培门冬酶和左旋门冬酰胺酶治疗NK/T细胞淋巴瘤的疗效和安全性

目的 观察比较培门冬酶(PEG-ASP)与左旋门冬酰胺酶(L-ASP)治疗NK/T细胞淋巴瘤的临床疗效及不良反应.方法 回顾性分析2009年9月-2015年7月青岛市商业职工医院肿瘤科收治的结外NK/T细胞淋巴瘤患者46例,其中24例采用PEG-ASP联合GDP方案(吉西他滨+顺铂+地塞米松)治疗的为PEG-ASP组,22例采用L-ASP联合GDP方案治疗的为L-ASP组,观察两组患者的疗效及不良反应.结果 PEG-ASP组CR 11例,PR 7例,完全缓解率和客观缓解率分别为45.83％和75.00％;L-ASP组CR 9例,PR 6例,完全缓解率和客观缓解率分别为40.91％和68.18％;两组患者客观缓解率的差异无统计学意义(x2=0.263,P=0.608).不良反应主要以1～2度为主,PEG-ASP组和L-ASP组患者骨髓抑制(25.00％:22.73％,x2=0.033,P=0.857)、凝血异常(8.33％:9.10％,x2=0.008,P=0.927)、肝肾功能异常(8.33％:18.18％,x2=0.982,P=0.322)、胃肠道反应(41.67％:40.91％,x2 =0.003,P=0.958)的发生率差异无统计学意义;PEG-ASP组过敏反应发生率明显低于L-ASP组 (4.17％:36.36％),差异有统计学意义(x2=7.561,P=0.006).PEG-ASP组患者平均住院时间为(10.04±1.63)d,L-ASP组为(13.09±2.76)d,差异有统计学意义(t=-4.612,P=0.000).结论 PEG-ASP与L-ASP联合化疗治疗NK/T细胞淋巴瘤疗效相当,但PEG-ASP过敏反应少,患者住院时间缩短,值得临床进一步推广应用.     

Therapeutic Efficacy of L-asparaginase in the Treatment of Refractory Midfacial Peripheral T-Cell Non-Hodgkin’s Lymphoma

Primary midficial peripheral T-cell non-Hodgkin's lymphoma (PMPTC-NHL) of the nasal cavity, paranasal sinuses, palate and nasopharynx occurs relatively high among Orientals. The incidence comprises approximately 3% of NHL in Hong Kong Chinese.[1] Previously, PMPTC-NHL has been designated by the names of lethal midline granuloma, midline reticulosis or polymorphic reticulosis, but recently it is considered as a distinct clinicopathological entity of NHL because the lesions show NK/T…     

Unexpected mortality from the use of E. coli L-asparaginase during remission induction therapy for childhood acute lymphoblastic leukemia: a report from the Taiwan Pediatric Oncology Group.

The relative efficacy and toxicity of E. coli L-asparaginase and epidoxorubicin used in remission induction therapy for childhood acute lymphoblastic leukemia (ALL) were assessed in a randomized trial conducted in Taiwan. All patients had standard-risk ALL, defined as a leukocyte count <10 x 10(9)/l and were aged between 1 and 2 or 7 and 10 years, or a leukocyte count <50 x 10(9)/l and were aged between 2 and 7 years, without evidence of a T cell or mature B cell immunophenotype, central nervous system leukemia or expression of two or more myeloid-associated antigens. Ninety-three patients were randomized to receive E. coli L-asparaginase at 10,000 IU/m2 thrice weekly for nine doses and 108 to receive epidoxorubicin at 20 mg/m2 weekly for two doses during remission induction with daily prednisolone, weekly vincristine and, on day 22, a dose of etoposide plus cytarabine. Patients treated with L-asparaginase had a significantly higher rate of fatal infection with or without hemorrhage than did those who received epidoxorubicin during remission induction (six of 93 vs none of 108, P = 0.009), resulting in a lower rate of complete remission in the former group (93.6 vs 99.1%, P = 0.05). In addition, patients treated with L-asparaginase had a higher frequency of hyperglycemia and hypoalbuminemia. The overall rate of event-free survival was lower in patients treated with L-asparaginase than in other patients (P = 0.06); estimated 3-year rates were 72% (95% confidence interval, 55-89%) and 87.2% (78-96%), respectively. We conclude that L-asparaginase (Leunase) given at 10,000 IU/m2 for nine doses was poorly tolerated and resulted in excessive toxicity, both through its effects as a single agent and possibly through potentiation of etoposide.     

A case report of complete remission of liver metastases from colorectal cancer treated with continuous hepatic arterial infusion

We encountered a patient with liver metastases from colorectal cancer in whom continuous hepatic arterial infusion brought complete remission. A 58-year-old man was admitted to our hospital for advanced rectal cancer with multiple liver metastases. He underwent a low anterior resection (D2). Continuous hepatic arterial infusion of 5-FU (250 mg/day) with a weekly arterial infusion of MMC (4 mg) was performed for 14 days. Six continuous hepatic arterial infusions resulted in a complete remission. The patient has been free from any sign of recurrence for 37 months after the operation. Continuous hepatic arterial infusion using 5-FU and MMC seems to be effective in the treatment of multiple liver metastases from colorectal cancer.     

A case report--a patient with gingiva carcinoma showing complete remission after combination chemotherapy with nedaplatin and 5-fluorouracil

We report a patient showing a complete remission after combination chemotherapy with nedaplatin and 5-fluorouracil (5-FU). A 63-year-old man was admitted to our hospital for advanced carcinoma of gingiva. 5-FU was administered at a dose of 1,000 mg/body (700 mg/m2) by continuous infusion for 120 hours on days 1 to 5. Nedaplatin was administered at a dose of 140 mg/body (90 mg/m2) by drip infusion for 120 minutes on day 5. This combination chemotherapy resulted in a complete remission of the tumor after 2 weeks. There has been no sign of recurrence for 6 months after the chemotherapy.     

Clinical effect and pharmacokinetics of intermediate dose Ara-C therapy in a patient with acute non-lymphocytic leukemia with two CNS recurrences

A case of two repeated CNS recurrences of acute non-lymphocytic leukemia (M2) was treated with intermediate dose Ara-C therapy and achieved 2 complete remissions. The clinical effect and pharmacokinetics of intermediate dose Ara-C therapy in this patient were discussed. A 55-year-old male with acute non-lymphocytic leukemia (M2) achieved complete remission by combination chemotherapy of Behenoyl-ara-C, Daunorubicin, 6-Mercaptopurine and Prednisolone in July, 1985. He subsequently received consolidation and intensification therapy with periodical intrathecal injection of Methotrexate (MTX), but 13 months later he developed his first CNS recurrence which was resistant to the intrathecal administration of Ara-C and MTX. As he also relapsed systemically, Ara-C was administered in intermediate dose (1 g/m2 every 12 hrs for 5 days) and he achieved complete remission both in the CNS and systemic manifestations. Six months later he was diagnosed as having a second CNS recurrence and another systemic relapse. Intermediate dose Ara-C was administered again, and he achieved complete remission in the CNS and partial remission in systemic manifestations. Pharmacokinetic study revealed high peaks of Ara-C concentration in plasma (6.2 microM immediately after the end of the infusion) and high degree of its penetration into the CNS (5.6 microM at 3 hr after the end of the infusion) suggesting the effective and perhaps a uniform level of Ara-C is achieved throughout the CNS by this therapy. In 3 other patients without CNS involvement 0.88 +/- 0.44 microM of Ara-C, which is enough concentrations for its cytostatic effect, was detected at 3 hr after the end of infusion, suggesting the efficacy of the therapy for CNS prophylaxis. In this case the relapse occurred after repeated administration of antileukemic drugs, including Behenoyl-ara-C, an analog of Ara-C, and was resistant to the intrathecal administration of Ara-C. These findings suggest that intermediate dose Ara-C therapy was effective to overcome a resistance to antileukemic drugs, including Ara-C, and also, in some cases, more effective than intrathecal injection of antileukemic drugs for the treatment of CNS leukemia.     

Complete remission obtained in refractory acute lymphocytic leukemia using high-dose cytosine arabinoside combined with low-dose L-asparaginase

A 41-year-old male was diagnosed as acute lymphocytic leukemia (ALL) in November, 1982 and partial remission was obtained by a combination chemotherapy of LVP, DVP ABOP and VAMP. In January, 1983, peripheral blood showed an increasing number of leukemic cells and he was readmitted to our hospital. WBC count in the peripheral blood was 13,200/mm3 and an 82% ratio of leukemic cells was observed. Bone marrow aspiration showed a hypercellularity of 89.4% leukemic cells. High-dose Ara-C therapy was started at a dose of 3 g/m2 i.v. every 12 hours for 6 days. Leukemic cells in peripheral blood were rapidly decreased in number, and the nucleated cell count of bone marrow was also reduced after 3 weeks of treatment, however 95% of leukemic cells remained. Low-dose L-asparaginase was then supplemented at a dose of 2000 U for 3 days, and 2 months later complete remission was achieved. The side effects associated with this high-dose Ara-C therapy were nausea, vomiting, diarrhea, fever and conjunctivitis, although these were tolerable. These observations suggest that high-dose Ara-C combined with L-asparaginase should be added to the treatment of leukemia which is refractory to conventional chemotherapy.     

Phase I trial of volasertib,a Polo‐like kinase inhibitor,in Japanese patients with acute myeloid leukemia

This phase I trial conducted in Japanese patients with acute myeloid leukemia evaluated the safety, maximum tolerated dose and pharmacokinetics of volasertib (BI 6727), a selective Polo‐like kinase inhibitor. The primary endpoints were the maximum tolerated dose of volasertib and the incidence of dose‐limiting toxicities. Secondary endpoints were best response and remission duration. Other endpoints included safety and pharmacokinetics. Patients who were ineligible for standard induction therapy or with relapsed or refractory disease received volasertib monotherapy as a 2‐h infusion on days 1 and 15 of a 28‐day cycle, with dose escalation following a 3 + 3 design. A total of 19 patients were treated with three volasertib doses: 350, 400 and 450 mg. One patient receiving volasertib 450 mg reported a dose‐limiting toxicity of grade 4 abnormal liver function test and 450 mg was determined as the maximum tolerated dose. The most frequently reported adverse events were febrile neutropenia (78.9%), decreased appetite (42.1%), nausea and rash (36.8% each), and sepsis, fatigue, hypokalemia, stomatitis and epistaxis (26.3% each). Best responses were complete remission (n = 3), complete remission with incomplete blood count recovery (n = 3) and partial remission (n = 1). The median remission duration of the six patients with complete remission or complete remission with incomplete blood count recovery was 85 days (range 56–358). Volasertib exhibited multi‐compartmental pharmacokinetic behavior with a fast distribution after the end of infusion followed by slower elimination phases. Volasertib monotherapy was clinically manageable with acceptable adverse events and anti‐leukemic activity.     

High-dose cytarabine treatment with asparaginase (Capizzi schedule) in recurrent or refractory AML in the adult

4 patients with refractory AML or AML in relapse were treated with high dose Ara-C and L-asparaginase. Although only one patient was resistant against this type of treatment, a durable complete remission could be achieved in only one case. Severe myelosuppression was observed in all 4 cases; non-hematologic toxicity, however, was minimal.     

Successful management of severe L-asparaginase-associated pancreatitis by continuous regional arterial infusion of protease inhibitor and antibiotic

BACKGROUND.: L-asparaginase is a key drug in the treatment of childhood acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). However, L-asparaginase can cause a fatal complication of pancreatitis, and an effective treatment for L-asparaginase-associated pancreatitis (AAP) has not been developed to date. The authors investigated whether rapidly treating children with AAP by continuous regional arterial infusion (CRAI) of protease inhibitor and antibiotic would quickly resolve AAP. METHODS.: Between 2000 and 2007, 104 pediatric patients with ALL or LBL were treated at the authors' affiliated hospitals with intensive regimens that included Escherichia coli-derived L-asparaginase. Six of 104 patients developed severe AAP. One patient was treated with intravenous infusion of protease inhibitor, and the remaining 5 patients received CRAI of protease inhibitor and antibiotic within 48 hours of the onset of AAP. RESULTS.: The patient who received intravenous protease inhibitor had pseudocyst formation and developed a subsequent leukemic recurrence after the interruption of chemotherapy for 4.5 months. In the other patients, AAP subsided within 2 to 6 days after the start of CRAI, and serious complications did not emerge. Significantly, chemotherapy could be resumed within 4 weeks (range, 12-23 days) afterthe onset of AAP, and the patients were in complete remission from 4 months to 44 months with further chemotherapy that excluded L-asparaginase. CONCLUSIONS.: The current results indicated that early introduction of CRAI of protease inhibitor and antibiotic is suitable for treating severe AAP. Cancer 2008. (c) 2008 American Cancer Society.     

A case of submandibular gland cancer in elderly patients showed significant effect by S-1 and intravenous docetaxel chemotherapy concurrent with radiotherapy

An elderly case of with advanced head and neck cancer treated by intravenous infusion chemotherapy with weekly docetaxel( DOC)and concurrent radiotherapy was reported. The patient was a 77-year-old man. Clinical diagnosis was submandibular gland carcinoma. He was treated by intravenous infusion chemotherapy with weekly DOC and concurrent radiotherapy (total dose 66 Gy). Two months after irradiation, PET-CT showed a partial response (PR). Therefore, chemotherapy of S-1 (80 mg/day) for 2 weeks every 3 weeks was performed. Two months after the end of chemotherapy, PET-CT showed a complete response(CR). This therapy is effective for the treatment of advanced head and neck cancers for elderly inoperable patients.     

Successful treatment with Erwinia L-asparaginase for recurrent natural killer/T cell lymphoma

We describe a patient with natural killer (NK)/T cell lymphoma who relapsed after autologous peripheral blood stem cell transplantation (auto-PBSCT) and was successfully treated with Escherichia coli (E. coli) and Erwinia L-asparaginase. A 38-year-old male patient with ulcerated tumor at the left thigh was diagnosed as having nasal type NK/T cell lymphoma on the basis of histopathological and flowcytometric findings of tumor, revealing diffuse infiltration of atypical lymphoid cells into blood vessels and expression of CD7 and CD56 antigens, but not CD3. He had tumor infiltration in the bone marrow and at the right lower lung field. After five cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) therapy, the patient achieved complete remission and received high-dose chemotherapy with auto-PBSCT, although the tumor recurred in the right leg 10 months later. Despite salvage chemotherapy, followed by local irradiation and surgical amputation, a tumor recurred at the left upper gingiva 10 days after. Using E. coli L-asparaginase (6000 U/m2/day), the tumor regressed, fever was alleviated and the serum lactate dehydrogenase decreased to normal range after several days. The asparagine synthetase expression in tumor cells was immunohistochemically negative on paraffin-embedded tissues. Because of the anaphylactoid reaction developing after E. coli L-asparaginase, alternative Erwinia L-asparaginase (6000 U/m2/day) was administered, resulting in regression of tumor and fever lysis. L-asparaginase is a promising agent for the treatment of NK/T cell lymphoma.     

A case responding to weekly paclitaxel therapy as second-line chemotherapy for gastric cancer previously treated with TS-1

A 58-year-old male patient with the recurrence of para-aortic lymphnodes after TS-1 treatment was treated by a weekly infusion of paclitaxel as second-line chemotherapy. Paclitaxel was administered at a weekly dose of 70 mg/m2/day for three weeks followed by a one week interval. After 2 courses, the tumor was reduced, and the reduction was judged as PR. Moreover, after 5 courses, the tumor was more remarkably reduced and the reduction was judged as CR. The grade 2 leukopenia, neutropenia, and grade 1 alopecia were observed as adverse events. Recently, we treated 11 patients of advanced or recurrent gastric cancers with measurable lesions, using the weekly paclitaxel therapy after TS-1 treatment. The response rate was 36.4%. The median duration of PR was 130 days. Therefore, a weekly paclitaxel regimen was considered to be one of the promising regimens for advanced or recurrent gastric cancer as the second-line chemotherapy after TS-1 treatment.     

Treatment outcomes with paclitaxel for advanced gastric cancer patients previously treated with TS-1

In the present report, we describe the treatment results of paclitaxel in patients with metastatic gastric cancer previously treated with TS-1 or combination chemotherapy of TS-1 and CDDP. Paclitaxel was administered to 4 patients at a weekly dose of 80 mg/m2/day for three weeks followed by a one week interval. Remarkable tumor reduction was observed in 2 patients. Case 1: A 52-year-old male patient with gastric cancer and multiple liver metastases was treated by weekly infusion of paclitaxel as a 2nd line chemotherapy. After 1 course, the tumor was remarkably reduced, and the reduction was judged PR. Case 2: A 31-year-old male patient presented with lymphoangitis carcinomatosa and obstructive jaundice resulting from cancerous lymphoadenopathy. After 1 course, chest radiographs and abdominal CT scan showed remarkable reduction of these lesions. The adverse effects observed with this drug were leucocytopenia and liver dysfunction, both of which improved soon. These results indicate paclitaxel is effective for advanced gastric cancer pretreated with TS-1.     

Treatment of childhood lymphocytic leukaemia with high white-cell counts.

Combination chemotherapy with cytosine arabinoside, cyclophosphamide and L-asparaginase (Asnase) was given to 22 children with acute lymphocytic leukaemia (ALL) with a white-cell count greater than 30 X 10(9)/1, and other features suggestive of poor prognosis. Complete remission was induced in all patients--in 19 after 2 courses of chemotherapy and in the remainder after a third course. During induction, neutropenia occurred in 18 and severe infection in 3. Anaphylaxis to Asnase occurred in 8 patients after the second course and one other had transient Asnase-induced diabetes. All patients received central-nervous-system prophylaxis after achieving remission, during which they were also treated with weekly vincristine and a 2-week course of prednisolone. Continuation therapy consisted of short cycles of intermittent chemotherapy and BCG inoculation or long cycles of intermittent chemotherapy +/- BCG. Life-table analysis shows 46% complete remission rate at 28 months, with 6 patients all in complete remission followed up between 28 and 41 months. There were minimal complications of continuation therapy, and BCG inoculation was well tolerated.     

Complete response of gastric cancer with interaorticocaval lymph node recurrence to weekly administration of paclitaxel--a case report

We report a case in which weekly administration of paclitaxel produced a complete response for gastric cancer with interaorticocaval lymph node recurrence. A 55-year-old man who underwent total gastrectomy for advanced gastric cancer had pathological findings of tub2, se, n2, ly2, v2, stage IIIB. As an outpatient, he was first treated with TS-1 (100 mg/day) for 5 cycles. CEA increased gradually however, and 7 months postoperatively he was found to have interaorticocaval lymph node swelling in upper abdominal CT and was diagnosed with a recurrence of gastric cancer. He underwent weekly administration of paclitaxel as second-line chemotherapy. Paclitaxel was administered by 1-hour intravenous infusion at a dose of 90 mg/body weekly after short premedication as an outpatient. This was continued for 3 weeks followed by 1 week of rest. CEA decreased gradually, and the swollen lymph node had responded completely after 10 cycles. The only toxic side effect was alopecia (grade 1). No major adverse effects such as hypersensitivity, leukopenia or peripheral neuropathy were observed.     

Two cases of recurrent breast cancer successfully treated with paclitaxel weekly therapy

The patients were a 57-year-old and a 38-year-old woman who had supraclavicular lymph node and multiple lung metastases from breast cancer. They were given 3 and 4 courses of paclitaxel (TXL) weekly therapy (80 mg/m2, day 1, 8, 15, repeated every 4 weeks). One patient had received docetaxel (TXT) and CEF therapy previously. There were no severe adverse effects except leukopenia, neutropenia and alopecia. The weekly TXL therapy brought complete remission against the supraclavicular lymph node and multiple lung metastases. The durations of the response to this weekly therapy were 15 and 5 months, respectively, and their effects have continued to the present. We believe that the weekly TXL therapy is a well-tolerated, feasible and safe administration schedule on an outpatient basis, and improves the patient's quality of life. Furthermore, we suggest the possibility of TXL being effective against both TXT and anthracycline-resistant breast cancer.     

High-dose treatment

High dose administration of anticancer drugs was discussed putting an emphasis on methotrexate and cytosine arabinoside. High dose methotrexate in combination with leucovorin rescue was effective on various kinds of cancer which had become resistant to conventional doses of anti-cancer drugs. The administration of high-dose methotrexate, however, should be performed with meticulous precautions to prevent serious side effects. Side effects included gastrointestinal mucositis, hepatic dysfunction, nausea and vomiting. Central nervous system manifestations were sometimes observed. High-dose cytosine arabinoside of 3 g/m2 per 12 hours X 12 was given by 2-hours infusion to patients with acute leukemia who had become resistant to conventional combination chemotherapy, or to relapsed patients. This regimen in combination with L-asparaginase or anthracyclines resulted in a fairly high remission rate among those intractable cases. High-dose cytosine arabinoside in combination with anthracyclines has recently been tried on patients with acute leukemia as an initial treatment for remission induction and consolidation. In this case, no intensification treatment was performed to maintain remission. Patients treated with this regimen as an initial medication showed a high remission induction rate and long remission duration. Forty percent of the patients were still alive after 3 years.     

贝伐单抗联合FOLFOX4方案治疗12例初治失败转移性结直肠癌的临床观察

目的探讨贝伐单抗(bevacizumab,BEV)联合FOLFOX4方案治疗初治失败的转移性结直肠癌的近期疗效和安全性。方法 12例晚期转移性结直肠癌患者初治失败后应用贝伐单抗5 mg/kg,第1天,每2周1次,联合奥沙利铂85 mg/m2,静脉滴注2 h,第1天;亚叶酸钙200 mg/m2静脉滴注2 h,第1～2天;5-Fu 400 mg/m2静脉推注,第1～2天,5-Fu 600 mg/m2持续深静脉滴注22 h,第1～2天;每2周重复1次,每治疗4个周期评价疗效。结果 12例患者中,CR无1例(0),PR 1例(8.3%),SD 8例(66.7%),PD 3例(25.0%),RR为8.3%,DCR为75.0%。治疗相关不良反应主要为轻度血压增高和蛋白尿,中性粒细胞减少,患者耐受性良好。结论贝伐单抗联合FOLFOX4方案治疗初治失败的转移性结直肠癌近期疗效确切,不良反应轻微,可使大部分患者临床获益。     

PEG-asparaginase in BFM-90 regimen improves outcomes in adults with newly diagnosed lymphoblastic lymphoma

Objective:Although L-asparaginase (L-ASP) is a standard treatment for lymphoblastic lymphoma (LBL),hypersensitivity reactions by some patents limit its application.Polyethylene glycol-conjugated asparaginase (PEGASP) has a lower immunogenicity and is a standard treatment in all pediatric acute lymphoblastic leukemia (ALL).In this study,we investigated the efficacy and toxicity of PEG-ASP instead of L-ASP as used in the BFM-90 regimen (PEG-ASP-BFM-90) for adult LBL.Methods:Between June 2012 and July 2015,we treated 30 adult patients with newly diagnosed LBL,using PEGASP-BFM-90 in a prospective,multicenter and single-arm clinical study at 5 participating institutions in China.Results:All the 30 patients,including 19 males and 11 females with a median age of 30 (range:18-62) years,completed 128 times of the PEG-ASP,with the median of 4 (range:2-6) times.Patients did not receive radiotherapy at this time.The overall response rate was 86.7％ (26/30),vith 50.0％ (15/30) complete response and 36.7％ (11/30) partial rcsponsc.Thc 3-year overall survival was 46.0％ [95％ confidence interval (95％ CI),28.2％-64.8％],and the 3-year progression-free survival was 43.0％ (95％ CI,25.7％-62.0％).Major adverse events were myelosuppression,reduced fibrinogen,liver dysfunction and digestive tract toxicities.No allergic reaction and no treatment-related mortality or severe complications were recorded.Conclusions:Our clinical data and observed outcomes indicate that 1 dose of PEG-ASP can replace multiple doses of native L-ASP in BFM-90,with predominantly grade 3-4 neutropenia for adult LBL,and no therapyrelated deaths.The effect is similar to previous reports of PEG-ASP-containing regimens for adult ALL.Major advantages include less serious allergic reactions,2-3 weeks of action duration,and convenience for patients and physicians.