Objective: Radiotherapy is usually recommended following radical hysterectomy (RH) in early-stage cervical cancer with intermediate risk. However, adjuvant radiotherapy only decreases recurrence but not overall survival. This study aimed to compare different adjuvant modalities’s efficacy and to identify prognostic factors among these patients. Methods: A single-center retrospective study was conducted between 2001 and 2015 on FIGO stage IB–IIA cervical cancer patients with intermediate risk following RH. 97 patients were enrolled for analysis. The patients underwent either RH and chemotherapy (n = 24), RH and radiotherapy (n = 21), or RH and close surveillance (n = 52). Prognostic factors that affected disease-free survival (DFS) and overall survival (OS), were compared by Kaplan-Meier analysis. Cox regression was used for univariate and multivariate analyses. Results: The median follow-up period was 117.7 months. There was no statistical difference between 5-year DFS and OS among patients receiving different adjuvant treatments, but patients with non-squamous histology had a lower 5-year DFS (p = 0.014). Multivariate analysis demonstrated no factors but only non-squamous histology significantly predicted DFS (HR = 3.565, 95% CI 1.334–9.531). Conclusions: Non-squamous histology, but not different adjuvant treatment, affects DFS in patients with stage IB–IIA cervical cancer with intermediate pathological risk following RH.
Cervical cancer is the fourth most common cancer in women worldwide . Owing
to the promotion of cervical smear screening since 1995, the age-standardized
incidence rate of cervical cancer in Taiwan has decreased from 12.8 per 100,000
women in 2008, to 8.1 per 100,000 in 2016 . Although the 3-year Pap smear
screening rate among Taiwanese women aged
The Taiwan Clinical Practice Guidelines for Cervical Cancer  and the National Comprehensive Cancer Network guidelines  both recommend radical hysterectomy (RH) for patients with early-stage cervical cancer, with the administration of adjuvant treatment if final pathological characteristics indicate risk of recurrent disease [4,5]. The presentation of positive surgical margins, parametrium involvement, or confirmed pelvic lymph node metastasis after RH indicate a high risk of recurrence, for which adjuvant concurrent chemoradiation therapy (CCRT) is recommended . Adjuvant radiotherapy is typically recommended for patients with an intermediate risk of recurrence, which is defined by pathological features which meet the Sedlis criteria, including the presence of lymph-vascular space invasion (LVSI), deep stromal invasion (SI), and large tumor size .
The Gynecologic Oncology Group (GOG) randomized trial #92  noted that, in patients with an intermediate risk, adjuvant radiotherapy (RT) led to a 47% reduction in recurrence; however, follow-up of the same cohort demonstrated that adjuvant RT only reduced the risk of recurrence, but created no significant improvement in overall survival (OS) . Therefore, this study aimed to identify potential prognostic factors, including modalities of adjuvant treatment, that contribute to oncologic outcomes among patients with stage IB–IIA cervical cancer with intermediate risk following RH.
This retrospective cohort study was performed at the Department of Obstetrics
and Gynecology, Kaohsiung Chang Gung Memorial Hospital (KCGMH), and was approved
by the Ethics Committee and the Institutional Review Board of KCGMH
(IRB201902292B0). Between January 2001 and December 2015, a total of 424 patients
with cervical cancer, staged at IB–IIA according to the 2009 International
Federation of Gynecology and Obstetrics (FIGO) staging system and who received
standard RH and pelvic lymphadenectomy by laparotomy as primary treatment, were
identified. Experienced pathologists performed the pathological reviews of
patients’ surgical specimens to evaluate the risk of recurrence. The diagnosis
was defined as intermediate risk if any of the Sedlis criteria from GOG protocol
#92  were met: (1) positive LVSI and involvement of deep one-third SI; (2)
positive LVSI, middle one-third SI, tumor size
All patients who received adjuvant chemotherapy (CT) underwent 3–6 cycles of
one of the following cisplatin-based combination chemotherapy regimens: (1) 50
Patients in the adjuvant RT group received whole-pelvic RT, which was administered using either the four-field box technique  or intensity-modulated radiation therapy (IMRT) ; the latter of which replaced the four-field box technique at our institute from 2006 onwards. The dose of external-beam RT was administered with a daily fraction of 1.8 Gy for five fractions per week. Based on the radiologists’ preference, some patients also received additional intravaginal brachytherapy at a total dose of 800 cGy administered by two fractions.
Patients were regularly followed up every three months for three years, and then every six months thereafter, starting from the commencement of close surveillance after RH (i.e., the RH only group) or after completion of adjuvant therapy. The performed surveillance modalities included symptom review, pelvic examination, vaginal cuff cytology, and chest radiographs. If symptoms or suspicion of recurrence, computed tomography or magnetic resonance imaging were performed for surveillance following RH. Any recurrence noted during follow-up was categorized as either local recurrence (involving the pelvis), distant failure (outside the pelvis), or a combination of both.
Descriptive statistics were reported as the mean and range. Mann-Whitney U
tests or Kruskal-Wallis one-way ANOVAs were used to compare continuous variables.
Chi-squared tests or Fisher’s exact tests were used to compare categorical
variables. Disease-free survival (DFS) and overall survival were defined as the
interval between the date of surgery and the date of first evidence of recurrence
or disease-specific death, respectively. Patients who died of intercurrent
diseases without recurrence, or who were lost to follow-up, were censored at the
time of last known follow-up. Actuarial rates of survival were estimated using
the Kaplan-Meier method, and statistical differences between groups were examined
using the log-rank test. A Cox regression model was used to determine the
independent factors associated with survival. Data management and analysis were
performed using the SPSS software for Windows (version 22.0) (IBM, Armonk, NY,
Detailed pathological review revealed 113 patients with stage IB–IIA cervical
cancer who met the criteria of intermediate risk following RH. Sixteen patients
were excluded for treatment heterogeneity, rare histologic type, or loss to
follow-up; therefore, 97 patients were enrolled in this study cohort. These
patients all received standard RH and pelvic lymphadenectomy by laparotomy, and
there was an average of 37.5 lymph nodes harvested in each patient. Demographic
characteristics of the study cohort are listed according to the different
treatment modalities in Table 1. The mean age of patients at diagnosis was 50.7
years (range, 30–72 years). Twenty-one patients (21.6%) underwent RH and
radiotherapy, 24 patients (24.7%) underwent RH and chemotherapy, and 52 patients
(53.6%) received RH and close surveillance. Sixty-eight patients (70.1%) were
diagnosed with squamous cell carcinoma (SCC), while the 29 patients (29.9%) with
non-SCC histology were either diagnosed with adenosquamous carcinoma (ASC) (n =
14) or adenocarcinoma (AC) (n = 15). Regarding intermediate risk factors, 16.5%
of patients presented with
|Mean age (range)||50.7 (30–72)||47.0 (30–66)||50.7 (36–69)||52.4 (31–72)||0.079|
|SCC||68 (70.1)||15 (62.5)||15 (71.4)||38 (73.1)|
|Non-SCC||29 (29.9)||9 (37.5)||6 (28.6)||14 (26.9)|
|2009 FIGO stage|
|IB||96 (99.0)||24 (100)||21 (100)||51 (98.1)|
|IIA1||1 (1.0)||0 (0)||0 (0)||1 (1.9)|
|Tumor size (cm)||0.015|
|81 (83.5)||21 (87.5)||13 (61.9)||47 (90.4)|
|16 (16.5)||3 (12.5)||8 (38.1)||5 (9.6)|
|12 (12.4)||2 (8.3)||2 (9.5)||8 (15.4)|
|85 (87.6)||22 (91.7)||19 (90.5)||44 (84.6)|
|No||12 (12.4)||0 (0.0)||5 (23.8)||7 (13.5)|
|Yes||85 (87.6)||24 (100.0)||16 (76.2)||45 (86.5)|
|FIGO, International Federation of Gynecology and Obstetrics; RH+CT, radical
hysterectomy followed by adjuvant chemotherapy; RH+RT, radical hysterectomy
followed by adjuvant radiotherapy; RH only, radical hysterectomy followed by
close surveillance; SCC, squamous cell carcinoma; non-SCC, non-squamous cell
carcinoma, such as adenocarcinoma or adenosquamous cell carcinoma; LVSI,
lymph-vascular space invasion. Values are presented as the number of cases and
percentages in brackets. |
Statistics: Kruskal-Wallis one-way ANOVA; Chi-squared test/Fisher’s exact test; Kaplan-Meier analysis and Cox regression.
The median duration of follow-up was 117.7 months (range, 6.9–218.3 months). The Kaplan-Meier DFS and OS survival curves of the 97 patients receiving different modalities of adjuvant treatments are shown in Fig. 1A,B. There were no statistically significant differences in 5-year DFS (RH+CT: 82.6%, RH+RT: 70.8%, RH only: 88.1%, p = 0.350) and OS (RH+CT: 91.3%, RH+RT: 85.4%, RH only: 95.8%, p = 0.343) between the different modalities of adjuvant treatment. The overall recurrence rate was 20.6%, with local and distant recurrence accounting for 65% and 35%, respectively (Table 2). There were no obvious differences in local or distant recurrence rates between adjuvant treatment modalities (p = 0.964). In addition, the deaths of two patients in RH+RT group, two patients in RH+CT group, and three patients in RH only group were related to recurrent disease.
Comparing the efficacy between different adjuvant management. (A) Comparison of DFS between the different modalities of adjuvant management. (B) Comparison of OS between the different modalities of adjuvant management. RH+CT, radical hysterectomy followed by adjuvant chemotherapy; RH+RT, radical hysterectomy followed by adjuvant radiotherapy; RH only, radical hysterectomy followed by close surveillance.
|RH+CT||24||5 (20.8)||3 (60.0)|
|RH+RT||21||6 (28.6)||4 (66.7)|
|RH only||52||9 (17.3)||6 (66.7)|
|Overall||97||20 (20.6)||13 (65.0)|
|RH+CT, radical hysterectomy followed by adjuvant chemotherapy; RH+RT, radical
hysterectomy followed by adjuvant radiotherapy; RH only, radical hysterectomy
followed by close surveillance. Values are presented as the number of cases and
percentages in brackets. |
Statistics: Chi-squared test/Fisher’s exact test.
The Kaplan-Meier curves for DFS and OS of the 97 patients, grouped by histological type, are shown in Fig. 2A,B. Univariate analysis showed that patients with SCC-type histology had a better DFS compared to patients with non-SCC histology (p = 0.014). However, no differences in OS were observed between histology types (p = 0.489). In addition, the overall rate of recurrence was higher in patients with non-SCC histology than those with SCC histology (35.5% vs. 14.7%, P = 0.028) (Table 3). Multivariate analysis showed that non-SCC histology was the only significant variable that predicted DFS. The hazard ratio and 95% confidence interval for predicting recurrence was 3.565 (1.334–9.531; p = 0.011) (Table 4). Age, histological type, depth of SI, presence of LVSI, tumor size, and different modalities of adjuvant management were not significant factors predicting OS in either univariate or multivariate analyses.
Comparing the prognosis between different histologic types. (A) Comparison of DFS between SCC and non-SCC histological types. (B) Comparison of OS between SCC and non-SCC histological types. SCC, Squamous cell carcinoma; Non-SCC, Non-squamous cell carcinoma, such as adenocarcinoma or adenosquamous cell carcinoma.
|SCC||68||10 (14.7)||6 (60.0)|
|Non-SCC||29||10 (35.5)||7 (70.0)|
|Overall||97||20 (20.6)||13 (65)|
SCC, Squamous cell carcinoma; Non-SCC, Non-squamous cell carcinoma, such as
adenocarcinoma or adenosquamous cell carcinoma. Values are presented as the
number of cases and percentages in brackets. |
Statistics: Chi-squared test/Fisher’s exact test.
|Variable||5-year DFS (%)||HR (95% CI)||p-value||HR (95% CI)||p-value|
|Non-SCC||70.8||2.866 (1.189–6.908)||3.565 (1.334–9.531)|
|SCC, Squamous cell carcinoma; Non-SCC, Non-squamous cell carcinoma, such as
adenocarcinoma or adenosquamous cell carcinoma; LVSI, lymph-vascular space
invasion; RH+CT, radical hysterectomy followed by adjuvant chemotherapy; RH+RT,
radical hysterectomy followed by adjuvant radiotherapy; RH only, radical
hysterectomy followed by close surveillance. |
Statistics: Kaplan-Meier method for survival analysis; Cox regression for univariate and multivariate analyses.
Our study revealed a significant difference in DFS between SCC and non-SCC histological types in stage IB–IIA cervical cancer patients with intermediate risk following RH. Univariate and multivariate analyses both showed that histological type, but not adjuvant treatment modality, was a significant prognostic factor for recurrence. The main controversy of dual-modality treatments (RH+RT) is that they may be related to the risk of long-term morbidities, which include lower limb lymphedema and ureteral and gastrointestinal obstruction [8,14]. Considering the increased long-term morbidity associated with adjuvant RT, and its uncertain prognostic outcome [8,15,16], the gynecologic oncologists at our institute also provided adjuvant CT or close surveillance for intermediate-risk patients. Interestingly, we found that close surveillance following RH also yielded a similar survival outcome when compared to adjuvant RT or CT.
The impact of histological type on the prognosis of cervical cancer has been
extensively investigated [17-19]. Shingleton et al.  analyzed the
cancer register database in United States between 1984 and 1990. They found no
significant difference in 5-year survival when comparing SCC, AC, and ASC types;
however, the enrolled cohort involved patients from a wide spectrum of clinical
stage and treatment heterogeneity. A 1995 GOG study , that focused primarily
on surgically-staged stage IB cervical cancer, demonstrated that histology had a
significant impact on survival (p = 0.02), but not recurrence (p
= 0.29), after adjusting for LVSI status, SI depth, and tumor size, poor
survival was remain noted in patients with ASC. Grisaru et al. 
grouped patients with similar features such as in the aforementioned GOG study,
and also reported a poorer 5-year DFS among patients with ASC (p
The GOG #92 trial  was pivotal in creating support for the role of adjuvant
RT in intermediate-risk patients, although the follow-up study indicated that the
impact of adjuvant RT on OS was inconclusive . The major limitation of GOG
trial #92 was that the inclusion criterion for tumor size were assessed by
visual inspection and palpation during pelvic examination rather than by more
quantitative/homogenous methods. Moreover, the extent of surgery was not
standardized in the study protocol. Several retrospective studies also
investigating the role of adjuvant RT in intermediate-risk patients following
surgery. Although retrospective in nature, unique surgical protocols were used in
these studies, and imaging or pathological assessment of tumor size was adopted,
which reflected the clinical staging of the modern era. For example, Cibula
et al.  reported a recurrence rate of 6.3% in the RH only group, of
which one-fourth were categorized as local pelvic recurrence. This extremely low
local failure rate was thought to be associated with the extensive nature of
surgery undergone by the RH only group, which involved with a greater degree of
lymph node retrieval and higher proportion of radical parametrectomies when
compared to the RH+RT group. They further indicated that the only independent
factor found to predict recurrence was tumor size
The efficacy of adjuvant CT has been validated in some retrospective studies [24-26]. A nationwide retrospective study in Japan, which enrolled 555 women with stage IB cervical cancer in the intermediate-risk group, demonstrated that adjuvant chemotherapy was not associated with a significant difference in 5-year DFS (p = 0.90) and 5-year cause-specific survival (p = 0.99) when compared to adjuvant RT or adjuvant CCRT . Similarly, a meta-analysis published in 2018 also demonstrated no statistical difference in disease recurrence between patients with early-stage cervical cancer and those who received adjuvant CT, compared to adjuvant RT after RH . In our study, intermediate-risk patients managed with adjuvant CT after RH achieved comparable oncologic outcomes to those who received adjuvant RT.
Our study specifically focused on stage IB–IIA cervical cancer patients at intermediate risk of recurrence following radical hysterectomy, who were enrolled after pathological review. The results presented here are subject to some limitations. For example, our study was a retrospective, single-center design, across the long study period. Besides, only limited case number enrolled in this study. There were also some uneven distributions in certain pathological features among the three treatment groups; such as, tumor size, LVSI, and the heterogeneity in the adjuvant chemotherapy regimen that the patients received. Despite these limitations, we identified that non-SCC histology, but not adjuvant treatment modalities, had an influence on DFS in stage IB–IIA cervical cancer patients with intermediate pathological risk following RH. Therefore, close surveillance after RH may be a viable option for patients with SCC-type histology. A prospective study evaluating the efficacy of more aggressive adjuvant management to reduce the recurrence rate for intermediate-risk patients with non-SCC histology may be warranted.
Non-squamous histology, but not modes of adjuvant treatment, affects DFS in patients with stage IB–IIA cervical cancer with intermediate pathological risk following RH.
Y-WW, HL, H-CF, C-CCC, Y-CO, and C-HW were responsible substantial contributions to the conception or design of the work. Y-WW, HL, H-CF, Y-CO, P-HL, C-CH, and C-HW were responsible for the acquisition, analysis, or interpretation of data. YW, HL, CW were responsible for drafting the work and revising it critically for important intellectual content. Y-WW, HL, H-CF, C-CCC, Y-CO, P-HL, C-CH, and C-HW were responsible for final approval of the version to be published, and all of them agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
The present study was approved by the Ethics Committee and the Institutional Review Board of KCGMH (IRB201902292B0). Due to the retrospective nature of the study, informed consent were not applicable.
We especially thank the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for assistance with the statistical analysis in this study. We would also like to thank Uni-edit (www.uni-edit.net) for editing and proofreading this manuscript.
This research received no external funding.
The authors declare no conflict of interest.