Therapeutic efficacy of chemotherapy cycles within
different FIGO stage
Exploratory subgroup analyses of PFS and OS were generally consistent
with the overall findings that ≥5 cycles of chemotherapy was superior to
1-4 cycles (Figure 3 ). An additional analysis by FIGO stage
also suggested that significant
improvements in PFS and OS were identified in
long-course chemotherapy in FIGO
stage IIB-IIIC (n=17 for ≥5 cycles, n=24 for 1-4 cycles;
HRPFS 0.41, 95% CI 0.18-0.92; HROS0.41, 95% CI 0.17-0.95), but not entirely significant improvements in
FIGO stage I-IIA (n=32 for ≥5 cycles, n=30 for 1-4 cycles;
HRPFS 0.67, 95% CI 0.34-1.34; HROS0.88, 95% CI 0.40-1.97); these results were also confirmed in survival
curves (Figure 4 ). Additionally, in multivariate analyses, ≥5
cycles of chemotherapy significantly reduced the risk of disease
progress and death, and was independently prognostic for PFS and OS in
FIGO stage IIB-IIIC after adjusting for age and histology; nevertheless,
such significances were not achieved in FIGO stage I-IIA (Table
S4 ). These findings indicated that the survival benefit of long-course
chemotherapy in SCNEC can be predicted by FIGO stages; ≥5 cycles of
chemotherapy was inclined to achieve favourable survival outcomes in
FIGO stage IIB-IIIC, but comparable survivals in FIGO stage I-IIA.
Interaction effect of
chemotherapy cycles and regimen
Because of the multiple chemotherapy regimens used in the cohort, we
then evaluated the optimal regimen for SCNEC. We observed that patients
who received EP regimen had obvious prolonged PFS (median PFS: EPvs non-EP, 44.7 months vs 18.0 months; Figure
S1A ) and OS (median OS: EP vs non-EP, 63.3 months vs 41.0
months; Figure S1B ) than those treated with non-EP regimen,
although the statistic significances were not achieved partly owing to
the limited sample size. Next, we investigated the interaction between
chemotherapy regimens and courses by incorporating them together, and
divided the patients into the following four groups: EP with 1-4 cycles
(EP 1-4), EP with ≥5 cycles (EP ≥5), non-EP with 1-4 cycles (non-EP 1-4
cycles), and non-EP with ≥5 cycles (non-EP ≥5). Of the whole cohort, we
observed significantly different PFS among these four groups, with EP ≥5
obtaining most satisfied survival (P = 0.011, Figure
S2A ); whereas the statistic significance of OS was not achieved
(P = 0.160, Figure S2B ). Then we performed subgroup
analyses stratified by FIGO stage; interestingly, we identified that
these four groups obtained
significances of both PFS (P =
0.026, Figure S2E ) and OS (P = 0.042, Figure
S2F ) in FIGO stage IIB-IIIC, but neither significant of PFS (P =
0.370, Figure S2C ) nor OS (P = 0.860, Figure
S2D ) in FIGO stage I-IIA. Hence, we can conclude that EP regimen with
≥5 cycles should be proposed for patients with FIGO IIB-IIIC
SCNEC, nonetheless the optimal regimen
and course for FIGO stage I-IIA SCNEC need further investigation.
Discussion
In this retrospective cohort of SCNEC, we observed an inverse
correlation between chemotherapy cycles and progression/death; the risks
of disease progression and mortality decreased sharply until 5 cycles of
chemotherapy. Long-course chemotherapy was associated with significantly
superior PFS and OS than short-course chemotherapy. Additionally, FIGO
stage was predictive to the therapeutic efficacy of long-course
chemotherapy; ≥5 cycles of chemotherapy was superior to <5
cycles of chemotherapy in terms of PFS and OS in FIGO stage IIB-IIIC,
whereas such superiority was not observed in FIGO I-IIA. Furthermore,
chemotherapy regimen was identified to be relevant to survival outcomes;
EP regimen demonstrated obvious prolonged PFS and OS than those treated
with non-EP regimen.
SCNEC is one of the most lethal gynecological malignancies that
characterized with high mitotic rate, extensive necrosis, frequent
lymph-vascular space involvement (LVSI) and strong association with HPV
18 [17-19]. It is highly aggressive with extremely
high risk of local and distant failure, even for patients at early stage[14, 19]. In our series, treatment failure was
identified in approximately 60% of patients, and the majority presented
with hematogenous dissemination to distant organs, including liver,
lung, bone marrow and multiple sites; median PFS and OS for the entire
cohort were 30.8 (95% CI 24.4-37.2) months and 53.5 (95% CI,
25.2-81.8) months, respectively, which was consistent with previous
reports [8, 12, 14]. Therefore, a major challenge
in improving the prognosis of SCNEC is to adopt a comprehensive
treatment approach to reduce the risk of disease failure. Nonetheless,
the optimal treatment strategies, especially the most appropriate
chemotherapy regimen and course for patients with SCNEC is under
determined as yet [20]. We hence carried out this
study to identify the association between chemotherapy intensity and
survival outcomes, and aimed to establish a risk-based systemic
treatment recommendation for patients with SCNEC.
Foremost, this study represents a critical step toward understanding the
cycle-dependent effect of chemotherapy on survival outcomes in SCNEC.
The necessity of chemotherapy for improving survival is well recognized
for SCNEC on account of the very high risk of hematogenous dissemination[21]. Nonetheless, the optimal chemotherapy
regimen and course is under determined owing to the rarity of this
disease. In SCLC, a regimen of 4-6 cycles of EP is most commonly
recommended because of its superiority in both efficacy and toxicity.
Similarly, this regimen was also empirically proposed for SCNEC
regardless of tumor extent because of its clinical biological similarity
with SCLC. Whereas, there were only a small amount of data focus on this
topic and the evidence proving the validity and safety of this regimen
was limited. This raises questions whether EP regimen chemotherapy still
works in SCNEC, and what’s the optimal cycle that possess both satisfied
effectiveness and acceptable toxicity. Research into these topics is
essential to optimize treatment strategies and individualize treatment
plans for SCNEC. Generally, the prognosis of SCNEC is associated with
tumor burden, namely FIGO stage. Patients with early staged tumor (FIGO
I-IIA) usually demonstrated superior prognosis than those with advanced
tumor (FIGO IIB and above). Hence it is reasonable to hypothesize that
treatment may be streamlined according to FIGO stage, namely systemic
de-intensification for early staged SCNEC, whereas intensification for
advanced staged SCNEC to reduce the risk of distant metastasis. In the
current study, we observed inverse correlation between chemotherapy
cycles with the risks (HR) of disease progression and death;
≥5 cycles was associated with
significantly reduced risks of PFS and OS. Nonetheless, not all patients
benefited from ≥5 cycles of chemotherapy. Long course chemotherapy with
≥5 cycles mainly showed survival benefit in patients with FIGO stage
IIB-IIIC, while a short course of 1-4 cycles was adequate for early
staged SCNEC. Hence, we can conclude that chemotherapy was essential for
patients with SCNEC, and the intensity of chemotherapy could be modified
according to the tumor burden. We proposed a maximum of 4 cycles for
those with FIGO stage I-IIA, whereas ≥5 cycles for those with FIGO stage
IIB-IIIC was essential.
Additionally, our results support the use of EP chemotherapy regimen as
preferred regimen for SCNEC. In our cohort, EP regimen tended to achieve
prolonged PFS and OS than non-EP regimen, although the significances
were not obtained due to the limited sample size. The combination of
cisplatin and etoposide was
initially developed in patients with previously treated SCLC[22], and soon became the most commonly used
regimen for patients with SCLC due to the strong evidence showing
promising results [23-24]. Additionally, EP
regimen was whereafter identified as the first-line chemotherapy for
small cell neuroendocrine tumors of other sites such as esophagus[25], ileum [26], and
bladder [27] due to the akin natural history to
SCLC and their propensity for distant spread. Likewise, EP regimen was
also recommended for SCNEC [14, 21] considering
evidences showing the superiority of EP regimen over other regimens with
better outcome and lower toxicity [28-29]. Chang
and colleagues used to report significant survival benefit for patients
who treated by vincristine, adriamycin, and cyclophosphamide alternating
with EP (VAC/PE) regimen compared to those treated with cisplatin,
vinblastine, and bleomycin (PVB) combination (5-year survival VAC/PEvs PVB, 68% vs 33%, P =0.0078)[30]. Similarly, Zivanovic et al also reported
that the patients who received postoperative EP regimen chemotherapy had
a significant higher 3-year recurrence-free survival than those who did
not receive adjuvant chemotherapy (83% vs 0%) for in early
stage SCNEC [8]. Hence, EP regimen was firstly
proposed as preferred regimen for SCNEC in the latest version of
National Comprehensive Cancer Network guidelines (version 1 2021)[21].
Notably, we did not focus on the sequence of chemotherapy in terms of
efficacy, since this was beyond the scope of the current study.
Additionally, selection bias was obvious in this cohort because
induction chemotherapy (IC) was mainly performed in patients with higher
tumor burden, whereas adjuvant chemotherapy (ACT) was undertaken in
almost all patients. Hence, it is infeasible for the efficacy comparison
of IC and ACT in our cohort. Generally, IC was considered to have better
tolerated and could eradicate micrometastases earlier, compared with
adjuvant sequencing. Nonetheless, IC can also put off the time of
radical treatment, which may result in tumor progress. Currently, the
role of IC in treatment SCNEC is controversial, since the very small
sample sizes of relevant studies make it difficult to draw definitive
conclusions [15, 31]. Chang et al. observed a high
complete response rate in 6 out of 7 patients that treated with
neoadjuvant VAC/PE before hysterectomy; however, microscopic residual
tumor was identified in all cases, and additional three courses of ACT
were given after surgery [31]. Additionally, Lee
et al. reported no survival benefit among 6 patients that received IC[15]. In our cohort, IC alone was only performed
in 4 patients, but we still observed inferior survival outcomes in these
patients compared with IC+ACT and ACT (median PFS, IC vs IC+ACTvs IC+ACT: 5.8 vs 31.7 vs 31.4 months; median OS,
12.4 vs 53.5 vs 44.3 months; Figure S3 ). Hence,
we believe that neoadjuvant sequencing was not adequate for patients
with SCNEC, and ACT was essential for the treatment of SCNEC. Other
caveats of our study included inherent biases considering the
retrospective nature of this study and the patient recruitment from a
single institution. Nonetheless, because of the rarity of the disease,
it is infeasible to conduct a prospective randomized study in SCNEC.
Hence, a solution was to include a consecutive, well-characterized
cohort that encompassing early to advanced stages of disease to improve
the reliability of our conclusion. Additionally, the conclusions of our
study need further validation in external cohort.
In conclusion, our results implied that chemotherapy cycles had inverse
correlation with risks of disease progression and death; long-course
chemotherapy of ≥5 cycles significantly reduced the risks of PFS and OS
in patients with FIGO stage IIB-IIIC, while a short course of 1-4 cycles
was enough for early staged SCNEC. We proposed a maximum of 4 cycles for
those with FIGO stage I-IIA, but ≥5 cycles for those with FIGO stage
IIB-IIIC. Although this study was retrospective in design, with a
limited number of patients, it is still one of the largest series
reported to date. We hope that our experience contributes to the
foundation of knowledge regarding this rare but aggressive tumor.