Long-term outcome of argon plasma coagulation therapy for bleeding caused by chronic radiation proctopathy

Digestive and Liver Disease 35 (2003) 806–810

Digestive Endoscopy

Long-term outcome of argon plasma coagulation therapy for bleeding caused by chronic radiation proctopathy G. Rotondano a , M.A. Bianco a , R. Marmo a , R. Piscopo a , L. Cipolletta a,b,∗ a

Division of Gastroenterology and Digestive Endoscopy ASL NA5–Hospital “Agostino Maresca”, Torre del Greco, Italy b Via S.Domenico al Vomero 24 I-80126 Naples, Italy Received 9 January 2003; accepted 7 July 2003

Abstract Background. Radiation-induced proctopathy is a serious complication of radiation therapy for pelvic malignancy. Aim. To assess the safety and efficacy of argon plasma coagulation in the treatment of haemorrhagic radiation-induced proctopathy. Patients. Twenty-four patients with rectal bleeding due to radiation-induced proctopathy were prospectively enrolled in the study. Methods. Indications for treatment were iron deficiency anaemia (n = 16) and persistent bleeding, despite pharmacotherapy (n = 8). Argon flow and power used were 0.8–1.2 l/min and 40 W, respectively. An interval of at least 4 weeks was allowed between treatment sessions. Haemoglobin level, bleeding severity score, number of admissions and transfusion requirements were recorded after endoscopic coagulation and before 12 and 24 months. Results. A median of 2.5 therapeutic sessions per patient were performed (range 1–6). All patients reported clinical improvement and/or cessation of rectal bleeding. The mean value of the bleeding severity score decreased from 2.9 to 0.8 (P < 0.01), while average haemoglobin levels increased by a mean of 1.9 mg/dl at the end of the treatments (P < 0.05). During a minimum follow-up of 24 months (range 24–60), rectal bleeding recurred in two cases and was successfully retreated endoscopically. One patient developed a recto-vaginal fistula. Conclusions. Argon plasma coagulation appears to be a safe and effective technique for management of rectal bleeding caused by radiation-induced proctopathy. © 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Argon plasma coagulation; Endoscopic treatment; Radiation-induced proctopathy

1. Introduction Chronic radiation-induced proctopathy (CRP) occurs as a delayed negative outcome in 5–20 % of the patients submitted to radiation therapy (XRT) for pelvic malignancies [1]. Recurrent rectal outlet bleeding from angioectasias is the most vexing problem of CRP, it is very disabling and can be severe enough to result in chronic anaemia and transfusion dependency. Bleeding is due to mucosal friability and may develop from six months to over one year, after completion of XRT course. Medical therapy with steroids, sulfasalazine or short-chain fatty acids is often ineffective [2,3], whereas sucralfate enemas [4], formalin instillation [5] and antioxidant—vitamins ∗ Corresponding author. Tel.: +39-081-8490102; fax: +39-081-8490109. E-mail address: [email protected] (L. Cipolletta).

E and C [6] were shown to give some benefit results. Surgical management is associated with high morbidity and mortality, and, therefore, should be reserved as a last resort for intractable cases as well as for other major complications of XRT, i.e. obstruction, perforation or fistulae [7,8]. Endoscopic therapy, by means of contact bipolar electrocoagulation or heater probe, has been applied with good results [9,10]. Laser therapy with both Nd:YAG and Argon, can be effective in controlling bleeding, decreasing transfusion requirements and increasing haemoglobin levels; but it is technically difficult, time consuming and carries a related risk of complications [11]. Argon plasma coagulation (APC) is an innovative no-touch electro-coagulation technique in which high-frequency monopolar alternating current is delivered to the tissue through ionised argon gas [12–15]. The aim of this prospective study was to evaluate the long-term safety and efficacy of APC for the treatment of haemorrhagic radiation proctopathy.

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G. Rotondano et al. / Digestive and Liver Disease 35 (2003) 806–810

2. Patients and methods From June 1997 through June 2000, twenty-four patients with recurrent lower gastrointestinal bleeding (due to CRP) underwent APC treatment, and were prospectively followed over time. To be enrolled in the study, patients had to have chronic haematochezia with either iron-dependent or transfusion-dependent anaemia, bleeding refractory to medical management, no tumour recurrence and no post-radiation fistulae or strictures. Complete colonoscopy was first performed in all patients to determine the proximal extent of the disease and exclude other potential sources of bleeding. Multiple biopsies were also taken to exclude other causes of chronic inflammation. All patients received a 4-week medical therapy by using topical agents (5-aminosalicylic acid, corticosteroids or sucralfate enemas), prior to endotherapy.

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At the time of APC treatment, full colon preparation with oral polyethylene glycol-based colon purgation was always performed. Enemas were avoided to minimise contactinduced bleeding, which will obscure the vascular bleeding lesion and complicate the therapy. Most treatments were performed on an outpatient basis, using conscious sedation when needed. Procedures were carried out with standard single-channel CF-100S, CF-Q140L or CF-Q145L videocolonoscopes (Olympus Europe, Co, Hamburg, GmbH), using an argon source coupled with a high-frequency generator (Erbe APC 300 and ICC 200, Movi, Italia) and flexible 2.3 mm axial probes. Mean applied power output was 40 W and gas flow rates ranged from 0.8 to 1.2 l/min. A technique incorporating both single-shot targeting and trawl-back manoeuvres was used (Fig. 1). Retroflexion was employed to examine the distal rectum; lesions at and just above the dentate line were treated with an end-on approach. Minimal

Fig. 1. Endoscopic APC treatment of CRP. (a) Coagulation of angectasias using the axial APC probe with the trawl-back technique. (b) End of treatment with complete coagulation of the rectal surface. (c) Control after 2 weeks, with healing superficial ulcerations. (d) Control after 3 months, almost all lesions have disappeared.

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G. Rotondano et al. / Digestive and Liver Disease 35 (2003) 806–810

insufflation and frequent aspiration with the probe in place were done to prevent over-distension of the colon. The goal of the treatment was to coagulate all visible angioectasias. Lesions with active, oozing haemorrhage or with stigmata of recent bleeding were targeted first. In most cases, more than one APC session was required to complete the treatment. An interval of at least 4 weeks was allowed between sessions to allow healing of the injured tissue. Eradication was defined as the complete disappearance of any angioectasia. Recurrence was defined as recurrence of haematochezia. Transfusion of red blood cells was indicated for patients with a haemoglobin level <8 gr/dl. The clinical efficacy of APC treatment was evaluated by an independent physician. Outcome measures were: decrease in rectal bleeding, reduction in transfusion requirements, increase in haemoglobin levels and reduction in hospital admissions. Outcome assessment was made at predetermined intervals of 6, 12 and 24 months after APC therapy. Endoscopic success, i.e. improved rectal appearance on follow-up endoscopies, was a surrogate end-point subject to potential bias and was therefore not considered. Bleeding recurrence after successful treatment was also registered. The severity of rectal bleeding was graded as follows: 0 = no blood; 1 = blood on toilet paper or stool; 2 = blood in toilet bowl; 3 = heavy bleeding with clots; and 4 = bleeding necessitating transfusions. Follow-up endoscopy was scheduled at 6 months intervals for the first year and annually thereafter. Statistical analysis was carried out using the statistical package SPSS version 7.0 (M.J. Norusis, Chicago, IL). Paired data were analysed using the Student’s t-test or the Wilcoxon sum rank test, when appropriate. Analysis of variance was performed for parametric and non-parametric tests for repeated measures. Significance was assumed for P < 0.05.

3. Results Twenty-four patients who received prior pelvic XRT for carcinoma of the endometrium (n = 13), cervix

(n = 6) or prostate (n = 5), were enrolled in the study. Intracavitary irradiation followed external XRT in 13 females (nine with uterine and four with cervical cancer). Mean age of the patients was 69.2 years (range 22–81). Symptoms occurred within an average of 16 months (range 6–31) after the completion of XRT course. These were intermittent rectal bleeding with iron deficiency anaemia in 16 cases and persistent bleeding requiring blood transfusion in 8 cases (with an average of 2.2 units of RBC) (Table 1). Endoscopically, multiple friable bleeding angioectasias in a pale or erythematous mucosa were observed in all patients, extending proximally 5–20 cm from the anal verge. The lesions were localised in five patients and diffused in nineteen. A total of 69 therapeutic sessions were performed (with a median of 2.5 sessions per patient and a range of 1–6). All patients reported clinical improvement or cessation of rectal bleeding, and most of them reported after first APC session. Clinical improvement clearly correlated with endoscopic eradication of angioectasias. Average haemoglobin level increased from 9.2 ± 2.4 gr/dl (before therapy) to 13.6 ± 1.1 gr/dl (12 months later) (P < 0.05). Mean severity score for rectal bleeding decreased from 2.9 to 0.8 (P < 0.01). The mean number of hospital admissions decreased from 2.4 before endoscopic therapy to 0.6, one year after APC (P < 0.05) (Table 1). During a minimum follow-up period of 24 months (range, 24–60; median, 41 months), recurrent bleeding was observed in two patients (8.3%) who were successfully retreated with the same method. No patient was lost to follow-up or require blood transfusion after APC treatment. Negative outcomes related to the technique were mild bloating and cramping caused by distension of the gastrointestinal tract in five patients and transient anal pain in one patient 24 h after treatment of lesions adjacent to the dentate line. This patient then developed a non-symptomatic rectal stenosis 11 months after the first APC session. Five patients died of recurrent disease, and one

Table 1 Clinical features of the study population (total n = 24) and long-term outcome after APC treatment

Total no. of patients (males/females) Mean age (years, range) Mean time to symptoms after XRT (months, range) No. of patients requiring iron therapy No. of patients requiring transfusion Mean no. of RBC units transfused Mean bleeding severity score Mean haemoglobin levels (gr/dl) Mean no. of hospital admissions (range)

Baseline

6 months

12 months

24 months

24 (5/19) 69.2 (22–81) 16 (6–31) 16 8 2.2 2.9 9.2 ± 2.4 2.4 (1–4)

4 0 0∗ 0.8∗ 10.6 ± 1.1∗∗ 0.6 (0–1)∗∗∗

0 0 0∗ 0.8∗ 13.6 ± 1.1∗∗ 0.6 (0–1)∗∗∗

0 0 0∗ 0.7∗ 12.8 ± 1.7∗∗ 0.5 (0–1)∗∗∗

Minimum follow-up was 24 months (range 24–60 and a median of 41 months); no patient was lost to follow-up. NSAIDS: non-steroidal anti-inflammatory drugs; XRT: external radiation therapy. ∗ P < 0.01 vs. baseline. ∗∗ P < 0.05 vs. baseline and 6 months. ∗∗∗ P < 0.05 vs. baseline.

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discontinued APC treatment when a recto-vaginal fistula developed.

4. Discussion Radiation proctopathy (a better term then ‘radiation proctitis’, since there is no inflammation on histology) is a frustrating problem for patients and the managing physicians. Medical treatment of CRP is often unsatisfactory. The use of diluted topical formalin (4% formaldehyde) may offer an effective and inexpensive first-line treatment [5], but in most of the instances, endoscopic coagulation therapy remains the most effective. Contact thermal and laser probes are successful in CRP [9–11] although less preferable because they are time-consuming, cumbersome to manoeuvre and can induce bleeding from probe sticking. APC has essentially replaced laser coagulation therapy for CRP in our practice. The device is readily available for use in any procedure room. The advantages of this method include technical ease in treating large areas as well as achievement of superficial coagulation with controllable depth of injury [12–15]. As a result, treated areas heal more quickly and the endpoint of therapy can be reached sooner. However, when the catheter tip touches the mucosa, the APC becomes a monopolar probe and can cause unpredictable deeper injury including perforation, non-healing ulcers and strictures. Further evidence of the potential for APC to cause transmural damage comes from case reports of perforation and subcutaneous emphysema following APC [16,17]. These risks have been elegantly demonstrated in animal studies, where injury to the muscolaris propria occurred and the depth of injury was dependent on the duration of therapy and total energy delivered [18]. Either the axial or the side-fire APC probes can be used. Whenever possible, treat all visible angectasias, targetting with single shots, trying to avoid ‘painting’ of mucosa. Single-shot technique limits coagulation depth and avoids treatment of unaffected areas. A number of retrospective and prospective case series using APC treatment for CRP have been published [19–29], all of which are consistent with an almost complete resolution of the clinical picture in the order of 90% and complete disappearance of bleeding of around 80%, after one to three sessions. The effectiveness of APC seems to be superior to that of the laser, with some patients cured by APC, where laser treatment had been ineffective. The absence of any randomised controlled study as well as the limited follow-up of most studies should, however, be acknowledged. One of the two studies with longest mean follow-up (23 months) was published only in abstract form [22], whereas mean follow-up was less than 12 months in the two prospective studies published so far [27,28]. The present prospective study followed a standardised treatment protocol, assessing outcome in a predetermined fashion. Results compare favourably with those reported in the literature. Long-term clinical outcome was satisfactory in

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all treated patients, who experienced a marked improvement in their condition with no more transfusion dependency at a minimum follow-up of 2 years. Complications of APC treatment are not rare (14–20%) and, although most of them are ‘minor’ (asymptomatic stenosis and pain); perforations and extensive necrosis were observed [22]. Low power output must be used in order to minimise the risk of serious negative outcomes. Tam et al. [25] detailed the results of APC with 60 W power in a group of 15 patients. Clinical picture improved in all instances, but two rectal strictures required dilation. A group from Indianapolis employed a 45–50 W APC treatment in 21 patients [29]. Retrospective analysis documented a 14% short-term and a 19% long-term complication rate (rectal pain, tenesmus, diarrhoea). Two groups of French endoscopists performed APC in 11 patients with 50 W power setting [28], and reported good clinical outcome in 82% of the cases, but a striking 43% of complications (one deep rectal ulcer and two rectal strictures requiring dilation). No significant complications were reported after APC therapy with 40 W power [26,27]. In our experience, power settings of 40 W were sufficient for effective coagulation of mucosal lesions and minimised the risk of major complications (one patient, 4.1%). The recto-vaginal fistula after APC may have resulted from deeper thermal injury anteriorily to a fragile rectal wall already thinned by previous irradiation. In conclusion, the initial therapy for problematic rectal bleeding related to radiation-induced proctopathy should be endoscopic therapy. The argon plasma coagulation is safe and effective, and can be considered as a valid therapeutic option in these patients.

Conflict of interest statement None declared.

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