|Year : 2020 | Volume
| Issue : 1 | Page : 76-83
Efficacy and tolerability of nimotuzumab in combination with chemotherapy in recurrent and metastatic squamous cell carcinoma of head and neck at a cancer center in Northern India
Abhishek Yadav, Pankaj Goyal, Chaturbhuj R Agrawal, Sneha J Bothra, Parveen Jain, Kumardeep Dutta Choudhury, Sunil Kumar Gupta, Manish Sharma, Rajat Bajaj, Amitabh Upadhyay, Prashanta Dash, Dinesh C Doval
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
|Date of Submission||19-Jul-2018|
|Date of Decision||01-Mar-2019|
|Date of Acceptance||02-Mar-2019|
|Date of Web Publication||26-Feb-2020|
Chaturbhuj R Agrawal
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
Source of Support: None, Conflict of Interest: None
Introduction: Squamous cell carcinoma of head and neck (SCCHN) account for approximately 30-33% of all cancer and the median survival for recurrent and metastatic(R/M) SCCHN remains less than 1 year despite modern advances in therapy. Chemotherapy, usually single agent remains the backbone of therapy in these patients. EGFR antibodies are being used in (R/M) SCCHN. Nimotuzumab is one such agent that has anti-EGFR action similar to other agents without similar skin toxicity.
Methods: Prospective, interventional, non-randomized study done at Rajiv Gandhi Cancer Institute and Research Centre. A total 124 patients were enrolled and divided into Arm A (Chemotherapy + Nimotuzumab) and Arm B (Chemotherapy) in a ratio of 1:1 i.e., 62 in each arm. They were evaluated and treated as per protocol after a written informed consent. Statistical analysis was done using the SPSS software. Quantitative variables were compared using Unpaired t-test/Mann-Whitney Test. Qualitative variables were compared using Chi-Square test /Fisher's exact test. Kaplan-Meier analysis was used to assess the PFS, with log rank test for comparison between the groups. A p value of < 0.05 was considered statistically significant.
Results: The most frequent primary location of tumor was oral cavity (n=38, 69%) and (n=33, 56.9%) in both arms. The overall response rate in Arm A was 38.2% and 19% in Arm B (p= 0.023). The disease control rate in Arm A was 74.5% and 43.1% Arm B (p= 0.0007). The median PFS in Arm A was 5.2 months whereas it was 3.2 months in Arm B (p= 0.009).
Conclusion: In this study, the combination of Nimotuzumab plus platinum/taxane based chemotherapy was active and well tolerated in Indian patients in R/M SCCHN. Addition of Nimotuzumab to chemotherapy had a response rate of 38.2% and median PFS of 5.2 months are strong arguments for clinically testing this combination.
Keywords: Anti-EGFR therapy, nimotuzumab, recurrent or metastatic head and neck squamous cell cancer
|How to cite this article:|
Yadav A, Goyal P, Agrawal CR, Bothra SJ, Jain P, Choudhury KD, Gupta SK, Sharma M, Bajaj R, Upadhyay A, Dash P, Doval DC. Efficacy and tolerability of nimotuzumab in combination with chemotherapy in recurrent and metastatic squamous cell carcinoma of head and neck at a cancer center in Northern India. Indian J Cancer 2020;57:76-83
|How to cite this URL:|
Yadav A, Goyal P, Agrawal CR, Bothra SJ, Jain P, Choudhury KD, Gupta SK, Sharma M, Bajaj R, Upadhyay A, Dash P, Doval DC. Efficacy and tolerability of nimotuzumab in combination with chemotherapy in recurrent and metastatic squamous cell carcinoma of head and neck at a cancer center in Northern India. Indian J Cancer [serial online] 2020 [cited 2022 Oct 4];57:76-83. Available from: https://www.indianjcancer.com/text.asp?2020/57/1/76/279173
Squamous cell carcinoma of head and neck (SCCHN) accounts for approximately 30%–33% of all cancers (WHO). In India, male SCCHN is the most common cancer followed by lung, stomach, and colon cancer. In female, it is fifth most common cancer after breast, cervix, colorectal, and ovary. Majority of patients develop local and/or regional recurrences, and distant metastases occur in 20%–30% of patients.,,,, However, most patients with recurrent or metastatic (R/M) disease qualify for palliative treatment with chemotherapy/immunotherapy. Treatment choice depends on some factors such as symptoms, co-morbidity, performance status (PS), prior treatment, patient preference, and logistics.
The median overall survival for R/M SCCHN remains less than a year despite modern advances in therapy. For patients who have a low-disease burden and are asymptomatic, use of single agent regimens are appropriate to balance treatment with side effects. Single agent drugs used in the treatment of R/M SCCHN include docetaxel, paclitaxel, cetuximab, capecitabine, and methotrexate. New therapies such as mTOR inhibitors, anti-angiogenic agents, and IGF1R inhibitors are still under investigation. Palliative chemotherapy and the epidermal growth factor receptor inhibitors (cetuximab) constitute the backbone of treatment for the patients with R/M HNSCC.
Nimotuzumab is a humanized IgG1 isotype monoclonal anti-EGFR antibody. It was obtained by transplanting the complementarity determining regions (CDR) of the murine IgG2a monoclonal EGFR3, to a human framework assisted by computer modeling.
Given the poor prognosis for most patients with R/M HNSCC, enrolment in clinical trials and investigating novel approaches to therapy should be encouraged. Till now nimotuzumab has been studied and found beneficial in combination with radiation and/or chemotherapy in patients with unresectable and locally advanced SCCHN.,, Based on the above fact and on performance of cetuximab in R/M SCCHN, this study has been planned to evaluate efficacy and tolerability of nimotuzumab in recurrent and metastatic disease.
Nimotuzumab's anti-tumor activity is mediated by its ability to inhibit proliferation, survival, and angiogenesis. Nimotuzumab can also cause tumor cell lysis by its capacity to cause antibody dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). Anti-tumor activity of nimotuzumab was observed in absence of skin, renal, and gastrointestinal mucosa toxicities commonly associated with EGFR-targeting antibodies, cetuximab, and panitumumab.
| » Aims|| |
The primary aim was to assess response rate of nimotuzumab in combination with chemotherapy in R/M SCCHN. It could also assess tolerability, toxicity, and progression-free survival (PFS) in patients receiving combination of nimotuzumab and chemotherapy.
| » Methods|| |
This was a prospective, interventional, non-randomized, comparative study. Patients were enrolled at Rajiv Gandhi Cancer Institute and Research Centre (RGCIRC), a comprehensive tertiary care cancer institute in India, from June 2015 to July 2016 and date of last follow up was June 1, 2017. Patients who had measurable and histologically or cytologically proven SCCHN region, which was recurrent after locoregional therapy (post-surgery + radiotherapy or chemotherapy + radiotherapy) or metastatic at presentation, were enrolled in this study.
Using hazard ratio as effect size, the minimum required sample size with 80% power of study and two-sided alpha of 5% was 54 patients per group. So, sample size taken was 110 (55 per group). Formula used
Where Zα is value of Z at two-sided alpha error of 5% and Zβ is value of Z at power of 80% and ES is effect size.
| » Patient Selection Criteria|| |
Patients with histologically or cytologically confirmed SCCHN with age >18 years, ECOG PS 0-2 who were willing to be a part of the study, having measurable disease (defined as at least one lesion that could be accurately measured in at least one dimension, radiologically, and clinically) and who had adequate renal, liver, cardiac, and bone marrow function.
Any patient with prior treatment with any anti-EGFR therapy having poor PS (ECOG >2) or evidence of severe or uncontrolled systemic disease or infection or women who were pregnant, or breastfeeding (women in child-bearing age group were advised to use contraception during the course of treatment). Any patient treatable with curative intent was excluded).
| » Methodology|| |
Informed written consent was taken from all the patients (thumb impression if the patient was illiterate).
Pre-treatment evaluation included a complete medical history (including endoscopic procedure in the past), physical exam, a complete blood cell (CBC) count, a standard bio-chemical profile (KFT, LFT, and serum electrolytes), random blood sugar, calculated creatinine clearance using the modified Cockcroft and Gault formula, an electrocardiogram, echocardiography/MUGA, chest X-rays, and a radiologic imaging study for tumor measurement, mostly CT/MRI scan of oral cavity and neck/PET scan, along with a histological proof of SCC. Patients were staged according to TNM staging system. Patients were categorized as tobacco user in any form or non-user.
| » Treatment Protocol|| |
Chemotherapy and targeted therapy was administered as in-patient basis. Each treatment cycle lasted 3 weeks. Standard treatment was defined as six cycles, unless there was disease progression or unacceptable toxicity. Both chemotherapy and nimotuzumab were administered intravenously.
Treatments to be compared were administered as follows (with premedication and hydration): Arm A (Nimotuzumab plus chemotherapy): Nimotuzumab was administered in weekly doses of 200 mg mixed in 200 ml normal saline over 2 hours in combination with chemotherapy (paclitaxel 135-175 mg/m2 or docetaxel 75 mg/m2 + cisplatin 60-75 mg/m2 or carboplatin AUC 5) 3 weekly as per protocol. Arm B (Chemotherapy alone): Paclitaxel 135-175 mg/m2 or docetaxel 75 mg/m2 + cisplatin 60-75 mg/m2 or carboplatin AUC 5, 3 weekly, as per protocol.
Evaluations before each cycle of therapy included a complete history, physical examination, CBC count, calculation of creatinine clearance, and measurement of blood chemistry values. The duration of any grade 3 or 4 toxicity was documented by retesting every other day. To administer chemotherapy, patients were required to maintain a WBC >4,000/mm3, ANC >1,500/mm3, platelet count >100,000/mm3, and serum creatinine <1.4 mg%.
Response was evaluated as per Response Evaluation Criteria in Solid Tumours version 1.1. Responses were assessed just prior to fourth cycle of chemotherapy and 3 weeks after completion of 6 cycles by clinical tumor measurements and documentation of the tumor size of measurable and non-measurable disease, using CT/MRI/PET scans (depending on scan used in baseline evaluation and follow up for individual patient). All sites with measurable lesions were followed for response. Response based on target and non-target lesions was defined as the duration of response was calculated from the time of first objective assessment of CR/PR to the first time of progression or death due to any cause. The PFS was calculated from time of study entry to the first clinical or radiological observation of disease progression.
| » Toxicity Evaluation|| |
Tolerability and toxicity were assessed at each visit as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Dose delays or modifications were specified for hematologic, gastrointestinal, neurologic, and renal toxicities. For all grade 4 toxicities, treatment was withheld until complete resolution of the toxicity and then resumed with dose modification. Hematologic requirements for subsequent cycles included an absolute neutrophil count of 1,500/mm3 and a platelet count of 100,000/mm3 on day 1 of treatment. Treatment was delayed until recovery to these values. All chemotherapy doses were reduced by 20% for nadir grade 4 thrombocytopenia or nadir grade 4 neutropenia persisting longer than 5 days or for febrile neutropenia requiring hospitalization and antibiotics. Grade 3 mucositis required a 20% dose reduction of paclitaxel in subsequent treatment cycles. For grade 2 hepatic toxicity, treatment was to be held until toxicity resolved to grade 1 and then administered without dose reduction. For grade 3 hepatic toxicity, paclitaxel was withheld until toxicity resolved to grade 1 and then administered at 80% of the previously calculated dose. For grade 2 sensory or motor neuropathy, carboplatin was substituted for cisplatin, and the doses of taxanes were not changed. If grade 2 neuropathy persisted for an additional cycle, then paclitaxel was reduced to 80% of the previously calculated dose. For a creatinine clearance of 50 mL/min, carboplatin was substituted for cisplatin.
Categorical variables were presented in number and percentage (%) and continuous variables were presented as mean ± SD and median. Normality of data was tested by Kolmogorov-Smirnov test. If the normality was rejected then non-parametric test was used. Statistical tests applied were as follows:
- Quantitative variables were compared using Unpaired t-test/Mann-Whitney Test (when the data sets were not normally distributed) between the two groups
- Qualitative variables were compared using Chi-Square test/Fisher's exact test
- Kaplan-Meier survival analysis was used to assess the PFS and survival with log rank test for comparison between the groups. A P value of <0.05 was considered statistically significant.
The data were entered in MS Excel spreadsheet and analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0. All statistical analyses were performed by using SPSS for Windows (SPSS Inc, Chicago, IL, USA). Tests and tools as applicable were applied.
| » Observations and Results|| |
Patients with histology-proven R/M SCCHN were screened. Of the 140 patients, 8 patients did not meet inclusion or exclusion criteria, 5 withdrew consent, and 3 were not enrolled due to logistics. A total of 124 patients were then enrolled into the study and divided into Arm A (chemotherapy + nimotuzumab) and Arm B (chemotherapy) in a ratio of 1:1, that is, 62 in each arm. In Arm A, three patients did not receive therapy because of deterioration in general condition due to rapid tumor progression after registration but before treatment, and these patients were not included in the analysis. Four patients were lost to follow up without a radiologic response evaluation. Hence, 55 patients were taken up for final analysis. In Arm B, one patient had an acute myocardial infarction before treatment started, one deteriorated due to rapid tumor progression, and two were lost to follow up. Thus, 58 patients were evaluated for response, PFS, and toxicity. Baseline patient and disease characteristics of both arms are listed in [Table 1].
The median age at presentation was 52.0 years (range 32-71 years). There were 51 men and 4 women. The most frequent primary location of tumor was oral cavity (n = 38, 69%). Majority of tumors were moderately differentiated squamous cell carcinoma (n = 25, 45.5%). Most of the patients at the time of presentation were in stage III-IV (n = 47, 85.5%). All except two patients had received prior therapy for cancer: Surgery (n = 46, 83.6%), radiotherapy (n = 43, 78.2%), and induction chemotherapy (n = 3, 5.5%). After initial multimodality therapy, 71.7% of patients presented as recurrent disease and 28.3% presented as metastatic (including recurrent); only two patients were upfront metastatic.
The median age at presentation was 55.0 years (range 33-69 years). There were 50 men and 8 women. The most frequent primary location of tumor was oral cavity (n = 33, 56.9%). Majority of tumors were moderately differentiated squamous cell carcinoma (n = 34, 58.6%). most of the patients at the time of presentation were stage III-IV (n = 49, 84.5%). All except three patients had received prior therapy for cancer: Surgery (n = 42, 72.4%), radiotherapy (n = 47, 81%), induction chemotherapy (n = 6, 10.3%). After initial multimodality therapy, 74.1% of patients presented as recurrent disease and 25.9% presented as metastatic (including recurrent); only three patients were upfront metastatic. As depicted in [Table 2], majority of the patients were between the ages of 40-60 years in both arms. Most of the patients with performance status of 2 were above 50 years of age.
| » Treatment Administration|| |
These patients received a median number of 6 cycles of nimotuzumab per patient (range 2-6 cycles) with median number of 18 week per patient (range 6-18 weeks). A total of 20 patients (36.4%) had one or more adjustment including dose delay (n = 10, 18.2%) and dose reduction (n = 14, 25.5%). Grade 3 or 4 neutropenia caused dose delays, omissions, or reductions in 16.2% of treated patients, and grade 3 or 4 thrombocytopenia was the reason for adjustment in 14.5% of treated patients. In three patients, dose was delayed and reduced due to grade 3 neuropathy. In all, 36 (65.5%) patients received cisplatin-based chemotherapy while 19 patients (34.5%) were given carboplatin-based regimes. Carboplatin was administered to those patients who had either poor PS or advance age (>65 years). During study, four patients were shifted from cisplatin to carboplatin (three due to neuropathy and one due to decline in renal function).
Chemotherapy was administered with median number of 3 cycles per patient (range 2-6 cycles). A total of 20 patients (34.5%) had one or more adjustment including dose delay (n = 9, 15.5%) and dose reduction (n = 15, 25.9%). Grade 3 or 4 neutropenia caused dose delays, omissions, or reductions in 19% of treated patients, and grade 3 or 4 thrombocytopenia was the reason for adjustment in 12% of treated patients. In two patients, dose was delayed and reduced due to grade 3 neuropathy. In all, 33 patients (56.9%) patients received cisplatin-based chemotherapy while 25 patients (43.1%) were given carboplatin-based regimes. Carboplatin was administered to those patients who had either poor PS or advanced age (>65 years). During study, four patients were shifted from cisplatin to carboplatin (two each due to neuropathy and decline in renal function).
| » Response to Treatment|| |
Fifty five patients in Arm A and 58 in Arm B were assessed for response. As shown in [Table 3], the overall response rate in Arm A was 38.2%, whereas it was 19% in Arm B and the difference is statistically significant (P = 0.023).
The disease control rate in Arm A was 74.5% and it was 43.1% in Arm B and the difference was again statistically significant (P = 0.0007) (CR – complete response; PR – partial response; PD – progressive disease; SD – stable disease; ORR – overall response rate; DCR – disease control rate).
The median PFS in Arm A was 5.2 months, whereas it was 3.2 months in Arm B and the difference was statistically significant (P = 0.009) [Figure 1].
Both hematologic as well as non-hematologic toxicity was evaluated in all patients and in all cycles. Overall, grade 3-4 AEs were reported in 81.8% patients in Arm A and in 77.6% in Arm B [Table 4]. The difference was not significant statistically. Most common grade 3 or 4 hematological toxicity in both the arms was leucopenia, the incidence of which was almost similar in both the arms as depicted in [Table 4]. Febrile neutropenia occurred in 4 (7.2%) and 5 (8.6%) patients in Arms A and B, respectively. Grade 3 or 4 anemia occurred in 15 (27.3%) in Arm A and in 13 (22.4%) patients in Arm B. Incidence of grade 3 or 4 thrombocytopenia was also similar in both the arms (18.2% in Arm A versus 15.5% in Arm B). No patient in any of the arms required platelet transfusion for management of thrombocytopenia because no patient experienced significant hemorrhage or risk for hemorrhage.
The most common grade 3-4 non-hematological adverse events were GI toxicity and mucositis in both the arms. It happened in 13 (23.6%) patients in Arm A and in 16 (27.6%) patients in Arm B. The difference was not statistically significant. Grade 3 nausea/vomiting were experienced by seven patients (12.7%) in Arm A and nine (15.5%) patients in Arm B. The incidence of grade 3 or 4 diarrhea was also similar in both the arms (8% in Arm A versus 6% in Arm B). The most common GI AEs were Anorexia, seen in 22 (40%) patients in Arm A and 18 (31%) in Arm B. The difference was not significant statistically.
There were five cardiac events in both the arms but only one patient (1.8%) in Arm A and two patients (3.4%) in Arm B had grade 3 events, rest had grade 1-2. One patient (1.8%) in Arm A and two patients (3.4%) in Arm B who were on cisplatin-based therapy developed grade 3 renal dysfunction. The most common grade 3-4 electrolyte abnormality reported was hypokalemia which occurred in two (3.6%) patients in Arm A as well as in Arm B (3.4%). Only one incidence of significant hypomagnesemia was observed in the study and it was in Arm A.
Nimotuzumab-related grade 3 infusion reaction developed in just one patient. During treatment in Arm A, six patients (10.9%) developed severe infection, three patients had pneumonia, two had GI infection, and one had cellulitis. One patient with pneumonia developed septic shock but he recovered with treatment. In Arm B, the incidence of severe infection was 8 (13.8%) which was similar to that observed in Arm A. With nimotuzumab, 4 patients (7.27%) developed rashes but in no patient the rash was grade 3-4.
| » Discussion|| |
Most studies on anti-EGFR monoclonal antibodies in combination with chemotherapy in R/M SCCHN have been reported from western countries and none of them have included nimotuzumab. As Indian patients are culturally and ethnically different from their western counterparts, the course of disease and response to various chemotherapeutic regimens is different in an Indian scenario. Nimotuzumab offers an interesting option after studies proved its efficacy when given concurrently with radiotherapy in locally advanced SCCHN.,, Most importantly it proved to be efficacious without displaying the advanced side effects of anti-EGFR monoclonal antibodies.
Previous studies on other anti-EGFR monoclonal antibodies in combination with chemotherapy in R/M SCCHN showed improved response rates and survival but there is not much data regarding use of nimotuzumab in this setting. Thus, the present study was prospectively designed to look at the efficacy, PFS and, tolerability of nimotuzumab in combination with platinum- and taxane-based chemotherapy regimes in patients with R/M SCCHN who presented at a tertiary care cancer hospital of North India.
In the present study, the median age at presentation was 53 years which is slightly younger than most of the published studies on the subject. In EXTREME trial with cetuximab, the median age was 56 years, and in the SPECTRUM trial of panitumumab, it was 58 years. The majority of the patients were male (91.8%), with performance status 0-1 (81%) and which is also similar to reported literature.
There was no statistically significant correlation seen between the age of the patient and the ECOG PS [Table 1]. However, most of the patients with PS of 2 were beyond their fifth decade. In our study population, 83.2% of patients were tobacco users in any form (smoke/non-smoke) which is almost similar to global statistics.
The present study demonstrates that the combination of nimotuzumab with platinum (cisplatin/carboplatin) and taxane (paclitaxel/docetaxel) was effective in R/M SCCHN. Among 55 patients, 21 receiving nimotuzumab + chemotherapy showed response (ORR 38.2%) which is similar to what observed in cetuximab and chemotherapy arm in the EXTREME trial (ORR 36%) and in the SPECTRUM trail of panitumumab (ORR 37%).
Median PFS reported in nimotuzumab plus chemotherapy arm in the study was 5.2 months; which is similar to median PFS achieved in studies by combining other anti-EGFR monoclonal antibodies with chemotherapy (EXTREME and SPECTRUM trials). The PFS advantage achieved by combining nimotuzumab with chemotherapy (5.2 months versus 3.2 months) was statistically significant (P = 0.00763, CI 95%) as observed in SPECTRUM and EXTREME trials [Table 5].,
|Table 5: Clinical trials of anti-EGFR monoclonal antibody plus chemotherapy in R/M SCCHN|
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Overall, the combination of cetuximab with chemotherapy was very well tolerated in our study. The addition of nimotuzumab to chemotherapy did not add on to toxicity. The incidence and severity of rash as well as electrolyte imbalances such as hypomagnesemia observed in the present trial with nimotuzumab were much lesser compared to that observed in the cetuximab arm in the EXTREME trial and panitumumab arm in the SPECTRUM trial [Table 6]. Moreover, there was no statistically significant difference in incidence of these adverse events in the nimotuzumab with chemotherapy arm versus chemotherapy arm in the present study.
This excellent safety profile of nimotuzumab has been observed in other studies as well.,, There are very few published studies regarding outcomes of Targeted therapy in combination with chemotherapy in patients with R/M SCCHN in India. To the best of our knowledge, there is no published literature of Indian patients regarding the use of nimotuzumab in combination of chemotherapy in R/M SCCHN.
One possible limitation to the study is the lack of complete follow up to give an assessment of OS and 1-2 years survival rates which would allow a comprehensive comparison with other studies and a better assessment of the efficacy of the chemotherapy regimen.
The findings of our study may have significant implications for clinical practice. The clinical outcome of patients receiving nimotuzumab with chemotherapy for R/M SCCHN has been observed to be similar to that reported from combination of other anti-EGFR monoclonal antibodies with chemotherapy. The major finding in our study was that nimotuzumab displayed efficacy without producing clinically significant toxicity which is typical to other monoclonal antibodies. It is very well tolerated due to its excellent safety profile with good compliance to treatment.
| » Conclusion|| |
Based on our experience with this study, it can be concluded that the combination of nimotuzumab plus platinum/taxane-based chemotherapy is active and well tolerated in Indian patients in R/M SCCHN. Addition of nimotuzumab- to chemotherapy-improved response rate and PFS without any significant increase in toxicity. The response rate of 38.2% and a promising median PFS of 5.2 months are strong arguments for further clinical trials of the combination in R/M SCCHN. To the best of our knowledge, this is the first such study conducted in India. However, this study is an open label non-randomized study. Hence, larger randomized clinical trials are required for confirmation of efficacy and tolerability of this regime.
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Conflicts of interest
There are no conflicts of interest.
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[Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 1]
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