Value of adjuvant chemotherapy in IB–lIA cervical adenocarcinoma: A multicenter retrospective study

To the Editor: Adenocarcinoma is the second most common type of cervical cancer, marked by insidious early lesions and a low detection rate with routine cytological screening. Its incidence rate is increasing annually, accounting for ~25% of cervical cancer cases.^[1] Cervical adenocarcinoma is characterized by high heterogeneity and invasiveness, which makes it more prone to recurrence and metastasis, and has a worse prognosis than squamous cervical cancer.^[2] Given its reduced sensitivity to radiotherapy (RT), radical resection is a more effective treatment than concurrent chemoradiotherapy (CCRT).^[3] Patients with cervical adenocarcinoma with intermediate risk factors (tumor diameter ≥3 cm, lymphovascular stromal infiltration, and ≥ two-thirds of cervical interstitial infiltration) have a higher incidence of pelvic recurrence and distant metastasis than those with squamous cell carcinoma.^[4] For this group of patients, the current treatment protocol refers to the four-factor model proposed by Ryu et al^[5] in 2014 and consists of postoperative adjuvant RT or CCRT. However, the overall efficacy of RT for cervical adenocarcinoma remains lower than that for squamous cervical cancer.^[6] In this study, we analyzed the clinical data of patients with cervical adenocarcinoma who underwent surgical treatment. The significance of systemic chemotherapy (SCT) for the treatment of cervical adenocarcinoma was further explored to provide a reference for postoperative adjuvant treatment (AT) of cervical adenocarcinoma.

To further explore the implications of SCT for the treatment of cervical adenocarcinoma, we conducted a multicenter retrospective cohort study. Patients who were older than 18 years, had 2018 International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging of stage IB and IIA, had pathologically confirmed adenocarcinoma of the cervix or adenosquamous carcinoma, and had radical surgery as their primary treatment were included in the study. The study was approved by the Ethics Committee of the Cancer Hospital of the Chinese Academy of Medical Sciences (ethical approval number: NCC-015378).

From June 2012 to June 2023, a total of 233 patients were enrolled. Patients with high-risk factors (paracervical invasion, lymph node metastasis, or positive resection margins) were categorized as a high-risk group based on postoperative pathology. If no high-risk factors were present, a four-factor model of cervical adenocarcinoma was applied to group patients according to the number of risk factors. Detailed baseline information is shown in Supplementary Table 1, http://links.lww.com/CM9/C509. Prognostic analysis was performed for patients in different risk subgroups, with detailed information provided in Supplementary Figure 1, http://links.lww.com/CM9/C509. The dynamic recurrence risk in patients of the different risk subgroups was also evaluated.

The peak of recurrence occurred at ~6 years after diagnosis regardless of the risk group [Supplementary Figure 2A, http://links.lww.com/CM9/C509]. A prognostic analysis of patients in the intermediate- and high-risk groups under different treatment regimens showed that progression-free survival (PFS) (hazard ratio [HR] = infinite, P = 0.63) and overall survival (OS) (HR = infinite, P = 0.23) of patients in the low- and intermediate-risk groups with ≤1 risk factor did not significantly differ among patients that did not receive postoperative treatment, those that received RT or CCRT, and those that received SCT with or without RT (SCT ± RT) [Supplementary Figure 2B, C, http://links.lww.com/CM9/C509]. In the subgroup comprising intermediate-risk patients with ≥2 risk factors, patients who received SCT ± RT had significantly better PFS than those who received only RT or CCRT. Subgroup analysis of patients receiving SCT in the group with ≥2 risk factors showed that RT supplementation did not significantly affect either OS (HR = 6.63, 95% confidence interval [CI]: 0.80–55.05, P = 0.058) or PFS (HR = 2.09, 95% CI: 0.26–16.98, P = 0.45). Patients who received SCT ± RT also had better OS (HR = 0.46, 95% CI: 0.07–3.20, P = 0.24) compared with the other two subgroups, although the difference was not statistically significant. Patients who did not receive AT after surgery had the worst PFS (HR = 0.51, 95% CI: 0.12–2.20, P = 0.006). All the patients in the high-risk group received RT. We observed that PFS (HR = 0.28, 95% CI: 0.11–0.69, P = 0.027) and OS (HR = 0.34, 95% CI: 0.12–0.96, P = 0.072) were significantly prolonged in patients receiving RT and SCT relative to that observed in patients treated with CCRT [Supplementary Figure 2D–I, http://links.lww.com/CM9/C509]. We also performed multivariate Cox regression analysis simultaneously for the (1) intermediate-risk and (2) high-risk groups with ≥2 risk factors, adjusting for confounders, and visualized the results for OS and PFS with forest plots [Supplementary Figure 3, http://links.lww.com/CM9/C509].

At present, cervical adenocarcinoma treatment is based on the diagnosis and treatment plan of squamous cervical cancer. The treatment options for cervical adenocarcinoma and the risk factors affecting its prognosis remain controversial.^[7] Our study confirmed that ovarian metastasis is an independent risk factor affecting the prognosis of cervical adenocarcinoma. The clinical incidence of ovarian metastasis from cervical adenocarcinoma is ~3%. Cervical adenocarcinoma may originate from reserve cells in the transformation zone, which is located close to the lower uterine segment, a region associated with a more invasive phenotype. This may explain why ovarian metastases are more common in cervical adenocarcinoma than in squamous cell carcinoma.

Based on the four-factor model of cervical adenocarcinoma, we explored the differences in recurrence and prognosis among intermediate-risk patients with different numbers of risk factors. There was no difference in prognosis between patients in the low-risk group and those in the intermediate-risk group with one risk factor. For this group of patients, postoperative observation could be a viable approach. Patients in the intermediate-risk group with two or three risk factors had similar PFS and OS but significantly worse prognosis compared with patients with no or one risk factor, but better than patients in the high-risk group. This provided a basis for the histopathologic staging of the patients.

Patients in the intermediate-risk group with two or three risk factors who underwent SCT with or without RT had significantly better PFS than patients who received only RT or CCRT. Patients who did not receive postoperative AT had the worst PFS. The results for OS were not statistically significant among the three groups. Moreover, subgroup analysis showed that there was no significant difference in OS or PFS between patients receiving SCT only and those receiving SCT plus RT. The above findings confirmed that SCT is a protective factor for intermediate-risk patients with two or three risk factors, leading to prolonged PFS.

For patients with cervical cancer presenting with a combination of high-risk factors, current National Comprehensive Cancer Network (NCCN) guidelines recommend AT with pelvic external irradiation radiotherapy or cisplatin-based CCRT.^[8] The poor sensitivity of cervical adenocarcinoma to RT renders this malignancy prone to distant metastasis when combined with high-risk factors, and its prognosis is worse than that of squamous cell carcinoma. For such patients, whether to use SCT as an adjuvant to surgery remains controversial.^[9] Here, we compared the efficacy of postoperative SCT combined with RT or CCRT for the treatment of cervical adenocarcinoma or adenosquamous carcinoma in high-risk individuals. We found that SCT combined with RT significantly reduced the recurrence rate and significantly improved OS and PFS, which further confirmed the importance of SCT as a postoperative adjuvant therapy for patients with cervical adenocarcinoma.

Recurrence risk curve analysis showed that the recurrence pattern was similar between the group with ≥2 risk factors and the high-risk group, with a bimodal pattern in the early stage, peaking at ~2 years, and then declining. The peak of recurrence occurred at ~6 years regardless of the risk group, and there was no significant difference in the site of recurrence between the two groups. This finding is critical for developing a follow-up strategy for patients with cervical adenocarcinoma. Patients should receive intensive follow-up at least every 3 months in postoperative years 5 and 6 to promptly detect and manage recurrences.

Our study had some limitations. First, we excluded patients who received immunologic or targeted therapy as the initial treatment. The efficacy of chemotherapy combined with immunotherapy or targeted therapy in cervical adenocarcinoma is still unclear and warrants future investigation. Future large-scale multicenter prospective studies are still needed to confirm the relevant points of this study.

Here, we retrospectively analyzed the clinical data of patients with cervical adenocarcinoma who underwent surgical treatment and proposed a new grouping model stratified by risk factors. The risk of recurrence was significantly increased in the presence of ≥2 risk factors. We also demonstrated that postoperative SCT supplementation improved PFS in patients in the intermediate- and high-risk groups. However, the improvement in OS was more limited. Individualized clinical decision-making for patients with cervical adenocarcinoma can improve their survival and quality of life.

Funding

This work was supported by grants from the Capital Health Development Research Project (No. 2020-2-4024), Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2019L03), and the special research fund for central universities, Peking Union Medical College (No. 3332023025).

Conflicts of interest

None.

Supplementary Material

cm9-138-2192-s001.docx ^{(880.3KB, docx)}