Abstract
Objective
To compare the efficacy and safety of neoadjuvant chemotherapy combined with concurrent chemoradiotherapy (NACT+CCRT) vs. concurrent chemoradiotherapy (CCRT) in locally advanced cervical cancer (LACC) patients with large tumor masses.
Methods
LACC patients with localized tumor diameter >4 cm, were randomly allocated in an unblinded 1:1 ratio to NACT+CCRT or CCRT groups. Patients in the NACT+CCRT group were given paclitaxel combined with cisplatin (TP) NACT every 3 weeks for 2 cycles, followed by CCRT, with the chemotherapy regimen the same as for NACT. CCRT group were given CCRT with the same as for NACT.
Results
From March 1, 2019, to June 30, 2021, 146 patients were included in the final analysis. Sixty-eight (93.2%) patients in the NACT+CCRT group and 66 (90.4%) patients in the CCRT group completed the expected treatment course. The complete response (CR) rate in the NACT+CCRT group was significantly higher than in the CCRT group (87.7% vs. 67.6%, χ2=54.540, p=0.000). In the NACT+CCRT group, the 1- and 2-year overall survival (OS) rates were significantly higher than those in the CCRT group (96% vs. 89% and 89% vs. 79%, χ2=5.737, p=0.017). Additionally, the rate of recurrences and distant metastases was significantly lower in the NACT+CCRT group than in the CCRT group (4.11% vs. 7.35%, χ2=4.059, p=0.021). Most treatment-related adverse events in both groups were grade 3.
Conclusion
Compared to CCRT, NACT+CCRT might improve the treatment completion rate, increase CR rate and 1- and 2-year OS rates, and reduce distant metastases rate for LACC patients with large tumor masses.
Keywords: Locally Advanced Cervical Cancer, Randomized Controlled Study, Efficacy and Safety
Synopsis
Compared to concurrent chemoradiotherapy (CCRT), neoadjuvant chemotherapy combined with CCRT (NACT+CCRT) improved the complete response rate in LACC with large tumor masses. NACT+CCRT also prolonged the 1- and 2-year overall survival rates and reduce distant metastasis. Compared to CCRT, NACT+CCRT did not increase the toxic and side effects.
INTRODUCTION
Cervical cancer is one of the most prevalent malignant tumors that threaten women's health. Approximately 570,000 new cases and 310,000 deaths occur worldwide annually [1], with 80% of new cases occurring in underdeveloped countries [2]. Every year, approximately 110,000 new cases of cervical cancer are diagnosed in China, with nearly 34,000 deaths [3]. Women with locally advanced cervical cancer (LACC) (stage IB3 to IVA, Federation International of Gynecology and Obstetrics, FIGO 2018) have a higher rate of recurrence and poorer survival prognosis than those with early-stage disease (stage IA to IB2). After surgery alone, relapse rates are at least 30%, and 5-year survival rates range from 80% for stage IB disease to 30% for stage III disease [4,5].
In 5 phase III clinical trials reported in 1999, concurrent chemoradiotherapy (CCRT) was shown to reduce the incidence of LACC recurrence by 50% compared to radiotherapy alone [6,7,8,9,10]. A meta-analysis covering 13 clinical trials revealed that CCRT in patients with LACC could improve 5-year overall survival (OS) and progression-free survival (PFS) by 10% and 13%, respectively [11]. Despite this, the 5-year survival rate following platinum-based CCRT remains low, with local recurrence and distant metastasis remaining the primary causes of death. Therefore, new treatment modalities for LACC need to be explored. A preliminary study demonstrated that neoadjuvant chemotherapy (NACT) combined with conformal radiotherapy (NACT+CCRT) could reduce tumor volume with tolerable adverse effects in the treatment of LACC [12]. However, the effect of NACT+CCRT on survival is unknown, necessitating further study. An earlier retrospective analysis of ours demonstrated that paclitaxel plus platinum (TP)-based NACT+CCRT could improve survival in patients with LACC, particularly those with tumor diameter >4 cm [13]. In the present study, we conducted a prospective randomized trial to compare the efficacy and safety of TP-based NACT+CCRT vs. CCRT in LACC patients with large tumor masses.
MATERIALS AND METHODS
1. Study design
This study is a prospective, single-center, open-label randomized controlled clinical trial. The ethics committees of the Affiliated Cancer Hospital of Guizhou Medical University approved the study protocol. The study conformed to the Declaration of Helsinki, and all patients provided their signed informed consent. The study was registered at ClinicalTrials.gov (number ChiCTR1900023257). The primary endpoints of this study were complete response (CR) rate and safety, and the secondary endpoints were the 1- and 2-year OS and PFS.
2. Study subjects
Before randomization, all patients underwent biopsy for histopathological evaluation and imaging examination from the chest to pelvis to assess the tumor size, extent of invasion, and whether there was distant metastasis. In addition, the electrocardiographic examination and some laboratory tests are also required to evaluate whether there are contraindications to radiotherapy and chemotherapy. Two gynecologists sequentially performed gynecological examinations and staged them according to the FIGO 2018 staging criteria for cervical cancer.
Inclusion criteria: 1) The pathological diagnosis was squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma on cervical biopsy before any anti-tumor treatment; 2) FIGO stages IB2 to IVA, and the cervical tumor diameter is greater than 4 cm, as measured at the largest slice in the horizontal axis of pelvic magnetic resonance imaging (MRI) T2WI imaging; 3) Aged 18–65 years; 4) With a Karnofsky performance score of ≥70; 5) Having never previously received radiotherapy, chemotherapy, or surgery before; 6) In the blood routine test, the white blood cell count was greater than 4.0×109/L, the platelet count was greater than 100×109/L, and the hemoglobin level was greater than 70 g/L; 7) With alanine aminotransferase and aspartate aminotransferase <1.5 times the upper limit of normal (ULN), total bilirubin <1.5×ULN and serum creatinine <1.5×ULN; 8) Without major organ dysfunction or severe comorbidities; 9) With a thorough understanding of the study and has signed the informed consent form.
Exclusion criteria: 1) Patients with small cell carcinoma, sarcoma, and carcinosarcoma; 2) With a history of invasive malignancy (other than non-malignant melanoma skin cancer); 3) Receiving systemic chemotherapy within the last 3 years; 4) Receiving pelvic or abdominal radiation therapy previously; 5) Concurrently receiving additional chronic systemic immunotherapy or hormone therapy; 6) Pregnant or breastfeeding women; 7) Suffering from medical conditions that require hospitalization or impede the study, such as unstable angina, congestive heart failure, exacerbation of a chronic obstructive pulmonary disease, acquired immunodeficiency disease, and other immunocompromised states; 8) With a physical or mental illness, or who have no or limited capacity for civil conduct, and who, in the investigator's opinion, cannot fully comprehend the potential complications of this study.
3. Randomization and treatment
The sample calculation refers to the literature reporting a CR rate of 75% for CCRT, which assumes that NACT+CCRT increases CR rate by approximately 10%, and α requires that the probability of committing a class I error is less than 1%, the probability of class II error is not more than 10%. One-sided t0.01=2.326, t0.1=1.645, n=2 [(2.326 + 1.645) × 0.75/0.1] = 60 cases were obtained by looking up the degree of freedom of a row in the t-bound table. The eligible patients were randomly assigned to NACT+CCRT or CCRT group, using an unblinded 1:1 digital table method. In the NACT+CCRT group, the patients completed 2 cycles of NACT, and the subsequent concurrent chemotherapy and radiotherapy doses were identical to those in the CCRT group.
The regimen of the NACT+CCRT group was: 1) For TP-NACT, after pre-treatment with cimetidine and dexamethasone, paclitaxel was intravenously infused at 135–175 mg/m2 for 3 hours, and cisplatin was intravenously infused at 60–80 mg/m2, with a course of 21 days per cycle for 2 consecutive cycles. 2) Two weeks after NACT, external beam radiation therapy (EBRT) and intensity modulated radiotherapy was administered in CCRT. Regarding cases with lymph node metastasis, the radiotherapy physician would boost the dose of lymph node metastasis locally accordingly. The gross tumor volume of lymph node metastasis dose of 56.35–60.2Gy and clinical target volume dose of 50.4 Gy in 28 fractions in 6 weeks were administered at a dose of 1.8–2.15 Gy per fraction daily, 5 days a week, 3-dimensional Brachytherapy was given at the end of EBRT (6Gy per fraction, mostly 5 fractions, Ir192 based).Target delineation, and organ dose limitation were carried out per the principles of NCCN [11], ICRU89 [14], and RTOG0415 [15] on cervical cancer EBRT and post-installation brachytherapy: V45G y ≤200 cm3 and D2cm3 ≤65Gy for the small intestine, V40G y ≤50% and D2cm3 ≤73Gy for rectum, V45G y ≤50% and D2cm3 ≤80Gy for the bladder. The CCRT group was treated with the same chemoradiotherapy regimen as the NACT+CCRT group. In this study, there are 3 main nodes for imaging examination. For patients in the NACT+CCRT group, pelvic MRI was performed before and after NACT, and prior to brachytherapy. For patients in the CCRT group, pelvic MRI was performed before CCRT and prior to brachytherapy. The radiotherapy plan was revised after 17 radiotherapy sessions to adjust the radiotherapy target area in real time.
4. Follow-up
After completing all treatments, patients were followed up by face-to-face or telephone consultation every 3 months in years 1–2 and every 6 months in years 3–5. Outpatient re-examinations were performed 12 weeks after CCRT, including a gynecological examination, contrast-enhanced abdominal computed tomography (CT), pelvic MRI, chest X-ray or CT, and, if necessary, a whole-body bone scan. Two oncologists conducted the efficacy evaluation according to the Response Evaluation Criteria in Solid Tumors standard (version 1.1) [16].
The OS was defined as the time from randomization to death for any cause, and the PFS was defined as the time from randomization to tumor progression or death. Adverse events of anticancer therapies were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) [17]. The radiation-induced toxic and side effects acute and late adverse reactions was aseessed according to the RTOG/EORTC grading standard [18].
5. Statistical analysis
Statistical analysis was performed using SPSS 20.0 software (SPSS, Chicago, IL, USA). Continuous variables were described using means and standard deviations, while categorical variables were described using proportions. Two groups of quantitative data were compared using the Wilcoxon rank-sum test for 2 independent sample comparisons. Categorical outcomes such as response rate, survival rate, and incidence of adverse effects were compared using the χ2 test or Fisher’s exact test. The Kaplan-Meier method was used for survival analysis, and the log-rank test was used to compare survival rates. The difference was considered statistically significant if p<0.05.
RESULTS
1. Patients
From March 1, 2019, to June 30, 2021, 160 patients from the Affiliated Cancer Hospital of Guizhou Medical University were screened the inclusion and exclusion criteria, and 148 of them were enrolled and randomly assigned. At the beginning of the treatment, 2 patients refused to continue to receive medical intervention for personal reasons. Finally, 146 patients were included in the analysis, 73 cases from the NACT+CCRT group, and 73 cases from the CCRT group (Fig. 1).
Fig. 1. CONSORT flow diagram of study design.
CCRT, concurrent chemoradiotherapy; NACT+CCRT, neoadjuvant chemotherapy combined with concurrent chemoradiotherapy.
As shown in Table 1, there were no significant differences between 2 groups in baseline characteristics such as age, physical performance status, histopathological type, stage, and tumor size. The follow-up time point ended on March 31, 2022, with a 100% completion rate and a median time of 21 months (8–37 months).
Table 1. Baseline demographics and clinical characteristics for all randomly assigned patients.
| Characteristic | NACT+CCRT (n=73) | CCRT (n=73) | χ2 | p-value | |
|---|---|---|---|---|---|
| No. of patients | No. of patients | ||||
| Age (yr) | 51 (35–69) | 53 (30–68) | 0.558 | 0.456 | |
| KPS | 90 (70–100) | 90 (80–100) | 1.077 | 0.331 | |
| Histopathological diagnosis | 1.126 | 0.228 | |||
| Squamous cell carcinoma | 65 (89.0) | 64 (87.7) | |||
| Adenocarcinoma | 6 (8.2) | 6 (8.2) | |||
| Adenosquamous carcinoma | 2 (2.8) | 3 (4.1) | |||
| Disease stage (FIGO 2009) | 1.803 | 0.181 | |||
| II B | 49 (67.1) | 50 (68.5) | |||
| III A | 4 (5.5) | 3 (4.1) | |||
| III B | 18 (24.7) | 19 (26.0) | |||
| IV A | 2 (2.7) | 1 (1.4) | |||
| Disease stage (FIGO 2018) | 2.443 | 0.12 | |||
| II B | 27 (37.0) | 28 (38.4) | |||
| III A | 2 (2.7) | 3 (4.1) | |||
| III B | 14 (19.2) | 13 (17.8) | |||
| III C1r | 28 (38.4) | 27 (37.0) | |||
| IV A | 2 (2.7) | 2 (2.7) | |||
| Maximum diameter of the largest (cm) | 5.1 (4.7–7.4) | 5.2 (4.5–7.3) | 0.729 | 0.395 | |
| Hemoglobin at baseline (g/dL) | 10.2 (7.4–13.6) | 11.7 (7.2–14.1) | 0.974 | 0.621 | |
Values are presented as median (range) or number (%).
CCRT, concurrent chemoradiotherapy; FIGO, International Federation of Gynecology and Obstetrics; KPS, Karnofsky performance score; NACT+CCRT, neoadjuvant chemotherapy combined with concurrent chemoradiotherapy.
2. Treatment completion rate
Paclitaxel was given at a dose of 148 mg (143–162) in the NACT+CCRT group, and DDP was given at a dose of 72 mg (60–76). One patient had peripheral neuropathy and grade 2 abnormal renal function, which improved after a 20% reduction in chemotherapy dosage. Five patients completed only one cycle of concurrent chemotherapy due to grade 2–3 gastrointestinal reactions during CCRT. Paclitaxel was given at a dose of 149 mg (145–164), and DDP was given at a dose of 71 mg in the CCRT group (60–74). Due to grade 2–3 gastrointestinal reactions, 7 patients only completed one cycle of concurrent chemotherapy.
In the NACT+CCRT group, all patients completed 2 cycles of NACT with paclitaxel and cisplatin, only 1 (1.4%) patient receiving a 20% dose reduction. Subsequently, 68 (93.2%) patients completed 2 cycles of chemotherapy during CCRT while 5 (6.8%) patients completed only 1 cycle. All patients completed radiotherapy, including external radiation and brachytherapy.
In the CCRT group, 66 patients (90.4%) completed 2 cycles of chemotherapy, while 7 patients (6.8%) completed only 1 cycle. Furthermore, 5 patients (6.8%) did not complete radiotherapy and survival analysis because of intolerable adverse effects.
The completion rate of radiotherapy in the NACT+CCRT group was significantly higher than that in the CCRT group, with a significant difference (χ2=12.332, p=0.001), As shown in Table 2.
Table 2. Treatment details of the different groups.
| Treatment | NACT+CCRT (n=73) | CCRT (n=73) | χ2 | p-value | |
|---|---|---|---|---|---|
| No. of patients | No. of patients | ||||
| Neoadjuvant chemotherapy | |||||
| TP (No. of cycles) | 2 | NA | |||
| NACT dose reduction | |||||
| Yes | 1 (1.4) | NA | |||
| No | 72 (98.6) | NA | |||
| CCRT cycles | 0.245 | 0.621 | |||
| 1 | 5 (6.8) | 7 (9.6) | |||
| 2 | 68 (93.2) | 66 (90.4) | |||
| Completion of radiation therapy | 12.332 | 0.001 | |||
| Yes | 73 (100) | 68 (93.2) | |||
| No | 0 (0) | 5 (6.8) | |||
| Days of radiotherapy | 58 (48–61) | 57 (48–67) | 1.486 | 0.225 | |
Values are presented as median (range) or number (%).
CCRT, concurrent chemoradiotherapy; NA, not applicable; NACT, neoadjuvant chemotherapy; TP, paclitaxel combined with cisplatin.
3. Efficacy
The follow-up was performed as outpatient, with a frequency of once every 12 weeks, and the contents included a pelvic MRI and a gynecological examination. At 12 weeks, the NACT+CCRT group had 58 cases of CR (79.5%) and 15 cases of partial response (PR) (20.5%) in, while the CCRT group had 38 cases of CR (55.9%) and 30 cases of PR (44.1%), with a significant difference (χ2=12.032, p=0.002). At one year,the CR and PR rates were 87.7% (64/73; 95% CI: 77–95) and 12.3% (9/73; 95% CI: 34–52) in the NACT+CCRT group, while 67.6% (46/68; 95% CI: 57-78) and 30.9% (12/68; 95% CI: 21-43) in the CCRT group, respectively. The CR rate of patients in the NACT+CCRT group was significantly higher than that in the CCRT group, with a significant difference (χ2=54.540, p=0.000).
4. Survival analysis
In the CCRT group, 19.1% (13/68) patients died before the last follow-up. 5 patients were not included in the survival analysis because of incomplete radiotherapy, and the 1- and 2-year OS rates were 89% and 79% respectively. In the NACT+CCRT group, 9.6% (7/73) patients died before the last follow-up, and the 1- and 2-year OS rates were 96% and 89%, respectively, which were significantly higher than those in the CCRT group (χ2=5.737, p=0.017). In the CCRT group, 17.6% (12/68) patients had disease progression before the last follow-up, including 3 pelvic recurrences, 4 retroperitoneal lymph node metastasis, and 5 distant metastasis. The 1- and 2-year PFS rates were 85% and 78%, respectively. In the NACT+CCRT group, 11.0% (8/73) patients had disease progression, including 3 pelvic recurrences, 2 retroperitoneal lymph node metastases, and 3 distant metastases. The 1- and 2-year PFS rates were 90% and 81% respectively, with no significant difference compared with the CCRT group (χ2=0.909, p=0.340), The NACT+CCRT group had a significantly lower rate of recurrences and distant metastases than the CCRT group (χ2=4.059, p=0.021), as shown in Fig. 2. Further analysis revealed that in the NACT+CCRT group, the 1- and 2-year OS rates of CR patients (99% and 87%) were significantly greater than those of PR patients (62% and 56%) (χ2=39.161, p=0.000), The 1- and 2-year PFS rates of CR patients (99% and 80%) were significantly greater than those of PR patients (67% and 59%) (χ2=42.525, p=0.000), as shown in Fig. 3.
Fig. 2. Kaplan-Meier plots of OS (A) and PFS (B) for NACT+CCRT vs. CCRT group.
CCRT, concurrent chemoradiotherapy; CI, confidence interval; HR, hazard ratio; NACT+CCRT, neoadjuvant chemotherapy combined with concurrent chemoradiotherapy; OS, overall survival; PFS, progression-free survival.
Fig. 3. Kaplan-Meier plots of OS (A) and PFS (B) for CR vs. PR.
CI, confidence interval; CR, complete response; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PR, partial response.
5. Safety
As shown in Table 3, most treatment-related adverse reactions in the 2 groups during treatment and within one month after treatment were grade 3, whereas grade 4 reactions were less frequent. While grade 3/4 radiation proctitis (6.8% vs. 1.4%, p=0.001), grade 3/4 radiation cystitis (1.5% vs. 0, p=0.047), treatment-related abdominal pain (p<0.05) and renal toxicity (p<0.05) were significantly more prevalent in the CCRT group than in the NACT+CCRT group, including 2 cases of grade 4 radiation proctitis in the CCRT group, only thrombocytopenia was more prevalent in the NACT+CCRT group than in the CCRT group (16.4 vs. 13.2%, p=0.045).
Table 3. Acute toxicities in 2 groups.
| Toxicity | NACT+CCRT (n=73) | CCRT (n=68) | χ2 | p-value | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Grade0 No. | Grade1 No. | Grade2 No. | Grade3 No. | Grade4 No. | Grade0 No. | Grade1 No. | Grade2 No. | Grade3 No. | Grade4 No. | ||||
| Hematologic | |||||||||||||
| Leukocyte | 7 | 0 | 18 | 41 | 7 | 4 | 4 | 16 | 39 | 5 | 1.504 | 0.222 | |
| Neutropenia | 13 | 6 | 21 | 27 | 6 | 11 | 4 | 22 | 24 | 7 | 0.067 | 0.796 | |
| Anemia | 3 | 7 | 33 | 29 | 1 | 1 | 13 | 30 | 23 | 1 | 0.241 | 0.624 | |
| Thrombocytopenia | 25 | 17 | 19 | 9 | 3 | 26 | 15 | 18 | 7 | 2 | 4.110 | 0.045 | |
| Radiation | |||||||||||||
| Proctitis | 62 | 5 | 5 | 1 | 0 | 54 | 8 | 6 | 3 | 2a | 9.612 | 0.001 | |
| Cystitis | 63 | 6 | 3 | 0 | 0 | 60 | 4 | 3 | 1 | 0 | 4.000 | 0.047 | |
| Nausea/vomiting | 19 | 35 | 16 | 3 | 0 | 18 | 26 | 20 | 4 | 0 | 1.611 | 0.206 | |
| Constipation | 73 | 0 | 0 | 0 | 0 | 66 | 1 | 1 | 0 | 0 | 0.821 | 0.402 | |
| Abdominal pain | 65 | 7 | 1 | 0 | 0 | 56 | 9 | 2 | 1 | 0 | 7.767 | 0.006 | |
| Liver toxicity | 39 | 25 | 8 | 1 | 0 | 45 | 26 | 6 | 1 | 0 | 0.609 | 0.437 | |
| Renal toxicity | 57 | 16 | 0 | 0 | 0 | 44 | 22 | 1 | 1 | 0 | 6.889 | 0.010 | |
| Fatigue | 18 | 29 | 26 | 0 | 0 | 12 | 27 | 29 | 0 | 0 | 2.203 | 0.079 | |
Toxicity was measured weekly while in the study and again 30 days after the last study treatment. Five patients in the CCRT group had a severe adverse event after starting treatment, so they stopped early. Consequently, 68 patients with other toxic side effects were analyzed.
CCRT, concurrent chemoradiotherapy; NACT+CCRT, neoadjuvant chemotherapy combined with concurrent chemoradiotherapy.
DISCUSSION
Platinum-based CCRT is the standard treatment for LACC patients. However, 25%–40% of patients still experienced recurrence and metastasis [19]. As a non-specific platinum on the cell cycle, cisplatin has a potent, broad-spectrum anti-cancer effect and is effective against gynecological tumors. As a specific cell cycle drug acting on -tubulin and -tubulin of the spindle, Paclitaxel causes cancer cell division to be arrested in the G2 and M phases, thereby exerting a cytotoxic effect and demonstrating outstanding cervical cancer efficacy [20]. In the treatment of cervical cancer, single-agent cisplatin and platinum-containing combination CCRT regimens have been compared. The study conducted by Thakur et al. indicated that a platinum-containing double-drug regimen could improve the disease-free survival while at the expense of increased adverse effects [21]. A meta-analysis revealed that CCRT containing a platinum double-drug regimen could increase patient survival in those with better performance status [22].
Conversely, NACT provided a good foundation for CCRT by increasing sensitivity, enhancing efficacy, reducing tumor burden, and decreasing micrometastasis [23]. In phase II clinical trial NCT01973101, CCRT was administered to LACC patients after 3 cycles of cisplatin plus gemcitabine (GP)-based NACT [24]. The results showed that the 3-year PFS and OS of the NACT+CCRT group and the CCRT group were 40.9 vs. 60.4% (p=0.033) and 60.7 vs. 86.6% (p=0.006), respectively, indicating that the GP regimen failed to improve survival prognosis and was therefore unsuitable as a NACT program. Another study from India showed that TP-based NACT+CCRT improved the CR rate of LACC patients (85% vs. 82.5% in the CCRT group) without significantly increasing adverse effects [25]. However, de Azevedo et al.’s study [26] revealed that the combination of NACT and CCRT did not significantly improve survival in patients with stage IB2-IVA cervical cancer. [26]. It has been reported that LACC with stage IIB or higher and a substantial mass has a 5-year OS of approximately 40% with CCRT [27]. A retrospective study found that TP-based NACT+CCRT improved disease-specific survival (DSS) and PFS in LACC compared to CCRT alone [28].
The INTERLACE study (NCT01566240) is an international, multicenter, phase III clinical trial that aims to investigate the efficacy of NACT in a specific group of cervical cancer patients. Eligible participants for this study have histologically confirmed FIGO stage IB2-IVA squamous, adeno, or adenosquamous carcinoma of the cervix (except FIGO IIIA). Patients with histologically confirmed FIGO stage IB1 and positive lymph nodes are also considered eligible for inclusion. The focus of our research is on LACC patients with large cervical tumors, with the objective of identifying potential beneficiaries of new NACT approaches. In contrast to the treatment regimen used in the INTERLACE study, which employs a weekly combination of paclitaxel and carboplatin for induction chemotherapy, our study adopted a 3-week regimen of TP. As of now, the INTERLACE study is still in the recruitment phase, with an anticipated completion date of December 2026. We look forward to the release of its research findings. In conclusion, the role of NACT combined with CCRT in LACC remains controversial, and further research is required to determine which patients may benefit from NACT.
The CR of NACT has been reported to be an independent factor affecting survival prognosis. The OS and PFS of the CR group are significantly higher than those of other groups, indicating that a high CR rate can be converted into survival advantage [29]. In the current study, 68 (93.2%) of NACT+CCRT patients and 66 (90.4%) of CCRT patients completed 2 treatment cycles, all patients in the NACT+CCRT group received radiotherapy, whereas 5 patients in the CCRT group did not receive radiotherapy due to chemoradiotherapy toxicity, indicating that NACT improved the completion rate of CCRT (p<0.05). In this study, the CR rates of the NACT+CCRT group and the CCRT group were 87.7% and 67.6%, respectively (p<0.05). It was similar to the results of another study [25], which showed that the CR rate of the NACT+CCRT group was 85%. Furthermore, the 1- and 2-year OS of the NACT+CCRT group versus the CCRT group was 96% vs. 89% and 89% vs. 79%, respectively (p<0.05), suggesting that NACT+CCRT might be able to improve the prognosis of LACC by increasing the CR rate. Although there was no significant difference in the 1- and 2-year PFS between NACT+CCRT and CCRT groups (90% vs. 85%, 81% vs. 78%, respectively) (p>0.05), further analysis found that, when compared to CCRT, NACT+CCRT significantly reduced the risk of distant metastasis while not affecting local control rate.
Although the combined modality therapy with paclitaxel, cisplatin chemotherapy and concurrent radiation might potentially increase toxic and side effects, relevant literature analysis shows that the proportion of severe adverse reactions was low, and the drugs were well tolerated [30,31]. It has also been reported that the duration of radiotherapy is an independent prognostic factor affecting the local control rate and survival and that the prognosis for patients undergoing radiotherapy for more than 60 days is poor [32]. In this study, all patients completed radiotherapy within 60 days, indicating that the safety of the regimen conducted in this study was well. Most adverse reactions were grade 3, grade 4 reactions were uncommon, and all were manageable, with the CCRT group experiencing a significantly higher incidence than the NACT+CCRT group.
The majority of the participants in this study came from Guizhou, China's poorest province. Because of financial and healthcare constraints, most cervical cancer patients in this region are in advanced stages and have a sizeable local mass when they are admitted. Our study showed that compared to CCRT, NACT+CCRT might improve the treatment completion rate, increase CR and OS, and distant metastases and reduce radiation-related adverse effects for LACC patients with large tumor masses. However, further validation of this result requires extended follow-up periods.
ACKNOWLEDGEMENTS
The authors wish to acknowledge Guizhou anti-cancer association, Jiaying Bai and Zhi Huang for their passionate support to the project.
Footnotes
Funding: This work was supported by grants from the Affiliated Cancer Hospital of Guizhou Medical University (grant No. YJ2019020) and Guizhou anti-cancer association (grant No.014[2023]).
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
- Conceptualization: L.F., M.F., Y.S.
- Formal analysis: D.Y.
- Project administration: H.L., H.W .
- Writing – original draft: L.F.
- Writing – review & editing: L.J.
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