Concurrent chemoradiotherapy plus anlotinib vs. concurrent chemoradiotherapy alone in locally advanced nasopharyngeal carcinoma: An interim analysis of a multicenter randomized controlled trial
- Authors:
- Published online on: July 27, 2023 https://doi.org/10.3892/ol.2023.13978
- Article Number: 392
-
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Nasopharyngeal carcinoma (NPC) is one of the most common types of cancer in Southeast Asia and is particularly observed in Southern China, including Guangxi Zhuang Autonomous Region (1,2). NPC had an incidence of >20 cases per 100,000 individuals and a mortality risk of 6 cases per 100,000 individuals in Southern China between 2004 and 2005 (2). At initial diagnosis, >80% of patients present with locoregionally advanced NPC (LA-NPC) (3). Despite use of intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy (CCRT), treatment of LA-NPC is not satisfactory, with a 5-year survival rate of 80% (4). The latest phase 3 trial suggests that application of gemcitabine combined with cisplatin induction therapy before chemoradiotherapy significantly extends recurrence-free and overall survival of patients with LA-NPC; however, 15.3% of patients develop local recurrence and 9.5% experience distant metastasis, which are primary reasons for treatment failure in these patients (5). The addition of targeted therapy to CCRT increases local control rate and decreases occurrence of distant metastasis (6,7).
Anlotinib is a small-molecule, multi-tyrosine kinase inhibitor targeting tumor angiogenesis and proliferation (8); it may inhibit vascular endothelial growth factor receptor (VEGFR), fibroblast and platelet-derived growth factor receptor, epidermal growth factor receptor (EGFR) and kinases (8,9). Anlotinib was approved by the National Medical Products Administration as a third-line treatment for advanced non-squamous non-small cell lung cancer without a driver gene and small cell lung cancer and as a second-line treatment for soft tissue sarcoma and locally advanced or metastatic medullary thyroid carcinoma (8,10–12).
EGFR and VEGFR are highly expressed in 60–80% of patients with LA-NPC and this is associated with poor prognosis (13,14). This suggests potential effectiveness of anlotinib against LA-NPC. An interim analysis of a phase 2 trial shows promising efficacy of anlotinib as a third-line or further treatment for advanced NPC (trial no. NCT03906058) (15). Nevertheless, the role of CCRT + anlotinib for LA-NPC is still uncertain. Therefore, the present study aimed to assess the effect of CCRT + anlotinib in patients with LA-NPC.
Materials and methods
Study design
To assess the safety and effectiveness of CCRT + anlotinib vs. CCRT alone in patients with LA-NPC (www.chictr.org.cn; Chinese Clinical Trial Registry identifier: ChiCTR1900022969), patients were recruited from four tertiary hospitals in Guangxi, China between July 1, 2019, and February 20, 2021. The four hospitals were Guiping People's Hospital, The First People's Hospital of Nanning, The People's Hospital of Guangxi Zhuang Autonomous Region and The First Affiliated Hospital of Guangxi Medical University. The present study was approved by the Ethics Committees of these four hospitals.
Participants
Eligible patients were aged 18–70 years with newly treated stage III–IVA NPC, as diagnosed according to the 8th Union for International Cancer Control and American Joint Committee on Cancer (16), with histologically confirmed non-keratinization. Other inclusion criteria included Karnofsky performance status (KPS) score ≥70 and adequate bone marrow (white blood cell count >4.0×109/l; absolute neutrophil count >2.0×109/l; hemoglobin >90 g/l; platelet count >100×109/l), renal and hepatic function (creatinine clearance rate >60 ml/min; urinary protein <2+; serum total bilirubin ≤1.5×ULN; aspartate aminotransferase ≤2.5×ULN; alanine aminotransferase ≤2.5×ULN; seralbumin >28 g/l). The exclusion criteria included previous malignancy, previous antitumor treatment of NPC, contraindication to magnetic resonance imaging (MRI), pregnancy or lactation, severe bleeding tendency or any severe coexisting disease. Patients aged ≥70 years were not included since elderly patients are generally less tolerant of adverse events (17). In addition to complete patient history and physical exam, routine pretreatment assessments also included hematology (key items include white blood cell count, absolute neutrophil count, hemoglobin and platelet count) and biochemistry analyses (key items include creatinine clearance rate, urinary protein, serum total bilirubin, aspartate aminotransferase, alanine aminotransferase, seralbumin and fasting blood glucose), as well as NP fiber-optic endoscopy, histopathological diagnosis, chest and abdomen computed tomography (CT) scan, nasopharynx and neck enhanced MRI and skeletal scintigraphy. Written informed consent to participate was obtained from all patients included in the study.
Randomization and masking
Randomization was performed (via sealed envelopes) centrally at Guiping People's Hospital (Guiping, China). Patients were randomized to the CCRT + anlotinib or the CCRT alone cohort. The random allocation of the treatment was not concealed.
Treatment procedure
The present study compared CCRT plus anlotinib with CCRT alone. All patients received radical IMRT at a cumulative dose of ≥70 Gy to the primary tumor at 2.12–2.27 Gy/fraction with five daily fractions/week for 6–7 weeks, 66–70 Gy to associated areas of the neck, 60 Gy to high-risk subclinical areas and 54 Gy to low-risk subclinical areas. MRI fusion with treatment planning CT images was proposed to determine total tumor volume, including the primary tumor and metastatic lymph nodes. High-risk clinical target tumor volume was defined as the total nasopharynx tumor volume with a 5–10 mm margin (2–3 mm posteriorly if contiguous to the brainstem or spinal cord) encompassing the entire nasopharynx and high-risk areas of microscopic extension. Low-risk clinical target tumor volume was defined as high-risk clinical target tumor volume with 5–10 mm margin (2–3 mm posteriorly if contiguous to the brainstem or spinal cord) encompassing the low-risk areas of microscopic extension, including retropharyngeal nodal regions, skull base, clivus, sphenoid sinus, parapharyngeal space, pterygoid fossae, posterior third of the nasal cavity or maxillary sinuses including the pterygopalatine fossae and level II–V lymph node regions. The level IB nodal region was radiated in the case of any nodal involvement at this level. The ipsilateral level IB nodal region should be covered if there is gross involvement of the ipsilateral submandibular gland, anterior half of the nasal cavity, oral cavity or ipsilateral level IIA lymph nodes with extra-capsular extension or maximum nodal axial diameter >2 cm (18).
All patients received intravenous cisplatin (100 mg/m2) on day 1 of every cycle of 3 weeks, with three cycles in total. Oral anlotinib (12 mg/day) was administrated to patients in the CCRT + anlotinib cohort on days 1–14 of every cycle of 3 weeks, with three cycles in total. Both cisplatin and anlotinib were administered concurrently with radiotherapy.
Treatment response rates were evaluated using Response Evaluation Criteria in Solid Tumors (version 1.1) (19) through physical examination, nasopharyngoscopy and head and neck MRI at 1 week and 3 and 6 months post-radiotherapy. Patients were evaluated at least once every 3 months for 2 years post-radiotherapy and every 6 months thereafter. The nasopharynx and neck MRI, chest CT scan and abdominal sonography were conducted every 3 months for the first 2 years post-radiotherapy and every 6 months thereafter. Biopsy was conducted when tumor relapse was suspected. Acute toxic effects were assessed weekly during treatment and graded according to the Common Terminology Criteria for Adverse Events (version 5.0) (20).
Statistical analysis
Statistical analysis was performed using SPSS 26.0 software (IBM Corp.). All categorical variables are reported as numbers with percentages. Continuous variables are expressed as median and range. P-values were calculated using χ2 test or Fisher's exact test for categorical variables. P<0.05 was considered to indicate a statistically significant difference.
Results
Patient characteristics
From July 2019 to February 2021, 73 patients with LA-NPC randomly received CCRT + anlotinib (n=36) or CCRT alone (n=37) (Fig. 1). The baseline characteristics of patients were well balanced between the two treatment cohorts (Table I).
All patients in both treatment arms completed the scheduled dose of radiotherapy. However, one patient from the CCRT + anlotinib arm withdrew from treatment after 3 weeks. In the CCRT + anlotinib cohort, 24 patients (66.7%) achieved three cisplatin treatment cycles as planned, but 12 (33.3%) did not achieve this therapy target. A total of eight patients and four patients reached two and one cycle, respectively; four patients were unwilling to continue chemotherapy and eight patients experienced adverse events. A total of 32 patients (88.9%) achieved three concurrent anlotinib treatment cycles; four patients (11.1%) did not achieve three anlotinib treatment cycles (three and one patient reached two cycles and one cycle, respectively; three patients were unwilling to continue anlotinib treatment and one patient had experienced adverse events). In the CCRT cohort, 27 patients (73.0%) achieved three concurrent cisplatin treatment cycles; ten patients (27.0%) did not reach the planned therapy target (nine and one patient reached two cycles and one cycle, respectively; two patients were unwilling to continue chemotherapy and eight experienced adverse events). Treatment procedures and outcomes are shown in Fig. 1.
Therapeutic effects
Treatment responses were evaluated for eligible patients (Table II). The complete response (CR) rate in the CCRT + anlotinib group 1 week post-radiotherapy was 81.1% compared 60.0% in the CCRT group. However, this difference was not significant (P=0.10). At 3 months post-radiotherapy, the CR rates in the CCRT + anlotinib cohort and in the CCRT cohort were 91.4 and 81.1%, respectively, without significant difference (P=0.35). CR rates increased to 97.1 and 91.9%, respectively, at 6-month follow-up; however, the difference was not significant (P=0.65). Furthermore, no significant differences were found between groups at 3 months post-radiotherapy for nasopharyngeal (P=0.50) and neck lymph node lesions (P=0.77).
With a median follow-up of 13.6 months (range 6.1–26.2 months), 2 (5.5%) and 4 (10.8%) of patients in the CCRT + anlotinib cohort and CCRT alone cohort, respectively, experienced tumor progression. In the CCRT + anlotinib cohort, one patient developed bone metastasis at 7.6 months and another developed liver metastasis 6 months after randomization. In the CCRT cohort, one patient experienced lung metastasis at 5.1 months, while two patients experienced liver metastasis and another patient developed bone metastasis at 10.7, 11.0 and 12.3 months, respectively, after randomization.
Adverse reactions
The acute toxicity during treatment is shown in Table III. Grade 3/4 mucositis and myelosuppression, particularly leucopenia, were the most common severe toxicities. In the CCRT + anlotinib cohort, the incidence of grade 3/4 mucositis and leucopenia were 36.1 and 27.7%, respectively, compared with incidence rates of 29.7 and 21.6% in the CCRT arm (P=0.56 and P=0.54, respectively). A total of five patients displayed grade 3 hypertension during treatment, one developed grade 3 hepatotoxicity due to a hepatitis B flare up, one reported grade 4 nephrotoxicity after three cycles of concurrent cisplatin and required short-term dialysis therapy and two reported hemorrhage (grade 1 or 2). No patient presented with grade 3/4 hemorrhage or adverse event-associated death.
Discussion
The present interim analysis reports on an ongoing multicenter randomized controlled trial comparing CCRT + anlotinib with CCRT alone in patients with LA-NPC. The primary objective was to define the toxicity and compliance of chemoradiotherapy + anlotinib in LA-NPC. The results revealed that concurrent administration of chemoradiation + anlotinib had acceptable toxicity profiles, good compliance and encouraging efficacy.
EGFR and VEGFR are highly expressed and associated with increased therapeutic tolerance and poor prognosis in patients with nasopharyngeal carcinoma (21–24). EGFR- and VEGFR-blocking drugs may offer a potential treatment for LA-NPC.
Studies have confirmed that anti-EGFR antibodies, such as cetuximab, nimotuzumab and endostar, plus CCRT for patients with LA-NPC is well tolerated and safe (25–27). To the best of our knowledge, however, most studies have shown no survival benefit (26,28,29). Xu et al (30) performed a contrasting study of induction chemotherapy followed by concomitant cisplatin-chemoradiotherapy (CRT) or cetuximab-radiotherapy (ERT). ERT was not superior to CRT. The three-year disease-free survival rates of CRT and ERT were 78.3 and 85.7%, respectively (P=0.547), and ERT was more likely to cause acute adverse events. In a phase 2 trial by Huang et al (7), chemoradiation + nimotuzumab was well-tolerated, grade 3/4 serious toxicity was observed in 14 of 23 (60.9%) patients, while grade 3/4 oral mucositis was recorded in 8 (34.8%) patients; CR rates of nasopharynx and regional nodal involvement were 91.3 and 95.5%, respectively; 2-year progression-free and overall survival reached 83.5 and 95.0%, respectively. However, the aforementioned study did not establish a control cohort. By contrast, a study by Kang et al (31) demonstrated that the efficacy of radiotherapy + endostar is comparable to radiotherapy + chemotherapy in LA-NPC but acute adverse reactions are milder.
Several retrospective studies have explored the effect of cetuximab or nimotuzumab in LA-NPC: Li et al (28) reported that patients with stage II–IV NPC receive no additional benefit from cetuximab + CCRT, with similar 3-year progression-free, local relapse-free, distant metastasis-free survival (DMFS) and overall survival but resulted in more severe acute mucositis and acneiform rash. Similar results were achieved in a retrospective study by You et al (32), where cetuximab/nimotuzumab + IMRT produced similar disease-free, locoregional recurrence-free and overall survival and DMFS compared with CCRT. Skin reaction and mucositis appeared more frequently in the cetuximab/nimotuzumab cohort.
The additional benefit of combined EGFR-blocking drugs + CCRT for LA-NPC treatment remains controversial. The aforementioned studies did not report positive results, which may be due to small sample size with low statistical power or EGFR-blocking drugs combined with radiotherapy instead of CCRT. For studies where EGFR-blocking drugs were combined with CCRT, the inclusion of low-risk stage II patients may be a possible cause of failure.
Cai et al (15) reported that the disease control rate of anlotinib as a third-line or further treatment for advanced NPC is 76.5% (trial no. NCT03906058). In the present study, anlotinib was combined with CCRT for stage III–IVA NPC. Only one patient discontinued CCRT + anlotinib after one treatment cycle. A total of 66.7% of patients in the CCRT + anlotinib cohort achieved the planned three cycles of cisplatin treatment, compared with 73.0% of the CCRT cohort. The total dose of cisplatin in the CCRT alone cohort was similar to those in previous studies (28,30–32). The most common causes of interruption of concurrent cisplatin were grade 3/4 treatment toxicity and patient refusal. Anlotinib was also well-tolerated, with 91.7% of patients completing three cycles of concurrent anlotinib therapy. The present data revealed a slight increase in CR rate after anlotinib therapy, but this increase was not significant. These preliminary results suggested non-inferiority of CCRT + anlotinib compared with CCRT alone in terms of CR rates. Nevertheless, long-term follow-up is required to determine the long-term effects of anlotinib on survival. The common acute adverse events during treatment were leucopenia, neutropenia, anemia, thrombocytopenia, dermatitis, mucositis and vomiting. The major grade 3/4 hematological events in the CCRT + anlotinib group were mucositis (36.1%), leucopenia (27.7%) and neutropenia (16.7%), which were manageable by using drugs for symptomatic treatment. Grade 3/4 hypertension was observed in 5 patients in the CCRT + anlotinib group, whereas no grade 3/4 hypertension occurred in the CCRT group. The incidence of grade 3/4 hypertension (13.9%) was consistent with that reported by ALTER 0303 Trial (13.6%), a phase 3 trial confirming the efficacy of anlotinib treatment for advanced non-small cell lung cancer (11). No patient presented with grade 3/4 hemorrhage or adverse event-related death. The incidences of grade 3/4 neutropenia, anemia and thrombocytopenia were higher than those in similar treatment cohorts reported in a previous study by Zhang et al (5) (13.5 vs. 10.5, 16.7 vs. 0.8, 5.4 vs. 1.3%, respectively), which may be due to a higher number of enrolled patients aged >45 years in the present study.
The present study has limitations. Firstly, the small sample size may lead to underpowered statistics and potential selection bias. Secondly, the present study only collected short-term follow-up data to assess therapy efficacy and acute toxicity. Hence, a follow-up period of ≥5 years is required to observe other treatment-associated events and evaluate the therapeutic impact and late toxic effects of CCRT + anlotinib in LA-NPC. Thirdly, some patients ceased treatment or were lost to follow-up. Furthermore, the latest phase 3 trial (5) suggests that induction chemotherapy with gemcitabine + cisplatin added to CCRT significantly improves recurrence-free and overall survival of patients with high-risk LA-NPC, which made induction chemotherapy with gemcitabine + cisplatin followed by CCRT a standard treatment regimen for LA-NPC. The present study was initiated earlier than the publication of the phase 3 trial above, so induction chemotherapy with gemcitabine + cisplatin was not performed in this study. However, to the best of our knowledge, the present study is the first to assess the effectiveness and toxicity of CCRT + anlotinib in LA-NPC.
In conclusion, concurrent anlotinib has acceptable toxicity profiles, good compliance and encouraging efficacy with a favorable CR rate in patients with LA-NPC. However, further studies with larger cohorts, long-term follow-up and new induction regimens are required to confirm the clinical value of CCRT + anlotinib.
Acknowledgements
Not applicable.
Funding
The present study was supported by the Department of Health of Guangxi Zhuang Autonomous Region Self-Raised Funds Project (grant no. Z20190097), Scientific Research Projects funded by Guangxi Health Department (grant no. Z20200024), and Nanning Qingxiu District Science and Technology Plan Project (Key R&D Project grant no. 2019042).
Availability of data and materials
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
KC, GX, YL, PL, WG, ZL, WL, ZT, JC, XH and YX contributed to the study conception and design. KC, GX, YL, PL and WG analyzed data. KC and GX wrote the manuscript. All authors have read and approved the final manuscript. KC and YX confirm the authenticity of all the raw data.
Ethics approval and consent to participate
The present study was performed in line with the principles of the Declaration of Helsinki. Approval (no. 2019-001) was granted by the Ethics Committee of Guiping People's Hospital (Guiping, China), The First People's Hospital of Nanning (Nanning, China), The People's Hospital of Guangxi Zhuang Autonomous Region (Nanning, China) and The First Affiliated Hospital of Guangxi Medical University (Nanning, China). Written informed consent to participate was obtained from all participants included in the study.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Xia C, Yu XQ, Zheng R, Zhang S, Zeng H, Wang J, Liao Y, Zou X, Zuo T, Yang Z and Chen W: Spatial and temporal patterns of nasopharyngeal carcinoma mortality in China, 1973–2005. Cancer Lett. 401:33–38. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Chen L, Hu CS, Chen XZ, Hu GQ, Cheng ZB, Sun Y, Li WX, Chen YY, Xie FY, Liang SB, et al: Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicentre randomised controlled trial. Eur J Cancer. 75:150–158. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Y, Chen L, Hu GQ, Zhang N, Zhu XD, Yang KY, Jin F, Shi M, Chen YP, Hu WH, et al: Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma. N Engl J Med. 381:1124–1135. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
O'Sullivan B: Nasopharynx cancer: Therapeutic value of chemoradiotherapy. Int J Radiat Oncol Biol Phys. 69 (Suppl 2):S118–S121. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Huang JF, Zhang FZ, Zou QZ, Zhou LY, Yang B, Chu JJ, Yu JH, Zhang HW, Yuan XP, Tai GM, et al: Induction chemotherapy followed by concurrent chemoradiation and nimotuzumab for locoregionally advanced nasopharyngeal carcinoma: Preliminary results from a phase II clinical trial. Oncotarget. 8:2457–2465. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Sun Y, Niu W, Du F, Du C, Li S, Wang J, Li L, Wang F, Hao Y, Li C and Chi Y: Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol. 9:1052016. View Article : Google Scholar : PubMed/NCBI | |
|
Taurin S, Yang CH, Reyes M, Cho S, Coombs DM, Jarboe EA, Werner TL, Peterson CM and Janát-Amsbury MM: Endometrial cancers harboring mutated fibroblast growth factor receptor 2 protein are successfully treated with a new small tyrosine kinase inhibitor in an orthotopic mouse model. Int J Gynecol Cancer. 28:152–160. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Li D, Chi Y, Chen X, Ge M, Zhang Y, Guo Z, Wang J, Chen J, Zhang J, Cheng Y, et al: Anlotinib in locally advanced or metastatic medullary thyroid carcinoma: A randomized, double-blind phase IIB trial. Clin Cancer Res. 27:3567–3575. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Han B, Li K, Wang Q, Zhang L, Shi J, Wang Z, Cheng Y, He J, Shi Y, Zhao Y, et al: Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: The ALTER 0303 Phase 3 randomized clinical trial. JAMA Oncol. 4:1569–1575. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Cheng Y, Wang Q, Li K, Shi J, Liu Y, Wu L, Han B, Chen G, He J, Wang J, et al: Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: A randomised, double-blind, placebo-controlled Phase 2 study. Br J Cancer. 125:366–371. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Ma BB, Poon TC, To KF, Zee B, Mo FK, Chan CM, Ho S, Teo PM, Johnson PJ and Chan AT: Prognostic significance of tumor angiogenesis, Ki 67, p53 oncoprotein, epidermal growth factor receptor and HER2 receptor protein expression in undifferentiated nasopharyngeal carcinoma-a prospective study. Head Neck. 25:864–872. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Lu Y, Chen D, Liang J, Gao J, Luo Z, Wang R, Liu W, Huang C, Ning X, Liu M and Huang H: Administration of nimotuzumab combined with cisplatin plus 5-fluorouracil as induction therapy improves treatment response and tolerance in patients with locally advanced nasopharyngeal carcinoma receiving concurrent radiochemotherapy: A multicenter randomized controlled study. BMC Cancer. 19:12622019. View Article : Google Scholar : PubMed/NCBI | |
|
Cai Q, Su N, Fang Y, Zou Q, Xia Y, Ma S, Cai J, Liu P, Wang J and Zhang Y: Anlotinib for patients with recurrent or metastatic nasopharyngeal carcinoma: A phase II study. J Clin Oncol. 40 (Suppl 16):e180202022. View Article : Google Scholar | |
|
Rice TW, Patil DT and Blackstone EH: 8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: Application to clinical practice. Ann Cardiothorac Surg. 6:119–130. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Xu TT, Hu CS and LiI BS: Clinical consensus on the treatment of locally advanced squamous cell carcinoma of the head and neck with anti-EGFR monoclonal antibody (2023 edition). China Oncology. 33:81–94. 2023. | |
|
Lee AW, Ng WT, Pan JJ, Poh SS, Ahn YC, Alhussain H, Corry J, Grau C, Grégoire V, Harrington KJ, et al: International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma. Radiother Oncol. 126:25–36. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
US Department of Health and Human Services, . National Institutes of Health, National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Published:. November 27–2017. | |
|
Li HP, Huang CY, Lui KW, Chao YK, Yeh CN, Lee LY, Huang Y, Lin TL, Kuo YC, Huang MY, et al: Combination of epithelial growth factor receptor blockers and CDK4/6 inhibitor for nasopharyngeal carcinoma treatment. Cancers (Basel). 13:29542021. View Article : Google Scholar : PubMed/NCBI | |
|
Luo Y, Wang J, Wang F, Liu X, Lu J, Yu X, Ma X, Peng X and Li X: Foxq1 promotes metastasis of nasopharyngeal carcinoma by inducing vasculogenic mimicry via the EGFR signaling pathway. Cell Death Dis. 12:4112021. View Article : Google Scholar : PubMed/NCBI | |
|
Wakisaka N, Hirota K, Kondo S, Sawada-Kitamura S, Endo K, Murono S and Yoshizaki T: Induction of lymphangiogenesis through vascular endothelial growth factor-C/vascular endothelial growth factor receptor 3 axis and its correlation with lymph node metastasis in nasopharyngeal carcinoma. Oral Oncol. 48:703–708. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Peng QX, Han YW, Zhang YL, Hu J, Fan J, Fu SZ, Xu S and Wan Q: Apatinib inhibits VEGFR-2 and angiogenesis in an in vivo murine model of nasopharyngeal carcinoma. Oncotarget. 8:52813–52822. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
You R, Hua YJ, Liu YP, Yang Q, Zhang YN, Li JB, Li CF, Zou X, Yu T, Cao JY, et al: Concurrent chemoradiotherapy with or without Anti-EGFR-Targeted treatment for Stage II–IVb nasopharyngeal carcinoma: Retrospective analysis with a large cohort and long follow-up. Theranostics. 7:2314–2324. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Lin M, You R, Liu YP, Zhang YN, Zhang HJ, Zou X, Yang Q, Li CF, Hua YJ, Yu T, et al: Beneficial effects of anti-EGFR agents, Cetuximab Or Nimotuzumab, in combination with concurrent chemoradiotherapy in advanced nasopharyngeal carcinoma. Oral Oncol. 80:1–8. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Yin Y, Zhou Z, Li Z, Shen M, Qin Y, Yang C, Wang R and Kang M: Efficacy of concurrent chemoradiotherapy plus Endostar compared with concurrent chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma: A retrospective study. Radiat Oncol. 17:1352022. View Article : Google Scholar : PubMed/NCBI | |
|
Li Y, Chen QY, Tang LQ, Liu LT, Guo SS, Guo L, Mo HY, Chen MY, Guo X, Cao KJ, et al: Concurrent chemoradiotherapy with or without cetuximab for stage II to IVb nasopharyngeal carcinoma: A case-control study. BMC Cancer. 17:5672017. View Article : Google Scholar : PubMed/NCBI | |
|
Wang N, Wang K, Song F and Liu Y: Cetuximab in combination with chemoradiotherapy for nasopharyngeal carcinoma: A meta-analysis. Indian J Cancer. 55:196–200. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Xu T, Liu Y, Dou S, Li F, Guan X and Zhu G: Weekly cetuximab concurrent with IMRT aggravated radiation-induced oral mucositis in locally advanced nasopharyngeal carcinoma: Results of a randomized phase II study. Oral Oncol. 51:875–879. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Kang M, Wang F, Liao X, Zhou P and Wang R: Intensity-modulated radiotherapy combined with endostar has similar efficacy but weaker acute adverse reactions than IMRT combined with chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma. Medicine (Baltimore). 97:e111182018. View Article : Google Scholar : PubMed/NCBI | |
|
You R, Sun R, Hua YJ, Li CF, Li JB, Zou X, Yang Q, Liu YP, Zhang YN, Yu T, et al: Cetuximab or nimotuzumab plus intensity-modulated radiotherapy versus cisplatin plus intensity-modulated radiotherapy for stage II–IVb nasopharyngeal carcinoma. Int J Cancer. 141:1265–1276. 2017. View Article : Google Scholar : PubMed/NCBI |
