To the editor,
Cervical cancer most commonly affects young women, and between 2012 and 2014, it was
estimated that approximately one in 368 women younger than 50 years of age will be
diagnosed with invasive cervical cancer in the United States [1]. In this population
of young women, future fertility is often desired, and thus preservation of reproductive
function can be a key treatment concern [1]. Fertility-sparing surgery with trachelectomy
is the treatment of choice in these women, however, trachelectomy has generally been
only offered to women with at most stage IB1 cervical cancer with a tumor size less
than or equal to 2 cm per the current guideline recommendations [2]. To date, population-based
statistics regarding utilization of trachelectomy in women with stage IB1 cervical
cancer with tumors larger than 2 cm are lacking. This study examined trends and characteristics
of reproductive-aged women who underwent trachelectomy for stage IB1 cervical cancer
with tumors larger than 2 cm.
A retrospective study examining the Surveillance, Epidemiology, and End Results (SEER)
program between 1998 and 2014 was conducted. This database is a population-based tumor
registry that is supported and managed by the National Cancer Institute in the United
States. It is both publicly available and de-identified, thus this study was deemed
exempt by the University of Southern California Institutional Review Board. Women
less than 45 years of age with stage IB1 cervical cancer and tumor size 2.1–4.0 cm
were included. Cases prior to 1998 were excluded due to lack of detailed information
regarding the surgical procedure. Histology types examined in this study were squamous
cell carcinoma, adenocarcinoma, and adenosquamous carcinoma, as these 3 types are
generally recommended for trachelectomy per the current guidelines in the United States
[2]. Other rare histology types were excluded from the study.
Information extracted from the database included patient demographics (age, race/ethnicity,
marital status, registry area, and calendar year at diagnosis), tumor information
(histology type and tumor differentiation grade), treatment types (surgery type for
trachelectomy or radical hysterectomy, use of pelvic lymphadenectomy, adjuvant radiotherapy,
and adjuvant chemotherapy), and survival outcome (cause-specific survival). Clinico-pathological
characteristics and oncologic outcomes were compared between women who underwent trachelectomy
and those who had hysterectomy.
The primary interest of this analysis was to examine trends in utilization of trachelectomy
in young women with stage IB1 cervical cancer and tumors larger than 2.0 cm in size.
The secondary interest of this analysis was to identify factors contributing to trachelectomy
use as well as impact on cervical cancer mortality compared to hysterectomy.
The Joinpoint Regression Program (version 4.6.0.0) provided by the National Cancer
Institute (Bethesda, MD, USA) was utilized to evaluate temporal trends, which were
analyzed by linear segmented regression. Log-transformation was then performed to
determine the annual percent change of the slope with 95% confidence intervals (CIs)
as previously described [3
4
5]. Multivariable analysis with a binary logistic regression model (conditional backward
method) was used to determine the independent contributing factors for trachelectomy
use. In this model, all covariates with a p-value of less than 0.05 on univariable
analysis were entered into the initial model, and the least significant covariate
was removed from the model sequentially until the final model retained only covariates
with p-values of less than 0.05. The Hosmer-Lemeshow test was then utilized to assess
the goodness-of-fit in the final model, and a p-value of greater than 0.05 was considered
a good-fit model.
For survival analysis, the Kaplan-Meier method was used to construct survival curves
for cause-specific survival, and the log-rank test was used to assess statistical
significance between the curves. Cause-specific survival was defined as the time interval
between cervical cancer diagnosis and death from cervical cancer. Cases deemed to
be alive at the last follow-up were censored. A p-value of less than 0.05 was considered
statistically significant (all, 2-tailed hypothesis). Statistical Package for Social
Sciences (version 25.0; IBM SPSS, Armonk, NY, USA) was used for statistical analysis.
There were 1,457 women younger than 45 years of age who met the inclusion criteria,
with stage IB1 cervical cancer and tumor size greater than 2.0 cm. Among those eligible
cases, 29 (2.0%, 95% CI=1.3–2.7) women underwent trachelectomy. Patient demographics
are shown in Table 1. Women who underwent trachelectomy were significantly younger
than those who had hysterectomy (median, 31 vs. 37, p<0.001). The proportion of women
who underwent trachelectomy significantly increased during the study period (0.5%
in 1998–2002, 2.2% in 2003–2008, and 2.9% in 2009–2014, p=0.04). The annual percent
change between 2000 and 2014 was 11.2, 95% CI=2.5–20.7 (p=0.019, Fig. 1A). Other clinico-pathological
factors were similar between the 2 groups (all, p>0.05). On multivariable analysis
(Table 1), younger age and more recent year of diagnosis were independent factors
associated with performance of trachelectomy (both, adjusted-p<0.05).
The median follow-up of the entire cohort was 6.3 years (inter-quartile range=2.8–10.9),
and there were 120 (8.2%) cervical cancer deaths. Although it did not reach statistical
significance, women who underwent trachelectomy had a higher 5-year cervical cancer-specific
mortality rate than those who had hysterectomy (14.4% vs. 8.4%, unadjusted-hazard
ratio=1.61; 95% CI=0.51–5.06; p=0.41; Fig. 1B).
Although performance of trachelectomy remained uncommon, our study showed a gradual
increase in the utilization of trachelectomy for reproductive-aged women with stage
IB1 cervical cancer with tumors larger than 2 cm in the United States. Our results
partly support the recent study using the National Cancer Database that demonstrated
a significant increase in the utilization of fertility-sparing trachelectomy for women
aged younger than 30 years with early-stage cervical cancer in the United States [6].
However, population-based statistics specific to stage IB1 cervical cancer with tumor
size larger than 2 cm have not been examined previously. Thus, our results certainly
imply that both surgeons and patients are seeking out opportunities for fertility
preservation beyond the current guideline recommendations, which reserve trachelectomy
in stage IB1 disease for tumors less than 2 cm. A recent retrospective study, however,
reported that nearly one third of women with tumors 2–4 cm may be candidates for trachelectomy,
emphasizing that expansion of the indication criteria for trachelectomy would allow
these women the option of future fertility [7].
Yet, the safety of trachelectomy for tumors of the cervix larger than 2 cm remains
undetermined. While recent population-based studies show that survival outcomes are
comparable between less invasive surgery including trachelectomy and definitive hysterectomy
for early-stage cervical cancer, these studies did not specifically examine trachelectomy
for stage IB1 disease with tumor size larger than 2 cm [6,8]. In this specific subset
of patients with tumors larger than 2 cm, our study and a prior pooled analysis reported
a 6%–17% recurrence risk and a 1%–4% death rate. Given that current studies are limited
by both sample size and follow-up, further studies are needed before trachelectomy
can be considered a safe treatment option for women with tumors larger than 2 cm in
diameter [7,9].
A limitation of our study is that this is a retrospective population-based study,
and there may be possible confounding factors that could have impacted results. For
instance, route of surgical approach for both trachelectomy and hysterectomy was not
available in this database. A recent phase III randomized controlled trial found that
minimally invasive hysterectomy was significantly associated with increased risk of
recurrence and cancer mortality compared to abdominal approach [10]. Moreover, other
surgical-pathological factors that certainly impact clinical and treatment decision-making
such as lympho-vascular space invasion, depth of cervical stromal invasion, details
of nodal status, and information regarding parametrial invasion are missing in the
SEER database, and thus detailed risk-adjustment was not applicable in this study.
Surgeon quality and surgical volume per institution were also not available in the
SEER database, both of which may impact patient prognosis. Finally, details of chemotherapy
including use of neoadjuvant chemotherapy were not retrievable in the SEER database.
In summary, there has been a significant increase in the use of fertility-sparing
surgery with trachelectomy in young women with stage IB1 cervical cancer with tumors
larger than 2 cm in recent years in the United States. While this trend may be encouraging
for reproductive-aged women with cervical cancer who desire future fertility, oncologic
safety remains undetermined in this subset of women with tumors >2 cm. At this time,
when trachelectomy is considered in women with stage IB1 cervical cancer with tumors
>2 cm, careful counseling and individualized treatment discussions with patients are
imperative given the unknown safety of fertility-sparing treatment in this population.