Gynecologic Oncology 146 (2017) 1–2
Contents lists available at ScienceDirect
Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno
Editorial
Management Of Early Stage Cervical Cancer: When Is Non-Randomized
Data Good Enough?
The standard surgical management for early cervical cancer beyond
stage IA1 with no lymphovascular space invasion (LVSI) has historically
been radical hysterectomy with pelvic lymphadenectomy. It is
acknowledged that morbidity increases with increasing radicality of
surgery. A randomized study of class II versus class III hysterectomy
for stage IB-IIA cervical carcinoma, demonstrated that the risk of urolog-
ic complications including prolonged self-catherization time,
hydroureteronephrosis, stress incontinence, bladder atony and low
bladder compliance, was 5% among patients who underwent class II
versus 30% for class III hysterectomy without radiation [1]. In a similar
study comparing class I to class III hysterectomy, there were no patients
in the class I group with neurologic bladder dysfunction, ureterovaginal
fistula or hydroureteronephrosis [2]. The autonomic nerve damage from
radical surgery also causes sexual dysfunction and colorectal motility
disorders [3–5]. In attempt to reduce surgical morbidity and improve
quality of life, many gynecologic oncologists have abandoned the type
III in favour of the type II radical hysterectomy for the surgical manage-
ment of early cervical cancer (stage IB1).
It should be pointed out that there were no randomized studies to
indicate that non-radical surgery without lymphadenectomy was ade-
quate for patients with stage IA1 disease (neg LVSI), but rather observa-
tional data that demonstrated the risk of parametrial invasion (PI) and
lymph node metastasis was extremely low for these patients [6,7]. Ac-
cordingly, cone biopsy or simple hysterectomy has become standard
surgical management. Investigators have continued to examine wheth-
er there are other groups of early stage cervical cancer patients for
whom the morbidity of parametrectomy outweigh the oncologic
benefit.
In 1995 Kinney identified a subset of 83 patients with stage I squa-
mous cell carcinoma, with depth of invasion N3mm, tumor diameter
≤2 cm, and no LVSI, none of whom had parametrial lymph node metas-
tases [8]. In 2002, Covens reported on 842 patients who underwent rad-
ical hysterectomy for stage IA1 to IB1 cervical carcinoma, and
demonstrated that the risk of PI among 536 patients with negative
lymph nodes, tumor size ≤ 2 cm, and stromal invasion ≤ 10 mm was
0.6% [9]. As 40% of patients with an isolated pelvic recurrence will be
cured with chemoradiation, the estimated maximum incremental sur-
vival benefit of radical versus non-radical surgery for this group of
low-risk patients is 0.4% [9]. Subsequently, multiple studies have dem-
onstrated similar findings, that the risk of PI for low risk tumors
(tumor diameter ≤ 2 cm, negative LVSI and negative pelvic lymph
nodes), is b1% [10]. Although nodal status is not necessarily known at
the time of surgery, most patients will receive adjuvant (chemo)radia-
tion therapy for nodal metastases, such that microscopic parametrial
http://dx.doi.org/10.1016/j.ygyno.2017.06.006
0090-8258/© 2017 Elsevier Inc. All rights reserved.
tumor spread will also receive treatment. However, some centers use
adjuvant chemotherapy alone for positive lymph nodes. In this case,
the above algorithm may not be applicable, as the effect of adjuvant che-
motherapy (without radiation) on microscopic parametrial metastases
is unclear. These clinicians need to use caution when considering the
above management.
In this month’s issue of Gynecologic Oncology, Baiocchi et al. present
additional data to support the safety of non-radical surgery for early cer-
vical cancer. The authors highlight the risk factors for PI: tumor size,
LVSI, depth of stromal invasion and pelvic lymph node status. Among
81 patients with tumor diameter ≤ 2 cm, negative LVSI, and negative
pelvic lymph nodes, there were no cases of PI. All patients with tumor
diameter ≤2 cm and PI had positive pelvic lymph nodes. The authors
are to be congratulated on their work. This study represents the first ex-
amining risk factors for parametrial invasion from a middle-income
country.
Observational studies of non-radical surgery for selected patients
with cervical carcinoma stage ≤ IB1 show similar oncologic outcomes
to radical surgery. A literature review by Ramirez et al. identified 247 pa-
tients with stage IA1 (positive LVSI) to stage IB1 cervical cancer man-
aged with cervical conisation, simple trachelectomy, or simple
hysterectomy [10]. Approximately 80% of the included patients had
stage IB1 disease. Of all the reports, there were 2 recurrences and 1
death from recurrent disease. A more recent review of fertility sparing
management in cervical cancer found that among 185 patients with
tumor diameter b2 cm who underwent cervical conisation or simple
trachelectomy, the crude recurrence and mortality rates were 2.7 %
and 0.5 % respectively [11].
Although the available evidence suggests that oncologic outcomes
are favourable in women with low-risk tumors who have non-radical
surgery, no randomized data has been published to confirm the safety
of this practice. However, there are a number of ongoing trials designed
to answer this question. The SHAPE Trial (NCT01658930) is a random-
ized non-inferiority trial comparing non radical to radical surgery for
patients with stage IA2 or IB1 cervical carcinoma (tumor diameter ≤2
cm, b 10 mm stromal invasion or b50% invasion on MRI). All patients
undergo pelvic lymph node dissection (PLND) with or without sentinel
lymph node biopsy (SLNB). The primary outcome is pelvic recurrence-
free survival (RFS). Secondary outcomes include extra-pelvic RFS, over-
all survival, morbidity, quality of life, and cost-effectiveness. Target en-
rollment is 700 subjects. The ConCerv trial (NCT01048853) is a
prospective, international, multicenter cohort study of cervical
conisation or simple hysterectomy with SLNB and PLND for patients
with stage IA2 or IB1 (tumor diameter ≤2 cm, b10mm stromal invasion,
2 Editorial
no LVSI). The primary objective is to determine rate of parametrial in-
volvement. The secondary outcomes include recurrence rates, morbidi-
ty and quality of life as well as the performance characteristics of SLNB.
Target enrollment is 100 patients. GOG 278 (NCT01649089) is a large
multi-center prospective cohort study of a projected 225-600 patients
undergoing cone biopsy or simple hysterectomy with PLND for stage
IA1 (positive LVSI), IA2- IB1 (tumor diameter ≤2 cm, ≤10 mm stromal
invasion). The primary outcomes include rates of bladder, bowel, and
sexual dysfunction. Secondary outcomes are surgical complications,
changes in quality of life, fertility rates and efficacy.
Sentinel lymph node biopsy has been associated with an absolute
risk reduction of 20% for surgical morbidity, 13% for early post-
operative neurological symptoms and 33% for lymphedema compared
to PLND [12,13]. One large publication to date, demonstrated no differ-
ence in recurrence-free survival between patients with negative SLNB
alone versus negative full PLND [14]. This data is further supported by
multiple studies demonstrating the high sensitivity and negative pre-
dictive value of the sentinel lymph node procedure for cervical tumors
≤ 2 cm. Randomized trials evaluating the oncologic safety and quality
of life of the SLN procedure in early cervical cancer are being contem-
plated by both GINECO and NRG. Obtaining conclusive evidence from
such trials is challenging, given the required sample size to demonstrate
non-inferiority when the risk of lymph node metastasis in this patient
population is low, and its effect on survival further mitigated by radia-
tion in the adjuvant or recurrent setting.
So, how should we manage patients with tumor diameters ≤2 cm
today? Enroll them in a clinical trial! However, if no clinical trial is avail-
able or the patient ineligible, we have a duty of care to provide what we
believe is the best possible care, including minimizing morbidity if we
can achieve equivalent efficacy. If clinicians accept the premise that a
b1% risk of parametrial invasion among patient with tumor diameter
≤ 2cm, stromal invasion b 10mm and negative pelvic lymph nodes is
too low to justify radical surgery, then management becomes easy. In
patients with tumor diameters b 2cm, perform a cone biopsy or LEEP ex-
cision to determine depth of stromal invasion, and if b 10mm, perform
non-radical surgery (repeat cone biopsy or simple hysterectomy) and
pelvic lymph node assessment. Patients with nodal metastases are
then administered adjuvant (chemo)radiation, thus treating potential
metastatic parametrial involvement.
What will be the standard of care for early cervical cancer in the fu-
ture? It will undoubtedly minimize the morbidity of local tumor resec-
tion with non-radical procedures for low risk patients. While the
definition of low risk is as yet to be universally accepted, it will likely
be similar to that listed above. LVSI is a strong predictor of lymph
node metastases and recurrence, however, its prevalence of 30-60% in
stage I disease makes it overly restrictive in defining low risk patients
[9]. Undoubtedly, SLNB alone will replace pelvic lymph node dissection,
reducing lymphedema, neuro-vascular injuries, and operating time. It is
only a matter of time for studies to complete accrual, data to mature,
and investigators adapt to new paradigms of management.
Conflict of Interest
The authors, Drs. Lennox and Covens have no conflicts of interest to
declare.
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Genevieve K. Lennox
Division of Gynecologic Oncology, Department of Obstetrics and
Gynecology, University of Toronto, M700-610 University Avenue, Toronto,
ON M5G 2M9, Canada
Allan Covens
Division of Gynecologic Oncology, T2051 Odette Cancer Centre, University
of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada
Corresponding author.
E-mail address: al.covens@sunnybrook.ca