binedChemoradiationfortheManagementofNasalNaturalKiller(NK)/
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binedChemoradiationfortheManagementofNasalNaturalKiller(NK),T-cellLymphoma:ElucidatingtheSignificanceofSystemicChemotherapy
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Ye Guo *1 , Jia-De Lu *2 , Xue-Jun Ma 3 , Bi-Yun Wang 1 , Xiao-Nan Hong 1 , Xiao-Qiu Li 4 , Jin Li 1
1. Department of Medical Oncology, Cancer Hospital of Fudan University , Shanghai , China
2. Department of Radiation Oncology, National University Hospital , Singapore , Singapore
3. Department of Radiation Oncology, Cancer Hospital of Fudan University , Shanghai , China
4. Department of Pathology, Cancer Hospital of Fudan University , Shanghai , China
* Both authors contributed equally to this manuscript
【 Abstract 】 Purpose The objective of this analysis was to evaluate the efficacy and treatment outcome of CHOP and CHOP combined with nitrosourea chemotherapy in natural killer (NK)/T-cell lymphoma of nasal cavity. Methods and Materials Sixty-three patients with NK/T-cell lymphoma of nasal cavity were treated with CHOP or CHOP combined with oral nitrosourea chemotherapy between January 1997 and June 2005. By the Ann Arbor Lymphoma Staging Classification, 57 patients (90.5%) had Stage I E or II E disease and 6 patients (9.5%) had Stage III or IV disease. All patients with Stage I E or II E disease were intended to be treated curatively with combined chemoradiation; and patients who had Stage III or IV disease were treated with chemotherapy alone with curative intention. Chemotherapy consisted of 1) up to six cycles of the standard CHOP based regimen, or 2) up to six cycles of the standard CHOP based regimen with oral Semustine dosed at 120 mg (or Lomustine dosed at 100 mg) on day 1 of each chemotherapy cycle. External beam radiation therapy was delivered by daily conventional fractionation by Co-60 or 6MVx linear accelerator for patients with Stage I E or II E disease. The radiation dose to the tumor bed was between 36-50 Gy with a median dose of 45Gy. Fifty-three patients received chemotherapy prior to radiation, and 4 patients were treated with involved field radiation before chemotherapy. Results The median follow up for all 44 surviving patients was 30.8 months (range, 6-104 months). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 59.8% and 70.4%, respectively. The PFS and OS of patients who were treated with or without oral nitrosourea in addition to CHOP were 72.6% vs. 43.8% ( P =0.035) and 75.4% vs. 64% ( P =0.276), respectively. Nine patients with Stage I E or II E diseases developed disease progression during their planned treatment and died within 10 months after the initiation of treatment; Six patients who achieved complete response (CR) after planned chemoradiation developed systemic recurrence and died at 13-48 months despite salvage treatment; one patient died of Hemophagocytic Syndrome during radiotherapy after achieving CR from chemotherapy. Three patients with Stage III or IV disease died during chemotherapy or during salvage treatment at 2,4, and 19 months, respectively. Among the 59 patients who received chemotherapy as their initial treatment, 29, 6, 12, and 12 patients had complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) respectively after chemotherapy. The two-year overall survival rates for these four groups of patients were 100%, 75%, 60%, and 17%, respectively. ( P <0.0001) Multivariate analysis revealed that International Prognostic Index (IPI) for Lymphoma, perforation as a presenting symptom, "B" symptoms, ECOG performance, as well as response after chemotherapy, were significant independent prognostic factors for this group of patients. Conclusions The extent of response after induction chemotherapy is significantly related to the treatment outcome of patients with nasal NK/T-cell lymphoma. CHOP based chemotherapy combined with oral nitrosourea followed by involved field radiotherapy may provide improved treatment results compared to conventional CHOP chemotherapy and radiation. This strategy needs to be optimized and then tested in a prospective trial for its efficacy.
【 Key Words 】 Nasal NK/T-cell lymphoma; Nitrosourea; Chemotherapy; Radiation therapy
Introduction
Primary nasal lymphoma is a rare form of malignancy of the head and neck area. In Western countries, most cases of non-Hodgkin lymphoma developed in nasal cavity or paranasal sinuses are B-cell type . [1, 2] H owever, natural killer (NK)/T-cell lymphoma is a more common subtype of sino nasal lymphoma in East Asia and some areas in South America . [3, 4] NK/T-cell lymphoma is an aggressive entity of non-Hodgkin lymphoma with distinctive clinicopathologic features. Although this malignancy has drawn much attention in Asian countries recently , the optimal treatment for NK/T-cell lymphoma and its biological behavior s are not well understood for several reasons. Firstly, the rarity of this disease and its uneven geographic distribution have precluded multi-institution prospective trials, especially in more developed countries or regions. Secondly, the treatment modalities utilized for this disease have varied significantly between countries. NK/T-cell lymphoma has been diversely treated with combination chemotherapy, locoregional radiation, or combined chemoradiation. Therefore, most reports on a single treatment regimen or one particular treatment combination have been limited by small sample sizes; large retrospective reports usually included patients treated with a range of modalities. [5-8] Such situation explain s , at least in part, the substantially different treatment outcomes documented in the literature s . Most the nasal NK/T-cell lymphoma cases are diagnosed in early stages; however, the 5-year overall survival rates of this malignancy reported in recent series are only of the order of 50%, although aggressive combined chemoradiation with standard CHOP based chemotherapy regimen were partly utilized in these studies. [9, 10] Clearly, the treatment outcome from such combination is relatively dismal compare to other forms or aggressive lymphoma, and more efficacious treatment s are needed for the management of this malignancy. Since the early 1970's, low dose oral nitrosourea, especially Lomustine (chloroethylnitrosourea [CCNU]), then one of the only few available chemotherapeutic agents, has been utilized for the treatment of NK/T-cell lymphoma in combination with locoregional radiation therapy at the Cancer Hospital of Fudan University, Shanghai , China . CCNU is a nitrosourea with proven activity in hematological and solid tumors, and has been utilized in the treatment of recurrent and refractory non-Hodgkin's Lymphoma. [11-14] Empirically, patients treated at our institute with oral nitrosourea in addition to radiotherapy reported reduced local symptoms such as malodor and progression of ulceration. Alkylation and carbamoylation by nitrosourea metabolites interfere with the synthesis and function of DNA, RNA, and proteins. Since the introduction of CHOP regimens for aggressive non-Hodgkin lymphoma, the management strategies for NK/T-cell lymphoma have evolved, and combined radiation therapy with CHOP chemotherapy has become the standard modality in our institution; however, the use of low dose oral nitrosourea in addition to CHOP chemotherapy and radiotherapy has remained as a viable option in the treatment. The efficacy of nitrosourea as a single agent or in combination in the management of Non- Hodgkin Lymphoma has been tested in a number of trials; [11-14] however, its use in the treatment of nasal NK/T-cell lymphoma, especially in combination with CHOP regimen, has not been previously documented. The objectives of the current study is to document the efficacy and the treatment outcome of a group of patients with nasal NK/T-cell lymphoma who were treated with oral nitrosourea in addition to locoregional radiotherapy and CHOP chemotherapy. In addition, we attempt to analyze the prognostic factors of this malignancy.......（后略) ......
Ye Guo *1 , Jia-De Lu *2 , Xue-Jun Ma 3 , Bi-Yun Wang 1 , Xiao-Nan Hong 1 , Xiao-Qiu Li 4 , Jin Li 1
1. Department of Medical Oncology, Cancer Hospital of Fudan University , Shanghai , China
2. Department of Radiation Oncology, National University Hospital , Singapore , Singapore
3. Department of Radiation Oncology, Cancer Hospital of Fudan University , Shanghai , China
4. Department of Pathology, Cancer Hospital of Fudan University , Shanghai , China
* Both authors contributed equally to this manuscript
【 Abstract 】 Purpose The objective of this analysis was to evaluate the efficacy and treatment outcome of CHOP and CHOP combined with nitrosourea chemotherapy in natural killer (NK)/T-cell lymphoma of nasal cavity. Methods and Materials Sixty-three patients with NK/T-cell lymphoma of nasal cavity were treated with CHOP or CHOP combined with oral nitrosourea chemotherapy between January 1997 and June 2005. By the Ann Arbor Lymphoma Staging Classification, 57 patients (90.5%) had Stage I E or II E disease and 6 patients (9.5%) had Stage III or IV disease. All patients with Stage I E or II E disease were intended to be treated curatively with combined chemoradiation; and patients who had Stage III or IV disease were treated with chemotherapy alone with curative intention. Chemotherapy consisted of 1) up to six cycles of the standard CHOP based regimen, or 2) up to six cycles of the standard CHOP based regimen with oral Semustine dosed at 120 mg (or Lomustine dosed at 100 mg) on day 1 of each chemotherapy cycle. External beam radiation therapy was delivered by daily conventional fractionation by Co-60 or 6MVx linear accelerator for patients with Stage I E or II E disease. The radiation dose to the tumor bed was between 36-50 Gy with a median dose of 45Gy. Fifty-three patients received chemotherapy prior to radiation, and 4 patients were treated with involved field radiation before chemotherapy. Results The median follow up for all 44 surviving patients was 30.8 months (range, 6-104 months). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 59.8% and 70.4%, respectively. The PFS and OS of patients who were treated with or without oral nitrosourea in addition to CHOP were 72.6% vs. 43.8% ( P =0.035) and 75.4% vs. 64% ( P =0.276), respectively. Nine patients with Stage I E or II E diseases developed disease progression during their planned treatment and died within 10 months after the initiation of treatment; Six patients who achieved complete response (CR) after planned chemoradiation developed systemic recurrence and died at 13-48 months despite salvage treatment; one patient died of Hemophagocytic Syndrome during radiotherapy after achieving CR from chemotherapy. Three patients with Stage III or IV disease died during chemotherapy or during salvage treatment at 2,4, and 19 months, respectively. Among the 59 patients who received chemotherapy as their initial treatment, 29, 6, 12, and 12 patients had complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) respectively after chemotherapy. The two-year overall survival rates for these four groups of patients were 100%, 75%, 60%, and 17%, respectively. ( P <0.0001) Multivariate analysis revealed that International Prognostic Index (IPI) for Lymphoma, perforation as a presenting symptom, "B" symptoms, ECOG performance, as well as response after chemotherapy, were significant independent prognostic factors for this group of patients. Conclusions The extent of response after induction chemotherapy is significantly related to the treatment outcome of patients with nasal NK/T-cell lymphoma. CHOP based chemotherapy combined with oral nitrosourea followed by involved field radiotherapy may provide improved treatment results compared to conventional CHOP chemotherapy and radiation. This strategy needs to be optimized and then tested in a prospective trial for its efficacy.
【 Key Words 】 Nasal NK/T-cell lymphoma; Nitrosourea; Chemotherapy; Radiation therapy
Introduction
Primary nasal lymphoma is a rare form of malignancy of the head and neck area. In Western countries, most cases of non-Hodgkin lymphoma developed in nasal cavity or paranasal sinuses are B-cell type . [1, 2] H owever, natural killer (NK)/T-cell lymphoma is a more common subtype of sino nasal lymphoma in East Asia and some areas in South America . [3, 4] NK/T-cell lymphoma is an aggressive entity of non-Hodgkin lymphoma with distinctive clinicopathologic features. Although this malignancy has drawn much attention in Asian countries recently , the optimal treatment for NK/T-cell lymphoma and its biological behavior s are not well understood for several reasons. Firstly, the rarity of this disease and its uneven geographic distribution have precluded multi-institution prospective trials, especially in more developed countries or regions. Secondly, the treatment modalities utilized for this disease have varied significantly between countries. NK/T-cell lymphoma has been diversely treated with combination chemotherapy, locoregional radiation, or combined chemoradiation. Therefore, most reports on a single treatment regimen or one particular treatment combination have been limited by small sample sizes; large retrospective reports usually included patients treated with a range of modalities. [5-8] Such situation explain s , at least in part, the substantially different treatment outcomes documented in the literature s . Most the nasal NK/T-cell lymphoma cases are diagnosed in early stages; however, the 5-year overall survival rates of this malignancy reported in recent series are only of the order of 50%, although aggressive combined chemoradiation with standard CHOP based chemotherapy regimen were partly utilized in these studies. [9, 10] Clearly, the treatment outcome from such combination is relatively dismal compare to other forms or aggressive lymphoma, and more efficacious treatment s are needed for the management of this malignancy. Since the early 1970's, low dose oral nitrosourea, especially Lomustine (chloroethylnitrosourea [CCNU]), then one of the only few available chemotherapeutic agents, has been utilized for the treatment of NK/T-cell lymphoma in combination with locoregional radiation therapy at the Cancer Hospital of Fudan University, Shanghai , China . CCNU is a nitrosourea with proven activity in hematological and solid tumors, and has been utilized in the treatment of recurrent and refractory non-Hodgkin's Lymphoma. [11-14] Empirically, patients treated at our institute with oral nitrosourea in addition to radiotherapy reported reduced local symptoms such as malodor and progression of ulceration. Alkylation and carbamoylation by nitrosourea metabolites interfere with the synthesis and function of DNA, RNA, and proteins. Since the introduction of CHOP regimens for aggressive non-Hodgkin lymphoma, the management strategies for NK/T-cell lymphoma have evolved, and combined radiation therapy with CHOP chemotherapy has become the standard modality in our institution; however, the use of low dose oral nitrosourea in addition to CHOP chemotherapy and radiotherapy has remained as a viable option in the treatment. The efficacy of nitrosourea as a single agent or in combination in the management of Non- Hodgkin Lymphoma has been tested in a number of trials; [11-14] however, its use in the treatment of nasal NK/T-cell lymphoma, especially in combination with CHOP regimen, has not been previously documented. The objectives of the current study is to document the efficacy and the treatment outcome of a group of patients with nasal NK/T-cell lymphoma who were treated with oral nitrosourea in addition to locoregional radiotherapy and CHOP chemotherapy. In addition, we attempt to analyze the prognostic factors of this malignancy.......（后略) ......
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