|Ahead of print publication
Endoscopic and clinical correlation with dose to sigmoid colon in carcinoma cervix patients treated with radical radiotherapy
Jyosthna Elagandula1, TR Arulponni2
1 Department of Medical Oncology, Sri Aurobindo Institute of Medical Sciences, Indore, Madhya Pradesh, India
2 Department of Radiation Oncology, Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India
|Date of Submission||01-Oct-2019|
|Date of Decision||25-Nov-2019|
|Date of Acceptance||07-Jan-2020|
|Date of Web Publication||06-Oct-2020|
Department of Radiation Oncology, Ramaiah Medical College and Hospital, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Context: Sigmoid colon, due to its close proximity to central tandem in intracavitary brachytherapy (BT), is at risk of receiving high dose, the clinical significance of which is not documented.
Aim: This study was designed to assess the dose received by sigmoid colon following radical treatment and to correlate clinically with the sigmoid mucosal changes seen on sigmoidoscopy.
Settings and Design: This is a prospective study.
Subjects and Methods: Thirty histologically proven carcinoma cervix patients treated with radical radiotherapy were accrued. A baseline sigmoidoscopy was done and repeated at 6 months following completion of BT. The dose–volume parameters (DVP) were used to calculate the dose received by the sigmoid colon and correlate with symptoms along with the sigmoid mucosal changes.
Statistics: The following were the statistical methods used: frequency; percentages; and descriptive statistics such as mean ± standard deviation, Chi-square test, Kolmogorov–Smirnov test, and independent sample t-test. P < 0.05 was considered statistically significant.
Results: The dose of the sigmoid colon in patients with a sigmoidoscopy score of ≥2 was significantly high compared to that of patients with a score of <2 for DVP such as D0.1cc, D1cc, D2cc, D5cc, and mean dose, whereas max dose was not significantly high.
Conclusions: The dose received by the sigmoid colon is directly proportional to the mucosal changes and hence possibly a higher morbidity. Tighter dose–volume constraints, better optimization techniques, and close follow-up sigmoidoscopy will help in the prevention and early treatment of long-term morbidity.
Keywords: Carcinoma cervix, intracavitary brachytherapy, radiotherapy, sigmoid toxicity, sigmoidoscopy
|How to cite this URL:|
Elagandula J, Arulponni T R. Endoscopic and clinical correlation with dose to sigmoid colon in carcinoma cervix patients treated with radical radiotherapy. J Can Res Ther [Epub ahead of print] [cited 2021 Jan 19]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=297394
| > Introduction|| |
In India, cervical cancer accounts for 25% of the total cervical cancer deaths worldwide. The standard treatment for carcinoma cervix from the Federation Internationale of Gynaecology and Obstetrics (FIGO) Stage IB2 onwards is concurrent chemoradiation as per the NCI Alert 1999 followed by brachytherapy (BT). Radiation is delivered in the form of external beam radiotherapy (EBRT) followed by BT. Three-dimensional conformal planning, image-compatible applicators, dose computation facilities, and accurate dose–volume parameters (DVP) aid in quantifying the dose versus volume in both EBRT and BT. The dose received by organs at risk (OARs) reflects the toxicity. Rectal toxicity was studied by various authors. Sigmoid colon by virtue of its close proximity to central tandem in intracavitary BT (ICBT) is at high risk of receiving excessive dose, the clinical significance of which has not been well studied. In this study, we analyzed the dose received by sigmoid colon and the sigmoid mucosal changes and correlated clinically.
| > Subjects and Methods|| |
This prospective study was conducted after ethical clearance and informed consent on thirty histologically proven carcinoma cervix patients receiving radical radiotherapy. Following baseline investigations as per the institution protocol, all patients underwent flexible sigmoidoscopy before the start of external beam radiation (EBRT) using Olympus CF-Type Q 180 video colonoscope (Tokyo, Japan). Postoperative, recurrent carcinoma cervix, patients with a history of inflammatory bowel disease were excluded from the study. After immobilization with pelvic Orfit aquaplast (Kalyani Radiotherapy Specilaty India Pvt Ltd., Trichy, Tamil Nadu, India), a contrast-enhanced computed tomography (CT) scan of the abdomen and pelvis of 3-mm slice thickness was performed as a part of radiotherapy planning. The sigmoid colon was delineated instilling rectal contrast prepared by mixing 10-ml iodinated contrast with 40-ml normal saline during the planning CT scan of EBRT and ICBT.
External beam radiotherapy
Target volume and OARs were contoured as per the department protocol. The sigmoid colon was contoured from the rectosigmoid flexure up to a level of 2 cm above the uterine fundus. All patients were treated with three-dimensional conformal radiotherapy (3DCRT) to a dose of 45 Gy in 25 fractions (fr), 5 fr per week, over 5 weeks, along with concurrent weekly cisplatin to a dose of 40 mg/m2 body surface area. Treatment planning was done on Prowess Panther 4.71 (Concord, California, USA) treatment planning system (TPS). DVPs of sigmoid colon were generated. Treatment was executed on 6 MV Linear Accelerator-Elekta synergy basic unit (Model –MRT 8501 NFB; Stockholm, Sweden).
ICBT was performed within 10–14 days of completion of EBRT. The procedure was performed under spinal anesthesia using a CT/magnetic resonance imaging -compatible Fletcher-style tandem ovoid applicator. Planning CT scan of pelvis with 3-mm slice thickness was done. Apart from other OARs, sigmoid colon delineation was done using rectal contrast similar to EBRT procedure. Target and OARs were contoured. Any sigmoid adjacent and/or above the uterus or BT applicator was contoured as per the Radiation Therapy Oncology Group (RTOG) guidelines. A dose of 6.5 Gy ×4 Fr or 7.5 Gy ×3 Fr was prescribed to high-risk clinical target volume, and all fractions were delivered in a single application over 2 days 6 h apart between the fractions. All patients were treated on Cobalt 60 high-dose radiation (HDR) units (Bebig Multisource high dose rate [HDR] afterloader, Eckert & Zeigler, Germany). TPS software used was HDR plus 3.04 version (Germany). DVPs of sigmoid colon were generated.
After the completion of treatment, patients were followed up every 2 months. At 6-month follow-up, repeat flexible sigmoidoscopy was done. The five components of mucosal changes such as erythema, telangiectasia, stricture, ulceration, and necrosis were analyzed according to Crespi et al. The 6-scale scoring system proposed by the Medical University of Vienna determined from the endoscopic terminology of the World Organization for Digestive Endoscopy was adopted for reporting endoscopic findings. RTOG scale was used to assess the acute and late effects of radiation.
All the qualitative parameters such as stage and comorbidities were presented using frequency and percentages. Variables such as age and DVP were presented using descriptive statistics such as mean ± standard deviation (SD). Chi-square test was used to find the association between age, stage, and chemotherapy with sigmoidoscopy score. Kolmogorov–Smirnov test was used to test the normality DVP, and it was observed that data were normally distributed. Independent sample t-test was used to compare the DVP between patients with a score of <2 and ≥2. P < 0.05 was considered statistically significant.
| > Results|| |
The patient characteristics are summarized in [Table 1]. The mean age of the study population was 52 years, with age ranging from 38 to 65 years. All the patients belonged to Stage IIA–IIB as per the Internationale FIGO and received concurrent chemoradiation with EBRT to a dose of 45 Gy in 25 fr, 5 fr/week, over 5 weeks, by 3DCRT technique and weekly cisplatin following baseline sigmoidoscopy. ICBT dose was 6.5–7.5 Gy/fr delivered in 3–4 fr in a single application over 2 days with a minimum interfraction interval of six hours. The mean duration of the occurrence of proctitis was 8–10 months from the completion of BT.
The baseline sigmoidoscopy was normal in all the thirty patients. During sigmoidoscopy at 6-week follow-up, the five components of mucosal changes were evaluated. The distance from the anal verge was documented in the follow-up sigmoidoscopy. Majority of the patients showed a few to multiple telangiectatic spots at 10–20 cm from the anal verge. One patient showed telangiectasia with ulceration at 40 cm from the anal verge. Patchy areas of hyperemia at rectum were noted in a few patients. Out of the thirty patients, 15 had no mucosal changes, one had Grade 2 mucosal erythema, 13 had Grade 2 telengiectasia, one had both Grade 2 telengiectasia and Grade 3 stricture, and none had ulceration or necrosis. The maximum score of sigmoid colon was evaluated. Fifteen patients had score 0 (50%), one patient each had score 1 and score 5 (3% each), and 13 (43%) patients had score 2. Age, FIGO stage, and concurrent chemotherapy were not significantly associated with the development of score ≥2 sigmoid complications [Table 2].
The dose was normalized to total equieffective dose (EQD2). The mean values with SD of DVP for EBRT, ICBT, and combined dose are summarized in [Table 3]. Difference in the combined (EBRT + ICBT) mean EQD2 doses for patients with a sigmoidoscopy score <2 versus ≥2 is shown in [Table 4]. The dose received by patients with score ≥2 was significantly high compared to those patients with score <2 for D0.1cc, D1cc, D2cc, D5cc, and mean dose, whereas max dose DVP was not significantly high.
|Table 3: Dose-volume parameters of mean dose to sigmoid colon during external beam radiotherapy, intracavitary brachytherapy, and combined external beam radiotherapy and intracavitary brachytherapy|
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|Table 4: Mean value of combined (external beam radiotherapy + intracavitary brachytherapy) dose-volume parameters according to sigmoidoscopy score|
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Difference in the mean EQD2 dose from EBRT received by patients with a score ≥2 was not significantly greater compared to patients with a score <2. The mean values of DVP among patients with a score ≥2 versus <2 were D0.1cc (46.71 Gy, P = 0.76), D1cc(46.53Gy vs 46.47Gy), D2 (46.40Gy vs 46.35 Gy, P = 0.84), and D5cc (46.18 Gy vs. 46.15 Gy, P = 0.90). The mean dose was 41.66 Gy vs. 39.05 Gy, P = 0.12, and max dose was 46.96 Gy vs. 46.76 Gy, P = 0.48 in patients with a sigmoidoscopic score ≥2 versus <2. Difference in the mean EQD2 doses from ICBT for the patients with a sigmoidoscopic score <2 versus ≥2 is shown in [Table 5]. The dose received by patients with a score ≥2 was significantly high compared to patients with a score <2 for D0.1cc, D1cc, D2cc, and D5cc, whereas the mean and max DVP were not significantly high. The mean D2cc dose per fraction with a score <2 was 3.044 Gy compared to 3.671 Gy in patients with a score ≥2, which was statistically significant (P = 0.017).
|Table 5: Mean value of intracavitary brachytherapy dose-volume parameters according to sigmoidoscopy score|
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| > Discussion|| |
CT-based planning in ICBT helps in the accurate determination of DVP and thereby correlation of toxicities. These were not possible in the two-dimensional era where only dose-to-bladder and rectal points were recorded as per the International Commission on Radiation Units (ICRU) 38. The present study was designed to assess the radiation dose received by sigmoid colon and correlate it clinically along with sigmoidoscopic findings. Similar studies in which DVP for sigmoid colon were determined are by Koom et al., Georg et al., Kim et al., Hallock et al., Kim et al., Kirisits et al., and Lang et al. However, only Koom et al. and Kim et al. have correlated DVP with sigmoidoscopic findings.
The mean age of the patients in the present study was 52 years, which is comparable to 56 years in the study by Koom et al. The majority of patients in our study were in the age group of 40–60 years and belonged to FIGO Stage IIB (86.7%), whereas Koom et al. included Stage IB–IIIB patients. As a department protocol, we perform interstitial BT from Stage III onward for a better target coverage. Hence, we did not include Stage IIIB patients in our study, whereas Koom et al. administered parametrial boost by EBRT with central shielding for Stage IIIB patients. In our study, age of the patient (P = 0.491) and concurrent chemotherapy (P = 0.574) were not significantly correlated with the development of score ≥2 sigmoiditis. Similar results were observed by Koom et al. with respect to age and concurrent chemotherapy. There was no significant correlation between FIGO stage and the development of score ≥2 sigmoid complication (P = 0.886) in our study. This is in contrast to the study by Koom et al., where they found significant increase in the incidence of score ≥2 (P = 0.01), wherein there was tumor infiltration in the lateral direction. We did not include Stage III patients in our study and also, there is an unequal distribution among Stages IIA (13.3%) and IIB (86.7%). For ICBT dose prescription, various authors have used various fractionation schedules. Our department policy for HDR ICBT in carcinoma cervix is 6.5 Gy ×4 fr or 7.5 Gy ×3 fr based on Orton's data of low dose rate (LDR) to HDR conversion and the total dose delivered is 80–90 Gy which is the tumoricidal dose.
To calculate the combined dose received by sigmoid colon, each tissue volume element irradiated by both EBRT and BT should be matched. This systematic image-matching procedures require complex calculations based on image-based dose–volume assessment. Hence, for these calculations, the assumption suggested by Pötter et al. is that the volume of interest has received the full dose of EBRT. Furthermore, the tumor volume shrinks during each insertion in fractionated BT, thereby change in its configuration and normal tissue topography. Hence, the location of high-dose region from BT may not be identical for each fraction. In addition with each insertion of BT applicator, the normal tissue topography changes, and it will not be the exact replica of previous application. However, at our institution, we performed all fractions of BT in a single application, delivering the fractions over 2 days and hence, the location of high-dose region is presumed to be identical in all fractions.
As per the Groupe Européen de Curiethérapie European Society for Radiotherapy & Oncology (GEC ESTRO) guidelines of recommendations for recording and reporting 3D gynecological BT, D0.1cc, D1cc, and D2cc are mandatory, whereas D5cc and D10cc are optional for OARs. ICBT for cervical cancer creates a highly heterogeneous dose distribution. Thus, the minimal doses applied to the respective maximal irradiated volume, i.e., D0.1cc, D1cc, and D2cc were more reliable estimates for predicting dose-limiting complications than were the mean doses.
According to Kirisits et al., D0.1cc corresponded to the maximal dose as determined by conventional radiography and a volume of 1, 2, or 5cc would correspond to a defined late effect, such as circumscribed inflammation, ulceration, or fistula.
In our study, we included mean and max doses along with D0.1cc, D1cc, D2cc, and D5cc to find whether there would be any correlation with sigmoid toxicity. The mean of D0.1cc, D1cc, D2cc, D5cc, mean dose, and max dose was 81.75, 74, 71, 66.48, 52.24, and 83.55 Gy, respectively. In similar studies, where dose to sigmoid colon was quantified, only D0.1cc, D1cc, and D2cc were determined, which is mandatory as per the GEC ESTRO guidelines, and few studies also assessed D5cc. The DVPs assessed in various studies are summarized in [Table 6]. In a study by Kim et al., DVPs of sigmoid together with rectum were recorded. Our mean values of DVP are comparable with other studies.
|Table 6: Mean values of dose-volume parameters of sigmoid colon by various authors|
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Location of sigmoid colon with respect to tandem and ovoid
The average distance of the sigmoid colon from the tandem was 14 mm, with a median value of 15.5 mm and a mode of 17 mm. The maximum distance of sigmoid colon from the tandem was 24 mm. The sigmoid colon of three patients was at 10, 14, and 16 mm from the ovoid. The prescription isodose was on the sigmoid colon in one of the patients.
Correlation of dose–volume parameters with sigmoidoscopy score
Flexible sigmoidoscopy was performed once at baseline and at 6th month post BT. The mean value of combined (EBRT + ICBT) DVP according to sigmoidoscopy score is shown in [Table 4]. Patients with a sigmoidoscopy score ≥2 received a significantly higher total dose compared to score <2 based on the mean values of D0.1cc, D1cc, D2cc, D5cc, and mean dose, and a trend toward significance was observed with respect to the max dose. A similar significance was observed in the study by Koom et al. between score <2 and ≥2, who assessed rectosigmoid colon [Table 7]. In our study, the mean D0.1cc for score <2 was 78.29 Gy and score ≥2 was 85.72 Gy, compared to their study wherein it was 85 Gy and 93 Gy, respectively. The variation can be due to their combined rectosigmoid colon assessment and acceptance of dose to OARs up to 90% of the prescribed dose, whereas in our study, we assessed sigmoid colon alone and accepted a dose not more than 85% of the prescribed dose. The mean, D1cc, and D2cc values are comparable between theirs and our study. The mean D1cc was 71.55 Gy and 76.81 Gy for scores <2 and ≥2, respectively, in our study compared to 73 Gy and 80 Gy in their study, and the mean D2cc was 68.94 Gy and 73.36 Gy for scores <2 and ≥2, respectively, in our study compared to 69 Gy and 75 Gy in their study. [Table 8] shows the EBRT and ICBT dose per fraction along with cumulative LDR-equivalent dose to sigmoid colon in Gy. The mean cumulative dose to sigmoid colon was 65.6±5.5 Gy.
|Table 7: Correlation of mean values of dose-volume parameters with sigmoidoscopic score|
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|Table 8: External beam radiotherapy and intracavitary brachytherapy dose per fraction along with cumulative LDR equivalent dose to sigmoid colon in Gy|
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The unique feature in our study is that we correlated sigmoidoscopy score with EBRT and EQD2 doses separately. It was found that there is no significant correlation between EBRT DVP and score <2 versus ≥2. With ICBT DVP, a significant correlation was found for <2 versus ≥2. This implies that uniform doses are received by sigmoid colon across all patients during EBRT, whereas the ICBT had made difference for significant dose differences between scores <2 and ≥2, hence contributing to the toxicity.
During ICBT, the dose received by patients with a score ≥2 are significantly greater compared to patients with a score <2 for D0.1cc, D1cc, D2cc, and D5cc in our study. The mean and max DVP were not significantly different among score ≥2 versus <2.
In our study, one patient developed Grade 3 sigmoid stricture (D2cc = 77.36 Gy, D1cc = 85.22 Gy, and D0.1cc = 105.1 Gy). In the study by Hallock et al., where they reported their experience using HDR BT with CT imaging for locally advanced cervix cancer, sigmoid stricture was noted in one patient, which required hemicolectomy (D2cc = 62.6 Gy, D1cc = 66 Gy, and D0.1cc = 75 Gy). No dose limit for sigmoid colon was set in their study. In a study by Georg et al., who studied DVP and late side effects in cervical cancer BT, a total of three patients had sigmoid colon stricture. One patient had Grade 2 stricture, who presented with alternating diarrhea and constipation for which no surgical treatment was needed. Two patients had Grade 4 stricture (complete obstruction) of rectosigmoid junction and underwent surgical intervention with permanent colostomies. The DVPs of these three patients were D2cc 77 ± 11 Gy, D1cc 84 ± 14 Gy, and D0.1cc 104 ± 24 Gy. Koom et al. reported two patients with sigmoid stricture: one patient with Grade 3 and the other with Grade 2. There was no mention about the dose received by sigmoid colon in these patients. The dose received by sigmoid colon with sigmoid stricture in our study is comparable with that of available literature.
Our patient with sigmoid stricture presented with constipation. During follow-up sigmoidoscopy, biopsy was taken from the area of stricture, which was reported to be nonspecific colitis [Figure 1]. Dilatation procedure was suggested after evaluation with barium enema. However, the patient did not undergo due to various reasons. She was started on conservative management and was symptom free on subsequent follow-up.
|Figure 1: High-power microscopic picture showing features of sigmoiditis – edema and inflammatory cells such as lymphocytes, plasma cells, and eosinophils (arrow) in lamina propria|
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In our study, three patients required argon plasma coagulation (APC) for control of rectal bleeding. However, only two patients underwent APC procedure during which the telangiectatic spots were ablated both in sigmoid colon and rectum. One patient did not undergo APC for various reasons. One patient required blood transfusion prior to APC. In a study by Hallock et al., four patients underwent APC for minor rectal bleeding (Grade 2) as it was the standard practice at their institution; none required blood transfusion prior to APC.
The merits of our study are that all our patients underwent baseline sigmoidoscopy. We not only assessed dose received by sigmoid colon but also correlated it with mucosal changes on follow-up sigmoidoscopy and compared with clinical toxicity. We have correlated the sigmoid colon dose separately and not combined with rectum as done by Koom et al. We have evaluated the contribution of dose to sigmoid colon from EBRT and ICBT separately. There are no such studies in literature.
Unlike other authors, we have not done multiple BT applications, and we have completed all the BT fractions over 2 days with single application. Hence, the realistic estimation of dose received by sigmoid colon in all the fractions was estimated with one-time CT simulation.
The limitations of our study are a relatively small sample size and a short follow-up of 6 months. Longer follow-up till 2 years may give us a better understanding of the chronic changes in the sigmoid mucosa.
| > Conclusions|| |
In the era of 3D-BT, it is possible to document and correlate dose received by the sigmoid colon with the mucosal changes on endoscopy. The dose received by the sigmoid colon is directly proportional to the mucosal changes and hence possibly a higher morbidity. Tighter dose–volume constraints (D2cc ≤3 Gy), better optimization techniques, and close follow-up sigmoidoscopy will help in the prevention and early treatment of long-term morbidity.
Dr. Umesh Jalihal, Prof & HOD, Dr Lokesh, Dept of Gastroenterology, Ramaiah Hospitals, Ramaiah Medical College.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]