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

Abstract

Background: 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 researches are needed to evaluate the curative effects.

Aims: We aim to identify the therapeutic effects and prognosis after induction chemotherapy plus concurrent chemoradiotherapy in the treatment of locally advancedNPC under the intensity modulated radiotherapy mode.

Methods: The patients (N= 544) with locally advanced NPC (III and IVa) 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 OS, PFS, LRRFS, and 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. Following, the chemotherapy drug base on DOC provided more beneficial effect of survival rate compared with TXT but there was no significant difference between chemotherapy drug base on DDP and NDP treated with NPC patients. The therapeutic effects of induction chemotherapy revealed no difference between TPF and TP. In addition, there was also no significant change between concurrent chemotherapy with TP dual drugs or platinum single drug. Moreover, the survival rate showed no difference between platinum accumulation dose ofmore and less than 150mg/m2for concurrent chemotherapy.

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 neck tumors (1). The characteristics of NPC incidence have been observed with regional, ethnic, and familial epidemiological. 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 showssignificant regional differences. In South China, it has been reported the highest prevalence of Hunan, Guangdong, Guangxi, and Fujian (3). Because of the special location andhighly sensitive response to radiotherapy, surgery is not an appropriate therapeutic method and radiotherapy is the only curative treatment for non-metastatic NPC (4, 5). Nowadays, staging system and target volume delineation base on magnetic resonance imaging (MRI) ,and treatment with intensity modulated radiotherapy (IMRT) technique, are standard mode for the NPC patients(6).

On clinical, 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 provides the occult nature and leads to diagnostic difficulty. Accordingly, over 70% of NPC patients are diagnosed as locally advanced stage(7).

According to the report published in 1998, therapeutic protocol using platinum drugs for concurrent chemoradiotherapy plus three-cycle platinum drugs plus 5-FU (PF) as the adjuvant chemotherapy for locally advanced NPC has been used for more than 10 years. Nowadays, concurrent chemoradiotherapy which is the major therapeutic method for NPC is still the footstone,but the utilization rate ofadjuvant chemotherapy is decreasing and induction chemotherapyis 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 patientsand providemore 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-cycle with TPF or GP of induction chemotherapy plus concurrent chemoradiotherapy significantly increased PFS and OS in locally advanced NPC patient compared to the patient who 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 NPCunder the intensity modulated radiotherapy mode to further explore their therapeutic effects and prognosis.

Methods

Results

Patient’s clinical characteristics

We  included 544 patients in this study and the patients’ clinical characteristics were indicated in Table 1. The averaging age and BMI of patients were 46.09±11.16 years and 22.71±3.29 kg/m², the gender ratio was 2.60:1 (male/female=393/151), 41.91% of patients smoked. The major pathology type was undifferentiated, nonkeratinizing squamous cell carcinoma (97.61%). The clinical stages of patients were 64.52% in stage 3 and 35.48% in stage 4a. The methods of induction chemotherapy were 418 (76.84%) patients with TP and 126 (23.16%) patients with TPF, and of concurrent chemotherapy were 167 (30.70%) patients with TP and 377 (69.30%) patients with P. The drugs of induction and concurrentChemotherapy were 504 (92.65%) patients with DOC and 40 (7.35%) patients with TXT, and were 142 (26.10%) patients with DDP and 402 (73.90%) patients with NDP. There were 53.49% of patients received ≥150 mg/m² of platinum dose of CCRT while the other 46.51% was <150 mg/m². 

Clinical outcomes 

Overall survival results 

The median follow-up time was 64 months (4~114 months).There were 112 (20.59%) PFS, 83 (15.26%) death, 45 (8.27%) LRRFS, and 76 (13.97%) DMFS being observed in follow-up. Figure 1 shows the overall survival results of all patients in OS, PFS, LRRFS, and DMFS. The 5-year estimated survival rates of OS, PFS, LRRFS, and DMFS were 85.21%, 78.51%, 90.71%, and 85.21%, respectively. Figure 2 further illustrates the survival trends by clinical stages. All log-rank test results were significant between stage 3 and 4a (P from 0.039 to <0.001). The 5-year estimated survival rates in stage 3 of OS, PFS, LRRFS, and DMFS were 90.49%, 84.71%, 92.30%, and 90.94%, respectively. And the 5-year estimated survival rates in stage 4a of OS, PFS, LRRFS, and DMFS were 76.01%, 67.49%, 87.84%, and 74.91%, respectively.

Stratified analysis of OS, PFS, LRRFS, and DMFS

Table 2 shows the univariately stratified analyses of all endpoints by all independent variables. The significant variables which were associated with higher risk of each endpoint were listed as follows. For OS, higher age, N stage, clinical stage,    lower platinum dose of CCRT, and concurrent CT of P. For PFS, higher BMI, N stage, clinical stage, and concurrent CT of P. For LRRFS, smoking and higher clinical stage. For DMFS, higher BMI, N stage, clinical stage, concurrent CT of P, and CT drug base on TXT. 

Associated factors to OS, PFS, LRRFS, and DMFS

To further investigate the associated factors to endpoints, multivariate Cox proportional-hazard regression was carried out and results are listed in Table3. 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). Clinical stage was still associated with all endpoints (all P<0.05). CT drug base on TXT had higher risk of OS, PFS, and DMFS (all P<0.05). 

Accute side effects

The CTC4.0 levels of hematological results, radiation-induced 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%).

Discussion

In summary, we obtained that the 5 years 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 treated with induction chemotherapy with TPF plus concurrent chemoradiotherapy showed the 5 years OS (85.6%), PFS (77.4%), LRRFS rate (90.7%) and DMFS (88%) (12), which were similar to our results.

Mainly, there are four 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 four therapeutic protocols. Following, TPF and GP are the NCCN Guidelines Class 1A recommendation, but considering the higher hematological toxicity of TPF and GP,TP with less toxicicy is also commonly used clinically. We discovered that there was no significant difference in OS, PFS, LRRFS, and DMFS between TPF and TP formularies. Following, 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 lead to strong side effects such as severe kidney injury, acute allergic reactions, decreased immune response, gastrointestinal injury, hemorrhage reactions. Patients treated with NDP will also lead to several side effects but less than DDP (13). Following, our data showed that the survival rate was no significant difference 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 compared NPC patients who were treated with TP or P for concurrent chemoradiotherapy and showed the survival rate was no difference between these two groups. Accordingly, in locally advanced lung cancerand esophageal cancer, the concurrent chemoradiotherapy regimen is the use of double-drug regimen containing platinum (15, 16). Recently, a retrospective analysis obtained that the treament with double-drug regimen containing platinum for concurrent chemotherapy for NPC was better than single platinum drug but the side effects increased significantly(17). Our results suggests that under the premise of induction chemotherapy, concurrent chemotherapy of 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 chemodrug used on clinical patients (13). Moreover, the previous studies indicated that the mechanism of action of DOC was through decreased Bcl-2 expression and lead to mitochondria-dependent apoptosis but TXT was regulation of the microtubules stabilization to arrest cell cycle (18, 19). Our study indicated that patients treated with DOC could extend the survival rate compared with patientstreated with TXT. These findings may provide the possibility that DOC is more suitable for chemotherapy of NPC. In addition, previous research found that more than 200 mg/m² of platinum accumulated dosage during CCRT could extend the survival rate (20) base on concurrent chemoradiotherapy only without induction chemotherapy. Accordingly, the patients treated with induction chemotherapy plus concurrent chemoradiotherapy whether can decreased the accumulation of platinum dosage ,needing more pieces of evidence. Moreover, other research had shown that under the premise of induction chemotherapy, more or less than 160 mg/m² of accumulation of platinum dose during CCRT period was no difference in survival rate ,suggesting that the accumulation of platinum dosage can be reduced to 160 mg/m² (21). In this study, we obtained that the survival rate of patients did not significantly change between platinum dose of over 150 mg/m² and less than 150 mg/m². These messages indicate that the accumulation of platinum doseduring CCRT under the premise of induction chemotherapy is worthy of further research.

Although our study provides the beneficial effects of concurrent chemoradiotherapy plus induction chemotherapy under intensity modulated radiotherapy 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 nasopharyngeal carcinoma shows beneficial efficacy and safety ,and it is worthy of further research.

Declarations

Funding

None declared.

Conflicts of interest

There are no conflicts of interest of the authors.

Availability of data and material 

All data generated or analyzed during this study are included in this published article.

Code availability 

Not applicable.

Author Contributions 

Kai Liao and Rong-Hui Zheng conceived and designed the project. Kai Liao, Hao-Yun Tao and Ze-Jiang Zhan collected the data. Kai Liao, Hao-Yun Tao and Wen-ze Qiu analyzed and interpreted the data. Rong-Hui Zheng and Kai Liao drafted the manuscript. All authors read and approved the final manuscript.

Acknowledgments: We sincerely express our gratitude to Affiliated Cancer Hospital & Institute of Guangzhou Medical University and patients in this study.

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Tables

Table 1. Patient’s clinical characteristics

Table 2. Stratified analysis of independent variables to OS, PFS, LRRFS, and DMFS

Table 3. Multivariate Cox proportional-hazard regression of independent variables to OS, PFS, LRRFS, and DMFS

Table 4. Side effects