1 Department of Medicine and 2 Cancer Center, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan
Received 1 December 2003; accepted 23 December 2003
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ABSTRACT |
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To clarify the role of intention to treat for patients with localized nasal natural killer (NK)/T-cell lymphoma, and to determine the prognostic factors for these patients.
Patients and methods:
We conducted a retrospective review of 46 patients with localized nasal NK/T-cell lymphomas treated at a single institute between January 1988 and July 2002.
Results:
The type of intended treatment was a significant factor for overall survival (OS) (5-year OS: RT versus CT = 83.3% versus 28.6%, P = 0.0269) or failure-free survival (FFS) (5-year FFS: RT versus CT = 83.3% versus 27.1%, P = 0.0247). In the intended chemotherapy group, salvage with radiotherapy was superior to chemotherapy alone for OS (5-year OS: 42.2% versus 20.0%, P = 0.0252) or FFS (5-year FFS: 41.0% versus 20.0%, P = 0.0352). On multivariate analysis, both N stage and serum lactate hehydrogenase level were independent factors for OS and FFS. No radiotherapy was an independent adverse factor for OS; advanced T stage and more than one extranodal involvement were independent adverse factors for FFS.
Conclusions:
Patients with localized nasal NK/T-cell lymphomas were better managed with radiotherapy as front-line therapy. The advantage of radiotherapy persisted even as palliative therapy after chemotherapy.
Key words: chemotherapy, combined modality, intent to treat, International Prognostic Index (IPI), nasal NK/T-cell lymphoma, radiotherapy
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Introduction |
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The initial diagnosis of NK/T malignancies can be difficult due to the lack of immunophenotypic clonality, heterogeneity of morphology, and a poor correlation between cytomorphology and prognosis. There has been controversy in diagnosis because of the difficulty in separating the T-lineage from the natural killer (NK) lineage, both being derived from the same bipotential T/NK precursor [5, 6]. However, nasal NK/T-cell lymphomas are now a distinct clinicopathological entity, but the optimal therapy and treatment outcome are undetermined. Therapeutic recommendations for nasal NK/T lymphoma are derived from the experience of a few retrospective studies [717]. Nasal NK/T lymphomas with localized stage often respond to intended radiotherapy [715], and those with extensive stage warranted more aggressive therapy, such as intensive chemotherapy, autologous, or allogenic stem cell transplantation [16, 17]. Owing to the rarity of this type of lymphoma, many series contained only a small number of patients. Although some series favor the frontal use of radiotherapy, others suggested the combination of chemotherapy with radiation therapy. Whether the addition of radiotherapy to chemotherapy offers any benefits to patient survival is questionable in most series [1822].
To address these issues, we performed a retrospective study to analyze the clinical characteristics and effect of treatment modalities with a consecutive cohort of diagnosed localized nasal NK/T lymphomas. Furthermore, we also investigated the clinical prognostic factors and examined the prognostic value of the International Prognostic Index (IPI) in these patients.
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Patients and methods |
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Histological and immunophenotypical diagnosis
All biopsy specimens were conducted on paraffin sections of formalin- or B5-fixed tissue after staining with hematoxylineosin. Immunohistochemical studies were performed on the following markers: CD45 (leukocyte-common antigen, LCA; Dakopatts, Globstrup, Denmark), CD43 (MT1; Euro-Diagnostica, Malmo, Sweden), CD45RO (UCHL1; Dakopatts), CD3 (PS1; Dakopatts), CD20 (L26; Dakopatts) and CD56 (Dakopatts). The in-situ hybridization for EpsteinBarr virus (EBV) encoded RNA was not performed in every case.
Treatment
All treatment that patients received was recorded. Treatment modalities were classified by intended chemotherapy or radiotherapy. Primary radiotherapy involved the delivery of 5460 Gy equivalent in daily fractions of 1.82.0 Gy, using a lateral opposing field from a linear accelerator, covering the nasal, paranasal cavities, nasopharynx and the Waldeyers ring. The field was extended to cover the cervical region if cervical nodes were present at diagnosis. The intended chemotherapy-containing regimens included CHOP/CEOP, m-BACOD and ProMACE-CytaBOM and were re-evaluated every three courses. The choice of regimen was at the discretion of the attending physician. If complete remission was not achieved after three or six chemotherapy courses, radiotherapy was given. The salvage involved field radiotherapy of 4450 Gy, with a field size, daily fractions and source similar to those given to patients receiving radiotherapy as primary treatment. However, salvage chemotherapy was also applied to those patients without response or who had relapsed after first-line chemotherapy regimen. The salvage chemotherapy regimens included ESHAP and EPOCH. High-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) or allogeneic HSCT were offered to selected patients [17].
Statistical analysis
Remission rates were compared with Fishers exact test. Complete remission (CR) was defined as complete resolution of symptoms and signs, and normalization of all imaging studies. Overall survival (OS) was measured from diagnosis to death or last follow-up. Failure-free survival (FFS) was measured from the diagnosis to the beginning of the first relapse. OS and FFS were computed by the KaplanMeier method [24]. Survival curves were compared by the log-rank test. Three patients underwent autologous bone marrow transplantation, and all survivals were censored at the time of transplantation. Prognostic factors included age, gender, location, neck lymph node involvement or not, preformace status, LDH level, number of extranodal involvement, and IPI. Significant variables in the univariate analysis were considered as variables for the multipvariate analysis of survival. The latter was performed by Coxs proportional hazard regression model [25, 26].
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Results |
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Discussion |
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Data on localized nasal NK/T-cell lymphoma managed with radiotherapy as the primary treatment are not rare [717]. The benefit of upfront radiotherapy remained controversial; some studies showed that it might be beneficial to patients with limited stage nasal NK/T-cell lymphomas. Kim et al. [18] described how four cycles of CHOP followed by RT is not satisfactory for treating patients with localized nasal NK/T-cell lymphoma, and they suggest further exploration for improved therapy is needed. Our data show that 5-year OS and FFS are superior in the intended radiotherapy as compared with the intended chemotherapy groups (5-year OS 83.3% versus 28.5%, P = 0.0269; 5-year FFS 83.3% versus 27.7%, P = 0.0247). This supports the front-line use of radiotherapy in localized nasal NK/T-cell lymphoma and other EBV-related malignancies, such as NPC and Hodgkins lymphoma. However, in view of the small number of patients receiving primary radiotherapy in these studies, a definite advantage of early or upfront radiotherapy should be validated in larger, prospective studies.
We also compared chemotherapy alone with combination chemotherapy/radiotherapy to analyse the treatment outcome of three to six cycles of chemotherapy followed by involved field radiotherapy for stage III nasal NK/T-cell lymphoma. Our data show that the 5-year OS and FFS are superior in the combined modalities group as compared with the chemotherapy alone group (5-year OS 37.5% versus 23.0%, P = 0.0252; 5-year FFS 26.5% versus 23.0%, P = 0.0352). If localized nasal NK/T-cell lymphoma patients were managed with chemotherapy as the primary therapy, palliative or adjuvant radiotherapy is recommended for these patients. The benefit of radiotherapy for localregional control persisted even after a period of intended chemotherapy.
In the present series, we documented higher resistance to chemotherapy than radiotherapy. The 5-year OS and FFS were inferior in those never receiving radiotherapy as compared with those who did receive radiotherapy (5-year OS 49.7% versus 23.0%, P = 0.0170; 5-year FFS 48.7% versus 23.0%, P = 0.0251).
The reasons for the common resistance to chemotherapy and general aggressiveness of these tumors are not clear. Poor drug delivery owing to tissue necrosis related to angiodestruction and frequent expression of multidrug resistance (P-glycoprotein positive) phenotype [29, 30] might be important contributing factors. Homophilic binding of CD56 to tissues expressing high levels of this neural cell adhesion molecule (e.g. skin, testis, gastrointestinal tracts, neural tissue) may explain the high propensity for the tumor to disseminate widely [11, 31].
The outcome of T-cell lymphoma is unfavorable compared with that of B-cell lymphoma, and the outcome of NK-cell lymphoma even worse [32, 33]. The prognostic impact of IPI, initially shown in aggressive non-Hodgkins lymphomas [19], has been validated subsequently in lymphomas ranging from low, intermediate to high grades [20]. Moreover, the IPI is also of prognostic significance in less conventional lymphomas, including extranodal gastric lymphomas [34], and peripheral T-cell lymphomas [3537]. In primary nasal NK-cell lymphomas, two previous studies had failed to show a prognostic impact of IPI on the CR, and one revealed a positive result on OS in Chims study [7]. In our study, IPI was a prognostic factor for both OS and FFS, but lost the independent predictive value in the multivariate analysis. In the studies discussing IPI and nasal NK/T-cell lymphoma, most of the patients with negative results were managed by radiotherapy as frontal therapy. Chims and our study were the only two positive results, and chemotherapy was used in most patients within the studies. The reasons for the discrepancy for application of IPI between intended treatment by radiotherapy or chemotherapy are unclear. However, our study validates the use of IPI in prognosis of nasal NK-cell lymphomas.
In view of the rarity of this tumor type, it is difficult to perform a prospective randomized trial. However, several of our findings have important implications on the treatment of nasal NK/T-cell lymphomas, including the high efficacy of radiotherapy in inducing CR, although observed in a relatively small number. If it is managed with chemotherapy as the primary therapy, palliative or adjuvant radiotherapy is recommended for these patients before distal metastasis. However, a definite advantage of early or upfront radiotherapy, even concurrent chemoradiotherapy, should be validated in larger, prospective studies.
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FOOTNOTES |
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