Your Health and Fitness Partner: Androxal & FitHub

We are also excited to expand our scope by including valuable information on Androxal, a potent medication beneficial in various medical conditions. This remarkable drug, derived from the testosterone molecule, has made its mark significantly in the field of endocrinology. Patients and medical professionals can rely on our comprehensive, unbiased, and scientifically grounded content on Androxal for gaining a robust understanding of its uses, side effects, and the latest studies related to it. We understand the necessity of accurate information when it comes to medication. Our newly launched section dedicated to Androxal aims at not only educating the readers about its nuances but also at contributing beneficially to their wellbeing. Stay tuned for insightful articles unraveling the potential of Androxal in medical science.
Sitemap | Policies | Feedback    
 About the Journal
Editorial Board
Journal Subscription
Instructions for Authors
E-mail Alerts
Forthcoming Events
Advertise with Us
Contact Us
 
Article Options
FULL TEXT
ABSTRACT
PDF
Printer Friendly Version
Search Pubmed for
Search Google Scholar for
Article Statistics
Bookmark and Share
Quarterly Reviews
 
Chronic Radiation Proctitis: A Challenging and Enigmatic Problem
Keywords : Radiotherapy; Complications; Chronic Radiation Proctitis.
Dipankar Ray, Gautam Chattopadhyay
Department of Surgical Gastroenterology, Medical College Kolkata, West Bengal.


Corresponding Author:
Dr Dipankar Ray
Email: dray3453@yahoo.co.in

DOI: http://dx.doi.org/10.7869/tg.604

Abstract

Pelvic radiation is commonly used for management of genitourinary and lower gastrointestinal malignancies. Radiation induced damage to rectum can present as acute radiation proctitis or chronic radiation proctitis (CRP), which presents months later.  In India, cancer cervix is second common cancer in women (after breast cancer) and globally one fourth of cases are in India only. Radiotherapy is primary modality of treatment in early stage. Rectal complications are quite common in these cases. Therefore, incidences of chronic radiation proctitis are common in India. Pain, irregular bowel, and most importantly bleeding leading to anemia – these make quality of life very poor for these patients. Diagnosis is confirmed by endoscopy. Clinical and endoscopic findings determine grade of disease. Management of CRP is not standardized. Endoscopic, non-endoscopic and surgical modalities have a role in management of this condition. The management options vary depending upon the severity of the disease, complications and co-morbidities of the patient. Drugs are needed for pain, irregular bowel, and anemia. But most common distressing complain of rectal bleeding needs further intervention like topical sucralfate enema, formalin instillation or endoscopic intervention with argon plasma coagulation (APC), laser, heater probes or radio- frequency (RFA). Surgery in form of diversion, resection or reconstruction is reserved for cases of CRP presenting with complications like stenosis, severe bleeding, incontinence, or fistulas. This review gives an over-view of diagnostic criteria, prognostic scoring, and treatment algorithm for this common disabling condition, keeping in mind,  cost and expertise available in our country.

48uep6bbphidcol2|ID
48uep6bbphidvals|2990
48uep6bbph|2000F98CTab_Articles|Fulltext
Introduction

Radiotherapy for treatment of genitourinary and lower gastrointestinal malignancies can cause damage to rectum including left colon. It commonly leads to acute radiation proctitis. If symptoms persist more than 3 months after finishing radiotherapy or develop later, it is chronic radiation proctitis (CRP). The term radiation proctitis can be misleading as the epithelial damage to the rectum is due to radiation with minimal inflammation and probably more appropriately called ‘chronic radiation proctopathy’1.
Cancers of the cervix, prostate, rectum, bladder, testicles, and uterus are commonly treated with pelvic irradiation. Among these prostate malignancy is the most frequent cause in western countries1. But in India cancer cervix is the commonest cause of CRP. Incidence of chronic radiation proctitis can be as high as 20 to 30%1,2. 
The method of radiation delivery is an important predictor of the risk for radiation proctitis. The rate of colorectal complications with brachytherapy is lower compared to external beam radiation. The use of newer conformal radiation therapy techniques maximizes the dosage directed to the tumor while minimizing the dosage of radiation to the rectum1,2. CRP may be more frequent in patients with inflammatory bowel disease, diabetes, hypertension, or peripheral vascular disease and in those who develop severe acute proctitis1. 

Diagnosis

CRP should be suspected in patients who develop symptoms such as diarrhea, urgency, tenesmus, or bleeding, usually 3 months or more after pelvic radiation3. Bleeding occurs due to rupture of radiation induced telangiectasias in friable, ischemic mucosa. It leads to anemia and need repeated blood transfusions. Diagnosis can be confirmed bysigmoidoscopy2. Endoscopic findings of CRP are mucosal pallor, telangiectasias, hemorrhage, edema, and friability. Less frequent findings are ulcers, strictures, and fistulas. Routine rectal biopsy is not necessary except to rule out other pathology like colitis, IBD or malignancy.

Acute Vs Chronic Radiation Proctitis 

The diagnosis of radiation proctitis can be separated into two distinct categories, acute or chronic, based on the timing to the development of symptoms and they have different presenting symptoms, incidence, histopathological findings, and treatment approaches which are summarized in Table 1. Symptoms that develop within 3 months from the initiation of radiation are classified as acute while those developing after are chronic. Brisk acute injury can persist into a consequential late effect, or late proctitis can develop in the absence of acute proctitis after a latent period of months to years after initial exposure. The median time for the development of chronic symptoms after radiation treatment is between 8 to 13 months in many series1,4. Although, a few series do report a considerably longer latent period, with initial symptoms developing more than 30 years after completing radiation4. A key distinction between acute and late proctitis is the relative lack of inflammatory infiltrate in the latter. Therefore, the term “proctitis’ is misleading and better known as chronic radiation proctopathy. (Table 1)



Scoring

For diagnosis, assessment of severity, prognosis and response to treatment different scoring systems are followed. They are based on symptoms, endoscopic findings, or both. Two commonly used clinical grading systems are LENT-SOMA scale rectum (Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scales) and Modified Radiation Therapy Oncology Group rectal toxicity scale. (Table 2 and 3)



Management

Management of CRP is mostly conservative with surgical intervention needed for intractable bleeding, rectovaginal fistula, rectal/anal stricture, or perforation. Available management options are listed in table 4.



Medical Treatment

There is no treatment only with oral drugs. Different combination of topical and oral medications used effectively.
Sucralfate is a highly sulfated polyanionic disaccharide. This drug acts via two mechanisms. First, sucralfate mechanically protects the gastrointestinal mucosa by forming a protective coating. Second, it is thought to stimulate epithelial healing by increasing angiogenesis. Numerous studies have been performed using sucralfate in oral and endorectal topical preparation (Table 5)



Despite mixed results for the oral preparation, the endorectal topical preparation of sucralfate can be considered an effective medical therapy for radiation proctitis with minimal side effects. Patients should take sucralfate enema twice daily, prepared using sucralfate suspensions (1 Gm /10ml diluted with water) applied per rectal with large syringe.

Formalin Therapy

Topical formalin application has been successfully used in patients with hemorrhagic cystitis. Since Rubinstein reported in 1986 the first successful treatment using a rectal wash with formalin, many authors have published on the treatment of hemorrhagic CRP using this therapy. Formalin, an aldehyde, functions as a local sclerosant and causes chemical cauterization of neovascular telangiectasias which stops recurrent bleeding.
In an email survey of the American Society of Colon Rectal Surgeons, formalin therapy was found to be the most popular method to treat CRP. Of the 327 respondents, 85% favored to formalin, while 42% used APC. Only 25% of practitioners reported using sucralfate (more than one modality could be chosen). Success rates vary from 27% up to 100%1. Unfortunately, formalin therapy is yet to be standardized. It has been used in different concentrations(commonly used as 4% solution), in different ways like instillation in the rectum through flexible endoscope (avoiding contact with anoderm or skin), irrigation in small aliquots, or applying soaked pledgets of cotton throughproctoscope/rigid sigmoidoscope. Therapy can be repeated in interval of three weeks or more until rectal bleeding stops. It should be avoided in cases of large rectal ulcer or stricture.
Patel et al9, in a retrospective study, evaluated the combination of oral vitamin A with formalin application. The addition of vitamin A led to a significant decrease in the number of formalin sessions and a significantly shorter time for resolution. Supplementation with vitamin A also has a better success rate in controlling rectal bleeding than formalin alone (94% vs. 64%). Few recent series are in Table 6. 



The advantages of formalin application include low cost, wide availability,and good efficacy in general. Despite this, complications have been reported, including chemical colitis, anorectal pain, anal and rectal strictures, rectal perforation, fissures, incontinence, and diarrhea2. 

Bipolar Cautery and Heater Probe

Endoscopic thermal coagulation with bipolar cautery or heater probeiseffective to control bleeding in CRP. The Bipolar probes have pair of electrodes (negative and positive) at its end through which current is passed using the tissue as a conduction surface. Both devices are directed in the setting of active bleeding. They cause less tissue injury (in comparison to laser therapy), permit tangential application of cautery, and both are relatively inexpensive and widely accessible. The disadvantage of both methods is char formation on the tip of the probe, requiring catheter retrieval and repeated cleaning and heater probe can cause deep coagulation. 
In a randomized prospective trial by Jensen et al16, 21 patients with bleeding CRP were followed for 12 months with medical management. Then 9 patients were treated with heater probe and 12 with bipolar (power of 10-15 W). Bleeding episodes were significantly reduced without a statistically significant difference between the methods. There was hematocrit improvement and no major complications noted.
Lenz et al17 compared BiCAP with APC in a prospective randomized trial. 15 patients in each arm, all with active bleeding, were randomly selected for one treatment modality and success was defined as eradication of all viable telangiectasias. Both treatments were found to be equally effective with only one failure per group, and no differences were observed in number of sessions or relapses. Bipolar cautery was associated with a relatively higher rate of complications than the argon plasma coagulation group. 

Argon Plasma Coagulation

Argon plasma coagulation (APC) is a non­contact thermal method of coagulation and hemostasis. APC uses high-frequency energy transmitted to tissue by ionized gas forming an arc which breaks once the tissue is desiccated. The theoretic advantage is a uniform, more predictable and limited depth of coagulation (0.5-3 mm), which minimizes the risks of perforation, stenosis, and fistulization. 
APC is more commonly used as the endoscopic treatment of radiation proctitis, with a recent review showing around 80% of all current endoscopic specific literature focused on APC18. 


Complications are usually minor in 5% to 20% cases like pain, fever, and rectal ulcer but rarely it can cause serious complications like explosions, rectal necrosis, stricture1,4.

Laser Therapy

Lasers cause thermal destruction by tissue absorption of laser light and have been used to CRP in small retrospective series. The Nd: YAG laser and KTP lasers have been used to coagulate bleeding vessels in the gastrointestinal tract. Taylor et al24 used KTP laser for treating 26 patients with bleeding secondary to CRP using 4­10 W and a median of two sessions. They reported a symptomatic improvement in 65% patients while there was no change in 7 (30%), and symptom like hematochezia increased in 1 (5%)
Laser treatment has limitations compared to other endoscopic interventions due to its high cost and inability to control the depth of penetration, which may increase risk of transmural necrosis, perforation, and fistulas. Therefore, its use in CRP has declined.

Radiofrequency Ablation

In Radiofrequency ablation (RFA) a needle electrode is used to transmit an alternating radiofrequency current into the tissue. At tissue temperaturesabove 60, the cell necrosis occurs. RFA is restricted to superficial tissue only avoiding deep tissue injury in ischemic mucosa. So,complications like deep ulceration and stricture formation rare and it allows re-epithelization. 
There are few small studies with this technique, but the largest study on RFA was reported by Rustagi et al25, it included 39 patients. All experienced complete resolution of rectal bleeding after a mean follow up of 28 months. The common side effects were mild to moderate anorectal pain, temporary fecal incontinence, and perianal ulceration. However, despite these theoretical advantages, there are some limitations. These studies were retrospective, and conclusions are limited by the lack of a control group. They were also non-powered and even considering all published works, only a few dozen patients with CRP have been treated with RFA. Another important limitation is that no sigmoid or proximal rectal lesions were ablated, thus safety in those areas (with a thinner wall) remains uncertain. The cost of the RFA energy generator (applicable in only a few indications) and the price of the Halo catheter can be another drawback. Therefore, additional controlled studies are required to compare RFA to other therapeutic modalities for CRP.

Hyperbaric Oxygen Therapy

Hyperbaric oxygen (HBO) therapy enhances the innate healing abilities of a person through the inhalation of 100% oxygen, delivered in daily fractions over a period of weeks via a full body chamber with increased atmospheric pressure. HBO induces the regrowth of damaged vascular endothelial cells in marginally perfused tissue, improves the activity of antioxidant enzymes thereby reducing free radical damage, inhibit bacterial overgrowth and toxin production. 
Side effects of HBO are mild like anxiety, otic barotraumas but need repeated sessions, efficacy questionable and costly. Though it can be considered as a treatment modality over more invasive procedures, it is not widely available or accepted.



Surgical Therapy

Surgical interventions should be reserved for those patients with either symptoms refractory to endoscopic therapy or for patients with complications such as brisk hemorrhage, perforation, fistula, or obstructing stricture. The need for such intervention is quite rare, in less than 10% of all patients with radiation proctitis4. Surgical options are diversion, reconstruction, or excision like proctectomy or pelvic exenteration.
Diverting stoma improves symptoms such as pain, tenesmus, drainage, infection and help in incontinence or stricture. Though a small study by Ayerdi et al29 showed improvement of rectal bleeding, usually fecal diversion has limited role in bleeding radiation proctitis. Fecal diversion like temporary colostomy is also required for management of strictures and fistula.  Quality of life before and after diversion was studies in several reports. Pricolo et al30 reported a 30­ year review of the experience at a single institution including 60 patients treated with diverting ostomy in addition to other surgical approaches. Quality of life was examined and for some patients a diversion was so effective additional intervention was no longer needed. 
Local excision with reconstruction by well vascularised advancement flap is used for fistulas or strictures. Proctectomy or pelvic exenteration is the most definitive as well as most extreme intervention. It should be offered only in cases of failure of other intervention to control bleeding, intractable pain, or fecal incontinence.

Discussion

Chronic hemorrhagic radiation proctitis is a difficult problem. Prevention can be ideal. Newer conformal radiation therapy techniques include intensity-modulated radiationtherapy and intensity-guided radiation therapies minimize the dose of radiation tothe rectum while maximizing dose to the tumor.Amifostine is a prodrug that is metabolized to a thiol metabolite whichscavenges harmful reactive oxygen species. When administered intravenously, it has shownsome benefit in preventing symptoms of acuteproctitis as well as decreasing the severity of chronic proctitis symptoms1,4. But toxicity of Amifostine, particularly hypotension, limits its routine use for prevention of late radiation proctitis. Sucralfate is extensively used for prophylaxis against acute radiation injury. However, placebo-controlled phase III trials have detected no benefit from either topical or oralsucralfate.
Despite there are many options of treating CRP still we don’t have clear recommendations or guidelines for management. Lack of detailed account of diagnosis, background co-morbidities, accepted clinical / endoscopic scoring system and outcome of treatment are the limitations. We need many more randomized data with head-to-head comparative studies for guiding protocol.
Few head­to­head comparative trials have been performed on different treatment methods for radiation proctitis. Two important studies comparing between APC and formalin which are commonly used. First, a study by Alfadhli et al19 retrospectively compared outcomes for 22 patients who were treated with APC alone (n = 11), formalin instillation alone (n = 8) or both (n = 3). Patients treated with APC had a significantly improved chance for control of rectal bleeding while those treated with formalin had an increased likelihood of adverse events including nausea, vomiting, cramps and rectal pain. The second study, by Yeoh et al22, reported on 30 men with intractable chronic proctitis after receiving radiation for prostate cancer. All men were randomized to APC or topical formalin. Reduction in rectal bleeding was achieved in 94% of the APC group and 100% of the formalin group after a median of 2 sessions in either arm. There were no differences between side effects of the two treatment modalities.
Based on the available evidence it can be concluded that management of CRP should be a ‘step-up’ approach. Many of the patients can be managed effectively at home with sucralfate enema with or without metronidazole, which is cheap, effective and without toxicity. More severe disease or patients not responding to sucralfate enema should be treated with 4% formalin instillation or APC. Between these two, 4% formalin is cheap, easily prepared and preferably should be given in low dose contact instillation through proctoscope or sigmoidoscope to limit toxicity. Argon plasma coagulation is effective but costly and need endoscopic expertise. APC may be a better option in cases of radiation colitis. These two endoscopic methods should be complementary. Hyperbaric oxygen therapy is difficult option in our country, but RFA may be a promising method considering its effect on re- epithelization in radiated tissue. Surgery is mostly needed for stricture, fistula, life-threatening bleeding but many times diverting stoma can improve patients’ quality of life.

References
  1. Lenz L, Rohr R, Nakao F, Libera E, Ferrari A. Chronic radiation proctopathy: A practical review of endoscopic treatment. World J Gastrointest Surg 2016;8(2):151-16.
  2. Sarin A, Safar B. Management of radiation proctitis. Gastroenterol Clin North Am 2013;42:913-925.
  3. Do NL, Nagle D, Poylin VY. Radiation proctitis: current strategies in management. Gastroenterol Res Pract 2011:917 -941.
  4. Weiner JP, Wong AT, Schwartz D, Martinez M, Aytaman A, Schreiber D .Endoscopic and non­endoscopic approaches for the management of radiation­induced rectal bleeding. World J Gastroenterol 2016; 22(31):6972­6986.
  5. Kochhar R, Patel F, Dhar A et al. Radiation­induced proctosigmoiditis. Prospective, randomized, double­blind controlled trial of oral sulfasalazine plus rectal steroids versus rectal sucralfate. Dig Dis Sci1991;36:103­107.
  6. Kochhar R, Sriram PV, Sharma SC, Goel RC, Patel F. Natural history of late radiation proctosigmoiditis treated with topical sucralfate suspension. Dig Dis Sci1999;44: 973­978.
  7. Cavcic J, Turcic J, Martinac P et al .Metronidazole in the treatment of chronic radiation proctitis: clinical trial. Croat Med J 2000;41:314-318.
  8. Senthil Kumar R, Vivekanandan S, Pai D, Sahai A, Narasimhan R. Prospective randomised double blind controlled trial to compare rectal sucralfate-steroid combination enema and short chain fatty acid enema in patients with radiation induced proctosigmoiditis. A dissertation submitted to Pondicherry University in partial fulfillment of the requirement for the award of the degree of M.S. Surgery 2000.
  9. Patel P, Subhas G, Gupta A, Chang YJ, Mittal VK, McKendrick A.Oral vitamin A enhances the effectiveness of formalin 8% in treating chronic hemorrhagic radiation proctopathy. Dis Colon Rectum 2009;52:1605-1609.
  10. NelamangalaRamakrishnaiah VP, Javali TD, Dharanipragada K, Reddy KS, Krishnamachari S. Formalin dab, the effective way of treating haemorrhagic radiation proctitis: a randomized trial from a tertiary care hospital in South India. Colorectal Dis 2012;14:876-882.
  11. Guo GH, Yu FY, Wang XJ, Lu F.A randomized controlled clinical trial of formalin for treatment of chronic hemorrhagic radiation proctopathy in cervical carcinoma patients. Support Care Cancer2015;23:441-446.
  12. Wong MT, Lim JF, Ho KS, Ooi BS, Tang CL, Eu KW.Radiation proctitis: a decade’s experience. Singapore Med J 2010;51:315-319.
  13. Parikh S, Hughes C, Salvati EP, Eisenstat T, Oliver G, Chinn B, et al. Treatment of hemorrhagic radiation proctitis with 4 percent formalin.Dis Colon Rectum 2003;46:596–600.
  14. Ismail MA, Qureshi MA. Formalin dab for haemorrhagic radiation proctitis. Ann R Coll Surg Engl. 2002;84:263–264.
  15. Chattopadhyay G, Ray D, Chakravartty S, Mandal S.Formalin instillation for uncontrolled radiation induced haemorrhagic proctitis. Trop Gastroenterol2010; 31:291–294.
  16. Jensen DM, Machicado GA, Cheng S, Jensen ME, Jutabha R.  A randomized prospective study of endoscopic bipolar electrocoagulation and heater probe treatment of chronic rectal bleeding from radiation telangiectasia. GastrointestEndosc1997; 45: 20-25.
  17. Lenz L, Tafarel J, Correia L et al. Comparative study of bipolar eletrocoagulation versus argon plasma coagulation for rectal bleeding due to chronic radiation coloproctopathy. Endoscopy 2011; 43: 697-701.
  18. Hanson B, MacDonald R, Shaukat A .Endoscopic and medical therapy for chronic radiation proctopathy: a systematic review. Dis Colon Rectum 2012; 55:1081­1095.
  19. Alfadhli AA, Alazmi WM, Ponich T et al.Efficacy of argon plasma coagulation compared to topical formalin application for chronic radiation proctopathy. Can J Gastroenterol 2008; 22: 129-132.
  20. Swan MP, Moore GT, Sievert W, Devonshire DA.Efficacy and safety of single­sessionargon plasma coagulation in the management of chronic radiation proctitis. GastrointestEndosc2010; 72: 150­154.
  21. Sato Y, Takayama T, Sagawa T et al. Argon plasma coagulation treatment of hemorrhagic radiation proctopathy: the optimal settings for application and long­termoutcome. GastrointestEndosc 2011; 73: 543­549.
  22. Yeoh E, Tam W, Schoeman M, Moore J, Thomas M, Botten R, Di Matteo A. Argon plasma coagulation therapy versus topical formalin for intractable rectal bleeding and anorectal dysfunction after radiation therapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2010;87: 954-959.
  23. Karamanolis G, Psatha P, Triantafyllou K. Endoscopic treatments for chronic radiation proctitis. World J GastrointestEndosc 2013; 5: 308-312.
  24. Taylor JG, Disario JA, Bjorkman DJ.KTP laser therapy for bleeding from chronic radiation proctopathy. GastrointestEndosc2000; 52: 353­357.
  25. Rustagi T, Corbett FS, MashimoH.Treatment of chronic radiation proctopathy with radiofrequency ablation (with video). GastrointestEndosc 2015;81: 428­436.
  26. Clarke RE, Tenorio LM, Hussey JR et al.Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and controlled double-blind crossover trial with long-term follow-up. Int J Radiat Oncol Biol Phys 2008; 72: 134-143.
  27. Tahir AR, Westhuyzen J, Dass J et al.Hyperbaric oxygen therapy for chronic radiationinduced tissue injuries: Australasia’s largest study. Asia Pac J Clin Oncol 2015;11: 68-77.
  28. Glover M, Smerdon GR, Andreyev HJ et al. Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double­blind, sham­controlled phase 3 trial. Lancet Oncol 2016; 17: 224­233.
  29. Ayerdi J, Moinuddeen K, Loving A, Wiseman J, Deshmukh N. Diverting loop colostomy for the treatment of refractory gastrointestinal bleeding secondary to radiation proctitis. Mil Med 2001; 166: 1091­1093.
  30. Pricolo VE, ShellitoPC .Surgery for radiation injury to the large intestine - Variables influencing outcome. Dis Colon Rectum 1994; 37: 675­684.

© 2008 Tropical Gastroenterology
ISSN: Print - 0250-636X