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A randomised trial of intrapericardial bleomycin for malignant invasion of the heart and pericardium

Kunitoh H, et al. Br J Cancer (2009) 100(3):464-9

Introduction
Malignant invasion of the heart and pericardium occurs in one-tenth of all patients with a neoplastic disease, and one-third of these will die as a consequence of such involvement [1]. Some of these patients may be misdiagnosed ante-mortem because the malignant disease was unsuspected or clinically occult. Conversely, symptomatic pericardial effusion and even cardiac tamponade may be the first clinical manifestation of an occult malignancy.
Myocardial Disease


Primary tumors of the pericardium are extremely rare. Secondary (metastatic) malignant pericardial disease is much more common and arises in the majority of cases from lung and breast tumors, less frequently from gastrointestinal, hematological malignancies, and melanoma.

Although pericardiocentesis alone can occasionally provide prolonged relief, other measures usually have to be used  to prevent recurrences. Management of the neoplastic effusion relapses mainly includes [1-3]: pericardial sclerosis, surgical creation of pleuropericardial or pleuroperitoneal window, systemic chemotherapy, radiotherapy, and percutaneous balloon pericardiotomy [4].

The advantage of intrapericardial antineoplastic treatment, as a locoregional approach, should be seen in addition to systemic tumor treatment. The pathophysiological principle of  this adjunctive effect relies on the antineoplastic property of the specific drug used and its additional non-specific sclerosing effect.

A number of different intrapericardial treatment regimens have been applied in recent years:  radionuclides e.g. 32-Phosphor, the antimetabolite 5-Fluorouracil for breast, colorectal, esophageal, and gastric tumors, the plant alkaloid Vinblastin for breast and lung carcinoma, Hodgkin’s and Non-Hodgkin’s lymphoma.

The antitumor antibiotics Bleomycin and Mitomycin C have been used for the same indications. Anthracyclines such as mitoxantrone have been utilized for lung and breast cancer, acute myeloid leukemia, as well as the non-Hodgkin’s lymphoma, whereas the Adriamycin has been avoided because of its well-known cardiotoxicity.

Alkylating agents, which have been used for intrapericardial therapy were Cispalatin and Carboplatin for ovarian cancer, tumors of the head and neck area, osteosarcoma and carcinoma of the bladder [1].  There is also a limited experience with intrapericardial instillation of interferon alpha, -beta, and interleukin-2 as well as with OK-432. In addition, nitrogen mustard and quinacrine were used for intrapericardial instillation in the 1970s, but severe pain and bone marrow toxicity occurred.

Summary of the paper

In the February issue of British Journal of Cancer, Kunitoh et al (Tokyo, Japan) have published results of their randomized trial on safety and efficacy of intrapericardial treatment with bleomycin  following pericardial drainage in patients with malignant pericardial effusion and lung cancer. Eighty patients with pathologically documented lung cancer, who had undergone pericardial drainage for malignant pericardial effusion within 72 h of enrolment, were randomised to either arm A (observation alone after drainage) or arm B (intrapericardial treatment with bleomycin at 15 mg, followed by additional 10 mg every 48 h). Only patients with non-small-cell lung cancer or chemotherapy treated small cell cancer were included in order to minimise the influence of systemic chemotherapy. The drainage catheter was removed when daily drainage was 20 ml or less.

The primary end point was survival with control of malignant pericardial effusion (effusion failure-free survival) at 2 months. Effusion failure-free survival at 2 months was better with intrapericardial treatment (29% in arm A and 46% in arm B). However, level of statistical significance was not reached (one-sided P=0.086 by Fisher's exact test). However, Arm B tended to favour effusion free survival with a hazard ratio of 0.64 (95% confidence interval: 0.40-1.03, one-sided P=0.030 by log-rank test). No significant differences in the acute toxicities or complications were observed. The median survival was 79 days and 119 days in arm A and arm B, respectively.

With regard to the mechanism of intrapericardial action of bleomycin, it is difficult to differentiate its cytostatic and sclerosing effect. Yano et al. [32] examined the efficacy of bleomycin on the local control of malignant pericardial effusion in seven patients with malignant pericardial effusion and cardiac tamponade (non-small cell carcinoma of the lung). After the effusions were completely drained, 5 mg of bleomycin were instilled locally via the catheter. In all patients but one, the draining catheter could be successfully removed. The duration of drainage ranged from four to 13 days (mean: 9.2 days). Five of the seven patients achieved a complete remission of pericardial effusions.

Clinical efficacy and toxicity of bleomycin as sclerosing agents in the primary management of malignant pericardial effusion was also compared with doxycycline [6]. Twenty-seven consecutive adult patients were alternately assigned to undergo bleomycin or doxycycline pericardial sclerosis after pericardiocentesis and complete drainage of pericardial effusion. They mainly had lung (70%) and breast cancers (11%), and all had clinical and echocardiography evidence of cardiac tamponade. One patient in each group failed to respond to sclerosis with the initial agent, but both were sclerosed successfully with the other agent. Sclerosis was achieved with a median of two instillations for each agent and total median doses of bleomycin 20 mg and doxycycline 1,250 mg. Seventy percent of doxycycline patients developed significant retrosternal pain, compared with no bleomycin patients (P = .04). Doxycycline patients required a median of 3.5 more days of hospitalization (8.5 vs. 5) and two more days of pericardial catheterization (7 vs. 5) compared with bleomycin patients. Tamponade recurred in one bleomycin patient at 253 days, and in no doxycycline patient.

Van Belle et al. [7] treated five patients with pericardial tamponade of neoplastic origin by pericardiocentesis, drainage and local instillation of bleomycin. The pericardial effusion was adequately controlled in all patients and the side effects were minimal. Survival was not influenced by the pericardial involvement.

Intrapericardial instillation of mitomycin C was effective in controlling the malignant pericardial effusion in 70% of 20 patients without causing side effects, except for pericardial constriction seven months later in one subject [8]. Kaira et al. [9] have treated eight patients with cardiac tamponade or symptomatic large pericardial effusion caused by advanced non-small cell lung cancer with pericardiocentesis, pericardial drainage and subsequent instillation of 2 mg of mitomycin C. Only patients with cytologically confirmed neoplastic effusion and no chemotherapy, radiotherapy or surgery at least 1 month prior to the intrapericardial treatment were included in the study. The duration of pericardial drainage ranged from 7 to 14 days (median 10.5 days). Six of the eight patients achieved a complete remission of pericardial effusions without any adverse effects.

In addition, Fukuoka et al. [10] have treated 24 patients with malignant pericardial effusion with pericardial drainage and intrapericardial instillation of Carbazilquinone, Mitomycin-C or ACNU. The range of survival time from the instillation of anti-cancer drug was 3-365 days. In only 4/24 patients, reaccumulation of pericardial effusion was recognized. There were no serious complications with this procedure.

Experience with intrapericardial administration of aclarubicin hydrochloride (both sclerosing and cytotoxic agent) is limited to five patients with malignant pericardial effusion and cardiac tamponade. All patients were women, and all were initially treated surgically for breast cancer (two patients), or lung cancer (three patients). All patients received 15 mg of aclarubicin hydrochloride intrapericardially after pericardiocentesis and drainage of pericardial effusion. Two patients (40%) had a complete remission of the malignant pericardial effusion. The other three patients were difficult to evaluate because nonpericardial metastases limited their survival. All patients, however, showed disappearance of malignant cells from the pericardial sac with no cytopathologically demonstrable recurrence.

Conclusion:

In conclusion, further, multicenter randomized trials are needed to evaluate efficacy of intrapericardial therapy for neoplastic pericardial effusion in lung cancer patients, probably comparing bleomycin with cisplatin and prolonged pericardial drainage.

References


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Notes to editor


By Ass. Prof. Dr. A. Ristic
Department of Cardiology, Clinical Center of Serbia and Belgrade
University School of Medicine, Koste Todorovica 8, Belgrade, Serbia
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.