Annals of Oncology Advance Access published online on August 5, 2008
Annals of Oncology, doi:10.1093/annonc/mdn551
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Effective second-line chemotherapy for extranodal NK/T-cell lymphoma consisting of etoposide, ifosfamide, methotrexate, and prednisolone
1 Department of Internal Medicine, Seoul Municipal Boramae Hospital, Seoul
2 Department of Internal Medicine, Seoul
3 Department of Pathology, Seoul National University Hospital, Seoul
4 Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul
5 Department of Internal Medicine, Center for Gastric Cancer, National Cancer Center Hospital, Goyang-si, Gyeonggi-do, South Korea
* Correspondence to: Prof D. S. Heo, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, South Korea. Tel: +82-2-2072-2857; Fax: +82-2-742-6689; E-mail: heo1013{at}snu.ac.kr
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Abstract |
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Background: Many patients with extranodal natural killer/T-cell lymphoma (NTCL) fail to the front-line therapy and need an effective second-line chemotherapy.
Patients and methods: This was single-institutional, phase II study. The primary end point was response rate and secondary end points were toxicity, time to treatment failure (TTF), and overall survival (OS). Patients with relapsed or refractory NTCL were eligible. They received the chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone and it was repeated every 3 weeks.
Results: Thirty-two patients were enrolled and 15 patients had achieved partial remission (PR) or complete remission (CR) after the front-line chemotherapy. The International Prognostic Index scores were 0–1 in thirteen, 2 in five, 3 in five, and 4–5 in nine patients. Twelve and two patients achieved CR and PR, respectively. Median OS and TTF of all patients were 8.2 and 3.7 months, respectively. Non-hematologic toxic effects were well tolerated, but grade 3/4 leukopenia occurred in 11.7% of all cycles. Four patients developed febrile neutropenia and one patient died due to pneumonia.
Conclusions: This chemotherapy regimen was moderately effective for relapsed/refractory extranodal NTCL, nasal type. Toxic effects were moderate, but caution should be exercised to prevent severe infection.
NK/T-cell lymphoma, salvage chemotherapy, second-line chemotherapy
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introduction |
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Extranodal natural killer/T-cell lymphoma (NTCL), nasal type is an Epstein–Barr virus (EBV)-associated lymphoid malignancy and it is believed to be of natural killer (NK) cell origin [1]. NTCL frequently presents as a series of infiltrative and ulcerative lesions around the nasal cavity and other midline facial structures. It can also involve the skin, gastrointestinal tract, salivary gland, and testis [2]. NTCL is rare in western populations, but is more common among Orientals, Mexicans, and South Americans of Native American heritage [3]. A nationwide study about malignant lymphoma in Korea revealed that NTCL accounts for 8.7% of all non-Hodgkin's lymphomas and 74.1% of lymphomas which arise in the nasal cavity or paranasal sinuses [4]. The most characteristic pathologic finding of NTCL is the angiocentricity and immunohistochemistry shows the expression of NK cell marker CD56, lack of surface CD3 expression, presence of cytoplasmic CD3, and positive EBV in situ hybridization [5].
Because of the rarity of NTCL, it is very difficult to perform a prospective randomized trial and the outcomes of only several retrospective studies are available. Patients with stage I/II NTCL often responded to the radiotherapy alone and 
70% of them could achieve complete remission (CR) [6–17]. However, long-term outcomes were generally poor due to the frequent systemic relapses and only 40% of patients survived longer than 5 years [8, 9]. Primary chemotherapy in stage I/II NTCL yielded CR rates of 40%–45% and about a half of them could enjoy the long-term survival [6, 10, 13, 15, 18–20]. The benefit of combined modality therapy of radiation plus chemotherapy is controversial. Only two studies suggested that the incorporation of chemotherapy into a front-line radiotherapy regimen reduced systemic failures [21, 22], but other studies found no additional benefit [7, 11, 17, 23, 24]. Disseminated NTCL requires the up-front combination chemotherapy, but it is usually refractory to anthracycline-based chemotherapy (CR rate 25%–40%) and follows a very aggressive clinical course [18].
Therefore, many patients with NTCL fail to the front-line therapy and need the effective salvage chemotherapy. Various second-line chemotherapy regimens for the relapsed aggressive lymphomas were developed over the last two decades. They reported CR rates of 27%–34% and long-term survival rates of 25%–30%, but they included mostly B-cell lineage lymphomas and gave little information about NTCL [25–27]. The salvage regimen consisting of etoposide, ifosfamide, and methotrexate (IMVP-16) proved to be effective for the relapsed lymphoma (CR rate 37%–43%, median disease-free survival 12 months) [25]. In addition, we reported the promising result of etoposide, ifosfamide, methotrexate, and prednisolone (IMVP-16/Pd) regimen as a front-line chemotherapy for NTCL [28]. Therefore, we tried to investigate the role of IMVP-16/Pd regimen as a second-line chemotherapy for NTCL.
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patients and methods |
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eligibility criteria
This was a single-institution, prospective, open-label, phase II study. NTCL patients who failed (refractory or relapsed after achieving response) to the front-line chemotherapy containing anthracycline were included in this study. The eligibility criteria of this study were age of at least 18 years old, Eastern Cooperative Oncology Group (ECOG) performance status of zero to three, at least one measurable lesion, adequate hematologic (neutrophil count
1.5 x 109/l, platelet count 75 x 109/l), hepatic (serum bilirubin 
1.25 x upper normal limit), and renal (serum creatinine 1.25 x upper normal limit) functions. The exclusion criteria were prior or concomitant malignant tumors and any coexisting medical problems of sufficient severity to prevent full compliance with the study protocol. Prior radiotherapy or chemotherapy had been completed >4 weeks before patients' entry into the study. This study was approved by our institutional review board and each patient signed written informed consent before enrollment.
treatment and dose modification
Ifosfamide (1.0 g/m2) was administered as an i.v. infusion over 1 h on days 1–5. Postchemotherapy hydration and sodium 2-mercaptoethane sulfonate were coadministered in order to prevent hemorrhagic cystitis. Methotrexate (30 mg/m2) was administered as an i.v. injection on days 3 and 10 without leucovorin rescue. Etoposide (100 mg/m2) was administered as an i.v. infusion over 90 min on days 1–3. In addition, patients received prednisolone at a dosage of 120 mg/day orally on days 1–5. It was in accordance with the original IMVP-16 presented by Cabanillas et al. [25] except that prednisolone was added. A standard antiemetic regimen consisting of 5HT3 antagonists was also administered. This chemotherapy regimen was repeated every 21 days to a maximum of six cycles, unless unacceptable toxic effects, signs of disease progression, or withdrawal of patient consent occurred.
The administration of all drugs was delayed for 7 days, if grade 2 or higher hematologic toxic effects appeared before each cycle. Dose reduction was not required after the first occurrence of grade 2 hematologic toxicity, but dosage of drugs except prednisolone was reduced by 25% after the second grade 2 or the first grade 3 hematologic toxicity. If the third grade 2 or the second grade 3 hematologic toxicity appeared, dosage of drugs except prednisolone was reduced by 50% from the initial dose. If patients experienced grade 2 or higher non-hematologic toxic effects, treatment was interrupted until the toxicity resolved to grades 0–1. Dose modification by non-hematologic toxic effects followed the same rules as hematologic toxic effects. Prophylactic use of granulocyte colony-stimulating factor (G-CSF) and antibiotics against any infectious organisms was not permitted and they were administered when a patient developed neutropenic fever.
patient and tumor evaluation
The original pathological diagnosis and immunophenotype were reviewed using the Revised European-American Lymphoma classification by one of the authors. In situ hybridization to EBER was also assessed. The baseline evaluation work-ups started during the 14-day period before the chemotherapy and they included medical history taking, a physical examination, complete blood count (CBC), serum biochemistry, lactate dehydrogenase (LDH), computerized tomography (CT) or magnetic resonance imaging (MRI) of the disease sites, CT of chest, abdomen, and pelvis, and bone marrow aspiration and biopsy. All patients were staged according to the Cotswolds modification of the Ann Arbor staging system.
Every patient received medical history taking, physical examination, CBC, serum biochemistry, LDH, and simple chest X-ray before each cycle. CT scan or MRI of the disease site was repeated every two cycles and then at 12-week intervals until disease progression.
assessment
The primary end point of this study was response rate and secondary end points were toxicity, time to treatment failure (TTF), and overall survival (OS). Hematologic and non-hematologic toxic effects were graded according to the World Health Organization (WHO) toxicity criteria. Tumor responses were assessed according to the WHO criteria and the best response was reported. Response rate was calculated as the proportion of patients achieving CR or partial remission (PR) among all enrolled patients. CR duration was measured from the date of CR confirmation to the date of relapse or the last follow-up. TTF was defined as the time from the date of enrollment into this study to the date of disease progression, discontinuation of treatment due to toxicity, or death due to any cause and was censored at the date of the last follow-up visit. OS was measured from the date of enrollment to the date of death from any cause and was censored at the date of the last follow-up visit.
statistical methods
We hypothesized that maximum response rate of this regimen was 40% and minimum was 20% when inferred from the outcomes of previous retrospective studies. According to the optimal Simon's two-stage design (P value 0.05, power 80%), a sample size of 43 was required to accept the above hypothesis. In the initial stage, 13 assessable patients were to be enrolled into the study and if responses were three or less, accrual was to be stopped. If four or more responses were observed, then 30 additional patients were to be entered in the second stage. If 12 or less responses occurred in total, the above hypothesis was to be rejected.
To compare CR rates between patient subgroups, chi-square test was utilized and a two-sided P value of <0.05 was considered to be significant. The Kaplan–Meier method was used to calculate the CR duration, TTF, and OS. CR duration, TTF, and OS were compared via log-rank tests. The SPSS version 12.0 statistical software program (SPSS, Chicago, IL) was used for all statistical analyses. GraphPad Prism (version 5.0, GraphPad Software, San Diego, CA) was used to plot the survival curves.
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patient characteristics
Since the latter half of 2002, the policy of our institute was changed and this IMVP-16/Pd regimen was given to newly diagnosed NTCL patients. Therefore, patient enrollment was slowed and authors decided to stop further patients recruitment. From October 1996 to February 2002, 32 patients (18 men and 14 women) were enrolled into this study. Pathologic confirmation of relapse was carried out in 16 patients, while it was not done in other patients because of primary refractoriness, short duration before relapse, and the same clinical characteristics as the initial presentation. All patients were assessable and included in all analyses. Their basic characteristics at enrollment are shown in Table 1. The median age of patients was 45 years and 26 patients were <60 years. Ten patients presented with B symptoms and one patient was complicated with hemophagocytosis. Bone marrow was involved in only one patient. Fifteen patients still had a locoregional disease (stage I/II) and 17 had a disseminated disease (stage III/IV) at the time of enrollment. According to International Prognostic Index (IPI), scores were 0–1 in 13 (40.6%), 2 in five (15.6%), 3 in five (15.6%), and 4–5 in nine patients (28.2%). In situ hybridization to EBER was carried out in 21 patients and 17 patients (81.0%) were positive. CD56 was stained in 27 patients and 24 (88.9%) were positive.
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Table 2 shows the detailed history of previous treatments. Fifteen patients received the combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone regimen as a front-line therapy and 17 patients were on the cyclophosphamide, infusional vincristine/doxorubicin/bleomycin, procarbazine, prednisolone (COPBLAM-V) regimen. Fifteen patients had responded to front-line chemotherapy and relapsed later, but 17 patients were stable or primarily refractory to it. Median response duration to front-line chemotherapy was 5.5 months. Twelve patients received radiotherapy to nasal cavity or the upper aerodigestive tract and cervical lymph nodes after the front-line chemotherapy (radiation dose 3600–5580 cGy, median 4500 cGy). Eight patients among them relapsed later within radiation field.
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treatment outcome
In the initial stage, 13 patients entered into the study and five patients showed CR or PR and we proceeded to the second stage. When patient enrollment was closed, 12 patients achieved CR (37.5%), two patients showed PR, and the response rate was 43.8%. In addition, one patient exhibited stable disease and the remaining 17 showed progressive disease. The detailed clinical characteristics of 12 CR patients were presented in Table 3. Five patients who had achieved CR relapsed in 3.3, 4.9, 7.3, 12.1, and 21.3 months and the median CR duration was not reached (Figure 1A). Relapse pattern was locoregional in one patient and systemic in the other four patients. Twenty-four patients discontinued treatment or died due to disease progression or toxicity and median TTF was 3.7 months (5-year rate of TTF 24.6%) (Figure 1B). After a median follow-up of 59 months (26–84 months), 23 patients died and the median OS of all patients was 8.2 months (5-year rate of OS 24.8%) (Figure 1C). Only one patient died of a treatment-related complication and the others died due to a disease progression. Two patients who attained CR or PR received adjuvant radiotherapy after IMVP-16/Pd regimen. Patients who failed to IMVP-16/Pd regimen then received various salvage treatments (radiotherapy three, surgery for bowel perforation two, chemotherapy 10) and one patient underwent autologous peripheral stem-cell transplantation when he was found to have the residual disease. This patient died later due to a disease progression.
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prognostic factor analysis
In order to identify the prognostic factors of NTCL patients treated with second-line IMVP-16/Pd regimen, we tested several clinical variables such as age, B symptoms, and stage at enrollment, IPI, chemosensitivity, and LDH. Chemosensitivity was categorized into ‘sensitive’ and ‘refractory’ by response to the front-line chemotherapy. Sensitive was defined as the first relapse after achieving CR/PR by the front-line chemotherapy and refractory meant that NTCL had progressed or was stable during the front-line chemotherapy. Table 4 shows that the chemosensitivity is a statistically significant predictor for CR (chi-square test, P = 0.014), TTF (log-rank test, P = 0.020), and OS (log-rank test, P = 0.003). IPI could predict CR, TTF, and OS with only marginal significance. Among 12 patients achieving CR by IMVP-16/Pd regimen, CR duration of sensitive patients seemed to be longer than that of refractory patients (not reached versus 4.9 months). However, this difference was statistically insignificant because of small patient number (P = 0.122). Figure 2 illustrates CR duration, TTF, and OS according to the chemosensitivity.
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toxic effects
Of 136 cycles administered, 51 cycles required a 25% dose reduction primarily due to insufficient hematologic recovery. The incidences of common adverse events, as defined by the WHO toxicity criteria, are listed in Table 5. Grade 3/4 leukopenia and neutropenia occurred in 11.7% and 16.2% of all cycles, respectively. However, severe thrombocytopenia and anemia occurred only infrequently throughout the study. Four patients experienced neutropenic fever and received an appropriate antibiotic therapy and G-CSF support, but one patient died as a result of infection. This patient was a 60-year-old man and had the disseminated disease from onset. He had progressed after the first cycle of front-line COPBLAM-V chemotherapy. At enrollment, his performance status was ECOG two and IPI was five. He attained PR after the second cycle of IMVP-16/Pd chemotherapy, but died of neutropenic fever and pneumonia after the sixth cycle (probably due to Pneumocystis carinii pneumonia, on the basis of clinical observation and CT findings). Non-hematologic toxic effects such as nausea/vomiting, diarrhea, and peripheral neuropathy were generally well tolerated.
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In the present study, 32 patients were enrolled and 14 patients responded to IMVP-16/Pd regimen (CR 12, PR two). This result was comparable to the previous studies about second-line regimens in relapsed lymphoma and might suggest that our hypothesis was acceptable although the planned patient recruitment was not completed. In addition, the study regimen produced median TTF of 3.7 months and median OS of 8.2 months, which is also similar to the previous reports in relapsed lymphoma [25–27]. Toxicity profiles were also equivalent to the previous studies. Non-hematologic toxic effects such as nausea/vomiting, diarrhea, and peripheral neuropathy were generally well tolerated. Although hematologic toxic effects and infection risk of this study did not exceed that of the previous studies for relapsed lymphoma, they were still substantial and one patient died of pneumonia in neutropenic status. Therefore, prophylactic usage of G-CSF or antibiotic therapy should be considered to reduce the infection risk.
Univariate prognostic factor analysis showed that the chemosensitivity was the most important predictor for CR, TTF, and OS. IPI also showed marginal significance. However, this finding could not be confirmed by multivariate analysis because of small patient number. It is universal finding that chemosensitive relapse can have better prognosis than primary refractory lymphoma and this study agreed with it. However, the prognostic significance of IPI in NTCL was uncertain and the large retrospective study recently carried out in Korea reported that the prognostic value of IPI in NTCL was not better than other variables [29]. CR duration of patients with chemosensitive relapse also tended to be longer than that of refractory patients, although it was not significant because of small patient number. The above findings suggest that NTCL patients can be divided into two subgroups by the chemosensitivity and treatment strategy should be different according to the sensitivity to previous chemotherapy.
NTCL is characterized by its association with EBV and there has been a concern that EBV could adversely affect the prognosis of lymphoma. In this study, in situ hybridization to EBER was carried out only in 21 patients and 17 showed EBER positivity. Although this small number makes it impossible to carry out a statistical analysis, EBV-positive NTCL showed the tendency toward shorter survival as illustrated in Figure 3. In addition, EBV-positive NTCL responded to chemotherapy relatively poorly considering that six from 17 EBV-positive and two from four EBV-negative NTCL patients achieved CR, respectively. It is interesting question whether EBV can affect the prognosis of NTCL, but our study does not have enough power to prove it. We hope larger study will address this issue soon.
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Among patients who were enrolled into this study, adjuvant radiotherapy to nasal and cervical area had been administered to 12 patients soon after they finished the front-line chemotherapy. Eight of them relapsed within the radiation field and only four patients relapsed outside it, which is compatible with the previous report that front-line radiotherapy could not prevent the frequent systemic relapse and the prognosis of NTCL is still poor [8]. After the second-line IMVP-16/Pd regimen, only two patients could receive adjuvant radiotherapy while other patients had already received radiation (n = 12), their disease progressed systemically (n = 17), or they could not tolerate further therapy because of poor performance status (n = 1). Those two patients enjoyed long-term relapse-free survival after 78.8 and 26.1 months since the start of IMVP-16/Pd regimen. This finding suggests that they had better underlying conditions as well as radiotherapy might have an important role in NTCL [28].
There are a few case reports or small retrospective studies as to salvage chemotherapy for NTCL until now and their outcomes are summarized in Table 6 [30–34]. Among them, L-asparaginase showed the promising activity both as a single agent and in combination with other chemotherapeutic agents. High-dose chemotherapy and autologous hematopoietic stem-cell transplantation are established strategies for the relapsed aggressive lymphoma and also merit a large-scale clinical trial in chemosensitive, relapsed NCTL. In conclusion, IMVP-16/Pd regimen showed the promising activity against chemosensitive, relapsed NTCL, but poorly salvaged the patients with refractory NTCL. Chemosensitivity was a more important prognostic factor than IPI and other variables.
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Korea Health 21 R&D Project, Ministry of Health & Welfare (0412-CR01-0704-0001); Innovative Research Institute for Cell Therapy (A062260), Republic of Korea.
Received for publication January 6, 2008. Revision received June 30, 2008. Accepted for publication July 9, 2008.
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