIb to IVa, good general condition estimated based on the reference scale of the Eastern Cooperative Oncology Group or performance status 0 to 2 [21] and the completed CCRT treatment. Criteria for exclusion from the research were the presence of mental illness, pregnancy and lactation.

Standard CCRT treatment included:

  1. Cisplatin-based chemopotentiation: at a dose of 40 mg/m2 calculated body surface area using Mosteller’s formula, administered 2 hours before radiotherapy course, once a week.

  2. Radiotherapy (EBRT + brachytherapy).

The study included two cohorts of patients treated in identical manner according to the hospital protocol, the only difference being different radiotherapy techniques used to adjust for the effect of a radiotherapy technique on the occurrence of acute radiation toxicity manifestations.

2.3 2D-RT

EBRT planning was conducted on an X-ray simulator. Radiotherapy was performed on a linear accelerator, in a 5 day regimen, with parallel opposite fields (2D technique) and photons of energy from 6 to 10 MV. A EBRT dose from 45 to 50.4 Gy was applied using a standard fractionation regimen (1.8 Gy per day). In patients with verified paraaortic lymphadenopathy involvement, expanded fields were used [22].

2.4 3D-CRT

3D-CRT planning was conducted on a computer tomography (CT) simulator. The same fractionation and dosing regimen were used as for the patients treated with 2D-RT with four fields (box technique). Target volume delineation and organ at risk were contoured according to the Radiation Therapy Oncology Group [23].

2.5 Brachytherapy

High-dose rate (HDR) brachytherapy was performed using a remote afterloading technique. All patients were treated with a dose of 6–7 Gy per fraction in four to five sessions [24]. The dose at point A and point B was calculated based on the recommendations of the International Commission on Radiation Units (ICRU Report No. 38) [25]. Rectal and bladder doses were calculated to the ICRU points using two orthogonal radiographies with the contrast placed in these organs at risk.

2.6 Personal therapy, patients and treatment characteristics

Prior to commencement of cancer treatment, patients were receiving their usual therapeutic doses of ACE inhibitors and β-blockers as prescribed by a general practitioner or cardiologist and in accordance with therapeutic indications. The use of the following ACE inhibitors was recorded: enalapril (10–20 mg daily), perindopril (4–8 mg daily), ramipril (5–10 mg daily), fosinopril (10–20 mg daily). Patients were receiving selective and non-selective beta blockers – propranolol (40–160 mg), atenolol (100 mg), and bisoprolol (5 mg).

The following variables were examined: sociodemographic data (age, education, Charlson’s comorbidity–age combined risk score [26] and presence of hypertension); patients habits (cigarette smoking and alcohol consumption); data from the medical records (previous abdominal or pelvic surgery, number of years since intervention, pathohistological type of tumor, FIGO stage, administration of ACE inhibitors, β-blockers and over four cycles of chemotherapy), parameters related to radiotherapy technique (surface of radiation fields, paraaortic fields, photon energy, uterine probe over 5 cm, bladder and rectal doses and duration of radiotherapy treatment), adherence to the prescribed diet regime, relevant measurements of interest in terms of body height and weight, waist circumference and bi-spinal diameter (with the help of a Breisky pelvimeter). Based on available parameters, pelvic gross volume was obtained using the formula for calculating the volume of a sealed coupe:

V=Hπ3(R2+Rr+r2)

where H is radiotherapy fields height, R is bi-spinal diameter and r is radiotherapy field width.

In contrast to the patients who received 2D-RT, in the patients treated with 3D-CRT, we measured the pelvic gross volume, subcutaneous fatty tissue and the volumes of organs at risk (bladder, rectal and bowel bag) using a CT-based three-dimensional approach. The pelvic volume was determined by contouring the volume beginning from the front of the pelvic spines, back to the L4–L5 vertebrae level and then to the vaginal introitus.

Although all examined variables were monitored and recorded weekly, the values for analyzed clinical variables presented in the Section 3 were measured immediately prior to initiation of therapy.

2.7 Statistics

The collected data were processed using descriptive statistics. For continuous variables, the significance of the difference was tested using the parametric Student’s t-test and nonparametric tests (Mann–Whitney U test) in case of nonnormal data distribution. The χ2 test was used for categorical variables. The differences in the compared data were considered statistically significant if the probability of the null hypothesis was less than 5% (p < 0.05). The variables which turned out to be significant predictors for ART after univariate logistic analysis were then put through a multivariate binary logistic regression. Benjamini–Hochberg method was used to control the false discovery rate for multicomparison p-value correction. SPSS-18 statistical software for Windows was used to calculate and process the data.

3 Results

Fifty-four patients treated with 3D-CRT and 84 patients treated with 2D-RT who had given their informed consent and had completed the entire CCRT treatment were included in this study.

3.1 3D-CRT

The main characteristics of the patients treated with 3D-CRT and the differences between groups are presented in Table 1. Univariate analysis showed that cigarette smoking had a statistically significant impact on the onset ART. The analysis of the specific drugs used during radiotherapy, the chemotherapy regime, showed that ACE inhibitor therapy, concurrent with radiotherapy, had a statistically significant effect on the appearance of ART. The parameters related to the applied radiotherapy technique, which proved to be statistically significant, were a pause in therapy of more than 7 days and bladder volume. In addition to the constitutional parameters that proved to be statistically significant, we assessed the possible impact on the appearance of ART of weight ≤ 60 kg, BMI under 21 kg/m2, gross pelvic volume and volume of the pelvic subcutaneous fatty tissue.

Table 1

Analysis of potential risk factors important for ART onset in patient treated with 3D-CRT

VariablesUnivariate analysisMultivariate analysis
With toxicity (n = 27)Without toxicity (n = 27)Test and p-valuesExp(B) (95% CI for ExpB)p
Age50.41 (±9.162)49.78 (±9.078)t = −254
p = 0.801a
Education groups of patients (years)
Primary school3 (11.1%)1 (3.7%)χ2 = 1.730
high school16 (59.3%)20 (74.1%)p = 0.421
College8 (26.6%)6 (22.2%)
Charlson's comorbidity-age combined risk score
Score 2 (mildly ill)5 (18.5%)5 (18.5%)χ2 = 0.929
Score 3 (moderately ill)5 (18.5%)7 (25.9%)p = 0.818
Score 4 (severely ill)7 (25.9%)8 (29.6%)
Score 5 (severely ill)10 (37.0%)7 (25.9%)
Hypertension8 (44.4%)10 (37.0%)χ2 = 0.247
p = 0.619
Smoking16 (59.3%)8 (29.6%)χ2 = 4.8001.043 (0.109–9.991)p = 0.971
p = 0.028
Alcohol4 (14.8%)3 (11.1%)χ2 = 0.164
p = 0.685
Surgery in the abdomen or small pelvis10 (37.0%)9 (33.3%)χ2 = 0.081
p = 0.776
Patohistological type of tumor
Squamocellular26 (96.3%)24 (88.9%)χ2 = 1.080
Adenocarcinoma3 (11.1%)1 (3.7%)p = 0.299
FIGO stage
IIb9 (33.3%)7 (25.9%)χ2 = 1.972
IIIa7 (25.9%)10 (37.0%)p = 0.578
IIIb8 (29.6%)5 (18.5%)
IVa3 (11.1%)5 (18.5%)
ACE inhibitors15 (55.6%)7 (25.9%)χ2 = 4.9090.060 (0.004–0.817)p = 0.035
p = 0.027
β-Blockers4 (14.8%)10 (37.0%)χ2 = 3.471
p = 0.062
Over 4 chemotherapy cycles9 (33.3%)10 (37.0%)χ2 = 0.081
p = 0.776
Radiation in hospital conditions5 (18.5%)10 (37.0%)χ2 = 2.308
p = 0.129
Intrauterine probe ≥5 cm20 (74.1%)22 (81.5%)χ2 = 0.429
p = 0.513
Rectal dose 62.089 (±11.184)55.370 (±16.559)t = −1.474
p = 0.087a
Bladder dose 59.952% (±16.384)52.223% (±13.136)t = −1.910
p = 0.062a
Total radiotherapy duration over 56 days21 (77.8%)17 (63.0%)χ2 = 1.421
p = 0.233
Pause over 7 days14 (51.9%)5 (18.5%)χ2 = 6.5776.384 (0.544–74.991)p = 0.140
p = 0.010
Adherence to the proposed diet
Yes7 (25.9%)11 (40.6%)χ2 = 2.222
No12 (44.4%)12 (44.4%)p = 0.329
Partially8 (29.6%)4 (14.8%)
Bladder volume (cm3)273.653 (±41.652)226.653 (±35.209)t = −4.4831.034 (1.003–1.085)p = 0.034
p < 0.001a
Rectal volume (cm3)133.596 (±24.649)125.474 (±19.311)t = −1.348
p = 184a
Bowel bag volume (cm3)792.690 (±85.687)764.777 (±143.053)t = −0.870
p < 0.388a
Height ≥175 cm9 (33.3%)5 (18.5%)χ2 = 1.543
p = 0.214
Weight ≤60 kg12 (44.4%)4 (14.8%)χ2 = 5.6841.767 (0.047–66.503)p = 0.758
p = 0.017
Body mass index (BMI) under 21 kg/m213 (48.1%)21 (77.8%)χ2 = 5.0820.745 (0.494–1.125)p = 0.162
p = 0.024
Pelvic gross volume (cm3)4675.74 (±934.061) 6162.667 (±1433.513) t = 4.5161.000 (0.998–1.003)p = 0.276
p < 0.001a
Volume of the pelvic subcutaneous fatty tissue (cm3)1384.180 (±0.555)2402.629 (±0.959)t = 4.7720.998 (0.995–1.001)p = 0.234
p < 0.001a

Data represent the mean value ± 1 standard deviation (SD).

  1. a

    Student’s t test for independent samples.

We analyzed variables that had been proven to be statistically significant (p < 0.05) in the univariate analysis (Table 1). By using multivariate logistic regression, ACE inhibitors (ORadjusted = 0.060, 95% CI = 0.004–0.817; p = 0.035) and bladder volume (ORadjusted = 1.034, 95% CI = 1.003–1.085; p = 0.034) were isolated as factors with a potential impact on the ART. Hosmer-Lemeshow Goodness-of-Fit Test for logistic regression was Chi-square = 5.694; df = 8; p = 0.682 (Cox & Snell R2 0.605, Nagelkerke R2 0.807). There were significant variables after corrections for multiple comparisons (Table 3).

3.2 2D-RT

The main characteristics of the patients treated with 2D-RT, as well as the differences between groups, are presented in Table 2. Univariate analysis showed that all the following factors significantly affected ART occurrence: level of education and FIGO stage and specific drugs used during radiotherapy, the chemotherapy regime and the radiotherapy technique, ACE inhibitors and β-blockers therapy, more than four cycles of chemotherapy administration, treatment duration and treatment pause and parameters related to the brachytherapy application, such as intrauterine probe >5 cm in length, rectal dose and bladder dose. Among the analyzed patient’s constitutional characteristics, it was found that weight less than 60 kg, BMI, waist circumference and pelvic gross volume are significant factors in the occurrence of ART.

Table 2

Analysis of potential risk factors important for ART onset in patient treated with 2D-RT

VariablesUnivariate analysisMultivariate analysis
With toxicity (n = 42)Without toxicity (n = 42)Test and p-valuesExp(B) (95% CI for ExpB)p
Age56.07 (±11.221)52.29 (±9.470)t = 1.733
p = 0.087a
Education groups of patients (years)
Primary school16 (38.1%)5 (11.9%)χ2 = 7.8390.310 (0.068–1.410)p = 0.130
High school20 (47.6%)30 (71.4%)p = 0.020
College6 (14.3%)7 (8.3%)
Charlson’s comorbidity-age combined risk score
Score 2 (mildly ill)7 (16.75%)10 (23.8%)χ2 = 0.840
Score 3 (moderately ill)10 (23.8%)10 (23.8%)p = 0.840
Score 4 (severely ill)9 (21.4%)9 (21.4%)
Score 5 (severely ill)16 (38.1%)13(31.0%)
Hypertension13 (31.0%)10 (23.8%)χ2 = 0.539
p = 0.463
Smoking28 (66.7%)22 (52.4%)χ2 = 1.779
p = 0.182
Alcohol6 (14.3%)3 (7.1%)χ2 = 1.120
p = 0.220
Surgery in the abdomen or small pelvis18 (42.9%)10 (23.8%)χ2 = 3.429
p = 0.064
Surgery before 10 years10 (83.3%)13 (61.9%)χ2 = 1.660
p = 0.198
Patohistological type of tumor
Squamocellular33 (78.6%)38 (90.5%)χ2 = 2.275
Adenocarcinoma9 (21.4%)4 (9.5%)p = 0.131
FIGO stage
IIb11 (26.2%)23 (54.8%)χ2 = 9.2751.537 (0.676–3.494)p = 0.305
IIIa13 (31.0%)12 (28.6%)p = 0.026
IIIb12 (28.6%)4 (9.5%)
IVa6 (14.3%)3 (7.1%)
ACE inhibitors16 (38.1%)6 (14.3%)χ2 = 6.1580.037 (0.002–0.768)p = 0.033
p = 0.013
β-Blockers11 (26.2%)4 (9.5%)χ2 = 3.9775.513 (0.243–125.332)p = 0.284
p = 0.046
Single dose of cisplatin70.544 (±5.765)72.349 (±6.496)t = −1.347
p = 0.182a
Over 4 chemotherapy cycles13 (31.0%)23 (54.8%)χ2 = 4.8613.427 (0.574–20.473)p = 0.177
p = 0.027
Radiation in hospital conditions12 (14.3%)7 (8.3%)χ2 = 1.700
p = 0.192
Surface of radiation field (cm2)279.909 (±50.467)275.909 (±43.345)t = 0.390
p = 0.289a
Paraaortic field5 (11.9%)3 (7.1%)χ2 = 0.553
p = 0.457
Energy (MV)6.95 (±1.724)7.33 (±1.908)t = −0.960
p = 0.059a
Intrauterine probe ≥5 cm41 (97.6%)35 (83.3%)χ2 = 4.97453.092 (0.422–6683.327)p = 0.107
p = 0.026
Rectal dose64.605 (±15.178)48.819 (±14.567)t = 4.9971.065 (1.001–1.133)p = 0.045
p < 0.001a
Bladder dose61.693 (±16.433)43.282 (±13.621)t = 5.5901.072 (1.002–1.147)p = 0.044
p < 0.001a
Total radiotherapy duration (days)79.67 (±22.168)64.05 (±25.251)Z = −3.8010.981 (0.926–1.038)p = 0.506
p < 0.001b
Pause (days)20.33 (±22.139)6.79 (±12.193)t = 3.4741.075 (0.982–1.178)p = 0.117
p < 0.001a
Adherence to the proposed diet
Yes12 (28.6%)20 (47.6%)χ2 = 3.244
No20 (47.6%)15 (35.7%)p = 0.198
Partially10 (23.8%)7 (16.7%)
Height ≥ 175 cm10 (23.8%)6 (14.3%)χ2 = 1.235
p = 0.266
Weight ≤ 60  kg15 (35.7%)5 (11.9%)χ2 = 6.5634.854 (0.484–48.715)p = 0.179
p = 0.010
BMI (kg/m2)24.000 (±3.438)26.000 (±4.710)t = −2.2230.709 (0.523–0.962)p = 0.027
p = 0.029
Waist size82.14 (±10.873)86.67 (±9.869)t = −1.9971.063 (0.952–1.188)p = 0.276
p = 0.049a
Bruto pelvic volume (cm3)6753.34 (±1433.27) 7656.28 (±1480.94) t = −2.8391,000 (0.999–1.000)p = 0.513
p = 0.006a

Data represent the mean value ± 1 standard deviation.

  1. a

    Student’s t-test for independent samples.

  2. b

    Mann–Whitney U test.

Using multivariate logistic regression, the following factors were identified, which significantly affect ART occurrence in patients treated with 2D-RT: ACE inhibitors (ORadjusted = 0.037, 95% CI = 0.002–0.768; p = 0.033), BMI (ORadjusted = 0.709, 95% CI = 0.523–0.962; p = 0.027), brachytherapy rectal (ORadjusted = 1.065, 95% CI = 1.001–1.133; p = 0.045) and bladder dose (ORadjusted = 1.072, 95% CI = 1.002–1.147; p = 0.044). Hosmer-Lemeshow Goodness-of-Fit Test for logistic regression was Chi-square = 3.118; df = 8; p = 0.927 (Cox & Snell R2 0.525, Nagelkerke R2 0.700). There were significant variables after corrections for multiple comparisons (Table 3).

Table 3

Benjamini–Hochberg correction for adjusted p-value

VariablesUnadjusted p-valuesAdjusted p-values
3D-CRTa
Smoking0.0280.028
ACE inhibitors0.0270.028
Pause over 7 days0.0100.020
Bladder volume (cm3)0.0000.000
Weight ≤ 60 kg0.0170.027
BMI less than 21 kg/m20.0240.028
Pelvic gross volume (cm3)0.0000.000
2D-RTb
ACE inhibitors0.0330.045
Rectal dose0.0450.045
Bladder dose0.0440.045
BMI (kg/m2)0.0270.045
  1. a

    3D-CRT.

  2. b

    2D-RT.

The toxicity observed during the treatment was usually of mild to moderate intensity (Figure 1). In the group treated with 3D-CRT, there were no manifestations of ART of grade 4.

Figure 1 Distribution of acute radiation toxicity depending on radiotherapy technique.
Figure 1

Distribution of acute radiation toxicity depending on radiotherapy technique.

4 Discussion

The risk factors for ART occurrence can be identified (at a certain level) based on the anamnestic data and the data from the disease history and then by physical examination or simple anthropometric measurements.

It is interesting to note that brachytherapy dose escalation-associated factors have a significant effect on ART onset, while the brachytherapy initiation coincides with the peak of ART manifestation, especially in the case of genitourinary toxicity [7,8,27]. As with other studies, doses received via the rectum and bladder are factors of major influence. The ideal duration of the CCRT treatment should be between 50 and 55 days due to optimal compliance and treatment tolerance [28,29]. In developing countries, usually due to delays in intracavitary brachytherapy initiation, the treatment lasts for about 10 weeks on average [30]. In this study, it was shown that the treatment duration and the occurrence of pauses during radiotherapy, as well as the FIGO stage of the disease, significantly affected the onset of ART in patients treated with 2D-RT. For the majority of patients, prolonged treatment and the duration of treatment pauses were the result of technical and financial limitations, rather than the intensity and appearance of ART. In contrast, patients treated with 3D-CRT for the total duration of their radiotherapy showed no statistical significance for the onset of ART related to the aforementioned factors. Since most patients had mild to moderate radiation toxicity, they were paused during treatment for up to 7 days. However, only patients with delaying in initiating brachytherapy for technical reasons had pause over 7 days. Pause of over 7 days is still an important factor in the emergence of ART, unless it is a consequence of ART.

A very important aspect of each specific oncological therapy is the implementation of the total planned course of treatment. The literature suggests that only 65–92% of patients receive the planned number of chemotherapy cycles [31]. This is often caused by the appearance of serious manifestations of ART [31]. It has been shown that patients from the control group received more than four cycles of chemotherapy. This is statistically significant and suggests that they were in better general condition and thus able to endure a higher number of chemotherapy cycles. The appearance of ART disrupted the planned chemotherapy regime and in this way had a long-term effect on disease control and patient survival.

A recent study by Diaz et al. [32] confirmed that the presence of comorbidity is a very important prognostic factor in patients with cervical cancer. In earlier studies, the influence of patient personal therapy, applied simultaneously with radiotherapy, has been neglected in connection with the occurrence of ART. It is interesting that widely used ACE inhibitors are recognized as mitigators or as agents that can prevent the onset and decrease the intensity of ART. Their effect is most pronounced during and immediately after radiotherapy [33,34]. The Federal Drug Administration has confirmed that the treatment of hypertension with drugs in this group, in therapeutic doses, during a specific oncological treatment also reduces the growth of different types of tumors, which multiplies the effectiveness of the treatment several times [34]. It is known that ACE inhibitors during radiotherapy reduce the occurrence of radiation pneumonitis, nephropathy and optic neuropathy [29,35,36]. However, a detailed analysis of the literature found only one study conducted by Wedlake et al., concerning the analysis of the effect of ACE inhibitors on ART during radiotherapy of pelvic tumors [19]. They point out that ACE inhibitors, simultaneously with the use of statins, reduce gastrointestinal toxicity.

In this study, ACE inhibitors and β-blockers were found to have an effect on ART although the presence of hypertension was not shown to be a statistically significant factor (Tables 1 and 2). The case group patients had associated comorbidities that required a greater number of ACE inhibitors or beta blockers, in contrast to the control group patients. Although ACE inhibitors were identified as independent protective factors against the emergence of ART in both radiotherapy techniques, this study also raised suspicion that β-blockers might be involved because although multivariate analysis ruled out their influence, univariate was positive; with an increase in the sample size, the association of β-blockers and the ART may turned to be significant even after adjustment for other confounders. Beta-blockers may be useful in reducing radiation damage through modulation of the inflammatory response, but their importance should be further examined [11,12]. The results in Tables 1 and 2 indicate the control patients in both cohorts were stout, with a higher BMI and a higher volume of subcutaneous adipose tissue (Tables 1), indicating that they probably had a larger volume of abdominal fat. The literature data show adipocytes secrete hormones, growth factors and cytokines, the adipose tissue being an extremely hormonally active tissue. It was also found that angiotensin II, the major bioactive peptide hormone of the renin-angitensin-aldosterone system (RAAS), stimulates inflammation in adipocytes, potentiating in turn the formation of reactive oxygen species (ROS) via angiotensin type receptors 1 (AT1R) and NADPH oxidase interactions, followed by activation of MAPK/PI signaling pathways. Further, hypoxia, excessive ROS production, and oxidative stress can cause cell damage or death. When obesity is present, adipocytes secrete large amounts of angiotensinogens. Angiotensinogen mRNA expression is more pronounced in visceral than in subcutaneous fat. Inhibition of ACE, i.e. the blockade of AT1R and AT2R can be an interesting target for radioprotective therapy since it reduces oxidative stress and production of free radicals, which may indicate a protective anti-inflammatory effect in obesity, hypertension and other diseases, and reduction of damage caused by radiotherapy. There are data indicating that a particularly beneficial effect of antihypertensives affecting the RAAS system was observed in obese patients [37–39]. It might be that the protective effect of ACE inhibitors, determined by the statistical analysis of our study, was identified due to higher BMI of control patients in both cohorts, in whom a stronger mitigating effect of ACE inhibitors was shown when compared to the case group.

Other factors that were associated with the ART in the univariate analysis, but ruled out by the multivariate analysis, are weight, waist volume and pelvic gross volume. The possibility of their relationship with the ART merits new investigations with larger patient sample to differentiate the effects of confounders from true effects of these factors. The development of ART may be explained also by the patient’s constitution, regardless of the technique used. A study conducted by Smits et al. shows that obesity and BMI over 30 kg/m2 are not associated with higher grades of ART [40]. Similarly, another study show that obesity in young patients with endometrial cancer is not associated with the onset of genitourinary and gastrointestinal toxicities [41]. Lim et al. have found that obesity reduces the rectal dose during HDR brachytherapy due to larger quantity of fat tissue in the recto-uterine space, but does not affect the occurrence of acute gastrointestinal toxicity [42]. We have identified the following constitutional characteristics as predictive in the onset of ART: body weight less than 60 kg, small waist volume, low BMI and small pelvic gross volume. These results are confirmed by the analysis of the acute effects of 3D-CRT, in which weight ≤ 60 kg, BMI less than 21 kg/m2, pelvic gross volume, pelvic subcutaneous fatty tissue and bladder volume were identified as the most significant risk factors. This could be explained by the fact that the pelvic organs are concentrated in a small space. It is likely that the small intestines are fixed and positioned lower in the pelvis in patients with smaller body weight, without much fat tissue between, which implies a higher total volume of the intestines within the radiotherapy field. These results support the conclusion that the outcome of treatment is affected not only by the amount of fat tissue between the bowels but also by the volume of the pelvic subcutaneous fatty tissue. The occurrence of ART may also be affected by the volume of the bladder, as organ at risk.

The main factors that limit this study are the small sample size and unicenterdness as impact of local practices on outcome could not be excluded.

5 Conclusion

This study has shown that BMI, radiation dose received by the bladder and rectum are of exceptional importance for occurrence of the ART and also shown that therapy with ACE inhibitors was associated with the decreased chances of the ART. Since these drugs are often applied in practice, it is necessary to further examine their putative radioprotective effect for this indication.

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  1. Conflict of interest: The author(s) claimed no conflicts of interest.

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Received: 2020-03-02
Revised: 2020-06-24
Accepted: 2020-07-16
Published Online: 2020-09-02

© 2020 Marija Zivkovic Radojevic et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/med-2020-0222
Keywords for this article
cervical cancer; radiotherapy; acute radiation toxicity; ACE inhibitors
Creative Commons
BY 4.0

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  40. Research Article
  41. The characterization of Enterococcus genus: resistance mechanisms and inflammatory bowel disease
  42. Case Report
  43. Inflammatory fibroid polyp: an unusual cause of abdominal pain in the upper gastrointestinal tract A case report
  44. Research Article
  45. microRNA-204-5p participates in atherosclerosis via targeting MMP-9
  46. LncRNA LINC00152 promotes laryngeal cancer progression by sponging miR-613
  47. Can keratin scaffolds be used for creating three-dimensional cell cultures?
  48. miRNA-186 improves sepsis induced renal injury via PTEN/PI3K/AKT/P53 pathway
  49. Case Report
  50. Delayed bowel perforation after routine distal loopogram prior to ileostomy closure
  51. Research Article
  52. Diagnostic accuracy of MALDI-TOF mass spectrometry for the direct identification of clinical pathogens from urine
  53. The R219K polymorphism of the ATP binding cassette subfamily A member 1 gene and susceptibility to ischemic stroke in Chinese population
  54. miR-92 regulates the proliferation, migration, invasion and apoptosis of glioma cells by targeting neogenin
  55. Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma
  56. NF2 inhibits proliferation and cancer stemness in breast cancer
  57. Body composition indices and cardiovascular risk in type 2 diabetes. CV biomarkers are not related to body composition
  58. S100A6 promotes proliferation and migration of HepG2 cells via increased ubiquitin-dependent degradation of p53
  59. Review Article
  60. Focus on localized laryngeal amyloidosis: management of five cases
  61. Research Article
  62. NEAT1 aggravates sepsis-induced acute kidney injury by sponging miR-22-3p
  63. Pericentric inversion in chromosome 1 and male infertility
  64. Increased atherogenic index in the general hearing loss population
  65. Prognostic role of SIRT6 in gastrointestinal cancers: a meta-analysis
  66. The complexity of molecular processes in osteoarthritis of the knee joint
  67. Interleukin-6 gene −572 G > C polymorphism and myocardial infarction risk
  68. Case Report
  69. Severe anaphylactic reaction to cisatracurium during anesthesia with cross-reactivity to atracurium
  70. Research Article
  71. Rehabilitation training improves nerve injuries by affecting Notch1 and SYN
  72. Case Report
  73. Myocardial amyloidosis following multiple myeloma in a 38-year-old female patient: A case report
  74. Research Article
  75. Identification of the hub genes RUNX2 and FN1 in gastric cancer
  76. miR-101-3p sensitizes non-small cell lung cancer cells to irradiation
  77. Distinct functions and prognostic values of RORs in gastric cancer
  78. Clinical impact of post-mortem genetic testing in cardiac death and cardiomyopathy
  79. Efficacy of pembrolizumab for advanced/metastatic melanoma: a meta-analysis
  80. Review Article
  81. The role of osteoprotegerin in the development, progression and management of abdominal aortic aneurysms
  82. Research Article
  83. Identification of key microRNAs of plasma extracellular vesicles and their diagnostic and prognostic significance in melanoma
  84. miR-30a-3p participates in the development of asthma by targeting CCR3
  85. microRNA-491-5p protects against atherosclerosis by targeting matrix metallopeptidase-9
  86. Bladder-embedded ectopic intrauterine device with calculus
  87. Case Report
  88. Mycobacterial identification on homogenised biopsy facilitates the early diagnosis and treatment of laryngeal tuberculosis
  89. Research Article
  90. The will of young minors in the terminal stage of sickness: A case report
  91. Extended perfusion protocol for MS lesion quantification
  92. Identification of four genes associated with cutaneous metastatic melanoma
  93. Case Report
  94. Thalidomide-induced serious RR interval prolongation (longest interval >5.0 s) in multiple myeloma patient with rectal cancer: A case report
  95. Research Article
  96. Voluntary exercise and cardiac remodeling in a myocardial infarction model
  97. Electromyography as an intraoperative test to assess the quality of nerve anastomosis – experimental study on rats
  98. Case Report
  99. CT findings of severe novel coronavirus disease (COVID-19): A case report of Heilongjiang Province, China
  100. Commentary
  101. Directed differentiation into insulin-producing cells using microRNA manipulation
  102. Research Article
  103. Culture-negative infective endocarditis (CNIE): impact on postoperative mortality
  104. Extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome
  105. Plasma microRNAs in human left ventricular reverse remodelling
  106. Bevacizumab for non-small cell lung cancer patients with brain metastasis: A meta-analysis
  107. Risk factors for cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage
  108. Problems and solutions of personal protective equipment doffing in COVID-19
  109. Evaluation of COVID-19 based on ACE2 expression in normal and cancer patients
  110. Review Article
  111. Gastroenterological complications in kidney transplant patients
  112. Research Article
  113. CXCL13 concentration in latent syphilis patients with treatment failure
  114. A novel age-biomarker-clinical history prognostic index for heart failure with reduced left ventricular ejection fraction
  115. Case Report
  116. Clinicopathological analysis of composite lymphoma: A two-case report and literature review
  117. Trastuzumab-induced thrombocytopenia after eight cycles of trastuzumab treatment
  118. Research Article
  119. Inhibition of vitamin D analog eldecalcitol on hepatoma in vitro and in vivo
  120. CCTs as new biomarkers for the prognosis of head and neck squamous cancer
  121. Effect of glucagon-like peptide-1 receptor agonists on adipokine level of nonalcoholic fatty liver disease in rats fed high-fat diet
  122. 72 hour Holter monitoring, 7 day Holter monitoring, and 30 day intermittent patient-activated heart rhythm recording in detecting arrhythmias in cryptogenic stroke patients free from arrhythmia in a screening 24 h Holter
  123. FOXK2 downregulation suppresses EMT in hepatocellular carcinoma
  124. Case Report
  125. Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  126. Research Article
  127. Clinical prediction for outcomes of patients with acute-on-chronic liver failure associated with HBV infection: A new model establishment
  128. Case Report
  129. Combination of chest CT and clinical features for diagnosis of 2019 novel coronavirus pneumonia
  130. Research Article
  131. Clinical significance and potential mechanisms of miR-223-3p and miR-204-5p in squamous cell carcinoma of head and neck: a study based on TCGA and GEO
  132. Review Article
  133. Hemoperitoneum caused by spontaneous rupture of hepatocellular carcinoma in noncirrhotic liver. A case report and systematic review
  134. Research Article
  135. Voltage-dependent anion channels mediated apoptosis in refractory epilepsy
  136. Prognostic factors in stage I gastric cancer: A retrospective analysis
  137. Circulating irisin is linked to bone mineral density in geriatric Chinese men
  138. Case Report
  139. A family study of congenital dysfibrinogenemia caused by a novel mutation in the FGA gene: A case report
  140. Research Article
  141. CBCT for estimation of the cemento-enamel junction and crestal bone of anterior teeth
  142. Case Report
  143. Successful de-escalation antibiotic therapy using cephamycins for sepsis caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia: A sequential 25-case series
  144. Research Article
  145. Influence factors of extra-articular manifestations in rheumatoid arthritis
  146. Assessment of knowledge of use of electronic cigarette and its harmful effects among young adults
  147. Predictive factors of progression to severe COVID-19
  148. Procedural sedation and analgesia for percutaneous trans-hepatic biliary drainage: Randomized clinical trial for comparison of two different concepts
  149. Acute chemoradiotherapy toxicity in cervical cancer patients
  150. IGF-1 regulates the growth of fibroblasts and extracellular matrix deposition in pelvic organ prolapse
  151. NANOG regulates the proliferation of PCSCs via the TGF-β1/SMAD pathway
  152. An immune-relevant signature of nine genes as a prognostic biomarker in patients with gastric carcinoma
  153. Computer-aided diagnosis of skin cancer based on soft computing techniques
  154. MiR-1225-5p acts as tumor suppressor in glioblastoma via targeting FNDC3B
  155. miR-300/FA2H affects gastric cancer cell proliferation and apoptosis
  156. Hybrid treatment of fibroadipose vascular anomaly: A case report
  157. Surgical treatment for common hepatic aneurysm. Original one-step technique
  158. Neuropsychiatric symptoms, quality of life and caregivers’ burden in dementia
  159. Predictor of postoperative dyspnea for Pierre Robin Sequence infants
  160. Long non-coding RNA FOXD2-AS1 promotes cell proliferation, metastasis and EMT in glioma by sponging miR-506-5p
  161. Analysis of expression and prognosis of KLK7 in ovarian cancer
  162. Circular RNA circ_SETD2 represses breast cancer progression via modulating the miR-155-5p/SCUBE2 axis
  163. Glial cell induced neural differentiation of bone marrow stromal cells
  164. Case Report
  165. Moraxella lacunata infection accompanied by acute glomerulonephritis
  166. Research Article
  167. Diagnosis of complication in lung transplantation by TBLB + ROSE + mNGS
  168. Case Report
  169. Endometrial cancer in a renal transplant recipient: A case report
  170. Research Article
  171. Downregulation of lncRNA FGF12-AS2 suppresses the tumorigenesis of NSCLC via sponging miR-188-3p
  172. Case Report
  173. Splenic abscess caused by Streptococcus anginosus bacteremia secondary to urinary tract infection: a case report and literature review
  174. Research Article
  175. Advances in the role of miRNAs in the occurrence and development of osteosarcoma
  176. Rheumatoid arthritis increases the risk of pleural empyema
  177. Effect of miRNA-200b on the proliferation and apoptosis of cervical cancer cells by targeting RhoA
  178. LncRNA NEAT1 promotes gastric cancer progression via miR-1294/AKT1 axis
  179. Key pathways in prostate cancer with SPOP mutation identified by bioinformatic analysis
  180. Comparison of low-molecular-weight heparins in thromboprophylaxis of major orthopaedic surgery – randomized, prospective pilot study
  181. Case Report
  182. A case of SLE with COVID-19 and multiple infections
  183. Research Article
  184. Circular RNA hsa_circ_0007121 regulates proliferation, migration, invasion, and epithelial–mesenchymal transition of trophoblast cells by miR-182-5p/PGF axis in preeclampsia
  185. SRPX2 boosts pancreatic cancer chemoresistance by activating PI3K/AKT axis
  186. Case Report
  187. A case report of cervical pregnancy after in vitro fertilization complicated by tuberculosis and a literature review
  188. Review Article
  189. Serrated lesions of the colon and rectum: Emergent epidemiological data and molecular pathways
  190. Research Article
  191. Biological properties and therapeutic effects of plant-derived nanovesicles
  192. Case Report
  193. Clinical characterization of chromosome 5q21.1–21.3 microduplication: A case report
  194. Research Article
  195. Serum calcium levels correlates with coronary artery disease outcomes
  196. Rapunzel syndrome with cholangitis and pancreatitis – A rare case report
  197. Review Article
  198. A review of current progress in triple-negative breast cancer therapy
  199. Case Report
  200. Peritoneal-cutaneous fistula successfully treated at home: A case report and literature review
  201. Research Article
  202. Trim24 prompts tumor progression via inducing EMT in renal cell carcinoma
  203. Degradation of connexin 50 protein causes waterclefts in human lens
  204. GABRD promotes progression and predicts poor prognosis in colorectal cancer
  205. The lncRNA UBE2R2-AS1 suppresses cervical cancer cell growth in vitro
  206. LncRNA FOXD3-AS1/miR-135a-5p function in nasopharyngeal carcinoma cells
  207. MicroRNA-182-5p relieves murine allergic rhinitis via TLR4/NF-κB pathway
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