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Surgery for chronic radiation enteritis: outcome and risk factors
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Surgery for chronic radiation enteritis: outcome and risk factors Yuhua Huang, MD, Feilong Guo, MD, Danhua Yao, MD, PhD, Yousheng Li, MD, PhD,* and Jieshou Li, MD Department of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
article info
abstract
Article history:
Background: Surgery is required in approximately one-third of patients with chronic radi-
Received 5 January 2016
ation enteritis (CRE). The aim of this study was to explore the short- and long-term out-
Received in revised form
comes after surgery for CRE and risk factors of postoperative morbidity.
9 March 2016
Methods: Clinical features and surgical outcomes of patients undergoing surgery for CRE
Accepted 6 May 2016
were retrospectively reviewed. Risk factors of postoperative morbidity were analyzed
Available online xxx
using univariate and multivariate analysis. Survival and reoperation rates for CRE were evaluated.
Keywords:
Results: Among the 404 patients included, 351 patients (86.88%) received resectional sur-
Chronic radiation enteritis
gery, whereas the remaining patients received conservative procedures. No differences
Outcome
were detected between patients with resection and those without resection with regard to
Risk factor
major morbidity (P ¼ 0.486) and surgical complications (P ¼ 0.715). Laparoscopy resulted in
Postoperative morbidity
a shorter postoperative hospital stay (P ¼ 0.035). After multivariate analysis, history of hypertension (odds ratio [OR] ¼ 2.490; P ¼ 0.046), previous acute radiation enteritis (OR ¼ 1.832; P ¼ 0.033), intraoperative blood loss of more than 200 mL (OR ¼ 2.235; P ¼ 0.006), and thrombocytopenia (OR ¼ 2.544; P ¼ 0.016) were determined as independent predictors of postoperative major morbidity. During follow-up, 22 patients required reoperation for CRE recurrence, and the reoperation rate was significantly lower in patients receiving resectional surgery (P ¼ 0.005). Conclusions: Resection is feasible for CRE with acceptable postoperative morbidity and lower reoperation rate. Correction of preoperative thrombocytopenia, minimizing intraoperative blood loss, and close monitoring of hypertensive patients and those with history of acute radiation enteritis are critical to reduce postoperative complications. ª 2016 Elsevier Inc. All rights reserved.
Introduction Chronic radiation enteritis (CRE) is a common complication faced by patients who have received radiotherapy for abdominal and pelvic malignancies. An estimated incidence of CRE has been reported to be 5%-55%, depending on the symptoms and definition of CRE1 and number of patients
seeking medical care. Owing to the wider use of radiotherapy and improved life expectancy of patients with cancer, the incidence of CRE has increased.2 Factors that play a role in the risk of developing radiation-induced intestinal damage include radiation dose, previous abdominal surgery, body mass index, diabetes mellitus, hypertension, and concurrent chemotherapy.3
* Corresponding author. Department of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China. Tel.: þ86-25-80860137; fax: þ86-25-8480396. E-mail address: [email protected] (Y. Li). 0022-4804/$ e see front matter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2016.05.014
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CRE may develop as early as 2 mo or as long as 30 y after exposure to radiation,4 with various clinical manifestations including abdominal pain, diarrhea, rectal bleeding, malabsorption, intestinal obstruction, external fistula, and perforation.5 The characterized pathologic changes of CRE are obliterative endarteritis and fibrosis of absorptive epithelium.6 Therapeutic regimens for CRE have been controversial for decades. Home parenteral nutrition (PN) was proposed for CRE by physicians, due to the extreme difficulty and high risk of complications of surgical treatment.7 However, approximately one-third of the patients with CRE need to be operated on during follow-up,8 but there is no agreement as yet on the best surgical method for CRE. To avoid postoperative complications, some surgeons prefer conservative surgery without resection of radiation-injured lesion by bypass or simple stomy,9 whereas others suggest radical resection of diseased intestinal segments to avoid recurrence of CRE. Yet, subjects of previous studies are no more than 200, and limited large cohort research has been conducted regarding the surgical outcomes of patients with CRE and risk factors of early postoperative complications. The present study aimed to evaluate the short- and longterm outcomes of surgical treatment of CRE and to identify potential risk factors of postoperative morbidity.
Grading system The severity of intraperitoneal adhesion was graded from 0 to IV, according to an adhesion grade system specific for CRE10: grade 0 meant no adhesion between the affected intestinal lesions and surrounding organs; grade I indicated adhesion and fibrosis limited to the right or left pelvis, whereas grade II was defined as strong adhesion and fibrosis affecting the whole pelvis; grade III referred to grade II adhesion extending between the intestine and anterior pelvic wall, and grade IV referred to grade III adhesion extending between the intestine and anterior abdominal wall. The grading of postoperative morbidity was in accordance with the Clavien-Dindo classification,11 which was based on the therapeutic consequences of complications. Morbidity was graded ranging from I to V, with grade III or greater being considered as major morbidity. In addition, postoperative total parenteral nutrition (TPN) over 2 wk was regarded as grade II morbidity on the basis of the Clavien-Dindo classification. For patients who underwent staged surgery, the morbidity rate was calculated as the total episodes of two procedures. The Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema12 was used for the assessment of severity of CRE. Essentially, obstruction and bleeding requiring surgery belonged to grade III, whereas fistula and perforation were grouped under grade IV.
Patients and methods
Follow-up
Study patients
Patients were followed up until death or the start of data collection on June 2015. In addition, patients’ survival status and causes of death were noted by reviewing medical records and telephone follow-up. The reoperation for recurrence of CRE was recorded, and associated factors were analyzed.
A consecutive series of adult patients receiving surgical management for CRE in our department specializing in gastrointestinal surgery between January 2005 and June 2015 were retrospectively reviewed. Patients with tumor recurrence were excluded. The ethics committee of Jinling Hospital approved this study. Demographic and clinical information, including primary malignancy, details of radiotherapy (radiation type and cumulative radiation dosage), clinical manifestations, interval from completion of radiotherapy to symptom onset, American Association of Anesthesiologist score, preoperative nutrition support, intraperitoneal adhesion grade, intraoperative blood loss, residual small bowel length, and postoperative morbidity, mortality, and hospital stay were extracted from a prospective medical database. In this study, acute radiation enteritis (ARE) referred to symptoms, such as diarrhea and abdominal pain, presented shortly after a course of radiotherapy and resolved spontaneously over 2-12 wk,3 whereas CRE developed 6 mo after the completion of irradiation. Postoperative short bowel syndrome (SBS) was defined as the length of remnant small intestine less than 200 cm. Only the first postoperative hospital stay was recorded if a patient had staged surgery. The most recent preoperative blood test, including serum albumin, platelet and lymphocyte count, hemoglobin, C-reactive protein, and total cholesterol, was also reviewed. Some of the above-mentioned parameters were analyzed to discover possible risk factors of postoperative complications.
Statistical analysis Continuous variables were compared using Mann-Whitney U test or Student’s t test, as appropriate. Pearson’s chisquare test or Fisher’s exact test was performed for univariate analysis of risk factors of postoperative morbidity. All factors with P < 0.1 in the univariate analysis were further evaluated by multivariate analysis using multiple logistic regression. The reoperation rate was analyzed using KaplanMeier method and compared using log-rank test. Results with a two tailed P < 0.05 were accepted as statistically significant. All analyses were performed using SPSS version 19.0 (IBM Analytics, Armonk, NY, USA).
Results Patient characteristics A cohort of 404 adult patients comprising 310 females and 94 males were included in the present study. The characteristics of these patients are listed in Table 1. Gynecologic and rectum carcinoma were two main primary malignancies. The majority of the patients (n ¼ 331, 81.93%) received radiotherapy after
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Table 1 e Demographic and clinical characteristics. Variable
Values
Gender (M/F)
94/310
Age (y)*
50.85 10.48 (23-76)
Primary malignancy Gynecologic (cervix, ovary, endometrium, vagina, and tubal)
282 (69.80)
Table 2 e Perioperative status of 404 patients with chronic radiation enteritis. Variable
ASA II
251 (62.13)
ASA III
133 (32.92)
ASA IV
Rectum
94 (23.27)
Preoperative intestinal decompression
Colon
11 (2.72)
Preoperative nutrition supporty
Testis
8 (1.98)
None
Others (kidney, bladder, small intestinal, and so forth)
9 (2.23)
TPN dependence
Cumulative radiation dosage (Gy)*,y
52.47 14.64 (10.8-128)
Radiation therapy
No. of patients
Preoperative ASA grade
20 (4.95) 131 (43.67)*
46 (11.39) 209 (51.73)
EN
84 (20.79)
PN þ EN
57 (14.11)
Operative strategy
Preoperative
7 (1.73)
Postoperative
331 (81.93)
Laparoscopic surgery
67 (16.58)
5 (1.24)
One-stage operation
369 (91.34)
Two-stage operation
35 (8.66)
Preoperative and postoperative Radical irradiation
61 (15.10)
Endocavitary irradiation
61(15.10)
Chemotherapy
239 (59.16)
Interval from RT to CRE onset (mo) 12
*
19.52 34.58 (1-288) 291 (72.03)
12-24
55 (13.61)
>24
58 (14.36)
BMI on admission (kg/m2)
Open surgery
Intraoperative blood loss (mL) <100
215 (53.22)
18.5
189 (46.78)
144 (35.64)
200
101 (25.00)
Intraperitoneal adhesion grade None (0)
Severe (3-4)
Hypertensionz
31 (7.67)
Postoperative hospital stay (d, mean SD, range)
Diabetes mellitusz
12 (3.00)
Postoperative small bowel length (cm)
History of ARE
130 (32.18)
Previous abdominopelvic surgery
80 (19.80)
ARE ¼ acute radiation enteritis; BMI ¼ body mass index; CRE ¼ chronic radiation enteritis; RT ¼ radiotherapy. Values are number of patients (percentage), unless noted otherwise. * Values are mean standard deviation and (range). y Radiation dosage was unknown in 45 patients. z Patients have a history of hypertension or diabetes mellitus and need drugs to control blood pressure or blood glucose preoperatively.
resection of the primary tumor, and 61 patients (15.10%) had radical irradiation without surgery. Total radiation dosage was acquired in 359 patients (88.86%), with a mean dose of 52.47 14.64 Gy (range: 10.8128 Gy). The mean interval from the completion of radiotherapy to onset of digestive symptoms was 19.52 34.58 mo (range: 1-288 mo). A total of 130 patients (32.18%) had ARE, of whom 31 evolved from ARE to CRE directly without a symptom-free interval.
159 (39.36)
100-200
Moderate (1-2)
<18.5
337 (83.42)
200
23 (5.69) 244 (60.40) 137 (33.91) 17.83 16.62 (2-180)
322 (79.70)
150-200
46 (11.39)
100-150
27 (6.68)
<100
9 (2.23)
ASA ¼ American Association of Anesthesiologist; EN ¼ enteral nutrition; PN ¼ parenteral nutrition; SD ¼ standard deviation; TPN ¼ total parenteral nutrition. Values are number of patients (percentage). * Only patients with obstruction were included for calculation. y Preoperative nutrition support was unclear in eight patients.
gastrostomy/jejunostomy (PEG/J) or a long small bowel decompression tube. The majority of the patients (n ¼ 350, 86.63%) had nutrition support before surgery, and more than half of them were TPN dependent because of complete intestinal obstruction at presentation. Enteral nutrition therapy was preferred for those without obstruction and attempted after small bowel depression in patients with obstruction. If patients had poor enteral nutrition tolerance or insufficient energy intake, PN would be instituted to meet the nutrition requirement.
Preoperative status Clinical features and surgical procedures Table 2 presents the preoperative parameters in detail. Small intestinal decompression was performed in 131 patients with intestinal obstruction using percutaneous endoscopic
Symptomatic intestinal obstruction was the main etiology for surgery (n ¼ 300, 74.26%), followed by fistula, severe radiation
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Table 3 e Details of chronic radiation enteritis lesion location/type and surgical procedures. CRE type/location
Surgical procedures
Obstruction Ileum/ileocecal
No. of patients 300
Ileocecal R/A
139
Ileal R/A
91
Ileal resection and ileostomy
14
Ileocecal resection and ileostomy
6
Ileostomy/colostomy
7
Bypass
5
Intestinal enterolysis
2
Rectosigmoid
Colostomy
Ileum and rectosigmoid
Ileocolonic R/A and colostomy
22
4
Ileocolonic resection and ileostomy
6
Entire intestinal
Ileostomy/colostomy
3
Jejunum and transverse colon
Intestinal bypass, transverse colon R/A
1
Fistula Ileocutaneous*
80 Ileocecal R/A
28
Ileal R/A
6
Ileal resection and ileostomy
2
Rectovaginaly
Proximal colostomy
Ileovaginal
Ileocecal R/A and vaginal repair
6
Ileal resection and ileostomy
1
Rectovesicaly
Ileovesical*
Colocutaneous
Free perforation
17
Ileostomy
1
Fistula resection, colostomy, and bladder repair
2
Fistula resection, colostomy, and ileal neobladder
2
Fistula resection and colostomy
3
Ileocecal/ileal R/A and bladder repair
5
Ileocecal R/A and ileal neobladder
2
Fistula exclusion
2
Fistula resection and ileostomy
1
Fistula resection and colostomy
1
Fistula R/A
1
Resection and jejunostomy/colostomy
4 (continued)
Table 3 e (continued ) CRE type/location
Surgical procedures
Chronic radiation proctitis
Resection and colostomy Colostomy
No. of patients 6 14y
CRE ¼ chronic radiation enteritis; R/A ¼ resection and anastomosis. * Six patients with ileocutaneous and one patient with ileovesical had concomitant radiation proctitis, and all of them received additional colostomy. y Five patients (two with rectovaginal, two with rectovesical, and one with chronic radiation proctitis) were found radiation small bowel injury during operation and had ileal/ileocecal resection and anastomosis.
proctitis (including hematochezia and diarrhea), and free perforation. Table 3 shows the details of CRE lesion locations and surgical procedures. Small bowel was involved in 358 patients (88.61%), with end ileum and ileocecus being most likely injured by pelvic radiation. Three hundred sixty-three patients (89.85%) presented with a single digestive site of lesion, whereas 41 (10.15%) had multiple intestinal sites. For the patients involving only the small intestine, the median length of lesion was 40 cm (range: 5-250 cm). Concomitant radiation uropathy, such as ureter stenosis and radiation cystitis, occurred in 41 patients. Intestinal resection (with or without anastomosis) was performed in 351 patients (86.88%) during the first operation, and 202 of them had ileocecal resection. The remaining 53 patients (13.12%) received only conservative operations including diverting stomy (n ¼ 43), bypass (n ¼ 6), intestinal enterolysis (n ¼ 2), and fistula exclusion (n ¼ 2). Sixty-seven patients underwent laparoscopy, among whom 58 patients had primary clinical manifestations of intestinal obstruction; the remaining 337 patients underwent laparotomy, yet the intraoperative blood loss did not differ between the two groups (P ¼ 0.308). Emergency surgery was performed in five patients, four had intestinal perforation, and one had strangulated intestinal obstruction.
Short-term surgical outcomes The mean postoperative hospital stay was 17.83 16.62 d (range: 2-180 d), and it was significantly shorter in patients undergoing laparoscopic procedures (P ¼ 0.035). Postoperative SBS was observed in 82 patients (20.30%), of whom nine patients had residual small bowel less than 100 cm. Postoperative morbidity and mortality according to the Clavien-Dindo classification are summarized in Table 4. In total, 206 patients (50.99%) experienced adverse episodes after surgery, and 75 (18.56%) of them suffered major morbidity. Surgical complications,1 including anastomotic leak, external fistula, intra-abdominal abscess, postoperative obstruction, intra-abdominal hemorrhage, and postoperative peritonitis, occurred in 44 patients (10.89%). Particularly, among 192 patients who had ileocecal resection followed by anastomosis on
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Table 4 e Postoperative morbidity according to the Clavien-Dindo classification. Clavien-Dindo classification
No. of patients
Grade I
62 (15.35%)
Diarrhea
35
Incisional infection
21
Diarrhea and incisional infection
2
Uroschesis
2
Delayed gastric emptying
2
Grade II
69 (17.08%)
Catheter infection
15
Wound infection
11
Total parenteral nutrition
9
Infectious diarrhea
7
Urinary tract infection
7
Early postoperative obstruction
6
Pulmonary infection
4
Intra-abdominal infection
4
Cholecystitis
2
Other*
4
Grade III
62 (15.35%)
Cholestasis and biliary drainage
12
Pleural effusion and drainage
10
Anastomotic leak
9
Intra-abdominal hemorrhage
7
Intra-abdominal abscess
5
Seroperitoneum and drainage
4
Wound infection/dehiscence
4
Early postoperative obstruction and reoperation
4
Intestinal fistula
3
Urinary fistula
3
Gastrointestinal Hemorrhage
1
Grade IV
patients (2.72%) required relaparotomy for postoperative complications. Four patients (0.99%) died postoperatively: one died of uncontrolled septic shock due to an intestinal fistula, one died of severe pulmonary and respiratory failure, and the other two deaths were caused by multiple-organ dysfunction. All the deaths occurred in the resectional group but did not significantly differ from the conservative group (P ¼ 1.000).
Risk factors of postoperative morbidity Potential risk factors of postoperative morbidity analyzed using univariate analysis are listed in Table 5. Hypertension, American Association of Anesthesiologist scores of III and IV, remnant small bowel length <200 cm, intraoperative blood loss 200 mL, intraperitoneal adhesion grades III and IV, and preoperative C-reactive protein 8 mg/L contributed significantly to both overall and major morbidity. A higher Radiation Therapy Oncology Group/ETROC grade was also markedly related to a higher overall morbidity rate. In addition, history of ARE, preoperative platelet count <100 109/L, and total cholesterol < 3 mmol/L were associated with major complications, but patients with gynecologic malignancy demonstrated less major morbidity. Table 6 shows the results of multiple logistic regression analysis of risk factors, which revealed that hypertension and blood loss 200 mL during operation were two independent risk factors of overall and major morbidity. Postoperative SBS was independently related to overall complications as well. In addition, ARE and a low preoperative platelet count were found to be remarkable predictive factors of major morbidity independently.
Follow-up
9 (2.23%)
Respiratory failure
3
Anastomotic leak and acute kidney injury
1
Renal failure
1
Anastomotic leak, heart failure, and renal failure
1
Intra-abdominal infection, respiratory failure, and renal failure
1
Bleeding and ICU
1
Multiorgans dysfunction
1
Grade V
5
4 (0.99%)
ICU ¼ intensive care unit. * Including bacteremia, antibiotics allergy, and deep vein thrombus.
the ascending or transverse colon, only nine patients (4.69%) had anastomotic leak. Overall and major morbidity rates were comparable between laparoscopy and laparotomy. Moreover, although the overall morbidity rate was significantly higher in patients with intestinal resection than those without (P ¼ 0.038), no differences were detected in major morbidities (P ¼ 0.486) and surgical complications (P ¼ 0.715). Eleven
Of all the patients, 372 (92.08%) were followed up, with a median follow-up period of 42 mo. Death occurred in 25 patients during follow-up; of note, 20 patients died of tumor recurrence, three patients exhibiting symptoms of SBS died of PN-associated complications, and the remaining two patients’ deaths were caused by multiple-organ dysfunction as a result of late postoperative complications. During follow-up, surgery for recurrence of CRE after the first operation was performed in 22 patients, and seven of them previously underwent conservative procedure. The reasons necessitating reoperation were obstruction (n ¼ 13), fistula (n ¼ 7), and severe diarrhea or hemorrhage (n ¼ 2). The no-reoperation rate in patients with resection was significantly higher compared with nonresection ones (P ¼ 0.005, log-rank test; Figure). Moreover, nonresection was a possible risk factor of reoperation for CRE (13.21% versus 4.27%; P ¼ 0.016).
Discussion To our knowledge, this is the largest cohort study so far, reviewing surgical outcomes and risk factors of postoperative morbidity of CRE, which may help clinical physicians to both formulate targeted therapeutic regimens and improve
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Table 5 e Univariate analysis of the potential risk factors of postoperative morbidity. Variable
Overall morbidity P value
OR (95% CI)
Major morbidity P value
OR (95% CI)
Age (50/>50), y
0.414
d
0.674
d
Gender (M/F)
0.470
d
0.282
d
RTOG/ETROC grade (IV/III)
0.045
0.851
d
Gynecologic malignancy (Y/N)
0.411
d
0.040
0.582 (0.346-0.980)
Radiation dosage (<50/50), Gy
0.141
d
0.123
d
Endocavitary irradiation (Y/N)
0.421
d
0.399
d
Concomitant radiation uropathy (Y/N)
0.975
d
0.556
d
Chemotherapy (Y/N)
0.818
d
0.084
1.594 (0.936-1.731)
Intraperitoneal chemotherapy (Y/N)
0.330
d
1.000
d
History of ARE (Y/N)
0.224
d
0.015
1.879 (1.124-3.142)
Interval from RT to CRE onset (6/>6), mo
0.716
d
0.477
d d
1.645 (1.08-2.685)
Previous abdominopelvic surgery (Y/N)
0.763
d
0.712
Diabetes mellitus (Y/N)
0.091
2.970 (0.792-11.134)
0.864
d
Hypertension (Y/N)
0.007
2.985 (1.302-6.843)
0.041
2.256 (1.015-5.017)
Smoking history (Y/N)
0.077
1.877 (0.927-3.799)
0.616
d
ASA grade (III-IV/I-II)
0.004
1.812 (1.205-2.726)
0.023
1.788 (1.078-2.966)
Laparoscopic surgery (Y/N)
0.965
d
0.591
d
Staged surgery (Y/N)
0.265
d
0.255
d
2.841 (1.683-4.797)
0.031
1.861 (1.052-3.292)
d
0.332
d
<0.001
Remnant small bowel length (<200/200), cm Previous surgery for CRE (Y/N)
0.358 <0.001
2.773 (1.716-4.479)
<0.001
2.804 (1.652-4.759)
Intraperitoneal adhesion grade (III-IV/0-II)
0.006
1.871 (1.196-2.925)
0.007
2.041 (1.207-3.453)
Preoperative gastrointestinal decompression (Y/N)
0.895
d
0.423
d
Anastomotic fashion (side to side/end to side)
0.484
d
0.529
d
Stomy surgery (Y/N)
0.211
d
0.338
d
Intro-operative blood loss (200/<200), mL
Preoperative anemia (Y/N)
0.484
d
0.160
d
Preoperative platelet count (<100/100) 109/L
0.258
d
0.005
2.675 (1.321-5.416)
Preoperative serum albumin (<35/35), g/L
0.669
d
0.683
d
Preoperative CRP (8/<8), mg/L
0.087
1.467 (0.945-2.277)
0.062
1.799 (0.965-3.353)
0.073
1.534 (0.959-2.452)
0.041
1.773 (1.020-3.083)
0.273
d
0.861
d
Preoperative TC (<3/3), mmol/L 9
Preoperative lymphocyte count (<800/800) 10 /L
ARE ¼ acute radiation enteritis; ASA ¼ American Association of Anesthesiologist; CI ¼ confidence interval; CRE ¼ chronic radiation enteritis; CRP ¼ C-reactive protein; ETROC ¼ European Organization for Research and Treatment of Cancer; OR ¼ odds ratio; RT ¼ radiotherapy; RTOG ¼ Radiation Therapy Oncology Group; TC ¼ total cholesterol.
patients’ prognosis. Although some surgeons advocate conservative operation for CRE, owing to high rates of postoperative complications of resection,9 in our study, resection did not increase postoperative major morbidity, surgical complication, and mortality rates. This result is consistent with an earlier study showing no difference of operative morbidity between conservative and resectional methods.8 Onodera et al.13 evaluated surgical therapy for CRE and reported a surgical morbidity of 21.7% without anastomotic leakage occurrence in patients undergoing resection. Over the longer term, resection enabled patients to have a significantly lower cumulative reoperation rate and seemed to be a protective factor against CRE recurrence. Patients who undergo bypass or simple stomy instead of resection have increased risk of bleeding, fistula, occlusion, abscess formation, and
bacterial translocation because the diseased intestinal segment or a blind loop remains in the abdomen.8 These short- and long-term findings suggest that the goal of surgery for CRE should be to resect rather than conserve. Extensive resection can expose patients to a high risk of SBS, especially for those who have a large volume of bowel injured by radiation. However, because of poor blood supply to the irradiated bowel due to obliterative endarteritis, incomplete resection of radiation-injured intestine may cause devastating complications such as anastomotic leakage.14 However, the margin of injured intestine is difficult to identify, and in our study, it is currently determined by intraoperative gross examination of the serosa and mucosa of intestine. Moreover, the location of anastomosis also matters. Galland and Spencer15 reported a reduction of the
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Table 6 e Multivariable analysis of the potential risk factors of postoperative morbidity. Variable*
Overall morbidity
Major morbidity
P value
OR (95% CI)
P value
OR (95% CI)
RTOG/ETROC grade (IV/III)
0.281
d
d
d
Diabetes mellitus (Y/N)
0.186
d
d
d
Hypertension (Y/N)
0.011
3.222 (1.312-7.915)
0.046
2.490 (1.017-6.1010)
Smoking history (Y/N)
0.236
d
d
d
ASA grade (III-IV/I-II)
0.444
d
0.669
d
Remnant small bowel length (<200/200), cm
0.001
2.576 (1.482-4.475)
0.139
d
Intro-operative blood loss (200/<200), mL
0.002
2.222 (1.328-3.720)
0.006
2.235 (1.260-3.967)
Intraperitoneal adhesion grade (III-IV/0-II)
0.118
d
0.060
d
d
d
0.401
d
Gynecologic malignancy (Y/N) Chemotherapy (Y/N)
d
d
0.185
d
History of ARE (Y/N)
d
d
0.033
1.832 (1.048-3.200)
Preoperative platelet count (<100/100) 109/L
d
d
0.016
2.544 (1.191-5.434)
Preoperative CRP (8/<8), mg/L
0.076
d
0.078
d
Preoperative TC (<3/3), mmol/L
0.238
d
0.266
d
ARE ¼ acute radiation enteritis; ASA ¼ American Association of Anesthesiologist; CI ¼ confidence interval; CRP ¼ C-reactive protein; ETROC ¼ European Organization for Research and Treatment of Cancer; OR ¼ odds ratio; RTOG ¼ Radiation Therapy Oncology Group; TC ¼ total cholesterol. * Only the factors with P < 0.1 in the univariate analysis were included in multivariable analysis.
anastomotic leak rate from 50% to 7% after performing ileotransverse colon anastomosis because ascending and transverse colon were relatively free of radiation damage; this was further confirmed by Lefevre et al.1 Our results showed an anastomotic leak rate of 4.69% in patients who had ileocecal resection followed by anastomosis on the ascending or transverse colon. In addition, we found that remnant small intestine less than 200 cm was not an independent predictor of major morbidity. Thus, wide resection of all involved intestine and the use of healthy bowel margins for anastomosis
can promote better long-term outcomes, even with a short bowel.16 Another concern about resectional operation for CRE lies in the technical difficulties of dissecting the adherent intestine resulting from pathologic change of radiation. However, blunt dissection between the intestinal loop and the peritoneum has been demonstrated to be technically possible14 and was performed successfully in the majority of patients receiving resection in this study. In addition, our results revealed that the severity of adhesion was not independently related to
Figure e Reoperation for chronic radiation enteritis (CRE) in patients with or without resection during the first operation for CRE (P [ 0.005, log-rank test). 5.4.0 DTD YJSRE13794_proof 25 May 2016 9:08 pm ce
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postoperative morbidity. Therefore, resection for CRE should not be postponed even if adhesion exits. Sixty-seven patients have undergone laparoscopic surgery for CRE since 2012, and most of them had primary clinical manifestation of obstruction. Fistula and free perforation usually need peritoneal lavage and drainage during operation, especially when complicated with extensive intestinal inflammation or intra-abdominal abscess; thus, they are not recommended for laparoscopy. We found that a laparoscopic procedure did not increase overall and major morbidity but shortened the postoperative hospital stay. Yet, no decreased intraoperative blood loss was observed in laparoscopy, which may due to the strong adhesion in some cases in which conversion to laparotomy is necessary.17 According to our previous study, the presence of strong adhesion beneath the anterior abdominal wall is regarded as a relative contraindication to laparoscopy because it can affect the visual field and the pneumoperitoneum.10 Moreover, because of the high risk of organ injury, grade IV adhesion is considered an absolute contraindication to laparoscopic surgery. In this case, a preoperative computed tomography scan is necessary for adhesion assessment. As reported by Turina et al., the incidence of SBS was nearly 10% after surgical intervention for CRE-related bowel obstruction.18 A higher rate of 19% was detected at the end of follow-up for CRE patients from an earlier study,8 which was similar to our results, with an SBS rate of 20.30%. In the present study, postoperative SBS was demonstrated as an independent risk factor of overall, but not major, morbidity after surgery. This can be explained by malnutrition and diarrhea due to reduced absorptive area, rapid bowel transit, and loss of terminal ileum,5 which lead to a poor general condition and slower recovery. Furthermore, routine requirement of PN in SBS patients results in catheter-related bloodstream infection, as well as increases the rate of TPN over 2 wk postoperatively. For these patients, a comprehensive treatment including antisecretion, nutrition support, and intestinal rehabilitation is necessary. Intraoperative blood loss contributed independently to overall and major morbidity. Although intraoperative transfusion has been detected as an independent predictor of complications after surgery for CRE,19 we were unable to evaluate this factor because of the lack of complete records. Despite this, the necessity of transfusion is closely associated with intraoperative blood loss. In a study of 305 patients with hepatectomy, those who suffered postoperative complications had significantly larger intraoperative blood loss, with a cutoff of 800 mL.20 Increased blood loss during surgery may indicate aggravated hypoperfusion of organs, such as the intestinal tract, which could increase postoperative complications.21 Because blood loss during an operation is a surgeoncontrolled factor and surgery for CRE is technically demanding, experienced surgeons are required and doctors with less experience should operate on highly selective patients. Hypertension and history of ARE were demonstrated as two independent indicators associated with major morbidity. Because these two factors are patient related and can hardly be controlled by surgeons, consequently, more careful perioperative management and particular attention are required
for those patients who have hypertension or have ever undergone ARE, to avoid postoperative complications or immediately discover and resolve them. Of all the blood test parameters considered in this study, thrombocytopenia, which may result from bone marrow suppression caused by radiotherapy, was the only independent risk factor identified for major morbidity. A lower preoperative platelet count was confirmed to be independently associated with increased major complications in resection of hepatocellular carcinoma.22 In the category of critically ill patients, persistent thrombocytopenia brought about poorer outcome as well.23 Patients who required emergent surgery 90 d after irradiation sustained increased morbidity and mortality, and death was independently related to thrombocytopenia.24 Accordingly, timing of surgery for CRE patients with a low platelet count should be decided based on some considerations, such as after correction of thrombocytopenia and optimization of the nutritional status. Meanwhile, a staged operation could be taken into consideration when necessary.
Conclusions Among all the surgical procedures, resection is recommended for its acceptable postoperative morbidity and better longterm outcome with a low reoperation rate. Use of laparoscopy is feasible in selective CRE patients without strong adhesion or fistula but requires more clinical experience. Particular attention should be paid to those patients with a history of ARE to effectively avoid postoperative morbidity or detect and manage such morbidity without delay. Correction of preoperative thrombocytopenia, reducing blood loss during operation, and careful perioperative management of hypertensive patients can also improve the outcomes of surgery for CRE.
Acknowledgment Authors’ contributions: Y.H. designed the study, collected and analyzed the data, and wrote the article. F.G. collected and analyzed the data. D.Y. collected the data. Y.L. and J.L. designed the study and critically revised the article. The authors declare that they have no sources of funding for this article.
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
1. Lefevre JH, Amiot A, Joly F, Bretagnol F, Panis Y. Risk of recurrence after surgery for chronic radiation enteritis. Br J Surg. 2011;98:1792e1797.
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2. Andreyev HJ. Gastrointestinal problems after pelvic radiotherapy: the past, the present and the future. Clin Oncol. 2007;19:790e799. 3. Theis VS, Sripadam R, Ramani V, Lal S. Chronic radiation enteritis. Clin Oncol. 2010;22:70e83. 4. Harb AH, Abou Fadel C, Sharara AI. Radiation enteritis. Curr Gastroenterol Rep. 2014;16:383. 5. Webb GJ, Brooke R, De Silva AN. Chronic radiation enteritis and malnutrition. J Dig Dis. 2013;14:350e357. 6. MacNaughton WK. Review article: new insights into the pathogenesis of radiation-induced intestinal dysfunction. Aliment Pharmacol Ther. 2000;14:523e528. 7. Scolapio JS, Ukleja A, Burnes JU, Kelly DG. Outcome of patients with radiation enteritis treated with home parenteral nutrition. Am J Gastroenterol. 2002;97:662e666. 8. Regimbeau JM, Panis Y, Gouzi JL, Fagniez PL. Operative and long term results after surgery for chronic radiation enteritis. Am J Surg. 2001;182:237e242. 9. Smith DH, DeCosse JJ. Radiation damage to the small intestine. World J Surg. 1986;10:189e194. 10. Wang J, Yao D, Zhang S, Mao Q, Li Y, Li J. Laparoscopic surgery for radiation enteritis. J Surg Res. 2015;194:415e419. 11. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205e213. 12. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the radiation therapy Oncology group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31:1341e1346. 13. Onodera H, Nagayama S, Mori A, Fujimoto A, Tachibana T, Yonenaga Y. Reappraisal of surgical treatment for radiation enteritis. World J Surg. 2005;29:459e463. 14. Zhu W, Gong J, Li Y, Li N, Li J. A retrospective study of surgical treatment of chronic enteritis. J Surg Oncol. 2012;105:632e636.
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15. Galland RB, Spencer J. Surgical management of radiation enteritis. Surgery. 1986;99:133e139. 16. Amiot A, Joly F, Lefevre JH, et al. Long-term outcome after extensive intestinal resection for chronic radiation enteritis. Dig Liver Dis. 2013;45:110e114. 17. van Goor H. Consequences and complications of peritoneal adhesions. Colorectal Dis. 2007;9:25e34. 18. Turina M, Mulhall AM, Mahid SS, Yashar C, Galandiuk S. Frequency and surgical management of chronic complications related to pelvic radiation. Arch Surg. 2008;143:46e52. 19. Li N, Zhu W, Gong J, et al. Ileal or ileocecal resection for chronic radiation enteritis with small bowel obstruction: outcome and risk factors. Am J Surg. 2013;206:739e747. 20. Yang T, Zhang J, Lu J, Yang G, Wu M, Yu W. Risk factors influencing postoperative outcomes of major hepatic resection of hepatocellular carcinoma for patients with underlying liver diseases. World J Surg. 2011;35:2073e2082. 21. Li B, Xia Z, Li C, Liu W, Wen S, Liu K. The incidence and risk factors of gastrointestinal complications after hepatectomy: a retrospective observational study of 1329 consecutive patients in a single center. J Surg Res. 2014;192:440e446. 22. Maithel SK, Kneuertz PJ, Kooby DA, et al. Importance of low preoperative platelet count in selecting patients for resection of hepatocellular carcinoma: a multi-institutional analysis. J Am Coll Surg. 2011;212:638e648. 23. Wu Q, Ren J, Wang G, et al. Effect of persistent thrombocytopenia on mortality in surgical critical care patients: a retrospective study. Clin Appl Thromb Hemost. 2015 [Epub ahead of print]. Q3 24. Sullivan MC, Roman SA, Sosa JA. Emergency surgery in patients who have undergone recent radiotherapy is associated with increased complications and mortality: review of 536 patients. World J Surg. 2012;36:31e38.
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Available online at www.sciencedirect.com
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Surgery for chronic radiation enteritis: outcome and risk factors Yuhua Huang, MD, Feilong Guo, MD, Danhua Yao, MD, PhD, Yousheng Li, MD, PhD,* and Jieshou Li, MD Department of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
article info
abstract
Article history:
Background: Surgery is required in approximately one-third of patients with chronic radi-
Received 5 January 2016
ation enteritis (CRE). The aim of this study was to explore the short- and long-term out-
Received in revised form
comes after surgery for CRE and risk factors of postoperative morbidity.
9 March 2016
Methods: Clinical features and surgical outcomes of patients undergoing surgery for CRE
Accepted 6 May 2016
were retrospectively reviewed. Risk factors of postoperative morbidity were analyzed
Available online xxx
using univariate and multivariate analysis. Survival and reoperation rates for CRE were evaluated.
Keywords:
Results: Among the 404 patients included, 351 patients (86.88%) received resectional sur-
Chronic radiation enteritis
gery, whereas the remaining patients received conservative procedures. No differences
Outcome
were detected between patients with resection and those without resection with regard to
Risk factor
major morbidity (P ¼ 0.486) and surgical complications (P ¼ 0.715). Laparoscopy resulted in
Postoperative morbidity
a shorter postoperative hospital stay (P ¼ 0.035). After multivariate analysis, history of hypertension (odds ratio [OR] ¼ 2.490; P ¼ 0.046), previous acute radiation enteritis (OR ¼ 1.832; P ¼ 0.033), intraoperative blood loss of more than 200 mL (OR ¼ 2.235; P ¼ 0.006), and thrombocytopenia (OR ¼ 2.544; P ¼ 0.016) were determined as independent predictors of postoperative major morbidity. During follow-up, 22 patients required reoperation for CRE recurrence, and the reoperation rate was significantly lower in patients receiving resectional surgery (P ¼ 0.005). Conclusions: Resection is feasible for CRE with acceptable postoperative morbidity and lower reoperation rate. Correction of preoperative thrombocytopenia, minimizing intraoperative blood loss, and close monitoring of hypertensive patients and those with history of acute radiation enteritis are critical to reduce postoperative complications. ª 2016 Elsevier Inc. All rights reserved.
Introduction Chronic radiation enteritis (CRE) is a common complication faced by patients who have received radiotherapy for abdominal and pelvic malignancies. An estimated incidence of CRE has been reported to be 5%-55%, depending on the symptoms and definition of CRE1 and number of patients
seeking medical care. Owing to the wider use of radiotherapy and improved life expectancy of patients with cancer, the incidence of CRE has increased.2 Factors that play a role in the risk of developing radiation-induced intestinal damage include radiation dose, previous abdominal surgery, body mass index, diabetes mellitus, hypertension, and concurrent chemotherapy.3
* Corresponding author. Department of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China. Tel.: þ86-25-80860137; fax: þ86-25-8480396. E-mail address: [email protected] (Y. Li). 0022-4804/$ e see front matter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2016.05.014
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131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195
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CRE may develop as early as 2 mo or as long as 30 y after exposure to radiation,4 with various clinical manifestations including abdominal pain, diarrhea, rectal bleeding, malabsorption, intestinal obstruction, external fistula, and perforation.5 The characterized pathologic changes of CRE are obliterative endarteritis and fibrosis of absorptive epithelium.6 Therapeutic regimens for CRE have been controversial for decades. Home parenteral nutrition (PN) was proposed for CRE by physicians, due to the extreme difficulty and high risk of complications of surgical treatment.7 However, approximately one-third of the patients with CRE need to be operated on during follow-up,8 but there is no agreement as yet on the best surgical method for CRE. To avoid postoperative complications, some surgeons prefer conservative surgery without resection of radiation-injured lesion by bypass or simple stomy,9 whereas others suggest radical resection of diseased intestinal segments to avoid recurrence of CRE. Yet, subjects of previous studies are no more than 200, and limited large cohort research has been conducted regarding the surgical outcomes of patients with CRE and risk factors of early postoperative complications. The present study aimed to evaluate the short- and longterm outcomes of surgical treatment of CRE and to identify potential risk factors of postoperative morbidity.
Grading system The severity of intraperitoneal adhesion was graded from 0 to IV, according to an adhesion grade system specific for CRE10: grade 0 meant no adhesion between the affected intestinal lesions and surrounding organs; grade I indicated adhesion and fibrosis limited to the right or left pelvis, whereas grade II was defined as strong adhesion and fibrosis affecting the whole pelvis; grade III referred to grade II adhesion extending between the intestine and anterior pelvic wall, and grade IV referred to grade III adhesion extending between the intestine and anterior abdominal wall. The grading of postoperative morbidity was in accordance with the Clavien-Dindo classification,11 which was based on the therapeutic consequences of complications. Morbidity was graded ranging from I to V, with grade III or greater being considered as major morbidity. In addition, postoperative total parenteral nutrition (TPN) over 2 wk was regarded as grade II morbidity on the basis of the Clavien-Dindo classification. For patients who underwent staged surgery, the morbidity rate was calculated as the total episodes of two procedures. The Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema12 was used for the assessment of severity of CRE. Essentially, obstruction and bleeding requiring surgery belonged to grade III, whereas fistula and perforation were grouped under grade IV.
Patients and methods
Follow-up
Study patients
Patients were followed up until death or the start of data collection on June 2015. In addition, patients’ survival status and causes of death were noted by reviewing medical records and telephone follow-up. The reoperation for recurrence of CRE was recorded, and associated factors were analyzed.
A consecutive series of adult patients receiving surgical management for CRE in our department specializing in gastrointestinal surgery between January 2005 and June 2015 were retrospectively reviewed. Patients with tumor recurrence were excluded. The ethics committee of Jinling Hospital approved this study. Demographic and clinical information, including primary malignancy, details of radiotherapy (radiation type and cumulative radiation dosage), clinical manifestations, interval from completion of radiotherapy to symptom onset, American Association of Anesthesiologist score, preoperative nutrition support, intraperitoneal adhesion grade, intraoperative blood loss, residual small bowel length, and postoperative morbidity, mortality, and hospital stay were extracted from a prospective medical database. In this study, acute radiation enteritis (ARE) referred to symptoms, such as diarrhea and abdominal pain, presented shortly after a course of radiotherapy and resolved spontaneously over 2-12 wk,3 whereas CRE developed 6 mo after the completion of irradiation. Postoperative short bowel syndrome (SBS) was defined as the length of remnant small intestine less than 200 cm. Only the first postoperative hospital stay was recorded if a patient had staged surgery. The most recent preoperative blood test, including serum albumin, platelet and lymphocyte count, hemoglobin, C-reactive protein, and total cholesterol, was also reviewed. Some of the above-mentioned parameters were analyzed to discover possible risk factors of postoperative complications.
Statistical analysis Continuous variables were compared using Mann-Whitney U test or Student’s t test, as appropriate. Pearson’s chisquare test or Fisher’s exact test was performed for univariate analysis of risk factors of postoperative morbidity. All factors with P < 0.1 in the univariate analysis were further evaluated by multivariate analysis using multiple logistic regression. The reoperation rate was analyzed using KaplanMeier method and compared using log-rank test. Results with a two tailed P < 0.05 were accepted as statistically significant. All analyses were performed using SPSS version 19.0 (IBM Analytics, Armonk, NY, USA).
Results Patient characteristics A cohort of 404 adult patients comprising 310 females and 94 males were included in the present study. The characteristics of these patients are listed in Table 1. Gynecologic and rectum carcinoma were two main primary malignancies. The majority of the patients (n ¼ 331, 81.93%) received radiotherapy after
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261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325
Table 1 e Demographic and clinical characteristics. Variable
Values
Gender (M/F)
94/310
Age (y)*
50.85 10.48 (23-76)
Primary malignancy Gynecologic (cervix, ovary, endometrium, vagina, and tubal)
282 (69.80)
Table 2 e Perioperative status of 404 patients with chronic radiation enteritis. Variable
ASA II
251 (62.13)
ASA III
133 (32.92)
ASA IV
Rectum
94 (23.27)
Preoperative intestinal decompression
Colon
11 (2.72)
Preoperative nutrition supporty
Testis
8 (1.98)
None
Others (kidney, bladder, small intestinal, and so forth)
9 (2.23)
TPN dependence
Cumulative radiation dosage (Gy)*,y
52.47 14.64 (10.8-128)
Radiation therapy
No. of patients
Preoperative ASA grade
20 (4.95) 131 (43.67)*
46 (11.39) 209 (51.73)
EN
84 (20.79)
PN þ EN
57 (14.11)
Operative strategy
Preoperative
7 (1.73)
Postoperative
331 (81.93)
Laparoscopic surgery
67 (16.58)
5 (1.24)
One-stage operation
369 (91.34)
Two-stage operation
35 (8.66)
Preoperative and postoperative Radical irradiation
61 (15.10)
Endocavitary irradiation
61(15.10)
Chemotherapy
239 (59.16)
Interval from RT to CRE onset (mo) 12
*
19.52 34.58 (1-288) 291 (72.03)
12-24
55 (13.61)
>24
58 (14.36)
BMI on admission (kg/m2)
Open surgery
Intraoperative blood loss (mL) <100
215 (53.22)
18.5
189 (46.78)
144 (35.64)
200
101 (25.00)
Intraperitoneal adhesion grade None (0)
Severe (3-4)
Hypertensionz
31 (7.67)
Postoperative hospital stay (d, mean SD, range)
Diabetes mellitusz
12 (3.00)
Postoperative small bowel length (cm)
History of ARE
130 (32.18)
Previous abdominopelvic surgery
80 (19.80)
ARE ¼ acute radiation enteritis; BMI ¼ body mass index; CRE ¼ chronic radiation enteritis; RT ¼ radiotherapy. Values are number of patients (percentage), unless noted otherwise. * Values are mean standard deviation and (range). y Radiation dosage was unknown in 45 patients. z Patients have a history of hypertension or diabetes mellitus and need drugs to control blood pressure or blood glucose preoperatively.
resection of the primary tumor, and 61 patients (15.10%) had radical irradiation without surgery. Total radiation dosage was acquired in 359 patients (88.86%), with a mean dose of 52.47 14.64 Gy (range: 10.8128 Gy). The mean interval from the completion of radiotherapy to onset of digestive symptoms was 19.52 34.58 mo (range: 1-288 mo). A total of 130 patients (32.18%) had ARE, of whom 31 evolved from ARE to CRE directly without a symptom-free interval.
159 (39.36)
100-200
Moderate (1-2)
<18.5
337 (83.42)
200
23 (5.69) 244 (60.40) 137 (33.91) 17.83 16.62 (2-180)
322 (79.70)
150-200
46 (11.39)
100-150
27 (6.68)
<100
9 (2.23)
ASA ¼ American Association of Anesthesiologist; EN ¼ enteral nutrition; PN ¼ parenteral nutrition; SD ¼ standard deviation; TPN ¼ total parenteral nutrition. Values are number of patients (percentage). * Only patients with obstruction were included for calculation. y Preoperative nutrition support was unclear in eight patients.
gastrostomy/jejunostomy (PEG/J) or a long small bowel decompression tube. The majority of the patients (n ¼ 350, 86.63%) had nutrition support before surgery, and more than half of them were TPN dependent because of complete intestinal obstruction at presentation. Enteral nutrition therapy was preferred for those without obstruction and attempted after small bowel depression in patients with obstruction. If patients had poor enteral nutrition tolerance or insufficient energy intake, PN would be instituted to meet the nutrition requirement.
Preoperative status Clinical features and surgical procedures Table 2 presents the preoperative parameters in detail. Small intestinal decompression was performed in 131 patients with intestinal obstruction using percutaneous endoscopic
Symptomatic intestinal obstruction was the main etiology for surgery (n ¼ 300, 74.26%), followed by fistula, severe radiation
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326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390
4
391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455
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Table 3 e Details of chronic radiation enteritis lesion location/type and surgical procedures. CRE type/location
Surgical procedures
Obstruction Ileum/ileocecal
No. of patients 300
Ileocecal R/A
139
Ileal R/A
91
Ileal resection and ileostomy
14
Ileocecal resection and ileostomy
6
Ileostomy/colostomy
7
Bypass
5
Intestinal enterolysis
2
Rectosigmoid
Colostomy
Ileum and rectosigmoid
Ileocolonic R/A and colostomy
22
4
Ileocolonic resection and ileostomy
6
Entire intestinal
Ileostomy/colostomy
3
Jejunum and transverse colon
Intestinal bypass, transverse colon R/A
1
Fistula Ileocutaneous*
80 Ileocecal R/A
28
Ileal R/A
6
Ileal resection and ileostomy
2
Rectovaginaly
Proximal colostomy
Ileovaginal
Ileocecal R/A and vaginal repair
6
Ileal resection and ileostomy
1
Rectovesicaly
Ileovesical*
Colocutaneous
Free perforation
17
Ileostomy
1
Fistula resection, colostomy, and bladder repair
2
Fistula resection, colostomy, and ileal neobladder
2
Fistula resection and colostomy
3
Ileocecal/ileal R/A and bladder repair
5
Ileocecal R/A and ileal neobladder
2
Fistula exclusion
2
Fistula resection and ileostomy
1
Fistula resection and colostomy
1
Fistula R/A
1
Resection and jejunostomy/colostomy
4 (continued)
Table 3 e (continued ) CRE type/location
Surgical procedures
Chronic radiation proctitis
Resection and colostomy Colostomy
No. of patients 6 14y
CRE ¼ chronic radiation enteritis; R/A ¼ resection and anastomosis. * Six patients with ileocutaneous and one patient with ileovesical had concomitant radiation proctitis, and all of them received additional colostomy. y Five patients (two with rectovaginal, two with rectovesical, and one with chronic radiation proctitis) were found radiation small bowel injury during operation and had ileal/ileocecal resection and anastomosis.
proctitis (including hematochezia and diarrhea), and free perforation. Table 3 shows the details of CRE lesion locations and surgical procedures. Small bowel was involved in 358 patients (88.61%), with end ileum and ileocecus being most likely injured by pelvic radiation. Three hundred sixty-three patients (89.85%) presented with a single digestive site of lesion, whereas 41 (10.15%) had multiple intestinal sites. For the patients involving only the small intestine, the median length of lesion was 40 cm (range: 5-250 cm). Concomitant radiation uropathy, such as ureter stenosis and radiation cystitis, occurred in 41 patients. Intestinal resection (with or without anastomosis) was performed in 351 patients (86.88%) during the first operation, and 202 of them had ileocecal resection. The remaining 53 patients (13.12%) received only conservative operations including diverting stomy (n ¼ 43), bypass (n ¼ 6), intestinal enterolysis (n ¼ 2), and fistula exclusion (n ¼ 2). Sixty-seven patients underwent laparoscopy, among whom 58 patients had primary clinical manifestations of intestinal obstruction; the remaining 337 patients underwent laparotomy, yet the intraoperative blood loss did not differ between the two groups (P ¼ 0.308). Emergency surgery was performed in five patients, four had intestinal perforation, and one had strangulated intestinal obstruction.
Short-term surgical outcomes The mean postoperative hospital stay was 17.83 16.62 d (range: 2-180 d), and it was significantly shorter in patients undergoing laparoscopic procedures (P ¼ 0.035). Postoperative SBS was observed in 82 patients (20.30%), of whom nine patients had residual small bowel less than 100 cm. Postoperative morbidity and mortality according to the Clavien-Dindo classification are summarized in Table 4. In total, 206 patients (50.99%) experienced adverse episodes after surgery, and 75 (18.56%) of them suffered major morbidity. Surgical complications,1 including anastomotic leak, external fistula, intra-abdominal abscess, postoperative obstruction, intra-abdominal hemorrhage, and postoperative peritonitis, occurred in 44 patients (10.89%). Particularly, among 192 patients who had ileocecal resection followed by anastomosis on
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Table 4 e Postoperative morbidity according to the Clavien-Dindo classification. Clavien-Dindo classification
No. of patients
Grade I
62 (15.35%)
Diarrhea
35
Incisional infection
21
Diarrhea and incisional infection
2
Uroschesis
2
Delayed gastric emptying
2
Grade II
69 (17.08%)
Catheter infection
15
Wound infection
11
Total parenteral nutrition
9
Infectious diarrhea
7
Urinary tract infection
7
Early postoperative obstruction
6
Pulmonary infection
4
Intra-abdominal infection
4
Cholecystitis
2
Other*
4
Grade III
62 (15.35%)
Cholestasis and biliary drainage
12
Pleural effusion and drainage
10
Anastomotic leak
9
Intra-abdominal hemorrhage
7
Intra-abdominal abscess
5
Seroperitoneum and drainage
4
Wound infection/dehiscence
4
Early postoperative obstruction and reoperation
4
Intestinal fistula
3
Urinary fistula
3
Gastrointestinal Hemorrhage
1
Grade IV
patients (2.72%) required relaparotomy for postoperative complications. Four patients (0.99%) died postoperatively: one died of uncontrolled septic shock due to an intestinal fistula, one died of severe pulmonary and respiratory failure, and the other two deaths were caused by multiple-organ dysfunction. All the deaths occurred in the resectional group but did not significantly differ from the conservative group (P ¼ 1.000).
Risk factors of postoperative morbidity Potential risk factors of postoperative morbidity analyzed using univariate analysis are listed in Table 5. Hypertension, American Association of Anesthesiologist scores of III and IV, remnant small bowel length <200 cm, intraoperative blood loss 200 mL, intraperitoneal adhesion grades III and IV, and preoperative C-reactive protein 8 mg/L contributed significantly to both overall and major morbidity. A higher Radiation Therapy Oncology Group/ETROC grade was also markedly related to a higher overall morbidity rate. In addition, history of ARE, preoperative platelet count <100 109/L, and total cholesterol < 3 mmol/L were associated with major complications, but patients with gynecologic malignancy demonstrated less major morbidity. Table 6 shows the results of multiple logistic regression analysis of risk factors, which revealed that hypertension and blood loss 200 mL during operation were two independent risk factors of overall and major morbidity. Postoperative SBS was independently related to overall complications as well. In addition, ARE and a low preoperative platelet count were found to be remarkable predictive factors of major morbidity independently.
Follow-up
9 (2.23%)
Respiratory failure
3
Anastomotic leak and acute kidney injury
1
Renal failure
1
Anastomotic leak, heart failure, and renal failure
1
Intra-abdominal infection, respiratory failure, and renal failure
1
Bleeding and ICU
1
Multiorgans dysfunction
1
Grade V
5
4 (0.99%)
ICU ¼ intensive care unit. * Including bacteremia, antibiotics allergy, and deep vein thrombus.
the ascending or transverse colon, only nine patients (4.69%) had anastomotic leak. Overall and major morbidity rates were comparable between laparoscopy and laparotomy. Moreover, although the overall morbidity rate was significantly higher in patients with intestinal resection than those without (P ¼ 0.038), no differences were detected in major morbidities (P ¼ 0.486) and surgical complications (P ¼ 0.715). Eleven
Of all the patients, 372 (92.08%) were followed up, with a median follow-up period of 42 mo. Death occurred in 25 patients during follow-up; of note, 20 patients died of tumor recurrence, three patients exhibiting symptoms of SBS died of PN-associated complications, and the remaining two patients’ deaths were caused by multiple-organ dysfunction as a result of late postoperative complications. During follow-up, surgery for recurrence of CRE after the first operation was performed in 22 patients, and seven of them previously underwent conservative procedure. The reasons necessitating reoperation were obstruction (n ¼ 13), fistula (n ¼ 7), and severe diarrhea or hemorrhage (n ¼ 2). The no-reoperation rate in patients with resection was significantly higher compared with nonresection ones (P ¼ 0.005, log-rank test; Figure). Moreover, nonresection was a possible risk factor of reoperation for CRE (13.21% versus 4.27%; P ¼ 0.016).
Discussion To our knowledge, this is the largest cohort study so far, reviewing surgical outcomes and risk factors of postoperative morbidity of CRE, which may help clinical physicians to both formulate targeted therapeutic regimens and improve
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Table 5 e Univariate analysis of the potential risk factors of postoperative morbidity. Variable
Overall morbidity P value
OR (95% CI)
Major morbidity P value
OR (95% CI)
Age (50/>50), y
0.414
d
0.674
d
Gender (M/F)
0.470
d
0.282
d
RTOG/ETROC grade (IV/III)
0.045
0.851
d
Gynecologic malignancy (Y/N)
0.411
d
0.040
0.582 (0.346-0.980)
Radiation dosage (<50/50), Gy
0.141
d
0.123
d
Endocavitary irradiation (Y/N)
0.421
d
0.399
d
Concomitant radiation uropathy (Y/N)
0.975
d
0.556
d
Chemotherapy (Y/N)
0.818
d
0.084
1.594 (0.936-1.731)
Intraperitoneal chemotherapy (Y/N)
0.330
d
1.000
d
History of ARE (Y/N)
0.224
d
0.015
1.879 (1.124-3.142)
Interval from RT to CRE onset (6/>6), mo
0.716
d
0.477
d d
1.645 (1.08-2.685)
Previous abdominopelvic surgery (Y/N)
0.763
d
0.712
Diabetes mellitus (Y/N)
0.091
2.970 (0.792-11.134)
0.864
d
Hypertension (Y/N)
0.007
2.985 (1.302-6.843)
0.041
2.256 (1.015-5.017)
Smoking history (Y/N)
0.077
1.877 (0.927-3.799)
0.616
d
ASA grade (III-IV/I-II)
0.004
1.812 (1.205-2.726)
0.023
1.788 (1.078-2.966)
Laparoscopic surgery (Y/N)
0.965
d
0.591
d
Staged surgery (Y/N)
0.265
d
0.255
d
2.841 (1.683-4.797)
0.031
1.861 (1.052-3.292)
d
0.332
d
<0.001
Remnant small bowel length (<200/200), cm Previous surgery for CRE (Y/N)
0.358 <0.001
2.773 (1.716-4.479)
<0.001
2.804 (1.652-4.759)
Intraperitoneal adhesion grade (III-IV/0-II)
0.006
1.871 (1.196-2.925)
0.007
2.041 (1.207-3.453)
Preoperative gastrointestinal decompression (Y/N)
0.895
d
0.423
d
Anastomotic fashion (side to side/end to side)
0.484
d
0.529
d
Stomy surgery (Y/N)
0.211
d
0.338
d
Intro-operative blood loss (200/<200), mL
Preoperative anemia (Y/N)
0.484
d
0.160
d
Preoperative platelet count (<100/100) 109/L
0.258
d
0.005
2.675 (1.321-5.416)
Preoperative serum albumin (<35/35), g/L
0.669
d
0.683
d
Preoperative CRP (8/<8), mg/L
0.087
1.467 (0.945-2.277)
0.062
1.799 (0.965-3.353)
0.073
1.534 (0.959-2.452)
0.041
1.773 (1.020-3.083)
0.273
d
0.861
d
Preoperative TC (<3/3), mmol/L 9
Preoperative lymphocyte count (<800/800) 10 /L
ARE ¼ acute radiation enteritis; ASA ¼ American Association of Anesthesiologist; CI ¼ confidence interval; CRE ¼ chronic radiation enteritis; CRP ¼ C-reactive protein; ETROC ¼ European Organization for Research and Treatment of Cancer; OR ¼ odds ratio; RT ¼ radiotherapy; RTOG ¼ Radiation Therapy Oncology Group; TC ¼ total cholesterol.
patients’ prognosis. Although some surgeons advocate conservative operation for CRE, owing to high rates of postoperative complications of resection,9 in our study, resection did not increase postoperative major morbidity, surgical complication, and mortality rates. This result is consistent with an earlier study showing no difference of operative morbidity between conservative and resectional methods.8 Onodera et al.13 evaluated surgical therapy for CRE and reported a surgical morbidity of 21.7% without anastomotic leakage occurrence in patients undergoing resection. Over the longer term, resection enabled patients to have a significantly lower cumulative reoperation rate and seemed to be a protective factor against CRE recurrence. Patients who undergo bypass or simple stomy instead of resection have increased risk of bleeding, fistula, occlusion, abscess formation, and
bacterial translocation because the diseased intestinal segment or a blind loop remains in the abdomen.8 These short- and long-term findings suggest that the goal of surgery for CRE should be to resect rather than conserve. Extensive resection can expose patients to a high risk of SBS, especially for those who have a large volume of bowel injured by radiation. However, because of poor blood supply to the irradiated bowel due to obliterative endarteritis, incomplete resection of radiation-injured intestine may cause devastating complications such as anastomotic leakage.14 However, the margin of injured intestine is difficult to identify, and in our study, it is currently determined by intraoperative gross examination of the serosa and mucosa of intestine. Moreover, the location of anastomosis also matters. Galland and Spencer15 reported a reduction of the
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Table 6 e Multivariable analysis of the potential risk factors of postoperative morbidity. Variable*
Overall morbidity
Major morbidity
P value
OR (95% CI)
P value
OR (95% CI)
RTOG/ETROC grade (IV/III)
0.281
d
d
d
Diabetes mellitus (Y/N)
0.186
d
d
d
Hypertension (Y/N)
0.011
3.222 (1.312-7.915)
0.046
2.490 (1.017-6.1010)
Smoking history (Y/N)
0.236
d
d
d
ASA grade (III-IV/I-II)
0.444
d
0.669
d
Remnant small bowel length (<200/200), cm
0.001
2.576 (1.482-4.475)
0.139
d
Intro-operative blood loss (200/<200), mL
0.002
2.222 (1.328-3.720)
0.006
2.235 (1.260-3.967)
Intraperitoneal adhesion grade (III-IV/0-II)
0.118
d
0.060
d
d
d
0.401
d
Gynecologic malignancy (Y/N) Chemotherapy (Y/N)
d
d
0.185
d
History of ARE (Y/N)
d
d
0.033
1.832 (1.048-3.200)
Preoperative platelet count (<100/100) 109/L
d
d
0.016
2.544 (1.191-5.434)
Preoperative CRP (8/<8), mg/L
0.076
d
0.078
d
Preoperative TC (<3/3), mmol/L
0.238
d
0.266
d
ARE ¼ acute radiation enteritis; ASA ¼ American Association of Anesthesiologist; CI ¼ confidence interval; CRP ¼ C-reactive protein; ETROC ¼ European Organization for Research and Treatment of Cancer; OR ¼ odds ratio; RTOG ¼ Radiation Therapy Oncology Group; TC ¼ total cholesterol. * Only the factors with P < 0.1 in the univariate analysis were included in multivariable analysis.
anastomotic leak rate from 50% to 7% after performing ileotransverse colon anastomosis because ascending and transverse colon were relatively free of radiation damage; this was further confirmed by Lefevre et al.1 Our results showed an anastomotic leak rate of 4.69% in patients who had ileocecal resection followed by anastomosis on the ascending or transverse colon. In addition, we found that remnant small intestine less than 200 cm was not an independent predictor of major morbidity. Thus, wide resection of all involved intestine and the use of healthy bowel margins for anastomosis
can promote better long-term outcomes, even with a short bowel.16 Another concern about resectional operation for CRE lies in the technical difficulties of dissecting the adherent intestine resulting from pathologic change of radiation. However, blunt dissection between the intestinal loop and the peritoneum has been demonstrated to be technically possible14 and was performed successfully in the majority of patients receiving resection in this study. In addition, our results revealed that the severity of adhesion was not independently related to
Figure e Reoperation for chronic radiation enteritis (CRE) in patients with or without resection during the first operation for CRE (P [ 0.005, log-rank test). 5.4.0 DTD YJSRE13794_proof 25 May 2016 9:08 pm ce
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8
911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975
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postoperative morbidity. Therefore, resection for CRE should not be postponed even if adhesion exits. Sixty-seven patients have undergone laparoscopic surgery for CRE since 2012, and most of them had primary clinical manifestation of obstruction. Fistula and free perforation usually need peritoneal lavage and drainage during operation, especially when complicated with extensive intestinal inflammation or intra-abdominal abscess; thus, they are not recommended for laparoscopy. We found that a laparoscopic procedure did not increase overall and major morbidity but shortened the postoperative hospital stay. Yet, no decreased intraoperative blood loss was observed in laparoscopy, which may due to the strong adhesion in some cases in which conversion to laparotomy is necessary.17 According to our previous study, the presence of strong adhesion beneath the anterior abdominal wall is regarded as a relative contraindication to laparoscopy because it can affect the visual field and the pneumoperitoneum.10 Moreover, because of the high risk of organ injury, grade IV adhesion is considered an absolute contraindication to laparoscopic surgery. In this case, a preoperative computed tomography scan is necessary for adhesion assessment. As reported by Turina et al., the incidence of SBS was nearly 10% after surgical intervention for CRE-related bowel obstruction.18 A higher rate of 19% was detected at the end of follow-up for CRE patients from an earlier study,8 which was similar to our results, with an SBS rate of 20.30%. In the present study, postoperative SBS was demonstrated as an independent risk factor of overall, but not major, morbidity after surgery. This can be explained by malnutrition and diarrhea due to reduced absorptive area, rapid bowel transit, and loss of terminal ileum,5 which lead to a poor general condition and slower recovery. Furthermore, routine requirement of PN in SBS patients results in catheter-related bloodstream infection, as well as increases the rate of TPN over 2 wk postoperatively. For these patients, a comprehensive treatment including antisecretion, nutrition support, and intestinal rehabilitation is necessary. Intraoperative blood loss contributed independently to overall and major morbidity. Although intraoperative transfusion has been detected as an independent predictor of complications after surgery for CRE,19 we were unable to evaluate this factor because of the lack of complete records. Despite this, the necessity of transfusion is closely associated with intraoperative blood loss. In a study of 305 patients with hepatectomy, those who suffered postoperative complications had significantly larger intraoperative blood loss, with a cutoff of 800 mL.20 Increased blood loss during surgery may indicate aggravated hypoperfusion of organs, such as the intestinal tract, which could increase postoperative complications.21 Because blood loss during an operation is a surgeoncontrolled factor and surgery for CRE is technically demanding, experienced surgeons are required and doctors with less experience should operate on highly selective patients. Hypertension and history of ARE were demonstrated as two independent indicators associated with major morbidity. Because these two factors are patient related and can hardly be controlled by surgeons, consequently, more careful perioperative management and particular attention are required
for those patients who have hypertension or have ever undergone ARE, to avoid postoperative complications or immediately discover and resolve them. Of all the blood test parameters considered in this study, thrombocytopenia, which may result from bone marrow suppression caused by radiotherapy, was the only independent risk factor identified for major morbidity. A lower preoperative platelet count was confirmed to be independently associated with increased major complications in resection of hepatocellular carcinoma.22 In the category of critically ill patients, persistent thrombocytopenia brought about poorer outcome as well.23 Patients who required emergent surgery 90 d after irradiation sustained increased morbidity and mortality, and death was independently related to thrombocytopenia.24 Accordingly, timing of surgery for CRE patients with a low platelet count should be decided based on some considerations, such as after correction of thrombocytopenia and optimization of the nutritional status. Meanwhile, a staged operation could be taken into consideration when necessary.
Conclusions Among all the surgical procedures, resection is recommended for its acceptable postoperative morbidity and better longterm outcome with a low reoperation rate. Use of laparoscopy is feasible in selective CRE patients without strong adhesion or fistula but requires more clinical experience. Particular attention should be paid to those patients with a history of ARE to effectively avoid postoperative morbidity or detect and manage such morbidity without delay. Correction of preoperative thrombocytopenia, reducing blood loss during operation, and careful perioperative management of hypertensive patients can also improve the outcomes of surgery for CRE.
Acknowledgment Authors’ contributions: Y.H. designed the study, collected and analyzed the data, and wrote the article. F.G. collected and analyzed the data. D.Y. collected the data. Y.L. and J.L. designed the study and critically revised the article. The authors declare that they have no sources of funding for this article.
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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