Efficacy and safety of intensity-modulated radiotherapy alone versus intensity-modulated radiotherapy plus chemotherapy for treatment of intermediate-risk nasopharyngeal carcinoma

Background This study directs to evaluate the efficacy and safety of intensity-modulated radiotherapy (IMRT) alone versus IMRT plus chemotherapy in intermediate-risk NPC (stage II and T3N0M0). Methods A total of 124 patients with stage II and T3N0M0 NPC were pair-matched (1:1 ratio) to form two groups: an IMRT-alone group and an IMRT/chemotherapy group. Survival outcomes (overall survival [OS], disease–free survival [DFS], locoregional relapse–free survival [LRRFS], distant metastasis–free survival [DMFS]) and treatment-related grade 3–4 acute toxicity events were compared between the groups. Results Survival outcomes for patients with stage II and T3N0M0 NPC were quiet comparable between patients treated with IMRT alone versus patients treated with IMRT/chemotherapy: 5-year OS was 91.9% vs. 90.3%, respectively (P = 0.727); DFS was 87.1% vs. 88.7%, respectively (P = 0.821); LRFFS was 96.8% vs. 95.2%, respectively (P = 0.646), and DMFS was 91.9% vs. 91.5%, respectively (P = 0.955). Grade 3 acute toxicities were significantly higher with IMRT/chemotherapy than with IMRT alone: mucositis, 15% vs. 5% (P = 0.004); leukopenia/neutropenia, 8% vs. 1% (P <  0.015); and nausea/vomiting, 22% vs. 3% (P <  0.001). Conclusion For intermediate-risk (stage II and T3N0M0) NPC patients, the addition of chemotherapy to IMRT does not appear to provide any survival benefit. Moreover, grade 3 acute toxicities are also more common in patients receiving IMRT plus chemotherapy.


Background
Nasopharyngeal carcinoma (NPC) is common in the southern regions of China, particularly in Guangdong and Guangxi provinces [1,2]. Because of the biological characteristics of NPC, radiotherapy is the primary treatment modality.
Earlier, in the era of two-dimensional radiotherapy (2D-RT), chemoradiotherapy was the standard treatment for intermediate-risk NPC (stage II and T3N0M0). Concurrent chemoradiotherapy (CCRT) was shown to provide a considerable survival benefit for patients with stage II NPC [3,4]. At present, "three-dimensional conformal radiotherapy (3DCRT) and the more advanced intensity-modulated radiotherapy (IMRT) have largely replaced 2D-RT, which enable the delivery of a higher and more accurate dose to a tumor target while sparing organs at risk [5], but CCRT is still considered the most suitable treatment for locoregionally advanced NPC [6]. However, some researchers reported that patients treated with CCRT have similar survival outcomes as those treated with only IMRT [7]. Moreover, stratified analysis demonstrated that, the addition of chemotherapy to IMRT did not significantly improve survival in stage II NPC subgroups. For example, Chen et al. and Sun et al. reported that the stage T3N0M0 subgroup have similar survival to stage II [5,8] . Whether CCRT is superior to the IMRT alone for intermediate-risk NPC needs to be clarified. Hence, we included stage II and T3N0M0 disease as intermediate-risk NPC in our study, which would help in establishing individualized IMRT treatment protocols for stage II and T3N0M0 NPC.
The focus of the present study was to compare the efficacy and safety of IMRT alone versus IMRT plus chemotherapy in intermediate-risk (stage II and T3N0M0) NPC patients.

Patients
The patients for this retrospective study were selected from among those hospitalized between 2011 and 2014 in the Department of Radiation Oncology at the affiliated hospital of Guilin Medical University, Nanxishan Hospital of Guangxi Zhuang Autonomous Region and the Wuzhou Red Cross Hospital. Patients were eligible for inclusion in this study if they had 1) newly diagnosed, intermediate-risk (stage II and T3N0M0) NPC; 2) Eastern Cooperative Oncology Group performance status ≤1; and 3) completed radical IMRT with or without chemotherapy (i.e., induction chemotherapy, neoadjuvant chemotherapy, and/or CCRT). Patients were excluded if they had 1) history of previous anticancer treatment or 2) history of another malignant tumor.
Patients were pair-matched [9] to maximize comparability between groups. Matching was performed for the following factors, with a descending hierarchy of priority: treatment regimen (IMRT vs. IMRT-chemotherapy); T category (T1 vs. T2 vs. T3); N category (N0 vs. N1); TNM stage (II vs. III [T3N0M0]); sex (male vs. female); age (≤ 45 years vs. > 45 years); and WHO histology (type II vs. type III). When multiple matched-pair combinations were possible, the pair with the closest admission dates was selected. All pairs were matched for at least five of the seven factors. Thus, we had two matched groups: one group comprising patients treated with IMRT alone (the IMRT-alone group) and another group comprising patients treated with IMRT plus chemotherapy (the IMRT/chemotherapy group). Survival outcomes and treatment-related toxicities were compared between the groups. This study was approved by the Medical Ethics Committee of Affiliated Hospital of Guilin Medical University, Nanxishan Hospital of Guangxi Zhuang Autonomous Region and Wuzhou Red Cross Hospital. The need for informed consent was waived in view of the retrospective nature of the study.

Pretreatment workup
Initial workup included clinical and laboratory examinations (hematologic and biochemistry profiles); fiberoptic endoscopy of nasopharynx; magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CECT) of the head and neck to evaluate the extent of the primary tumor and regional lymph nodes involvement; and bone scintigraphy, chest radiography or CECT, and ultrasonography of the abdominal region to exclude distant metastasis. All patients were restaged according to the 7th edition of the Union International Centre le Cancer /American Joint Committee on Cancer (UICC/AJCC) system [10].

Radiotherapy
All patients received radical IMRT with 6-MV X-rays. The gross tumor volume (GTVnx) included the primary tumor as defined on MRI. Metastatic cervical lymph nodes were defined as GTVnd. The high-risk region was defined as clinical target volume 1 (CTV1) and included the whole nasopharyngeal cavity plus the GTVnx, with a margin of 5-10 mm. The low-risk area was defined as CTV2 and encompassed CTV1 with a margin of 3-5 mm, clivus, parapharyngeal space, skull base, sphenoid sinus, pterygoid fossae and the lower neck, cervical lymph nodes and the supraclavicular lymphatic drainage region have been included in CTV2 according to the NCCN guideline. The total prescribed dose was 66-70 Gy/31-33 fractions to the planning target volume (PTV) of GTVnx and 66-70 Gy/32-33 fractions to the PTV of GTVnd; a dose of 56-60 Gy/30 fractions to the PTV of CTV1 and 50 Gy/30 fractions to the PTV of CTV2 were delivered with first 30 fractions. All patients received one fraction per day, 5 days per week.

Chemotherapy
Patients in the IMRT/chemotherapy group received three cycles of chemotherapy (cisplatium, 80 mg/m 2 ) concurrently with radiotherapy, with intervals of 21 days between cycles.

Follow-up
Follow-up duration was calculated from the first day of therapy to the date of last examination or death. At each follow-up visit, patients underwent physical examination, nasopharyngoscopy, ultrasonography of the abdomen, and chest radiography. CT scan or MRI of the head and neck region was conducted every 3 months during the first 2 years, and then every 6-12 months until the end of the  All data are n (%) IMRT Intensity-modulated radiotherapy, WHO World Health Organization study or death. For patients with suspected locoregional recurrence or distant metastasis, additional examinations were performed at the discretion of the treating physician. The primary endpoint was overall survival (OS), and the secondary endpoints were disease-free survival (DFS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and treatment-related toxicity. OS was defined as the time from registration to death from any cause or last follow-up; DFS was defined as the time from registration to treatment failure or death from any case; LRRFS was defined as the time from registration to first local or regional relapse or last follow-up; and DMFS was defined as the time from registration to first detection of distant metastasis or death from any cause. The Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria [6] and Common Terminology Criteria for Adverse Events (version 3.0) were used to grade the late toxicities of radiotherapy.

Statistical analysis
The chi-square test and Fisher exact test were used to compare patient characteristics between the IMRT-alone group and the IMRT/chemotherapy group. Kaplan-Meier method and the log-rank test were used to analyze OS, DFS, LRRFS, and DMFS. Multivariate Cox proportional hazards model with backward elimination was used to identify the independent predictors of different outcomes; the hazard ratios (HRs), with 95% confidence intervals (CIs), were calculated. SPSS 19.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. All statistical tests were two-sided, and P ≤ 0.05 was considered statistically significant.

Patient characteristics
Out of 215 patients assessed, 124 met the study eligibility criteria. These 124 patients included 88 men and 36 women (male-female ratio, 2.4:1), with a median age of 45 years (range 18-70 years). The 124 patients were separated into two pair-matched groups: the IMRT-alone group (n = 62) and the IMRT/chemotherapy group (n = 62). The two groups were approximate with respect to baseline characteristics ( Table 1). All patients were restaged according to the 7th edition AJCC/UICC staging system; 22 patients were reclassified as T1, 75 were reclassified as T2, and 17 as T3. In addition, 40 patients were reclassified as N0, and 84 were reclassified as N1.

Treatment toxicities and compliance
All patients in both treatment arms completed the prescribed dose of IMRT. However, not all patients completed chemotherapy; the reasons for withdrawal of cisplatin included refusal by the patient, severe    (Table 4). No grade 4 or 5 toxicity (death) occurred during treatment. The incidence of grade 3 acute toxic effects was significantly higher in the IMRT/chemotherapy group than in the IMRT-alone group: the incidence of grade 3 hematologic toxicity (leukopenia/neutropenia) was 8% vs. 1%, respectively (P < 0.015); the incidence of grade 3 gastrointestinal toxicity (nausea/vomiting) was 22% vs. 3%, respectively (P < 0.001); and the incidence of grade 3 mucositis was 15% vs. 5%, respectively (P = 0.004). No patient had grade 4 mucositis.

Discussion
This study directs to set side by side the efficacy and safety of IMRT plus chemotherapy versus IMRT alone in intermediate-risk NPC patients. We found approximate survival outcomes (5-year OS, DFS, LRFFS and DMFS) with IMRT alone and IMRT plus chemotherapy. Treatment-related toxicities were significantly more in the group treated with IMRT plus chemotherapy. Nowadays, satisfactory disease control is relatively easily achieved with multimodality treatment in a variety of malignancies; however, the focus is to individualize treatment to achieve the best possible results in each patient. There are still some differing opinions on whether the benefit gained with radiotherapy in stage II and T3N0M0 NPC could be enhanced by the addition of chemotherapy. Guo et al. reported that the addition of chemotherapy could improve LRRFS (HR = 0.263, 95% CI: 0.083-0.839; P = 0.024), especially for T1N1 patients (HR = 0.209, 95% CI: 0.046-0.954; P = 0.043) [11]. However, our pair-matched analysis of 124 stage II and T3N0M0 NPC patients showed no significant survival benefit with the use of IMRT plus chemotherapy. Our results are in line with a retrospective study by Xu et al. that demonstrated similar OS, LRRFS, and DMFS in stage II NPC patients treated with IMRT alone and with IMRT plus chemotherapy. Patients with T3N0M0 NPC represent a group at special risk for distant metastasis, but our study found almost similar 5-year OS in patients treated with IMRT plus chemotherapy and with IMRT alone. Multivariate analyses showed that treatment regimen (IMRT/chemotherapy vs. IMRT-alone) was not an independent prognostic factor for OS in these patients. A meta-analysis by Cheng et al. also found similar OS, LRRFS, and DMFS in stage III (T3N0M0) NPC patients treated with CCRT and with IMRT alone [12]. In subgroup analysis, The IMRT plus chemotherapy showed longer DFS compared to the IMRT alone in stage III (T3N0M0) NPC patients, The possible reasons may be due to the small number of patients in T3N0M0 subgroup. The benefits of adding chemotherapy to T3N0M0 needs to be confirmed by prospective studies. In the present study, the overall incidence of grade 3 acute toxic effects was higher in the IMRT/chemotherapy group than in the IMRT-only group; significantly higher incidence was seen of grade 3 leukopenia/neutropenia, nausea/vomiting, and mucositis. Some earlier studies have reported similar findings [7,13]. We separated the patients into different subgroups according to various baseline factors. No significant difference was seen between the different strata in each subgroup. Therefore, assessment of patients with precise population stratification may reduce the benefits of CCRT to a non-significant effect, which could apply equally to other diseases.
We offer two possible explanations for the similarity in survival outcomes between the IMRT/chemotherapy and the IMRT-alone groups in this study. First, IMRT provides better local tumor control than 2D-RT [14,15] and so the potential gains achieved with the addition of chemotherapy may not as obvious [16]. Second, the high frequency of severe adverse reactions in patients treated with IMRT/chemotherapy may have masked any survival benefit in this group [17]. Lan et al. have also found that addition of chemotherapy to IMRT does not significantly improve OS; additionally, the authors reported that the higher the incidence of grade 3-4 acute toxicities (especially hematological events such as leucopenia and neutropenia [13]) increases the possibility of discontinuation of treatment. Thus, it seems that IMRT alone may be more suitable than CCRT for patients with stage II and T3N0M0 NPC.
Some limitations of this study should be kept in mind when interpreting the results. First, this is a retrospective study, and some bias is inevitable; for example, patients received different chemotherapy regimens, and this may have influenced the results. Second, the sample size was relatively small.

Conclusion
In intermediate-risk (stage II and T 3 N 0 M 0 ) NPC, IMRT provides survival outcome comparable to that with IMRT plus chemotherapy. Moreover, grade 3 acute toxicities are fewer with IMRT alone than with IMRT plus chemotherapy. Well-designed large randomized clinical trials comparing CCRT with IMRT alone are needed to confirm our findings and to help formulate individualized therapies for stage II and T3N0M0 NPC patients.