T1-2N1M0 nasopharyngeal carcinoma chemotherapy or not: A retrospective study

Pei-Jing Li; Ming Chen; Ye Tian

doi:10.1371/journal.pone.0279252

Abstract

Background

Radiotherapy (RT) combined with chemotherapy is the standard treatment for T_1-2N₁M₀ nasopharyngeal carcinoma (NPC) based on conventional radiotherapy. However, intensity-modulated radiotherapy (IMRT) has narrowed the treatment gap between RT and chemoradiotherapy. Thus, this retrospective study aimed to compare the efficacy of RT and chemoradiotherapy (RT-chemo) in treating T_1-2N₁M₀ NPC in the IMRT era.

Materials and methods

From January 2008 to December 2016, 343 consecutive patients with T_1-2N₁M₀ NPC in two cancer centers were included. All patients received RT or RT-chemo, chemotherapy including induction chemotherapy (IC) + concurrent chemoradiotherapy (CCRT), CCRT, or CCRT + adjuvant chemotherapy (AC). The number of patients who received RT, CCRT, IC + CCRT, and CCRT + AC was 114, 101, 89, and 39. The survival rates were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariable analysis was performed to identify valuable prognostic factors.

Results

The median follow-up time for survivors was 93 (range: 55–144) months. The 5-year overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS) for the RT-chemo and RT groups were 93.7%, 88.5%, 93.8%, 93.8% and 93.0%, 87.7%, 91.9%, 91.2%, respectively (P>0.05 for all outcomes). No significant survival differences were found between the two groups. The T₁N₁M₀ or T₂N₁M₀ subgroup analysis showed that treatment outcomes had no significant differences between the RT and RT-chemo groups. After adjusting for various factors, treatment mode was not identified as an independent prognostic factor for all survival rates.

Conclusions

In this study, outcomes of T_1-2N₁M₀ NPC patients treated by IMRT alone were comparable to chemoradiotherapy, supporting the omission or postponement of chemotherapy.

Citation: Li P-J, Chen M, Tian Y (2023) T_1-2N₁M₀ nasopharyngeal carcinoma chemotherapy or not: A retrospective study. PLoS ONE 18(3): e0279252. https://doi.org/10.1371/journal.pone.0279252

Editor: Seok Ho Lee, Gachon University Gil Medical Center, REPUBLIC OF KOREA

Received: August 24, 2022; Accepted: December 3, 2022; Published: March 2, 2023

Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: As the data contain potentially sensitive information, we cannot share the data without restriction. All data used in this study will be uploaded to the ‘Scientific research electronic file management system’ of our hospital. Reasonable requests for data can be made by contacting our Ethics Committee (E-mail: ec@zjcc.org.cn) or the first author (E-mail: lipjlszj@163.com) or the corresponding author (E-mail: dryetian@126.com).

Funding: This study was funded by Jiangsu Medical Innovation Team [grant number CXDT-37]; and Suzhou Science and Technology Development Program [grant number SZS201509]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Nasopharyngeal carcinoma (NPC) has an extremely skewed geographic distribution. Over 70% of the cases were reported in East and Southeast Asia [1, 2]. Induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) or CCRT ± adjuvant chemotherapy (AC) is currently the standard treatment for patients with stage II NPC based on two-dimensional conventional radiotherapy (2DRT) [3]. Intensity-modulated radiotherapy (IMRT) has been widely used since1990s. The 5-year overall survival (OS) rate for stage II NPC patients increased from 85% using 2DRT to 95% using IMRT alone [4–6]. With the excellent outcomes of IMRT, chemotherapy is becoming unnecessary for patients with T₂N₀M₀ NPC unless they have high-risk features such as bulky tumor volumes or high plasma/serum EBV DNA copy numbers [7]. However, N-positive disease is an established high-risk factor for distant metastasis, making patients with T_1-2N₁M₀ NPC a unique subgroup within the stage II disease [8]. There are no definitive evidence-based recommendations for managing T_1-2N₁ disease in the IMRT era [7]. Only one retrospective study with small sample size and short follow-up focusing on T_1-2N₁M₀ NPC (AJCC 6th edition) patients explored the efficacy of CCRT [9] in the context of IMRT. Therefore, this study aimed to explore the role of chemotherapy in T_1-2N₁M₀ NPC patients treated with radical IMRT in a large cohort and with extended follow-up.

Materials and methods

Patients

This study retrospectively collected data of 343 consecutive patients with T_1-2N₁M₀ NPC from two cancer centers between January 2008 and December 2016. The inclusion criteria were histopathologically confirmed non-keratinizing NPC, T_1-2N₁M₀ disease were re-staged by the American Joint Committee on Cancer (AJCC) TNM 8th edition staging system, age 18–80 years, completion of radical radiation, and without other malignancies. Demographic (age, gender, etc.) and clinical (stage, treatment, disease outcomes and survival, etc.) data were collected. The study was conducted in accordance with the Declaration of Helsinki for all human or animal experimental investigations and approved by the Ethics Committee of Zhejiang Cancer Hospital(IRB-2021-90). The informed consent requirement has been waived due to the retrospective nature of this study.

Treatment and follow-up

Whether patients received RT alone or chemoradiotherapy depended on a combination of the individual’s will and the physician’s recommendation after case discussion because the treatment of patients with stage II NPC was controversial during the time patients were included in this study. The induction regimens were based on platinum: PF (cisplatin/nedaplatin + 5-fluorouracil), TP (docetaxel + cisplatin), or TPF (docetaxel, cisplatin + 5-fluorouracil), repeated every 21 days for 2–3 cycles. Concurrent chemotherapy regimens were cisplatin or nedaplatin, administered weekly (3–6 cycles) or every 3 weeks (2–3 cycles). Adjuvant chemotherapy regimens were PF, TP, or capecitabine, administered every 3 to 4 weeks for 2–4 cycles. All patients underwent radical IMRT. Simultaneously modulated accelerated radiation therapy (SMART) technique was used. We delivered 2.12–2.18 Gy/F to PGTV (planning target for the primary tumor and positive lymph node) while delivering 2 Gy/F to PTV1 (planning target for the high-risk subclinical lesions) and 1.8 Gy/F to PTV2 (planning target for the low-risk subclinical lesions). The total dose for PGTV, PTV1, and PTV2 was 68–70 Gy, 60–64 Gy, and 54–58 Gy, completed in 30-32F, 5F per week. The detailed IMRT plan was the same as previous studies [10, 11]. Outpatient workup is the main form of follow-up. The final follow-up date was August 31, 2021.

Statistical analysis

All patients were divided into the RT and chemoradiotherapy groups (RT-chemo, including IC+CCRT, CCRT, CCRT+AC). We evaluated treatment outcomes of locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and OS in this study. Progression is defined as disease progression or death from any cause. Cancer-specific survival (CSS) was added to highlight cancer-related events and defined as individuals who die of NPC. All endpoints were defined as the time from the onset of treatment to the time of event occurrence or the last follow-up in the absence of an event. The Kaplan–Meier method was used to analyze the time-to-event endpoints. The log-rank test was performed to compare differences between groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression analysis. Multivariate analyses were used to identify valuable predictive factors. Categorical and continuous variables were compared using Pearson’s χ² test, Fisher’s exact test, and t-test. R software (R version 4.0.2) and SPSS version 25.0 (IBM Corp., Armonk, NY, USA) were used for data analyses. Statistical significance was set at p < 0.05.

Results

Patient characteristics

The median follow-up time for the 303 survivors was 93 (range: 55–144) months. A total of 284 (93.7%) survivors were followed up for at least 5 years. The median survival was not reached. The male-to-female ratio was 2.61:1. The baseline characteristics were well-balanced between the groups in the whole group analysis and the T₁/T₂N₁M₀ subgroup analysis (all P > 0.05). The details are summarized in Table 1 and S1 Table.

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Table 1. Baseline characteristics.

https://doi.org/10.1371/journal.pone.0279252.t001

Failure patterns

Overall, 39 deaths were recorded up to the last follow-up: 15 (13.2%) in the RT group and 24 (10.5%) in the RT-chemo group without statistical significance between the groups (P = 0.462). Thirty-six patients died due to cancer-related causes, and no difference was found between the two groups either (12.3% vs. 9.6%, P = 0.447). A total of 52 patients experienced treatment failure. The progression, locoregional relapse, and distant metastasis had no significant differences between the two groups (all P > 0.05, Table 2). In subgroup analyses, death, cancer-specific death, progression, relapse, and metastasis had no significant differences between the RT alone and RT-chemo groups either in the T₁N₁ or T₂N₁ populations (all P > 0.05, Table 2). We compared the event incidence between the CCRT, IC + CCRT, CCRT + AC, and RT alone populations regarding different chemotherapy sequences. Similarly, no significant differences were found in any analyzed events (S2 Table).

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Table 2. Comparison of events incidence between the RT and RT-chemo groups.

https://doi.org/10.1371/journal.pone.0279252.t002

Survival outcomes

The 5- and 10-year OS rates of the RT-chemo group were similar to those of the RT group (93.7% vs. 93.0%, and 79.8% vs. 76.2%, HR: 0.874, 95%CI: 0.463–1.651, P = 0.679, Fig 1A and S3 Table). The RT-chemo group did not show significant improvement in the 5- and 10-year PFS, CSS, LRFFS, or DMFS rates compared with the RT group (Fig 1B, S1A–S1C Fig, and S3 Table). Similar trends were observed in the T₁N₁ and T₂N₁ subgroup analyses. There was no significant survival difference between the RT and RT-chemo groups, either in T₁N₁M₀ or T₂N₁M₀ disease population (all P > 0.05, Fig 1C–1F, and S1D–S1I Fig). When different chemotherapy sequences were analyzed separately as the RT, CCRT, IC + CCRT, and CCRT + AC groups, no significant survival differences were found among the groups (all P > 0.05, Fig 2, S2 Fig).

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Fig 1. Kaplan–Meier survival curves for the RT and RT-chemo groups.

(A–B) whole group analysis: overall survival and progression-free survival, (C–D) T₁N₁ subgroup analysis: overall survival and progression-free survival, (E–F) T₂N₁ subgroup analysis: overall survival and progression-free survival. HRs are calculated with an unadjusted Cox proportional hazards model. P values are calculated with the unadjusted log-rank test. CI = confidence interval, RT = radiotherapy, RT-chemo = chemoradiotherapy.

https://doi.org/10.1371/journal.pone.0279252.g001

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Fig 2. Kaplan–Meier survival curves for the RT, CCRT, IC + CCRT, and CCRT + AC groups.

(A) overall survival, (B) progression-free survival. P values are calculated with the χ² test. Abbreviation: RT = radiotherapy, CCRT = concurrent chemoradiotherapy, IC = induction chemotherapy, AC = adjuvant chemotherapy.

https://doi.org/10.1371/journal.pone.0279252.g002

Multivariate analysis

In multivariable analyses, after adjusting for age, sex, and T stage, the combined chemotherapy did not significantly improve OS, PFS, CSS, LRFFS, and DMFS. Treatment mode was not identified as an independent prognostic factor for all survival rates (all P >0.05, Fig 3 and S4 Table). Then, age was an independent prognostic factor for OS, CSS, PFS, and DMFS and inversely related to these outcomes. However, age was not a predictor of LRFFS.

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Fig 3. Cox Forest plots for the death of patients with T_1-2N₁M₀ NPC.

HRs and P values are calculated with the adjusted Cox proportional hazards model. HR = hazard ratio, CI = confidence interval, RT = radiotherapy, CCRT = concurrent chemoradiotherapy, IC = induction chemotherapy, AC = adjuvant chemotherapy. ^# = reference category.

https://doi.org/10.1371/journal.pone.0279252.g003

Discussion

The present retrospective study demonstrated that IMRT alone could achieve an equivalent prognosis to chemoradiotherapy for treating patients with T_1-2N₁M₀ NPC in the IMRT era.

Cheng et al. [12] retrospectively reviewed 44 patients with I-II NPC (AJCC 5th edition): 11 with stage I disease and 1 with stage II NPC received RT alone, and 32 patients with stage II NPC were treated with CCRT. The 3-year LRFFS and DMFS rates were similar in the two arms suggesting that the unfavorable prognosis of stage II NPC patients was reversed by concurrent chemotherapy. A post-hoc analysis conducted by Chua et al. [13] indicated that adding IC to RT (n = 98) significantly improved OS (79% vs. 67%, P = 0.048) and DMFS (86% vs. 71%, P = 0.005) of stage II NPC patients (AJCC 5th edition) comparing with RT alone (n = 110). Chen and Li [4, 14] carried out a randomized clinical trial revealing that CCRT was significantly superior to 2DRT in treating stage II NPC (Chinese 1992 stage) (OS: 83.6% vs. 65.8%, CSS: 86.2% vs. 71.9%, PFS: 76.7% vs. 64.0%, DMFS: 94.0% vs. 83.3%, P < 0.05 for all). A retrospective study focused on T₂N₁M₀ patients demonstrated that cisplatin-based CCRT significantly improved relapse-free survival (91.5% vs. 77.3%, P = 0.008) but not overall survival when comparing RT alone [15]. Studies confirming the therapeutic advantage of chemoradiotherapy have focused more on the treatment of stage II NPC patients other than the T_1-2N₁M₀ subgroup. In addition, all the above studies were based on the 2DRT technique.

IMRT generates a uniform dose distribution in the target region and a sharp dose gradient transition to the adjacent vital organs, allowing better protection of the normal tissue and appropriately increased dose of the target volume. Then, the SMART technique shortens the time of radiotherapy. Lai et al. [16] retrospectively reviewed the outcomes of 1276 NPC patients who received 2DRT or IMRT, showing that IMRT provided survival benefits, especially in early-stage T disease. In the IMRT era, the efficacy gap between RT alone and chemoradiotherapy has narrowed. Whether the ceiling effect appears in early-stage NPC treatment using IMRT is worth further discussion. The treatment outcomes of adding chemotherapy to RT in the different eras were utterly different. One study revealed that CCRT ± AC had no advantages in improving the prognosis of patients with II NPC (AJCC 7th edition) compared with IMRT alone [5]. Su et al. [6] retrospectively reviewed 249 patients with stage II NPC (AJCC 7th edition) and indicated that there was no significant difference in prognosis between IMRT alone (n = 106) and CCRT (n = 143). Chen et al. [17] conducted a prospective study in stage II NPC patients (AJCC 7th edition) and revealed that CCRT + AC(n = 81) did not gain favorable 5-year OS and DMFS rates when compared with IMRT (n = 79) (OS: 91.4 vs. 88.6%, DMFS: 93.82% vs. 93.67%, all P > 0.05). Moreover, a phase II clinical study [18] of 84 patients with stage II NPC (AJCC 7th edition) explored the efficacy of concurrent chemotherapy. The OS, local failure-free survival (LFFS), regional failure-free survival (RFFS), disease-free survival (DFS), and DMFS of the IMRT (n = 43) and CCRT (n = 41) groups were 100% vs. 94.0%, 93.0% vs. 89.3%, 97.7% vs. 95.1%, 90.4% vs. 86.6%, and 95.2% vs. 94.5%, respectively (P > 0.05 for all). However, there were different voices. Sun et al. [19] retrospectively reviewed 3808 stage II patients treated from 1990 to 2012, indicating that the absence of chemotherapy was still a risk factor for poor prognosis after adjusting for radiotherapy technique (2DRT, 3DRT, and IMRT), family history, personal history, and stage. Studies focused on the T_1-2N₁M₀ disease population are extremely limited. A retrospective study demonstrated that patients with T_1-2N₁ NPC (AJCC 5th edition) had a relatively poor prognosis than T₂N₀ disease [20]. The authors deemed positive regional lymph node(s) a high-risk factor of distant metastasis and suggested a more aggressive therapy for the T_1-2N₁ population. Besides, Luo et al. [8] retrospectively analyzed 69 patients with stage I-II NPC (AJCC 6th edition) from China’s non-endemic region. They found that the T₂N₁ classification was a subgroup with a higher risk of distant metastasis. A more apparent separation of the survival curves was observed in the T₂N₁ subgroup analyses than in the overall evaluation of the whole group (3-year OS, LRFFS, DMFS were 100% vs. 78.6%, 100% vs. 79.5%, 100% vs. 79.6%, all P < 0.05). By far, only one retrospective study focusing on T_1-2N₁M₀ NPC (AJCC 6th edition) patients explored the efficacy of CCRT [9] in the context of IMRT. A group of paired patients received CCRT (n = 43) or IMRT (n = 43), the 3-year OS, PFS, LRFFS, and DMFS in each group were 100% vs. 94.8%, 89.9% vs. 90%, 92.3% vs. 95%, 97.6% vs. 91.7%, respectively (all P > 0.05). Their results indicated that the omission of chemotherapy did not affect the prognosis. Although with a well-balanced cohort, the sample size was small and the follow-up (median: 37.4 months, range: 4.8–66.2 months) was not long enough in the above study regarding a disease with a relatively good prognosis (5-year OS is more than 90%).

The AJCC NPC staging system has undergone four editions of updates from 1997 to 2017. The T stage of the AJCC 8th edition staging system is markedly different from the previous versions. T₂ in the latest staging system includes tumors extending to the parapharyngeal space and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles), covering a fraction of T₄ disease in previous editions. Therefore, the results of the above studies must be taken with caution. We re-staged NPC patients in our database according to the AJCC 8th edition staging system and screened 343 patients with T_1-2N₁M₀ NPC for analysis. This retrospective study represents the largest analysis of T_1-2N₁M₀ NPC patients to date, focusing on chemotherapy. Considering that the TNM staging system has long been recognized as the most important prognostic indicator for NPC, we performed a subgroup analysis of T₁N₁M₀ and T₂N₁M₀ diseases. Similar to the overall evaluation, the combination chemotherapy group still did not show any survival advantage in either subgroup. In addition, we divided all patients into the RT, CCRT, IC + CCRT, and CCRT + AC groups. The incidence of events and survival outcomes were not significantly different between the IMRT alone and the other chemoradiotherapy groups. Using IMRT, the radiation dose of the primary tumor and positive retropharyngeal lymph node is almost the same as 2DRT. However, due to the limitation of toxicity, the dose of positive cervical lymph nodes in 2DRT (60–62 Gy) [4] is lower than that of IMRT (66–70 Gy). This difference might explain why IMRT enhances the locoregional control rate and offset the improvement of concurrent chemotherapy on locoregional control. Moreover, advances in imaging technology have made the target volume more accurate in the IMRT era. The present findings corroborate previous reports suggesting that IMRT is sufficient for treating patients with T_1-2N₁M₀ NPC. We believe it may be feasible to omit or postpone chemotherapy in T_1-2N₁M₀ NPC when using IMRT for radiotherapy.

This study also confirms that the failure risk persists 5 years after treatment, which is consistent with the findings of Qin et al. [21] and Chua et al. [20]. Therefore, it is of great importance to maintain a longer follow-up and report long-term results when the data are mature in studies of NPC. The median follow-up of nearly 10 years indicates the reliability of the results in this study. As a retrospective study, this study had some limitations. First, plasma/serum EBV DNA has become an effective prognostic biomarker in recent decades [22, 23], complementing the TNM staging system for selecting patients at a high risk of developing distant metastasis. However, EBV DNA data are lacking in the present study due to incomplete data. Future prospective studies can be designed to better incorporate biomarkers such as plasma/serum EBV DNA levels with the TNM staging system for risk stratification. Second, the toxicity profile of the treatment was not assessed in the present study. Nevertheless, previous studies have shown that chemotherapy increased acute treatment-related toxicities [5, 6, 17, 18]. Overall, our report is noteworthy because of the large population, long-term follow-up, and adoption of multivariate analyses.

Conclusions

This study showed that T_1-2N₁M₀ NPC patients receiving IMRT and chemoradiotherapy had comparable treatment outcomes, supporting the omission or postponement of chemotherapy. However, prospective studies are warranted to validate the findings in the present study.

Supporting information

S1 Table. Baseline characteristics of the T₁N₁M₀ and T₂N₁M₀ subgroups.

https://doi.org/10.1371/journal.pone.0279252.s001

(DOCX)

S2 Table. Comparison of events incidence in the RT, CCRT, IC + CCRT, and CCRT + AC groups.

https://doi.org/10.1371/journal.pone.0279252.s002

(DOCX)

S3 Table. Survival outcomes of patients in the RT and RT-chemo groups.

https://doi.org/10.1371/journal.pone.0279252.s003

(DOCX)

S4 Table. Multivariable analyses of prognostic factors for all treatment outcomes.

https://doi.org/10.1371/journal.pone.0279252.s004

(DOCX)

S1 Fig. Kaplan–Meier survival curves for the RT and RT-chemo groups.

(A–C) Whole group analysis: cancer-specific survival, locoregional failure-free survival, and distant metastasis-free survival; (D–F) T₁N₁ subgroup analysis: cancer-specific survival, locoregional failure-free survival, and distant metastasis-free survival; (G–I) T₂N₁ subgroup analysis: cancer-specific survival, locoregional failure-free survival, and distant metastasis-free survival. HRs are calculated with the unadjusted Cox proportional hazards model. P values are calculated with the unadjusted log-rank test. CI = confidence interval, RT = radiotherapy, RT-chemo = radiation + chemotherapy.

https://doi.org/10.1371/journal.pone.0279252.s005

(TIF)

S2 Fig. Kaplan–Meier survival curves for the RT, CCRT, IC + CCRT, and CCRT + AC groups.

(A) Cancer-specific survival, (B) Locoregional failure-free survival, (C) Distant metastasis-free survival. P values are calculated with log-rank test (pairwise over strata). RT = radiotherapy, CCRT = concurrent chemoradiotherapy, IC = induction chemotherapy, AC = adjuvant chemotherapy.

https://doi.org/10.1371/journal.pone.0279252.s006

(TIF)

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71: 209–249. pmid:33538338
- View Article
- PubMed/NCBI
- Google Scholar
2. Lv X, He H, Yang Y, Han L, Guo Z, Chen H, et al. Radiation-induced hippocampal atrophy in patients with nasopharyngeal carcinoma early after radiotherapy: a longitudinal MR-based hippocampal subfield analysis. Brain Imaging Behav. 2019;13: 1160–1171. pmid:30054872
- View Article
- PubMed/NCBI
- Google Scholar
3. Pfister DG, Spencer S, Adelstein D, Adkins D, Anzai Y, Brizel DM, et al. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 3.2021. Natl Compr Cancer Netw. 2021. pmid:32634781
- View Article
- PubMed/NCBI
- Google Scholar
4. Chen Q-Y, Wen Y-F, Guo L, Liu H, Huang P-Y, Mo H-Y, et al. Concurrent Chemoradiotherapy vs Radiotherapy Alone in Stage II Nasopharyngeal Carcinoma: Phase III Randomized Trial. J Natl Cancer Inst. 2011;103: 1761–1770. pmid:22056739
- View Article
- PubMed/NCBI
- Google Scholar
5. Chen KH, Zhu XD, Li L, Qu S, Liang ZQ, Liang X, et al. Comparison of the efficacy between concurrent chemoradiotherapy with or without adjuvant chemotherapy and intensity-modulated radiotherapy alone for stage II nasopharyngeal carcinoma. Oncotarget. 2016;7: 69041–50. pmid:27634892
- View Article
- PubMed/NCBI
- Google Scholar
6. Su Z, Mao YP, Tang J, Lan XW, OuYang PY, Xie FY. Long-term outcomes of concurrent chemoradiotherapy versus radiotherapy alone in stage II nasopharyngeal carcinoma treated with IMRT: a retrospective study. Tumor Biol. 2016;37: 4429–4438. pmid:26499947
- View Article
- PubMed/NCBI
- Google Scholar
7. Chen Y-P, Ismaila N, Chua MLK, Colevas AD, Haddad R, Huang SH, et al. Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline. J Clin Oncol. 2021;39: 840–859. pmid:33405943
- View Article
- PubMed/NCBI
- Google Scholar
8. Luo S, Zhao L, Wang J, Xu M, Li J, Zhou B, et al. Clinical outcomes for early-stage nasopharyngeal carcinoma with predominantly WHO II histology treated by intensity-modulated radiation therapy with or without chemotherapy. Head Neck. 2014;36: 841–847. pmid:23720240
- View Article
- PubMed/NCBI
- Google Scholar
9. Xu T, Shen C, Zhu G, Hu C. Omission of chemotherapy in early stage nasopharyngeal carcinoma treated with IMRT a paired cohort study. Med. 2015;94: e1457. pmid:26426610
- View Article
- PubMed/NCBI
- Google Scholar
10. Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, et al. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016;17: 1509–1520. pmid:27686945
- View Article
- PubMed/NCBI
- Google Scholar
11. Sun Y, Yu XL, Luo W, Lee AWM, Wee JTS, Lee N, et al. Recommendation for a contouring method and atlas of organs at risk in nasopharyngeal carcinoma patients receiving intensity-modulated radiotherapy. Radiother Oncol. 2014;110: 390–397. pmid:24721546
- View Article
- PubMed/NCBI
- Google Scholar
12. Cheng SH, Tsai SYC, Lawrence Yen K, Jian JJM, Chu NM, Chan KY, et al. Concomitant radiotherapy and chemotherapy for early-stage nasopharyngeal carcinoma. J Clin Oncol. 2000;18: 2040–2045. pmid:10811668
- View Article
- PubMed/NCBI
- Google Scholar
13. Chua DTT, Ma J, Sham JST, Mai H-Q, Choy DTK, Hong M-H, et al. Improvement of survival after addition of induction chemotherapy to radiotherapy in patients with early-stage nasopharyngeal carcinoma: Subgroup analysis of two Phase III trials. Int J Radiat Oncol Biol Phys. 2006;65: 1300–6. pmid:16750333
- View Article
- PubMed/NCBI
- Google Scholar
14. Li XY, Chen QY, Sun XS, Liu SL, Yan JJ, Guo SS, et al. Ten-year outcomes of survival and toxicity for a phase III randomised trial of concurrent chemoradiotherapy versus radiotherapy alone in stage II nasopharyngeal carcinoma. Eur J Cancer. 2019;110: 24–31. pmid:30739837
- View Article
- PubMed/NCBI
- Google Scholar
15. Xu T, Hu C, Wang X, Shen C. Role of chemoradiotherapy in intermediate prognosis nasopharyngeal carcinoma. Oral Oncol. 2011;47: 408–413. pmid:21459659
- View Article
- PubMed/NCBI
- Google Scholar
16. Lai S-Z, Li W-F, Chen L, Luo W, Chen Y-Y, Liu L-Z, et al. How Does Intensity-Modulated Radiotherapy Versus Conventional Two-Dimensional Radiotherapy Influence the Treatment Results in Nasopharyngeal Carcinoma Patients? Int J Radiat Oncol Biol Phys. 2011;80: 661–668. pmid:20643517
- View Article
- PubMed/NCBI
- Google Scholar
17. Chen S, Meng Y, Shen Y, Ning X, Xiong C, Lin Z, et al. Chemotherapy May Not be Necessary in Stage II Nasopharyngeal Carcinoma Treated with Intensity-Modulated Radiation Therapy (Oral scientific session). Int J Radiat Oncol Biol Phys. 2018;3: S125–6.
- View Article
- Google Scholar
18. Huang X, Chen X, Zhao C, Wang J, Wang K, Wang L, et al. Adding Concurrent Chemotherapy to Intensity-Modulated Radiotherapy Does Not Improve Treatment Outcomes for Stage II Nasopharyngeal Carcinoma: A Phase 2 Multicenter Clinical Trial. Front Oncol. 2020;10: 1314. pmid:32850414
- View Article
- PubMed/NCBI
- Google Scholar
19. Sun XS, Liu DH, Liu SL, Chen QY, Guo SS, Wen YF, et al. Patterns of failure and survival trends in 3,808 patients with stage II nasopharyngeal carcinoma diagnosed from 1990 to 2012: A large-scale retrospective cohort study. Cancer Res Treat. 2019;51: 1449–1463. pmid:30913870
- View Article
- PubMed/NCBI
- Google Scholar
20. Chua DTT, Sham JST, Kwong DLW, Au GKH. Treatment outcome after radiotherapy alone for patients with Stage I-II nasopharyngeal carcinoma. Cancer. 2003;98: 74–80. pmid:12833458
- View Article
- PubMed/NCBI
- Google Scholar
21. Qin DX, Hu YH, Yan JH, Xu GZ, Cai WM, Wu XL, et al. Analysis of 1379 patients with nasopharyngeal carcinoma treated by radiation. Cancer. 1988;61: 1117–1124. pmid:3342372
- View Article
- PubMed/NCBI
- Google Scholar
22. Fai Leung S, Chan ATC, Zee B, Ma B, Chan LYS, Johnson PJ, et al. Pretherapy quantitative measurement of circulating Epstein—Barr virus DNA is predictive of posttherapy distant failure in patients with early-stage nasopharyngeal carcinoma of undifferentiated type. Cancer. 2003;98: 288–291. pmid:12872347
- View Article
- PubMed/NCBI
- Google Scholar
23. Lin J-C, Wang W-Y, Chen KY, Wei Y-H, Liang W-M, Jan J-S, et al. Quantification of Plasma Epstein–Barr Virus DNA in Patients with Advanced Nasopharyngeal Carcinoma. N Engl J Med. 2004;350: 2461–2470. pmid:15190138
- View Article
- PubMed/NCBI
- Google Scholar

[ref1] 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71: 209–249. pmid:33538338
View Article
PubMed/NCBI
Google Scholar

[2] View Article

[3] PubMed/NCBI

[4] Google Scholar

[ref2] 2. Lv X, He H, Yang Y, Han L, Guo Z, Chen H, et al. Radiation-induced hippocampal atrophy in patients with nasopharyngeal carcinoma early after radiotherapy: a longitudinal MR-based hippocampal subfield analysis. Brain Imaging Behav. 2019;13: 1160–1171. pmid:30054872
View Article
PubMed/NCBI
Google Scholar

[6] View Article

[7] PubMed/NCBI

[8] Google Scholar

[ref3] 3. Pfister DG, Spencer S, Adelstein D, Adkins D, Anzai Y, Brizel DM, et al. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 3.2021. Natl Compr Cancer Netw. 2021. pmid:32634781
View Article
PubMed/NCBI
Google Scholar

[10] View Article

[11] PubMed/NCBI

[12] Google Scholar

[ref4] 4. Chen Q-Y, Wen Y-F, Guo L, Liu H, Huang P-Y, Mo H-Y, et al. Concurrent Chemoradiotherapy vs Radiotherapy Alone in Stage II Nasopharyngeal Carcinoma: Phase III Randomized Trial. J Natl Cancer Inst. 2011;103: 1761–1770. pmid:22056739
View Article
PubMed/NCBI
Google Scholar

[14] View Article

[15] PubMed/NCBI

[16] Google Scholar

[ref5] 5. Chen KH, Zhu XD, Li L, Qu S, Liang ZQ, Liang X, et al. Comparison of the efficacy between concurrent chemoradiotherapy with or without adjuvant chemotherapy and intensity-modulated radiotherapy alone for stage II nasopharyngeal carcinoma. Oncotarget. 2016;7: 69041–50. pmid:27634892
View Article
PubMed/NCBI
Google Scholar

[18] View Article

[19] PubMed/NCBI

[20] Google Scholar

[ref6] 6. Su Z, Mao YP, Tang J, Lan XW, OuYang PY, Xie FY. Long-term outcomes of concurrent chemoradiotherapy versus radiotherapy alone in stage II nasopharyngeal carcinoma treated with IMRT: a retrospective study. Tumor Biol. 2016;37: 4429–4438. pmid:26499947
View Article
PubMed/NCBI
Google Scholar

[22] View Article

[23] PubMed/NCBI

[24] Google Scholar

[ref7] 7. Chen Y-P, Ismaila N, Chua MLK, Colevas AD, Haddad R, Huang SH, et al. Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline. J Clin Oncol. 2021;39: 840–859. pmid:33405943
View Article
PubMed/NCBI
Google Scholar

[26] View Article

[27] PubMed/NCBI

[28] Google Scholar

[ref8] 8. Luo S, Zhao L, Wang J, Xu M, Li J, Zhou B, et al. Clinical outcomes for early-stage nasopharyngeal carcinoma with predominantly WHO II histology treated by intensity-modulated radiation therapy with or without chemotherapy. Head Neck. 2014;36: 841–847. pmid:23720240
View Article
PubMed/NCBI
Google Scholar

[30] View Article

[31] PubMed/NCBI

[32] Google Scholar

[ref9] 9. Xu T, Shen C, Zhu G, Hu C. Omission of chemotherapy in early stage nasopharyngeal carcinoma treated with IMRT a paired cohort study. Med. 2015;94: e1457. pmid:26426610
View Article
PubMed/NCBI
Google Scholar

[34] View Article

[35] PubMed/NCBI

[36] Google Scholar

[ref10] 10. Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, et al. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016;17: 1509–1520. pmid:27686945
View Article
PubMed/NCBI
Google Scholar

[38] View Article

[39] PubMed/NCBI

[40] Google Scholar

[ref11] 11. Sun Y, Yu XL, Luo W, Lee AWM, Wee JTS, Lee N, et al. Recommendation for a contouring method and atlas of organs at risk in nasopharyngeal carcinoma patients receiving intensity-modulated radiotherapy. Radiother Oncol. 2014;110: 390–397. pmid:24721546
View Article
PubMed/NCBI
Google Scholar

[42] View Article

[43] PubMed/NCBI

[44] Google Scholar

[ref12] 12. Cheng SH, Tsai SYC, Lawrence Yen K, Jian JJM, Chu NM, Chan KY, et al. Concomitant radiotherapy and chemotherapy for early-stage nasopharyngeal carcinoma. J Clin Oncol. 2000;18: 2040–2045. pmid:10811668
View Article
PubMed/NCBI
Google Scholar

[46] View Article

[47] PubMed/NCBI

[48] Google Scholar

[ref13] 13. Chua DTT, Ma J, Sham JST, Mai H-Q, Choy DTK, Hong M-H, et al. Improvement of survival after addition of induction chemotherapy to radiotherapy in patients with early-stage nasopharyngeal carcinoma: Subgroup analysis of two Phase III trials. Int J Radiat Oncol Biol Phys. 2006;65: 1300–6. pmid:16750333
View Article
PubMed/NCBI
Google Scholar

[50] View Article

[51] PubMed/NCBI

[52] Google Scholar

[ref14] 14. Li XY, Chen QY, Sun XS, Liu SL, Yan JJ, Guo SS, et al. Ten-year outcomes of survival and toxicity for a phase III randomised trial of concurrent chemoradiotherapy versus radiotherapy alone in stage II nasopharyngeal carcinoma. Eur J Cancer. 2019;110: 24–31. pmid:30739837
View Article
PubMed/NCBI
Google Scholar

[54] View Article

[55] PubMed/NCBI

[56] Google Scholar

[ref15] 15. Xu T, Hu C, Wang X, Shen C. Role of chemoradiotherapy in intermediate prognosis nasopharyngeal carcinoma. Oral Oncol. 2011;47: 408–413. pmid:21459659
View Article
PubMed/NCBI
Google Scholar

[58] View Article

[59] PubMed/NCBI

[60] Google Scholar

[ref16] 16. Lai S-Z, Li W-F, Chen L, Luo W, Chen Y-Y, Liu L-Z, et al. How Does Intensity-Modulated Radiotherapy Versus Conventional Two-Dimensional Radiotherapy Influence the Treatment Results in Nasopharyngeal Carcinoma Patients? Int J Radiat Oncol Biol Phys. 2011;80: 661–668. pmid:20643517
View Article
PubMed/NCBI
Google Scholar

[62] View Article

[63] PubMed/NCBI

[64] Google Scholar

[ref17] 17. Chen S, Meng Y, Shen Y, Ning X, Xiong C, Lin Z, et al. Chemotherapy May Not be Necessary in Stage II Nasopharyngeal Carcinoma Treated with Intensity-Modulated Radiation Therapy (Oral scientific session). Int J Radiat Oncol Biol Phys. 2018;3: S125–6.
View Article
Google Scholar

[66] View Article

[67] Google Scholar

[ref18] 18. Huang X, Chen X, Zhao C, Wang J, Wang K, Wang L, et al. Adding Concurrent Chemotherapy to Intensity-Modulated Radiotherapy Does Not Improve Treatment Outcomes for Stage II Nasopharyngeal Carcinoma: A Phase 2 Multicenter Clinical Trial. Front Oncol. 2020;10: 1314. pmid:32850414
View Article
PubMed/NCBI
Google Scholar

[69] View Article

[70] PubMed/NCBI

[71] Google Scholar

[ref19] 19. Sun XS, Liu DH, Liu SL, Chen QY, Guo SS, Wen YF, et al. Patterns of failure and survival trends in 3,808 patients with stage II nasopharyngeal carcinoma diagnosed from 1990 to 2012: A large-scale retrospective cohort study. Cancer Res Treat. 2019;51: 1449–1463. pmid:30913870
View Article
PubMed/NCBI
Google Scholar

[73] View Article

[74] PubMed/NCBI

[75] Google Scholar

[ref20] 20. Chua DTT, Sham JST, Kwong DLW, Au GKH. Treatment outcome after radiotherapy alone for patients with Stage I-II nasopharyngeal carcinoma. Cancer. 2003;98: 74–80. pmid:12833458
View Article
PubMed/NCBI
Google Scholar

[77] View Article

[78] PubMed/NCBI

[79] Google Scholar

[ref21] 21. Qin DX, Hu YH, Yan JH, Xu GZ, Cai WM, Wu XL, et al. Analysis of 1379 patients with nasopharyngeal carcinoma treated by radiation. Cancer. 1988;61: 1117–1124. pmid:3342372
View Article
PubMed/NCBI
Google Scholar

[81] View Article

[82] PubMed/NCBI

[83] Google Scholar

[ref22] 22. Fai Leung S, Chan ATC, Zee B, Ma B, Chan LYS, Johnson PJ, et al. Pretherapy quantitative measurement of circulating Epstein—Barr virus DNA is predictive of posttherapy distant failure in patients with early-stage nasopharyngeal carcinoma of undifferentiated type. Cancer. 2003;98: 288–291. pmid:12872347
View Article
PubMed/NCBI
Google Scholar

[85] View Article

[86] PubMed/NCBI

[87] Google Scholar

[ref23] 23. Lin J-C, Wang W-Y, Chen KY, Wei Y-H, Liang W-M, Jan J-S, et al. Quantification of Plasma Epstein–Barr Virus DNA in Patients with Advanced Nasopharyngeal Carcinoma. N Engl J Med. 2004;350: 2461–2470. pmid:15190138
View Article
PubMed/NCBI
Google Scholar

[89] View Article

[90] PubMed/NCBI

[91] Google Scholar

Figures

Abstract

Background

Materials and methods

Results

Conclusions

Introduction

Materials and methods

Patients

Treatment and follow-up

Statistical analysis

Results

Patient characteristics

Failure patterns

Survival outcomes

Multivariate analysis

Discussion

Conclusions

Supporting information

S1 Table. Baseline characteristics of the T1N1M0 and T2N1M0 subgroups.

S2 Table. Comparison of events incidence in the RT, CCRT, IC + CCRT, and CCRT + AC groups.

S3 Table. Survival outcomes of patients in the RT and RT-chemo groups.

S4 Table. Multivariable analyses of prognostic factors for all treatment outcomes.

S1 Fig. Kaplan–Meier survival curves for the RT and RT-chemo groups.

S2 Fig. Kaplan–Meier survival curves for the RT, CCRT, IC + CCRT, and CCRT + AC groups.

References

S1 Table. Baseline characteristics of the T₁N₁M₀ and T₂N₁M₀ subgroups.