Pathological evaluation, staging, treatment and
follow-up
Detailed information on the diagnosis, treatment, and surveillance for
SCNEC were illustrated in Supplementary Materials (online
only ). All patients in each cohort were restaged by two radiation
oncologists (FPC and XDH) specialized in gynecological cancer according
to the 2018 International Federation of Gynecology and Obstetrics (FIGO)
staging system [16], with disagreements resolved
by consensus.
Statistical
analysis
The primary endpoint was progress-free survival (PFS), which was
calculated from the initial diagnostic biopsy to date of first relapse
regardless of site or a 25% or more increase in size of any
pre-existing lesion and/or death from any cause. Secondary endpoint was
overall survival (OS), calculated from initial diagnostic biopsy to date
of death from any cause, or date of last follow-up visit.
Survival analyses were performed
using the Kaplan-meier method and compared by the log-rank test.
Categorical variables were classified based on clinical findings, and
continuous variables were transformed into categorical variables based
on median values of our cohort. Because of the complexity of
chemotherapy regimens, we classified the multimodal regimens as
etoposide plus platinum (EP) and non-EP. Differences of continuous
variables were compared using Mann-Whitney U test, and categorical
variables were compared using the
chi-square or Fisher exact test. The
cox proportional hazards regression was performed to calculate hazard
ratios (HR) and 95% confidence interval (CI). Multivariable analyses
using cox proportional hazards models were performed to evaluate the
potential prognostic factors adjusted for age, histology and FIGO stage.
The restricted cubic splines (RCS) that estimated from the full cox
regression model was used to evaluate the relationships (in HR) between
chemotherapy cycles with PFS and OS. All statistical tests were
two-sided, and a P -value of <0.05 was considered
significant. Statistical analyses were performed in R version 3.4.4
(http://www.r-project.org/),
and SPSS 23.0 software (SPSS Inc,
IL).
All end points were updated in January 2021.
Results
Patient characteristics
and treatment outcomes
The characteristics of the patients are listed in Table 1 . Of
the 103 patients, FIGO stage I-IIA was diagnosed in 62 (60.2%)
patients, and stage IIB-IIIC in 41 (39.8%) patients. All of the
enrolled patients have received chemotherapy; EP regimen was carried out
in 66 (64.1%) patients, non-EP alone regimens in 37 (35.9%) patient
(Table 1 ).
The breakdown of the sites of relapses of these cohorts is detailed inTable S1 (online only) . Median PFS and OS of the entire cohort
were 30.8 (95% confidence interval [CI], 24.4-37.2) months and 53.5
(95% CI, 25.2-81.8) months, respectively.
Cycle-dependent
effect of chemotherapy cycles on survivals
To quantify the cycle-dependent effect on survival outcomes, we entered
chemotherapy cycles into the RCS fitted cox regression to allow for
nonlinear relationships between chemotherapy course and survivals. The
models identified that the risks (HR) of disease progression and death
decreased as the cycles increased; 5 cycles of chemotherapy was
identified as threshold that consistent for risk discretization to PFS
and OS (Figure 2A and 2B ). Hence, we classified chemotherapy as
short-course (1-4 cycles) and long-course (≥5 cycles) based on the
threshold (Table S2 ). Through Kaplan-Meier plots, we observed
that patients who received ≥5 cycles of chemotherapy demonstrated
significantly superior PFS (≥5 vs 1-4: median PFS, 58.6 monthsvs 25.4 months, P =0.027; Figure 2C ) and
prolonged OS (≥5 vs 1-4: median OS, 65.1 months vs 37.7
months, P =0.168; Figure 2D ) than those treated with 1-4
cycles. After adjustment for potential prognostic covariates (age,
histology and FIGO stage) in multivariable analysis, chemotherapy cycles
were independently significant for PFS (HR 0.52, 95% CI 0.30-0.88;P =0.015; Table S3 ), and OS (0.57, 0.31-1.00; P=0.050; Table S3 ). These findings indicate that treatment with
≥5 cycles of chemotherapy contribute to survival improvement in patients
with SCNEC. Given that heterogeneity in terms of tumor extension and
prognosis was obvious among the patients, we then performed subgroup
analyses to determine the therapeutic effect of chemotherapy cycles
within different FIGO stages.