Retrospective Analysis of Induction Chemotherapy plus Concurrent Chemoradiotherapy under Intensity-Modulated Radiotherapy Mode for Locally Advanced Nasopharyngeal Carcinoma

Introduction: Nasopharyngeal carcinoma (NPC) originates from the mucous epithelium of the nasopharynx. Although induction chemotherapy plus concurrent chemoradiotherapy is the major therapeutic protocol used for locally advanced NPC without metastasis, more research studies are needed to evaluate the curative effects. We aim to identify the therapeutic effects and prognosis after induction chemotherapy plus concurrent chemoradiotherapy in the treatment of locally advanced NPC under the intensity-modulated radiotherapy mode. Methods: The patients (N = 544) with locally advanced NPC (III and Iva, UICC 8th) after intensity-modulated radiotherapy with induction chemotherapy and concurrent chemoradiotherapy were included in this study. We analyzed the characteristics of patients including gender, age, smoking status, tumor node staging system, clinical stage, pathological type, the therapy protocol of induction chemotherapy and concurrent chemoradiotherapy, and chemotherapy prescription. Results: We have found the 5-year survival rates of overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 85.21%, 78.51%, 90.71%, and 85.21% in follow-up, and these data indicated that our therapeutic procedure provided beneficial effects on survival rates. Subsequently, the chemotherapy drug based on docetaxel (DOC) provided a more beneficial effect on survival rate compared with taxol (TXT) (all estimated HR >1; p = 0.005, 0.004, and <0.001 of OS, PFS, and DMFS), but there was no significant difference between chemotherapy drugs based on cisplatin (DDP) and nedaplatin (NDP) in treating NPC patients (p = 0.390, 0.549, 0.364, and 0.645 of OS, PFS, LRRFS, and DMFS). The therapeutic effects of induction chemotherapy revealed no difference between TPF and TP (T: DOC or TXT, P: DDP or NDP, and F: 5-fluorouracil) (p = 0.541, 0.897, 0.498, and 0.765 of OS, PFS, LRRFS, and DMFS). In addition, there was also no significant change between concurrent chemotherapy with TP dual drugs or a single platinum drug (being excluded in the multivariate model using forward [Wald] procedure). Moreover, the survival rate showed no difference between platinum accumulation dose of more or less than 150 mg/m2 for concurrent chemotherapy (being excluded in the multivariate model using forward [Wald] procedure). Conclusion: Our results indicate that induction chemotherapy plus concurrent chemoradiotherapy under intensity-modulated radiotherapy which is the standard therapeutic method for locally advanced NPC provides beneficial therapeutic effects, and it is worthy of further study.


Abstract
Introduction: Nasopharyngeal carcinoma (NPC) originates from the mucous epithelium of the nasopharynx. Although induction chemotherapy plus concurrent chemoradiotherapy is the major therapeutic protocol used for locally advanced NPC without metastasis, more research studies are needed to evaluate the curative effects. We aim to identify the therapeutic effects and prognosis after induction chemotherapy plus concurrent chemoradiotherapy in the treatment of locally advanced NPC under the intensity-modulated radiotherapy mode. Methods: The patients (N = 544) with locally advanced NPC (III and Iva, UICC 8th) after intensitymodulated radiotherapy with induction chemotherapy and concurrent chemoradiotherapy were included in this study. We analyzed the characteristics of patients including gender, age, smoking status, tumor node staging system, clinical stage, pathological type, the therapy protocol of induction chemotherapy and concurrent chemoradiotherapy, and chemotherapy prescription. Results: We have found the 5-year survival rates of overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 85.21%, 78.51%, 90.71%, and 85.21% in follow-up, and these data indicated that our therapeutic procedure provided beneficial effects on survival rates. Subsequently, the chemotherapy drug based on docetaxel (DOC) provided a more beneficial effect on survival rate compared with taxol (TXT) (all estimated HR >1; p = 0.005, 0.004, and <0.001 of OS, PFS, and DMFS), but there was no significant difference between chemotherapy drugs based on cisplatin (DDP) and nedaplatin (NDP) in treating NPC patients (p = 0.390, 0.549, 0.364, and 0.645 of OS, PFS, LRRFS, and DMFS). The therapeutic effects of induction chemotherapy revealed no difference between TPF and TP (T: DOC or TXT, P: DDP or NDP, and F: 5-fluorouracil) (p = 0.541, 0.897, 0.498, and 0.765 of OS, PFS, LRRFS, and DMFS). In addition, there was also no significant change between concurrent chemotherapy with TP dual drugs or a single platinum drug (being excluded in the multivariate model using forward [Wald] procedure). Moreover, the survival rate showed no difference between platinum accumulation dose of more or less than 150 mg/m 2 for concurrent chemotherapy (being excluded in the multivariate model using forward [Wald] procedure). Conclusion: Our results indicate that induction chemotherapy plus concurrent chemoradiotherapy under intensity-modulated radiotherapy which is the standard therapeutic method for locally advanced NPC provides beneficial therapeutic effects, and it is worthy of further study.

Introduction
Nasopharyngeal carcinoma (NPC) originates from the mucous epithelium of the nasopharynx and is the most commonly diagnosed malignant head and neck tumor, which accounts for approximately 60% of all head and Oncol Res Treat 2021;44:602-612 DOI: 10.1159/000519278 neck tumors [1]. The characteristics of NPC incidence have been observed with regional, ethnic, and familial epidemiology. Moreover, the incidence of NPC shows the difference from region to region and is prevalent in East Asia, Southeast Asia, East Africa, and North Africa. For now, China accounts for approximately 47.7% of all new cases of NPC worldwide [2]. Accordingly, the incidence of NPC in China also shows significant regional differences. In South China, it has been reported that Hunan, Guangdong, Guangxi, and Fujian have the highest prevalence [3]. Because of the special location and highly sensitive response to radiotherapy, surgery is not an appropriate therapeutic method, and radiotherapy is the only curative treatment for nonmetastatic NPC [4,5]. Nowadays, staging system and target volume delineation based on MRI and treatment with the intensity-modulated radiotherapy (IMRT) technique are standard modes for NPC patients [6].
Clinically, radical radiotherapy is a standard therapeutic method for the early stage of NPC to provide the best therapeutic effect. However, the special location of NPC is occult in nature and leads to diagnostic difficulty. Accordingly, over 70% of NPC patients are diagnosed at a locally advanced stage [7].
According to the report published in 1998, a therapeutic protocol using platinum drugs for concurrent chemoradiotherapy plus 3-cycle platinum drugs plus 5-FU (PF) as the adjuvant chemotherapy for locally advanced NPC has been used for >10 years. Nowadays, concurrent chemoradiotherapy which is the major therapeutic method for NPC is still the footstone, but the utilization rate of adjuvant chemotherapy is decreasing and induction chemotherapy is gradually increasing. The clinical trial report from Sun Yat-sen University [5] indicated that compared with the concurrent chemoradiotherapy group, the 3-cycle PF regimen adjuvant chemotherapy failed to further improve the patient's prognosis, but increased adverse reactions. Accordingly, induction chemotherapy before radiotherapy will decrease the metastasis rate of NPC patients and provide more therapeutic tolerance and sensitivity compared with adjuvant chemotherapy [8]. Importantly, the research from Sun Yat-sen University using induction chemotherapy instead of adjuvant chemotherapy showed the results that 3 cycles with TPF or GP of induction chemotherapy plus concurrent chemoradiotherapy significantly increased PFS and OS of locally advanced NPC patients compared to the patients who were treated with concurrent chemoradiotherapy only [9,10]. Taken together, induction chemotherapy plus concurrent chemoradiotherapy is an important therapeutic protocol for patients with locally advanced NPC but still needs more evidence to confirm the therapeutic effects. Therefore, this study conducted a retrospective analysis of induction chemotherapy plus concurrent chemoradiotherapy in the treatment of locally advanced NPC under the IMRT mode to further explore their therapeutic effects and prognosis.

Study Patients
In this study, we evaluated the patients with locally advanced NPC (III and IVa, UICC 8th) after IMRT with induction chemotherapy and concurrent chemoradiotherapy. Finally

Concurrent Chemoradiotherapy
Radiotherapy is the main treatment for NPC. All patients were irradiated with IMRT. After being immobilized with head and neck thermoplastic masks while in the supine position, patients were scanned with a CT simulator. Noncontrast and contrast CT images were collected with 3 mm per slice from the vertex to 2 cm below the clavicle head. The target volumes were contoured according to the Sun Yat-sen University Cancer Center institutional treatment protocol [5,11], which is in agreement with the International Commission on Radiation Units and Measurements Reports 50 and 62. The prescribed radiation dose to the gross tumor volume of nasopharyngeal tumors (GTVnx) was 70 Gy, and the prescribed radiation dose to the gross tumor volume of lymph nodes (GTVnd) was 68 Gy. The high-risk clinical target volume (CTV1) and the low-risk clinical target volume (CTV2) were prescribed 62 Gy and 56 Gy, respectively. All patients were irradiated with 32-33 fractions in total, once daily, Monday through Friday, and the median treatment time of radiotherapy was 45 days (44∼52 days). Patients were treated with 1∼3 cycles of DDP/NDP (75∼100 mg/m 2 , d1/75∼100 mg/m 2 , d1) every 21 days during radiotherapy or were given DDP/NDP (75∼80 mg/m 2 , d1/75∼80 mg/m 2 , d1) and docetaxel/taxol (75∼80 mg/m 2 , d1/135∼175 mg/m 2 d1) which was repeated every 21 days for 1∼3 cycles during radiotherapy.

Follow-Up
After treatment, the patients were followed every 3 months for 2 years, every 6 months from the 3rd to 5th year, and every year thereafter. Follow-up data were obtained from outpatient and inpatient medical records and telephone counseling. OS was calcu- lated from the date of diagnosis until the follow-up deadline or death. PFS was defined as the time from initial diagnosis to tumor progression or death; DMFS was defined as the time to tumor metastasis, and LRRFS was defined as the time to the first locoregional recurrence. Hematologic toxicity, liver and kidney function, and oral mucosal responses were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE 4.0).

Statistical Analysis
There were 4 major endpoints in this study, including OS, PFS, LRRFS, and DMFS. Continuous data were indicated with mean ± standard deviation (SD) while categorical data were indicated with number and percentage (%). Univariate Cox proportional-hazard regression was used for the stratified analysis of all independent variables. Furthermore, a multivariate Cox proportional-hazard regression with forward (Wald) procedure was used to investigate the associated factors to OS, PFS, LRRFS, and DMFS. The variables which were significant in univariate Cox regression results would be entered into the multivariate model with the following 6 variables: clinical stage, induction chemotherapy, concurrent chemotherapy, CT drug based on DOC/TXT, CT drug based on DDP/ NDP, and platinum dose of CCRT. Then, the variables which were significant in the multivariate model would be recognized as associated factors to OS, PFS, LRRFS, or DMFS. Kaplan-Meier survival analysis and log-rank test were used to compare the survival trends of categorical variables. A p < 0.05 would be recognized as reaching the significance of each test, 2-tailed. All analyses were performed using IBM SPSS Version 25 (SPSS Statistics V25; IBM Corporation, Somers, NY, USA).

Patients' Clinical Characteristics
We included 544 patients in this study, and the patients' clinical characteristics are indicated in Table 1

Stratified Analysis of OS, PFS, LRRFS, and DMFS
Associated Factors to OS, PFS, LRRFS, and DMFS To further investigate the associated factors to endpoints, multivariate Cox proportional-hazard regression was carried  Table 3. As indicated, age over 46 was associated with the risk of OS (p = 0.024). Higher BMI was associated with the risk of DMFS (p = 0.033). Higher N stage was associated with the risk of OS, PFS, and DMFS (all p < 0.05). The clinical stage was still associated with all endpoints (all p < 0.05). CT drug based on TXT had a higher risk of OS, PFS, and DMFS (all p < 0.05).

Acute Side Effects
The CTC4.0 levels of hematological results, radiationinduced oral mucositis, gastrointestinal reaction, liver function, and renal function during IC + CCRT are listed in Table 4. Most patients were at level 1-2 in hematology results (59.50%), radiation-induced oral mucositis (73.85%), and gastrointestinal reaction (88.21%). Most patients were at level 0 in liver function (62.35%) and renal function (88.49%). The results were also compared between TP and TPF chemotherapy groups. As indicated, the side effects of liver function and renal function were only observed in the TPF group. No significant difference was found in the side effect of radiation-induced oral mucositis between groups (p = 0.765). Comparatively, higher side effect levels were observed in the TPF group in hematological results and gastrointestinal reaction than the TP group (both p < 0.001).

Discussion
In summary, we obtained that the 5-year survival rates of OS, PFS, LRRFS, and DMFS were 85.21%, 78.51%, 90.71%, and 85.21%, showing beneficial effects after induction chemotherapy plus concurrent chemoradiotherapy on clinical patients with locally advanced NPC. Moreover, the previous study indicated that the NPC patients who were treated with induction chemotherapy with TPF plus concurrent chemoradiotherapy showed the 5-year OS (85.6%), PFS (77.4%), LRRFS (90.7%), and DMFS (88%) [12], which were similar to our results.
Mainly, there are 4 therapeutic protocols of induction chemotherapy formulary such as TP, TPF, GP, and PF for locally advanced NPC. However, there is no prospective clinical trial evidence to compare the difference between the 4 therapeutic protocols. Subsequently, TPF and GP are the NCCN Guidelines Class 1A recommendation, but considering the higher hematological toxicity of TPF and GP, TP with less toxicity is also commonly used clinically. We discovered that there was no significant difference in OS, PFS, LRRFS, and DMFS between TPF and TP formularies. Hence, these results show that TP for induction chemotherapy on locally advanced NPC patients may be enough, but we still need more prospective research to provide evidence to confirm this result. Moreover, the previous study indicated that cancer patients treated with DDP usually had strong side effects such as severe kidney injury, acute allergic reactions, decreased immune response, gastrointestinal injury, and hemorrhage reactions. Patients treated with NDP also had several side effects but less than DDP [13]. Therefore, our data showed that the survival rate was not significantly different between locally advanced NPC patients who were treated with DDP or NDP. Taken together, the above information suggests that choosing NDP as the chemodrug used for NPC patients will not change the curative effect and may decrease the side effect [14]. Moreover, we also com-pared NPC patients who were treated with TP or P for concurrent chemoradiotherapy and showed the survival rate was no different between these 2 groups. Accordingly, a double-drug regimen containing platinum is used for concurrent chemoradiotherapy in locally advanced lung cancer and esophageal cancer [15,16]. Recently, a retrospective analysis obtained that the treatment with a double-drug regimen containing platinum for concurrent chemotherapy for NPC was better than a single platinum drug, but the side effects increased significantly [17]. Our results suggest that under the premise of induction chemotherapy, concurrent chemotherapy of a single platinum drug for NPC may be sufficient but need more studies to confirm. Accordingly, paclitaxel drugs such as DOC and TXT are the first-line chemodrugs used in clinical patients [13]. Moreover, the previous studies indicated that the mechanism of action of DOC was through decreasing Bcl-2 expression and leading to mitochondria-dependent apoptosis, but TXT regulated the microtubule stabiliza-tion to arrest the cell cycle [18,19]. Our study indicated that patients treated with DOC could have extended survival rate compared to patients treated with TXT. These findings may provide the possibility that DOC is more suitable for chemotherapy of NPC. In addition, previous research found that >200 mg/m 2 of platinum accumu-   [20] based on concurrent chemoradiotherapy only without induction chemotherapy. Accordingly, whether platinum accumulation dose of the patients treated with induction chemotherapy plus concurrent chemoradiotherapy can be decreased needs more pieces of evidence. Moreover, other research studies had shown that under the premise of induction chemotherapy, more or less than 160 mg/m 2 of platinum accumulation dose during the CCRT period showed no difference in survival rate, suggesting that the platinum accumulation dose can be reduced to 160 mg/m 2 [21]. In this study, we obtained that the survival rate of patients did not significantly change between the platinum dose of over 150 mg/m 2 and <150 mg/m 2 . These messages indicate that the platinum accumulation dose during CCRT under the premise of induction chemotherapy is worthy of further research. Although our study provides the beneficial effects of induction chemotherapy plus concurrent chemoradiotherapy under IMRT to treat locally advanced NPC patients, there are still some limitations of this study. In retrospective studies, it is difficult to avoid that potential prognostic-related factors are not included and cause deviations such as EBV-DNA because our center was unable to perform this test before 2015. Moreover, because of the incomplete data records of the medical records, the long-term toxicity after radiotherapy could not be counted and reported. This study confirms that induction chemotherapy plus concurrent chemoradiotherapy which is the standard therapeutic mode for locally advanced NPC shows beneficial efficacy and safety, and it is worthy of further research.