Neoadjuvant Chemotherapy Reduces Adjuvant Radiation Therapy in Patients with Locally Advanced Cervical Cancer

Abstract

Background: To investigated whether carboplatin-paclitaxel neoadjuvant chemotherapy (NACT) benefits patients with locally advanced cervical cancer (LACC) through avoiding or delaying postoperative radiation.

Methods: Patients with International Federation of Gynecology and Obstetrics (FIGO 2009) stage IB2-IIA2 who received carboplatin-paclitaxel chemotherapy followed by radical surgery (NACT group) or received primary radical surgery (PRS group) between 2007 and 2017 at our hospital were included. Their clinicopathological characteristics, treatments and follow-up data were retrospectively collected and analyzed. The clinical outcomes, including adjuvant radiation, progression-free survival (PFS), and overall survival (OS), were compared between the groups.

Results: There were 197 and 217 patients included in the NACT group and PRS group, respectively. The baseline characteristics were significantly different between the groups, with more patients with more advanced tumor stages and larger tumor sizes in the NACT group. Postoperative pathology examination revealed lower incidences of deep stromal invasion in the NACT group than in the PRS group. More importantly, the cumulative postoperative radiation rate was significantly lower in the NACT group (P = 0.041), while the differences in 5-year OS and PFS were not statistically significant between the groups.

Conclusions: NACT reduces the pathological risk factors and adjuvant radiation without compromising survival in patients with LACC, which may protect younger patients from radiation-related side effects and subsequently improve the quality of life.

Background

Cervical cancer is a major cause of cancer mortality in women worldwide. According to global cancer statistics, there were 604,000 new cases and 342,000 cervical cancer-related deaths in 2020 (1). While radical surgery is accepted as the standard treatment for early-stage cervical cancer, the optimal treatment for patients with stage IB2-IIA2 remains controversial.

Though concurrent chemoradiation is recommended as the standard treatment (2), it sometimes brings serious complications, such as bladder dysfunction, sexual dysfunction and gastrointestinal dysfunction. Therefore, how to reduce the need for radiotherapy to improve the quality of patients’ life is still a challenge. Neoadjuvant chemotherapy (NACT) followed by radical surgery has been widely used for patients with locally advanced cervical cancer (LACC) to reduce tumor volume, improve the rate of resection and control the potential micro-metastasis. Previous studies have also shown that NACT may have an impact on the clinicopathological risk factors and postoperative radiotherapy (3–5). One phase III trial reported that NACT with BOMP (bleomycin, vincristine, mitomycin and cisplatin) regimen before radical surgery significantly reduced both the proportion of patients who met the criteria for postoperative radiation and the proportion of patients who received postoperative radiation compared to primary radical surgery (PRS) (6). Similar results were also reported in another multicenter study with NACT consisting of IP (irinotecan plus cisplatin) and TP (paclitaxel plus cisplatin) regimens (3). However, Lei Li et al. failed to identify these findings in their study with NACT of TC (paclitaxel plus carboplatin), TP and PF (fluorouracil plus cisplatin) regimens (7), as well as another study with four different chemotherapy regimens (8). In these studies, the NACT regimens were different and the response rates varies from 58.8–75.7%, the inconsistent results impacted the credibility of the effect of NACT on postoperative radiotherapy. Therefore, the potential benefits of different regimens of NACT on postoperative adjuvant radiotherapy need to be tested further.

There have been no study investigating the effect of NACT with carboplatin-paclitaxel on adjuvant radiation, which has been recognized as one of the most effective regimens with a high response rate of 95% and mild toxicity (9). Thus, we performed this retrospective study to investigate whether NACT with paclitaxel and carboplatin reduces the clinicopathological risk factors and adjuvant radiation in patients with LACC, and compare the oncologic outcomes between patients underwent NACT followed by radical surgery and patients underwent PRS.

Methods

Management

All patients underwent radical hysterectomy and pelvic lymphadenectomy. For the NACT group, carboplatin-paclitaxel regimen was used. Patients intravenously received paclitaxel (paclitaxel liposome for injection, Luye Pharma Group Ltd., Nanjing, China) at 135–175 mg/m² on the first day and carboplatin (carboplatin for injection, Qilu Phama Ltd., China) at an area under curve (AUC) = 5 on the second day every 3 weeks, the number of NACT cycles ranged from 2 to 3. Assessment of the response to NACT was based on the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) (10). Complete response (CR) was defined as complete disappearance of all target lesions; partial response (PR) was defined as a ≥ 30% decrease in the sum of the diameters of target lesions; progressive disease (PD) was defined as a ≥ 20% increase in the sum of the diameters of target lesions or the appearance of new target lesions; stable disease (SD) was defined as the status between PR and PD. The NACT responders (NACT-R) was defined as patients with CR or PR, while the non-responders (NACT-NR) was defined as patients with SD or PD. Deep stromal invasion was defined as ≥ 1/3 cervical stromal invasion. After radical surgery, adjuvant therapy was recommended if patients exhibit any of the high risk factors of lymph node metastasis, parametrial involvement or positive surgical margins, and in patients with 2 or more intermediate risk factors including LVSI, deep stromal invasion, and tumor size ≥ 2cm.

Follow Up

The follow up was performed according to the National Comprehensive Center Network (NCCN) (2). The items mainly included gynecological examination, vaginal stump cytological examination, pelvic ultrasound and chest X-ray. The overall survival (OS) was defined as the time from completion of operation to death or to the date of last contact. The Progression-free survival (PFS) was defined as the time from completion of operation to the first appearance of progressive disease or to the date of last contact.

Results

Neoadjuvant Chemotherapy Reduced Risk Factors And Adjuvant Radiation

To investigate whether NACT could reduce the risk factors associated with recurrence and death that are prerequisites for adjuvant radiotherapy, we compared the clinicopathological risk factors between the two groups. As shown in Table 2, after NACT, the tumor volume in the NACT group significantly shrank, and there were more tumors ≤ 2.0 cm in the NACT group than in the PRS group (36.0% vs 19.8%, P < 0.001). The postoperative pathology examination also revealed a lower incidence of deep stromal invasion in the NACT group than in the PRS group (46.7% vs 59.5%, P = 0.023), whereas the two groups showed no significant differences in parametrial involvement, lymph node metastasis, LVSI and positive surgical margin.

Furthermore, we compared the cumulative postoperative radiation rates in different groups to determine whether NACT reduced the adjuvant radiation in patients with LACC. As shown in Fig. 1A, the cumulative radiation rate of the NACT group was significantly lower than that of the PRS group (54.7% vs 65.1%; P = 0.041). In the subgroup analysis (Fig. 1B), the cumulative radiation rate of the NACT responders was significantly lower than that of the PRS group (54.2% vs 65.1%; P = 0.013), but there was no significant difference between the non-responders and PRS group (58.8% vs 65.1%; P = 0.695).

Survival

We then compared the OS and PFS rates between the two groups to investigate whether NACT impacts the survival of patients with LACC. The median follow-up time was 45 (range, 3 ~ 150) months. The 5-year OS (78.3% vs 83.0%, P = 0.306) (Fig. 1C) and PFS (64.5% vs 70.6%, P = 0.207) (Fig. 1D) of the NACT group were comparable with those in the PRS group, suggesting that NACT did not compromise the survival.

Discussion

As the age at which women develop cervical cancer is decreasing and radiation may have serious implications that reduce the quality of patients’ life, reducing radiation is an important challenge for patients with LACC. In this study, our results revealed that NACT with paclitaxel and carboplatin significantly reduced the clinicopathological risk factors and cumulative adjuvant radiation rate when compared to the PRS group, without compromising the survival. These findings may provide important help in the management of LACC to improve the quality of life.

Though concurrent chemoradiation is recommended as the standard treatment for patients with LACC, as the age at which women develop cervical cancer is decreasing, treatment that protects physiological function and improves quality of life is important, and radical surgery has been chosen for LACC. However, after radical surgery, some patients still present with pelvic lymph node metastasis, parametrial involvement, positive surgery margin, LVSI and deep stromal invasion, which are identified as risk factors for recurrence and death (11, 12), and adjuvant radiation is recommended if patients exhibit these risk factors. These patients are then faced with increased treatment and complications.

In an effort to improve the prognosis and quality of life of patients with LACC, NACT followed by radical surgery has been proposed as a promising strategy for LACC (13), which was believed to be able to reduce the risk factors of recurrence and death, and reduce the need for postoperative adjuvant radiotherapy. According to a randomized study, the pelvic lymph node metastasis (25.0% vs 42.9%, P = 0.025) and parametrial infiltration (25.0% vs 41.4%, P = 0.038) rates were significantly lower in the NACT (with cisplatin, mitomycin and 5-fluorouracil) group than in the PRS group (14). Yang et al. reported in their multicenter study that the incidence of LVSI and deep stromal invasion were both significantly reduced after NACT with IP and TP when compared to the PRS group (4.7% vs 18.2%, P = 0.002; 45.8% vs 68.2%, P = 0.001) (3), and Kim et al. also obtained similar results in their study with NACT consisting of paclitaxel/carboplatin, 5-fluorouracil/cisplatin and 5-fluorouracil/carboplatin (15). In this study, we observed that the rates of patients with tumor > 2cm and deep stromal invasion in the NACT group were significantly lower than those in the PRS group, while there were more patients with more advanced stages and larger primary tumor sizes in the NACT group.

Regarding postoperative radiation, our results showed that the cumulative radiation rate was significantly reduced in the NACT group compared to the PRS group (54.7% vs 65.1%; P = 0.041), especially for the responders. Similarly, another study with NACT consisting of paclitaxel and cisplatin/carboplatin also reported that the adjuvant radiotherapy was administered to less patients in NACT group compared to PRS group (13). Katsumata N revealed that the proportion of patients who met the criteria for postoperative radiation (72% vs 89%, P = 0.015) and patients who received postoperative radiation (58% vs 79%, P = 0.015) were both significantly lower in the NACT group than in the PRS group (6). Yang et al also reported that the rates of postoperative adjuvant radiotherapy and chemoradiation in the NACT group were lower than that of the PRS group, though without significant difference (3).

While the short-term efficacy of NACT is certain, whether NACT affects locally advanced cervical cancer patients with long-term survival remains controversial (16, 17). Yin et al. performed a retrospective study to compare the long-term survival of NACT followed by radical surgery and primary radical surgery, and the results showed that the NACT group had significantly higher PFS (HR = 1.870, P = 0.0031) and OS (HR = 1.813, P = 0.0175) rates than the PRS group (16). However, there were also studies that failed to obtain similar results. A phase III trial was conducted to determine whether NACT impacts the survival of LACC, and it finally failed to find any benefit of NACT group, with similar PFS rates (56.2% vs 53.8%) and OS rates (63.3% vs 60.7%) in the NACT group compared to the PRS group (18), which was in consistence with our previous study (19). In the present study, the 5-year OS and PFS of the NACT group (78.3% and 64.5%) were similar to those of the PRS group (83.0% and 70.6%). All these results indicated that NACT may be useful for improving the survival of patients with LACC or may confer comparable survival, it at least did not worsen the long-term survival.

Our study clarified the impact of carboplatin-paclitaxel NACT on postoperative risk factors and cumulative radiotherapy in patients with LACC. However, it had several limitations. First, it was a single-center retrospective study in which selection bias and confounding bias were inevitable; second, the patients in NACT group and PRS group were not very well matched; third, in terms of OS and PFS, we did not make comparisons to concurrent chemoradiation, which is also effective against LACC. Thus, further multicenter and randomized trials are need to verify the effect of NACT on adjuvant radiation.

Conclusions

In conclusion, our results suggest that carboplatin-paclitaxel NACT before RS can reduce the rate of patients who received postoperative radiotherapy, without compromising the survival.

Abbreviations

Neoadjuvant chemotherapy (NACT)

Locally advanced cervical cancer (LACC)

Progression-free survival (PFS)

Overall survival (OS)

Primary radical surgery, PRS

Bleomycin, vincristine, mitomycin and cisplatin regimen, BOMP

Irinotecan plus cisplatin regimen, IP

Paclitaxel plus cisplatin regimen, TP

Fluorouracil plus cisplatin, PF

Magnetic Resonance Imaging, MRI

Computed Tomography, CT

Lymph vascular space invasion, LVSI

Area under curve, AUC

Complete response, CR

Partial response, PR

Progressive disease, PD

Stable disease, SD

NACT responders, NACT-R

NACT non-responders, NACT-NR)

National Comprehensive Center Network, NCCN

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Tongji Medical College, Huazhong University of Science and Technology (No. 2018S452).

Consent for publication

Not applicable

Availability of data and materials

Data available within the article or its supplementary materials.

Competing interests

The authors have no conflicts of interest to declare.

Funding

This study was supported by the National Natural Science Foundation of China (81974413) and the Natural Science Foundation of Hubei Province, China (2019CFB704).

Authors' contributions

Conception & Design of Study: Zehua Wang and Zhoufang Xiong

Data Collection: Yuhui Huang, Lei Chen, Lu Yang and Jing Zhao

Data Analysis & Interpretation : Jing Cai and Si Sun 

Responsible Surgeon : Lu Yang, Zhoufang Xiong and Zehua Wang

Statistical Analysis: Yuhui Huang and Jing Zhao

Manuscript Preparation: Yuhui Huang and Lei Chen

Acknowledgements

We thanked Dr. Qinghui Zhou for her help of data collection.

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