Introduction: A significant proportion of cervical cancer (CC) patients are diagnosed at a locally advanced stage. Concurrent chemoradiotherapy (CCRT) is the cornerstone of treatment for patients with locally advanced CC. However, the role of adjuvant chemotherapy (AC) after CCRT is controversial. In this study, we analyzed the efficacy of AC after CCRT in stage III CC patients. Methods: We performed a multicenter, retrospective analysis of 139 International Federation of Gynecology and Obstetrics stage III CC patients treated with CCRT of whom 45.3% received AC. Our goal was to determine the impact of AC on survival in these patients. Results: Five-year progression-free survival (PFS) was 37.5% and 16% in patients receiving CCRT with and without AC, respectively (p = 0.008). Median PFS was 30.9 months (CI 95% 14.8–46.9) and 16.6 months (CI 95% 9.3–23.9) in patients receiving CCRT with and without AC, respectively. Five-year overall survival (OS) was 78.2% and 28.4% in patients receiving CCRT with and without AC, respectively (p < 0.001). Median OS was 132.2 months (CI 95, %66.5–197.8) and 34.9 months (CI 95% 23.1–46.7) in patients receiving CCRT with and without AC, respectively. Conclusion: Our study suggests that AC provides OS and PFS benefit in stage III CC patients. Larger studies are needed to identify subgroups of patients who would benefit from AC.

Cervical cancer (CC) is the third most common gynecologic cancer diagnosis and cause of death among gynecologic cancers [1]. CC has lower incidence and mortality rates than uterine corpus and ovarian cancer, as well as many other cancer sites. However, CC remains a significant source of cancer morbidity and mortality in countries that do not have access to CC screening and prevention programs [2].

A significant proportion of CC patients are diagnosed at a locally advanced stage. Concurrent chemoradiotherapy (CCRT) is the cornerstone of treatment for patients with locally advanced CC [3]. Several randomized clinical trials demonstrated a 30–50% decrease in the risk of death in locally advanced CC with the addition of concurrent platinum-based chemoradiotherapy when compared with radiotherapy alone [4‒8]. Even though chemoradiotherapy has improved locoregional control and outcome, approximately 40% of patients have recurrence and death from the disease [9]. As a result, research into new therapeutic modalities to complement chemoradiotherapy is ongoing. In a phase III trial, women who received two cycles of systemic intravenous cisplatin plus gemcitabine after chemoradiation had significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with women who received cisplatin-alone-based chemoradiation and no further chemotherapy [10]. By contrast, in a randomized trial, the addition of adjuvant four cycles carboplatin and paclitaxel after chemoradiotherapy did not demonstrate an OS benefit in locally advanced CC patients [11]. According to the International Federation of Gynecology and Obstetrics (FIGO) version 2018, stage III CC is defined as a tumor that extends to the pelvic sidewall and/or involves the lower third of the vagina, and/or causes hydronephrosis or a nonfunctioning kidney [12]. There may be a potential benefit of adjuvant chemotherapy (AC) after chemoradiotherapy treatment in stage III CC patients. In this retrospective study, we aimed to investigate the impact of AC in stage III CC patients treated with CCRT.

Study Population and Data Collection

In this multicenter study, we retrospectively analyzed the clinical records of patients diagnosed with FIGO stage IIIA, IIIB, IIIC1, and IIIC2 CC treated with CCRT with or without AC between 2012 and 2019. Exclusion criteria were aged <18 years old, metastatic disease at diagnosis, treated with neoadjuvant chemotherapy, progression during CCRT, and patients with secondary primary cancer and with missing data (Fig. 1). Data about the age, histology, FIGO stage, HPV status, presence of hydronephrosis, presence of brachytherapy, concurrent chemotherapy regimen, toxicity, AC regimen, and the number of cycles were collected. Toxicity was evaluated according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0 [13].

Fig. 1.

Flowchart of our study population.

Fig. 1.

Flowchart of our study population.

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Clinical staging was done by vaginal and rectal exploration, after evaluating the results of total body pelvic magnetic resonance imaging (MRI) and/or computed tomography (CT); patients underwent positron emission tomography (PET) in case of suspected lymph node metastases detected at MRI or CT to evaluate more accurately pelvic and para-aortic nodes. Sigmoidoscopy and cystoscopy were performed only whenever clinically indicated.

Treatment Schedule

All patients had been treated with definitive CCRT in our study. In the planning and treatment, evacuated rectum and full bladder conditions were provided in all patients, and they were immobilized in the supine position. External radiotherapy planning was done with intensity-modulated, applied 5 days a week, at doses of 1.8–2 Gy per fraction, for a total of 45–50.4 Gy. In patients with pathological lymph node involvement in FDG-PET-CT, a total of 54 Gy was given with an additional dose of 9–10 Gy or a simultaneous integrated boost dose. In patients treated with brachytherapy, response to external treatment and parametrial involvement were evaluated with MRI and examination before brachytherapy. An additional dose of 10–14 Gy radiotherapy was given to those with continued parametrial involvement. All patients received 40 mg/m2 cisplatin intravenously (IV) over 60–90 min per week concurrently for minimum 5 cycles during external radiotherapy.

In this multicenter study, regarding the centers’ and authors’ experiences, some patients had received AC containing more than 3 h of paclitaxel 175 mg/m2 IV and more than 1 h of carboplatin area under curve (5) IV was administered to patients scheduled for AC 4 weeks after the end of CCRT. AC treatment was repeated every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

The metabolic response was evaluated with PET-CT in the third month after the treatment in patients received CCRT with AC and 2 weeks after last cycle of chemotherapy in patients received CCRT with AC. The response obtained by clinical examination and vaginal smear after 6 months were evaluated pathologically. Complete response was defined as lack of metabolic involvement observed in tumor areas in the PET-CT. Partial response (PR) was defined as 50% involvement relative to the first PET-CT findings. Larger area of involvement in PET-CT when compared with the first PET-CT was considered as a progressive disease. The diagnosis of local recurrence was based on examination of biopsy, and clinical findings and radiological evaluation after complete clinical and metabolic response were obtained. In the subsequent controls, examination and MR evaluation were performed every 6 months. Control examinations were performed every 3 months after the end of treatment. In this study, PFS was defined as the time from the diagnosis to the recurrence or metastasis and OS was defined as the time from the initial diagnosis to the death or last visit.

Statistical Analyses

Descriptive statistics were conducted using percentages for clinical and demographic features. The χ2 test or Fisher’s exact test, where appropriate, was used to compare these variables in different groups. The Kaplan-Meier survival estimates were calculated. The effect of AC on OS and PFS was investigated using the Log-rank test.

The possible factors identified with univariate analyses have a p value of <0.20 and were further entered into the Cox-regression analysis, with entering a selection, to determine independent predictors of survival. Strongly correlated variables were excluded and only those with clinical significance were included. A p value of <0.05 was used to infer statistical significance.

This study included 139 stage III CC female patients with a median age of 52.4 years (24–79 years). Of these patients, 63 (45.3%) had received CCRT with AC and others (54.7%) received only CCRT (Table 1). Most of our patients had FIGO stage IIIB (n = 28, 20.1%) and stage IIIC1 (n = 67, 48.2%) disease, and 52 (37.4%) patients had positive HPV status. One hundred and twenty-six patients (90.6%) had squamous histology. Fourteen (10.1%) patients had hydronephrosis at the time of diagnosis. One hundred and twenty (86.3%) patients were treated with brachytherapy. Eighty patients (57.5%) had grade ≥3 adverse events during CCRT. Two patients (1.4%) had stable disease, 41 (29.5%) patients had PR, and 87 (62.6%) patients had complete response. Seventy-one patients (51.1%) progressed and 57 (41%) patients had died during the follow-up (Table 1).

Table 1.

Demographics, clinical, and pathological features of study population

 Demographics, clinical, and pathological features of study population
 Demographics, clinical, and pathological features of study population

Tumor stage (p: 0.020), presence of adverse events during CCRT (p: 0.003), response to CCRT with or without AC (p: 0.008), presence of progression (p < 0.001), and mortality (p < 0.001) were significantly different between treatment groups (Table 1). Univariate analysis of PFS revealed age, stage IIIC2 disease, stable disease, and PR after CCRT with or without AC as the most significant factors (p: 0.02, p: 0.007, p < 0.001, p: 0.004, respectively). Multivariate analysis showed that adenocarcinoma histology was an independent risk factor for PFS (p: 0.03) (Table 2). The univariate analysis of OS showed age, stable disease and PR after CCRT with or without AC as the most significant factors (p: 0.009, p: 0.001, respectively). Multivariate analysis showed that adenocarcinoma histology was an independent risk factor for OS (p: 0.03) (Table 3).

Table 2.

Univariate and multivariate analysis for PFS

 Univariate and multivariate analysis for PFS
 Univariate and multivariate analysis for PFS
Table 3.

Univariate and multivariate analysis for OS

 Univariate and multivariate analysis for OS
 Univariate and multivariate analysis for OS

The median follow-up time was 35 months in the study population. Median OS was 104.2 months (CI 95%, 90–118.4) and median PFS was 19 months (CI 95%, 14.3–23.8) in the entire population.

The Kaplan-Meier analysis demonstrated 5-year PFS was 37.5% and 16% in patients receiving CCRT with and without AC, respectively (p = 0.008). Median PFS was 30.9 months (CI 95%, 14.8–46.9) and 16.6 months (CI 95%, 9.3–23.9) in patients receiving CCRT with and without AC, respectively (Fig. 2). Five-year OS was 78.2% and 28.4% in patients receiving CCRT with and without AC, respectively (p < 0.001). Median OS was 132.2 months (CI 95%, 66.5–197.8) and 34.9 months (CI 95%, 23.1–46.7) in patients receiving CCRT with and without AC, respectively (Fig. 3). We found statistically significant difference regarding grade 3–4 toxicity between two groups receiving CCRT with and without AC (71.6% vs. 48.6%, respectively).

Fig. 2.

PFS in patients receiving CCRT with and without AC.

Fig. 2.

PFS in patients receiving CCRT with and without AC.

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Fig. 3.

OS in patients receiving CCRT with and without AC.

Fig. 3.

OS in patients receiving CCRT with and without AC.

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This study was conducted to evaluate the effect of AC in FIGO stage III CC patients treated with CCRT. To the best of our knowledge, this is the first real-world study assessing the effect of AC in patients with stage III CC and treated with CCRT and we found that AC provided a significant PFS and OS advantage in these patients.

Our results demonstrated that adenocarcinoma histology was a worse prognostic factor in PFS and OS in multivariate analysis. It is not clear that patients with adenocarcinoma have a worse prognosis in the literature. It is questionable that cervical adenocarcinoma metastasizes earlier or may not be detected earlier. Moreover, apparent poorer prognosis may be related with a poorer response to radiotherapy or with the inclusion of special subtypes like clear cell carcinoma [14].

In our study, we found that AC provided a significant PFS and OS advantage. In a randomized trial (OUTBACK) including 919 patients with locally advanced CC, those assigned to standard cisplatin-based chemoradiation followed by four cycles of adjuvant carboplatin and paclitaxel experienced similar OS at 5 years as those assigned to CCRT only (72 vs. 71%; HR 0.91, 95% CI 0.70–1.18) [11]. PFS at 5 years was also similar between the groups (63 vs. 61%; HR 0.87, 95% CI 0.70–1.08) [11]. In this trial, the study population consisted of locally advanced CC (FIGO 2008 stage IB1 and node-positive, IB2, II, IIIB, or IVA). In OUTBACK trial, it was reported that AC did not add any benefit neither to patients with FIGO stage IB/IIA nor to patients with stage IIB nor to patients with III/IVa disease. Although OUTBACK trial has similar features to our study, there are important differences from our study at some points. First of all, in the OUTBACK trial, FIGO stage was a stratification factor which was performed according to FIGO 2008. However, in our study, the CC patients were staged according to FIGO 2018 which differs from FIGO 2008. As it was shown in a recent report, reclassification to stage IIIC1 disease based on the new 2018 FIGO system was observed in some of stage IB1, IB2, and II disease based on the 2008 FIGO system [15]. Therefore, comparing patients staged with the 2008 FIGO and 2018 FIGO staging systems may be one reason for the difference in our results. Another important feature that may explain the difference in the results is that while CC patients with L3/4 nodal disease were not included in OUTBACK trial, 25% of our patients included in this study were stage IIIC2 (para-aortic lymph node metastasis) which may benefit from AC. Grade ≥3 adverse events within a year of randomization occurred in 81 versus 62%, respectively [11]. In our cohort grade ≥3 adverse events occurred 71.6 versus 48.6%. In another trial patients who received two cycles of systemic intravenous cisplatin plus gemcitabine after chemoradiation had significant improvements in both PFS and OS compared with women who received cisplatin-alone-based chemoradiation and no further chemotherapy [10]. In that study, an absolute improvement in PFS of 9% (from 65% to 74%) at 3 years was reported [10]. However, as discussed above, it is not clear if the survival benefit was due to combination chemotherapy delivered with RT, following RT, or both. In a study of 78 patients conducted by Choi et al. [16], half of patients received cisplatin + 5-fluorouracil concurrent with radiotherapy, while half received three additional courses of this regimen. In that study, the rate of OS was higher in patients treated with consolidation chemotherapy after CCRT than patients treated with CCRT alone (92.7% vs. 69.9%, p = 0.042), whereas the difference in PFS between the groups was not statistically significant (70.1% vs. 55.1%, p = 0.079) [16]. In our study, chemotherapy given simultaneously with radiotherapy was weekly cisplatin and the preferred AC was carboplatin-paclitaxel.

The limitations of the current study were its retrospective design and comparably lower sample size. However, the strength of our study is that it is a multicenter study and presents a real-life data.

In conclusion, our study suggests AC provides OS and PFS benefit in stage III CC patients. Larger studies are needed to identify subgroups of patients who would benefit from AC.

This study protocol was reviewed and approved by the University of Health Sciences, Prof. Dr. Cemil Tascioglu City Hospital Ethics Committee (approval number: E-4867071-514.10/12). Written informed consent has been obtained from all patients before this study.

The authors have no conflicts of interest to declare.

There has been not any funding source for this study.

Concept – M.M.A., B.A., M.D., A.S., O.C., and A.H.O.; design – A.S., M.M.A., B.A., O.S., M.D., and A.H.O.; supervision – A.S., M.M.A., B.A., O.S., O.C., and A.H.O.; resources – B.A., M.D., M.M.A., O.S., and N.O.; materials – M.M.A., A.S., B.A., M.D., İ.C., B.D.Y., T.A.T., O.C., S.G.A., N.O., and A.H.O.; data Collection and/or processing – B.A., M.M.A., S.A., M.D., İ.C., O.S., B.D.Y., T.A.T., S.G.A., and N.O.; analysis and/or interpretation – M.D., A.S., B.A., O.S., M.M.A., İ.C., T.A.T., O.C., and S.G.A.; literature Search – B.A., M.M.A., İ.C., and B.D.Y.; writing manuscript – M.M.A., B.A., M.D., and A.S.; and critical review – M.M.A., O.S., B.A., M.D., and S.G.A.; other – O.S., T.A.T., O.C., and N.O.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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