Vaginal dose of radical radiotherapy for cervical cancer in China: a multicenter study

Locally advanced cervical cancer, which is classified as stage ≥IB2 as per the International Federation of Gynecology and Obstetrics (FIGO) criteria, is treated with a concurrent radiochemotherapy. Radiotherapy involves the administration of pelvic external-beam radiotherapy (EBRT) as well as brachytherapy (BT). However, in cases of locally advanced cervical cancer, the upper part of the vagina is considered a target organ for radiotherapy, which puts the higher part of the vagina at risk of radiotherapy-induced injury. Despite this, investigations on vaginal morbidity after radiotherapy have been scarce.

Our previous analysis on vaginal morbidity in cervical cancer patients treated with the current treatment strategies revealed that the incidence of vaginal radiation injury was 84.4% (238/282), and the incidence rates of radiation injury of grades II, and III were 29.8% (84/282) and 3.9% (11/282, P < 0.05), respectively [1]. Kirchheiner et al. found that vaginal morbidity occurred in 255 of 630 (40.5%) patients, with morbidity rates for grades II and III being 17, and 1%, respectively [2]. Similarly, Susko et al. found that of the morbidity rates for grades II and III or higher vaginal toxicity were 41.7 and 17.6%, respectively, in 36 of 62 cervical cancer or uterine cancer patients [3]. Multi-factor analysis indicated that the dose of BT was an independent factor affecting the occurrence of vaginal radiation-induced injury (P = 0.043) [1].

To identify a simple and reliable representation of the radiation exposure in the vagina and establish a method suitable for both EBRT and BT, the Medical University of Vienna proposed a novel vaginal dose-reporting method [4]. This method allows for the determination of the total (EBRT+BT) dose (EQD2) administered to the upper, mid, and lower parts of the vagina. Further, this evaluation system can be used for 2D and 3D BT. In this study, we sought to test the applicability of this method in Chinese patients and determine the vaginal dose administered in patients, with a view to identifying the influencing factors for vaginal radiation injury in the future.

This investigation was designed as an observational study of patients who underwent concurrent radiochemotherapy at any of the 13 participating hospitals between December 2016 and June 2018. The study was registered as a clinical trial (NCT03257475) and approved by the ethics committee of the First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2017LSK-11). Informed consent was obtained from all patients who participated in this study.

In all, we selected 936 of the 1194 cases, for which complete data were available, excluded 30 patients for lack of complete clinical information and exclued 228 patients aged > 60 years, since elasticity and length of the vagina are affected by estrogen level. All patients were diagnosed with cervical carcinoma of stages IIA1 to IVB (except for IIIA), classified as per the 2009 FIGO criteria [5]. Twelve patients who had enlargement of para-aortic lymph nodes received extended field radiation. EBRT was delivered to the entire pelvis at 1.8–2.0 Gy per fraction, for a total of 25 fractions and 45–50 Gy (3D-conformal radiotherapy [CRT] or intensity-modulated radiotherapy [IMRT]), with concurrent weekly administration of cisplatin (25 mg/m², [6] or cisplatin (25 mg/m², day 1–day 3) combined with liposome paclitaxel (135 mg/m², day 1). The target was contoured according to recommendations of the Radiation Therapy Oncology Group (RTOG) with three-dimensional (3D) computed tomography (CT)-assisted treatment planning [7].

High-dose rate (HDR) BT was administered at doses of 24 or 30 Gy in 4 to 5 fractions after EBRT using the Fletcher-Suit-Delclos set with a microSelectron HDR (Elektra Brachy, Sweden).The planning aim at point A was 82–90 Gy in EQD2. BT was administered via the CT/simulation (CT/SIM)-guided technique with a tandem-ovoid applicator. A CT/SIM scan of the pelvis was performed in the first and third BT fractions. The obtained images were transferred onto Oncentra TPS. For treatment planning, the point A dose-evaluation method was used, with the loading dose based on the Manchester system of BT, with the objective of delivering 6 Gy, which at EQD2 was 8 Gy to point A. A sum of the BT and EBRT doses was determined applying the linear-quadratic model, with an α/β ratio of 10 Gy.

The dose administered at the target area and the irradiation volume are closely related to the occurrence of radiotherapy-related injury of the rectum and bladder; accordingly, some restrictions have been established for safe dosage amounts of radiation for the rectum and bladder [10, 11]. Similar to the case in bladder and rectal, radiotherapy-induced injury in the vagina may occur at any time within the first 2 years of radiation treatment. A new method for dose evaluation in the vagina using the PIBS points was recently proposed by the EMBRACE study [12]. In the PIBS system, the dose variations at PIBS points are determined by the demarcation of the EBRT border, the extent of vaginal involvement at the time of BT and the VRL [4]. Our findings suggest that this method of assessing the total EBRT and BT dose administered in the upper, middle (PIBS+ 2 cm), and lower (PIBS and PIBS-2 cm) parts of the vagina is applicable even in a multicenter setting. In our cohort, the lower border for the EBRT field was located approximately at the level of the PIBS or below; thus, the vagina above the PIBS level received a radiation dose of 50 Gy from EBRT. Variations in the dose administered to the upper segment of the vagina can be mainly attributed to variations in the BT dose. And at the time of BT, the residual lesions were mainly localized at the level of the vaginal fornix. This implies that the VRL plays an important role in the dose variation at the PIBS.

It is obvious that the VRL value of Chinese patients is much shorter than that reported by studies conducted in other regions. Accordingly, the median VRL among our patients was 4.5 (1.3–8.4) cm, which is considerably different from the VRL 6.1 (1.6–11.0) cm reported in 2013 and 5.4 (1.0–8.3) cm in 2016 on conventional radiographsin by Westerveld et al. [4, 13]. The value of VRL depends on many factors, such as genetic, ethnic, geographical [14, 15], the residual lesions and the position of the vaginal applicator at time of BT. For instance, a large remnant tumor mass after EBRT may decrease the VRL. Radiotherapy (EBRT) may lead to vascular toxicity and fibrosis, rendering the vagina short and narrow [16].. Berger et al. concluded that geometrical shifts of even 1 mm lead to a 25% change in the estimated dose to the vagina [17]. Therefore, BT was performed after EBRT. The vaginal applicator was placed and fixed firmly, as better repeatability among every fraction of BT can reduce dose variations at the PIBS. In our study, statistical analysis showed no significant difference between the doses of the two fractions of BT. In the present study, we selected patients of age ≤ 60 years because age is also a factor that can affect the VRL, as the VRL decreases with age. .

Interestingly, the median doses reported in our series differed from those reported in the series by Westerveld et al. [4, 16] (Table 5). At point PIBS+ 2 cm, the median total (EBRT + BT) doses reported by Westerveld et al. in their 2013 and 2016 studies were 49.6 (32.1–89.6) Gy and 54 (32–109) Gy, respectively, whereas that in our study was 82.5 (52.7–392.1) Gy. Thus, compared to their results, ours showed that the dose at PIBS+ 2 cm was 30 Gy higher. At the PIBS point, the values in Westerveld et al. studies were 36.7 (3.1–68.2) Gy and 41 (3–81) Gy, respectively, whereas that in our study was 56.2 (51.4–82.1) Gy. Thus, the dose at point PIBS in our study was equivalent to the dose reported for the PIBS+ 2 cm point by Westerveld et al. Because the VRL in the Chinese women included in our study was 1.5–2 cm less than that reported for European patients, more volume of the vagina received high-dose radiation. Further, the PIBS-2 cm point represents the level of the vaginal introitus, and the dose values observed here indicate that patients received extremely low doses at this level that did not cause serious radiation injury in most cases. Figure 1 shows that the dose at the PIBS+ 2 cm point varied drastically with differing VRL on account of near of the source. However, dose changes at the PIBS point with variation in the VRL were moderate. So the PIBS point could be considered as a good indicator of the radiation dose applied to the vagina and predictor of late morbidity caused by high-dose exposure of the vagina, especially in patients with a VRL shorter than 4.5 cm.

The above-mentioned findings can be explained by a few points. First, the VRL is the basis of the dose determination using the PIBS system. Second, the type of applicator used may influence the dose received by the vagina. In the multicenter study by Westerveld et al., it was evident that different applicators led to variation in the radiation dose applied at the vaginal wall. For example, the tandem-ovoid applicator normally administers higher doses at the anterior and posterior vaginal walls as compared to the tandem-ring applicators, whereas the latter administers higher doses at the lateral wall of the upper part of the vagina as compared to the former [9]. Third, the application of the point A dose evaluation system, which is different from the dose–volume evaluation system used in studies from other countries, may also influence the vaginal doses received. This is evident from the fact that our patients received a higher vaginal dose as compared with those reported in other studies.

To better understand the correlation of the VRL and dose variation at the PIBS system points, we classified our patients into two groups according to the median value of VRL, which was 4.5 cm. The results indicated significant differences in the dose values for patients with a VRL ≤4.5 cm versus a VRL > 4.5 cm. Thus, for patients with a short (< 4.5 cm) VRL, a greater volume of the vagina was exposed to high doses. This would mean an increased risk of vaginal morbidity in the future.

Our study has a few limitations. First, we used the point A dose-evaluation system to evaluate the BT dose. The dose for the vagina and surrounding OARs may have been lower if we had used the dose–volume evaluation system, especially in cases of large tumors. Second, patients underwent a CT scan only at the time of the first (BT1) and third (BT3) fractions of BT, and using the average values of the BT1 and BT3 for evaluating the other parameters. Therefore, some deviation is possible. Lastly, we only assessed the vaginal dose in cervical cancer using the new evaluation system and did not evaluate the data of incidence of vaginal toxicity. Further studies are required to clarify these issues.

This observational study indicated that the radiation dose administered at the PIBS points differs significantly with variation in the VRL and that the VRL values for Chinese women were much less than those for European and American women. Therefore, Chinese patients with cervical cancer received higher radiation doses for total EBRT and BT in the upper 2/3 of the vagina when using the PIBS evaluation system. Therefore, it is important to pay attention to the radiation dose received by the vaginal region in order to reduce vaginal radiation injury. The findings of this study provide the basis for the efficient use of PIBS in the evaluation of the vaginal radiation dose in Chinese patients. Further studies are necessary to correlate these parameters with vaginal morbidity.