|Year : 2018 | Volume
| Issue : 8 | Page : 120-124
Incidence of radiation enteritis in cervical cancer patients treated with definitive radiotherapy versus adjuvant radiotherapy
Yinuo Wang1, Weimin Kong1, Nanan Lv1, Fengshuang Li1, Jiao Chen1, Simeng Jiao1, Ding Ding2, Hui Zhao1, Dan Song1
1 Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
2 Department of Family Planning, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
|Date of Web Publication||26-Mar-2018|
Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026
Source of Support: None, Conflict of Interest: None
Objective: The study aimed to evaluate the incidence of early and late radiation enteritis in cervical cancer patients receiving definitive or adjuvant radiotherapy (RT).
Materials and Methods: Three hundred and twenty-four cervical cancer patients receiving definite or adjuvant RT in our hospital from January 2010 to December 2012 were divided into definitive (132 patients) or adjuvant RT (192 patients) and performed detailed analysis.
Results: Early radiation enteritis was found in 54.3%, and late radiation enteritis was found in 17.9% of cervical patients. Early (P < 0.007) and late (P < 0.003) radiation enteritis appeared more frequently in patients treated with definitive RT than that with adjuvant RT. In the definitive RT group, incidence of both early and late radiation enteritis in the RT group was higher than in the radiochemotherapy (RCHT) group, and the difference was statistically significant (P < 0.004). Severe cases of late radiation enteritis (Grade 3 and 4) can be seen higher in the definitive radiation group (both the RT and RCHT group) than in the adjuvant radiation group, and the difference was statistically significant (P < 0.005).
Conclusion: The incidence of both early and late radiation enteritis in the definitive RT group is higher than in the adjuvant RT group. The occurrence of side effects was associated with the prolongation of total irradiation time due to necessary interruptions of RT. Methods to decrease the interruptions in the RT and the irradiated volume of the small bowel will further lessen enteric morbidity.
Keywords: Adjuvant radiotherapy, definitive radiotherapy, incidence, radiation enteritis
|How to cite this article:|
Wang Y, Kong W, Lv N, Li F, Chen J, Jiao S, Ding D, Zhao H, Song D. Incidence of radiation enteritis in cervical cancer patients treated with definitive radiotherapy versus adjuvant radiotherapy. J Can Res Ther 2018;14, Suppl S1:120-4
|How to cite this URL:|
Wang Y, Kong W, Lv N, Li F, Chen J, Jiao S, Ding D, Zhao H, Song D. Incidence of radiation enteritis in cervical cancer patients treated with definitive radiotherapy versus adjuvant radiotherapy. J Can Res Ther [serial online] 2018 [cited 2019 Nov 18];14:120-4. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/120/163762
| > Introduction|| |
Worldwide, cervical cancer is the third most common malignancy and the second most common cancer (after breast cancer) in women. Radiotherapy (RT) is a well-established treatment for pelvic malignancies, often with curative intent. RT, alongside with surgery and chemotherapy, is an important part of the therapeutic process in women suffering from cervical cancer. The irradiation of the pelvis is the key component of a definitive or adjuvant treatment of cervical cancer patients. The high dose of RT can cause obliterative endarteritis, submucosal fibrosis, and new vessel formation, which may lead to the clinical symptoms of rectal bleeding, strictures, tenesmus, and diarrhea. As a result, this can be particularly problematic in the treatment of cervical cancer extending to the distal vagina. It is estimated that 90% of patients develop a permanent change in their bowel habit after pelvic RT, 50% of which have an associated reduction in their quality of life. The largest obstacles to the successful management of these patients are accurate diagnosis and access to effective treatments.
Radiation enteritis is damage to the lining of the intestines (bowels) caused by radiation therapy, which is the most frequent complication of RT for cervical cancer. Radiation enteritis, with symptoms of nausea, vomiting, diarrhea, pain, bleeding, weight loss, and intestinal fistula being reported, is therefore an almost inevitable consequence of therapeutic abdominal irradiation administered to patients with abdominal or gynecologic malignancy. No satisfactory method has been found to control the symptoms of diarrhea and weight loss, which are frequently severe enough to limit or delay further doses of treatment. In 15–20% of patients, prolongation of RT has been implicated as a factor in the reduction of the chance of cure. Symptoms may occur within 3 months after radiation treatment (called acute radiation enteritis), or longer than 3 months after the treatment (called chronic radiation enteritis). In many studies, authors have underlined that around 50% of patients irradiated to the pelvis might exhibit early and late exhibited radiation enteritis after RT., It is associated with the treatment method (radical RT including in combination with chemotherapy or adjuvant RT) and radiation dose (combining tele RT and brachytherapy [BRT]).
Given the morbidity of radiation enteritis postpelvic RT and the negative impact on quality of life, there is an imperative to develop a better understanding of this complex clinical scenario. Although there are few treatments for acute enteritis, late enteritis can usually be effectively managed by detecting the specific consequential effects of radiation, e.g., bile salt malabsorption, small intestinal bacterial overgrowth, etc., and providing specific treatments. The definite diagnosis has the most impact on the prognosis of the disease. It is very important to evaluate the incidence of radiation enteritis. Comparing the incidence between the definitive and adjuvant RT group might contribute to protocol more reasonable RT scheme.
| > Materials and Methods|| |
Patients and grouping
From January 2010 to December 2012, 324 cervical cancer patients receiving definite or adjuvant RT at the Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital were involved in the study, which were divided into definitive (132 patients) or adjuvant RT (192 patients), and were performed statistical analysis.
The definitive RT group consisted of 132 women diagnosed as International Federation of Gynecology and Obstetrics (FIGO) stage IIB and IIIB cervical cancer treated with radical RT (RT exclusively or radiochemotherapy [RCHT]). All the definite RT, group patients received both external-beam radiation therapy (EBRT) and BRT. Sixty-two patients were treated with definitive RT; the other 70 were given RCHT-cisplatin (40 mg/m 2) administered once a week over the RT period.
External conformal RT was performed using 60 Co with 4-field-box technique. Clinical target volume comprised the tumor of the cervix along with the corpus uteri, vaginal wall and fornix, parametrium, and lymph nodes of the pelvis. Fractionation dose was 1.8 Gy given 5 times a week. In the area of higher dose of low-dose-rate BRT (LDR), a central shield was used during tele RT assuming an International Commission on Radiation (ICR) Units and Measurements-compliant dose of 85 Gy to point A. The correctness of tele RT was evaluated with portal images and in vivo dosimetry. In the case of BRT, both physical and biological doses (equivalent dose 2) were measured.
An average EBRT dose of patients was 34.3 Gy (range 12.6–56 Gy); an average BRT LDR was 45 Gy (20–60 Gy). In the group, patients treated with high-dose-rate (HDR) BRT received 28 Gy in four fractions and a total external-beam dose of 45 Gy/T. For the IIIB stage patients, the external-beam dose to the parametrium was increased to 50.4 Gy/T.
The adjuvant RT group consisted of 224 patients receiving an adjuvant RT following surgery for FIGO stage I-IIIA cervical cancer. The patients qualified to the adjuvant RT group had poor prognostic factors from histopathological tests.
Conformal EBRT was also delivered using 60 Co with 4-field-box technique; 45 patients were treated with inter modulate radiation therapy. The target volume included the lymph nodes of the pelvis. The fractionation dose was 1.8 Gy delivered 5 times a week. Total average dose to the planning target volume was 51.4 Gy/T ± 5 Gy.
All the patients received HDR BRT -three fractions of 6.0 Gy, administered weekly. The dose was fixed at 0.5 cm from the applicator surface, its diameter adjusted to the anatomy of patient's vagina (2.0–4.0 cm).
Observation and evaluation of patients and grading of the radiation enteritis
The patients were observed prospectively on the course of treatment and evaluations were made periodically during 2 years follow-up. They were analyzed for general health status, laboratory test results, and radiation reactions of the intestines and urinary system. The analysis related to the course of RT also included interruptions in RT. The RT was evaluated based on medical documentation and irradiation sheets.
The study employed FIGO staging for cervical carcinomas (2009). Both early (occurring earlier than 3 months after RT) and late radiation enteritis (occurring later than 3 months after RT) were observed during 2 years follow-up. All patients were arranged periodically follow-up after RT, and if they missed, the patients would be provided telephone follow-up.
Radiation enteritis was graded according to the European Organization for Research and Treatment of Cancer (EORTC)/radiation therapy oncology group (RTOG) morbidity scoring for the rectum.
The EORTC/RTOG scale was used to evaluate radiation toxicity. In further analysis, Grade 1 and 2 reactions were collectively rated as mild while Grade 3 and 4 reactions were rated as severe.
The statistical analysis was carried out using the Chi-square, Mann–Whitey U-test, and Fisher's exact tests. P < 0.05 was considered as statistically significant.
| > Results|| |
Comparison of radiation enteritis between the definitive radiotherapy group and adjuvant radiotherapy group
The whole studied group (324 patients) revealed a higher rate of radiation enteritis. The radiation enteritis, both early and late cases, occurred more frequently in the definite RT group than in the adjuvant RT group, and the difference was statistically significant (P < 0.005). Early radiation enteritis accounted for 54.3% of all the involved patients. The incidence of early radiation enteritis in the definitive RT group (29.2%) was higher than in the adjuvant group (25.1%), and the difference was statistically significant (P < 0.005).
In all the involved patients, 17.9% patients had late radiation enteritis, in which 11.7% patients were treated with definitive RT, and 6.2% patients were treated with adjuvant RT, and the difference was statistically significant (P < 0.005).
Cervical cancer patients treated with definite RT were statistically significantly older than that receiving adjuvant RT. The mean age of patients treated with definitive RT was 66.5 years ± 10.2 versus 53.6 years ± 7.5 for those treated with RT [Table 1].
|Table 1: Comparison of radiation enteritis between the definitive RT group (both RT and RCHT group) and adjuvant RT group|
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Evaluation of early radiation enteritis
The cervical cancer patients receiving definitive RT accounted highest incidence of early radiation enteritis, of which 60.1% were treated with RT and 39.9% with RCHT, and the difference was statistically significant (P < 0.005). A higher percentage of severe cases (Grade 3 and 4) in the definitive radiation group (both the RT and RCHT group) than in the adjuvant radiation group can be noted, and the difference was significant (P < 0.005) [Table 2].
|Table 2: Comparison of incidence of early radiation enteritis between the definitive RT group (RCHT and RT) and adjuvant RT group|
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Evaluation of late radiation enteritis
Analysis results for late radiation enteritis were similar to that of early radiation enteritis. In the definitive RT group, 38 cervical cancer patients had late radiation enteritis, of which 63.7% were treated with RT and 36.3% with RCHT, and the difference was statistically significant (P < 0.005). Of note, severe cases of late radiation enteritis (Grade 3 and 4) can be seen higher in the definitive radiation group (both the RT and RCHT group) than in the adjuvant radiation group, and the difference was statistically significant (P < 0.005) [Table 3].
|Table 3: Comparison of incidence of late radiation enteritis between the definitive group (RCHT and RT) and adjuvant group|
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| > Discussion|| |
Radiation is a cost-effective treatment, which plays an important role in cancer treatment and is a major cure for 25% of all cancers. The study aimed to analyze the incidence of radiation enteritis in cervical cancer patients treated with various RT methods including definitive and adjuvant RT.
The analysis of patients managed in the Gynecologic Oncology Department of the Beijing Obstetrics and Gynecology Hospital showed that a statistically higher percentage of patients who had developed both early and late radiation enteritis in definitive RT than in adjuvant RT group (P < 0.007 and P < 0.006). Early radiation enteritis accounted for 54.3% of all the involved patients versus 17.9% of late radiation enteritis. Toita et al. reported similar results in a multi-institutional study. This should be associated with a higher physical and biological dose delivered to the organs at risk. Combined with LDR and HDR brachytherapy, definitive external-beam radiation (by 5.4 Gy) renders a higher dose to critical organs than the adjuvant RT. Researchers have observed complications would increase with higher radiation doses. A greater incidence of pelvic complications has been consistently observed in patients treated with higher doses to the whole pelvis (above 40–50 Gy). Perez et al. found that total doses to the rectal point (RP) had significantly impacted on the morbidity. These factors were also highlighted in the study by Rodríguez et al.
In the definitive radiation therapy group, the incidence of early radiation enteritis in the RT group (60.1%) was higher than that in the RCHT group (39.9%), and the difference was statistically significant (P < 0.005). Patients receiving RT only were statistically significantly older (P < 0.01) and it was them who showed more incidence of radiation enteritis (whether, early or late), which might due to the less vulnerable and endurable to the RT. Age is another factor that may influence the treatment intolerance. The analysis made in this study showed the statistically significant age difference between the two subgroups. Older patients had a higher rate of complications. These results are consistent with those reported by van den Aardweg, et al.
The evaluation of both subgroups showed that those receiving RT only had a higher rate of radiation enteritis, both early and late, than patients receiving RCHT and adjuvant RT. Other authors, however, indicated the relatively more serious adverse effects be in concurrent chemotherapy and adjuvant RT than in the definite RT. Hysterectomy/other pelvic surgery and irradiating pelvic/sidewalls nodes can cause the surrounding damage, which might increase the incidence of the radiation enteritis. However, in our study, the higher incidence of the radiation enteritis indefinite RT group may be related to our patients' high clinical stage of the disease; concurrence of renal failures and other diseases; as well as old age disqualifying them from RT.
In the definitive RT group, the incidence of higher grade of late radiation enteritis group was higher in the RT group (63.7%) than in the RCHT group (36.3%), and the difference was statistically significant (P < 0.005). The group receiving adjuvant RT was also observed to show a higher rate of Grade 3 radiation enteritis (no Grade 4 was recorded). Despite higher incidence in the group in the group treated with RT alone, it should be stressed that severe complications occurred more frequently in patients receiving combined RT and chemotherapy, which may be related to the joint, synergistic activity of both modalities. The combination of two toxic factors leads to the increase in the incidence of radiation enteritis. Severe reactions during and after RT in the range of 3–5% have been observed by many authors. This may have been related to the use of cisplatin. Predisposing factors related to chronic radiation enteritis are a low body mass index, previous abdominal surgery, concomitant use of chemotherapy, the presence of co-morbid conditions, RT fractionation, and the RT field and RT dose of ICR.
As note should be taken that total radiation doses in patients treated with RT is not the only factor that may influence the incidence of radiation enteritis. However, the dose is only one of the factors determining the occurrence of radiation enteritis, aside from those commonly recognized such as age, metabolic diseases, chronic gastrointestinal, or urinary., Several studies have analyzed the correlation between the radiation dose and the development of radiation enteritis after pelvic RT. These studies have suggested rectal doses >80 Gy, biologically effective dose (BED) at the RP >125 Gy3, ratio of the rectal dose to the point A dose >70%, and the measured rectal BED >110 Gy3 as predisposing factors for radiation enteritis.
| > Conclusion|| |
We considered that the incidence of radiation enteritis is high in the cervical cancer patients, which is mainly related to the radiation dose. Although there are already some effective treatment methods, the radiation enteritis has greatly disturbed the life of the postradiation cervical cancer patients. It is very important to study the incidence of radiation enteritis in various RT treatments, which may be helpful to formulate more reasonable RT scheme to reduce the incidence of radiation enteritis. In a further study, we will study whether increasing each single irradiation dose and prolonging the interval between each irradiation can reduce the incidence of the radiation enteritis.
The incidence of both early and late radiation enteritis in the definitive RT group is higher than in the adjuvant RT group. Interruptions in RT of more than 7 days caused by the occurrence of adverse radiation effects were more often found in patients treated with definitive RT than adjuvant RT. This led to the prolongation of total treatment time in those patients. The occurrence of side effects was associated with the prolongation of total irradiation time due to necessary interruptions of RT. The methods to decrease the interruptions in the RT and the volume of small bowel irradiated will further lessen enteric morbidity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Leiper K, Morris AI. Treatment of radiation proctitis. Clin Oncol (R Coll Radiol) 2007;19:724-9.
Andreyev HJ, Vlavianos P, Blake P, Dearnaley D, Norman AR, Tait D. Gastrointestinal symptoms after pelvic radiotherapy: Role for the gastroenterologist? Int J Radiat Oncol Biol Phys 2005;62:1464-71.
Andreyev HJ, Muls AC, Norton C, Ralph C, Watson L, Shaw C, et al.
Guidance: The practical management of the gastrointestinal symptoms of pelvic radiation disease. Frontline Gastroenterol 2015;6:53-72.
Czito BG, Willett CG. Radiation injury. In: Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 9th
ed., Ch. 39. Philadelphia, PA: Saunders Elsevier; 2010.
Stacey R, Green JT. Radiation-induced small bowel disease: Latest developments and clinical guidance. Ther Adv Chronic Dis 2014;5:15-29.
Do NL, Nagle D, Poylin VY. Radiation proctitis: Current strategies in management. Gastroenterol Res Pract 2011;2011:917941.
Henson C. Chronic radiation proctitis: Issues surrounding delayed bowel dysfunction post-pelvic radiotherapy and an update on medical treatment. Therap Adv Gastroenterol 2010;3:359-65.
Bondar' GV, Basheev VK, Zolotukhin SÉ, Sovpel' IV, Sovpel' OV. Neoadjuvant chemotherapy and radiation therapy of resectable cancer recti of distal localization. Klin Khir 2013:44-7.
Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO. Radiation dose-volume effects in radiation-induced rectal injury. Int J Radiat Oncol Biol Phys 2010;76:S123-9.
Cox JD, Stetz J, Pajak TF. Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341-6.
Shadad AK, Sullivan FJ, Martin JD, Egan LJ. Gastrointestinal radiation injury: Prevention and treatment. World J Gastroenterol 2013;19:199-208.
Toita T, Kato S, Niibe Y, Ohno T, Kazumoto T, Kodaira T, et al.
Prospective multi-institutional study of definitive radiotherapy with high-dose-rate intracavitary brachytherapy in patients with nonbulky (<4-cm) stage I and II uterine cervical cancer (JAROG0401/JROSG04-2). Int J Radiat Oncol Biol Phys 2012;82:e49-56.
Perez CA, Grigsby PW, Lockett MA, Chao KS, Williamson J. Radiation therapy morbidity in carcinoma of the uterine cervix: Dosimetric and clinical correlation. Int J Radiat Oncol Biol Phys 1999;44:855-66.
Rodríguez ML, Martín MM, Padellano LC, Palomo AM, Puebla YI. Gastrointestinal toxicity associated to radiation therapy. Clin Transl Oncol 2010;12:554-61.
van den Aardweg GJ, Olofsen-van Acht MJ, van Hooije CM, Levendag PC. Radiation-induced rectal complications are not influenced by age: A dose fractionation study in the rat. Radiat Res 2003;159:642-50.
Eifel PJ, Winter K, Morris M, Levenback C, Grigsby PW, Cooper J, et al.
Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: An update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 2004;22:872-80.
Paganetti H, Niemierko A, Ancukiewicz M, Gerweck LE, Goitein M, Loeffler JS, et al.
Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 2002;53:407-21.
DeSimone C, Kufrimoti M, Baldwin L, Weiss H, Randall M. Risk factors for fistula formation in patients with cervical cancer treated with radiation therapy include post-radiation biopsy. Gynecol Oncol 2011;120:S114.
Portelance L, Chao KS, Grigsby PW, Bennet H, Low D. Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation. Int J Radiat Oncol Biol Phys 2001;51:261-6.
Halkett G, Aoun S, Hayne D, Lund JA, Gruen A, Villa J, et al.
EORTC radiation proctitis-specific quality of life module – Pretesting in four European countries. Radiother Oncol 2010;97:294-300.
Theis VS, Sripadam R, Ramani V, Lal S. Chronic radiation enteritis. Clin Oncol (R Coll Radiol) 2010;22:70-83.
Goldner G, Pötter R, Kranz A, Bluhm A, Dörr W. Healing of late endoscopic changes in the rectum between 12 and 65 months after external beam radiotherapy. Strahlenther Onkol 2011;187:202-5.
[Table 1], [Table 2], [Table 3]