Abstract
Aim: The prognosis of high-risk, locally advanced cervical cancer (LACC) remains poor following concurrent chemoradiotherapy (CCRT). We investigated whether the effect of CCRT can be enhanced by programmed cell death protein 1 (PD-1) inhibitor.
Methods: A retrospective cohort study was conducted to compare the efficacy and safety of CCRT group (n = 82) and PD-1 inhibitor plus CCRT group (n = 70).
Results: Compared with the CCRT group, the PD-1 inhibitor plus CCRT group had significantly higher objective response rate, median progression-free survival, leukopenia and fatigue. The addition of PD-1 inhibitor to CCRT showed a favorable trend in overall survival without statistical significance.
Conclusion: PD-1 inhibitor plus CCRT presented a significant survival benefit and a manageable safety profile in high-risk LACC.
Keywords: : concurrent chemoradiotherapy, efficacy, local advanced cervical cancer, PD-1 inhibitor, safety
Plain language summary
Article highlights.
The prognosis of high-risk locally advanced cervical cancer (LACC) (FIGO 2014 stage IB2–IIB with positive para-aortic lymph nodes and stage IIIA–IVA) remains poor after concurrent chemoradiotherapy (CCRT).
Programmed death ligand-1 (PD-1) inhibitors have shown efficacy in patients with cervical cancer, and whether the effect of CCRT can be enhanced by PD-1 inhibitor is a hot topic in high-risk LACC research.
This retrospective cohort study was conducted to compare the efficacy and safety of CCRT alone (n = 82 patients) and PD-1 inhibitor plus CCRT (n = 70 patients).
Compared with the CCRT-alone group, the PD-1 inhibitor plus CCRT group had a significantly higher objective response rate and median progression-free survival (PFS) but also higher incidence of leukopenia and fatigue. The addition of PD-1 inhibitor to CCRT showed a favorable trend in overall survival (OS) without statistical significance.
Compared with the PD-L1-negative subgroup, PFS (p = 0.002) and OS (p = 0.032) in the PD-L1-positive subgroup were significantly improved.
Multivariate analysis showed that total radiotherapy duration >56 days (hazard ratio [HR]: 4.799), FIGO 2009 stage IVA (HR: 6.464), and combined PD-1 inhibitor (HR: 0.324) were independent determinants of disease progression.
PD-1 inhibitor plus CCRT presented a significant survival benefit and a manageable safety profile in high-risk LACC. It can be considered as a new alternative treatment for this patient population.
The effects of different timing of PD-1 inhibitor combination with radiotherapy and different duration of PD-1 inhibitor maintenance therapy on survival outcomes need to be further explored in future studies.
This is an exploratory study that adds to the literature on high-risk LACC and PD-1 inhibitor, prospective studies are needed to determine the value of PD-1 inhibitor plus CCRT for high-risk LACC.
1. Background
Cervical cancer is widely recognized as the most prevalent malignant tumor within the field of gynecology [1], with ~50% of cases diagnosed as locally advanced cervical cancer (LACC) [2]. According to the guidelines issued by the National Comprehensive Cancer Network (NCCN), the recommended course of treatment for LACC is concurrent chemoradiotherapy (CCRT) [3]. However, after CCRT, the 5-year overall survival (OS) rate of Federation Internationale of Gynecologie and Obstetrigue (FIGO) 2009 stage IB2–IIB patients with positive para-aortic lymph nodes, IIIA, IIIB and IVA patients was only 16.0–41.4%. The 5-year OS rate of LACC in other stages is 60.8–83.3% [4,5]. Therefore, patients with stage IB2–IIB with positive para-aortic lymph nodes and stage IIIA–IVA in LACC are high-risk types with worse prognosis [6]. How to improve the prognosis of these patients has been widely concerned [7–11]. PD-1 inhibitor has shown efficacy in patients with cervical cancer [12]. The effect of CCRT may be enhanced by immunotherapy [13]. In recent years, NCCN guidelines have recommended PD-1 inhibitor as the first line of treatment for recurrent or metastatic cervical cancer [14], and this breakthrough in research progress marked the beginning of a new era for treating high-risk LACC. In recurrent or metastatic cervical cancer, the objective response rate (ORR) of PD-1 inhibitor is only 12.2% [15]; however, when combined with radiotherapy, the efficacy of PD-1 inhibitor significantly increases [16–18]. The application of radiotherapy has been observed to induce the activation and proliferation of T cells, improve the tumor microenvironment, and exhibit a synergistic impact when combined with PD-1 inhibitor [12,19,20]. Therefore, PD-1 inhibitor plus CCRT is expected to improve the prognosis of high-risk LACC. At present, there are registered clinical trials focusing on this research hotspot, but the jury is still out [21–23]. The current study aimed to investigate whether the effect of CCRT can be enhanced by PD-1 inhibitor.
2. Patients & methods
2.1. Patient selection
A retrospective cohort study was conducted. Clinical data of 311 cervical cancer patients diagnosed with FIGO2009 stage IB2–IVA admitted to the First Affiliated Hospital of Zhengzhou University from June 2020 to June 2022 were collected and further screened on the basis of inclusion and exclusion criteria. Para-aortic lymph nodes were considered positive if they were confirmed by 64-slice enhanced CT scan or 3.0T MRI or PETCT scan with a short diameter ≥1 cm. Periuterine or vaginal invasion was mainly based on gynecologist's internal examination. Cystoscopy or colonoscopy should have been performed to confirm the suspected bladder or rectal invasion indicated by imaging.
2.2. Inclusion criteria
Inclusion criteria included patient age 18–75 years; pathological diagnosis of cervical squamous cell carcinoma, adenocarcinoma, or adenocarcinoma; FIGO2009 stage IB2–IVA; no history of relevant surgery or chemotherapy; and having an Eastern Cooperative Oncology Group (ECOG) score of 0–2.
2.3. Exclusion criteria
Patients with FIGO2009 stage IB2–IIB without positive para-aortic lymph nodes; recurrent or metastatic cancer; no CCRT treatment; comorbid serious medical disease; comorbid malignancies; pregnancy or lactation; presence of autoimmune disease; or having missing data related to records that require analysis were excluded from the study.
Overall, of 311 patients, 205 patients met the inclusion criteria, 53 were excluded and 152 patients were ultimately included in the analysis. Among them, 70 high-risk LACC (FIGO2009 stage IB2–IIB with positive para-aortic lymph nodes and IIIA-IVA) patients receiving PD-1 inhibitor plus CCRT were included in the observation group, and 82 high-risk LACC patients receiving CCRT were included in the control group. The screening flowchart for case cohorts is shown in Figure 1.
Figure 1.
Flow chart of the selection process.
CCRT: Concurrent chemoradiotherapy; ECOG: Eastern Cooperative Oncology Group; FIGO: Federation Internationale of Gynecologie and Obstetrigue.
The complete response (CR) rate, ORR, disease control rate (DCR), progression free survival (PFS), OS and safety of the two groups were compared, and programmed death ligand-1 (PD-L1)-positive and PD-L1-negative subgroup analysis was carried out. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University.
2.4. Definition & measurements
A total of 152 patients received Volumetric Modulated Arc Therapy with a total dose of 45.0–48.6 Gy, 1.8 Gy each time, once a day, five-times a week. The radiotherapy dose of metastatic lymph nodes was increased synchronously to 60.0–64.8 Gy, 2.4 Gy each time. At the end of external radiation therapy, brachytherapy was combined. Brachytherapy was conducted by intracavitary ± interstitial brachytherapy guided by CT images. A brachytherapy machine equipped with 192Ir radiation source was used, 6 Gy each time, twice a week, for a total of five or six times. Cervical high-risk clinical target dose ≥87 Gy. During radiotherapy, five or six cycles of platinum drug chemotherapy were synchronized, with cisplatin 30–40 mg/m2 or carboplatin area under the curve = 2, once a week; The treatment group was combined with PD-1 inhibitor terriplizumab injection (Shanghai Junsil Biomedical Technology Co., LTD, Shanghai, China) or camrelizumab injection (Suzhou Shengdia Pharmaceutical Co., LTD, Suzhou, China) during CCRT, 200 mg each time, once every 3 weeks. After radiotherapy, PD-inhibitor maintenance therapy was given once every 3 weeks for 1–2 years. In the event of immune-related adverse reactions, the drug should be discontinued or delayed for a maximum of 9-week intervals. For persistent cervical cancer after CCRT, systemic treatment such as platinum-based chemotherapy ± bevacizumab was performed according to NCCN guidelines.
Dako monoclonal mouse anti-human PD-L1 clone 22C3 (Agilent Technologies Inc., CA, USA) was used to detect the expression of PD-L1 in cervical biopsy tissues before treatment, and a combined positive score (CPS) ≥1 was considered positive.
The efficacy was evaluated according to Response Evaluation Criteria In Solid Tumors version 1.1, and the efficacy was divided into CR, partial response (PR), stable disease (SD) and disease progression (PD) [24]. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [25]. Chronic radiation cystitis and chronic radiation proctitis were observed >6 months after the initiation of radiation therapy and were evaluated according to the toxicity criteria of the Radiation Therapy Oncology Group and the European organization for research and treatment of cancer [26].
2.5. Follow-up
Patients were recommended to return to the outpatient or inpatient department for follow-up, and those who could not return to the hospital were followed up by telephone. Follow-up was conducted every 3 months for 2 years after the end of radiotherapy and every 6 months after 2 years. PFS is the time from the start of treatment to disease progression or death. OS is the time from the start of treatment to death (from any cause). Patients were followed until June 2023.
2.6. Statistical analysis
Categorical variables were described as percentages. Continuous variables were tested for Kolmogorov–Smirnov normality. Variables with normal distribution were presented by mean ± standard deviation, and those with a skewed distribution were described by median and quartiles. Patients' baseline features, treatment and prognosis were compared between groups. Categorical variables were assessed by the chi-square or Fisher's exact test. All baseline parameters and treatment data were compared by the univariable Cox proportional hazards model between patients who progressed and those who did not. Candidate predictors with p < 0.1 were included in the multivariable Cox regression. The variables were selected by a forward stepwise (likelihood ratio) procedure based on the p-value. Cumulative survival for different groups was described by Kaplan–Meier curves. Data analysis was performed with SPSS (version 26.0, NY, USA). A p-value < 0.05 was considered significant. GraphPad Prism (Version 6.0, CA, USA) was used for graphing.
3. Results
3.1. Patient characteristics
After screening, 152 patients were included in the analysis including 70 patients in the observation group and 82 patients in the control group (Figure 1). The mean ages of the observation group and the control group were 52.3 ± 10.1 years and 41.6 ± 10.0 years, respectively. Baseline characteristics such as age, BMI, ECOG score, pathological type, FIGO 2009 stage, tumor diameter, and drugs and rounds of concurrent chemotherapy were well balanced and comparable between the observation group and the control group (p > 0.05), as shown in Table 1. Baseline characteristics such as age, BMI, ECOG score, pathological type, FIGO 2009 stage, tumor diameter, drugs and rounds of concurrent chemotherapy, and types of PD-1 inhibitor were well balanced and comparable between patients in the PD-L1-positive and PD-L1-negative subgroups (p > 0.05).
Table 1.
Comparison of baseline characteristics of high-risk locally advanced cervical cancer cervical cancer between the programmed cell death protein 1 inhibitor plus concurrent chemoradiotherapy and concurrent chemoradiotherapy alone groups.
| Characteristic | PD-1 inhibitor combined CCRT (n = 70) | CCRT (n = 82) | p-value |
|---|---|---|---|
| Age ≥50 years, cases (%) | 36 (51.4) | 47 (57.3) | 0.467 |
| BMI ≥18.5 kg/m2, cases (%) | 65 (92.9) | 77 (93.9) | 1 |
| ECOG score, cases (%) | 0.958 | ||
| 0 | 5 (7.1) | 10 (12.2) | |
| 1 | 57 (81.4) | 59 (72.0) | |
| 2 | 8 (11.4) | 13 (15.9) | |
| Histological type, cases (%) | 0.563 | ||
| Squamous | 60 (85.7) | 75 (91.5) | |
| Adenomatous | 7 (10.0) | 5 (6.1) | |
| Adenosquamous | 3 (4.3) | 2 (2.4) | |
| FIGO 2009 stage, cases (%) | 0.548 | ||
| IB2-IIB with PALN+ | 11 (15.7) | 8 (9.8) | |
| IIIA | 11 (15.7) | 10 (12.2) | |
| IIIB | 44 (62.9) | 60 (73.2) | |
| IVA | 4 (5.7) | 4 (4.9) | |
| Diameter of tumor ≥4 cm, cases (%) | 64 (91.4) | 75 (91.5) | 0.994 |
| Total RT duration >56 days, cases (%) | 8 (11.4) | 19 (23.2) | 0.059 |
| More than five rounds of concurrent chemotherapy, cases (%) | 62 (88.6) | 69 (84.1) | 0.431 |
| Platinum drugs, cases (%) | 0.649 | ||
| Cis-platinum | 41 (58.6) | 51 (62.2) | |
| Carboplatin | 29 (41.4) | 31 (37.8) | |
| PD-1 inhibitor, cases (%) | |||
| Triplimab | 40 (57.1) | – | |
| Carelizumab | 30 (42.9) | – |
CCRT: Concurrent chemoradiotherapy; ECOG: Eastern Cooperative Oncology Group; FIGO: Federation Internationale of Gynecologie and Obstetrigue; PALN+: Para-aortic lymph nodes were positive; PDL-1: Programmed death ligand-1; RT: Radiotherapy.
3.2. Antitumor activity
Compared with the control group, the ORR in the observation group (92.9 vs 81.7%; p = 0.043) was significantly higher. The CR rate (67.1 vs 53.7%; p = 0.091) and DCR (95.7 vs 90.2%; p = 0.194) were also increased without statistical significance, as shown in Table 2.
Table 2.
Comparison of antitumor activity of high-risk locally advanced cervical cancer between the PD-1 inhibitor plus concurrent chemoradiotherapy and concurrent chemoradiotherapy alone groups.
| Short-term efficacy | PD-1 inhibitor combined CCRT (n = 70) | CCRT (n = 82) | p-value |
|---|---|---|---|
| CR, cases (%) | 47 (67.1) | 44 (53.7) | 0.091 |
| PR, cases (%) | 18 (25.7) | 24 (29.3) | 0.625 |
| SD, cases (%) | 2 (2.9) | 7 (8.5) | 0.179 |
| PD, cases (%) | 3 (4.3) | 8 (9.8) | 0.194 |
| ORR (%) | 65 (92.9) | 67 (81.7) | 0.043 |
| DCR (%) | 67 (95.7) | 74 (90.2) | 0.194 |
CCRT: Concurrent chemoradiotherapy; CR: Complete response; DCR: Disease control rate; ORR: Objective response rate; PD: Progression disease; PDL-1: Programmed death ligand-1; PR: Partial response; SD: Stable disease.
Compared with the PD-L1-negative subgroup, the CR rate in the PD-L1-positive subgroup was significantly higher (81.8 vs 42.3%; p = 0.001). The ORR (97.7 vs 84.6%; p = 0.060) and DCR (97.7 vs 92.3%; p = 0.055) were also increased without statistical significance.
3.3. Survival analysis
The median follow-up time of 152 patients was 25.0 (20.0–30.0) months, and the median follow-up time of observation group and control group was 25.5 (19.0–31.0) months and 25.0 (21.0–30.0) months, respectively. The median maintenance time of PD-1 inhibitor was 12.0 (10.0–13.25) months, and the median number of PD-1 inhibitor administration was 15.0 (12.0–16.25) times. The median PFS was significantly longer in the observation group than in the control group (not reaching vs 21.0 months; p < 0.001). The median OS of the two groups was not reached, and the difference was not statistically significant (p = 0.075). The 1-, 2-, and 3-year PFS rates in the observation and control groups were 95.7 vs 72.0%, 79.0 vs 49.2% and 76.7 vs 49.2%, respectively. The 1-, 2-, and 3-year OS rates of observation and control groups were 100 vs 98.8%, 97.1 vs 90.2% and 84.9 vs 72.7%, respectively.
The median follow-up time of PD-L1-positive subgroup and PD-L1-negative subgroup was 25.5 (21.0–31.5) months and 24.0 (17.0–30.0) months, respectively. The median PFS and median OS of the two groups were not reached. Compared with the PD-L1-negative subgroup, PFS (p = 0.002) and OS (p = 0.032) in the PD-L1-positive subgroup were significantly improved. The 1-, 2- and 3-year PFS rates of PD-L1-positive and PD-L2-negative subgroups were 97.7 vs 92.3%, 92.2 vs 56.7% and 88.5 vs 56.7%, respectively. The 1-, 2-, and 3-year OS rates of PD-L1-positive and PD-L1-negative subgroups were 100 vs 100%, 97.6 vs 96.2% and 97.6 vs 63.1%, respectively (Figure 2).
Figure 2.
Survival outcomes of high-risk locally advanced cervical cancer patients. (A) Progression-free survival (PD-1 inhibitor plus CCRT group vs CCRT group). (B) Overall survival (PD-1 inhibitor plus CCRT group vs CCRT group). (C) Progression-free survival (PD-L1-positive vs PD-L1-negative groups). (D) Overall survival (PD-L1-positive vs PD-L1-negative groups).
CCRT: Concurrent chemoradiotherapy; LACC: Locally advanced cervical cancer; PD-1+CCRT: PD-1 inhibitor plus CCRT group; PDL-1: Programmed death ligand-1.
3.4. Safety profile
There was no significant difference in the incidence of anemia (p = 0.100), thrombocytopenia (p = 0.250), nausea or vomiting (p = 0.226), diarrhea (p = 0.733), liver function injury (p = 0.790), radiation cystitis (p = 0.401), and radiation proctitis (p = 0.422) between the observation group and control group. However, the incidence of leukopenia (p = 0.004) and fatigue (p < 0.001) in the observation group was significantly higher than that in control group. Immune-related side effects such as fever (7.1%), capillary hyperplasia (drug-specific side effects of carrelizumab; 31.4%), hypothyroidism (35.7%) and pruritus (10%) in the observation group were all grade 1–2, and no grade 3–4 immune-related side effects were found (Table 3).
Table 3.
Comparison of adverse events of high-risk locally advanced cervical cancer cervical cancer between the PD-1 inhibitor plus CCRT and CCRT groups.
| Adverse event | PD-1 inhibitor combined CCRT (n = 70) |
CCRT (n = 82) |
p-value | ||
|---|---|---|---|---|---|
| Grade 1–2 | Grade 3–4 | Grade 1–2 | Grade 3–4 | ||
| Leukopenia | 48 (68.6) | 11 (15.7) | 61 (74.4) | 12 (14.6) | 0.004 |
| Anemia | 56 (80.0) | 1 (1.4) | 70 (85.4) | 3 (3.7) | 0.1 |
| Thrombocytopenia | 51 (72.9) | 5 (7.1) | 66 (80.5) | 5 (6.1) | 0.25 |
| Fatigue | 34 (48.6) | 0 (0) | 15 (18.3) | 0 (0) | 0 |
| Nausea or vomiting | 49 (70.0) | 0 (0) | 64 (78.0) | 0 (0) | 0.226 |
| Diarrhea | 5 (7.1) | 0 (0) | 4 (4.9) | 0 (0) | 0.733 |
| Liver function injury | 43 (61.4) | 0 (0) | 48 (58.5) | 0 (0) | 0.79 |
| Fever | 5 (7.1) | 0 (0) | – | – | – |
| Capillary hyperplasia | 22 (31.4) | 0 (0) | – | – | – |
| Hypothyroidism | 25 (35.7) | 0 (0) | – | – | – |
| Pruritus | 7 (10.0) | 0 (0) | – | – | – |
| Radiation cystitis | 35 (50.0) | 1 (1.4) | 34 | 2 (2.4) | 0.401 |
| Radiation proctitis | 47 (67.1) | 6 (8.6) | 58 | 8 (9.8) | 0.422 |
CCRT: Concurrent chemoradiotherapy; PDL-1: Programmed death ligand-1.
3.5. Prognostic analysis of clinical factors
Univariate analysis showed that the total radiotherapy duration >56 days (hazard ratio [HR]: 4.843, 95% CI: 2.790–8.408; p < 0.001) and five or fewer rounds of concurrent chemotherapy (HR: 2.873, 95% CI: 1.561–5.286; p = 0.001), FIGO2009 stage IVA (HR: 8.285, 95% CI: 2.062–33.293; p = 0.003), and combination of PD-1 inhibitor (HR: 0.313, 95% CI: 0.170–0.577; p < 0.001) were significantly associated with disease progression. Multivariate analysis showed that total radiotherapy duration >56 days (HR: 4.799, 95% CI: 2.668–8.632; p < 0.001) and FIGO2009 stage IVA (HR: 6.464, 95% CI: 1.577–26.490; p = 0.010) and combined PD-1 inhibitor (HR: 0.324, 95% CI: 0.175–0.600; p < 0.001) were independent determinants of disease progression (Table 4).
Table 4.
Univariate and multifactorial Cox regression analyses to identify predictors for disease progression (n = 152) of high-risk locally advanced cervical cancer patients in the original cohort.
| Initial parameter | Univariate analysis |
p-value | Multivariate analysis |
p-value | ||
|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | |||
| Age ≥50 years | 0.958 | 0.561–1.637 | 0.876 | – | – | – |
| BMI ≥18.5 kg/m2 | 1.019 | 0.368–2.822 | 0.972 | – | – | – |
| ECOG score (compared with ECOG = 0) | 0.48 | – | – | – | ||
| 1 | 1.268 | 0.503–3.200 | 0.615 | |||
| 2 | 0.737 | 0.213–2.549 | 0.63 | |||
| Total RT duration >56 days | 4.843 | 2.790–8.408 | <0.001 | 4.799 | 2.668–8.632 | <0.001 |
| Diameter of tumor ≥4 cm | 2.756 | 0.671–11.318 | 0.16 | – | – | – |
| Fewer than five rounds of concurrent chemotherapy | 2.873 | 1.561–5.286 | 0.001 | – | – | – |
| Histological type (compared with squamous) | 0.056 | – | – | – | ||
| Adenomatous | 2.512 | 1.182–5.340 | 0.017 | |||
| Adenosquamous | 1.315 | 0.318–5.434 | 0.705 | |||
| FIGO 2009 stage (compared with IB2–IIB with PALN+) | 0.011 | 0.056 | ||||
| IIIA | 1.855 | 0.464–7.418 | 0.382 | 2.082 | 0.519–8.352 | 0.301 |
| IIIB | 2.705 | 0.836–8.758 | 0.097 | 2.952 | 0.903–9.649 | 0.073 |
| IVA | 8.285 | 2.062–33.293 | 0.003 | 6.464 | 1.577–26.490 | 0.01 |
| PD-1 inhibitor combined CCRT group | 0.313 | 0.170–0.577 | <0.001 | 0.324 | 0.175–0.600 | <0.001 |
| Carboplatin (compared with cis-platinum) | 1.056 | 0.613–1.818 | 0.844 | – | – | – |
CCRT: Concurrent chemoradiotherapy; ECOG: Eastern Cooperative Oncology Group; FIGO: Federation Internationale of Gynecologie and Obstetrigue; HR: Hazard ratio; PALN+: Para-aortic lymph nodes were positive; RT: Radiotherapy.
4. Discussion
The prognosis for high-risk LACC remains poor after CCRT as recommended by guidelines [27–29]. Moreover, in developing countries such as China, the population of high-risk LACC patients remains large, and how to improve the prognosis of high-risk LACC is an urgent clinical problem [30,31]. Many previous studies have attempted CCRT followed by sequential systemic chemotherapy [32] or neoadjuvant chemotherapy followed by concurrent chemoradiotherapy [32–36]. However, all of these attempts to improve the prognosis of high-risk LACC have failed. However, the efficacy of neoadjuvant chemotherapy combined with camrelizumab (PD-1 inhibitor) in the treatment of LACC has been preliminarily confirmed in the NACI study. Median follow-up was 11.0 months, ORR was 98%, and 19% of patients achieved CR [11]. This also reflects the value of PD-1 inhibitors in the treatment of LACC. In recent years, the combined application of radiotherapy and PD-1 inhibitors has made breakthrough progress in a variety of solid tumors such as lung cancer, and the combination of immunotherapy and radiotherapy achieved a 1 + 1> 2 effect [19,37–41]. Therefore, whether the combination of PD-1 inhibitors can significantly improve the efficacy of CCRT in the treatment of cervical cancer has attracted wide attention [23].
Many previous studies regarded FIGO 2009 IB2–IIB stage cervical cancer with positive pelvic lymph nodes as high-risk LACC. In fact, the prognosis of these patients was significantly better than that of FIGO 2009 IB2–IIB patients with positive para-aortic lymph nodes and IIIA–IVA patients (58.7–62.8% vs 16.0–41.4%) [42]. This is one of the main reasons why the rationality of FIGO 2018 cervical cancer staging standards has been questioned [43]. In this study, the high-risk LACC included in our analysis did not include patients with FIGO2009IB2-IIB stage with positive pelvic lymph nodes.
An important characteristics of cervical cancer is that it evades the surveillance function of the host immune system and avoids being cleared by upregulating the expression of immune checkpoint PD-L1 [44]. PD-L1 can bind to PD-1 after T-cell activation and induce the secretion of inhibitory cytokines, play a negative role in regulating T-cell activity, and then affect the function of antitumor T cells and promote tumor progression. Radiotherapy can directly induce immunogenic death of tumor cells, regulate tumor cell phenotype, normalize tumor blood vessels and promote local infiltration of immune cells and systemic therapeutic agents [45,46]. Local radiotherapy can also activate the immune system and trigger immune cells to attack tumor cells far away from the irradiated area (distant effect) [47]. Clinical radiotherapy itself rarely produces distant effects, but immunotherapy can enhance the immune induction effect of radiotherapy and increase the occurrence of distant effect [12,48]. There is a synergistic effect between radiotherapy and immunotherapy. Radiotherapy combined with immunotherapy has made significant progress in the second- and first-line treatment of recurrent or metastatic cervical cancer. The NCCN Cervical Cancer Guidelines already recommend pembrolizumab (PD-1 inhibitor) for first-line treatment of patients with PD-L1-positive, recurrent or metastatic cervical cancer.
In recent years, the combination of an immune checkpoint inhibitor and CCRT in the treatment of LACC has become a research hotspot. The NiCOL study reported a phase I study of nivolumab (PD-1 inhibitor) plus CCRT, followed by nivolumab maintenance therapy for IB3–IVA cervical cancer (n = 16), with an ORR of 93.8% and a 1-year PFS rate of 81.2% [49]. GOTIC-018 reported a phase I study of nivolumab plus CCRT for LACC (n = 30), which showed that the ORR of PD-1 inhibitor and CCRT simultaneous treatment was 100% regardless of whether it was induced by PD-1 inhibitor or not [50]. Despite the retrospective nature of our study, the sample size was larger than that of NiCOL and GOTIC-018 studies. Considering the high-risk nature of the patients with LACC in our trial, we obtained favorable outcomes. Compared with the CCRT group (n = 82), ORR (92.9 vs 81.7%) and PFS rates at 1 year (95.7 vs 72.0%), 2 years (79.0 vs 49.2%) and 3 years (76.7 vs 49.2%) were increased in the PD-1 inhibitor plus CCRT group (n = 70).
In the ongoing randomized, open, multicenter phase III KEYNOTE-A18 study of pembrolizumab (PD-1 inhibitor) plus CCRT for LACC, the preliminary findings showed that pembrolizumab plus CCRT for LACC is well-tolerated and poses no significant safety concerns. In the first interim analysis assigned to the KENOTE-A18 study, the median follow-up was 17.9 months. Pembrolizumab plus CCRT showed a statistically significant improvement in PFS compared with the CCRT group (57.3 and 67.8% PFS at 24 months, respectively). The addition of pembrolizumab to CCRT showed a trend of OS prolongation, but the difference was not statistically significant. The US FDA has accepted the application of pembrolizumab plus concurrent chemoradiotherapy for the treatment of newly diagnosed high-risk locally advanced cervical cancer, which is expected to be included in the clinical recommendation [21]. The result of our study was consistent with KEYNOTE-A18. In our study, the incidence of leukopenia (p = 0.004) and fatigue (p < 0.001) in the PD-1 inhibitor plus CCRT group was significantly higher than that in the CCRT group; however, all patients recovered quickly after symptomatic treatment and did not affect the routine treatment process. There was no significant difference in the incidence of other major adverse events between the two groups (p > 0.005), and no immune-related side effects grades 3–4, indicating that the patients tolerated the treatment well. Furthermore, our study also demonstrated that PFS and OS were significantly improved in the PD-L1-positive (CPS ≥1) subgroup compared with the PD-L1-negative (CPS <1) subgroup, indicating that PD-L1-positive patients are the main beneficiaries of PD-1 inhibitor plus CCRT regimen. KEYNOTE-A18 study showed that PD-1 inhibitor plus CCRT could significantly increase the expression level of PD-L1 in cervical tissues of patients [21], this might be why PFS in the PD-1 inhibitor plus CCRT group (regardless of whether PD-L1-positive or not) was significantly higher than that in the CCRT group.
In addition to the study of PD-1 inhibitor plus CCRT in the treatment of LACC, the findings of the randomized, multicenter, double-blind phase III CALLA study showed that the ORR of PD-L1 inhibitor (durvalumab) plus CCRT in the treatment of LACC was 82.6%.The CALLA study had a sample size of 770, with Asian populations accounting for 39% (n = 300). Compared with placebo, the durvalumab group did not significantly improve median PFS (HR: 0.84, 95% CI: 0.65–1.08; p = 0.174). The 12-month PFS rate in the durvalumab and placebo groups were 76 and 73.3%, respectively, and the incidence of grade ≥3 treatment-related adverse events (TRAE) was 41.6 and 43.2%, respectively [51]. Results from the NRG GY-017 study showed an 82% ORR for atezolizumab as a pre-CCRT induction therapy [22]. As reported in the prior studies, when PD-L1 inhibitor combined with CCRT in LACC treatment, the ORR of PD-1 inhibitors plus CCRT was higher (82.0–82.6% vs 92.9–100%). Compared with the CCRT group, there was no significant difference in ORR and PFS in the CALLA study of PD-L1 inhibitor plus CCRT group, whereas in our study, the ORR and PFS in the PD-1 inhibitor plus CCRT group were significantly improved (p < 0.05). On one hand, the findings suggest that PD-1 inhibitors plus CCRT may have more advantages in the treatment of LACC [52]. Conversely, our study specifically focused high-risk patients in LACC who may benefit more from combined immunotherapy, making it is easier to acquire favorable outcomes.
The optimal sequence of CCRT and immunotherapy remains controversial. The COLIBRI study (N = 40) initially showed that patients with FIGO IB3–IVA stage cervical squamous cell carcinoma were treated with nivolumab combined with ipilimumab as neoadjuvant therapy before CCRT, followed by maintenance therapy with nivolumab monotherapy, and it is effective and safe [53]. The GY017 study (N = 40) preliminarily showed that neoadjuvant therapy (sequential CCRT) with atezolizumab was more effective than simultaneous CCRT with atezolizumab for LACC (day 28 pathological response rate [CR + PR]: 69 vs 40%) [22]. A randomized phase II study (N = 96) preliminarily suggests that sequential use of pembrolizumab following CCRT and simultaneous use of pembrolizumab with CCRT were both effective regimen for the treatment of LACC, but it remains to be determined which regimen is better [53].
Preliminary results from a single-arm, open-label, phase II trial (N = 24) suggested that toripalimab combined with bevacizumab and platinum-containing chemotherapy was effective in first-line treatment of patients with refractory, recurrent, or metastatic cervical cancer (ORR 77.3%, DCR 95.5%). The most common grade ≥3 TRAEs were neutropenia (41.7%) and leukopenia (16.7%). A prospective, single-arm, phase II NACI study (N = 85) preliminarily demonstrated that camrelizumab combined with chemotherapy for neoadjuvant treatment of locally advanced cervical cancer has good antitumor activity (ORR 97.65%) and manageable toxicity (incidence of grade ≥3 TRAE 40%) [11]. On the basis of these research results, and considering the accessibility of PD-1 inhibitors such as pembrolizumab in China, the PD-1 inhibitors we selected for treatment were toripalimab or camrelizumab produced in China, and the results also showed that they were safe and effective.
Multivariate analysis of clinical factors related to prognosis showed that the total duration of radiotherapy >56 days (p < 0.001), the FIGO2009 stage IVA (p = 0.010), and combined PD-1 inhibitor (p < 0.001) were independent influencing factors for disease progression, which was consistent with the results of previous relevant studies. Univariate analysis showed that fewer than five rounds of concurrent chemotherapy (HR: 2.873, 95% CI: 1.561–5.286; p = 0.001) was a correlated factor for disease progression; however, multivariate analysis showed that it was not an independent factor for disease progression. This may be because both fewer than five rounds of concurrent chemotherapy and total duration of radiotherapy >56 days may be caused by severe myelosuppression, whereas it is the total duration of radiotherapy >56 days that actually has an impact on disease progression [54–56].
This study has several limitations. First, it was retrospective, single-center, and limited in number of patients. Although our study demonstrates the potential clinical efficacy and safety of PD-1 inhibitor plus CCRT, these findings need to be validated in future prospective, multicenter, large-sample clinical trials. Second, the duration of patient follow-up was insufficient to assess the median PFS and OS in the PD-L1 inhibitor plus CCRT group, which may lead to misestimates of the effect of the treatment regimen on PFS and OS. Moreover, tumor molecular markers such as microsatellite status, tumor mutation burden, T-cell receptor status, KEAP1 and PIK3CA mutations, and tumor immune cell infiltration were associated with different risk of disease progression and survival outcomes in high-risk LACC patients [57–59]. Therefore, it is necessary to include pathological, immunological, and molecular prognostic markers in further studies for risk stratification [60–62].
5. Conclusion
We compared and analyzed the efficacy and safety of PD-1 inhibitor plus CCRT and CCRT in the treatment of high-risk LACC in this retrospective study. We found that PD-1 inhibitor plus CCRT presented a significant survival benefit and comparable incidence of toxicity in high-risk LACC patients, especially in PD-L1-positive individuals. It could offer an alternative treatment for high-risk LACC patients, especially PD-L1-positive patients. However, the effects of different timing of PD-1 inhibitor combination with radiotherapy and different duration of PD-1 inhibitor maintenance therapy on survival outcomes need to be further explored in future studies.
Funding Statement
This study was supported by the key Research and Development and Promotion Special Project (Science and Technology Research) of Henan Provincial Science and Technology Department in 2023. The project name is “Study on Synergistic Effect and Mechanism of Anti-PD-1 Monoclonal Antibody Combined with Radiotherapy through Remodeling T-Cell Receptor Pool in Cervical Cancer Patients,” project no. is 232102311037. It was supported by the Key Scientific Research Project of Henan Provincial Colleges and Universities in 2022, the project name is “The Influence of Vaginal Microorganisms on Radiotherapy Efficacy of Cervical Squamous Cell Cancer and Related Immune Mechanism Research,” project no. 22A320059.
Author contributions
Y Cheng contributed to conception and design; C Wang and L Liu contributed to statistical analysis and manuscript writing; X Li, J Lei, and H Shi contributed to data collection; and Y Li and Z Shen managed the patients. All authors read and approved the final manuscript.
Financial disclosure
This study was supported by the key Research and Development and Promotion Special Project (Science and Technology Research) of Henan Provincial Science and Technology Department in 2023. The project name is “Study on Synergistic Effect and Mechanism of Anti-PD-1 Monoclonal Antibody Combined with Radiotherapy through Remodeling T-Cell Receptor Pool in Cervical Cancer Patients,” project no. is 232102311037. It was supported by the Key Scientific Research Project of Henan Provincial Colleges and Universities in 2022, the project name is “The Influence of Vaginal Microorganisms on Radiotherapy Efficacy of Cervical Squamous Cell Cancer and Related Immune Mechanism Research,” project no. 22A320059.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval (Ethics Committees of The First Affiliated Hospital of Zhengzhou University (approval no. 2022-KY-0383-002)) and/or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.
The informed consent requirement was waived by the ethics committees based on the nature of this retrospective study, in which patient data were kept confidential.
References
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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