Keywords
proctitis - radiotherapy - argon plasma coagulation - bleeding
Introduction
Pelvic cancers are frequently treated through radiotherapy, but although radiation
can be beneficial in reducing the tumor and even mortality, it can also lead to adverse
injuries, especially due to the proximity and anatomical relationship among pelvic
organs. In this scenario, the rectum and the sigmoid colon are the structures most
commonly affected, and the most prevalent (and feared) complication after radiotherapy
sessions is actinic proctitis.[1]
This condition consists of mucosal inflammation due to radiation toxicity, and it
may cause a wide range of intestinal symptoms, such as diarrhea, abdominal pain, mucous
discharge, tenesmus, and bleeding.[2]
[3]
[4] Moreover, rectal bleeding affects around one third of patients submitted to radiotherapy,[5] and it is considered a serious complication, not only due to its impact on the patient's
quality of life, but also because rectal bleeding may require hospitalization and
blood transfusion.[4]
[6]
[7]
[8] Despite that, the treatment of this condition remains uncertain.
Three different therapeutic approaches are currently available: medications, surgery,
and endoscopy. However, none of these have been standardized as the ideal treatment.[2]
[9]
[10]
[11]
[12] Surgical procedures seem to have little effect, and they are associated with the
occurrence of postoperative complications, which makes them the last resort.[2]
[4]
[12]
[13]
[14] On the other hand, medications have been used as the first-line treatment due to
their safety, but contemporary studies have suggested that they also have little effect
on the resolution of rectal bleeding.[13]
[14]
In this context, the endoscopic approach, such as argon plasma coagulation (APC),
has been frequently recommended as a possible first-line treatment.[15] A non-tactile ablative therapy that consists of thermic coagulation directly into
the lesion, it has been suggested that APC reduces rectal bleeding in rates of up
to 80%.[16] However, studies on this technique[4]
[7]
[10]
[11]
[12]
[15]
[16]
[23] are still controversial, so the aim of the present work is to review the literature
to verify the effectiveness of APC in the treatment of patients with actinic proctitis
induced by radiation therapies, as well as to evaluate the technique regarding the
number of sessions required to control the bleeding and the common complications.
Methods
Literature Search
A systematic search was conducted on the MEDLINE/PubMed, LILACS, SCIELO and Cochrane
Central Register of Controlled Trials databases using the following terms: (proctitis) and (radiation) and (argon plasma coagulation) and (bleeding), with only a few adaptions for each database. Our search strategy included studies
available in English, Portuguese or Spanish published between January 2000 and December
2018.
Study Selection
All articles found were meticulously evaluated, and they were excluded if they: were
animal studies; were descriptive studies, such as editorials, case reports or case
series; had unavailable text or data; did not investigate APC as a treatment for actinic
proctitis; studied the association between different types of treatment; and assessed
neither rectal bleeding nor actinic proctitis by scores. Moreover, duplicate papers
were also excluded.
The process of article evaluation occurred through a paired selection. Two independent
reviewers analyzed each article to determine if it should be included or not. In cases
of divergent opinions, the final decision was made in a meeting, after discussion
and agreement.
Data Analysis
Randomized clinical trials had their quality assessed through the Consolidated Standards
of Reporting Trials (CONSORT)[17] statement, and the following aspects were analyzed: adequate randomization, patient
allocation, blinding of the participants, blinding of the investigators, losses, exclusions
after randomization, referred limitations, and other sources of potential bias. Furthermore,
observational studies were evaluated through the application of the Strengthening
the Reporting of Observational Studies in Epidemiology (STROBE) statement.[18]
In both cases, the articles were only included in the present review if they had contemplated
at least 70% of the CONSORT or STROBE checklists, and these tools were also independently
applied by two reviewers. Divergence was, once again, discussed until an agreement
was reached. Moreover, the Preferred Reporting Items for Systematic Reviews and Meta-analyses
(PRISMA)[19] statement was used as a guide for the present systematic review.
Variables of Interest
Once included in the protocol, all articles were evaluated, and the following variables
were collected: author's information, title, year of publication, sample size, duration
of the treatment, APC technique, number of APC sessions performed, complications,
and patient's characteristics (age, gender, previous malignancy, diagnosis of anemia,
and blood transfusion).
Results
Search Results
After screening the titles and abstracts, we identified 81 studies, 8 of which fulfilled
the inclusion criteria. Among those, 3 articles were excluded for reporting less than
70% of the STROBE checklist; therefore, 5 papers were included in the present review.
[Figure 1] summarizes the PRISMA flowchart for article selection.
Fig. 1 PRISMA flowchart of the selection of articles.
Studies Characteristics
Only cohort studies ended up being included in the present review and the characteristics
of each one is available in [Table 1].
Table 1
Methodological characteristics of the selected studies
|
Author
|
Year of publication
|
Country
|
Study design
|
Average follow-up
|
Limitations
|
|
Sultania et al.[20]
|
2019
|
India
|
Prospective cohort
|
6 months
|
It does not compare argon plasma coagulation with other known treatments
|
|
Weiner et al.[11]
|
2017
|
United States
|
Retrospective cfohort
|
112 months
|
Not reported
|
|
Swan et al.[15]
|
2010
|
Australia
|
Prospective cohort
|
20.6 months
|
Not a randomized clinical trial
|
|
Karamanolis et al.[21]
|
2009
|
Greece
|
Prospective cohort
|
12 months
|
Not reported
|
|
Sebastian et al.[7]
|
2004
|
Ireland
|
Prospective cohort
|
14 months
|
Not reported
|
Moreover, regarding all 5 articles, a total of 236 patients were analyzed. Most participants
were men (67.7%) with an average age of 66.6 years; 134 were anemic, 56 of whom required
blood transfusion ([Table 2]).
Table 2
Patient characteristics
|
Author
|
Sample
(n)
|
Mean age
(years)
|
Gender proportion
male/female (%)
|
Malignancy:
n (%)
|
Anemic patients: n (%)
|
Blood transfusion:
n (%)
|
|
Sultania et al.[20]
|
70
|
51.9
|
0 / 100
|
Cervical: 63 (90);
endometrial: 7 (10)
|
65 (92.8)
|
23 (32.8)
|
|
Weiner et al.[11]
|
35
|
72.0
|
100 / 0
|
Prostatic: 35 (100)
|
15 (42.9)
|
15 (42.9)
|
|
Swan et al.[15]
|
50
|
72.1
|
90 / 10
|
Prostatic: 45 (90);
endometrial: 2 (4);
cervical: 2 (4);
vaginal: 1 (2)
|
21 (42.0)
|
Not reported
|
|
Karamanolis et al.[21]
|
56
|
68.4
|
100 / 0
|
Prostatic: 56 (100)
|
15 (26.7)
|
9 (16.0)
|
|
Sebastian et al.[7]
|
25
|
69.0
|
96 / 4
|
Prostatic: 23 (92);
bladder: 2 (8)
|
18 (72.0)
|
9 (36.0)
|
Additionally, the treatment for prostate cancer was the main cause of actinic proctitis
(in 67.3% of the cases), as seen on [Figure 2].
Fig. 2 Most prevalent types of cancer associated with actinic proctitis.
All selected studies reported a predetermined scale to assess the severity of actinic
proctitis and/or rectal bleeding. Three studies[11]
[15]
[20] reported the same score to assess the severity of actinic proctitis, and categorized
their population into “mild,” “moderate,” and “severe” based on the distribution of
telangiectasias, the involved surface area, and the presence of fresh blood. Karamanolis
et al.,[21] on the other hand, used a modified scale considering only two factors of the previously-used
score: distribution of telangiectasias and involved surface area. Thus, patients were
categorized into “mild” or “severe” proctitis. However, when it comes to the stratification
of rectal bleeding, the tool varied according to each study, but all papers regarded
the periodicity and volume of the bleeding ([Table 3]).
Table 3
Severity scores for rectal bleeding and actinic proctitis
|
Author
|
Rectal bleeding
|
Actinic proctitis
|
|
Score
|
Severity
|
Score
|
Severity
|
|
Sultania et al.[20]
|
Rectal Bleeding Grade (RBG):
no bleeding = 0;
bleeding once a week = 1;
bleeding 2 or more times a week = 2;
daily bleeding = 3;
bleeding requiring blood transfusion = 4
|
Median (range):
3 (2–4)
|
Total Colonoscopic Severity Score (TCSS): previously described by Zinicola et al.,[8] based on the
distribution of telangiectasias.
Distal rectum (within 10 cm of the anal verge): 1 point;
more than 10 cm: 2 points;
surface area covered by telangiectasias:
less than 50%: 1 point;
more than 50%: 2 points;
presence of fresh blood:
no: 0 points;
yes 1 point.
There are three categories of endoscopic severity for CRP:
1. grade A (mild): 2 points;
2. brade B (moderate): 3 points;
3. grade C (severe): 4 or 5 points
|
Grade A (mild):
23 (32.86%);
grades B or C
(moderate or severe):
47 (67.14%)
|
|
Weiner et al.[11]
|
Not reported
|
Not reported
|
Total Colonoscopic Severity Score (TCSS): described previously by Zinicola et al.[8] All items were depicted above.
|
Not reported
|
|
Swan et al.[15]
|
Modified bleeding scoring system.
No rectal bleeding: 0;
minor, intermittent: 1;
minor, daily: 2;
moderate, daily: 3;
heavy, daily: 4
|
Mean (standard deviation):
2.03 ± 0.93
|
Total Colonoscopic Severity Score (TCSS): previously described by Zinicola et al.[8] All items were depicted above.
|
Grade A (mild):
17 (34%);
grade B (moderate):
23 (46%);
grade C (severe):
10 (20%)
|
|
Karamanolis et al.[21]
|
Not reported
|
Not reported
|
Modified scoring system based on the aforementioned TCSS.[8] After the total score was calculated according to the distribution of telangiectasias
and the surface area covered by them, only 2 categories were established:
· mild: 1–2 points;
· severe: 3–4 points
|
Mild: 27 (48%);
severe: 29 (52%)
|
|
Sebastian et al.[7]
|
Bleeding severity score.
No blood: 0;
blood on the toilet paper: 1;
intermittent visible
bleeding: 2;
regular and heavy
bleeding: 3;
bleeding
necessitating blood
transfusion: 4
|
Median score: 3
|
Not reported
|
Not reported
|
Combining the results of the 5 studies, 66 posttreatment occurrences were observed,
and rectal pain was the most reported symptom. Moreover, the mean number of sessions
performed was 1.67, and bleeding control was achieved in 83.8% of the cases. The characteristics
of the applied technique are evident in [Table 4].
Table 4
Characteristics of the protocol for argon plasma coagulation
|
Author
|
Protocol
|
Mean number of sessions
|
Complications n (%)
|
Bleeding control rate
n (%)
|
|
Flow (L/min)
|
Wattage (W)
|
|
Sultania et al.[20]
|
1
|
45–50
|
2
|
Rectal pain and mucous discharge: 12 (21.0);
deep ulcers: 8(14.0)
|
48 (85.70)
|
|
Weiner et al.[11]
|
1
|
60–70
|
2
|
Deep ulcers: 8 (22.9);
colovesiculal fistulas: 2 (5.7); 1 patient died from this complication
|
30 (85.70)
|
|
Swan et al.[15]
|
1.4 - 2.0
|
50
|
1.36
|
Rectal pain: 13 (26.0);
mucous discharge: 4 (8.0);
fecal incontinence: 1 (2.0);
fever:1 (2.0);
bleeding: 1 (2.0);
asymptomatic rectal stricture: 1 (2.0)
|
49 (98.0)
|
|
Karamanolis et al.[21]
|
2
|
40
|
2
|
Colonic explosion: 1 (1.78%)
|
50 (89.0)
|
|
Sebastian et al.[7]
|
1.5
|
25–50
|
1
|
Rectal pain: 1 (4.0)
|
81 (21.0)
|
Discussion
In the present systematic review, we found that APC is a safe and effective endoscopic
treatment for actinic proctitis, with a high rate of therapeutic success (83.3%),
and these findings support the previous literature[7]
[15]
[22] that recommends APC as first-line treatment for patients with actinic proctitis.
However, it is important to mention that there is no consensus about the exact number
of APC sessions to achieve bleeding control. In the present review, the mean number
was 1.67, which is close to the one reported by Higuera et al.[12] (mean of 1.9 session). Nevertheless, Sudha and Kadambari[10] reported a mean of 5 sessions to achieve bleeding control. The wide variation in
the number of sessions required for therapeutic success may include several factors,
such as the flow and potential applied during the performance of technique. In addition,
Tjandra and Sengupta[23] and Siow et al.[24] suggested a correlation between the number of APC sessions necessary to interrupt
the bleeding and the intensity of the bleeding since its onset.
Another important aspect is the absence of a standardized score to evaluate the severity
of actinic proctitis and rectal bleeding. The divergence among the scores can lead
to an overestimation of some cases, and consequently favor certain studies. Although
three[11]
[15]
[20] out the five[7]
[11]
[15]
[20]
[21] selected studies used the same severity score for actinic proctitis (the Total Colonoscopic
Severity Score, TCSS), one of the articles (Karamanolis et al.[21]) used a modified version of the tool. With this perspective of different classifications,
many patients who could have been categorized as “moderate” ended up being categorized
as “mild” or “severe,” which influences the statistical analysis.
The same issue of standardization also affects the interpretation of therapeutic success.
Sultania et al.[20] understood the treatment as effective if there was a reduction in the bleeding scale,
which was previously documented (from ≥ 2 points to ≤ 1 point). Weiner et al.,[11] on the other hand, defined therapeutic success as the cessation of bleeding, in
other words, no evidence of macroscopic rectal bleeding. For Swan et al.,[15] the same aspect was defined as a bleeding severity score ≤ 1 after treatment, while
for Karamanolis et al.[21] the definition was the interruption of bleeding or the presence of some occasional
traces of bleeding in feces without anemia recurrence. Lastly, Sebastian et al.[7] considered the reduction in the bleeding severity score < 2 points during the minimum
period of 6 months. Therefore, the rates of success will diverge when different limits
for the establishment of therapeutic success are used.
Furthermore, the present study has some limitations that must be taken into consideration.
It only involved cohort studies, which is not an ideal methodology to define treatment
options. However, this is a reflection of what is available in the scientific literature.
Moreover, we did not perform a statistical analysis with the data extracted from the
articles, which could have provided more accurate information about these studies
and the role of APC on the treatment of actinic proctitis.
Conclusion
Argon plasma coagulation is a well-tolerated and effective treatment to control rectal
bleeding in patients who underwent radiotherapy, and the number of sessions varies
from 1 to 2, according to the case. This technique is not exempt from complications,
but most of them seem to be short-term occurrences. Nevertheless, further studies
are needed before establishing APC as the initial therapy for patients with actinic
proctitis.
