Phase 2 trial of "sandwich" L-asparaginase, vincristine, and prednisone chemotherapy with radiotherapy in newly diagnosed, stage IE to IIE, nasal type, extranodal natural killer/T-cell lymphoma

BACKGROUND:

Extranodal natural killer/T‐cell lymphoma (ENKTL), nasal‐type, is a distinct entity of lymphoid tissue. ENKTL is sensitive to radiotherapy (RT), but the prognosis is poorer than for other types of early lymphoma. The treatment schedule is controversial.

METHODS:

A phase 2 study was conducted of “sandwich” protocols, with earlier RT after an initial 2 to 3 cycles of LVP (L ‐asparaginase, vincristine, and prednisone), followed by further “consolidation” cycles. Patients aged 18 years and older who had previously untreated ENKTL and localized lesions in the upper aerodigestive tract were enrolled. The primary endpoints were objective response rate and complete remission rate. The secondary endpoints were 2‐year overall survival, 2‐year progression‐free survival, and toxicity. This study is registered with www.Chictr.org , number ChicTR‐TNC‐00000394, and is ongoing for long‐term follow‐up.

RESULTS:

Twenty‐six patients completed total therapy, which resulted in 88.5% response that included 21 patients (80.8%) with complete response (CR) and 2 patients (7.7%) with partial response. Three (11.5%) of 26 patients progressed during therapy. With a median follow‐up of 27 months (range, 4‐35 months), the 2‐year overall survival was 88.5%, and the 2‐year progression‐free survival was 80.6%. Patients with CR had better prognosis than patients without CR. Only 2 patients (7.7%) experienced grade 3 leukocytopenia. No grade 4 toxicity or treatment‐related deaths were observed.

CONCLUSIONS:

The research showed that the “sandwich” protocol of LVP combined with RT was a safe and effective treatment for localized nasal natural killer/T‐cell lymphoma, and the results warrant further investigation into this protocol. Cancer 2011. © 2011 American Cancer Society.     

A prognostic model based on pretreatment platelet lymphocyte ratio for stage IE/IIE upper aerodigestive tract extranodal NK/T cell lymphoma,nasal type

Nonopioid Sigma1 receptor (Sig1R), which regulates various metabolism functions, has been implicated in cancers; yet, its role in hilar cholangiocarcinoma remains unclear. In the present study, we examined Sig1R expression in hilar cholangiocarcinoma (HC) tissues and explored its possible clinical values. Tissue microarray blocks containing 92 HC tissues and matched non-cancerous bile duct tissues were examined immunohistochemically for expression of Sig1R protein. Overexpression of Sig1R was found in 43 (46.7 %) of the 92 primary tumor tissues. Overexpression of Sig1R was significantly associated with poor/undifferentiation (P = 0.011), tumor invasion (P = 0.001), lymph node metastasis (P = 0.047), and advanced disease stage (P = 0.024) of HC patients. Kaplan–Meier analysis showed that patients overexpressing Sig1R had an earlier recurrence and worse overall survival than those not overexpressing Sig1R. Cox regression analysis revealed that Sig1R was an independent factor to predict HC recurrence and prognosis of HC patients. Our results suggest that Sig1R is frequently activated in human HC tissue and overexpression of Sig1R might serve as a predictor for tumor recurrence and a prognostic biomarker for HC patients.     

Primary extranodal lymphomas of Waldeyer's ring, stage IE and IIE

We reviewed 45 cases of Waldeyer's ring lymphomas (25 stage IE, 20 IIE): 73% had high-grade histology according to Kiel's classification. Fourteen patients received radiotherapy alone and 31 chemotherapy, combined with radiotherapy in 28. Complete remission rate was 95% and relapse rate 32%. At 8 years overall disease-related survival (DRS) and event-free survival (EFS) were 69% and 57% respectively. Combined treatment provided both significantly better DRS (82% vs 42%) and EFS (76% vs 25%) than radiotherapy alone. Most of the patients with high-grade histology (26/33) received the combined treatment and this subgroup achieved a long-term EFS of 78%. Both DRS and EFS were also significantly longer in patients under 60. At multivariate analysis favorable prognostic factors were lower age for DRS and combined treatment for EFS.     

Combined chemotherapy and external beam radiation for stage IE and IIE natural killer T-cell lymphoma of nasal cavity

To evaluate the outcome of CHOP chemotherapy and radiotherapy in Stage IE and IIE nasal natural killer (NK)/T-cell lymphoma, 53 patients with stage IE and IIE nasal NK/T-cell lymphoma were studied. By the Ann Arbor Lymphoma Staging Classification, 41 patients (77%) had Stage IE disease and 12 patients (23%) had Stage IIE disease. All patients were treated curatively using chemotherapy, followed by radiotherapy. Chemotherapy consisted of up to six cycles of the standard CHOP based regimen. The median radiation dose to the tumor bed was 45 Gy for all patients. The median follow-up for all 39 surviving patients was 30.2 months (range, 6 - 104 months). Twenty-six patients had complete response after chemotherapy, and all patients who completed first line chemotherapy achieved complete response after radiotherapy. The 2-year overall survival and progression-free survival rates were 75.6% and 61.8%, respectively. Multivariate analysis revealed that perforation as a presenting symptom, elevated pretreatment serum lactate dehydrogenase level, and ECOG performance status >or=2 were significant independent prognostic factors for this group of patients. Combined chemotherapy followed by involved field radiation produced suboptimal outcome for patients with early stage nasal NK/T-cell lymphoma. Further investigations, preferably prospective clinical trials, for more efficacious treatment strategies are needed to improve the treatment outcome of this malignancy.     

早期结外鼻型NK/T细胞淋巴瘤GDL方案治疗的临床观察

目的:评价吉西他滨、地塞米松和左旋门冬酰胺酶组成的GDL方案对结外鼻型NK/T细胞淋巴瘤的疗效和毒副作用。方法:GDL方案:盐酸吉西他滨1 000mg/m2加入生理盐水100mL中,静脉滴入,d1、d8;地塞米松10mg/m2,静脉滴入,d1～d5;左旋门冬酰胺酶5 000U/m2加入5%葡萄糖250mL中,静脉滴入,d1～d7,21d为1个周期。全组48例患者接受4个周期化疗后评价疗效,3周后行累及野放射治疗后。结果:完全缓解(CR)率为54.2%(26/48),部分缓解(PR)率为35.4%(17/48),疾病稳定(SD)率为8.3%(4/48),疾病进展(PD)率为2.1%(1/48),经放射治疗后全组CR率91.7%(44/48),PR率为8.3%(4/48),有效率100%。中位随访36(10～58)个月,预期3年生存率和无进展生存期分别为79%和75%。主要不良反应为骨髓抑制、胃肠道反应和血糖波动等,大多为轻中度,且化疗停止后很快缓解。无治疗相关死亡。结论:GDL方案治疗结外鼻型NK/T细胞淋巴瘤的疗效佳,毒副作用下且能耐受,联合累及野放疗治疗能够取得较为满意的疗效,值得进一步临床推广使用。     

结外NK/T细胞淋巴瘤，鼻型的诊断与治疗进展

结外NK/T细胞淋巴瘤,鼻型（extranodal natural killer/T-cell lymphoma ,nasal type,ENKL）是非霍奇金淋巴瘤（non-hodgkin lymphoma,NHL ）的一种少见亚型,其侵袭性强且预后较差。ENKL 主要发生于鼻腔,其次是皮肤、胃肠道等。该病以血管的侵犯和组织破坏为主要病理学表现。ENKL 与EBV 的感染密切相关,EBV 水平对其辅助诊断有重要的意义。NK/T细胞表面的特征性标志物和特异性遗传学改变也可以帮助诊断该病。目前对于ENKL 的治疗尚在讨论中,虽然对早期患者采用放疗± 化疗联合治疗,以及对中晚期患者采用以左旋门冬酰胺酶为基础的化疗和造血干细胞移植得到了一定疗效,但仍需进一步的研究探索以形成规范的治疗原则。     

每周小剂量多西他赛同步适形放疗后DP巩固化疗治疗Ⅲ期非小细胞肺癌

背景与目的同步放化疗是目前局部晚期非小细胞肺癌的标准治疗,但化疗药物的选择、剂量强度、放疗剂量及巩固化疗的作用仍没最终确定。本研究目的是比较多西他赛(Docetaxel,DTX)每周小剂量化疗与系统化疗同步适形放疗后DP方案巩固化疗对Ⅲ期非小细胞肺癌的疗效和毒副反应差异。方法44例初治的Ⅲ期非小细胞肺癌随机分为多西他赛每周小剂量化疗组(研究组)和系统化疗组(对照组)行同步放化疗。放疗采用三维适形累及野照射,常规分割,靶区总剂量66 Gy～70 Gy。放疗同时研究组给予DTX 20 mg.m~(-2).w~(-1)化疗,对照组给予DP方案(DTX 60 mg/m~2第1天 DDP 30 mg/m~2第1-3天,21天为一周期)化疗2周期。两组放疗结束后均给予DP方案化疗2-4周期。结果研究组和对照组的总有效率分别为81.8%、86.4%(x~2=0.120,P=0.942),完全缓解率均为27.3%,中位生存期分别为20个月和16个月,1、2年生存率分别为69.8%、48.1%和66.5%、40.2%,差异无统计学意义。3级以上白细胞减少和食管炎分别占患者的26.3%、14.3%和15.8%、28.6% (x~2=0.765,P=0.382;x~2=1.108,P=0.292),3级以上肺毒性少见。结论每周多西他赛同步适形放疗后多西他赛和顺铂巩固化疗治疗Ⅲ期非小细胞肺癌疗效较好,毒副反应可耐受。     

Concurrent Etoposide,Steroid, High-dose Ara-C and Platinum chemotherapy with radiation therapy in localised extranodal natural killer (NK)/T-cell lymphoma,nasal type

PurposeRadiation combined with chemotherapy has recently been proposed to treat patients with localised extranodal natural killer (NK)/T lymphoma (ENKTL), nasal type. However, the modalities of the chemoradiotherapy combination and drug choices remain a matter of debate. We conducted a concurrent chemoradiotherapy (CCRT) study with the ESHAP (Etoposide, Steroid, High-dose Ara-C and Platinum) regimen.MethodsAn induction phase with two upfront courses of CCRT delivering a 40 Gy dose of radiation concurrently with two cycles of the ESHAP chemotherapy regimen, followed by a consolidation phase with 2–3 cycles of ESHAP chemotherapy alone.ResultsThirteen patients with localised ENKTL nasal type were enrolled between January 2005 and December 2014. The median age was 62 years. Ten and three patients had Ann Arbor stage IE and IIE disease, respectively. They all completed the induction CCRT phase. A median of two consolidation ESHAP cycles were delivered. During consolidation, 8/13 (62%) patients had a reduction in the number of chemotherapy cycles or reduced chemotherapy doses, due to haematologically adverse events. The other five patients (38%) received the full number of ESHAP cycles of chemotherapy scheduled without a dose reduction. All but one patient (92%) experienced grade 3–4 haematological toxicity. The main non-haematological grade 3–4 toxicity was mucositis in 6/13 (46%) patients. All but one patient (92%) achieved a complete remission. Two-year overall survival was 72%.ConclusionsWith optimal management of the specific toxicities induced by this treatment modality, CCRT with the ESHAP regimen yielded high efficacy against localised ENKTL, nasal type.     

Intensive therapy can improve long-term survival in newly diagnosed,advanced-stage extranodal NK/T-cell lymphoma: A multi-institutional,real-world study

The study investigated the treatment and prognosis of advanced-stage extranodal natural killer/T-cell lymphoma (ENKTL). With a median follow-up of 75.03 months, the median overall survival (mOS) for the 195 newly diagnosed stage III/IV ENKTL patients was 19.43 months, and estimated 1-, 2-, 3- and 5-year OS were 59.5%, 46.3%, 41.8% and 35.1%, respectively. Chemotherapy (CT) + radiotherapy (RT) compared to CT alone (P = .007), and hematopoietic stem cell transplantation (HSCT) compared to non-HSCT (P < .001), both improved OS. For patients ≤60 years and ineligible for HSCT, other therapies with complete remission led to comparable OS (P = .141). Nine patients ever treated with chidamide achieved a median progression-free survival (mPFS) and mOS of 53.63 (range, 3.47-92.33) and 54.80 (range, 5.50-95.70) months, and four with chidamide maintenance therapy (MT) achieved a mPFS and mOS of 55.83 (range, 53.27-92.33) and 60.65 (range, 53.70-95.70) months, possibly providing an alternative option for non-HSCT patients. Non-anthracycline (ANT)- compared to ANT-, asparaginase (Aspa)- compared to non-Aspa- and gemcitabine (Gem)- compared to non-Gem-based regimens, prolonged PFS (P = .031; P = .005; P = .009) and OS (P = .010; P = .086; P = .003), respectively. Multivariate analysis demonstrated that Gem-based regimens improved PFS (HR = 0.691, P = .061) and OS (HR = 0.624, P = .037). Gem + Aspa combinations slightly improved PFS and OS compared to regimens containing Gem or Aspa alone (P > 0.05). First-line “intensive therapy,” including CT (particularly Gem + Aspa regimens), RT, HSCT and alternative chidamide MT, was proposed and could improve long-term survival for advanced-stage ENKTLs. Ongoing prospective clinical studies may shed further light on the value of chidamide MT.     

早期结外鼻型NK/T细胞淋巴瘤同期放化疗疗效分析

目的:探讨Ⅰ E～ⅡE期结外鼻型NK/T细胞淋巴瘤同期放化疗的疗效,并进一步分析其可行性.方法:回顾分析18例早期结外鼻型NK/T细胞淋巴瘤患者,以序贯化放疗50例为对照.18例同期放化疗患者中诱导化疗+同期放化疗+辅助化疗3例,诱导化疗十同期放化疗13例,同期放化疗十辅助化疗1例,单纯同期放化疗1例,全组放疗中位剂量54 Gy.结果:诱导化疗后的总缓解率为50.0％(8/16),治疗结束后为100.0％(18/18).同期放化疗组与对照组的5年总生存率分别为80.8％和54.3％(x2=3.66,P=0.05),5年无进展生存率(PFS)分别为75.8％和43.3％(x2=6.13,P=0.01),5年局部控制(LC)率分别为94.1％和56.7％(x2=6.32,P-0.01).同期放化疗过程中出现Ⅲ～Ⅳ度骨髓抑制率为27.8％(5/18),Ⅲ度口腔黏膜反应率为16.7％(3/18),Ⅲ度咽喉反应率为5.6％(1/18),其余不良反应均 为Ⅰ～Ⅱ度,Ⅲ～Ⅳ反应经对症处理后未影响下一步治疗.结论:同期放化疗是早期结外鼻型NK/T细胞淋巴瘤安全、有效的治疗方法,相对其他接受放疗患者有提高局部控制率和生存时间的趋势,其毒副反应可以耐受.     

Therapeutic outcome of extranodal NK/T-cell lymphoma initially treated with chemotherapy--result of chemotherapy in NK/T-cell lymphoma

The therapeutic outcome of chemotherapy in NK/T cell lymphoma (NTCL) has not been well documented until now. The aims of this study were to investigate the outcome of chemotherapy and to evaluate the clinical factors influencing the responsiveness to chemotherapy. Between 1995 and 2000, 59 patients received anthracycline-based chemotherapy as an initial treatment. Forty-five patients had nasal NTCL, whereas 14 had extranasal NTCL. Forty-one patients had stage I/II and 18 had stage III/IV disease. Epstein-Barr virus status was positive in 67.6% of cases. The results of initial chemotherapy were complete remission in 35.6% of the patients, 2-year disease-free survival in 22.9% and 2-year overall survival in 44.2%. Adjuvant radiotherapy after chemotherapy did not improve outcome in stage I/II nasal NTCL. The International Prognostic Index was a significant prognostic factor of complete remission rate, and stage was also significant for disease-free survival.     

结外鼻型NK/T细胞淋巴瘤放化疗研究进展

结外鼻型NK/T细胞淋巴瘤（extranodal NK/T-cell lymphoma,nasal type ENKTL）是侵袭性非霍奇金淋巴瘤的一种特殊类型,由于发病率低,目前临床治疗证据大部分来自回顾性分析或小样本的Ⅱ期临床试验,缺乏大型的随机对照研究,暂无统一的治疗标准。放疗、化疗是ENKTL的主要治疗方法,但目前放、化疗策略选择仍存在争议性,是否联合放化疗、放化疗联合方式、化疗方案选择等方面均未形成统一的认识。对于早期（Ⅰ/Ⅱ期）患者目前多以放疗联合化疗的治疗方法,Ⅲ/Ⅳ期患者多采用以全身化疗为主。以L-门冬酰胺酶（L-ASP）为基础的化疗药物在各期及复发难治性ENKTL中疗效结果显示均较CHOP或CHOP样化疗方案好。最佳的化疗方案以及化疗与放疗结合方式仍需通过更多的、更大型的Ⅲ期随机对照试验来证实。寻找准确的预后因素进行风险分层,根据风险分层结果进行治疗是未来的研究热点和方向。本文将有关放、化疗的研究进展进行综述,以期对该病的治疗提供参考性指导。     

肠道结外鼻型NK/T细胞淋巴瘤临床特点及预后

目的：分析肠道结外鼻型NK/T细胞淋巴瘤患者的临床特点,以提高对该疾病的认识及诊疗水平。方法：回顾性分析我院曾收治的23例肠道结外鼻型NK/T细胞淋巴瘤患者的临床资料,从性别、年龄、临床症状、镜下表现、实验室检查、病理特征、治疗手段、预后情况等多方面进行分析总结。结果：男女比例2.83∶1,中位年龄45岁,中位生存期60天（95%CI：44.4~75.6）,1年生存率26.1%。常见症状有发热、腹痛、腹泻、便血等,最常见部位为大肠（56.5%）,其次为小肠（26.1%）、小肠＋大肠（17.4%）。内镜下肠道病变以弥漫不规则多发溃疡为主（65.2%）,其次为局限性溃疡（17.4%）、黏膜病变（13.0%）、息肉样隆起（4.3%）,首次肠镜＋活检确诊率17.4%。其常见并发症为穿孔、大出血。EBER阳性（P＝0.003）、急诊手术（P＝0.001）是肠道NKTCL预后不良的预测因素。结论：肠道NK/T细胞淋巴瘤发病以中青年男性为主,临床表现无特异性,易误诊。免疫组化在诊断及鉴别诊断上具有重要意义。诊断困难,预后差,穿孔或大出血前进行手术治疗可能会改善预后。临床中遇到腹痛、腹泻、便血并伴有B症状、LDH升高、EBV阳性且病情进展快的患者,应警惕NK/T细胞淋巴瘤的可能。     

自体外周血干细胞移植治疗鼻型结外NK/T细胞淋巴瘤

目的:探讨自体外周血干细胞移植(autologous peripheral blood stem cell transplantation,APBSCT)治疗鼻型结外NK/T细胞淋巴瘤的疗效。方法:在我院自2000年1月-2009年12月结束治疗的31例经病理形态学及免疫组织化学检查确诊的鼻型结外NK/T细胞淋巴瘤患者,经交替应用CHOP方案、VDLP方案和MEOP方案各2疗程化疗后,均应用直线加速器进行原发部位的三维适形放射治疗。随后经化疗联合重组人粒细胞集落刺激因子(rh G-CSF)方法动员自体外周血干细胞,经TBI联合VEMAC方案实施预处理后,进行自体外周血干细胞移植。随访观察时间为3-5年。结果:放化疗的主要不良反应为骨髓抑制及轻度局部黏膜损伤。全部患者均获得造血重建,无特殊并发症出现。随访1年时,治疗总有效率96.8%;随访3年时,无病存活率占全组患者的87.1%;随访5年时,无病存活患者占该组随访5年患者的81.5%。结论:自体外周血干细胞移植治疗鼻型结外NK/T细胞淋巴瘤可取得满意疗效。     

结外鼻型NK/T细胞淋巴瘤117例临床病理分析

 目的　分析结外鼻型NK／T细胞淋巴瘤（NKTL）的临床病理特点,探讨其与疾病预后的关系,为临床个体化治疗提供依据。方法　回顾117例确诊为NKTL患者的病理临床资料。病理诊断均采用常规组织学、免疫组织化学、T细胞重排和原位杂交方法检测EB病毒（EBV）编码小RNA（EBER）。EBV DNA拷贝数检测采用PCR方法。所有患者经过国际预后指数（IPI）和Ki-67等指标临床评估后均采用化疗和放疗联合治疗。随访患者并对临床指标与2年总生存（OS）率和无进展生存（PFS）率的关系进行单因素分析。结果　免疫组织化学结果提示各指标阳性率：CD3为90.6 %,CD56为94.0 %,CD45RO为92.9 %,TIA为97.9 %,Granzyme B为97.7 %,EBER为100.0 %。117例患者中位年龄为43.2岁（14～77岁）,原发鼻者95例（81.2 %）,Ki-67平均值为（48.3±2.6）%;原发非鼻者22例（18.8 %）,包括原发咽喉、舌、扁桃体、淋巴结、皮肤、肝、肠、中枢神经系统和睾丸。与原发鼻的NKTL患者相比,原发肝和肠者Ki-67值较高,且Ki-67值大于80 %的NKTL患者均在1年内死亡。Ki-67值为60 %～80 %的45例2年OS率为60.0 %,与Ki-67值为30 %～60 %的33例OS率（86.3 %）和Ki-67值小于30 %的8例OS率（100.0 %）分别相比,差异均有统计学意义（P＝0.047、0.011）。Ki-67值为60 %～80 %者2年PFS率为36.0 %,与Ki-67值为30 %～60 %者PFS率（57.5 %）相比,差异无统计学意义（P＝0.07）,与Ki-67值小于30 %者PFS率（78.0 %）相比,差异有统计学意义（P＝0.02）。CD56阴性的8例CD3表达阳性,TCR重排均为阳性,提示为T细胞来源,原发部位均为鼻部,无全身症状,2年OS率和PFS率分别为100.0 %和70.0 %,高于CD56阳性患者,差异均有统计学意义（P＝0.03、0.02）。13例检测了EBV DNA拷贝数,5例高于正常值者OS率为60.0 %,余8例OS率为100.0 %。结论　除了IPI外,NKTL原发部位和病理特征,尤其是Ki-67、CD56、EBER和EBV DNA拷贝数与其临床预后的关系不容忽视,也是NKTL预后判断的独立因素。     

First-line ifosfamide, methotrexate, etoposide and prednisolone chemotherapy +/- radiotherapy is active in stage I/II extranodal NK/T-cell lymphoma

Although most patients diagnosed with extranodal NK/T-cell lymphoma (NTCL) have localized disease, radiotherapy alone is unsatisfactory because of frequent systemic failure and conventional doxorubicin-based chemotherapy has low efficacy. Twenty-six patients with NTCL received ifosfamide, methotrexate, etoposide and prednisolone (IMEP) chemotherapy as first-line treatment [ifosfamide 1.5 g/m² (days 1 - 3), methotrexate 30 mg/m² (days 3 and 10), etoposide 100 mg/m² (days 1 - 3) and prednisolone 120 mg (days 1 - 5)]. Radiotherapy was administered only to patients with Ann Arbor stage I/II that had not achieved complete remission (CR) or to those that developed local failure after completing chemotherapy. Sixteen patients (group A) had nasal or upper aerodigestive tract localization (stage I/II) and 10 (group B) had extranasal or disseminated disease. Of the 14 evaluable patients in group A, 11 (79%) achieved CR after IMEP alone and 13 (93%) after chemotherapy ± additional radiotherapy. Although, out of the 11 patients who achieved CR with chemotherapy alone, seven developed recurrence, all recurrences were local failure and successfully treated by additional curative radiotherapy. However, patients in group B responded poorly (CR 13%). IMEP regimen was active in NTCL patients with nasal or upper aerodigestive tract localization. Considering local failure rate after IMEP alone, initial IMEP chemotherapy followed by radiotherapy may be a promising treatment strategy in this subset of NTCL.