First-line combination of gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE extranodal natural killer/T-cell lymphoma

Authors

  • Liang Wang MD,

    1. Department of Hematological Oncology. Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
    2. State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, People's Republic of China
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    • The first 3 authors contributed equally to this article.

  • Zhi-hui Wang MD,

    1. Department of Medical Oncology. The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People's Republic of China
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    • The first 3 authors contributed equally to this article.

  • Xiao-qin Chen MD,

    1. Department of Hematological Oncology. Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
    2. State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, People's Republic of China
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    • The first 3 authors contributed equally to this article.

  • Ya-jun Li MD,

    1. State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, People's Republic of China
    2. Department of Medical Oncology. Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
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  • Ke-feng Wang MD,

    1. Department of Hematological Oncology. Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
    2. State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, People's Republic of China
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  • Yun-fei Xia MD,

    1. State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, People's Republic of China
    2. Department of Radiotherapy. Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
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  • Zhong-jun Xia MD

    Corresponding author
    1. Department of Hematological Oncology. Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
    2. State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, People's Republic of China
    • Department of Hematological Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, 510060 Guangzhou, Guangdong, People's Republic of China

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    • Fax: (011) 86-20-87363019


Abstract

BACKGROUND:

Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma in which the upper aerodigestive tract is the most commonly involved site. To date, optimal treatment strategies and prognosis for patients with ENKTL have not been fully defined.

METHODS:

This prospective study was conducted to evaluate the efficacy and safety profiles of first-line combined gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE ENKTL. The primary endpoints were the complete response rate, the objective response rate, and toxicities. Secondary endpoints were overall survival and progression-free survival.

RESULTS:

Twenty-seven patients with newly diagnosed ENKTL were enrolled and completed the entire course of treatment. At the end of treatment, the overall response rate was 96.3%, including 20 patients (74.1%) who attained a complete response and 6 patients (22.2%) who attained a partial response. No patients developed disease progression during therapy. Grade 1 and 2 toxicities were frequent during GELOX, but grade 3 and 4 toxicities were few, and no treatment-related deaths occurred. At a median follow-up of 27.37 months, 7 patients (25.9%) experienced disease progression, and 4 of those patients died of disease. The rates of 2-year overall and progression-free survival were both 86%, and patients who attained a complete response at the end of treatment had significantly longer progression-free survival (P = .012) and overall survival (P = .021) than patients who did not attain a complete response.

CONCLUSIONS:

The current results indicated that GELOX followed by involved-field radiation therapy can be an effective and feasible treatment strategy for patients with stage IE/IIE ENKTL of the upper aerodigestive tract. These results will require further investigation in larger prospective trials. Cancer 2013. © 2012 American Cancer Society.

INTRODUCTION

Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is a distinct subtype of natural killer (NK) cell lymphoma. Although it is uncommon in western countries, it makes up 5% to 10% of all lymphomas in the Chinese population.1 ENKTL can present with either nasal or extranasal involvement, and the upper aerodigestive tract is the most frequently involved site.2, 3 Because ENKTL is a recently recognized, distinct clinicopathologic entity in the World Health Organization classification,4 to date, optimal treatment strategies for ENKTL and the prognosis for patients with the disease have not been fully defined. For patients with localized nasal disease, radiation therapy (RT) is widely administered, because the response is rapid: RT produces complete response (CR) rates of up to 70%.5-7 However, approximately 50% of patients who receive RT alone experience local relapse, and systemic failure reportedly occurs in approximately 25% of patients.5 Therefore, the addition of chemotherapy is emphasized to reduce the risk of recurrence.8-12 Chemotherapy is essential for advanced stages of nasal and extranasal ENKTL. However, treatment outcomes with conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy are dismal, and >60% of patients have resistant disease.10-13 The high incidence of resistance to conventional chemotherapy with this subtype of lymphoma may be related to overexpression of the multidrug-resistant (MDR) gene, with an increase in the amount of P-glycoprotein in NK/T-cell lymphoma cells.14 P-glycoprotein can actively export doxorubicin and vincristine, the prime components of the CHOP regimen, leading to inferior treatment outcomes. Recently, more and more novel regimens have emerged with promising results, especially L-asparaginase–based regimens like combined dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE)15 and combined asparaginase, methotrexate, and dexamethasone (AspaMetDex).16 Although high response rate can be attained with SMILE, the toxicities are nearly unacceptable. Whether the AspaMetDex regimen can achieve superior results in initial treatment needs to be investigated in additional clinical trials. A gemcitabine and oxaliplatin salvage regimen has been proven effective for patients with refractory or relapsed B-cell lymphoma.17 Thus, we designed an induction chemotherapy regimen that consisted of combined gemcitabine, oxaliplatin, and L-asparaginase (GELOX), all agents that are not affected by P-glycoprotein. In addition, we added involved-field RT (IFRT). The objective of this single-center, prospective study was to investigate the efficacy and safety of GELOX followed by IFRT for the treatment of stage IE/IIE ENKTL.

MATERIALS AND METHODS

Patients

From January 2008 to July 2011, 35 patients with ENKTL were admitted to the Department of Hematological Oncology, including 8 patients with stage III/IV disease, and all of these patients received GELOX as induction chemotherapy. Of these, 27 patients with newly diagnosed stage I and II ENKTL were enrolled in this study. The primary site of all patients was the upper aerodigestive tract. All patients signed a written informed consent form before enrollment, and the study was approved by the Sun Yat-sen University Cancer Center Research Ethics Board. The inclusion criteria for this study were as follows: 1) a biopsy-proven diagnosis of ENKTL; 2) patients who were previously untreated; 3) Ann Arbor stage IE through IIE disease; 4) adequate hematologic function (eg, hemoglobin ≥90 g/L, absolute neutrophil count >1.5 × 109/L, and platelet count >100 × 109/L), renal function (eg, serum creatinine ≤1.5 mg/dL and creatinine clearance ≥50 mL/minute), and hepatic function (eg, total bilirubin ≤2 times the upper limit of normal and aspartate and alanine transaminase levels ≤3 times the upper limit of normal); and 5) an Eastern Cooperative Oncology Group performance status of 0 to 2. The diagnosis was made according to the presence of histologic characteristics and immunophenotypes consistent with ENKTL.4 Exclusion criteria included previous or concomitant malignancies and any coexisting medical problems that could cause poor compliance with the study protocol. Other subtypes of non-Hodgkin lymphoma and ENKTL with primary sites other than the upper aerodigestive tract were excluded.

Patients were staged based on the Ann Arbor staging system, and International Prognostic Index (IPI) scores were calculated based on demographic characteristics; physical examination; routine blood tests; computed tomography (CT) scans of the chest, abdomen, and pelvis; magnetic resonance imaging studies of the head and neck; and bilateral bone marrow aspiration or biopsy. Positron emission tomography-CT scans, bone marrow Epstein-Barr virus-encoded small RNA (EBER) staining, and Epstein-Barr virus (EBV) DNA blood levels were not routine staging investigations in the current study.

Treatment Protocol

The GELOX regimen consisted of gemcitabine (1000 mg/m2 as an intravenous drip on days 1 and 8), oxaliplatin (130 mg/m2 as an intravenous drip on day 1), and L-asparaginase (6000 IU/m2 daily as an intravenous drip on days 1-7). The treatment cycle was repeated every 21 days. Before the administration of L-asparaginase, an intradermal skin test was performed with 50 IU L-asparaginase dissolved in 1 mL normal saline. After 1 hour, if no obvious rash, erythema, pruritis, or other allergic reaction occurred, then the patients received intravenous L-asparaginase 6000 IU/m2. Patients who experienced hypersensitivity to L-asparaginase received pegaspargase instead; and, according to the dose intensity (ie, the dose of effective drug administered per unit of time [in mg/m2 per week]), the GELOX regimen was modified as follows: gemcitabine (1250 mg/m2 as an intravenous drip on day 1), oxaliplatin (85 mg/m2 as an intravenous drip on day 1), and pegaspargase (2500 IU/m2 daily as an intramuscular injection on day 1) repeated every 14 days. In the GELOX regimen, the dose intensity of gemcitabine and oxaliplatin was 667 mg/m2 per week and 43 mg/m2 per week, respectively; and it was 625 mg/m2 per week and 42.5 mg/m2 per week, respectively, for the pegaspargase-containing regimen). During chemotherapy intervals, patients with hematologic toxicities who had a peripheral white blood cell count <2.0 × 109/L received granulocyte-colony–stimulating factor (5 μg/kg daily) until neutrophil recovery. Patients received the chemotherapy regimens only if their the absolute neutrophil count was ≥1.5 × 109/L and their platelet count was ≥75 × 109/L before each cycle. If patients developed grade 4 hematologic toxicity, then the doses of all chemotherapy drugs were reduced by 20% in all subsequent cycles. After at least 2 cycles of GELOX, patients were referred for IFRT. Then, they received GELOX for 2 to 4 cycles within 1 week after the completion of IFRT, resulting in a maximum total of 6 cycles of GELOX. Second-line chemotherapy was received by patients who suffered from progressive disease during GELOX chemotherapy. Primary IFRT was delivered using 6-MeV linear accelerator using 3-dimensional conformal treatment planning. The IFRT dose was 56 grays (Gy) in 28 fractions, with 2 Gy a day and 5 fractions each week. We defined the clinical target volume of limited stage IE disease as the bilateral nasal cavity, bilateral ethmoid sinuses, and ipsilateral maxillary sinus; and the clinical target volume extended to involved tissues for patients who had extensive stage IE disease. For patients who had stage IIE disease, the clinical target volume also included the bilateral cervical lymph node area.

Response and Safety Assessments

Tumor response was assessed after every 2 cycles of chemotherapy or before and after RT on the basis of standardized response criteria for non-Hodgkin lymphoma.18 After the completion of therapy, patients were evaluated by their oncologists in the outpatient department. The follow-up frequency after treatment was every 2 months in the first 2 years, then every 6 months for the next 3 years, and annually thereafter. Each follow-up visit included a physical examination, routine blood tests, and a CT or magnetic resonance imaging scan of the involved area for each patient. The primary endpoints were toxicity and the response rate (the proportion of patients who achieved a CR and a partial response [PR]). All adverse effects after chemotherapy were graded based on version 3.0 of National Cancer Institute Common Terminology Criteria of Adverse Events. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). PFS was calculated from the date of diagnosis to the date of disease progression and was censored at the date of the last follow-up visit. OS was calculated from the date of diagnosis to the date of death from any cause and was censored at the date of the last follow-up visit.

Statistical Analysis

All statistical analyses were performed using PASW Statistics 18.0 software (Apache Software Foundation, Forest Hill, Md). Survival functions were estimated using the Kaplan-Meier method and were compared using the log-rank test. Differences between the results from comparative tests were considered significant if the 2-sided P value was <.05.

RESULTS

Patient Characteristics

Characteristics of all patients are provided in Table 1. Tumor immunophenotypic analysis indicated that all 27 patients had CD56-positive disease, and 25 patients (92.6%) had cytoplasmic CD3-positive status. T-cell intracellular antigen was expressed in all 27 patients (100%). Among the 24 patients had in situ hybridization analysis of EBV RNA, all 24 (100%) were positive for EBER. In this cohort of 27 patients with ENKTL, 16 patients (59.3%) were men. The mean patient age was 47 years (range, 21-74 years), and 4 patients (14.8%) were aged >60 years. B symptoms were present in 10 patients (37%), and serum lactate dehydrogenase levels were increased in only 3 patients (11.1%). Locoregional lymph nodes were involved in 11 patients (40.7%). The distribution of IPI score included 22 patients (81.5%) with an IPI score of 0 and 5 patients (18.5%) with an IPI score of 1.

Table 1. Patient Demographic and Clinical Characteristics
CharacteristicNo. of Patients%
  1. Abbreviations: ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index; LDH, lactate dehydrogenase; LN, lymph node.

Age, y  
 ≤602385.2
 >60414.8
Sex  
 Men1659.3
 Women1140.7
ECOG performance status  
 0518.5
 11866.7
 2414.8
Ann Arbor stage  
 IE1866.7
 IIE933.3
“B” symptoms  
 Absent1763
 Present1037
Serum LDH  
 Normal2488.9
 Increased311.1
IPI  
 02281.5
 1518.5
Locoregional LN invasion  
 Absent1659.3
 Present1140.7

Response to Treatment

All patients with stage IE/IIE disease received at least 2 cycles of GELOX followed by IFRT. In total, 138 cycles of GELOX treatment were administered, and the median number of cycles per patient was 6 for the entire group (range, 2-6 cycles per patients). After 2 cycles of GELOX, there were 15 CRs (55.6%), 10 PRs (37%), and 2 patients had stable disease (7.4%). All patients responded to chemotherapy, and no patient experienced disease progression during chemotherapy. IFRT was received by all patients and was delivered as scheduled after at least 2 cycles of chemotherapy. After IFRT, the CR rate increased to 66.7% (18 of 27 patients), the PR rate was 29.6% (8 of 27 patients), and only 1 patient (3.7%) retained stable disease. At the end of treatment, the objective response rate was 96.3%, which included 20 patients (74.1%) who had a CR and 6 patients who had a PR (22.2%). No patients suffered from disease progression during therapy. Table 2 indicates that there was no significant difference in treatment outcomes between the L-asparaginase–containing regimen and the pegaspargase-containing regimen.

Table 2. Treatment Outcomes by Type of Asparaginase
Type of ASPResponse Rate After 2 Cycles of CT, %PaResponse Rate at the End of Treatment, %Pa2-Year OS Rate, %Pa2-Year PFS Rate, %Pa
  • Abbreviations: ASP, asparaginase; CT, chemotherapy; CR, complete response; OS, overall survival; PFS, progression-free survival; PR, partial response.

  • a

    Chi-square test.

L-ASP, n = 20CR 50/PR 40.785CR 65/PR 30.24284.34473.783
Pegaspargase, n = 7CR 71.4/PR 28.6 CR 100 100 100 

Eight patients with stage III/IV disease received GELOX off study. Two patients were lost to follow-up after the first cycle of treatment. Of the remaining 6 patients (2 with stage III disease and 4 with stage IV disease; 6-8 cycles of GELOX were received), 2 patients attained a CR after 4 cycles of GELOX, 3 patients attained a PR at the end of treatment, and 1 patient had progressive disease after the first cycle of GELOX that was successfully salvaged with infusional etoposide, vincristine, and doxorubicin with bolus cyclophosphamide (the EPOCH regimen). After a median follow-up of 10.84 months (range, 3.14-27.21 months), 2 patients died 3.14 months and 7.80 months after the start of treatment, and the remaining 4 patients remained alive without disease progression.

Toxicity

The adverse effects of GELOX are summarized in Table 3. Grade 1 and 2 toxicities were frequent during GELOX treatment. The major side effects were leukopenia, anemia, thrombocytopenia, nausea, vomiting, liver dysfunction, hypoalbuminemia, and dysfunction of blood coagulation. In total, 24 patients developed a decrease in fibrinogen, which was treated with fresh-frozen plasma and cryoprecipitate. Grade 3 and 4 toxicities were few. Five patients experienced grade 4 leukopenia or thrombocytopenia. Three of 27 patients (11.1%) had a delay in chemotherapy because of an abnormal liver function test (grade 3 in 1 patient and grade 2 in 2 patients). A diabetic individual (1 of 27 patients; 3.7%) refused L-asparaginase therapy after 2 cycles of GELOX (this patient received only gemcitabine and oxaliplatin in the subsequent 4 cycles of chemotherapy) because of uncontrolled hyperglycemia. Seven patients had a positive reaction to the L-asparaginase skin test, but pegaspargase was well tolerated in all of them. Grade 1 and 2 mucositis and dermatitis were frequent during IFRT, and the rates of grade 3 mucositis and dermatitis were 14.8% and 11.1%, respectively. No patient developed grade 4 adverse effects during IFRT. There were no treatment-related deaths.

Table 3. Toxicity Profiles
 Adverse Event From Chemotherapy and Event Grade
 No. of Events No. of Events 
ToxicityGrade 1Grade 2Grades 1+2, %Grade 3Grade 4Grades 3+4, %
Hematologic      
 Anemia13670.4207.4
 Leukopenia12770.46333.3
 Thrombocytopenia13774.76229.6
Nonhematologic      
 Nausea9551.9207.4
 Vomiting6540.73011.1
 Anorexia9655.64014.8
 Increased transaminases13463103.7
 Hyperbilirubinaemia3218.5207.4
 Hypoalbuminemia10555.6103.7
 Decreased fibrinogen15574.13114.8
 Hyperglycemia207.4000
 Hypersensitivity7025.9000
 Thrombosis000000

Relapse and Survival

At a median follow-up of 27.37 months (range, 2.86-48.69 months), 7 of 27 patients (25.9%) experienced disease progression at a median of 22.93 months (range, 5.03-29.01 months), and 4 of those patients died of disease at a median of 19.22 months (range, 5.03-28.85 months). Figure 1 indicates that the 2-year OS rate and the 2-year PFS rate were both 86%. Three patients developed distant progression during follow-up, including 1 patient who experienced a relapse in his lung and 2 who developed liver metastasis. All 3 of these died after failure of the salvage treatment. Local progression was observed in 4 patients, including 1 patient who had a relapse in the submandibular lymph nodes, 1 patient who had a relapse in the left maxillary sinus within his prior radiation field, and 2 patients who had relapses in the nasal cavity. After disease progression, patients received either combined ifosfamide, etoposide, and methotrexate (IMVP-16) or combined dexamethasone, high-dose cytarabine, and cisplatin (DHAP) chemotherapy as salvage treatment. Figure 2 demonstrates that the patients who had a CR at the end of treatment had significantly longer PFS (P = .012) and OS (P = .021) than patients who did not have a CR.

Figure 1.

These survival curves indicate (A) 2-year and 3-year overall survival rates of 86% and 78%, respectively; and (B) 2-year and 3-year progression-free survival rates of 86% and 75%, respectively.

Figure 2.

Patients who attained a complete response (CR) at the end of treatment had significantly longer (A) overall survival (P = .021) and (B) and progression-free survival (P = .012) compared with patients who did not attain a CR.

DISCUSSION

In this pilot study, we explored frontline treatment with nonanthracycline-based chemotherapy, including gemcitabine, oxaliplatin, and L-asparaginase (GELOX), followed by IFRT for the treatment of patients with stage IE/IIE nasal ENKTL. In non-Hodgkin lymphoma, gemcitabine is considered a promising substitute for cytarabine because of its greater single-drug activity, good safety features, and synergistic effect with platinum complexes.19-21 Moreover, oxaliplatin is also an effective drug in non-Hodgkin lymphoma, and its single-drug activity can reach an objective response rate of 27% to 40%.22 When gemcitabine and oxaliplatin were used in combination, a promising synergistic effect was observed in vitro and in clinical studies with lymphoma.19, 23 L-asparaginase has a special anticancer mechanism. It can hydrolyze and exhaust serum asparagines in NK/T-cell lymphoma cells, which cannot synthesize L-asparagines by themselves, and finally produces an anticancer effect.24 Previous studies have demonstrated that L-asparaginase–based chemotherapy regimens produced outstanding response rates in patients with refractory or relapsed ENKTL.25 The GELOX regimen takes advantage of the combination of gemcitabine, oxaliplatin, and L-asparaginase, all of which are nonanthracycline drugs that demonstrated significant activity and nonoverlapping toxicity in previous studies. In the current study, using GELOX, we achieved a satisfactory response rate with acceptable toxicity.

RT is an important treatment modality for ENKTL and is useful to control locoregional disease. The 5-year OS rate ranged from 37.9% to 66% in patients with stage IE through IIE disease who received IFRT alone,26-28 which was attributed to local relapse and distant progression after RT. Because of the high systemic failure rate after RT, combined chemotherapy plus RT is the mainstay of treatment. However, in previous studies, anthracycline-based chemotherapy like CHOP followed by RT resulted in a CR rate of 58%, and scheduled RT was received by only 35% of patients because of early progression.10 As an historical control, 125 patients at our center who had stage I through II ENKTL with good IPI scores (0-1) received with CHOP plus IFRT; after induction chemotherapy with CHOP, their CR rate was 31.8%, which increased to 69.6% after RT; the 2-year OS and PFS rates were 60.2% and 49.1%, respectively (unpublished data). In our current study, the CR rate at the end of treatment was 74.1%, which is higher than the rates reported in the previous study that used anthracycline-based chemotherapy followed by RT.10 It is noteworthy that all but of 2 patients (92.6%) in our current study responded to chemotherapy, and the remaining 2 patients achieved disease control after 2 cycles of GELOX. None of these patients experienced disease progression during chemotherapy; thus, the planned RT was delivered on time for all patients. Moreover, the 2-year OS rate and the 2-year PFS rate both were 86.0% in our study, which is significantly higher than our historical control data, indicating that GELOX chemotherapy was more active than anthracycline-based chemotherapy. The frontline use of “sandwich” L-asparaginase, vincristine, and prednisone with RT, which also is a nonanthracycline-based chemotherapy regimen, produced a response rate of 88.5%, which included an 80.8% CR rate and a 7.7% PR rate in patients with newly diagnosed stage IE/IIE ENKTL.29 This CR rate was comparable to that in our current study, but our objective response rate was slightly higher. However, 3 of 26 patients (11.5%) progressed during sandwich L-asparaginase, vincristine, and prednisone treatment; and no patients in our study experienced such progression. Compared with the results from another study that used dose-intensified CHOP followed by RT,30 our distant relapse rate was lower (11.1% vs 29.4%, respectively). Therefore, our treatment strategy with GELOX and IFRT may reduce local relapse and systemic relapse. At a median follow-up of 27.37 months, only 7 of our 27 patients (25.9%) experienced disease progression. Although the follow-up in our study was relatively short, the recurrence peak did not appear 2 years after the completion of treatment. This demonstrates the efficacy of GELOX and indicates that RT should be added to these nonanthracycline-based chemotherapy regimens.

Although grade 1 and 2 toxicities were frequent during GELOX, grades 3 and 4 toxicities were few. The most common adverse effects, such as liver dysfunction, hypoalbuminemia, and dysfunction of blood coagulation, can be well controlled by supportive treatments. It is important to note that 7 patients (25.9%) had positive results from the L-asparaginase skin test, and pegaspargase was used instead, which resulted in similar rates of CR, 2-year OS, and 2-year PFS. However, the sample size was too small in the pegaspargase-containing arm; thus, further trials comparing these 2 regimens are required. Because L-asparaginase is a nonhuman protein, antibody response results not only in anaphylactic and other immunologic side effects but also in inactivation of the product.31 Pegaspargase, the monoethoxypolyethylene glycol succinimidyl conjugate of Escherichia coli L-asparaginase, has decreased immunogenicity and has a longer half-life than L-asparaginase,32 and it maintains asparagine depletion equivalent to higher doses and prolonged administration of the native preparations. Thus, if antibodies to L-asparaginase are detected in patients who previously received L-asparaginase therapy or if patients exhibit hypersensitivity to L-asparaginase, then L-asparaginase may be switched to pegaspargase. The hematologic toxicities in our study were much milder than those reported with the CHOP and SMILE regimens.15 During the study period, no thrombosis occurred in our patients. However, thrombosis is a known adverse event of asparaginase; thus, patients must be monitored closely for thrombosis during follow-up and in subsequent trials.

An analysis of EBV DNA was not included in our study. However, more and more studies have indicated that the plasma EBV DNA load at presentation is associated with clinical disease stage and treatment response,33 and patients with a high EBV DNA load have a poorer prognosis (the 3-year OS rates were 42.9% and 94.4% in patients with positive and negative plasma EBV DNA status, respectively; P = .0009).34 Thus, our study protocol will be modified to include an analysis of EBV DNA, and we suggest it should be included in subsequent trials that investigate NK/T-cell lymphoma to evaluate the role of EBV DNA detection for uniformly treated patients. Thus, we conclude that GELOX followed by IFRT can be a feasible and effective treatment strategy for patients with stage IE through IIE upper aerodigestive tract ENKTL and requires further investigation in larger prospective trials.

Acknowledgements

We thank all of the physicians at Sun Yat-sen University Cancer Center for allowing us to include their patients. We also appreciate the cooperation of all the pathologists at Sun Yat-sen University Cancer Center for their support.

FUNDING SOURCES

No specific funding was disclosed

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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