Intraperitoneal radioimmunochemotherapy of ovarian cancer: a phase I study

A phase I trial was designed to examine the feasibility of combining interferon and Taxol with intraperitoneal radioimmunotherapy (177Lu-CC49). Patients with recurrent or persistent ovarian cancer confined to the abdominal cavity after first line therapy, Karnofsky performance status > 60, adequate liver, renal and hematologic function, and tumor that reacted with CC49 antibody were enrolled. Human recombinant alpha interferon (IFN) was administered as 4 subcutaneous injections of 3 x 10(6) U on alternate days beginning 5 days before RIT to increase the expression of the tumor-associated antigen, TAG-72. The addition of IFN increased hematologic toxicity such that the maximum tolerated dose (MTD) of the combination was 40 mCi/m2 compared to 177Lu-CC49 alone (45 mCi/m2). Taxol, which has radiosensitizing effects as well as antitumor activity against ovarian cancer, was given intraperitoneally (i.p.) 48 hrs before RIT. It was initiated at 25 mg/m2 and escalated at 25 mg/m2 increments to 100 mg/m2. Subsequent groups of patients were treated with IFN + 100 mg/m2 Taxol + escalating doses of 177Lu-CC49. Three or more patients were treated in each dose group and 34 patients were treated with the 3-agent combination. Therapy was well tolerated with the expected reversible hematologic toxicity. The MTD for 177Lu-CC49 was 40 mCi/m2 when given with IFN + 100 mg/m2 Taxol. Interferon increased the effective whole body half-time of radioactivity and the whole body radiation dose. Taxol did not have a significant effect on pharmacokinetic or dosimetry parameters. Four of 17 patients with CT measurable disease had a partial response (PR) and 4 of 27 patients with non-measurable disease have progression-free intervals of 18+, 21+, 21+, and 37+ months. The combination of intraperitoneal Taxol chemotherapy (100 mg/m2) with RIT using 177Lu-CC49 and interferon was well tolerated, with bone marrow suppression as the dose-limiting toxicity.     

Cisplatin modulates tumor cell susceptibility to tumor-infiltrating lymphocytes in vivo

We investigated the in vivo augmentation of susceptibility of tumor cells to tumor-infiltrating lymphocytes (TILs) with cisplatin (CDDP). TILs showed cytotoxicity against autologous and established tumor cells. Pretreatment of tumor cells with CDDP 2 mu g/ml for 12 h enhanced the susceptibility of tumor cells to TILs in vitro. TILs and autologous tumor cells were obtained from malignant ascites of patients, before and after the intraperitoneal administration of CDDP. TILs had higher cytotoxicity against autologous tumor cells of CDDP treated as compared to untreated control tumor cells, providing direct evidence of in vivo immunomodulatory effect of CDDP in cancer patients.     

Feasibility of peritonectomy associated with intraperitoneal hyperthermic perfusion in patients with Pseudomyxoma peritonei

AIMS AND BACKGROUND: Pseudomyxoma peritonei is a rare disease characterized by a complete redistribution of mucin within the peritoneal cavity. It can be classified into three histologic groups: disseminated peritoneal adenomucinosis, peritoneal mucinous carcinomatosis, and an intermediate group. The aim of the present study was to evaluate the feasibility of cytoreductive surgery requiring peritonectomy procedures associated with intraperitoneal hyperthermic perfusion, a technique that combines hyperthermia and high drug doses administered locally. METHODS: Twenty-seven patients with pseudomyxoma peritonei (19 males and 8 females) were enrolled in a phase II clinical trial. Twenty-two cases underwent cytoreductive surgery plus intraperitoneal hyperthermic perfusion, and 6 received debulking surgery only. One patient was operated on twice for disease recurrence. All patients with peritoneal mucinous carcinomatosis presented serous ascites, whereas all but one patient with disseminated peritoneal adenomucinosis or in the intermediate group presented mucinous ascites. Cytoreductive surgery was performed with peritonectomy procedures. The closed abdomen technique was adopted for intraperitoneal hyperthermic perfusion using a preheated polysaline perfusate containing cisplatin (25 mg/m2/L) plus mitomycin-C (3.3 mg/m2/L) through a heart-lung pump at a mean flow of 600 mL/min for 60 mins from the hyperthermic phase (42.5 degrees C). RESULTS: All but one of the patients with disseminated peritoneal adenomucinosis and 2 of the 3 patients in the intermediate group were optimally cytoreduced. Patients with serous ascites (all patients with peritoneal mucinous carcinomatosis and 1 patient with disseminated peritoneal adenomucinosis) were considered ineligible for treatment because of tumor diffusion. The morbidity rate was 22%. There was one case of treatment-related mortality 30 days after treatment. CONCLUSIONS: The following conclusions can be drawn from this phase II clinical trial: 1) patients with pseudomyxoma peritonei originating from undifferentiated mucinous adenocarcinoma (peritoneal mucinous carcinomatosis), with complete distribution into the peritoneal cavity, are not eligible for the cytoreductive surgery plus intraperitoneal hyperthermic perfusion technique; 2) the presence of serous ascites would seem to exclude patients from the treatment; 3) cytoreductive surgery associated with intraperitoneal hyperthermic perfusion is the most suitable approach for patients with disseminated peritoneal adenomucinosis and in the intermediate group.     

IL-2联合腹腔热灌注化疗治疗恶性腹水临床观察

目的观察IL-2联合腹腔热灌注化疗治疗恶性腹水的近期疗效及不良反应。方法将60例细胞学确诊为恶性腹水的患者随机分成治疗组(n=30)和对照组(n=30),治疗组给予顺铂60 mg/m2腹腔热灌注,IL-2 100IU/d,第2-8天,3周1次,共完成2～4次;对照组仅给予顺铂60 mg/m2腹腔热灌注化疗,同时对比两组治疗效果及记录不良反应。结果治疗组总有效率为57.3%,对照组总有效率为43.3%,无IL-2相关不良反应出现。结论IL-2联合腹腔热灌注化疗治疗恶性腹水效果明显,是一种安全、有效的治疗手段,值得临床推广应用。     

Influence of interferon on the growth of primary ovarian carcinoma cells in a semi-solid agar system: comparison with clinical effects of interferon therapy

The sensitivity of primary human ovarian cancer cells to interferon (IFN) was studied in vitro by the use of a tumor cloning system in semi-solid agar. Tumor colonies were found in 37% (34/93) of the experiments with tumor cells from ascites and in 35% (6/17) of the experiments with solid tumors. The relative colony-forming ability could not be correlated to prior treatment. In 15 out of 18 patients the ascitic tumor cells were sensitive to IFN-alpha. Sensitivity was found in one test out of three with solid tumors. The sensitivity was dependent on the dose of IFN but could vary for the natural IFNs alpha and gamma. In seven patients the relation between in vitro and in vivo sensitivity of the tumor cells to IFN could be studied. Any correlation between in vitro and in vivo sensitivity could not be revealed in this small group of patients.     

Antitumor effect of recombinant human interferon alpha A/D on Meth-A sarcoma in mice

Recombinant human interferon alpha A/D (IFN alpha A/D) is known to be as active on murine cells as on human cells. We studied the antitumor effect of pure IFN alpha A/D on Meth-A sarcoma subcutaneously transplanted into female syngeneic BALB/c mice. When administered systematically (intraperitoneally), IFN alpha A/D was only marginally (but significantly, P less than 0.05) effective in inhibiting tumor growth. With intralesional injection, however, IFN alpha A/D strongly suppressed the growth of Meth-A sarcoma, even leading to complete tumor regression and to subsequent immunity to Meth-A sarcoma cells in the host mice when the treatment was started early after tumor transplantation and with a high IFN alpha A/D dose. We also found that treatment of mice with IFN alpha A/D increased the level of serum alpha 1-acid glycoprotein, one of the acute-phase proteins.     

Selective intraperitoneal biochemical modulation of methotrexate by dipyridamole

Dipyridamole increases the toxicity of methotrexate in a concentration-dependent manner. We hypothesized that concurrent intraperitoneal administration of both drugs would result in high peritoneal concentrations with much lower plasma concentrations, permitting a selective increase in the activity of methotrexate against intraperitoneal tumors without enhancing systemic toxicity. Initially, 2.16 mg/m2/d methotrexate and 12 mg/m2/d dipyridamole were delivered together as a constant intraperitoneal infusion for 48 hours. With escalation of chemotherapy, eventually 4.32 mg/m2/d methotrexate was administered for 168 hours. Forty-seven courses were administered to 18 patients. The mean peritoneal to plasma concentration ratios of methotrexate and non-protein bound dipyridamole were 71.6 +/- 34.8 and over 2,300, respectively. Chemical peritonitis was the dose-limiting toxicity. Three patients had some evidence of a response (two with decreasing tumor markers, and the third with a reduction in ascites). We conclude that the drug concentrations are in an appropriate range for selective intraperitoneal biochemical modulation of methotrexate, and that it is feasible to expose tumors confined to the peritoneal cavity to these drugs for long periods of time.     

The in vivo immunomodulatory effects of recombinant interferon gamma plus recombinant tumor necrosis factor-alfa

We conducted a phase I study in which an intramuscular injection of interferon gamma (IFN gamma) at 10, 50, or 100 micrograms/m2 was followed 5 minutes later by an intramuscular injection of 10, 50, or 100 micrograms/m2 of tumor necrosis factor-alfa (TNF alpha) at another site every other day for 20 days (10 doses). The addition of TNF alpha to IFN gamma reduced both the magnitude and duration of IFN gamma-mediated effects on peripheral blood monocyte expression of Fc receptors (FcRs) and HLA-DR and production of hydrogen peroxide. This inhibition was related to the dose of TNF alpha. On the other hand, TNF alpha and IFN gamma appeared to have an additive stimulatory effect on the production of neopterin by monocytes. The highest serum levels of neopterin were detected in patients who received the highest doses of both IFN gamma and TNF alpha. Thus, conflicting conclusions regarding the effect of the combination on immune activation are possible. If the activation of peripheral blood monocytes is the appropriate surrogate measure of the immune enhancement of the combination, then the simultaneous administration of IFN gamma and TNF alpha is ineffective, and future attempts to exploit the potential additive or synergistic effects of this combination of cytokines in humans may need to explore sequential administration schemata. On the other hand, if serum neopterin levels are a more reliable index of immune activation, simultaneous administration of 100 micrograms/m2 IFN gamma and 50 micrograms/m2 TNF alpha every other day (the maximally tolerated dose [MTD]) should be used in phase II testing. This dilemma points out the limitations of currently available methods of human immune assessment and the inadequacies in our capacity to gauge what particular immune measure or set of measures predict for in vivo antitumor effects.     

Effect of intraperitoneal recombinant human tumour necrosis factor alpha on malignant ascites

29 patients with refractory malignant ascites due to metastatic peritoneal spread of adenocarcinomas originating from the ovary, gastrointestinal tract, liver, breast and uterus were treated in a phase I trial of intraperitoneal infusions of recombinant human tumour necrosis factor alpha (rhTNF-α). Patients received 40–350 μg/m² rhTNF-α intraperitoneally once weekly for 2 months or for a shorter period in case of early resolution of ascites. Systemic side-effects resembled those reported for rhTNF-α given intravenously. No dose-limiting toxicities were found and thus a maximum tolerated dose of intraperitoneal rhTNF-α was not established. Out of 29 patients, 22 responded with a complete (16) or partial (6) resolution of their ascites. There was a less than 50% reduction in 4, and no increase in ascites in 1. 1 patient showed progressive ascites formation, and another patient was not eligible because of early death unrelated to treatment. Trials in patients with smaller tumour burden are warranted.     

Immunotherapy of malignant ascites with trifunctional antibodies

A new class of intact bispecific antibodies shows unmet effector qualities by activation of not only T cells but also simultaneous activation of Fcgamma receptor type I/III+ cells (macrophages, NK-cells and DC). These trifunctional antibodies (trAb) lead to efficient specific killing of targeted tumor cells without any pre- or co-stimulation. This concept was investigated in vivo in patients with malignant ascites in a clinical situation that allowed monitoring of tumor cell elimination and correlation with clinical effects. In a prospective study, 8 patients with malignant ascites due to peritoneal carcinomatosis were treated with intraperitoneal application of trAb, which bound either the EpCAM- or Her2/neu-antigen on tumor cells. Treatment consisted of 4-6 applications within 9-23 days with a total amount of 145-940 microg. Seven of eight patients required no further paracentesis during follow-up or until death with a mean paracentesis-free interval of 38 weeks (median = 21.5, range = 4-136). Tumor cell monitoring showed a complete elimination of tumor cells in ascites already at total doses as low as 40-140 microg. Clinical response with disappearance of ascites accumulation was seen in all patients, which was correlated with elimination of tumor cells (p = 0.0014). Severe adverse events were not observed. Clinically relevant side effects were fever, moderate abdominal pain and skin reactions. Intraperitoneal immunotherapy with trAb showed convincing efficacy in patients with malignant ascites. This treatment offers new therapeutic options for patients with peritoneal carcinomatosis.     

恩度联合多西他赛序贯腹腔灌注治疗胃癌伴恶性腹水的临床观察

目的:回顾性分析恩度联合多西他赛序贯腹腔灌注治疗胃癌伴恶性腹水的疗效及不良反应。方法:收集72例胃癌伴腹水患者,曾接受过二线及以上方案化疗,观察组35例,采用恩度45 mg联合多西他赛35 mg/m2 d1,d5序贯腹腔灌注1周期;对照组37例,采用多西他赛35 mg/m2 d1,d5腹腔灌注1周期,统计患者腹水控制有效率、KPS改善率、腹水控制时间及不良反应。结果:治疗组中腹水控制有效率71.43%;对照组中腹水控制有效率48.65%,P=0.049,两组具有统计学差异;治疗组中KPS改善率77.14%,对照组中KPS改善率54.05%,P=0.04,两组具有统计学差异;观察组中腹水控制时间8~90天,中位控制时间44天,对照组中腹水控制时间5~66天,中位控制时间28天,两组控制时间比较,P=0.048,具有统计学差异;III级以上不良反应发生率低,无治疗相关性死亡,两组不良反应比较,P>0.05,无统计学差异。结论:恩度联合多西他赛序贯腹腔灌注治疗体力状况（performance status,PS）评分较差的胃癌伴恶性腹水患者,腹水控制较好,能明显提高患者生活质量,未见明显不良反应。     

Bikunin plus paclitaxel markedly reduces tumor burden and ascites in mouse model of ovarian cancer

Our previous studies of intraperitoneal ovarian carcinoma in a mouse model demonstrated that bikunin gene transfection could prevent ascites formation and intraperitoneal disseminated metastasis. Although ascites was almost completely inhibited, tumor burden was variably reduced. Several reports have indicated that bikunin may be involved in tumor survival. In the present study, the effectiveness of exogenous bikunin and the biodistribution characteristics of (125)I-bikunin were initially examined in a mouse model of human ovarian cancer HRA cells. The once-daily i.p. administration of bikunin significantly decreased progressive growth of HRA tumors and ascites formation in a dose-dependent manner. Maximal radioisotope tumor uptake peaked at 7.4% injected dose/g at 3 hr. Bikunin binding specificity was demonstrated by reduced tumor uptake after coinjection of excess nonradioactive bikunin. Bikunin was rapidly excreted renally. The bikunin therapy produced the significant inhibition in expression of the proteolysis (uPA and uPAR) and angiogenesis-related molecules (VEGF and bFGF). The second purpose of our study was to optimize the antimetastatic activity of bikunin in combination with paclitaxel against HRA cells growing orthotopically in mice. The once-daily i.p. administration of bikunin (25 microg/g body weight/day) in combination with paclitaxel (i.p., 100 microg/20 g at days 2 and 5) significantly decreased progressive growth of HRA cells in a synergistic fashion. In conclusion, combination therapy with bikunin plus paclitaxel may be an effective way to markedly reduce i.p. tumor growth and ascites in ovarian carcinoma possibly through suppression of uPA, uPAR, VEGF and bFGF expression.     

Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer

Angiogenesis is essential for both primary and metastatic tumor growth. Tumor blood vessel formation is complex and regulated by many factors. Ovarian carcinomas have a poor prognosis, often associated with multifocal intraperitoneal dissemination accompanied by intense neovascularization. To examine tumor angiogenesis in the tumor microenvironment, we studied malignant ascites of patients with untreated ovarian carcinoma. We observed high numbers of plasmacytoid dendritic cells (PDCs) and significant stromal-derived factor (CXCL-12/SDF)-1 in their malignant ascites, attracting PDCs into the tumor environment. We now show that tumor-associated PDCs induced angiogenesis in vivo through production of tumor necrosis factor alpha and interleukin 8. By contrast, myeloid dendritic cells (MDCs) were absent from malignant ascites. MDCs derived in vitro suppressed angiogenesis in vivo through production of interleukin 12. Thus, the tumor may attract PDCs to augment angiogenesis while excluding MDCs to prevent angiogenesis inhibition, demonstrating a novel mechanism for modulating tumor neovascularization. Because dendritic cells (DCs) have long been known to affect tumor immunity, our data also implicate DCs in regulation of tumor neoangiogenesis, suggesting a novel role of DCs in tumor pathology.     

腹腔内贝伐珠单抗联合腹腔热灌注化疗治疗卵巢癌腹腔积液的临床观察

目的 观察腹腔内贝伐珠单抗联合腹腔热灌注化疗治疗卵巢癌腹腔积液的疗效和安全性,分析腹水内血管内皮生长因子（VEGF）水平对贝伐珠单抗治疗卵巢癌腹腔积液的临床意义。方法 将46例卵巢癌伴腹腔积液患者随机分为治疗组（n=25）和对照组（n=21）,均应用TC方案（紫杉醇135mg／m2静脉注射d1+卡铂 AUC=5 静脉注射d1）全身化疗,3周重复1次;同时腹腔内给予顺铂40mg／m2+43～45℃ 0.9%生理盐水1500～3000ml热灌注化疗,每2周重复1次,连续治疗6周。治疗组在上述治疗基础上每次热灌注化疗后腹腔内注入贝伐珠单抗300mg,治疗6周。评价患者疗效、生活质量改善及不良反应。酶联免疫吸附法（ELISA）检测46例患者治疗前、后腹水中VEGF水平。结果 治疗组治疗后腹水VEGF水平为（468.30±42.80）pg/ml,明显低于治疗前的（2785.89±305.22）pg/ml（P＜0.05）;治疗组治疗后腹水VEGF水平明显低于对照组治疗后的（820.20±61.49）pg/ml（P＜0.05）。治疗组的有效率（RR）为92.0％（23／25）,对照组为61.9％（13／21）,差异有统计学意义（P＜0.05）。治疗组中VEGF阳性者的RR达1000％,VEGF阴性者为50.0％,差异有统计学意义（P＜0.05）。治疗组的生活质量（QOL）改善率为92.0％,对照组为57.1％,差异有统计学意义（P＜0.05）。46例患者对治疗的耐受良好,无严重不良反应。结论 腹腔内贝伐珠单抗联合腹腔热灌注化疗治疗卵巢癌腹腔积液的疗效优于单纯腹腔热灌注化疗,生活质量明显改善,安全性好,尤其对于腹水VEGF阳性卵巢癌患者更加适合。     

Phase I study of 90Y-CC49 monoclonal antibody therapy in patients with advanced non-small cell lung cancer: effect of chelating agents and paclitaxel co-administration

PURPOSE: This trial was designed to evaluate strategies to improve the efficacy of a radiolabeled monoclonal antibody (mCC49) against tumor-associated glycoprotein-72 (TAG-72) in patients with non-small cell lung cancer (NSCLC). The aims of this study were to determine: safety and maximum tolerated dose (MTD) of (90)Y-mCC49 in combination with interferon alpha2beta (IFN); whether calcium disodium versonate (EDTA) or diethylenetriamine penta-acetic acid (DTPA) could reduce myelosuppression; and safety and MTD of paclitaxel (Taxol) in combination with (90)Y-mCC49. EXPERIMENTAL DESIGN: Patients with advanced (TAG-72 positive) non-small cell lung cancer were entered in three phases; the first was the dose escalation of a single agent (90)Y-mCC49. In the second phase, the dose escalation of (90)Y-mCC49 was attempted with concurrent EDTA or DTPA chelator therapy. In the third phase, radiosensitization with a continuous infusion of paclitaxel (96-hour) was administered with (90)Y-mCC49. All patients received IFN for TAG-72 up-regulation. RESULTS: Thirty-four patients were evaluable. Reversible Grade 4 neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs). The MTD of (90)Y-mCC49/IFN was 14 mCi/m(2). EDTA did not alter toxicity, while there was a modest reduction of myelosuppression with DTPA. The MTD of continuous infusion paclitaxel in combination with 14 mCi/m(2) of (90)Y-CC49 was 60 mg/m(2). There were no objective tumor responses. CONCLUSIONS: (90)Y-mCC49/IFN was well tolerated at a dose of 14 mCi/m(2). The clinical effect of adjunctive chelating therapy with DTPA was modest. The MTD of coadministered continuous infusion (96-hour) paclitaxel was 60 mg/m(2). Because of the immunogenicity of the murine compound, future studies are planned using a humanized version of CC49.     

热疗联合顺铂与多西他赛化疗治疗晚期胃癌腹水的临床观察

为了探讨热疗联合化疗治疗晚期胃癌腹水的临床疗效,对9例伴有腹水的晚期胃癌患者,利用内生场局部热疗仪治疗腹部转移病灶,加温至41℃,持续1h,配合顺铂40 mg/m2腹腔给药,多西他赛30 mg/m2静脉滴入化疗,均每周1次,连续3周为1个周期.观察腹水疗效、腹部实体病灶缓解程度和热化疗后的不良反应.结果热化疗后9例患者中有3例腹水消退,6例腹水得到控制;腹部可测量病灶部分缓解4例,稳定2例;没有出现热化疗不良反应叠加.初步研究结果提示,热疗联合顺铂腹腔给药与多西他赛静脉滴入能够较好控制晚期胃癌腹水,并可获得较好的局部病灶缓解.     

经腹腔和静脉应用多西紫杉醇治疗胃癌恶性腹腔积液

目的 观察多西紫杉醇经腹腔和静脉双途径应用治疗胃癌恶性腹腔积液的疗效和安全性.方法 选取35例晚期胃癌伴恶性腹腔积液的患者随机分为两组,A组15例采用腹腔和静脉同时用药方法,用药方案为多西紫杉醇37.5mg/m2腹腔注入,同时多西紫杉醇37.5mg/m2静脉滴注,顺铂20mg/m2静脉滴注第1-5天,5-氟尿嘧啶每天750 mg/m2持续输注120小时,B组20例全部采用静脉用药方法,药物种类与剂量同A组,21天为1周期,每2个周期按WHO标准评价疗效及不良反应.结果 35例入组患者中完成2个周期者4例,3个周期者10例,4个周期者21例.35例患者均可评价疗效,A组CR 3例(20.0%),PR 7例(46.7%),SD3例(20.0%),PD2例(13.3%),总有效率(CR+PR)为66.7%;B组CR 1例(5.0%),PR 7例(35.0%),SD 8例(40．0%),PD 4例(20．0%),总有效率(CR+PR)为40.0%,两组比较无显著性差异（P>0.05).A组中位疾病进展时间(TTP)为6．8月,中位生存时间(MST)为15．2月;B组中位疾病进展时间(TTP)为5．9月,中位生存时间(MST)为14．6月,两组比较无显著性差异（P>0.05).主要不良反应有骨髓抑制、腹痛、腹泻、恶心呕吐、肌肉关节痛、口腔黏膜炎和脱发等,两组无显著性差异（P>0.05),均未见过敏反应及明显的肝肾功能受损,无治疗相关性死亡.〖HT5"H〗结论 多西紫杉醇腹腔应用对胃癌恶性腹腔积液的疗效和安全性较好,值得进一步探索和研究.     

静脉和腹腔化疗联合热疗治疗晚期胃癌伴腹水的疗效观察

目的观察多西他赛+氟尿嘧啶(5-Fu)静脉滴注全身化疗和腹腔内灌注顺铂局部化疗及热疗治疗晚期胃癌伴腹水的疗效及不良反应。方法 56例晚期胃癌合并癌性腹水患者采用联合静脉滴注多西他赛+持续静脉滴注5-Fu全身化疗和腹腔内灌注顺铂局部化疗并予局部热疗方案治疗;治疗2⁶个周期,每2个周期后评价疗效、临床受益及不良反应。结果 56例均可评价疗效,其中完全缓解(CR)12例(21.4%),部分缓解(PR)23例(41.1%),总有效率(RR)为62.5%,肿瘤进展时间(TTP)为8.7个月,中位生存期(OS)为13.4个月。腹水CR 15例(26.7%),PR 28例(50.0%),RR为76.7%。主要不良反应为骨髓抑制、消化道反应和口腔黏膜炎,其中Ⅲ6个周期,每2个周期后评价疗效、临床受益及不良反应。结果 56例均可评价疗效,其中完全缓解(CR)12例(21.4%),部分缓解(PR)23例(41.1%),总有效率(RR)为62.5%,肿瘤进展时间(TTP)为8.7个月,中位生存期(OS)为13.4个月。腹水CR 15例(26.7%),PR 28例(50.0%),RR为76.7%。主要不良反应为骨髓抑制、消化道反应和口腔黏膜炎,其中Ⅲ^Ⅳ度白细胞及血小板下降率为19.6%,ⅢⅣ度白细胞及血小板下降率为19.6%,Ⅲ^Ⅳ度血小板下降率为7.1%,ⅠⅣ度血小板下降率为7.1%,Ⅰ^Ⅱ度恶心呕吐、腹泻腹痛的发生率为58.9%,ⅢⅡ度恶心呕吐、腹泻腹痛的发生率为58.9%,Ⅲ^Ⅳ度为5.4%。无治疗相关性死亡。结论静脉化疗(多西他赛+5-Fu)和腹腔化疗(顺铂)的改良DCF方案及热疗是治疗晚期胃癌伴腹水的有效手段,不良反应可以耐受,值得临床进一步研究。     

Synergistic antiproliferative activity of human fibroblast interferon in combination with alpha-difluoromethylornithine against human gastric cancer cells in vitro.

The author has studied the effects of alpha-difluoromethylornithine (alpha DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase; human fibroblast interferon (IFN beta); and their combination on human gastric cancer cell growth in vitro. alpha DFMO (from 0.1 to 4 mmol/l) inhibited cell growth in a dose-dependent manner. Both alpha DFMO (0.1 mmol/l) and higher doses of IFN beta (100 and 1000 IU/ml) caused only limited inhibition of cell growth. When alpha DFMO (0.1 mmol/l) was administered in combination with IFN beta (100 and 1000 IU/ml), synergistic antiproliferative activity was observed 7 days after continuous exposure. Although the mechanisms by which this effect occurs are unclear, it appears to be associated with direct inhibition of tumor cell proliferation, possibly by modulation of polyamine metabolism.     

Weekly systemic combination of cisplatin and interferon alpha 2a in diffuse malignant pleural mesothelioma

The treatment of diffuse malignant pleural mesothelioma (DMPM) remains grim. Neither surgery, radiotherapy nor chemotherapy can be considered as a standard therapy. Immunotherapy with interferon (IFN) in combination with chemotherapy may be an interesting new approach. In 13 consecutive patients with DMPM, we used a weekly combination of cisplatin (CDDP) (60 mg/m2; day 2) and IFN alpha 2a (6 MU/day; days 1-4) in a protocol of two cycles of 4 weeks on/4 weeks off followed by 3 weeks on/3 weeks off. Total treatment duration was thus 25 weeks. In responders, IFN as maintenance monotherapy was continued for a further 6 months. There were nine males and four females with an average age of 65.3 years (range 51-72 years). Eleven had epithelial, one had mixed and one had a sarcomatoid form of DMPM. Five patients were classified as stage II, six as stage III and two as stage IV, as per the International Mesothelioma Interest Group. Thirty-five cycles were administered with a median of three cycles/patient (range 0.75-4). The median total cumulative dose of CDDP was 596 mg/m2 (range 114-861) and that of IFN alpha 2a was 264 MU (range 72-336). Four patients received IFN maintenance therapy, one for 3 months and three for 6 months. One patient had a complete response, four had a partial response, six had a stable disease and the disease progressed in one. One patient was non evaluable for response. All patients were assessable for toxicity. Hematological toxicity was the most frequently observed but was manageable (grade 3 anemia in five patients, grade 3 thrombocytopenia in three patients, grade 3 neutropenia in five patients). Grade 1 renal toxicity was observed in six patients, grade 2-3 asthenia in six patients and an average 5-kg weight loss was noted in nine patients. In conclusion, systemic combination of CDDP and IFN alpha 2a in large doses is effective at the expense of non-negligible toxicity.