Abstract
Background/Aim: To examine late vaginal mucosal reactions in patients following interstitial brachytherapy (ISBT) compared with that of intracavitary brachytherapy (ICBT). Patients and Methods: We introduced a modified Dische score to examine late reactions in vaginal mucosa of patients with gynecological cancer who underwent vaginal brachytherapy at 6, 12, 18, 24, 36, and 60 months after treatment. A comparison was made between patients who underwent ISBT (n=37) and those under conventional ICBT (n=63) with a median follow-up time of 41 months. The ICBT group included only patients with newly diagnosed cervical cancer, whereas the ISBT group included 17 patients with recurrent and 20 with newly-diagnosed cancer. Results: Grade 1 reactions of bleeding and discharge were exhibited by <12% of patients. Erythema was detected in approximately 30% (mainly grade 1) of the patients. A total of two (3%) patients developed superficial ulceration after ICBT, whereas three (8%) grade 1 ulcers were detected in patients after ISBT. Telangiectasias were detected in approximately 70% (60% grade 1 and 10% grade 2) of patients. No statistically significant difference was found between the patients after ISBT and ICBT. After ISBT, patients have a higher stenosis rate than after ICBT (p=0.003). The pallor scores showed a strong correlation with stenosis (p<0.0001) and were higher in patients after ICBT than in patients after ISBT (p=0.006). Conclusion: After ISBT, patients exhibited milder but similar late mucosal reactions compared to those after ICBT, except the fact that the stenosis was more severe and the pallor reaction was milder in these patients. It can be, therefore, concluded that the pallor reaction is related to stenosis.
Interstitial brachytherapy (ISBT) is useful for the treatment of recurrent gynecological malignancies (1). In the 1990s, we introduced fractionated high-dose rate (HDR) interstitial brachytherapy for recurrent cancer of the pelvic region and have since explored its role in treatment of both recurrent and newly-diagnosed gynecological cancer (2-8). Severe adverse grade 3 reactions or higher are rarely reported (6, 8). However, late injuries of the vagina should not be ignored because they may be potentially serious complications of radiotherapy in gynecological cancer (9). Furthermore, mild-to-moderate toxicity (grade 1 or 2) analyses are often poorly and ambiguously reported in the literature. Several scoring systems, such as the Radiation Therapy Oncology Group (RTOG) and the French–Italian glossary of complications, have been introduced, but no standard system has been established yet (10). To examine the vaginal morbidity after ISBT, we introduced a modified Dische scoring system to assess the radiation toxicity of the pelvic lesions. This scoring system has been primarily used as an established scoring system for cancer of the head and neck (11). The purpose of this study was to assess the feasibility of ISBT by comparing late vaginal sequelae observed in patients after ISBT with those after conventional intracavitary brachytherapy (ICBT).
Patients and Methods
In the present study, we retrospectively included 100 patients with gynecological cancer (median age, 61 years; range, 33-88 years) who were treated between 1993 and 2011. The patient characteristics are listed in Table I. Out of the 100 patients, 90 were diagnosed with cervical cancer (79 newly-diagnosed, 11 recurrent), six with endometrial cancer, one with ovarian cancer, and three with vaginal cancer. Elderly patients usually received ICBT more often than ISBT (p=0.03). The data of 63 patients after ICBT (median follow-up, 41 months; range, 6-144 months) and 37 patients after ISBT (median follow-up, 45 months; range, 6-130 months, from 2001) were collected. The ICBT group included only patients with newly-diagnosed cervical cancer, whereas the ISBT group included 17 patients with recurrent cancer (including one of ovarian cancer that recurred at the distal vagina) and 20 with newly-diagnosed cancer.
According to previously reported methods, ICBT was performed with a combination of external radiotherapy (12). In brief, 30 Gy in 2-Gy fractions (0-50.4; 0 Gy for two patients with stage Ib; 1.8-2 Gy fractionations) of external irradiation was administered to the entire pelvic field (WP), and 20 Gy (10-40 Gy; 40 Gy for stage Ib) to the center-shielded field (CS; entire pelvis plus midline block). Source loading corresponded to the Manchester system for cervical cancer. Furthermore, an average of 30 Gy (range, 16.5-47 Gy) was administered to a patient in ICBT on an average of 4 (range, 2–5 Gy fractions) fractions once a week over an average time period of four (range, 2-5 weeks) weeks.
ISBT for previously untreated cervical cancer was administered at 30-36 Gy (6 Gy per fraction, twice per day) combined with external beam radiotherapy (5). They received a median prescribed dose of 30 Gy (range, 0-50 Gy; 0 Gy for two patients aged ≥80 years) to the WP and 20 Gy (range, 0-30 Gy) to the CS. We performed ISBT between the WP and CS. HDR-ISBT for patients with recurrent tumors was performed using a range of 42-51 Gy/7-8 fractions over 2-5 days (twice per day) without external irradiation for re-irradiation cases. The eligibility criteria for undergoing ISBT were determined on the basis of the recommendations of the American Brachytherapy Society (bulky lesion, narrow vagina, inability to enter the cervical os, extension to the lateral parametrium or pelvic side wall, and lower vaginal extension) (7). The seed implantation was performed in the operating room under lumbar anesthesia and continuous epidural anesthesia. The implantation was monitored using a transrectal ultrasound (TRUS) (Hitachi Aloka Medical Ltd. Tokyo, Japan). After July 2005, all patients underwent computed tomography (CT) and magnetic resonance imaging (MRI) during the planning phase. The CT-based planning was performed using MRI as a reference to contour the high-risk clinical target volume (HR CTV) and organs at risk (OARs; rectum, bladder, sigmoid colon, and small intestine). The definition of these contours was based on the recommendation from the gynecological Groupe Européen de Curiethérapie-European Society of Therapeutic Radiation Oncology working group for reporting 3D-sectional imaging-assisted brachytherapy of cervical cancer (8). The HR CTV and OARs were delineated with the assistance of axial T2-weighted MRI. Clinical examinations and data from the marker seed, which was implanted at the edge of gross tumor volume for brachytherapy (GTVB), were also used for delineation. HR CTV included GTVB and the entire cervix. Intermediate risk CTV (IR CTV) included the HR CTV with a safety margin of 0.5-1.5 cm. The treatment planning was performed using the PLATO planning system (software version 14.2; Nucletron, Veenendaal, the Netherlands) with manual modification after computer optimization. For recurrent cancer and CTV-based dose prescription, the PLATO planning system was used with manual modification to cover the CTV by the 100% isodose line on each slice after computer optimization using a geometrical optimization algorithm (4).
An additional irradiation boost (6-10 Gy in 2-Gy fractions) to the pelvic lymph node and/or to the para-aortic lymph node metastases was administered for 13 patients with newly diagnosed disease (nine ICBT and four ISBT). We used microSelectron-HDR (Elekta Ab, Stockholm, Sweden) with 192iridium as the treatment source for brachytherapy. All patients received the prescribed doses or more (a remotely controlled after-loading system and WP doses) with the proximal vagina as CTV.
The original vaginal (vagina and cervix) Dische scores based on the bleeding (type and severity), discharge (frequency and type), erythema, ulceration, telangiectasia, and stenosis in the vaginal mucosal tissue of the patients were graded according to two or three grades. We introduced additional modifications according to late effects observed in normal tissues as per subjective, objective, management, and analytic scales (LENT SOMA®), and pallor of mucosa according to mucosal reaction from the head and neck scoring system in the original Dische score for meticulous grading (Table II). These changes were supplemented to the original Dische scores (modified Dische score) (Table II) and were assessed at 6, 12, and, 18 months and 2, 3, and 5 years after radiotherapy. The maximum score was assigned to each evaluated side-effect. These assessments were conducted by the same physician (KY) throughout the examination period and were later confirmed by another physician (HY) using a photograph. We compared the late mucosal reactions between ICBT and ISBT. The biologically equivalent dose was calculated into equivalent 2-Gy fractions (EQD2) using a linear quadratic model, where a/b=10 for tumors and a/b=3 for OARs.
Concurrent or neoadjuvant chemotherapy were administered to 39 patients (27 ICBT and 12 ISBT). Chemotherapy consisted of the following: cisplatin in 23, carboplatin in one, pepleomycin, ifomide, and cisplatin in four, paclitaxel, ifosfamide, and cisplatin in four, and intra-arterial infusion (cisplatin plus mytomycin C) in seven.
For statistical analyses, Student's t-test for normally distributed data and the Mann–Whitney U-test for skewed data were used. The percentages were analyzed using the chi-square test. Results with p<0.05 were considered statistically significant (two-sided).
Results
Results of the analyses are shown in Table III. The assessment of bleeding (type and severity) and discharge (frequency and type) showed that <12% of patients experienced grade 1 reactions after brachytherapy while the remaining patients had less severe complications. Thus, only mild reactions which were similar in patients of both ICBT and ISBT groups appeared. Erythema was observed in approximately 30% of patients (mainly grade 1) after brachytherapy. Two patients (3%) exhibited superficial ulceration after ICBT, whereas three patients (8%) exhibited grade 1 ulcerations after ISBT (not significant). No patient had ulceration lasting for six months or more. Telangiectasias of ≥grade 1 were seen in ≥70% of the patients; however, no difference was observed between patients of the ICBT and ISBT groups. Patients after ISBT had a higher stenosis rate than those after the ICBT (p=0.003). The pallor score was higher in patients after ICBT than in patients after ISBT (p=0.006). A higher grade of vaginal stenosis was noted in patients with severe pallor changes (Table III) (p<0.0001). Grade 3 stenosis (unable to insert a speculum) appeared in two patients with ISBT, one with grade T3a (lower vaginal invasion) cervical cancer, and the other with recurrent T1b tumor (short vagina). The maximal score of each end-point was assessed on the basis of the cumulative dose and was then computed using the cumulative contribution of EBRT and brachytherapy, which was normalized to 2 Gy per fraction (EQD2) using the linear-quadratic model with an α/β ratio of 3 Gy. The ICBT group received 85±13.3 Gy and the ISBT group received 87.5±8.6 Gy (not significantly different). In addition, no correlation was found between the treatment EQD2 and the late reaction score. The influence of chemotherapy was also analyzed, but no significant correlation was found.
Discussion
The vaginal mucosa is reasonably tolerant to radiation and an irradiation tolerance level of the proximal vagina was suggested in the 1980s (13). None of the patients treated with a maximum dose of 140 Gy developed severe complications or necrosis in the proximal vagina. A report of 274 patients with cervical cancer treated from 1987 to 1997 led to an estimated tolerance dose of 175 Gy within five years with a 5% complication rate for combined external-beam radiotherapy and brachytherapy (14). These studies included serious complications such as mucosal necrosis or fistula formation and milder complications such as vaginal stenosis or shortening, telangiectasia formation (which can lead to bleeding), thinning of the vaginal mucosa, and/or dryness. A study documented the decrease in vaginal length after intracavitary radiation therapy (15) in patients with cervical or endometrial cancer. A mean vaginal shortening of 1.5 cm in patients was noted compared with that of pre-treatment values. In another study, patients were asked to document vaginal changes for one year after the radiation and 48% of the patients reported that their vaginal dimensions had decreased following radiation for cervical cancer (16). Our data concurred with a previous report that 12%-13% of patients required a smaller speculum because of stenosis during the examination period.
To date, no standard system has been accepted by the majority of physicians to record and report late radiation morbidity in gynecological malignancies. For example, when comparing the RTOG and the French–Italian glossary of complications system, the RTOG system has no scoring criteria for a fissure because a fissure is a common presentation in acute toxicity. In addition, the RTOG system's late-toxicity scoring for the vagina is not sufficiently detailed regarding vaginal stenosis and telangiectasia (10). Although the RTOG defines severe telangiectasia as grade 3 morbidity, multiple telangiectasias are less severe than grade 3. We concur with the RTOG recommendations because almost all patients who displayed telangiectasias had no serious complaints in the present study. Ultimately, asymptomatic telangiectasia scored as grade 2 (12% in this study) would cause a false-positive increase in grade 2 vaginal toxicity. To construct a meticulous scoring system, we introduced a Dische score modified by the LENT/SOMA criteria and introduced an assessment of pallor because it may be easier to detect changes in mucosal pallor compared with that of mucosal erythema by visual inspection. Mucosal pallor seems to be related to mucosal thinning, atrophy, and/or fibrosis in patients, and was found to be correlated to vaginal stenosis. Interestingly, after ICBT patients had a higher pallor score than that of those after ISBT; however, after ICBT patients revealed a milder stenosis rate than that in those after ISBT, partly because of the smaller irradiated field customized for small tumors using image-guided ISBT (4, 5). Therefore, ICBT may have a broader distal treatment area. However, after ISBT patients with risk factors predicting poor condition, such as postoperative recurrence with a shortened vagina or bulky tumor, experienced more severe vaginal stenosis. Therefore, the proposed modified Dishce score is valuable for meticulous evaluation of gynecological cancer to confirm the feasibility of ISBT in comparison with conventional ICBT for treating patients with gynecological cancer.
Patients' characteristics.
Pallor of mucosa (grade 1-3).
Modified Diche score for late vagina- 1 mucosal reaction.
Recently, with the availability of image-guided technology, we performed MRI scans after catheter insertion (5) to optimize the distribution using a modern computer-associated planning system. Previously, we reported on the utility of dose-volume histogram (DVH) analysis in image-guided ISBT for previously untreated cervical cancer, but only for the bladder and rectum (5), and not for the vagina. Fidarova et al. performed DVH analysis of the vagina, in which the D2cc dose showed no correlation with vaginal side-effects (17) and speculated that this finding was due to contouring and geometrical positioning of the vagina (18), as they reported that 31/37 (83%) patients experienced telangiectasia and 22/37 (59%) vaginal shortening of grade 1 or more. Thus, our next step will be to analyze vaginal DVH data, which is beyond the scope of this article, because we have included patients treated using a former modality that employed two-dimensional images.
Results of assessment for late vaginal reactions.
The irradiated dose used in Japan is reported to be lower than the one used in the United States and European countries. The recommended dose for a T3 tumor was 30 Gy (WP) + 20 Gy (CS) + 24 Gy/4 (BT) fractions (EQD2=58 Gy, α/β=10) in Japan (20), whereas the recommended dose was 45 Gy (WP) + 30 Gy/5 (BT) fractions in the United States (EQD2=88 Gy) (7). Hints et al. (13) and Au et al. (14) reported that the vaginal tolerance dose ranged from 140 Gy to 175 Gy, which is estimated as an EQD2 of 470 Gy (α/β=3). The prescribed dose in our study was 50-60 Gy (EQD2=80-90 Gy), which was lower than that reported in the Western studies. Accordingly, the Western studies reported several severe toxicities. Gondi et al. reported that in patients treated in the United States, the probability of severe late toxicity of the vagina at three years after treatment was 20.2% for radiotherapy-alone and 35.1% for concomitant chemoradiotherapy (19). Güth et al. reported that out of 98 patients with cervical cancer who received chemoradiation therapy in the United Kingdom 8.2% of patients experienced severe late toxicities and 3.1% (three patients) total vaginal necrosis (9). The patients in this study mostly experienced almost mild reactions and not severe complications such as total vaginal necrosis, which concurred with a report by Toita et al. (20), in which a Japanese treatment schedule that used a lower total dose was reported to be a good option without compromising tumor control or survival (12,20).
In conclusion, patients after ISBT had mild late mucosal reactions, similar to patients after ICBT, except for a more severe stenosis and milder pallor reaction. Pallor reaction is likely to be related to stenosis.
Acknowledgements
We would like to thank Tadashi Takenaka RTT, Kazumasa Aramoto RTT, Shunsuke Miyake RTT, Mari Ueda RTT, Aki Narikiyo, Shigetoshi Yamada MD, Keiji Tatsumi MD, Chiaki Ban MD and the other staff of the Departments of Radiology, Obstetrics and Gynecology, Anesthesiology and Nursing staff for helping us in many ways during the completion of this article.
Footnotes
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Conflicts of Interest
The Authors indicate no potential conflicts of interest.
- Received July 9, 2013.
- Revision received July 22, 2013.
- Accepted July 23, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
