Phase 2 Clinical Trial of Simultaneous Boost Intensity Modulated Radiation Therapy With 3 Dose Gradients in Patients With Stage I-II Nasal Type Natural Killer/T-Cell Lymphoma: Long-Term Outcomes of Survival and Quality of Life

AbbreviationsASTROAmerican Society for Radiation OncologyALPAlkaline phosphataseALTAlanine aminotransferase,ASTAspartate aminotransferaseCIConformity indexCRComplete remissionCRFCase Report FormCTComputed tomographyCTVClinical target volumeDMDistant metastasisEBVEpstein-Barr virusECOGEastern Cooperative Oncology GroupEIS-IMRTExpanded involved-site IMRTENKTLExtranodal natural killer/T-cell lymphomaGCPGood Clinical PracticeGTVGross tumor volumeHIHomogeneity indexiChTInduction chemotherapyILROGInternational Lymphoma Radiation Oncology GroupLCRLocal control ratesLDHLactate dehydrogenaseLNLymph nodesLRFSLocal-regional recurrence-free survivalLRRLocal-regional recurrenceMRIMagnetic resonance imagingNC-NKTLNasal cavity natural killer/T-cell lymphomaNHLNon-Hodgkin lymphomaNKTLnatural killer/T-cell lymphomaOARsOrgans at riskOSOverall survivalPET/CTPositron emission tomography/computed tomographyPFSProgression-free survivalPINKPrognostic index of natural killer lymphomaPRPartial remissionPTIPrimary tumor invasionPTVPlanning target volumeQOLQuality of lifeRTRadiation therapySAEsSerious adverse eventsSDStable diseaseSIB-IMRTSimultaneous-boost intensity modulated radiotherapyUADTUpper aerodigestive tractULNUpper limit of normalWR-NKTLWaldeyer's ring natural killer/T-cell lymphoma3D-CRTThree-dimensional conformal radiotherapy American Society for Radiation Oncology Alkaline phosphatase Alanine aminotransferase, Aspartate aminotransferase Conformity index Complete remission Case Report Form Computed tomography Clinical target volume Distant metastasis Epstein-Barr virus Eastern Cooperative Oncology Group Expanded involved-site IMRT Extranodal natural killer/T-cell lymphoma Good Clinical Practice Gross tumor volume Homogeneity index Induction chemotherapy International Lymphoma Radiation Oncology Group Local control rates Lactate dehydrogenase Lymph nodes Local-regional recurrence-free survival Local-regional recurrence Magnetic resonance imaging Nasal cavity natural killer/T-cell lymphoma Non-Hodgkin lymphoma natural killer/T-cell lymphoma Organs at risk Overall survival Positron emission tomography/computed tomography Progression-free survival Prognostic index of natural killer lymphoma Partial remission Primary tumor invasion Planning target volume Quality of life Radiation therapy Serious adverse events Stable disease Simultaneous-boost intensity modulated radiotherapy Upper aerodigestive tract Upper limit of normal Waldeyer's ring natural killer/T-cell lymphoma Three-dimensional conformal radiotherapy Extranodal natural killer/T-cell lymphoma (ENKTL), nasal-type, is a distinct subtype of non-Hodgkin lymphoma (NHL) with unique clinicopathological characteristics [1, 2]. It is more prevalent in Asian and Latin American but rare in European and North American populations [3]. The most frequent primary site was located in the upper aerodigestive tract (UADT), especially the nasal cavity and Waldeyer's ring, with early stage disease in 70%-80% of patients at diagnosis. The pathological mechanism of ENKTL is related to Epstein-Barr virus (EBV) infection, and EBV DNA copy in peripheral blood is an important prognostic indicator [4] . SCHEMA Lymphoma Histology: natural killer/T-cell lymphoma (NKTL). Curative radiation therapy (RT) is the most important treatment for patients with early stage ENKTCL [5]. Based on the results of previous studies, radiotherapy has better outcomes than chemotherapy with reduced locoregional failure, and it was considered to be first-line therapy [6]. Hence, the appropriate target volumes delineation and dose setting can be vital to the locoregional radiotherapeutic effect, to an overall successful treatment as well, and also to an optimal post-treatment quality of life (QOL). RT is the primary treatment for patients with early stage ENKTL [7]. Clinical studies have shown that the radiotherapy dose for cure of ENKTL lesions should not be less than 50Gy, while less than 45Gy is associated with increased local recurrence rate, and it is reasonable to give a boost to the initial tumor [7-9]. The failure pattern after RT was mainly local-regional lymph nodes recurrence (LRR), and the proportion of LRR was mostly more than 30% [9]. The high rate of LRR may be related to unreasonable range of radiotherapy target and/or prescription dose. Although target delineation and dose setting have been described in previous studies, specific details of target setting have not been elaborated. Therefore, the appropriate target volumes delineation and dose setting can be vital to the locoregional radiotherapeutic effect, to an overall successful treatment as well, and also to an optimal post-treatment quality of life (QOL). The clinical characteristics of ENKTL are extensive primary tumor invasion (PTI) and destruction, often accompanied by local necrosis, mixed with obstructive paranasal sinusitis, and easy to spread along the mucosa or submucosa without obvious tumor formation[10]. From December 1990 to December 2011, 209 nasal cavity NKTL patients who were initially treated in our center, 147 patients (70.3%) had PTI, including maxillary sinus, nasal dorsalis, nasal vestibule, nasopharynx and orbit. PTI was also an important prognostic indicator for ENKTL patients. This suggests that a high dose of high-risk clinical target should be given around the primary lesion, including the surrounding vulnerable structures, to reduce the risk of local recurrence. Li et al. summarized the clinical data of 214 stage I and stage II NC-NKTCL patients, only 4 patients (1.9%) presented regional lymph node failure [11]. Therefore, prophylactic irradiation to cervical lymph node was not recommended. With the rapid development of radiation technology, IMRT has been widely used in clinical work with the advantages in dose uniformity and target volume coverage, as well as the protection of organs at risk (OARs) [12, 13]. Based on the technical support of our cancer center, RT of all patients enrolled was delivered using IMRT. Some studies have been published on the target volumes and/or prescribed radiotherapy dose, however, consensus detailed description of target volumes delineation and dose setting had never been documented. Our research group performed this prospective phase II clinical trial of SIB-IMRT with three dose gradients for treating patients with early stage ENKTL arising from nasal cavity (NC-NKTCL) and Waldeyer's ring (WR-NKTCL). In this study, SIB-IMRT scheme was uniformly adopted, with 54.6Gy for primary tumor (GTVt) and positive lymph nodes (GTVnd), 50.7Gy for high-risk clinical target volume (CTV1), and 45.5Gy for low-risk clinical target volume (CTV2), all delivered in 26 daily fractions.This paper was to provide the panoramic view of the study with long-term outcome of survival, pattern of failure, and quality of life. The primary end point is Overall survival (OS), which is defined as the time from initial treatment to death from any cause. Progression-free survival (PFS): PFS is defined as the interval between initial treatment and distant metastasis, loco-regional failure, or death from any cause, which ever happened first. Loco-regional relapse-free survival (LRFS): LRFS is defined as the interval from initial treatment to the first local or regional recurrence, or death from any cause. Note: If both distant metastasis and loco-regional recurrence occur simultaneously, patients are considered as having an event for both PFS and LRFS. Safety includes the incidence of acute toxicity (either hematological or non-hematological) during radiotherapy or within the first three months following its completion. The Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, will be used for grading of toxic effects Late radiation toxicities will be assessed when appearing three months to three years post-radiotheapy according to the Radiation Therapy Oncology Group (RTOG) and European Organisation for Research and Treatment of Cancer (EORTC) late radiation morbidity scoring scheme, including skin, neck tissue damage, hypothyroidism, dry mouth, dysphagia, trismus, and other adverse events. Health-related quality of life is measured through paper-based questionnaires using the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3.0. Assessments will be considered complete only if all the questions were answered. aPatients with newly histologically confirmed (ENKTL), nasal-type (according to WHO classification of tumors of hematopoietic and lymphoid tissues). The pathologic features included angiocentric necrosis and polymorphism of individual cells, and tumor cells expressed NK or T-cell markers, including positive CD2, CD3ε, cytotoxic granule proteins (TIA-1, Granzyme-B, and perforin), and CD56 immunohistochemistry, and positive EBV encoded small RNAs (EBERs) in situ hybridization, and negative expressions of B-cell markers such as CD20 and CD79α.bAge between 13 and 75 years old.cPrimary tumor located in nasal cavity (NC) or Waldeyer's ring (WR), and staged as I-II (according to the Ann Arbor Staging System).dNo evidence of distant metastasis (M0).eSatisfactory performance status: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.fThe iChT effects were complete remission (CR), partial remission (PR) and stable disease (SD)gAdequate bone marrow: leucocyte count > 4 × 109 /L, neutrophil count > 2 × 109 /L, hemoglobin > 130 g/L for males, > 120 g/L for females, and platelet count > 100 × 109 /L.hNormal liver function tests: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) < 1.5 × the upper limit of normal (ULN) concomitant with alkaline phosphatase (ALP) < 2.5 × ULN, and bilirubin < ULN.iAdequate renal function: creatinine clearance ≥ 60 ml/min.jPatients must be informed of the investigational nature of this study and give written informed consent. aa Magnetic resonance imaging (MRI) or enhanced computed tomography (CT) of the nasopharynx and the neck.bb Whole body CT scan and/or pretreatment positron emission tomography/computed tomography (PET/CT) .cc Bone marrow aspiration and/or biopsy. aAge > 75 or < 13.bPrior history of other malignancies.cPregnancy or lactation (consider a pregnancy test in women of child-bearing age and emphasize effective contraception during the treatment period).dPrior chemotherapy or surgery (except diagnostic) for primary tumors or nodes.eAny severe intercurrent disease, which might bring unacceptable risk or affect the compliance of the trial, for example, unstable cardiac disease requiring treatment, renal disease, chronic hepatitis, diabetes with poor control (fasting plasma glucose > 1.5 × ULN), and emotional disturbance. aDisease progression.bUnacceptable toxic effects. The reason(s) must be recorded.cTreatment delayed continuously more than 3 weeks, whatever the reason for 14 treatment delay.dPatients suffering from an intercurrent disease or having other conditions that significantly affect the assessment of clinical status or necessitate discontinuation of the drug, or both.ePoor compliance to drugs or clinical observation, or receipt other anti-tumor treatment.fA patient might withdraw from the study at any point for any reason. RT of all the patients was delivered using 6- or 8-MV photon beams of modern linear accelerators. Patients were immobilized in a supine position with a perforated thermoplastic head mask, and then followed by 3-mm slice-thickness CT scan from the vertex of the skull to the inferior of the clavicular heads. It has to be noted that a 5mm bolus and a customized bite-block were routinely applied to compensate the defect of dose distribution in nasal skin and minimize radiation dose to tongue. Treatment planning was calculated using the Eclipse® (Varian Medical Systems, Inc., Palo Alto, CA, USA) or Monaco® (Elekta AB, Stockholm, Sweden) systems. The unified SIB-IMRT dose setting with three dose gradients was as follows: 54.6 Gy for primary tumor (GTVt) and positive lymph nodes (GTVnd), 50.7 Gy for high-risk clinical target volume (CTV1), and 45.5 Gy for low-risk clinical target volume (CTV2), all delivered in 26 fractions, 5 times each week. A detailed protocol of target volume delineation was established. Delineation of Gross tumor volume (GTVt and GTVnd) was based on the most obvious lesions (primary tumor and involved lymph nodes) on the images before RT (in most patients, the diagnostic image before iChT), including MRI and/or CT of the head and neck, and PET/CT in 40 patients, regardless of tumor remission after iChT. CTV1 was defined as high-risk clinical target volume, including:(1)for NC-NKTCL, the entire nasal mucosa, and front and middle ethmoid sinus; for WR-NKTCL involving nasopharynx, the entire nasopharyngeal cavity, and posterior half of nasal cavity proper.(2)medial half of ipsilateral maxillary sinus if not involved, or whole maxillary sinus if involved;(3)when the primary tumor involved the posterior one third of the nasal cavity, the nasopharyngeal mucosa was included with ipsilateral retropharyngeal lymph nodes (LN);(4)when nasopharynx and/or palatine tonsils or root of tongue was involved, the entire Waldeyer's ring and the parapharyngeal space were included;(5)when ethmoid sinus was involved, the entire ethmoid sinus and part of sphenoid sinus and frontal sinus were included.(6)when orbit involved, 0.5-1.0cm of expansion to para- to retro-eyeball region, and if CR after iChT, vision preservation can be pursued.(7)when palatine involved, adjacent part of alveolus/gingiva was included. Outside of CTV1, CTV2 was defined as low-risk clinical target volume, including the following additional parts besides CTV1:(1)for NC-NKTCL, entire nose, including soft tissue of nasal dorsum, and soft and hard palatine;for WR-NKTCL involving nasopharynx, the entire nasal cavity proper.(2)the whole ipsilateral maxillary sinus when primary tumor limited within unilateral nasal cavity, and the medial half of contralateral maxillary sinus;(3)most or entire para- and retro-eyeball region, when orbit invasion confirmed (including erosions of lamina papyracea);(4)neck lymphatic drainage area did not receive routine prophylactic irradiation, except that: (a) when nasopharynx or retropharyngeal LN were involved, the upper cervical lymphnode (II and III regions) received prophylactic irradiation; (b) when nasal vestibule, nasal dorsum, or the skin around nose were involved, the ipsilateral facial arteriovenous lymphatic drainage area (i.e., IX region), Ib region and the upper cervical lymphnode (II and III regions) received prophylactic irradiation; (c) when upper cervical lymphnode was involved, entire cervical lymph node region should receive prophylactic irradiation. A 3mm isotropic expansion of the CTV was used to create the planning target volume (PTV), while it can be reduced to 1-2mm when PTV near the orbit, optic nerve or skin. Normal tissue dose constraints by structureTabled 1StructureDose constraintsSpinal cord_PRVDmax*<45 GyBrain stem_PRVDmax < 50 GyOptic nerves_PRVDmax < 50 GyOptic chiasm_PRVDmax < 50 GyTemporal lobeDmax < 60 GyLensDmean‡ < 12 GyPituitaryDmax < 60 GyThyroidDmean < 35 GyEyesDmean < 35 GyTemporomandibular JointDmax < 70 GyParotidDmean < 26 GyCochleaDmean < 50 GyLarynxDmean < 45 GyTracheaDmean < 45 GyPRV = planning organ at risk volume.* Maximum point dose to the target volume.† Dose received by 1% of the target volume.‡Mean dose to the target volume. Open table in a new tab PRV = planning organ at risk volume. * Maximum point dose to the target volume. † Dose received by 1% of the target volume. ‡Mean dose to the target volume. Quality assurance of target delineation and dose coverage will be performed by the research team at Sun Yat-sen University Cancer Center. Because the treatment plan implemented by the institute conforms to the current standard principles and indications of treatment, the costs incurred are borne by the patients themselves. Grade 3 or higher non-hematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. Other anti-tumor treatments (such as chemotherapy, biological therapy, anti-tumor traditional Chinese medicine, etc.) should be discontinued during the clinical trial. Symptomatic treatment can be given when adverse reactions occur during treatment. The mid-term analysis will be conducted when 50% of the cases are enrolled. The study will follow up with all cases. Follow-up period: from the start of treatment to tumor recurrence in patients or 5 years after the end of treatment for the last enrolled case. Follow-up frequency: every 3 months at first 2 years after treatment, and then every 6 months until 5 years after treatment. The clinical trial will be conducted from August 2011 to August 2015. 1)Definition. Adverse events are defined as any adverse medical event that occurs after the time the patient is enrolled in the trial until the last follow-up time, regardless of whether it is causally related to the trial. All adverse events during the trial will be recorded truthfully, including the time of occurrence, severity, duration, measures taken, and outcome.2)Criteria of severity of adverse events. It is referred to the NCI CTC 3.0 criteria. For adverse reactions that are not listed in the table, the following categories are recommended: Mild:which does not affect the normal function of the subject; Moderate:which somewhat affects the normal function of the subject; Severe:which significantly affects the normal function of the subject.3)Criteria for judging the relationship between adverse events and the trial plan. The investigator should evaluate the possible relationship between adverse events and the trial plan according to the following criteria. Definitely related. The time of occurrence of the adverse events conforms to the treatment sequence, and the adverse events conforms to the known type of treatment reaction. A definitely related adverse events could be improved after stopping treatment, but reappear after retreatment. Possibly related. The time of occurrence of the adverse events conforms to the treatment sequence, and the adverse events conforms to the known type of treatment reaction. But the patient's clinical status or other treatment methods may also cause the reaction. Possibly unrelated. The time of occurrence of the adverse events does not conform to the treatment sequence, or the adverse events does not quite conform to the known type of treatment reaction. In fact, the patient's clinical status or other treatment methods may also cause the reaction. Unrelated. The time of occurrence of the reaction does not conform to the treatment sequence, and the reaction does not conform to the known type of treatment reaction. The patient's clinical status or other treatment methods may also cause the reaction, the response is eliminated by improving the disease state or stopping other treatment methods, and the reaction reappears when other treatment methods are repeated. Cannot be judged. There is no clear relationship between the time of occurrence of adverse events and the time of medication. Though the reaction is similar to the known reaction type of the trial treatment, other drugs or treatment used simultaneously may also cause the same reaction. Serious Adverse Events (SAEs) are any events that result in death, are life-threatening, require hospitalization or prolongation of existing hospitalization, result in persistent or significant disability or incapacity, or cause a congenital anomaly or birth defect. Any SAE that occurs during the clinical trial or within 30 days of the last treatment, regardless of whether it is related to the treatment or not, should be reported within 24 hours by phone to the project leader, clinical trial sponsor, and ethics committee. Before enrolling patients in the trial, the research physician is responsible for fully and comprehensively explaining the purpose of the study, the performance of the treatment, and the potential toxic side effects and risks. Patients should be informed of their rights, the risks they need to assume, and the benefits. Patients should sign an informed consent form before enrollment, which should be kept in the CRF. A sample informed consent form is attached. This clinical trial must comply with the Helsinki Declaration (2000 edition), the Good Clinical Practice (GCP) guidelines issued by the SFDA, and relevant regulations. Before the trial begins, the study protocol must be approved by the ethics committee of the lead institution. Any modifications to the trial protocol during the clinical trial should be reported to and recorded by the ethics committee. The clinical researchers and clinical sponsors must follow the requirements of the Good Clinical Practice (GCP) guidelines throughout the entire clinical trial process, which ensured the accurate trial data and reliable conclusions. Specific requirements for sponsors and researchers include:(1)Responsible for obtaining signed informed consent from every participant or their agent;(2)Fill out the Case Report Form (CRF) as required;(3)Regularly visit participants;(4)Keep complete records of laboratory tests, clinical records, and participants’ original medical records. The CRF is filled out by the researcher in a timely manner. The CRF should generally not be altered. If there are errors that need to be corrected, they should be signed at the correction site (see CRF instructions). The completed CRF should be submitted to the hospital and sponsor for safekeeping after the trial ends. After the CRF is reviewed by the clinical monitor, the data can be entered. The content of the CRF should not be modified. After receiving the CRF, the statisticians will verify any questionable areas with the researchers, who should respond as soon as possible. The statisticians will establish the database in a timely manner. After the database is reviewed, it will be locked by the principal investigator, sponsor, statistician, and clinical monitor to ensure data security. The data statistics should be backed up. This study is a phase II clinical trial without a control group. The sample size was assumed by Logrank Tests using Weibull Model, with a one-sided type I error of 5% and power of 80%. Based on previously published data, 5-year OS rate for stage I-II ENKTL patients who were treated with standard CRT was estimated to be about 70%, and the 5-year OS rate of patients enrolled in this clinical trial was estimated to be 84%. The sample size was estimated to comprise 53 patients. Considering a 10% dropout rate, 60 patients were to be enrolled in this study. Efficacy analyses are performed in the intention-to-treat population, which included all assigned patients. Safety data and life quality data comprise all patients who had started treatment. A comparison of the OS, the primary end point, using the log-rank test will be used to evaluate efficacy. Similar comparisons will be made for LRRS, and PFS. Cox regression analyses will be performed to quantify the effect of predictors on the survival outcomes. P value < 0.05 is considered statistically significant. Analysis includes:aGeneral information: The distribution of clinical factors, including age, sex, and stages, are summarized using descriptive statistics.bAdverse effects: Acute and late radiation-related toxicities and sequelae are summarized using descriptive statistics.cLong-term curative effect:dTotal data analysis: 5-year OS, PFS, and LRFS rates are calculated according to follow-up visits. An overall analysis is conducted after data summarization.eQuality of life: The modified EORTC QLQ-H&N35 scale questionnaire was used to quantify the post-radiotherapy symptoms. The questionnaire consisted of 43 items, categorized as 8 multi-item scales and 15 single items. These symptom scales/items were scored following the instruction from EORTC QLQ-C30 Scoring Manual. The raw score (RS), is firstly calculated as the average of the component items: RS= (Item1+ Item2+…+ Itemn)/n. Next, RS were standardized with a linear transformation algorithm: Score= {(RS-1)/range}x100, in which range was the difference between the maximum possible value of items and the minimum possible value. Scores represent the severity of symptoms and high scores indicate worse symptoms. Researchers should ensure the complete preservation of data. According to GCP principles, data would be preserved for more than 5 years. Ethical norms: This clinical trial must comply with the Helsinki Declaration, and related regulations. Before the commencement of this experiment, the approval of the ethics committee of our center must be obtained. During the clinical study, any changes made to this trial protocol should be reported to the Ethics Committee and placed on record. Informed consent: Patients must provide informed consent to participate in the trial before receiving treatment to protect the legitimate rights and interests of the patients. It is the responsibility of the researcher to provide the subject, or his or her designated representative, with a complete and comprehensive description of the purpose of the study, the effects of the drug, the possible side effects, and possible risks, and to inform the subject of their rights. Conversation is a very important part of the informed consent process. If the subject and his or her legal representative are illiterate, the informed consent process shall be attended by a witness, who shall sign the informed consent form after oral consent by the subject or his or her legitimate representative. A copy of the informed consent form and the contact information for the researcher and the ethics committee must be provided to the patient on request. Emergency measures: The test site must be equipped with the necessary medical rescue equipment, first aid drugs, and emergency measures. We thank all the patients and clinicians who participated in this study. Research data are stored in an institutional repository and will be shared upon request to the corresponding author. Shao-qing Niu, and Yi-yang Li drafted the manuscript and performed the statistical analysis. Han Shao, Jiang Hu, Han-yu Wang, and Ji-jin Wang collected clinical data. Yu-jing Zhang conceived the study, and participated in its design and coordination. All authors read and approved the final manuscript. None. Appendix Staging Lugano Modification of Ann Arbor Staging System* (for primary nodal lymphomas)Tabled 1StageInvolvementExtranodal (E) statusLimited Stage IOne node or a group of adjacent nodesSingle extranodal lesions without nodal involvementStage IITwo or more nodal groups on the same side of the diaphragmStage I or II by nodal extent with limited contiguous extranodal involvementStage II bulky**II as above with “bulky” diseaseNot applicableAdvanced Stage IIINodes on both sides of the diaphragmNot applicableNodes above the diaphragm with spleen involvementStage IVAdditional non-contiguous extralymphatic involvementNot applicable Open table in a new tab 1. Vose, J., et al., International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol, 2008. 26(25): p. 4124-30.2. Cheung, M.M., et al., Early stage nasal NK/T-cell lymphoma: clinical outcome, prognostic factors, and the effect of treatment modality. Int J Radiat Oncol Biol Phys, 2002. 54(1): p. 182-90.3. Aozasa, K., et al., Nasal NK/T-cell lymphoma: epidemiology and pathogenesis. Int J Hematol, 2008. 87(2): p. 110-117.4. Peh, S.C. and Q.W. Quen, Nasal and nasal-type natural killer (NK)/T-cell lymphoma: immunophenotype and Epstein-Barr virus (EBV) association. Med J Malaysia, 2003. 58(2): p. 196-204.5. Li, Y.X., et al., Radiotherapy as primary treatment for stage IE and IIE nasal natural killer/T-cell lymphoma. J Clin Oncol, 2006. 24(1): p. 181-9.6. Kim, S.J. and W.S. Kim, Treatment of localized extranodal NK/T cell lymphoma, nasal type. Int J Hematol, 2010. 92(5): p. 690-6.7. You, J.Y., et al., Radiation therapy versus chemotherapy as initial treatment for localized nasal natural killer (NK)/T-cell lymphoma: a single institute survey in Taiwan. Ann Oncol, 2004. 15(4): p. 618-25.8. Koom, W.S., et al., Angiocentric T-cell and NK/T-cell lymphomas: radiotherapeutic viewpoints. Int J Radiat Oncol Biol Phys, 2004. 59(4): p. 1127-37.9. Li, C.C., et al., Treatment outcome and pattern of failure in 77 patients with sinonasal natural killer/T-cell or T-cell lymphoma. Cancer, 2004. 100(2): p. 366-75.10. Kim, T.M., et al., Local tumor invasiveness is more predictive of survival than International Prognostic Index in stage I(E)/II(E) extranodal NK/T-cell lymphoma, nasal type. Blood, 2005. 106(12): p. 3785-90.11. Li, Y.X., et al., Failure patterns and clinical implications in early stage nasal natural killer/T-cell lymphoma treated with primary radiotherapy. Cancer, 2011. 117(22): p. 5203-11.12. Hatano, K., et al., [3D-CRT and intensity modulated radiation therapy (IMRT)]. Gan To Kagaku Ryoho, 2003. 30(13): p. 2050-5.13. Wenyong, T., et al., Dosimetric comparison between intensity-modulated with coplanar field and 3D conformal radiotherapy with noncoplanar field for postocular invasion tumor. Med Dosim, 2010. 35(2): p. 128-34. Figure 1,Figure 2,Table 1,Table 2,Table 3, Table 4Fig. 2Kaplan-Meier survival curves for 60 patients in this study. A: Subgroup analysis of LRFS by iChT effects (CR vs. PR+SD, p=0.038). B: Subgroup analysis of LRFS by primary site (NC vs. WR, p=0.021). C: Subgroup analysis of PFS by primary site (NC vs. WR, p=0.042).Show full captionAbbreviation:iChT: induction chemotherapy; CR: complete remission; PR: partial remission; SD: stable disease; NC: nasal cavity; WR: Waldeyer's Ring.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Patient characteristics and univariate Cox analysis of prognostic factors for 60 patients.Prognostic FactorNo.5-y LRFS5-y PFS5-y OS% p% p% pAge, years≤605583.60.99481.80.91389.10.607>60580.080.080.0Primary siteNC4987.80.02185.70.04287.80.772WR1163.663.690.9Ann Arbor stageI3786.50.30283.80.44691.90.258II2378.378.382.6“B” symptomNo3183.90.62980.60.43383.90.277Yes2982.882.893.1Serum LDH*Serum LDH were unavailable in 5 patients before treatment;Normal3982.10.99582.10.87189.70.476Elevated1681.375.081.3EBV DNA copy before treatment$EBV DNA data were unavailable in 4 patients at diagnosis;Normal2487.50.59887.50.50395.80.182Elevated3278.175.081.3PTINo1478.60.44778.60.58892.90.527Yes4684.882.687.0ECOG PS score0-15983.10.63581.40.62088.10.724≥21100100100PINK05583.60.99481.80.91389.10.6071580.080.080.0≥20---PINK-E#PINK-E scores were unavailable in 4 patients at diagnosis because of EBV DNA data missing.0-15282.70.61180.80.59188.50.6012475.075.075.0≥30---Efficacy of iChTCR3584.30.03891.90.08194.30.087PR+SD2568.068.080.0Abbreviation: NC: nasal cavity; WR: Waldeyer's ring; LDH: lactate dehydrogenase; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EBV DNA: Epstein-Barr virus DNA; PTI: primary tumor invasion; PINK: Prognostic index of natural killer lymphoma; PINK-E: PINK model combined with EBV DNA data; iChT: induction chemotherapy; CR: complete remission; PR: partial remission; SD: stable disease. Serum LDH were unavailable in 5 patients before treatment;$ EBV DNA data were unavailable in 4 patients at diagnosis;# PINK-E scores were unavailable in 4 patients at diagnosis because of EBV DNA data missing. Open table in a new tab Table 2Failure patterns of 13 patients after radiotherapy.No.Gender/AgePrimary siteStage“B” symptomPTIL-R RegionsNeck LNDMPFS(m)Salvage Tx ChT/RT/ITOS(m)OutcomeIn-FMO-F1F/32WRIYesNo+--41.7ChT+RT+IT123.1Alive2F/50NCIINoYes+++25.6None26.2Died3M/33NCINoYes+--41.4ChT47.1Died4F/68NCINoNo+-+41.3ChT+IT58.0Died5M/41WRIIYesYes+--41.2ChT+RT100.5Alive6M/50WRIINoYes+--62.9IT94.9Alive7M/42WRIYesNo++-55.2IT95.5Alive8M/49WRIIYesYes+++5.0ChT14.0Died9M/44NCINoNo+--61.2None83.9Alive10F/56NCINoYes-+34.4ChT+RT101.5Alive11F/47NCIINoYes-+4.2ChT7.3Died12M/49NCINoYes-+7.0ChT11.1Died13M/21NCIIYesYes-+8.0ChT13.6DiedAbbreviation:F: female; M: male; NC: nasal cavity; WR: Waldeyer's ring; PTI: primary tumor invasion; DM: distant metastasis;LR regions:Local-Recurrence Regions; I-F: In field; M: Marginal, O-F: Out-field; ChT/RT/IT: chemotherapy/radiotherapy/immunotherapy. Open table in a new tab Table 3Multivariable Cox analysis of prognostic factors for LRFS, PFS and OS in 60 patients.Prognostic FactorLRFSPFSOSpHR (95%CI)pHR (95%CI)pHR (95%CI)Age0.9720.0000.9710.0000.9770.001(≤60 vs >60)(0.000-4.082E+211)(0.000-5.191E+189)(0.000-2.786E+205)Primary site0.4461.7810.3462.0530.4870.396(NC vs WR)(0.404-7.861)(0.460-9.157)(0.029-5.400)Ann Arbor stage0.4871.7380.8131.1960.3632.523(I vs II)(0.365-8.267)(0.272-5.257)(0.344-18.500)“B” symptom0.3210.5090.1530.3910.1060.222(No vs Yes)(0.134-1.931)(0.108-1.418)(0.036-1.378)Serum LDH0.9981.0010.5711.4650.7461.380(Normal vs Elevated)(0.257-3.905)(0.391-4.492)(0.196-9.697)EBV DNA copy before treatment0.9610.9660.7321.2650.4162.767(Normal vs Elevated)(0.241-3.873)(0.330-4.847)(0.239-32.089)PTI0.8080.8180.8530.8660.8781.215(No vs Yes)(0.163-4.117)(0.190-3.946)(0.101-14.645)ECOG PS score0.9690.0000.9670.0000.9710.000(0-1 vs ≥2)(0.000-1.555E+211)(0.000-1.728E+189)(0.000-4.966E+204)PINK-E0.9710.0000.9710.0000.9770.000(0-1 vs 2)(0.000-2.849E+211)(0.000-4.657E+189)(0.000-2.637E+205)Efficacy of iChT0.1013.2830.1692.5360.0924.789(CR vs PR+SD)(0.792-13.611)(0.674-9.546)(0.774-29.648)Abbreviation:NC: nasal cavity; WR: Waldeyer's ring; LDH: lactate dehydrogenase; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EBV DNA: Epstein-Barr virus DNA; PTI: primary tumor invasion; Prognostic index of natural killer lymphoma (PINK); PINK-E: PINK model combined with EBV DNA data; iChT: induction chemotherapy; CR: complete remission; PR: partial remission; SD: stable disease. Open table in a new tab Table 4Summary result of 47 patients using EORTC QLQ-C30 head&neck35.ScalesItemsRaw scoreStandardized scoreMeanMedian [IQR*]Incidence rate (Score >0)a Pain1,2,3,4(a1+a2+a3+a4)/4(an-1)/3*1000.3550[0∼0]4.2%b Swallowing5,6,7,8(b5+b6+b7+b8)/4(bn-1)/3*1000.5320[0∼0]8.3%c Senses problems13,14(c13+c14)/2(cn-1)/3*1008.1560[0∼16.667]31.2%d Speech problems16,23,24(d16+d23+d24)/3(dn-1)/3*10000[0∼0]2.1%e Trouble with social eating19,20,21,22(e19+e20+e21+e22)/4(en-1)/3*1001.0640[0∼0]10.4%f Trouble with social contact18,25,26,27,28(f18+f25+f26+f27+f28)/5(fn-1)/3*1000.5670[0∼0]10.4%g Less sexuality29,30(g29+g30)/2(gn-1)/3*10010.2840[0∼0]20.8%h Teeth9h9(hn-1)/3*10020.5670[0∼33.333]45.8%i Opening mouth10i10(in-1)/3*1000.7090[0∼0]4.2%j Dry mouth11j11(jn-1)/3*10014.8940[0∼33.333]39.6%k Sticky saliva12k12(kn-1)/3*1005.6740[0∼0]16.7%l Coughing15l15(ln-1)/3*10000[0∼0]2.1%m Felt ill17m17(mn-1)/3*1000.7090[0∼0]4.2%n nose_problems#Nine additional items (31 to 38, 43) were added at the basis of EORTC QLQ-H&N35 questionnaire, to investigate nasal, optical and aural problems, including nose bleeding, nasal congestion, altered nose appearance, mycteroxerosis, runny nose, watery eyes, hearing loss, vision loss, and cataract.31,32,33,34,35(n31+n32+n33+n34+n35)/5(nn-1)/3*1006.0996.667[0∼6.667]60.4%o impaired vision#Nine additional items (31 to 38, 43) were added at the basis of EORTC QLQ-H&N35 questionnaire, to investigate nasal, optical and aural problems, including nose bleeding, nasal congestion, altered nose appearance, mycteroxerosis, runny nose, watery eyes, hearing loss, vision loss, and cataract.38,43(o38+o43)/2(on-1)/3*1001.4180[0∼0]6.2%p paradoxic lacrimation#Nine additional items (31 to 38, 43) were added at the basis of EORTC QLQ-H&N35 questionnaire, to investigate nasal, optical and aural problems, including nose bleeding, nasal congestion, altered nose appearance, mycteroxerosis, runny nose, watery eyes, hearing loss, vision loss, and cataract.36p36(pn-1)/3*1004.9650[0∼0]14.6%q hearing lose#Nine additional items (31 to 38, 43) were added at the basis of EORTC QLQ-H&N35 questionnaire, to investigate nasal, optical and aural problems, including nose bleeding, nasal congestion, altered nose appearance, mycteroxerosis, runny nose, watery eyes, hearing loss, vision loss, and cataract.37q37(qn-1)/3*1000.7090[0∼0]4.2%r Pain killers39r39(rn-1)*10000[0∼0]2.1%s Nutritional supplements40s40(sn-1)*10000[0∼0]2.1%t Feeding tube41t41(tn-1)*10000[0∼0]2.1%u Weight loss42u42(un-1)*10000[0∼0]2.1%Note: *IQR: Inter-Quartile Range.# Nine additional items (31 to 38, 43) were added at the basis of EORTC QLQ-H&N35 questionnaire, to investigate nasal, optical and aural problems, including nose bleeding, nasal congestion, altered nose appearance, mycteroxerosis, runny nose, watery eyes, hearing loss, vision loss, and cataract. Open table in a new tab Abbreviation:iChT: induction chemotherapy; CR: complete remission; PR: partial remission; SD: stable disease; NC: nasal cavity; WR: Waldeyer's Ring. Abbreviation: NC: nasal cavity; WR: Waldeyer's ring; LDH: lactate dehydrogenase; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EBV DNA: Epstein-Barr virus DNA; PTI: primary tumor invasion; PINK: Prognostic index of natural killer lymphoma; PINK-E: PINK model combined with EBV DNA data; iChT: induction chemotherapy; CR: complete remission; PR: partial remission; SD: stable disease. Abbreviation:F: female; M: male; NC: nasal cavity; WR: Waldeyer's ring; PTI: primary tumor invasion; DM: distant metastasis;LR regions:Local-Recurrence Regions; I-F: In field; M: Marginal, O-F: Out-field; ChT/RT/IT: chemotherapy/radiotherapy/immunotherapy. Abbreviation:NC: nasal cavity; WR: Waldeyer's ring; LDH: lactate dehydrogenase; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EBV DNA: Epstein-Barr virus DNA; PTI: primary tumor invasion; Prognostic index of natural killer lymphoma (PINK); PINK-E: PINK model combined with EBV DNA data; iChT: induction chemotherapy; CR: complete remission; PR: partial remission; SD: stable disease. Note: *IQR: Inter-Quartile Range. The authors declare that they have no competing interests. Medical Scientific Research Foundation of Guangdong Province of China (A2022121 to Shaoqing Niu). Natural Science Foundation of Guangdong Province, China (2023A1515011600 to Shaoqing Niu).