Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03561727 |
| Other study ID # |
1WB1/3D179 |
| Secondary ID |
2017/26/D/NZ5/00 |
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2018 |
| Est. completion date |
May 30, 2021 |
Study information
| Verified date |
December 2019 |
| Source |
Medical University of Warsaw |
| Contact |
Michal Grat, MD, PhD |
| Phone |
+48225992541 |
| Email |
michal.grat[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
RESEARCH PROJECT OBJECTIVES The aim of this planned study is to evaluate factors, with
particular reference to surgical technique of abdominal closure, accumulation of advanced
glycation end products, and collagen content in the transversalis fascia, that are associated
with the development of incisional hernias after transverse epigastric incisions in patients
operated due to malignant tumors.
RESEARCH PROJECT METHODOLOGY:
The study is designed as prospective and is planned to include 392 patients undergoing
abdominal surgery due to malignant tumors of the alimentary system performed through
transverse incisions in the epigastrium. Primary end-point of the study is defined as the
occurrence of burst abdomen during immediate postoperative period or incisional hernia over 2
year postoperative follow-up. Assessment of the association between the type of surgical
technique and development of hernia will be based on comparison of mass (1 layer) continuous
suture and layered (2 layers) continuous suture using slowly absorbable material and applying
suture to wound length ratio of more than 4. Type of the utilized surgical technique will be
based on randomization. The method of abdominal closure will remain unknown for patients and
investigators assessing the presence of incisional hernias. Assessment of overall collagen
content and type I to type III ratio will be performed by obtaining a fragment of tissue
during operation, preparation of formalin-fixed and paraffin embedded blocks, cutting of
4-micrometer thick sections, staining with picrosirius red and immunohistochemical
procedures. Images will be analyzed with dedicated computer software. Accumulation of
advanced glycation end products will be evaluated indirectly by measuring skin
autofluorescence utilizing a method based on the use of photodiodes. Postoperative follow-up
will include the period of postoperative hospitalization and two additional control visits at
1 and 2 years after the operation. Assessment of the presence of incisional hernia will
comprise clinical examination, ultrasonographical study, and analysis of images from other
available radiological studies. Irrespective of the primary end-point, additional analyses
will be performed concerning associations between evaluated factors and occurrence of burst
abdomen and the impact of incisional hernia on patients quality of life using the EORTC QLQ
C-30 questionnaires. Statistical analyses will, among other, include Kaplan-Meier method,
log-rank test, Cox proportional hazards regression and logistic regression
Description:
RESEARCH PROJECT OBJECTIVES The aim of the presented scientific project is to establish the
factors, with special reference to the type of surgical technique, tissue accumulation of
advanced glycation end products, and collagen content in transversalis fascia, associated
with development of incisional hernia after transverse incision in the epigastric region in
patients operated for malignant tumors WORK PLAN This study is planned as a prospective
evaluation of factors associated with the development of incisional hernias after transverse
incisions in the epigastric region in patients undergoing surgical treatment of malignant
tumors of the alimentary system. The main hypothesis of this study, which forms the basis for
sample size calculations, is the presence of an association between application of mass
continuous abdominal closure and reduction of the risk of incisional hernia from 35% down to
20% as compared to layered continuous suture. Using a threshold for the level of type I error
of 0.05 and a threshold for the probability of type II error on the level of 20%, the total
number of patients who should be included in the study is 284 (142 patients in either of the
2 arms). However, considering the approximate value of 2-year patient survival of 20% and a
further 10% rate of losses to follow-up, the study is planned to include a cumulative number
of 392 patients (196 in either of the two arms).
The primary end-point of this study is the development of burst abdomen in the immediate
postoperative period (until discharge from hospital) or incisional hernia over a 2-year
follow-up period (combined end-point). The follow-up protocol used for the assessment of
incisional hernias at discharge from hospital and two control visits at 1 and 2 years
postoperatively. Evaluation of the presence of incisional hernia will, in each case, be based
upon both clinical and ultrasonographical examination.
The primary factor that will be assessed for potential association with the development of
incisional hernias is the surgical technique applied for abdominal closure. The technique
comprising continuous suture and mass closure (one layer of sutures involving peritoneum,
transversalis fascia, posterior and anterior layer of rectus abdominis muscle fascia and
potentially, fascia of the oblique abdominal muscles) will be compared to the technique 2
separate layers of continuous sutures involving peritoneum, transversalis fascia, and
posterior layer of rectus abdominis muscle fascia (first layer), and anterior layer of rectus
abdominis muscle fascia and potentially, with oblique abdominal muscles fascia (second
layer), respectively. Patients will be randomly assigned to one of the two arms in a 1:1
ratio basing on drawing a sealed envelope with code specific for the type of intervention.
Neither the patients included in the study nor the investigators assessing the presence of
incisional hernia during follow-up visits will be aware of the type of surgical technique
used for abdominal closure (double-blinded study).
Only the professionals present in the operating room during surgical procedure, including
operator, assistants, anesthesiologist, and nurses, will be aware of the type of assigned
intervention. Besides the type of surgical technique and independent of random assignment to
one of the two arms of the study, all included patients will be subject to the assessment of
accumulation of advanced glycation end products within the skin and collagen in general, type
I collagen and type III collagen within the transversalis fascia in order to evaluate
potential associations between these factors and occurrence of the primary end-point.
Analyses on the influence of the type of surgical technique used for abdominal closure,
accumulation of advanced glycation end products, and collagen content within the
transversalis fascia on the risk of incisional hernia formation will be adjusted for the
effects of remaining known risk factors, including: age, sex, weight, height, primary disease
being an indication for the procedure, history of previous hernia, history of previous
abdominal operations, preoperative chemotherapy, cigarette smoking, excessive alcohol intake,
presence of liver disease, obesity, arterial hypertension, chronic obstructive pulmonary
disease, heart failure, anemia, race, width of subcutaneous adipose tissue, particular type
and length of the incision, intraoperative transfusions of packed red blood cells, and
occurrence of surgical site infection in the postoperative period.
Analyses concerning the primary end-point of the study will be performed 2 years after the
date of surgical procedure in the last patient included in the study cohort. Additionally, an
early analysis only with respect to the occurrence of burst abdomen is planned to be done 30
days after the date of surgical procedure in the last patient included in the study cohort.
Independently of the primary end-point, separate analyses will be performed to evaluate the
impact of the analyzed factors and the occurrence of incisional hernias on the quality of
patients' life.
RESEARCH METHODOLOGY Recruitment of patients into the planned research project will be
performed on the basis of strict inclusion and exclusion criteria. Inclusion criteria will
comprise: age over 18 years, scheduled operative treatment due to malignant tumor of the
alimentary system (including liver, bile ducts, and pancreas) through transverse incision in
the epigastric region, and provision of informed consent to participate in the study.
Exclusion criteria will comprise: necessity to perform an urgent operation, a history of
previous surgery performed with transverse incision in the epigastric region, and a body mass
index >35 kg/m2.
Following inclusion of patient in the study, baseline anthropometric measurements will be
performed (height, weight, and waist circumference), along with physical examination and
collection of patient's medical history. All medical documents and additional laboratory,
radiological and any other type of findings will be analyzed and relevant data collected in
order to provide information on the previously established risk factors for the development
of incisional hernia. All the data will be gathered both as paper documentation and as
records in a dedicated electronic database. In the next step, accumulation of advanced
glycation end products in the skin of the forearm will be evaluated using an indirect
measurement method based on the assessment of skin autofluorescence. This phenomenon is a
characteristic finding caused by the presence of several advanced glycation end products and
its quantitative assessment within the skin was found to precisely reflect the magnitude of
accumulation of advanced glycation and products in general in other tissues, which was
previously confirmed by comparing skin autofluorescence findings with the results of tissue
biopsies [29]. Due to its non-invasive character and reliable results, evaluation of advanced
glycation end products accumulation using the method of quantitative assessment of skin
autofluorescence was utilized in numerous clinical studies worldwide. In the planned research
project, quantitative measurement of skin autofluorescence will be performed with a
non-invasive device, which use was previously validated in a clinical setting (AGE-reader
connect, www.diagnoptics.com, DiagnOptics BV, Groningen, The Netherlands). Accordingly, skin
autofluorescence will be excited by emission of ultraviolet (UV-A) light with a wavelength of
375 nm (E=7.81E-01 Wm2 @ 0.2m). Light emitted in response by the skin will be measured using
a system based on photodiodes. Calculation of arbitrary units is performed by a dedicated
software of the device. Three separate 12-second measurements will be performed in each
patient on the anterior side of the forearm approximately 10 cm below the elbow fold to
decrease the potential risk of measurement error. The final skin autofluorescence value will
be the mean score of these 3 separate measurements. Importantly, this parameter will only be
assessed in patients with skin phototypes I, II, and III according to the Fitzpatrick
classification. Skin autofluorescence will also be assessed during the two postoperative
follow-up visits at 1 and 2 years.
In the preoperative period, all the patients will be subject to a baseline quality of life
assessment. Therefore, all patients will be asked to fill the polish version of the quality
of life questionnaire core 30 (QLQ-C30) form prepared by the European Organization for
Research and Treatment of Cancer (EORTC). The EORTC QLQ-C30 is a widely used tool for
evaluation of the quality of life in patients with malignant tumors, which consists of 30
questions (most current third version) and has already been used in more than 3 thousand
clinical studies across the globe (http://groups.eortc.be/qol/eortc-qlq-c30). Notably, the
version of EORTC QLQ-C30 questionnaire translated to polish has already been validated in a
clinical setting. The questionnaire provides information on a total of 15 health-related
quality of life outcomes including: physical function, role function, cognitive function,
emotional function, social function, fatigue, nausea and vomiting, pain, dyspnea, insomnia,
appetite loss, constipation, diarrhea, financial impact, and global quality of life. For the
purposes of this study, both particular health-related quality of life outcome measures (with
particular reference to physical, emotional, and social functions, pain, financial impact,
and global quality of life scales) and a summary score derived from the EORTC QLQ-C30
questionnaire will be analyzed. Importantly, robustness of the latter was recently proven by
replication and validation of higher order models by Giesinger and coworkers.
In the postoperative period, assessment of health-related quality of life will be performed
at the time of discharge from the hospital and at two follow-up visits at 1 and 2 years after
the surgical procedure.
Patients will be randomly assigned to one of the two techniques of abdominal closure during
the operative procedure and after its main part has been completed, just before the beginning
of closure of the abdominal cavity. Randomization will be performed in a 1:1 ratio and in
blocks of 20 patients. This procedure of random assignment will be done in the operating room
by the nurse through drawing of a sealed envelope with a technique-specific intervention
code. Before the beginning of the abdominal closure procedure, a 5 x 5 mm specimen will be
procured from the transversalis fascia for further histopathological analyses of the content
of collagen in general and specifically, content of type I collagen and type III collagen.
Tissue specimens will be fixed in 4% buffered solution of formalin. Subsequently, they will
be rinsed in water and automatically processed through 70%, 96% and absolute ethanol
solutions, alcohol and xylene solutions, and a series of xylenes. Afterwards, specimens will
be embedded in paraffin in a temperature of 60 degrees Celsius to form tissue blocks. The
latter will be cut into 3-4 micrometer thick sections using microtome device. Sections will
be transferred to microscope slides. First, hematoxylin and eosin staining will be performed
and slides will be evaluated for the adequacy of procured tissue sample. For the assessment
of overall collagen content, Picrosirius Red staining will be performed and slides will be
observed in a microscope coupled with a video camera. Initial evaluation of type I collagen
and type III collagen will be assessed by observation of microscopic slides under polarized
light. According to the method proposed by Casanova and coworkers, overall collagen content
in the obtained specimen will be analyzed by counting the ratio of refringent
(collagen-positive) to non-refringent (collagen-negative) areas in 5 randomly selected visual
fields observed at 100 magnification. In order to initially establish the content of type I
and type III collagen, additional 5 randomly selected visual fields will be assessed at 400
magnification with evaluation of the refringent areas tending to look green, which is
characteristic for type III collagen, and those tending to look orange, which is
characteristic for type I collagen. In all cases, the final results will be derived from the
average of the results from 5 inspected visual fields. Electronic images will be taken and
analyzed in a computer image-processing software. A ratio of type I to type III collagen will
be calculated.
In order to perform conventional immunohistochemical stainings, specimens will be
deparaffinised using xylene, a series of ethanol solutions with decreasing concentrations,
and water. The process of antigen retrieval will be performed in a TRIS/EDTA buffer with a pH
of 9. Endogenous peroxidase will be blocked with a 3% hydrogen peroxide solution. Protein
Block Serum-Free and 2.5% solution of donkey serum will be applied to block non-specific
sites of antigen binding. Detection of type I and type III collagen will be performed by
using specific anti-collagen I and anti-collagen III primary antibodies, respectively, in an
amount of 200 µL per microscopic slide. In the next step, secondary antibodies combined with
peroxidase particles will be used. (3-3')diaminobenzidine (1 mL of buffer with 1 drop of
substrate) will be used as chromogen, causing brown staining of immune-positive structures.
Basophilic structures will be illustrated with hematoxylin contrast staining. Specimens will
then be dehydrated with a series of increasing concentration (70%, 96%, and 99.8%) ethanol
solutions, acetone, and xylene. Following these procedures, specimens will be closed in an
automated fashion. Additionally, double immunofluorescence method will be utilized using
secondary antibodies combined with fluorochromes, Vectashield medium, and observation in
confocal and fluorescence microscopes.
Closure of the abdominal cavity will be performed with one of the two analyzed surgical
techniques, basing on the results of random assignment. Independent of the type of surgical
technique, abdominal closure will be done with polydioxanone material (synthetic,
monofilament, and slowly absorbable) in the loop form, size 0 according to United States
Pharmacopeia, and 36 mm needle. This material is characterized by effective tissue retention
period of 90 days and complete absorption period in the range between 182 to 238 days. In
both techniques, the intersuture spaces and tissue bites will be of 5 mm, which defines the
small bites method. In case of assignment to mass closure technique, abdominal cavity will be
closed by a single layer of 2 continuous sutures beginning on the opposite ends of the wound
towards the median line and involving peritoneum, transversalis fascia, posterior and
anterior layer of rectus abdominis muscle fascia and, in case of incisions beyond the lateral
border of rectus abdominis muscle, also the oblique abdominal muscles fascia. In case of
assignment to layered closure technique, abdominal cavity will be closed with two separate
layers of continuous sutures. The first layer will include peritoneum, transversalis fascia
and posterior layer of the rectus abdominis muscle fascia closed with 2 continuous sutures
beginning at both ends of the wound and processed medially. In case of incisions not
exceeding the lateral border of rectus abdominis muscle, the second layer of 2 continuous
sutures will involve only the anterior layer of the rectus abdominis muscle fascia beginning
on the lateral ends and processed medially. In case of incisions exceeding the lateral border
of rectus abdominis muscle, the second layer of the continuous suture will start at the
lateral border of rectus abdominis muscle, process laterally to the lateral end of the wound
involving internal oblique abdominal muscle fascia. Subsequently, the suture will be led out
on the anterior surface of the external oblique abdominal muscle, put through by the created
loop in the medial direction and processed medially to close the external oblique abdominal
muscle fascia and anterior layer of the rectus abdominis muscle fascia. Regardless of the
applied surgical technique, continuous sutures processing medially will be terminated
provided that there is a minimum of 2 cm long segment of overlapping sutures from both sides.
Moreover, attention will be given to close only the aponeuroses and to avoid the presence of
any muscle or adipose tissue within the sutures. The skin will be closed either with
interrupted non-absorbable sutures or with a stapler.
Several parameters will be measured and evaluated intraoperatively. First, the depth of
subcutaneous adipose tissue will be measured in centimeters at three sites: median line and
bilaterally, in the middle between the median line and lateral end of the wound. Time will be
measured from the beginning of abdominal closure to the end of aponeurosis closure. Wound
length will be measured in a standard fashion in centimeters. The length of suture used for
abdominal closure will be assessed by subtracting the length of the sutures remaining after
abdominal closure form the cumulative original length of the sutures. The suture length to
wound length ratio will be calculated. Finally, the quality of the abdominal wall with
respect to potential risk of burst abdomen and incisional hernia will subjectively be
assessed by the operating surgeon in a semiquantitative fashion using the following scale: 1
- poor quality, high risk; 2 - moderate quality, average risk; 3 - good quality, low risk.
Inclusion of this variable in risk factor analyses may provide some insight into the
reliability of subjective assessment of burst abdomen and incisional hernia by the operating
surgeon.
In the immediate postoperative period (until discharge of patient from the hospital) patients
will be observed for the development of surgical site infections, defined and classified
according to the CDC (Centers for Disease Control) recommendations. More specifically,
surgical site infections will be divided into superficial incisional, deep incisional, and
organ/space infections. Additionally, each operative procedure will be classified as clean,
clean-contaminated, contaminated, and dirty or infected based on the type of operation and
intraoperative findings. Data on the duration of postoperative hospitalization (in days) will
be collected. All complications of grade III or higher according to Clavien-Dindo
classification will be reported in detail. In case of reoperation due to a reason other than
occurrence of burst abdomen in the immediate postoperative period, observations for the
occurrence of burst abdomen and incisional hernia will be censored.
All patients included in the study will be invited for two follow-up visits at 1 and 2 years
(+/- 3 months) following the operative procedure, primarily to evaluate the presence of
incisional hernia. During the follow-up visits, a detailed postoperative patient history will
be taken, physical examination will be performed, and ultrasonographic examination of the
postoperative scar will be done. Regardless of these, images from computed tomography and/or
magnetic resonance imaging performed in the course of oncological follow-up protocols (the
only additional imaging examination planned as part of this research project is the
ultrasonographical examination) will be assessed for the presence of incisional hernia. Data
on potential diagnoses and treatment of incisional hernias prior to the follow-up visit in
other centers, if such situation occurs, will be collected and analyzed. During each of the
follow-up visits, patients will be asked to fill the EORTC QLQ-C30 questionnaires and will
undergo skin autofluorescence measurement, as previously described.
Obtained data will be analyzed statistically. Quantitative and qualitative data will be
presented as medians with interquartile ranges and numbers with frequencies, respectively.
Chi-square test and Fisher's exact test will be used for intergroup comparisons of
qualitative variables. Mann-Whitney U test will be applied for intergroup comparisons of
quantitative variables. Baseline analysis of the association between the type of surgical
technique used for abdominal closure and the occurrence of primary end-point of this study
will be performed by comparison of the probability curves for the presence of burst abdomen
and incisional hernia over time up to two years with the log-rank test. Analyses of the
associations between the remaining factors included in this study and the occurrence of the
primary end-point, as well as multivariable analyses will be performed using Cox proportional
hazards regression models. Establishment of the optimal cut-offs for quantitative variables
for prediction of the development of incisional hernias will be based upon analysis of the
receiver operating characteristics curves and Youden index. Initial analysis focused on the
risk factors for burst abdomen will be done with Fisher's exact test (surgical technique) and
logistic regression models (remaining factors and multivariable analysis). The level of
significance was set to 0.05 (two-sided p value). Statistical analyses are planned to be
computed in STATISTICA (Dell Inc.) and SAS (SAS Institute) software.
