Elsevier

Lung Cancer

Volume 58, Issue 3, December 2007, Pages 362-368
Lung Cancer

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

https://doi.org/10.1016/j.lungcan.2007.07.009Get rights and content

Summary

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 1 mg/kg (maximum 60 mg/body), the OK-432 arm: OK-432 0.2 Klinische Einheit units (KE)/kg (maximum 10 KE/body), or the PE arm: cisplatin (80 mg/m2) and etoposide (80 mg/m2). 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.

Introduction

Malignant pleural effusion (MPE) is a significant problem in the treatment of patients with advanced malignancies and is a major cause of poor prognosis [1]. The most widely used therapy for MPE is tube drainage with intrapleural instillation of sclerosing agents to prevent fluid reaccumulation [2].

Despite many reported trials of chemical pleurodesis, there has been no agreement as to the optimal treatment protocol for MPE [3], [4], [5]. The variety of response rates of individual agents among those studies has resulted from heterogeneous patient populations and differences in treatment procedures and response criteria [2], [3], [6]. To resolve these problems, we conducted a randomized phase II trial in which patient selection was limited to previously untreated patients with MPE due to non-small cell lung cancer (NSCLC) and, in view of adequate estimation of the efficacy of each intrapleural therapy regimen, single instillation of chemical agents and uncomplicated study-specific response criteria were applied. In this study, to select the most promising regimen for intrapleural therapy consisting of sclerosing or chemotherapeutic agents, we chose three regimens—BLM, OK-432 and cisplatin plus etoposide (PE). BLM was chosen because it is one of the most frequently used agents and is considered to have high efficacy, low toxicity and high availability [3], [5], [7], [8]. OK-432 (a preparation of Streptococcus pyogenes, type A3, Chugai Pharmaceutical Co., Tokyo) has been used as an anti-tumor immunomodulator for lung cancer [9], [10] and is reported to give superior responses for MPE compared to mitomycin C [11] and BLM [12]. At the beginning of this study, PE regimens were considered one of the standard combination chemotherapy regimens for NSCLC, and a phase II trial using this regimen for intrapleural therapy suggested potential survival benefit as well as local control effects [13].

Section snippets

Patient selection

The eligibility criteria were as follows: cytologically or histologically proven malignant pleural effusion associated with newly diagnosed NSCLC; no prior chemotherapy, thoracic radiotherapy or thoracic surgery; age of 75 years or less; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2 after tube thoracostomy; full lung reexpansion after tube thoracostomy; adequate bone marrow reserve (WBC count ≥4000 μL−1, hemoglobin ≥9.5 g/dL, and platelet count ≥100,000 μL−1), and liver

Patients

From May 1996 to August 1999, 105 patients were enrolled onto this study from the 21 participating institutions. The clinical characteristics of the patients are listed in Table 1. Three patients were later found to be ineligible (one patient per group): one had malignant pleural effusion secondary to colon cancer; one had no reexpansion of the affected lung after tube drainage; and one had poor renal function. Thus, 102 patients were assessable for response and survival. Four patients did not

Discussion

To date, numerous chemical agents for treatment of MPE have been studied. These were antibiotics, antineoplastic agents, biological response modifiers (BRMs) and others that showed varied degrees of chemical sclerosis. Among them, BLM and talc are most frequently used for the management of MPE [5], [7], [17], [18]. BLM is an antineoplastic antibiotic used in sclerotherapy with a success rate of 63–85% [7], [8], [18], [19], [20], [21]. Talc applied as either slurry or poudrage is superior to

Conflict of interest

None declared.

Acknowledgements

We are indebted to Ms. M. Imai and Dr. M. Niimi for data management and to Dr. N. Ishizuka for statistical analysis. We thank all of the investigators who contributed to study development and patient enrollment.

Supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan.

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