Clinical Oncology 27 (2015) 536e541 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Acute and Late Bowel Toxicity in Radiotherapy Patients with Inflammatory Bowel Disease: A Systematic Review D. Tromp *y, D.R.H. Christie zx * Gold
Coast University Hospital, Southport, Queensland, Australia Griffith University Gold Coast Campus, Southport, Queensland, Australia z Genesis CancerCare Queensland, Tugun, Queensland, Australia x Bond University, Robina, Queensland, Australia y
Received 5 February 2015; received in revised form 17 April 2015; accepted 4 May 2015
Abstract Aims: Inflammatory bowel disease has traditionally been considered a relative contraindication for radiotherapy due to a perceived increased risk of disease exacerbation and bowel toxicity. The aim of this review was to evaluate the current literature regarding rates of radiotherapy-induced acute and late bowel toxicity in patients with inflammatory bowel disease and to compare these data with those of patients without the disease. Materials and methods: An Ovid Medline search was conducted to identify original articles pertaining to the review question. Using the PRISMA convention a total of 442 articles screened, resulting 8 articles which were suitable for inclusion in the review. Results: In general, the grading of toxicity was scored using either the Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events scoring systems. It was found that acute bowel toxicity of grade 3 occurred in 20% of patients receiving external beam radiotherapy (EBRT) and in 7% of patients receiving brachytherapy. Late bowel toxicity grade 3 occurred in 15% of EBRT patients and in 5% of patients receiving brachytherapy. Brachytherapy was shown to have similar rates of toxicity and EBRT produced a moderate increase in both acute and late toxicity when compared with individuals without inflammatory bowel disease. Conclusion: In view of these results, we suggest that brachytherapy should be considered as a suitable treatment option for treating pelvic malignancy in patients with inflammatory bowel disease, whereas EBRT should be used with caution. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Bowel toxicity; brachytherapy; inflammatory bowel disease; radiotherapy
Introduction Ulcerative colitis and Crohn’s disease are idiopathic inflammatory diseases involving the gastrointestinal tract. Collectively they are termed inflammatory bowel disease (IBD) and typically have a relapsing and remitting clinical course. Epidemiologically, the peak age of onset is between 15 and 30 years of age, affecting as many as 1.4 million people in the USA and 2.2 million in Europe [1]. Crohn’s disease is characterised by transmural inflammation typically involving the terminal ileum and colon, but can affect any part of the gastrointestinal tract, producing skip lesions. Ulcerative colitis is characterised by mucosal inflammation, Author for correspondence: D. Tromp, 37 Mitchell Ave, Molendinar, Queensland, 4214, Australia. Tel: þ61-409-643-212. E-mail address: [email protected] (D. Tromp).
which always involves the rectum, with possible extension into the colon. The cause of IBD has not been precisely explained, but it is largely thought to result from a dysregulated mucosal immune response to environmental factors in susceptible patients [2]. IBD has historically been associated with increased risk of colorectal cancer, which has been thought to be associated with longstanding chronic inflammation [3], although recent data show that this risk is reducing, probably secondary to better control of intestinal inflammation [4]. In addition, an increased risk of extra-intestinal malignancies such as lung, skin, urinary bladder, liver-biliary cancer and leukaemia have been described and may have some relation to the use of thiopurines and monoclonal antibody therapies [5]. Despite increased rates of malignancy in IBD sufferers, there has been a historical reluctance to consider radiotherapy as part of the treatment for cancer in these patients. This is
http://dx.doi.org/10.1016/j.clon.2015.05.001 0936-6555/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
D. Tromp, D.R.H. Christie / Clinical Oncology 27 (2015) 536e541
probably due to the perceived risk of further aggravating the underlying mucosal inflammatory processes, and has therefore labelled IBD as a relative contraindication for radiotherapy. The aim of this review was to analyse the current literature to answer the question of whether radiotherapy causes increased rates of acute and late bowel toxicity in patients with IBD.
Materials and Methods An Ovid Medline (1946 to February 2015) search was conducted to identify original study articles pertaining to the question of whether radiotherapy caused increased rates of gastrointestinal toxicity in patients with IBD. The search terms used were radiotherapy OR radiation therapy OR brachytherapy AND inflammatory bowel disease OR Crohn’s disease OR ulcerative colitis AND toxicity. This produced 439 results, with a further three studies found by hand-searching. After initial screening, 12 studies were identified that were relevant to the review question. Four of the studies were excluded from the review: one article had a sample size of only two patients, one was a personal view article, one study was presented at a conference but the results were not published and the last article was a review that had only evaluated a small number of older case series.
537
This process followed the PRISMA convention [6] and is summarised in Figure 1.
Results Eight trials in total were included in the review. The demographics of each study are summarised in Table 1. The total number of individuals across the studies was 144, with ulcerative colitis sufferers making up around 60% of participants. There were significantly higher numbers of men across the studies, which was probably due to increased representation of prostate cancer among these groups. Five studies involved external beam radiotherapy (EBRT), with average radiation doses ranging from 40 to 54 Gy. The remaining three studies focused primarily on brachytherapy, with prescription radiation doses of 100e150 Gy. The status of IBD at the time of radiotherapy was recorded in six of the studies, with between 0 and 43% of participants reporting the presence of active IBD symptoms. Interestingly, no studies recorded the rates or severity of bowel symptoms before radiotherapy. In general, the rates of bowel toxicity for EBRT and brachytherapy were recorded using either the Radiation Therapy Oncology Group (RTOG) or the Common Terminology Criteria for Adverse Events (CTCAE) systems, with
Fig 1. Flow diagram describing the data collection process following the PRISMA convention.
538
Table 1 Study demographics [8]
[9]
[10]
[11]
[12]
[13]
[14]
15 1960e1994 27 (5e57) 16/31 N/S
28 1970e1999 58 (36e78) 6/22 CD 10 UC 18
19 1997e2012 64 (35e84) 4/15 CD 5 UC 14
24 1992e2004 N/S Male CD 7 UC 17
13 1999e2009 67 (55e83) Male CD 3 UC 10
N/S
12/28
1/19
15 1983e2011 57 (30e71) 5/10 CD 4 UC 8 NOS 3 0/15
6 1991e1996 N/S Male CD 3 UC 3
Active IBD at time of radiotherapy IBD medications at time of radiotherapy Primary neoplasm
24 1979e2001 50 (16e84) 8/16 CD 15 UC 7 NOS 2 10/24
N/S
0/24
2/13
N/S
11
15
6
0
4
11
N/S
15 rectal
17 colorectal, 7 prostate, 2 endometrial, 1 pancreatic, 1 small bowel EBRT: conventional þ specialised
8 prostate, 5 UGI, 14 colorectal, 2 head and neck, 1 anal 3 rectal/anal, 8 chest, 17 abdomen/pelvis, 3 liver 1 TBI
Prostate
Prostate
Prostate
EBRT
EBRT: IMRT (14), EBRT: IMRT, 3D-CRT (5) 4-field, 3-field, or AP/PA
125
125
Radiation dose (Gy) Median 50.4 (0.5e55.8)
54 (30e78)
45e52
Prescription dose 150
Concurrent chemotherapy
8
N/S
N/S
Radiotherapy method
EBRT: 4-field (8), 3-field (2), AP/PA (5)
Mean conventional Median 45 (0.9e70.2) 40 (10e50.4); specialised 51.1 (12.4e75.6) 13 11 (colorectal 15 (5-FU leucovorin) cancer e 5-FU)
I brachytherapy
I brachytherapy 125I brachytherapy (15),103Pd (6),103Pd þ EBRT (3) Prescription Prescription 144 125 I 160 103 Pd 124 total or 100 þ EBRT 45 N/S N/S
N/S, not stated; CD, Crohn’s disease; UC, ulcerative colitis; EBRT, external beam radiotherapy; IMRT, intensity-modulated radiotherapy; UGI, upper gastrointestinal; IBD, inflammatory bowel disease; TBI, total body irradiation; AP/PA, anterior-posterior/posterio-anterior; 5-FU, 5-Fluorouracil; NOS, not otherwise stated; 3D-CRT, 3-dimensional conformal radiotherapy.
D. Tromp, D.R.H. Christie / Clinical Oncology 27 (2015) 536e541
[7] No. patients Period Mean age (range) Female/male IBD type
D. Tromp, D.R.H. Christie / Clinical Oncology 27 (2015) 536e541
the exception of Willett et al. [8], who characterised severe acute effects if radiotherapy was stopped early due to enteral toxicity and scored late effects if the patient required hospitalisation or surgery after radiotherapy. For EBRT (Table 2), the mean rate of acute bowel toxicity grade 3 was 20% and ranged between 11 and 27%. The mean rate of late bowel toxicity grade 3 was 15% and ranged between 5 and 29%. Only one study provided data for grade 2 toxicity, reporting rates of 48% for acute and 21% for late toxicity. For brachytherapy (Table 3), the mean rate of acute bowel toxicity grade 3 was 7%, ranging from 0 to 23%. The mean rate of late bowel toxicity grade 3 was 5% and ranged from 0 to 15%. All three studies included rates of grade 2 toxicity, with average rates of 14% for acute and 21% for late toxicity.
Discussion IBD has historically been regarded as a relative contraindication for radiotherapy due to concerns of inducing higher rates of gastrointestinal toxicity. This has resulted in clinicians being hesitant to recommend radiotherapy to this patient group, despite higher incidence of intestinal and extra-intestinal malignancies [5]. A review of eight studies was conducted to ascertain whether the rates of bowel toxicity were indeed greater in patients with IBD. The primary end point for the investigation was grade 3 toxicity, which represents clinically significant adverse events. It was found that acute bowel toxicity grade 3 occurred in 20% of patients receiving EBRT and 7% of patients receiving brachytherapy. Late bowel toxicity grade 3 occurred in 15% of EBRT patients and 5% of patients receiving brachytherapy. A comparison was made between €us et al. [15], who these results and those found by Buda evaluated the functional outcomes and complications in 15 trials encompassing 6298 prostate cancer patients treated with radiotherapy (3D conformal radiotherapy/intensitymodulated radiotherapy or brachytherapy) using either the RTOG or CTCAE systems. In that review, acute bowel toxicity grade 3 ranged between 0 and 6% and late bowel toxicity
539
Table 3 Rates of acute and late gastrointestinal toxicity after prostate brachytherapy in inflammatory bowel disease
Toxicity scoring No. patients Acute toxicity grade 2 % (no. patients) Acute toxicity grade 3 % (no. patients) Late toxicity grade 2 % (no. patients) Late toxicity grade 3 % (no. patients)
[12]
[13]
[14]
RTOG 6 0%
CTCAE 24 4% (1)
RTOG 13 38% (5)
0%
0%
23% (3)
0%
17% (4)
38% (5)
0%
0%
15% (2)
RTOG, Radiation Therapy Oncology Group; CTCAE, Common Terminology Criteria for Adverse Events.
grade 3 ranged between 0.1 and 10%. This represents a moderate increase in toxicity for those patients with IBD receiving EBRT, whereas brachytherapy showed similar rates of toxicity as patients without IBD. These results are similar to those found for malignancies in organs other than the prostate. A study of bowel toxicity in patients with cervical and endometrial cancer treated with intensity-modulated radiotherapy found that 6.5% of patients experienced acute or late bowel toxicity grade 3 [16]. Swellengrebel et al. [17] investigated 147 rectal cancer patients receiving radiotherapy and reported acute grade 3 bowel toxicity in 10.1% of patients. A review by Kavanagh et al. [18] reported late small bowel toxicity in the form of obstruction or perforation at a rate of 2e9%. All of the studies investigating EBRT included patients with concomitant chemotherapy, which has been shown to increase rates of acute toxicity caused by radiotherapy in the small bowel [18]. Of particular note is that all of the patients experiencing acute and late toxicity grade 3 reported by Song et al. [9] were receiving concomitant chemotherapy. Newer radiotherapy methods, such as image-guided intensity-modulated radiotherapy, have been shown to produce lower levels of toxicity by delivering a very precise radiation dose and avoiding surrounding tissues [19]. This
Table 2 Rates of acute and late gastrointestinal toxicity after external beam radiotherapy in inflammatory bowel disease [7]
[6]
[9]
[10]
[11]
Toxicity scoring
RTOG
RTOG
CTCAE v4.0
RTOG
No. patients Acute toxicity grade 2 % (no. patients) Acute toxicity grade 3 % (no. patients) Late toxicity grade 2 % (no. patients) Late toxicity grade 3 % (no. patients)
15 N/S
Acute: cessation of radiotherapy Late: hospitalisation or surgery 28 N/S
24 N/S
19 48% (9)
15 N/S
20% (3)
21% (6)
11% (2)
27% (4)
N/S
N/S
21% (5) All had chemotherapy N/S
21% (4)
N/S
13% (2)
29% (8)
5% (1)
13% (2)
8% (2) All had chemotherapy
N/S, not stated; RTOG, Radiation Therapy Oncology Group; CTCAE, Common Terminology Criteria for Adverse Events.
540
D. Tromp, D.R.H. Christie / Clinical Oncology 27 (2015) 536e541
was represented within the EBRT studies reviewed here. Willet et al. [8] reported a lower rate of severe late toxicity in patients treated with specialised techniques and White et al.[10] found lower rates of acute grade 2 toxicity in patients treated with intensity-modulated radiotherapy. Novel techniques such as the use of intra-prostatic fiducial markers and the injection of tissue spacing agents have been shown to reduce rectal radiation during treatment for prostate cancer [20]. These methods have not been included in any of the studies included in this review and leaves room for future investigation into the effect these could have in reducing bowel toxicity in patients with IBD. Furthermore, the use of ablative methods such as highintensity focused ultrasound and cryotherapy have not been specifically studied in patients with IBD. Although this review investigated the effects of radiotherapy in IBD, mention must be made of the risks of surgery in this same group of patients. In particular, the concomitant use of anti-inflammatory and diseasemodifying medications has been shown to produce higher rates of wound dehiscence and infection [21]. These medications may be withheld in the peri-operative period, with an increased risk of disease exacerbations during this interval. A major limitation of this review was the low population sizes in each study, which is a reflection on the tendency for clinicians to avoid radiotherapy in patients with IBD as well as the low prevalence of the disease itself. In addition, the studies by Green et al. [7], Willett et al. [8] and Song et al. [9] included patients treated in the 1960s and 1970s, predating modern treatment techniques and imaging modalities. For the purpose of comparison, the assumption was made that the RTOG and CTCAE systems for classifying toxicity are essentially equivalent. However, the RTOG system has been criticised for lacking sensitivity and objectivity [22,23]. Another potential limitation, when comparing the EBRT studies, arises due to the many different treatment sites and methods encompassed within these studies, leading to possible varying small bowel or rectum doses. Lastly, none of the studies in this review recorded the level of pre-existing bowel symptoms in their patients, which could be a confounding factor when trying to ascertain radiotherapy-related bowel symptoms.
Conclusion Although further research is needed with larger sample sizes, there is more evidence to support the use of EBRT or brachytherapy in patients with IBD than other methods such as high-intensity focused ultrasound or cryotherapy. In this review, brachytherapy was shown to have similar rates of toxicity in patients with IBD when compared with those in patients without the disease. EBRT produced a moderate increase in both acute and late toxicity, but could represent an acceptable level of toxicity considering potential gains in long-term survival. In view of these results, we suggest that brachytherapy should be considered as a suitable treatment
option for treating pelvic malignancy in patients with IBD, whereas EBRT should be used with caution.
References [1] Loftus Jr EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 2004;126(6):1504e1517. [2] Corridoni D, Arseneau KO, Cominelli F. Inflammatory bowel disease. Immunol Lett 2014;161(2):231e235. [3] Rubin DC, Shaker A, Levin MS. Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Front Immunol 2012;3:107. [4] Sebastian S, Hern andez V, Myrelid P, et al. Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I). J Crohns Colitis 2014;8(1):5e18. [5] Burisch J, Jess T, Martinato M, Lakatos PL. ECCO -EpiCom. The burden of inflammatory bowel disease in Europe. J Crohns Colitis 2013;7(4):322e337. [6] PRISMA Transparent Reporting of Systematic Reviews and Meta-Analyses. Available at: http://www.prisma-statement. org/statement.htm. [accessed 13.12.14]. [7] Green S, Stock RG, Greenstein AJ. Rectal cancer and inflammatory bowel disease: natural history and implications for radiation therapy. Int J Radiat Oncol Biol Phys 1999;44(4):835e840. [8] Willett CG, Ooi CJ, Zietman AL, et al. Acute and late toxicity of patients with inflammatory bowel disease undergoing irradiation for abdominal and pelvic neoplasms. Int J Radiat Oncol Biol Phys 2000;46(4):995e998. [9] Song DY, Lawrie WT, Abrams RA, et al. Acute and late radiotherapy toxicity in patients with inflammatory bowel disease. Int J Radiat Oncol Biol Phys 2001;51(2):455e459. [10] White EC, Murphy JD, Chang DT, Koong AC. Low toxicity in inflammatory bowel disease patients treated with abdominal and pelvic radiation therapy. Am J Clin Oncol 2014 [Epub ahead of print]. [11] Chang BW, Kumar AM, Koyfman SA, Kalady M, Lavery I, Abdel-Wahab M. Radiation therapy in patients with inflammatory bowel disease and colorectal cancer: risks and benefits. Int J Colorectal Dis 2015;30(3):403e408. [12] Grann A, Wallner K. Prostate brachytherapy in patients with inflammatory bowel disease. Int J Radiat Oncol Biol Phys 1998;40(1):135e138. [13] Peters CA, Cesaretti JA, Stone NN, Stock RG. Low-dose rate prostate brachytherapy is well tolerated in patients with a history of inflammatory bowel disease. Int J Radiat Oncol Biol Phys 2006;66(2):424e429. [14] Pai HH, Keyes M, Morris WJ, Christie J. Toxicity after (125)I prostate brachytherapy in patients with inflammatory bowel disease. Brachytherapy 2013;12(2):126e133. [15] Bud€ aus L, Bolla M, Bossi A, et al. Functional outcomes and complications following radiation therapy for prostate cancer: a critical analysis of the literature. Eur Urol 2012;61(1):112e127. [16] Poorvu PD, Sadow CA, Townamchai K, Damato AL, Viswanathan AN. Duodenal and other gastrointestinal toxicity in cervical and endometrial cancer treated with extended-field intensity modulated radiation therapy to paraaortic lymph nodes. Int J Radiat Oncol Biol Phys 2013;85(5):1262e1268. [17] Swellengrebel HM, Marijnen CM, Verwaal VJ, et al. Toxicity and complications of preoperative chemoradiotherapy for locally advanced rectal cancer. Br J Surg 2011;98(3):418e426. [18] Kavanagh BD, Pan CC, Dawson LA, et al. Radiation dosevolume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S101eS107.
D. Tromp, D.R.H. Christie / Clinical Oncology 27 (2015) 536e541 € ld PM, Deasy JO, et al. Improvement in [19] Sveistrup J, Rosenscho toxicity in high risk prostate cancer patients treated with image-guided intensity-modulated radiotherapy compared to 3D conformal radiotherapy without daily image guidance. Radiat Oncol 2014;9:44. [20] Ng M, Brown E, Williams A, Chao M, Lawrentschuk N, Chee R. Fiducial markers and spacers in prostate radiotherapy: current applications. BJU Int 2014;113(Suppl. 2):13e20. [21] Busti AJ, Hooper JS, Amaya CJ, Kazi S. Effects of perioperative antiinflammatory and immunomodulating therapy on surgical wound healing. Pharmacotherapy 2005;25(11):1566e1591.
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[22] Yoshida K, Yamazaki H, Nakamara S, et al. Comparison of common terminology criteria for adverse events v3.0 and radiation therapy oncology group toxicity score system after high-dose-rate interstitial brachytherapy as monotherapy for prostate cancer. Anticancer Res 2014;34(4): 2015e2018. [23] Heemsbergen WD, Peeters ST, Koper PC, Hoogeman MS, Lebesque JV. Acute and late gastrointestinal toxicity after radiotherapy in prostate cancer patients: consequential late damage. Int J Radiat Oncol Biol Phys 2006;66(1):3e10.
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Acute and Late Bowel Toxicity in Radiotherapy Patients with Inflammatory Bowel Disease: A Systematic Review D. Tromp *y, D.R.H. Christie zx * Gold
Coast University Hospital, Southport, Queensland, Australia Griffith University Gold Coast Campus, Southport, Queensland, Australia z Genesis CancerCare Queensland, Tugun, Queensland, Australia x Bond University, Robina, Queensland, Australia y
Received 5 February 2015; received in revised form 17 April 2015; accepted 4 May 2015
Abstract Aims: Inflammatory bowel disease has traditionally been considered a relative contraindication for radiotherapy due to a perceived increased risk of disease exacerbation and bowel toxicity. The aim of this review was to evaluate the current literature regarding rates of radiotherapy-induced acute and late bowel toxicity in patients with inflammatory bowel disease and to compare these data with those of patients without the disease. Materials and methods: An Ovid Medline search was conducted to identify original articles pertaining to the review question. Using the PRISMA convention a total of 442 articles screened, resulting 8 articles which were suitable for inclusion in the review. Results: In general, the grading of toxicity was scored using either the Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events scoring systems. It was found that acute bowel toxicity of grade 3 occurred in 20% of patients receiving external beam radiotherapy (EBRT) and in 7% of patients receiving brachytherapy. Late bowel toxicity grade 3 occurred in 15% of EBRT patients and in 5% of patients receiving brachytherapy. Brachytherapy was shown to have similar rates of toxicity and EBRT produced a moderate increase in both acute and late toxicity when compared with individuals without inflammatory bowel disease. Conclusion: In view of these results, we suggest that brachytherapy should be considered as a suitable treatment option for treating pelvic malignancy in patients with inflammatory bowel disease, whereas EBRT should be used with caution. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Bowel toxicity; brachytherapy; inflammatory bowel disease; radiotherapy
Introduction Ulcerative colitis and Crohn’s disease are idiopathic inflammatory diseases involving the gastrointestinal tract. Collectively they are termed inflammatory bowel disease (IBD) and typically have a relapsing and remitting clinical course. Epidemiologically, the peak age of onset is between 15 and 30 years of age, affecting as many as 1.4 million people in the USA and 2.2 million in Europe [1]. Crohn’s disease is characterised by transmural inflammation typically involving the terminal ileum and colon, but can affect any part of the gastrointestinal tract, producing skip lesions. Ulcerative colitis is characterised by mucosal inflammation, Author for correspondence: D. Tromp, 37 Mitchell Ave, Molendinar, Queensland, 4214, Australia. Tel: þ61-409-643-212. E-mail address: [email protected] (D. Tromp).
which always involves the rectum, with possible extension into the colon. The cause of IBD has not been precisely explained, but it is largely thought to result from a dysregulated mucosal immune response to environmental factors in susceptible patients [2]. IBD has historically been associated with increased risk of colorectal cancer, which has been thought to be associated with longstanding chronic inflammation [3], although recent data show that this risk is reducing, probably secondary to better control of intestinal inflammation [4]. In addition, an increased risk of extra-intestinal malignancies such as lung, skin, urinary bladder, liver-biliary cancer and leukaemia have been described and may have some relation to the use of thiopurines and monoclonal antibody therapies [5]. Despite increased rates of malignancy in IBD sufferers, there has been a historical reluctance to consider radiotherapy as part of the treatment for cancer in these patients. This is
http://dx.doi.org/10.1016/j.clon.2015.05.001 0936-6555/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
D. Tromp, D.R.H. Christie / Clinical Oncology 27 (2015) 536e541
probably due to the perceived risk of further aggravating the underlying mucosal inflammatory processes, and has therefore labelled IBD as a relative contraindication for radiotherapy. The aim of this review was to analyse the current literature to answer the question of whether radiotherapy causes increased rates of acute and late bowel toxicity in patients with IBD.
Materials and Methods An Ovid Medline (1946 to February 2015) search was conducted to identify original study articles pertaining to the question of whether radiotherapy caused increased rates of gastrointestinal toxicity in patients with IBD. The search terms used were radiotherapy OR radiation therapy OR brachytherapy AND inflammatory bowel disease OR Crohn’s disease OR ulcerative colitis AND toxicity. This produced 439 results, with a further three studies found by hand-searching. After initial screening, 12 studies were identified that were relevant to the review question. Four of the studies were excluded from the review: one article had a sample size of only two patients, one was a personal view article, one study was presented at a conference but the results were not published and the last article was a review that had only evaluated a small number of older case series.
537
This process followed the PRISMA convention [6] and is summarised in Figure 1.
Results Eight trials in total were included in the review. The demographics of each study are summarised in Table 1. The total number of individuals across the studies was 144, with ulcerative colitis sufferers making up around 60% of participants. There were significantly higher numbers of men across the studies, which was probably due to increased representation of prostate cancer among these groups. Five studies involved external beam radiotherapy (EBRT), with average radiation doses ranging from 40 to 54 Gy. The remaining three studies focused primarily on brachytherapy, with prescription radiation doses of 100e150 Gy. The status of IBD at the time of radiotherapy was recorded in six of the studies, with between 0 and 43% of participants reporting the presence of active IBD symptoms. Interestingly, no studies recorded the rates or severity of bowel symptoms before radiotherapy. In general, the rates of bowel toxicity for EBRT and brachytherapy were recorded using either the Radiation Therapy Oncology Group (RTOG) or the Common Terminology Criteria for Adverse Events (CTCAE) systems, with
Fig 1. Flow diagram describing the data collection process following the PRISMA convention.
538
Table 1 Study demographics [8]
[9]
[10]
[11]
[12]
[13]
[14]
15 1960e1994 27 (5e57) 16/31 N/S
28 1970e1999 58 (36e78) 6/22 CD 10 UC 18
19 1997e2012 64 (35e84) 4/15 CD 5 UC 14
24 1992e2004 N/S Male CD 7 UC 17
13 1999e2009 67 (55e83) Male CD 3 UC 10
N/S
12/28
1/19
15 1983e2011 57 (30e71) 5/10 CD 4 UC 8 NOS 3 0/15
6 1991e1996 N/S Male CD 3 UC 3
Active IBD at time of radiotherapy IBD medications at time of radiotherapy Primary neoplasm
24 1979e2001 50 (16e84) 8/16 CD 15 UC 7 NOS 2 10/24
N/S
0/24
2/13
N/S
11
15
6
0
4
11
N/S
15 rectal
17 colorectal, 7 prostate, 2 endometrial, 1 pancreatic, 1 small bowel EBRT: conventional þ specialised
8 prostate, 5 UGI, 14 colorectal, 2 head and neck, 1 anal 3 rectal/anal, 8 chest, 17 abdomen/pelvis, 3 liver 1 TBI
Prostate
Prostate
Prostate
EBRT
EBRT: IMRT (14), EBRT: IMRT, 3D-CRT (5) 4-field, 3-field, or AP/PA
125
125
Radiation dose (Gy) Median 50.4 (0.5e55.8)
54 (30e78)
45e52
Prescription dose 150
Concurrent chemotherapy
8
N/S
N/S
Radiotherapy method
EBRT: 4-field (8), 3-field (2), AP/PA (5)
Mean conventional Median 45 (0.9e70.2) 40 (10e50.4); specialised 51.1 (12.4e75.6) 13 11 (colorectal 15 (5-FU leucovorin) cancer e 5-FU)
I brachytherapy
I brachytherapy 125I brachytherapy (15),103Pd (6),103Pd þ EBRT (3) Prescription Prescription 144 125 I 160 103 Pd 124 total or 100 þ EBRT 45 N/S N/S
N/S, not stated; CD, Crohn’s disease; UC, ulcerative colitis; EBRT, external beam radiotherapy; IMRT, intensity-modulated radiotherapy; UGI, upper gastrointestinal; IBD, inflammatory bowel disease; TBI, total body irradiation; AP/PA, anterior-posterior/posterio-anterior; 5-FU, 5-Fluorouracil; NOS, not otherwise stated; 3D-CRT, 3-dimensional conformal radiotherapy.
D. Tromp, D.R.H. Christie / Clinical Oncology 27 (2015) 536e541
[7] No. patients Period Mean age (range) Female/male IBD type
D. Tromp, D.R.H. Christie / Clinical Oncology 27 (2015) 536e541
the exception of Willett et al. [8], who characterised severe acute effects if radiotherapy was stopped early due to enteral toxicity and scored late effects if the patient required hospitalisation or surgery after radiotherapy. For EBRT (Table 2), the mean rate of acute bowel toxicity grade 3 was 20% and ranged between 11 and 27%. The mean rate of late bowel toxicity grade 3 was 15% and ranged between 5 and 29%. Only one study provided data for grade 2 toxicity, reporting rates of 48% for acute and 21% for late toxicity. For brachytherapy (Table 3), the mean rate of acute bowel toxicity grade 3 was 7%, ranging from 0 to 23%. The mean rate of late bowel toxicity grade 3 was 5% and ranged from 0 to 15%. All three studies included rates of grade 2 toxicity, with average rates of 14% for acute and 21% for late toxicity.
Discussion IBD has historically been regarded as a relative contraindication for radiotherapy due to concerns of inducing higher rates of gastrointestinal toxicity. This has resulted in clinicians being hesitant to recommend radiotherapy to this patient group, despite higher incidence of intestinal and extra-intestinal malignancies [5]. A review of eight studies was conducted to ascertain whether the rates of bowel toxicity were indeed greater in patients with IBD. The primary end point for the investigation was grade 3 toxicity, which represents clinically significant adverse events. It was found that acute bowel toxicity grade 3 occurred in 20% of patients receiving EBRT and 7% of patients receiving brachytherapy. Late bowel toxicity grade 3 occurred in 15% of EBRT patients and 5% of patients receiving brachytherapy. A comparison was made between €us et al. [15], who these results and those found by Buda evaluated the functional outcomes and complications in 15 trials encompassing 6298 prostate cancer patients treated with radiotherapy (3D conformal radiotherapy/intensitymodulated radiotherapy or brachytherapy) using either the RTOG or CTCAE systems. In that review, acute bowel toxicity grade 3 ranged between 0 and 6% and late bowel toxicity
539
Table 3 Rates of acute and late gastrointestinal toxicity after prostate brachytherapy in inflammatory bowel disease
Toxicity scoring No. patients Acute toxicity grade 2 % (no. patients) Acute toxicity grade 3 % (no. patients) Late toxicity grade 2 % (no. patients) Late toxicity grade 3 % (no. patients)
[12]
[13]
[14]
RTOG 6 0%
CTCAE 24 4% (1)
RTOG 13 38% (5)
0%
0%
23% (3)
0%
17% (4)
38% (5)
0%
0%
15% (2)
RTOG, Radiation Therapy Oncology Group; CTCAE, Common Terminology Criteria for Adverse Events.
grade 3 ranged between 0.1 and 10%. This represents a moderate increase in toxicity for those patients with IBD receiving EBRT, whereas brachytherapy showed similar rates of toxicity as patients without IBD. These results are similar to those found for malignancies in organs other than the prostate. A study of bowel toxicity in patients with cervical and endometrial cancer treated with intensity-modulated radiotherapy found that 6.5% of patients experienced acute or late bowel toxicity grade 3 [16]. Swellengrebel et al. [17] investigated 147 rectal cancer patients receiving radiotherapy and reported acute grade 3 bowel toxicity in 10.1% of patients. A review by Kavanagh et al. [18] reported late small bowel toxicity in the form of obstruction or perforation at a rate of 2e9%. All of the studies investigating EBRT included patients with concomitant chemotherapy, which has been shown to increase rates of acute toxicity caused by radiotherapy in the small bowel [18]. Of particular note is that all of the patients experiencing acute and late toxicity grade 3 reported by Song et al. [9] were receiving concomitant chemotherapy. Newer radiotherapy methods, such as image-guided intensity-modulated radiotherapy, have been shown to produce lower levels of toxicity by delivering a very precise radiation dose and avoiding surrounding tissues [19]. This
Table 2 Rates of acute and late gastrointestinal toxicity after external beam radiotherapy in inflammatory bowel disease [7]
[6]
[9]
[10]
[11]
Toxicity scoring
RTOG
RTOG
CTCAE v4.0
RTOG
No. patients Acute toxicity grade 2 % (no. patients) Acute toxicity grade 3 % (no. patients) Late toxicity grade 2 % (no. patients) Late toxicity grade 3 % (no. patients)
15 N/S
Acute: cessation of radiotherapy Late: hospitalisation or surgery 28 N/S
24 N/S
19 48% (9)
15 N/S
20% (3)
21% (6)
11% (2)
27% (4)
N/S
N/S
21% (5) All had chemotherapy N/S
21% (4)
N/S
13% (2)
29% (8)
5% (1)
13% (2)
8% (2) All had chemotherapy
N/S, not stated; RTOG, Radiation Therapy Oncology Group; CTCAE, Common Terminology Criteria for Adverse Events.
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D. Tromp, D.R.H. Christie / Clinical Oncology 27 (2015) 536e541
was represented within the EBRT studies reviewed here. Willet et al. [8] reported a lower rate of severe late toxicity in patients treated with specialised techniques and White et al.[10] found lower rates of acute grade 2 toxicity in patients treated with intensity-modulated radiotherapy. Novel techniques such as the use of intra-prostatic fiducial markers and the injection of tissue spacing agents have been shown to reduce rectal radiation during treatment for prostate cancer [20]. These methods have not been included in any of the studies included in this review and leaves room for future investigation into the effect these could have in reducing bowel toxicity in patients with IBD. Furthermore, the use of ablative methods such as highintensity focused ultrasound and cryotherapy have not been specifically studied in patients with IBD. Although this review investigated the effects of radiotherapy in IBD, mention must be made of the risks of surgery in this same group of patients. In particular, the concomitant use of anti-inflammatory and diseasemodifying medications has been shown to produce higher rates of wound dehiscence and infection [21]. These medications may be withheld in the peri-operative period, with an increased risk of disease exacerbations during this interval. A major limitation of this review was the low population sizes in each study, which is a reflection on the tendency for clinicians to avoid radiotherapy in patients with IBD as well as the low prevalence of the disease itself. In addition, the studies by Green et al. [7], Willett et al. [8] and Song et al. [9] included patients treated in the 1960s and 1970s, predating modern treatment techniques and imaging modalities. For the purpose of comparison, the assumption was made that the RTOG and CTCAE systems for classifying toxicity are essentially equivalent. However, the RTOG system has been criticised for lacking sensitivity and objectivity [22,23]. Another potential limitation, when comparing the EBRT studies, arises due to the many different treatment sites and methods encompassed within these studies, leading to possible varying small bowel or rectum doses. Lastly, none of the studies in this review recorded the level of pre-existing bowel symptoms in their patients, which could be a confounding factor when trying to ascertain radiotherapy-related bowel symptoms.
Conclusion Although further research is needed with larger sample sizes, there is more evidence to support the use of EBRT or brachytherapy in patients with IBD than other methods such as high-intensity focused ultrasound or cryotherapy. In this review, brachytherapy was shown to have similar rates of toxicity in patients with IBD when compared with those in patients without the disease. EBRT produced a moderate increase in both acute and late toxicity, but could represent an acceptable level of toxicity considering potential gains in long-term survival. In view of these results, we suggest that brachytherapy should be considered as a suitable treatment
option for treating pelvic malignancy in patients with IBD, whereas EBRT should be used with caution.
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