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.     

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.     

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。     

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。     

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.     

The treatment of metastatic pleural effusion in breast cancer: report of 25 cases

We report our experience in the treatment of pleural effusion in 25 patients with metastatic breast cancer. Seventeen patients received initial systemic therapy and in 13 of them local intrapleural therapy was subsequently employed; the remaining 8 patients received local therapy only. Several modalities of local treatment were used: intrapleural chemotherapy with thiotepa and 5-fluorouracil; the production of pleural adhesion by the use of chest drainage alone or associated with instillation of sclerosing agents, such as nitrogen mustard or tetracycline. Of the 21 patients who were subjected to local therapy, 19 (90.5%) achieved an objective response (16 complete (76.2%) and 3 (14.34%) partial). Complete responses were observed exclusively in patients who had pleurodesis. Our data suggest that pleurodesis is the treatment of choice for neoplastic pleural effusion and that the use of tetracycline as a sclerosing agent is the most useful because of its availability, low cost and low morbidity.     

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.     

Clinical evaluation of intrapleural or peritoneal administration of lentinan and OK-432 for malignant effusion

It is very important to control the Th2-dominant condition in cancer patients while they are undergoing immunotherapy. OK-432 powerfully guides Th1 cytokine, but sometimes it can not eliminate the Th2 dominant state in cancer patients, which is needed to induce Th2 cytokine. Premedication with combined LTN and OK-432 is an effective therapy for controlling the Th1/Th2 balance. We tried administering LTN and OK-432 in the pleural or peritoneal cavity for patients with malignant effusion. Of all 9 lesions of the 8 cases, 6 showed complete remission and 1 showed partial response. The level of IL-12 (p70) and IFN-gamma in the pleural effusion or ascites of the combination group was higher than the OK-432 only group. In conclusion, LTN and OK-432 combined therapy appears to be an effective local treatment.     

Randomized phase II trial of three intrapleural therapy regimens for the management of malignant pleural effusion in previously untreated non-small cell lung cancer: JCOG 9515

To evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin (BLM), OK-432 (a pulverized product of heat-killed Streptococcus pyogenes) or cisplatin plus etoposide (PE) for the management of malignant pleural effusion (MPE) in previously untreated non-small cell lung cancer. Eligible patients were randomized to the BLM arm: BLM 1mg/kg (maximum 60mg/body), the OK-432 arm: OK-432 0.2 Klinische Einheit units (KE)/kg (maximum 10KE/body), or the PE arm: cisplatin (80mg/m(2)) and etoposide (80mg/m(2)). Pleural response was evaluated every 4 weeks according to the study-specific criteria. All responders received systemic chemotherapy consisting of PE every 3-4 weeks for two or more courses. Pleural progression-free survival (PPFS) was defined as the time from randomization to the first observation of pleural progression or death due to any cause. The primary endpoint was the 4-week PPFS rate. Of 105 patients enrolled, 102 were assessed for response. The 4-week PPFS rate for the BLM arm was 68.6%, 75.8% for the OK-432 arm, and 70.6% for PE arm. Median survival time (MST) for the BLM arm was 32.1 weeks, 48.1 weeks for the OK-432 arm, and 45.7 weeks for the PE arm. However, the outcomes did not differ significantly between groups. Toxicity was tolerable in all arms except for one treatment-related death due to interstitial pneumonia induced by BLM. We will select intrapleural treatment using OK-432 in the management of MPE in NSCLC for further investigation because it had the highest 4-week PPFS rate.     

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.     

Vandetanib and Indwelling Pleural Catheter for Non–Small-Cell Lung Cancer With Recurrent Malignant Pleural Effusion

Introduction/BackgroundNon–small-cell lung cancer patients with malignant pleural effusion have a poor overall median survival (4.3 months). VEGF is a key regulator of pleural effusion production. It is unknown if pharmacological inhibition of VEGF signaling modifies the disease course of non–small-cell lung cancer patients with recurrent malignant pleural effusion. We report the final results of a single-arm phase II clinical trial of the VEGF receptor inhibitor, vandetanib, combined with intrapleural catheter placement in patients with non–small-cell lung cancer and recurrent malignant pleural effusion, to determine whether vandetanib reduces time to pleurodesis.Patients and MethodsNon–small-cell lung cancer patients with proven metastatic disease to the pleural space using pleural fluid cytology or pleural biopsy who required intrapleural catheter placement were eligible for enrollment. On the same day of the intrapleural catheter insertion, the patients were started on a daily oral dose of 300 mg vandetanib, for a maximum of 10 weeks. The primary end point was time to pleurodesis, with response rate as the secondary end point. Exploratory analyses included measurement of pleural fluid cytokines and angiogenic factors before and during therapy.ResultsTwenty eligible patients were included in the trial. Eleven patients completed 10 weeks of treatment. Median time to pleurodesis was 35 days (95% confidence interval, 15-not applicable). Median time to pleurodesis in the historical cohort was 63 days (95% confidence interval, 45-86) when adjusted for Eastern Cooperative Oncology Group performance status ≤ 2.ConclusionVandetanib therapy was well tolerated; however, it did not significantly reduce time to pleurodesis.     

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。     

Ultrasound-guided small-bore Elecath tube insertion for the rapid sclerotherapy of malignant pleural effusion

BACKGROUND: Traditional pleurodesis for malignant pleural effusion is performed by large-bore chest tube insertion with the instillation of sclerosing agents after the compressed lung re-expansion and pleural fluid drainage of 100-150 ml/day. This study was carried out to evaluate the possibility of rapid sclerotherapy for malignant pleural effusions by insertion of a small-bore Elecath tube (12-French) under ultrasound guidance and intrapleural injection of bleomycin 60 IU. METHODS: Twenty-six patients, with 28 cytopathologically proven malignant pleural effusions (two patients had bilateral pleural effusions) and receiving the insertion of the Elecath tube for drainage, were included in our series. This rapid and short-term sclerosing method was performed and completed by intrapleural injection of bleomycin when the pleural effusion had been clearly drained by the small-bore Elecath tube and the compressed lung had fully re-expanded on follow-up chest radiographs. RESULTS: Twenty patients with 22 pleural effusions underwent the intrapleural injection of bleomycin, with the results of pleurodesis being complete response 41% (9/22), partial response 36% (8/22) and failure 23% (5/22). Interestingly, among the 17 successful procedures of pleurodesis (complete response and partial response), 71% (12) procedures could be completed within 2 days (seven within one day and five within 2 days). The remaining unsuccessful procedures carried out on six patients without the injection of bleomycin were due to a non-re-expanded lung (n = 3) and inadequate drainage (n = 3); of these, four patients also received the large-bore chest tube insertion after the removal of the Elecath tube, but the compressed lung still could not re-expand. The complications of the bleomycin injection were fever [77% (17/22)], vomiting [14% (3/22)] and hiccup [5% (1/22)]. CONCLUSION: The method of rapid sclerotherapy for malignant pleural effusions by small-bore Elecath tube is promising, with a success rate achieving 77%, usually within 2 days.      

Prospective randomized trial of intrapleural bleomycin versus interferon alfa-2b via ultrasound-guided small-bore chest tube in the palliative treatment of malignant pleural effusions.

PURPOSE: To compare bleomycin pleurodesis and immunotherapy with intrapleural interferon alfa-2b (IFN) in the palliation of malignant pleural effusions. PATIENTS AND METHODS: One hundred sixty patients with rapidly recurrent malignant pleural effusion were randomly assigned to intrapleural bleomycin (83 patients) or IFN (77 patients). A 9-French intrapleural catheter was placed under sonographic guidance, and pleural effusion was completely drained before starting the treatment. Bleomycin 0.75 mg/kg was administered as a single dose. An additional dose was given if daily fluid output did not drop to less than 100 mL/d within 3 days. IFN 1 million units/10 kg was administered for six courses at 4-day intervals. Thirty-day and long-term responses were evaluated under the intention-to-treat principle. RESULTS: Thirty-day response was 84.3% in the bleomycin arm and 62.3% in IFN arm (P =.002). Median time to progression was 93 days (range, 12 to 395 days) in bleomycin group, and 59 days (range, 7 to 292 days) in the IFN group (P <.001). Median survival was 96 days (range, 15 to 395) and 85 days (range, 16 to 292) in the bleomycin and IFN groups, respectively. Twenty-three patients received two doses of bleomycin, as their daily fluid output remained higher than 100 mL after the first dose. Thirteen of them had complete response, which lasted until death. CONCLUSION: Intrapleural bleomycin is more effective than IFN and is a valid option for the palliative treatment of massive, rapidly recurrent malignant pleural effusions. The administration of a second dose of bleomycin to patients not responding to the first one can remarkably improve the overall outcome of the treatment.     

Intrapleural administration with OK-432 and cultured autologous pleural effusion lymphocytes for breast cancer patients with malignant pleural effusions: analysis of 84 patients over a 14-year period

Autologous effusion lymphocytes cultured for 9-13 days with condition medium containing T cell growth factor were transferred after intrapleural administration with a streptococcal preparation, OK-432, for 84 breast cancer patients with cytologically-confirmed malignant pleural effusion. Effusion disappeared in 54 and decreased in 19 patients, while in 11 the treatment was ineffective (87% response). A positive cytology changed to negative in 52 of 55 (95%) of the patients tested, while in 29 patients, effusion sample could not be obtained after treatment. A multivariate analysis of prognostic factors showed a significantly poorer prognosis in patients with the following concomitant metastases: liver metastasis, lung metastasis with lymphangitis carcinomatosa, and simultaneous bilateral effusions. Median survival time (MST) of all patients was 9 months (5-year survival: 18%). However, MST of the patients with limited disease (patients without liver metastasis, lymphangitis, or bilateral effusion) was 23 months (5-year survival: 28%). Ten patients survived more than 5 years (3 survived over 10 years) after the treatment among 46 patients with follow-up periods of > 5 years.     

Clinical evaluation of intrapleural or peritoneal repetitive administration of Lentinan and OK-432 for malignant effusion

LTN and OK-432 combined therapy is effective for controlling Th1/Th2 balance. We tried a repetitive administration of LTN and OK-432 in the pleural or peritoneal cavity for patients with malignant effusion. Of all 11 lesions of the 10 cases, 7 revealed complete remission and 1 revealed partial response. The level of IL-12 (p70) and IFN-gamma in ascites of two gastric cancer patients after the second administration of LTN and OK-432 was much higher than those after the first administration, whereas the level of IL-10 was not suppressed strongly. In 8 lesions that we could confirm complete remission or partial response, 7 lesions were improved after two or three administrations of LTN and OK-432. In conclusion, a repetitive intracavital administration of LTN and OK-432 is effective for malignant effusion.     

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.     

Two patients of recurrent breast cancer with carcinomatous pleurisy well controlled pleural effusion

We report two patients of recurrent breast cancer with carcinomatous pleurisy well controlled pleural effusion. One patient is a 49-year-old woman. She underwent radical mastectomy for right breast cancer in September 1993. She suffered from multiple liver metastases in June 2000, so CEF therapy contained hepatic arterial infusion chemotherapy and extended right lobectomy of the liver were performed in December 2001. Right pleural effusion was detected in December 2003, then, pleurodesis was carried out with OK-432 after thoracic drainage. After pleurodesis, a weekly paclitaxel therapy was started and she was taking the regimen continuously. Another patient is a 55-year-old woman. She underwent radical mastectomy for left breast cancer in September 1999. Local recurrent lesions on the left chest and left pleural effusion were found in May 2003. After thoracic drainage, infectious pleurisy was complicated, so the drainage tube was removed after the therapy for preventing infection. After pleurodesis, CE therapy followed by peroral chemo-endocrine therapy was performed. Both of the two patients are receiving outpatient treatment without recurrent pleural effusion as of July 2005.     

Clinical evaluation of the combination treatment of intrapleural or intraperitoneal administration of lentinan and OK-432 for malignant effusion

The combination treatment of non-specific immunomodulator Lentinan (LNT) and OK-432 is effective for controlling Th1/Th2 balance and inducing Th1 dominant status in cancer patients. According to this rationale, we tried an administration of LNT and OK-432 in the pleural or peritoneal cavity for patients with malignant effusion. In all 21 lesions of the 20 cases, 10 revealed a complete disappearance and 7 revealed diminution of the effusion. The efficacy of this treatment is 81%. All patients developed a clinical efficacy in 1 to 3 courses of this treatment, and 9 lesions developed clinical efficacy in only 1 course. None of patients developed toxic symptoms LNT, and 10 developed a low grade fever by OK-432. The combination of LNT and OK-432 is effective and for QOL conserving loco-regional treatment.     

Study on adjuvant immunochemotherapy with long-term OK-432 administration in colorectal cancer

The effect of OK-432 on the survival of patients with colorectal cancer who had undergone surgical resection was studied. As postoperative chemotherapeutic agents, mitomycin C and tegafur were administered. The survival time in the OK-432 group was prolonged in comparison with that in the chemotherapy-alone group (control) among patients given curative resection, but not among those not given curative resection. The effect of OK-432 was especially significant in patients with Dukes C-Stage and Dukes C rectal cancer (p less than 0.05). Moreover, OK-432 significantly inhibited the recurrence of cancer at the original lesion in patients with Dukes C cancer who had received curative resection. These results indicate that long-term administration of OK-432 is effective as a postoperative adjuvant for curatively resected colorectal cancer, especially Dukes C cancer.