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

We included patients who were treated with RT/CRT for cervical cancer of Fédération Internationale de Gynécologie et d`Obstétrique (FIGO) stages I–IVA. Patients with distant metastases or paraaortic lymph node spread were excluded. The staging procedures were performed according to the respective guidelines [19, 20] at our gynecological cancer center or at a hospital selected by the patient. Patients received abdominal ultrasound and chest radiograph or a CT scan of the chest and abdomen. A pelvic MRI scan was performed for local tumor staging. A rectoscopy or cystoscopy was performed in patients with clinical or radiological suspicion of invasion into rectum or bladder. According to local practice, surgical staging was not routinely performed. The treatment strategies (e.g., definitive RT/CRT vs. primary surgery) were discussed and determined on an individual basis in the multidisciplinary tumor board. Owing to the changes in treatment strategies over the study period of approximately two decades and to the retrospective study design, it is difficult to further concretize and generalize the indications. Overall, patients with FIGO stages IIIA-IVA were preferably treated with definitive RT/CRT. The options in patients with FIGO stage IIB were, depending on further clinical factors, primary surgery, definitive RT/CRT, and neoadjuvant RT/CRT. Patients with FIGO stages I–IIA preferably underwent primary surgery. The indication for adjuvant RT/CRT was determined depending on histopathological adverse features. A neoadjuvant RT/CRT for cervical cancer is not routinely used outside of clinical trials. Here, according to local practice at our gynecological cancer center, the indication could be set after particularly intense discussion in the tumor board. Patients were informed in detail about the individual treatment character before informed consent was given.

EBRT was applied with 6‑MeV or 20-MeV linear accelerator photons. The target volumes were defined according to the respective guidelines [21, 22]. The planning target volume was defined by adding a 10-mm margin to the clinical target volume. The International Commission on Radiation Units and Measurements (ICRU) reports provided the basis for plan calculation [23, 24]. In 3DCRT, a four-field box technique (anteroposterior/right and left lateral) was used. In definitive RT/CRT, a two-field technique (anteroposterior/posteroanterior) with central shielding was used for boost therapy [25]. VMAT was performed using RapidArc® (Varian Medical Systems, Palo Alto, USA). The treatment plans were calculated with the progressive resolution algorithm in Eclipse. These dose constraints were used for both 3DCRT and VMAT: small bowel ≥50 Gy in ≤10 cm³ volume and ≥40 Gy in ≤100 cm³ volume; rectum ≥65 Gy in ≤17% volume and ≥40 Gy in ≤50% volume; bladder ≥65 Gy in ≤25% volume and ≥40 Gy in ≤50% volume. Fig. 1a, b and Supplementary Figs. 1a, b and 2 illustrate a comparison of dose distributions and dose–volume histograms with 3DCRT and VMAT.

Where indicated, high-dose-rate brachytherapy was administered. In definitive RT/CRT, in patients with stages IB2–IVA, MRI was performed after EBRT. The treating radiation oncologist chose between an intracavitary or a combined intracavitary/interstitial approach, depending on tumor shrinkage and patient anatomy. The brachytherapy was delivered to a total dose of 24 Gy (weekly sessions of 6 Gy). In postoperative RT/CRT, in patients with close or positive vaginal margins, intracavitary brachytherapy was applied (10 Gy, two sessions of 5 Gy in 1 week).

Where indicated, chemotherapy was given concurrently with RT. Standardly, weekly cisplatin (40 mg/m² total body surface area, total 240 mg/m², six cycles) was administered. In cases of decreased renal function, a different regimen was selected or chemotherapy was omitted.

The Common Terminology Criteria for Adverse Events (CTCAE) criteria (version 5.0) [26] were used to assess acute toxicities. Patients were monitored at least weekly, including physical examination and the acquisition of blood samples. After RT/CRT, patients were monitored at least every second week until symptoms were satisfactorily controlled. The highest score of skin toxicity, proctitis, enteritis, and urinary toxicity was used to classify the grade of overall acute toxicity. The “Late Effects of Normal Tissues-subjective, objective, management, and analytic” (LENT-SOMA) criteria [27] were used to assess late toxicities. Patients were monitored at least annually for 5 years. The highest score of skin toxicity, proctitis, small bowel toxicity, urinary toxicity and vaginal toxicity was used to classify the grade of overall late toxicity.

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 comparison of patient characteristics and toxicity (cut-off p < 0.05). A multivariable model (ordinal logistic regression [28], cut-off p < 0.05) was established in cases of differences in toxicity endpoints in the univariable analysis. First, the variables were dichotomized (see Supplementary Table S1). Secondly, parameters with a tendency towards an influence on toxicity (p < 0.2) were included in the multivariable model. The survival times (overall survival, OS; progression-free survival, PFS; and locoregional control, LC) were calculated from the day of RT/CRT initiation. The log-rank test was performed to compare treatment groups (cut-off p < 0.05). We used SPSS v12.0 (IBM) for Kendall’s tau test, Mann–Whitney U test, and ordinal logistic regression. The chi-square test and the log-rank test were performed using STATISTICA v.10.0.1011.0 (StatSoft Inc.).

In total, 105 consecutive patients (treatment between 11/1995 and 06/2014) met the inclusion criteria. Among these, 75 (71%) were treated with 3DCRT and 30 (29%) with VMAT. During the time period, 8 patients were irradiated with IMRT. Since this study focused on patients treated with VMAT, these patients were not considered in further analysis. Additionally, during the period, in 9 patients, the paraaortic region was included in treatment volumes. Due to the relevant bias for outcomes and toxicities, these patients were excluded from further analysis, too. In the study cohort, the median follow-up was 56.1 months (range 5.0–287.2) for the 3DCRT cohort and 29.3 months (range 5.2–65.3) for the VMAT cohort. Treatment groups were balanced in baseline clinical characteristics (Table 1).

Definitive RT/CRT was performed in 53 patients (50%), adjuvant RT/CRT was performed in 31 patients (30%), and neoadjuvant RT/CRT was applied in 21 patients (20%; Table 2). The reasons for omission of brachytherapy were patient refusal (n = 4), technical infeasibility (n = 6), and deterioration of patient condition (n = 1). In total, in 36/53 (68%) patients with definitive RT/RCT, in 23/31 patients (74%) with adjuvant RT/RCT, and in 21/21 patients (100%) with neoadjuvant RT/RCT, concomitant chemotherapy was applied. Patients who were not suitable for cisplatin received mitomycin C (n = 4), 5‑fluorouracil/mitomycin C (n = 1), or carboplatin (n = 1).

There were no significant differences in outcome between 3DCRT-treated and VMAT-treated patients.

In patients who underwent definitive RT/CRT, the 2‑year OS was 61% for both 3DCRT and VMAT (p = 0.9). The 2‑year PFS was 80% for 3DCRT and 74% for VMAT (p = 0.5). The 2‑year LC was 85% for 3DCRT and 74% for VMAT (p = 0.6).

In patients who received adjuvant RT/CRT, 2‑year OS was 96% for 3DCRT and 100% for VMAT (p = 0.6). The 2‑year PFS was 88% for 3DCRT and 100% for VMAT (p = 0.5). The 2‑year LC was 96% for 3DCRT and 100% for VMAT (p = 0.6).

In patients who underwent neoadjuvant RT/CRT, the 2‑year OS was 82% for 3DCRT and 90% for VMAT (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).

Overall acute urinary toxicity occurred more frequently during VMAT treatment, whereas high-grade (≥grade 3) urinary toxicity occurred in only a very small number of patients (n = 1 for 3DCRT and VMAT, Table 3 [acute organ toxicity] and Supplementary Table S2 [hematologic toxicity]). The late toxicity data were available for 64 3DCRT-treated patients (85.3%) and for 26 VMAT-treated patients (86.7%). Late small bowel toxicity and overall late toxicity were significantly less frequent in the VMAT group (Table 4).

In multivariable analysis, the VMAT treatment was independently associated with an increased risk of acute urinary toxicity (p = 0.01, Table 5 and Supplementary Table S1). In VMAT-treated patients, the risk for late small bowel toxicity was significantly reduced (p = 0.03). The overall occurrence of late toxicity was significantly more frequent in patients with low BMI (p = 0.03) and in patients with overall acute toxicity ≥grade 2 (p < 0.01).