A RANDOMIZED TRIAL COMPARING RADICAL HYSTERECTOMY AND PELVIC
NODE DISSECTION VS SIMPLE HYSTERECTOMY AND PELVIC NODE DISSECTION
IN PATIENTS WITH LOW RISK EARLY STAGE CERVICAL CANCER

Cancer of the cervix is the second leading worldwide cause of cancer death in
women. Most recent global statistics indicate that in 2002, the estimated
incidence was 493,243 new cases with 273,505 deaths [Parkin 2006]. The disease
is much more prevalent in developing as opposed to developed nations. There is
an almost two-fold increase in lifetime probability risk of developing cervical
cancer (1.48% vs. 0.76%) and a more than three-fold increase in dying from it
(0.84% vs. 0.25%) in underdeveloped countries [Global Cancer Facts and Figures
2007]. In Canada, the projected number of new cases in 2010 was 1300, with 370
deaths [Canadian Cancer Statistics, 2010].
As a result of effective screening in developed countries, the overall
incidence of cervical cancer has decreased over the past 20 years, while the
proportion of younger women presenting with low-risk early-stage disease has
increased. As surgical therapy is highly efficacious in providing durable
disease control in women with low-risk disease, these patients are at risk of
suffering *survivorship* issues related to long-term surgical effects,
including compromised sexual, bowel and bladder function, as well as
infertility. The NCIC CTG CX.5 / GCIG SHAPE trial uses a non-inferiority design
to test whether, in the long-term, less invasive surgical approaches can
maintain high rates of disease control and improve quality of life through a
reduction in late-effects associated with the surgical procedure.
Data from the recent 24th annual International Federation of Gynecology and
Obstetrics (FIGO) report indicates that the 5-year stage-specific overall
survivals of patients with stage IA2 squamous carcinoma were 99.1% (97.1% for
adenocarcinoma) and for stage IB1 squamous carcinoma were 92.3% (91.8% for
adenocarcinoma) [FIGO Annual Report, 2009]. The FIGO report emphasizes that
from an international perspective, extensive practice variation occurs in
managing patients with micro-invasive disease. Overall, 75% of patients were
treated with surgery alone. Among these patients, one-third underwent
conization, one-third simple hysterectomy (with or without lymphadenectomy) and
one-third radical hysterectomy (again with or without lymphadenectomy). The
remaining 25% of patients received some form of adjuvant therapy. Overall, 20%
of patients underwent lymph node removal, presumably when lymphovascular
involvement was detected on the conization specimen [FIGO Annual Report, 2009].
The major reason for such discrepant practices is the lack of high-quality
evidence upon which clinicians can base their decisions and advice to these
women. There is a need to standardize treatments and potentially identify the
patient and disease specifics associated with advantages with radical or more
limited surgical approaches.
There are no studies comparing the efficacy and morbidity of simple
hysterectomy to that of radical hysterectomy in patients with early-stage
disease. However, as the purpose of removing the parametria at the time of the
hysterectomy is to ensure safe and wide margins around the cervical tumour
and/or to remove potential spread to the parametrial lymph nodes and, as will
be described below, the occurrence of disease in these locations is essentially
nonexistent in patients with low-risk disease, important advantages may be
associated with a simple hysterectomy. This premise provides the foundation for
this trial.

Primary objective:
To evaluate whether treatment with simple hysterectomy and pelvic node
dissection is non-inferior to treatment with radical hysterectomy and pelvic
node dissection in terms of pelvic relapse-free survival.

Secondary objectives:

To compare the two treatment arms with respect to:
- Extrapelvic relapse-free survival
- Relapse-free survival (any site)
- Overall survival
- Treatment-related toxicity
- Patient Reported Outcomes including global quality of life and measures of
sexual health
- Cost-effectiveness and cost-utility

To observe rates of the following in this patient population:
- Sentinel node detection
- Parametrial involvement
- Involvement of surgical margins
- Pelvic node involvement

This is a multi-centre, international, prospective, randomized phase III trial
of radical hysterectomy and pelvic node dissection versus simple hysterectomy
and pelvic node dissection in patients with previously untreated, low-risk
cervical cancer. The planned sample size is 700 participants (1:1 randmization
in both arms). The smple size is calculated based on non-inferiority at 0.05
level with 80% power.

Arm 1 - Radical Hysterectomy (Type 2)
This procedure may be performed abdominally, laparoscopically, robotically or
vaginally. The uterus, cervix, medial 1/3 of parametria, 2 cm of the
uterosacral ligaments and upper 2 cm of the vagina are to be removed en bloc.
The uterine artery is ligated laterally to the ureters and the ureters are
unroofed to the ureterovesical junction.

Arm 2 - Simple Hysterectomy (Extrafascial Hysterectomy)
This procedure may be performed abdominally, laparoscopically, robotically or
vaginally. Extrafascial hysterectomy involves removal of the uterus with cervix
without adjacent parametria. The uterine arteries are transected medial to the
ureters at the level of the isthmus and the uterosacral ligaments are
transected at the level of the cervix. Surgeons should pay special attention to
make sure that the whole cervix is removed. As such, a maximum 0.5 cm of
vaginal cuff can be removed to ensure the complete removal of the cervix.

Both arms: Lymphadenectomy and Sentinel Node Mapping
Protocol therapy on both treatment arms will include pelvic lymph node
dissection. Centres may choose to perform sentinel node mapping for some or all
of their CX.5 patients if that is part of their usual practice. For centers not
performing sentinel node mapping, a complete pelvic node dissection is
considered protocol therapy. All the nodes are submitted for routine
pathological analysis as per the Surgery/Pathology Manual. Frozen section
analyses of sentinel nodes are not permitted for this trial unless the node is
visually suggestive of metastatic spread.

Pelvic Lymphadenectomy
This procedure can be performed by open or laparoscopic technique. Bilateral
skeletonization is to be performed with removal of all lymph node tissue from
lower half of common iliac vessels, external iliac vessels, internal iliac
vessels and the obturator fossa. The anatomic boundaries are to include the
lower half of the common iliac artery proximally, the deep circumflex iliac
vein distally, the mid portion of the psoas muscle laterally, to the ureters
medially and above the obturator nerve in the obturator fossa inferiorly.
Following the complete bilateral pelvic node dissection, the nodes are
submitted for routine pathological analysis as per the Surgery/Pathology Manual.

Sentinel Node (SN) Mapping
Only experienced surgeons are permitted to perform sentinel node biopsies as
part of this trial. In order to be eligible for this procedure, individual
surgeons will be required to have successfully performed at least 10 previous
SN procedures in cervix or endometrial cancer patients. Following the surgery,
a quality assurance exercise will be conducted in the first 5 CX.5 patients
treated by each surgeon.

With regard to possible benefit there is evidence that especially long term
urological complication after surgery for cervical cancer depend on the extend
of parametrial dissection. Hence women in whom the parametrium is not dissected
(arm 2: experimental arm, simple hysterectomy) may have benefit with regard to
less long term (urological) morbidity compared to women in whom the parametrium
is dissected (amr 1: control arm, radical hysterectomy)

The possible risk associated with participation is, if randomized into the
experimental arm, that parametrial involvement is not diagnosed nor treated,
however there is a body of evidence justiying testing the less radical approach
in both stage IA2 and 1B1.Based on the data below, routine parametrectomy in
patients with low-risk cervical cancer appears to be potentially unnecessary
given the very low rate of parametrial extension seen with retrospective
reviews and acknowledging the morbidity of the procedure. However, there are no
randomized trials demonstrating the safety of simple hysterectomy in low-risk
stage IB1 patients. This trial will provide a unique opportunity to compare the
rate of lymph node metastasis, parametrial infiltration and outcome between the
two procedures, and produce results that can drive a change in clinical
practice.

Outcomes Justifying Testing of Less Radical Approaches in Stage IA2
There is a growing body of literature suggesting that more conservative surgery
can safely be performed in patients with stage IA2 disease, providing careful
pathological evaluation is undertaken. A literature review performed by van
Meurs identified 1063 patients with stage IA2 disease and reported an overall
recurrence rate of 3.6% [van Meurs 2009]. No patients had parametrial
infiltration and 4.8% (range 0 to 9.7%) were found to have lymph node
metastasis, indicating the importance of accurate measurement of depth and
lateral extension of microinvasive disease, particularly with adenocarcinomas.
This principle is highlighted by the author*s finding that following a thorough
review of 47 cases that were previously identified in the Netherland registry
as having IA2 disease, only 14 cases (30%) fulfilled criteria for stage IA2
[van Meurs 2009]. These authors also noted that the rate of lymph node
metastasis was 12% in patients with lymphovascular space involvement (LVSI)
compared with 1.3% in LVSI negative patients [van Meurs 2009].

However, other investigators have not observed the same risks to be associated
with LVSI. Rogers conducted an extensive literature review and compared the
rate of lymph node metastasis and recurrence in a series that used strict
FIGO-defined selection criteria for microinvasion with a series that did not
comply with this definition [Rogers 2009]. In the former group, the rates of
node metastasis and recurrence were 0.5% and 2.9%, whereas rates were 7.3% and
3.1% in the latter group. Careful pathological assessment is thus essential
when considering conservative treatment.

These data are supported by findings of Bisseling, who reviewed more than 1565
patients with microinvasive adenocarcinomas, of which 52% (814) underwent lymph
node dissection [Bisseling 2007]. Lymph node metastases were identified in only
1.5% of cases. The presence of LVSI did not seem to be associated with nodal
metastasis. Parametria were removed in 713 cases (46%) and reported in 356
cases; none of these cases were found to have parametrial involvement. The
authors emphasized the difficulty in distinguishing microinvasive
adenocarcinoma from adenocarcinoma in situ and the importance of obtaining
multiple serial sections for review by an experienced gynecologic pathologist.
The authors conclude that: i) in cases with extensive LVSI positivity, lymph
node dissection is advised; ii) given the low-risk of lymph node metastasis,
lymph node dissection may not be necessary in the vast majority of stage IA2
cases, although sentinel node mapping may be of interest as a less morbid
alternative; and, iii) the very low rate of parametrial infiltration does not
justify its routine removal. Therefore, local treatment together with lymph
node assessment, particularly in the presence of LVSI would be the favored
approach for patients with stage IA2 adenocarcinomas [Bisseling 2007]. Of note,
microinvasive adenocarcinomas do not appear to be associated with higher rates
of lymph node metastasis as compared with stage-matched squamous carcinoma
[Rogers 2009].

In 92 patients with IA2 disease treated with radical hysterectomy, Jones found
no cases with pathologic involvement of the parametrial or regional lymph nodes
[Jones 1993]. On a subsequent pathologic analysis of 25 patients with
microinvasive adenocarcinomas, again no cases with lymph node metastasis and no
parametrial invasion were detected. Poynor concluded that conisation alone (if
fertility preservation is desired) or simple hysterectomy should be considered
adequate treatment for microinvasive adenocarcinomas [Poynor 2006].

The Gynecologic Oncology Group (GOG) reported results of a prospective study of
51 patients with stage IA2 disease confirmed by conization and treated with
radical hysterectomy [Creasman 1998]. No patients had residual disease detected
with the pathologic hysterectomy specimen, including none with lymph node
metastasis [Creasman 1998]. Recently, Suri confirmed that patients with IA2
disease and negative pathologic margins following a loop electrosurgical
excision procedure (LEEP) or cone procedure have a very low-risk of disease
detection on the radical hysterectomy pathology specimen [Suri 2009]. In their
series of 42 patients, only one patient was found to have positive nodes (2.4%)
and in this patient LVSI was present on her cone specimen. The authors
concluded that in carefully selected women with IA2 disease and negative
pathology margins with LEEP or cone procedures could be treated more
conservatively, but patients with LVSI may require nodal assessment [Suri 2009].


Outcomes Justifying Testing of Less Radical Approaches in Stage IB1

Fewer data are available regarding the safety of conservative treatment for the
subset of patients with early-stage IB1 disease, defined as a tumour measuring
less than 2 cm. In a retrospective study of 842 patients, Covens questioned the
necessity of the parametrectomy based on observing a rate of parametrial
extension of 0.6% and 2 and 5-year recurrence-free survivals of 98% and 96% in
patients with low-risk features (tumour < 2cm, depth of stromal invasion < 10mm
and negative pelvic nodes) [Covens 2002]. Wright conducted a retrospective
review of 594 patients who underwent a radical hysterectomy; 0.4% of patients
with lesions measuring < 2cm, negative nodes and no LVSI had parametrial spread
and their recurrence rate was 0.7% [Wright 2007]. The authors concluded that
simple hysterectomy in combination with pelvic lymphadenectomy may be adequate
treatment for these patients. In a similar study plus literature review of 799
patients, only 0.63% of those with low-risk features had parametrial spread
[Stegeman 2007]. Further supporting data include:
• In a retrospective analysis of 120 patients by Steed, no patients with
negative nodes had parametrial infiltration. Parametrial infiltration was
associated with tumour size (3 vs. 2 cm) and depth of stromal invasion [Steed
2006].
• In a retrospective analysis of 83 patients by Kinney, no parametrial node
metastases were seen in those with lesions measuring < 2cm in diameter and
negative LVSI. Only 4 patients had pelvic node metastasis (4.8%), and the
5-year survival was 97.6% [Kinney 1995].
• In a retrospective analysis of 136 patients by Frumovitz, no patients with
tumours measuring < 2cm with negative LVSI had parametrial infiltration
[Frumovitz 2009]. This group is now prospectively testing conservative surgery
for patients with