Trial Information

A Collagen-Fibrin Patch (Tachosil®) for the Prevention of Symptomatic Lymphoceles After Pelvic Lymphadenectomy in Women With Gynecologic Malignancies: a Randomized Clinical Trial

1. Background Women with gynecologic malignancies such as cervical and endometrial cancer
routinely undergo pelvic lymphadenectomy based on tumor characteristics assessed prior to or
during surgery. Pelvic lymphadenectomy may be performed by open surgery or laparoscopy
(1-4). Postoperative complications during and after pelvic lymphadenectomy include local
abscess, bleeding, lymphocele, and chronic lymphedema of the lower extremities, which has an
incidence of 1 to 2% (2,3). In the present trial, we will focus on pelvic lymphoceles, one
of the most common complications of pelvic lymphadenectomy. Simonato et al. described a rate
of 19/30 (63%) of sonographically detected lymphoceles in men undergoing pelvic
extraperitoneal lymphadenectomy for prostate cancer (4). In this trial, 4/19 men with
lymphoceles were symptomatic and required medical interventions. In women with cervical
cancer, asymptomatic lymphoceles detected by ultrasound have been noted in up to 11% of
women after pelvic lymphadenectomy (1,3,5). In 2% of women, clinical symptoms will require a
therapeutic intervention (5).

Tachosil® is a fibrin-collagen coated patch and heas been licensed in 2004 and 2007 in
Europe for surgical use in humans to support surgical hemostatic interventions. The efficacy
and safety of Tachosil® has been demonstrated in liver resection, pulmonary lobectomy, and
kidney tumor resection trials (6-8). In men, but not in women, it has been demonstrated that
the application of a collagen-fibrin patch to the lymphadenectomy surgery site may prevent a
significant proportion of lymphoceles. In a randomized trial, Simonato et al. found that the
pelvic application of two Tachosil® patches to the obturator fossa and the femoral canal was
sufficient to significantly reduce the rate of sonographically detected lymphoceles within 4
weeks after surgery from 19/30 to 5/30 cases (p=0.001) as well as the mean drainage volume
from 190 to 64 ml. Percutaneous puncture of a symptomatic lymphocele was necessary in 1/30
individuals in the intervention group compared to 4/30 individuals in the control group.
(4). In women with gynecologic malignancies a single center randomized controlled trial has
found, that Tachosil® seems effective to reduce the rate of lymphoceles after pelvic
lymphadenectomy (5). 7/30 (23.3%) women in the treatment group compared to 9/28 (57.7%)
women in the control group developed asymptomatic lymphoceles (p<0.05) (5). No significant
differences between the two groups were observed in the development of symptomatic
lymphoceles or the rate of interventions (5). This may be attributable to the small sample
size of this study. As symptomatic lymphoceles are more relevant for the patient, it seems
clinically more important to the evaluate the impact of Tachosil® on the rate of symptomatic
lymphoceles after pelvic lymphadenectomy.

Symptomatic lymphoceles are defined by the CTCA 4.03 grading system as lymphoceles grade >2.
This includes all lymphoceles needing medical intervention. Thus this definition comprises,
lymphoceles with the presence of localized pelvic pain, pelvic abscess, fever, and/or leg
edema in the presence of a sonographically verified pelvic lymphocele.

In summary, the data available in the literature demonstrate that pelvic lymphocles occur in
11 to 63% of individuals undergoing pelvic lymphadenectomy. Symptomatic lymphoceles seem to
occur in about 32% of patients undergoing pelvic lymphadenectomy. Intraoperative application
of a collagen-fibrin patch may reduce the number of lymphoceles, mean drainage volume, and
the necessity of medical interventions such as percutaneous puncture.

Therefore, we intend to perform a multi center randomized clinical trial assessing the
efficacy of a collagen-fibrin patch for preventing symptomatic lymphoceles in women
undergoing pelvic lymphadenectomy for gynecologic malignancies, ie cervical and endometrial
cancer. We hypothesize that, based on the data of Simonato et al. and Tinelli et al., the
application of a collagen-fibrin patch (Tachosil®) will reduce the number of symptomatic
pelvic lymphoceles by at least 66%.

Primary outcome variable:

2.1. To evaluate the incidence of symptomatic pelvic lymphoceles defined by CTCAE 4.03 grade
>2 within 4 weeks after surgery in women undergoing open or laparoscopic pelvic
lymphadenectomy for cervical and endometrial cancer with and without the application of
Tachosil® during surgery.

Secondary outcome variables:

2.2. To evaluate the incidence of sonographically detected pelvic lymphoceles of at least
2cm in the largest diameter 4 weeks after surgery in women undergoing open or laparoscopic
pelvic lymphadenectomy for cervical and endometrial cancer with and without the application
of Tachosil® during surgery.

2.3. To evaluate the rate and type of medical interventions for clinically symptomatic
pelvic lymphoceles such as analgesics and/or lymphocele puncture and drainage.

3. Study Hypothesis We hypothesize that the intraoperative application of two
collagen-fibrin patches (Tachosil®) to the obturator fossa and the femoral canal will reduce
the number of symptomatic pelvic lymphoceles by at least 66% (primary study end point).

4. Study Design Prospective randomized clinical intervention trial of 140 women undergoing
open or laparoscopic pelvic lymphadenectomy for cervical or endometrial cancer.
Randomization will be by a computerized randomization list. Women will be centrally
randomized by the principal investigator (CT). Allocation will be communicated by telephone
after informed consent has been obtained and after lymphadenectomy has been completed. This
is a single-blinded study, ie patients, but not surgeons, will be blinded to the treatment
allocation. Outcome assessment will not be performed by the surgeon, who has performed the
lymphadenectomy. Outcome assessors will be blinded to the treatment allocation.

5. Treatment

All women will undergo open or laparoscopic surgery. Within this procedure, as deemed
appropriate by the surgeon, women will undergo pelvic lymphadenectomy. The procedure will be
performed as follows:

The peritoneum will be incised parallel to the iliac vessels. Then, the iliac vessels will
be screened for the presence of bulky lymph nodes. If a lymph node debulking is performed,
no patch will be applied. In women who undergo routine pelvic lymphadenectomy, lymph node
tissue will be removed from the external iliac vessels, the obturator fossa, the interiliac
region, and the common iliac region after identification and appropriate preparation of
surgical landmarks, ie iliac vessels, femoral canal, chorda, and obturator nerve. At the end
of the procedure, hemostasis will be checked. A Tachosil® patch of 4.8x4.8cm will be
attached to the obturator fossa and a Tachosil® patch of 4.8x4.8cm will be attached to the
femoral canal of each side of surgery in the intervention group. In the control group, no
Tachosil® patch will be used. No specific drainage of the retroperitoneum will be performed.
All surgical procedures will be performed by the study team members Clemens Tempfer, Lukas
Hefler, and Alexander Reinthaller, experienced in open and laparoscopic pelvic lymph node
dissection. In order to ensure adequate application of the Tachosil® patch by laparoscopy,
all surgeons will perform at least two laparoscopic training operations during which they
roll the Tachosil® patch around a laparoscopic instrument, move it through a 10mm trocar
into the abdomen, and flatten it out.

8. Statistical analysis A power calculation demonstrated that, with a sample size of 70 per
group, a two-arm study has a power of 80% to detect a 66% absolute difference in treatment
efficacy at a significance level of 0.05 regarding the primary outcome parameter, ie
symptomatic lymphoceles CTCAE 4.03 grade >2. This calculation was based on published data by
Tinelli et al. observing a rate of 32% of symptomatic lymphoceles in the placebo group and
10% in the Tachosil® group (5). Assuming a 10% drop out-rate, 140 women will be randomized.
The chi-square test will used for comparisons of frequencies and cross-tabulations. One Way
ANOVA on ranks will be used on means. Descriptive statistics (means, standard deviations,
and ranges) will be used for demographic data. Bonferroni's correction will be used for
multiple comparisons of secondary outcomes.

10. Follow-up All women will undergo a gynecologic examination and a transvaginal and
transabdominal ultrasound examination at the time of discharge of the hospital, performed by
a physician experienced in transvaginal and transabdominal ultrasound examinations, who has
not participated in the original surgical procedure and is blinded to the treatment
allocation. All women will be scheduled for a follow-up visit 4 weeks after surgery
including a gynecologic examination and a transvaginal and transabdominal ultrasound
examination, performed by a physician experienced in transvaginal and transabdominal
ultrasound examinations, who has not participated in the original surgical procedure and is
blinded to the treatment allocation.