Fate of patients with nasopharyngeal cancer who developed distant metastasis as first failure after definitive radiation therapy

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1 ORIGINAL ARTICLE Fate of patients with nasopharyngeal cancer who developed distant metastasis as first failure after definitive radiation therapy Ji Hyun Chang, MD, 1,3 Yong Chan Ahn, MD, PhD, 1 * Hyojung Park, MD, 1 Dongryul Oh, MD, 1 Jae Myoung Noh, MD, 1 Jong-Mu Sun, MD, PhD, 2 Myung-Ju Ahn, MD, PhD, 2 Keunchil Park, MD, PhD 2 1 Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 2 Department of Medicine (Division of Hematology Oncology), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 3 Department of Radiation Oncology, Seoul St. Mary s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Accepted 18 December 2014 Published online 26 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. No consensus has been reached on the optimal treatment for patients with nasopharyngeal cancer (NPC) who develop distant metastasis after initial radiation therapy (RT). Methods. Two hundred eighty-two patients with NPC received curative RT (1/- chemotherapy). Forty-six patients (16.3%) who developed distant metastasis as first failure formed the study group for the current analysis. Results. The median interval from initial RT until distant metastasis was 11.6 months. With a median follow-up of 30 months among survivors, overall survival (OS) rates at 2 and 5 years were 53.7% and 30.5%, respectively. On multivariate analyses, 18F-fluorodeoxyglucose (FDG)- positron emission tomography (PET)/CT for initial staging, RT plus chemotherapy as initial treatment, metastatic lesion number <6, disease-free interval >9 months, distant metastasis only to lungs, and treatment with curative intent after distant metastasis were predictive of significantly better OS. Conclusion. Combined with FDG-PET/CT, an aggressive treatment approach using locoregional modalities might be beneficial to patients with NPC with favorable prognostic factors, even after distant metastasis. VC 2015 Wiley Periodicals, Inc. Head Neck 38: E293 E299, 2016 KEY WORDS: nasopharyngeal cancer, distant metastasis, radiation, treatment, positron emission tomography (PET) INTRODUCTION The incidence rates of nasopharyngeal cancer (NPC) in South Korea are higher than those in Western countries, but lower than in the endemic area of southern China. No nationwide study on the exact incidence of NPC has been performed; however, according to the annual statistics of South Korea for the year 2010, NPC accounted for 0.2% of all registered cancers. 1 Although NPC is chemoresponsive and radioresponsive, the management of distant metastasis after the initial curative treatment remains a challenging issue. In previous studies, the distant metastasis rate was reported to be 30% to 60%, whereas after radiation therapy (RT) with or without chemotherapy in a more recent series, ranged from approximately 10% to 20%. 2 6 Previous studies reported on the combined group of synchronous and metachronous metastasis from NPC These 2 groups have quite different natures, but it is uncertain whether their prognoses differ because the reported data are not consistent. 9,10 Conventionally, the *Corresponding author: Y. C. Ahn, Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Irwon-dong, Gangnam-gu, Seoul , Republic of Korea. ycahn.ahn@sasmung.com treatment approach for patients with NPC with distant metastasis was mainly palliative in both groups. More recent reports suggested a long-term survival benefit in patients with NPC with distant metastasis at initial diagnosis, after curative therapy for the primary lesion However, little is known about the fate of distant metastasis that develops after the initial curative treatment in the modern era. With recent developments in imaging and treatment regimens, a good survival outcome and high locoregional control might be achieved. In addition, the use of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with CT for metastatic workup has allowed early and sensitive detection of distant metastasis. 14 As early detection can enhance the survival outcome by achieving accurate staging, the treatment strategy after distant metastasis is crucial. Much remains to be discovered about the significance of prognostic factors or the survival outcome of patients with NPC with distant metastasis. There was an attempt to subdivide the M1 stage into subcategories, as in colorectal cancer, 8 but there seemed to be discordance regarding the prognosis when the specific metastatic site was considered. Lung metastasis, for example, was found by Ong et al 15 to have a negative impact on survival, but current consensus is that lung metastasis implies good prognosis compared with metastasis to other sites. 6,8,15,16 HEAD & NECK DOI /HED APRIL 2016 E293

2 CHANG ET AL. TABLE 1. Patient characteristics. Factors Distant metastasis as first event (group I, 46 patients) No or other event (group II, 236 patients) p value Total 282 patients Median age, y 46 (15 77) 50 (11 86) (11 86) Sex.427 Male 40 (87.0%) 184 (78.0%) 224 (79.4%) Female 6 (13.0%) 52 (22.0%) 58 (20.6%) WHO classification.280 Keratinizing 15 (32.6%) 46 (19.5%) 61 (21.6%) Non-keratinizing 14 (30.4%) 65 (27.5%) 79 (28.0%) Undifferentiated 17 (37.0%) 125 (53.0%) 142 (50.4%) T classification.053 T1 15 (32.6%) 117 (49.6%) 132 (46.8%) T2 7 (15.2%) 27 (11.5%) 34 (12.0%) T3 8 (17.4%) 48 (20.3%) 56 (19.9%) T4 16 (34.8%) 44 (18.6%) 60 (21.3%) N classification.855 N0 4 (8.7%) 44 (18.6%) 48 (17.0%) N1 12 (26.1%) 68 (28.8%) 80 (28.4%) N2 18 (39.1%) 96 (40.7%) 114 (40.4%) N3 12 (26.1%) 28 (11.9%) 40 (14.2%) AJCC stage.001 I 1 (2.2%) 25 (10.6%) 26 (9.2%) II 5 (10.9%) 47 (20.0%) 52 (18.4%) III 13 (28.2%) 98 (41.4%) 111 (39.4%) IV 27 (58.7%) 66 (28.0%) 93 (33.0%) Staging by FDG-PET/CT.972 No 9 (19.6%) 52 (22.0%) 61 (21.6%) Yes 37 (80.4%) 184 (78.0%) 221 (78.4%) Initial treatment.153 RT 1 chemotherapy 41 (89.1%) 186 (78.8%) 227 (80.5%) RT alone 5 (10.9%) 50 (21.2%) 55 (19.5%) Initial response.670 Complete response 41 (89.1%) 225 (95.4%) 266 (94.3%) Partial response 5 (10.9%) 10 (4.2%) 15 (5.3%) Progressive disease 1 (0.4%) 1 (0.4%) Abbreviations: WHO, World Health Organization; AJCC, American Joint Committee on Cancer; FDG-PET, fluorodeoxyglucose-positron emission tomography; RT, radiotherapy. If a good long-term survival outcome can be achieved in a certain group even in a metastatic setting, the treatment approach for patients with NPC with distant metastasis should become more aggressive with a curative aim rather than being mainly palliative. As most of the previous studies were performed in an endemic area, it would also be of value to review the disease course in nonendemic areas. Also, synchronous and metachronous distant metastasis needs to be assessed separately for further clarification. In the current study, we evaluated the clinical outcomes and analyzed prognostic factors of patients who developed distant metastasis after initial curative therapy for NPC. MATERIALS AND METHODS Review of the database of the Radiation Oncology Department at Samsung Medical Center identified 282 patients who were diagnosed as having NPC without systemic metastasis and who received high-dose definitive RT between July 2000 and May The study was approved by the institutional review board. Detailed information on the patients characteristics is summarized in Table 1. The stage assignment was performed according to the American Joint Committee on Cancer (AJCC) seventh edition. In addition to routine tests, including chest X-ray and blood tests, the systemic workup tools before 2004 were whole body bone scans plus ultrasonography of the upper abdomen, which were mainly replaced by FDG-PET/CT scans thereafter. After thermoplastic mask fitting and CT-based simulation, all of the patients received high-dose definitive RT by either 3D conformal RT or intensity modulation RT (IMRT). Delineation of the gross tumor volume (GTV) and the clinical target volume (CTV) was based on all available clinical and diagnostic image information. The GTV was designated to include all of the clinically evident gross disease and the CTV was designed to cover the clinically uninvolved adjacent soft tissues or lymphatics that were suspected to harbor probable subclinical micrometastasis. The levels of cervical lymphatics to be covered within the CTV were determined on an individual basis based on the location and size of the GTV and the clinical T classification and N classification. High-risk CTV was defined as GTV plus a margin for microscopic disease coverage. Intermediate-risk CTV usually included the entire nasopharynx, base of skull, parapharyngeal spaces, inferior sphenoid sinus, posterior nasal cavity, posterior maxillary sinus, and the grossly involved cervical lymphatics plus margins. The bilateral level II E294 HEAD & NECK DOI /HED APRIL 2016

3 DISTANT METASTASIS AFTER DEFINITIVE RT FOR NPC lymphatics were included in intermediate-risk CTV if there was no clinically positive lymph node. Low-risk CTV involved the cervical lymphatics that included 1 nodal level further from the most distally involved lymph nodes. The typical radiation dose schedule using 3D conformal RT was 70 Gy over 7 weeks in the form of 2 Gy daily to the GTV, 54 Gy over 5.5 weeks to high-risk CTV, and 36 Gy over 3.5 weeks to low-risk CTV, with 2 consecutive adaptive replannings for shrinking fields. When using IMRT, the dose schedule was to deliver 66 to 68.4 Gy to the GTV and high-risk CTV in the form of approximately 2.2 to 2.4 Gy daily, 60 Gy to intermediaterisk CTV as 2 Gy daily, and 36 to 39.6 Gy to the lowrisk CTV as 2 Gy daily over 6 weeks, with 1 adaptive replanning. The adaptive replannings were performed in all patients in order to accommodate changes in the GTV, CTV, and the body contour, typically at the end of the third week of the RT course. The decision to add systemic chemotherapy to RT mainly depended on the clinical stage, age, or performance status of the individual patient, and chemotherapy was most commonly delivered concurrently with RT. The typical in-house recommendations for patients with NPC at the authors institute were RT alone for T1-2N0 stage and concurrent chemoradiotherapy (CRT) for T3-4 with any N or any T with N(1) stages. RT alone was optionally recommended for patients with advanced stage disease who were not considered suitable for an aggressive concurrent CRT approach. Induction or adjuvant chemotherapy before or after RT was optionally and exceptionally adopted mainly on the basis of clinical trials. The initial response evaluation by Response Evaluation Criteria in Solid Tumors criteria was based on neck CT images taken within 1 month of completing the RT course. All patients were instructed to visit the outpatient clinic on a regular basis thereafter. Neck CT and FDG- PET/CT were alternately performed at 3- to 4-month intervals during the first 2 to 3 years and at 6- to 12- month intervals thereafter. In addition to the regular checkup visits, patients were encouraged to visit the clinic if they experienced any unusual symptoms or signs. Among all patients, 46 (16.3%) developed distant metastasis either as the sole failure site or as a component of the first failure during the follow-up, and these patients formed the basis of the current study. The decision on the treatment aim and the modality selection after distant metastasis were based on the extent of metastatic disease, the disease-free interval from the initial RT, and the patient s general condition. Comparison of characteristics between the patient groups was performed by independent t test for age and by Pearson s chi-square test for other variables. The clinical outcomes of 46 patients who developed distant metastasis after definitive RT were analyzed. The duration of overall survival (OS) was defined as the time from the date of diagnosis of distant metastasis until the date of death or censoring, and the OS rates at 2 and 5 years were calculated using the Kaplan Meier method. All deaths were related to the current disease, and OS was identical to cause-specific survival. The significance of OS according to probable prognostic variables, including age, sex, performance status at diagnosis, initial T/N classifications, year of initial diagnosis, initial treatment, response to initial treatment, number of metastatic organs, number of metastatic lesions, disease-free interval, involved organ, and subsequent treatment aim, were evaluated using the log-rank test and Cox proportional hazards model. Statistical analysis was performed using SPSS statistical software (version 21.0; SPSS, Chicago, IL). RESULTS Patients As summarized in Table 1, the median age of all 282 patients was 50 years (range years), and men were more common than women (224 patients; 79.4% men). The 46 patients who developed distant metastasis as the first failure (group I) were younger than those who did not (group II; median age 46 years vs 50 years; p 5.051). There was an apparent tendency toward more advanced initial T and N classifications in group I compared with group II, but the difference was not statistically significant (p =.053 and.855, respectively). It was, however, evident that the initial AJCC stage was more advanced in group I than in group II (p =.001). The initial AJCC stages of group I patients were stage I in 1 patient (2.2%), stage II in 5 patients (10.9%), stage III in 13 patients (28.2%), and stage IV in 27 patients (58.7%), whereas those of group II patients were stage I in 25 patients (10.6%), stage II in 47 patients (20.0%), stage III in 98 patients (41.4%), and stage IV in 66 patients (28.0%). FDG-PET/CT as the systemic workup was performed in 221 patients (78.4%), and there was no difference between groups I and II (80.4% vs 78.0%; p =.972). Systemic chemotherapy was added to RT in 227 patients (80.5%), and there was no difference between groups I and II (89.1% vs 78.8%; p =.153). The RT techniques applied to group I patients were 3D conformal RT in 31 patients (67.4%) and IMRT in 15 patients (32.6%). The mode of chemotherapy actually delivered in group I patients was upfront concurrent CRT in 31 patients (67.4%), and induction chemotherapy plus concurrent CRT in 10 patients (21.7%). Five patients received definitive RT alone; 3 patients with old age and poor performance, 1 patient with abnormal liver function, and 1 patient with ct1n0 disease. There were no differences between groups I and II with respect to RT technique or mode of chemotherapy. The initial responses were complete response in 266 patients (94.3%), partial response in 15 patients (5.3%), and progression in 1 patient (0.4%), and there was no difference between groups I and II (p =.670). Distribution of metastatic lesions and salvage treatment Of 46 patients in group I, 41 patients (89.1%) had distant metastasis only, and 5 patients (10.9%) had synchronous distant metastasis and locoregional recurrence. The sites of accompanying locoregional recurrences were the cervical lymph nodes in 4 patients (8.7%), and the primary site in 1 patient (2.2%). The median interval from the initial RT to the diagnosis of distant metastasis in group I patients was 11.6 months (range, months). The most common metastatic organ was the lung in 27 patients HEAD & NECK DOI /HED APRIL 2016 E295

4 CHANG ET AL. FIGURE 1. Sites of metastasis of nasopharyngeal carcinoma. (58.7%), followed by the bone in 13 patients (28.3%), and the liver in 12 patients (26.1%; see Figure 1). The majority of patients (35; 76.1%) had single organ failure: lung in 18 patients; bone in 10 patients; liver in 5 patients; brain in 1 patient; and skin in 1 patient. Eleven patients (23.9%) had synchronous multiorgan failures, and 27 patients had 6 or more metastatic lesions (58.7%). Supportive management with no anticancer treatment after distant metastasis was recommended for 4 patients (8.7%) with consideration of the extensive and widespread nature of metastatic lesions and/or patient condition. Forty-two patients (91.3%) underwent some form of anticancer treatment after distant metastasis: chemotherapy in 26 patients (56.5%); RT in 9 patients (19.6%); surgery in 3 patients (6.5%); concurrent CRT in 2 patients (4.3%); chemotherapy plus radiofrequency ablation in 1 patient (2.2%); and surgery plus RT in 1 patient (2.2%). The treatment aims were mainly palliative in 33 patients (71.7%), although a potentially curative approach was applied in 9 patients (19.6%) on the condition that the metastatic lesion(s) could be treated with an appropriate local modality (Table 2). Clinical outcomes and prognostic factors There were 26 deaths, all of which were related to distant metastasis from NPC. With a median follow-up of 30 FIGURE 2. Overall survival curve of 46 patients who developed distant metastasis after radiation therapy for initially nonmetastatic nasopharyngeal cancer. months (range, 6 74 months), the estimated median OS duration was 33 months (range, months), and the OS rates at 2 and 5 years were 53.7% and 30.5%, respectively (see Figure 2). It is noteworthy that 5 patients (10.9%) had been living for longer than 50 months after distant metastasis at the time of analysis. Nine of 46 patients (19.6%) had a disease-free interval shorter than 6 months from the initial RT to distant metastasis. Among these 9 patients, 8 were known to have undergone the traditional systemic metastatic workup instead of FDG-PET/CT staging. In univariate analyses, the factors associated with significantly better OS at 2 years were performance status of Eastern Cooperative Oncology Group (ECOG) 0 to 2 at diagnosis of distant metastasis (p <.0001), recent treatment (from ) compared to earlier treatment (from ; p 5.03), use of FDG-PET/CT as the initial systemic workup (p =.004), fewer than 6 metastatic lesions (p =.039), disease-free interval longer than 9 months (p =.032), and distant metastasis only to the lung (p =.011). Complete response to the initial RT was associated with better OS with marginal significance (p =.061). The OS rate at 2 years was significantly different according to the treatment modality and aim after distant metastasis, which was categorized as potentially curative, TABLE 2. Patients with potentially curative salvage treatment. Patient # Metastatic organ No. of lesions Salvage treatment 1 Lung 1 RT (stereotactic body RT with 60 Gy/5 fx), 2 Lung 1 RT (stereotactic body RT with 60 Gy/5 fx), surgery, chemotherapy 3 Lung, hilar lymph node 5 (multiple metastatic Concurrent CRT (3D-CRT with 60 Gy/15 fx) lymph nodes) 4 Lung >5 (small nodules)* RT (hypofractionated RT with 60 Gy/15 fx) 5 Liver 1 Surgery 6 Liver 1 Surgery 7 Liver 1 Radiofrequency ablation 8 Bone 1 RT (3D-CRT with 30 Gy/10 fx) 9 Bone 1 RT (tomotherapy with 50 Gy/10 fx) Abbreviations: RT, radiotherapy; Gy, Gray; fx, fractions; concurrent CRT, concurrent chemoradiotherapy; 3D-CRT, 3D conformal radiotherapy. * Initially indeterminate, later confirmed to be metastasis. E296 HEAD & NECK DOI /HED APRIL 2016

5 DISTANT METASTASIS AFTER DEFINITIVE RT FOR NPC FIGURE 3. Overall survival profiles based on treatment aims for distant metastasis. mainly palliative, and supportive only (p <.0001; see Figure 3). Subsequent multivariate analyses revealed that use of FDG-PET/CT staging as the initial systemic workup (p =.001), RT plus chemotherapy as the initial treatment (p <.0001), the number of metastatic lesions <6 (p=.009), disease-free interval longer than 9 months (p =.022), distant metastasis only to the lung (p <.0001), and potentially curative treatment aim after distant metastasis (p =.005) were predictive of significantly better OS rates at 2 years (Table 3). Single-organ metastasis had a trend toward more favorable OS than did multiorgan metastasis, with marginal statistical significance (p 5.055). TABLE 3. Prognostic factors for overall survival. p-value Factors No. of patients 2-year OS Univariate* Multivariate Age, y (21.7%) 77.8% >45 36 (78.3%) 46.7% Performance status < ECOG (84.8%) 61.0% ECOG >2 7 (15.2%) 14.3% AJCC stage I III 19 (41.3%) 60.0% IV 27 (58.7%) 49.1% Year of initial diagnosis (26.1%) 25.0% (73.9%) 64.9% FDG-PET/CT staging Yes 37 (80.4%) 61.3% No 9 (19.6%) 11.1% Initial treatment.225 <.0001 RT 1 chemotherapy 41 (89.1%) 55.2% RT alone 5 (10.9%) 40.0% Complete response to initial RT Yes 41 (89.1%) 55.9% No 5 (10.9%) 40.0% No. of metastatic lesion(s) (41.3%) 71.1% >5 27 (58.7%) 41.3% No. of metastatic organ(s) Single 35 (76.1%) 57.3% Multiple 11 (23.9%) 42.4% Disease-free interval mo 19 (41.3%) 39.5% >9 mo 27 (58.7%) 63.0% Metastasis only to lung.011 <.0001 Yes 18 (39.1%) 76.0% No 28 (60.9%) 38.5% Metastasis only to bone Yes 10 (21.7%) 28.1% No 36 (78.3%) 59.6% Salvage treatment < Potentially curative 9 (19.6%) 87.5% Palliative 33 (71.7%) 49.0% No treatment 4 (8.7%) 0% Abbreviations: OS, overall survival; ECOG, Eastern Cooperative Oncology Group; AJCC, American Joint Committee on Cancer; FDG-PET, fluorodeoxyglucose-positron emission tomography; RT, radiotherapy. * Log-rank test. Cox proportional hazard regression model. HEAD & NECK DOI /HED APRIL 2016 E297

6 CHANG ET AL. DISCUSSION We have witnessed gradual improvements in clinical outcomes of NPC as a result of refinements in diagnostic imaging tools, the techniques of RT delivery, and the mode of chemotherapy administration together with RT. 2,17 19 Most investigators who have reported on NPC focused on patients without distant metastasis, and the optimal treatment for those who develop distant metastasis after the initial definitive RT has not been determined. In fact, previous studies on patients with NPC with distant metastasis were either case report series with unexpectedly long-term survival or feasibility studies on various chemotherapeutic regimens since the early 1990s However, after the report by Teo et al, 10 there were several attempts to document the prognostic factors related to improved survival and to subclassify distant metastasis. 8 10,16 Setton et al 13 reported 5 patients with NPC who were initially metastatic, and were long-term survivors after aggressive treatments for both the local and systemic disease. Similarly, Lin et al 11 reported favorable progression-free survival and OS outcomes in patients with distant metastasis at the time of initial diagnosis because of the addition of primary RT to chemotherapy. Consequently, there is a current trend to apply both chemotherapy and definitive local RT with curative aim to those who are newly diagnosed with distant metastasis. 11,13,23 The current study focusing on patients who developed distant metastasis after initial curative RT for NPC indicates that not all patients had dismal survival outcomes, even after distant metastasis. Moreover, the 2-year OS rates were >70% in some patient subgroups, including age 45 years or younger, fewer than 6 metastatic lesions, distant metastasis only to the lung, and the application of potentially curative treatment after distant metastasis (Table 3). In addition, factors shown to be significantly favorable on multivariate analyses included use of FDG-PET/CT as the initial staging, initial concurrent CRT, fewer than 6 metastatic lesions, disease-free interval longer than 9 months, distant metastasis confined only to the lung, and potentially curative treatment aim for distant metastasis. The metastatic workup imaging modalities varied among the institutions according to the availability of diagnostic tools. Traditional imaging tools included simple chest radiographs for evaluating the lung, skeletal scintigraphy for the bone, and abdominal ultrasonography for the upper abdomen. Many previous studies used these conventional workup tools for initial staging. 9,10 FDG- PET/CT is known to have favorable overall diagnostic accuracy in evaluation of the extent of systemic as well as locoregional disease in both initial and recurrent cases. 18,24,25 Based on this high accuracy, in 2004, the authors replaced the traditional imaging modalities with FDG-PET/CT, which was used in almost four fifths of the patients in the current study (221; 78.4%). Based on the fact that most patients with a disease-free interval <6 months did not undergo initial FDG-PET/CT staging, it seemed quite evident that probable understaging by the traditional staging workup tools led to a significantly worse clinical outcome. Analysis of tumor/patient characteristics between the patients with or without FDG-PET/ CT revealed no differences (data not shown). The incidence of organ involvements in distant metastasis from NPC might depend on the post-rt surveillance method. Bone was the most frequent site of distant metastasis in other studies, 26,27 whereas the lung was the most frequent in the current study. Skeletal metastasis is more likely to cause subjective symptoms and signs in patients at an earlier stage of disease than is lung metastasis, and skeletal scintigraphy, even though performed optionally only for symptomatic patients, seems to be quite effective in detecting skeletal metastasis. The classic surveillance methods for lung evaluation typically included routine chest radiographs, which have an unsatisfactory detection rate. The metastatic nodules in the lung are usually small and unlikely to cause any symptoms or signs. When FDG- PET/CT was used as a routine post-rt surveillance tool in the current study because of its advantages over simple radiographs, the lung was found to be the most frequent metastatic organ. Some authors previously reported that single metastasis was a favorable prognostic factor Based on the current study, however, fewer than 6 metastatic lesions was one of the favorable prognostic factors. Moreover, metastasis only to the lung, but not to the bone only, was correlated with better OS. We speculate that lung metastasis is able to be detected by routine FDG- PET/CT at an earlier stage than bone metastasis. 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