Radiotherapy As Primary Treatment for Stage IE and IIE Nasal Natural Killer/T-Cell Lymphoma
the Departments of Radiation Oncology, Medical Oncology, and Pathology, Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China.
ABSTRACT
PURPOSE: The optimal therapy remains unclear for nasal natural killer (NK)/T–cell lymphoma. The purpose of this study is to analyze the outcome of radiotherapy as the primary treatment for localized stage IE and IIE diseases.
PATIENTS AND METHODS: One hundred five patient cases were reviewed. There were 83 stage IE and 22 stage IIE patients. All except three patients received radiotherapy (RT) alone or RT combined with chemotherapy (CT; combined-modality therapy [CMT]). Overall, 31 patients were treated with RT alone, 34 with RT followed by CT, 37 with CT followed by RT, and three with CT alone.
RESULTS: Five-year overall survival (OS) and progression-free survival (PFS) for all patients were 71% and 59%, respectively. The 5-year OS and PFS were 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. Complete response (CR) was achieved in 91 patients (87%) after RT and/or CT. Initial RT resulted in a superior CR as compared with initial CT, with 54 (83%) of 65 patients achieving CR with initial RT, versus only eight (20%) of 40 after initial CT. For 102 patients who received RT with or without CT, the outcome of primary treatment with RT alone was compared with that of CMT. Five-year OS and PFS was 66% and 61% for RT alone, and 76% and 61%% for CMT, respectively (OS, P = .6433; PFS, P = .8391).
CONCLUSION: RT as primary therapy resulted in good outcome in early-stage disease, and the addition of CT to RT was not accompanied by an improvement in survival.
INTRODUCTION
Nasal non-Hodgkin's lymphoma (NHL) is a rare clinical entity in Western countries,1-6 but it is common in East Asian countries and Latin American.7-12 The majority of nasal lymphoma from Chinese patients are of natural killer (NK)/T-cell origin, whereas primary lymphomas of the Waldeyer's ring are predominantly B-cell type.7,13-18 In the Revised European-American Lymphoma and WHO classification, primary nasal and nasal-type NK/T-cell lymphoma are recognized as distinct clinicopathologic entities.19-20 Tumors resembling the prototype of nasal NK/T-cell lymphoma that occurred in a variety of extranodal sites other than the nasal cavity are referred to as nasal-type.21 Pathologically, nasal NK/T-cell lymphomas show a broad morphologic spectrum, frequent angioinvasion and angiocentricity with zone necrosis, and a frequent association with Epstein-Barr virus (EBV) infection.22,23 Immunophenotypically, the tumor cells most frequently express CD2+, CD3–, CD3+, and CD56+.13,23-26 Clinically, this entity is characterized by a predominance in young males, is seen in a large proportion of localized stage I and II diseases, is refractory to conventional chemotherapy (CT), and sensitive to radiotherapy (RT). Reported overall survival (OS) varies widely between the series.11,13,26-31 Overall, for patients with early-stage, diffuse large-cell lymphoma, CT followed by involved-field RT is considered the standard treatment.32-36 In contrast, the optimal therapy remains unclear for nasal NK/T-cell lymphoma. The management of this disease has been based largely on extrapolation from the experience with aggressive NHL, and has been limited to small institutional series, heterogeneous treatments, and variable diagnostic criteria.11,13,26-31 In addition, many early clinical studies of nasal lymphoma have actually included B-cell lymphoma, which is distinct from NK/T-cell lymphoma.7-9,37 Several recent studies have suggested that up-front RT results in better outcome as compared with CT, and that the addition of doxorubicin-based CT to RT does not improve survival in early-stage nasal and nasal-type NK/T-cell lymphoma.13,26-28,30,31 In view of the small number of patients receiving primary RT in these studies, a definite advantage of early or upfront RT needs to be ascertained and confirmed in a large study.13,26,28 It has been our policy to consider RT as a primary treatment for patients with early-stage nasal NK/T-cell lymphoma. In our previously reported large study of 175 patients with nasal lymphoma, most of them with NK/T-cell lymphomas, primary RT with or without CT resulted in a good outcome.7 Therefore, the purpose of this investigation is to focus on the initial response and treatment outcome following primary RT in early-stage nasal NK/T-cell lymphoma. Furthermore, we also analyzed the prognostic factors and examine the prognostic value of a modification of the International Prognostic Index (IPI).
PATIENTS AND METHODS
Between January 1983 and December 2003, 329 patients with previously untreated nasal non-Hodgkin's lymphoma (NHL) were referred to the Cancer Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Among them, 107 patients were diagnosed with a nasal NK/T-cell lymphoma after a review of clinicopathologic and immunohistochemical studies. Two of the patients with stage IV are excluded, and the remaining 105 patients with stage IE and IIE form the population of this study.
The pathological diagnosis and classification of nasal NK/T-cell lymphoma was based on the criteria described by Jaffe et al.21 The inclusion criteria in this study were (1) primary symptoms and the majority of the tumor bulky localized in the nasal cavity; (2) histopathological examination showing the features of angiocentric infiltration, necrosis, and polymorphism of individual cells; and (3) expression of NK/T-cell markers in the absence of B-cell markers. Immunohistochemical studies were performed on the following markers: CD45, CD43, CD45RO, CD2, CD3, CD79, CD20, TIA, and other markers. All patients were positive for at least one NK or T-cell marker, and negative for B-cell markers. In recent years, CD56 and CD57 have been available for 22 of 105 patients. The TCR gene and in situ hybridization for Epstein-Barr virus (EBV) –encoded RNA were not performed in every case.
Stage
The patients were staged according to a modification of the Ann Arbor system. Limited stage IE tumors were confined to the nasal cavity, whereas extensive stage IE tumors extended beyond the nasal cavity and into the neighboring structures without any sign of nodal or distant dissemination.7 Complete evaluation of patients included a medical record review, physical examination, blood chemistry, chest radiograph, computed tomography of the head, neck, chest, and abdomen, and bone marrow aspiration.
Treatment
Radiotherapy was the primary therapy for localized nasal NK/T-cell lymphoma (Table 1). All except three patients received RT alone or combined-modality therapy (CMT). Overall, 31 patients were treated with RT alone, three patients with CT alone, 34 with RT followed by CT (RT + CT), and 37 patients with CT followed by RT (CT + RT). For the latter patients, 20 patients received one to two cycles of CT, 16 patients received three to four cycles, and only one patient received five cycles of CT before RT. Furthermore, 26 of these 37 patients received two to four additional cycles of combination CT after CT and RT. Of the 83 patients with stage IE disease, 26 of them were primarily treated with RT alone, 30 with RT + CT, and 27 with CT + RT.
Radiotherapy was given with a 6-MV or 8-MV linear accelerator. The median dose was 50 Gy with a range of 40 to 65 Gy, at a dose per fraction of 2 Gy. The clinical target and radiation fields have been described previously.7 Of 74 patients receiving CT, 64 were treated with CHOP (cyclophosphaminde, doxorubicin, vincristine, prednisone) or CHOP-bleo (CHOP + bleomycin), nine with COBVP-16 (cisplatin, vincristine, bleomycin, prednisone), and one with COPP (cyclophosphaminde, vincristine, procarbazine, prednisone).7
Statistical Analysis
Tumor response was assessed after completion of either RT, CT, or a combination of RT and CT.38 Complete response (CR) was defined as a complete regression of all visible/palpable tumors and radiographic disease. OS and progression-free survival (PFS) were estimated by the product-limit Kaplan-Meier method.39 OS was measured from the start of initial treatment until time of death of any causes, or until last follow-up. PFS was measured from the start of initial treatment until time of first local or distant progression or relapse, or until last follow-up, or death. The differences between survival curves were calculated by the log-rank test.40 Multivariate analysis was performed using the Cox model.41 Prognostic factors included age, sex, performance status, localization, "B" symptoms, paranasal extension, lactate dehydrogenase, Ann Arbor stage, and stage-modified IPI (mIPI). In the mIPI, risk factors were used as initially described by Shipp et al, except that the adverse risk factor for Ann Arbor stage was the stage IIE disease, but not stages III or IV.42 Comparison of the qualitative data was done by 2 analysis.
RESULTS
Patient Characteristics
Patient characteristics are presented in Table 2. Paranasal extension within the vicinity of the primary tumor was present in 64 of 105 patients. Of them, 46 had paranasal extension only, without any nodal or distant dissemination, and 18 had involvement of lymph nodes as well. The majority of patients with stage IIE disease (82%) had paranasal extension, and only four of them (18%) had their primary tumor limited to the nasal cavity. In contrast, 37 (45%) of 83 patients with Ann Arbor stage IE presented with disease limited to the nasal cavity. The most frequently involved organs by the primary tumor were the ethmoid sinus, the maxillary sinus, and the nasopharynx.
Response to Treatment
Table 3 describes the response rates after treatment. Overall, a CR was achieved in 91 (87%) of 105 patients. A much lower CR rate (20%) was achieved after initial CT as compared with those (83%) with initial RT (P = .0001). For these 37 patients receiving CT followed by RT, only seven (19%) of 37 patients achieved a CR, and 15 (40%) of 37 patients achieved PR, whereas the remaining 15 patients (40%) showed stable disease (SD) or progressive disease (PD) after CT. Of the latter 30 patients with PR, SD, and PD, 27 had persistent disease, regrowth, or progression of local disease, and three developed systemic progression. However, 23 of these 27 patients with a local failure achieved CR after completion of subsequent RT. When the tumor responses of the two groups were compared after completion of RT or a combination of RT and CT, the CR rate of the CT + RT group (30 of 37 patients, 81%) was similar to that of RT alone and RT + CT (60 of 65 patients, 92%; P = .387). Similar response rates were observed in the subgroup of 83 stage IE patients.
Survival and Prognostic Factors
With a median follow-up time of 52 months, 5-year OS and PFS for all patients were 71% and 59%, respectively (Fig 1). Twenty-six patients had died. Of these, 22 died of lymphoma, three of intercurrent diseases, and one of a treatment-related complication.
The patient characteristics were evaluated for prognostic significance on OS and PFS (Table 4). On univariate analysis, Ann Arbor stage, performance status, and mIPI were found to be significant factors influencing both OS and PFS. Patients without paranasal extension showed a trend toward a better OS and a statistically significant better PFS. The 5-year OS and PFS were 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. There was a trend toward a better OS than those with extensive stage IE, with a 5-year OS of 82% for limited stage IE and 75% for extensive stage IE, respectively (P = .0763). The corresponding difference in PFS was highly significant, with 80% for limited stage IE and 45% for extensive stage IE, respectively (P = .0123; Fig 2). Using the mIPI, patients without any adverse factors had very limited disease and a corresponding 5-year OS and PFS exceeding 90%. On multivariate analysis, Ann Arbor stage, paranasal extension, and mIPI were significant prognostic factors for OS and PFS.
Treatment Outcome According to the Treatment Modalities in Stage IE and IIE
The outcome of primary treatment with RT alone was compared with that of RT + CT or CT + RT. These patients were comparable with respect to age, sex, Ann Arbor stage, lactate dehydrogenase, performance status, and mIPI (Table 5). However, patients treated with CMT were more likely to have B symptoms and paranasal extension. The 5-year OS and PFS was 66% and 61% for RT alone, 77% and 74% for RT + CT, and 74% and 43% for CT + RT, respectively, with no significant differences between the three groups. To analyze whether the addition of CT to RT modified the outcome, we compared the treatment outcome between RT alone and CMT. The 5-year OS and PFS were 76% and 61% for CMT, compared with 66% and 61% for RT alone (P = .6433 for OS, P = .8391 for PFS; Fig 3).
Concerning the three stage IIE patients receiving CT alone, two died of their disease, and one was lost to follow-up at 2 months.
Treatment Outcome According to the Treatment Modalities in Stage IE
We subsequently evaluated the outcome in 83 stage IE patients according to the treatment options. Patients who received CMT had more B symptoms and extensive stage IE. There was no statistically significant difference in 5-year OS and PFS between the various treatment modalities (Table 6). Furthermore, no survival benefit was observed after the addition of CT to RT. The 5-year OS and PFS were 73% and 63% for RT alone as compared to 80% and 64% for CMT (P = .9274 for OS and P = .8533 for PFS; Fig 4).
Patterns of Failure
Twelve patients progressed during the treatment, and 21 relapsed between 2 and 72 months after treatment. The majority of patients (12 of 21, 57%) relapsed within 2 years, and one, beyond 5 years. Figure 5 shows the patterns of progression and relapse in 31 available patients. Distant extranodal dissemination was the primary patterns of failure. The most frequent sites of extranodal failure were observed in skin (11 cases), bone marrow (five patients), lung (four patients), and liver (three patients).
DISCUSSION
After the Waldeyer's ring, nasal lymphoma is the second most common site of primary extranodal NHL in China.7,14,16-18 In contrast to NHL of Waldeyer's ring, which are predominantly B-cell type, nasal NHL are mainly NK/T-cell lymphoma, accounting for 74% to 98% of nasal lymphoma in China.7-9,14,26,27,43-45 The majority (67% to 98%) of nasal NK/T-cell lymphoma patients present with stage I-II diseases, though distant involvement is rare at the onset.24-27,46,47
Although chemotherapy followed by involved-field RT is a standard treatment for early-stage, diffuse large-cell lymphoma, the optimal therapy for nasal NK/T-cell lymphoma has not yet been clearly defined.32-36,48 Before 2000, few studies addressed the nasal NK/T-cell lymphoma as a separate entity, and most of them included a mixture of nasal T-cell, B-cell, or nasal-type NK/T-cell lymphoma.7,8,24,37,49 Furthermore, the treatment options for nasal NK/T-cell lymphoma show geographic variations between different countries or even between different institutions. In our institution, the majority of patients received up-front RT, with or without CT. For patients receiving CT first, short courses (usually one to four cycles) of combination CT were applied before RT due to poor initial response.
The reported CR rate for patients with stage I-II nasal-type NK/T-cell lymphoma ranged from 52% to 100% after RT, whereas it was between 8% and 59% after CT, most of the CR rate after CT being lower than 40% (Table 7). 1,11,13,25-28,30,31,50 In contrast, CR rate was between 85% and 90% for early-stage, diffuse large B-cell lymphoma.51 In the current study, a CR rate of 19% for CT and 83% for RT was consistent with previous large studies.13,26,27,30,31 The low CR rate and poor prognosis after CT alone reflect the resistance to conventional CT in these patients. It has been reported that the resistance to conventional CT in nasal NHL may be associated with frequent expression of p-glycoprotein and loss of p53 function.52-56 However, these results were not confirmed in another study.57
Prognosis of nasal NK/T-cell lymphoma varied from series to series, with 5-year OS ranging from 34% to 86%.11,13,23,26-28,30,58 This discrepancy of outcome could be due to the fact that CT was given as initial therapy in some series, but also to the high proportion of advanced clinical stage and high local failure. In this series, an overall CR rate of 87% can be achieved, and the 5-year OS and PFS were 71% and 59% for stage I and II diseases combined, 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. In our previous study on 175 patients with nasal lymphoma, the 5-year OS and disease-free survival (DFS) for all stage I-IV patients was 65% and 57%, respectively.7 The 5-year OS and DFS was 75% and 68% for stage I, 35% and 28% for stage II, and 31% and 19% for stage III-IV disease, respectively. These results are similar to those reported in the previous studies.11,13,31,45 To date, the Mexican study and ours are the only two large studies in which the vast majority of patients with localized nasal NK/T-cell lymphoma were treated uniformly with primary RT with or without CT.11 Interestingly, the Mexican data showed that in 108 patients with early-stage nasal NK/T-cell lymphoma treated with RT followed by four cycles of CHOP-bleo, the CR rate was 92% and the 8-year OS and DFS was 86%. Similarly, another Chinese team reported a 5-year OS of 63% for stage I-II, in 120 patients with nasal and nasal-type NK/T-cell lymphoma.45
Table 7 summarizes the large series of treatment outcome for nasal-type NK/T-cell lymphoma of the head and neck. Three large retrospective studies indicated that the outcome with primary RT was superior to initial CT or CT alone.26-28 In three other large series, RT resulted in the same survival as CMT, reflecting that the addition of CT to RT does not improve survival.13,30,31 The high CR rate and OS with RT indicate that patients with localized nasal NK/T-cell lymphoma should be considered for primary therapy with RT as a curative intent. In general, it should be repeated that for patients with localized aggressive NHL, RT alone can cure some patients, with 5-year OS of 40% to 60% and 5-year DFS of 31% to 50%.14,59-64
Our series demonstrated that clinical stage, extension of primary tumor, and mIPI were important prognostic factors in nasal NK/T-cell lymphoma. Patients with stage IIE disease carried a worse prognosis, with a 5-year OS of 46%. As observed by others, patients with stage IIE as well as stage IIIE/IV disease have a poor prognosis.27,29,45 In the Korean study, the 5-year OS and DFS was 64.4% and 47.6% for stage IE, and 25.2% and 15.2% for stage IIE.29 Similarly, Tang et al reported 2-year OS of 23.6% and a median survival of 5 months for stage III and IV disease,45 and Cheung et al reported 5-year OS of 19% for stage II disease.13 Prior studies have found the IPI to be effective in predicting outcome in patients with aggressive NHL and extranodal lymphoma.42,66 Several studies have also specifically addressed the utility of the IPI in nasal-type NK/T-cell lymphoma.11,13,25-27 Like the current report, some groups found a superior OS or DFS in the low-risk group,25-27 and in contrast, other groups did not.11,13 In this series, patients without any adverse factors (mIPI = 0) had very limited disease, and the corresponding 5-year OS and PFS was in excess of 90%.
Given the evidence of the high efficacy of RT, the relative resistance to CT, the absence of benefit with the addition of doxorubicin-based CT to RT, and the successful salvage with RT after initial CT, RT is recommended as the primary treatment for early-stage nasal NK/T-cell lymphoma. For those patients with stage IE disease without any adverse factors, RT alone should be considered for curative-intent treatment. Radiotherapy followed by consolidation CT should be considered for patients with one or more adverse factors or for stage IIE disease. The extranodal progression and relapse observed in patients with stage IIE-IV disease clearly illustrates the need for innovative systemic treatments.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Ye-Xiong Li
Financial support: Ye-Xiong Li
Administrative support: Ye-Xiong Li
Provision of study materials or patients: Ye-Xiong Li, Shu-Lian Wang, Li-Qiang Zhou, Xiao-Hui He, Ning Lu
Collection and assembly of data: Ye-Xiong Li, Bo Yao, Jing Jin, Wei-Hu Wang, Yue-Ping Liu, Yong-Wen Song, Xin-Fan Liu, Zi-Hao Yu
Data analysis and interpretation: Ye-Xiong Li
Manuscript writing: Ye-Xiong Li
Final approval of manuscript: Ye-Xiong Li
ACKNOWLEDGMENTS
The authors thank René -Olivier Mirimanoff, MD, professor of the Department of Radiation Oncology, University of Lausanne, Switzerland, for his assistance in article revision.
NOTES
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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ABSTRACT
PURPOSE: The optimal therapy remains unclear for nasal natural killer (NK)/T–cell lymphoma. The purpose of this study is to analyze the outcome of radiotherapy as the primary treatment for localized stage IE and IIE diseases.
PATIENTS AND METHODS: One hundred five patient cases were reviewed. There were 83 stage IE and 22 stage IIE patients. All except three patients received radiotherapy (RT) alone or RT combined with chemotherapy (CT; combined-modality therapy [CMT]). Overall, 31 patients were treated with RT alone, 34 with RT followed by CT, 37 with CT followed by RT, and three with CT alone.
RESULTS: Five-year overall survival (OS) and progression-free survival (PFS) for all patients were 71% and 59%, respectively. The 5-year OS and PFS were 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. Complete response (CR) was achieved in 91 patients (87%) after RT and/or CT. Initial RT resulted in a superior CR as compared with initial CT, with 54 (83%) of 65 patients achieving CR with initial RT, versus only eight (20%) of 40 after initial CT. For 102 patients who received RT with or without CT, the outcome of primary treatment with RT alone was compared with that of CMT. Five-year OS and PFS was 66% and 61% for RT alone, and 76% and 61%% for CMT, respectively (OS, P = .6433; PFS, P = .8391).
CONCLUSION: RT as primary therapy resulted in good outcome in early-stage disease, and the addition of CT to RT was not accompanied by an improvement in survival.
INTRODUCTION
Nasal non-Hodgkin's lymphoma (NHL) is a rare clinical entity in Western countries,1-6 but it is common in East Asian countries and Latin American.7-12 The majority of nasal lymphoma from Chinese patients are of natural killer (NK)/T-cell origin, whereas primary lymphomas of the Waldeyer's ring are predominantly B-cell type.7,13-18 In the Revised European-American Lymphoma and WHO classification, primary nasal and nasal-type NK/T-cell lymphoma are recognized as distinct clinicopathologic entities.19-20 Tumors resembling the prototype of nasal NK/T-cell lymphoma that occurred in a variety of extranodal sites other than the nasal cavity are referred to as nasal-type.21 Pathologically, nasal NK/T-cell lymphomas show a broad morphologic spectrum, frequent angioinvasion and angiocentricity with zone necrosis, and a frequent association with Epstein-Barr virus (EBV) infection.22,23 Immunophenotypically, the tumor cells most frequently express CD2+, CD3–, CD3+, and CD56+.13,23-26 Clinically, this entity is characterized by a predominance in young males, is seen in a large proportion of localized stage I and II diseases, is refractory to conventional chemotherapy (CT), and sensitive to radiotherapy (RT). Reported overall survival (OS) varies widely between the series.11,13,26-31 Overall, for patients with early-stage, diffuse large-cell lymphoma, CT followed by involved-field RT is considered the standard treatment.32-36 In contrast, the optimal therapy remains unclear for nasal NK/T-cell lymphoma. The management of this disease has been based largely on extrapolation from the experience with aggressive NHL, and has been limited to small institutional series, heterogeneous treatments, and variable diagnostic criteria.11,13,26-31 In addition, many early clinical studies of nasal lymphoma have actually included B-cell lymphoma, which is distinct from NK/T-cell lymphoma.7-9,37 Several recent studies have suggested that up-front RT results in better outcome as compared with CT, and that the addition of doxorubicin-based CT to RT does not improve survival in early-stage nasal and nasal-type NK/T-cell lymphoma.13,26-28,30,31 In view of the small number of patients receiving primary RT in these studies, a definite advantage of early or upfront RT needs to be ascertained and confirmed in a large study.13,26,28 It has been our policy to consider RT as a primary treatment for patients with early-stage nasal NK/T-cell lymphoma. In our previously reported large study of 175 patients with nasal lymphoma, most of them with NK/T-cell lymphomas, primary RT with or without CT resulted in a good outcome.7 Therefore, the purpose of this investigation is to focus on the initial response and treatment outcome following primary RT in early-stage nasal NK/T-cell lymphoma. Furthermore, we also analyzed the prognostic factors and examine the prognostic value of a modification of the International Prognostic Index (IPI).
PATIENTS AND METHODS
Between January 1983 and December 2003, 329 patients with previously untreated nasal non-Hodgkin's lymphoma (NHL) were referred to the Cancer Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Among them, 107 patients were diagnosed with a nasal NK/T-cell lymphoma after a review of clinicopathologic and immunohistochemical studies. Two of the patients with stage IV are excluded, and the remaining 105 patients with stage IE and IIE form the population of this study.
The pathological diagnosis and classification of nasal NK/T-cell lymphoma was based on the criteria described by Jaffe et al.21 The inclusion criteria in this study were (1) primary symptoms and the majority of the tumor bulky localized in the nasal cavity; (2) histopathological examination showing the features of angiocentric infiltration, necrosis, and polymorphism of individual cells; and (3) expression of NK/T-cell markers in the absence of B-cell markers. Immunohistochemical studies were performed on the following markers: CD45, CD43, CD45RO, CD2, CD3, CD79, CD20, TIA, and other markers. All patients were positive for at least one NK or T-cell marker, and negative for B-cell markers. In recent years, CD56 and CD57 have been available for 22 of 105 patients. The TCR gene and in situ hybridization for Epstein-Barr virus (EBV) –encoded RNA were not performed in every case.
Stage
The patients were staged according to a modification of the Ann Arbor system. Limited stage IE tumors were confined to the nasal cavity, whereas extensive stage IE tumors extended beyond the nasal cavity and into the neighboring structures without any sign of nodal or distant dissemination.7 Complete evaluation of patients included a medical record review, physical examination, blood chemistry, chest radiograph, computed tomography of the head, neck, chest, and abdomen, and bone marrow aspiration.
Treatment
Radiotherapy was the primary therapy for localized nasal NK/T-cell lymphoma (Table 1). All except three patients received RT alone or combined-modality therapy (CMT). Overall, 31 patients were treated with RT alone, three patients with CT alone, 34 with RT followed by CT (RT + CT), and 37 patients with CT followed by RT (CT + RT). For the latter patients, 20 patients received one to two cycles of CT, 16 patients received three to four cycles, and only one patient received five cycles of CT before RT. Furthermore, 26 of these 37 patients received two to four additional cycles of combination CT after CT and RT. Of the 83 patients with stage IE disease, 26 of them were primarily treated with RT alone, 30 with RT + CT, and 27 with CT + RT.
Radiotherapy was given with a 6-MV or 8-MV linear accelerator. The median dose was 50 Gy with a range of 40 to 65 Gy, at a dose per fraction of 2 Gy. The clinical target and radiation fields have been described previously.7 Of 74 patients receiving CT, 64 were treated with CHOP (cyclophosphaminde, doxorubicin, vincristine, prednisone) or CHOP-bleo (CHOP + bleomycin), nine with COBVP-16 (cisplatin, vincristine, bleomycin, prednisone), and one with COPP (cyclophosphaminde, vincristine, procarbazine, prednisone).7
Statistical Analysis
Tumor response was assessed after completion of either RT, CT, or a combination of RT and CT.38 Complete response (CR) was defined as a complete regression of all visible/palpable tumors and radiographic disease. OS and progression-free survival (PFS) were estimated by the product-limit Kaplan-Meier method.39 OS was measured from the start of initial treatment until time of death of any causes, or until last follow-up. PFS was measured from the start of initial treatment until time of first local or distant progression or relapse, or until last follow-up, or death. The differences between survival curves were calculated by the log-rank test.40 Multivariate analysis was performed using the Cox model.41 Prognostic factors included age, sex, performance status, localization, "B" symptoms, paranasal extension, lactate dehydrogenase, Ann Arbor stage, and stage-modified IPI (mIPI). In the mIPI, risk factors were used as initially described by Shipp et al, except that the adverse risk factor for Ann Arbor stage was the stage IIE disease, but not stages III or IV.42 Comparison of the qualitative data was done by 2 analysis.
RESULTS
Patient Characteristics
Patient characteristics are presented in Table 2. Paranasal extension within the vicinity of the primary tumor was present in 64 of 105 patients. Of them, 46 had paranasal extension only, without any nodal or distant dissemination, and 18 had involvement of lymph nodes as well. The majority of patients with stage IIE disease (82%) had paranasal extension, and only four of them (18%) had their primary tumor limited to the nasal cavity. In contrast, 37 (45%) of 83 patients with Ann Arbor stage IE presented with disease limited to the nasal cavity. The most frequently involved organs by the primary tumor were the ethmoid sinus, the maxillary sinus, and the nasopharynx.
Response to Treatment
Table 3 describes the response rates after treatment. Overall, a CR was achieved in 91 (87%) of 105 patients. A much lower CR rate (20%) was achieved after initial CT as compared with those (83%) with initial RT (P = .0001). For these 37 patients receiving CT followed by RT, only seven (19%) of 37 patients achieved a CR, and 15 (40%) of 37 patients achieved PR, whereas the remaining 15 patients (40%) showed stable disease (SD) or progressive disease (PD) after CT. Of the latter 30 patients with PR, SD, and PD, 27 had persistent disease, regrowth, or progression of local disease, and three developed systemic progression. However, 23 of these 27 patients with a local failure achieved CR after completion of subsequent RT. When the tumor responses of the two groups were compared after completion of RT or a combination of RT and CT, the CR rate of the CT + RT group (30 of 37 patients, 81%) was similar to that of RT alone and RT + CT (60 of 65 patients, 92%; P = .387). Similar response rates were observed in the subgroup of 83 stage IE patients.
Survival and Prognostic Factors
With a median follow-up time of 52 months, 5-year OS and PFS for all patients were 71% and 59%, respectively (Fig 1). Twenty-six patients had died. Of these, 22 died of lymphoma, three of intercurrent diseases, and one of a treatment-related complication.
The patient characteristics were evaluated for prognostic significance on OS and PFS (Table 4). On univariate analysis, Ann Arbor stage, performance status, and mIPI were found to be significant factors influencing both OS and PFS. Patients without paranasal extension showed a trend toward a better OS and a statistically significant better PFS. The 5-year OS and PFS were 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. There was a trend toward a better OS than those with extensive stage IE, with a 5-year OS of 82% for limited stage IE and 75% for extensive stage IE, respectively (P = .0763). The corresponding difference in PFS was highly significant, with 80% for limited stage IE and 45% for extensive stage IE, respectively (P = .0123; Fig 2). Using the mIPI, patients without any adverse factors had very limited disease and a corresponding 5-year OS and PFS exceeding 90%. On multivariate analysis, Ann Arbor stage, paranasal extension, and mIPI were significant prognostic factors for OS and PFS.
Treatment Outcome According to the Treatment Modalities in Stage IE and IIE
The outcome of primary treatment with RT alone was compared with that of RT + CT or CT + RT. These patients were comparable with respect to age, sex, Ann Arbor stage, lactate dehydrogenase, performance status, and mIPI (Table 5). However, patients treated with CMT were more likely to have B symptoms and paranasal extension. The 5-year OS and PFS was 66% and 61% for RT alone, 77% and 74% for RT + CT, and 74% and 43% for CT + RT, respectively, with no significant differences between the three groups. To analyze whether the addition of CT to RT modified the outcome, we compared the treatment outcome between RT alone and CMT. The 5-year OS and PFS were 76% and 61% for CMT, compared with 66% and 61% for RT alone (P = .6433 for OS, P = .8391 for PFS; Fig 3).
Concerning the three stage IIE patients receiving CT alone, two died of their disease, and one was lost to follow-up at 2 months.
Treatment Outcome According to the Treatment Modalities in Stage IE
We subsequently evaluated the outcome in 83 stage IE patients according to the treatment options. Patients who received CMT had more B symptoms and extensive stage IE. There was no statistically significant difference in 5-year OS and PFS between the various treatment modalities (Table 6). Furthermore, no survival benefit was observed after the addition of CT to RT. The 5-year OS and PFS were 73% and 63% for RT alone as compared to 80% and 64% for CMT (P = .9274 for OS and P = .8533 for PFS; Fig 4).
Patterns of Failure
Twelve patients progressed during the treatment, and 21 relapsed between 2 and 72 months after treatment. The majority of patients (12 of 21, 57%) relapsed within 2 years, and one, beyond 5 years. Figure 5 shows the patterns of progression and relapse in 31 available patients. Distant extranodal dissemination was the primary patterns of failure. The most frequent sites of extranodal failure were observed in skin (11 cases), bone marrow (five patients), lung (four patients), and liver (three patients).
DISCUSSION
After the Waldeyer's ring, nasal lymphoma is the second most common site of primary extranodal NHL in China.7,14,16-18 In contrast to NHL of Waldeyer's ring, which are predominantly B-cell type, nasal NHL are mainly NK/T-cell lymphoma, accounting for 74% to 98% of nasal lymphoma in China.7-9,14,26,27,43-45 The majority (67% to 98%) of nasal NK/T-cell lymphoma patients present with stage I-II diseases, though distant involvement is rare at the onset.24-27,46,47
Although chemotherapy followed by involved-field RT is a standard treatment for early-stage, diffuse large-cell lymphoma, the optimal therapy for nasal NK/T-cell lymphoma has not yet been clearly defined.32-36,48 Before 2000, few studies addressed the nasal NK/T-cell lymphoma as a separate entity, and most of them included a mixture of nasal T-cell, B-cell, or nasal-type NK/T-cell lymphoma.7,8,24,37,49 Furthermore, the treatment options for nasal NK/T-cell lymphoma show geographic variations between different countries or even between different institutions. In our institution, the majority of patients received up-front RT, with or without CT. For patients receiving CT first, short courses (usually one to four cycles) of combination CT were applied before RT due to poor initial response.
The reported CR rate for patients with stage I-II nasal-type NK/T-cell lymphoma ranged from 52% to 100% after RT, whereas it was between 8% and 59% after CT, most of the CR rate after CT being lower than 40% (Table 7). 1,11,13,25-28,30,31,50 In contrast, CR rate was between 85% and 90% for early-stage, diffuse large B-cell lymphoma.51 In the current study, a CR rate of 19% for CT and 83% for RT was consistent with previous large studies.13,26,27,30,31 The low CR rate and poor prognosis after CT alone reflect the resistance to conventional CT in these patients. It has been reported that the resistance to conventional CT in nasal NHL may be associated with frequent expression of p-glycoprotein and loss of p53 function.52-56 However, these results were not confirmed in another study.57
Prognosis of nasal NK/T-cell lymphoma varied from series to series, with 5-year OS ranging from 34% to 86%.11,13,23,26-28,30,58 This discrepancy of outcome could be due to the fact that CT was given as initial therapy in some series, but also to the high proportion of advanced clinical stage and high local failure. In this series, an overall CR rate of 87% can be achieved, and the 5-year OS and PFS were 71% and 59% for stage I and II diseases combined, 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. In our previous study on 175 patients with nasal lymphoma, the 5-year OS and disease-free survival (DFS) for all stage I-IV patients was 65% and 57%, respectively.7 The 5-year OS and DFS was 75% and 68% for stage I, 35% and 28% for stage II, and 31% and 19% for stage III-IV disease, respectively. These results are similar to those reported in the previous studies.11,13,31,45 To date, the Mexican study and ours are the only two large studies in which the vast majority of patients with localized nasal NK/T-cell lymphoma were treated uniformly with primary RT with or without CT.11 Interestingly, the Mexican data showed that in 108 patients with early-stage nasal NK/T-cell lymphoma treated with RT followed by four cycles of CHOP-bleo, the CR rate was 92% and the 8-year OS and DFS was 86%. Similarly, another Chinese team reported a 5-year OS of 63% for stage I-II, in 120 patients with nasal and nasal-type NK/T-cell lymphoma.45
Table 7 summarizes the large series of treatment outcome for nasal-type NK/T-cell lymphoma of the head and neck. Three large retrospective studies indicated that the outcome with primary RT was superior to initial CT or CT alone.26-28 In three other large series, RT resulted in the same survival as CMT, reflecting that the addition of CT to RT does not improve survival.13,30,31 The high CR rate and OS with RT indicate that patients with localized nasal NK/T-cell lymphoma should be considered for primary therapy with RT as a curative intent. In general, it should be repeated that for patients with localized aggressive NHL, RT alone can cure some patients, with 5-year OS of 40% to 60% and 5-year DFS of 31% to 50%.14,59-64
Our series demonstrated that clinical stage, extension of primary tumor, and mIPI were important prognostic factors in nasal NK/T-cell lymphoma. Patients with stage IIE disease carried a worse prognosis, with a 5-year OS of 46%. As observed by others, patients with stage IIE as well as stage IIIE/IV disease have a poor prognosis.27,29,45 In the Korean study, the 5-year OS and DFS was 64.4% and 47.6% for stage IE, and 25.2% and 15.2% for stage IIE.29 Similarly, Tang et al reported 2-year OS of 23.6% and a median survival of 5 months for stage III and IV disease,45 and Cheung et al reported 5-year OS of 19% for stage II disease.13 Prior studies have found the IPI to be effective in predicting outcome in patients with aggressive NHL and extranodal lymphoma.42,66 Several studies have also specifically addressed the utility of the IPI in nasal-type NK/T-cell lymphoma.11,13,25-27 Like the current report, some groups found a superior OS or DFS in the low-risk group,25-27 and in contrast, other groups did not.11,13 In this series, patients without any adverse factors (mIPI = 0) had very limited disease, and the corresponding 5-year OS and PFS was in excess of 90%.
Given the evidence of the high efficacy of RT, the relative resistance to CT, the absence of benefit with the addition of doxorubicin-based CT to RT, and the successful salvage with RT after initial CT, RT is recommended as the primary treatment for early-stage nasal NK/T-cell lymphoma. For those patients with stage IE disease without any adverse factors, RT alone should be considered for curative-intent treatment. Radiotherapy followed by consolidation CT should be considered for patients with one or more adverse factors or for stage IIE disease. The extranodal progression and relapse observed in patients with stage IIE-IV disease clearly illustrates the need for innovative systemic treatments.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Ye-Xiong Li
Financial support: Ye-Xiong Li
Administrative support: Ye-Xiong Li
Provision of study materials or patients: Ye-Xiong Li, Shu-Lian Wang, Li-Qiang Zhou, Xiao-Hui He, Ning Lu
Collection and assembly of data: Ye-Xiong Li, Bo Yao, Jing Jin, Wei-Hu Wang, Yue-Ping Liu, Yong-Wen Song, Xin-Fan Liu, Zi-Hao Yu
Data analysis and interpretation: Ye-Xiong Li
Manuscript writing: Ye-Xiong Li
Final approval of manuscript: Ye-Xiong Li
ACKNOWLEDGMENTS
The authors thank René -Olivier Mirimanoff, MD, professor of the Department of Radiation Oncology, University of Lausanne, Switzerland, for his assistance in article revision.
NOTES
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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