Abstract
Objectives
The objective of this study was to explore a better adjuvant treatment for patients with high-grade (HG) neuroendocrine cervical carcinomas (NECC) who had undergone surgery as a primary treatment.
Design
A retrospective cohort study, which involved women diagnosed as HG-NECC, was conducted in the Obstetrics and Gynecology Hospital of Fudan University. All patients had undergone radical surgery and pelvic lymphadenectomy with a laparotomy or a minimally invasive surgery. An analysis was made of the prognosis of HG-NECC.
Methods
Overall survival (OS) and progression-free survival (PFS) curves were drawn using the Kaplan-Meier method to be compared via log-rank tests. A Cox proportional hazards model was used to estimate the independent prognostic factors.
Results
A number of 110 patients diagnosed as HG-NECC at the pathological stage IA2 to IIIC2 according to the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging system were initially treated with a primary surgery between 2008 and 2020. The eligible patients had the median age of 42.5 years (range: 22–76), with the median follow-up period of 39.6 months (range: 1.0–156.6). The 5-year OS of the patients at pathological stage I, II, and III accounted for 84.9%, 85.7%, and 60.9%, respectively. The Kaplan-Meier survival curves revealed no significant differences in OS and PFS between postoperative chemoradiotherapy and chemotherapy alone (OS: p = 0.77; PFS: p = 0.41). Etoposide plus platinum therapy did not improve OS when compared with platinum plus paclitaxel therapy after surgery (p = 0.71). The univariable analysis showed that chemotherapy with cycles ≥4 presented a better prognosis than with cycles <4 (OS: p = 0.01; HR = 6.71; PFS: p = 0.02; HR = 5.18). The multivariate analysis indicated that the cycles of chemotherapy (p = 0.02; HR 0.29) were a prognostic factor for PFS.
Limitations
A retrospective design and the absence of partial follow-up data are limitations of the study.
Conclusions
In initially surgically treated HG-NECC, postoperative chemotherapy alone showed no inferiority when compared with chemoradiotherapy for HG-NECC, and 4+ cycles of chemotherapy tended to produce a better prognosis than 4-ones.
Keywords: Adjuvant treatment, Neuroendocrine cervical carcinomas, Overall survival prognosis, Progression-free survival
Introduction
Nowadays, neuroendocrine carcinoma accounts for 1–1.5% of all cervical cancer cases [1, 2]. Neuroendocrine cervical carcinoma (NECC), an aggressive histological type, is classified into four categories: typical carcinoid, atypical carcinoid, small-cell neuroendocrine carcinoma, and large-cell neuroendocrine carcinoma [3]; the former two are categorized as low-grade neuroendocrine carcinomas and the latter two as high-grade (HG) neuroendocrine carcinomas. It is well known that HG-NECCs are much more aggressive, which are prone to hematologic and lymphatic metastases, even at an early stage [4]. There has been a dearth of research works on HG-NECC, especially of the related prospective multicenter studies on various management strategies, which could have been ascribed to its rare incidence. Surgery has been the primary treatment for early-stage NECC [5, 6]; however, treatment options remain debatable in the case of advanced HG-NECC. Additionally, no consensus has been reached on the adjuvant postoperative treatments, and few investigations have been reported on the prognosis of HG-NECC patients after a primarily treated surgery. To explore an ideally formulated adjuvant regimen for the HG-NECC patient who has undergone a primarily treated surgery, we conducted a retrospective cohort study at a single institute and also evaluated the surgical prognosis of HG-NECCs.
Materials and Methods
The study, approved by the Institutional Ethics Review Committee of the Obstetrics and Gynecology Hospital of Fudan University, was a retrospective cohort study. The participants enrolled were the women who were diagnosed as HG-NECC and underwent surgery as a primary treatment at a single institute from January 2008 to December 2020. The patients were pathologically diagnosed as small-cell-, large-cell-, or HG-NECC. It was worth mentioning that HG-NECC here was of small-cell type or large-cell one, for sometimes, it was difficult to be pathologically identified to be either. The data on tumor-composition diagnosis were obtained from both biopsy and hysterectomy specimens. The presence of non-neuroendocrine carcinomatous component was recorded as a mixed type, which included adenocarcinoma, squamous carcinoma, and adenosquamous carcinoma. Immunohistochemical analysis was performed to confirm the neuroendocrine features using the markers of chromogranin A, synaptophysin, and cluster of differentiation 56. The inclusion criteria referred to those who had received surgery as a primary treatment. The exclusion criteria were as follows: no surgery accepted or inadequate extent of surgery, neoadjuvant therapy, and other carcinomas involved. Patients diagnosed as stage IA-IIB before surgery were enrolled based on the FIGO 2008 system. All histopathologic reviews were conducted by gynecological pathologists. As shown in online supplementary Figure 1 (for all online suppl. material, see www.karger.com/doi/10.1159/000527661), the diagram of the study population was made via Consolidated Standards of Reporting Trials.
From the archived medical records, we obtained the data on the clinicopathological characteristics: age, histology, tumor size, deep stromal invasion, lymphovascular invasion, parametrial (PM) involvement, resected margin (RM) involvement, lymph node (LN) metastasis, and surgical information (e.g., surgical approach and extent). Deep stromal invasion was classified into three categories of invasion depth according to the pathology of <1/3, 1/3–2/3, and >2/3. Since FIGO staging was updated to the 2018 system recently [7], all the patients were restaged based on their pathological findings accordingly.
The postoperative adjuvant treatment, which was determined according to the stage and pathological findings, varied with oncologists' choices since no standard therapy has been established for HG-NECC. The adjuvant treatments included systemic chemotherapy alone or co-therapies such as either concurrent systemic chemotherapy with radiotherapy (CCRT) or sequential chemotherapy followed by radiotherapy. Recurrence was confirmed with radiologic examinations such as computerized tomography, magnetic resonance image, and positron emission tomography/computerized tomography, as well as with the biopsy-based definitive diagnosis.
The progression-free survival time (PFS) was defined as the period that ranged from the date of surgery to that of recurrence or progression or to the last follow-up investigation known. The overall survival (OS) time was defined as the period that ranged from the date of surgery to that of death or to the last follow-up investigation known.
Statistics
OS and PFS curves were drawn using the Kaplan-Meier (K-M) method to be compared via log-rank tests. A Cox proportional hazards model was used to estimate independent prognostic factors. Statistical analysis was performed with SPSS software, version 23.0 (IBM SPSS, Inc., Chicago, IL, USA). p value <0.05 was considered statistically significant.
Results
Baseline Characteristics
A total of 110 Han Chinese patients of HG-NECC were enrolled into the analysis, with a list made of their clinicopathologic characteristics (shown in Table 1). The median age was 42.5 years (range: 22–76), and the median follow-up period was 39.6 months (range: 1.0–156.6). Three patients (2.7%) were lost to postoperative follow-up. In the patients, pathological stage IIIC1 and IB1 accounted for the most (34, 30.9% and 30, 27.3%). 20 (18.2%) patients underwent open surgery; 90 (81.8%) accepted minimally invasive surgery (MIS); 2 with carcinoma of the cervical stump underwent extensive cervical resection and pelvic lymphadenectomy plus bilateral adnexectomy; and the remaining ones received radical hysterectomy and pelvic lymphadenectomy, 12 of them having para-aortic LN biopsy.
Table l.
Clinicopathologic information of the enrolled patients
| Characteristics | N (%) | Recurrence, n | Death, n |
|---|---|---|---|
| Age at initial diagnosis | |||
| Age ≤40 years | 49 (44.5) | 13 | 10 |
| Age >40 years | 61 (55.5) | 24 | 19 |
| Surgical approaches | |||
| Laparotomy | 20 (18.2) | 9 | 7 |
| Laparoscopy | 87 (79.1) | 28 | 22 |
| Robotic-assisted laparoscopy | 3 (2.7) | 0 | 0 |
| Histological type | |||
| Small cell | 62 (56.4) | 18 | 13 |
| Large cell | 2 (1.8) | 0 | 0 |
| Unsubdivided | 46 (41.8) | 19 | 16 |
| Histological heterogeneity | |||
| Pure | 63 (57.3) | 24 | 21 |
| Mixa | 47 (42.7) | 13 | 8 |
| 2018 FIGO stage | |||
| IA2 | 1 (0.9) | 0 | 0 |
| IB1 | 30 (27.3) | 8 | 7 |
| IB2 | 29 (26.4) | 9 | 6 |
| IB3 | 5 (4.5) | 0 | 0 |
| IIA1 | 6 (5.5) | 4 | 1 |
| IIA2 | 1 (0.9) | 0 | 0 |
| I IB | 2 (1.8) | 1 | 1 |
| IIIC1 | 34 (30.9) | 14 | 13 |
| IIIC2 | 2 (1.8) | 1 | 1 |
| Tumor size | |||
| ≤2 cm | 36 (32.7) | 11 | 10 |
| 2~4 cm | 51 (46.4) | 20 | 13 |
| <4 cm | 23 (20.9) | 6 | 6 |
| Lymphovascular invasion | |||
| No | 27 (24.5) | 5 | 3 |
| Yes | 83 (75.5) | 32 | 26 |
| Depth of invasion | |||
| <1/3 | 12 (10.9) | 3 | 1 |
| 1/3–2/3 | 18 (16.4) | 7 | 7 |
| >2/3 | 49 (44.5) | 17 | 14 |
| Not determinedb | 31 (28.2) | 10 | 7 |
| Vaginal invasion | |||
| No | 89 (80.9) | 25 | 21 |
| Yes | 21 (19.1) | 12 | 8 |
| Parametrium involvement | |||
| No | 98 (89.1) | 29 | 21 |
| Yes | 12 (10.9) | 8 | 8 |
| RM involvement | |||
| No | 103 (93.6) | 31 | 25 |
| Yes | 7 (6.4) | 6 | 4 |
| LN metastasis | |||
| No | 74 (67.3) | 22 | 15 |
| Yes | 36 (32.7) | 15 | 14 |
| Adjuvant treatment | |||
| Chemoradiotherapy | 64 (58.2) | 18 | 11 |
| Chemotherapy | 14 (12.7) | 4 | 3 |
| Not certain | 30 (27.3) | 15 | 15 |
| No adjuvant treatment | 2 (1.8) | 0 | 0 |
| Chemotherapy regimens | |||
| EP + EC | 33 (30) | 8 | 4 |
| TP + TC | 35 (31.8) | 12 | 10 |
| Not certain | 42 (38.2) | 17 | 15 |
| Chemotherapy courses | |||
| <4 | 20 (18.2) | 10 | 6 |
| ≥4 | 52 (47.3) | 10 | 7 |
| Not certain | 38 (34.5) | 17 | 16 |
| Immunohistology markers | |||
| CgA (n = 105) | 90 (85.7) | 31 | 25 |
| Syn (n = 108) | 98 (90.7) | 35 | 29 |
| CD56 (n = 70) | 53 (75.7) | 22 | 18 |
| HPV (n = 42) | |||
| HPV16 | 8 (19.0) | 2 | 1 |
| HPV18 | 23 (54.8) | 8 | 6 |
EP, cisplatin/etoposide; EC, carboplatin/etoposide; TP, cisplatin/paclitaxel; TC, carboplatin/paclitaxel; CgA, chromogranin A; Syn, synaptophysin; CD56, cluster of differentiation 56; LN, lymph node.
Mix, the mixed type including adenocarcinoma, squamous carcinoma, and adenosquamous carcinoma.
Not determined, the deep stromal invasion is hard to judge pathologically.
Survival Outcomes
Before the last follow-up defined, it was found that 37 patients (33.7%) relapsed or progressed, of whom 29 (26.4%) died. According to the 2018 FIGO stage, the patients were divided into three groups: stage I, II, and III. The survival curves were drawn for each group (shown in Fig. 1). No significant differences were observed in OS among the groups (p = 0.06; HR 5.71). By group comparison, the patients of stage III carried a 5.20-fold higher risk for death (p = 0.02) than those of stage I. The outcomes did not differ significantly between those of stage II and those of stage III (p = 0.96; HR 0.003). As shown in the K-M survival curves, significant differences were observed in PFS among the three groups (p = 0.04; HR 6.35). By group comparison, the patients of stage II carried a 6.29-fold higher risk for progression (p = 0.01) than those of stage I. The 5-year OS of the patients at pathological stage I, II, and III accounted for 84.9%, 85.7%, and 60.9%, respectively, and their 5-year PFS were 73.2%, 38.1%, and 60.5%, respectively.
Fig. 1.
OS (a) and PFS (b) stratified by the 2018 FIGO stage of HG-NECC.
Adjuvant Therapy and Prognostic Factors
Concerning the adjuvant treatment, 64 patients (58.2%) received co-therapy of radiotherapy and chemotherapy, and 14 (12.7%) received systematic chemotherapy only. Two patients (1.8%) rejected adjuvant treatment and the remaining 30 had incomplete information of adjuvant treatment. No significant difference was found between the adjuvant chemoradiotherapy and chemotherapy alone in OS and PFS (shown in Fig. 2).
Fig. 2.
OS (a) and PFS (b) stratified by adjuvant regimen for HG-NECC.
Of those who underwent adjuvant chemotherapy, 33 patients (30%) received cisplatin/etoposide (EP) or carboplatin/etoposide (EC) regimen, and 35 (31.8%) received cisplatin or carboplatin plus paclitaxel (TP/TC) regimen. Even though it showed a trend for improved survival than TP/TC therapy (shown in online suppl. Fig. 2), the group of EP/EC failed to reach statistical significance.
In the patients who accepted postoperative chemotherapy, twenty (18.2%) accepted <4 chemotherapy cycles, and 52 (47.3%) accepted ≥4 cycles. As indicated by the K-M analysis (shown in Fig. 3), those who received chemotherapy cycles <4 carried a 5.18-fold higher risk for progression (p = 0.02) and 6.71-fold greater likelihood of death (p = 0.01) than those with cycles ≥4.
Fig. 3.
OS(a) and PFS (b) stratified by chemotherapy cycles of HG-NECC.
The univariate cox analysis indicated that age, histological heterogeneity, FIGO stage, PM involvement, LN involvement, and chemotherapy cycles were significantly associated with OS, and that surgical approaches, chemotherapy cycles, RM, and PM involvement were significantly related with PFS (shown in Table 2).
Table 2.
Univariate Cox regression analysis of the prognostic factors affecting survival outcomes in the whole cases receiving surgery at primary treatment
| Variables | OS |
PFS |
||||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | p value | HR | 95% CI | p value | |||
| Age (years) | 3.834 | 1.110–13.246 | 0.034 | 1.646 | 0.764–3.545 | 0.203 | ||
| 2018 FIGO stage | 1.716 | 1.054–2.795 | 0.030 | 1.376 | 0.938–2.021 | 0.103 | ||
| Operation type (laparotomy vs. MIS) | 0.738 | 0.214–2.552 | 0.632 | 0.385 | 0.175–0.848 | 0.018 | ||
| Tumor homology (simple/mixed) | 0.325 | 0.107–0.989 | 0.048 | 0.553 | 0.251–1.215 | 0.140 | ||
| Pathologic size | 1.497 | 0.780–2.873 | 0.225 | 1.124 | 0.682–1.854 | 0.646 | ||
| Lymphovascular invasion | 2.363 | 0.683–8.179 | 0.175 | 2.643 | 0.918–7.603 | 0.072 | ||
| DSI | 2.124 | 0.748–6.027 | 0.157 | 1.185 | 0.664–2.116 | 0.565 | ||
| Resection margin involvement | 1.322 | 0.176–9.951 | 0.787 | 5.736 | 2.133–15.425 | 0.001 | ||
| Vaginal invasion | 1.838 | 0.654–5.166 | 0.249 | 1.188 | 0.438–3.224 | 0.735 | ||
| Parametrium involvement | 6.118 | 2.172–17.236 | 0.001 | 5.310 | 1.990–14.163 | 0.001 | ||
| LN involvement | 2.941 | 1.163–7.432 | 0.023 | 1.491 | 0.693–3.211 | 0.307 | ||
| Adjuvant treatment | 1.263 | 0.262–6.085 | 0.771 | 0.541 | 0.124–2.349 | 0.412 | ||
| Chemotherapy regimens (EP/EC vs. TP/TC) | 0.778 | 0.209–2.900 | 0.708 | 0.989 | 0.378–2.587 | 0.982 | ||
| Chemotherapy courses (<4/≥4) | 0.184 | 0.044–0.773 | 0.021 | 0.342 | 0.130–0.901 | 0.030 | ||
| CgA | 1.307 | 0.299–5.720 | 0.722 | 0.750 | 0.285–1.974 | 0.560 | ||
| Syn | 24.517 | 0.049–12321.785 | 0.313 | 1.572 | 0.374–6.613 | 0.537 | ||
| CD56 | 1.146 | 0.323–4.064 | 0.833 | 1.722 | 0.507–5.849 | 0.383 | ||
MIS, minimally invasive surgery; EP, cisplatin/etoposide; EC, carboplatin/etoposide; TP, cisplatin/paclitaxel; TC, carboplatin/paclitaxel; CgA, chromogranin A; Syn, synaptophysin; CD56, cluster of differentiation 56; DSI, deep stromal invasion; LN, lymph node.
Thereafter, all the six risk factors were put into multivariate analyses on OS, which failed to produce a statistical significance, which indicated that none of the six prognostic factors acted as the determinants in the OS of HG-NECC. Multivariate analyses, involving four risk factors: surgical approaches, chemotherapy cycles, PM, and RM involvement, were also carried out for PFS, the results of which showed that the number of chemotherapy cycles was the only significant prognostic factor for PFS (p = 0.02; HR 0.29).
Discussion
In the current retrospective cohort study, we explored the prognosis of various adjuvant treatments after surgically treating HG-NECC of the cervix, finding that postoperative chemotherapy alone showed no inferiority to chemoradiotherapy in treating HG-NECC. Moreover, we observed no statistical difference in OS between those who received EP/EC therapy and those who accepted TP/TC therapy. Additionally, 4+ cycles of chemotherapy alone were likely to produce a better prognosis than 4− cycles.
Primary Surgery Treatment
As to the patients at FIGO stage III who underwent surgery as a primary treatment, their 5-year OS and PFS were 60.9% and 60.5%, respectively, which were both better than those previously reported [8]. According to the updated FIGO stage system 2018 [7], LN metastasis was upstaged as IIIC. In terms of the survival curves of stage III, the prognosis based on FIGO 2018 tended to be better than that from FIGO 2009, reaching statistical significance in PFS [9]. Based on the modest improvements in survival of stage III, it was hypothesized that radical surgery could be an initial approach to advanced-stage HG-NECC. Previously, the patients whose imaging indicated suspected LN metastasis would undergo CCRT, and they would probably have better OS than those who took primary surgery; however, there were only 13 patients at stage IIB-IVB who received primary surgery [8]. In another research on 95 patients with small-cell NECC at stage III, 15 were treated with radical surgery, which showed no significant difference in OS between different treatment strategies [10].
In some recently published reports, there existed controversy on the therapeutic equivalency of open versus MIS approaches to cervical cancer [11, 12]. However, these research works did not involve any patients with HG-NECC [11]. In our study, the survival outcomes were compared between the approaches of MIS and laparotomy, showing no significant correlation by the multivariate analysis, which was consistent with the previously reported conclusion [13].
Postoperative Adjuvant Treatment
To date, no consensus has been reached on the adjuvant postoperative regiments. The British Gynecological Cancer Society (BGCS) advocates either CCRT or EP followed by pelvic irradiation [14]. According to NCCN guidelines, chemotherapy or chemoradiation is recommended as adjuvant treatment [15]. Controversy still exists on postoperative radiation, for this, it is still unknown whether adjuvant radiation/CCRT improves OS when compared with adjuvant chemotherapy alone. In a single institution retrospective study, 9 patients with stage I-II HG-NECC who underwent radical hysterectomy followed by adjuvant chemotherapy presented better survival rates than the other group of nine who received radiotherapy and CCRT as adjuvant treatment [16]. In a multicenter retrospective study on 48 patients with small-cell NECC at stage IB and IIA who received a postoperative adjuvant treatment [17], no significant differences were observed in the survival outcomes between the two groups of adjuvant chemotherapy (n = 24) and chemoradiation (n = 24) [17]. It was reported that postoperative radiotherapy did not appear to improve the prognosis of NECC [18], which was consistent with the recently published results from a multicenter research on 125 patients with stage I-IIA HG-NECC who underwent surgery as primary treatment [19]. In the current study, we also found that the survival prognosis of NECC was not related to the choice of adjuvant treatment. Given the evidence found above and also considering the adverse effects of radiotherapy; therefore, it is preferable that postoperative chemotherapy alone be recommended for NECC.
With respect to chemotherapy, EP has been widely identified as the initial treatment [9, 15, 16, 18]. TC was also reported to improve survival in patients with early-stage small-cell NECC [20], as indicated by the evidence that TC showed a better prognosis than EP based on PFS [19]. Although the K-M survival curve showed a better trend with EP/EC, no significant differences were explored between various chemotherapy regimens in our study as in the same conclusion recently published [21]. The cycles of chemotherapy have been reported to be related to survival as well [9, 22]; in the current research as well, we found that the number of chemotherapy cycles was a risk factor for PFS, as indicated by the evidence that those who received ≥4 cycles produced a better survival rate than those who underwent <4 ones. Of note, both BGCS and MD Anderson recommend 4–6 cycles of chemotherapy [14, 22].
Conclusion
In conclusion, postoperative chemoradiotherapy did not appear to improve the prognosis of HG-NECC when compared with chemotherapy alone. It is preferable that postoperative chemotherapy alone be recommended for HG-NECC and that its efficacy be strengthened by ≥4 cycles. However, the current research had its limitations, i.e., a retrospective design, the absence of partial adjuvant treatment therapy, and follow-up data. Given the long period of patient inclusion, selection bias cannot be avoided in the study. Prospective multicentered studies are needed to explore an evidence-based recommendation of a better regiment for HG-NECC.
Statement of Ethics
All procedures performed involving human participants were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants in the study. The current study protocol was reviewed and approved by the Institutional Ethics Review Committee of the Obstetrics and Gynecology Hospital of Fudan University, approval number 2021-239.
Conflict of Interest Statement
All the authors have no conflicts of interest to disclose.
Funding Sources
This research received no particular grant from any funding agency in the public, private, or not-for-profit sectors.
Author Contributions
Rongmin Wang: protocol development, data collection, data analysis, and manuscript writing. Yinping Xiao: data collection and pathology. Lingwei Ma: data collection. Zhiyong Wu: protocol development and data management. Hexia Xia: protocol development and manuscript editing.
Data Availability Statement
The data that support the findings of the study are available on request from the corresponding author. The data are not publicly available due to ethical restrictions. Further inquiries can be directed to the corresponding author.
Supplementary Material
Supplementary data
Supplementary data
Funding Statement
This research received no particular grant from any funding agency in the public, private, or not-for-profit sectors.
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Supplementary data
Data Availability Statement
The data that support the findings of the study are available on request from the corresponding author. The data are not publicly available due to ethical restrictions. Further inquiries can be directed to the corresponding author.
