Pleuritis carcinomatosa

The most used standard therapy for malignant pleural effusion(MPE)is tube thoracostomy drainage, except in cases where there are few pleural effusions or no symptoms. It has been reported that instilling an intrapleural agent is necessary for producing pleurodesis after tube thoracostomy drainage. To date, numerous chemical agents for the treatment of MPE have been studied. These include antibiotics, antineoplastic agents, biological response modifiers and others, that showed various degrees of chemical sclerosis. It was entered on a randomized comparison of tetracycline and bleomycin for treatment of MPE. The rate and time to recurrence were both significantly greater with bleomycin. In comparison, Talc was superior to bleomycin for control of MPE. Therefore, thoracoscopic pleurodesis with talc is now considered to be the gold standard treatment for MPE. However, talc has not been commercially available in Japan. We sought to evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin, OK-432 or cisplatin plus etoposide(PE), for the management of malignant pleural effusion in previously untreated non-small cell lung cancer. The primary endpoint, pleural progression-free survival did not differ significantly between groups. Intrapleural treatment using OK-432 in the management of MPE was selected because it had the highest 4-week pleural progression-free survival rate and toxicity was tolerable. At present, OK- 432 is the standard agent used in Japan.     

Intrapleural chemotherapy--current status and problems in Japan

The efficacy of anti neoplastic agents for chest catheter pleurodesis remains controversial, and little is known regarding the optimal treatment protocol. Of the various anti neoplastic agents, bleomycin and cisplatin are preferred for intrapleural therapy in Japan, and a wide variation among institutions is evident in agent doses and medication methods for pleurodesis. In many reported trials of anti neoplastic pleurodesis, problems exist such as disease heterogeneity, small sample size and differences in response criteria, and randomized control trials (RCTs) are needed to establish evidence. The JCOG 9515 trial randomly assigned patients to either the bleomycin (BLM) arm, the OK-432 arm, or the cisplatin+etoposide (PE) arm. Among them, OK-432 was demonstrated to be more effective than BLM or PE in terms of pleural progression-free survival. Intrapleural combination therapy (chemotherapy plus biological response modifiers) appeared to be superior to either alone, and further randomized studies are warranted.     

局部灌注沙培林和羟基喜树碱治疗恶性胸腔积液

[目的]观察沙培林(0K-432)和羟基喜树碱(HCPT)治疗恶性胸腔积液的近期临床疗效。[方法]对62例恶性胸腔积液患者采用胸腔置入贝朗可分裂中心静脉管持续引流，胸腔积液排放完后，给予沙培林5KE胸腔内注入，dl，HCPT30mg胸腔内注入，d2，每周2次，观察临床疗效与不良反应。[结果]沙培林与HCPT联合治疗恶性胸腔积液总有效率为88．7％，主要不良反应为发热和骨髓抑制。[结论]胸穿置管引流局部灌注沙培林和羟基喜树碱治疗恶性胸积液有较好的近期临床疗效，毒副反应可以耐受。     

Intrathoracic infusion with a combination of low-dose minocycline, OK-432 and cisplatin for malignant pleural effusion

We investigated the effectiveness and complications of intrathoracic infusion with a combination of cisplatin, OK-432, and minocycline for malignant pleural effusion. All patients were hospitalized with chest tube drainage of pleural effusion until the daily drainage volume was less than 100 ml. Twenty-five mg of minocycline, 1 to 3 KE of OK-432, and 5 to 10 mg of cisplatin were instilled into the pleural space. The administration was repeated until drainage effusion disappeared. Therapeutic effect was evaluated according to the following criteria: (1) excellent, no fluid reaccumulation for at least 4 weeks as determined by chest radiogram and clinical evaluation; (2) effective, fluid reaccumulation less than 50% of original effusion with no need of thoracentesis for symptomatic relief within 4 weeks after treatment; and (3) failure, reaccumulation of more than 50% of the original effusion requiring thoracentesis to relieve symptoms within 4 weeks of treatment. Twelve patients with malignant effusion received the combination treatment; 11 patients had primary lung cancer and one had metastatic lung tumor from cancer of the rectum. In all cases, the histology or cytology revealed adenocarcinoma. Eleven of the 12 patients had an excellent response with relief of clinical symptoms. The remaining case failed to show any improvement. Complications such as local pain, fever, nausea, and vomiting were mild and transient. We conclude that combination administration of low-dose minocycline, OK-432, and cisplatin into the thoracic cavity for malignant effusion is an effective alternative treatment with the potential for improvement of the general condition and reduced morbidity.     

Comparison of intrapleural OK-432 and cisplatin for malignant pleural effusion in lung cancer patients

Malignant pleural effusion is typical of complications in advanced lung cancer patients, most of whom complain of dyspnea. The standard treatment for symptomatic pleural effusion is intrapleural administration of a chemical agent. In Japan, OK-432, a streptococcal preparation, and cisplatin (CDDP) have been among the most frequently used chemical agents. There have been very few reports on the efficacy of chemical agents for malignant pleural effusion. We compared therapeutic efficacy and toxicity of intrapleural OK-432 with CDDP in a case-control study. The subjects consisted of 32 lung cancer patients with malignant pleural effusion who were admitted to our hospital between January 2000 and June 2004. The therapeutic efficacy was assessed from duration of chest drainage after intrapleural administration, response rate, time to progression of malignant pleural effusion, and survival time. No statistically significant difference was observed for therapeutic efficacy. Although the OK-432-treated group had only grade 1 fever, chest pain, nausea, the CDDP-treated group had a grade 2 increase in creatinine and grade 3 nausea. Intrapleural OK-432 seemed to be better tolerated in the treatment of malignant pleural effusion than intrapleural CDDP.     

Phase II study of OK-432 intrapleural administration followed by systemic cisplatin and gemcitabine for non-small cell lung cancer with pleuritis carcinomatosa

We conducted a phase II study of OK-432 intrapleural administration followed by systemic chemotherapy using cisplatin with gemcitabine to determine their combined effects on non-small cell lung cancer (NSCLC) with pleuritis carcinomatosa. Between December 1999 and October 2001, 15 patients were registered in the study. Fourteen patients had an Eastern Cooperative Oncology Group performance status (PS) of 1, and one patient had a PS of 2. Ten patients had adenocarcinoma, one had squamous cell carcinoma, and four had malignant mesothelioma. Patients underwent thoracocentesis and received an OK-432 intrapleural injection. They were then treated every three weeks with chemotherapy consisting of 80 mg/m2 cisplatin on day 1 and 1000 mg/m2 gemcitabine on days 1 and 8. Thirteen patients received two or more courses of chemotherapy. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in five, two and three patients, respectively. Non-hematological toxicities were mild, except for one patient who experienced a grade 3 elevation of transaminase and two patients who experienced grade 3 nausea. Of the 15 patients, one achieved partial response (PR), 13 a stable disease (SD) rating, and one a progressive disease (PD) rating, and the overall response rate was 6.7%. The median survival time was 13.5 months and the one-year survival rate was 60.0%. In conclusion, OK-432 intrapleural administration followed by cisplatin and gemcitabine systemic chemotherapy did not reduce patients' tumors but did prolong their survival time. A large-scale phase II study of the efficacy of this combination therapy is required.     

顺铂联合甘露聚糖肽与联合OK-432胸腔注射治疗恶性胸腔积液的临床分析

[目的]对比观察中心静脉导管胸腔引流并顺铂联合甘露聚糖肽（多抗）或OK-432（沙培林）治疗恶性胸腔积液的临床疗效和毒副反应。[方法]99例恶性胸腔积液病人，随机分为2组：甘露聚糖肽组（A组）53例，OK432组（B组）46例。行中心静脉导管胸腔引流术，A组胸腔注射甘露聚糖肽和顺铂，B组胸腔注射0K432和顺铂。两组均每周重复，连续2～4周。[结果]A组RR43例（81．1％）。B组RR39例（84．8％），两组有效率无统计学差异（P=0．631）。A组有3例（5．7％）病人发热，B组有24例（52．2％）病人发热（P〈0．001）。[结论]中心静脉导管胸腔引流并顺铂联合甘露聚糖肽或OK432治疗恶性胸腔积液均较安全且方便，临床疗效相似，但沙培林组发热的发生率远高于甘露聚糖肽组。     

Comparison of OK-432 and mitomycin C pleurodesis for malignant pleural effusion caused by lung cancer. A randomized trial.

A prospective randomized study to compare the effectiveness of pleurodesis by two new sclerosing agents: OK-432 and mitomycin C were conducted in 53 patients with malignant pleural effusion caused by lung cancer. None of the patients received concomitant systemic chemotherapy or radiation therapy during the study. After complete drainage of pleural fluid, the patients were allocated randomly to receive 10 Klinische Einheit units of OK-432 or 8 mg of mitomycin C by intrapleural injection at weekly intervals. The treatment was terminated if the pleural effusion disappeared or the patients had received four consecutive procedures. There were 26 patients who received pleurodesis with OK-432 and 27, with mitomycin C. Patient characteristics in the two treatment groups (age, sex, histologic type, performance status, and prior treatment before pleurodesis) were compatible. These results showed that pleurodesis with OK-432 achieved a higher complete response rate (73%) than that of mitomycin C (41%). The rates of objective treatment response (complete response plus partial response) were comparable in both groups (88% for OK-432 and 67% for mitomycin C). The average number of intrapleural injections needed to achieve complete response was fewer in the OK-432 group (1.9 +/- 0.9) than in mitomycin C group (2.8 +/- 0.9). There was no significant difference in the median survival of the patients who received pleurodesis with OK-432 (5.8 months) or mitomycin C (5.1 months). However, the effusion-free period in the OK-432 group was significantly longer than that in the mitomycin C group (7.0 months versus 1.5 months). Patients who underwent OK-432 pleurodesis had a higher complication rate (80%) than did those in the mitomycin C group (30%). Transient febrile reaction was the most common reaction encountered. The immunologic study in OK-432 group showed an increase in peripheral leukocyte count and decrease in the OKT4/OKT8 ratio. The mitomycin C group had a mild reduction in peripheral blood leukocyte count and no significant change in the OKT4/OKT8 ratio. It was concluded that pleurodesis with OK-432 is an effective alternative treatment for malignant effusion in patients with lung cancer.     

Influence of OK-432 on intratumor 5-fluorouracil concentration in cases given UFT

The influence of OK-432 on the activation of UFT, consisting of tegafur and Uracil, was examined in patients with gastric cancer and colonic cancer. In 14 gastric cancer and 15 colonic cancer cases, to which UFT 400 mg/day and OK-432 2KE 2/W were administered orally and intra-muscularly for 2 weeks preoperatively until surgical treatment, intratumor 5-fluorouracil (5-FU) concentration was measured and compared with that of patients who given UFT 400 mg/day orally for 2 weeks (15 gastric cancer and 15 colonic cancer cases). As the results, in the groups of patients given OK-432, the concentration in gastric cancer tissue was 0.093 +/- 0.067 microgram/g and that in colonic cancer was 0.098 +/- 0.058 microgram/g. Both values exceeded 0.05 microgram/g which is considered to be the effective intratumor 5-FU concentration. No difference was observed in these cases given UFT alone. The ratio of intratumor 5-FU concentration vs. that of normal tissue was 2.5 for gastric cancer and 2.7 for colonic cancer and the ratio of tumor vs. serum 5-FU concentrations was 8.5 for gastric cancer and 10.9 for colonic cancer. No difference was also observed in these values in cases given UFT alone. From above results, it seemed that the clinical dose of OK-432 2KE 2/W had no influence on the activation of UFT, so that the combination therapy of UFT and OK-432 was found to be clinically useful.     

沙培林联合丝裂霉素一次性治疗恶性胸腔积液

目的本文观察了沙培林(OK-432)联合丝裂霉素一次性用药治疗恶性胸腔积液的疗效、不良反应及并发症.方法首先最大限度地排净胸水,然后将丝裂霉素10 mg NS 10 ml,沙培林20 KE NS 20 ml,地塞米松5 mg NS 10 ml,2%利多卡因10 ml分别注入胸膜腔,48 h后再尽量抽尽残留胸水后拨管.结果48例恶性胸腔积液患者中,显效12例,部分有效32例,总有效率91.7%.主要不良反应为发热、胸痛、一过性血白细胞升高.3例发生漏入性气胸,2例发生复张性肺水肿.结论沙培林(OK-432)联合丝裂霉素一次性用药治疗恶性胸腔积液疗效肯定,不良反应可以耐受.     

沙培林联合羟基喜树碱腔内给药治疗恶性胸腔积液

目的：为观察沙培林联合羟基喜树碱腔内给药治疗恶腔积液患的治疗。方法：60例恶性胸腔积液患采用胸腔穿刺，使用比利时生产的贝朗可分裂中心静脉导管置入胸腔、接负压瓶持续闭式引流排胸液。并随机分成两组，治疗组采用沙培林联合羟基喜树碱治疗（30例），第一周2次，每隔3天一次，由引流管注入生理盐40ml加羟基喜树碱30mg，第2周连续3天注入沙培林5KE/次、10KE/次、10KE/次，对照组单用羟基喜树碱治疗（30例），每一周2次，每隔3天一次，由引流管注入生理盐水40ml加羟基喜树碱30mg。结果：治疗组有效率90%[CR11例（37%） PR16例（53%）]，对照组有效率67%[CR8例（27%） PR12例（40例）]。经论：沙培林联合羟基喜树碱腔内注射治疗恶性胸腔积液优于单用羟基喜树碱，而胸腔穿刺置管引流创伤轻微，无倒流污染，引流通畅彻底，避免胸膜多房性包裹粘连的形成以至带来后续治疗困难，可防止医源性感染及气胸等并发症。     

Pharmacokinetics of intrapleural cisplatin for the treatment of malignant pleural effusions

We determined the toxicity and pharmacokinetics of high-dose intrapleural cisplatin (CDDP) as a treatment of malignant pleural effusions (MPE). Fourteen patients with MPE were enrolled in this study. After complete drainage of the fluid, a catheter was inserted into the pleural cavity during a thoracoscopy. CDDP (300 mg) was administered via the catheter in a 6-h infusion. Peak levels, the areas under the concentration curve (AUC), and drug half-lives were measured in pleural fluid and plasma samples collected at 0 (baseline), 6, and 24 h as well as 4, 14, and 21 days after intrapleural administration. The dosage of CDDP ranged from 153 to 203 mg/m2. The time interval between infusion was prolonged until a maximum of 109 days. Only 7/40 infusions were associated with adverse effects in 4 patients (18%). Residual concentrations in pleural fluid (0.66+/-0.07 microgram /ml) were three-fold higher than in plasma (0.13+/-0.07 microgram/ml). In pleural fluid, maximal concentration (Cmax) varied from 19 to 900 microgram/ml and in plasma from 0.34 to 3.65 microgram/ml. AUC in plasma during the three courses was 112+/-49 microgram/ml/d. The T1/2 was 31+/-33 days higher than that previously reported after intravenous administration (8-15 days). Although intrapleural CDDP has the potential advantage of treating the underlying malignancy in addition to controlling the malignant effusion with a good tolerance, it cannot be recommended for the standard control of malignant pleural effusion. Indeed we observed a great variability of intrapleural CDDP concentration depending on the extent of pleural invasion and plasma diffusion. Further studies are needed to determine the value of high-dose intrapleural CDDP for the treatment of MPE.     

Epidermal growth factor receptor in breast cancer: Correlation of quantitative immunocytochemical assays to prognostic factors

Summary Sixty-seven breast cancer patients with cytologically-confirmed malignant pleural effusion, who required intrapleural treatment, were analyzed retrospectively. The patients received their first thoracentesis between 1980 and 1990. Among them, 29 patients received intrapleural administration of OK-432, a streptococcal preparation, followed by the transfer of autologous pleural effusion lymphocytes cultured with interleukin-2. Other intrapleural treatments consisted of OK-432 alone (12 patients), chemotherapeutic agents alone (n = 9), a combination of OK-432 and chemotherapy (n = 16), or others (n = 1). Twenty-six of the 29 patients given OK-432 plus cultured effusion lymphocytes responded, while only 15 of the 38 patients who received other treatments did (p < 0.01). Median survival time and 5-year survival rate of patients who received OK-432 and cultured lymphocytes was 12 months and 36%, while those of the patients who received other treatments was 3 months and 0%, a significant (p< 0.001) difference in survival. Multivariate analysis using Cox's proportional hazard model revealed that the treatment (adoptive immunotherapy) was the most significant (p < 0.005) factor to prolong the survival of the patients among several prognostic factors. Thus, OK-432 and adoptive immunotherapy is a promising therapy that should be further evaluated in a prospective study.     

Effects of OK-432 (Picibanil) on estrogen receptor levels and tamoxifen treatment in 7,12-dimethylbenz[a]anthracene-induced rat mammary cancers

The effects of OK-432 (Picibanil) on estrogen receptor (ER) levels and subsequent tamoxifen (TAM) treatment were examined in 189 female Sprague-Dawley rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary cancers. When OK-432 was administered (0.1 KE/kg i.p. once weekly) for 12 weeks to the rats after DMBA, the average ER level of the TAM-responsive tumors in the OK-432-treated group was significantly higher than that in the control group. The antitumor effect of TAM was significantly greater in the OK-432-treated group. When OK-432 was administered to rats with established DMBA tumors, the average ER levels did not change significantly after 2 or 4 weeks of treatment. ER levels in the control group (no treatment) fell significantly after 2 or 4 weeks. These results suggest that hormone dependence of DMBA-induced rat mammary cancers may be maintained or augmented by the administration of OK-432.     

The prognostic advantage of preoperative intratumoral injection of OK-432 for gastric cancer patients

To investigate, by a multi-institutional randomized trial, the prognostic significance of the augmentation of tumour-infiltrating lymphocytes (TILs) by preoperative intratumoral injection of OK-432 (OK-432 it), a bacterial biological response modifier, in patients with gastric cancer. The 10-year survival and disease-free survival were examined and analysis of the factors showing survival benefit was performed. 370 patients who had undergone curative resection of gastric cancer were enrolled in this study and followed up for 10 years postoperatively. Patients were randomized into either an OK-432 it group or a control group. Ten Klinishe Einheit (KE) of OK-432 was endoscopically injected at 1 to 2 weeks before the operation in the OK-432 it group. Both groups received the same adjuvant chemoimmunotherapy consisting of a bolus injection of mitomycin C (0.4 mg kg(-1) i.v.) and administration of tegafur and OK-432 from postoperative day 14 up to 1 year later. Tegafur (600 mg day(-1)) was given orally and OK-432 (5 KE/2 weeks) was injected intradermally for a maintenance therapy. The TILs grades in resected tumour specimens and presence of metastasis and metastatic pattern in dissected lymph nodes were examined. Multivariate analysis was performed to determine the efficacy of OK-432 it on prognostic factors. All patients were followed up for 10 years. The overall 5- and 10-year survival rates and disease-free survival rates of the OK-432 it group were not significantly higher than those of the control group. However, OK-432 it significantly increased the 5- and 10-year survival rates of patients with stage IIIA + IIIB, moderate lymph node metastasis (pN2), and positive TILs. OK-432 it was most effective at prolonging the survival of patients who had both positive TILs and lymph node metastasis. The OK-432 it group with positive TILs showed a significant decrease in metastatic lymph node frequency and in the number of lymph node micro- metastatic foci when compared to the control group. This study showed that only one time preoperative OK-432 it, particularly when it triggers TILs, is effective for reduction of regional lymph node metastasis. OK-432 it probably acts partly by eliminating micro-metastatic foci in lymph nodes. Preoperative intratumoral injection of OK-432 is technically very easy and has no serious adverse effects, so it is a promising form of neoadjuvant immunotherapy for advanced gastric cancer.     

沙培林和顺铂联合胸膜腔内注射治疗恶性胸水的临床疗效观察

目的研究沙培林和顺铂联合胸腔内注射对恶性胸水的治疗效果。方法全组共75例患者,分治疗组和对照组,治疗组(45例)应用沙培林和顺铂治疗,对照组(30例)仅用顺铂治疗,治疗前后观察胸水的变化。结果治疗组和对照组对恶性胸水的有效率分别为95.6%和46.7%。两组对比有显著性差异(p<0.01)。结论沙培林和顺铂联合胸腔内注射治疗各种恶性胸水,毒性小,疗效肯定。     

Intraperitoneal chemotherapy through implantable injection port in patients with advanced ovarian (or tubal) carcinoma

A total of 38 cycles of intraperitoneal chemotherapy through implantable injection port were carried out in 9 patients with advanced or recurrent ovarian (tubal) carcinoma. The combination chemotherapy consisted of cisplatin 100 mg or carboplatin 450 mg, 5-FU 500 mg and OK-432 10 KE was administered every four weeks for a total of six cycles. Clinical response was evaluated after chemotherapy. Of the eight evaluated patients (in one patient chemotherapy is not completed yet), 1 had complete response, 3 partial response, 2 stable disease and 2 progressive disease. Therapy-related toxic effects were moderate, consisting chiefly of myelosuppression that seemed dose limiting.     

Chemotherapy of advanced non-small-cell lung cancer: A comparison of three active regimens. A randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.)

BACKGROUND: Cisplatin-based chemotherapy is generally considered the mostactive treatment for advanced non-small-cell lung cancer. Thecombination of cisplatin and etoposide had for some time beenthe standard treatment at our center. Of the other active regimens,cisplatin in combination with mitomycin-C, vindesine or ifosfamide(MVP or MIC) showed the highest response rates. We decided toperform a comparative trial of the three ‘best’regimens in order to define a possible standard regimen in advancedNSCLC. MATERIALS AND METHODS: From May 1989 to April 1992, 393 consecutive, previously untreatedNSCLC patients, stages TUB and IV, were randomized to receiveeither cisplatin (120 mg/sqm day 1) + etoposide (100 mg/sqmdays 1–3) every 3 weeks (PE) or cisplatin (120 mg/sqmevery 4 weeks) + mitomycin-C (8 mg/sqm days 1–29–71)+ vindesine (3 mg/sqm days 1–8–15–22) (MVP)or cisplatin (120 mg/sqm day 1) + mitomycin-C (6 mg/sqm day1) + ifosfamide (3 mg/ sqm day 2) every 3 weeks (MIC). Of these,382 were evalable for survival and 360 for response. RESULTS: Response rates were statistically higher for both MIC (40%)and MVP (36%) than for the PE arm (23%). Survival estimatesanalyzed by the log-rank test showed a significant benefit (p<0.04)for patients treated with three-drug regimens (MVP; MIC) ascompared to those in the PE arm. The main toxicity was myelosuppression;thrombocytopenia WHO grade 3–4 was worse in the MIC arm;nephrotoxicity grade 3–4 was also more frequent in theMIC arm. CONCLUSIONS: A three-drug cisplatin-based regimen (MVP; MIC) should be consideredas reference treatment in NSCLC. advanced NSCLC, cisplatin-based chemotherapy     

The combination therapy of local administration of OK-432 and radiation for 2 cases of lower bile duct carcinoma

The combination therapy of local administration of OK-432 and radiation was performed for two patients with lower bile duct carcinoma. Initially, 10KE of OK-432 was given locally, and irradiation was performed according to the schedule of 180-200 rad/5 fractions/week and given 5,000-5,220 rad totally. One case received 5KE of OK-432 locally 17 days after first injection. Both cases showed complete response and survived 4 months and 59 months without any sign of recurrence, respectively.     

A case of bronchial carcinoma showing regression upon intratumoral administration of OK-432

A 38-year-old female suffering from chronic respiratory symptoms due to lung cancer occupying the left main bronchus was treated by frequent intratumoral injections of OK-432. The immune-modifying therapy was performed as follows; 0.2 KE of OK-432 was injected intracutaneously once a week, then the dose was gradually increased to 3.0 KE once a week. Following immunization, intratumoral injection was done under endoscopy at a dose of 3.0 KE every two weeks. Three months later, the tumor showed remarkable regression, and clinical symptoms were diminished. In conclusion, intratumoral injection of OK-432 was considered to be very beneficial in lung cancer.