Influence of concurrent chemotherapy on locoregionally advanced nasopharyngeal carcinoma treated with neoadjuvant chemotherapy plus intensity-modulated radiotherapy: A retrospective matched analysis

Neoadjuvant chemotherapy (NAC) combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy (CC) will be the new standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) patients. However, many patients fail to receive CC for multiple reasons. We aimed to investigate long-term survival outcomes and toxicities in these patients with NPC treated with additional NAC plus concurrent chemoradiotherapy (CCRT) or IMRT alone. In total, 1,378 previously untreated, newly diagnosed locoregionally advanced NPC patients receiving NAC plus IMRT with or without CC were retrospectively reviewed. We used a propensity score-matched (PSM) method with 1:1 matching to identify paired patients according to various covariates. Survival outcomes and toxicities were compared between the two groups. In total, 288 pairs were identified. With a median follow-up of 86 (range: 8–110) months, the estimated 5-year locoregional relapse-free survival, distant metastasis-free survival, progression-free survival (PFS), and overall survival rates in patients treated with NAC plus CCRT vs. NAC plus IMRT alone were 96.1% vs. 94.7% (P = 0.201), 93.7% vs. 89.8% (P = 0.129), 91.3% vs. 85.1% (P = 0.024), and 93.0% vs. 90.6% (P = 0.362), respectively. Multivariate analysis showed that CC omission was a prognostic factor for worse PFS. In a subgroup analysis, PFS did not differ significantly between two groups of female patients or aged <60 years or stage T1–2 or stage N0-1 disease. However, fewer acute complications were observed in the NAC plus IMRT alone group. NAC with IMRT alone confers similar survival rates and less acute toxicities. Specifically, NAC plus IMRT alone may be enough for female patients <60 years with stage T1-2 or stage N0-1. However, a prospective randomised trial is needed to validate these results.

Patterns of treatment failure. Of all participants, 70 patients (12.2%) experienced "any" treatment failure during the last follow-up. In the NAC + CCRT group, 28 patients (9.7%) experienced "any" failure (locoregional relapse only occurred in 13 patients, distant metastases was observed in 15 patients, both locoregional and distant failure were found in five patients). In the NAC + IMRT group, 42 patients (14.9%) experienced "any" failure (locoregional recurrence was developed in 14 patients, distant metastases occurred in 25 patients, both locoregional and distant failure were observed in three patients). The details are summarised in Table 2. The median time to failure between the two groups was 92 months (range 9 to 106 months) and 61 months (range 8 to 106 months), respectively.

Prognostic factors.
We assessed the potential prognostic factors associated with LRRFS, DMFS, PFS, and OS by univariate and multivariate regression analysis models. Age, sex, T category, N category, clinical stage, NAC regimen, NAC cycle, AC, and treatment regimen were analysed as the possible prognostic factors for the NPC patients enrolled in the current study. On the univariate analysis, we found that T3-4 and IVA/B were significantly associated with poorer OS. And the 5-year DMFS and PFS of patients with clinical stage III were superior to those with IVA/B, but there were no statistically significant differences. While 5-year PFS in patients treated with NAC plus IMRT alone was worse than those receiving the addition of NAC to CCRT. The results of 576 patients with locoregionally advanced NPC by using univariate analysis are summarised in Table 3.

Discussion
Our study was a large-scale observational study of locoregionally advanced NPC patients treated with additional NAC before CCRT or NAC, followed by IMRT alone. We found that NAC + IMRT alone conferred comparable long-term survival outcomes when compared to adding NAC before CCRT for NPC female patients who were <60 years, or stage T1-2 or stage N0-1, while with less acute toxicities. To our knowledge, this is the first observational study to compare long-term survival and toxicities in locoregionally advanced NPC patients receiving additional NAC to IMRT alone with NAC before CCRT. Accordingly, we can conclude that the omission of CC from the standard treatment did not affect survival outcomes for special subgroups of NPC patients.
CCRT with or without AC is still the first line of treatment recommended by the National Comprehensive Cancer Network because of the improved survival advantages 23 . However, a phase III randomised trial performed by Sun et al. revealed that adding TPF-based NAC before CCRT achieved the benefit of failure-free survival for locoregionally advanced NPC with manageable toxicities 24 . A recent meta-analysis showed that the addition of NAC before CCRT significantly increased PFS and OS and was associated with more frequent complications in locoregionally advanced NPC patients 25 . Other previous studies indicated that the addition of NAC before CCRT or IMRT conferred the promising survival outcomes [26][27][28][29][30] . Thence, NAC + CCRT could be an alternative therapy of CCRT for locoregionally advanced NPC. Approximately 63% of patients were unable to receive CC due to toxicities 9 . Thus, the effect of omitting CC on the survival outcomes of locoregionally advanced NPC remains unclear.    www.nature.com/scientificreports www.nature.com/scientificreports/ In current matched study, we examined survival over a follow-up time of 86 months; 5-year LRRFS, DMFS, PFS, and OS rates for the cohort of locoregionally advanced NPC patients were 95.4%, 91.8%, 88.2%, and 91.7%, respectively. Compared with NAC followed by CCRT, the addition of NAC before IMRT alone yielded similar LRRFS (96.1% vs. 94.7%, P = 0.201), DMFS (93.7% vs. 89.8%, P = 0.129), OS (93.0% vs. 90.6%, P = 0.362) and worse PFS (91.3% vs. 85.1%, P = 0.024) for these patients. In addition, multivariate analyses indicated that NAC plus IMRT alone were associated with an unfavourable prognostic factor of PFS (P = 0.014). In the subgroup analysis, the 5-year PFS (92.9% vs. 88.4%, P = 0.297; 90.1% vs. 85.6%, P = 0.124; 88.6% vs. 87.2%, P = 0.543; 93.2% vs. 88.3%, P = 0.398) were similar in the two groups for NPC female patients who were <60 years, or T1-2 or N0-1.
The most commonly observed acute adverse events included haematologic and non-haematologic toxicities during the period of NAC and IMRT. Although all patients in this study received prophylactic leukocyte therapy by the use of recombinant granulocyte colony-stimulating factor (GCFS), a few patients still experienced grade 3/4 leukocytopenia and neutropenia during NAC administration and could continue with chemotherapy without delay by receiving GCSF. The incidences of grade 3/4 haematologic and non-haematologic toxicities during the NAC period were comparable in both groups. The acute side effects during the IMRT period revealed a significant decrease of leukocytopenia (23.3% vs. 13.9%, P = 0.005) and neutropenia (20.5% vs. 13.5%, P = 0.035) in the NAC + IMRT group. No statistically significant differences were observed in other haematologic toxicities in both arms. The acute non-haematologic toxicities included mucositis, dermatitis, diarrhoea, and nausea/vomiting during the IMRT period, and were mild to moderate. The incidences of grade 3/4 mucositis and nausea/ vomiting were significantly lower in NAC + IMRT alone group than in the NAC + CCRT group (mucositis: 26.4% vs. 13.9%, P < 0.0001; nausea/vomiting: 15.6% vs. 2.3%, P < 0.0001). Liu et al. found that the NPC patients who received NAC + RT developed less grade 3/4 mucositis (55% vs. 16%, P < 0.0001), neck dermatitis (31% vs. 16%, P < 0.004) and vomiting (23% vs. 0%, P < 0.0001) 31 . The previously reported incidences of grade 3/4 mucositis during CCRT with a weekly low-dose [34][35][36] and tri-weekly high-dose 9,24,37,38 cisplatin were 31.4-48.9% and 29-62%, respectively. The rate of grade 3/4 mucositis in the present study was slightly less due to the use of IMRT.  www.nature.com/scientificreports www.nature.com/scientificreports/ This large-scale observational study was conducted by a single centre in an endemic area. Our major limitation was that the results of a single-arm retrospective study provided relatively low power to indicate non-inferior outcomes of NAC + IMRT. This study only evaluated acute treatment-associated toxicities and no late complications. The acute toxicities were assessed according to medical record information. In addition, the NAC regimen and doses were heterogenetic due to the retrospective design. Hence, our results should be regarded as preliminary. Further prospective, randomised, multicentre clinical trials are paramount to be conducted in the future.

Conclusion
In conclusion, our study showed that NAC + IMRT alone obtained similar survival outcomes with NAC before CCRT for locoregionally advanced NPC patients, and a lower incidence of grade 3/4 acute toxicities. Therefore, the omission of CC did not affect overall survival outcomes. However, further randomised, controlled, multicentre phase III clinical trials are needed to assess the ultimate efficacy and toxicity of NAC + IMRT alone.

Patient selection. Between May 2008 and April 2014, patients who received treatment in the Department
of Radiation Oncology at Zhejiang Cancer Hospital were retrospectively reviewed. The eligible patients met the following criteria: (i) untreated, newly diagnosed locoregionally advanced NPC, (ii) Eastern Cooperative Oncology Group performance status ≤1, (iii) completion of radical IMRT, (iv) received NAC + IMRT with or without CC, and (v) no previous anticancer treatment. This retrospective study was approved by the Medical Ethics Committee and the Institutional Reviewed Board of Zhejiang Cancer Hospital. Each patient had signed an informed consent form.
The present study was an observational, matched study performed in accordance with the Declaration of Helsinki and good clinical practice guideline. The flowchart of patients is shown in Fig. 5. A total of 3,022 newly diagnosed locoregionally advanced NPC patients were registered at Zhejiang Cancer Hospital. A total of 576 NPC patients, identified by a propensity score-matched method, were enrolled in our study. All patients received NAC combined with definitive IMRT with or without CC.
Basic examinations. The patients had pre-treatment evaluations that included complete medical histories, physical examinations, haematology and biochemistry profiles, chest radiographs, abdominal sonography, bone scans, magnetic response images of the nasopharynx, and nasopharyngoscopies. All patients were staged according to the 2010 American Joint Committee on Cancer staging system. Tumour histology was classified per the World Health Organization classification.  www.nature.com/scientificreports www.nature.com/scientificreports/ IMRT. All patients were immobilised in the supine position with thermoplastic masks. Computed tomography with intravenous contrast (2.5 mm slices from the head to 2 cm below the sternoclavicular joints) were performed for planning. All patients underwent radical IMRT with a simultaneous integrated boost technique that used 6-MV photons with 2-3 weeks after NAC. The delineation of target volumes of NPC during the treatment of IMRT was described previously [39][40][41] . The prescribed radiation doses were 69 Gy or 72 Gy to planning gross target volume (PGTV)nx, 66 Gy to 69 Gy to PGTVnd, 63 Gy to 66 Gy to planning target volume (PTV)nx, 60 Gy to 63 Gy to PTV1, and 51 Gy to 54 Gy to PTV2, delivered in 30 or 33 fractions. Radiation was delivered once daily, in five fractions per week, for over 6-6.5 weeks for IMRT planning. The dose to organs at risk was limited based on the Radiation Therapy Oncology Group 0225 protocol. Patient evaluation and follow-up. The assessment of tumour response was performed thrice after the completion of IC, at the end of IMRT, and three months after RT, which was based on MRI and nasopharynx fiberscope according to the Response Evaluation Criteria for Solid Tumors. Systemic chemotherapy adverse effects were graded using the National Cancer Institute Common Toxicity Criteria (NCI CTCAE, version 4.0). In contrast, RT-induced toxicities were scored according to the Acute and Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group (RTOG).

Chemotherapy.
All the participants underwent weekly examinations for treatment response and toxicities during the IMRT. Patients were followed-up every three months in the first two years, every six months from the third to the fifth year, and then annually. Each follow-up included careful examination of the nasopharynx and neck nodes by an experienced physician, an MRI scan of the nasopharynx, nasopharynx fiberscope, chest computed tomography www.nature.com/scientificreports www.nature.com/scientificreports/ radiograph, and abdominal ultrasound were performed three months after the completion of RT and every 6-12 months after that. Additional examinations were performed when it was indicated to evaluate local relapse or distant metastasis.  www.nature.com/scientificreports www.nature.com/scientificreports/ Statistical analysis. The primary outcomes of the present study were locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), PFS, OS, and acute toxicities from NAC and IMRT. OS, LRRFS, DMFS, and PFS were defined as the time from the enrolment date in the trial to the date of death or the date of the last follow-up, the first local or regional relapse, the first distant metastasis occurrence, or the diagnosed evidence of disease progression or the last follow-up, respectively. After relapse or metastasis, patients received salvage therapy as determined by their physicians.
IBM SPSS Statistics version 22.0 was used for all the data analysis. We compared the patients' characteristics, acute toxicities, and patterns of failure between the two groups by the Chi-square test or Fisher's exact test. Survival curves were generated using the Kaplan-Meier method. The curves were compared using log-rank tests. Multivariate analysis was performed using Cox regression models to identify significant prognostic factors. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each prognostic factor. A P < 0.05 was considered statistically significant.
We adjusted potential biases related to treatment with specific therapeutic regimens using a PSM analysis 42,43 . We computed propensity scores for every patient by logistic regression according to sex, age category (<60 years/≥60 years), T-stage, N-stage, clinical stage, NAC regimen, and NAC cycle. PSM was performed using all the above covariates with a one-to-one nearest neighbour matching algorithm at a caliper of 0.02.